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efbffe1e9cbe0a4df3ba578dc50be6eec7e1c304	wikidoc	Transcortin	Transcortin Transcortin, also known as corticosteroid-binding globulin (CBG) or serpin A6, is a protein that in humans is encoded by the SERPINA6 gene. It is an alpha-globulin. # Function This gene encodes an alpha-globulin protein with corticosteroid-binding properties. This is the major transport protein for glucocorticoids and progestins in the blood of most vertebrates. The gene localizes to a chromosomal region containing several closely related serine protease inhibitors (serpins) which have evolved by duplication events. # Binding Transcortin binds several steroid hormones at high rates: - Cortisol - Approximately 75% of the cortisol in circulation is bound to transcortin. (The rest is bound to serum albumin.) Cortisol is thought to be biologically active only when it is not bound to transcortin. - Cortisone - Deoxycorticosterone (DOC) - Corticosterone - About 78% of serum corticosterone is bound to transcortin. - Aldosterone - Approximately 17% of serum aldosterone is bound to transcortin, while another 47% is bound to serum albumin. The remaining 36% is free. - Progesterone - Approximately 18% of serum progesterone is bound to transcortin, while another 80% of it is bound to serum albumin. The remaining 2% is free. - 17α-Hydroxyprogesterone In addition, approximately 4% of serum testosterone is bound to transcortin. A similarly small fraction of serum estradiol is bound to transcortin as well. # Synthesis Transcortin is produced by the liver and is increased by estrogens. # Clinical significance Mutations in this gene are rare. Only four mutations have been described, often in association with fatigue and chronic pain. This mechanism for these symptoms is not known. This condition must be distinguished from secondary hypocortisolism. Exogenous hydrocortisone does not appear to improve the fatigue. Hepatic synthesis of corticosteroid-binding globulin more than doubles in pregnancy; that is, unbound plasma cortisol in term pregnancy is approximately 2.5 times that of nonpregnant women.	Transcortin Transcortin, also known as corticosteroid-binding globulin (CBG) or serpin A6, is a protein that in humans is encoded by the SERPINA6 gene. It is an alpha-globulin.[1][2][3] # Function This gene encodes an alpha-globulin protein with corticosteroid-binding properties. This is the major transport protein for glucocorticoids and progestins in the blood of most vertebrates. The gene localizes to a chromosomal region containing several closely related serine protease inhibitors (serpins) which have evolved by duplication events.[3] # Binding Transcortin binds several steroid hormones at high rates: - Cortisol - Approximately 75% of the cortisol in circulation is bound to transcortin. (The rest is bound to serum albumin.) Cortisol is thought to be biologically active only when it is not bound to transcortin.[citation needed] - Cortisone[4] - Deoxycorticosterone (DOC)[4] - Corticosterone - About 78% of serum corticosterone is bound to transcortin. - Aldosterone - Approximately 17% of serum aldosterone is bound to transcortin, while another 47% is bound to serum albumin. The remaining 36% is free.[5] - Progesterone - Approximately 18% of serum progesterone is bound to transcortin, while another 80% of it is bound to serum albumin. The remaining 2% is free.[6] - 17α-Hydroxyprogesterone[4] In addition, approximately 4% of serum testosterone is bound to transcortin.[7] A similarly small fraction of serum estradiol is bound to transcortin as well.[citation needed] # Synthesis Transcortin is produced by the liver and is increased by estrogens.[8] # Clinical significance Mutations in this gene are rare. Only four mutations have been described, often in association with fatigue and chronic pain.[9] This mechanism for these symptoms is not known. This condition must be distinguished from secondary hypocortisolism. Exogenous hydrocortisone does not appear to improve the fatigue. Hepatic synthesis of corticosteroid-binding globulin more than doubles in pregnancy; that is, unbound plasma cortisol in term pregnancy is approximately 2.5 times that of nonpregnant women.[10]	https://www.wikidoc.org/index.php/Corticosteroid-binding_globulin
e16e15055950d2aee3d82dd36e4f5cadc3eede92	wikidoc	Cosyntropin	Cosyntropin # 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 Cosyntropin is an endocrine metabolic agent that is FDA approved for the diagnosis of adrenocortical insufficiency. Common adverse reactions include bradyarrhythmia, hypertension, tachycardia, anaphylaxis, and hypersensitivity reaction. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) # Indications - CORTROSYN® (cosyntropin) for Injection is intended for use as a diagnostic agent in the screening of patients presumed to have adrenocortical insufficiency. Because of its rapid effect on the adrenal cortex it may be utilized to perform a 30-minute test of adrenal function (plasma cortisol response) as an office or outpatient procedure, using only 2 venipunctures. - Severe hypofunction of the pituitary - adrenal axis is usually associated with subnormal plasma cortisol values but a low basal level is not per se evidence of adrenal insufficiency and does not suffice to make the diagnosis. Many patients with proven insufficiency will have normal basal levels and will develop signs of insufficiency only when stressed. For this reason a criterion which should be used in establishing the diagnosis is the failure to respond to adequate corticotropin stimulation. When presumptive adrenal insufficiency is diagnosed by a subnormal CORTROSYN® test, further studies are indicated to determine if it is primary or secondary. - Primary adrenal insufficiency (Addison’s disease) is the result of an intrinsic disease process, such as tuberculosis within the gland. The production of adrenocortical hormones is deficient despite high ACTH levels (feedback mechanism). Secondary or relative insufficiency arises as the result of defective production of ACTH leading in turn to disuse atrophy of the adrenal cortex. It is commonly seen, for example, as result of corticosteroid therapy, Sheehan’s syndrome and pituitary tumors or ablation. - The differentiation of both types is based on the premise that a primarily defective gland cannot be stimulated by ACTH whereas a secondarily defective gland is potentially functional and will respond to adequate stimulation with ACTH. Patients selected for further study as the result of a subnormal CORTROSYN® test should be given a 3 or 4 day course of treatment with Repository Corticotropin Injection USP and then retested. Suggested doses are 40 USP units twice daily for 4 days or 60 USP units twice daily for 3 days. Under these conditions little or no increase in plasma cortisol levels will be seen in Addison’s disease whereas higher or even normal levels will be seen in cases with secondary adrenal insufficiency. # Dosage - CORTROSYN® (cosyntropin) for Injection may be administered intramuscularly or as a direct intravenous injection when used as a rapid screening test of adrenal function. It may also be given as an intravenous infusion over a 4 to 8 hour period to provide a greater stimulus to the adrenal glands. Doses of CORTROSYN® 0.25 to 0.75 mg have been used in clinical studies and a maximal response noted with the smallest dose. - A suggested method for a rapid screening test of adrenal function has been described by Wood and Associates (1). A control blood sample of 6 to 7 mL is collected in a heparinized tube. Reconstitute 0.25 mg of CORTROSYN® with 1mL of 0.9% Sodium Chloride Injection, USP and inject intramuscularly. The reconstituted drug product should be inspected visually for particulate matter and discoloration prior to injection. Reconstituted CORTROSYN® should not be retained. In the pediatric population, aged 2 years or less, a dose of 0.125 mg will often suffice. A second blood sample is collected exactly 30 minutes later. Both blood samples should be refrigerated until sent to the laboratory for determination of the plasma cortisol response by some appropriate method. If it is not possible to send them to the laboratory or perform the fluorimetric procedure within 12 hours, then the plasma should be separated and refrigerated or frozen according to need. - Two alternative methods of administration are intravenous injection and infusion. CORTROSYN® can be injected intravenously in 2 to 5 mL of saline over a 2-minute period. When given as an intravenous infusion: CORTROSYN®, 0.25 mg may be added to glucose or saline solutions and given at the rate of approximately 40 micrograms per hour over a 6-hour period. It should not be added to blood or plasma as it is apt to be inactivated by enzymes. Adrenal response may be measured in the usual manner by determining urinary steroid excretion before and after treatment or by measuring plasma cortisol levels before and at the end of the infusion. The latter is preferable because the urinary steroid excretion does not always accurately reflect the adrenal or plasma cortisol response to ACTH. - The usual normal response in most cases is an approximate doubling of the basal level, provided that the basal level does not exceed the normal range. Patients receiving cortisone, hydrocortisone or spironolactone should omit their pre-test doses on the day selected for testing. Patients taking inadvertent doses of cortisone or hydrocortisone on the test day and patients taking spironolactone or women taking drugs which contain estrogen may exhibit abnormally high basal plasma cortisol levels. - A paradoxical response may be noted in the cortisone or hydrocortisone group as seen in a decrease in plasma cortisol values following a stimulating dose of CORTROSYN®. - In the spironolactone or estrogen group only a normal incremental response is to be expected. Many patients with normal adrenal function, however, do not respond to the expected degree so that the following criteria have been established to denote a normal response: - 1. The control plasma cortisol level should exceed 5 micrograms/100 mL. - 2. The 30-minute level should show an increment of at least 7 micrograms/100 mL above the basal level. - 3. The 30-minute level should exceed 18 micrograms/100 mL. Comparable figures have been reported by Greig and co-workers. - Plasma cortisol levels usually peak about 45 to 60 minutes after an injection of CORTROSYN® and some prefer the 60-minute interval for testing for this reason. While it is true that the 60-minute values are usually higher than the 30-minute values, the difference may not be significant enough in most cases to outweigh the disadvantage of a longer testing period. If the 60-minute test period is used, the criterion for a normal response is an approximate doubling of the basal plasma cortisol value (2). - In patients with a raised plasma bilirubin or in patients where the plasma contains free hemoglobin, falsely high fluorescence measurements will result. The test may be performed at any time during the day but because of the physiological diurnal variation of plasma cortisol the criteria listed by Wood cannot apply. It has been shown that basal plasma cortisol levels and the post CORTROSYN® increment exhibit diurnal changes. However, the 30-minute plasma cortisol level remains unchanged throughout the day so that only this single criterion should be used (3). - Parenteral drug products should be inspected visually for particulate matter and discoloration whenever solution and container permit. Reconstituted CORTROSYN® should not be retained. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Cosyntropin in adult patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Cosyntropin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - There is limited information regarding FDA-Labeled Use of Cosyntropin in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Cosyntropin in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Cosyntropin in pediatric patients. # Contraindications - The only contraindication to CORTROSYN® (cosyntropin) for Injection is a history of a previous adverse reaction to it. # Warnings - There is limited information regarding Warning of Cosyntropin in the drug label. # Adverse Reactions ## Clinical Trials Experience - Since CORTROSYN® (cosyntropin) for Injection is intended for diagnostic and not therapeutic use, adverse reactions other than a rare hypersensitivity reaction are not anticipated. A rare hypersensitivity reaction usually associated with a pre-existing allergic disease and/or a previous reaction to natural ACTH is possible. Symptoms may include slight whealing with splotchy erythema at the injection site. There have been rare reports of anaphylactic reaction. The following adverse reactions have been reported in patients after the administration of CORTROSYN® and the association has been neither confirmed nor refuted: ## Postmarketing Experience - There is limited information regarding Postmarketing Experience of Cosyntropin in the drug label. # Drug Interactions - Corticotropin may accentuate the electrolyte loss associated with diuretic therapy. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Pregnancy Category C. Animal reproduction studies have not been conducted with CORTROSYN® (cosyntropin) for Injection. It is also not known whether CORTROSYN® can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. CORTROSYN® should be given to a pregnant woman only if clearly needed. Pregnancy Category (AUS): - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cosyntropin in women who are pregnant. ### Labor and Delivery - There is no FDA guidance on use of Cosyntropin 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 CORTROSYN® (cosyntropin) for Injection is administered to a nursing woman. ### Pediatric Use - There is no FDA guidance on the use of Cosyntropin with respect to pediatric patients. ### Geriatic Use - There is no FDA guidance on the use of Cosyntropin with respect to geriatric patients. ### Gender - There is no FDA guidance on the use of Cosyntropin with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Cosyntropin with respect to specific racial populations. ### Renal Impairment - There is no FDA guidance on the use of Cosyntropin in patients with renal impairment. ### Hepatic Impairment - There is no FDA guidance on the use of Cosyntropin in patients with hepatic impairment. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Cosyntropin in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Cosyntropin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous - Intramuscularly ### Monitoring - There is limited information regarding Monitoring of Cosyntropin in the drug label. # IV Compatibility - There is limited information regarding IV Compatibility of Cosyntropin in the drug label. # Overdosage - There is limited information regarding Chronic Overdose of Cosyntropin in the drug label. # Pharmacology ## Mechanism of Action - The pharmacologic profile of CORTROSYN® is similar to that of purified natural ACTH. It has been established that 0.25 mg of CORTROSYN® will stimulate the adrenal cortex maximally and to the same extent as 25 units of natural ACTH. This dose of CORTROSYN® will produce maximal secretion of 17-OH corticosteroids, 17- ketosteroids and / or 17 - ketogenic steroids. ## Structure - CORTROSYN® (cosyntropin) for Injection is a sterile lyophilized powder in vials containing 0.25 mg of CORTROSYN® and 10 mg of mannitol to be reconstituted with 1 mL of 0.9% Sodium Chloride Injection, USP. Administration is by intravenous or intramuscular injection. Cosyntropin is α 1 - 24 corticotropin, a synthetic subunit of ACTH. It is an open chain polypeptide containing, from the N terminus, the first 24 of the 39 amino acids of natural ACTH. The sequence of amino acids in the 1 - 24 compound is as follows: ## Pharmacodynamics - There is limited information regarding Pharmacodynamics of Cosyntropin in the drug label. ## Pharmacokinetics - There is limited information regarding Pharmacokinetics of Cosyntropin in the drug label. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility - Long term studies in animals have not been performed to evaluate carcinogenic or mutagenic potential or impairment of fertility. A study in rats noted inhibition of reproductive function like natural ACTH. # Clinical Studies - There is limited information regarding Clinical Studies of Cosyntropin in the drug label. # How Supplied - Box of 10 vials of CORTROSYN® (cosyntropin) for Injection 0.25 mg NDC # 0548-5900-00 ## Storage - Store at 15-30°C (59-86°F). - CORTROSYN® is intended as a single dose injection and contains no antimicrobial preservative. Any unused portion should be discarded. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Cosyntropin in the drug label. # Precautions with Alcohol - Alcohol-Cosyntropin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - CORTROSYN ® # Look-Alike Drug Names There is limited information regarding Cosyntropin Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Cosyntropin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Cosyntropin is an endocrine metabolic agent that is FDA approved for the diagnosis of adrenocortical insufficiency. Common adverse reactions include bradyarrhythmia, hypertension, tachycardia, anaphylaxis, and hypersensitivity reaction. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) # Indications - CORTROSYN® (cosyntropin) for Injection is intended for use as a diagnostic agent in the screening of patients presumed to have adrenocortical insufficiency. Because of its rapid effect on the adrenal cortex it may be utilized to perform a 30-minute test of adrenal function (plasma cortisol response) as an office or outpatient procedure, using only 2 venipunctures. - Severe hypofunction of the pituitary - adrenal axis is usually associated with subnormal plasma cortisol values but a low basal level is not per se evidence of adrenal insufficiency and does not suffice to make the diagnosis. Many patients with proven insufficiency will have normal basal levels and will develop signs of insufficiency only when stressed. For this reason a criterion which should be used in establishing the diagnosis is the failure to respond to adequate corticotropin stimulation. When presumptive adrenal insufficiency is diagnosed by a subnormal CORTROSYN® test, further studies are indicated to determine if it is primary or secondary. - Primary adrenal insufficiency (Addison’s disease) is the result of an intrinsic disease process, such as tuberculosis within the gland. The production of adrenocortical hormones is deficient despite high ACTH levels (feedback mechanism). Secondary or relative insufficiency arises as the result of defective production of ACTH leading in turn to disuse atrophy of the adrenal cortex. It is commonly seen, for example, as result of corticosteroid therapy, Sheehan’s syndrome and pituitary tumors or ablation. - The differentiation of both types is based on the premise that a primarily defective gland cannot be stimulated by ACTH whereas a secondarily defective gland is potentially functional and will respond to adequate stimulation with ACTH. Patients selected for further study as the result of a subnormal CORTROSYN® test should be given a 3 or 4 day course of treatment with Repository Corticotropin Injection USP and then retested. Suggested doses are 40 USP units twice daily for 4 days or 60 USP units twice daily for 3 days. Under these conditions little or no increase in plasma cortisol levels will be seen in Addison’s disease whereas higher or even normal levels will be seen in cases with secondary adrenal insufficiency. # Dosage - CORTROSYN® (cosyntropin) for Injection may be administered intramuscularly or as a direct intravenous injection when used as a rapid screening test of adrenal function. It may also be given as an intravenous infusion over a 4 to 8 hour period to provide a greater stimulus to the adrenal glands. Doses of CORTROSYN® 0.25 to 0.75 mg have been used in clinical studies and a maximal response noted with the smallest dose. - A suggested method for a rapid screening test of adrenal function has been described by Wood and Associates (1). A control blood sample of 6 to 7 mL is collected in a heparinized tube. Reconstitute 0.25 mg of CORTROSYN® with 1mL of 0.9% Sodium Chloride Injection, USP and inject intramuscularly. The reconstituted drug product should be inspected visually for particulate matter and discoloration prior to injection. Reconstituted CORTROSYN® should not be retained. In the pediatric population, aged 2 years or less, a dose of 0.125 mg will often suffice. A second blood sample is collected exactly 30 minutes later. Both blood samples should be refrigerated until sent to the laboratory for determination of the plasma cortisol response by some appropriate method. If it is not possible to send them to the laboratory or perform the fluorimetric procedure within 12 hours, then the plasma should be separated and refrigerated or frozen according to need. - Two alternative methods of administration are intravenous injection and infusion. CORTROSYN® can be injected intravenously in 2 to 5 mL of saline over a 2-minute period. When given as an intravenous infusion: CORTROSYN®, 0.25 mg may be added to glucose or saline solutions and given at the rate of approximately 40 micrograms per hour over a 6-hour period. It should not be added to blood or plasma as it is apt to be inactivated by enzymes. Adrenal response may be measured in the usual manner by determining urinary steroid excretion before and after treatment or by measuring plasma cortisol levels before and at the end of the infusion. The latter is preferable because the urinary steroid excretion does not always accurately reflect the adrenal or plasma cortisol response to ACTH. - The usual normal response in most cases is an approximate doubling of the basal level, provided that the basal level does not exceed the normal range. Patients receiving cortisone, hydrocortisone or spironolactone should omit their pre-test doses on the day selected for testing. Patients taking inadvertent doses of cortisone or hydrocortisone on the test day and patients taking spironolactone or women taking drugs which contain estrogen may exhibit abnormally high basal plasma cortisol levels. - A paradoxical response may be noted in the cortisone or hydrocortisone group as seen in a decrease in plasma cortisol values following a stimulating dose of CORTROSYN®. - In the spironolactone or estrogen group only a normal incremental response is to be expected. Many patients with normal adrenal function, however, do not respond to the expected degree so that the following criteria have been established to denote a normal response: - 1. The control plasma cortisol level should exceed 5 micrograms/100 mL. - 2. The 30-minute level should show an increment of at least 7 micrograms/100 mL above the basal level. - 3. The 30-minute level should exceed 18 micrograms/100 mL. Comparable figures have been reported by Greig and co-workers. - Plasma cortisol levels usually peak about 45 to 60 minutes after an injection of CORTROSYN® and some prefer the 60-minute interval for testing for this reason. While it is true that the 60-minute values are usually higher than the 30-minute values, the difference may not be significant enough in most cases to outweigh the disadvantage of a longer testing period. If the 60-minute test period is used, the criterion for a normal response is an approximate doubling of the basal plasma cortisol value (2). - In patients with a raised plasma bilirubin or in patients where the plasma contains free hemoglobin, falsely high fluorescence measurements will result. The test may be performed at any time during the day but because of the physiological diurnal variation of plasma cortisol the criteria listed by Wood cannot apply. It has been shown that basal plasma cortisol levels and the post CORTROSYN® increment exhibit diurnal changes. However, the 30-minute plasma cortisol level remains unchanged throughout the day so that only this single criterion should be used (3). - Parenteral drug products should be inspected visually for particulate matter and discoloration whenever solution and container permit. Reconstituted CORTROSYN® should not be retained. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Cosyntropin in adult patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Cosyntropin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - There is limited information regarding FDA-Labeled Use of Cosyntropin in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Cosyntropin in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Cosyntropin in pediatric patients. # Contraindications - The only contraindication to CORTROSYN® (cosyntropin) for Injection is a history of a previous adverse reaction to it. # Warnings - There is limited information regarding Warning of Cosyntropin in the drug label. # Adverse Reactions ## Clinical Trials Experience - Since CORTROSYN® (cosyntropin) for Injection is intended for diagnostic and not therapeutic use, adverse reactions other than a rare hypersensitivity reaction are not anticipated. A rare hypersensitivity reaction usually associated with a pre-existing allergic disease and/or a previous reaction to natural ACTH is possible. Symptoms may include slight whealing with splotchy erythema at the injection site. There have been rare reports of anaphylactic reaction. The following adverse reactions have been reported in patients after the administration of CORTROSYN® and the association has been neither confirmed nor refuted: ## Postmarketing Experience - There is limited information regarding Postmarketing Experience of Cosyntropin in the drug label. # Drug Interactions - Corticotropin may accentuate the electrolyte loss associated with diuretic therapy. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Pregnancy Category C. Animal reproduction studies have not been conducted with CORTROSYN® (cosyntropin) for Injection. It is also not known whether CORTROSYN® can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. CORTROSYN® should be given to a pregnant woman only if clearly needed. Pregnancy Category (AUS): - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cosyntropin in women who are pregnant. ### Labor and Delivery - There is no FDA guidance on use of Cosyntropin 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 CORTROSYN® (cosyntropin) for Injection is administered to a nursing woman. ### Pediatric Use - There is no FDA guidance on the use of Cosyntropin with respect to pediatric patients. ### Geriatic Use - There is no FDA guidance on the use of Cosyntropin with respect to geriatric patients. ### Gender - There is no FDA guidance on the use of Cosyntropin with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Cosyntropin with respect to specific racial populations. ### Renal Impairment - There is no FDA guidance on the use of Cosyntropin in patients with renal impairment. ### Hepatic Impairment - There is no FDA guidance on the use of Cosyntropin in patients with hepatic impairment. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Cosyntropin in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Cosyntropin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous - Intramuscularly ### Monitoring - There is limited information regarding Monitoring of Cosyntropin in the drug label. # IV Compatibility - There is limited information regarding IV Compatibility of Cosyntropin in the drug label. # Overdosage - There is limited information regarding Chronic Overdose of Cosyntropin in the drug label. # Pharmacology ## Mechanism of Action - The pharmacologic profile of CORTROSYN® is similar to that of purified natural ACTH. It has been established that 0.25 mg of CORTROSYN® will stimulate the adrenal cortex maximally and to the same extent as 25 units of natural ACTH. This dose of CORTROSYN® will produce maximal secretion of 17-OH corticosteroids, 17- ketosteroids and / or 17 - ketogenic steroids. ## Structure - CORTROSYN® (cosyntropin) for Injection is a sterile lyophilized powder in vials containing 0.25 mg of CORTROSYN® and 10 mg of mannitol to be reconstituted with 1 mL of 0.9% Sodium Chloride Injection, USP. Administration is by intravenous or intramuscular injection. Cosyntropin is α 1 - 24 corticotropin, a synthetic subunit of ACTH. It is an open chain polypeptide containing, from the N terminus, the first 24 of the 39 amino acids of natural ACTH. The sequence of amino acids in the 1 - 24 compound is as follows: ## Pharmacodynamics - There is limited information regarding Pharmacodynamics of Cosyntropin in the drug label. ## Pharmacokinetics - There is limited information regarding Pharmacokinetics of Cosyntropin in the drug label. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility - Long term studies in animals have not been performed to evaluate carcinogenic or mutagenic potential or impairment of fertility. A study in rats noted inhibition of reproductive function like natural ACTH. # Clinical Studies - There is limited information regarding Clinical Studies of Cosyntropin in the drug label. # How Supplied - Box of 10 vials of CORTROSYN® (cosyntropin) for Injection 0.25 mg NDC # 0548-5900-00 ## Storage - Store at 15-30°C (59-86°F). - CORTROSYN® is intended as a single dose injection and contains no antimicrobial preservative. Any unused portion should be discarded. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Cosyntropin in the drug label. # Precautions with Alcohol - Alcohol-Cosyntropin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - CORTROSYN ®[1] # Look-Alike Drug Names There is limited information regarding Cosyntropin Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Cortrosyn
10168c344e9ded8d9fff08125a4ed0d378a91459	wikidoc	Cotton swab	Cotton swab # Overview Cotton swabs (British English: cotton buds) are used in first aid, cosmetics application, and a variety of other uses. They consist of a small wad of cotton wrapped around the end of a small rod, made of wood, rolled paper, or plastic. The most common type of usage is to dip the cotton end in a substance, then use the swab as an applicator for the substance. Sometimes swabs are also used for removal of substances such as wax from ear canals, though the instructions accompanying the swabs generally contain a warning that the swabs should not be inserted directly into the ear, as doing so is actually dangerous. Using a swab to remove wax can puncture the ear drum. It will remove only a fraction of the wax, which is visible on the removed swab, while pushing and packing the majority of the wax further into the ear canal. The inventor of the cotton swab is supposed to have been one Leo Gerstenzang, in 1923 . His product, which he named "Baby Gays", went on to become the most widely-sold brand name, "Q-tip". The traditional cotton swab has a single tip on a wooden handle, and these are still often used, especially in medical settings. They are usually relatively long, about six inches (15 cm or so). These often are packaged sterile, one or two to a paper or plastic sleeve. The advantage of the paper sleeve and the wooden handle is that the package can be autoclaved to be sterilized (plastic sleeves or handles would melt in the autoclave). These medical-type swabs are often used to take microbiological cultures. They are swabbed onto or into the infected area, then wiped across the culture medium, such as an agar plate, where any bacteria from the swab will grow. They are also used to take DNA samples from, most commonly, the inner cheek. As well, they can be used to apply medicines to a targeted area, to selectively remove substances from a targeted area, or to apply cleaning substances like Betadine. Cotton swabs produced for home use are usually shorter, about three inches (7.6 cm) long, and usually double-tipped. The handles were first made of wood, then made of rolled paper, which is still most common (although tubular plastic is becoming popular). They are often sold in large quantities, possibly 300 or more to a container. One recent innovation is to use a special type of double-tipped cotton swab for over-the-counter drug application. These swabs have hollow tubular plastic handles, which are full of the medicine. Breaking one marked end of the swab breaks an air seal, allowing the medicine to saturate the cotton at the other end so that it can be directly applied with the swab. Swabs exist in a wide variety of colors: purple, fuchsia, pink, green etc. However the cotton itself is white.	Cotton swab Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Cotton swabs (British English: cotton buds) are used in first aid, cosmetics application, and a variety of other uses. They consist of a small wad of cotton wrapped around the end of a small rod, made of wood, rolled paper, or plastic. The most common type of usage is to dip the cotton end in a substance, then use the swab as an applicator for the substance. Sometimes swabs are also used for removal of substances such as wax from ear canals, though the instructions accompanying the swabs generally contain a warning that the swabs should not be inserted directly into the ear, as doing so is actually dangerous. Using a swab to remove wax can puncture the ear drum. It will remove only a fraction of the wax, which is visible on the removed swab, while pushing and packing the majority of the wax further into the ear canal. The inventor of the cotton swab is supposed to have been one Leo Gerstenzang, in 1923 [2]. His product, which he named "Baby Gays", went on to become the most widely-sold brand name, "Q-tip". The traditional cotton swab has a single tip on a wooden handle, and these are still often used, especially in medical settings. They are usually relatively long, about six inches (15 cm or so). These often are packaged sterile, one or two to a paper or plastic sleeve. The advantage of the paper sleeve and the wooden handle is that the package can be autoclaved to be sterilized (plastic sleeves or handles would melt in the autoclave). These medical-type swabs are often used to take microbiological cultures. They are swabbed onto or into the infected area, then wiped across the culture medium, such as an agar plate, where any bacteria from the swab will grow. They are also used to take DNA samples from, most commonly, the inner cheek. As well, they can be used to apply medicines to a targeted area, to selectively remove substances from a targeted area, or to apply cleaning substances like Betadine. Cotton swabs produced for home use are usually shorter, about three inches (7.6 cm) long, and usually double-tipped. The handles were first made of wood, then made of rolled paper, which is still most common (although tubular plastic is becoming popular). They are often sold in large quantities, possibly 300 or more to a container. One recent innovation is to use a special type of double-tipped cotton swab for over-the-counter drug application. These swabs have hollow tubular plastic handles, which are full of the medicine. Breaking one marked end of the swab breaks an air seal, allowing the medicine to saturate the cotton at the other end so that it can be directly applied with the swab. Swabs exist in a wide variety of colors: purple, fuchsia, pink, green etc. However the cotton itself is white. # External links - The origin of Q-tips - Cotton Swabs and Ear Perforations - Q-tips official site (requires Macromedia Flash) de:Wattestäbchen nl:Wattenstaafje no:Bomullspinne	https://www.wikidoc.org/index.php/Cotton_swab
d061c7c8dfdf1966a03d53c469590e4d52de7449	wikidoc	Counternull	Counternull In statistics, and especially in the statistical analysis of psychological data, the counternull is a statistic used to aid the understanding and presentation of research results. It revolves around the effect size, which is the mean magnitude of some effect divided by the standard deviation. The counternull value is the effect size that is just as well supported by the data as the null hypothesis. In particular, when results are drawn from a distribution that is symmetrical about its mean, the counternull value is exactly twice the observed "effect". The null hypothesis is a hypothesis set up to be tested against an alternative. Thus the counternull is an alternative hypothesis that, when used to replace the null hypothesis, generates the same p-value as had the original null hypothesis of “no difference.” Some researchers contend that reporting the counternull, in addition to the p-value, serves to counter two common errors of judgment: - assuming that failure to reject the null hypothesis at the chosen level of statistical significance means that the observed size of the "effect" is zero; and - assuming that rejection of the null hypothesis at a particular p-value means that the measured "effect" is not only statistically significant, but also scientifically important. These arbitrary statistical thresholds create a discontinuity, causing unnecessary confusion and artificial controversy	Counternull In statistics, and especially in the statistical analysis of psychological data, the counternull is a statistic used to aid the understanding and presentation of research results. It revolves around the effect size, which is the mean magnitude of some effect divided by the standard deviation.[1] The counternull value is the effect size that is just as well supported by the data as the null hypothesis.[2] In particular, when results are drawn from a distribution that is symmetrical about its mean, the counternull value is exactly twice the observed "effect". The null hypothesis is a hypothesis set up to be tested against an alternative. Thus the counternull is an alternative hypothesis that, when used to replace the null hypothesis, generates the same p-value as had the original null hypothesis of “no difference.”[3] Some researchers contend that reporting the counternull, in addition to the p-value, serves to counter two common errors of judgment:[4] - assuming that failure to reject the null hypothesis at the chosen level of statistical significance means that the observed size of the "effect" is zero; and - assuming that rejection of the null hypothesis at a particular p-value means that the measured "effect" is not only statistically significant, but also scientifically important. These arbitrary statistical thresholds create a discontinuity, causing unnecessary confusion and artificial controversy[5]	https://www.wikidoc.org/index.php/Counternull
da905cf74ee9ca22a0a69f57e10536bd98ab62e9	wikidoc	Cow Parsnip	Cow Parsnip The Cow Parsnip (Heracleum maximum; also known as Indian Celery or Pushki) is the only member of the Hogweed genus native to North America. Its classification has caused some difficulty, with recent authoritative sources referring to it variously as Heracleum maximum or Heracleum lanatum , as H. linatum, or as either a subspecies, H. sphondylium subsp. montanum, or a variety, H. sphondylium var. linatum, of the Common Hogweed (H. sphondylium). The classification given here follows ITIS. The Cow Parsnip is found from coast to coast in North America; in the continental United States, it is absent only from the south eastern states, from Texas eastward. In the west it can be found as far north as Alaska and most of Canada. It can be found at altitudes of up to 2500 metres. Overall, it is an abundant plant and not a conservation concern, but in some localities it is becoming rarer; it is listed as endangered in Kentucky, whereas in the west it is sometimes regarded as an invasive weed. The Cow Parsnip is a tall herb, reaching to heights of over two metres. It has the characteristic flower umbels of the carrot family (Apiaceae), about 20 cm across; these may be flat-topped, as in the picture at right, or more rounded, and are always white. The leaves are large, up to 40 cm across, divided into lobes. The stems are stout and succulent. The juices of all parts contain a phototoxin that can act on contact with skin and exposure to ultraviolet light, causing anything from a mild rash to a blistering, severe dermatitis, depending on the sensitivity of the individual. The plant is a pernicious weed especially in pastures, where it can ruin the milk of cows that eat it. Various Native American peoples had many different uses for this plant; all parts of it were used by one nation or another. Perhaps the most common use was to make poultices to be applied to bruises or sores. In addition, the young stalks and leaf stems — before the plant reaches maturity — were widely used for food with the outer skin peeled off giving a sweetish flavor. The dried stems were also used as drinking straws for the old or infirm, and to make flutes for children. A yellow dye can be made from the roots, and an infusion of the flowers can be rubbed on the body to repel flies and mosquitoes.	Cow Parsnip The Cow Parsnip (Heracleum maximum; also known as Indian Celery or Pushki) is the only member of the Hogweed genus native to North America. Its classification has caused some difficulty, with recent authoritative sources referring to it variously as Heracleum maximum or Heracleum lanatum , as H. linatum, or as either a subspecies, H. sphondylium subsp. montanum, or a variety, H. sphondylium var. linatum, of the Common Hogweed (H. sphondylium). The classification given here follows ITIS. The Cow Parsnip is found from coast to coast in North America; in the continental United States, it is absent only from the south eastern states, from Texas eastward. In the west it can be found as far north as Alaska and most of Canada. It can be found at altitudes of up to 2500 metres. Overall, it is an abundant plant and not a conservation concern, but in some localities it is becoming rarer; it is listed as endangered in Kentucky, whereas in the west it is sometimes regarded as an invasive weed. The Cow Parsnip is a tall herb, reaching to heights of over two metres. It has the characteristic flower umbels of the carrot family (Apiaceae), about 20 cm across; these may be flat-topped, as in the picture at right, or more rounded, and are always white. The leaves are large, up to 40 cm across, divided into lobes. The stems are stout and succulent. The juices of all parts contain a phototoxin that can act on contact with skin and exposure to ultraviolet light, causing anything from a mild rash to a blistering, severe dermatitis, depending on the sensitivity of the individual. The plant is a pernicious weed especially in pastures, where it can ruin the milk of cows that eat it. Various Native American peoples had many different uses for this plant; all parts of it were used by one nation or another. Perhaps the most common use was to make poultices to be applied to bruises or sores. In addition, the young stalks and leaf stems — before the plant reaches maturity — were widely used for food with the outer skin peeled off giving a sweetish flavor. The dried stems were also used as drinking straws for the old or infirm, and to make flutes for children. A yellow dye can be made from the roots, and an infusion of the flowers can be rubbed on the body to repel flies and mosquitoes.[citation needed] # External links - Jepson Manual species treatment - Images from the CalPhotos archive - [1] Images from the Connecticut Botanical Society] - Plants for a Future report on the species sv:Björnloka	https://www.wikidoc.org/index.php/Cow_Parsnip
5d909be3d5a02b53bc2ba743f122babf92f6957a	wikidoc	Coxsackie B	Coxsackie B To go back to Coxsackie virus home page, click here. # Overview Coxsackie B is the name of a group of six serotypes of pathogenic enteroviruses that trigger illness ranging from mild gastrointestinal distress to full-fledged pericarditis, myocarditis, pericardial effusion, pleurodynia and hepatitis. # Viral Structure and Function Coxsackie B viruses are single-strange positive-sense RNA viruses that are resistant to a wide variety of chemical treatments. The viral particles themselves are roughly 30nm icosahedrons. The virus is most frequently distributed via the fecal-oral route, and infection commonly occurs after eating contaminated food. Coxsackie B viruses are cytolytic, and Coxsackie B2 and B5 viruses have been implicated in hand, foot and mouth disease as well as respiratory infection. Infection in infants is mostly asymptomatic, but sometimes results in the death of the infant, often due to myocarditis. Birth defects may also be present in a coxsackie B infected infant. ### Associated Conditions - The B4 strain of coxsackie viruses has been discovered to be a possible cause of Diabetes mellitus type 1. - Sjogren's syndorme is also thought to have a connections with coxsackie B virus. - Coxsackie B3 and B4 are related to acute flaccid myelitis. # Epidemiology and Demographics The various members of the Coxsackie B group were discovered almost entirely in the United States, appearing originally in Connecticut, Ohio, New York, and Kentucky, although a sixth member of the group has been found in the Philippines. That said, all six serotypes have a global distribution and are a relatively common cause of gastrointestinal upset. # Diagnosis ## History and Symptoms Symptoms of infection with viruses in the Coxsackie B grouping include fever, headache, sore throat, gastrointestinal distress, as well as chest and muscle pain. This presentation is known as pleurodynia or Bornholmes disease in many areas. Patients with chest pain should see a doctor immediately as it can progress to myocarditis or pericarditis, which result in permanent heart damage or death. Coxsackie B virus infection may also induce aseptic meningitis. As a group, they are the most common cause of unexpected sudden death, and may account for up to 50% of such cases. The incubation period for the Coxsackie B viruses is, like most of the Enteroviridae, highly variable, ranging from 2 to 35 days, and illness may last for up to two weeks, but may resolve as quickly as two days. Infection usually occurs between the months of June and October. ## Laboratory Findings Enterovirus infection is diagnosed mainly via serological tests such as ELISA and from cell culture. Because the same level and type of care is given regardless of type of Coxsackie B infection, it is mostly unnecessary for treatment purposes to diagnose which virus is causing the symptoms in question, though it may be epidemiologically useful. # Treatment ## Medical Therapy As of 2007, there is no treatment for the Coxsackie B group of viruses. Pallative care is available, however, and patients suffering chest pain or stiffness of the neck should be examined for signs of cardiac or central nervous system involvement, respectively. Some measure of prevention can usually be achieved by basic sanitation on the part of food-service workers, though the viruses are highly contagious. Care should be taken in washing ones hands and in cleaning the body after swimming. In the event of Coxsackie-induced myocarditis or pericarditis, antiinflammatories can be given to reduce damage to the heart muscle. There is no vaccine for any member of the group. ## Prevention Some measure of prevention can usually be achieved by basic sanitation on the part of food-service workers, though the viruses are highly contagious. Care should be taken in washing ones hands and in cleaning the body after swimming. In the event of Coxsackie-induced myocarditis or pericarditis,antiinflammatories can be given to reduce damage to the heart muscle. There is no vaccine for any member of the group.	Coxsackie B Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Usama Talib, BSc, MD [2] To go back to Coxsackie virus home page, click here. # Overview Coxsackie B is the name of a group of six serotypes of pathogenic enteroviruses that trigger illness ranging from mild gastrointestinal distress to full-fledged pericarditis, myocarditis, pericardial effusion, pleurodynia and hepatitis.[1] # Viral Structure and Function Coxsackie B viruses are single-strange positive-sense RNA viruses that are resistant to a wide variety of chemical treatments. The viral particles themselves are roughly 30nm icosahedrons.[2] The virus is most frequently distributed via the fecal-oral route, and infection commonly occurs after eating contaminated food. Coxsackie B viruses are cytolytic, and Coxsackie B2 and B5 viruses have been implicated in hand, foot and mouth disease as well as respiratory infection.[1] Infection in infants is mostly asymptomatic, but sometimes results in the death of the infant, often due to myocarditis.[3] Birth defects may also be present in a coxsackie B infected infant. ### Associated Conditions - The B4 strain of coxsackie viruses has been discovered to be a possible cause of Diabetes mellitus type 1. - Sjogren's syndorme is also thought to have a connections with coxsackie B virus. - Coxsackie B3 and B4 are related to acute flaccid myelitis.[4] # Epidemiology and Demographics The various members of the Coxsackie B group were discovered almost entirely in the United States, appearing originally in Connecticut, Ohio, New York, and Kentucky, although a sixth member of the group has been found in the Philippines.[1] That said, all six serotypes have a global distribution and are a relatively common cause of gastrointestinal upset. # Diagnosis ## History and Symptoms Symptoms of infection with viruses in the Coxsackie B grouping include fever, headache, sore throat, gastrointestinal distress, as well as chest and muscle pain. This presentation is known as pleurodynia or Bornholmes disease in many areas. Patients with chest pain should see a doctor immediately as it can progress to myocarditis or pericarditis, which result in permanent heart damage or death. Coxsackie B virus infection may also induce aseptic meningitis. As a group, they are the most common cause of unexpected sudden death, and may account for up to 50% of such cases.[5] The incubation period for the Coxsackie B viruses is, like most of the Enteroviridae, highly variable, ranging from 2 to 35 days, and illness may last for up to two weeks, but may resolve as quickly as two days. Infection usually occurs between the months of June and October.[1] ## Laboratory Findings Enterovirus infection is diagnosed mainly via serological tests such as ELISA[6] and from cell culture.[1] Because the same level and type of care is given regardless of type of Coxsackie B infection, it is mostly unnecessary for treatment purposes to diagnose which virus is causing the symptoms in question, though it may be epidemiologically useful. # Treatment ## Medical Therapy As of 2007, there is no treatment for the Coxsackie B group of viruses.[1] Pallative care is available, however, and patients suffering chest pain or stiffness of the neck should be examined for signs of cardiac or central nervous system involvement, respectively. Some measure of prevention can usually be achieved by basic sanitation on the part of food-service workers, though the viruses are highly contagious. Care should be taken in washing ones hands and in cleaning the body after swimming. In the event of Coxsackie-induced myocarditis or pericarditis, antiinflammatories can be given to reduce damage to the heart muscle. There is no vaccine for any member of the group. ## Prevention Some measure of prevention can usually be achieved by basic sanitation on the part of food-service workers, though the viruses are highly contagious. Care should be taken in washing ones hands and in cleaning the body after swimming. In the event of Coxsackie-induced myocarditis or pericarditis,antiinflammatories can be given to reduce damage to the heart muscle. There is no vaccine for any member of the group.	https://www.wikidoc.org/index.php/Coxsackie_B
389c6a91ebcfe8717f8a68113d27cb9db104d9d8	wikidoc	Crown ether	Crown ether Crown ethers are heterocyclic chemical compounds that, in their simplest form, are cyclic oligomers of ethylene oxide. The essential repeating unit of any simple crown ether is ethyleneoxy, i.e., -CH2CH2O-, which repeats twice in dioxane and six times in 18-crown-6. In general, macrocycles of the (-CH2CH2O-)n type in which n ≥ 4 are referred to as "crown" ethers rather than by their lengthier systematic names: for instance, the systematic name of 18-crown-6 is "1,4,7,10,13,16-hexaoxacyclooctadecane". "Crown" refers to the resemblance between the structure of a crown ether bound to a cation, and a crown sitting on a head; the first number in a crown ether's name refers to the number of atoms in the cycle, and the second number refers to the number of those atoms which are oxygen. Crown ethers are known for their ability to strongly solvate cations. In other words, the equilibrium is strongly towards the complex. The oxygen atoms are ideally situated to coordinate with a cation in the interior of the ring, whereas the exterior of the ring is hydrophobic. The result is that the complexed cation is soluble in nonpolar solvents. The size of the interior of the crown ether determines the size of the cation it can solvate. Therefore, 18-crown-6 has high affinity for potassium cation, 15-crown-5 for sodium cation and 12-crown-4 for lithium cation. The high affinity of 18-crown-6 for potassium ions contributes towards its toxicity in humans. Crown ethers are not the only macrocyclic ligands that have affinity for the potassium cation. Ionophores such as nonactin and valinomycin also display a marked preference for the potassium cation over other cations. Early reports of crown ethers concentrated on synthetic methods for their production; only later were their properties and the fundamental theoretical implications thereof realized. In 1967, Charles Pedersen, who was a chemist working at DuPont, discovered a simple method of synthesizing a crown ether when he was trying to prepare a complexing agent for divalent cations . His strategy was to link two catechols through one hydroxyl on each molecule. This would give him a compound that could partially envelop the cation and, by ionization of the phenolic hydroxyls, neutralize the bound dication. He was surprised to isolate a by-product that bound or complexed with potassium cation but had no ionizable hydroxyl group. Citing earlier work on the dissolution of potassium in 16-crown-4 , he realized that the cyclic polyethers represented a new class of complexing agents that were capable of binding alkali metal cations. He proceeded to report systematic studies of the synthesis and binding properties of crown ethers in a seminal series of papers. The fields of anionic synthetic reagents, phase transfer catalysts, biological ion transfer, and other emerging disciplines benefited profoundly from the discovery of crown ether. Pedersen shared the 1987 Nobel Prize in Chemistry for the discovery of the synthetic routes to, and binding properties, of crown ethers. Apart from its high affinity for potassium cations, 18-crown-6 can also bind to protonated amines and form very stable complexes in both solution and the gas phase. Some amino acids, such as lysine, contain a primary amine on their side chains. Those protonated amino groups can bind to the cavity of 18-crown-6 and form stable complexes in the gas phase. Hydrogen-bonds are formed between the three hydrogen atoms of protonated amines and three oxygen atoms of 18-crown-6. These hydrogen-bonds make the complex a stable adduct. Aza- analogues of crown ethers exist as well, in particular cyclen. - ↑ C. J. Pedersen, J. Am. Chem. Soc., 1967, 89, 7017. - ↑ D. G. Stewart. D. Y. Waddan and E. T. Borrows, British Patent 785,229, Oct. 23, 1957. - ↑ J. L. Down, J. Lewis, B. Moore and G. W. Wilkinson, Proc. Chem. Soc., 1959, 209; J. Chem. Soc., 1959, 3767.	Crown ether Crown ethers are heterocyclic chemical compounds that, in their simplest form, are cyclic oligomers of ethylene oxide. The essential repeating unit of any simple crown ether is ethyleneoxy, i.e., -CH2CH2O-, which repeats twice in dioxane and six times in 18-crown-6. In general, macrocycles of the (-CH2CH2O-)n type in which n ≥ 4 are referred to as "crown" ethers rather than by their lengthier systematic names: for instance, the systematic name of 18-crown-6 is "1,4,7,10,13,16-hexaoxacyclooctadecane". "Crown" refers to the resemblance between the structure of a crown ether bound to a cation, and a crown sitting on a head; the first number in a crown ether's name refers to the number of atoms in the cycle, and the second number refers to the number of those atoms which are oxygen. Crown ethers are known for their ability to strongly solvate cations. In other words, the equilibrium is strongly towards the complex. The oxygen atoms are ideally situated to coordinate with a cation in the interior of the ring, whereas the exterior of the ring is hydrophobic. The result is that the complexed cation is soluble in nonpolar solvents. The size of the interior of the crown ether determines the size of the cation it can solvate. Therefore, 18-crown-6 has high affinity for potassium cation, 15-crown-5 for sodium cation and 12-crown-4 for lithium cation. The high affinity of 18-crown-6 for potassium ions contributes towards its toxicity in humans. Crown ethers are not the only macrocyclic ligands that have affinity for the potassium cation. Ionophores such as nonactin and valinomycin also display a marked preference for the potassium cation over other cations. Early reports of crown ethers concentrated on synthetic methods for their production; only later were their properties and the fundamental theoretical implications thereof realized. In 1967, Charles Pedersen, who was a chemist working at DuPont, discovered a simple method of synthesizing a crown ether when he was trying to prepare a complexing agent for divalent cations [1]. His strategy was to link two catechols through one hydroxyl on each molecule. This would give him a compound that could partially envelop the cation and, by ionization of the phenolic hydroxyls, neutralize the bound dication. He was surprised to isolate a by-product that bound or complexed with potassium cation but had no ionizable hydroxyl group. Citing earlier work on the dissolution of potassium in 16-crown-4 [2] [3], he realized that the cyclic polyethers represented a new class of complexing agents that were capable of binding alkali metal cations. He proceeded to report systematic studies of the synthesis and binding properties of crown ethers in a seminal series of papers. The fields of anionic synthetic reagents, phase transfer catalysts, biological ion transfer, and other emerging disciplines benefited profoundly from the discovery of crown ether. Pedersen shared the 1987 Nobel Prize in Chemistry for the discovery of the synthetic routes to, and binding properties, of crown ethers. Apart from its high affinity for potassium cations, 18-crown-6 can also bind to protonated amines and form very stable complexes in both solution and the gas phase. Some amino acids, such as lysine, contain a primary amine on their side chains. Those protonated amino groups can bind to the cavity of 18-crown-6 and form stable complexes in the gas phase. Hydrogen-bonds are formed between the three hydrogen atoms of protonated amines and three oxygen atoms of 18-crown-6. These hydrogen-bonds make the complex a stable adduct. Aza- analogues of crown ethers exist as well, in particular cyclen. - ↑ C. J. Pedersen, J. Am. Chem. Soc., 1967, 89, 7017. - ↑ D. G. Stewart. D. Y. Waddan and E. T. Borrows, British Patent 785,229, Oct. 23, 1957. - ↑ J. L. Down, J. Lewis, B. Moore and G. W. Wilkinson, Proc. Chem. Soc., 1959, 209; J. Chem. Soc., 1959, 3767. # External links - Charles Pedersen's Nobel Lecture de:Kronenether it:Eteri corona nl:Kroonether	https://www.wikidoc.org/index.php/Crown_ether
0d4bbc8103dfb15485c119cee32a929f33722189	wikidoc	Cryobiology	Cryobiology Cryobiology is the study of living organisms, organs, biological tissues or biological cells at low temperatures. This knowledge is practically applied in three fields: cryonics, cryopreservation and cryosurgery. # Definitions/Distinctions Cryobiology is the branch of biology that studies the effects of low temperatures on organisms (most often for the purpose of achieving cryopreservation). The word cryobiology (from the Greek words "cryo" = cold, "bios" = life, and "logos" = science) literally signifies the science of life at low temperatures. In practice, this field comprises the study of any biological material or system (e.g., proteins, cells, tissues, organs, or organisms) subjected to any temperature below normal (ranging from moderately hypothermic conditions to cryogenic temperatures). At least 6 major areas of cryobiology can be identified: 1) study of cold-adaptation of microorganisms, plants (= cold hardiness), invertebrates, and animals (= hibernation), 2) cryopreservation of cells, tissues, gametes, and embryos of animal and human origin for (medical) purposes of long-term storage. This usually requires the addition of substances which protect the cells during freezing and thawing (cryoprotectants), 3) preservation of organs under hypothermic conditions for transplantation, 4) lyophilization (freeze-drying) of pharmaceuticals, 5) cryosurgery, a (minimally) invasive approach for the destruction of unhealthy tissue using cryogenic gases/fluids, and 6) physics of supercooling, ice nucleation/growth and mechanical engineering aspects of heat transfer during cooling and warming. # Historical Background Cryobiology history can be traced back to antiquity. As early as in 2500 BC low temperatures were used in Egypt in medicine. The use of cold was recommended by Hippocrates to stop bleeding and swelling. With the emergence of modern science, Robert Boyle studied the effects of low temperatures on animals. In 1949 sperm was cryopreserved for the first time by a team of scientists led by Christopher Polge (1926-2006). This led to a much wider use of cryopreservation today, with many organs, tissues and cells routinely stored in low temperatures. Large organs such as hearts are usually stored and transported, for short times only, at cool but not freezing temperatures for transplantation. Cell suspensions (like blood and semen) and thin tissue sections can sometimes be stored almost indefinitely at liquid nitrogen temperature (cryopreservation). Human sperm, eggs and embryos are routinely stored in fertility research and treatments. In the early 2000s a baby was born from a cryopreserved egg fertilized by a cryopreserved sperm. Cryosurgery (= intended and controlled tissue destruction by ice formation) was carried out by James Arnott in 1845 in an operation on a patient with cancer. Although not very widespread, cryosurgery has its benefits. Hypothermia, e.g. during heart surgery on a "cold" heart (generated by cold perfusion without any ice formation) allows for much longer operations and improves recovery rates for patients. # Modern developments Discussions of modern developments in cryobiology can be found under cryopreservation and vitrification. # Scientific Societies One of the two leading scientific societies in the field of cryobiology is the Society for Cryobiology. This society was founded in 1964 to bring together those from the biological, medical and physical sciences who have a common interest in the effect of low temperatures on biological systems. As of November 2006 the Society for Cryobiology had approximately 300 members from around the world, and one half of them are US based. The purpose of the Society is to promote scientific research in low temperature biology, to improve scientific understanding in this field, and to disseminate and apply this knowledge to the benefit of mankind. The Society requires of all its members the highest ethical and scientific standards in the performance of their professional activities. According to the Society's Bylaws membership may be refused to applicants whose conduct is deemed detrimental to the Society, this includes explicitly any practice or application of freezing deceased persons in the anticipation of their reanimation. This is the characteristic difference between "cryobiology" (which is a scientific discipline) and "cryonics". The Society organizes an annual scientific meeting dedicated to all aspects of low-temperature biology. This international meeting offers opportunities for presentation and discussion of the most up-to-date research in cryobiology as well as reviewing specific aspects through symposia and workshops. Members are also kept informed of news and forthcoming meetings through the Society newsletter, News Notes. The 2006-2007 President of the Society for Cryobiology is Andreas Sputtek. The Society for Low Temperature Biology was founded in 1964 and became a Registered Charity in 2003 (Charity Commission for England & Wales No. 1099747) with the purpose of promoting research into the effects of low temperatures on all types of organisms and their constituent cells, tissues and organs. As of 2006 the Society for Low Temperature Biology had approximately 130 (mostly British and European) members and holds at least one Annual General Meeting. The program usually includes both a symposium on a topical subject and a session of free communications on any aspect of low temperature biology. Recent symposia have included long-term stability, preservation of aquatic organisms, cryopreservation of embryos and gametes, preservation of plants, low temperature microscopy, vitrification (glass formation of aqueous systems during cooling), freeze drying and tissue banking. Members are informed through the Society Newsletter, which is presently published 3 times a year. The 2005-2006 Chair of the Society for Low Temperature Biology has been Tiantian Zhang . A list of additional scientific societies (mostly using "applied" cryobiology) can be found here. # Journals CRYOBIOLOGY, (publisher: Elsevier) is the foremost scientific publication in this area, with approximately 60 refereed contributions published each year. Articles concern any aspect of low temperature biology and medicine (e.g. freezing, freeze-drying, hibernation, cold tolerance and adaptation, cryoprotective compounds, medical applications of reduced temperature, cryosurgery, hypothermia, and perfusion of organs). There is an independent UK based rapid communication journal named CRYO LETTERS which publishes papers on the effects produced by low temperatures on a wide variety of biophysical and biological processes, or studies involving low temperature techniques in the investigation of biological and ecological topics. CELL PRESERVATION TECHNOLOGY is a peer-reviewed quarterly scientific journal published by Mary Ann Liebert, Inc. dedicated to the diverse spectrum of preservation technologies including cryopreservation, dry-state (anhydrobiosis), glassy-state and hypothermic maintenance. # Notes - ↑ Platt, Charles (1995). New Brain Study Shows Reduced Tissue Damage. CryoCare Report (4 ed.). CryoCare Foundation. Retrieved 2006-03-17..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} - ↑ Lemler J, Harris SB, Platt C, Huffman TM (2004). "The arrest of biological time as a bridge to engineered negligible senescence". Ann N Y Acad Sci. 1019: 559–63. PMID 15247086.CS1 maint: Multiple names: authors list (link) - ↑ Merkle RC (1992). "The technical feasibility of cryonics". Med Hypotheses. 39 (1): 6–16. PMID 1435395. - ↑ "Scientists' Open Letter on Cryonics". Immortality Institute. Retrieved 2007-04-13. - ↑ Andreas Sputtek - ↑ Tiantian Zhang	Cryobiology Cryobiology is the study of living organisms, organs, biological tissues or biological cells at low temperatures. This knowledge is practically applied in three fields: cryonics, cryopreservation and cryosurgery. # Definitions/Distinctions Cryobiology is the branch of biology that studies the effects of low temperatures on organisms (most often for the purpose of achieving cryopreservation). The word cryobiology (from the Greek words "cryo" = cold, "bios" = life, and "logos" = science) literally signifies the science of life at low temperatures. In practice, this field comprises the study of any biological material or system (e.g., proteins, cells, tissues, organs, or organisms) subjected to any temperature below normal (ranging from moderately hypothermic conditions to cryogenic temperatures). At least 6 major areas of cryobiology can be identified: 1) study of cold-adaptation of microorganisms, plants (= cold hardiness), invertebrates, and animals (= hibernation), 2) cryopreservation of cells, tissues, gametes, and embryos of animal and human origin for (medical) purposes of long-term storage. This usually requires the addition of substances which protect the cells during freezing and thawing (cryoprotectants), 3) preservation of organs under hypothermic conditions for transplantation, 4) lyophilization (freeze-drying) of pharmaceuticals, 5) cryosurgery, a (minimally) invasive approach for the destruction of unhealthy tissue using cryogenic gases/fluids, and 6) physics of supercooling, ice nucleation/growth and mechanical engineering aspects of heat transfer during cooling and warming. # Historical Background Cryobiology history can be traced back to antiquity. As early as in 2500 BC low temperatures were used in Egypt in medicine. The use of cold was recommended by Hippocrates to stop bleeding and swelling. With the emergence of modern science, Robert Boyle studied the effects of low temperatures on animals. In 1949 sperm was cryopreserved for the first time by a team of scientists led by Christopher Polge (1926-2006). This led to a much wider use of cryopreservation today, with many organs, tissues and cells routinely stored in low temperatures. Large organs such as hearts are usually stored and transported, for short times only, at cool but not freezing temperatures for transplantation. Cell suspensions (like blood and semen) and thin tissue sections can sometimes be stored almost indefinitely at liquid nitrogen temperature (cryopreservation). Human sperm, eggs and embryos are routinely stored in fertility research and treatments. In the early 2000s a baby was born from a cryopreserved egg fertilized by a cryopreserved sperm. Cryosurgery (= intended and controlled tissue destruction by ice formation) was carried out by James Arnott in 1845 in an operation on a patient with cancer. Although not very widespread, cryosurgery has its benefits. Hypothermia, e.g. during heart surgery on a "cold" heart (generated by cold perfusion without any ice formation) allows for much longer operations and improves recovery rates for patients. # Modern developments Discussions of modern developments in cryobiology can be found under cryopreservation and vitrification. # Scientific Societies One of the two leading scientific societies in the field of cryobiology is the Society for Cryobiology. This society was founded in 1964 to bring together those from the biological, medical and physical sciences who have a common interest in the effect of low temperatures on biological systems. As of November 2006 the Society for Cryobiology had approximately 300 members from around the world, and one half of them are US based. The purpose of the Society is to promote scientific research in low temperature biology, to improve scientific understanding in this field, and to disseminate and apply this knowledge to the benefit of mankind. The Society requires of all its members the highest ethical and scientific standards in the performance of their professional activities. According to the Society's Bylaws membership may be refused to applicants whose conduct is deemed detrimental to the Society, this includes explicitly any practice or application of freezing deceased persons in the anticipation of their reanimation. This is the characteristic difference between "cryobiology" (which is a scientific discipline) and "cryonics". The Society organizes an annual scientific meeting dedicated to all aspects of low-temperature biology. This international meeting offers opportunities for presentation and discussion of the most up-to-date research in cryobiology as well as reviewing specific aspects through symposia and workshops. Members are also kept informed of news and forthcoming meetings through the Society newsletter, News Notes. The 2006-2007 President of the Society for Cryobiology is Andreas Sputtek[5]. The Society for Low Temperature Biology was founded in 1964 and became a Registered Charity in 2003 (Charity Commission for England & Wales No. 1099747) with the purpose of promoting research into the effects of low temperatures on all types of organisms and their constituent cells, tissues and organs. As of 2006 the Society for Low Temperature Biology had approximately 130 (mostly British and European) members and holds at least one Annual General Meeting. The program usually includes both a symposium on a topical subject and a session of free communications on any aspect of low temperature biology. Recent symposia have included long-term stability, preservation of aquatic organisms, cryopreservation of embryos and gametes, preservation of plants, low temperature microscopy, vitrification (glass formation of aqueous systems during cooling), freeze drying and tissue banking. Members are informed through the Society Newsletter, which is presently published 3 times a year. The 2005-2006 Chair of the Society for Low Temperature Biology has been Tiantian Zhang [6]. A list of additional scientific societies (mostly using "applied" cryobiology) can be found here. # Journals CRYOBIOLOGY, (publisher: Elsevier) is the foremost scientific publication in this area, with approximately 60 refereed contributions published each year. Articles concern any aspect of low temperature biology and medicine (e.g. freezing, freeze-drying, hibernation, cold tolerance and adaptation, cryoprotective compounds, medical applications of reduced temperature, cryosurgery, hypothermia, and perfusion of organs). There is an independent UK based rapid communication journal named CRYO LETTERS which publishes papers on the effects produced by low temperatures on a wide variety of biophysical and biological processes, or studies involving low temperature techniques in the investigation of biological and ecological topics. CELL PRESERVATION TECHNOLOGY is a peer-reviewed quarterly scientific journal published by Mary Ann Liebert, Inc. dedicated to the diverse spectrum of preservation technologies including cryopreservation, dry-state (anhydrobiosis), glassy-state and hypothermic maintenance. # Notes - ↑ Platt, Charles (1995). New Brain Study Shows Reduced Tissue Damage. CryoCare Report (4 ed.). CryoCare Foundation. Retrieved 2006-03-17..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} - ↑ Lemler J, Harris SB, Platt C, Huffman TM (2004). "The arrest of biological time as a bridge to engineered negligible senescence". Ann N Y Acad Sci. 1019: 559–63. PMID 15247086.CS1 maint: Multiple names: authors list (link) - ↑ Merkle RC (1992). "The technical feasibility of cryonics". Med Hypotheses. 39 (1): 6–16. PMID 1435395. - ↑ "Scientists' Open Letter on Cryonics". Immortality Institute. Retrieved 2007-04-13. - ↑ Andreas Sputtek - ↑ Tiantian Zhang	https://www.wikidoc.org/index.php/Cryobiology
fddde65943b25fd881b2b9a0ba884d752533a33b	wikidoc	Cryosurgery	Cryosurgery # Overview Cryosurgery (cryotherapy) is the application of extreme cold to destroy abnormal or diseased tissue. The term comes from the Greek words cryo (κρύο) ("icy cold") and surgery (cheirourgiki - χειρουργική) meaning "hand work" or "handiwork". Cryosurgery is used to treat a number of diseases and disorders, especially a variety of benign and malignant skin conditions. Warts, moles, skin tags, solar keratoses, and small skin cancers are candidates for cryosurgical treatment. Several internal disorders are also treated with cryosurgery, including liver cancer, prostate cancer, cervical disorders and, more commonly in the past, hemorrhoids. Although found to be effective, this method of treatment is only appropriate for use against localized disease with no metastasis. Cryosurgery works by taking advantage of the destructive force of freezing temperatures on cells. At low temperatures, ice crystals form inside the cells, which can tear them apart. More damage occurs when blood vessels supplying the diseased tissue freeze. The most common method of freezing lesions is using liquid nitrogen as the cooling solution. The super-cooled liquid may be sprayed on the diseased tissue, circulated through a tube called a cryoprobe, or simply dabbed on with a cotton or foam swab. Less frequently, doctors use carbon dioxide "snow" formed into a cylinder or mixed with acetone to form a slush that is applied directly to the treated tissue. Recent advances in technology have allowed for the use of argon gas to drive ice formation using a principle known as the Joule-Thomson effect. This gives physicians excellent control of the ice, and minimizing complications using ultra-thin 17 gauge cryoneedles. Cryosurgery is a minimally invasive procedure, and is often preferred to more traditional kinds of surgery because of its minimal pain, scarring, and cost; however, as with any medical treatment, there are risks involved, primarily that of damage to nearby healthy tissue. Damage to nerve tissue is of particular concern. Patients undergoing cryosurgery usually experience minor-to-moderate localized pain and redness, which can be alleviated by oral administration of an analgesic such as aspirin, ibuprofen or acetaminophen (paracetamol). Blisters may form, but these usually scab over and peel away within several days.	Cryosurgery Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Cryosurgery (cryotherapy) is the application of extreme cold to destroy abnormal or diseased tissue.[1] The term comes from the Greek words cryo (κρύο) ("icy cold") and surgery (cheirourgiki - χειρουργική) meaning "hand work" or "handiwork". Cryosurgery is used to treat a number of diseases and disorders, especially a variety of benign and malignant skin conditions.[2] Warts, moles, skin tags, solar keratoses, and small skin cancers are candidates for cryosurgical treatment. Several internal disorders are also treated with cryosurgery, including liver cancer, prostate cancer, cervical disorders and, more commonly in the past, hemorrhoids. Although found to be effective, this method of treatment is only appropriate for use against localized disease with no metastasis. Cryosurgery works by taking advantage of the destructive force of freezing temperatures on cells. At low temperatures, ice crystals form inside the cells, which can tear them apart. More damage occurs when blood vessels supplying the diseased tissue freeze. The most common method of freezing lesions is using liquid nitrogen as the cooling solution. The super-cooled liquid may be sprayed on the diseased tissue, circulated through a tube called a cryoprobe, or simply dabbed on with a cotton or foam swab. Less frequently, doctors use carbon dioxide "snow" formed into a cylinder or mixed with acetone to form a slush that is applied directly to the treated tissue. Recent advances in technology have allowed for the use of argon gas to drive ice formation using a principle known as the Joule-Thomson effect. This gives physicians excellent control of the ice, and minimizing complications using ultra-thin 17 gauge cryoneedles. Cryosurgery is a minimally invasive procedure, and is often preferred to more traditional kinds of surgery because of its minimal pain, scarring, and cost; however, as with any medical treatment, there are risks involved, primarily that of damage to nearby healthy tissue. Damage to nerve tissue is of particular concern. Patients undergoing cryosurgery usually experience minor-to-moderate localized pain and redness, which can be alleviated by oral administration of an analgesic such as aspirin, ibuprofen or acetaminophen (paracetamol). Blisters may form, but these usually scab over and peel away within several days.	https://www.wikidoc.org/index.php/Cryocautery
eb30da41622edf94a89b2e336157754fa5d32421	wikidoc	Cryptomonad	Cryptomonad # Overview The cryptomonads are a small group of flagellates, most of which have chloroplasts. They are common in freshwater, and also occur in marine and brackish habitats. Each cell is around 10-50 μm in size and flattened in shape, with an anterior groove or pocket. At the edge of the pocket there are typically two slightly unequal flagella. Cryptomonads distinguished by the presence of characteristic extrusomes called ejectisomes, which consist of two connected spiral ribbons held under tension. If the cells are irritated either by mechanical, chemical or light stress, they discharge, propelling the cell in a zig-zag course away from the disturbance. Large ejectisomes, visible under the light microscope, are associated with the pocket; smaller ones occur elsewhere on the cell. Cryptomonads have one or two chloroplasts, except for Chilomonas which has leucoplasts and Goniomonas which lacks plastids entirely. These contain chlorophylls a and c, together with phycobiliproteins and other pigments, and vary in color from brown to green. Each is surrounded by four membranes, and there is a reduced cell nucleus called a nucleomorph between the middle two. This indicates that the chloroplast was derived from a eukaryotic symbiont, shown by genetic studies to have been a red alga. A few cryptomonads, such as Cryptomonas, can form palmelloid stages, but readily escape the surrounding mucus to become free-living flagellates again. Cryptomonad flagella are inserted parallel to one another, and are covered by bipartite hairs called mastigonemes, formed within the endoplasmic reticulum and transported to the cell surface. Small scales may also be present on the flagella and cell body. The mitochondria have flate cristae, and mitosis is open; sexual reproduction has also been reported. Originally the cryptomonads were considered close relatives of the dinoflagellates because of their similar pigmentation. Later botanists treated them as a separate division, Cryptophyta, while zoologists treated them as the flagellate order Cryptomonadida. There is considerable evidence that cryptomonad chloroplasts are closely related to those of the heterokonts and haptophytes, and the three groups are sometimes united as the Chromista. However, the case that the organisms themselves are closely related is not very strong, and they may have acquired chloroplasts independently.	Cryptomonad Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview The cryptomonads are a small group of flagellates, most of which have chloroplasts. They are common in freshwater, and also occur in marine and brackish habitats. Each cell is around 10-50 μm in size and flattened in shape, with an anterior groove or pocket. At the edge of the pocket there are typically two slightly unequal flagella. Cryptomonads distinguished by the presence of characteristic extrusomes called ejectisomes, which consist of two connected spiral ribbons held under tension. If the cells are irritated either by mechanical, chemical or light stress, they discharge, propelling the cell in a zig-zag course away from the disturbance. Large ejectisomes, visible under the light microscope, are associated with the pocket; smaller ones occur elsewhere on the cell. Cryptomonads have one or two chloroplasts, except for Chilomonas which has leucoplasts and Goniomonas which lacks plastids entirely. These contain chlorophylls a and c, together with phycobiliproteins and other pigments, and vary in color from brown to green. Each is surrounded by four membranes, and there is a reduced cell nucleus called a nucleomorph between the middle two. This indicates that the chloroplast was derived from a eukaryotic symbiont, shown by genetic studies to have been a red alga. A few cryptomonads, such as Cryptomonas, can form palmelloid stages, but readily escape the surrounding mucus to become free-living flagellates again. Cryptomonad flagella are inserted parallel to one another, and are covered by bipartite hairs called mastigonemes, formed within the endoplasmic reticulum and transported to the cell surface. Small scales may also be present on the flagella and cell body. The mitochondria have flate cristae, and mitosis is open; sexual reproduction has also been reported. Originally the cryptomonads were considered close relatives of the dinoflagellates because of their similar pigmentation. Later botanists treated them as a separate division, Cryptophyta, while zoologists treated them as the flagellate order Cryptomonadida. There is considerable evidence that cryptomonad chloroplasts are closely related to those of the heterokonts and haptophytes, and the three groups are sometimes united as the Chromista. However, the case that the organisms themselves are closely related is not very strong, and they may have acquired chloroplasts independently. Template:WH Template:WS	https://www.wikidoc.org/index.php/Cryptomonad
a6417e9610aedcea94f4e50a4db5747c13031505	wikidoc	Cubic meter	Cubic meter # Overview The cubic metre (US spelling: cubic meter, symbol: m³) is the SI derived unit of volume. It is the volume of a cube with edges one metre in length. An alternative name, which allowed a different usage with metric prefixes, was the stère. Another alternative name, not widely used any more, is the kilolitre. # Conversions 1 cubic metre is equivalent to: - 1,000 litres (exactly); - ~35.3 cubic feet (approximately) 1 cu ft = Template:Delimitnum m³ (exactly) - 1 cu ft = Template:Delimitnum m³ (exactly) - ~1.31 cubic yards (approximately) 1 cu yd = Template:Delimitnum m³ (exactly) - 1 cu yd = Template:Delimitnum m³ (exactly) - ~6.29 oil barrels (approximately) 1 oil bbl = Template:Delimitnum m³ (exactly) - 1 oil bbl = Template:Delimitnum m³ (exactly) A cubic metre of pure water at the temperature of maximum density (3.98 °C) and standard atmospheric pressure (101.325 kPa) has a mass of 1000 kg, or one tonne. At 0 °C, the freezing point of water, it is slightly less, 999.972 kilograms. It is sometimes abbreviated to cu m, m3, m^3 or m3 when superscript characters or markup are not available/accessible (i.e. in some typewritten documents and postings in Usenet newsgroups). Abbreviated CBM in the freight business and MTQ (or numeric code 49) in international trade. # Multiples and submultiples See 1 E-3 m³ for a comparison with other volumes. ## Multiples ## Submultiples # Notes - ↑ From 1901 to 1964 the litre was defined as the volume of one kilogram of pure water at 4°C and 760 millimetres of mercury pressure. During this time, a litre was about 1.000028 dm³. In 1964 the original definition was reverted to. - ↑ The cubic centimetre is the base unit of volume of the CGS system of units. The colloquial abbreviations "cc" and "ccm" are not SI but are common in some contexts such as cooking, engine displacement and medicine. af:Kubieke meter ast:Metru cúbicu be:Кубічны метр bs:Kubni metar br:Metr kub bg:Кубичен метър ca:Metre cúbic cs:Metr krychlový de:Kubikmeter el:Κυβικό μέτρο eo:Kubmetro eu:Metro kubiko fa:متر مکعب gl:Quilómetro cúbico ko:세제곱미터 hr:Kubični metar is:Rúmmetri it:Metro cubo he:מטר מעוקב la:Metrum cubicum hu:Köbméter nl:Kubieke meter no:Kubikkmeter nn:Kubikkmeter simple:Cubic metre sk:Kubický meter sl:Kubični meter sr:Кубни метар sh:Metar kubni fi:Kuutiometri sv:Kubikmeter th:ลูกบาศก์เมตร	Cubic meter # Overview The cubic metre (US spelling: cubic meter, symbol: m³) is the SI derived unit of volume. It is the volume of a cube with edges one metre in length. An alternative name, which allowed a different usage with metric prefixes, was the stère. Another alternative name, not widely used any more, is the kilolitre. # Conversions 1 cubic metre is equivalent to: - 1,000 litres (exactly);[1] - ~35.3 cubic feet (approximately) 1 cu ft = Template:Delimitnum m³ (exactly) - 1 cu ft = Template:Delimitnum m³ (exactly) - ~1.31 cubic yards (approximately) 1 cu yd = Template:Delimitnum m³ (exactly) - 1 cu yd = Template:Delimitnum m³ (exactly) - ~6.29 oil barrels (approximately) 1 oil bbl = Template:Delimitnum m³ (exactly) - 1 oil bbl = Template:Delimitnum m³ (exactly) A cubic metre of pure water at the temperature of maximum density (3.98 °C) and standard atmospheric pressure (101.325 kPa) has a mass of 1000 kg, or one tonne. At 0 °C, the freezing point of water, it is slightly less, 999.972 kilograms. It is sometimes abbreviated to cu m, m3, m^3 or m**3 when superscript characters or markup are not available/accessible (i.e. in some typewritten documents and postings in Usenet newsgroups). Abbreviated CBM in the freight business and MTQ (or numeric code 49) in international trade. # Multiples and submultiples See 1 E-3 m³ for a comparison with other volumes. ## Multiples ## Submultiples # Notes - ↑ From 1901 to 1964 the litre was defined as the volume of one kilogram of pure water at 4°C and 760 millimetres of mercury pressure. During this time, a litre was about 1.000028 dm³. In 1964 the original definition was reverted to. - ↑ The cubic centimetre is the base unit of volume of the CGS system of units. The colloquial abbreviations "cc" and "ccm" are not SI but are common in some contexts such as cooking, engine displacement and medicine. Template:Volume af:Kubieke meter ast:Metru cúbicu be:Кубічны метр bs:Kubni metar br:Metr kub bg:Кубичен метър ca:Metre cúbic cs:Metr krychlový de:Kubikmeter el:Κυβικό μέτρο eo:Kubmetro eu:Metro kubiko fa:متر مکعب gl:Quilómetro cúbico ko:세제곱미터 hr:Kubični metar is:Rúmmetri it:Metro cubo he:מטר מעוקב la:Metrum cubicum hu:Köbméter nl:Kubieke meter no:Kubikkmeter nn:Kubikkmeter simple:Cubic metre sk:Kubický meter sl:Kubični meter sr:Кубни метар sh:Metar kubni fi:Kuutiometri sv:Kubikmeter th:ลูกบาศก์เมตร Template:WH Template:WS	https://www.wikidoc.org/index.php/Cubic_meter
97267ee6a550eace7084a6629d26489ba67014f7	wikidoc	Curled Dock	Curled Dock Curled Dock (Rumex crispus), also known as Curley Dock or Yellow Dock, is a perennial flowering plant in the family Polygonaceae, native to Europe and western Asia. The mature plant is a reddish brown colour, and produces a stalk that grows to about 1 m high. It has smooth leaves shooting off from a large basal rosette, with distinctive waved or curled edges. On the stalk flowers and seeds are produced in clusters on branched stems, with the largest cluster being found at the apex. The seeds are shiny, brown and encased in the calyx of the flower that produced them. This casing enables the seeds to float on water and get caught in wool and animal fur, and this helps the seeds to spread to new locations. The root-structure is a large, a yellow, forking taproot. Curled Dock grows in roadsides, all types of fields, and low-maintenance crops. It prefers rich, moist and heavy soils. # Cultivation and uses Curled Dock is a widespread naturalised species throughout the temperate world, which has become a serious invasive species in many areas, including throughout North America, southern South America, New Zealand and parts of Australia. It spreads through the seeds contaminating crop seeds, and sticking to clothing. It is designated an "injurious weed" under the UK Weeds Act 1959. It is often seen in disturbed soils at the edges of roadsides, railroad beds, and parking lots. It can be used as a wild leaf vegetable; the young leaves should be boiled in several changes of water, or can be added directly to salads. Once the plant matures it becomes too bitter to consume. Dock leaves are an excellent source of both vitamine A and protein. The roots have also been used medicinally as an astringent, tonic, and laxative.	Curled Dock Curled Dock (Rumex crispus), also known as Curley Dock or Yellow Dock, is a perennial flowering plant in the family Polygonaceae, native to Europe and western Asia. The mature plant is a reddish brown colour, and produces a stalk that grows to about 1 m high. It has smooth leaves shooting off from a large basal rosette, with distinctive waved or curled edges. On the stalk flowers and seeds are produced in clusters on branched stems, with the largest cluster being found at the apex. The seeds are shiny, brown and encased in the calyx of the flower that produced them. This casing enables the seeds to float on water and get caught in wool and animal fur, and this helps the seeds to spread to new locations.[1] The root-structure is a large, a yellow, forking taproot. Curled Dock grows in roadsides, all types of fields, and low-maintenance crops. It prefers rich, moist and heavy soils. # Cultivation and uses Curled Dock is a widespread naturalised species throughout the temperate world, which has become a serious invasive species in many areas, including throughout North America, southern South America, New Zealand and parts of Australia. It spreads through the seeds contaminating crop seeds, and sticking to clothing. It is designated an "injurious weed" under the UK Weeds Act 1959[1]. It is often seen in disturbed soils at the edges of roadsides, railroad beds, and parking lots. It can be used as a wild leaf vegetable; the young leaves should be boiled in several changes of water, or can be added directly to salads.[2] Once the plant matures it becomes too bitter to consume. Dock leaves are an excellent source of both vitamine A and protein. The roots have also been used medicinally as an astringent, tonic, and laxative.[3]	https://www.wikidoc.org/index.php/Curled_Dock
a8813ff64d1705c9c488a38089a6c742f5985557	wikidoc	Cyanic acid	Cyanic acid # Overview Cyanic acid is a colourless poisonous liquid with a boiling point of 23.5°C and a melting point of -81°C. At 0°C cyanic acid is converted to cyamelide. In water, cyanic acid hydrolyses to carbon dioxide and ammonia. Cyanic acid (H-O-C≡N) is an isomer of fulminic acid (H-C=N-O). A tautomer exists for cyanic acid, H-N=C=O, isocyanic acid. It forms in a reaction between potassium cyanate and formic acid. The trimer of cyanic acid is cyanuric acid. Cyanic acid is the simplest stable chemical compound that contains carbon, hydrogen, nitrogen, and oxygen, the four most commonly-found atoms in organic chemistry (fulminic acid is not stable).	Cyanic acid Template:Chembox new # Overview Cyanic acid is a colourless poisonous liquid with a boiling point of 23.5°C and a melting point of -81°C. At 0°C cyanic acid is converted to cyamelide. In water, cyanic acid hydrolyses to carbon dioxide and ammonia. Cyanic acid (H-O-C≡N) is an isomer of fulminic acid (H-C=N-O). A tautomer exists for cyanic acid, H-N=C=O, isocyanic acid. It forms in a reaction between potassium cyanate and formic acid. The trimer of cyanic acid is cyanuric acid. Cyanic acid is the simplest stable chemical compound that contains carbon, hydrogen, nitrogen, and oxygen, the four most commonly-found atoms in organic chemistry (fulminic acid is not stable).	https://www.wikidoc.org/index.php/Cyanic_acid
1cb1a008a6ccb1d63d565c6891412d053c0f6f3e	wikidoc	Cybernetics	Cybernetics Cybernetics is the interdisciplinary study of the structure of complex systems, especially communication processes, control mechanisms and feedback principles. Cybernetics is closely related to control theory and systems theory. Contemporary cybernetics began as an interdisciplinary study connecting the fields of control systems, electrical network theory, mechanical engineering, logic modeling, evolutionary biology and neuroscience in the 1940s. Other fields of study which have influenced or been influenced by cybernetics include game theory, system theory (a mathematical counterpart to cybernetics), psychology (especially neuropsychology, behavioral psychology, cognitive psychology), philosophy, and architecture. # Overview The term cybernetics stems from the Greek Κυβερνήτης (kybernētēs, steersman, governor, pilot, or rudder — the same root as government). Cybernetics is a broad field of study, but the essential goal of cybernetics is to understand and define the functions and processes of systems that have goals, and that participate in circular, causal chains that move from action to sensing to comparison with desired goal to action. Studies of this field are all ultimately means of examining different forms of systems and applying what is known to make the design and function of any system, including artificial systems such as business management, more efficient and effective. Cybernetics was defined by Norbert Wiener, in his book of that title, as the study of control and communication in the animal and the machine. Stafford Beer called it the science of effective organization and Gordon Pask extended it to include information flows "in all media" from stars to brains. It includes the study of feedback, black boxes and derived concepts such as communication and control in living organisms, machines and organizations including self-organization. Its focus is how anything (digital, mechanical or biological) processes information, reacts to information, and changes or can be changed to better accomplish the first two tasks . A more philosophical definition, suggested in 1956 by Louis Couffignal, one of the pioneers of cybernetics, characterizes cybernetics as "the art of ensuring the efficacy of action" . The most recent definition has been proposed by Louis Kauffman, President of the American Society for Cybernetics, "Cybernetics is the study of systems and processes that interact with themselves and produce themselves from themselves" . Concepts studied by cyberneticists (or, as some prefer, cyberneticians) include, but are not limited to: learning, cognition, adaption, social control, emergence, communication, efficiency, efficacy and interconnectivity. These concepts are studied by other subjects such as engineering and biology, but in cybernetics these are removed from the context of the individual organism or device. Other fields of study which have influenced or been influenced by cybernetics include game theory; system theory (a mathematical counterpart to cybernetics); psychology, especially neuropsychology, behavioral psychology,cognitive psychology; philosophy; anthropology and even architecture. # History ## The Roots of Cybernetic theory The word cybernetics was first used in the context of "the study of self-governance" by Plato in The Laws to signify the governance of people. The words govern and governor are related to the same Greek root through the Latin cognates gubernare and gubernator. The word "cybernétique" was also used in 1834 by the physicist André-Marie Ampère (1775–1836) to denote the sciences of government in his classification system of human knowledge. The first artificial automatic regulatory system, a water clock, was invented by the mechanician Ktesibios. In his water clocks, water flowed from a source such as a holding tank into a reservoir, then from the reservoir to the mechanisms of the clock. Ktesibios's device used a cone-shaped float to monitor the level of the water in its reservoir and adjust the rate of flow of the water accordingly to maintain a constant level of water in the reservoir, so that it neither overflowed nor was allowed to run dry. This was the first artificial truly automatic self-regulatory device that required no outside intervention between the feedback and the controls of the mechanism. Although they did not refer to this concept by the name of Cybernetics (they considered it a field of engineering), Ktesibios and others such as Heron and Su Song are considered to be some of the first to study cybernetic principles. The study of teleological mechanisms (from the Greek τέλος or telos for end, goal, or purpose) in machines with corrective feedback dates from as far back as the late 1700s when James Watt's steam engine was equipped with a governor, a centripetal feedback valve for controlling the speed of the engine. Alfred Russel Wallace identified this as the principle of evolution in his famous 1858 paper. In 1868 James Clerk Maxwell published a theoretical article on governors, one of the first to discuss and refine the principles of self-regulating devices. Jakob von Uexküll applied the feedback mechanism via his model of functional cycle (Funktionskreis) in order to explain animal behaviour and the origins of meaning in general. ## The Early 20th century Contemporary cybernetics began as an interdisciplinary study connecting the fields of control systems, electrical network theory, mechanical engineering, logic modeling, evolutionary biology and neuroscience in the 1940s. Electronic control systems originated with the 1927 work of Bell Telephone Laboratories engineer Harold S. Black on using negative feedback to control amplifiers. The ideas are also related to the biological work of Ludwig von Bertalanffy in General Systems Theory. Early applications of negative feedback in electronic circuits included the control of gun mounts and radar antenna during World War Two. Jay Forrester, a graduate student at the Servomechanisms Laboratory at MIT during WWII working with Gordon S. Brown to develop electronic control systems for the U.S. Navy, later applied these ideas to social organizations such as corporations and cities as an original organizer of the MIT School of Industrial Management at the MIT Sloan School of Management. Forrester is known as the founder of System Dynamics. W. Edwards Deming, the Total Quality Management guru for whom Japan named its top post-WWII industrial prize, was an intern at Bell Telephone Labs in 1927 and may have been influenced by network theory. Deming made "Understanding Systems" one of the four pillars of what he described as "Profound Knowledge" in his book "The New Economics." Numerous papers spearheaded the coalescing of the field. In 1935 Russian physiologist P.K. Anokhin published a book in which the concept of feedback ("back afferentation") was studied. The Romanian scientist Ştefan Odobleja published Psychologie consonantiste (Paris, 1938), describing many cybernetic principles. The study and mathematical modelling of regulatory processes became a continuing research effort and two key articles were published in 1943. These papers were "Behavior, Purpose and Teleology" by Arturo Rosenblueth, Norbert Wiener, and Julian Bigelow; and the paper "A Logical Calculus of the Ideas Immanent in Nervous Activity" by Warren McCulloch and Walter Pitts. Cybernetics as a discipline was firmly established by Wiener, McCulloch and others, such as W. Ross Ashby and W. Grey Walter. Walter was one of the first to build autonomous robots as an aid to the study of animal behaviour. Together with the US and UK, an important geographical locus of early cybernetics was France. In the spring of 1947, Wiener was invited to a congress on harmonic analysis, held in Nancy, France. The event was organized by the Bourbaki, a French scientific society, and mathematician Szolem Mandelbrojt (1899-1983), uncle of the world-famous mathematician Benoît Mandelbrot. During this stay in France, Wiener received the offer to write a manuscript on the unifying character of this part of applied mathematics, which is found in the study of Brownian motion and in telecommunication engineering. The following summer, back in the United States, Wiener decided to introduce the neologism cybernetics into his scientific theory. The name cybernetics was coined to denote the study of "teleological mechanisms" and was popularized through his book Cybernetics, or Control and Communication in the Animal and Machine (Hermann & Cie, Paris, 1948). In the UK this became the focus for the Ratio Club. In the early 1940's John von Neumann, although better known for his work in mathematics and computer science, did contribute a unique and unusual addition to the world of cybernetics: Von Neumann cellular automata, and their logical follow up the Von Neumann Universal Constructor. The result of these deceptively simple thought-experiments was the concept of self replication which cybernetics adopted as a core concept. The concept that the same properties of genetic reproduction applied to social memes, living cells, and even computer viruses is further proof of the somewhat surprising universality of cybernetic study. Wiener popularized the social implications of cybernetics, drawing analogies between automatic systems (such as a regulated steam engine) and human institutions in his best-selling The Human Use of Human Beings : Cybernetics and Society (Houghton-Mifflin, 1950). While not the only instance of a research organization focused on cybernetics, the Biological Computer Lab at the University of Illinois, Urbana/Champaign, under the direction of Heinz von Foerster, was a major center of cybernetic research for almost 20 years, beginning in 1958. ## The Fall and Rebirth of Cybernetics For a time during the past 30 years, the field of cybernetics followed a boom-bust cycle of becoming more and more dominated by the subfields of artificial intelligence and machine-biological interfaces (ie. cyborgs) and when this research fell out of favor, the field as a whole fell from grace. In the 1970s new cybernetics has emerged in multiple fields, first in biology. Some biologists influenced by cybernetic concepts (Maturana and Varela, 1980); Varela, 1979; Atlan, 1979) realized that the cybernetic metaphors of the program upon which molecular biology had been based rendered a conception of the autonomy of the living being impossible. Consequently, these thinkers were led to invent a new cybernetics, one more suited to the organizations which mankind discovers in nature - organizations he has not himself invented. The possibility that this new cybernetics could also account for social forms of organization, remained an object of debate among theoreticians on self-organization in the 1980s. In political science, Project Cybersyn attempted to introduce a cybernetically controlled economy during the early 1970s. In the 1980s, unlike its predecessor, the new cybernetics concerns itself with the interaction of autonomous political actors and subgroups, and the practical and reflexive consciousness of the subjects who produce and reproduce the structure of a political community. A dominant consideration is that of recursiveness, or self-reference of political action both with regards to the expression of political consciousness and with the ways in which systems build upon themselves. Geyer and van der Zouwen in 1978 discussed a number of characteristics of the emerging "new cybernetics". One characteristic of new cybernetics is that it views information as constructed and reconstructed by an individual interacting with the environment. This provides an epistemological foundation of science, by viewing it as observer-dependent. Another characteristic of the new cybernetics is its contribution towards bridging the "micro-macro gap". That is, it links the individual with the society. Geyer and van der Zouwen also noted that a transition from classical cybernetics to the new cybernetics involves a transition from classical problems to new problems. These shifts in thinking involve, among others, a change from emphasis on the system being steered to the system doing the steering, and the factor which guides the steering decisions. And a new emphasis on communication between several systems which are trying to steer each other. Recent endeavors into the true focus of cybernetics, systems of control and emergent behavior, by such related fields as Game Theory (the analysis of group interaction), systems of feedback in evolution, and Metamaterials (the study of materials with properties beyond the newtonian properties of their constituent atoms), have led to a revived interest in this increasingly relevant field. # Subdivisions of the field Cybernetics is an earlier but still-used generic term for many subject matters. These subjects also extend into many others areas of science, but are united in their study of control of systems. ## Pure Cybernetics Pure cybernetics studies systems of control as a concept, attempting to discover the basic principles underlying such things as - Artificial intelligence - Robotics - Computer Vision - Control systems - Emergence - Learning organization - New Cybernetics - Second-order cybernetics - Interactions of Actors Theory - Conversation Theory ## In Biology Cybernetics in biology is the study of cybernetic systems present in biological organisms, primarily focusing on how animals adapt to their environment, and how information in the form of genes is passed from generation to generation. There is also a secondary focus on cyborgs. - Bioengineering - Biocybernetics - Bionics - Homeostasis - Medical cybernetics - Synthetic Biology - Systems Biology ## In Complexity Science Complexity Science attempts to analyze the nature of complex systems, and the reasons behind their unusual properties. - Complex Adaptive System - Complex systems - Complexity theory ## In Computer Science Computer science directly applies the concepts of cybernetics to the control of devices and the analysis of information. - Robotics - Decision support system - Cellular automaton - Simulation ## In Engineering Cybernetics in engineering is used to analyze cascading failures and System Accidents, in which the small errors and imperfections in a system can generate disasters. Other topics studied include: - Adaptive systems - Engineering cybernetics - Ergonomics - Biomedical engineering - Systems engineering ## In Management - Entrepreneurial cybernetics - Management cybernetics - Organizational cybernetics - Operations research - Systems engineering ## In Mathematics Mathematical Cybernetics focuses on the factors of information, interaction of parts in systems, and the structure of systems. - Dynamical system - Information theory - Systems theory ## In Psychology - Psycho-Cybernetics - Systems psychology ## In Sociology By examining group behavior through the lens of cybernetics, sociology seeks the reasons for such spontaneous events as smart mobs and riots, as well as how communities develop rules, such as etiquette, by consensus without formal discussion. Affect Control Theory explains role behavior, emotions, and labeling theory in terms of homeostatic maintenance of sentiments associated with cultural categories. These and other cybernetic models in sociology are reviewed in a book edited by McClelland and Fararo. - Affect Control Theory - Memetics - Sociocybernetics # Further reading - W. Ross Ashby (1956), Introduction to Cybernetics. Methuen, London, UK. PDF text. - Stafford Beer (1974), Designing Freedom, John Wiley, London and New York, 1975. - Lars Bluma, (2005), Norbert Wiener und die Entstehung der Kybernetik im Zweiten Weltkrieg, Münster. - Steve J. Heims (1980), John von Neumann and Norbert Wiener: From Mathematics to the Technologies of Life and Death, 3. Aufl., Cambridge. - Steve J. Heims (1993), Constructing a Social Science for Postwar America. The Cybernetics Group, 1946-1953, Cambridge University Press, London, UK. - Helvey, T.C. The Age of Information: An Interdisciplinary Survey of Cybernetics. Englewood Cliffs, N.J.: Educational Technology Publications, 1971. - Francis Heylighen, and Joslyn C. (2001), "Cybernetics and Second Order Cybernetics", in: R.A. Meyers (ed.), Encyclopedia of Physical Science & Technology (3rd ed.), Vol. 4, (Academic Press, New York), p. 155-170. - Hans Joachim Ilgauds (1980), Norbert Wiener, Leipzig. - P. Rustom Masani (1990), Norbert Wiener 1894-1964, Basel. - Eden Medina, "Designing Freedom, Regulating a Nation: Socialist Cybernetics in Allende's Chile." Journal of Latin American Studies 38 (2006):571-606. - Paul Pangaro (1990), "Cybernetics — A Definition", Eprint. - Gordon Pask (1972), "Cybernetics", entry in Encyclopaedia Britannica 1972. - B.C. Patten, and E.P. Odum (1981), "The Cybernetic Nature of Ecosystems", The American Naturalist 118, 886-895. - Plato, "Alcibiades 1", W.R.M. Lamb (trans.), pp. 93–223 in Plato, Volume 12, Loeb Classical Library, London, UK, 1927. - Heinz von Foerster, (1995), Ethics and Second-Order Cybernetics. - Stuart Umpleby (1989), "The science of cybernetics and the cybernetics of science", in: Cybernetics and Systems", Vol. 21, No. 1, (1990), pp. 109-121. - Norbert Wiener (1948), Cybernetics or Control and Communication in the Animal and the Machine, Paris, Hermann et Cie - MIT Press, Cambridge, MA.	Cybernetics Cybernetics is the interdisciplinary study of the structure of complex systems, especially communication processes, control mechanisms and feedback principles. Cybernetics is closely related to control theory and systems theory. Contemporary cybernetics began as an interdisciplinary study connecting the fields of control systems, electrical network theory, mechanical engineering, logic modeling, evolutionary biology and neuroscience in the 1940s. Other fields of study which have influenced or been influenced by cybernetics include game theory, system theory (a mathematical counterpart to cybernetics), psychology (especially neuropsychology, behavioral psychology, cognitive psychology), philosophy, and architecture.[1] # Overview The term cybernetics stems from the Greek Κυβερνήτης (kybernētēs, steersman, governor, pilot, or rudder — the same root as government). Cybernetics is a broad field of study, but the essential goal of cybernetics is to understand and define the functions and processes of systems that have goals, and that participate in circular, causal chains that move from action to sensing to comparison with desired goal to action. Studies of this field are all ultimately means of examining different forms of systems and applying what is known to make the design and function of any system, including artificial systems such as business management, more efficient and effective. Cybernetics was defined by Norbert Wiener, in his book of that title, as the study of control and communication in the animal and the machine. Stafford Beer called it the science of effective organization and Gordon Pask extended it to include information flows "in all media" from stars to brains. It includes the study of feedback, black boxes and derived concepts such as communication and control in living organisms, machines and organizations including self-organization. Its focus is how anything (digital, mechanical or biological) processes information, reacts to information, and changes or can be changed to better accomplish the first two tasks [2]. A more philosophical definition, suggested in 1956 by Louis Couffignal, one of the pioneers of cybernetics, characterizes cybernetics as "the art of ensuring the efficacy of action" [3]. The most recent definition has been proposed by Louis Kauffman, President of the American Society for Cybernetics, "Cybernetics is the study of systems and processes that interact with themselves and produce themselves from themselves" [4]. Concepts studied by cyberneticists (or, as some prefer, cyberneticians) include, but are not limited to: learning, cognition, adaption, social control, emergence, communication, efficiency, efficacy and interconnectivity. These concepts are studied by other subjects such as engineering and biology, but in cybernetics these are removed from the context of the individual organism or device. Other fields of study which have influenced or been influenced by cybernetics include game theory; system theory (a mathematical counterpart to cybernetics); psychology, especially neuropsychology, behavioral psychology,cognitive psychology; philosophy; anthropology and even architecture.[citation needed] # History ## The Roots of Cybernetic theory The word cybernetics was first used in the context of "the study of self-governance" by Plato in The Laws to signify the governance of people. The words govern and governor are related to the same Greek root through the Latin cognates gubernare and gubernator. The word "cybernétique" was also used in 1834 by the physicist André-Marie Ampère (1775–1836) to denote the sciences of government in his classification system of human knowledge. The first artificial automatic regulatory system, a water clock, was invented by the mechanician Ktesibios. In his water clocks, water flowed from a source such as a holding tank into a reservoir, then from the reservoir to the mechanisms of the clock. Ktesibios's device used a cone-shaped float to monitor the level of the water in its reservoir and adjust the rate of flow of the water accordingly to maintain a constant level of water in the reservoir, so that it neither overflowed nor was allowed to run dry. This was the first artificial truly automatic self-regulatory device that required no outside intervention between the feedback and the controls of the mechanism. Although they did not refer to this concept by the name of Cybernetics (they considered it a field of engineering), Ktesibios and others such as Heron and Su Song are considered to be some of the first to study cybernetic principles. The study of teleological mechanisms (from the Greek τέλος or telos for end, goal, or purpose) in machines with corrective feedback dates from as far back as the late 1700s when James Watt's steam engine was equipped with a governor, a centripetal feedback valve for controlling the speed of the engine. Alfred Russel Wallace identified this as the principle of evolution in his famous 1858 paper. In 1868 James Clerk Maxwell published a theoretical article on governors, one of the first to discuss and refine the principles of self-regulating devices. Jakob von Uexküll applied the feedback mechanism via his model of functional cycle (Funktionskreis) in order to explain animal behaviour and the origins of meaning in general. ## The Early 20th century Contemporary cybernetics began as an interdisciplinary study connecting the fields of control systems, electrical network theory, mechanical engineering, logic modeling, evolutionary biology and neuroscience in the 1940s. Electronic control systems originated with the 1927 work of Bell Telephone Laboratories engineer Harold S. Black on using negative feedback to control amplifiers. The ideas are also related to the biological work of Ludwig von Bertalanffy in General Systems Theory. Early applications of negative feedback in electronic circuits included the control of gun mounts and radar antenna during World War Two. Jay Forrester, a graduate student at the Servomechanisms Laboratory at MIT during WWII working with Gordon S. Brown to develop electronic control systems for the U.S. Navy, later applied these ideas to social organizations such as corporations and cities as an original organizer of the MIT School of Industrial Management at the MIT Sloan School of Management. Forrester is known as the founder of System Dynamics. W. Edwards Deming, the Total Quality Management guru for whom Japan named its top post-WWII industrial prize, was an intern at Bell Telephone Labs in 1927 and may have been influenced by network theory. Deming made "Understanding Systems" one of the four pillars of what he described as "Profound Knowledge" in his book "The New Economics." Numerous papers spearheaded the coalescing of the field. In 1935 Russian physiologist P.K. Anokhin published a book in which the concept of feedback ("back afferentation") was studied. The Romanian scientist Ştefan Odobleja published Psychologie consonantiste (Paris, 1938), describing many cybernetic principles. The study and mathematical modelling of regulatory processes became a continuing research effort and two key articles were published in 1943. These papers were "Behavior, Purpose and Teleology" by Arturo Rosenblueth, Norbert Wiener, and Julian Bigelow; and the paper "A Logical Calculus of the Ideas Immanent in Nervous Activity" by Warren McCulloch and Walter Pitts. Cybernetics as a discipline was firmly established by Wiener, McCulloch and others, such as W. Ross Ashby and W. Grey Walter. Walter was one of the first to build autonomous robots as an aid to the study of animal behaviour. Together with the US and UK, an important geographical locus of early cybernetics was France. In the spring of 1947, Wiener was invited to a congress on harmonic analysis, held in Nancy, France. The event was organized by the Bourbaki, a French scientific society, and mathematician Szolem Mandelbrojt (1899-1983), uncle of the world-famous mathematician Benoît Mandelbrot. During this stay in France, Wiener received the offer to write a manuscript on the unifying character of this part of applied mathematics, which is found in the study of Brownian motion and in telecommunication engineering. The following summer, back in the United States, Wiener decided to introduce the neologism cybernetics into his scientific theory. The name cybernetics was coined to denote the study of "teleological mechanisms" and was popularized through his book Cybernetics, or Control and Communication in the Animal and Machine (Hermann & Cie, Paris, 1948). In the UK this became the focus for the Ratio Club. In the early 1940's John von Neumann, although better known for his work in mathematics and computer science, did contribute a unique and unusual addition to the world of cybernetics: Von Neumann cellular automata, and their logical follow up the Von Neumann Universal Constructor. The result of these deceptively simple thought-experiments was the concept of self replication which cybernetics adopted as a core concept. The concept that the same properties of genetic reproduction applied to social memes, living cells, and even computer viruses is further proof of the somewhat surprising universality of cybernetic study. Wiener popularized the social implications of cybernetics, drawing analogies between automatic systems (such as a regulated steam engine) and human institutions in his best-selling The Human Use of Human Beings : Cybernetics and Society (Houghton-Mifflin, 1950). While not the only instance of a research organization focused on cybernetics, the Biological Computer Lab at the University of Illinois, Urbana/Champaign, under the direction of Heinz von Foerster, was a major center of cybernetic research for almost 20 years, beginning in 1958. ## The Fall and Rebirth of Cybernetics For a time during the past 30 years, the field of cybernetics followed a boom-bust cycle of becoming more and more dominated by the subfields of artificial intelligence and machine-biological interfaces (ie. cyborgs) and when this research fell out of favor, the field as a whole fell from grace. In the 1970s new cybernetics has emerged in multiple fields, first in biology. Some biologists influenced by cybernetic concepts (Maturana and Varela, 1980); Varela, 1979; Atlan, 1979) realized that the cybernetic metaphors of the program upon which molecular biology had been based rendered a conception of the autonomy of the living being impossible. Consequently, these thinkers were led to invent a new cybernetics, one more suited to the organizations which mankind discovers in nature - organizations he has not himself invented. The possibility that this new cybernetics could also account for social forms of organization, remained an object of debate among theoreticians on self-organization in the 1980s.[5] In political science, Project Cybersyn attempted to introduce a cybernetically controlled economy during the early 1970s. In the 1980s, unlike its predecessor, the new cybernetics concerns itself with the interaction of autonomous political actors and subgroups, and the practical and reflexive consciousness of the subjects who produce and reproduce the structure of a political community. A dominant consideration is that of recursiveness, or self-reference of political action both with regards to the expression of political consciousness and with the ways in which systems build upon themselves.[6] Geyer and van der Zouwen in 1978 discussed a number of characteristics of the emerging "new cybernetics". One characteristic of new cybernetics is that it views information as constructed and reconstructed by an individual interacting with the environment. This provides an epistemological foundation of science, by viewing it as observer-dependent. Another characteristic of the new cybernetics is its contribution towards bridging the "micro-macro gap". That is, it links the individual with the society. Geyer and van der Zouwen also noted that a transition from classical cybernetics to the new cybernetics involves a transition from classical problems to new problems. These shifts in thinking involve, among others, a change from emphasis on the system being steered to the system doing the steering, and the factor which guides the steering decisions. And a new emphasis on communication between several systems which are trying to steer each other.[7] Recent endeavors into the true focus of cybernetics, systems of control and emergent behavior, by such related fields as Game Theory (the analysis of group interaction), systems of feedback in evolution, and Metamaterials (the study of materials with properties beyond the newtonian properties of their constituent atoms), have led to a revived interest in this increasingly relevant field.[2] # Subdivisions of the field Cybernetics is an earlier but still-used generic term for many subject matters. These subjects also extend into many others areas of science, but are united in their study of control of systems. ## Pure Cybernetics Pure cybernetics studies systems of control as a concept, attempting to discover the basic principles underlying such things as - Artificial intelligence - Robotics - Computer Vision - Control systems - Emergence - Learning organization - New Cybernetics - Second-order cybernetics - Interactions of Actors Theory - Conversation Theory ## In Biology Cybernetics in biology is the study of cybernetic systems present in biological organisms, primarily focusing on how animals adapt to their environment, and how information in the form of genes is passed from generation to generation[8]. There is also a secondary focus on cyborgs. - Bioengineering - Biocybernetics - Bionics - Homeostasis - Medical cybernetics - Synthetic Biology - Systems Biology ## In Complexity Science Complexity Science attempts to analyze the nature of complex systems, and the reasons behind their unusual properties. - Complex Adaptive System - Complex systems - Complexity theory ## In Computer Science Computer science directly applies the concepts of cybernetics to the control of devices and the analysis of information. - Robotics - Decision support system - Cellular automaton - Simulation ## In Engineering Cybernetics in engineering is used to analyze cascading failures and System Accidents, in which the small errors and imperfections in a system can generate disasters. Other topics studied include: - Adaptive systems - Engineering cybernetics - Ergonomics - Biomedical engineering - Systems engineering ## In Management - Entrepreneurial cybernetics - Management cybernetics - Organizational cybernetics - Operations research - Systems engineering ## In Mathematics Mathematical Cybernetics focuses on the factors of information, interaction of parts in systems, and the structure of systems. - Dynamical system - Information theory - Systems theory ## In Psychology - Psycho-Cybernetics - Systems psychology ## In Sociology By examining group behavior through the lens of cybernetics, sociology seeks the reasons for such spontaneous events as smart mobs and riots, as well as how communities develop rules, such as etiquette, by consensus without formal discussion. Affect Control Theory explains role behavior, emotions, and labeling theory in terms of homeostatic maintenance of sentiments associated with cultural categories. These and other cybernetic models in sociology are reviewed in a book edited by McClelland and Fararo[9]. - Affect Control Theory - Memetics - Sociocybernetics # Further reading - W. Ross Ashby (1956), Introduction to Cybernetics. Methuen, London, UK. PDF text. - Stafford Beer (1974), Designing Freedom, John Wiley, London and New York, 1975. - Lars Bluma, (2005), Norbert Wiener und die Entstehung der Kybernetik im Zweiten Weltkrieg, Münster. - Steve J. Heims (1980), John von Neumann and Norbert Wiener: From Mathematics to the Technologies of Life and Death, 3. Aufl., Cambridge. - Steve J. Heims (1993), Constructing a Social Science for Postwar America. The Cybernetics Group, 1946-1953, Cambridge University Press, London, UK. - Helvey, T.C. The Age of Information: An Interdisciplinary Survey of Cybernetics. Englewood Cliffs, N.J.: Educational Technology Publications, 1971. - Francis Heylighen, and Joslyn C. (2001), "Cybernetics and Second Order Cybernetics", in: R.A. Meyers (ed.), Encyclopedia of Physical Science & Technology (3rd ed.), Vol. 4, (Academic Press, New York), p. 155-170. - Hans Joachim Ilgauds (1980), Norbert Wiener, Leipzig. - P. Rustom Masani (1990), Norbert Wiener 1894-1964, Basel. - Eden Medina, "Designing Freedom, Regulating a Nation: Socialist Cybernetics in Allende's Chile." Journal of Latin American Studies 38 (2006):571-606. - Paul Pangaro (1990), "Cybernetics — A Definition", Eprint. - Gordon Pask (1972), "Cybernetics", entry in Encyclopaedia Britannica 1972. - B.C. Patten, and E.P. Odum (1981), "The Cybernetic Nature of Ecosystems", The American Naturalist 118, 886-895. - Plato, "Alcibiades 1", W.R.M. Lamb (trans.), pp. 93–223 in Plato, Volume 12, Loeb Classical Library, London, UK, 1927. - Heinz von Foerster, (1995), Ethics and Second-Order Cybernetics. - Stuart Umpleby (1989), "The science of cybernetics and the cybernetics of science", in: Cybernetics and Systems", Vol. 21, No. 1, (1990), pp. 109-121. - Norbert Wiener (1948), Cybernetics or Control and Communication in the Animal and the Machine, Paris, Hermann et Cie - MIT Press, Cambridge, MA.	https://www.wikidoc.org/index.php/Cybernetics
d7211613e426ac1dc53833e5a61ad47235e944a0	wikidoc	Cyclazocine	Cyclazocine Cyclazocine is a mixed opiate agonist-antagonist related to dezocine, pentazocine and phenazocine. This family of opioid drugs is called the benzomorphans or benzazocines. # Use Research into the use of cyclazocine for the treatment of Bipolar patients with depression was undertaken by Fink and colleagues (1970). It showed that 8 out of 10 patients experienced moderate improvement. Research during the 1960s and 1970s into the possible use of cyclazocine for management of pain, and later for assisting treatment of narcotic addiction was severely hampered by the drug's psychotomimetic, dysphoric, and hallucinatory effects. # Dosage Dosages of 1-3mg were administered in the tests	Cyclazocine Cyclazocine is a mixed opiate agonist-antagonist related to dezocine, pentazocine and phenazocine. This family of opioid drugs is called the benzomorphans or benzazocines. # Use Research into the use of cyclazocine for the treatment of Bipolar patients with depression was undertaken by Fink and colleagues (1970). It showed that 8 out of 10 patients experienced moderate improvement. Research during the 1960s and 1970s into the possible use of cyclazocine for management of pain, and later for assisting treatment of narcotic addiction was severely hampered by the drug's psychotomimetic, dysphoric, and hallucinatory effects. # Dosage Dosages of 1-3mg were administered in the tests	https://www.wikidoc.org/index.php/Cyclazocine
cfa86425126174ec9729c9ec461f6fc79345ece2	wikidoc	Cyclothymia	Cyclothymia Synonyms and keywords: Cyclothymic disorder; cyclic disorder # Overview Cyclothymia, or cyclothymic disorder, is a mood disorder characterized by the co-occurrence of hypomanic and depressive symptoms over a period of at least two years, or one year in children and young adults. Symptoms must not meet the diagnostic criteria for manic/depressive episodes. Cyclothymia is considered a mild form of bipolar II disorder. There is evidence that cyclothymia may be the most common form of bipolar disorder. # Historical Perspective - In 1882, cyclothymia was characterized by recurring mood cycles. This was accomplished by Karl Ludwig Kahlbaum. Cyclothymia contains episodes, both of which occur in a milder form than in bipolar disorder: Melancholic episodes Manic episodes - Cyclothymia contains episodes, both of which occur in a milder form than in bipolar disorder: Melancholic episodes Manic episodes - Melancholic episodes - Manic episodes - In 1980, cyclothymia was included to the DSM. - Cyclothymia has been conceptualized in a variety of ways: As a subtype of bipolar disorder As a temperament As a personality trait As a personality disorder - As a subtype of bipolar disorder - As a temperament - As a personality trait - As a personality disorder - The two defining features of the disorder, according to DSM-5, are: The presence of depressive episodes The presence of hypomania - The presence of depressive episodes - The presence of hypomania # Classification - Cyclothymia is classified by the DSM-V as a mild form of bipolar II disorder. - There is disagreement among experts in the field of psychiatry as to whether this is an appropriate definition, or whether cyclothymia is actually better understood as a general instability of mood. - Cyclothymia has been conceptualized to include other characteristics such as: Mood reactivity Impulsivity Anxiety - Mood reactivity - Impulsivity - Anxiety ## Commonly Comorbid Conditions - Conditions that are commonly comorbid with cyclothymia include: ADHD Anxiety disorders - ADHD - Anxiety disorders # Differentiating Cyclothymia from other disorders - Cyclothymia must be differentiated from other disorders that present with similar symptomatology, including: Major depression Patients with cyclothymia can be distinguished from patients with major depression based on an earlier age of onset, a higher likelihood of having a family history of bipolar disorder, and a higher incidence of sleep disturbances. Bipolar disorder Cyclothymia can be distinguished from bipolar disorder by the relatively minimized intensity of the mood-altering episodes patients experience and a younger age of onset. - Major depression Patients with cyclothymia can be distinguished from patients with major depression based on an earlier age of onset, a higher likelihood of having a family history of bipolar disorder, and a higher incidence of sleep disturbances. - Patients with cyclothymia can be distinguished from patients with major depression based on an earlier age of onset, a higher likelihood of having a family history of bipolar disorder, and a higher incidence of sleep disturbances. - Bipolar disorder Cyclothymia can be distinguished from bipolar disorder by the relatively minimized intensity of the mood-altering episodes patients experience and a younger age of onset. - Cyclothymia can be distinguished from bipolar disorder by the relatively minimized intensity of the mood-altering episodes patients experience and a younger age of onset. # Epidemiology and Demographics - The prevalence of cyclothymic disorder is 400-1,000 per 100,000 (0.4%-1%) of the overall population. - There is evidence that suggests cyclothymia may be the most common form of bipolar disorder. - The estimated lifetime prevalence rate was found to be between 5%-8%, whereas other studies suggest a much lower rate ranging from 0.4%-2.5%. ## Age - Cyclothymia is most common in young adults. ## Gender - Men and women are equally likely to be affected by cyclothymia, though women may be more likely to seek treatment. ## Race - No racial predilection of cyclothymia has been observed. # Risk Factors - Risk factors for the development of cyclothymia include: Being an adolescent Childhood abuse Having a mentally ill parent Having problems at school Genetic predisposition - Being an adolescent - Childhood abuse - Having a mentally ill parent - Having problems at school - Genetic predisposition - The cause of cyclothymic disorder is unknown. - Genetics may play a role, as indicated by a range of twin studies involving dizygotic (fraternal) and monozygotic (identical) twins. - There is a high likelihood that a patient with cyclothymia will have a family history of mood disorders. # Natural History, Complications, and Prognosis - Cyclothymia usually manifests early in a patient’s life. - Possible complications include a progression to bipolar disorder, though this occurs in less than half of cyclothymic patients. Early intervention may allow patients to circumvent some of the complications associated with bipolar disorder. - Early intervention may allow patients to circumvent some of the complications associated with bipolar disorder. - Cyclothymia may remain a chronic condition or disappear over the course of a patient’s life. # Diagnosis ## Diagnostic Criteria DSM-V Diagnostic Criteria for Cyclothymic Disorder ## History and Symptoms - Symptoms of cyclothymia include: Periods of both mania (extreme mood elevation and energy) and depression (low mood and energy level) for at least two years, or one in children and young adults Mood swings that are not as severe as those observed in bipolar disorder Continuity of manic/depressive episodes (i.e., no more than 2 consecutive months without symptoms) - Periods of both mania (extreme mood elevation and energy) and depression (low mood and energy level) for at least two years, or one in children and young adults - Mood swings that are not as severe as those observed in bipolar disorder - Continuity of manic/depressive episodes (i.e., no more than 2 consecutive months without symptoms) ## Clinical Examination - A diagnosis of cyclothymia is made based on a patient’s mood history. - One prominent barrier to a diagnosis is a lack of consensus among clinicians about the precise distinction between syndromal and subsyndromal depression and mania. ## Laboratory Findings - Although no laboratory findings are diagnostic of cyclothymia, a healthcare provider may wish to order blood tests and/or urine tests in order to rule out other possible causes of mood swings. ## Imaging Findings - No imaging findings are diagnostic of cyclothymia, though limited evidence suggests that cyclothymia may be associated with activity in the left lingual gyrus. # Treatment ## Medical Therapy The treatment of cyclothymia may involve medications. - Medication Medication may involve: Mood-stabilizing drugs Antidepressants Commonly prescribed mood-stabilizers are: Lithium Anti-epileptic drugs Clinical evidence also supports the use of such antipsychotic drugs as quetiapine. Talk therapy is another source of treatment for cyclothymia. Support groups may be helpful for patients suffering from cyclothymia. - Medication may involve: Mood-stabilizing drugs Antidepressants - Mood-stabilizing drugs - Antidepressants - Commonly prescribed mood-stabilizers are: Lithium Anti-epileptic drugs - Lithium - Anti-epileptic drugs - Clinical evidence also supports the use of such antipsychotic drugs as quetiapine. - Talk therapy is another source of treatment for cyclothymia. Support groups may be helpful for patients suffering from cyclothymia. - Support groups may be helpful for patients suffering from cyclothymia.	Cyclothymia Template:DiseaseDisorder infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Irfan Dotani, Kiran Singh, M.D. [2], Haleigh Williams, B.S. Synonyms and keywords: Cyclothymic disorder; cyclic disorder # Overview Cyclothymia, or cyclothymic disorder, is a mood disorder characterized by the co-occurrence of hypomanic and depressive symptoms over a period of at least two years, or one year in children and young adults. Symptoms must not meet the diagnostic criteria for manic/depressive episodes.[1] Cyclothymia is considered a mild form of bipolar II disorder.[2] There is evidence that cyclothymia may be the most common form of bipolar disorder.[3] # Historical Perspective - In 1882, cyclothymia was characterized by recurring mood cycles. This was accomplished by Karl Ludwig Kahlbaum. Cyclothymia contains episodes, both of which occur in a milder form than in bipolar disorder: Melancholic episodes Manic episodes - Cyclothymia contains episodes, both of which occur in a milder form than in bipolar disorder: Melancholic episodes Manic episodes - Melancholic episodes - Manic episodes - In 1980, cyclothymia was included to the DSM.[3] - Cyclothymia has been conceptualized in a variety of ways:[4] As a subtype of bipolar disorder As a temperament As a personality trait As a personality disorder - As a subtype of bipolar disorder - As a temperament - As a personality trait - As a personality disorder - The two defining features of the disorder, according to DSM-5, are: The presence of depressive episodes The presence of hypomania - The presence of depressive episodes - The presence of hypomania # Classification - Cyclothymia is classified by the DSM-V as a mild form of bipolar II disorder.[2][5] - There is disagreement among experts in the field of psychiatry as to whether this is an appropriate definition, or whether cyclothymia is actually better understood as a general instability of mood.[6] - Cyclothymia has been conceptualized to include other characteristics such as:[7] Mood reactivity Impulsivity Anxiety - Mood reactivity - Impulsivity - Anxiety ## Commonly Comorbid Conditions - Conditions that are commonly comorbid with cyclothymia include:[8] ADHD Anxiety disorders - ADHD - Anxiety disorders # Differentiating Cyclothymia from other disorders - Cyclothymia must be differentiated from other disorders that present with similar symptomatology, including:[2][5] Major depression Patients with cyclothymia can be distinguished from patients with major depression based on an earlier age of onset, a higher likelihood of having a family history of bipolar disorder, and a higher incidence of sleep disturbances.[9][10] Bipolar disorder Cyclothymia can be distinguished from bipolar disorder by the relatively minimized intensity of the mood-altering episodes patients experience and a younger age of onset.[5][10] - Major depression Patients with cyclothymia can be distinguished from patients with major depression based on an earlier age of onset, a higher likelihood of having a family history of bipolar disorder, and a higher incidence of sleep disturbances.[9][10] - Patients with cyclothymia can be distinguished from patients with major depression based on an earlier age of onset, a higher likelihood of having a family history of bipolar disorder, and a higher incidence of sleep disturbances.[9][10] - Bipolar disorder Cyclothymia can be distinguished from bipolar disorder by the relatively minimized intensity of the mood-altering episodes patients experience and a younger age of onset.[5][10] - Cyclothymia can be distinguished from bipolar disorder by the relatively minimized intensity of the mood-altering episodes patients experience and a younger age of onset.[5][10] # Epidemiology and Demographics - The prevalence of cyclothymic disorder is 400-1,000 per 100,000 (0.4%-1%) of the overall population.[3][11][5] - There is evidence that suggests cyclothymia may be the most common form of bipolar disorder. - The estimated lifetime prevalence rate was found to be between 5%-8%, whereas other studies suggest a much lower rate ranging from 0.4%-2.5%.[6] ## Age - Cyclothymia is most common in young adults.[5] ## Gender - Men and women are equally likely to be affected by cyclothymia, though women may be more likely to seek treatment.[2][11] ## Race - No racial predilection of cyclothymia has been observed. # Risk Factors - Risk factors for the development of cyclothymia include:[2][5][12] Being an adolescent Childhood abuse Having a mentally ill parent Having problems at school Genetic predisposition - Being an adolescent - Childhood abuse - Having a mentally ill parent - Having problems at school - Genetic predisposition - The cause of cyclothymic disorder is unknown. - Genetics may play a role, as indicated by a range of twin studies involving dizygotic (fraternal) and monozygotic (identical) twins. - There is a high likelihood that a patient with cyclothymia will have a family history of mood disorders.[2] # Natural History, Complications, and Prognosis - Cyclothymia usually manifests early in a patient’s life.[2] - Possible complications include a progression to bipolar disorder, though this occurs in less than half of cyclothymic patients.[2] Early intervention may allow patients to circumvent some of the complications associated with bipolar disorder.[8] - Early intervention may allow patients to circumvent some of the complications associated with bipolar disorder.[8] - Cyclothymia may remain a chronic condition or disappear over the course of a patient’s life.[2] # Diagnosis ## Diagnostic Criteria DSM-V Diagnostic Criteria for Cyclothymic Disorder[5] ## History and Symptoms - Symptoms of cyclothymia include:[2] Periods of both mania (extreme mood elevation and energy) and depression (low mood and energy level) for at least two years, or one in children and young adults Mood swings that are not as severe as those observed in bipolar disorder Continuity of manic/depressive episodes (i.e., no more than 2 consecutive months without symptoms) - Periods of both mania (extreme mood elevation and energy) and depression (low mood and energy level) for at least two years, or one in children and young adults - Mood swings that are not as severe as those observed in bipolar disorder - Continuity of manic/depressive episodes (i.e., no more than 2 consecutive months without symptoms) ## Clinical Examination - A diagnosis of cyclothymia is made based on a patient’s mood history.[2] - One prominent barrier to a diagnosis is a lack of consensus among clinicians about the precise distinction between syndromal and subsyndromal depression and mania.[11] ## Laboratory Findings - Although no laboratory findings are diagnostic of cyclothymia, a healthcare provider may wish to order blood tests and/or urine tests in order to rule out other possible causes of mood swings.[2] ## Imaging Findings - No imaging findings are diagnostic of cyclothymia, though limited evidence suggests that cyclothymia may be associated with activity in the left lingual gyrus.[13] # Treatment ## Medical Therapy The treatment of cyclothymia may involve medications.[2] - Medication Medication may involve:[2] Mood-stabilizing drugs Antidepressants Commonly prescribed mood-stabilizers are: Lithium Anti-epileptic drugs Clinical evidence also supports the use of such antipsychotic drugs as quetiapine.[11] Talk therapy is another source of treatment for cyclothymia. Support groups may be helpful for patients suffering from cyclothymia.[2][11] - Medication may involve:[2] Mood-stabilizing drugs Antidepressants - Mood-stabilizing drugs - Antidepressants - Commonly prescribed mood-stabilizers are: Lithium Anti-epileptic drugs - Lithium - Anti-epileptic drugs - Clinical evidence also supports the use of such antipsychotic drugs as quetiapine.[11] - Talk therapy is another source of treatment for cyclothymia. Support groups may be helpful for patients suffering from cyclothymia.[2][11] - Support groups may be helpful for patients suffering from cyclothymia.[2][11]	https://www.wikidoc.org/index.php/Cyclic_disorder
e694d22578c54c02f90c1a3b8a835c7457b1a664	wikidoc	Hydrocarbon	Hydrocarbon # Overview In organic chemistry, a hydrocarbon is an organic compound consisting entirely of hydrogen and carbon. Hydrocarbons from which one hydrogen atom has been removed are functional groups, called hydrocarbyls. Aromatic hydrocarbons (arenes), alkanes, alkenes, cycloalkanes and alkyne-based compounds are different types of hydrocarbons. The majority of hydrocarbons found on Earth naturally occur in crude oil, where decomposed organic matter provides an abundance of carbon and hydrogen which, when bonded, can catenate to form seemingly limitless chains. # Types of hydrocarbons The classifications for hydrocarbons, defined by IUPAC nomenclature of organic chemistry are as follows: - Saturated hydrocarbons (alkanes) are the simplest of the hydrocarbon species. They are composed entirely of single bonds and are saturated with hydrogen. The general formula for saturated hydrocarbons is CnH2n+2 (assuming non-cyclic structures). Saturated hydrocarbons are the basis of petroleum fuels and are found as either linear or branched species. Substitution reaction is their characteristics property (like chlorination reaction to form chloroform). Hydrocarbons with the same molecular formula but different structural formulae are called structural isomers. As given in the example of 3-methylhexane and its higher homologues, branched hydrocarbons can be chiral. Chiral saturated hydrocarbons constitute the side chains of biomolecules such as chlorophyll and tocopherol. - Unsaturated hydrocarbons have one or more double or triple bonds between carbon atoms. Those with double bond are called alkenes. Those with one double bond have the formula CnH2n (assuming non-cyclic structures). Those containing triple bonds are called alkynes, with general formula CnH2n-2. - Cycloalkanes are hydrocarbons containing one or more carbon rings to which hydrogen atoms are attached. The general formula for a saturated hydrocarbon containing one ring is CnH2n. - Aromatic hydrocarbons, also known as arenes, are hydrocarbons that have at least one aromatic ring. Hydrocarbons can be gases (e.g. methane and propane), liquids (e.g. hexane and benzene), waxes or low melting solids (e.g. paraffin wax and naphthalene) or polymers (e.g. polyethylene, polypropylene and polystyrene). ## General properties Because of differences in molecular structure, the empirical formula remains different between hydrocarbons; in linear, or "straight-run" alkanes, alkenes and alkynes, the amount of bonded hydrogen lessens in alkenes and alkynes due to the "self-bonding" or catenation of carbon preventing entire saturation of the hydrocarbon by the formation of double or triple bonds. This inherent ability of hydrocarbons to bond to themselves is known as catenation, and allows hydrocarbon to form more complex molecules, such as cyclohexane, and in rarer cases, arenes such as benzene. This ability comes from the fact that the bond character between carbon atoms is entirely non-polar, in that the distribution of electrons between the two elements is somewhat even due to the same electronegativity values of the elements (~0.30), and does not result in the formation of an electrophile. Generally, with catenation comes the loss of the total amount of bonded hydrocarbons and an increase in the amount of energy required for bond cleavage due to strain exerted upon the molecule;in molecules such as cyclohexane, this is referred to as ring strain, and occurs due to the "destabilized" spatial electron configuration of the atom. In simple chemistry, as per valence bond theory, the carbon atom must follow the "4-hydrogen rule", which states that the maximum number of atoms available to bond with carbon is equal to the number of electrons that are attracted into the outer shell of carbon. In terms of shells, carbon consists of an incomplete outer shell, which comprises 4 electrons, and thus has 4 electrons available for covalent or dative bonding. Hydrocarbons are hydrophobic like lipids. Some hydrocarbons also are abundant in the solar system. Lakes of liquid methane and ethane have been found on Titan, Saturn's largest moon, confirmed by the Cassini-Huygens Mission. Hydrocarbons are also abundant in nebulae forming polycyclic aromatic hydrocarbon (PAH) compounds. ## Simple hydrocarbons and their variations # Usage Hydrocarbons are a primary energy source for current civilizations. The predominant use of hydrocarbons is as a combustible fuel source. In their solid form, hydrocarbons take the form of asphalt (bitumen). Mixtures of volatile hydrocarbons are now used in preference to the chlorofluorocarbons as a propellant for aerosol sprays, due to chlorofluorocarbons' impact on the ozone layer. Methane and ethane are gaseous at ambient temperatures and cannot be readily liquefied by pressure alone. Propane is however easily liquefied, and exists in 'propane bottles' mostly as a liquid. Butane is so easily liquefied that it provides a safe, volatile fuel for small pocket lighters. Pentane is a clear liquid at room temperature, commonly used in chemistry and industry as a powerful nearly odorless solvent of waxes and high molecular weight organic compounds, including greases. Hexane is also a widely used non-polar, non-aromatic solvent, as well as a significant fraction of common gasoline. The through alkanes, alkenes and isomeric cycloalkanes are the top components of gasoline, naphtha, jet fuel and specialized industrial solvent mixtures. With the progressive addition of carbon units, the simple non-ring structured hydrocarbons have higher viscosities, lubricating indices, boiling points, solidification temperatures, and deeper color. At the opposite extreme from methane lie the heavy tars that remain as the lowest fraction in a crude oil refining retort. They are collected and widely utilized as roofing compounds, pavement composition, wood preservatives (the creosote series) and as extremely high viscosity shear-resisting liquids. Hydrocarbon use is also prevalent in nature. Some eusocial arthropods, such as the Brazilian stingless bee Schwarziana quadripunctata, use unique hydrocarbon "scents" in order to determine kin from non-kin. The chemical hydrocarbon composition varies between age, sex, nest location, and hierarchal position. # Poisoning Hydrocarbon poisoning such as that of benzene and petroleum usually occurs accidentally by inhalation or ingestion of these cytotoxic chemical compounds. Intravenous or subcutaneous injection of petroleum compounds with intent of suicide or abuse is an extraordinary event that can result in local damage or systemic toxicity such as tissue necrosis, abscess formation, respiratory system failure and partial damage to the kidneys, the brain and the nervous system. Moaddab and Eskandarlou report a case of chest wall necrosis and empyema resulting from attempting suicide by injection of petroleum into the pleural cavity. # Reactions There are three main types of reactions : - Substitution Reaction - Addition Reaction - Combustion ## Substitution Reaction Substitution reaction only occur in saturated hydrocarbons (single carbon-carbon bonds). In this reaction, an alkane reacts with a chlorine molecule. One of the chlorine atoms displace an hydrogen atom. This forms hydrochloride acid as well as the hydrocarbon with one chlorine. e.g. CH4 + Cl2 →CH3Cl + HCl e.g. CH3Cl3 + Cl2 →CH2Cl2 + HCl All the way until CCl4 (Carbon tetrachloride) e.g. C2H6 + Cl2 →C2H5Cl1 + HCl e.g. C2H4Cl2 + Cl2 →C2H4Cl3 + HCl All the way until C2Cl4 (DiCarbon tetrachloride) ## Addition Reaction Addition reactions involve alkenes and alkynes. In this reaction a halogen molecule breaks the double or triple bond in the hydrocarbon and forms a bond. ## Combustion Hydrocarbons are currently the main source of the world's electric energy and heat sources (such as home heating) because of the energy produced when burnt. Often this energy is used directly as heat such as in home heaters, which use either petroleum or natural gas. The hydrocarbon is burnt and the heat is used to heat water, which is then circulated. A similar principle is used to create electric energy in power plants. Common properties of hydrocarbons are the facts that they produce steam, carbon dioxide and heat during combustion and that oxygen is required for combustion to take place. The simplest hydrocarbon, methane, burns as follows: In inadequate supply of air, CO gas and water vapour are formed: Another example of this reaction is propane: Burning of hydrocarbons is an example of an exothermic chemical reaction. Hydrocarbons can also be burned with elemental fluorine, resulting in carbon tetrafluoride and hydrogen fluoride products. ### Petroleum Extracted hydrocarbons in a liquid form are referred to as petroleum (literally "rock oil") or mineral oil, whereas hydrocarbons in a gaseous form are referred to as natural gas. Petroleum and natural gas are found in the Earth's subsurface with the tools of petroleum geology and are a significant source of fuel and raw materials for the production of organic chemicals. The extraction of liquid hydrocarbon fuel from sedimentary basins is integral to modern energy development. Hydrocarbons are mined from oil sands and oil shale, and potentially extracted from sedimentary methane hydrates. These reserves require distillation and upgrading to produce synthetic crude and petroleum. Oil reserves in sedimentary rocks are the source of hydrocarbons for the energy, transport and petrochemical industry. Economically important hydrocarbons include fossil fuels such as coal, petroleum and natural gas, and its derivatives such as plastics, paraffin, waxes, solvents and oils. Hydrocarbons – along with NOx and sunlight – contribute to the formation of tropospheric ozone and greenhouse gases. ### Bioremediation Bacteria in the gabbroic layer of the ocean's crust can degrade hydrocarbons; but the extreme environment makes research difficult. Other bacteria such as Lutibacterium anuloederans can also degrade hydrocarbons. Mycoremediation or breaking down of hydrocarbon by mycellium and mushroom is possible. # Safety Many hydrocarbons are highly flammable, therefore, care should be taken to prevent injury. Benzene and many aromatic compounds are possible carcinogens, and proper safety equipment must be worn to prevent these harmful compounds from entering the body. If hydrocarbons undergo combustion in tight areas, toxic carbon monoxide can form. Hydrocarbons should be kept away from fluorine compounds due to the high probability of forming toxic hydrofluoric acid.	Hydrocarbon Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview In organic chemistry, a hydrocarbon is an organic compound consisting entirely of hydrogen and carbon.[1] Hydrocarbons from which one hydrogen atom has been removed are functional groups, called hydrocarbyls.[2] Aromatic hydrocarbons (arenes), alkanes, alkenes, cycloalkanes and alkyne-based compounds are different types of hydrocarbons. The majority of hydrocarbons found on Earth naturally occur in crude oil, where decomposed organic matter provides an abundance of carbon and hydrogen which, when bonded, can catenate to form seemingly limitless chains.[3][4] # Types of hydrocarbons The classifications for hydrocarbons, defined by IUPAC nomenclature of organic chemistry are as follows: - Saturated hydrocarbons (alkanes) are the simplest of the hydrocarbon species. They are composed entirely of single bonds and are saturated with hydrogen. The general formula for saturated hydrocarbons is CnH2n+2 (assuming non-cyclic structures).[5] Saturated hydrocarbons are the basis of petroleum fuels and are found as either linear or branched species. Substitution reaction is their characteristics property (like chlorination reaction to form chloroform). Hydrocarbons with the same molecular formula but different structural formulae are called structural isomers.[6] As given in the example of 3-methylhexane and its higher homologues, branched hydrocarbons can be chiral.[7] Chiral saturated hydrocarbons constitute the side chains of biomolecules such as chlorophyll and tocopherol.[8] - Unsaturated hydrocarbons have one or more double or triple bonds between carbon atoms. Those with double bond are called alkenes. Those with one double bond have the formula CnH2n (assuming non-cyclic structures).[9] Those containing triple bonds are called alkynes, with general formula CnH2n-2.[10] - Cycloalkanes are hydrocarbons containing one or more carbon rings to which hydrogen atoms are attached. The general formula for a saturated hydrocarbon containing one ring is CnH2n.[6] - Aromatic hydrocarbons, also known as arenes, are hydrocarbons that have at least one aromatic ring. Hydrocarbons can be gases (e.g. methane and propane), liquids (e.g. hexane and benzene), waxes or low melting solids (e.g. paraffin wax and naphthalene) or polymers (e.g. polyethylene, polypropylene and polystyrene). ## General properties Because of differences in molecular structure, the empirical formula remains different between hydrocarbons; in linear, or "straight-run" alkanes, alkenes and alkynes, the amount of bonded hydrogen lessens in alkenes and alkynes due to the "self-bonding" or catenation of carbon preventing entire saturation of the hydrocarbon by the formation of double or triple bonds. This inherent ability of hydrocarbons to bond to themselves is known as catenation, and allows hydrocarbon to form more complex molecules, such as cyclohexane, and in rarer cases, arenes such as benzene. This ability comes from the fact that the bond character between carbon atoms is entirely non-polar, in that the distribution of electrons between the two elements is somewhat even due to the same electronegativity values of the elements (~0.30), and does not result in the formation of an electrophile. Generally, with catenation comes the loss of the total amount of bonded hydrocarbons and an increase in the amount of energy required for bond cleavage due to strain exerted upon the molecule;in molecules such as cyclohexane, this is referred to as ring strain, and occurs due to the "destabilized" spatial electron configuration of the atom. In simple chemistry, as per valence bond theory, the carbon atom must follow the "4-hydrogen rule", which states that the maximum number of atoms available to bond with carbon is equal to the number of electrons that are attracted into the outer shell of carbon. In terms of shells, carbon consists of an incomplete outer shell, which comprises 4 electrons, and thus has 4 electrons available for covalent or dative bonding. Hydrocarbons are hydrophobic like lipids. Some hydrocarbons also are abundant in the solar system. Lakes of liquid methane and ethane have been found on Titan, Saturn's largest moon, confirmed by the Cassini-Huygens Mission.[11] Hydrocarbons are also abundant in nebulae forming polycyclic aromatic hydrocarbon (PAH) compounds.[12] ## Simple hydrocarbons and their variations # Usage Hydrocarbons are a primary energy source for current civilizations. The predominant use of hydrocarbons is as a combustible fuel source. In their solid form, hydrocarbons take the form of asphalt (bitumen).[13] Mixtures of volatile hydrocarbons are now used in preference to the chlorofluorocarbons as a propellant for aerosol sprays, due to chlorofluorocarbons' impact on the ozone layer. Methane [1C] and ethane [2C] are gaseous at ambient temperatures and cannot be readily liquefied by pressure alone. Propane [3C] is however easily liquefied, and exists in 'propane bottles' mostly as a liquid. Butane [4C] is so easily liquefied that it provides a safe, volatile fuel for small pocket lighters. Pentane [5C] is a clear liquid at room temperature, commonly used in chemistry and industry as a powerful nearly odorless solvent of waxes and high molecular weight organic compounds, including greases. Hexane [6C] is also a widely used non-polar, non-aromatic solvent, as well as a significant fraction of common gasoline. The [6C] through [10C] alkanes, alkenes and isomeric cycloalkanes are the top components of gasoline, naphtha, jet fuel and specialized industrial solvent mixtures. With the progressive addition of carbon units, the simple non-ring structured hydrocarbons have higher viscosities, lubricating indices, boiling points, solidification temperatures, and deeper color. At the opposite extreme from [1C] methane lie the heavy tars that remain as the lowest fraction in a crude oil refining retort. They are collected and widely utilized as roofing compounds, pavement composition, wood preservatives (the creosote series) and as extremely high viscosity shear-resisting liquids. Hydrocarbon use is also prevalent in nature. Some eusocial arthropods, such as the Brazilian stingless bee Schwarziana quadripunctata, use unique hydrocarbon "scents" in order to determine kin from non-kin. The chemical hydrocarbon composition varies between age, sex, nest location, and hierarchal position.[14] # Poisoning Hydrocarbon poisoning such as that of benzene and petroleum usually occurs accidentally by inhalation or ingestion of these cytotoxic chemical compounds. Intravenous or subcutaneous injection of petroleum compounds with intent of suicide or abuse is an extraordinary event that can result in local damage or systemic toxicity such as tissue necrosis, abscess formation, respiratory system failure and partial damage to the kidneys, the brain and the nervous system. Moaddab and Eskandarlou report a case of chest wall necrosis and empyema resulting from attempting suicide by injection of petroleum into the pleural cavity.[15] # Reactions There are three main types of reactions : - Substitution Reaction - Addition Reaction - Combustion ## Substitution Reaction Substitution reaction only occur in saturated hydrocarbons (single carbon-carbon bonds). In this reaction, an alkane reacts with a chlorine molecule. One of the chlorine atoms displace an hydrogen atom. This forms hydrochloride acid as well as the hydrocarbon with one chlorine. e.g. CH4 + Cl2 →CH3Cl + HCl e.g. CH3Cl3 + Cl2 →CH2Cl2 + HCl All the way until CCl4 (Carbon tetrachloride) e.g. C2H6 + Cl2 →C2H5Cl1 + HCl e.g. C2H4Cl2 + Cl2 →C2H4Cl3 + HCl All the way until C2Cl4 (DiCarbon tetrachloride) ## Addition Reaction Addition reactions involve alkenes and alkynes. In this reaction a halogen molecule breaks the double or triple bond in the hydrocarbon and forms a bond. ## Combustion Hydrocarbons are currently the main source of the world's electric energy and heat sources (such as home heating) because of the energy produced when burnt.[16] Often this energy is used directly as heat such as in home heaters, which use either petroleum or natural gas. The hydrocarbon is burnt and the heat is used to heat water, which is then circulated. A similar principle is used to create electric energy in power plants. Common properties of hydrocarbons are the facts that they produce steam, carbon dioxide and heat during combustion and that oxygen is required for combustion to take place. The simplest hydrocarbon, methane, burns as follows: In inadequate supply of air, CO gas and water vapour are formed: Another example of this reaction is propane: Burning of hydrocarbons is an example of an exothermic chemical reaction. Hydrocarbons can also be burned with elemental fluorine, resulting in carbon tetrafluoride and hydrogen fluoride products. ### Petroleum Extracted hydrocarbons in a liquid form are referred to as petroleum (literally "rock oil") or mineral oil, whereas hydrocarbons in a gaseous form are referred to as natural gas. Petroleum and natural gas are found in the Earth's subsurface with the tools of petroleum geology and are a significant source of fuel and raw materials for the production of organic chemicals. The extraction of liquid hydrocarbon fuel from sedimentary basins is integral to modern energy development. Hydrocarbons are mined from oil sands and oil shale, and potentially extracted from sedimentary methane hydrates. These reserves require distillation and upgrading to produce synthetic crude and petroleum. Oil reserves in sedimentary rocks are the source of hydrocarbons for the energy, transport and petrochemical industry. Economically important hydrocarbons include fossil fuels such as coal, petroleum and natural gas, and its derivatives such as plastics, paraffin, waxes, solvents and oils. Hydrocarbons – along with NOx and sunlight – contribute to the formation of tropospheric ozone and greenhouse gases. ### Bioremediation Bacteria in the gabbroic layer of the ocean's crust can degrade hydrocarbons; but the extreme environment makes research difficult.[17] Other bacteria such as Lutibacterium anuloederans can also degrade hydrocarbons.[18] Mycoremediation or breaking down of hydrocarbon by mycellium and mushroom is possible.[19] # Safety Many hydrocarbons are highly flammable, therefore, care should be taken to prevent injury. Benzene and many aromatic compounds are possible carcinogens, and proper safety equipment must be worn to prevent these harmful compounds from entering the body. If hydrocarbons undergo combustion in tight areas, toxic carbon monoxide can form. Hydrocarbons should be kept away from fluorine compounds due to the high probability of forming toxic hydrofluoric acid.	https://www.wikidoc.org/index.php/Cyclic_hydrocarbon
4c862b9d18620ecd26b1ac4a64d2bc5e1b90da61	wikidoc	Cycloalkane	Cycloalkane # Overview Cycloalkanes (also called naphthenes) are chemicals with one or more hydrogen rings to which carbon atoms are attached according to the formula CnH2n. Cycloalkanes with a single ring are named analogously to their normal alkane counterpart of the same carbon count: cyclopropane, cyclobutane, cyclopentane, cyclohexane, etc. The larger cycloalkanes, with greater than 20 carbon atoms are typically called cycloparaffins. Cycloalkanes are classified into small, normal and bigger cycloalkanes, where cyclopropane and cyclobutane are the small ones, cyclopentane, cyclohexane, cycloheptane are the normal ones, and the rest are the bigger ones. # Nomenclature The naming of polycyclic alkanes such as bicyclic alkanes and spiro alkanes is more complex, with the base name indicating the number of carbons in the ring system, a prefix indicating the number of rings (eg, "bicyclo"), and a numeric prefix before that indicating the number of carbons in each part of each ring, exclusive of vertices. For instance, a bicyclooctane which consists of a six-member ring and a four member ring, which share two adjacent carbon atoms which form a shared edge, is -bicyclooctane. That part of the six-member ring, exclusive of the shared edge has 4 carbons. That part of the four-member ring, exclusive of the shared edge, has 2 carbons. The edge itself, exclusive of the two vertices that define it, has 0 carbons. The group of cycloalkanes are also known as naphthenes, as they are compounds of petroleum or naphtha. # Properties Cycloalkanes are similar to alkanes in their general physical properties, but they have higher boiling points, melting points, and densities than alkanes. This is due to stronger London forces because the ring shape allows for a larger area of contact. Cycloalkanes exhibit almost the same degree of unreactivity as alkanes, due to only containing unreactive C-C and C-H bonds; however, the ring strain (see below) can cause cycloalkanes to be more reactive. # Ring strain The carbon atoms in cycloalkanes are sp3 hybridized and therefore a deviation from the ideal tetrahedral bond angles of 109.47 degrees causes an increase in potential energy and an overall destabilizing effect. Eclipsing of hydrogen atoms is an important destabilizing effect as well. The strain energy of a cycloalkane is the theoretical increase in energy caused by the compound's geometry, and is calculated by comparing the experimental standard enthalpy change of combustion of the cycloalkane with the value calculated using average bond energies. Ring strain is highest for cyclopropane, in which the carbon atoms form a triangle and therefore have 60 degree C-C-C bond angles. There are also three pairs of eclipsed hydrogens. The ring strain is calculated to be around 120 kJ/mol. Cyclobutane has the carbon atoms in a puckered square with approximately 90 degree bond angles; by "puckering" it reduces the eclipsing interactions between hydrogen atoms. Its ring strain is slightly less, at around 110 kJ/mol. For a theoretical planar cyclopentane the C-C-C bond angles would be 108 degrees, very close to the tetrahedral angle. Actual cyclopentane molecules are puckered but this only changes the bond angles slightly so that angle strain is relatively small. The eclipsing interactions are also reduced, leaving a ring strain of about 25 kJ/mol. In cyclohexane the ring strain and eclipsing interactions are negligible because the puckering of the ring allows ideal tetrahedral bond angles to be achieved. As well, in the most stable chair form of cyclohexane, axial hydrogens on adjacent carbon atoms are pointed in opposite directions, virtually eliminating eclipsing strain. After cyclohexane, the molecules are unable to take a structure with no ring strain, resulting in an increase in strain energy, which peaks at 9 carbons (around 50 kJ/mol). After that, strain energy slowly decreases until 12 carbon atoms, where it drops significantly; at 14 another significant drop occurs and the strain is on a level comparable with 10 kJ/mol. After 14 carbon atoms, sources disagree on what happens to ring strain, some indicating that it increases steadily, others saying that it disappears entirely. # Reactions The simple and the bigger cycloalkanes are very stable, like alkanes, and their reactions for example radical chain reactions, are like alkanes. The small cycloalkanes - particularly cyclopropane - have a lower stability due to Baeyer strain and ring strain. They react similarly to alkenes, though they don't react in electrophilic addition but in nucleophilic aliphatic substitution. These reactions are ring opening reactions or ring cleavage reactions of alkyl cycloalkanes. Cycloalkanes can be formed in a Diels-Alder reaction followed by a catalytic hydrogenation.	Cycloalkane # Overview Cycloalkanes (also called naphthenes) are chemicals with one or more hydrogen rings to which carbon atoms are attached according to the formula CnH2n. Cycloalkanes with a single ring are named analogously to their normal alkane counterpart of the same carbon count: cyclopropane, cyclobutane, cyclopentane, cyclohexane, etc. The larger cycloalkanes, with greater than 20 carbon atoms are typically called cycloparaffins. Cycloalkanes are classified into small, normal and bigger cycloalkanes, where cyclopropane and cyclobutane are the small ones, cyclopentane, cyclohexane, cycloheptane are the normal ones, and the rest are the bigger ones. # Nomenclature The naming of polycyclic alkanes such as bicyclic alkanes and spiro alkanes is more complex, with the base name indicating the number of carbons in the ring system, a prefix indicating the number of rings (eg, "bicyclo"), and a numeric prefix before that indicating the number of carbons in each part of each ring, exclusive of vertices. For instance, a bicyclooctane which consists of a six-member ring and a four member ring, which share two adjacent carbon atoms which form a shared edge, is [4.2.0]-bicyclooctane. That part of the six-member ring, exclusive of the shared edge has 4 carbons. That part of the four-member ring, exclusive of the shared edge, has 2 carbons. The edge itself, exclusive of the two vertices that define it, has 0 carbons. The group of cycloalkanes are also known as naphthenes, as they are compounds of petroleum or naphtha. # Properties Cycloalkanes are similar to alkanes in their general physical properties, but they have higher boiling points, melting points, and densities than alkanes. This is due to stronger London forces because the ring shape allows for a larger area of contact. Cycloalkanes exhibit almost the same degree of unreactivity as alkanes, due to only containing unreactive C-C and C-H bonds; however, the ring strain (see below) can cause cycloalkanes to be more reactive. # Ring strain The carbon atoms in cycloalkanes are sp3 hybridized and therefore a deviation from the ideal tetrahedral bond angles of 109.47 degrees causes an increase in potential energy and an overall destabilizing effect. Eclipsing of hydrogen atoms is an important destabilizing effect as well. The strain energy of a cycloalkane is the theoretical increase in energy caused by the compound's geometry, and is calculated by comparing the experimental standard enthalpy change of combustion of the cycloalkane with the value calculated using average bond energies. Ring strain is highest for cyclopropane, in which the carbon atoms form a triangle and therefore have 60 degree C-C-C bond angles. There are also three pairs of eclipsed hydrogens. The ring strain is calculated to be around 120 kJ/mol. Cyclobutane has the carbon atoms in a puckered square with approximately 90 degree bond angles; by "puckering" it reduces the eclipsing interactions between hydrogen atoms. Its ring strain is slightly less, at around 110 kJ/mol. For a theoretical planar cyclopentane the C-C-C bond angles would be 108 degrees, very close to the tetrahedral angle. Actual cyclopentane molecules are puckered but this only changes the bond angles slightly so that angle strain is relatively small. The eclipsing interactions are also reduced, leaving a ring strain of about 25 kJ/mol. In cyclohexane the ring strain and eclipsing interactions are negligible because the puckering of the ring allows ideal tetrahedral bond angles to be achieved. As well, in the most stable chair form of cyclohexane, axial hydrogens on adjacent carbon atoms are pointed in opposite directions, virtually eliminating eclipsing strain. After cyclohexane, the molecules are unable to take a structure with no ring strain, resulting in an increase in strain energy, which peaks at 9 carbons (around 50 kJ/mol). After that, strain energy slowly decreases until 12 carbon atoms, where it drops significantly; at 14 another significant drop occurs and the strain is on a level comparable with 10 kJ/mol. After 14 carbon atoms, sources disagree on what happens to ring strain, some indicating that it increases steadily, others saying that it disappears entirely. # Reactions The simple and the bigger cycloalkanes are very stable, like alkanes, and their reactions for example radical chain reactions, are like alkanes. The small cycloalkanes - particularly cyclopropane - have a lower stability due to Baeyer strain and ring strain. They react similarly to alkenes, though they don't react in electrophilic addition but in nucleophilic aliphatic substitution. These reactions are ring opening reactions or ring cleavage reactions of alkyl cycloalkanes. Cycloalkanes can be formed in a Diels-Alder reaction followed by a catalytic hydrogenation.	https://www.wikidoc.org/index.php/Cycloalkane
971f901fd91335eb7758574f79f2e64c450149ff	wikidoc	Cyclohexane	Cyclohexane # Overview Cyclohexane is a cycloalkane with the molecular formula C6H12. Cyclohexane is used as a nonpolar solvent for the chemical industry, and also as a raw material for the industrial production of adipic acid and caprolactam, both of which are intermediates used in the production of nylon. On an industrial scale, cyclohexane is produced by reacting benzene with hydrogen. Due to its unique chemical and conformational properties, cyclohexane is also used in labs in analysis and as a standard. # Chemical conformation Contrary to popular belief, the 6 vertexed ring does not conform to the shape of a perfect hexagon. The conformation of a flat 2D planar hexagon has considerable angle strain due to the fact that its bonds are not 109.5 degrees; the torsional strain would also be considerable due to all eclipsed bonds. Therefore, to reduce torsional strain, cyclohexane adopts a three-dimensional structure known as the chair conformation. The new conformation puts the carbons at an angle of 109.5°. Half of the hydrogens are in the plane of the ring (equatorial) while the other half are perpendicular to the plane (axial). This conformation allows for the most stable structure of cyclohexane. Another conformation of cyclohexane exists, known as boat conformation, but it interconverts to the slightly more stable chair formation. If cyclohexane is mono-substituted with a large substituent, then the substituent will most likely be found attached in an equatorial position, as this is the slightly more stable conformation. Cyclohexane has the lowest angle and torsional strain of all the cycloalkanes, as a result cyclohexane has been deemed a 0 in total ring strain, a combination of angle and torsional strain. This also makes cyclohexane the most stable of the cycloalkanes and therefore will produce the least amount of heat when burned compared to the other cycloalkanes. # Reactions with cyclohexane Pure cyclohexane in itself is rather unreactive, being a non-polar, hydrophobic hydrocarbon. It can react with very strong acids such as the superacid system HF + SbF5 which will cause forced protonation and "hydrocarbon cracking". Substituted cyclohexanes, however, may be reactive under a variety of conditions, many of which are important to organic chemistry. # Cyclohexane derivatives The specific arrangement of functional groups in cyclohexane derivatives, and indeed in most cycloalkane molecules, is extremely important in chemical reactions, especially reactions involving nucleophiles. Substituents on the ring must be in the axial formation to react with other molecules. For example, the reaction of bromocyclohexane and a common nucleophile, a hydroxide anion (OH−), would result in cyclohexene: C6H11Br + OH− → C6H10 + H2O + Br− This reaction, commonly known as an elimination reaction or dehalogenation (specifically E2), requires that the bromine substituent be in the axial formation, opposing another axial H atom to react. Assuming that the bromocyclohexane was in the appropriate formation to react, the E2 reaction would commence as such: - The electron pair bond between the C-Br moves to the Br, forming Br− and setting it free from cyclohexane - The nucleophile (-OH) gives an electron pair to the adjacent axial H, setting H free and bonding to it to create H2O - The electron pair bond between the adjacent axial H moves to the bond between the two C-C making it C=C Note: All three steps happen simultaneously, characteristic of all E2 reactions. The reaction above will generate mostly E2 reactions and as a result the product will be mostly (~70%) cyclohexene. However, the percentage varies with conditions, and generally, two different reactions (E2 and Sn2) compete. In the above reaction, an Sn2 reaction would substitute the bromine for a hydroxyl (OH-) group instead, but once again, the Br must be in axial to react. Once the SN2 substitution is complete, the newly substituted OH group would flip back to the more stable equatorial position quickly (~1 millisecond). # Uses Commercially most of cyclohexane produced is converted into cyclohexanone-cyclohexanol mixture (or "KA oil") by catalytic oxidation. KA oil is then used as a raw material for adipic acid and caprolactam. Practically, if the cyclohexanol content of KA oil is higher than cyclohexanone, it is more likely(economical) to be converted into adipic acid, and the reverse case, caprolactam production is more likely. Such ratio in KA oil can be controlled by selecting suitable oxidation catalyts. Some of cyclohexane is used as an organic solvent. # Cyclohexane in research The usefulness of cyclohexane in research is not to be underestimated. Although much is already known about this cyclic hydrocarbon, research is still being done on cyclohexane and benzene mixtures and solid phase cyclohexane to determine hydrogen yields of the mix when irradiated at −195 °C. # History Unlike compounds like benzene, cyclohexane cannot easily be obtained from natural resources such as coal. Towards the end of the nineteenth century early chemical investigators had to depend on organic synthesis. It took them 30 years to flesh out the details. In 1867 Marcellin Berthelot reduced benzene with hydroiodic acid at elevated temperatures. He incorrectly identified the reaction product as n-hexane not only because of the convenient match in boiling point (69°C) but also because he did not believe benzene was a cyclic molecule (like his contemporary August Kekule) but rather some sort of association of acetylene. In 1870 one of his sceptics Adolf von Baeyer repeated the reaction and pronounced the same reaction product hexahydrobenzene and in 1890 Vladimir Markovnikov believed he was able to distill the same compound from Caucasus petroleum calling his concoction hexanaphtene In 1894 Baeyer synthesized cyclohexane starting with a Dieckmann condensation of pimelic acid followed by multiple reductions: and in the same year E. Haworth and W.H. Perkin Jr. (1860 - 1929) did the same in a Wurtz reaction of 1,6-dibromohexane. Surprisingly their cyclohexanes boiled higher by 10°C than either hexahydrobenzene or hexanaphtene but this riddle was solved in 1895 by Markovnikov, N.M. Kishner and Nikolay Zelinsky when they re-diagnosed hexahydrobenzene and hexanaphtene as methylcyclopentane, the result of an unexpected rearrangement reaction.	Cyclohexane Template:Chembox new Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Cyclohexane is a cycloalkane with the molecular formula C6H12. Cyclohexane is used as a nonpolar solvent for the chemical industry, and also as a raw material for the industrial production of adipic acid and caprolactam, both of which are intermediates used in the production of nylon. On an industrial scale, cyclohexane is produced by reacting benzene with hydrogen. Due to its unique chemical and conformational properties, cyclohexane is also used in labs in analysis and as a standard. # Chemical conformation Contrary to popular belief, the 6 vertexed ring does not conform to the shape of a perfect hexagon. The conformation of a flat 2D planar hexagon has considerable angle strain due to the fact that its bonds are not 109.5 degrees; the torsional strain would also be considerable due to all eclipsed bonds. Therefore, to reduce torsional strain, cyclohexane adopts a three-dimensional structure known as the chair conformation. The new conformation puts the carbons at an angle of 109.5°. Half of the hydrogens are in the plane of the ring (equatorial) while the other half are perpendicular to the plane (axial). This conformation allows for the most stable structure of cyclohexane. Another conformation of cyclohexane exists, known as boat conformation, but it interconverts to the slightly more stable chair formation. If cyclohexane is mono-substituted with a large substituent, then the substituent will most likely be found attached in an equatorial position, as this is the slightly more stable conformation. Cyclohexane has the lowest angle and torsional strain of all the cycloalkanes, as a result cyclohexane has been deemed a 0 in total ring strain, a combination of angle and torsional strain. This also makes cyclohexane the most stable of the cycloalkanes and therefore will produce the least amount of heat when burned compared to the other cycloalkanes. # Reactions with cyclohexane Pure cyclohexane in itself is rather unreactive, being a non-polar, hydrophobic hydrocarbon. It can react with very strong acids such as the superacid system HF + SbF5 which will cause forced protonation and "hydrocarbon cracking". Substituted cyclohexanes, however, may be reactive under a variety of conditions, many of which are important to organic chemistry. # Cyclohexane derivatives The specific arrangement of functional groups in cyclohexane derivatives, and indeed in most cycloalkane molecules, is extremely important in chemical reactions, especially reactions involving nucleophiles. Substituents on the ring must be in the axial formation to react with other molecules. For example, the reaction of bromocyclohexane and a common nucleophile, a hydroxide anion (OH−), would result in cyclohexene: C6H11Br + OH− → C6H10 + H2O + Br− This reaction, commonly known as an elimination reaction or dehalogenation (specifically E2), requires that the bromine substituent be in the axial formation, opposing another axial H atom to react. Assuming that the bromocyclohexane was in the appropriate formation to react, the E2 reaction would commence as such: - The electron pair bond between the C-Br moves to the Br, forming Br− and setting it free from cyclohexane - The nucleophile (-OH) gives an electron pair to the adjacent axial H, setting H free and bonding to it to create H2O - The electron pair bond between the adjacent axial H moves to the bond between the two C-C making it C=C Note: All three steps happen simultaneously, characteristic of all E2 reactions. The reaction above will generate mostly E2 reactions and as a result the product will be mostly (~70%) cyclohexene. However, the percentage varies with conditions, and generally, two different reactions (E2 and Sn2) compete. In the above reaction, an Sn2 reaction would substitute the bromine for a hydroxyl (OH-) group instead, but once again, the Br must be in axial to react. Once the SN2 substitution is complete, the newly substituted OH group would flip back to the more stable equatorial position quickly (~1 millisecond). # Uses Commercially most of cyclohexane produced is converted into cyclohexanone-cyclohexanol mixture (or "KA oil") by catalytic oxidation. KA oil is then used as a raw material for adipic acid and caprolactam. Practically, if the cyclohexanol content of KA oil is higher than cyclohexanone, it is more likely(economical) to be converted into adipic acid, and the reverse case, caprolactam production is more likely. Such ratio in KA oil can be controlled by selecting suitable oxidation catalyts. Some of cyclohexane is used as an organic solvent. # Cyclohexane in research The usefulness of cyclohexane in research is not to be underestimated. Although much is already known about this cyclic hydrocarbon, research is still being done on cyclohexane and benzene mixtures and solid phase cyclohexane to determine hydrogen yields of the mix when irradiated at −195 °C. # History Unlike compounds like benzene, cyclohexane cannot easily be obtained from natural resources such as coal. Towards the end of the nineteenth century early chemical investigators had to depend on organic synthesis. It took them 30 years to flesh out the details[1]. In 1867 Marcellin Berthelot reduced benzene with hydroiodic acid at elevated temperatures. He incorrectly identified the reaction product as n-hexane not only because of the convenient match in boiling point (69°C) but also because he did not believe benzene was a cyclic molecule (like his contemporary August Kekule) but rather some sort of association of acetylene. In 1870 one of his sceptics Adolf von Baeyer repeated the reaction and pronounced the same reaction product hexahydrobenzene and in 1890 Vladimir Markovnikov believed he was able to distill the same compound from Caucasus petroleum calling his concoction hexanaphtene In 1894 Baeyer synthesized cyclohexane starting with a Dieckmann condensation of pimelic acid followed by multiple reductions: and in the same year E. Haworth and W.H. Perkin Jr. (1860 - 1929) did the same in a Wurtz reaction of 1,6-dibromohexane. Surprisingly their cyclohexanes boiled higher by 10°C than either hexahydrobenzene or hexanaphtene but this riddle was solved in 1895 by Markovnikov, N.M. Kishner and Nikolay Zelinsky when they re-diagnosed hexahydrobenzene and hexanaphtene as methylcyclopentane, the result of an unexpected rearrangement reaction.	https://www.wikidoc.org/index.php/Cyclohexane
44d8a7eda2c55bff8ccd9f0e2d26d5bc7aba469a	wikidoc	Cyclophilin	Cyclophilin Cyclophilins are a family of proteins from vertebrates and other organisms that bind to ciclosporin (cyclosporin A), an immunosuppressant which is usually used to suppress rejection after internal organ transplants. These proteins have peptidyl prolyl isomerase activity, which catalyzes the isomerization of peptide bonds from trans form to cis form at proline residues and facilitates protein folding. Cyclophilin A is a cytosolic and highly abundant protein. The protein belongs to a family of isozymes, including cyclophilins B and C, and natural killer cell cyclophilin-related protein. Major isoforms have been found within single cells, including inside the Endoplasmic reticulum, and some are even secreted. # Cyclophilin A (CypA) Cyclophilin A also known as peptidylprolyl isomerase A, which is found in the cytosol, has a beta barrel structure with two alpha helices and a beta-sheet. Other cyclophilins have similar structures to cyclophilin A. The cyclosporin-cyclophilin A complex inhibits a calcium/calmodulin-dependent phosphatase, calcineurin, the inhibition of which is thought to suppress organ rejection by halting the production of the pro-inflammatory molecules TNF alpha and interleukin 2. Cyclophilin A is also known to be recruited by the Gag polyprotein during HIV-1 virus infection, and its incorporation into new virus particles is essential for HIV-1 infectivity. # Cyclophilin D Cyclophilin D, which is located in the matrix of mitochondria, is only a modulatory, but may or may not be a structural component of the mitochondrial permeability transition pore. The pore opening raises the permeability of the mitochondrial inner membrane, allows influx of cytosolic molecules into the mitochondrial matrix, increases the matrix volume, and disrupts the mitochondrial outer membrane. As a result, the mitochondria fall into a functional disorder, so the opening of the pore plays an important role in cell death. Cyclophilin D is thought to regulate the opening of the pore because cyclosporin A, which binds to CyP-D, inhibits the pore opening. However, mitochondria obtained from the cysts of Artemia franciscana, do not exhibit the mitochondrial permeability transition pore # Clinical significance ## Diseases Overexpression of Cyclophilin A has been linked to poor response to inflammatory diseases, the progression or metastasis of cancer, and aging. ## Cyclophilins as drug targets Cyclophilin inhibitors, such as cyclosporin, are being developed to treat neurodegenerative diseases. Cyclophilin inhibition may also be a therapy for liver diseases. # Examples Human genes encoding proteins containing the cyclophilin type peptidyl-prolyl cis-trans isomerase domain include: - PPIA, PPIB, PPIC, PPID, PPIE, PPIF, PPIG, PPIH - PPIL1, PPIL2, PPIL3, PPIL4, PPIAL4, PPIL6 - PPWD1	Cyclophilin Cyclophilins are a family of proteins from vertebrates and other organisms that bind to ciclosporin (cyclosporin A), an immunosuppressant which is usually used to suppress rejection after internal organ transplants.[1] These proteins have peptidyl prolyl isomerase activity, which catalyzes the isomerization of peptide bonds from trans form to cis form at proline residues and facilitates protein folding. Cyclophilin A is a cytosolic and highly abundant protein. The protein belongs to a family of isozymes, including cyclophilins B and C, and natural killer cell cyclophilin-related protein.[2][3][4] Major isoforms have been found within single cells, including inside the Endoplasmic reticulum, and some are even secreted. # Cyclophilin A (CypA) Cyclophilin A also known as peptidylprolyl isomerase A, which is found in the cytosol, has a beta barrel structure with two alpha helices and a beta-sheet. Other cyclophilins have similar structures to cyclophilin A. The cyclosporin-cyclophilin A complex inhibits a calcium/calmodulin-dependent phosphatase, calcineurin, the inhibition of which is thought to suppress organ rejection by halting the production of the pro-inflammatory molecules TNF alpha and interleukin 2. Cyclophilin A is also known to be recruited by the Gag polyprotein during HIV-1 virus infection, and its incorporation into new virus particles is essential for HIV-1 infectivity.[5] # Cyclophilin D Cyclophilin D, which is located in the matrix of mitochondria, is only a modulatory, but may or may not be a structural component of the mitochondrial permeability transition pore.[6][7] The pore opening raises the permeability of the mitochondrial inner membrane, allows influx of cytosolic molecules into the mitochondrial matrix, increases the matrix volume, and disrupts the mitochondrial outer membrane. As a result, the mitochondria fall into a functional disorder, so the opening of the pore plays an important role in cell death. Cyclophilin D is thought to regulate the opening of the pore because cyclosporin A, which binds to CyP-D, inhibits the pore opening. However, mitochondria obtained from the cysts of Artemia franciscana, do not exhibit the mitochondrial permeability transition pore [8][9] # Clinical significance ## Diseases Overexpression of Cyclophilin A has been linked to poor response to inflammatory diseases, the progression or metastasis of cancer, and aging.[10] ## Cyclophilins as drug targets Cyclophilin inhibitors, such as cyclosporin, are being developed to treat neurodegenerative diseases.[11] Cyclophilin inhibition may also be a therapy for liver diseases.[12] # Examples Human genes encoding proteins containing the cyclophilin type peptidyl-prolyl cis-trans isomerase domain include: - PPIA, PPIB, PPIC, PPID, PPIE, PPIF, PPIG, PPIH - PPIL1, PPIL2, PPIL3, PPIL4, PPIAL4, PPIL6 - PPWD1	https://www.wikidoc.org/index.php/Cyclophilin
8299b422a748f8bc3e27b226c8ed28d1920eb394	wikidoc	Cycloplegia	Cycloplegia # Overview Cycloplegia is paralysis of the ciliary muscle of the eye, resulting in a loss of accommodation. Because of the paralysis of the ciliary muscle, the curvature of the lens can no longer be adjusted to focus on nearby objects. This results in similar problems as those caused by presbyopia, in which the lens has lost elasticity and can also no longer focus on close-by objects. Cycloplegia with accompanying mydriasis (dilation of pupil) is usually due to topical application of muscarinic antagonists such as atropine and cyclopentolate. # Anatomy The iris is the heavily pigmented colored part of the eye. It has a contractile diaphragm in front of the lens with a central opening called the pupil. It is located between the lens and the cornea, and is attached radially to the ciliary body and the cornea via ligaments called pectinate ligaments. The iris contains two sets of muscles: - a radial group for enlargement of the pupil (dilator pupillae) - a circular group set to decrease pupil size on contraction (sphincter pupillae). The muscles regulate the amount of light entering the eye. The sphincter pupillae is stimulated through muscarinic receptors by the parasympathetic nervous system. The dilator pupillae is stimulated through noradrenergic receptors by the sympathetic nervous system. # Cycloplegic drugs Cycloplegic drugs are generally muscarinic receptor blockers. These include atropine, cyclopentolate, homatropine, scopolamine and tropicamide. They are indicated for use in cycloplegic refraction (to paralyze the ciliary muscle in order to determine the true refractive error of the eye) and the treatment of uveitis. All cycloplegics are also mydriatic (pupil dilating) agents and are used as such during eye examination to better visualize the retina. When cycloplegic drugs are used as a mydriatic to dilate the pupil, the pupil in the normal eye regains its function when the drugs are metabolized or carried away. Some cycloplegic drugs can cause dilation of the pupil for several days. Usually the ones used by ophthalmologists or optometrists wear off in hours, but when the patient leaves the office strong sunglasses are provided for comfort.	Cycloplegia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Cycloplegia is paralysis of the ciliary muscle of the eye, resulting in a loss of accommodation.[1] Because of the paralysis of the ciliary muscle, the curvature of the lens can no longer be adjusted to focus on nearby objects. This results in similar problems as those caused by presbyopia, in which the lens has lost elasticity and can also no longer focus on close-by objects. Cycloplegia with accompanying mydriasis (dilation of pupil) is usually due to topical application of muscarinic antagonists such as atropine and cyclopentolate. # Anatomy The iris is the heavily pigmented colored part of the eye. It has a contractile diaphragm in front of the lens with a central opening called the pupil. It is located between the lens and the cornea, and is attached radially to the ciliary body and the cornea via ligaments called pectinate ligaments. The iris contains two sets of muscles: - a radial group for enlargement of the pupil (dilator pupillae) - a circular group set to decrease pupil size on contraction (sphincter pupillae). The muscles regulate the amount of light entering the eye. The sphincter pupillae is stimulated through muscarinic receptors by the parasympathetic nervous system. The dilator pupillae is stimulated through noradrenergic receptors by the sympathetic nervous system. # Cycloplegic drugs Cycloplegic drugs are generally muscarinic receptor blockers. These include atropine, cyclopentolate, homatropine, scopolamine and tropicamide. They are indicated for use in cycloplegic refraction (to paralyze the ciliary muscle in order to determine the true refractive error of the eye) and the treatment of uveitis. All cycloplegics are also mydriatic (pupil dilating) agents and are used as such during eye examination to better visualize the retina. When cycloplegic drugs are used as a mydriatic to dilate the pupil, the pupil in the normal eye regains its function when the drugs are metabolized or carried away. Some cycloplegic drugs can cause dilation of the pupil for several days. Usually the ones used by ophthalmologists or optometrists wear off in hours, but when the patient leaves the office strong sunglasses are provided for comfort.	https://www.wikidoc.org/index.php/Cycloplegia
48ab39b6fbe86269d14d6ee223341d1ba14d486c	wikidoc	Cycloserine	Cycloserine # 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 Cycloserine is an antitubercular that is FDA approved for the treatment of active pulmonary and extrapulmonary tuberculosis and in the treatment of acute urinary tract infections caused by susceptible strains of gram positive and gram negative bacteria. Common adverse reactions include confusion, dizziness, headache and somnolence. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Cycloserine is indicated in the treatment of active pulmonary and extrapulmonary tuberculosis (including renal disease) when the causative organisms are susceptible to this drug and when treatment with the primary medications (streptomycin, isoniazid, rifampin, and ethambutol) has proved inadequate. - Dosage: initial, 250 mg, oral, every 12 h for 2 weeks, then as tolerated to 250 mg every 6 to 8 h; MAX 1 g daily - Cycloserine may be effective in the treatment of acute urinary tract infections caused by susceptible strains of gram positive and gram negative bacteria, especially Enterobacter spp. and Escherichia coli. - Dosage: 15 to 20 mg/kg; MAX 1 gram daily ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Cycloserine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Cycloserine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Cycloserine is indicated in the treatment of active pulmonary and extrapulmonary tuberculosis (including renal disease) when the causative organisms are susceptible to this drug and when treatment with the primary medications (streptomycin, isoniazid, rifampin, and ethambutol) has proved inadequate. - Dosage: 10 to 20 mg/kg/day ORALLY (divide every 12 h) ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Cycloserine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Cycloserine in pediatric patients. # Contraindications Administration is contraindicated in patients with any of the following: - Hypersensitivity to cycloserine - Epilepsy - Depression, severe anxiety, or psychosis - Severe renal insufficiency - Excessive concurrent use of alcohol # Warnings - Administration of cycloserine should be discontinued or the dosage reduced if the patient develops allergic dermatitis or symptoms of CNS toxicity, such as convulsions, psychosis, somnolence, depression, confusion, hyperreflexia, headache, tremor, vertigo, paresis, or dysarthria. - The toxicity of cycloserine is closely related to excessive blood levels (above 30 μg/mL), as determined by high dosage or inadequate renal clearance. The ratio of toxic dose to effective dose in tuberculosis is small. - The risk of convulsions is increased in chronic alcoholics. - Administration of cycloserine and other antituberculosis drugs has been associated in a few instances with vitamin B12 and/or folic–acid deficiency, megaloblastic anemia, and sideroblastic anemia. # Adverse Reactions ## Clinical Trials Experience Most adverse reactions occurring during therapy with cycloserine involve the nervous system or are manifestations of drug hypersensitivity. The following side effects have been observed in patients receiving cycloserine: - Nervous system symptoms (which appear to be related to higher dosages of the drug, i.e., more than 500 mg daily) - Convulsions - Drowsiness and somnolence - Headache - Tremor - Dysarthria - Vertigo - Confusion and disorientation with loss of memory - Psychoses, possibly with suicidal tendencies - Character changes - Hyperirritability - Aggression - Paresis - Hyperreflexia - Paresthesia - Major and minor (localized) clonic seizures - Coma - Cardiovascular - Sudden development of congestive heart failure in patients receiving 1 to 1.5 g of cycloserine daily has been reported - Allergy (apparently not related to dosage) - Skin rash - Miscellaneous - Elevated serum transaminase, especially in patients with preexisting liver disease. ## Postmarketing Experience There is limited information regarding Cycloserine Postmarketing Experience in the drug label. # Drug Interactions - Concurrent administration of ethionamide has been reported to potentiate neurotoxic side effects. - Alcohol and cycloserine are incompatible, especially during a regimen calling for large doses of the latter. Alcohol increases the possibility and risk of epileptic episodes. - Concurrent administration of isoniazid may result in increased incidence of CNS effects, such as dizziness or drowsiness. Dosage adjustments may be necessary and patients should be monitored closely for signs of CNS toxicity. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C A study in 2 generations of rats given doses up to 100 mg/kg/day demonstrated no teratogenic effect in offspring. It is not known whether cycloserine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Cycloserine should be given to a pregnant woman only if clearly needed. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cycloserine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Cycloserine during labor and delivery. ### Nursing Mothers A study in 2 generations of rats given doses up to 100 mg/kg/day demonstrated no teratogenic effect in offspring. It is not known whether cycloserine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Cycloserine should be given to a pregnant woman only if clearly needed. ### Pediatric Use Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use There is no FDA guidance on the use of Cycloserine in geriatric settings. ### Gender There is no FDA guidance on the use of Cycloserine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Cycloserine with respect to specific racial populations. ### Renal Impairment Blood levels should be determined at least weekly for patients with reduced renal function, for individuals receiving a daily dosage of more than 500 mg, and for those showing signs and symptoms suggestive of toxicity. The dosage should be adjusted to keep the blood level below 30 μg/mL. ### Hepatic Impairment There is no FDA guidance on the use of Cycloserine in patients with hepatic impairment. ### Females of Reproductive Potential and Males - A study in 2 generations of rats showed no impairment of fertility relative to controls for the first mating but somewhat lower fertility in the second mating. ### Immunocompromised Patients There is no FDA guidance one the use of Cycloserine in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring - Doses monitored by blood levels. - Blood levels should be determined at least weekly for patients with reduced renal function, for individuals receiving a daily dosage of more than 500 mg, and for those showing signs and symptoms suggestive of toxicity. # IV Compatibility There is limited information regarding the compatibility of Cycloserine and IV administrations. # Overdosage - Acute toxicity from cycloserine can occur if more than 1 g is ingested by an adult. Chronic toxicity from cycloserine is dose related and can occur if more than 500 mg is administered daily. - Patients with renal impairment will accumulate cycloserine and may develop toxicity if the dosing regimen is not modified. Patients with severe renal impairment should not receive the drug. - The central nervous system is the most common organ system involved with toxicity. Toxic effects may include headache, vertigo, confusion, drowsiness, hyperirritability, paresthesias, dysarthria and psychosis. - Following larger ingestions, paresis, convulsions, and coma often occur. - Ethyl alcohol may increase the risk of seizures in patients receiving cycloserine. - The oral median lethal dose in mice is 5290 mg/kg. - To obtain up–to–date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians’ Desk Reference (PDR). - In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient. - In adults, many of the neurotoxic effects of cycloserine can be both treated and prevented with the administration of 200 to 300 mg of pyridoxine daily. - The use of hemodialysis has been shown to remove cycloserine from the bloodstream. This procedure should be reserved for patients with life-threatening toxicity that is unresponsive to less invasive therapy. # Pharmacology ## Mechanism of Action Cycloserine inhibits cell–wall synthesis in susceptible strains of gram–positive and gram–negative bacteria and in Mycobacterium tuberculosis. ## Structure The molecular weight of cycloserine is 102.09, and it has an empirical formula of C3H6N2O2. ## Pharmacodynamics There is limited information regarding Cycloserine Pharmacodynamics in the drug label. ## Pharmacokinetics After oral administration, cycloserine is readily absorbed from the gastrointestinal tract, with peak blood levels occurring in 4 to 8 hours. Blood levels of 25 to 30 μg/mL can generally be maintained with the usual dosage of 250 mg twice a day, although the relationship of plasma levels to dosage is not always consistent. Concentrations in the cerebrospinal fluid, pleural fluid, fetal blood, and mother’s milk approach those found in the serum. Detectable amounts are found in ascitic fluid, bile, sputum, amniotic fluid, and lung and lymph tissues. Approximately 65 percent of a single dose of cycloserine can be recovered in the urine within 72 hours after oral administration. The remaining 35 percent is apparently metabolized to unknown substances. The maximum excretion rate occurs 2 to 6 hours after administration, with 50 percent of the drug eliminated in 12 hours. ## Nonclinical Toxicology Carcinogenesis and Mutagenicity - Studies have not been performed to determine potential for carcinogenicity. - The Ames test and unscheduled DNA repair test were negative. # Clinical Studies There is limited information regarding Cycloserine Clinical Studies in the drug label. # How Supplied Cycloserine is available as a 250 mg capsule - Bottles of 40 capsules - NDC 13845-1201-3 ## Storage Store at 20° to 25°C (68° to 77°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Cycloserine Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Cycloserine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Seromycin # Look-Alike Drug Names There is limited information regarding Cycloserine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Cycloserine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [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 Cycloserine is an antitubercular that is FDA approved for the treatment of active pulmonary and extrapulmonary tuberculosis and in the treatment of acute urinary tract infections caused by susceptible strains of gram positive and gram negative bacteria. Common adverse reactions include confusion, dizziness, headache and somnolence. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Cycloserine is indicated in the treatment of active pulmonary and extrapulmonary tuberculosis (including renal disease) when the causative organisms are susceptible to this drug and when treatment with the primary medications (streptomycin, isoniazid, rifampin, and ethambutol) has proved inadequate. - Dosage: initial, 250 mg, oral, every 12 h for 2 weeks, then as tolerated to 250 mg every 6 to 8 h; MAX 1 g daily - Cycloserine may be effective in the treatment of acute urinary tract infections caused by susceptible strains of gram positive and gram negative bacteria, especially Enterobacter spp. and Escherichia coli. - Dosage: 15 to 20 mg/kg; MAX 1 gram daily ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Cycloserine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Cycloserine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Cycloserine is indicated in the treatment of active pulmonary and extrapulmonary tuberculosis (including renal disease) when the causative organisms are susceptible to this drug and when treatment with the primary medications (streptomycin, isoniazid, rifampin, and ethambutol) has proved inadequate. - Dosage: 10 to 20 mg/kg/day ORALLY (divide every 12 h) ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Cycloserine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Cycloserine in pediatric patients. # Contraindications Administration is contraindicated in patients with any of the following: - Hypersensitivity to cycloserine - Epilepsy - Depression, severe anxiety, or psychosis - Severe renal insufficiency - Excessive concurrent use of alcohol # Warnings - Administration of cycloserine should be discontinued or the dosage reduced if the patient develops allergic dermatitis or symptoms of CNS toxicity, such as convulsions, psychosis, somnolence, depression, confusion, hyperreflexia, headache, tremor, vertigo, paresis, or dysarthria. - The toxicity of cycloserine is closely related to excessive blood levels (above 30 μg/mL), as determined by high dosage or inadequate renal clearance. The ratio of toxic dose to effective dose in tuberculosis is small. - The risk of convulsions is increased in chronic alcoholics. - Administration of cycloserine and other antituberculosis drugs has been associated in a few instances with vitamin B12 and/or folic–acid deficiency, megaloblastic anemia, and sideroblastic anemia. # Adverse Reactions ## Clinical Trials Experience Most adverse reactions occurring during therapy with cycloserine involve the nervous system or are manifestations of drug hypersensitivity. The following side effects have been observed in patients receiving cycloserine: - Nervous system symptoms (which appear to be related to higher dosages of the drug, i.e., more than 500 mg daily) - Convulsions - Drowsiness and somnolence - Headache - Tremor - Dysarthria - Vertigo - Confusion and disorientation with loss of memory - Psychoses, possibly with suicidal tendencies - Character changes - Hyperirritability - Aggression - Paresis - Hyperreflexia - Paresthesia - Major and minor (localized) clonic seizures - Coma - Cardiovascular - Sudden development of congestive heart failure in patients receiving 1 to 1.5 g of cycloserine daily has been reported - Allergy (apparently not related to dosage) - Skin rash - Miscellaneous - Elevated serum transaminase, especially in patients with preexisting liver disease. ## Postmarketing Experience There is limited information regarding Cycloserine Postmarketing Experience in the drug label. # Drug Interactions - Concurrent administration of ethionamide has been reported to potentiate neurotoxic side effects. - Alcohol and cycloserine are incompatible, especially during a regimen calling for large doses of the latter. Alcohol increases the possibility and risk of epileptic episodes. - Concurrent administration of isoniazid may result in increased incidence of CNS effects, such as dizziness or drowsiness. Dosage adjustments may be necessary and patients should be monitored closely for signs of CNS toxicity. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C A study in 2 generations of rats given doses up to 100 mg/kg/day demonstrated no teratogenic effect in offspring. It is not known whether cycloserine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Cycloserine should be given to a pregnant woman only if clearly needed. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cycloserine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Cycloserine during labor and delivery. ### Nursing Mothers A study in 2 generations of rats given doses up to 100 mg/kg/day demonstrated no teratogenic effect in offspring. It is not known whether cycloserine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Cycloserine should be given to a pregnant woman only if clearly needed. ### Pediatric Use Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use There is no FDA guidance on the use of Cycloserine in geriatric settings. ### Gender There is no FDA guidance on the use of Cycloserine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Cycloserine with respect to specific racial populations. ### Renal Impairment Blood levels should be determined at least weekly for patients with reduced renal function, for individuals receiving a daily dosage of more than 500 mg, and for those showing signs and symptoms suggestive of toxicity. The dosage should be adjusted to keep the blood level below 30 μg/mL. ### Hepatic Impairment There is no FDA guidance on the use of Cycloserine in patients with hepatic impairment. ### Females of Reproductive Potential and Males - A study in 2 generations of rats showed no impairment of fertility relative to controls for the first mating but somewhat lower fertility in the second mating. ### Immunocompromised Patients There is no FDA guidance one the use of Cycloserine in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring - Doses monitored by blood levels. - Blood levels should be determined at least weekly for patients with reduced renal function, for individuals receiving a daily dosage of more than 500 mg, and for those showing signs and symptoms suggestive of toxicity. # IV Compatibility There is limited information regarding the compatibility of Cycloserine and IV administrations. # Overdosage - Acute toxicity from cycloserine can occur if more than 1 g is ingested by an adult. Chronic toxicity from cycloserine is dose related and can occur if more than 500 mg is administered daily. - Patients with renal impairment will accumulate cycloserine and may develop toxicity if the dosing regimen is not modified. Patients with severe renal impairment should not receive the drug. - The central nervous system is the most common organ system involved with toxicity. Toxic effects may include headache, vertigo, confusion, drowsiness, hyperirritability, paresthesias, dysarthria and psychosis. - Following larger ingestions, paresis, convulsions, and coma often occur. - Ethyl alcohol may increase the risk of seizures in patients receiving cycloserine. - The oral median lethal dose in mice is 5290 mg/kg. - To obtain up–to–date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians’ Desk Reference (PDR). - In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient. - In adults, many of the neurotoxic effects of cycloserine can be both treated and prevented with the administration of 200 to 300 mg of pyridoxine daily. - The use of hemodialysis has been shown to remove cycloserine from the bloodstream. This procedure should be reserved for patients with life-threatening toxicity that is unresponsive to less invasive therapy. # Pharmacology ## Mechanism of Action Cycloserine inhibits cell–wall synthesis in susceptible strains of gram–positive and gram–negative bacteria and in Mycobacterium tuberculosis. ## Structure The molecular weight of cycloserine is 102.09, and it has an empirical formula of C3H6N2O2. ## Pharmacodynamics There is limited information regarding Cycloserine Pharmacodynamics in the drug label. ## Pharmacokinetics After oral administration, cycloserine is readily absorbed from the gastrointestinal tract, with peak blood levels occurring in 4 to 8 hours. Blood levels of 25 to 30 μg/mL can generally be maintained with the usual dosage of 250 mg twice a day, although the relationship of plasma levels to dosage is not always consistent. Concentrations in the cerebrospinal fluid, pleural fluid, fetal blood, and mother’s milk approach those found in the serum. Detectable amounts are found in ascitic fluid, bile, sputum, amniotic fluid, and lung and lymph tissues. Approximately 65 percent of a single dose of cycloserine can be recovered in the urine within 72 hours after oral administration. The remaining 35 percent is apparently metabolized to unknown substances. The maximum excretion rate occurs 2 to 6 hours after administration, with 50 percent of the drug eliminated in 12 hours. ## Nonclinical Toxicology Carcinogenesis and Mutagenicity - Studies have not been performed to determine potential for carcinogenicity. - The Ames test and unscheduled DNA repair test were negative. # Clinical Studies There is limited information regarding Cycloserine Clinical Studies in the drug label. # How Supplied Cycloserine is available as a 250 mg capsule - Bottles of 40 capsules - NDC 13845-1201-3 ## Storage Store at 20° to 25°C (68° to 77°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Cycloserine Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Cycloserine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Seromycin [1] # Look-Alike Drug Names There is limited information regarding Cycloserine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Cycloserine
eda27309f6d3c68ad702dad531d113bc92c1c373	wikidoc	Cyhalothrin	Cyhalothrin # Overview Cyhalothrin is an organic compound that is used as a pesticide. It is a pyrethroid, a class of man-made insecticides that mimic the structure and insecticidal properties of the naturally-occurring insecticide pyrethrum which comes from the flowers of chrysanthemums. Synthetic pyrethroids, like lambda-cyhalothrin, are often preferred as an active ingredient in insecticides because they remain effective for longer periods of time. It is a colorless solid, although samples can appear beige, with a mild odor. It has a low water solubility and is nonvolatile. It is used to control insects in cotton crops. # Structure Lambda-cyhalothrin is a mixture of isomers of cyhalothrin. Brand names include "Danger" by "OPAL Agrochemical Pakistan" 'Karate', 'Kung-fu', 'Matador', 'Cyzmic CS', and 'Demand CS' (Syngenta); Proaxis in Indonesia by PT Dow AgroSciences Indonesia; in the USA, 'Triazicide' and 'Hot Shot' are used in the home landscape and garden markets Home Depot carries a brand of the Lambda-cyhalothrin insecticide under the brand name Real Kill and Spectracide Bug Off. Terro also makes an outdoor ant and other insect prevention treatment similar to Home Defense using this ingredient. Syngenta held the patent for Lambda-cyhalothrin. This patent expired in most major markets in 2003. Lambda cyhalothrin may be marketed as Charge, Demand CS, Excaliber, Grenade, Hallmark, Icon, Karate, Matador, OMS 0321, PP321, Saber, Samurai, and Sentinel. Gamma-cyhalothrin is a single stereoisomer of the pyrethroid insecticide cyhalothrin, and as such shares physical, chemical, and biological properties with both cyhalothrin and lambda-cyhalothrin, which are mixtures of 4 and 2 isomers respectively. Gamma-cyhalothrin is the most insecticidally active isomer of cyhalothrin/lambda-cyhalothrin, and thus the technical gamma-cyhalothrin product may be considered a refined form of cyhalothrin/lambda-cyhalothrin in that it has been purified by removal of less active and inactive isomers. Thus, similar levels of insecticidal efficacy for gamma-cyhalothrin can be obtained with significantly reduced application rates as compared with either cyhalothrin or lambda-cyhalothrin. The tolerance under 40 CFR 180.438 currently identifies lambda-cyhalothrin as a 1:1 mixture of two isomers and their epimers, one of which is the gamma isomer. The gamma isomer is present at 42% in this mixture. By contrast in the proposed tolerance expression the gamma isomer is present at 98% in the mixture. Home Depot carries a brand of the Gamma-cyhalothrin insecticide under the brand name Spectracide Triazacide. # Mechanism of action Pyrethroids, including lambda-cyhalothrin, disrupt the functioning of the nervous system in an organism. By disrupting the nervous system of insects, lambdacyhalothrin may cause paralysis or death. Temperature influences its effectiveness. It is highly toxic to many fish and aquatic invertebrate species. Bioconcentration is possible in aquatic species, but bioaccumulation is not likely. Binding of lambda-cyhalothrin to soil and sediment reduces exposure and may lessen the risk to fish. Field studies found no significant adverse effects to fish. Lambda-cyhalothrin is also highly toxic to bees, although again field studies found few effects. In laboratory studies, alkaline water degraded lambda-cyhalothrin with an approximate half-life of 7 days, although at neutral and acidic pH's degradation did not occur. Sunlight accelerates degradation in water and soil. The half-life of lambda-cyhalothrin on plant surfaces is 5 days. Lambda-cyhalothrin has a low potential to contaminate ground water due to its low water solubility and high potential to bind to soil. # Regulation The LD50 is 79–56 mg/kg (rats, oral). It decomposes in extreme heat (257 °C), liberating toxic gases like CO and HCN. It is a potent irritant to mucous membranes and is highly toxic in concentrations higher than 97%.	Cyhalothrin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Cyhalothrin is an organic compound that is used as a pesticide.[1] It is a pyrethroid, a class of man-made insecticides that mimic the structure and insecticidal properties of the naturally-occurring insecticide pyrethrum which comes from the flowers of chrysanthemums. Synthetic pyrethroids, like lambda-cyhalothrin, are often preferred as an active ingredient in insecticides because they remain effective for longer periods of time. It is a colorless solid, although samples can appear beige, with a mild odor. It has a low water solubility and is nonvolatile. It is used to control insects in cotton crops.[2] # Structure Lambda-cyhalothrin is a mixture of isomers of cyhalothrin.[3] Brand names include "Danger" by "OPAL Agrochemical Pakistan" 'Karate', 'Kung-fu', 'Matador', 'Cyzmic CS', and 'Demand CS' (Syngenta); Proaxis in Indonesia by PT Dow AgroSciences Indonesia; in the USA, 'Triazicide' and 'Hot Shot' are used in the home landscape and garden markets[4][5][6] Home Depot carries a brand of the Lambda-cyhalothrin insecticide under the brand name Real Kill and Spectracide Bug Off. Terro also makes an outdoor ant and other insect prevention treatment similar to Home Defense using this ingredient. Syngenta held the patent for Lambda-cyhalothrin. This patent expired in most major markets in 2003.[7] Lambda cyhalothrin may be marketed as Charge, Demand CS, Excaliber, Grenade, Hallmark, Icon, Karate, Matador, OMS 0321, PP321, Saber, Samurai, and Sentinel. Gamma-cyhalothrin is a single stereoisomer of the pyrethroid insecticide cyhalothrin, and as such shares physical, chemical, and biological properties with both cyhalothrin and lambda-cyhalothrin, which are mixtures of 4 and 2 isomers respectively. Gamma-cyhalothrin is the most insecticidally active isomer of cyhalothrin/lambda-cyhalothrin, and thus the technical gamma-cyhalothrin product may be considered a refined form of cyhalothrin/lambda-cyhalothrin in that it has been purified by removal of less active and inactive isomers. Thus, similar levels of insecticidal efficacy for gamma-cyhalothrin can be obtained with significantly reduced application rates as compared with either cyhalothrin or lambda-cyhalothrin. The tolerance under 40 CFR 180.438 currently identifies lambda-cyhalothrin as a 1:1 mixture of two isomers and their epimers, one of which is the gamma isomer. The gamma isomer is present at 42% in this mixture. By contrast in the proposed tolerance expression the gamma isomer is present at 98% in the mixture.[8] Home Depot carries a brand of the Gamma-cyhalothrin insecticide under the brand name Spectracide Triazacide. # Mechanism of action Pyrethroids, including lambda-cyhalothrin, disrupt the functioning of the nervous system in an organism. By disrupting the nervous system of insects, lambdacyhalothrin may cause paralysis or death. Temperature influences its effectiveness. It is highly toxic to many fish and aquatic invertebrate species. Bioconcentration is possible in aquatic species, but bioaccumulation is not likely. Binding of lambda-cyhalothrin to soil and sediment reduces exposure and may lessen the risk to fish. Field studies found no significant adverse effects to fish. Lambda-cyhalothrin is also highly toxic to bees, although again field studies found few effects. In laboratory studies, alkaline water degraded lambda-cyhalothrin with an approximate half-life of 7 days, although at neutral and acidic pH's degradation did not occur. Sunlight accelerates degradation in water and soil. The half-life of lambda-cyhalothrin on plant surfaces is 5 days. Lambda-cyhalothrin has a low potential to contaminate ground water due to its low water solubility and high potential to bind to soil.[9] # Regulation The LD50 is 79–56 mg/kg (rats, oral).[2] It decomposes in extreme heat (257 °C),[10] liberating toxic gases like CO and HCN. [11][12] It is a potent irritant to mucous membranes and is highly toxic in concentrations higher than 97%.[13]	https://www.wikidoc.org/index.php/Cyhalothrin
a8dcc78cba2b2f1552fc766417a2350a3ab7e1cf	wikidoc	Cyproterone	Cyproterone # Overview Cyproterone acetate (Androcur®, Cyprostat®, Cyproteron®, Procur®, Cyprone®, Cyprohexal®, Ciproterona®, Cyproteronum®, Neoproxil®, Siterone®) is an antiandrogen, i.e. it suppresses the actions of testosterone (and its metabolite dihydrotestosterone) on tissues. It acts by blocking androgen receptors which prevents androgens from binding to them and suppresses luteinizing hormone (which in turn reduces testosterone levels). Its main indications are prostate cancer, benign prostatic hyperplasia, priapism, hypersexuality and other conditions in which androgen action maintains the disease process. Due to its anti-androgen effect, it can also be used to treat hirsutism, and is a common component in hormone therapy for male-to-female transgendered persons. Until the development of leuprolide, cyproterone was one of the few drugs used to treat precocious puberty. It was also used in animal experimentation to investigate the actions of androgens in fetal sexual differentiation. In addition, cyproterone acetate has weak progestational activity (e.g., it acts like progesterone) and can be used to treat hot flushes. As part of some combined oral contraceptive pills (Diane®) it decreases acne and hirsutism (male-pattern hair growth). # Pharmacology Cyproterone acetate is a synthetic derivative of 17-hydroxyprogesterone, and acts as an androgen receptor antagonist with weak progestational and glucocorticoid activity. Some portion is metabolized by hydrolysis to cyproterone and acetic acid. However, unlike many other steroid esters, cyproterone acetate is not extensively hydrolyzed, and much of its pharmacological activity is attributed to its acetate form. Cyproterone acetate has approximately three times the anti-androgenic activity of cyproterone. Cyproterone acetate inhibits the steroidogenic enzyme 21-hydroxylase and to a lesser extent 3beta-hydroxysteroid dehydrogenase, both of which are needed to synthesize cortisol. The blockade of 21-hydroxylase can also result in reduced production of aldosterone, the primary mineralcorticoid hormone. Mutations in the gene encoding 21-hydroxylase are fairly common in the human population, therefore some patients may be affected more than others. Although cyproterone has some glucocorticoid activity, this is offset by the fact that cyproterone acetate inhibits cortisol production and can act as a competitive inhibitor of cortisol at the glucocorticoid receptor, thus its adrenosuppressive effects are usually fairly minor. However, since the glucocorticoid effects appear to be due to metabolites, rather than cyproterone acetate itself, the net effect may vary depending on the rate at which cyproterone acetate is metabolized. The progestational and glucocorticoid effects reduce production of gonadotropins, which usually results in lower testosterone levels, however the blockade of adrenal 21-hydroxylase results in the accumulation of androgen precursors which may be converted to testosterone, reducing the efficacy of the antiandrogen treatment. Due to the possibility of increased adrenal androgens, cyproterone acetate is sometimes combined with the 5-alpha-reductase inhibitor finasteride, and studies of hirsutism treatment show increased efficacy of this combination over cyproterone acetate alone. Some in vitro studies have suggested that cyproterone or cyproterone acetate may have a slight inhibitory effect on 5-alpha-reductase, however no significant reduction in DHT production has been observed in vivo. Cyproterone acetate is metabolized by the CYP3A4 enzyme, forming the active metabolite 15β-hydroxycyproterone acetate, which retains its antiandrogen activity, but has reduced progestational activity. Therefore, use of cyproterone acetate in combination with substances which inhibit CYP3A4 may increase the progestational effects. Cyproterone acetate increases production of CYP3A4 by activating the pregnane x receptor. # Side effects The most serious potential side effect is liver toxicity, and patients should be monitored for changes in liver enzymes, especially if taking a high dose (200-300 mg/day). Toxicity is dose-dependent and the low doses used in birth control pills (2 mg) do not appear to represent a significant risk. Suppression of adrenal function and reduced response to ACTH have been reported. Low cortisol levels may impair carbohydrate metabolism, and patients with diabetes mellitus may require adjustments in insulin dosage. Low aldosterone levels may lead to salt loss and hyperkalemia (excess potassium). Patients taking cyproterone should have their cortisol levels and electrolytes monitored, and if hyperkalemia develops, reduce the consumption of food having a high potassium content. Used alone, cyproterone acetate does not appear to have a significant effect on blood clotting factors, however in combination with ethinylestradiol (as in combined oral contraceptive pills) presents an increased risk of deep vein thrombosis. There are conflicting reports as to whether there is a significant difference in the risk of thrombosis between oral contraceptives containing cyproterone acetate versus other types of combined oral contraceptives. Cyproterone has been associated with depressive mood changes in some patients, presumably due to androgen deprivation. However, others have reported significant antidepressant effects. This may be due to its effect on adrenal hormones, as similar antidepressant effects have been observed with other adrenal suppressants, such as metyrapone. Cyproterone acetate suppresses production of estrogen due to its antigonadotrophic effect, and long-term use without estrogen replacement may result in osteoporosis. Side-effects in men which directly result from its antiandrogenic action include gynecomastia (breast growth), galactorrhea (milk outflow), and erectile dysfunction. # Withdrawal effects Abrupt withdrawal of cyproterone acetate can be harmful, and the package insert from Schering AG recommends that the daily dose be reduced by no more than 50 mg, at intervals of several weeks. The primary concern is the manner in which cyproterone acetate affects the adrenal gland. Due to its glucocorticoid activity, high levels of cyproterone acetate may reduce ACTH, resulting in adrenal insufficiency if discontinued suddenly. In addition, although cyproterone acetate reduces androgen production in the gonads, it can increase adrenal androgen production, in some cases resulting in an overall rise in testosterone levels. Thus the sudden withdrawal of cyproterone acetate may result in undesirable androgenic effects. This is a particular concern because androgens, especially DHT, suppress adrenal function, further reducing cortisol production. In theory, 5-alpha-reductase inhibitors such as finasteride and dutasteride may be able to mitigate this effect somewhat by preventing the conversion of testosterone to the more potent DHT. A paradoxical effect occurs with certain prostate cancer cells which have genetic mutations in their androgen receptors. These altered androgen receptors can be stimulated, rather than inhibited, by cyproterone. In such cases, withdrawal of cyproterone results in a reduction in cancer growth, rather than the opposite. # Pharmacokinetics The pharmacokinetics of cyproterone are complicated due to its lipophilic nature. Although the mean elimination half-life is usually estimated at around 40 hours, this primarily reflects its accumulation in fat cells. Elimination from the bloodstream is considerably faster, and the amount stored in fat may be affected by food intake. Therefore it is recommended that this medication be given in divided doses 2-3 times per day, or in the form of a long-acting injection. # Dosage and administration As an oral contraceptive, 2mg cyproterone acetate is combined with 35 or 50 mcg ethinylestradiol and taken once daily for 21 days, followed by 7-day interval with placebo pills. For the treatment of hypersexuality, severe hirsutism, or for the treatment of male-to-female transsexuals, 25mg twice daily is usually sufficient, although up to 100mg/day is permitted. As side effects are dose-dependent, treatment with the lowest effective dose is advisable. Use during pregnancy is contraindicated, and for women of childbearing age, cyproterone should be administered with a combined oral contraceptive. To ensure that it does not interfere with regular withdrawal bleeding, additional cyproterone should be taken only on days 1-10 of a 28-day package of birth control pills. Doses up to 300 mg/day are used for the treatment of metastatic prostate cancer, however at high doses the risk of serious hepatic toxicity or adrenal suppression requires careful monitoring. In treatment of prostate cancer, cyproterone is often co-administered with a GnRH agonist and a 5-alpha-reductase inhibitor.	Cyproterone # Overview Cyproterone acetate (Androcur®, Cyprostat®, Cyproteron®, Procur®, Cyprone®, Cyprohexal®, Ciproterona®, Cyproteronum®, Neoproxil®, Siterone®) is an antiandrogen, i.e. it suppresses the actions of testosterone (and its metabolite dihydrotestosterone) on tissues. It acts by blocking androgen receptors which prevents androgens from binding to them and suppresses luteinizing hormone (which in turn reduces testosterone levels). Its main indications are prostate cancer, benign prostatic hyperplasia, priapism, hypersexuality and other conditions in which androgen action maintains the disease process. Due to its anti-androgen effect, it can also be used to treat hirsutism, and is a common component in hormone therapy for male-to-female transgendered persons. Until the development of leuprolide, cyproterone was one of the few drugs used to treat precocious puberty. It was also used in animal experimentation to investigate the actions of androgens in fetal sexual differentiation. In addition, cyproterone acetate has weak progestational activity (e.g., it acts like progesterone) and can be used to treat hot flushes. As part of some combined oral contraceptive pills (Diane®) it decreases acne and hirsutism (male-pattern hair growth). # Pharmacology Cyproterone acetate is a synthetic derivative of 17-hydroxyprogesterone, and acts as an androgen receptor antagonist with weak progestational and glucocorticoid activity. Some portion is metabolized by hydrolysis to cyproterone and acetic acid.[1] However, unlike many other steroid esters, cyproterone acetate is not extensively hydrolyzed, and much of its pharmacological activity is attributed to its acetate form.[2] Cyproterone acetate has approximately three times the anti-androgenic activity of cyproterone.[3] Cyproterone acetate inhibits the steroidogenic enzyme 21-hydroxylase and to a lesser extent 3beta-hydroxysteroid dehydrogenase, both of which are needed to synthesize cortisol.[4] The blockade of 21-hydroxylase can also result in reduced production of aldosterone, the primary mineralcorticoid hormone. Mutations in the gene encoding 21-hydroxylase are fairly common in the human population, therefore some patients may be affected more than others. Although cyproterone has some glucocorticoid activity,[5] this is offset by the fact that cyproterone acetate inhibits cortisol production and can act as a competitive inhibitor of cortisol at the glucocorticoid receptor,[6] thus its adrenosuppressive effects are usually fairly minor.[7] However, since the glucocorticoid effects appear to be due to metabolites, rather than cyproterone acetate itself, the net effect may vary depending on the rate at which cyproterone acetate is metabolized.[8] The progestational and glucocorticoid effects reduce production of gonadotropins, which usually results in lower testosterone levels, however the blockade of adrenal 21-hydroxylase results in the accumulation of androgen precursors which may be converted to testosterone, reducing the efficacy of the antiandrogen treatment. Due to the possibility of increased adrenal androgens, cyproterone acetate is sometimes combined with the 5-alpha-reductase inhibitor finasteride, and studies of hirsutism treatment show increased efficacy of this combination over cyproterone acetate alone.[9] Some in vitro studies have suggested that cyproterone or cyproterone acetate may have a slight inhibitory effect on 5-alpha-reductase, however no significant reduction in DHT production has been observed in vivo.[10] Cyproterone acetate is metabolized by the CYP3A4 enzyme, forming the active metabolite 15β-hydroxycyproterone acetate, which retains its antiandrogen activity, but has reduced progestational activity.[11][12][13] Therefore, use of cyproterone acetate in combination with substances which inhibit CYP3A4 may increase the progestational effects. Cyproterone acetate increases production of CYP3A4 by activating the pregnane x receptor.[14] # Side effects The most serious potential side effect is liver toxicity, and patients should be monitored for changes in liver enzymes, especially if taking a high dose (200-300 mg/day).[2] Toxicity is dose-dependent and the low doses used in birth control pills (2 mg) do not appear to represent a significant risk.[15] Suppression of adrenal function and reduced response to ACTH have been reported. Low cortisol levels may impair carbohydrate metabolism, and patients with diabetes mellitus may require adjustments in insulin dosage. Low aldosterone levels may lead to salt loss and hyperkalemia (excess potassium). Patients taking cyproterone should have their cortisol levels and electrolytes monitored, and if hyperkalemia develops, reduce the consumption of food having a high potassium content. Used alone, cyproterone acetate does not appear to have a significant effect on blood clotting factors, however in combination with ethinylestradiol (as in combined oral contraceptive pills) presents an increased risk of deep vein thrombosis.[16] There are conflicting reports as to whether there is a significant difference in the risk of thrombosis between oral contraceptives containing cyproterone acetate versus other types of combined oral contraceptives.[17] Cyproterone has been associated with depressive mood changes in some patients, presumably due to androgen deprivation. However, others have reported significant antidepressant effects. This may be due to its effect on adrenal hormones, as similar antidepressant effects have been observed with other adrenal suppressants, such as metyrapone. Cyproterone acetate suppresses production of estrogen due to its antigonadotrophic effect, and long-term use without estrogen replacement may result in osteoporosis. Side-effects in men which directly result from its antiandrogenic action include gynecomastia (breast growth), galactorrhea (milk outflow), and erectile dysfunction. # Withdrawal effects Abrupt withdrawal of cyproterone acetate can be harmful, and the package insert from Schering AG recommends that the daily dose be reduced by no more than 50 mg, at intervals of several weeks. The primary concern is the manner in which cyproterone acetate affects the adrenal gland. Due to its glucocorticoid activity, high levels of cyproterone acetate may reduce ACTH, resulting in adrenal insufficiency if discontinued suddenly. In addition, although cyproterone acetate reduces androgen production in the gonads, it can increase adrenal androgen production, in some cases resulting in an overall rise in testosterone levels.[18] Thus the sudden withdrawal of cyproterone acetate may result in undesirable androgenic effects. This is a particular concern because androgens, especially DHT, suppress adrenal function, further reducing cortisol production.[19] In theory, 5-alpha-reductase inhibitors such as finasteride and dutasteride may be able to mitigate this effect somewhat by preventing the conversion of testosterone to the more potent DHT. A paradoxical effect occurs with certain prostate cancer cells which have genetic mutations in their androgen receptors. These altered androgen receptors can be stimulated, rather than inhibited, by cyproterone. In such cases, withdrawal of cyproterone results in a reduction in cancer growth, rather than the opposite.[20] # Pharmacokinetics The pharmacokinetics of cyproterone are complicated due to its lipophilic nature. Although the mean elimination half-life is usually estimated at around 40 hours, this primarily reflects its accumulation in fat cells. Elimination from the bloodstream is considerably faster, and the amount stored in fat may be affected by food intake. Therefore it is recommended that this medication be given in divided doses 2-3 times per day, or in the form of a long-acting injection. # Dosage and administration As an oral contraceptive, 2mg cyproterone acetate is combined with 35 or 50 mcg ethinylestradiol and taken once daily for 21 days, followed by 7-day interval with placebo pills. For the treatment of hypersexuality, severe hirsutism, or for the treatment of male-to-female transsexuals, 25mg twice daily is usually sufficient, although up to 100mg/day is permitted. As side effects are dose-dependent, treatment with the lowest effective dose is advisable. Use during pregnancy is contraindicated, and for women of childbearing age, cyproterone should be administered with a combined oral contraceptive. To ensure that it does not interfere with regular withdrawal bleeding, additional cyproterone should be taken only on days 1-10 of a 28-day package of birth control pills. Doses up to 300 mg/day are used for the treatment of metastatic prostate cancer, however at high doses the risk of serious hepatic toxicity or adrenal suppression requires careful monitoring. In treatment of prostate cancer, cyproterone is often co-administered with a GnRH agonist and a 5-alpha-reductase inhibitor.	https://www.wikidoc.org/index.php/Cyproterone
0c2e6bf107d3892521ac07dc0dedea2110c15608	wikidoc	Ramucirumab	Ramucirumab # 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 Ramucirumab is a monoclonal antibody that is FDA approved for the treatment of advanced or metastatic, gastric or gastro-esophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy and metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypertension and diarrhea. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Recommended Dose and Schedule - The recommended dose of Ramucirumab either as a single agent or in combination with weekly paclitaxel is 8 mg/kg every 2 weeks administered as an intravenous infusion over 60 minutes. Continue Ramucirumab until disease progression or unacceptable toxicity. - When given in combination, administer Ramucirumab prior to administration of paclitaxel. - The recommended dose of Ramucirumab is 10 mg/kg administered by intravenous infusion over approximately 60 minutes on day 1 of a 21-day cycle prior to docetaxel infusion. Continue Ramucirumab until disease progression or unacceptable toxicity. ### Premedication - Prior to each Ramucirumab infusion, premedicate all patients with an intravenous histamine H1 antagonist (e.g., diphenhydramine hydrochloride). - For patients who have experienced a Grade 1 or 2 infusion-related reaction, also premedicate with dexamethasone (or equivalent) and acetaminophen prior to each Ramucirumab infusion. ### Dose Modifications - Reduce the infusion rate of Ramucirumab by 50% for Grade 1 or 2 IRRs. - Permanently discontinue Ramucirumab for Grade 3 or 4 IRRs. - Interrupt Ramucirumab for severe hypertension until controlled with medical management. - Permanently discontinue Ramucirumab for severe hypertension that cannot be controlled with antihypertensive therapy - Interrupt Ramucirumab for urine protein levels ≥2 g/24 hours. Reinitiate treatment at a reduced dose (see TABLE 1) once the urine protein level returns to <2 g/24 hours. If the protein level ≥2 g/24 hours reoccurs, interrupt Ramucirumab and reduce the dose (see TABLE 1) once the urine protein level returns to <2 g/24 hours. - Permanently discontinue Ramucirumab for urine protein level >3 g/24 hours or in the setting of nephrotic syndrome. - Interrupt Ramucirumab prior to scheduled surgery until the wound is fully healed. - Permanently discontinue Ramucirumab. ### Preparation for Administration Inspect vial contents for particulate matter and discoloration prior to dilution. Discard the vial, if particulate matter or discolorations are identified. Store vials in a refrigerator at 2°C to 8°C (36°F to 46°F) until time of use. Keep the vial in the outer carton in order to protect from light. - Calculate the dose and the required volume of Ramucirumab needed to prepare the infusion solution. Vials contain either 100 mg/10 mL or 500 mg/50 mL at a concentration of 10 mg/mL solution of Ramucirumab. - Withdraw the required volume of Ramucirumab and further dilute with only 0.9% Sodium Chloride Injection in an intravenous infusion container to a final volume of 250 mL. Do not use dextrose containing solutions. - Gently invert the container to ensure adequate mixing. - Do not freeze or shake the infusion solution. DO NOT dilute with other solutions or co-infuse with other electrolytes or medications. - Store diluted infusion for no more than 24 hours at 2°C to 8°C (36°F to 46°F) or 4 hours at room temperature (below 25°C ). - Discard vial with any unused portion of Ramucirumab. ### Administration - Visually inspect the diluted solution for particulate matter and discoloration prior to administration. If particulate matter or discolorations are identified, discard the solution. - Administer diluted Ramucirumab infusion via infusion pump over 60 minutes through a separate infusion line. Use of a protein sparing 0.22 micron filter is recommended. Flush the line with sterile sodium chloride (0.9%) solution for injection at the end of the infusion. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Ramucirumab in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Ramucirumab in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Ramucirumab 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 Ramucirumab in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Ramucirumab in pediatric patients. # Contraindications None. # Warnings ### Hemorrhage - Ramucirumab increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, the incidence of severe bleeding was 3.4% for Ramucirumab and 2.6% for placebo. In Study 2, the incidence of severe bleeding was 4.3% for Ramucirumab plus paclitaxel and 2.4% for placebo plus paclitaxel. - Patients with gastric cancer receiving nonsteroidal anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Studies 1 and 2; therefore, the risk of gastric hemorrhage in Ramucirumab-treated patients with gastric tumors receiving NSAIDs is unknown. Permanently discontinue Ramucirumab in patients who experience severe bleeding. - In Study 3, the incidence of severe bleeding was 2.4% for Ramucirumab plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDS or other anti-platelet therapy other than once daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from Study 3; therefore the risk of pulmonary hemorrhage in these groups of patients is unknown. ### Arterial Thromboembolic Events - Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received Ramucirumab as a single agent for gastric cancer in Study 1. Permanently discontinue Ramucirumab in patients who experience a severe ATE. ### Hypertension - An increased incidence of severe hypertension occurred in patients receiving Ramucirumab as a single agent (8%) as compared to placebo (3%) and in patients receiving Ramucirumab plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%) and in patients receiving Ramucirumab plus docetaxel (6%) as compared to placebo plus docetaxel (2%). - Control hypertension prior to initiating treatment with Ramucirumab. Monitor blood pressure every two weeks or more frequently as indicated during treatment. - Temporarily suspend Ramucirumab for severe hypertension until medically controlled. Permanently discontinue Ramucirumab if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy. ### Infusion-Related Reactions - Prior to the institution of premedication recommendations across clinical trials of Ramucirumab IRRs occurred in 6 out of 37 patients (16%), including two severe events. The majority of IRRs across trials occurred during or following a first or second Ramucirumab infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. - Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue Ramucirumab for Grade 3 or 4 IRRs. ### Gastrointestinal Perforations - Ramucirumab is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received Ramucirumab as a single agent in clinical trials experienced gastrointestinal perforation. In Study 2, the incidence of gastrointestinal perforations was also increased in patients that received Ramucirumab plus paclitaxel (1.2%) as compared to patients receiving placebo plus paclitaxel (0.3%). In Study 3, the incidence of gastrointestinal perforation was 1% for Ramucirumab plus docetaxel and 0.3% for placebo plus docetaxel. Permanently discontinue Ramucirumab in patients who experience a gastrointestinal perforation. ### Impaired Wound Healing - Ramucirumab has not been studied in patients with serious or non-healing wounds. Ramucirumab is an antiangiogenic therapy with the potential to adversely affect wound healing. - Withhold Ramucirumab prior to surgery. Resume following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue Ramucirumab until the wound is fully healed. ### Clinical Deterioration in Patients with Child-Pugh B or C Cirrhosis - Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome was reported in patients with Child-Pugh B or C cirrhosis who received single-agent Ramucirumab. Use Ramucirumab in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration. ### Reversible Posterior Leukoencephalopathy Syndrome - Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported with a rate of <0.1% in clinical studies with Ramucirumab Confirm the diagnosis of RPLS with MRI and discontinue Ramucirumab in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death # Adverse Reactions ## Clinical Trials Experience The following adverse drug reactions are discussed in greater detail in other sections of the label: - Hemorrhage - Arterial Thromboembolic Events - Hypertension - Infusion-Related Reactions - Gastrointestinal Perforation - Impaired Wound Healing - Patients with Child-Pugh B or C Cirrhosis - Reversible Posterior Leukoencephalopathy Syndrome ## 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. - Safety data are presented from two randomized, placebo controlled clinical trials in which patients received Ramucirumab: Study 1, a randomized (2:1), double-blind, clinical trial in which 351 patients received either Ramucirumab 8 mg/kg intravenously every two weeks or placebo every two weeks and Study 2, a double-blind, randomized (1:1) clinical trial in which 656 patients received paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 28-day cycle plus either Ramucirumab 8 mg/kg intravenously every two weeks or placebo every two weeks. Both trials excluded patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 or greater, uncontrolled hypertension, major surgery within 28 days, or patients receiving chronic anti-platelet therapy other than once daily aspirin. Study 1 excluded patients with bilirubin ≥1.5 mg/dL and Study 2 excluded patients with bilirubin >1.5 times the upper limit of normal. - Among 236 patients who received Ramucirumab (safety population) in Study 1, median age was 60 years, 28% were women, 76% were White, and 16% were Asian. Patients in Study 1 received a median of 4 doses of Ramucirumab; the median duration of exposure was 8 weeks, and 32 (14% of 236) patients received Ramucirumab for at least six months. - In Study 1, the most common adverse reactions (all grades) observed in Ramucirumab-treated patients at a rate of ≥10% and ≥2% higher than placebo were hypertension and diarrhea. The most common serious adverse events with Ramucirumab were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of Ramucirumab-treated patients versus 8.7% of patients who received placebo. - Clinically relevant adverse reactions reported in ≥1% and <5% of Ramucirumab-treated patients in Study 1 were: neutropenia (4.7% Ramucirumab versus 0.9% placebo), epistaxis (4.7% Ramucirumab versus 0.9% placebo), rash (4.2¢ Ramucirumab versus 1.7% placebo), intestinal obstruction (2.1% Ramucirumab versus 0% placebo), and arterial thromboembolic events (1.7% Ramucirumab versus 0% placebo). - Across clinical trials of Ramucirumab administered as a single agent, clinically relevant adverse reactions (including Grade ≥3) reported in Ramucirumab-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions. - In Study 1, according to laboratory assessment, 8% of Ramucirumab-treated patients developed proteinuria versus 3% of placebo-treated patients. Two patients discontinued Ramucirumab due to proteinuria. The rate of gastrointestinal perforation in Study 1 was 0.8% and the rate of infusion-related reactions was 0.4%. - Among 327 patients who received Ramucirumab (safety population) in Study 2, median age was 60 years, 31% were women, 63% were White, and 33% were Asian. Patients in Study 2 received a median of 9 doses of Ramucirumab; the median duration of exposure was 18 weeks, and 93 (28% of 327) patients received Ramucirumab for at least six months. - In Study 2, the most common adverse reactions (all grades) observed in patients treated with Ramucirumab plus paclitaxel at a rate of ≥30% and ≥2% higher than placebo plus paclitaxel were fatigue, neutropenia, diarrhea, and epistaxis. The most common serious adverse events with Ramucirumab plus paclitaxel were neutropenia (3.7%) and febrile neutropenia (2.4%); 19% of patients treated with Ramucirumab plus paclitaxel received granulocyte colony-stimulating factors. Adverse reactions resulting in discontinuation of any component of the Ramucirumab plus paclitaxel combination in 2% or more patients in Study 2 were neutropenia (4%) and thrombocytopenia (3%). Clinically relevant adverse reactions reported in ≥1% and <5% of the Ramucirumab plus paclitaxel treated patients in Study 2 were sepsis (3.1% Ramucirumab plus paclitaxel versus 1.8% placebo plus paclitaxel) and gastrointestinal perforations (1.2% Ramucirumab plus paclitaxel versus 0.3% for placebo plus paclitaxel). - Study 3 was a multinational, randomized, double-blind study conducted in patients with NSCLC with disease progression on or after one platinum-based therapy for locally advanced or metastatic disease. Patients received either Ramucirumab 10 mg/kg intravenously plus docetaxel 75 mg/m2 intravenously every 3 weeks or placebo plus docetaxel 75 mg/m2 intravenously every 3 weeks. Due to an increased incidence of neutropenia and febrile neutropenia in patients enrolled in East Asian sites, Study 3 was amended and 24 patients (11 Ramucirumab plus docetaxel, 13 placebo plus docetaxel) at East Asian sites received a starting dose of docetaxel at 60 mg/m2 every 3 weeks. - Study 3 excluded patients with an ECOG PS of 2 or greater, bilirubin greater than the upper limit of normal (ULN), uncontrolled hypertension, major surgery within 28 days, radiographic evidence of major airway or blood vessel invasion by cancer, radiographic evidence of intra-tumor cavitation, or gross hemoptysis within the preceding 2 months, and patients receiving therapeutic anticoagulation or chronic anti-platelet therapy other than once daily aspirin. The study also excluded patients whose only prior treatment for advanced NSCLC was a tyrosine kinase (epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase ALK) inhibitor). - The data described below reflect exposure to Ramucirumab plus docetaxel in 627 patients in Study 3. Demographics and baseline characteristics were similar between treatment arms. Median age was 62 years; 67% of patients were men; 84% were White and 12% were Asian; 33% had ECOG PS 0; 74% had non-squamous histology and 25% had squamous histology. Patients received a median of 4.5 doses of Ramucirumab; the median duration of exposure was 3.5 months, and 195 (31% of 627) patients received Ramucirumab for at least six months. - In Study 3, the most common adverse reactions (all grades) observed in Ramucirumab plus docetaxel-treated patients at a rate of ≥30% and ≥2% higher than placebo plus docetaxel were neutropenia, fatigue/asthenia, and stomatitis/mucosal inflammation. Treatment discontinuation due to adverse reactions occurred more frequently in Ramucirumab plus docetaxel-treated patients (9%) than in placebo plus docetaxel-treated patients (5%). The most common adverse events leading to treatment discontinuation of Ramucirumab were infusion-related reaction (0.5%) and epistaxis (0.3%). For patients with non-squamous histology, the overall incidence of pulmonary hemorrhage was 7% and the incidence of ≥Grade 3 pulmonary hemorrhage was 1% for Ramucirumab plus docetaxel compared to 6% overall incidence and 1% for ≥Grade 3 pulmonary hemorrhage for placebo plus docetaxel. For patients with squamous histology, the overall incidence of pulmonary hemorrhage was 10% and the incidence of ≥Grade 3 pulmonary hemorrhage was 2% for Ramucirumab plus docetaxel compared to 12% overall incidence and 2% for ≥Grade 3 pulmonary hemorrhage for placebo plus docetaxel. - The most common serious adverse events with Ramucirumab plus docetaxel were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in Ramucirumab plus docetaxel-treated patients versus 37% in patients who received placebo plus docetaxel. In patients ≥65 years, there were 18 (8%) deaths on treatment or within 30 days of discontinuation for Ramucirumab plus docetaxel and 9 (4%) deaths for placebo plus docetaxel. In patients <65 years, there were 13 (3%) deaths on treatment or within 30 days of discontinuation for Ramucirumab plus docetaxel and 26 (6%) deaths for placebo plus docetaxel. Clinically relevant adverse drug reactions reported in ≥1% and <5% of the Ramucirumab plus docetaxel-treated patients in Study 3 were hyponatremia (4.8% Ramucirumab plus docetaxel versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% Ramucirumab plus docetaxel versus 0.8% placebo plus docetaxel). ## Postmarketing Experience There is limited information regarding Ramucirumab Postmarketing Experience in the drug label. # Drug Interactions - No pharmacokinetic (PK) interactions were observed between ramucirumab and paclitaxel or between ramucirumab and docetaxel. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C ### Risk Summary - Based on its mechanism of action, Ramucirumab may cause fetal harm. Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no adequate or well controlled studies of ramucirumab in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. ### Animal Data - No animal studies have been specifically conducted to evaluate the effect of ramucirumab on reproduction and fetal development. In mice, loss of the VEGFR2 gene resulted in embryofetal death and these fetuses lacked organized blood vessels and blood islands in the yolk sac. In other models, VEGFR2 signaling was associated with development and maintenance of endometrial and placental vascular function, successful blastocyst implantation, maternal and feto-placental vascular differentiation, and development during early pregnancy in rodents and non-human primates. Disruption of VEGF signaling has also been associated with developmental anomalies including poor development of the cranial region, forelimbs, forebrain, heart, and blood vessels. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ramucirumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Ramucirumab during labor and delivery. ### Nursing Mothers - It is not known whether Ramucirumab is excreted in human milk. No studies have been conducted to assess Ramucirumab s impact on milk production or its presence in breast milk. Human IgG is excreted in human milk, but published data suggests that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted in human milk and because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, 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 Ramucirumab in pediatric patients have not been established. In animal studies, effects on epiphyseal growth plates were identified. In cynomolgus monkeys, anatomical pathology revealed adverse effects on the epiphyseal growth plate (thickening and osteochondropathy) at all doses tested (5-50 mg/kg). Ramucirumab exposure at the lowest weekly dose tested in the cynomolgus monkey was 0.2 times the exposure in humans at the recommended dose of ramucirumab as a single agent. ### Geriatic Use - Of the 563 Ramucirumab-treated patients in two randomized gastric cancer clinical studies, 36% were 65 and over, while 7% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. - Of the 1253 patients in Study 3, 455 (36%) were 65 and over and 84 (7%) were 75 and over. Of the 627 patients who received Ramucirumab plus docetaxel in Study 3, 237 (38%) were 65 and over, while 45 (7%) were 75 and over. In an exploratory subgroup analysis of Study 3, the hazard ratio for overall survival in patients less than 65 years old was 0.74 (95% CI: 0.62, 0.87) and in patients 65 years or older was 1.10 (95% CI: 0.89, 1.36). ### Gender There is no FDA guidance on the use of Ramucirumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Ramucirumab with respect to specific racial populations. ### Renal Impairment - No dose adjustment is recommended for patients with renal impairment based on population PK analysis. ### Hepatic Impairment - No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin within upper limit of normal and aspartate aminotransferase AST >ULN or total bilirubin >1.0-1.5 times ULN and any AST) based on population PK analysis. Clinical deterioration was reported in patients with Child-Pugh B or C cirrhosis who received single-agent Ramucirumab. ### Females of Reproductive Potential and Males ### Fertility - Advise females of reproductive potential that Ramucirumab may impair fertility. ### Contraception - Based on its mechanism of action, Ramucirumab may cause fetal harm. Advise females of reproductive potential to avoid getting pregnant while receiving Ramucirumab and for at least 3 months after the last dose of Ramucirumab. ### Immunocompromised Patients There is no FDA guidance one the use of Ramucirumab in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Ramucirumab Administration in the drug label. ### Monitoring There is limited information regarding Ramucirumab Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Ramucirumab and IV administrations. # Overdosage - There are no data on overdose in humans. Ramucirumab was administered at doses up to 10 mg/kg every two weeks without reaching a maximum tolerated dose. # Pharmacology ## Mechanism of Action Ramucirumab is a vascular endothelial growth factor receptor 2 antagonist that specifically binds VEGF Receptor 2 and blocks binding of VEGFR ligands, VEGF-A, VEGF-C, and VEGF-D. As a result, ramucirumab inhibits ligand-stimulated activation of VEGF Receptor 2, thereby inhibiting ligand-induced proliferation, and migration of human endothelial cells. Ramucirumab inhibited angiogenesis in an in vivo animal model. ## Structure There is limited information regarding Ramucirumab Structure in the drug label. ## Pharmacodynamics There is limited information regarding Ramucirumab Pharmacodynamics in the drug label. ## Pharmacokinetics - With the dosing regimen of 8 mg/kg every 2 weeks in patients with advanced gastric or gastro-esophageal junction cancer, the geometric means of the minimum ramucirumab concentrations (Cmin) were 50 μg/mL (6-228 μg/mL) after the third dose and 74 μg/mL (14-234 μg/mL) after the sixth dose. Similar Cmin values of ramucirumab were observed when ramucirumab was administered with paclitaxel. Based on a population PK analysis, the mean (% coefficient of variation ) volume of distribution at steady state for ramucirumab was 5.5 L (14%), the mean clearance was 0.014 L/hour (30%), and the mean elimination half-life was 15 days (24%). - With the dosing regimen of 10 mg/kg every 21 days in patients with NSCLC, the geometric means (ranges) of the minimum ramucirumab concentrations (Cmin) were 28 μg/mL (3-108 μg/mL) after the second dose and 38 μg/mL (3-128 μg/mL) after the fourth dose. Based on a population PK analysis in NSCLC patients, the mean (% coefficient of variation ) clearance for ramucirumab was 0.015 L/hour (27%), the mean volume of distribution at steady state (Vss) was 7.1 L (13%), and the mean elimination half-life was 23 days (24%). ### Specific Populations - Age, sex, and race had no clinically meaningful effect on the PK of ramucirumab based on a population PK analysis. - Renal Impairment: The effect of renal impairment on the average concentration of ramucirumab at steady state (Css) was evaluated in patients with mild (calculated creatinine clearance CLcr 60-89 mL/min, n=368), moderate (CLcr 30-59 mL/min, n=160) or severe (CLcr 15 -29 mL/min, n=4) renal impairment compared to patients with normal renal function (CLcr ≥90 mL/min, n=360) in a population PK analysis. No clinically meaningful differences in the average Css of ramucirumab were observed between patients with renal impairment and patients with normal renal function. - Hepatic Impairment: The effect of hepatic impairment on the average Css of ramucirumab was evaluated in patients with mild (total bilirubin within upper limit of normal and AST>ULN or total bilirubin >1.0-1.5 times ULN and any AST, n=143) compared to patients with normal hepatic function (total bilirubin and AST ≤ULN, n=735) in a population PK analysis. No clinically meaningful differences in the average Css of ramucirumab were found between patients with mild hepatic impairment and patients with normal hepatic function. No PK data were available from patients with moderate (total bilirubin >1.5-3.0 times ULN and any AST) or severe hepatic dysfunction (total bilirubin >3.0 times ULN and any AST). - Drug Interaction Studies No clinically meaningful changes in paclitaxel exposure or ramucirumab exposure were observed when Ramucirumab 8 mg/kg and paclitaxel 80 mg/m2 were co-administered in patients with solid tumors. No clinically meaningful changes in docetaxel exposure were observed when Ramucirumab 10 mg/kg and docetaxel 75 mg/m2 were co-administered in patients with solid tumors. Ramucirumab exposure appeared to be comparable regardless of concomitant docetaxel based on cross study comparisons in patients with solid tumors. - No clinically meaningful changes in paclitaxel exposure or ramucirumab exposure were observed when Ramucirumab 8 mg/kg and paclitaxel 80 mg/m2 were co-administered in patients with solid tumors. - No clinically meaningful changes in docetaxel exposure were observed when Ramucirumab 10 mg/kg and docetaxel 75 mg/m2 were co-administered in patients with solid tumors. Ramucirumab exposure appeared to be comparable regardless of concomitant docetaxel based on cross study comparisons in patients with solid tumors. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility - No animal studies have been performed to test ramucirumab for potential carcinogenicity or genotoxicity. - Inhibition of VEGFR2 signaling in animal models was shown to result in changes to hormone levels critical for pregnancy, and, in monkeys, an increased duration of the follicular cycle. In a 39 week animal study, female monkeys treated with ramucirumab showed dose dependent increases in follicular mineralization of the ovary. ### Animal Toxicology and/or Pharmacology - Adverse effects in the kidney (glomerulonephritis) occurred with doses of 16-50 mg/kg (0.7-5.5 times the exposure in humans at the recommended dose of ramucirumab as a single agent). - A single dose of ramucirumab resulting in an exposure approximately 10 times the exposure in humans at the recommended dose of ramucirumab as a single agent did not significantly impair wound healing in monkeys using a full-thickness incisional model. # Clinical Studies ### Gastric Cancer - Study 1 was a multinational, randomized, double-blind, multicenter study of Ramucirumab plus best supportive care (BSC) versus placebo plus BSC that randomized (2:1) 355 patients with locally advanced or metastatic gastric cancer (including adenocarcinoma of the gastro-esophageal junction ) who previously received platinum- or fluoropyrimidine-containing chemotherapy. The major efficacy outcome measure was overall survival and the supportive efficacy outcome measure was progression-free survival. Patients were required to have experienced disease progression either within 4 months after the last dose of first-line therapy for locally advanced or metastatic disease or within 6 months after the last dose of adjuvant therapy. Patients were also required to have ECOG PS of 0 or 1. Patients received either an intravenous infusion of Ramucirumab 8 mg/kg (n=238) or placebo solution (n=117) every 2 weeks. Randomization was stratified by weight loss over the prior 3 months (≥10% versus <10%), geographic region, and location of the primary tumor (gastric versus GEJ). - Demographic and baseline characteristics were similar between treatment arms. Median age was 60 years; 70% of patients were men; 77% were White, 16% Asian; the ECOG PS was 0 for 28% of patients and 1 for 72% of patients; 91% of patients had measurable disease; 75% of patients had gastric cancer; and 25% had adenocarcinoma of the GEJ. The majority of patients (85%) experienced disease progression during or following first-line therapy for metastatic disease. Prior chemotherapy for gastric cancer consisted of platinum/fluoropyrimidine combination therapy (81%), fluoropyrimidine-containing regimens without platinum (15%), and platinum-containing regimens without fluoropyrimidine (4%). In Study 1, patients received a median of 4 doses (range 1-34) of Ramucirumab or a median of 3 doses (range 1-30) of placebo. - Overall survival and progression-free survival were statistically significantly improved in patients randomized to receive Ramucirumab as compared to patients randomized to receive placebo. Efficacy results are shown in TABLE 5 and FIGURE 1. - Study 2 was a multinational, randomized, double-blind study of Ramucirumab plus paclitaxel versus placebo plus paclitaxel that randomized (1:1) 665 patients with locally advanced or metastatic gastric cancer (including adenocarcinoma of the gastro-esophageal junction) who previously received platinum- and fluoropyrimidine-containing chemotherapy. Patients were required to have experienced disease progression during, or within 4 months after the last dose of first-line therapy. Patients were also required to have ECOG PS of 0 or 1. Randomization was stratified by geographic region, time to progression from the start of first-line therapy (<6 months versus ≥6 months) and disease measurability. - Patients were randomized to receive either Ramucirumab 8 mg/kg (n=330) or placebo (n=335) as an intravenous infusion every 2 weeks (on days 1 and 15) of each 28-day cycle. Patients in both arms received paclitaxel 80 mg/m2 by intravenous infusion on days 1, 8, and 15 of each 28-day cycle. Prior to administration of each dose of paclitaxel, patients were required to have adequate hematopoietic and hepatic function. The paclitaxel dose was permanently reduced in increments of 10 mg/m2 for a maximum of two dose reductions for Grade 4 hematologic toxicity or Grade 3 paclitaxel-related non-hematologic toxicity. The major efficacy outcome measure was overall survival and the supportive efficacy outcome measures were progression-free survival and objective response rate. - Demographics and baseline characteristics were similar between treatment arms including the following: Median age was 61 years; 71% of patients were men; 61% were White, 35% Asian; the ECOG PS was 0 for 39% of patients, 1 for 61% of patients; 78% of patients had measurable disease; 79% of patients had gastric cancer; and 21% had adenocarcinoma of the GEJ. Two-thirds of the patients experienced disease progression while on first-line therapy (67%) and 25% of patients received an anthracycline in combination with platinum/fluoropyrimidine combination therapy. - Overall survival, progression-free survival, and objective response rate were statistically significantly improved in patients randomized to receive Ramucirumab plus paclitaxel compared to patients randomized to receive placebo plus paclitaxel. Efficacy results are shown in TABLE 6 and FIGURE 2. ### Non-Small Cell Lung Cancer Study 3 was a multinational, randomized, double-blind, study of Ramucirumab plus docetaxel versus placebo plus docetaxel, that randomized (1:1) 1253 patients with NSCLC with disease progression on or after one platinum-based therapy for locally advanced or metastatic disease. The major efficacy outcome measure was overall survival and the supportive efficacy outcome measures were progression-free survival and objective response rate. Patients were also required to have ECOG PS 0 or 1. Patients were randomized to receive either Ramucirumab at 10 mg/kg or placebo by intravenous infusion, in combination with docetaxel at 75 mg/m2 every 21 days. Sites in East Asia administered a reduced dose of docetaxel at 60 mg/m2 every 21 days. Patients who discontinued combination therapy because of an adverse event attributed to either Ramucirumab placebo or docetaxel were permitted to continue monotherapy with the other treatment component until disease progression or intolerable toxicity. Randomization was stratified by geographic region, gender, prior maintenance therapy, and ECOG PS. Demographics and baseline characteristics were similar between treatment arms. Median age was 62 years; 67% of patients were men; 82% were White and 13% were Asian; 32% had ECOG PS 0; 73% had nonsquamous histology and 26% had squamous histology. In addition to platinum chemotherapy (99%), the most common prior therapies were pemetrexed (38%), gemcitabine (25%), taxane (24%), and bevacizumab (14%). Twenty-two percent of patients received prior maintenance therapy. Tumor EGFR status was unknown for the majority of patients (65%). Where tumor EGFR status was known (n=445), 7.5% were positive for EGFR mutation (n=33). No data were collected regarding tumor ALK rearrangement status. Overall survival and progression-free survival were statistically significantly improved in patients randomized to receive Ramucirumab plus docetaxel compared to patients randomized to receive placebo plus docetaxel. Objective response rate (complete response + partial response) was 23% (95% CI: 20, 26) for Ramucirumab plus docetaxel and 14% (95% CI: 11, 17) for placebo plus docetaxel, p-value of <0.001. Efficacy results are shown in TABLE 7 and FIGURE 3. # How Supplied Ramucirumab is supplied in single-dose vials as a sterile, preservative-free solution. - NDC 0002-7669-01: 100 mg/10 mL (10 mg/mL), individually packaged in a carton - NDC 0002-7678-01: 500 mg/50 mL (10 mg/mL), individually packaged in a carton ## Storage - Store vials in a refrigerator at 2°C to 8°C (36°F to 46°F) until time of use. Keep the vial in the outer carton in order to protect from light. Do not freeze or shake the vial. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Advise patients: - That CYRAMZA can cause severe bleeding. Advise patients to contact their health care provider for bleeding or symptoms of bleeding including lightheadedness. - Of increased risk of an arterial thromboembolic event. - To undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms. - To notify their health care provider for severe diarrhea, vomiting, or severe abdominal pain. - That CYRAMZA has the potential to impair wound healing. Instruct patients not to undergo surgery without first discussing this potential risk with their health care provider. - Of the potential risk for maintaining pregnancy, risk to the fetus, or risk to postnatal development during and following treatment with CYRAMZA and the need to avoid getting pregnant, including use of adequate contraception, for at least 3 months following the last dose of CYRAMZA. - To discontinue nursing during CYRAMZA treatment. # Precautions with Alcohol Alcohol-Ramucirumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Cyramza® # Look-Alike Drug Names There is limited information regarding Ramucirumab Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Ramucirumab 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. # Black Box Warning # Overview Ramucirumab is a monoclonal antibody that is FDA approved for the treatment of advanced or metastatic, gastric or gastro-esophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy and metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypertension and diarrhea. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Recommended Dose and Schedule - The recommended dose of Ramucirumab either as a single agent or in combination with weekly paclitaxel is 8 mg/kg every 2 weeks administered as an intravenous infusion over 60 minutes. Continue Ramucirumab until disease progression or unacceptable toxicity. - When given in combination, administer Ramucirumab prior to administration of paclitaxel. - The recommended dose of Ramucirumab is 10 mg/kg administered by intravenous infusion over approximately 60 minutes on day 1 of a 21-day cycle prior to docetaxel infusion. Continue Ramucirumab until disease progression or unacceptable toxicity. ### Premedication - Prior to each Ramucirumab infusion, premedicate all patients with an intravenous histamine H1 antagonist (e.g., diphenhydramine hydrochloride). - For patients who have experienced a Grade 1 or 2 infusion-related reaction, also premedicate with dexamethasone (or equivalent) and acetaminophen prior to each Ramucirumab infusion. ### Dose Modifications - Reduce the infusion rate of Ramucirumab by 50% for Grade 1 or 2 IRRs. - Permanently discontinue Ramucirumab for Grade 3 or 4 IRRs. - Interrupt Ramucirumab for severe hypertension until controlled with medical management. - Permanently discontinue Ramucirumab for severe hypertension that cannot be controlled with antihypertensive therapy - Interrupt Ramucirumab for urine protein levels ≥2 g/24 hours. Reinitiate treatment at a reduced dose (see TABLE 1) once the urine protein level returns to <2 g/24 hours. If the protein level ≥2 g/24 hours reoccurs, interrupt Ramucirumab and reduce the dose (see TABLE 1) once the urine protein level returns to <2 g/24 hours. - Permanently discontinue Ramucirumab for urine protein level >3 g/24 hours or in the setting of nephrotic syndrome. - Interrupt Ramucirumab prior to scheduled surgery until the wound is fully healed. - Permanently discontinue Ramucirumab. ### Preparation for Administration Inspect vial contents for particulate matter and discoloration prior to dilution. Discard the vial, if particulate matter or discolorations are identified. Store vials in a refrigerator at 2°C to 8°C (36°F to 46°F) until time of use. Keep the vial in the outer carton in order to protect from light. - Calculate the dose and the required volume of Ramucirumab needed to prepare the infusion solution. Vials contain either 100 mg/10 mL or 500 mg/50 mL at a concentration of 10 mg/mL solution of Ramucirumab. - Withdraw the required volume of Ramucirumab and further dilute with only 0.9% Sodium Chloride Injection in an intravenous infusion container to a final volume of 250 mL. Do not use dextrose containing solutions. - Gently invert the container to ensure adequate mixing. - Do not freeze or shake the infusion solution. DO NOT dilute with other solutions or co-infuse with other electrolytes or medications. - Store diluted infusion for no more than 24 hours at 2°C to 8°C (36°F to 46°F) or 4 hours at room temperature (below 25°C [77°F]). - Discard vial with any unused portion of Ramucirumab. ### Administration - Visually inspect the diluted solution for particulate matter and discoloration prior to administration. If particulate matter or discolorations are identified, discard the solution. - Administer diluted Ramucirumab infusion via infusion pump over 60 minutes through a separate infusion line. Use of a protein sparing 0.22 micron filter is recommended. Flush the line with sterile sodium chloride (0.9%) solution for injection at the end of the infusion. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Ramucirumab in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Ramucirumab in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Ramucirumab 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 Ramucirumab in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Ramucirumab in pediatric patients. # Contraindications None. # Warnings ### Hemorrhage - Ramucirumab increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, the incidence of severe bleeding was 3.4% for Ramucirumab and 2.6% for placebo. In Study 2, the incidence of severe bleeding was 4.3% for Ramucirumab plus paclitaxel and 2.4% for placebo plus paclitaxel. - Patients with gastric cancer receiving nonsteroidal anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Studies 1 and 2; therefore, the risk of gastric hemorrhage in Ramucirumab-treated patients with gastric tumors receiving NSAIDs is unknown. Permanently discontinue Ramucirumab in patients who experience severe bleeding. - In Study 3, the incidence of severe bleeding was 2.4% for Ramucirumab plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDS or other anti-platelet therapy other than once daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from Study 3; therefore the risk of pulmonary hemorrhage in these groups of patients is unknown. ### Arterial Thromboembolic Events - Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received Ramucirumab as a single agent for gastric cancer in Study 1. Permanently discontinue Ramucirumab in patients who experience a severe ATE. ### Hypertension - An increased incidence of severe hypertension occurred in patients receiving Ramucirumab as a single agent (8%) as compared to placebo (3%) and in patients receiving Ramucirumab plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%) and in patients receiving Ramucirumab plus docetaxel (6%) as compared to placebo plus docetaxel (2%). - Control hypertension prior to initiating treatment with Ramucirumab. Monitor blood pressure every two weeks or more frequently as indicated during treatment. - Temporarily suspend Ramucirumab for severe hypertension until medically controlled. Permanently discontinue Ramucirumab if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy. ### Infusion-Related Reactions - Prior to the institution of premedication recommendations across clinical trials of Ramucirumab IRRs occurred in 6 out of 37 patients (16%), including two severe events. The majority of IRRs across trials occurred during or following a first or second Ramucirumab infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. - Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue Ramucirumab for Grade 3 or 4 IRRs. ### Gastrointestinal Perforations - Ramucirumab is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received Ramucirumab as a single agent in clinical trials experienced gastrointestinal perforation. In Study 2, the incidence of gastrointestinal perforations was also increased in patients that received Ramucirumab plus paclitaxel (1.2%) as compared to patients receiving placebo plus paclitaxel (0.3%). In Study 3, the incidence of gastrointestinal perforation was 1% for Ramucirumab plus docetaxel and 0.3% for placebo plus docetaxel. Permanently discontinue Ramucirumab in patients who experience a gastrointestinal perforation. ### Impaired Wound Healing - Ramucirumab has not been studied in patients with serious or non-healing wounds. Ramucirumab is an antiangiogenic therapy with the potential to adversely affect wound healing. - Withhold Ramucirumab prior to surgery. Resume following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue Ramucirumab until the wound is fully healed. ### Clinical Deterioration in Patients with Child-Pugh B or C Cirrhosis - Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome was reported in patients with Child-Pugh B or C cirrhosis who received single-agent Ramucirumab. Use Ramucirumab in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration. ### Reversible Posterior Leukoencephalopathy Syndrome - Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported with a rate of <0.1% in clinical studies with Ramucirumab Confirm the diagnosis of RPLS with MRI and discontinue Ramucirumab in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death # Adverse Reactions ## Clinical Trials Experience The following adverse drug reactions are discussed in greater detail in other sections of the label: - Hemorrhage - Arterial Thromboembolic Events - Hypertension - Infusion-Related Reactions - Gastrointestinal Perforation - Impaired Wound Healing - Patients with Child-Pugh B or C Cirrhosis - Reversible Posterior Leukoencephalopathy Syndrome ## 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. - Safety data are presented from two randomized, placebo controlled clinical trials in which patients received Ramucirumab: Study 1, a randomized (2:1), double-blind, clinical trial in which 351 patients received either Ramucirumab 8 mg/kg intravenously every two weeks or placebo every two weeks and Study 2, a double-blind, randomized (1:1) clinical trial in which 656 patients received paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 28-day cycle plus either Ramucirumab 8 mg/kg intravenously every two weeks or placebo every two weeks. Both trials excluded patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 or greater, uncontrolled hypertension, major surgery within 28 days, or patients receiving chronic anti-platelet therapy other than once daily aspirin. Study 1 excluded patients with bilirubin ≥1.5 mg/dL and Study 2 excluded patients with bilirubin >1.5 times the upper limit of normal. - Among 236 patients who received Ramucirumab (safety population) in Study 1, median age was 60 years, 28% were women, 76% were White, and 16% were Asian. Patients in Study 1 received a median of 4 doses of Ramucirumab; the median duration of exposure was 8 weeks, and 32 (14% of 236) patients received Ramucirumab for at least six months. - In Study 1, the most common adverse reactions (all grades) observed in Ramucirumab-treated patients at a rate of ≥10% and ≥2% higher than placebo were hypertension and diarrhea. The most common serious adverse events with Ramucirumab were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of Ramucirumab-treated patients versus 8.7% of patients who received placebo. - Clinically relevant adverse reactions reported in ≥1% and <5% of Ramucirumab-treated patients in Study 1 were: neutropenia (4.7% Ramucirumab versus 0.9% placebo), epistaxis (4.7% Ramucirumab versus 0.9% placebo), rash (4.2¢ Ramucirumab versus 1.7% placebo), intestinal obstruction (2.1% Ramucirumab versus 0% placebo), and arterial thromboembolic events (1.7% Ramucirumab versus 0% placebo). - Across clinical trials of Ramucirumab administered as a single agent, clinically relevant adverse reactions (including Grade ≥3) reported in Ramucirumab-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions. - In Study 1, according to laboratory assessment, 8% of Ramucirumab-treated patients developed proteinuria versus 3% of placebo-treated patients. Two patients discontinued Ramucirumab due to proteinuria. The rate of gastrointestinal perforation in Study 1 was 0.8% and the rate of infusion-related reactions was 0.4%. - Among 327 patients who received Ramucirumab (safety population) in Study 2, median age was 60 years, 31% were women, 63% were White, and 33% were Asian. Patients in Study 2 received a median of 9 doses of Ramucirumab; the median duration of exposure was 18 weeks, and 93 (28% of 327) patients received Ramucirumab for at least six months. - In Study 2, the most common adverse reactions (all grades) observed in patients treated with Ramucirumab plus paclitaxel at a rate of ≥30% and ≥2% higher than placebo plus paclitaxel were fatigue, neutropenia, diarrhea, and epistaxis. The most common serious adverse events with Ramucirumab plus paclitaxel were neutropenia (3.7%) and febrile neutropenia (2.4%); 19% of patients treated with Ramucirumab plus paclitaxel received granulocyte colony-stimulating factors. Adverse reactions resulting in discontinuation of any component of the Ramucirumab plus paclitaxel combination in 2% or more patients in Study 2 were neutropenia (4%) and thrombocytopenia (3%). Clinically relevant adverse reactions reported in ≥1% and <5% of the Ramucirumab plus paclitaxel treated patients in Study 2 were sepsis (3.1% Ramucirumab plus paclitaxel versus 1.8% placebo plus paclitaxel) and gastrointestinal perforations (1.2% Ramucirumab plus paclitaxel versus 0.3% for placebo plus paclitaxel). - Study 3 was a multinational, randomized, double-blind study conducted in patients with NSCLC with disease progression on or after one platinum-based therapy for locally advanced or metastatic disease. Patients received either Ramucirumab 10 mg/kg intravenously plus docetaxel 75 mg/m2 intravenously every 3 weeks or placebo plus docetaxel 75 mg/m2 intravenously every 3 weeks. Due to an increased incidence of neutropenia and febrile neutropenia in patients enrolled in East Asian sites, Study 3 was amended and 24 patients (11 Ramucirumab plus docetaxel, 13 placebo plus docetaxel) at East Asian sites received a starting dose of docetaxel at 60 mg/m2 every 3 weeks. - Study 3 excluded patients with an ECOG PS of 2 or greater, bilirubin greater than the upper limit of normal (ULN), uncontrolled hypertension, major surgery within 28 days, radiographic evidence of major airway or blood vessel invasion by cancer, radiographic evidence of intra-tumor cavitation, or gross hemoptysis within the preceding 2 months, and patients receiving therapeutic anticoagulation or chronic anti-platelet therapy other than once daily aspirin. The study also excluded patients whose only prior treatment for advanced NSCLC was a tyrosine kinase (epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase ALK) inhibitor). - The data described below reflect exposure to Ramucirumab plus docetaxel in 627 patients in Study 3. Demographics and baseline characteristics were similar between treatment arms. Median age was 62 years; 67% of patients were men; 84% were White and 12% were Asian; 33% had ECOG PS 0; 74% had non-squamous histology and 25% had squamous histology. Patients received a median of 4.5 doses of Ramucirumab; the median duration of exposure was 3.5 months, and 195 (31% of 627) patients received Ramucirumab for at least six months. - In Study 3, the most common adverse reactions (all grades) observed in Ramucirumab plus docetaxel-treated patients at a rate of ≥30% and ≥2% higher than placebo plus docetaxel were neutropenia, fatigue/asthenia, and stomatitis/mucosal inflammation. Treatment discontinuation due to adverse reactions occurred more frequently in Ramucirumab plus docetaxel-treated patients (9%) than in placebo plus docetaxel-treated patients (5%). The most common adverse events leading to treatment discontinuation of Ramucirumab were infusion-related reaction (0.5%) and epistaxis (0.3%). For patients with non-squamous histology, the overall incidence of pulmonary hemorrhage was 7% and the incidence of ≥Grade 3 pulmonary hemorrhage was 1% for Ramucirumab plus docetaxel compared to 6% overall incidence and 1% for ≥Grade 3 pulmonary hemorrhage for placebo plus docetaxel. For patients with squamous histology, the overall incidence of pulmonary hemorrhage was 10% and the incidence of ≥Grade 3 pulmonary hemorrhage was 2% for Ramucirumab plus docetaxel compared to 12% overall incidence and 2% for ≥Grade 3 pulmonary hemorrhage for placebo plus docetaxel. - The most common serious adverse events with Ramucirumab plus docetaxel were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in Ramucirumab plus docetaxel-treated patients versus 37% in patients who received placebo plus docetaxel. In patients ≥65 years, there were 18 (8%) deaths on treatment or within 30 days of discontinuation for Ramucirumab plus docetaxel and 9 (4%) deaths for placebo plus docetaxel. In patients <65 years, there were 13 (3%) deaths on treatment or within 30 days of discontinuation for Ramucirumab plus docetaxel and 26 (6%) deaths for placebo plus docetaxel. Clinically relevant adverse drug reactions reported in ≥1% and <5% of the Ramucirumab plus docetaxel-treated patients in Study 3 were hyponatremia (4.8% Ramucirumab plus docetaxel versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% Ramucirumab plus docetaxel versus 0.8% placebo plus docetaxel). ## Postmarketing Experience There is limited information regarding Ramucirumab Postmarketing Experience in the drug label. # Drug Interactions - No pharmacokinetic (PK) interactions were observed between ramucirumab and paclitaxel or between ramucirumab and docetaxel. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C ### Risk Summary - Based on its mechanism of action, Ramucirumab may cause fetal harm. Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no adequate or well controlled studies of ramucirumab in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. ### Animal Data - No animal studies have been specifically conducted to evaluate the effect of ramucirumab on reproduction and fetal development. In mice, loss of the VEGFR2 gene resulted in embryofetal death and these fetuses lacked organized blood vessels and blood islands in the yolk sac. In other models, VEGFR2 signaling was associated with development and maintenance of endometrial and placental vascular function, successful blastocyst implantation, maternal and feto-placental vascular differentiation, and development during early pregnancy in rodents and non-human primates. Disruption of VEGF signaling has also been associated with developmental anomalies including poor development of the cranial region, forelimbs, forebrain, heart, and blood vessels. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ramucirumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Ramucirumab during labor and delivery. ### Nursing Mothers - It is not known whether Ramucirumab is excreted in human milk. No studies have been conducted to assess Ramucirumab s impact on milk production or its presence in breast milk. Human IgG is excreted in human milk, but published data suggests that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted in human milk and because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, 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 Ramucirumab in pediatric patients have not been established. In animal studies, effects on epiphyseal growth plates were identified. In cynomolgus monkeys, anatomical pathology revealed adverse effects on the epiphyseal growth plate (thickening and osteochondropathy) at all doses tested (5-50 mg/kg). Ramucirumab exposure at the lowest weekly dose tested in the cynomolgus monkey was 0.2 times the exposure in humans at the recommended dose of ramucirumab as a single agent. ### Geriatic Use - Of the 563 Ramucirumab-treated patients in two randomized gastric cancer clinical studies, 36% were 65 and over, while 7% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. - Of the 1253 patients in Study 3, 455 (36%) were 65 and over and 84 (7%) were 75 and over. Of the 627 patients who received Ramucirumab plus docetaxel in Study 3, 237 (38%) were 65 and over, while 45 (7%) were 75 and over. In an exploratory subgroup analysis of Study 3, the hazard ratio for overall survival in patients less than 65 years old was 0.74 (95% CI: 0.62, 0.87) and in patients 65 years or older was 1.10 (95% CI: 0.89, 1.36). ### Gender There is no FDA guidance on the use of Ramucirumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Ramucirumab with respect to specific racial populations. ### Renal Impairment - No dose adjustment is recommended for patients with renal impairment based on population PK analysis. ### Hepatic Impairment - No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin within upper limit of normal [ULN] and aspartate aminotransferase AST >ULN or total bilirubin >1.0-1.5 times ULN and any AST) based on population PK analysis. Clinical deterioration was reported in patients with Child-Pugh B or C cirrhosis who received single-agent Ramucirumab. ### Females of Reproductive Potential and Males ### Fertility - Advise females of reproductive potential that Ramucirumab may impair fertility. ### Contraception - Based on its mechanism of action, Ramucirumab may cause fetal harm. Advise females of reproductive potential to avoid getting pregnant while receiving Ramucirumab and for at least 3 months after the last dose of Ramucirumab. ### Immunocompromised Patients There is no FDA guidance one the use of Ramucirumab in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Ramucirumab Administration in the drug label. ### Monitoring There is limited information regarding Ramucirumab Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Ramucirumab and IV administrations. # Overdosage - There are no data on overdose in humans. Ramucirumab was administered at doses up to 10 mg/kg every two weeks without reaching a maximum tolerated dose. # Pharmacology ## Mechanism of Action Ramucirumab is a vascular endothelial growth factor receptor 2 antagonist that specifically binds VEGF Receptor 2 and blocks binding of VEGFR ligands, VEGF-A, VEGF-C, and VEGF-D. As a result, ramucirumab inhibits ligand-stimulated activation of VEGF Receptor 2, thereby inhibiting ligand-induced proliferation, and migration of human endothelial cells. Ramucirumab inhibited angiogenesis in an in vivo animal model. ## Structure There is limited information regarding Ramucirumab Structure in the drug label. ## Pharmacodynamics There is limited information regarding Ramucirumab Pharmacodynamics in the drug label. ## Pharmacokinetics - With the dosing regimen of 8 mg/kg every 2 weeks in patients with advanced gastric or gastro-esophageal junction cancer, the geometric means of the minimum ramucirumab concentrations (Cmin) were 50 μg/mL (6-228 μg/mL) after the third dose and 74 μg/mL (14-234 μg/mL) after the sixth dose. Similar Cmin values of ramucirumab were observed when ramucirumab was administered with paclitaxel. Based on a population PK analysis, the mean (% coefficient of variation [CV%]) volume of distribution at steady state for ramucirumab was 5.5 L (14%), the mean clearance was 0.014 L/hour (30%), and the mean elimination half-life was 15 days (24%). - With the dosing regimen of 10 mg/kg every 21 days in patients with NSCLC, the geometric means (ranges) of the minimum ramucirumab concentrations (Cmin) were 28 μg/mL (3-108 μg/mL) after the second dose and 38 μg/mL (3-128 μg/mL) after the fourth dose. Based on a population PK analysis in NSCLC patients, the mean (% coefficient of variation [CV%]) clearance for ramucirumab was 0.015 L/hour (27%), the mean volume of distribution at steady state (Vss) was 7.1 L (13%), and the mean elimination half-life was 23 days (24%). ### Specific Populations - Age, sex, and race had no clinically meaningful effect on the PK of ramucirumab based on a population PK analysis. - Renal Impairment: The effect of renal impairment on the average concentration of ramucirumab at steady state (Css) was evaluated in patients with mild (calculated creatinine clearance CLcr 60-89 mL/min, n=368), moderate (CLcr 30-59 mL/min, n=160) or severe (CLcr 15 -29 mL/min, n=4) renal impairment compared to patients with normal renal function (CLcr ≥90 mL/min, n=360) in a population PK analysis. No clinically meaningful differences in the average Css of ramucirumab were observed between patients with renal impairment and patients with normal renal function. - Hepatic Impairment: The effect of hepatic impairment on the average Css of ramucirumab was evaluated in patients with mild (total bilirubin within upper limit of normal [ULN] and AST>ULN or total bilirubin >1.0-1.5 times ULN and any AST, n=143) compared to patients with normal hepatic function (total bilirubin and AST ≤ULN, n=735) in a population PK analysis. No clinically meaningful differences in the average Css of ramucirumab were found between patients with mild hepatic impairment and patients with normal hepatic function. No PK data were available from patients with moderate (total bilirubin >1.5-3.0 times ULN and any AST) or severe hepatic dysfunction (total bilirubin >3.0 times ULN and any AST). - Drug Interaction Studies No clinically meaningful changes in paclitaxel exposure or ramucirumab exposure were observed when Ramucirumab 8 mg/kg and paclitaxel 80 mg/m2 were co-administered in patients with solid tumors. No clinically meaningful changes in docetaxel exposure were observed when Ramucirumab 10 mg/kg and docetaxel 75 mg/m2 were co-administered in patients with solid tumors. Ramucirumab exposure appeared to be comparable regardless of concomitant docetaxel based on cross study comparisons in patients with solid tumors. - No clinically meaningful changes in paclitaxel exposure or ramucirumab exposure were observed when Ramucirumab 8 mg/kg and paclitaxel 80 mg/m2 were co-administered in patients with solid tumors. - No clinically meaningful changes in docetaxel exposure were observed when Ramucirumab 10 mg/kg and docetaxel 75 mg/m2 were co-administered in patients with solid tumors. Ramucirumab exposure appeared to be comparable regardless of concomitant docetaxel based on cross study comparisons in patients with solid tumors. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility - No animal studies have been performed to test ramucirumab for potential carcinogenicity or genotoxicity. - Inhibition of VEGFR2 signaling in animal models was shown to result in changes to hormone levels critical for pregnancy, and, in monkeys, an increased duration of the follicular cycle. In a 39 week animal study, female monkeys treated with ramucirumab showed dose dependent increases in follicular mineralization of the ovary. ### Animal Toxicology and/or Pharmacology - Adverse effects in the kidney (glomerulonephritis) occurred with doses of 16-50 mg/kg (0.7-5.5 times the exposure in humans at the recommended dose of ramucirumab as a single agent). - A single dose of ramucirumab resulting in an exposure approximately 10 times the exposure in humans at the recommended dose of ramucirumab as a single agent did not significantly impair wound healing in monkeys using a full-thickness incisional model. # Clinical Studies ### Gastric Cancer - Study 1 was a multinational, randomized, double-blind, multicenter study of Ramucirumab plus best supportive care (BSC) versus placebo plus BSC that randomized (2:1) 355 patients with locally advanced or metastatic gastric cancer (including adenocarcinoma of the gastro-esophageal junction [GEJ]) who previously received platinum- or fluoropyrimidine-containing chemotherapy. The major efficacy outcome measure was overall survival and the supportive efficacy outcome measure was progression-free survival. Patients were required to have experienced disease progression either within 4 months after the last dose of first-line therapy for locally advanced or metastatic disease or within 6 months after the last dose of adjuvant therapy. Patients were also required to have ECOG PS of 0 or 1. Patients received either an intravenous infusion of Ramucirumab 8 mg/kg (n=238) or placebo solution (n=117) every 2 weeks. Randomization was stratified by weight loss over the prior 3 months (≥10% versus <10%), geographic region, and location of the primary tumor (gastric versus GEJ). - Demographic and baseline characteristics were similar between treatment arms. Median age was 60 years; 70% of patients were men; 77% were White, 16% Asian; the ECOG PS was 0 for 28% of patients and 1 for 72% of patients; 91% of patients had measurable disease; 75% of patients had gastric cancer; and 25% had adenocarcinoma of the GEJ. The majority of patients (85%) experienced disease progression during or following first-line therapy for metastatic disease. Prior chemotherapy for gastric cancer consisted of platinum/fluoropyrimidine combination therapy (81%), fluoropyrimidine-containing regimens without platinum (15%), and platinum-containing regimens without fluoropyrimidine (4%). In Study 1, patients received a median of 4 doses (range 1-34) of Ramucirumab or a median of 3 doses (range 1-30) of placebo. - Overall survival and progression-free survival were statistically significantly improved in patients randomized to receive Ramucirumab as compared to patients randomized to receive placebo. Efficacy results are shown in TABLE 5 and FIGURE 1. - Study 2 was a multinational, randomized, double-blind study of Ramucirumab plus paclitaxel versus placebo plus paclitaxel that randomized (1:1) 665 patients with locally advanced or metastatic gastric cancer (including adenocarcinoma of the gastro-esophageal junction) who previously received platinum- and fluoropyrimidine-containing chemotherapy. Patients were required to have experienced disease progression during, or within 4 months after the last dose of first-line therapy. Patients were also required to have ECOG PS of 0 or 1. Randomization was stratified by geographic region, time to progression from the start of first-line therapy (<6 months versus ≥6 months) and disease measurability. - Patients were randomized to receive either Ramucirumab 8 mg/kg (n=330) or placebo (n=335) as an intravenous infusion every 2 weeks (on days 1 and 15) of each 28-day cycle. Patients in both arms received paclitaxel 80 mg/m2 by intravenous infusion on days 1, 8, and 15 of each 28-day cycle. Prior to administration of each dose of paclitaxel, patients were required to have adequate hematopoietic and hepatic function. The paclitaxel dose was permanently reduced in increments of 10 mg/m2 for a maximum of two dose reductions for Grade 4 hematologic toxicity or Grade 3 paclitaxel-related non-hematologic toxicity. The major efficacy outcome measure was overall survival and the supportive efficacy outcome measures were progression-free survival and objective response rate. - Demographics and baseline characteristics were similar between treatment arms including the following: Median age was 61 years; 71% of patients were men; 61% were White, 35% Asian; the ECOG PS was 0 for 39% of patients, 1 for 61% of patients; 78% of patients had measurable disease; 79% of patients had gastric cancer; and 21% had adenocarcinoma of the GEJ. Two-thirds of the patients experienced disease progression while on first-line therapy (67%) and 25% of patients received an anthracycline in combination with platinum/fluoropyrimidine combination therapy. - Overall survival, progression-free survival, and objective response rate were statistically significantly improved in patients randomized to receive Ramucirumab plus paclitaxel compared to patients randomized to receive placebo plus paclitaxel. Efficacy results are shown in TABLE 6 and FIGURE 2. ### Non-Small Cell Lung Cancer Study 3 was a multinational, randomized, double-blind, study of Ramucirumab plus docetaxel versus placebo plus docetaxel, that randomized (1:1) 1253 patients with NSCLC with disease progression on or after one platinum-based therapy for locally advanced or metastatic disease. The major efficacy outcome measure was overall survival and the supportive efficacy outcome measures were progression-free survival and objective response rate. Patients were also required to have ECOG PS 0 or 1. Patients were randomized to receive either Ramucirumab at 10 mg/kg or placebo by intravenous infusion, in combination with docetaxel at 75 mg/m2 every 21 days. Sites in East Asia administered a reduced dose of docetaxel at 60 mg/m2 every 21 days. Patients who discontinued combination therapy because of an adverse event attributed to either Ramucirumab placebo or docetaxel were permitted to continue monotherapy with the other treatment component until disease progression or intolerable toxicity. Randomization was stratified by geographic region, gender, prior maintenance therapy, and ECOG PS. Demographics and baseline characteristics were similar between treatment arms. Median age was 62 years; 67% of patients were men; 82% were White and 13% were Asian; 32% had ECOG PS 0; 73% had nonsquamous histology and 26% had squamous histology. In addition to platinum chemotherapy (99%), the most common prior therapies were pemetrexed (38%), gemcitabine (25%), taxane (24%), and bevacizumab (14%). Twenty-two percent of patients received prior maintenance therapy. Tumor EGFR status was unknown for the majority of patients (65%). Where tumor EGFR status was known (n=445), 7.5% were positive for EGFR mutation (n=33). No data were collected regarding tumor ALK rearrangement status. Overall survival and progression-free survival were statistically significantly improved in patients randomized to receive Ramucirumab plus docetaxel compared to patients randomized to receive placebo plus docetaxel. Objective response rate (complete response + partial response) was 23% (95% CI: 20, 26) for Ramucirumab plus docetaxel and 14% (95% CI: 11, 17) for placebo plus docetaxel, p-value of <0.001. Efficacy results are shown in TABLE 7 and FIGURE 3. # How Supplied Ramucirumab is supplied in single-dose vials as a sterile, preservative-free solution. - NDC 0002-7669-01: 100 mg/10 mL (10 mg/mL), individually packaged in a carton - NDC 0002-7678-01: 500 mg/50 mL (10 mg/mL), individually packaged in a carton ## Storage - Store vials in a refrigerator at 2°C to 8°C (36°F to 46°F) until time of use. Keep the vial in the outer carton in order to protect from light. Do not freeze or shake the vial. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Advise patients: - That CYRAMZA can cause severe bleeding. Advise patients to contact their health care provider for bleeding or symptoms of bleeding including lightheadedness. - Of increased risk of an arterial thromboembolic event. - To undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms. - To notify their health care provider for severe diarrhea, vomiting, or severe abdominal pain. - That CYRAMZA has the potential to impair wound healing. Instruct patients not to undergo surgery without first discussing this potential risk with their health care provider. - Of the potential risk for maintaining pregnancy, risk to the fetus, or risk to postnatal development during and following treatment with CYRAMZA and the need to avoid getting pregnant, including use of adequate contraception, for at least 3 months following the last dose of CYRAMZA. - To discontinue nursing during CYRAMZA treatment. # Precautions with Alcohol Alcohol-Ramucirumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Cyramza®[1] # Look-Alike Drug Names There is limited information regarding Ramucirumab Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Cyramza
240e54d759ce653038b66cbd48a57b0489b89f04	wikidoc	Cystercosis	Cystercosis # Background Cystercosis is a rare and recently recognized disease that affects the human nervous system. # Etiology Cystercosis is caused by consuming the larval form of the parasitic tapeworm Taenia solium. The larvae eventually affect the muscles and brain, and moving larvae can be detected in the affected person's eyes. In the brain, the larvae can severely damage the frontal lobe and cause personality changes. The disease has been found in a small number of patients in Mexico. It is not directly contagious between humans; it apparently spreads when people eat fruit and vegetables that have been contaminated with pig feces. However, it is extremely rare in First World countries like the U.S., which have strict laws that forbid farmers from allowing pigs to graze in fields where food is grown. # Incubation The period of incubation for cystercosis is unclear. It can take from two weeks to ten years for a person to fully develop the disease. # Symptoms The most common symptom among patients of this disease is mood swings. These might lead people who suffer cystercosis to act strange during certain days. It is recommended that one visit a doctor if one, or a close friend or relative, has visited Mexico and eaten fruits or vegetables there and begin to act in an improper or out of place manner. On 8 December 2004, Kevin Keogh, the chief financial officer of the city of Phoenix, Arizona, died from a bizarre stunt thought to have been induced by cystercosis (he had contracted it while traveling in Mexico two years earlier). He climbed onto the roof of his moving car after setting the cruise control to around 50 miles per hour. He then "surfed" on the top of his car, then jumped and fell to his death. # Treatment As with all serious brain damage, there is no direct treatment available for cystercosis. Patients are sometimes given antidepressants to help with the mood swings and psychotherapy to help them resist irrational impulses.	Cystercosis Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Background Cystercosis is a rare and recently recognized disease that affects the human nervous system. # Etiology Cystercosis is caused by consuming the larval form of the parasitic tapeworm Taenia solium. The larvae eventually affect the muscles and brain, and moving larvae can be detected in the affected person's eyes. In the brain, the larvae can severely damage the frontal lobe and cause personality changes. The disease has been found in a small number of patients in Mexico. It is not directly contagious between humans; it apparently spreads when people eat fruit and vegetables that have been contaminated with pig feces. However, it is extremely rare in First World countries like the U.S., which have strict laws that forbid farmers from allowing pigs to graze in fields where food is grown. # Incubation The period of incubation for cystercosis is unclear. It can take from two weeks to ten years for a person to fully develop the disease. # Symptoms The most common symptom among patients of this disease is mood swings. These might lead people who suffer cystercosis to act strange during certain days. It is recommended that one visit a doctor if one, or a close friend or relative, has visited Mexico and eaten fruits or vegetables there and begin to act in an improper or out of place manner. On 8 December 2004, Kevin Keogh, the chief financial officer of the city of Phoenix, Arizona, died from a bizarre stunt thought to have been induced by cystercosis (he had contracted it while traveling in Mexico two years earlier). He climbed onto the roof of his moving car after setting the cruise control to around 50 miles per hour. He then "surfed" on the top of his car, then jumped and fell to his death. # Treatment As with all serious brain damage, there is no direct treatment available for cystercosis. Patients are sometimes given antidepressants to help with the mood swings and psychotherapy to help them resist irrational impulses.	https://www.wikidoc.org/index.php/Cystercosis
06c0893ff4694be3cb8f78d805dc9b1f40aefeea	wikidoc	Cystic acne	Cystic acne Cystic acne, also known as nodulocystic acne, is a severe form of acne wherein acne develops into small cysts. Acne cysts are not true cysts in the sense that they are not abnormal dilations of skin structure, but rather nodules of inflammation. Although not uncommon, it is rarer than other types of acne. Like other forms, it is caused by an excess buildup of sebum in the pores and, contrary to popular belief, is not caused by, nor is it affected by, hygiene or the lack thereof. A common treatment for cystic acne is Isotretinoin, which cures most acne in about 90% of patients. Cystic acne can affect the face, chest, back, shoulders and, occasionally, upper arms. Like pimples, which are more common, cysts are usually filled with a white pus-like substance. They are usually several centimeters in diameter, and can be quite painful. If cystic acne is not treated early on, especially with antibiotics along with a topical cream, some degree of scarring will occur. This can be quite severe depending on the case. Although many scars can be treated, scars on the body often do not respond as well as those on the face. In most cases, it is unlikely that all scars can be removed. After cysts have mostly healed, macules, or "pseudo scars" may form. Macules are red patches of skin, sometimes raised slightly, where cysts used to be, and may resemble cysts in their appearance. They are sometimes known as "pseudo scars" because they resemble scars, but unlike true ones, macules usually only last up to six months and leave no permanent scar.	Cystic acne Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Cystic acne, also known as nodulocystic acne, is a severe form of acne wherein acne develops into small cysts. Acne cysts are not true cysts in the sense that they are not abnormal dilations of skin structure, but rather nodules of inflammation. Although not uncommon, it is rarer than other types of acne. Like other forms, it is caused by an excess buildup of sebum in the pores and, contrary to popular belief, is not caused by, nor is it affected by, hygiene or the lack thereof. A common treatment for cystic acne is Isotretinoin, which cures most acne in about 90% of patients. Cystic acne can affect the face, chest, back, shoulders and, occasionally, upper arms. Like pimples, which are more common, cysts are usually filled with a white pus-like substance. They are usually several centimeters in diameter, and can be quite painful. If cystic acne is not treated early on, especially with antibiotics along with a topical cream, some degree of scarring will occur. This can be quite severe depending on the case. Although many scars can be treated, scars on the body often do not respond as well as those on the face. In most cases, it is unlikely that all scars can be removed. After cysts have mostly healed, macules, or "pseudo scars" may form. Macules are red patches of skin, sometimes raised slightly, where cysts used to be, and may resemble cysts in their appearance. They are sometimes known as "pseudo scars" because they resemble scars, but unlike true ones, macules usually only last up to six months and leave no permanent scar.	https://www.wikidoc.org/index.php/Cystic_acne
ef71d1db30b9c6b7e6493d7614f4463181d27b42	wikidoc	Cystic duct	Cystic duct # Overview The cystic duct is the short duct that joins the gall bladder to the common bile duct. It usually lies next to the cystic artery. It is of variable length. It contains a 'spiral valve', which does not provide much resistance to the flow of bile. # Function Bile can flow in both directions between the gallbladder and the common hepatic duct and the (common) bile duct. In this way, bile is stored in the gallbladder in between meal times and released after a fatty meal. # Clinical significance During a cholecystectomy, the cystic duct is clipped two or three times and a cut is made between the clips, freeing the gallbladder to be taken out. # Additional images - The gall-bladder and bile ducts laid open. - The portal vein and its tributaries.	Cystic duct # Overview Template:Infobox Anatomy The cystic duct is the short duct that joins the gall bladder to the common bile duct. It usually lies next to the cystic artery. It is of variable length. It contains a 'spiral valve', which does not provide much resistance to the flow of bile. # Function Bile can flow in both directions between the gallbladder and the common hepatic duct and the (common) bile duct. In this way, bile is stored in the gallbladder in between meal times and released after a fatty meal. # Clinical significance During a cholecystectomy, the cystic duct is clipped two or three times and a cut is made between the clips, freeing the gallbladder to be taken out. # Additional images - The gall-bladder and bile ducts laid open. - The portal vein and its tributaries. # External links - Template:EMedicineDictionary - Template:SUNYAnatomyFigs - "The gallbladder and extrahepatic bile ducts." - Template:SUNYAnatomyLabs - "Stomach, Spleen and Liver: The Gallbladder and the Bile System" - Template:NormanAnatomy (Template:NormanAnatomyFig, Template:NormanAnatomyFig) Template:Digestive glands Template:WH Template:WS	https://www.wikidoc.org/index.php/Cystic_duct
44491f42d51ed7477986711f0ad42dca24ba4f32	wikidoc	Misoprostol	Misoprostol # 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 Misoprostol is a gastrointestinal agent that is FDA approved for the prophylaxis of NSAID (nonsteroidal anti-inflammatory drugs, including aspirin)–induced gastric ulcers in patients at high risk of complications from gastric ulcer. There is a Black Box Warning for this drug as shown here. Common adverse reactions include abdominal pain, diarrhea. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Misoprostol is indicated for reducing the risk of NSAID (nonsteroidal anti-inflammatory drugs, including aspirin)–induced gastric ulcers in patients at high risk of complications from gastric ulcer, e.g., the elderly and patients with concomitant debilitating disease, as well as patients at high risk of developing gastric ulceration, such as patients with a history of ulcer. Misoprostol Tablet has not been shown to reduce the risk of duodenal ulcers in patients taking NSAIDs. Misoprostol Tablets should be taken for the duration of NSAID therapy. Misoprostol Tablets has been shown to reduce the risk of gastric ulcers in controlled studies of 3 months' duration. It had no effect, compared to placebo, on gastrointestinal pain or discomfort associated with NSAID use. - Dosing Information - The recommended adult oral dose of Misoprostol Tablets for reducing the risk of NSAID-induced gastric ulcers is 200 mcg four times daily with food. If this dose cannot be tolerated, a dose of 100 mcg can be used. (See Clinical Pharmacology: Clinical studies.) Misoprostol Tablets should be taken for the duration of NSAID therapy as prescribed by the physician. Misoprostol Tablets should be taken with a meal, and the last dose of the day should be at bedtime. - Renal Impairment - Adjustment of the dosing schedule in renally impaired patients is not routinely needed, but dosage can be reduced if the 200-mcg dose is not tolerated. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Misoprostol in adult patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Misoprostol in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - There is limited information regarding FDA-Labeled Use of Misoprostol in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Misoprostol in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Misoprostol in pediatric patients. # Contraindications - See boxed WARNINGS. - Misoprostol Tablets should not be taken by pregnant women to reduce the risk of ulcers induced by nonsteroidal anti-inflammatory drugs (NSAIDs). - Misoprostol Tablets should not be taken by anyone with a history of allergy to prostaglandins. # Warnings - See boxed WARNINGS. ### Precautions - Caution should be employed when administering misoprostol to patients with pre-existing cardiovascular disease. Information for Patients - Women of childbearing potential using Misoprostol Tablets to decrease the risk of NSAID-induced ulcers should be told that they must not be pregnant when Misoprostol Tablets therapy is initiated, and that they must use an effective contraception method while taking Misoprostol Tablets. - See boxed WARNINGS. - Misoprostol Tablets is intended for administration along with nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, to decrease the chance of developing an NSAID-induced gastric ulcer. - Misoprostol Tablets should be taken only according to the directions given by a physician. - If the patient has questions about or problems with Misoprostol Tablets, the physician should be contacted promptly. - THE PATIENT SHOULD NOT GIVE MISOPROSTOL TABLETS TO ANYONE ELSE. Misoprostol Tablets has been prescribed for the patient's specific condition, may not be the correct treatment for another person, and may be dangerous to the other person if she were to become pregnant. - The Misoprostol Tablets package the patient receives from the pharmacist will include a leaflet containing patient information. The patient should read the leaflet before taking Misoprostol Tablets and each time the prescription is renewed because the leaflet may have been revised. - Keep Misoprostol Tablets out of the reach of children. - SPECIAL NOTE FOR WOMEN: Misoprostol Tablets may cause abortion (sometimes incomplete), premature labor, or birth defects if given to pregnant women. - Misoprostol Tablets is available only as a unit-of-use package that includes a leaflet containing patient information. See Patient Information at the end of this labeling. # Adverse Reactions ## Clinical Trials Experience - The following have been reported as adverse events in subjects receiving Misoprostol Tablets: Gastrointestinal - In subjects receiving Misoprostol Tablets 400 or 800 mcg daily in clinical trials, the most frequent gastrointestinal adverse events were diarrhea and abdominal pain. The incidence of diarrhea at 800 mcg in controlled trials in patients on NSAIDs ranged from 14 to 40% and in all studies (over 5,000 patients) averaged 13%. Abdominal pain occurred in 13 to 20% of patients in NSAID trials and about 7% in all studies, but there was no consistent difference from placebo. - Diarrhea was dose related and usually developed early in the course of therapy (after 13 days), usually was self-limiting (often resolving after 8 days), but sometimes required discontinuation of Misoprostol Tablets (2% of the patients). Rare instances of profound diarrhea leading to severe dehydration have been reported. Patients with an underlying condition such as inflammatory bowel disease, or those in whom dehydration, were it to occur, would be dangerous, should be monitored carefully if Misoprostol Tablets is prescribed. The incidence of diarrhea can be minimized by administering after meals and at bedtime, and by avoiding coadministration of Misoprostol Tablets with magnesium-containing antacids. Gynecological - Women who received Misoprostol Tablets during clinical trials reported the following gynecological disorders: spotting (0.7%), cramps (0.6%), hypermenorrhea (0.5%), menstrual disorder (0.3%) and dysmenorrhea (0.1%). Postmenopausal vaginal bleeding may be related to Misoprostol Tablets administration. If it occurs, diagnostic workup should be undertaken to rule out gynecological pathology. (See boxed WARNINGS.) Elderly - There were no significant differences in the safety profile of Misoprostol Tablets in approximately 500 ulcer patients who were 65 years of age or older compared with younger patients. - Additional adverse events which were reported are categorized as follows: Incidence greater than 1% - In clinical trials, the following adverse reactions were reported by more than 1% of the subjects receiving Misoprostol Tablets and may be causally related to the drug: nausea (3.2%), flatulence (2.9%), headache (2.4%), dyspepsia (2.0%), vomiting (1.3%), and constipation (1.1%). However, there were no significant differences between the incidences of these events for Misoprostol Tablets and placebo. Causal relationship unknown - The following adverse events were infrequently reported. Causal relationships between Misoprostol Tablets and these events have not been established but cannot be excluded: - Body as a whole: aches/pains, asthenia, fatigue, fever, chills, rigors, weight changes. - Skin: rash, dermatitis, alopecia, pallor, breast pain. - Special senses: abnormal taste, abnormal vision, conjunctivitis, deafness, tinnitus, earache. - Respiratory: upper respiratory tract infection, bronchitis, bronchospasm, dyspnea, pneumonia, epistaxis. - Cardiovascular: chest pain, edema, diaphoresis, hypotension, hypertension, arrhythmia, phlebitis, increased cardiac enzymes, syncope, myocardial infarction (some fatal), thromboembolic events (e.g., pulmonary embolism, arterial thrombosis, and CVA). - Gastrointestinal: GI bleeding, GI inflammation/infection, rectal disorder, abnormal hepatobiliary function, gingivitis, reflux, dysphagia, amylase increase. - Hypersensitivity: anaphylactic reaction - Metabolic: glycosuria, gout, increased nitrogen, increased alkaline phosphatase. - Genitourinary: polyuria, dysuria, hematuria, urinary tract infection. - Nervous system/Psychiatric: anxiety, change in appetite, depression, drowsiness, dizziness, thirst, impotence, loss of libido, sweating increase, neuropathy, neurosis, confusion. - Musculoskeletal: arthralgia, myalgia, muscle cramps, stiffness, back pain. - Blood/Coagulation: anemia, abnormal differential, thrombocytopenia, purpura, ESR increased. ## Postmarketing Experience - There is limited information regarding Postmarketing Experience of Misoprostol in the drug label. # Drug Interactions - See Clinical Pharmacology. Misoprostol Tablets has not been shown to interfere with the beneficial effects of aspirin on signs and symptoms of rheumatoid arthritis. Misoprostol Tablets does not exert clinically significant effects on the absorption, blood levels, and antiplatelet effects of therapeutic doses of aspirin. Misoprostol Tablets has no clinically significant effect on the kinetics of diclofenac or ibuprofen. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): X Pregnancy Category X Teratogenic Effects - See boxed WARNINGS. Congenital anomalies sometimes associated with fetal death have been reported subsequent to the unsuccessful use of misoprostol as an abortifacient, but the drug's teratogenic mechanism has not been demonstrated. Several reports in the literature associate the use of misoprostol during the first trimester of pregnancy with skull defects, cranial nerve palsies, facial malformations, and limb defects. - Misoprostol Tablets is not fetotoxic or teratogenic in rats and rabbits at doses 625 and 63 times the human dose, respectively. Nonteratogenic Effects - See boxed WARNINGS. Misoprostol Tablets may endanger pregnancy (may cause abortion) and thereby cause harm to the fetus when administered to a pregnant woman. Misoprostol Tablets may produce uterine contractions, uterine bleeding, and expulsion of the products of conception. Abortions caused by Misoprostol Tablets may be incomplete. If a woman is or becomes pregnant while taking this drug to reduce the risk of NSAID-induced ulcers, the drug should be discontinued and the patient apprised of the potential hazard 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 Misoprostol in women who are pregnant. ### Labor and Delivery - Misoprostol Tablets can induce or augment uterine contractions. Vaginal administration of Misoprostol Tablets, outside of its approved indication, has been used as a cervical ripening agent, for the induction of labor and for treatment of serious postpartum hemorrhage in the presence of uterine atony. A major adverse effect of the obstetrical use of Misoprostol Tablets is the hyperstimulation of the uterus which may progress to uterine tetany with marked impairment of uteroplacental blood flow, uterine rupture (requiring surgical repair, hysterectomy, and/or salpingo-oophorectomy), or amniotic fluid embolism. Pelvic pain, retained placenta, severe genital bleeding, shock, fetal bradycardia, and fetal and maternal death have been reported. - There may be an increased risk of uterine tachysystole, uterine rupture, meconium passage, meconium staining of amniotic fluid, and Cesarean delivery due to uterine hyperstimulation with the use of higher doses of Misoprostol Tablets, including the manufactured 100 mcg tablet. The risk of uterine rupture increases with advancing gestational ages and with prior uterine surgery, including Cesarean delivery. Grand multiparity also appears to be a risk factor for uterine rupture. - The effect of Misoprostol Tablets on later growth, development, and functional maturation of the child when Misoprostol Tablets is used for cervical ripening or induction of labor has not been established. Information on Misoprostol Tablet's effect on the need for forceps delivery or other intervention is unknown. ### Nursing Mothers - Misoprostol is rapidly metabolized in the mother to misoprostol acid, which is biologically active and is excreted in breast milk. There are no published reports of adverse effects of misoprostol in breast-feeding infants of mothers taking misoprostol. Caution should be exercised when misoprostol is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness of Misoprostol Tablets in pediatric patients have not been established. ### Geriatic Use - There is no FDA guidance on the use of Misoprostol with respect to geriatric patients. ### Gender - There is no FDA guidance on the use of Misoprostol with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Misoprostol with respect to specific racial populations. ### Renal Impairment - There is no FDA guidance on the use of Misoprostol in patients with renal impairment. ### Hepatic Impairment - There is no FDA guidance on the use of Misoprostol in patients with hepatic impairment. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Misoprostol in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Misoprostol in patients who are immunocompromised. # Administration and Monitoring ### Administration - The recommended adult oral dose of Misoprostol Tablets for reducing the risk of NSAID-induced gastric ulcers is 200 mcg four times daily with food. If this dose cannot be tolerated, a dose of 100 mcg can be used. Misoprostol Tablets should be taken for the duration of NSAID therapy as prescribed by the physician. Misoprostol Tablets should be taken with a meal, and the last dose of the day should be at bedtime. Renal impairment - Adjustment of the dosing schedule in renally impaired patients is not routinely needed, but dosage can be reduced if the 200-mcg dose is not tolerated. (See Clinical Pharmacology.) ### Monitoring - There is limited information regarding Monitoring of Misoprostol in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Misoprostol in the drug label. # Overdosage - The toxic dose of Misoprostol Tablets in humans has not been determined. Cumulative total daily doses of 1600 mcg have been tolerated, with only symptoms of gastrointestinal discomfort being reported. In animals, the acute toxic effects are diarrhea, gastrointestinal lesions, focal cardiac necrosis, hepatic necrosis, renal tubular necrosis, testicular atrophy, respiratory difficulties, and depression of the central nervous system. Clinical signs that may indicate an overdose are sedation, tremor, convulsions, dyspnea, abdominal pain, diarrhea, fever, palpitations, hypotension, or bradycardia. Symptoms should be treated with supportive therapy. - It is not known if misoprostol acid is dialyzable. However, because misoprostol is metabolized like a fatty acid, it is unlikely that dialysis would be appropriate treatment for overdosage. # Pharmacology ## Mechanism of Action ## Structure - Misoprostol oral tablets contain either 100 mcg or 200 mcg of misoprostol, a synthetic prostaglandin E1 analog. - Misoprostol contains approximately equal amounts of the two diastereomers presented below with their enantiomers indicated by (±): - Misoprostol is a water-soluble, viscous liquid. - Inactive ingredients of tablets are hydrogenated castor oil, microcrystalline cellulose, and crospovidone. ## Pharmacodynamics - Misoprostol has both antisecretory (inhibiting gastric acid secretion) and (in animals) mucosal protective properties. NSAIDs inhibit prostaglandin synthesis, and a deficiency of prostaglandins within the gastric mucosa may lead to diminishing bicarbonate and mucus secretion and may contribute to the mucosal damage caused by these agents. Misoprostol can increase bicarbonate and mucus production, but in man this has been shown at doses 200 mcg and above that are also antisecretory. It is therefore not possible to tell whether the ability of misoprostol to reduce the risk of gastric ulcer is the result of its antisecretory effect, its mucosal protective effect, or both. - In vitro studies on canine parietal cells using tritiated misoprostol acid as the ligand have led to the identification and characterization of specific prostaglandin receptors. Receptor binding is saturable, reversible, and stereospecific. The sites have a high affinity for misoprostol, for its acid metabolite, and for other E type prostaglandins, but not for F or I prostaglandins and other unrelated compounds, such as histamine or cimetidine. Receptor-site affinity for misoprostol correlates well with an indirect index of antisecretory activity. It is likely that these specific receptors allow misoprostol taken with food to be effective topically, despite the lower serum concentrations attained. - Misoprostol produces a moderate decrease in pepsin concentration during basal conditions, but not during histamine stimulation. It has no significant effect on fasting or postprandial gastrin nor on intrinsic factor output. Effects on gastric acid secretion - Misoprostol, over the range of 50 to 200 mcg, inhibits basal and nocturnal gastric acid secretion, and acid secretion in response to a variety of stimuli, including meals, histamine, pentagastrin, and coffee. Activity is apparent 30 minutes after oral administration and persists for at least 3 hours. In general, the effects of 50 mcg were modest and shorter lived, and only the 200-mcg dose had substantial effects on nocturnal secretion or on histamine and meal-stimulated secretion. Uterine effects - Misoprostol Tablets has been shown to produce uterine contractions that may endanger pregnancy. (See boxed WARNINGS.) Other pharmacologic effects - Misoprostol Tablets does not produce clinically significant effects on serum levels of prolactin, gonadotropins, thyroid-stimulating hormone, growth hormone, thyroxine, cortisol, gastrointestinal hormones (somatostatin, gastrin, vasoactive intestinal polypeptide, and motilin), creatinine, or uric acid. Gastric emptying, immunologic competence, platelet aggregation, pulmonary function, or the cardiovascular system are not modified by recommended doses of Misoprostol Tablets. ## Pharmacokinetics - Misoprostol is extensively absorbed, and undergoes rapid de-esterification to its free acid, which is responsible for its clinical activity and, unlike the parent compound, is detectable in plasma. The alpha side chain undergoes beta oxidation and the beta side chain undergoes omega oxidation followed by reduction of the ketone to give prostaglandin F analogs. - In normal volunteers, misoprostol is rapidly absorbed after oral administration with a Tmax of misoprostol acid of 12 ± 3 minutes and a terminal half-life of 20 to 40 minutes. - There is high variability of plasma levels of misoprostol acid between and within studies but mean values after single doses show a linear relationship with dose over the range of 200 to 400 mcg. No accumulation of misoprostol acid was noted in multiple dose studies; plasma steady state was achieved within two days. - Maximum plasma concentrations of misoprostol acid are diminished when the dose is taken with food and total availability of misoprostol acid is reduced by use of concomitant antacid. Clinical trials were conducted with concomitant antacid, however, so this effect does not appear to be clinically important. - After oral administration of radiolabeled misoprostol, about 80% of detected radioactivity appears in urine. Pharmacokinetic studies in patients with varying degrees of renal impairment showed an approximate doubling of T1/2, Cmax , and AUC compared to normals, but no clear correlation between the degree of impairment and AUC. In subjects over 64 years of age, the AUC for misoprostol acid is increased. No routine dosage adjustment is recommended in older patients or patients with renal impairment, but dosage may need to be reduced if the usual dose is not tolerated. - Drug interaction studies between misoprostol and several nonsteroidal anti-inflammatory drugs showed no effect on the kinetics of ibuprofen or diclofenac, and a 20% decrease in aspirin AUC, not thought to be clinically significant. - Pharmacokinetic studies also showed a lack of drug interaction with antipyrine and propranolol when these drugs were given with misoprostol. Misoprostol given for 1 week had no effect on the steady state pharmacokinetics of diazepam when the two drugs were administered 2 hours apart. - The serum protein binding of misoprostol acid is less than 90% and is concentration-independent in the therapeutic range. - After a single oral dose of misoprostol to nursing mothers, misoprostol acid was excreted in breast milk. The maximum concentration of misoprostol acid in expressed breast milk was achieved within 1 hour after dosing and was 7.6 pg/mL (CV 37%) and 20.9 pg/ml (CV 62%) after single 200 mg and 600 mg misoprostol administration, respectively. The misoprostol acid concentrations in breast milk declined to < 1 pg/ml at 5 hours post-dose. ## Nonclinical Toxicology Animal toxicology - A reversible increase in the number of normal surface gastric epithelial cells occurred in the dog, rat, and mouse. No such increase has been observed in humans administered Misoprostol Tablets for up to 1 year. - An apparent response of the female mouse to Misoprostol Tablets in long-term studies at 100 to 1000 times the human dose was hyperostosis, mainly of the medulla of sternebrae. Hyperostosis did not occur in long-term studies in the dog and rat and has not been seen in humans treated with Misoprostol Tablets. Carcinogenesis, Mutagenesis, Impairment of Fertility - There was no evidence of an effect of Misoprostol Tablets on tumor occurrence or incidence in rats receiving daily doses up to 150 times the human dose for 24 months. Similarly, there was no effect of Misoprostol Tablets on tumor occurrence or incidence in mice receiving daily doses up to 1000 times the human dose for 21 months. The mutagenic potential of Misoprostol Tablets was tested in several in vitro assays, all of which were negative. - Misoprostol, when administered to breeding male and female rats at doses 6.25 times to 625 times the maximum recommended human therapeutic dose, produced dose-related pre- and post-implantation losses and a significant decrease in the number of live pups born at the highest dose. These findings suggest the possibility of a general adverse effect on fertility in males and females. # Clinical Studies - In a series of small short-term (about 1 week) placebo-controlled studies in healthy human volunteers, doses of misoprostol were evaluated for their ability to reduce the risk of NSAID-induced mucosal injury. Studies of 200 mcg q.i.d. of misoprostol with tolmetin and naproxen, and of 100 and 200 mcg q.i.d. with ibuprofen, all showed reduction of the rate of significant endoscopic injury from about 70 to 75% on placebo to 10 to 30% on misoprostol. Doses of 25 to 200 mcg q.i.d. reduced aspirin-induced mucosal injury and bleeding. Reducing the risk of gastric ulcers caused by nonsteroidal anti-inflammatory drugs (NSAIDs) - Two 12-week, randomized, double-blind trials in osteoarthritic patients who had gastrointestinal symptoms but no ulcer on endoscopy while taking an NSAID compared the ability of 200 mcg of Misoprostol Tablets, 100 mcg of Misoprostol Tablets, and placebo to reduce the risk of gastric ulcer (GU) formation. Patients were approximately equally divided between ibuprofen, piroxicam, and naproxen, and continued this treatment throughout the 12 weeks. The 200-mcg dose caused a marked, statistically significant reduction in gastric ulcers in both studies. The lower dose was somewhat less effective, with a significant result in only one of the studies. - In these trials there were no significant differences between Misoprostol Tablets and placebo in relief of day or night abdominal pain. No effect of Misoprostol Tablets in reducing the risk of duodenal ulcers was demonstrated, but relatively few duodenal lesions were seen. - In another clinical trial, 239 patients receiving aspirin 650 to 1300 mg q.i.d. for rheumatoid arthritis who had endoscopic evidence of duodenal and/or gastric inflammation were randomized to misoprostol 200 mcg q.i.d. or placebo for 8 weeks while continuing to receive aspirin. The study evaluated the possible interference of Misoprostol Tablets on the efficacy of aspirin in these patients with rheumatoid arthritis by analyzing joint tenderness, joint swelling, physician's clinical assessment, patient's assessment, change in ARA classification, change in handgrip strength, change in duration of morning stiffness, patient's assessment of pain at rest, movement, interference with daily activity, and ESR. Misoprostol Tablets did not interfere with the efficacy of aspirin in these patients with rheumatoid arthritis. # How Supplied - Misoprostol Tablets 100-mcg tablets are round, white flat-faced beveled edge tablets, debossed "160" on one side and "n" on other side. - Misoprostol Tablets 200-mcg tablets are round, white flat-faced beveled edge bisected tablets, debossed "161" above the bisect and "n" below the bisect and plain on the other side. ## Storage - Store at 20° to 25°C (68° to 77°F) . Store in a dry area. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Information for Patients - Women of childbearing potential using Misoprostol Tablets to decrease the risk of NSAID-induced ulcers should be told that they must not be pregnant when Misoprostol Tablets therapy is initiated, and that they must use an effective contraception method while taking Misoprostol Tablets. - See boxed WARNINGS. - Misoprostol Tablets is intended for administration along with nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, to decrease the chance of developing an NSAID-induced gastric ulcer. - Misoprostol Tablets should be taken only according to the directions given by a physician. - If the patient has questions about or problems with Misoprostol Tablets, the physician should be contacted promptly. - THE PATIENT SHOULD NOT GIVE MISOPROSTOL TABLETS TO ANYONE ELSE. Misoprostol Tablets has been prescribed for the patient's specific condition, may not be the correct treatment for another person, and may be dangerous to the other person if she were to become pregnant. - The Misoprostol Tablets package the patient receives from the pharmacist will include a leaflet containing patient information. The patient should read the leaflet before taking Misoprostol Tablets and each time the prescription is renewed because the leaflet may have been revised. - Keep Misoprostol Tablets out of the reach of children. - SPECIAL NOTE FOR WOMEN: Misoprostol Tablets may cause abortion (sometimes incomplete), premature labor, or birth defects if given to pregnant women. - Misoprostol Tablets is available only as a unit-of-use package that includes a leaflet containing patient information. See Patient Information at the end of this labeling. ### MEDICATION GUIDE - Read this leaflet before taking Misoprostol Tablets and each time your prescription is renewed, because the leaflet may be changed. - Misoprostol Tablets is being prescribed by your doctor to decrease the chance of getting stomach ulcers related to the arthritis/pain medication that you take. - Do not take Misoprostol Tablets to reduce the risk of NSAID-induced ulcers if you are pregnant. (See boxed WARNINGS.) Misoprostol Tablets can cause abortion (sometimes incomplete which could lead to dangerous bleeding and require hospitalization and surgery), premature birth, or birth defects. It is also important to avoid pregnancy while taking this medication and for at least one month or through one menstrual cycle after you stop taking it. Misoprostol Tablets has been reported to cause the uterus to rupture (tear) when given after the eighth week of pregnancy. Rupture (tearing) of the uterus can result in severe bleeding, hysterectomy, and/or maternal or fetal death. - If you become pregnant during Misoprostol Tablets therapy, stop taking Misoprostol Tablets and contact your physician immediately. Remember that even if you are on a means of birth control it is still possible to become pregnant. Should this occur, stop taking Misoprostol Tablets and contact your physician immediately. - Misoprostol Tablets may cause diarrhea, abdominal cramping, and/or nausea in some people. In most cases these problems develop during the first few weeks of therapy and stop after about a week. You can minimize possible diarrhea by making sure you take Misoprostol Tablets with food. - Because these side effects are usually mild to moderate and usually go away in a matter of days, most patients can continue to take Misoprostol Tablets. If you have prolonged difficulty (more than 8 days), or if you have severe diarrhea, cramping and/or nausea, call your doctor. - Take Misoprostol Tablets only according to the directions given by your physician. - Do not give Misoprostol Tablets to anyone else. It has been prescribed for your specific condition, may not be the correct treatment for another person, and would be dangerous if the other person were pregnant. - This information sheet does not cover all possible side effects of Misoprostol Tablets. This patient information leaflet does not address the side effects of your arthritis/pain medication. See your doctor if you have questions. - Keep out of reach of children. # Precautions with Alcohol - Alcohol-Misoprostol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Cytotec # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price	Misoprostol Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [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 Misoprostol is a gastrointestinal agent that is FDA approved for the prophylaxis of NSAID (nonsteroidal anti-inflammatory drugs, including aspirin)–induced gastric ulcers in patients at high risk of complications from gastric ulcer. There is a Black Box Warning for this drug as shown here. Common adverse reactions include abdominal pain, diarrhea. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Misoprostol is indicated for reducing the risk of NSAID (nonsteroidal anti-inflammatory drugs, including aspirin)–induced gastric ulcers in patients at high risk of complications from gastric ulcer, e.g., the elderly and patients with concomitant debilitating disease, as well as patients at high risk of developing gastric ulceration, such as patients with a history of ulcer. Misoprostol Tablet has not been shown to reduce the risk of duodenal ulcers in patients taking NSAIDs. Misoprostol Tablets should be taken for the duration of NSAID therapy. Misoprostol Tablets has been shown to reduce the risk of gastric ulcers in controlled studies of 3 months' duration. It had no effect, compared to placebo, on gastrointestinal pain or discomfort associated with NSAID use. - Dosing Information - The recommended adult oral dose of Misoprostol Tablets for reducing the risk of NSAID-induced gastric ulcers is 200 mcg four times daily with food. If this dose cannot be tolerated, a dose of 100 mcg can be used. (See Clinical Pharmacology: Clinical studies.) Misoprostol Tablets should be taken for the duration of NSAID therapy as prescribed by the physician. Misoprostol Tablets should be taken with a meal, and the last dose of the day should be at bedtime. - Renal Impairment - Adjustment of the dosing schedule in renally impaired patients is not routinely needed, but dosage can be reduced if the 200-mcg dose is not tolerated. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Misoprostol in adult patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Misoprostol in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - There is limited information regarding FDA-Labeled Use of Misoprostol in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Misoprostol in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Misoprostol in pediatric patients. # Contraindications - See boxed WARNINGS. - Misoprostol Tablets should not be taken by pregnant women to reduce the risk of ulcers induced by nonsteroidal anti-inflammatory drugs (NSAIDs). - Misoprostol Tablets should not be taken by anyone with a history of allergy to prostaglandins. # Warnings - See boxed WARNINGS. ### Precautions - Caution should be employed when administering misoprostol to patients with pre-existing cardiovascular disease. Information for Patients - Women of childbearing potential using Misoprostol Tablets to decrease the risk of NSAID-induced ulcers should be told that they must not be pregnant when Misoprostol Tablets therapy is initiated, and that they must use an effective contraception method while taking Misoprostol Tablets. - See boxed WARNINGS. - Misoprostol Tablets is intended for administration along with nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, to decrease the chance of developing an NSAID-induced gastric ulcer. - Misoprostol Tablets should be taken only according to the directions given by a physician. - If the patient has questions about or problems with Misoprostol Tablets, the physician should be contacted promptly. - THE PATIENT SHOULD NOT GIVE MISOPROSTOL TABLETS TO ANYONE ELSE. Misoprostol Tablets has been prescribed for the patient's specific condition, may not be the correct treatment for another person, and may be dangerous to the other person if she were to become pregnant. - The Misoprostol Tablets package the patient receives from the pharmacist will include a leaflet containing patient information. The patient should read the leaflet before taking Misoprostol Tablets and each time the prescription is renewed because the leaflet may have been revised. - Keep Misoprostol Tablets out of the reach of children. - SPECIAL NOTE FOR WOMEN: Misoprostol Tablets may cause abortion (sometimes incomplete), premature labor, or birth defects if given to pregnant women. - Misoprostol Tablets is available only as a unit-of-use package that includes a leaflet containing patient information. See Patient Information at the end of this labeling. # Adverse Reactions ## Clinical Trials Experience - The following have been reported as adverse events in subjects receiving Misoprostol Tablets: Gastrointestinal - In subjects receiving Misoprostol Tablets 400 or 800 mcg daily in clinical trials, the most frequent gastrointestinal adverse events were diarrhea and abdominal pain. The incidence of diarrhea at 800 mcg in controlled trials in patients on NSAIDs ranged from 14 to 40% and in all studies (over 5,000 patients) averaged 13%. Abdominal pain occurred in 13 to 20% of patients in NSAID trials and about 7% in all studies, but there was no consistent difference from placebo. - Diarrhea was dose related and usually developed early in the course of therapy (after 13 days), usually was self-limiting (often resolving after 8 days), but sometimes required discontinuation of Misoprostol Tablets (2% of the patients). Rare instances of profound diarrhea leading to severe dehydration have been reported. Patients with an underlying condition such as inflammatory bowel disease, or those in whom dehydration, were it to occur, would be dangerous, should be monitored carefully if Misoprostol Tablets is prescribed. The incidence of diarrhea can be minimized by administering after meals and at bedtime, and by avoiding coadministration of Misoprostol Tablets with magnesium-containing antacids. Gynecological - Women who received Misoprostol Tablets during clinical trials reported the following gynecological disorders: spotting (0.7%), cramps (0.6%), hypermenorrhea (0.5%), menstrual disorder (0.3%) and dysmenorrhea (0.1%). Postmenopausal vaginal bleeding may be related to Misoprostol Tablets administration. If it occurs, diagnostic workup should be undertaken to rule out gynecological pathology. (See boxed WARNINGS.) Elderly - There were no significant differences in the safety profile of Misoprostol Tablets in approximately 500 ulcer patients who were 65 years of age or older compared with younger patients. - Additional adverse events which were reported are categorized as follows: Incidence greater than 1% - In clinical trials, the following adverse reactions were reported by more than 1% of the subjects receiving Misoprostol Tablets and may be causally related to the drug: nausea (3.2%), flatulence (2.9%), headache (2.4%), dyspepsia (2.0%), vomiting (1.3%), and constipation (1.1%). However, there were no significant differences between the incidences of these events for Misoprostol Tablets and placebo. Causal relationship unknown - The following adverse events were infrequently reported. Causal relationships between Misoprostol Tablets and these events have not been established but cannot be excluded: - Body as a whole: aches/pains, asthenia, fatigue, fever, chills, rigors, weight changes. - Skin: rash, dermatitis, alopecia, pallor, breast pain. - Special senses: abnormal taste, abnormal vision, conjunctivitis, deafness, tinnitus, earache. - Respiratory: upper respiratory tract infection, bronchitis, bronchospasm, dyspnea, pneumonia, epistaxis. - Cardiovascular: chest pain, edema, diaphoresis, hypotension, hypertension, arrhythmia, phlebitis, increased cardiac enzymes, syncope, myocardial infarction (some fatal), thromboembolic events (e.g., pulmonary embolism, arterial thrombosis, and CVA). - Gastrointestinal: GI bleeding, GI inflammation/infection, rectal disorder, abnormal hepatobiliary function, gingivitis, reflux, dysphagia, amylase increase. - Hypersensitivity: anaphylactic reaction - Metabolic: glycosuria, gout, increased nitrogen, increased alkaline phosphatase. - Genitourinary: polyuria, dysuria, hematuria, urinary tract infection. - Nervous system/Psychiatric: anxiety, change in appetite, depression, drowsiness, dizziness, thirst, impotence, loss of libido, sweating increase, neuropathy, neurosis, confusion. - Musculoskeletal: arthralgia, myalgia, muscle cramps, stiffness, back pain. - Blood/Coagulation: anemia, abnormal differential, thrombocytopenia, purpura, ESR increased. ## Postmarketing Experience - There is limited information regarding Postmarketing Experience of Misoprostol in the drug label. # Drug Interactions - See Clinical Pharmacology. Misoprostol Tablets has not been shown to interfere with the beneficial effects of aspirin on signs and symptoms of rheumatoid arthritis. Misoprostol Tablets does not exert clinically significant effects on the absorption, blood levels, and antiplatelet effects of therapeutic doses of aspirin. Misoprostol Tablets has no clinically significant effect on the kinetics of diclofenac or ibuprofen. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): X Pregnancy Category X Teratogenic Effects - See boxed WARNINGS. Congenital anomalies sometimes associated with fetal death have been reported subsequent to the unsuccessful use of misoprostol as an abortifacient, but the drug's teratogenic mechanism has not been demonstrated. Several reports in the literature associate the use of misoprostol during the first trimester of pregnancy with skull defects, cranial nerve palsies, facial malformations, and limb defects. - Misoprostol Tablets is not fetotoxic or teratogenic in rats and rabbits at doses 625 and 63 times the human dose, respectively. Nonteratogenic Effects - See boxed WARNINGS. Misoprostol Tablets may endanger pregnancy (may cause abortion) and thereby cause harm to the fetus when administered to a pregnant woman. Misoprostol Tablets may produce uterine contractions, uterine bleeding, and expulsion of the products of conception. Abortions caused by Misoprostol Tablets may be incomplete. If a woman is or becomes pregnant while taking this drug to reduce the risk of NSAID-induced ulcers, the drug should be discontinued and the patient apprised of the potential hazard 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 Misoprostol in women who are pregnant. ### Labor and Delivery - Misoprostol Tablets can induce or augment uterine contractions. Vaginal administration of Misoprostol Tablets, outside of its approved indication, has been used as a cervical ripening agent, for the induction of labor and for treatment of serious postpartum hemorrhage in the presence of uterine atony. A major adverse effect of the obstetrical use of Misoprostol Tablets is the hyperstimulation of the uterus which may progress to uterine tetany with marked impairment of uteroplacental blood flow, uterine rupture (requiring surgical repair, hysterectomy, and/or salpingo-oophorectomy), or amniotic fluid embolism. Pelvic pain, retained placenta, severe genital bleeding, shock, fetal bradycardia, and fetal and maternal death have been reported. - There may be an increased risk of uterine tachysystole, uterine rupture, meconium passage, meconium staining of amniotic fluid, and Cesarean delivery due to uterine hyperstimulation with the use of higher doses of Misoprostol Tablets, including the manufactured 100 mcg tablet. The risk of uterine rupture increases with advancing gestational ages and with prior uterine surgery, including Cesarean delivery. Grand multiparity also appears to be a risk factor for uterine rupture. - The effect of Misoprostol Tablets on later growth, development, and functional maturation of the child when Misoprostol Tablets is used for cervical ripening or induction of labor has not been established. Information on Misoprostol Tablet's effect on the need for forceps delivery or other intervention is unknown. ### Nursing Mothers - Misoprostol is rapidly metabolized in the mother to misoprostol acid, which is biologically active and is excreted in breast milk. There are no published reports of adverse effects of misoprostol in breast-feeding infants of mothers taking misoprostol. Caution should be exercised when misoprostol is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness of Misoprostol Tablets in pediatric patients have not been established. ### Geriatic Use - There is no FDA guidance on the use of Misoprostol with respect to geriatric patients. ### Gender - There is no FDA guidance on the use of Misoprostol with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Misoprostol with respect to specific racial populations. ### Renal Impairment - There is no FDA guidance on the use of Misoprostol in patients with renal impairment. ### Hepatic Impairment - There is no FDA guidance on the use of Misoprostol in patients with hepatic impairment. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Misoprostol in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Misoprostol in patients who are immunocompromised. # Administration and Monitoring ### Administration - The recommended adult oral dose of Misoprostol Tablets for reducing the risk of NSAID-induced gastric ulcers is 200 mcg four times daily with food. If this dose cannot be tolerated, a dose of 100 mcg can be used. Misoprostol Tablets should be taken for the duration of NSAID therapy as prescribed by the physician. Misoprostol Tablets should be taken with a meal, and the last dose of the day should be at bedtime. Renal impairment - Adjustment of the dosing schedule in renally impaired patients is not routinely needed, but dosage can be reduced if the 200-mcg dose is not tolerated. (See Clinical Pharmacology.) ### Monitoring - There is limited information regarding Monitoring of Misoprostol in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Misoprostol in the drug label. # Overdosage - The toxic dose of Misoprostol Tablets in humans has not been determined. Cumulative total daily doses of 1600 mcg have been tolerated, with only symptoms of gastrointestinal discomfort being reported. In animals, the acute toxic effects are diarrhea, gastrointestinal lesions, focal cardiac necrosis, hepatic necrosis, renal tubular necrosis, testicular atrophy, respiratory difficulties, and depression of the central nervous system. Clinical signs that may indicate an overdose are sedation, tremor, convulsions, dyspnea, abdominal pain, diarrhea, fever, palpitations, hypotension, or bradycardia. Symptoms should be treated with supportive therapy. - It is not known if misoprostol acid is dialyzable. However, because misoprostol is metabolized like a fatty acid, it is unlikely that dialysis would be appropriate treatment for overdosage. # Pharmacology ## Mechanism of Action - ## Structure - Misoprostol oral tablets contain either 100 mcg or 200 mcg of misoprostol, a synthetic prostaglandin E1 analog. - Misoprostol contains approximately equal amounts of the two diastereomers presented below with their enantiomers indicated by (±): - Misoprostol is a water-soluble, viscous liquid. - Inactive ingredients of tablets are hydrogenated castor oil, microcrystalline cellulose, and crospovidone. ## Pharmacodynamics - Misoprostol has both antisecretory (inhibiting gastric acid secretion) and (in animals) mucosal protective properties. NSAIDs inhibit prostaglandin synthesis, and a deficiency of prostaglandins within the gastric mucosa may lead to diminishing bicarbonate and mucus secretion and may contribute to the mucosal damage caused by these agents. Misoprostol can increase bicarbonate and mucus production, but in man this has been shown at doses 200 mcg and above that are also antisecretory. It is therefore not possible to tell whether the ability of misoprostol to reduce the risk of gastric ulcer is the result of its antisecretory effect, its mucosal protective effect, or both. - In vitro studies on canine parietal cells using tritiated misoprostol acid as the ligand have led to the identification and characterization of specific prostaglandin receptors. Receptor binding is saturable, reversible, and stereospecific. The sites have a high affinity for misoprostol, for its acid metabolite, and for other E type prostaglandins, but not for F or I prostaglandins and other unrelated compounds, such as histamine or cimetidine. Receptor-site affinity for misoprostol correlates well with an indirect index of antisecretory activity. It is likely that these specific receptors allow misoprostol taken with food to be effective topically, despite the lower serum concentrations attained. - Misoprostol produces a moderate decrease in pepsin concentration during basal conditions, but not during histamine stimulation. It has no significant effect on fasting or postprandial gastrin nor on intrinsic factor output. Effects on gastric acid secretion - Misoprostol, over the range of 50 to 200 mcg, inhibits basal and nocturnal gastric acid secretion, and acid secretion in response to a variety of stimuli, including meals, histamine, pentagastrin, and coffee. Activity is apparent 30 minutes after oral administration and persists for at least 3 hours. In general, the effects of 50 mcg were modest and shorter lived, and only the 200-mcg dose had substantial effects on nocturnal secretion or on histamine and meal-stimulated secretion. Uterine effects - Misoprostol Tablets has been shown to produce uterine contractions that may endanger pregnancy. (See boxed WARNINGS.) Other pharmacologic effects - Misoprostol Tablets does not produce clinically significant effects on serum levels of prolactin, gonadotropins, thyroid-stimulating hormone, growth hormone, thyroxine, cortisol, gastrointestinal hormones (somatostatin, gastrin, vasoactive intestinal polypeptide, and motilin), creatinine, or uric acid. Gastric emptying, immunologic competence, platelet aggregation, pulmonary function, or the cardiovascular system are not modified by recommended doses of Misoprostol Tablets. ## Pharmacokinetics - Misoprostol is extensively absorbed, and undergoes rapid de-esterification to its free acid, which is responsible for its clinical activity and, unlike the parent compound, is detectable in plasma. The alpha side chain undergoes beta oxidation and the beta side chain undergoes omega oxidation followed by reduction of the ketone to give prostaglandin F analogs. - In normal volunteers, misoprostol is rapidly absorbed after oral administration with a Tmax of misoprostol acid of 12 ± 3 minutes and a terminal half-life of 20 to 40 minutes. - There is high variability of plasma levels of misoprostol acid between and within studies but mean values after single doses show a linear relationship with dose over the range of 200 to 400 mcg. No accumulation of misoprostol acid was noted in multiple dose studies; plasma steady state was achieved within two days. - Maximum plasma concentrations of misoprostol acid are diminished when the dose is taken with food and total availability of misoprostol acid is reduced by use of concomitant antacid. Clinical trials were conducted with concomitant antacid, however, so this effect does not appear to be clinically important. - After oral administration of radiolabeled misoprostol, about 80% of detected radioactivity appears in urine. Pharmacokinetic studies in patients with varying degrees of renal impairment showed an approximate doubling of T1/2, Cmax , and AUC compared to normals, but no clear correlation between the degree of impairment and AUC. In subjects over 64 years of age, the AUC for misoprostol acid is increased. No routine dosage adjustment is recommended in older patients or patients with renal impairment, but dosage may need to be reduced if the usual dose is not tolerated. - Drug interaction studies between misoprostol and several nonsteroidal anti-inflammatory drugs showed no effect on the kinetics of ibuprofen or diclofenac, and a 20% decrease in aspirin AUC, not thought to be clinically significant. - Pharmacokinetic studies also showed a lack of drug interaction with antipyrine and propranolol when these drugs were given with misoprostol. Misoprostol given for 1 week had no effect on the steady state pharmacokinetics of diazepam when the two drugs were administered 2 hours apart. - The serum protein binding of misoprostol acid is less than 90% and is concentration-independent in the therapeutic range. - After a single oral dose of misoprostol to nursing mothers, misoprostol acid was excreted in breast milk. The maximum concentration of misoprostol acid in expressed breast milk was achieved within 1 hour after dosing and was 7.6 pg/mL (CV 37%) and 20.9 pg/ml (CV 62%) after single 200 mg and 600 mg misoprostol administration, respectively. The misoprostol acid concentrations in breast milk declined to < 1 pg/ml at 5 hours post-dose. ## Nonclinical Toxicology Animal toxicology - A reversible increase in the number of normal surface gastric epithelial cells occurred in the dog, rat, and mouse. No such increase has been observed in humans administered Misoprostol Tablets for up to 1 year. - An apparent response of the female mouse to Misoprostol Tablets in long-term studies at 100 to 1000 times the human dose was hyperostosis, mainly of the medulla of sternebrae. Hyperostosis did not occur in long-term studies in the dog and rat and has not been seen in humans treated with Misoprostol Tablets. Carcinogenesis, Mutagenesis, Impairment of Fertility - There was no evidence of an effect of Misoprostol Tablets on tumor occurrence or incidence in rats receiving daily doses up to 150 times the human dose for 24 months. Similarly, there was no effect of Misoprostol Tablets on tumor occurrence or incidence in mice receiving daily doses up to 1000 times the human dose for 21 months. The mutagenic potential of Misoprostol Tablets was tested in several in vitro assays, all of which were negative. - Misoprostol, when administered to breeding male and female rats at doses 6.25 times to 625 times the maximum recommended human therapeutic dose, produced dose-related pre- and post-implantation losses and a significant decrease in the number of live pups born at the highest dose. These findings suggest the possibility of a general adverse effect on fertility in males and females. # Clinical Studies - In a series of small short-term (about 1 week) placebo-controlled studies in healthy human volunteers, doses of misoprostol were evaluated for their ability to reduce the risk of NSAID-induced mucosal injury. Studies of 200 mcg q.i.d. of misoprostol with tolmetin and naproxen, and of 100 and 200 mcg q.i.d. with ibuprofen, all showed reduction of the rate of significant endoscopic injury from about 70 to 75% on placebo to 10 to 30% on misoprostol. Doses of 25 to 200 mcg q.i.d. reduced aspirin-induced mucosal injury and bleeding. Reducing the risk of gastric ulcers caused by nonsteroidal anti-inflammatory drugs (NSAIDs) - Two 12-week, randomized, double-blind trials in osteoarthritic patients who had gastrointestinal symptoms but no ulcer on endoscopy while taking an NSAID compared the ability of 200 mcg of Misoprostol Tablets, 100 mcg of Misoprostol Tablets, and placebo to reduce the risk of gastric ulcer (GU) formation. Patients were approximately equally divided between ibuprofen, piroxicam, and naproxen, and continued this treatment throughout the 12 weeks. The 200-mcg dose caused a marked, statistically significant reduction in gastric ulcers in both studies. The lower dose was somewhat less effective, with a significant result in only one of the studies. - In these trials there were no significant differences between Misoprostol Tablets and placebo in relief of day or night abdominal pain. No effect of Misoprostol Tablets in reducing the risk of duodenal ulcers was demonstrated, but relatively few duodenal lesions were seen. - In another clinical trial, 239 patients receiving aspirin 650 to 1300 mg q.i.d. for rheumatoid arthritis who had endoscopic evidence of duodenal and/or gastric inflammation were randomized to misoprostol 200 mcg q.i.d. or placebo for 8 weeks while continuing to receive aspirin. The study evaluated the possible interference of Misoprostol Tablets on the efficacy of aspirin in these patients with rheumatoid arthritis by analyzing joint tenderness, joint swelling, physician's clinical assessment, patient's assessment, change in ARA classification, change in handgrip strength, change in duration of morning stiffness, patient's assessment of pain at rest, movement, interference with daily activity, and ESR. Misoprostol Tablets did not interfere with the efficacy of aspirin in these patients with rheumatoid arthritis. # How Supplied - Misoprostol Tablets 100-mcg tablets are round, white flat-faced beveled edge tablets, debossed "160" on one side and "n" on other side. - Misoprostol Tablets 200-mcg tablets are round, white flat-faced beveled edge bisected tablets, debossed "161" above the bisect and "n" below the bisect and plain on the other side. ## Storage - Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Store in a dry area. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Information for Patients - Women of childbearing potential using Misoprostol Tablets to decrease the risk of NSAID-induced ulcers should be told that they must not be pregnant when Misoprostol Tablets therapy is initiated, and that they must use an effective contraception method while taking Misoprostol Tablets. - See boxed WARNINGS. - Misoprostol Tablets is intended for administration along with nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, to decrease the chance of developing an NSAID-induced gastric ulcer. - Misoprostol Tablets should be taken only according to the directions given by a physician. - If the patient has questions about or problems with Misoprostol Tablets, the physician should be contacted promptly. - THE PATIENT SHOULD NOT GIVE MISOPROSTOL TABLETS TO ANYONE ELSE. Misoprostol Tablets has been prescribed for the patient's specific condition, may not be the correct treatment for another person, and may be dangerous to the other person if she were to become pregnant. - The Misoprostol Tablets package the patient receives from the pharmacist will include a leaflet containing patient information. The patient should read the leaflet before taking Misoprostol Tablets and each time the prescription is renewed because the leaflet may have been revised. - Keep Misoprostol Tablets out of the reach of children. - SPECIAL NOTE FOR WOMEN: Misoprostol Tablets may cause abortion (sometimes incomplete), premature labor, or birth defects if given to pregnant women. - Misoprostol Tablets is available only as a unit-of-use package that includes a leaflet containing patient information. See Patient Information at the end of this labeling. ### MEDICATION GUIDE - Read this leaflet before taking Misoprostol Tablets and each time your prescription is renewed, because the leaflet may be changed. - Misoprostol Tablets is being prescribed by your doctor to decrease the chance of getting stomach ulcers related to the arthritis/pain medication that you take. - Do not take Misoprostol Tablets to reduce the risk of NSAID-induced ulcers if you are pregnant. (See boxed WARNINGS.) Misoprostol Tablets can cause abortion (sometimes incomplete which could lead to dangerous bleeding and require hospitalization and surgery), premature birth, or birth defects. It is also important to avoid pregnancy while taking this medication and for at least one month or through one menstrual cycle after you stop taking it. Misoprostol Tablets has been reported to cause the uterus to rupture (tear) when given after the eighth week of pregnancy. Rupture (tearing) of the uterus can result in severe bleeding, hysterectomy, and/or maternal or fetal death. - If you become pregnant during Misoprostol Tablets therapy, stop taking Misoprostol Tablets and contact your physician immediately. Remember that even if you are on a means of birth control it is still possible to become pregnant. Should this occur, stop taking Misoprostol Tablets and contact your physician immediately. - Misoprostol Tablets may cause diarrhea, abdominal cramping, and/or nausea in some people. In most cases these problems develop during the first few weeks of therapy and stop after about a week. You can minimize possible diarrhea by making sure you take Misoprostol Tablets with food. - Because these side effects are usually mild to moderate and usually go away in a matter of days, most patients can continue to take Misoprostol Tablets. If you have prolonged difficulty (more than 8 days), or if you have severe diarrhea, cramping and/or nausea, call your doctor. - Take Misoprostol Tablets only according to the directions given by your physician. - Do not give Misoprostol Tablets to anyone else. It has been prescribed for your specific condition, may not be the correct treatment for another person, and would be dangerous if the other person were pregnant. - This information sheet does not cover all possible side effects of Misoprostol Tablets. This patient information leaflet does not address the side effects of your arthritis/pain medication. See your doctor if you have questions. - Keep out of reach of children. # Precautions with Alcohol - Alcohol-Misoprostol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Cytotec # Look-Alike Drug Names - A® — B®[1] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Cytotec
b66fd9557a6cdffad5fdbdb0f1faab6d3b716e16	wikidoc	D.D. Palmer	D.D. Palmer Daniel David Palmer or D.D. Palmer (March 7, 1845 – October 20, 1913) was the founder of Chiropractic. # Biography Palmer was born in Pickering, Ontario, near Toronto, Canada to Katherine McVay and Thomas Palmer. At age twenty he moved to the United States with his family. Palmer held various jobs as a beekeeper, school teacher, and grocery store owner, and had an interest in the various health philosophies of his day, such as magnetic healing, and Spiritualism. Palmer practiced magnetic healing beginning in the mid-1880s in Burlington, Iowa, and Davenport, Iowa. Palmer read medical journals of his time and followed developments throughout the world regarding anatomy and physiology. While working as a magnetic healer in Davenport, Iowa, he encountered a deaf janitor who he discovered had a palpable lump in his back. He theorized that the lump and his deafness were related. After a reported successful restoration of the man's hearing, it led to the beginning of Chiropractic history. His theories revolved around the concept that altered nerve flow was the cause of all disease, and that misaligned spinal vertebrae had an effect on the nerve flow. He postulated that restoring these vertebra to their proper alignment would restore health. Palmer founded a school based on his work that would become the Palmer School of Chiropractic in 1897. By 1902 the school had graduated 15 chiropractors. In 1906, Palmer was prosecuted under the new medical arts law in Iowa for practicing medicine without a license, and chose to go to jail instead of paying the fine. As a result, he spent 17 days in jail, but then elected to pay the fine. Shortly thereafter, he sold the school of chiropractic to his son, B. J. Palmer. With the help of an arbitration committee, the deal was settled for $2,196.79, various books, and some specimens from the osteological collection. As soon as the sale of the school was finalized, D.D. Palmer went to the West Coast, where he helped to found chiropractic schools in Oklahoma, California, and Oregon. The relationship with his son BJ was tenuous and often bitter, especially after the sale of his school. Their subsequent disagreements regarding the direction of the emerging field of chiropractic were evident in D.D. Palmer's writings. Even the circumstances surrounding his death were postulated to be attributable to BJ. Court records reflect that during a founders day parade in Davenport in August 1913, DD was marching on foot and was allegedly struck from behind by a car driven by BJ. Others denied he was struck by BJ's vehicle. He died in Los Angeles, California on October 20, 1913. The official cause of death was typhoid fever, though some believe it was the consequence of his injuries. The courts exonerated BJ of any responsibility for his father's death. # Palmer's fundamental idea D.D. Palmer's effort to find a single cause for all disease led him to say: # Palmer's mysticism D.D. Palmer was a man with subjective and personal religious beliefs. As an active spiritist, he said he "received chiropractic from the other world" from a deceased medical physician named Dr. Jim Atkinson. According to B. J. Palmer "Father often attended the annual Mississippi Valley Spiritualists Camp Meeting at Clinton, Iowa... That is where he first received messages from Dr. Jim Atkinson on the principles of chiropractic." Such messages were normally received during seances, but Palmer claimed to have received them through "inspiration". In his book, The Chiropractor (published posthumously, 1914), Palmer described the situation: He regarded chiropractic as partly religious in nature. In a letter of May 4, 1911 he said: In his 1914 book, the first chapter expanded on his religious views of chiropractic: "The Moral and Religious Duty of a Chiropractor". In it he dealt with religious liberty and stated: Later in the book he distanced himself from actually renaming the profession to the "religion of chiropractic" and discussed the differences between a formal, objective religion and a personal, subjective ethical religious belief. (p. 6) He reaffirmed that chiropractors have a religious and moral duty, and ended the first chapter by stating: # Detractors Palmer met opposition and was accused of being a crank and a quack. An 1894 edition of the local paper, the Davenport Leader, wrote: # Quotes The following quotes are from D.D. Palmer's book, The Chiropractor's Adjuster (also called The Text-Book of the Science, Art and Philosophy of Chiropractic). The book was published in 1910 by the Portland Printing House Company of Portland, Oregon, and reprinted in 1966 by his grandson, David D. Palmer, 1966. - Disease: “The kind of disease depends upon what nerves are too tense or too slack.” - Chiropractic for intellectual abnormalities: “Chiropractors correct abnormalities of the intellect as well as those of the body.” - Life and Religion: "I have answered the time-worn question — what is life?”: “The dualistic system — spirit and body — united by intellectual life — the soul — is the basis of this science of biology” - "There can be no healing without Teaching..." - "There is a vast difference between treating effects and adjusting the causes." # Bibliography - The Chiropractor's Adjuster (also called The Text-Book of the Science, Art and Philosophy of Chiropractic), Daniel David Palmer, Portland Printing House, 1910 (reprint: 1966).	D.D. Palmer Daniel David Palmer or D.D. Palmer (March 7, 1845 – October 20, 1913) was the founder of Chiropractic. # Biography Palmer was born in Pickering, Ontario, near Toronto, Canada to Katherine McVay and Thomas Palmer.[1] At age twenty he moved to the United States with his family. Palmer held various jobs as a beekeeper, school teacher, and grocery store owner, and had an interest in the various health philosophies of his day, such as magnetic healing, and Spiritualism. Palmer practiced magnetic healing beginning in the mid-1880s in Burlington, Iowa, and Davenport, Iowa. Palmer read medical journals of his time and followed developments throughout the world regarding anatomy and physiology. While working as a magnetic healer in Davenport, Iowa, he encountered a deaf janitor who he discovered had a palpable lump in his back. He theorized that the lump and his deafness were related. After a reported successful restoration of the man's hearing,[2] it led to the beginning of Chiropractic history. His theories revolved around the concept that altered nerve flow was the cause of all disease, and that misaligned spinal vertebrae had an effect on the nerve flow. He postulated that restoring these vertebra to their proper alignment would restore health. Palmer founded a school based on his work that would become the Palmer School of Chiropractic in 1897. By 1902 the school had graduated 15 chiropractors. In 1906, Palmer was prosecuted under the new medical arts law in Iowa for practicing medicine without a license, and chose to go to jail instead of paying the fine. As a result, he spent 17 days in jail, but then elected to pay the fine. Shortly thereafter, he sold the school of chiropractic to his son, B. J. Palmer. With the help of an arbitration committee, the deal was settled for $2,196.79, various books, and some specimens from the osteological collection. As soon as the sale of the school was finalized, D.D. Palmer went to the West Coast, where he helped to found chiropractic schools in Oklahoma, California, and Oregon. The relationship with his son BJ was tenuous and often bitter, especially after the sale of his school. Their subsequent disagreements regarding the direction of the emerging field of chiropractic were evident in D.D. Palmer's writings. Even the circumstances surrounding his death were postulated to be attributable to BJ. Court records reflect that during a founders day parade in Davenport in August 1913, DD was marching on foot and was allegedly struck from behind by a car driven by BJ. Others denied he was struck by BJ's vehicle. He died in Los Angeles, California on October 20, 1913. The official cause of death was typhoid fever, though some believe it was the consequence of his injuries. The courts exonerated BJ of any responsibility for his father's death. # Palmer's fundamental idea D.D. Palmer's effort to find a single cause for all disease led him to say: # Palmer's mysticism D.D. Palmer was a man with subjective and personal religious beliefs. As an active spiritist, he said he "received chiropractic from the other world"[3] from a deceased medical physician named Dr. Jim Atkinson.[4] According to B. J. Palmer "Father often attended the annual Mississippi Valley Spiritualists Camp Meeting at Clinton, Iowa... That is where he first received messages from Dr. Jim Atkinson on the principles of chiropractic."[5] Such messages were normally received during seances, but Palmer claimed to have received them through "inspiration".[6] In his book, The Chiropractor (published posthumously, 1914), Palmer described the situation: He regarded chiropractic as partly religious in nature. In a letter of May 4, 1911 he said: In his 1914 book, the first chapter expanded on his religious views of chiropractic: "The Moral and Religious Duty of a Chiropractor".[6] In it he dealt with religious liberty and stated: Later in the book he distanced himself from actually renaming the profession to the "religion of chiropractic" and discussed the differences between a formal, objective religion and a personal, subjective ethical religious belief. (p. 6) He reaffirmed that chiropractors have a religious and moral duty, and ended the first chapter by stating: # Detractors Palmer met opposition and was accused of being a crank and a quack. An 1894 edition of the local paper, the Davenport Leader, wrote: # Quotes The following quotes are from D.D. Palmer's book, The Chiropractor's Adjuster (also called The Text-Book of the Science, Art and Philosophy of Chiropractic). The book was published in 1910 by the Portland Printing House Company of Portland, Oregon, and reprinted in 1966 by his grandson, David D. Palmer, 1966. - Disease: “The kind of disease depends upon what nerves are too tense or too slack.” - Chiropractic for intellectual abnormalities: “Chiropractors correct abnormalities of the intellect as well as those of the body.” - Life and Religion: "I have answered the time-worn question — what is life?”: “The dualistic system — spirit and body — united by intellectual life — the soul — is the basis of this science of biology” - "There can be no healing without Teaching..." - "There is a vast difference between treating effects and adjusting the causes." # Bibliography - The Chiropractor's Adjuster (also called The Text-Book of the Science, Art and Philosophy of Chiropractic), Daniel David Palmer, Portland Printing House, 1910 (reprint: 1966).	https://www.wikidoc.org/index.php/D.D._Palmer
3baa7aaebce36a0e0dbf1a45c16c496be1727b20	wikidoc	Diglyceride	Diglyceride # Overview A diglyceride, more correctly known as a diacylglycerol, is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages. Shown on the right is 1-palmitoyl-2-oleoyl-glycerol but diacylglycerol can have many different combinations of fatty acids attached at the C-1 and C-2 positions. # Food Additive Mono- and Diacylglycerols are common food additives used to blend together certain ingredients, such as oil and water, which would not otherwise blend well. The commercial source may be either animal (cow- or hog-derived) or vegetable, derived primarily from soy bean and canola oil. They may also be synthetically produced. They are often found in bakery products, beverages, ice cream, chewing gum, shortening, whipped toppings, margarine, and confections. # Function ## Activate PKC In biochemical signaling, diacylglycerol (DAG) functions as a second messenger signaling lipid, a resultant of a reaction conducted by enzyme phospholipase C (PLC) (a membrane-bound enzyme) that, through the same reaction, produces inositol triphosphate (IP3). Although inositol triphosphate (IP3) diffuses into the cytosol, diacylglycerol (DAG) stays close to the plasma membrane, due to its hydrophobic properties. IP3 stimulates the release of calcium ions from the smooth endoplasmic reticulum, whereas DAG is still membrane-associated and activates protein kinase C (PKC). However, for DAG to activate PKC, there needs to be a cytosolic increase in calcium ions, which is accomplished by IP3. Diacylglycerol can be mimicked by phorbol esters. Further reading: function of PKC ## Other In addition to activating PKC, diacylglycerol has a number of other functions in the cell: - a source for prostaglandins - a precursor of the endocannabinoid 2-arachidonoylglycerol - an activator of a subfamily of TRPC (Transient Receptor Potential Canonical) cation channels, TRPC3/6/7. # Metabolism Synthesis of diacylglycerol begins with glycerol-3-phosphate, which is derived primarily from dihydroxyacetone phosphate, a product of glycolysis (usually in the cytoplasm of liver or adipose tissue cells). Glycerol-3-phosphate is first acylated with acyl-coenzyme A (acyl-CoA) to form lysophosphatidic acid, which is then acylated with another molecule of acyl-CoA to yield phosphatidic acid. Phosphatidic acid is then de-phosphorylated to form diacylglycerol. Diacylglycerol is a precursor to triacylglycerol (triglyceride), which is formed in the addition of a third fatty acid to the diacylglycerol under the catalysis of diglyceride acyltransferase. Since diacylglycerol is synthesized via phosphatidic acid, it will usually contain a saturated fatty acid at the C-1 position on the glycerol moiety and an unsaturated fatty acid at the C-2 position. # Additional images - PIP2 cleavage to IP3 and DAG initiates intracellular calcium release and PKC activation.	Diglyceride Template:Chembox new # Overview A diglyceride, more correctly known as a diacylglycerol, is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages. Shown on the right is 1-palmitoyl-2-oleoyl-glycerol but diacylglycerol can have many different combinations of fatty acids attached at the C-1 and C-2 positions. # Food Additive Mono- and Diacylglycerols are common food additives used to blend together certain ingredients, such as oil and water, which would not otherwise blend well. The commercial source may be either animal (cow- or hog-derived) or vegetable, derived primarily from soy bean and canola oil. They may also be synthetically produced. They are often found in bakery products, beverages, ice cream, chewing gum, shortening, whipped toppings, margarine, and confections. # Function ## Activate PKC In biochemical signaling, diacylglycerol (DAG) functions as a second messenger signaling lipid, a resultant of a reaction conducted by enzyme phospholipase C (PLC) (a membrane-bound enzyme) that, through the same reaction, produces inositol triphosphate (IP3). Although inositol triphosphate (IP3) diffuses into the cytosol, diacylglycerol (DAG) stays close to the plasma membrane, due to its hydrophobic properties. IP3 stimulates the release of calcium ions from the smooth endoplasmic reticulum, whereas DAG is still membrane-associated and activates protein kinase C (PKC). However, for DAG to activate PKC, there needs to be a cytosolic increase in calcium ions, which is accomplished by IP3. Diacylglycerol can be mimicked by phorbol esters. Further reading: function of PKC ## Other In addition to activating PKC, diacylglycerol has a number of other functions in the cell: - a source for prostaglandins - a precursor of the endocannabinoid 2-arachidonoylglycerol - an activator of a subfamily of TRPC (Transient Receptor Potential Canonical) cation channels, TRPC3/6/7. # Metabolism Synthesis of diacylglycerol begins with glycerol-3-phosphate, which is derived primarily from dihydroxyacetone phosphate, a product of glycolysis (usually in the cytoplasm of liver or adipose tissue cells). Glycerol-3-phosphate is first acylated with acyl-coenzyme A (acyl-CoA) to form lysophosphatidic acid, which is then acylated with another molecule of acyl-CoA to yield phosphatidic acid. Phosphatidic acid is then de-phosphorylated to form diacylglycerol. Diacylglycerol is a precursor to triacylglycerol (triglyceride), which is formed in the addition of a third fatty acid to the diacylglycerol under the catalysis of diglyceride acyltransferase. Since diacylglycerol is synthesized via phosphatidic acid, it will usually contain a saturated fatty acid at the C-1 position on the glycerol moiety and an unsaturated fatty acid at the C-2 position. [1] # Additional images - PIP2 cleavage to IP3 and DAG initiates intracellular calcium release and PKC activation.	https://www.wikidoc.org/index.php/DAG
fae66f99d11df62bd21b19a6396c1eb5cd0d2660	wikidoc	DARS (gene)	DARS (gene) Aspartyl-tRNA synthetase, cytoplasmic is an enzyme that in humans is encoded by the DARS gene. Aspartyl-tRNA synthetase (DARS) is part of a multienzyme complex of aminoacyl-tRNA synthetases. Aspartyl-tRNA synthetase charges its cognate tRNA with aspartate during protein biosynthesis. # Clinical significance Mutations in DARS have been identified as the cause of leukoencephalopathy, hypomyelination with brain stem and spinal cord involvement and leg spasticity (HBSL).	DARS (gene) Aspartyl-tRNA synthetase, cytoplasmic is an enzyme that in humans is encoded by the DARS gene.[1][2] Aspartyl-tRNA synthetase (DARS) is part of a multienzyme complex of aminoacyl-tRNA synthetases. Aspartyl-tRNA synthetase charges its cognate tRNA with aspartate during protein biosynthesis.[2] # Clinical significance Mutations in DARS have been identified as the cause of leukoencephalopathy, hypomyelination with brain stem and spinal cord involvement and leg spasticity (HBSL).[3]	https://www.wikidoc.org/index.php/DARS_(gene)
a2961b578b8951a5ba3b1b9990318cd5b2375f35	wikidoc	DMC1 (gene)	DMC1 (gene) Meiotic recombination protein DMC1/LIM15 homolog is a protein that in humans is encoded by the DMC1 gene. Meiotic recombination protein Dmc1 is a homolog of the bacterial strand exchange protein RecA. Dmc1 plays the central role in homologous recombination in meiosis by assembling at the sites of programmed DNA double strand breaks and carrying out a search for allelic DNA sequences located on homologous chromatids. The name "Dmc" stands for "disrupted meiotic cDNA" and refers to the method used for its discovery which involved using clones from a meiosis-specific cDNA library to direct knock-out mutations of abundantly expressed meiotic genes. The Dmc1 protein is one of two homologs of RecA found in eukaryotic cells, the other being Rad51. In budding yeast, Rad51 serves as a strand exchange protein in mitosis where it is critical for the repair of DNA breaks. Rad51 is converted to an accessory factor for Dmc1 during meiosis by inhibition of its strand exchange activity. Homologs of DMC1 have been identified in many organisms including divergent fungi, plants and mammals including humans. # Discovery The DMC1 gene and protein were discovered in the budding yeast S. cerevisiae by Douglas Bishop when he was a postdoctoral fellow in the laboratory of Nancy Kleckner at Harvard University. # Function The protein encoded by this gene is essential for meiotic homologous recombination. Genetic recombination in meiosis plays an important role in generating diversity of genetic information and facilitates the reductional segregation of chromosomes that must occur for formation of gametes during sexual reproduction. Like other members of the Rad51/RecA family, Dmc1 stabilizes strand exchange intermediates (Rad1/RecA-stretched DNA, or RS-DNA) in stretched triplets similar to B form DNA. Each molecule of the protein binds a triplet of nucleotides, and the strength of that binding, as assessed by the change in Gibbs free energy, can be assessed by the length of time that a labelled dsDNA probe with a short homologous sequence remains bound to a DNA containing a short region of homology to it. A study of this type has shown that a mismatch in any of the three positions at the end of a stretch of homology will not increase the length of time that the probe remains bound, and in Rad51 or RecA constructs an internal mismatch will cause a similar reduction in binding time. All of the enzymes are capable of "stepping over" a mismatch and continuing to bind the probe more firmly if a longer region of homology exists. However, with Dmc1 a triplet with a single internal (but not terminal) mismatch will contribute to the stability of probe binding to a similar extent as one without a mismatch. In this way, Dmc1 is specially suited to its role as a meiosis-specific recombinase, as this activity permits it more effectively to catalyze recombination between sequences that are not perfectly matched. # Interactions DMC1 (gene) has been shown to interact with RAD51. The protein has also been shown to bind Tid1(Rdh54), Mei5/Sae3, and Hop2/Mnd1. All of these interacting proteins act to enhance Dmc1's activity in purified systems and are also implicated as being required for Dmc1 function in cells. ## Rad51 interaction with Dmc1 During meiosis, the two recombinases, Rad51 and Dmc1, interact with single-stranded DNA to form specialized filaments that are adapted for facilitating recombination between homologous chromosomes. Both Dmc1 and Rad51 have an intrinsic ability to self-aggregate. The presence of Rad51 filaments stabilizes adjacent Dmc1 filaments and conversely Dmc1 stabilizes adjacent Rad51 filaments. A model was proposed in which Dmc1 and Rad51 form separate filaments on the same single stranded DNA and cross-talk between the two recombinases affects their biochemical properties. During meiosis, even in the absence of Rad51 strand exchange activity, Dmc1 appears to be able to repair all meiotic DNA breaks, and this absence does not affect meiotic crossing over rates.	DMC1 (gene) Meiotic recombination protein DMC1/LIM15 homolog is a protein that in humans is encoded by the DMC1 gene.[1][2][3][4] Meiotic recombination protein Dmc1 is a homolog of the bacterial strand exchange protein RecA. Dmc1 plays the central role in homologous recombination in meiosis by assembling at the sites of programmed DNA double strand breaks and carrying out a search for allelic DNA sequences located on homologous chromatids. The name "Dmc" stands for "disrupted meiotic cDNA" and refers to the method used for its discovery which involved using clones from a meiosis-specific cDNA library to direct knock-out mutations of abundantly expressed meiotic genes. The Dmc1 protein is one of two homologs of RecA found in eukaryotic cells, the other being Rad51. In budding yeast, Rad51 serves as a strand exchange protein in mitosis where it is critical for the repair of DNA breaks. Rad51 is converted to an accessory factor for Dmc1 during meiosis by inhibition of its strand exchange activity.[5] Homologs of DMC1 have been identified in many organisms including divergent fungi, plants and mammals including humans.[1][2][3][4] # Discovery The DMC1 gene and protein were discovered in the budding yeast S. cerevisiae by Douglas Bishop when he was a postdoctoral fellow in the laboratory of Nancy Kleckner at Harvard University.[6] # Function The protein encoded by this gene is essential for meiotic homologous recombination. Genetic recombination in meiosis plays an important role in generating diversity of genetic information and facilitates the reductional segregation of chromosomes that must occur for formation of gametes during sexual reproduction. Like other members of the Rad51/RecA family, Dmc1 stabilizes strand exchange intermediates (Rad1/RecA-stretched DNA, or RS-DNA) in stretched triplets similar to B form DNA. Each molecule of the protein binds a triplet of nucleotides, and the strength of that binding, as assessed by the change in Gibbs free energy, can be assessed by the length of time that a labelled dsDNA probe with a short homologous sequence remains bound to a DNA containing a short region of homology to it. A study of this type has shown that a mismatch in any of the three positions at the end of a stretch of homology will not increase the length of time that the probe remains bound, and in Rad51 or RecA constructs an internal mismatch will cause a similar reduction in binding time. All of the enzymes are capable of "stepping over" a mismatch and continuing to bind the probe more firmly if a longer region of homology exists. However, with Dmc1 a triplet with a single internal (but not terminal) mismatch will contribute to the stability of probe binding to a similar extent as one without a mismatch. In this way, Dmc1 is specially suited to its role as a meiosis-specific recombinase, as this activity permits it more effectively to catalyze recombination between sequences that are not perfectly matched.[7] # Interactions DMC1 (gene) has been shown to interact with RAD51.[8] The protein has also been shown to bind Tid1(Rdh54), Mei5/Sae3, and Hop2/Mnd1. All of these interacting proteins act to enhance Dmc1's activity in purified systems and are also implicated as being required for Dmc1 function in cells. ## Rad51 interaction with Dmc1 During meiosis, the two recombinases, Rad51 and Dmc1, interact with single-stranded DNA to form specialized filaments that are adapted for facilitating recombination between homologous chromosomes. Both Dmc1 and Rad51 have an intrinsic ability to self-aggregate.[9] The presence of Rad51 filaments stabilizes adjacent Dmc1 filaments and conversely Dmc1 stabilizes adjacent Rad51 filaments. A model was proposed in which Dmc1 and Rad51 form separate filaments on the same single stranded DNA and cross-talk between the two recombinases affects their biochemical properties.[9] During meiosis, even in the absence of Rad51 strand exchange activity, Dmc1 appears to be able to repair all meiotic DNA breaks, and this absence does not affect meiotic crossing over rates.[10]	https://www.wikidoc.org/index.php/DMC1_(gene)
ef3bad353703b8a46aef273d965490afc30ceb65	wikidoc	DPT vaccine	DPT vaccine DPT, (sometimes DTP) is a mixture of three vaccines, to immunize against diphtheria, pertussis (whooping cough) and tetanus. DTP vaccine may be distinguished as "DTwP" and "DTaP", with "wP" referring to "whole cell pertussis" and "aP" referring to "acellular pertussis". (The acellular form is considered safer and contains far fewer antigens than the older preparation.) Current versions of DTP in Europe do not contain preservatives; older ones contained Thiomersal. In the Netherlands, DTP refers to a mixture of diphtheria, tetanus and poliomyelitis vaccines. Moderate reactions to DPT vaccines occur in 0.1% to 1.0% of children and include ongoing crying (for three hours or more), a high fever (up to 40 °C / 105 °F), and an unusual, high-pitched crying. Severe problems closely following DPT immunization happen very rarely. These include a serious allergic reaction, prolonged seizures, a decrease in consciousness, lasting brain disease, or even death. Such severe neurologic events occur after approximately 1 in 140,000 doses of the DPT vaccine (0.0007%). Most of the reactions to DPT injection are thought to be from the pertussis component. In 1994, the Institute of Medicine of the US National Academy of Sciences published a report stating that if the first symptoms of neurological damage occurred within the first seven days following vaccination with whole-cell pertussis vaccine, the evidence was compatible with the possibility that it could be the cause of permanent brain damage in otherwise apparently healthy children. It continued by stating: A safer acellular pertussis vaccine (DTaP) was introduced in the US in 1991; since 2002, whole-cell pertussis vaccines are no longer used in the US. The usual course of immunisation is five doses between 2 months and 15 years. Also known by the trademarked name Triple Antigen™. # DTaP DTaP is an acronym for the combined diphtheria, tetanus, and acellular pertussis vaccine. The "a" denotes the vaccine's acellular pertussis components, distinguishing it from whole-cell, inactivated DTP (aka DTwP) vaccine. The acellular vaccine uses antigenic fragments of the pertussis pathogen to induce immunity. The advantage of the acellular vaccine is that it causes substantially fewer side-effects (estimated at 90% fewer), which commonly include local pain and redness, and/or fever. Both DTP and DTaP appear to equally efficacious in generating immunity, but DTaP is universally accepted as safer. Most of the developed world has switched to DTaP, but developing countries continue to use DTP, which is substantially cheaper. # TDaP Tdap is the acronym for the collective vaccines preventing tetanus, diphtheria, and pertussis in adolescents and adults that were licensed in the United States in spring of 2005. These vaccines differ from the childhood DTaP vaccines in their indication. The concentration of diphtheria has been reduced in these formulations to prevent adverse reactions. Two Tdap vaccines are available in the U.S. Adacel(R),manufactured by sanofi pasteur, is licensed for use in adults ages 11 to 64. Boostrix(R), manufactured by GlaxoSmithKline, is licensed for use in adolescents ages 10 to 19. The U.S.'s Advisory Committee on Immunization Practices (ACIP) and Canada's National Advisory Committee on Immunization (NACI) both recommended adolescents and adults receive Tdap in place of their next Td booster (recommend to be given every 10 years). Tdap can be used as prophylaxis for tetanus wound management. Five years between doses of Td or doses of Td and Tdap is the current standard of care; frequent exposure to tetanus toxoid can cause local reactions. People who will be in contact with young infants are encouraged to get Tdap even if it has been less than 5 years since Td or TT to reduce the risk of infants being exposed to pertussis. The ACIP statement on Tdap use in adolescents encourages 5 years between Td and Tdap to reduce this risk; however, both suggest that shorter intervals may be appropriate in some circumstances, such as for protection in pertussis outbreaks. NACI suggests intervals shorter than 5 years can be used for catch-up programs and other instances where programmatic concerns make 5-year intervals difficult.	DPT vaccine DPT, (sometimes DTP) is a mixture of three vaccines, to immunize against diphtheria, pertussis (whooping cough) and tetanus. DTP vaccine may be distinguished as "DTwP" and "DTaP", with "wP" referring to "whole cell pertussis" and "aP" referring to "acellular pertussis". (The acellular form is considered safer and contains far fewer antigens than the older preparation.) Current versions of DTP in Europe do not contain preservatives; older ones contained Thiomersal. In the Netherlands, DTP refers to a mixture of diphtheria, tetanus and poliomyelitis vaccines. Moderate reactions to DPT vaccines occur in 0.1% to 1.0% of children and include ongoing crying (for three hours or more), a high fever (up to 40 °C / 105 °F), and an unusual, high-pitched crying. Severe problems closely following DPT immunization happen very rarely. These include a serious allergic reaction, prolonged seizures, a decrease in consciousness, lasting brain disease, or even death. Such severe neurologic events occur after approximately 1 in 140,000 doses of the DPT vaccine (0.0007%). Most of the reactions to DPT injection are thought to be from the pertussis component. In 1994, the Institute of Medicine of the US National Academy of Sciences published a report stating that if the first symptoms of neurological damage occurred within the first seven days following vaccination with whole-cell pertussis vaccine, the evidence was compatible with the possibility that it could be the cause of permanent brain damage in otherwise apparently healthy children. It continued by stating: A safer acellular pertussis vaccine (DTaP) was introduced in the US in 1991; since 2002, whole-cell pertussis vaccines are no longer used in the US. The usual course of immunisation is five doses between 2 months and 15 years. Also known by the trademarked name Triple Antigen™[1]. # DTaP DTaP is an acronym for the combined diphtheria, tetanus, and acellular pertussis vaccine. The "a" denotes the vaccine's acellular pertussis components, distinguishing it from whole-cell, inactivated DTP (aka DTwP) vaccine. The acellular vaccine uses antigenic fragments of the pertussis pathogen to induce immunity. The advantage of the acellular vaccine is that it causes substantially fewer side-effects (estimated at 90% fewer), which commonly include local pain and redness, and/or fever. Both DTP and DTaP appear to equally efficacious in generating immunity, but DTaP is universally accepted as safer. Most of the developed world has switched to DTaP, but developing countries continue to use DTP, which is substantially cheaper. # TDaP Tdap is the acronym for the collective vaccines preventing tetanus, diphtheria, and pertussis in adolescents and adults that were licensed in the United States in spring of 2005. These vaccines differ from the childhood DTaP vaccines in their indication. The concentration of diphtheria has been reduced in these formulations to prevent adverse reactions. Two Tdap vaccines are available in the U.S. Adacel(R),manufactured by sanofi pasteur, is licensed for use in adults ages 11 to 64. Boostrix(R), manufactured by GlaxoSmithKline, is licensed for use in adolescents ages 10 to 19. The U.S.'s Advisory Committee on Immunization Practices (ACIP) and Canada's National Advisory Committee on Immunization (NACI) both recommended adolescents and adults receive Tdap in place of their next Td booster (recommend to be given every 10 years).[2] [3] [4] Tdap can be used as prophylaxis for tetanus wound management. Five years between doses of Td or doses of Td and Tdap is the current standard of care; frequent exposure to tetanus toxoid can cause local reactions. People who will be in contact with young infants are encouraged to get Tdap even if it has been less than 5 years since Td or TT to reduce the risk of infants being exposed to pertussis. The ACIP statement on Tdap use in adolescents encourages 5 years between Td and Tdap to reduce this risk; however, both suggest that shorter intervals may be appropriate in some circumstances, such as for protection in pertussis outbreaks. NACI suggests intervals shorter than 5 years can be used for catch-up programs and other instances where programmatic concerns make 5-year intervals difficult.	https://www.wikidoc.org/index.php/DPT_vaccine
5182e936f4cd5403ae083bbf53e95cdf941fe8c3	wikidoc	Dacarbazine	Dacarbazine # 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 Dacarbazine is an antineoplastic agent and alkylating agent that is FDA approved for the treatment of metastatic malignant melanoma and also indicated for Hodgkin's disease as a secondary-line therapy when used in combination with other effective agents.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include anorexia, nausea, and vomiting, influenza-like syndrome of fever to 39°C, myalgias, malaise and alopecia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dacarbazine for injection is indicated in the treatment of metastatic malignant melanoma. - Dosage - The recommended dosage is 2 to 4.5 mg/kg/day for 10days.Treatment may be repeated at 4 week intervals. - An alternate recommended dosage is 250 mg/square meter body surface/day IV for 5 days. Treatment may be repeated every 3 weeks. - In addition, dacarbazine for injection is also indicated for Hodgkin's disease as a secondary-line therapy when used in combination with other effective agents. - Dosage - The recommended dosage of dacarbazine for injection in the treatment of Hodgkin's Disease is 150 mg/square meter body surface/day for 5 days, in combination with other effective drugs. Treatment may be repeated every 4 weeks.5 An alternative recommended dosage is 375 mg/square meter body surface on day 1, in combination with other effective drugs, to be repeated every 15 days. - Dacarbazine for injection 200 mg/vial is reconstituted with 19.7 mL of sterile water for injection, USP. Dacarbazine for injection 500 mg/vial is reconstituted with 49.25 mL of sterile water for injection, USP. The resulting solution contains 10 mg/mL of dacarbazine having a pH of 3.0 to 4.0. The calculated dose of the resulting solution is drawn into a syringe and administered only intravenously. - The reconstituted solution may be further diluted with 5% dextrose injection or sodium chloride injection and administered as an intravenous infusion. - After reconstitution and prior to use, the solution in the vial may be stored at 4°C for up to 72 hours or at normal room conditions (temperature and light) for up to 8 hours. If the reconstituted solution is further diluted in 5% dextrose injection or sodium chloride injection, the resulting solution may be stored at 4°C for up to 24 hours or at normal room conditions for up to 8 hours. - Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.7–12 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of dacarbazine in adult patients. ### Non–Guideline-Supported Use - Cyclophosphamide 750 mg/square meter (m(2)) and vincristine 1.4 mg/m(2) on day 1, and dacarbazine 400 mg/m(2) on days 1 and 2; all were given intravenously and repeated every 21 days. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of dacarbazine in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of dacarbazine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of dacarbazine in pediatric patients. # Contraindications - Dacarbazine for injection is contraindicated in patients who have demonstrated a hypersensitivity to it in the past. # Warnings - [Bone marrow suppression # Adverse Reactions ## Clinical Trials Experience - Symptoms of anorexia, nausea, and vomiting are the most frequently noted of all toxic reactions. Over 90% of patients are affected with the initial few doses. The vomiting lasts 1–12 hours and is incompletely and unpredictably palliated with phenobarbital and/or prochlorperazine. Rarely, intractable nausea and vomiting have necessitated discontinuance of therapy with dacarbazine for injection. Rarely, dacarbazine for injection has caused diarrhea. Some helpful suggestions include restricting the patient's oral intake of food for 4–6 hours prior to treatment. The rapid toleration of these symptoms suggests that a central nervous system mechanism may be involved, and usually these symptoms subside after the first 1 or 2 days. - There are a number of minor toxicities that are infrequently noted. Patients have experienced an influenza-like syndrome of fever to 39°C, myalgias and malaise. These symptoms occur usually after large single doses, may last for several days, and they may occur with successive treatments. - Alopecia has been noted as has facial flushing and facial paresthesia. There have been few reports of significant liver or renal function test abnormalities in man. However, these abnormalities have been observed more frequently in animal studies. - Erythematous and urticarial rashes have been observed infrequently after administration of dacarbazine for injection. Rarely, photosensitivity reactions may occur. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of dacarbazine in the drug label. # Drug Interactions There is limited information regarding Dacarbazine Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Dacarbazine for injection has been shown to be teratogenic in rats when given in doses 20 times the human daily dose on day 12 of gestation. Dacarbazine when administered in 10 times the human daily dose to male rats (twice weekly for 9 weeks) did not affect the male libido, although female rats mated to male rats had higher incidence of resorptions than controls. In rabbits, dacarbazine daily dose 7 times the human daily dose given on days 6–15 of gestation resulted in fetal skeletal anomalies. There are no adequate and well controlled studies in pregnant women. Dacarbazine for injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of dacarbazine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of dacarbazine 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 tumorigenicity shown for dacarbazine for injection in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use There is no FDA guidance on the use of dacarbazine with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of dacarbazine with respect to geriatric patients. ### Gender There is no FDA guidance on the use of dacarbazine with respect to specific gender populations. ### Race There is no FDA guidance on the use of dacarbazine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of dacarbazine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of dacarbazine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of dacarbazine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of dacarbazine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring There is limited information regarding Monitoring of dacarbazine in the drug label. - Description # IV Compatibility There is limited information regarding IV Compatibility of dacarbazine in the drug label. # Overdosage Give supportive treatment and monitor blood cell counts. # Pharmacology ## Mechanism of Action - Although the exact mechanism of action of dacarbazine for injection is not known, three hypotheses have been offered: - Inhibition of DNA synthesis by acting as a purine analog - Action as an alkylating agent - Interaction with SH groups ## Structure - Dacarbazine for injection, USP is a colorless to an ivory colored solid which is light sensitive. Each 20 mL vial contains 200 mg of dacarbazine (active ingredient). Each vial also contains anhydrous citric acid and mannitol. Dacarbazine for injection is reconstituted and administered intravenously (pH 3–4). Dacarbazine for injection is an anticancer agent. Chemically, dacarbazine for injection is 5-(3,3-Dimethyl-1-triazeno) imidazole-4-carboxamide (dacarbazine) with the following structural formula: ## Pharmacodynamics There is limited information regarding Pharmacodynamics of dacarbazine in the drug label. ## Pharmacokinetics - After intravenous administration of dacarbazine for injection, the volume of distribution exceeds total body water content suggesting localization in some body tissue, probably the liver. Its disappearance from the plasma is biphasic with initial half-life of 19 minutes and a terminal half-life of 5 hours.1 In a patient with renal and hepatic dysfunctions, the half-lives were lengthened to 55 minutes and 7.2 hours.1 The average cumulative excretion of unchanged dacarbazine in the urine is 40% of the injected dose in 6 hours.1 Dacarbazine is subject to renal tubular secretion rather than glomerular filtration. - At therapeutic concentrations dacarbazine is not appreciably bound to human plasma protein. - In man, dacarbazine is extensively degraded. Besides unchanged dacarbazine, 5-aminoimidazole -4 carboxamide (AIC) is a major metabolite of dacarbazine excreted in the urine. AIC is not derived endogenously but from the injected dacarbazine, because the administration of radioactive dacarbazine labeled with 14C in the imidazole portion of the molecule (dacarbazine-2-14C) gives rise to AIC-2-14C.1 ## Nonclinical Toxicology - Carcinogenicity of dacarbazine was studied in rats and mice. Proliferative endocardial lesions, including fibrosarcomas and sarcomas were induced by dacarbazine in rats. In mice, administration of dacarbazine resulted in the induction of angiosarcomas of the spleen. # Clinical Studies There is limited information regarding Clinical Studies of dacarbazine in the drug label. # How Supplied ## Storage Store in a refrigerator 2°C to 8°C (36°F to 46°F). Use within 8 hours of reconstitution. Protect from light. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of dacarbazine in the drug label. # Precautions with Alcohol - Alcohol-dacarbazine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Dtic-Dome® # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price	Dacarbazine 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. # Black Box Warning # Overview Dacarbazine is an antineoplastic agent and alkylating agent that is FDA approved for the treatment of metastatic malignant melanoma and also indicated for Hodgkin's disease as a secondary-line therapy when used in combination with other effective agents.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include anorexia, nausea, and vomiting, influenza-like syndrome of fever to 39°C, myalgias, malaise and alopecia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dacarbazine for injection is indicated in the treatment of metastatic malignant melanoma. - Dosage - The recommended dosage is 2 to 4.5 mg/kg/day for 10days.Treatment may be repeated at 4 week intervals. - An alternate recommended dosage is 250 mg/square meter body surface/day IV for 5 days. Treatment may be repeated every 3 weeks. - In addition, dacarbazine for injection is also indicated for Hodgkin's disease as a secondary-line therapy when used in combination with other effective agents. - Dosage - The recommended dosage of dacarbazine for injection in the treatment of Hodgkin's Disease is 150 mg/square meter body surface/day for 5 days, in combination with other effective drugs. Treatment may be repeated every 4 weeks.5 An alternative recommended dosage is 375 mg/square meter body surface on day 1, in combination with other effective drugs, to be repeated every 15 days. - Dacarbazine for injection 200 mg/vial is reconstituted with 19.7 mL of sterile water for injection, USP. Dacarbazine for injection 500 mg/vial is reconstituted with 49.25 mL of sterile water for injection, USP. The resulting solution contains 10 mg/mL of dacarbazine having a pH of 3.0 to 4.0. The calculated dose of the resulting solution is drawn into a syringe and administered only intravenously. - The reconstituted solution may be further diluted with 5% dextrose injection or sodium chloride injection and administered as an intravenous infusion. - After reconstitution and prior to use, the solution in the vial may be stored at 4°C for up to 72 hours or at normal room conditions (temperature and light) for up to 8 hours. If the reconstituted solution is further diluted in 5% dextrose injection or sodium chloride injection, the resulting solution may be stored at 4°C for up to 24 hours or at normal room conditions for up to 8 hours. - Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.7–12 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of dacarbazine in adult patients. ### Non–Guideline-Supported Use - Cyclophosphamide 750 mg/square meter (m(2)) and vincristine 1.4 mg/m(2) on day 1, and dacarbazine 400 mg/m(2) on days 1 and 2; all were given intravenously and repeated every 21 days. [1] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of dacarbazine in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of dacarbazine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of dacarbazine in pediatric patients. # Contraindications - Dacarbazine for injection is contraindicated in patients who have demonstrated a hypersensitivity to it in the past. # Warnings - [Bone marrow suppression # Adverse Reactions ## Clinical Trials Experience - Symptoms of anorexia, nausea, and vomiting are the most frequently noted of all toxic reactions. Over 90% of patients are affected with the initial few doses. The vomiting lasts 1–12 hours and is incompletely and unpredictably palliated with phenobarbital and/or prochlorperazine. Rarely, intractable nausea and vomiting have necessitated discontinuance of therapy with dacarbazine for injection. Rarely, dacarbazine for injection has caused diarrhea. Some helpful suggestions include restricting the patient's oral intake of food for 4–6 hours prior to treatment. The rapid toleration of these symptoms suggests that a central nervous system mechanism may be involved, and usually these symptoms subside after the first 1 or 2 days. - There are a number of minor toxicities that are infrequently noted. Patients have experienced an influenza-like syndrome of fever to 39°C, myalgias and malaise. These symptoms occur usually after large single doses, may last for several days, and they may occur with successive treatments. - Alopecia has been noted as has facial flushing and facial paresthesia. There have been few reports of significant liver or renal function test abnormalities in man. However, these abnormalities have been observed more frequently in animal studies. - Erythematous and urticarial rashes have been observed infrequently after administration of dacarbazine for injection. Rarely, photosensitivity reactions may occur. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of dacarbazine in the drug label. # Drug Interactions There is limited information regarding Dacarbazine Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Dacarbazine for injection has been shown to be teratogenic in rats when given in doses 20 times the human daily dose on day 12 of gestation. Dacarbazine when administered in 10 times the human daily dose to male rats (twice weekly for 9 weeks) did not affect the male libido, although female rats mated to male rats had higher incidence of resorptions than controls. In rabbits, dacarbazine daily dose 7 times the human daily dose given on days 6–15 of gestation resulted in fetal skeletal anomalies. There are no adequate and well controlled studies in pregnant women. Dacarbazine for injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of dacarbazine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of dacarbazine 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 tumorigenicity shown for dacarbazine for injection in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use There is no FDA guidance on the use of dacarbazine with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of dacarbazine with respect to geriatric patients. ### Gender There is no FDA guidance on the use of dacarbazine with respect to specific gender populations. ### Race There is no FDA guidance on the use of dacarbazine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of dacarbazine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of dacarbazine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of dacarbazine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of dacarbazine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring There is limited information regarding Monitoring of dacarbazine in the drug label. - Description # IV Compatibility There is limited information regarding IV Compatibility of dacarbazine in the drug label. # Overdosage Give supportive treatment and monitor blood cell counts. # Pharmacology ## Mechanism of Action - Although the exact mechanism of action of dacarbazine for injection is not known, three hypotheses have been offered: - Inhibition of DNA synthesis by acting as a purine analog - Action as an alkylating agent - Interaction with SH groups ## Structure - Dacarbazine for injection, USP is a colorless to an ivory colored solid which is light sensitive. Each 20 mL vial contains 200 mg of dacarbazine (active ingredient). Each vial also contains anhydrous citric acid and mannitol. Dacarbazine for injection is reconstituted and administered intravenously (pH 3–4). Dacarbazine for injection is an anticancer agent. Chemically, dacarbazine for injection is 5-(3,3-Dimethyl-1-triazeno) imidazole-4-carboxamide (dacarbazine) with the following structural formula: ## Pharmacodynamics There is limited information regarding Pharmacodynamics of dacarbazine in the drug label. ## Pharmacokinetics - After intravenous administration of dacarbazine for injection, the volume of distribution exceeds total body water content suggesting localization in some body tissue, probably the liver. Its disappearance from the plasma is biphasic with initial half-life of 19 minutes and a terminal half-life of 5 hours.1 In a patient with renal and hepatic dysfunctions, the half-lives were lengthened to 55 minutes and 7.2 hours.1 The average cumulative excretion of unchanged dacarbazine in the urine is 40% of the injected dose in 6 hours.1 Dacarbazine is subject to renal tubular secretion rather than glomerular filtration. - At therapeutic concentrations dacarbazine is not appreciably bound to human plasma protein. - In man, dacarbazine is extensively degraded. Besides unchanged dacarbazine, 5-aminoimidazole -4 carboxamide (AIC) is a major metabolite of dacarbazine excreted in the urine. AIC is not derived endogenously but from the injected dacarbazine, because the administration of radioactive dacarbazine labeled with 14C in the imidazole portion of the molecule (dacarbazine-2-14C) gives rise to AIC-2-14C.1 ## Nonclinical Toxicology - Carcinogenicity of dacarbazine was studied in rats and mice. Proliferative endocardial lesions, including fibrosarcomas and sarcomas were induced by dacarbazine in rats. In mice, administration of dacarbazine resulted in the induction of angiosarcomas of the spleen. # Clinical Studies There is limited information regarding Clinical Studies of dacarbazine in the drug label. # How Supplied ## Storage Store in a refrigerator 2°C to 8°C (36°F to 46°F). Use within 8 hours of reconstitution. Protect from light. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of dacarbazine in the drug label. # Precautions with Alcohol - Alcohol-dacarbazine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Dtic-Dome® # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/DTIC
310b3f304c98cdd1013fc766d4073cf9805f42af	wikidoc	Daclatasvir	Daclatasvir # 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 Daclatasvir is a hepatitis C virus (HCV) NS5A inhibitor that is FDA approved for the treatment of patients with chronic HCV genotype 1 or 3 infection with sofosbuvir and with or without ribavirin. Common adverse reactions include headache, anemia, nausea, and fatigue (≥10%). # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Daclatasvir is indicated for use with sofosbuvir, with or without ribavirin, for the treatment of patients with chronic hepatitis C virus (HCV) genotype 1 or genotype 3 infection. - Limitations of Use: Sustained virologic response (SVR12) rates are reduced in HCV genotype 3-infected patients with cirrhosis receiving Daclatasvir in combination with sofosbuvir for 12 weeks. - Testing Prior to Initiation of Therapy NS5A Resistance Testing in HCV Genotype 1a-Infected Patients with Cirrhosis: Consider screening for the presence of NS5A polymorphisms at amino acid positions M28, Q30, L31, and Y93 in patients with cirrhosis who are infected with HCV genotype 1a prior to the initiation of treatment with Daclatasvir and sofosbuvir with or without ribavirin. - Recommended Dosage - The recommended dosage of Daclatasvir is 60 mg, taken orally, once daily, with or without food. - Table 1 provides the recommended Daclatasvir-containing treatment regimens and duration based on HCV genotype and patient population. The optimal duration of Daclatasvir and sofosbuvir with or without ribavirin has not been established for HCV genotype 3 patients with cirrhosis or for HCV genotype 1 patients with Child-Pugh C cirrhosis. - For patients with HCV/HIV-1 coinfection, follow the dosage recommendations in Table 1. - For specific dosage recommendations for sofosbuvir, refer to the prescribing information. - For HCV genotype 1 or 3 patients with Child-Pugh B or C cirrhosis or post-transplantation patients, the starting dose of ribavirin is 600 mg once daily, increasing up to 1000 mg daily as tolerated. The starting dose and on-treatment dose of ribavirin can be decreased based on hemoglobin and creatinine clearance. - For HCV genotype 3 patients with compensated cirrhosis (Child-Pugh A), the recommended dosing of ribavirin is based on weight (1000 mg for patients weighing less than 75 kg and 1200 mg for those weighing at least 75 kg administered orally in two divided doses with food). - Table 1:Recommended Treatment Regimen and Duration for Daclatasvir in Patients with Genotype 1 or 3 HCV DAKLINZA: Daclatasvir's Brand name - Dosage Modification Due to Drug Interactions Refer to the drug interactions and contraindications sections for other drugs before coadministration with Daclatasvir. - Table 2:Recommended Daclatasvir Dosage Modification with CYP3A Inhibitors and Inducers DAKLINZA: Daclatasvir's Brand name Dosage reduction of Daclatasvir for adverse reactions is not recommended. - Discontinuation of Therapy If sofosbuvir is permanently discontinued in a patient receiving Daclatasvir with sofosbuvir, then Daclatasvir should also be discontinued. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Daclatasvir in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Daclatasvir in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness of Daclatasvir in pediatric patients younger than 18 years of age have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Daclatasvir in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Daclatasvir in pediatric patients. # Contraindications - When Daclatasvir is used in combination with other agents, the contraindications applicable to those agents are applicable to the combination regimen. Refer to the respective prescribing information for a list of contraindications. - Daclatasvir is contraindicated in combination with drugs that strongly induce CYP3A and, thus, may lead to lower exposure and loss of efficacy of Daclatasvir. Contraindicated drugs include, but are not limited to those listed in Table 3. - Table 3:Drugs that are Contraindicated with Daclatasvir Daclatasvir: Daclatasvir's Brand name # Warnings The concomitant use of Daclatasvir and other drugs may result in known or potentially significant drug interactions, some of which may lead to: - loss of therapeutic effect of Daclatasvir and possible development of resistance, - dosage adjustments of concomitant medications or Daclatasvir, - possible clinically significant adverse reactions from greater exposures of concomitant drugs or Daclatasvir. See Table 3 for drugs contraindicated with Daclatasvir due to loss of efficacy and possible development of resistance. See Table 7 for steps to prevent or manage other possible and known significant drug interactions. Consider the potential for drug interactions before and during Daclatasvir therapy, review concomitant medications during Daclatasvir therapy, and monitor for the adverse reactions associated with the concomitant drugs. Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is coadministered with sofosbuvir in combination with another HCV direct-acting antiviral, including Daclatasvir. A fatal cardiac arrest was reported in a patient receiving a sofosbuvir-containing regimen (ledipasvir/sofosbuvir). Bradycardia has generally occurred within hours to days, but cases have been observed up to 2 weeks after initiating HCV treatment. Patients also taking beta blockers or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with coadministration of amiodarone. Bradycardia generally resolved after discontinuation of HCV treatment. The mechanism for this bradycardia effect is unknown. Coadministration of amiodarone with Daclatasvir in combination with sofosbuvir is not recommended. For patients taking amiodarone who have no alternative treatment options and who will be coadministered Daclatasvir and sofosbuvir: - Counsel patients about the risk of serious symptomatic bradycardia. - Cardiac monitoring in an inpatient setting for the first 48 hours of coadministration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment. Patients who are taking sofosbuvir in combination with Daclatasvir who need to start amiodarone therapy due to no other alternative treatment options should undergo similar cardiac monitoring as outlined above. Due to amiodarone’s long elimination half-life, patients discontinuing amiodarone just prior to starting sofosbuvir in combination with Daclatasvir should also undergo similar cardiac monitoring as outlined above. Patients who develop signs or symptoms of bradycardia should seek medical evaluation immediately. Symptoms may include near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion, or memory problems. If Daclatasvir and sofosbuvir are administered with ribavirin, the warnings and precautions for ribavirin, in particular the pregnancy avoidance warning, apply to this combination regimen. Refer to the ribavirin prescribing information for a full list of the warnings and precautions for ribavirin. # Adverse Reactions ## Clinical Trials Experience If Daclatasvir and sofosbuvir are administered with ribavirin, refer to the prescribing information for ribavirin regarding ribavirin-associated adverse reactions. The following serious adverse reaction is described below and elsewhere in the labeling: - Serious Symptomatic Bradycardia When Coadministered with Sofosbuvir and Amiodarone. 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. Approximately 2400 subjects with chronic HCV infection have been treated with the recommended dose of Daclatasvir in combination with other anti-HCV drugs in clinical trials. Six hundred seventy-nine subjects have received a Daclatasvir and sofosbuvir-based regimen. Safety experience from three clinical trials of Daclatasvir and sofosbuvir with or without ribavirin is presented. - Daclatasvir and Sofosbuvir In the ALLY-3 trial, 152 treatment-naive and treatment-experienced subjects with HCV genotype 3 infection were treated with Daclatasvir 60 mg once daily in combination with sofosbuvir for 12 weeks. The most common adverse reactions (frequency of 10% or greater) were headache and fatigue. All adverse reactions were mild to moderate in severity. No subjects discontinued therapy for adverse events. In the ALLY-2 trial, 153 treatment-naive and treatment-experienced subjects with HCV/HIV-1 coinfection were treated with Daclatasvir 60 mg once daily (dose-adjusted for concomitant antiretroviral use) in combination with sofosbuvir for 12 weeks. The most common adverse reaction (frequency of 10% or greater) was fatigue. The majority of adverse reactions were mild to moderate in severity. No subjects discontinued therapy for adverse events. Adverse reactions considered at least possibly related to treatment and occurring at a frequency of 5% or greater in ALLY-3 or ALLY-2 are presented in Table 4. - Table 4:Adverse Reactions (All Severity) Reported at ≥5% Frequency, Daclatasvir + Sofosbuvir, Studies ALLY-3 and ALLY-2 - Daclatasvir, Sofosbuvir, and Ribavirin In the ALLY-1 trial, 113 subjects with chronic HCV infection, including 60 subjects with Child-Pugh A, B, or C cirrhosis and 53 subjects with recurrence of HCV after liver transplantation, were treated with Daclatasvir 60 mg once daily in combination with sofosbuvir and ribavirin for 12 weeks. The most common adverse reactions (frequency of 10% or greater) among the 113 subjects were headache, anemia, fatigue, and nausea. The majority of adverse reactions were mild to moderate in severity. Of the 15 (13%) subjects who discontinued study drug for adverse events, 13 (12%) subjects discontinued ribavirin only and 2 (2%) subjects discontinued all study drugs. During treatment, 4 subjects in the cirrhotic cohort underwent liver transplantation. Adverse reactions considered at least possibly related to treatment and occurring at a frequency of 5% or greater in either treatment cohort in ALLY-1 are presented in Table 5. - Table 5:Adverse Reactions (All Severity) Reported at ≥5% Frequency in Either Treatment Cohort, Daclatasvir + Sofosbuvir + Ribavirin, Study ALLY-1 Daclatasvir: Daclatasvir's Brand name - Laboratory Abnormalities Selected Grade 3 and 4 treatment-emergent laboratory abnormalities observed in clinical trials of Daclatasvir in combination with sofosbuvir with or without ribavirin are presented in Table 6. - Table 6:Selected Grade 3 and 4 Laboratory Abnormalities in Clinical Trials of Daclatasvir + Sofosbuvir ± Ribavirin, Studies ALLY-3, ALLY-2, and ALLY-1 Daclatasvir: Daclatasvir's Brand name ## Postmarketing Experience The following adverse reactions have been identified during postapproval use of Daclatasvir. 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: Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiate treatment with sofosbuvir in combination with another HCV direct-acting antiviral, including Daclatasvir. # Drug Interactions Daclatasvir is a substrate of CYP3A. Therefore, moderate or strong inducers of CYP3A may decrease the plasma levels and therapeutic effect of daclatasvir. Strong inhibitors of CYP3A (eg, clarithromycin, itraconazole, ketoconazole, ritonavir) may increase the plasma levels of daclatasvir. Daclatasvir is an inhibitor of P-glycoprotein transporter (P-gp), organic anion transporting polypeptide (OATP) 1B1 and 1B3, and breast cancer resistance protein (BCRP). Administration of Daclatasvir may increase systemic exposure to medicinal products that are substrates of P-gp, OATP 1B1 or 1B3, or BCRP, which could increase or prolong their therapeutic effect or adverse reactions (see TABLE 7). Refer to the prescribing information for other agents in the regimen for drug interaction information. The most conservative recommendation should be followed. Table 7 provides clinical recommendations for established or potentially significant drug interactions between Daclatasvir and other drugs. Clinically relevant increase in concentration is indicated as “↑” and clinically relevant decrease as “↓” for drug interaction data. - Table 7:Established and Other Potentially Significant Drug Interactions Daclatasvir: Daclatasvir's Brand name Based on the results of drug interaction trials, no clinically relevant changes in exposure were observed for cyclosporine, darunavir (with ritonavir), dolutegravir, escitalopram, ethinyl estradiol/norgestimate, lopinavir (with ritonavir), methadone, midazolam, tacrolimus, or tenofovir with concomitant use of daclatasvir. No clinically relevant changes in daclatasvir exposure were observed with cyclosporine, darunavir (with ritonavir), dolutegravir, escitalopram, famotidine, lopinavir (with ritonavir), omeprazole, sofosbuvir, tacrolimus, or tenofovir. No dosage adjustment for daclatasvir is necessary with darunavir/cobicistat or moderate CYP3A inhibitors, including atazanavir (unboosted), fosamprenavir, ciprofloxacin, diltiazem, erythromycin, fluconazole, or verapamil. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Risk Summary No adequate human data are available to determine whether or not Daclatasvir poses a risk to pregnancy outcomes. In animal reproduction studies in rats and rabbits, no evidence of fetal harm was observed with oral administration of daclatasvir during organogenesis at doses that produced exposures up to 6 and 22 times, respectively, the recommended human dose (RHD) of 60 mg of Daclatasvir. However, embryofetal toxicity was observed in rats and rabbits at maternally toxic doses that produced exposures of 33 and 98 times the human exposure, respectively, at the RHD of 60 mg of Daclatasvir. In rat pre- and postnatal developmental studies, no developmental toxicity was observed at maternal systemic exposure (AUC) to daclatasvir approximately 3.6 times higher than the RHD of Daclatasvir. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. If Daclatasvir and sofosbuvir are administered with ribavirin, the combination regimen is contraindicated in pregnant women and in men whose female partners are pregnant. Refer to the ribavirin prescribing information for more information on use in pregnancy. - Data - Animal Data Daclatasvir was administered orally to pregnant rats at doses of 0, 50, 200, or 1000 mg/kg/day on gestation days 6 to 15. Maternal toxicity (mortality, adverse clinical signs, body-weight losses, and reduced food consumption) was noted at doses of 200 and 1000 mg/kg/day. In the offspring, malformations of the fetal brain, skull, eyes, ears, nose, lip, palate, or limbs were observed at doses of 200 and 1000 mg/kg. The dose of 1000 mg/kg was associated with profound embryolethality and lower fetal body weight. No malformations were noted at 50 mg/kg/day. Systemic exposure (AUC) at 50 mg/kg/day in pregnant females was 6 times higher than exposures at the RHD. In rabbits, daclatasvir was initially administered at doses of 0, 40, 200, or 750 mg/kg/day during the gestation days 7 to 19. Daclatasvir dosing was modified due to vehicle toxicity during the study to doses of 20, 99, and 370 mg/kg/day, respectively. Maternal toxicity was noted at doses of 200/99 and 750/370 mg/kg/day with adverse clinical signs and severe reductions in body weight and food consumption. Mortality and euthanasia occurred in multiple dams at 750/370 mg/kg/day. At 200/99 mg/kg/day, fetal effects included increased embryofetal lethality, reduced fetal body weights, and increased incidences of fetal malformations of the ribs as well as head and skull. No malformations were noted in rabbits at 40/20 mg/kg/day. Systemic exposures (AUC) at 40/20 mg/kg/day were 22 times higher than exposures at the RHD. In a pre- and postnatal developmental study, daclatasvir was administered orally at 0, 25, 50, or 100 mg/kg/day from gestation day 6 to lactation day 20. At 100 mg/kg/day, maternal toxicity included mortality and dystocia; developmental toxicity included slight reductions in offspring viability in the perinatal and neonatal periods and reductions in birth weight that persisted into adulthood. There was neither maternal nor developmental toxicity at doses up to 50 mg/kg/day. Systemic exposures (AUC) at this dose were 3.6 times higher than the RHD. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Daclatasvir in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Daclatasvir during labor and delivery. ### Nursing Mothers - Risk Summary It is not known whether Daclatasvir is present in human milk, affects human milk production, or has effects on the breastfed infant. Daclatasvir was present in the milk of lactating rats. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Daclatasvir and any potential adverse effects on the breastfed child from Daclatasvir or from the underlying maternal condition. If Daclatasvir is administered with ribavirin, the nursing mothers information for ribavirin also applies to this combination regimen. Refer to ribavirin prescribing information for additional information. - Data Milk concentrations of daclatasvir were evaluated on lactation day 10 as part of the rat pre- and postnatal development study. Daclatasvir was present in rat milk with concentrations 1.7 to 2 times maternal plasma levels. ### Pediatric Use Safety and effectiveness of Daclatasvir in pediatric patients younger than 18 years of age have not been established. ### Geriatic Use Of 1184 subjects treated with the recommended dose of Daclatasvir in ten clinical trials, 7% of subjects were 65 years of age or older. Safety was similar across older and younger subjects and there were no safety findings unique to subjects 65 years and older. SVR12 rates were comparable among older and younger subjects. No dosage adjustment of Daclatasvir is required for elderly patients. ### Gender There is no FDA guidance on the use of Daclatasvir with respect to specific gender populations. ### Race There is no FDA guidance on the use of Daclatasvir with respect to specific racial populations. ### Renal Impairment No dosage adjustment of Daclatasvir is required for patients with any degree of renal impairment. Refer also to the sofosbuvir and ribavirin prescribing information for information regarding use in patients with renal impairment. ### Hepatic Impairment Based on a hepatic impairment study in non–HCV-infected subjects, no dosage adjustment of Daclatasvir is required for patients with mild (Child-Pugh A), moderate (Child-Pugh B), or severe (Child-Pugh C) hepatic impairment. ### Females of Reproductive Potential and Males If Daclatasvir and sofosbuvir are administered with ribavirin, the information for ribavirin with regard to pregnancy testing, contraception, and infertility also applies to this combination regimen. Refer to ribavirin prescribing information for additional information. ### Immunocompromised Patients There is no FDA guidance one the use of Daclatasvir in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Daclatasvir Administration in the drug label. ### Monitoring There is limited information regarding Daclatasvir Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Daclatasvir and IV administrations. # Overdosage There is no known antidote for overdose of Daclatasvir. Treatment of overdose with Daclatasvir should consist of general supportive measures, including monitoring of vital signs and observation of the patient’s clinical status. Because daclatasvir is highly protein bound (>99%), dialysis is unlikely to significantly reduce plasma concentrations of the drug. # Pharmacology ## Mechanism of Action Daclatasvir is a direct-acting antiviral agent (DAA) against the hepatitis C virus. ## Structure Daclatasvir is an inhibitor of HCV nonstructural protein 5A (NS5A). The chemical name for drug substance daclatasvir dihydrochloride is carbamic acid, N,N′--4,4′-diylbis]]bis-, C,C′-dimethyl ester, hydrochloride (1:2). Its molecular formula is C40H50N8O62HCl, and its molecular weight is 738.88 (free base). Daclatasvir dihydrochloride has the following structural formula: Daclatasvir dihydrochloride drug substance is white to yellow. Daclatasvir is freely soluble in water (>700 mg/mL). This drug contain 60 mg daclatasvir (equivalent to 66 mg daclatasvir dihydrochloride) and the inactive ingredients anhydrous lactose (116 mg), microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate, and Opadry green. Daclatasvir 30 mg tablets (equivalent to 33 mg daclatasvir dihydrochloride) contain the inactive ingredients anhydrous lactose (58 mg), microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate, and Opadry green. Daclatasvir 90 mg tablets (equivalent to 99 mg daclatasvir dihydrochloride) contain the inactive ingredients anhydrous lactose (173 mg), microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate, and Opadry green. Opadry green contains hypromellose, titanium dioxide, polyethylene glycol 400, FD&C blue #2/indigo carmine aluminum lake, and yellow iron oxide. ## Pharmacodynamics Cardiac Electrophysiology At a dose 3 times the maximum recommended dose, daclatasvir did not prolong the QT interval to any clinically relevant extent. ## Pharmacokinetics The pharmacokinetic properties of daclatasvir were evaluated in healthy adult subjects and in subjects with chronic HCV. Administration of daclatasvir tablets in HCV-infected subjects resulted in approximately dose-proportional increases in Cmax, AUC, and Cmin up to 60 mg once daily. Steady state is anticipated after approximately 4 days of once-daily daclatasvir administration. Exposure of daclatasvir was similar between healthy and HCV-infected subjects. Population pharmacokinetic estimates for daclatasvir 60 mg once daily in chronic HCV-infected subjects are shown in Table 8. - Table 8:Population Pharmacokinetic Estimates for Daclatasvir in Chronic HCV-Infected Subjects Receiving Daclatasvir 60 mg Once Daily and Sofosbuvir 400 mg Once Daily In HCV-infected subjects following multiple oral doses of daclatasvir tablet ranging from 1 mg to 100 mg once daily, peak plasma concentrations occurred within 2 hours post dose. In vitro studies with human Caco-2 cells indicated that daclatasvir is a substrate of P-gp. The absolute bioavailability of the tablet formulation is 67%. - Effect of Food on Oral Absorption In healthy subjects, administration of a daclatasvir 60 mg tablet after a high-fat, high-caloric meal (approximately 951 total kcal, 492 kcal from fat, 312 kcal from carbohydrates, 144 kcal from protein) decreased daclatasvir Cmax and AUC(0-inf) by 28% and 23%, respectively, compared with fasted conditions. A food effect was not observed with administration of a daclatasvir 60 mg tablet after a low-fat, low-caloric meal (approximately 277 total kcal, 41 kcal from fat, 190 kcal from carbohydrates, 44 kcal from protein) compared with fasted conditions. With multiple dosing, protein binding of daclatasvir in HCV-infected subjects was approximately 99% and independent of dose at the dose range studied (1-100 mg). In subjects who received daclatasvir 60 mg tablet orally followed by 100 μg -daclatasvir intravenous dose, estimated volume of distribution at steady state was 47 L. Daclatasvir is a substrate of CYP3A, with CYP3A4 being the primary CYP isoform responsible for metabolism. Following single-dose oral administration of 25 mg 14C-daclatasvir in healthy subjects, the majority of radioactivity in plasma was predominately attributed to parent drug (97% or greater). Following single-dose oral administration of 25 mg 14C-daclatasvir in healthy subjects, 88% of total radioactivity was recovered in feces (53% of the dose as unchanged daclatasvir) and 6.6% of the dose was excreted in the urine (primarily as unchanged daclatasvir). Following multiple-dose administration of daclatasvir in HCV-infected subjects, with doses ranging from 1 mg to 100 mg once daily, the terminal elimination half-life of daclatasvir ranged from approximately 12 to 15 hours. In subjects who received daclatasvir 60 mg tablet orally followed by 100 μg -daclatasvir intravenous dose, the total clearance was 4.2 L/h. - Renal Impairment The pharmacokinetics of daclatasvir following a single 60 mg oral dose was studied in non–HCV-infected subjects with renal impairment. Using a regression analysis, the predicted AUC(0-inf) of daclatasvir was estimated to be 26%, 60%, and 80% higher in subjects with creatinine clearance (CLcr) values of 60, 30, and 15 mL/min, respectively, relative to subjects with normal renal function (CLcr of 90 mL/min, defined using the Cockcroft-Gault CLcr formula), and daclatasvir unbound AUC(0-inf) was predicted to be 18%, 39%, and 51% higher for subjects with CLcr values of 60, 30, and 15 mL/min, respectively, relative to subjects with normal renal function. Using observed data, subjects with end-stage renal disease requiring hemodialysis had a 27% increase in daclatasvir AUC(0-inf) and a 20% increase in unbound AUC(0-inf) compared to subjects with normal renal function as defined using the Cockcroft-Gault CLcr formula. Daclatasvir is highly protein bound to plasma proteins and is unlikely to be removed by dialysis. - Hepatic Impairment The pharmacokinetics of daclatasvir following a single 30 mg oral dose was studied in non–HCV-infected subjects with mild (Child-Pugh A), moderate (Child-Pugh B), and severe (Child-Pugh C) hepatic impairment compared to a corresponding matched control group. The Cmax and AUC(0-inf) of total daclatasvir (free and protein-bound drug) were lower by 46% and 43%, respectively, in Child-Pugh A subjects; by 45% and 38%, respectively, in Child-Pugh B subjects; and by 55% and 36%, respectively, in Child-Pugh C subjects. The Cmax and AUC(0‑inf) of unbound daclatasvir were lower by 43% and 40%, respectively, in Child-Pugh A subjects; by 14% and 2%, respectively, in Child-Pugh B subjects; and by 33% and 5%, respectively, in Child-Pugh C subjects. - Pediatric Patients The pharmacokinetics of daclatasvir in pediatric patients has not been evaluated. - Geriatric Patients Population pharmacokinetic analysis in HCV-infected subjects showed that within the age range (18-79 years) analyzed, age did not have a clinically relevant effect on the pharmacokinetics of daclatasvir. - Gender Population pharmacokinetic analyses in HCV-infected subjects estimated that female subjects have a 30% higher daclatasvir AUC compared to male subjects. This difference in daclatasvir AUC is not considered clinically relevant. - Race Population pharmacokinetic analyses in HCV-infected subjects indicated that race had no clinically relevant effect on daclatasvir exposure. - Cytochrome P450 (CYP) Enzymes Daclatasvir is a substrate of CYP3A. In vitro, daclatasvir did not inhibit (IC50 greater than 40 microM) CYP enzymes 1A2, 2B6, 2C8, 2C9, 2C19, or 2D6. Daclatasvir did not have a clinically relevant effect on the exposure of midazolam, a sensitive CYP3A substrate. - Transporters Daclatasvir is a substrate of P-gp. However, cyclosporine, which inhibits multiple transporters including P-gp, did not have a clinically relevant effect on the pharmacokinetics of daclatasvir. Daclatasvir, in vitro, did not inhibit OCT2 and did not have a clinically relevant effect on the pharmacokinetics of tenofovir, an OAT substrate. Daclatasvir demonstrated inhibitory effects on digoxin (a P-gp substrate) and rosuvastatin (an OATP 1B1, OATP 1B3, and BCRP substrate) in drug-drug interaction trials. Drug interaction studies were conducted with daclatasvir and other drugs likely to be coadministered or drugs used as probes to evaluate potential drug-drug interactions. The effects of daclatasvir on the Cmax, AUC, and Cmin of the coadministered drug are summarized in Table 9, and the effects of the coadministered drug on the Cmax, AUC, and Cmin of daclatasvir are summarized in Table 10. For information regarding clinical recommendations. Drug interaction studies were conducted in healthy adults unless otherwise noted. - Table 9:Effect of Daclatasvir on the Pharmacokinetics of Concomitant Drugs DAKLINZA: Daclatasvir's Brand name - Table 10:Effect of Coadministered Drugs on Daclatasvir Pharmacokinetics DAKLINZA: Daclatasvir's Brand name No clinically relevant interaction is anticipated for daclatasvir or the following concomitant medications: peginterferon alfa, ribavirin, or antacids. No clinically relevant interaction is anticipated for daclatasvir with concomitant use of rilpivirine. - Mechanism of Action Daclatasvir is an inhibitor of NS5A, a nonstructural protein encoded by HCV. Daclatasvir binds to the N-terminus of NS5A and inhibits both viral RNA replication and virion assembly. Characterization of daclatasvir-resistant viruses, biochemical studies, and computer modeling data indicate that daclatasvir interacts with the N-terminus within Domain 1 of the protein, which may cause structural distortions that interfere with NS5A functions. - Antiviral Activity Daclatasvir had median EC50 values of 0.008 nM (range, 0.002-0.03 nM; n=35), 0.002 nM (range, 0.0007-0.006 nM; n=30), and 0.2 nM (range, 0.006-3.2 nM; n=17) against hybrid replicons containing genotypes 1a, 1b, and 3a subject-derived NS5A sequences, respectively, without detectable daclatasvir resistance-associated polymorphisms at NS5A amino acid positions 28, 30, 31, or 93. Daclatasvir activity was reduced against genotypes 1a, 1b, and 3a subject-derived replicons with resistance-associated polymorphisms at positions 28, 30, 31, or 93, with median EC50 values of 76 nM (range, 4.6-2409 nM; n=5), 0.05 nM (range, 0.002-10 nM; n=12), and 13.5 nM (range, 1.3-50 nM; n=4), respectively. Similarly, the EC50 values of daclatasvir against 3 genotype 3b and 1 genotype 3i subject-derived NS5A sequences with polymorphisms (relative to a genotype 3a reference) at positions 30+31 (genotype 3b) or 30+62 (genotype 3i) were ≥3620 nM. Daclatasvir was not antagonistic with interferon alfa, HCV NS3/4A protease inhibitors, HCV NS5B nucleoside analog inhibitors, and HCV NS5B non-nucleoside inhibitors in cell culture combination antiviral activity studies using the cell-based HCV replicon system. - Resistance - In Cell Culture HCV genotype 1a, 1b, and 3a replicon variants with reduced susceptibility to daclatasvir were selected in cell culture, and the genotype and phenotype of daclatasvir-resistant NS5A amino acid variants were characterized. Phenotypic analysis of genotype 1a replicons expressing single NS5A M28T, Q30E, Q30H, Q30R, L31V, Y93C, Y93H, and Y93N substitutions exhibited 500-, 18500-, 1083-, 900-, 2500-, 1367-, 8500-, and 34833-fold reduced susceptibility to daclatasvir, respectively. For genotype 1b, L31V and Y93H single substitutions and L31M/Y93H and L31V/Y93H combinations exhibited 33-, 30-, 16000-, and 33667-fold reduced susceptibility to daclatasvir, respectively. A P32-deletion (P32X) in genotype 1b reduced daclatasvir susceptibility by >1,000,000-fold. For genotype 3a, single A30K, L31F, L31I, and Y93H substitutions exhibited 117-, 320-, 240-, and 3733-fold reduced susceptibility to daclatasvir, respectively. - In Clinical Studies Among subjects with HCV genotype 1 or genotype 3 infection and treated in the ALLY-1, -2, and -3 trials with Daclatasvir and sofosbuvir with or without ribavirin for 12 weeks, 31 subjects (11 with genotype 1a, 1 with genotype 1b, and 19 with genotype 3) qualified for resistance analysis due to virologic failure. Post-baseline NS5A and NS5B population-based nucleotide sequence analysis results were available for 31 and 28 subjects, respectively. Virus from all 31 subjects at the time of virologic failure harbored one or more of the following NS5A resistance-associated substitutions (including pre-existing amino acid polymorphisms or treatment-emergent substitutions): M28T, Q30H/K/R, L31M/V, H54R, H58D/P, or Y93C/N for genotype 1a subjects, P32-deletion (P32X) for the genotype 1b subject, and A30K/S, L31I, S62A/L/P/R/T, or Y93H for genotype 3 subjects. Among HCV genotype 1a virologic failure subjects, the most common NS5A amino acid substitutions occurred at position Q30 (Q30H/K/R; 73% , all treatment-emergent). Among HCV genotype 3 virologic failure subjects, the most common NS5A amino acid polymorphism or treatment-emergent substitution was Y93H (89% , treatment-emergent in 11 of 17 subjects). For NS5B, 6 of 28 subjects at the time of virologic failure had virus with NS5B substitutions possibly associated with sofosbuvir resistance or exposure: A112T, L159F, E237G, or Q355H (genotype 1a subjects), or S282T+Q355H (genotype 3 subject). - Persistence of Resistance-Associated Substitutions Limited data for Daclatasvir and sofosbuvir regimens on the persistence of daclatasvir resistance-associated substitutions are available. In a separate long-term follow-up study of predominately HCV genotype 1-infected subjects treated with daclatasvir-containing regimens in phase 2/3 clinical trials, viral populations with treatment-emergent NS5A resistance-associated substitutions persisted at detectable levels for more than 1 year in most subjects. - Effect of Baseline HCV Amino Acid Polymorphisms on Treatment Response Genotype 1a NS5A polymorphisms: In HCV genotype 1a-infected subjects with cirrhosis, the presence of an NS5A amino acid polymorphism at position M28, Q30, L31, or Y93 (defined as any change from reference identified by population-based nucleotide sequencing) was associated with reduced efficacy of Daclatasvir and sofosbuvir with or without ribavirin for 12 weeks in the ALLY-1 and ALLY-2 trials (see Table 11). Due to the limited sample size, insufficient data are available to determine the impact of specific NS5A polymorphisms at these positions on SVR12 rates in subjects with cirrhosis. Six of 54 subjects (11%) with cirrhosis had one of the following specific NS5A polymorphisms at baseline: M28V/T (n=2), Q30R (n=1), L31M (n=2), or Y93N (n=1); 2 subjects with M28V or Q30R achieved SVR12 while 4 subjects with M28T, L31M, or Y93N did not achieve SVR. Eleven of 112 subjects (10%) without cirrhosis had one or more of the following specific NS5A polymorphisms at baseline: M28T/V (n=3), Q30H/L/R (n=5), L31M (n=1), and Y93C/H/S (n=4); all noncirrhotic subjects with these baseline NS5A polymorphisms achieved SVR12. Based on an analysis of 1026 HCV genotype 1a NS5A amino acid sequences from pooled clinical trials, the prevalence of polymorphisms at these positions was 11% overall, and 11% in the U.S. Genotype 1b NS5A polymorphisms: In a pooled analysis of 43 subjects infected with HCV genotype 1b with available baseline nucleotide sequence data in ALLY-1 and -2, virus from 21% (n=9) of subjects receiving Daclatasvir and sofosbuvir with or without ribavirin had one of the following baseline NS5A amino acid polymorphisms: R30K/M/Q (n=4), L31M (n=2), or Y93H (n=3). All 9 subjects with NS5A polymorphisms achieved SVR12, including 5 who were noncirrhotic and 4 who were in the post-transplant period. Genotype 3 NS5A polymorphisms: In the ALLY-3 trial in which HCV genotype 3-infected subjects received Daclatasvir and sofosbuvir for 12 weeks, the presence of an NS5A Y93H polymorphism was associated with a reduced SVR12 rate (see Table 11). In a pooled analysis of 175 subjects infected with HCV genotype 3 with available baseline nucleotide sequence data in the ALLY-1, -2, and -3 trials, virus from 7% (13/175) of subjects had the NS5A Y93H polymorphism, and all 13 of these subjects were in the ALLY-3 trial. Phylogenetic analysis of NS5A sequences indicated that all genotype 3 subjects with available data in the ALLY-1, -2, and -3 trials (n=175) were infected with HCV subtype 3a. - Table 11:Impact of NS5A Amino Acid Polymorphisms on SVR12 Rates in Subjects with HCV Genotype 1a or Genotype 3 Infection in Phase 3 Trials of Daclatasvir + Sofosbuvir ± Ribavirin DAKLINZA: Daclatasvir's Brand name - Cross-Resistance Based on resistance patterns observed in cell culture replicon studies and HCV-infected subjects, cross-resistance between daclatasvir and other NS5A inhibitors is expected. Cross-resistance between daclatasvir and other classes of direct-acting antivirals is not expected. The impact of prior daclatasvir treatment experience on the efficacy of other NS5A inhibitors has not been studied. Conversely, the efficacy of Daclatasvir in combination with sofosbuvir has not been studied in subjects who have previously failed treatment with regimens that include an NS5A inhibitor. ## Nonclinical Toxicology - Carcinogenesis and Mutagenesis A 2-year carcinogenicity study in Sprague Dawley rats and a 6-month study in transgenic (Tg rasH2) mice were conducted with daclatasvir. In the 2-year study in rats, no drug-related increase in tumor incidence was observed at doses up to 50 mg/kg/day (both sexes). Daclatasvir exposures at these doses were approximately 6-fold (males and females) the human systemic exposure at the therapeutic daily dose of Daclatasvir. In transgenic mice no drug-related increase in tumor incidence was observed at doses of 300 mg/kg/day (both sexes). Daclatasvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity (Ames) assays, mammalian mutation assays in Chinese hamster ovary cells, or in an in vivo oral micronucleus study in rats. If Daclatasvir and sofosbuvir are administered in a regimen containing ribavirin, the information for ribavirin on carcinogenesis and mutagenesis also applies to this combination regimen (see prescribing information for ribavirin). - Impairment of Fertility Daclatasvir had no effects on fertility in female rats at any dose tested. Daclatasvir exposures at these doses in females were approximately 24-fold the human systemic exposure at the therapeutic daily dose of Daclatasvir. In male rats, effects on reproductive endpoints at 200 mg/kg/day included reduced prostate/seminal vesicle weights, minimally increased dysmorphic sperm, as well as increased mean pre-implantation loss in litters sired by treated males. Daclatasvir exposures at the 200 mg/kg/day dose in males were approximately 26-fold the human systemic exposure at the therapeutic daily dose of Daclatasvir. Exposures at 50 mg/kg/day in males produced no notable effects and was 4.7-fold the exposure in humans at the recommended daily dose of Daclatasvir. If Daclatasvir and sofosbuvir are administered with ribavirin, the information for ribavirin on impairment of fertility also applies to this combination regimen. # Clinical Studies The efficacy of Daclatasvir in combination with sofosbuvir and with or without ribavirin was evaluated in three phase 3 clinical trials, as summarized in Table 12. HCV RNA levels were measured during these 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 was the primary endpoint and was defined as HCV RNA below the LLOQ at post-treatment week 12 (SVR12). - Table 12:Genotype 1 and 3 Patient Populations from Daclatasvir Trials DAKLINZA: Daclatasvir's Brand name ALLY-3 was an open-label trial that included 152 subjects with chronic HCV genotype 3 infection and compensated liver disease who were treatment naive (n=101) or treatment experienced (n=51). Most treatment-experienced subjects had failed prior treatment with peginterferon/ribavirin, but 7 subjects had been treated previously with a sofosbuvir regimen and 2 subjects with a regimen containing an investigational agent. Previous exposure to NS5A inhibitors was prohibited. Subjects received Daclatasvir 60 mg plus sofosbuvir 400 mg once daily for 12 weeks and were monitored for 24 weeks post treatment. The 152 treated subjects in ALLY-3 had a median age of 55 years (range, 24-73); 59% of the subjects were male; 90% were white, 5% were Asian, and 4% were black. Most subjects (76%) had baseline HCV RNA levels greater than or equal to 800,000 IU per mL; 21% of the subjects had compensated cirrhosis, and 40% had the IL28B rs12979860 CC genotype. SVR12 and outcomes in subjects without SVR12 in ALLY-3 are shown by patient population in Table 13. SVR12 rates were comparable regardless of HCV treatment history, age, gender, IL28B allele status, or baseline HCV RNA level. For SVR outcomes related to baseline NS5A amino acid polymorphisms. - Table 13:ALLY-3: SVR12 in Treatment-Naive and Treatment-Experienced Subjects with or without Cirrhosis with Genotype 3 HCV Treated with Daclatasvir in Combination with Sofosbuvir for 12 Weeks ALLY-2 was an open-label trial that included 153 subjects with chronic hepatitis C and HIV coinfection who received Daclatasvir and sofosbuvir for 12 weeks. Subjects with HCV genotype 1, 2, 3, 4, 5, or 6 infection were eligible to enroll. Subjects were HCV treatment-naive (n=101) or HCV treatment-experienced (n=52). Prior exposure to NS5A inhibitors was prohibited. The dose of Daclatasvir was 60 mg once daily (dose-adjusted for concomitant antiretroviral use) and the dose of sofosbuvir was 400 mg once daily. The 153 treated subjects had a median age of 53 years (range, 24-71); 88% of subjects were male; 63% were white, 33% were black, and 1% were Asian. Sixty-eight percent of subjects had HCV genotype 1a, 15% had HCV genotype 1b, 8% had genotype 2, 7% had genotype 3, and 2% had genotype 4. Most subjects (80%) had baseline HCV RNA levels greater than or equal to 800,000 IU per mL; 16% of the subjects had compensated cirrhosis, and 73% had IL28B rs12979860 non-CC genotype. Concomitant HIV therapy included PI-based regimens (darunavir + ritonavir, atazanavir + ritonavir, or lopinavir/ritonavir) for 46% of subjects, NNRTI-based regimens (efavirenz, nevirapine, or rilpivirine) for 26%, integrase-based regimens (raltegravir or dolutegravir) for 26%, and nucleoside-only regimens (abacavir + emtricitabine + zidovudine) for 1%. Two patients were not receiving treatment for HIV. SVR and outcomes in subjects with HCV genotype 1 without SVR12 in ALLY-2 are shown by patient population in Table 14. Available data on subjects with HCV genotype 2, 4, 5, or 6 infection are insufficient to provide recommendations for these genotypes; therefore, these results are not presented in Table 14. SVR12 rates were comparable regardless of antiretroviral therapy, HCV treatment history, age, race, gender, IL28B allele status, HCV genotype 1 subtype, or baseline HCV RNA level. For SVR outcomes related to baseline NS5A amino acid polymorphisms. No subjects switched their antiretroviral therapy regimen due to loss of plasma HIV-1 RNA suppression. There was no change in absolute CD4+ T-cell counts at the end of 12 weeks of treatment. - Table 14:ALLY-2: SVR12 in Subjects with Genotype 1 and 3 HCV/HIV Coinfection Treated with Daclatasvir in Combination with Sofosbuvir for 12 Weeks ALLY-1 was an open-label trial of Daclatasvir, sofosbuvir, and ribavirin that included 113 subjects with chronic HCV infection and Child-Pugh A, B, or C cirrhosis (n=60) or HCV recurrence after liver transplantation (n=53). Subjects with HCV genotype 1, 2, 3, 4, 5, or 6 infection were eligible to enroll. Subjects could be HCV treatment-naive or treatment-experienced, although prior exposure to NS5A inhibitors was prohibited. Subjects received Daclatasvir 60 mg once daily, sofosbuvir 400 mg once daily, and ribavirin for 12 weeks and were monitored for 24 weeks post treatment. Subjects received an initial ribavirin dose of 600 mg or less daily with food; the initial and on-treatment dosing of ribavirin was modified based on hemoglobin and creatinine clearance measurements. If tolerated, the ribavirin dose was titrated up to 1000 mg per day. A high proportion of reductions in ribavirin dosing occurred in the trial. By week 6, approximately half of the subjects received 400 mg per day or less of ribavirin. In total, 16 subjects (15%) completed less than 12 weeks and 11 subjects (10%) completed less than 6 weeks of ribavirin therapy, respectively. For the cohort of patients with cirrhosis (Child-Pugh A, B, or C), the median time to discontinuation of ribavirin was 43 days (range, 8-82, n=9). For the post-transplant cohort, the median time to discontinuation of ribavirin was 20 days (range, 3-57, n=7). The 113 treated subjects in ALLY-1 had a median age of 59 years (range, 19-82); 67% of the subjects were male; 96% were white, 4% were black, and 1% Asian. Most subjects (59%) were treatment-experienced, and most (71%) had baseline HCV RNA levels greater than or equal to 800,000 IU per mL. Fifty-eight percent of subjects had HCV genotype 1a, 19% had HCV genotype 1b, 4% had genotype 2, 15% had genotype 3, 4% had genotype 4, and 1% had genotype 6, 77% had IL28B rs12979860 non-CC genotype. Among the 60 subjects in the cirrhosis cohort, 20% were Child-Pugh A, 53% were Child-Pugh B, and 27% were Child-Pugh C, and 35% had a Baseline Model for End-Stage Liver Disease (MELD) score of 15 or greater. Most (55%) of the 53 subjects in the post-transplant cohort had F3 or F4 fibrosis (based on FibroSURE® results). SVR12 and outcomes in subjects without SVR12 in ALLY-1 are shown for subjects with HCV genotype 1 by patient population in Table 15. Available data on subjects with HCV genotype 2, 4, 5, or 6 infection are insufficient to provide recommendations; therefore, these results are not presented in Table 15. SVR12 rates were comparable regardless of age, gender, IL28B allele status, or baseline HCV RNA level. For SVR12 outcomes related to baseline NS5A amino acid polymorphisms. No HCV genotype 1 or genotype 3 subjects with Child-Pugh C cirrhosis had baseline resistance-associated NS5A amino acid polymorphisms. SVR12 rates were comparable between genotype 3 (5/6 with Child-Pugh B or C cirrhosis and 10/11 post-liver transplant) and genotype 1 subjects with or without decompensated cirrhosis. - Table 15:ALLY-1: SVR12 in Genotype 1 Subjects with Child-Pugh A, B, or C Cirrhosis or with HCV Genotype 1 Recurrence after Liver Transplantation Treated with Daclatasvir in Combination with Sofosbuvir and Ribavirin for 12 Weeks # How Supplied Daclatasvir is packaged in bottles as described in the table. ## Storage Store Daclatasvir tablets at 25°C (77°F), with excursions permitted between 15°C and 30°C (59°F and 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). - Drug Interactions Inform patients of the potential for drug interactions with Daclatasvir, and that some drugs should not be taken with Daclatasvir. - Symptomatic Bradycardia When Used in Combination with Sofosbuvir and Amiodarone Advise patients to seek medical evaluation immediately for symptoms of bradycardia, such as near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion or memory problems. - Daclatasvir Combination Therapy with Sofosbuvir Inform patients that Daclatasvir should not be used alone. Daclatasvir should be used in combination with sofosbuvir with or without ribavirin for the treatment of HCV genotype 1 or HCV genotype 3 infection. - Missed Doses Advise patients to take Daclatasvir every day at the regularly scheduled time with or without food. Inform patients that it is important not to miss or skip doses and to take Daclatasvir for the duration that is recommended by the physician. For instructions for missed doses of other agents in the regimen, refer to the respective prescribing information. - Pregnancy Advise patients to avoid pregnancy during combination treatment with Daclatasvir and sofosbuvir with ribavirin for 6 months after completion of treatment. Inform patients to notify their healthcare provider immediately in the event of a pregnancy. # Precautions with Alcohol Alcohol-Daclatasvir interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names DAKLINZA™ # Look-Alike Drug Names There is limited information regarding Daclatasvir Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Daclatasvir 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 Daclatasvir is a hepatitis C virus (HCV) NS5A inhibitor that is FDA approved for the treatment of patients with chronic HCV genotype 1 or 3 infection with sofosbuvir and with or without ribavirin. Common adverse reactions include headache, anemia, nausea, and fatigue (≥10%). # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Daclatasvir is indicated for use with sofosbuvir, with or without ribavirin, for the treatment of patients with chronic hepatitis C virus (HCV) genotype 1 or genotype 3 infection. - Limitations of Use: Sustained virologic response (SVR12) rates are reduced in HCV genotype 3-infected patients with cirrhosis receiving Daclatasvir in combination with sofosbuvir for 12 weeks. - Testing Prior to Initiation of Therapy NS5A Resistance Testing in HCV Genotype 1a-Infected Patients with Cirrhosis: Consider screening for the presence of NS5A polymorphisms at amino acid positions M28, Q30, L31, and Y93 in patients with cirrhosis who are infected with HCV genotype 1a prior to the initiation of treatment with Daclatasvir and sofosbuvir with or without ribavirin. - Recommended Dosage - The recommended dosage of Daclatasvir is 60 mg, taken orally, once daily, with or without food. - Table 1 provides the recommended Daclatasvir-containing treatment regimens and duration based on HCV genotype and patient population. The optimal duration of Daclatasvir and sofosbuvir with or without ribavirin has not been established for HCV genotype 3 patients with cirrhosis or for HCV genotype 1 patients with Child-Pugh C cirrhosis. - For patients with HCV/HIV-1 coinfection, follow the dosage recommendations in Table 1. - For specific dosage recommendations for sofosbuvir, refer to the prescribing information. - For HCV genotype 1 or 3 patients with Child-Pugh B or C cirrhosis or post-transplantation patients, the starting dose of ribavirin is 600 mg once daily, increasing up to 1000 mg daily as tolerated. The starting dose and on-treatment dose of ribavirin can be decreased based on hemoglobin and creatinine clearance. - For HCV genotype 3 patients with compensated cirrhosis (Child-Pugh A), the recommended dosing of ribavirin is based on weight (1000 mg for patients weighing less than 75 kg and 1200 mg for those weighing at least 75 kg administered orally in two divided doses with food). - Table 1:Recommended Treatment Regimen and Duration for Daclatasvir in Patients with Genotype 1 or 3 HCV DAKLINZA: Daclatasvir's Brand name - Dosage Modification Due to Drug Interactions Refer to the drug interactions and contraindications sections for other drugs before coadministration with Daclatasvir. - Table 2:Recommended Daclatasvir Dosage Modification with CYP3A Inhibitors and Inducers DAKLINZA: Daclatasvir's Brand name Dosage reduction of Daclatasvir for adverse reactions is not recommended. - Discontinuation of Therapy If sofosbuvir is permanently discontinued in a patient receiving Daclatasvir with sofosbuvir, then Daclatasvir should also be discontinued. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Daclatasvir in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Daclatasvir in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness of Daclatasvir in pediatric patients younger than 18 years of age have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Daclatasvir in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Daclatasvir in pediatric patients. # Contraindications - When Daclatasvir is used in combination with other agents, the contraindications applicable to those agents are applicable to the combination regimen. Refer to the respective prescribing information for a list of contraindications. - Daclatasvir is contraindicated in combination with drugs that strongly induce CYP3A and, thus, may lead to lower exposure and loss of efficacy of Daclatasvir. Contraindicated drugs include, but are not limited to those listed in Table 3. - Table 3:Drugs that are Contraindicated with Daclatasvir Daclatasvir: Daclatasvir's Brand name # Warnings The concomitant use of Daclatasvir and other drugs may result in known or potentially significant drug interactions, some of which may lead to: - loss of therapeutic effect of Daclatasvir and possible development of resistance, - dosage adjustments of concomitant medications or Daclatasvir, - possible clinically significant adverse reactions from greater exposures of concomitant drugs or Daclatasvir. See Table 3 for drugs contraindicated with Daclatasvir due to loss of efficacy and possible development of resistance. See Table 7 for steps to prevent or manage other possible and known significant drug interactions. Consider the potential for drug interactions before and during Daclatasvir therapy, review concomitant medications during Daclatasvir therapy, and monitor for the adverse reactions associated with the concomitant drugs. Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is coadministered with sofosbuvir in combination with another HCV direct-acting antiviral, including Daclatasvir. A fatal cardiac arrest was reported in a patient receiving a sofosbuvir-containing regimen (ledipasvir/sofosbuvir). Bradycardia has generally occurred within hours to days, but cases have been observed up to 2 weeks after initiating HCV treatment. Patients also taking beta blockers or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with coadministration of amiodarone. Bradycardia generally resolved after discontinuation of HCV treatment. The mechanism for this bradycardia effect is unknown. Coadministration of amiodarone with Daclatasvir in combination with sofosbuvir is not recommended. For patients taking amiodarone who have no alternative treatment options and who will be coadministered Daclatasvir and sofosbuvir: - Counsel patients about the risk of serious symptomatic bradycardia. - Cardiac monitoring in an inpatient setting for the first 48 hours of coadministration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment. Patients who are taking sofosbuvir in combination with Daclatasvir who need to start amiodarone therapy due to no other alternative treatment options should undergo similar cardiac monitoring as outlined above. Due to amiodarone’s long elimination half-life, patients discontinuing amiodarone just prior to starting sofosbuvir in combination with Daclatasvir should also undergo similar cardiac monitoring as outlined above. Patients who develop signs or symptoms of bradycardia should seek medical evaluation immediately. Symptoms may include near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion, or memory problems. If Daclatasvir and sofosbuvir are administered with ribavirin, the warnings and precautions for ribavirin, in particular the pregnancy avoidance warning, apply to this combination regimen. Refer to the ribavirin prescribing information for a full list of the warnings and precautions for ribavirin. # Adverse Reactions ## Clinical Trials Experience If Daclatasvir and sofosbuvir are administered with ribavirin, refer to the prescribing information for ribavirin regarding ribavirin-associated adverse reactions. The following serious adverse reaction is described below and elsewhere in the labeling: - Serious Symptomatic Bradycardia When Coadministered with Sofosbuvir and Amiodarone. 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. Approximately 2400 subjects with chronic HCV infection have been treated with the recommended dose of Daclatasvir in combination with other anti-HCV drugs in clinical trials. Six hundred seventy-nine subjects have received a Daclatasvir and sofosbuvir-based regimen. Safety experience from three clinical trials of Daclatasvir and sofosbuvir with or without ribavirin is presented. - Daclatasvir and Sofosbuvir In the ALLY-3 trial, 152 treatment-naive and treatment-experienced subjects with HCV genotype 3 infection were treated with Daclatasvir 60 mg once daily in combination with sofosbuvir for 12 weeks. The most common adverse reactions (frequency of 10% or greater) were headache and fatigue. All adverse reactions were mild to moderate in severity. No subjects discontinued therapy for adverse events. In the ALLY-2 trial, 153 treatment-naive and treatment-experienced subjects with HCV/HIV-1 coinfection were treated with Daclatasvir 60 mg once daily (dose-adjusted for concomitant antiretroviral use) in combination with sofosbuvir for 12 weeks. The most common adverse reaction (frequency of 10% or greater) was fatigue. The majority of adverse reactions were mild to moderate in severity. No subjects discontinued therapy for adverse events. Adverse reactions considered at least possibly related to treatment and occurring at a frequency of 5% or greater in ALLY-3 or ALLY-2 are presented in Table 4. - Table 4:Adverse Reactions (All Severity) Reported at ≥5% Frequency, Daclatasvir + Sofosbuvir, Studies ALLY-3 and ALLY-2 - Daclatasvir, Sofosbuvir, and Ribavirin In the ALLY-1 trial, 113 subjects with chronic HCV infection, including 60 subjects with Child-Pugh A, B, or C cirrhosis and 53 subjects with recurrence of HCV after liver transplantation, were treated with Daclatasvir 60 mg once daily in combination with sofosbuvir and ribavirin for 12 weeks. The most common adverse reactions (frequency of 10% or greater) among the 113 subjects were headache, anemia, fatigue, and nausea. The majority of adverse reactions were mild to moderate in severity. Of the 15 (13%) subjects who discontinued study drug for adverse events, 13 (12%) subjects discontinued ribavirin only and 2 (2%) subjects discontinued all study drugs. During treatment, 4 subjects in the cirrhotic cohort underwent liver transplantation. Adverse reactions considered at least possibly related to treatment and occurring at a frequency of 5% or greater in either treatment cohort in ALLY-1 are presented in Table 5. - Table 5:Adverse Reactions (All Severity) Reported at ≥5% Frequency in Either Treatment Cohort, Daclatasvir + Sofosbuvir + Ribavirin, Study ALLY-1 Daclatasvir: Daclatasvir's Brand name - Laboratory Abnormalities Selected Grade 3 and 4 treatment-emergent laboratory abnormalities observed in clinical trials of Daclatasvir in combination with sofosbuvir with or without ribavirin are presented in Table 6. - Table 6:Selected Grade 3 and 4 Laboratory Abnormalities in Clinical Trials of Daclatasvir + Sofosbuvir ± Ribavirin, Studies ALLY-3, ALLY-2, and ALLY-1 Daclatasvir: Daclatasvir's Brand name ## Postmarketing Experience The following adverse reactions have been identified during postapproval use of Daclatasvir. 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: Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiate treatment with sofosbuvir in combination with another HCV direct-acting antiviral, including Daclatasvir. # Drug Interactions Daclatasvir is a substrate of CYP3A. Therefore, moderate or strong inducers of CYP3A may decrease the plasma levels and therapeutic effect of daclatasvir. Strong inhibitors of CYP3A (eg, clarithromycin, itraconazole, ketoconazole, ritonavir) may increase the plasma levels of daclatasvir. Daclatasvir is an inhibitor of P-glycoprotein transporter (P-gp), organic anion transporting polypeptide (OATP) 1B1 and 1B3, and breast cancer resistance protein (BCRP). Administration of Daclatasvir may increase systemic exposure to medicinal products that are substrates of P-gp, OATP 1B1 or 1B3, or BCRP, which could increase or prolong their therapeutic effect or adverse reactions (see TABLE 7). Refer to the prescribing information for other agents in the regimen for drug interaction information. The most conservative recommendation should be followed. Table 7 provides clinical recommendations for established or potentially significant drug interactions between Daclatasvir and other drugs. Clinically relevant increase in concentration is indicated as “↑” and clinically relevant decrease as “↓” for drug interaction data. - Table 7:Established and Other Potentially Significant Drug Interactions Daclatasvir: Daclatasvir's Brand name Based on the results of drug interaction trials, no clinically relevant changes in exposure were observed for cyclosporine, darunavir (with ritonavir), dolutegravir, escitalopram, ethinyl estradiol/norgestimate, lopinavir (with ritonavir), methadone, midazolam, tacrolimus, or tenofovir with concomitant use of daclatasvir. No clinically relevant changes in daclatasvir exposure were observed with cyclosporine, darunavir (with ritonavir), dolutegravir, escitalopram, famotidine, lopinavir (with ritonavir), omeprazole, sofosbuvir, tacrolimus, or tenofovir. No dosage adjustment for daclatasvir is necessary with darunavir/cobicistat or moderate CYP3A inhibitors, including atazanavir (unboosted), fosamprenavir, ciprofloxacin, diltiazem, erythromycin, fluconazole, or verapamil. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Risk Summary No adequate human data are available to determine whether or not Daclatasvir poses a risk to pregnancy outcomes. In animal reproduction studies in rats and rabbits, no evidence of fetal harm was observed with oral administration of daclatasvir during organogenesis at doses that produced exposures up to 6 and 22 times, respectively, the recommended human dose (RHD) of 60 mg of Daclatasvir. However, embryofetal toxicity was observed in rats and rabbits at maternally toxic doses that produced exposures of 33 and 98 times the human exposure, respectively, at the RHD of 60 mg of Daclatasvir. In rat pre- and postnatal developmental studies, no developmental toxicity was observed at maternal systemic exposure (AUC) to daclatasvir approximately 3.6 times higher than the RHD of Daclatasvir. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. If Daclatasvir and sofosbuvir are administered with ribavirin, the combination regimen is contraindicated in pregnant women and in men whose female partners are pregnant. Refer to the ribavirin prescribing information for more information on use in pregnancy. - Data - Animal Data Daclatasvir was administered orally to pregnant rats at doses of 0, 50, 200, or 1000 mg/kg/day on gestation days 6 to 15. Maternal toxicity (mortality, adverse clinical signs, body-weight losses, and reduced food consumption) was noted at doses of 200 and 1000 mg/kg/day. In the offspring, malformations of the fetal brain, skull, eyes, ears, nose, lip, palate, or limbs were observed at doses of 200 and 1000 mg/kg. The dose of 1000 mg/kg was associated with profound embryolethality and lower fetal body weight. No malformations were noted at 50 mg/kg/day. Systemic exposure (AUC) at 50 mg/kg/day in pregnant females was 6 times higher than exposures at the RHD. In rabbits, daclatasvir was initially administered at doses of 0, 40, 200, or 750 mg/kg/day during the gestation days 7 to 19. Daclatasvir dosing was modified due to vehicle toxicity during the study to doses of 20, 99, and 370 mg/kg/day, respectively. Maternal toxicity was noted at doses of 200/99 and 750/370 mg/kg/day with adverse clinical signs and severe reductions in body weight and food consumption. Mortality and euthanasia occurred in multiple dams at 750/370 mg/kg/day. At 200/99 mg/kg/day, fetal effects included increased embryofetal lethality, reduced fetal body weights, and increased incidences of fetal malformations of the ribs as well as head and skull. No malformations were noted in rabbits at 40/20 mg/kg/day. Systemic exposures (AUC) at 40/20 mg/kg/day were 22 times higher than exposures at the RHD. In a pre- and postnatal developmental study, daclatasvir was administered orally at 0, 25, 50, or 100 mg/kg/day from gestation day 6 to lactation day 20. At 100 mg/kg/day, maternal toxicity included mortality and dystocia; developmental toxicity included slight reductions in offspring viability in the perinatal and neonatal periods and reductions in birth weight that persisted into adulthood. There was neither maternal nor developmental toxicity at doses up to 50 mg/kg/day. Systemic exposures (AUC) at this dose were 3.6 times higher than the RHD. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Daclatasvir in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Daclatasvir during labor and delivery. ### Nursing Mothers - Risk Summary It is not known whether Daclatasvir is present in human milk, affects human milk production, or has effects on the breastfed infant. Daclatasvir was present in the milk of lactating rats. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Daclatasvir and any potential adverse effects on the breastfed child from Daclatasvir or from the underlying maternal condition. If Daclatasvir is administered with ribavirin, the nursing mothers information for ribavirin also applies to this combination regimen. Refer to ribavirin prescribing information for additional information. - Data Milk concentrations of daclatasvir were evaluated on lactation day 10 as part of the rat pre- and postnatal development study. Daclatasvir was present in rat milk with concentrations 1.7 to 2 times maternal plasma levels. ### Pediatric Use Safety and effectiveness of Daclatasvir in pediatric patients younger than 18 years of age have not been established. ### Geriatic Use Of 1184 subjects treated with the recommended dose of Daclatasvir in ten clinical trials, 7% of subjects were 65 years of age or older. Safety was similar across older and younger subjects and there were no safety findings unique to subjects 65 years and older. SVR12 rates were comparable among older and younger subjects. No dosage adjustment of Daclatasvir is required for elderly patients. ### Gender There is no FDA guidance on the use of Daclatasvir with respect to specific gender populations. ### Race There is no FDA guidance on the use of Daclatasvir with respect to specific racial populations. ### Renal Impairment No dosage adjustment of Daclatasvir is required for patients with any degree of renal impairment. Refer also to the sofosbuvir and ribavirin prescribing information for information regarding use in patients with renal impairment. ### Hepatic Impairment Based on a hepatic impairment study in non–HCV-infected subjects, no dosage adjustment of Daclatasvir is required for patients with mild (Child-Pugh A), moderate (Child-Pugh B), or severe (Child-Pugh C) hepatic impairment. ### Females of Reproductive Potential and Males If Daclatasvir and sofosbuvir are administered with ribavirin, the information for ribavirin with regard to pregnancy testing, contraception, and infertility also applies to this combination regimen. Refer to ribavirin prescribing information for additional information. ### Immunocompromised Patients There is no FDA guidance one the use of Daclatasvir in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Daclatasvir Administration in the drug label. ### Monitoring There is limited information regarding Daclatasvir Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Daclatasvir and IV administrations. # Overdosage There is no known antidote for overdose of Daclatasvir. Treatment of overdose with Daclatasvir should consist of general supportive measures, including monitoring of vital signs and observation of the patient’s clinical status. Because daclatasvir is highly protein bound (>99%), dialysis is unlikely to significantly reduce plasma concentrations of the drug. # Pharmacology ## Mechanism of Action Daclatasvir is a direct-acting antiviral agent (DAA) against the hepatitis C virus. ## Structure Daclatasvir is an inhibitor of HCV nonstructural protein 5A (NS5A). The chemical name for drug substance daclatasvir dihydrochloride is carbamic acid, N,N′-[[1,1′-biphenyl]-4,4′-diylbis[1H-imidazole-5,2-diyl-(2S)-2,1-pyrrolidinediyl[(1S)-1-(1-methylethyl)-2-oxo-2,1-ethanediyl]]]bis-, C,C′-dimethyl ester, hydrochloride (1:2). Its molecular formula is C40H50N8O6•2HCl, and its molecular weight is 738.88 (free base). Daclatasvir dihydrochloride has the following structural formula: Daclatasvir dihydrochloride drug substance is white to yellow. Daclatasvir is freely soluble in water (>700 mg/mL). This drug contain 60 mg daclatasvir (equivalent to 66 mg daclatasvir dihydrochloride) and the inactive ingredients anhydrous lactose (116 mg), microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate, and Opadry green. Daclatasvir 30 mg tablets (equivalent to 33 mg daclatasvir dihydrochloride) contain the inactive ingredients anhydrous lactose (58 mg), microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate, and Opadry green. Daclatasvir 90 mg tablets (equivalent to 99 mg daclatasvir dihydrochloride) contain the inactive ingredients anhydrous lactose (173 mg), microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate, and Opadry green. Opadry green contains hypromellose, titanium dioxide, polyethylene glycol 400, FD&C blue #2/indigo carmine aluminum lake, and yellow iron oxide. ## Pharmacodynamics Cardiac Electrophysiology At a dose 3 times the maximum recommended dose, daclatasvir did not prolong the QT interval to any clinically relevant extent. ## Pharmacokinetics The pharmacokinetic properties of daclatasvir were evaluated in healthy adult subjects and in subjects with chronic HCV. Administration of daclatasvir tablets in HCV-infected subjects resulted in approximately dose-proportional increases in Cmax, AUC, and Cmin up to 60 mg once daily. Steady state is anticipated after approximately 4 days of once-daily daclatasvir administration. Exposure of daclatasvir was similar between healthy and HCV-infected subjects. Population pharmacokinetic estimates for daclatasvir 60 mg once daily in chronic HCV-infected subjects are shown in Table 8. - Table 8:Population Pharmacokinetic Estimates for Daclatasvir in Chronic HCV-Infected Subjects Receiving Daclatasvir 60 mg Once Daily and Sofosbuvir 400 mg Once Daily In HCV-infected subjects following multiple oral doses of daclatasvir tablet ranging from 1 mg to 100 mg once daily, peak plasma concentrations occurred within 2 hours post dose. In vitro studies with human Caco-2 cells indicated that daclatasvir is a substrate of P-gp. The absolute bioavailability of the tablet formulation is 67%. - Effect of Food on Oral Absorption In healthy subjects, administration of a daclatasvir 60 mg tablet after a high-fat, high-caloric meal (approximately 951 total kcal, 492 kcal from fat, 312 kcal from carbohydrates, 144 kcal from protein) decreased daclatasvir Cmax and AUC(0-inf) by 28% and 23%, respectively, compared with fasted conditions. A food effect was not observed with administration of a daclatasvir 60 mg tablet after a low-fat, low-caloric meal (approximately 277 total kcal, 41 kcal from fat, 190 kcal from carbohydrates, 44 kcal from protein) compared with fasted conditions. With multiple dosing, protein binding of daclatasvir in HCV-infected subjects was approximately 99% and independent of dose at the dose range studied (1-100 mg). In subjects who received daclatasvir 60 mg tablet orally followed by 100 μg [13C,15N]-daclatasvir intravenous dose, estimated volume of distribution at steady state was 47 L. Daclatasvir is a substrate of CYP3A, with CYP3A4 being the primary CYP isoform responsible for metabolism. Following single-dose oral administration of 25 mg 14C-daclatasvir in healthy subjects, the majority of radioactivity in plasma was predominately attributed to parent drug (97% or greater). Following single-dose oral administration of 25 mg 14C-daclatasvir in healthy subjects, 88% of total radioactivity was recovered in feces (53% of the dose as unchanged daclatasvir) and 6.6% of the dose was excreted in the urine (primarily as unchanged daclatasvir). Following multiple-dose administration of daclatasvir in HCV-infected subjects, with doses ranging from 1 mg to 100 mg once daily, the terminal elimination half-life of daclatasvir ranged from approximately 12 to 15 hours. In subjects who received daclatasvir 60 mg tablet orally followed by 100 μg [13C,15N]-daclatasvir intravenous dose, the total clearance was 4.2 L/h. - Renal Impairment The pharmacokinetics of daclatasvir following a single 60 mg oral dose was studied in non–HCV-infected subjects with renal impairment. Using a regression analysis, the predicted AUC(0-inf) of daclatasvir was estimated to be 26%, 60%, and 80% higher in subjects with creatinine clearance (CLcr) values of 60, 30, and 15 mL/min, respectively, relative to subjects with normal renal function (CLcr of 90 mL/min, defined using the Cockcroft-Gault CLcr formula), and daclatasvir unbound AUC(0-inf) was predicted to be 18%, 39%, and 51% higher for subjects with CLcr values of 60, 30, and 15 mL/min, respectively, relative to subjects with normal renal function. Using observed data, subjects with end-stage renal disease requiring hemodialysis had a 27% increase in daclatasvir AUC(0-inf) and a 20% increase in unbound AUC(0-inf) compared to subjects with normal renal function as defined using the Cockcroft-Gault CLcr formula. Daclatasvir is highly protein bound to plasma proteins and is unlikely to be removed by dialysis. - Hepatic Impairment The pharmacokinetics of daclatasvir following a single 30 mg oral dose was studied in non–HCV-infected subjects with mild (Child-Pugh A), moderate (Child-Pugh B), and severe (Child-Pugh C) hepatic impairment compared to a corresponding matched control group. The Cmax and AUC(0-inf) of total daclatasvir (free and protein-bound drug) were lower by 46% and 43%, respectively, in Child-Pugh A subjects; by 45% and 38%, respectively, in Child-Pugh B subjects; and by 55% and 36%, respectively, in Child-Pugh C subjects. The Cmax and AUC(0‑inf) of unbound daclatasvir were lower by 43% and 40%, respectively, in Child-Pugh A subjects; by 14% and 2%, respectively, in Child-Pugh B subjects; and by 33% and 5%, respectively, in Child-Pugh C subjects. - Pediatric Patients The pharmacokinetics of daclatasvir in pediatric patients has not been evaluated. - Geriatric Patients Population pharmacokinetic analysis in HCV-infected subjects showed that within the age range (18-79 years) analyzed, age did not have a clinically relevant effect on the pharmacokinetics of daclatasvir. - Gender Population pharmacokinetic analyses in HCV-infected subjects estimated that female subjects have a 30% higher daclatasvir AUC compared to male subjects. This difference in daclatasvir AUC is not considered clinically relevant. - Race Population pharmacokinetic analyses in HCV-infected subjects indicated that race had no clinically relevant effect on daclatasvir exposure. - Cytochrome P450 (CYP) Enzymes Daclatasvir is a substrate of CYP3A. In vitro, daclatasvir did not inhibit (IC50 greater than 40 microM) CYP enzymes 1A2, 2B6, 2C8, 2C9, 2C19, or 2D6. Daclatasvir did not have a clinically relevant effect on the exposure of midazolam, a sensitive CYP3A substrate. - Transporters Daclatasvir is a substrate of P-gp. However, cyclosporine, which inhibits multiple transporters including P-gp, did not have a clinically relevant effect on the pharmacokinetics of daclatasvir. Daclatasvir, in vitro, did not inhibit OCT2 and did not have a clinically relevant effect on the pharmacokinetics of tenofovir, an OAT substrate. Daclatasvir demonstrated inhibitory effects on digoxin (a P-gp substrate) and rosuvastatin (an OATP 1B1, OATP 1B3, and BCRP substrate) in drug-drug interaction trials. Drug interaction studies were conducted with daclatasvir and other drugs likely to be coadministered or drugs used as probes to evaluate potential drug-drug interactions. The effects of daclatasvir on the Cmax, AUC, and Cmin of the coadministered drug are summarized in Table 9, and the effects of the coadministered drug on the Cmax, AUC, and Cmin of daclatasvir are summarized in Table 10. For information regarding clinical recommendations. Drug interaction studies were conducted in healthy adults unless otherwise noted. - Table 9:Effect of Daclatasvir on the Pharmacokinetics of Concomitant Drugs DAKLINZA: Daclatasvir's Brand name - Table 10:Effect of Coadministered Drugs on Daclatasvir Pharmacokinetics DAKLINZA: Daclatasvir's Brand name No clinically relevant interaction is anticipated for daclatasvir or the following concomitant medications: peginterferon alfa, ribavirin, or antacids. No clinically relevant interaction is anticipated for daclatasvir with concomitant use of rilpivirine. - Mechanism of Action Daclatasvir is an inhibitor of NS5A, a nonstructural protein encoded by HCV. Daclatasvir binds to the N-terminus of NS5A and inhibits both viral RNA replication and virion assembly. Characterization of daclatasvir-resistant viruses, biochemical studies, and computer modeling data indicate that daclatasvir interacts with the N-terminus within Domain 1 of the protein, which may cause structural distortions that interfere with NS5A functions. - Antiviral Activity Daclatasvir had median EC50 values of 0.008 nM (range, 0.002-0.03 nM; n=35), 0.002 nM (range, 0.0007-0.006 nM; n=30), and 0.2 nM (range, 0.006-3.2 nM; n=17) against hybrid replicons containing genotypes 1a, 1b, and 3a subject-derived NS5A sequences, respectively, without detectable daclatasvir resistance-associated polymorphisms at NS5A amino acid positions 28, 30, 31, or 93. Daclatasvir activity was reduced against genotypes 1a, 1b, and 3a subject-derived replicons with resistance-associated polymorphisms at positions 28, 30, 31, or 93, with median EC50 values of 76 nM (range, 4.6-2409 nM; n=5), 0.05 nM (range, 0.002-10 nM; n=12), and 13.5 nM (range, 1.3-50 nM; n=4), respectively. Similarly, the EC50 values of daclatasvir against 3 genotype 3b and 1 genotype 3i subject-derived NS5A sequences with polymorphisms (relative to a genotype 3a reference) at positions 30+31 (genotype 3b) or 30+62 (genotype 3i) were ≥3620 nM. Daclatasvir was not antagonistic with interferon alfa, HCV NS3/4A protease inhibitors, HCV NS5B nucleoside analog inhibitors, and HCV NS5B non-nucleoside inhibitors in cell culture combination antiviral activity studies using the cell-based HCV replicon system. - Resistance - In Cell Culture HCV genotype 1a, 1b, and 3a replicon variants with reduced susceptibility to daclatasvir were selected in cell culture, and the genotype and phenotype of daclatasvir-resistant NS5A amino acid variants were characterized. Phenotypic analysis of genotype 1a replicons expressing single NS5A M28T, Q30E, Q30H, Q30R, L31V, Y93C, Y93H, and Y93N substitutions exhibited 500-, 18500-, 1083-, 900-, 2500-, 1367-, 8500-, and 34833-fold reduced susceptibility to daclatasvir, respectively. For genotype 1b, L31V and Y93H single substitutions and L31M/Y93H and L31V/Y93H combinations exhibited 33-, 30-, 16000-, and 33667-fold reduced susceptibility to daclatasvir, respectively. A P32-deletion (P32X) in genotype 1b reduced daclatasvir susceptibility by >1,000,000-fold. For genotype 3a, single A30K, L31F, L31I, and Y93H substitutions exhibited 117-, 320-, 240-, and 3733-fold reduced susceptibility to daclatasvir, respectively. - In Clinical Studies Among subjects with HCV genotype 1 or genotype 3 infection and treated in the ALLY-1, -2, and -3 trials with Daclatasvir and sofosbuvir with or without ribavirin for 12 weeks, 31 subjects (11 with genotype 1a, 1 with genotype 1b, and 19 with genotype 3) qualified for resistance analysis due to virologic failure. Post-baseline NS5A and NS5B population-based nucleotide sequence analysis results were available for 31 and 28 subjects, respectively. Virus from all 31 subjects at the time of virologic failure harbored one or more of the following NS5A resistance-associated substitutions (including pre-existing amino acid polymorphisms or treatment-emergent substitutions): M28T, Q30H/K/R, L31M/V, H54R, H58D/P, or Y93C/N for genotype 1a subjects, P32-deletion (P32X) for the genotype 1b subject, and A30K/S, L31I, S62A/L/P/R/T, or Y93H for genotype 3 subjects. Among HCV genotype 1a virologic failure subjects, the most common NS5A amino acid substitutions occurred at position Q30 (Q30H/K/R; 73% [8/11], all treatment-emergent). Among HCV genotype 3 virologic failure subjects, the most common NS5A amino acid polymorphism or treatment-emergent substitution was Y93H (89% [17/19], treatment-emergent in 11 of 17 subjects). For NS5B, 6 of 28 subjects at the time of virologic failure had virus with NS5B substitutions possibly associated with sofosbuvir resistance or exposure: A112T, L159F, E237G, or Q355H (genotype 1a subjects), or S282T+Q355H (genotype 3 subject). - Persistence of Resistance-Associated Substitutions Limited data for Daclatasvir and sofosbuvir regimens on the persistence of daclatasvir resistance-associated substitutions are available. In a separate long-term follow-up study of predominately HCV genotype 1-infected subjects treated with daclatasvir-containing regimens in phase 2/3 clinical trials, viral populations with treatment-emergent NS5A resistance-associated substitutions persisted at detectable levels for more than 1 year in most subjects. - Effect of Baseline HCV Amino Acid Polymorphisms on Treatment Response Genotype 1a NS5A polymorphisms: In HCV genotype 1a-infected subjects with cirrhosis, the presence of an NS5A amino acid polymorphism at position M28, Q30, L31, or Y93 (defined as any change from reference identified by population-based nucleotide sequencing) was associated with reduced efficacy of Daclatasvir and sofosbuvir with or without ribavirin for 12 weeks in the ALLY-1 and ALLY-2 trials (see Table 11). Due to the limited sample size, insufficient data are available to determine the impact of specific NS5A polymorphisms at these positions on SVR12 rates in subjects with cirrhosis. Six of 54 subjects (11%) with cirrhosis had one of the following specific NS5A polymorphisms at baseline: M28V/T (n=2), Q30R (n=1), L31M (n=2), or Y93N (n=1); 2 subjects with M28V or Q30R achieved SVR12 while 4 subjects with M28T, L31M, or Y93N did not achieve SVR. Eleven of 112 subjects (10%) without cirrhosis had one or more of the following specific NS5A polymorphisms at baseline: M28T/V (n=3), Q30H/L/R (n=5), L31M (n=1), and Y93C/H/S (n=4); all noncirrhotic subjects with these baseline NS5A polymorphisms achieved SVR12. Based on an analysis of 1026 HCV genotype 1a NS5A amino acid sequences from pooled clinical trials, the prevalence of polymorphisms at these positions was 11% overall, and 11% in the U.S. Genotype 1b NS5A polymorphisms: In a pooled analysis of 43 subjects infected with HCV genotype 1b with available baseline nucleotide sequence data in ALLY-1 and -2, virus from 21% (n=9) of subjects receiving Daclatasvir and sofosbuvir with or without ribavirin had one of the following baseline NS5A amino acid polymorphisms: R30K/M/Q (n=4), L31M (n=2), or Y93H (n=3). All 9 subjects with NS5A polymorphisms achieved SVR12, including 5 who were noncirrhotic and 4 who were in the post-transplant period. Genotype 3 NS5A polymorphisms: In the ALLY-3 trial in which HCV genotype 3-infected subjects received Daclatasvir and sofosbuvir for 12 weeks, the presence of an NS5A Y93H polymorphism was associated with a reduced SVR12 rate (see Table 11). In a pooled analysis of 175 subjects infected with HCV genotype 3 with available baseline nucleotide sequence data in the ALLY-1, -2, and -3 trials, virus from 7% (13/175) of subjects had the NS5A Y93H polymorphism, and all 13 of these subjects were in the ALLY-3 trial. Phylogenetic analysis of NS5A sequences indicated that all genotype 3 subjects with available data in the ALLY-1, -2, and -3 trials (n=175) were infected with HCV subtype 3a. - Table 11:Impact of NS5A Amino Acid Polymorphisms on SVR12 Rates in Subjects with HCV Genotype 1a or Genotype 3 Infection in Phase 3 Trials of Daclatasvir + Sofosbuvir ± Ribavirin DAKLINZA: Daclatasvir's Brand name - Cross-Resistance Based on resistance patterns observed in cell culture replicon studies and HCV-infected subjects, cross-resistance between daclatasvir and other NS5A inhibitors is expected. Cross-resistance between daclatasvir and other classes of direct-acting antivirals is not expected. The impact of prior daclatasvir treatment experience on the efficacy of other NS5A inhibitors has not been studied. Conversely, the efficacy of Daclatasvir in combination with sofosbuvir has not been studied in subjects who have previously failed treatment with regimens that include an NS5A inhibitor. ## Nonclinical Toxicology - Carcinogenesis and Mutagenesis A 2-year carcinogenicity study in Sprague Dawley rats and a 6-month study in transgenic (Tg rasH2) mice were conducted with daclatasvir. In the 2-year study in rats, no drug-related increase in tumor incidence was observed at doses up to 50 mg/kg/day (both sexes). Daclatasvir exposures at these doses were approximately 6-fold (males and females) the human systemic exposure at the therapeutic daily dose of Daclatasvir. In transgenic mice no drug-related increase in tumor incidence was observed at doses of 300 mg/kg/day (both sexes). Daclatasvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity (Ames) assays, mammalian mutation assays in Chinese hamster ovary cells, or in an in vivo oral micronucleus study in rats. If Daclatasvir and sofosbuvir are administered in a regimen containing ribavirin, the information for ribavirin on carcinogenesis and mutagenesis also applies to this combination regimen (see prescribing information for ribavirin). - Impairment of Fertility Daclatasvir had no effects on fertility in female rats at any dose tested. Daclatasvir exposures at these doses in females were approximately 24-fold the human systemic exposure at the therapeutic daily dose of Daclatasvir. In male rats, effects on reproductive endpoints at 200 mg/kg/day included reduced prostate/seminal vesicle weights, minimally increased dysmorphic sperm, as well as increased mean pre-implantation loss in litters sired by treated males. Daclatasvir exposures at the 200 mg/kg/day dose in males were approximately 26-fold the human systemic exposure at the therapeutic daily dose of Daclatasvir. Exposures at 50 mg/kg/day in males produced no notable effects and was 4.7-fold the exposure in humans at the recommended daily dose of Daclatasvir. If Daclatasvir and sofosbuvir are administered with ribavirin, the information for ribavirin on impairment of fertility also applies to this combination regimen. # Clinical Studies The efficacy of Daclatasvir in combination with sofosbuvir and with or without ribavirin was evaluated in three phase 3 clinical trials, as summarized in Table 12. HCV RNA levels were measured during these 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 was the primary endpoint and was defined as HCV RNA below the LLOQ at post-treatment week 12 (SVR12). - Table 12:Genotype 1 and 3 Patient Populations from Daclatasvir Trials DAKLINZA: Daclatasvir's Brand name ALLY-3 was an open-label trial that included 152 subjects with chronic HCV genotype 3 infection and compensated liver disease who were treatment naive (n=101) or treatment experienced (n=51). Most treatment-experienced subjects had failed prior treatment with peginterferon/ribavirin, but 7 subjects had been treated previously with a sofosbuvir regimen and 2 subjects with a regimen containing an investigational agent. Previous exposure to NS5A inhibitors was prohibited. Subjects received Daclatasvir 60 mg plus sofosbuvir 400 mg once daily for 12 weeks and were monitored for 24 weeks post treatment. The 152 treated subjects in ALLY-3 had a median age of 55 years (range, 24-73); 59% of the subjects were male; 90% were white, 5% were Asian, and 4% were black. Most subjects (76%) had baseline HCV RNA levels greater than or equal to 800,000 IU per mL; 21% of the subjects had compensated cirrhosis, and 40% had the IL28B rs12979860 CC genotype. SVR12 and outcomes in subjects without SVR12 in ALLY-3 are shown by patient population in Table 13. SVR12 rates were comparable regardless of HCV treatment history, age, gender, IL28B allele status, or baseline HCV RNA level. For SVR outcomes related to baseline NS5A amino acid polymorphisms. - Table 13:ALLY-3: SVR12 in Treatment-Naive and Treatment-Experienced Subjects with or without Cirrhosis with Genotype 3 HCV Treated with Daclatasvir in Combination with Sofosbuvir for 12 Weeks ALLY-2 was an open-label trial that included 153 subjects with chronic hepatitis C and HIV coinfection who received Daclatasvir and sofosbuvir for 12 weeks. Subjects with HCV genotype 1, 2, 3, 4, 5, or 6 infection were eligible to enroll. Subjects were HCV treatment-naive (n=101) or HCV treatment-experienced (n=52). Prior exposure to NS5A inhibitors was prohibited. The dose of Daclatasvir was 60 mg once daily (dose-adjusted for concomitant antiretroviral use) and the dose of sofosbuvir was 400 mg once daily. The 153 treated subjects had a median age of 53 years (range, 24-71); 88% of subjects were male; 63% were white, 33% were black, and 1% were Asian. Sixty-eight percent of subjects had HCV genotype 1a, 15% had HCV genotype 1b, 8% had genotype 2, 7% had genotype 3, and 2% had genotype 4. Most subjects (80%) had baseline HCV RNA levels greater than or equal to 800,000 IU per mL; 16% of the subjects had compensated cirrhosis, and 73% had IL28B rs12979860 non-CC genotype. Concomitant HIV therapy included PI-based regimens (darunavir + ritonavir, atazanavir + ritonavir, or lopinavir/ritonavir) for 46% of subjects, NNRTI-based regimens (efavirenz, nevirapine, or rilpivirine) for 26%, integrase-based regimens (raltegravir or dolutegravir) for 26%, and nucleoside-only regimens (abacavir + emtricitabine + zidovudine) for 1%. Two patients were not receiving treatment for HIV. SVR and outcomes in subjects with HCV genotype 1 without SVR12 in ALLY-2 are shown by patient population in Table 14. Available data on subjects with HCV genotype 2, 4, 5, or 6 infection are insufficient to provide recommendations for these genotypes; therefore, these results are not presented in Table 14. SVR12 rates were comparable regardless of antiretroviral therapy, HCV treatment history, age, race, gender, IL28B allele status, HCV genotype 1 subtype, or baseline HCV RNA level. For SVR outcomes related to baseline NS5A amino acid polymorphisms. No subjects switched their antiretroviral therapy regimen due to loss of plasma HIV-1 RNA suppression. There was no change in absolute CD4+ T-cell counts at the end of 12 weeks of treatment. - Table 14:ALLY-2: SVR12 in Subjects with Genotype 1 and 3 HCV/HIV Coinfection Treated with Daclatasvir in Combination with Sofosbuvir for 12 Weeks ALLY-1 was an open-label trial of Daclatasvir, sofosbuvir, and ribavirin that included 113 subjects with chronic HCV infection and Child-Pugh A, B, or C cirrhosis (n=60) or HCV recurrence after liver transplantation (n=53). Subjects with HCV genotype 1, 2, 3, 4, 5, or 6 infection were eligible to enroll. Subjects could be HCV treatment-naive or treatment-experienced, although prior exposure to NS5A inhibitors was prohibited. Subjects received Daclatasvir 60 mg once daily, sofosbuvir 400 mg once daily, and ribavirin for 12 weeks and were monitored for 24 weeks post treatment. Subjects received an initial ribavirin dose of 600 mg or less daily with food; the initial and on-treatment dosing of ribavirin was modified based on hemoglobin and creatinine clearance measurements. If tolerated, the ribavirin dose was titrated up to 1000 mg per day. A high proportion of reductions in ribavirin dosing occurred in the trial. By week 6, approximately half of the subjects received 400 mg per day or less of ribavirin. In total, 16 subjects (15%) completed less than 12 weeks and 11 subjects (10%) completed less than 6 weeks of ribavirin therapy, respectively. For the cohort of patients with cirrhosis (Child-Pugh A, B, or C), the median time to discontinuation of ribavirin was 43 days (range, 8-82, n=9). For the post-transplant cohort, the median time to discontinuation of ribavirin was 20 days (range, 3-57, n=7). The 113 treated subjects in ALLY-1 had a median age of 59 years (range, 19-82); 67% of the subjects were male; 96% were white, 4% were black, and 1% Asian. Most subjects (59%) were treatment-experienced, and most (71%) had baseline HCV RNA levels greater than or equal to 800,000 IU per mL. Fifty-eight percent of subjects had HCV genotype 1a, 19% had HCV genotype 1b, 4% had genotype 2, 15% had genotype 3, 4% had genotype 4, and 1% had genotype 6, 77% had IL28B rs12979860 non-CC genotype. Among the 60 subjects in the cirrhosis cohort, 20% were Child-Pugh A, 53% were Child-Pugh B, and 27% were Child-Pugh C, and 35% had a Baseline Model for End-Stage Liver Disease (MELD) score of 15 or greater. Most (55%) of the 53 subjects in the post-transplant cohort had F3 or F4 fibrosis (based on FibroSURE® results). SVR12 and outcomes in subjects without SVR12 in ALLY-1 are shown for subjects with HCV genotype 1 by patient population in Table 15. Available data on subjects with HCV genotype 2, 4, 5, or 6 infection are insufficient to provide recommendations; therefore, these results are not presented in Table 15. SVR12 rates were comparable regardless of age, gender, IL28B allele status, or baseline HCV RNA level. For SVR12 outcomes related to baseline NS5A amino acid polymorphisms. No HCV genotype 1 or genotype 3 subjects with Child-Pugh C cirrhosis had baseline resistance-associated NS5A amino acid polymorphisms. SVR12 rates were comparable between genotype 3 (5/6 with Child-Pugh B or C cirrhosis and 10/11 post-liver transplant) and genotype 1 subjects with or without decompensated cirrhosis. - Table 15:ALLY-1: SVR12 in Genotype 1 Subjects with Child-Pugh A, B, or C Cirrhosis or with HCV Genotype 1 Recurrence after Liver Transplantation Treated with Daclatasvir in Combination with Sofosbuvir and Ribavirin for 12 Weeks # How Supplied Daclatasvir is packaged in bottles as described in the table. ## Storage Store Daclatasvir tablets at 25°C (77°F), with excursions permitted between 15°C and 30°C (59°F and 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). - Drug Interactions Inform patients of the potential for drug interactions with Daclatasvir, and that some drugs should not be taken with Daclatasvir. - Symptomatic Bradycardia When Used in Combination with Sofosbuvir and Amiodarone Advise patients to seek medical evaluation immediately for symptoms of bradycardia, such as near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion or memory problems. - Daclatasvir Combination Therapy with Sofosbuvir Inform patients that Daclatasvir should not be used alone. Daclatasvir should be used in combination with sofosbuvir with or without ribavirin for the treatment of HCV genotype 1 or HCV genotype 3 infection. - Missed Doses Advise patients to take Daclatasvir every day at the regularly scheduled time with or without food. Inform patients that it is important not to miss or skip doses and to take Daclatasvir for the duration that is recommended by the physician. For instructions for missed doses of other agents in the regimen, refer to the respective prescribing information. - Pregnancy Advise patients to avoid pregnancy during combination treatment with Daclatasvir and sofosbuvir with ribavirin for 6 months after completion of treatment. Inform patients to notify their healthcare provider immediately in the event of a pregnancy. # Precautions with Alcohol Alcohol-Daclatasvir interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names DAKLINZA™ # Look-Alike Drug Names There is limited information regarding Daclatasvir Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Daclatasvir
08399b46649b0a176d9d4b1eda2219c50637afea	wikidoc	Dacomitinib	Dacomitinib # 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 Dacomitinib is a kinase inhibitor that is FDA approved for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations as detected by an FDA-approved test. Common adverse reactions include diarrhea, rash, paronychia, stomatitis, decreased appetite, dry skin, decreased weight, alopecia, cough, and pruritus. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Indication - Dacomitinib is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations as detected by an FDA-approved test. Dosage - Recommended Dosage: 45 mg orally once daily with or without food. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding dacomitinib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding dacomitinib Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety and effectiveness of dacomitinib in pediatrics have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding dacomitinib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding dacomitinib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications None. # Warnings - Severe and fatal ILD/pneumonitis occurred in patients treated with dacomitinib and occurred in 0.5% of the 394 dacomitinib-treated patients; 0.3% of cases were fatal. - Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. Withhold dacomitinib and promptly investigate for ILD in patients who present with worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough, and fever). Permanently discontinue dacomitinib if ILD is confirmed. - Severe and fatal diarrhea occurred in patients treated with dacomitinib. Diarrhea occurred in 86% of the 394 dacomitinib-treated patients; Grade 3 or 4 diarrhea was reported in 11% of patients and 0.3% of cases were fatal. - Withhold dacomitinib for Grade 2 or greater diarrhea until recovery to less than or equal to Grade 1 severity, then resume dacomitinib at the same or a reduced dose depending on the severity of diarrhea. Promptly initiate anti-diarrheal treatment (loperamide or diphenoxylate hydrochloride and atropine sulfate) for diarrhea. - Rash and exfoliative skin reactions occurred in patients treated with dacomitinib. Rash occurred in 78% of the 394 dacomitinib-treated patients; Grade 3 or 4 rash was reported in 21% of patients. Exfoliative skin reactions of any severity were reported in 7% of patients. Grade 3 or 4 exfoliative skin reactions were reported in 1.8% of patients. - Withhold dacomitinib for persistent Grade 2 or any Grade 3 or 4 dermatologic adverse reaction until recovery to less than or equal to Grade 1 severity, then resume dacomitinib at the same or a reduced dose depending on the severity of the dermatologic adverse reaction. The incidence and severity of rash and exfoliative skin reactions may increase with sun exposure. At the time of initiation of dacomitinib, initiate use of moisturizers and appropriate measures to limit sun exposure. Upon development of Grade 1 rash, initiate treatment with topical antibiotics and topical steroids. Initiate oral antibiotics for Grade 2 or more severe dermatologic adverse reactions. - Based on findings from animal studies and its mechanism of action, dacomitinib can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of dacomitinib to pregnant rats during the period of organogenesis resulted in an increased incidence of post-implantation loss and reduced fetal body weight at doses resulting in exposures near the exposure at the 45 mg human dose. The absence of EGFR signaling has been shown to result in embryolethality as well as post-natal death in animals. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with dacomitinib and for at least 17 days after the final dose. # 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 in the Warnings and Precautions section reflect exposure to dacomitinib in 394 patients with first-line or previously treated NSCLC with EGFR exon 19 deletion or exon 21 L858R substitution mutations who received dacomitinib at the recommended dose of 45 mg once daily in 4 randomized, active-controlled trials and one single-arm trial . The median duration of exposure to dacomitinib was 10.8 months (range 0.07–68) - The data described below reflect exposure to dacomitinib in 227 patients with EGFR mutation-positive, metastatic NSCLC enrolled in a randomized, active-controlled trial (ARCHER 1050); 224 patients received was 250 mg orally once daily in the active control arm. Patients were excluded if they had a history of ILD, interstitial pneumonitis, or brain metastases. The median duration of exposure to dacomitinib was 15 months (range 0.07–37). - The most common (>20%) adverse reactions in patients treated with dacomitinib were diarrhea (87%), rash (69%), paronychia (64%), stomatitis (45%), decreased appetite (31%), dry skin (30%), decreased weight (26%), alopecia (23%), cough (21%), and pruritus (21%). - Serious adverse reactions occurred in 27% of patients treated with dacomitinib. The most common (≥1%) serious adverse reactions were diarrhea (2.2%) and interstitial lung disease (1.3%). Dose interruptions occurred in 57% of patients treated with dacomitinib. The most frequent (>5%) adverse reactions leading to dose interruptions were rash (23%), paronychia (13%), and diarrhea (10%). Dose reductions occurred in 66% of patients treated with dacomitinib. The most frequent (>5%) adverse reactions leading to dose reductions were rash (29%), paronychia (17%), and diarrhea (8%). - Adverse reactions leading to permanent discontinuation of dacomitinib occurred in 18% of patients. The most common (>0.5%) adverse reactions leading to permanent discontinuation of dacomitinib were: rash (2.6%), interstitial lung disease (1.8%), stomatitis (0.9%), and diarrhea (0.9%). - Tables 3 and 4 summarize the most common adverse reactions and laboratory abnormalities, respectively, in ARCHER 1050. ARCHER 1050 was not designed to demonstrate a statistically significant difference in adverse reaction rates for dacomitinib or for gefitinib for any adverse reaction or laboratory value listed in Table 3 or 4. - Additional adverse reactions (All Grades) that were reported in <10% of patients who received dacomitinib in ARCHER 1050 include: General: fatigue 9% Skin and subcutaneous tissue: skin fissures 9%, hypertrichosis 1.3%, skin exfoliation/exfoliative skin reactions 3.5% Gastrointestinal: vomiting 9% Nervous system: dysgeusia 7% Respiratory: interstitial lung disease 2.6% Ocular: keratitis 1.8% Metabolism and nutrition: dehydration 1.3% - General: fatigue 9% - Skin and subcutaneous tissue: skin fissures 9%, hypertrichosis 1.3%, skin exfoliation/exfoliative skin reactions 3.5% - Gastrointestinal: vomiting 9% - Nervous system: dysgeusia 7% - Respiratory: interstitial lung disease 2.6% - Ocular: keratitis 1.8% - Metabolism and nutrition: dehydration 1.3% ## Postmarketing Experience There is limited information regarding Dacomitinib Postmarketing Experience in the drug label. # Drug Interactions - Concomitant use with a PPI decreases dacomitinib concentrations, which may reduce dacomitinib efficacy. Avoid the concomitant use of PPIs with dacomitinib. As an alternative to PPIs, use locally-acting antacids or an H2-receptor antagonist. Administer dacomitinib at least 6 hours before or 10 hours after taking an H2-receptor antagonist. - Concomitant use of dacomitinib increases the concentration of drugs that are CYP2D6 substrates which may increase the risk of toxicities of these drugs. Avoid concomitant use of dacomitinib with CYP2D6 substrates where minimal increases in concentration of the CYP2D6 substrate may lead to serious or life-threatening toxicities. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Risk Summary - Based on findings from animal studies and its mechanism of action, dacomitinib can cause fetal harm when administered to a pregnant woman. There are no available data on dacomitinib use in pregnant women. In animal reproduction studies, oral administration of dacomitinib to pregnant rats during the period of organogenesis resulted in an increased incidence of post-implantation loss and reduced fetal body weight at doses resulting in exposures near the exposure at the 45 mg human dose. The absence of EGFR signaling has been shown to result in embryolethality as well as post-natal death in animals. Advise pregnant women of the potential risk to a fetus. - In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Animal Data - Daily oral administration of dacomitinib to pregnant rats during the period of organogenesis resulted in an increased incidence of post-implantation loss, maternal toxicity, and reduced fetal body weight at 5 mg/kg/day (approximately 1.2 times the exposure based on area under the curve at the 45 mg human dose). - Disruption or depletion of EGFR in mouse models has shown EGFR is critically important in reproductive and developmental processes including blastocyst implantation, placental development, and embryo-fetal/post-natal survival and development. Reduction or elimination of embryo-fetal or maternal EGFR signaling in mice can prevent implantation, and can cause embryo-fetal loss during various stages of gestation (through effects on placental development), developmental anomalies, early death in surviving fetuses, and adverse developmental outcomes in multiple organs in embryos/neonates. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dacomitinib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Dacomitinib during labor and delivery. ### Nursing Mothers Risk Summary - There is no information regarding the presence of dacomitinib or its metabolites in human milk or their effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants from dacomitinib, advise women not to breastfeed during treatment with dacomitinib and for at least 17 days after the last dose. ### Pediatric Use - The safety and effectiveness of dacomitinib in pediatrics have not been established. ### Geriatic Use - Of the total number of patients (N=394) in five clinical studies with EGFR mutation-positive NSCLC who received dacomitinib at a dose of 45 mg orally once daily 40% were 65 years of age and older. - Exploratory analyses across this population suggest a higher incidence of Grade 3 and 4 adverse reactions (67% versus 56%, respectively), more frequent dose interruptions (53% versus 45%, respectively), and more frequent discontinuations (24% versus 10%, respectively) for adverse reactions in patients 65 years or older as compared to those younger than 65 years. ### Gender There is no FDA guidance on the use of Dacomitinib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Dacomitinib with respect to specific racial populations. ### Renal Impairment - No dose adjustment is recommended for patients with mild or moderate renal impairment (creatinine clearance 30 to 89 mL/min estimated by Cockcroft-Gault). The recommended dose of dacomitinib has not been established for patients with severe renal impairment (CLcr <30 mL/min). ### Hepatic Impairment - No dose adjustment is recommended in patients with mild (total bilirubin ≤ upper limit of normal with AST > ULN or total bilirubin > 1 to 1.5 × ULN with any AST) or moderate (total bilirubin > 1.5 to 3 × ULN and any AST) hepatic impairment. The recommended dose of dacomitinib has not been established for patients with severe hepatic impairment (total bilirubin > 3 to 10 × ULN and any AST). ### Females of Reproductive Potential and Males Pregnancy Testing - Verify the pregnancy status of females of reproductive potential prior to initiating dacomitinib. Contraception - Dacomitinib can cause fetal harm when administered to a pregnant woman. Females - Advise females of reproductive potential to use effective contraception during treatment with dacomitinib and for at least 17 days after the final dose. ### Immunocompromised Patients There is no FDA guidance one the use of Dacomitinib in patients who are immunocompromised. # Administration and Monitoring ### Administration - Select patients for the first-line treatment of metastatic NSCLC with dacomitinib based on the presence of an EGFR exon 19 deletion or exon 21 L858R substitution mutation in tumor specimens. Information on FDA-approved tests for the detection of EGFR mutations in NSCLC is available at: . - The recommended dosage of dacomitinib is 45 mg taken orally once daily, until disease progression or unacceptable toxicity occurs. Dacomitinib can be taken with or without food. - Take dacomitinib the same time each day. If the patient vomits or misses a dose, do not take an additional dose or make up a missed dose but continue with the next scheduled dose. - Reduce the dose of dacomitinib for adverse reactions as described in Table 1. Dosage modifications for specific adverse reactions are provided in Table 2. - Avoid the concomitant use of proton pump inhibitors (PPIs) while taking dacomitinib. As an alternative to PPIs, use locally-acting antacids or if using an histamine 2 (H2)-receptor antagonist, administer dacomitinib at least 6 hours before or 10 hours after taking an H2-receptor antagonist. ### Monitoring There is limited information regarding Dacomitinib Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Dacomitinib and IV administrations. # Overdosage There is limited information regarding Dacomitinib overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action - Dacomitinib is an irreversible inhibitor of the kinase activity of the human EGFR family (EGFR/HER1, HER2, and HER4) and certain EGFR activating mutations (exon 19 deletion or the exon 21 L858R substitution mutation). In vitro dacomitinib also inhibited the activity of DDR1, EPHA6, LCK, DDR2, and MNK1 at clinically relevant concentrations. - Dacomitinib demonstrated dose-dependent inhibition of EGFR and HER2 autophosphorylation and tumor growth in mice bearing subcutaneously implanted human tumor xenografts driven by HER family targets including mutated EGFR. Dacomitinib also exhibited antitumor activity in orally-dosed mice bearing intracranial human tumor xenografts driven by EGFR amplifications. ## Structure - Dacomitinib is an oral kinase inhibitor with a molecular formula of C24H25ClFN5O2 ∙ H2O and a molecular weight of 487.95 Daltons. ## Pharmacodynamics Cardiac Electrophysiology - The effect of dacomitinib on the QT interval corrected for heart rate (QTc) was evaluated using time-matched electrocardiograms (ECGs) evaluating the change from baseline and corresponding pharmacokinetic data in 32 patients with advanced NSCLC. Dacomitinib had no large effect on QTc (i.e., >20 ms) at maximum dacomitinib concentrations achieved with dacomitinib 45 mg orally once daily. Exposure-Response Relationships - Higher exposures, across the range of exposures with the recommended dose of 45 mg daily, correlated with an increased probability of Grade ≥3 adverse events, specifically dermatologic toxicities and diarrhea. ## Pharmacokinetics - The maximum dacomitinib plasma concentration (Cmax) and AUC at steady state increased proportionally over the dose range of dacomitinib 2 mg to 60 mg orally once daily (0.04 to 1.3 times the recommended dose) across dacomitinib studies in patients with cancer. At a dose of 45 mg orally once daily, the geometric mean Cmax was 108 ng/mL (35%) and the AUC0–24h was 2213 ng∙h/mL (35%) at steady state in a dose-finding clinical study conducted in patients with solid tumors. Steady state was achieved within 14 days following repeated dosing and the estimated geometric mean (CV%) accumulation ratio was 5.7 (28%) based on AUC. Absorption - The mean absolute bioavailability of dacomitinib is 80% after oral administration. The median dacomitinib time to reach maximum concentration (Tmax) occurred at approximately 6.0 hours (range 2.0 to 24 hours) after a single oral dose of dacomitinib 45 mg in patients with cancer. Effect of Food - Administration of dacomitinib with a high-fat, high-calorie meal (approximately 800 to 1000 calories with 150, 250, and 500 to 600 calories from protein, carbohydrate and fat, respectively) had no clinically meaningful effect on dacomitinib pharmacokinetics. Distribution - The geometric mean (CV%) volume of distribution of dacomitinib (Vss) was 1889 L (18%). In vitro binding of dacomitinib to human plasma proteins is approximately 98% and is independent of drug concentrations from 250 ng/mL to 1000 ng/mL. Elimination - Following a single 45 mg oral dose of dacomitinib in patients with cancer, the mean (CV%) plasma half-life of dacomitinib was 70 hours (21%), and the geometric mean (CV%) apparent plasma clearance of dacomitinib was 24.9 L/h (36%). Metabolism - Hepatic metabolism is the main route of clearance of dacomitinib, with oxidation and glutathione conjugation as the major pathways. Following oral administration of a single 45 mg dose of dacomitinib, the most abundant circulating metabolite was O-desmethyl dacomitinib, which had similar in vitro pharmacologic activity as dacomitinib. The steady-state plasma trough concentration of O-desmethyl dacomitinib ranges from 7.4% to 19% of the parent. In vitro studies indicated that cytochrome P450 (CYP) 2D6 was the major isozyme involved in the formation of O-desmethyl dacomitinib, while CYP3A4 contributed to the formation of other minor oxidative metabolites. Excretion - Following a single oral 45 mg dose of radiolabeled dacomitinib, 79% of the radioactivity was recovered in feces (20% as dacomitinib) and 3% in urine (<1% as dacomitinib). Specific Populations Patients with Renal Impairment - Based on population pharmacokinetic analyses, mild (60 mL/min ≤ CLcr <90 mL/min; N=590) and moderate (30 mL/min ≤ CLcr <60 mL/min; N=218) renal impairment did not alter dacomitinib pharmacokinetics, relative to the pharmacokinetics in patients with normal renal function (CLcr ≥90 mL/min; N=567). The pharmacokinetics of dacomitinib has not been adequately characterized in patients with severe renal impairment (CLcr <30 mL/min) (N=4) or studied in patients requiring hemodialysis. Patients with Hepatic Impairment - In a dedicated hepatic impairment trial, following a single oral dose of 30 mg dacomitinib, dacomitinib exposure (AUCinf and Cmax) was unchanged in subjects with mild hepatic impairment (Child-Pugh A; N=8) and decreased by 15% and 20%, respectively in subjects with moderate hepatic impairment (Child-Pugh B; N=9) when compared to subjects with normal hepatic function (N=8). Based on this trial, mild and moderate hepatic impairment had no clinically important effects on pharmacokinetics of dacomitinib. In addition, based on a population pharmacokinetic analysis of 1381 patients, in which 158 patients had mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin > 1 to 1.5 × ULN with any AST) and 5 patients had moderate hepatic impairment (total bilirubin > 1.5 to 3 × ULN and any AST), no effects on pharmacokinetics of dacomitinib were observed. The effect of severe hepatic impairment (total bilirubin > 3 to 10 × ULN and any AST) on dacomitinib pharmacokinetics is unknown. Drug Interaction Studies Clinical Studies Effect of Acid-Reducing Agents on Dacomitinib - Coadministration of a single 45 mg dose of dacomitinib with multiple doses of rabeprazole (a proton pump inhibitor) decreased dacomitinib Cmax by 51% and AUC0–96h by 39%. - Coadministration of dacomitinib with a local antacid (Maalox® Maximum Strength, 400 mg/5 mL) did not cause clinically relevant changes dacomitinib concentrations. - The effect of H2 receptor antagonists on dacomitinib pharmacokinetics has not been studied. Effect of Strong CYP2D6 Inhibitors on Dacomitinib - Coadministration of a single 45 mg dose of dacomitinib with multiple doses of paroxetine (a strong CYP2D6 inhibitor) in healthy subjects increased the total AUClast of dacomitinib plus its active metabolite (O-desmethyl dacomitinib) in plasma by approximately 6%, which is not considered clinically relevant. Effect of Dacomitinib on CYP2D6 Substrates - Coadministration of a single 45 mg oral dose of dacomitinib increased dextromethorphan (a CYP2D6 substrate) Cmax by 9.7-fold and AUClast by 9.6-fold. In Vitro Studies - Effect of Dacomitinib and O-desmethyl Dacomitinib on CYP Enzymes: Dacomitinib and its metabolite O-desmethyl dacomitinib do not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4/5. Dacomitinib does not induce CYP1A2, CYP2B6, or CYP3A4. - Effect of Dacomitinib on Uridine 5' diphospho-glucuronosyltransferase (UGT) Enzymes: Dacomitinib inhibits UGT1A1. Dacomitinib does not inhibit UGT1A4, UGT1A6, UGT1A9, UGT2B7, or UGT2B15. - Effect of Dacomitinib on Transporter Systems: Dacomitinib is a substrate for the membrane transport protein P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). Dacomitinib inhibits P-gp, BCRP, and organic cation transporter (OCT)1. Dacomitinib does not inhibit organic anion transporters (OAT)1 and OAT3, OCT2, organic anion transporting polypeptide (OATP)1B1, and OATP1B3. ## Nonclinical Toxicology - Carcinogenicity studies have not been performed with dacomitinib. - Dacomitinib was not mutagenic in a bacterial reverse mutation (Ames) assay or clastogenic in an in vitro human lymphocyte chromosome aberration assay or clastogenic or aneugenic in an in vivo rat bone marrow micronucleus assay. - Daily oral administration of dacomitinib at doses ≥ 0.5 mg/kg/day to female rats (approximately 0.14 times the exposure based on AUC at the 45 mg human dose) resulted in reversible epithelial atrophy in the cervix and vagina. Oral administration of dacomitinib at 2 mg/kg/day to male rats (approximately 0.6 times the human exposure based on AUC at the 45 mg clinical dose) resulted in reversible decreased secretion in the prostate gland. # Clinical Studies - The efficacy of dacomitinib was demonstrated in a randomized, multicenter, multinational, open-label study (ARCHER 1050; ). Patients were required to have unresectable, metastatic NSCLC with no prior therapy for metastatic disease or recurrent disease with a minimum of 12 months disease-free after completion of systemic therapy; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; EGFR exon 19 deletion or exon 21 L858R substitution mutations. EGFR mutation status was prospectively determined by local laboratory or commercially available tests (e.g., therascreen® EGFR RGQ PCR and cobas® EGFR Mutation Test). - Patients were randomized (1:1) to receive dacomitinib 45 mg orally once daily or gefitinib 250 mg orally once daily until disease progression or unacceptable toxicity. Randomization was stratified by region (Japanese versus mainland Chinese versus other East Asian versus non-East Asian), and EGFR mutation status (exon 19 deletions versus exon 21 L858R substitution mutation). The major efficacy outcome measure was progression-free survival (PFS) as determined by blinded Independent Radiologic Central (IRC) review per RECIST v1.1. Additional efficacy outcome measures were overall response rate (ORR), duration of response (DoR), and overall survival (OS). - A total of 452 patients were randomized to receive dacomitinib (N=227) or gefitinib (N=225). The demographic characteristics were 60% female; median age 62 years (range: 28 to 87), with 40% aged 65 years and older; and 23% White, 77% Asian, and less than 1% Black. Prognostic and tumor characteristics were ECOG performance status 0 (30%) or 1 (70%); 59% with exon 19 deletion and 41% with exon 21 L858R substitution; Stage IIIB (8%) and Stage IV (92%); 64% were never smokers; and 1% received prior adjuvant or neoadjuvant therapy. - ARCHER 1050 demonstrated a statistically significant improvement in PFS as determined by the IRC. Results are summarized in Table 5 and Figures 1 and 2. - The hierarchical statistical testing order was PFS followed by ORR and then OS. No formal testing of OS was conducted since the formal comparison of ORR was not statistically significant. # How Supplied - Dacomitinib is supplied in strengths and package configurations as described in Table 6 below: ## Storage - Store at 20 °C to 25 °C (68 °F to 77 °F); excursions permitted between 15 °C to 30 °C (59 °F to 86 °F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Interstitial Lung Disease (ILD) - Advise patients of the risks of severe or fatal ILD, including pneumonitis. Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms. Diarrhea - Advise patients to contact their healthcare provider at the first signs of diarrhea. Advise patients that intravenous hydration and/or anti-diarrheal medication (e.g., loperamide) may be required to manage diarrhea. Dermatologic Adverse Reactions - Advise patients to initiate use of moisturizers and to minimize sun exposure with protective clothing and use of sunscreen at the time of initiation of dacomitinib. Advise patients to contact their healthcare provider immediately to report new or worsening rash, erythematous and exfoliative reactions. Drug Interactions - Advise patients to avoid use of PPIs while taking dacomitinib. Short-acting antacids or H2 receptor antagonists may be used if needed. Advise patients to take dacomitinib at least 6 hours before or 10 hours after taking an H2-receptor antagonist. Embryo-Fetal Toxicity - Advise females of reproductive potential that dacomitinib can result in fetal harm and to use effective contraception during treatment with dacomitinib and for 17 days after the last dose of dacomitinib. Advise females of reproductive potential to contact their healthcare provider with a known or suspected pregnancy. Lactation - Advise women not to breastfeed during treatment with dacomitinib and for 17 days after the last dose of dacomitinib. # Precautions with Alcohol Alcohol-Dacomitinib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names Vizimpro # Look-Alike Drug Names There is limited information regarding Dacomitinib Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Dacomitinib Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Zach Leibowitz [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 Dacomitinib is a kinase inhibitor that is FDA approved for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations as detected by an FDA-approved test. Common adverse reactions include diarrhea, rash, paronychia, stomatitis, decreased appetite, dry skin, decreased weight, alopecia, cough, and pruritus. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Indication - Dacomitinib is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations as detected by an FDA-approved test. Dosage - Recommended Dosage: 45 mg orally once daily with or without food. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding dacomitinib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding dacomitinib Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety and effectiveness of dacomitinib in pediatrics have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding dacomitinib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding dacomitinib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications None. # Warnings - Severe and fatal ILD/pneumonitis occurred in patients treated with dacomitinib and occurred in 0.5% of the 394 dacomitinib-treated patients; 0.3% of cases were fatal. - Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. Withhold dacomitinib and promptly investigate for ILD in patients who present with worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough, and fever). Permanently discontinue dacomitinib if ILD is confirmed. - Severe and fatal diarrhea occurred in patients treated with dacomitinib. Diarrhea occurred in 86% of the 394 dacomitinib-treated patients; Grade 3 or 4 diarrhea was reported in 11% of patients and 0.3% of cases were fatal. - Withhold dacomitinib for Grade 2 or greater diarrhea until recovery to less than or equal to Grade 1 severity, then resume dacomitinib at the same or a reduced dose depending on the severity of diarrhea. Promptly initiate anti-diarrheal treatment (loperamide or diphenoxylate hydrochloride and atropine sulfate) for diarrhea. - Rash and exfoliative skin reactions occurred in patients treated with dacomitinib. Rash occurred in 78% of the 394 dacomitinib-treated patients; Grade 3 or 4 rash was reported in 21% of patients. Exfoliative skin reactions of any severity were reported in 7% of patients. Grade 3 or 4 exfoliative skin reactions were reported in 1.8% of patients. - Withhold dacomitinib for persistent Grade 2 or any Grade 3 or 4 dermatologic adverse reaction until recovery to less than or equal to Grade 1 severity, then resume dacomitinib at the same or a reduced dose depending on the severity of the dermatologic adverse reaction. The incidence and severity of rash and exfoliative skin reactions may increase with sun exposure. At the time of initiation of dacomitinib, initiate use of moisturizers and appropriate measures to limit sun exposure. Upon development of Grade 1 rash, initiate treatment with topical antibiotics and topical steroids. Initiate oral antibiotics for Grade 2 or more severe dermatologic adverse reactions. - Based on findings from animal studies and its mechanism of action, dacomitinib can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of dacomitinib to pregnant rats during the period of organogenesis resulted in an increased incidence of post-implantation loss and reduced fetal body weight at doses resulting in exposures near the exposure at the 45 mg human dose. The absence of EGFR signaling has been shown to result in embryolethality as well as post-natal death in animals. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with dacomitinib and for at least 17 days after the final dose. # 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 in the Warnings and Precautions section reflect exposure to dacomitinib in 394 patients with first-line or previously treated NSCLC with EGFR exon 19 deletion or exon 21 L858R substitution mutations who received dacomitinib at the recommended dose of 45 mg once daily in 4 randomized, active-controlled trials [ARCHER 1050 (N=227), Study A7471009 (N=38), Study A7471011 (N=83), and Study A7471028 (N=16)] and one single-arm trial [Study A7471017 (N=30)]. The median duration of exposure to dacomitinib was 10.8 months (range 0.07–68) - The data described below reflect exposure to dacomitinib in 227 patients with EGFR mutation-positive, metastatic NSCLC enrolled in a randomized, active-controlled trial (ARCHER 1050); 224 patients received was 250 mg orally once daily in the active control arm. Patients were excluded if they had a history of ILD, interstitial pneumonitis, or brain metastases. The median duration of exposure to dacomitinib was 15 months (range 0.07–37). - The most common (>20%) adverse reactions in patients treated with dacomitinib were diarrhea (87%), rash (69%), paronychia (64%), stomatitis (45%), decreased appetite (31%), dry skin (30%), decreased weight (26%), alopecia (23%), cough (21%), and pruritus (21%). - Serious adverse reactions occurred in 27% of patients treated with dacomitinib. The most common (≥1%) serious adverse reactions were diarrhea (2.2%) and interstitial lung disease (1.3%). Dose interruptions occurred in 57% of patients treated with dacomitinib. The most frequent (>5%) adverse reactions leading to dose interruptions were rash (23%), paronychia (13%), and diarrhea (10%). Dose reductions occurred in 66% of patients treated with dacomitinib. The most frequent (>5%) adverse reactions leading to dose reductions were rash (29%), paronychia (17%), and diarrhea (8%). - Adverse reactions leading to permanent discontinuation of dacomitinib occurred in 18% of patients. The most common (>0.5%) adverse reactions leading to permanent discontinuation of dacomitinib were: rash (2.6%), interstitial lung disease (1.8%), stomatitis (0.9%), and diarrhea (0.9%). - Tables 3 and 4 summarize the most common adverse reactions and laboratory abnormalities, respectively, in ARCHER 1050. ARCHER 1050 was not designed to demonstrate a statistically significant difference in adverse reaction rates for dacomitinib or for gefitinib for any adverse reaction or laboratory value listed in Table 3 or 4. - Additional adverse reactions (All Grades) that were reported in <10% of patients who received dacomitinib in ARCHER 1050 include: General: fatigue 9% Skin and subcutaneous tissue: skin fissures 9%, hypertrichosis 1.3%, skin exfoliation/exfoliative skin reactions 3.5% Gastrointestinal: vomiting 9% Nervous system: dysgeusia 7% Respiratory: interstitial lung disease 2.6% Ocular: keratitis 1.8% Metabolism and nutrition: dehydration 1.3% - General: fatigue 9% - Skin and subcutaneous tissue: skin fissures 9%, hypertrichosis 1.3%, skin exfoliation/exfoliative skin reactions 3.5% - Gastrointestinal: vomiting 9% - Nervous system: dysgeusia 7% - Respiratory: interstitial lung disease 2.6% - Ocular: keratitis 1.8% - Metabolism and nutrition: dehydration 1.3% ## Postmarketing Experience There is limited information regarding Dacomitinib Postmarketing Experience in the drug label. # Drug Interactions - Concomitant use with a PPI decreases dacomitinib concentrations, which may reduce dacomitinib efficacy. Avoid the concomitant use of PPIs with dacomitinib. As an alternative to PPIs, use locally-acting antacids or an H2-receptor antagonist. Administer dacomitinib at least 6 hours before or 10 hours after taking an H2-receptor antagonist. - Concomitant use of dacomitinib increases the concentration of drugs that are CYP2D6 substrates which may increase the risk of toxicities of these drugs. Avoid concomitant use of dacomitinib with CYP2D6 substrates where minimal increases in concentration of the CYP2D6 substrate may lead to serious or life-threatening toxicities. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Risk Summary - Based on findings from animal studies and its mechanism of action, dacomitinib can cause fetal harm when administered to a pregnant woman. There are no available data on dacomitinib use in pregnant women. In animal reproduction studies, oral administration of dacomitinib to pregnant rats during the period of organogenesis resulted in an increased incidence of post-implantation loss and reduced fetal body weight at doses resulting in exposures near the exposure at the 45 mg human dose. The absence of EGFR signaling has been shown to result in embryolethality as well as post-natal death in animals. Advise pregnant women of the potential risk to a fetus. - In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Animal Data - Daily oral administration of dacomitinib to pregnant rats during the period of organogenesis resulted in an increased incidence of post-implantation loss, maternal toxicity, and reduced fetal body weight at 5 mg/kg/day (approximately 1.2 times the exposure based on area under the curve [AUC] at the 45 mg human dose). - Disruption or depletion of EGFR in mouse models has shown EGFR is critically important in reproductive and developmental processes including blastocyst implantation, placental development, and embryo-fetal/post-natal survival and development. Reduction or elimination of embryo-fetal or maternal EGFR signaling in mice can prevent implantation, and can cause embryo-fetal loss during various stages of gestation (through effects on placental development), developmental anomalies, early death in surviving fetuses, and adverse developmental outcomes in multiple organs in embryos/neonates. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dacomitinib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Dacomitinib during labor and delivery. ### Nursing Mothers Risk Summary - There is no information regarding the presence of dacomitinib or its metabolites in human milk or their effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants from dacomitinib, advise women not to breastfeed during treatment with dacomitinib and for at least 17 days after the last dose. ### Pediatric Use - The safety and effectiveness of dacomitinib in pediatrics have not been established. ### Geriatic Use - Of the total number of patients (N=394) in five clinical studies with EGFR mutation-positive NSCLC who received dacomitinib at a dose of 45 mg orally once daily [ARCHER 1050 (N=227), Study A7471009 (N=38), Study A7471011 (N=83), Study A7471028 (N=16), and Study A7471017 (N=30)] 40% were 65 years of age and older. - Exploratory analyses across this population suggest a higher incidence of Grade 3 and 4 adverse reactions (67% versus 56%, respectively), more frequent dose interruptions (53% versus 45%, respectively), and more frequent discontinuations (24% versus 10%, respectively) for adverse reactions in patients 65 years or older as compared to those younger than 65 years. ### Gender There is no FDA guidance on the use of Dacomitinib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Dacomitinib with respect to specific racial populations. ### Renal Impairment - No dose adjustment is recommended for patients with mild or moderate renal impairment (creatinine clearance [CLcr] 30 to 89 mL/min estimated by Cockcroft-Gault). The recommended dose of dacomitinib has not been established for patients with severe renal impairment (CLcr <30 mL/min). ### Hepatic Impairment - No dose adjustment is recommended in patients with mild (total bilirubin ≤ upper limit of normal [ULN] with AST > ULN or total bilirubin > 1 to 1.5 × ULN with any AST) or moderate (total bilirubin > 1.5 to 3 × ULN and any AST) hepatic impairment. The recommended dose of dacomitinib has not been established for patients with severe hepatic impairment (total bilirubin > 3 to 10 × ULN and any AST). ### Females of Reproductive Potential and Males Pregnancy Testing - Verify the pregnancy status of females of reproductive potential prior to initiating dacomitinib. Contraception - Dacomitinib can cause fetal harm when administered to a pregnant woman. Females - Advise females of reproductive potential to use effective contraception during treatment with dacomitinib and for at least 17 days after the final dose. ### Immunocompromised Patients There is no FDA guidance one the use of Dacomitinib in patients who are immunocompromised. # Administration and Monitoring ### Administration - Select patients for the first-line treatment of metastatic NSCLC with dacomitinib based on the presence of an EGFR exon 19 deletion or exon 21 L858R substitution mutation in tumor specimens. Information on FDA-approved tests for the detection of EGFR mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics. - The recommended dosage of dacomitinib is 45 mg taken orally once daily, until disease progression or unacceptable toxicity occurs. Dacomitinib can be taken with or without food. - Take dacomitinib the same time each day. If the patient vomits or misses a dose, do not take an additional dose or make up a missed dose but continue with the next scheduled dose. - Reduce the dose of dacomitinib for adverse reactions as described in Table 1. Dosage modifications for specific adverse reactions are provided in Table 2. - Avoid the concomitant use of proton pump inhibitors (PPIs) while taking dacomitinib. As an alternative to PPIs, use locally-acting antacids or if using an histamine 2 (H2)-receptor antagonist, administer dacomitinib at least 6 hours before or 10 hours after taking an H2-receptor antagonist. ### Monitoring There is limited information regarding Dacomitinib Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Dacomitinib and IV administrations. # Overdosage There is limited information regarding Dacomitinib overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action - Dacomitinib is an irreversible inhibitor of the kinase activity of the human EGFR family (EGFR/HER1, HER2, and HER4) and certain EGFR activating mutations (exon 19 deletion or the exon 21 L858R substitution mutation). In vitro dacomitinib also inhibited the activity of DDR1, EPHA6, LCK, DDR2, and MNK1 at clinically relevant concentrations. - Dacomitinib demonstrated dose-dependent inhibition of EGFR and HER2 autophosphorylation and tumor growth in mice bearing subcutaneously implanted human tumor xenografts driven by HER family targets including mutated EGFR. Dacomitinib also exhibited antitumor activity in orally-dosed mice bearing intracranial human tumor xenografts driven by EGFR amplifications. ## Structure - Dacomitinib is an oral kinase inhibitor with a molecular formula of C24H25ClFN5O2 ∙ H2O and a molecular weight of 487.95 Daltons. ## Pharmacodynamics Cardiac Electrophysiology - The effect of dacomitinib on the QT interval corrected for heart rate (QTc) was evaluated using time-matched electrocardiograms (ECGs) evaluating the change from baseline and corresponding pharmacokinetic data in 32 patients with advanced NSCLC. Dacomitinib had no large effect on QTc (i.e., >20 ms) at maximum dacomitinib concentrations achieved with dacomitinib 45 mg orally once daily. Exposure-Response Relationships - Higher exposures, across the range of exposures with the recommended dose of 45 mg daily, correlated with an increased probability of Grade ≥3 adverse events, specifically dermatologic toxicities and diarrhea. ## Pharmacokinetics - The maximum dacomitinib plasma concentration (Cmax) and AUC at steady state increased proportionally over the dose range of dacomitinib 2 mg to 60 mg orally once daily (0.04 to 1.3 times the recommended dose) across dacomitinib studies in patients with cancer. At a dose of 45 mg orally once daily, the geometric mean [coefficient of variation (CV%)] Cmax was 108 ng/mL (35%) and the AUC0–24h was 2213 ng∙h/mL (35%) at steady state in a dose-finding clinical study conducted in patients with solid tumors. Steady state was achieved within 14 days following repeated dosing and the estimated geometric mean (CV%) accumulation ratio was 5.7 (28%) based on AUC. Absorption - The mean absolute bioavailability of dacomitinib is 80% after oral administration. The median dacomitinib time to reach maximum concentration (Tmax) occurred at approximately 6.0 hours (range 2.0 to 24 hours) after a single oral dose of dacomitinib 45 mg in patients with cancer. Effect of Food - Administration of dacomitinib with a high-fat, high-calorie meal (approximately 800 to 1000 calories with 150, 250, and 500 to 600 calories from protein, carbohydrate and fat, respectively) had no clinically meaningful effect on dacomitinib pharmacokinetics. Distribution - The geometric mean (CV%) volume of distribution of dacomitinib (Vss) was 1889 L (18%). In vitro binding of dacomitinib to human plasma proteins is approximately 98% and is independent of drug concentrations from 250 ng/mL to 1000 ng/mL. Elimination - Following a single 45 mg oral dose of dacomitinib in patients with cancer, the mean (CV%) plasma half-life of dacomitinib was 70 hours (21%), and the geometric mean (CV%) apparent plasma clearance of dacomitinib was 24.9 L/h (36%). Metabolism - Hepatic metabolism is the main route of clearance of dacomitinib, with oxidation and glutathione conjugation as the major pathways. Following oral administration of a single 45 mg dose of [14C] dacomitinib, the most abundant circulating metabolite was O-desmethyl dacomitinib, which had similar in vitro pharmacologic activity as dacomitinib. The steady-state plasma trough concentration of O-desmethyl dacomitinib ranges from 7.4% to 19% of the parent. In vitro studies indicated that cytochrome P450 (CYP) 2D6 was the major isozyme involved in the formation of O-desmethyl dacomitinib, while CYP3A4 contributed to the formation of other minor oxidative metabolites. Excretion - Following a single oral 45 mg dose of [14C] radiolabeled dacomitinib, 79% of the radioactivity was recovered in feces (20% as dacomitinib) and 3% in urine (<1% as dacomitinib). Specific Populations Patients with Renal Impairment - Based on population pharmacokinetic analyses, mild (60 mL/min ≤ CLcr <90 mL/min; N=590) and moderate (30 mL/min ≤ CLcr <60 mL/min; N=218) renal impairment did not alter dacomitinib pharmacokinetics, relative to the pharmacokinetics in patients with normal renal function (CLcr ≥90 mL/min; N=567). The pharmacokinetics of dacomitinib has not been adequately characterized in patients with severe renal impairment (CLcr <30 mL/min) (N=4) or studied in patients requiring hemodialysis. Patients with Hepatic Impairment - In a dedicated hepatic impairment trial, following a single oral dose of 30 mg dacomitinib, dacomitinib exposure (AUCinf and Cmax) was unchanged in subjects with mild hepatic impairment (Child-Pugh A; N=8) and decreased by 15% and 20%, respectively in subjects with moderate hepatic impairment (Child-Pugh B; N=9) when compared to subjects with normal hepatic function (N=8). Based on this trial, mild and moderate hepatic impairment had no clinically important effects on pharmacokinetics of dacomitinib. In addition, based on a population pharmacokinetic analysis of 1381 patients, in which 158 patients had mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin > 1 to 1.5 × ULN with any AST) and 5 patients had moderate hepatic impairment (total bilirubin > 1.5 to 3 × ULN and any AST), no effects on pharmacokinetics of dacomitinib were observed. The effect of severe hepatic impairment (total bilirubin > 3 to 10 × ULN and any AST) on dacomitinib pharmacokinetics is unknown. Drug Interaction Studies Clinical Studies Effect of Acid-Reducing Agents on Dacomitinib - Coadministration of a single 45 mg dose of dacomitinib with multiple doses of rabeprazole (a proton pump inhibitor) decreased dacomitinib Cmax by 51% and AUC0–96h by 39%. - Coadministration of dacomitinib with a local antacid (Maalox® Maximum Strength, 400 mg/5 mL) did not cause clinically relevant changes dacomitinib concentrations. - The effect of H2 receptor antagonists on dacomitinib pharmacokinetics has not been studied. Effect of Strong CYP2D6 Inhibitors on Dacomitinib - Coadministration of a single 45 mg dose of dacomitinib with multiple doses of paroxetine (a strong CYP2D6 inhibitor) in healthy subjects increased the total AUClast of dacomitinib plus its active metabolite (O-desmethyl dacomitinib) in plasma by approximately 6%, which is not considered clinically relevant. Effect of Dacomitinib on CYP2D6 Substrates - Coadministration of a single 45 mg oral dose of dacomitinib increased dextromethorphan (a CYP2D6 substrate) Cmax by 9.7-fold and AUClast by 9.6-fold. In Vitro Studies - Effect of Dacomitinib and O-desmethyl Dacomitinib on CYP Enzymes: Dacomitinib and its metabolite O-desmethyl dacomitinib do not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4/5. Dacomitinib does not induce CYP1A2, CYP2B6, or CYP3A4. - Effect of Dacomitinib on Uridine 5' diphospho-glucuronosyltransferase (UGT) Enzymes: Dacomitinib inhibits UGT1A1. Dacomitinib does not inhibit UGT1A4, UGT1A6, UGT1A9, UGT2B7, or UGT2B15. - Effect of Dacomitinib on Transporter Systems: Dacomitinib is a substrate for the membrane transport protein P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). Dacomitinib inhibits P-gp, BCRP, and organic cation transporter (OCT)1. Dacomitinib does not inhibit organic anion transporters (OAT)1 and OAT3, OCT2, organic anion transporting polypeptide (OATP)1B1, and OATP1B3. ## Nonclinical Toxicology - Carcinogenicity studies have not been performed with dacomitinib. - Dacomitinib was not mutagenic in a bacterial reverse mutation (Ames) assay or clastogenic in an in vitro human lymphocyte chromosome aberration assay or clastogenic or aneugenic in an in vivo rat bone marrow micronucleus assay. - Daily oral administration of dacomitinib at doses ≥ 0.5 mg/kg/day to female rats (approximately 0.14 times the exposure based on AUC at the 45 mg human dose) resulted in reversible epithelial atrophy in the cervix and vagina. Oral administration of dacomitinib at 2 mg/kg/day to male rats (approximately 0.6 times the human exposure based on AUC at the 45 mg clinical dose) resulted in reversible decreased secretion in the prostate gland. # Clinical Studies - The efficacy of dacomitinib was demonstrated in a randomized, multicenter, multinational, open-label study (ARCHER 1050; [NCT01774721]). Patients were required to have unresectable, metastatic NSCLC with no prior therapy for metastatic disease or recurrent disease with a minimum of 12 months disease-free after completion of systemic therapy; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; EGFR exon 19 deletion or exon 21 L858R substitution mutations. EGFR mutation status was prospectively determined by local laboratory or commercially available tests (e.g., therascreen® EGFR RGQ PCR and cobas® EGFR Mutation Test). - Patients were randomized (1:1) to receive dacomitinib 45 mg orally once daily or gefitinib 250 mg orally once daily until disease progression or unacceptable toxicity. Randomization was stratified by region (Japanese versus mainland Chinese versus other East Asian versus non-East Asian), and EGFR mutation status (exon 19 deletions versus exon 21 L858R substitution mutation). The major efficacy outcome measure was progression-free survival (PFS) as determined by blinded Independent Radiologic Central (IRC) review per RECIST v1.1. Additional efficacy outcome measures were overall response rate (ORR), duration of response (DoR), and overall survival (OS). - A total of 452 patients were randomized to receive dacomitinib (N=227) or gefitinib (N=225). The demographic characteristics were 60% female; median age 62 years (range: 28 to 87), with 40% aged 65 years and older; and 23% White, 77% Asian, and less than 1% Black. Prognostic and tumor characteristics were ECOG performance status 0 (30%) or 1 (70%); 59% with exon 19 deletion and 41% with exon 21 L858R substitution; Stage IIIB (8%) and Stage IV (92%); 64% were never smokers; and 1% received prior adjuvant or neoadjuvant therapy. - ARCHER 1050 demonstrated a statistically significant improvement in PFS as determined by the IRC. Results are summarized in Table 5 and Figures 1 and 2. - The hierarchical statistical testing order was PFS followed by ORR and then OS. No formal testing of OS was conducted since the formal comparison of ORR was not statistically significant. # How Supplied - Dacomitinib is supplied in strengths and package configurations as described in Table 6 below: ## Storage - Store at 20 °C to 25 °C (68 °F to 77 °F); excursions permitted between 15 °C to 30 °C (59 °F to 86 °F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Interstitial Lung Disease (ILD) - Advise patients of the risks of severe or fatal ILD, including pneumonitis. Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms. Diarrhea - Advise patients to contact their healthcare provider at the first signs of diarrhea. Advise patients that intravenous hydration and/or anti-diarrheal medication (e.g., loperamide) may be required to manage diarrhea. Dermatologic Adverse Reactions - Advise patients to initiate use of moisturizers and to minimize sun exposure with protective clothing and use of sunscreen at the time of initiation of dacomitinib. Advise patients to contact their healthcare provider immediately to report new or worsening rash, erythematous and exfoliative reactions. Drug Interactions - Advise patients to avoid use of PPIs while taking dacomitinib. Short-acting antacids or H2 receptor antagonists may be used if needed. Advise patients to take dacomitinib at least 6 hours before or 10 hours after taking an H2-receptor antagonist. Embryo-Fetal Toxicity - Advise females of reproductive potential that dacomitinib can result in fetal harm and to use effective contraception during treatment with dacomitinib and for 17 days after the last dose of dacomitinib. Advise females of reproductive potential to contact their healthcare provider with a known or suspected pregnancy. Lactation - Advise women not to breastfeed during treatment with dacomitinib and for 17 days after the last dose of dacomitinib. # Precautions with Alcohol Alcohol-Dacomitinib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names Vizimpro # Look-Alike Drug Names There is limited information regarding Dacomitinib Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Dacomitinib
60e3a374c77da2c6d7b581bab505748e95a42a0c	wikidoc	Dalbavancin	Dalbavancin # 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 Dalbavancin is an antibacterial that is FDA approved for the treatment of acute bacterial skin and skin structure infections. Common adverse reactions include gastrointestinal hemorrhage, melena, hematochezia, abdominal pain, hepatotoxicity, hypoglycemia, flushing, phlebitis, wound hemorrhage, spontaneous hematoma. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - DALVANCE™ (dalbavancin) for injection is indicated for the treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of the following Gram-positive microorganisms: Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant strains), Streptococcus pyogenes, Streptococcus agalactiae and Streptococcus anginosus group (including S. anginosus, S. intermedius, S. constellatus). - To reduce the development of drug-resistant bacteria and maintain the effectiveness of DALVANCE and other antibacterial agents, DALVANCE should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. - For treatment of adults with ABSSSI, the recommended two-dose regimen of DALVANCE is 1000 mg followed one week later by 500 mg. DALVANCE should be administered over 30 minutes by intravenous infusion. - In patients with renal impairment whose known creatinine clearance is less than 30 mL/min and who are not receiving regularly scheduled hemodialysis, the recommended two-dose regimen of DALVANCE is 750 mg followed one week later by 375 mg. No dosage adjustment is recommended for patients receiving regularly scheduled hemodialysis, and DALVANCE can be administered without regard to the timing of hemodialysis. - DALVANCE(dalbavancin) for injection must be reconstituted with Sterile Water for Injection, USP, and subsequently diluted only with 5% Dextrose Injection, USP, to a final concentration of 1 mg/mL to 5 mg/mL. - Reconstitution - DALVANCE must be reconstituted under aseptic conditions, using 25 mL of Sterile Water for Injection, USP, for each 500 mg vial. To avoid foaming, alternate between gentle swirling and inversion of the vial until its contents are completely dissolved. Do not shake. The reconstituted vial contains 20 mg/mL dalbavancin as a clear, colorless to yellow solution. - Reconstituted vials may be stored either refrigerated at 2 to 8 °C (36 to 46 °F), or at controlled room temperature 20 to 25 °C (68 to 77 °F). Do not freeze. - Dilution - Aseptically transfer the required dose of reconstituted dalbavancin solution from the vial(s) to an intravenous bag or bottle containing 5% Dextrose Injection, USP. The diluted solution must have a final dalbavancin concentration of 1 mg/mL to 5 mg/mL. Discard any unused portion of the reconstituted solution. - Once diluted into an intravenous bag or bottle as described above, DALVANCE may be stored either refrigerated at 2 to 8 °C (36 to 46 °F) or at a controlled room temperature of 20 to 25 °C (68 to 77 °F). Do not freeze. - The total time from reconstitution to dilution to administration should not exceed 48 hours. - Like all parenteral drug products, diluted DALVANCE should be inspected visually for particulate matter prior to infusion. If particulate matter is identified, do not use. - After reconstitution and dilution, DALVANCE is to be administered via intravenous infusion, using a total infusion time of 30 minutes. - Do not co-infuse DALVANCE with other medications or electrolytes. Saline-based infusion solutions may cause precipitation and should not be used. The compatibility of reconstituted DALVANCE with intravenous medications, additives, or substances other than 5% Dextrose Injection, USP has not been established. - If a common intravenous line is being used to administer other drugs in addition to DALVANCE, the line should be flushed before and after each DALVANCE infusion with 5% Dextrose Injection, USP. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Dalbavancin in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Dalbavancin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Dalbavancin in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Dalbavancin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Dalbavancin in pediatric patients. # Contraindications - DALVANCE is contraindicated in patients with known hypersensitivity to dalbavancin. No data are available on cross-reactivity between dalbavancin and other glycopeptides, including vancomycin. # Warnings - Serious hypersensitivity (anaphylactic) and skin reactions have been reported in patients treated with DALVANCE. If an allergic reaction occurs, treatment with DALVANCE should be discontinued. Before using DALVANCE, inquire carefully about previous hypersensitivity reactions to glycopeptides, and due to the possibility of cross-sensitivity, exercise caution in patients with a history of glycopeptide allergy. - DALVANCE is administered via intravenous infusion, using a total infusion time of 30 minutes to minimize the risk of infusion-related reactions. Rapid intravenous infusions of DALVANCE can cause reactions that resemble "Red-Man Syndrome," including flushing of the upper body, urticaria, pruritus, and/or rash. Stopping or slowing the infusion may result in cessation of these reactions. - In Phase 2 and 3 clinical trials, more DALVANCE- than comparator-treated subjects with normal baseline transaminase levels had post-baseline alanine aminotransferase (ALT) elevation greater than 3 times the upper limit of normal (ULN). Overall, abnormalities in liver tests (ALT, AST, bilirubin) were reported with similar frequency in the DALVANCE and comparator arms. - Clostridium difficile-associated diarrhea (CDAD) has been reported in users of nearly all systemic antibacterial drugs, including DALVANCE, with severity ranging from mild diarrhea to fatal colitis. Treatment with antibacterial agents can alter the normal flora of the colon, and may permit overgrowth of C. difficile. - C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antibacterial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents. - If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile should be discontinued, if possible. Appropriate measures such as fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. - Prescribing DALVANCE in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of DALVANCE cannot be directly compared to rates in the clinical trials of another drug and may not reflect rates observed in practice. - Adverse reactions were evaluated for 1778 patients treated with DALVANCE and 1224 patients treated with comparator antibacterial drugs in seven Phase 2 and Phase 3 clinical trials. A causal relationship between study drug and adverse reactions was not always established. The median age of patients treated with DALVANCE was 47 years, ranging between 16 and 93 years old. Patients treated with DALVANCE were predominantly male (60%) and Caucasian (78%). - Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation - Serious adverse reactions occurred in 109/1778 (6.1%) of patients treated with DALVANCE and in 80/1224 (6.5%) of patients treated with comparator. DALVANCE was discontinued due to an adverse reaction in 53/1778 (3%) patients and the comparator was discontinued due to an adverse reaction in 35/1224 (2.8%) patients. - The most common adverse reactions in patients treated with DALVANCE were nausea (5.5%), headache (4.7%), and diarrhea (4.4%). The median duration of adverse reactions was 4.0 days in both treatment groups. - Table 1 lists selected adverse reactions occurring in more than 2% of patients treated with DALVANCE in clinical trials. - The following selected adverse reactions were reported in DALVANCE treated patients at a rate of less than 2% in these clinical trials: - Blood and lymphatic system disorders - Anemia, hemorrhagic anemia, leucopenia, neutropenia, thrombocytopenia, petechiae, eosinophilia, thrombocytosis - Gastrointestinal disorders - Gastrointestinal hemorrhage, melena, hematochezia, abdominal pain - General disorders and administration site conditions - Infusion-related reactions - Hepatobiliary disorders - Hepatotoxicity - Immune system disorders - Anaphylactoid reaction - Infections and infestations - Clostridium difficile colitis, oral candidiasis, vulvovaginal mycotic infection - Investigations - Hepatic transaminases increased, blood alkaline phosphatase increased, international normalized ratio increased - Metabolism and nutrition disorders - Hypoglycemia - Nervous System disorders - Dizziness - Respiratory, thoracic and mediastinal disorders - Bronchospasm - Skin and Subcutaneous Tissue disorders - Urticaria - Vascular disorders - Flushing, phlebitis, wound hemorrhage, spontaneous hematoma - Alanine Aminotransferase (ALT) Elevations - Among patients with normal baseline ALT levels, more DALVANCE- than comparator-treated patients had post-baseline ALT elevations greater than 3 times the upper limit of normal (ULN), 12 (0.8%) vs. 2 (0.2%), respectively including three subjects with post-baseline ALT values greater than 10 times ULN. Eight of 12 patients treated with DALVANCE and one comparator patient had underlying conditions which could affect liver enzymes, including chronic viral hepatitis and a history of alcohol abuse. In addition, one DALVANCE-treated subject in a Phase 1 trial had post-baseline ALT elevations greater than 20 times ULN. ALT elevations were reversible in all subjects. No comparator-treated subject with normal baseline transaminases had post-baseline ALT elevation greater than 10 times ULN. ## Postmarketing Experience There is limited information regarding Dalbavancin Postmarketing Experience in the drug label. # Drug Interactions - Drug-laboratory test interactions have not been reported. - No clinical drug-drug interaction studies have been conducted with DALVANCE. There is minimal potential for drug-drug interactions between DALVANCE and cytochrome P450 (CYP450) substrates, inhibitors, or inducers. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - There have been no adequate and well-controlled studies with dalbavancin in pregnant women. DALVANCE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - No evidence of embryo or fetal toxicity was found in the rat or rabbit at a dose of 15 mg/kg/day (1.2 and 0.7 times the human dose on an exposure basis, respectively). Delayed fetal maturation was observed in the rat at a dose of 45 mg/kg/day (3.5 times the human dose on an exposure basis). - In a rat prenatal and postnatal development study, increased embryo lethality and increased offspring deaths during the first week post-partum were observed at a dose of 45 mg/kg/day (3.5 times the human dose on an exposure basis). Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dalbavancin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Dalbavancin during labor and delivery. ### Nursing Mothers - Dalbavancin is excreted in the milk of lactating rats. It is not known whether dalbavancin or its metabolite is excreted in human milk; therefore, caution should be exercised when DALVANCE is administered to a nursing woman. ### Pediatric Use There is no FDA guidance on the use of Dalbavancin in pediatric settings. ### Geriatic Use - Of the 1778 patients treated with DALVANCE in Phase 2 and 3 clinical trials, 313 patients (17.7%) were 65 years of age or older. The efficacy and tolerability of DALVANCE were similar to comparator regardless of age. The pharmacokinetics of dalbavancin were not significantly altered with age; therefore, no dosage adjustment is necessary based on age alone. - DALVANCE is substantially excreted by the kidney, and the risk of adverse reactions 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 in this age group. ### Gender There is no FDA guidance on the use of Dalbavancin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Dalbavancin with respect to specific racial populations. ### Renal Impairment - In patients with renal impairment whose known creatinine clearance is less than 30 mL/min and who are not receiving regularly scheduled hemodialysis, the recommended two-dose regimen for DALVANCE is 750 mg followed one week later by 375 mg. No dosage adjustment is recommended for patients receiving regularly scheduled hemodialysis, and DALVANCE can be administered without regard to the timing of hemodialysis ### Hepatic Impairment - No dosage adjustment of DALVANCE is recommended for patients with mild hepatic impairment (Child-Pugh Class A). Caution should be exercised when prescribing dalbavancin to patients with moderate or severe hepatic impairment (Child-Pugh Class B or C) as no data are available to determine the appropriate dosing in these patients ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Dalbavancin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Dalbavancin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Dalbavancin in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Dalbavancin in the drug label. # Overdosage - Specific information is not available on the treatment of overdose with DALVANCE, as dose-limiting toxicity has not been observed in clinical studies. In Phase 1 studies, healthy volunteers have been administered single doses of up to 1500 mg, and cumulative doses of up to 4500 mg over a period of up to 8 weeks, with no signs of toxicity nor laboratory results of clinical concern. Treatment of overdose with DALVANCE should consist of observation and general supportive measures. Although no information is available specifically regarding the use of hemodialysis to treat overdose, in a Phase 1 study in patients with renal impairment less than 6% of the recommended dalbavancin dose was removed # Pharmacology There is limited information regarding Dalbavancin Pharmacology in the drug label. ## Mechanism of Action ## Structure ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Dalbavancin in the drug label. ## Pharmacokinetics - Dalbavancin pharmacokinetic parameters have been characterized in healthy subjects, patients, and specific populations. Pharmacokinetic parameters following administration of a single intravenous 1000 mg dose were as shown in Table 3. The pharmacokinetics of dalbavancin can be described using a three-compartment model. - Figure 2. Mean (± standard deviation) dalbavancin plasma concentrations versus time in healthy subjects (n=10) following IV administration over 30 minutes of 1000 mg dalbavancin (Day 1) and 500 mg dalbavancin (Day 8). - No apparent accumulation of dalbavancin was observed following multiple IV infusions administered once weekly for up to eight weeks, with 1000 mg on Day 1 followed by up to seven weekly 500 mg doses, in healthy adults with normal renal function. - Distribution - Dalbavancin is reversibly bound to human plasma proteins, primarily to albumin. The plasma protein binding of dalbavancin is approximately 93% and is not altered as a function of drug concentration, renal impairment, or hepatic impairment. The mean concentrations of dalbavancin achieved in skin blister fluid remain above 30 mg/L up to 7 days (approximately 146 hours) post dose, following 1000 mg IV dalbavancin. The mean ratio of the AUC0-144 hrs in skin blister fluid/AUC0-144 hrs in plasma is 0.60 (range 0.44 to 0.64). - Metabolism - In vitro studies using human microsomal enzymes and hepatocytes indicate that dalbavancin is not a substrate, inhibitor, or inducer of CYP450 isoenzymes. A minor metabolite of dalbavancin (hydroxy-dalbavancin) has been observed in the urine of healthy subjects. Quantifiable concentrations of the hydroxy-dalbavancin metabolite have not been observed in human plasma (lower limit of quantitation = 0.4 µg/mL) . - Excretion - Following administration of a single 1000 mg dose in healthy subjects, 20% of the dose was excreted in feces through 70 days post dose. An average of 33% of the administered dalbavancin dose was excreted in urine as unchanged dalbavancin and approximately 12% of the administered dose was excreted in urine as the metabolite hydroxy-dalbavancin through 42 days post dose. - Renal Impairment - The pharmacokinetics of dalbavancin were evaluated in 28 subjects with varying degrees of renal impairment and in 15 matched control subjects with normal renal function. Following a single dose of 500 mg or 1000 mg dalbavancin, the mean plasma clearance (CLT) was reduced 11%, 35%, and 47% in subjects with mild (CLCR 50 to 79 mL/min), moderate (CLCR 30 to 49 mL/min), and severe (CLCR less than 30 mL/min), renal impairment, respectively, compared to subjects with normal renal function. The clinical significance of the decrease in mean plasma CLT, and the associated increase in AUC0-∞ noted in these pharmacokinetic studies of dalbavancin in subjects with severe renal impairment has not been established. - No dosage adjustment is necessary for patients with CLCR greater than 30 mL/min or patients receiving hemodialysis. The recommended two-dose regimen for dalbavancin in patients with severe renal impairment who are not receiving regularly scheduled hemodialysis is 750 mg followed one week later by 375 mg. - Dalbavancin pharmacokinetic parameters in subjects with end-stage renal disease receiving regularly scheduled hemodialysis (three times/week) are similar to those observed in subjects with mild to moderate renal impairment, and less than 6% of an administered dose is removed after three hours of hemodialysis. Therefore, no dosage adjustment is recommended for patients receiving regularly scheduled hemodialysis, and dalbavancin may be administered without regard to the timing of hemodialysis in such patients. - Hepatic Impairment - The pharmacokinetics of dalbavancin were evaluated in 17 subjects with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B or C) and compared to those in nine matched healthy subjects with normal hepatic function. The mean AUC0-336 hrs was unchanged in subjects with mild hepatic impairment compared to subjects with normal hepatic function; however, the mean AUC0-336 hrs decreased 28% and 31% in subjects with moderate and severe hepatic impairment respectively, compared to subjects with normal hepatic function. The clinical significance of the decreased AUC0-336 hrs in subjects with moderate and severe hepatic function is unknown. - No dosage adjustment is recommended for patients with mild hepatic impairment. Caution should be exercised when prescribing dalbavancin to patients with moderate or severe hepatic impairment as no data are available to determine the appropriate dosing. - Gender - Clinically significant gender-related differences in dalbavancin pharmacokinetics have not been observed either in healthy subjects or in patients with infections. No dosage adjustment is recommended based on gender. - Geriatric Patients - Clinically significant age-related differences in dalbavancin pharmacokinetics have not been observed in patients with infections. No dosage adjustment is recommended based solely on age. - Pediatric Patients - The pharmacokinetics of dalbavancin in pediatric populations <12 years of age have not been established. - Nonclinical studies demonstrated that dalbavancin is not a substrate, inhibitor, or inducer of CYP450 isoenzymes. In a population pharmacokinetic analysis, dalbavancin pharmacokinetics were not affected by co‑administration with known CYP450 substrates, inducers or inhibitors, nor by individual medications including acetaminophen, aztreonam, fentanyl, metronidazole, furosemide, proton pump inhibitors (omeprazole, esomeprazole, pantoprazole, lansoprazole), midazolam, and simvastatin. - Dalbavancin, a semisynthetic lipoglycopeptide, interferes with cell wall synthesis by binding to the D‑alanyl-D-alanine terminus of the stem pentapeptide in nascent cell wall peptidoglycan, thus preventing cross-linking. Dalbavancin is bactericidal in vitro against Staphylococcus aureus and Streptococcus pyogenes at concentrations similar to those sustained throughout treatment in humans treated according to the recommended dosage regimen. - The development of bacterial isolates resistant to dalbavancin has not been observed, either in vitro, in studies using serial passage, or in animal infection experiments. - When tested in vitro, dalbavancin demonstrated synergistic interactions with oxacillin and did not demonstrate antagonistic or synergistic interactions with any of the following antibacterial agents of various classes: gentamicin, vancomycin, levofloxacin, clindamycin, quinupristin/dalfopristin, linezolid, aztreonam, rifampin or daptomycin. The clinical significance of these in vitro findings is unknown. - Dalbavancin has been shown to be active against the following microorganisms, both in vitro and in clinical infections. - Staphylococcus aureus (including methicillin-resistant isolates) - Streptococcus pyogenes - Streptococcus agalactiae - Streptococcus anginosus group (including S. anginosus, S. intermedius, S. constellatus) - The following in vitro data are available, but their clinical significance is unknown. In addition, at least 90% of organisms in the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the dalbavancin susceptible breakpoint of 0.12 mcg/mL. However, the safety and efficacy of dalbavancin in treating clinical infections due to these bacteria have not been established in adequate well-controlled clinical trials. - Enterococcus faecium (vancomycin-susceptible isolates only) - Enterococcus faecalis (vancomycin-susceptible isolates only) - When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug for treatment. - Quantitative methods are used to determine minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method.1,2 When determining dalbavancin MICs, polysorbate-80 (P-80), should be added at a final concentration of 0.002% to freshly prepared or frozen microtiter trays. The MIC values should be interpreted according to the criteria provided in Table 4. - Dalbavancin disks for diffusion susceptibility testing are not available. Disk diffusion is not a reliable method for determining the in vitro activity of dalbavancin. ## Nonclinical Toxicology - Long-term studies in animals to determine the carcinogenic potential of dalbavancin have not been conducted. - Dalbavancin was not genotoxic in a mammalian HGPRT gene mutation assay, an in vitro chromosome aberration assay in Chinese Hamster Ovary cells, or an in vivo mouse micronucleus assay. - Impaired fertility in the rat was not observed at a dose of 15 mg/kg/day (1.2 times the human dose on an exposure basis). Reductions in male and female fertility and increased embryo resorptions occurred at a dose of 45 mg/kg/day (3.5 times the human dose on an exposure basis), at which signs of parental toxicity were also observed. - Increases in serum levels of liver enzymes (ALT, AST), associated with microscopic findings in the liver were noted in toxicology studies in rats and dogs where dalbavancin was administered daily for 28 to 90 days. Hepatocellular necrosis was observed in dogs dosed at ≥10 mg/kg/day for longer than 2 months, i.e., at approximately 5 to 7 times the expected human dose on an exposure basis. Histiocytic vacuolation and hepatocyte necrosis were observed in rats dosed daily at 40 and 80 mg/kg/day, respectively, for 4 weeks, (approximately 3 and 6 times the expected human dose on an exposure basis, respectively). In addition, renal toxicity characterized by increases in serum BUN and creatinine and microscopic kidney findings was observed in rats and dogs at doses 5 to 7 times the expected human dose on an exposure basis. The relationship between these findings in the animal toxicology studies after 28 and 90 consecutive days of dosing to the indicated clinical dosing of 2 doses 7 days apart are unclear. # Clinical Studies - Acute Bacterial Skin and Skin Structure Infections: Adult patients with ABSSSI were enrolled in two Phase 3, randomized, double-blind, double-dummy clinical trials of similar design (Trial 1 and Trial 2). The Intent-to-Treat (ITT) population included 1,312 randomized patients. - Patients were treated for two weeks with either a two-dose regimen of intravenous DALVANCE (1000 mg followed one week later by 500 mg) or intravenous vancomycin (1000 mg or 15 mg/kg every 12 hours, with the option to switch to oral linezolid after 3 days). DALVANCE-treated patients with creatinine clearance of less than 30 mL/min received 750 mg followed one week later by 375 mg. Approximately 5% of patients also received a protocol-specified empiric course of treatment with intravenous aztreonam for coverage of Gram-negative pathogens. - The specific infections in these trials included cellulitis (approximately 50% of patients across treatment groups), major abscess (approximately 30%), and wound infection (approximately 20%). The median lesion area at baseline was 341 cm2. In addition to local signs and symptoms of infection, patients were also required to have at least one systemic sign of disease at baseline, defined as temperature 38°C or higher (approximately 85% of patients), white blood cell count greater than 12,000 cells/mm3 (approximately 40%), or 10% or more band forms on white blood cell differential (approximately 23%). Across both trials, 59% of patients were from Eastern Europe and 36% of patients were from North America. Approximately 89% of patients were Caucasian and 58% were males. The mean age was 50 years and the mean body mass index was 29.1 kg/m2. - The primary endpoint of these two ABSSSI trials was the clinical response rate where responders were defined as patients who had no increase from baseline in lesion area 48 to 72 hours after initiation of therapy, and had a temperature consistently at or below 37.6° C upon repeated measurement. Table 6 summarizes overall clinical response rates in these two ABSSSI trials using the pre‑specified primary efficacy endpoint in the ITT population. # How Supplied - DALVANCE (dalbavancin) for injection is supplied in the following packaging configuration: - 500 mg/vial: package of 1 (NDC 57970-100-01) ## Storage - Unreconstituted DALVANCE (dalbavancin) for injection should be stored at 25ºC (77ºF); excursions permitted to 15 to 30ºC (59 to 86ºF) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be advised that allergic reactions, including serious allergic reactions, could occur, and that serious allergic reactions require immediate treatment. Patients should inform their healthcare provider about any previous hypersensitivity reactions to DALVANCE, or other glycopeptides. - Patients should be counseled that antibacterial drugs including DALVANCE should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When DALVANCE is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of treatment, and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by DALVANCE and other antibacterial drugs in the future. - Patients should be advised that diarrhea is a common problem caused by antibacterial drugs and usually resolves when the drug is discontinued. Sometimes, frequent watery or bloody diarrhea may occur and may be a sign of a more serious intestinal infection. If severe watery or bloody diarrhea develops, patients should contact their healthcare provider. # Precautions with Alcohol - Alcohol-Dalbavancin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - DALVANCE® # Look-Alike Drug Names There is limited information regarding Dalbavancin Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Dalbavancin 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 Dalbavancin is an antibacterial that is FDA approved for the treatment of acute bacterial skin and skin structure infections. Common adverse reactions include gastrointestinal hemorrhage, melena, hematochezia, abdominal pain, hepatotoxicity, hypoglycemia, flushing, phlebitis, wound hemorrhage, spontaneous hematoma. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - DALVANCE™ (dalbavancin) for injection is indicated for the treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of the following Gram-positive microorganisms: Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant strains), Streptococcus pyogenes, Streptococcus agalactiae and Streptococcus anginosus group (including S. anginosus, S. intermedius, S. constellatus). - To reduce the development of drug-resistant bacteria and maintain the effectiveness of DALVANCE and other antibacterial agents, DALVANCE should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. - For treatment of adults with ABSSSI, the recommended two-dose regimen of DALVANCE is 1000 mg followed one week later by 500 mg. DALVANCE should be administered over 30 minutes by intravenous infusion. - In patients with renal impairment whose known creatinine clearance is less than 30 mL/min and who are not receiving regularly scheduled hemodialysis, the recommended two-dose regimen of DALVANCE is 750 mg followed one week later by 375 mg. No dosage adjustment is recommended for patients receiving regularly scheduled hemodialysis, and DALVANCE can be administered without regard to the timing of hemodialysis. - DALVANCE(dalbavancin) for injection must be reconstituted with Sterile Water for Injection, USP, and subsequently diluted only with 5% Dextrose Injection, USP, to a final concentration of 1 mg/mL to 5 mg/mL. - Reconstitution - DALVANCE must be reconstituted under aseptic conditions, using 25 mL of Sterile Water for Injection, USP, for each 500 mg vial. To avoid foaming, alternate between gentle swirling and inversion of the vial until its contents are completely dissolved. Do not shake. The reconstituted vial contains 20 mg/mL dalbavancin as a clear, colorless to yellow solution. - Reconstituted vials may be stored either refrigerated at 2 to 8 °C (36 to 46 °F), or at controlled room temperature 20 to 25 °C (68 to 77 °F). Do not freeze. - Dilution - Aseptically transfer the required dose of reconstituted dalbavancin solution from the vial(s) to an intravenous bag or bottle containing 5% Dextrose Injection, USP. The diluted solution must have a final dalbavancin concentration of 1 mg/mL to 5 mg/mL. Discard any unused portion of the reconstituted solution. - Once diluted into an intravenous bag or bottle as described above, DALVANCE may be stored either refrigerated at 2 to 8 °C (36 to 46 °F) or at a controlled room temperature of 20 to 25 °C (68 to 77 °F). Do not freeze. - The total time from reconstitution to dilution to administration should not exceed 48 hours. - Like all parenteral drug products, diluted DALVANCE should be inspected visually for particulate matter prior to infusion. If particulate matter is identified, do not use. - After reconstitution and dilution, DALVANCE is to be administered via intravenous infusion, using a total infusion time of 30 minutes. - Do not co-infuse DALVANCE with other medications or electrolytes. Saline-based infusion solutions may cause precipitation and should not be used. The compatibility of reconstituted DALVANCE with intravenous medications, additives, or substances other than 5% Dextrose Injection, USP has not been established. - If a common intravenous line is being used to administer other drugs in addition to DALVANCE, the line should be flushed before and after each DALVANCE infusion with 5% Dextrose Injection, USP. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Dalbavancin in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Dalbavancin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Dalbavancin in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Dalbavancin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Dalbavancin in pediatric patients. # Contraindications - DALVANCE is contraindicated in patients with known hypersensitivity to dalbavancin. No data are available on cross-reactivity between dalbavancin and other glycopeptides, including vancomycin. # Warnings - Serious hypersensitivity (anaphylactic) and skin reactions have been reported in patients treated with DALVANCE. If an allergic reaction occurs, treatment with DALVANCE should be discontinued. Before using DALVANCE, inquire carefully about previous hypersensitivity reactions to glycopeptides, and due to the possibility of cross-sensitivity, exercise caution in patients with a history of glycopeptide allergy. - DALVANCE is administered via intravenous infusion, using a total infusion time of 30 minutes to minimize the risk of infusion-related reactions. Rapid intravenous infusions of DALVANCE can cause reactions that resemble "Red-Man Syndrome," including flushing of the upper body, urticaria, pruritus, and/or rash. Stopping or slowing the infusion may result in cessation of these reactions. - In Phase 2 and 3 clinical trials, more DALVANCE- than comparator-treated subjects with normal baseline transaminase levels had post-baseline alanine aminotransferase (ALT) elevation greater than 3 times the upper limit of normal (ULN). Overall, abnormalities in liver tests (ALT, AST, bilirubin) were reported with similar frequency in the DALVANCE and comparator arms. - Clostridium difficile-associated diarrhea (CDAD) has been reported in users of nearly all systemic antibacterial drugs, including DALVANCE, with severity ranging from mild diarrhea to fatal colitis. Treatment with antibacterial agents can alter the normal flora of the colon, and may permit overgrowth of C. difficile. - C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antibacterial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents. - If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile should be discontinued, if possible. Appropriate measures such as fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. - Prescribing DALVANCE in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of DALVANCE cannot be directly compared to rates in the clinical trials of another drug and may not reflect rates observed in practice. - Adverse reactions were evaluated for 1778 patients treated with DALVANCE and 1224 patients treated with comparator antibacterial drugs in seven Phase 2 and Phase 3 clinical trials. A causal relationship between study drug and adverse reactions was not always established. The median age of patients treated with DALVANCE was 47 years, ranging between 16 and 93 years old. Patients treated with DALVANCE were predominantly male (60%) and Caucasian (78%). - Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation - Serious adverse reactions occurred in 109/1778 (6.1%) of patients treated with DALVANCE and in 80/1224 (6.5%) of patients treated with comparator. DALVANCE was discontinued due to an adverse reaction in 53/1778 (3%) patients and the comparator was discontinued due to an adverse reaction in 35/1224 (2.8%) patients. - The most common adverse reactions in patients treated with DALVANCE were nausea (5.5%), headache (4.7%), and diarrhea (4.4%). The median duration of adverse reactions was 4.0 days in both treatment groups. - Table 1 lists selected adverse reactions occurring in more than 2% of patients treated with DALVANCE in clinical trials. - The following selected adverse reactions were reported in DALVANCE treated patients at a rate of less than 2% in these clinical trials: - Blood and lymphatic system disorders - Anemia, hemorrhagic anemia, leucopenia, neutropenia, thrombocytopenia, petechiae, eosinophilia, thrombocytosis - Gastrointestinal disorders - Gastrointestinal hemorrhage, melena, hematochezia, abdominal pain - General disorders and administration site conditions - Infusion-related reactions - Hepatobiliary disorders - Hepatotoxicity - Immune system disorders - Anaphylactoid reaction - Infections and infestations - Clostridium difficile colitis, oral candidiasis, vulvovaginal mycotic infection - Investigations - Hepatic transaminases increased, blood alkaline phosphatase increased, international normalized ratio increased - Metabolism and nutrition disorders - Hypoglycemia - Nervous System disorders - Dizziness - Respiratory, thoracic and mediastinal disorders - Bronchospasm - Skin and Subcutaneous Tissue disorders - Urticaria - Vascular disorders - Flushing, phlebitis, wound hemorrhage, spontaneous hematoma - Alanine Aminotransferase (ALT) Elevations - Among patients with normal baseline ALT levels, more DALVANCE- than comparator-treated patients had post-baseline ALT elevations greater than 3 times the upper limit of normal (ULN), 12 (0.8%) vs. 2 (0.2%), respectively including three subjects with post-baseline ALT values greater than 10 times ULN. Eight of 12 patients treated with DALVANCE and one comparator patient had underlying conditions which could affect liver enzymes, including chronic viral hepatitis and a history of alcohol abuse. In addition, one DALVANCE-treated subject in a Phase 1 trial had post-baseline ALT elevations greater than 20 times ULN. ALT elevations were reversible in all subjects. No comparator-treated subject with normal baseline transaminases had post-baseline ALT elevation greater than 10 times ULN. ## Postmarketing Experience There is limited information regarding Dalbavancin Postmarketing Experience in the drug label. # Drug Interactions - Drug-laboratory test interactions have not been reported. - No clinical drug-drug interaction studies have been conducted with DALVANCE. There is minimal potential for drug-drug interactions between DALVANCE and cytochrome P450 (CYP450) substrates, inhibitors, or inducers. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - There have been no adequate and well-controlled studies with dalbavancin in pregnant women. DALVANCE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - No evidence of embryo or fetal toxicity was found in the rat or rabbit at a dose of 15 mg/kg/day (1.2 and 0.7 times the human dose on an exposure basis, respectively). Delayed fetal maturation was observed in the rat at a dose of 45 mg/kg/day (3.5 times the human dose on an exposure basis). - In a rat prenatal and postnatal development study, increased embryo lethality and increased offspring deaths during the first week post-partum were observed at a dose of 45 mg/kg/day (3.5 times the human dose on an exposure basis). Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dalbavancin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Dalbavancin during labor and delivery. ### Nursing Mothers - Dalbavancin is excreted in the milk of lactating rats. It is not known whether dalbavancin or its metabolite is excreted in human milk; therefore, caution should be exercised when DALVANCE is administered to a nursing woman. ### Pediatric Use There is no FDA guidance on the use of Dalbavancin in pediatric settings. ### Geriatic Use - Of the 1778 patients treated with DALVANCE in Phase 2 and 3 clinical trials, 313 patients (17.7%) were 65 years of age or older. The efficacy and tolerability of DALVANCE were similar to comparator regardless of age. The pharmacokinetics of dalbavancin were not significantly altered with age; therefore, no dosage adjustment is necessary based on age alone. - DALVANCE is substantially excreted by the kidney, and the risk of adverse reactions 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 in this age group. ### Gender There is no FDA guidance on the use of Dalbavancin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Dalbavancin with respect to specific racial populations. ### Renal Impairment - In patients with renal impairment whose known creatinine clearance is less than 30 mL/min and who are not receiving regularly scheduled hemodialysis, the recommended two-dose regimen for DALVANCE is 750 mg followed one week later by 375 mg. No dosage adjustment is recommended for patients receiving regularly scheduled hemodialysis, and DALVANCE can be administered without regard to the timing of hemodialysis ### Hepatic Impairment - No dosage adjustment of DALVANCE is recommended for patients with mild hepatic impairment (Child-Pugh Class A). Caution should be exercised when prescribing dalbavancin to patients with moderate or severe hepatic impairment (Child-Pugh Class B or C) as no data are available to determine the appropriate dosing in these patients ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Dalbavancin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Dalbavancin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Dalbavancin in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Dalbavancin in the drug label. # Overdosage - Specific information is not available on the treatment of overdose with DALVANCE, as dose-limiting toxicity has not been observed in clinical studies. In Phase 1 studies, healthy volunteers have been administered single doses of up to 1500 mg, and cumulative doses of up to 4500 mg over a period of up to 8 weeks, with no signs of toxicity nor laboratory results of clinical concern. Treatment of overdose with DALVANCE should consist of observation and general supportive measures. Although no information is available specifically regarding the use of hemodialysis to treat overdose, in a Phase 1 study in patients with renal impairment less than 6% of the recommended dalbavancin dose was removed # Pharmacology There is limited information regarding Dalbavancin Pharmacology in the drug label. ## Mechanism of Action - ## Structure - ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Dalbavancin in the drug label. ## Pharmacokinetics - Dalbavancin pharmacokinetic parameters have been characterized in healthy subjects, patients, and specific populations. Pharmacokinetic parameters following administration of a single intravenous 1000 mg dose were as shown in Table 3. The pharmacokinetics of dalbavancin can be described using a three-compartment model. - Figure 2. Mean (± standard deviation) dalbavancin plasma concentrations versus time in healthy subjects (n=10) following IV administration over 30 minutes of 1000 mg dalbavancin (Day 1) and 500 mg dalbavancin (Day 8). - No apparent accumulation of dalbavancin was observed following multiple IV infusions administered once weekly for up to eight weeks, with 1000 mg on Day 1 followed by up to seven weekly 500 mg doses, in healthy adults with normal renal function. - Distribution - Dalbavancin is reversibly bound to human plasma proteins, primarily to albumin. The plasma protein binding of dalbavancin is approximately 93% and is not altered as a function of drug concentration, renal impairment, or hepatic impairment. The mean concentrations of dalbavancin achieved in skin blister fluid remain above 30 mg/L up to 7 days (approximately 146 hours) post dose, following 1000 mg IV dalbavancin. The mean ratio of the AUC0-144 hrs in skin blister fluid/AUC0-144 hrs in plasma is 0.60 (range 0.44 to 0.64). - Metabolism - In vitro studies using human microsomal enzymes and hepatocytes indicate that dalbavancin is not a substrate, inhibitor, or inducer of CYP450 isoenzymes. A minor metabolite of dalbavancin (hydroxy-dalbavancin) has been observed in the urine of healthy subjects. Quantifiable concentrations of the hydroxy-dalbavancin metabolite have not been observed in human plasma (lower limit of quantitation = 0.4 µg/mL) [see Drug Interactions (7.2)]. - Excretion - Following administration of a single 1000 mg dose in healthy subjects, 20% of the dose was excreted in feces through 70 days post dose. An average of 33% of the administered dalbavancin dose was excreted in urine as unchanged dalbavancin and approximately 12% of the administered dose was excreted in urine as the metabolite hydroxy-dalbavancin through 42 days post dose. - Renal Impairment - The pharmacokinetics of dalbavancin were evaluated in 28 subjects with varying degrees of renal impairment and in 15 matched control subjects with normal renal function. Following a single dose of 500 mg or 1000 mg dalbavancin, the mean plasma clearance (CLT) was reduced 11%, 35%, and 47% in subjects with mild (CLCR 50 to 79 mL/min), moderate (CLCR 30 to 49 mL/min), and severe (CLCR less than 30 mL/min), renal impairment, respectively, compared to subjects with normal renal function. The clinical significance of the decrease in mean plasma CLT, and the associated increase in AUC0-∞ noted in these pharmacokinetic studies of dalbavancin in subjects with severe renal impairment has not been established. - No dosage adjustment is necessary for patients with CLCR greater than 30 mL/min or patients receiving hemodialysis. The recommended two-dose regimen for dalbavancin in patients with severe renal impairment who are not receiving regularly scheduled hemodialysis is 750 mg followed one week later by 375 mg. - Dalbavancin pharmacokinetic parameters in subjects with end-stage renal disease receiving regularly scheduled hemodialysis (three times/week) are similar to those observed in subjects with mild to moderate renal impairment, and less than 6% of an administered dose is removed after three hours of hemodialysis. Therefore, no dosage adjustment is recommended for patients receiving regularly scheduled hemodialysis, and dalbavancin may be administered without regard to the timing of hemodialysis in such patients. - Hepatic Impairment - The pharmacokinetics of dalbavancin were evaluated in 17 subjects with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B or C) and compared to those in nine matched healthy subjects with normal hepatic function. The mean AUC0-336 hrs was unchanged in subjects with mild hepatic impairment compared to subjects with normal hepatic function; however, the mean AUC0-336 hrs decreased 28% and 31% in subjects with moderate and severe hepatic impairment respectively, compared to subjects with normal hepatic function. The clinical significance of the decreased AUC0-336 hrs in subjects with moderate and severe hepatic function is unknown. - No dosage adjustment is recommended for patients with mild hepatic impairment. Caution should be exercised when prescribing dalbavancin to patients with moderate or severe hepatic impairment as no data are available to determine the appropriate dosing. - Gender - Clinically significant gender-related differences in dalbavancin pharmacokinetics have not been observed either in healthy subjects or in patients with infections. No dosage adjustment is recommended based on gender. - Geriatric Patients - Clinically significant age-related differences in dalbavancin pharmacokinetics have not been observed in patients with infections. No dosage adjustment is recommended based solely on age. - Pediatric Patients - The pharmacokinetics of dalbavancin in pediatric populations <12 years of age have not been established. - Nonclinical studies demonstrated that dalbavancin is not a substrate, inhibitor, or inducer of CYP450 isoenzymes. In a population pharmacokinetic analysis, dalbavancin pharmacokinetics were not affected by co‑administration with known CYP450 substrates, inducers or inhibitors, nor by individual medications including acetaminophen, aztreonam, fentanyl, metronidazole, furosemide, proton pump inhibitors (omeprazole, esomeprazole, pantoprazole, lansoprazole), midazolam, and simvastatin. - Dalbavancin, a semisynthetic lipoglycopeptide, interferes with cell wall synthesis by binding to the D‑alanyl-D-alanine terminus of the stem pentapeptide in nascent cell wall peptidoglycan, thus preventing cross-linking. Dalbavancin is bactericidal in vitro against Staphylococcus aureus and Streptococcus pyogenes at concentrations similar to those sustained throughout treatment in humans treated according to the recommended dosage regimen. - The development of bacterial isolates resistant to dalbavancin has not been observed, either in vitro, in studies using serial passage, or in animal infection experiments. - When tested in vitro, dalbavancin demonstrated synergistic interactions with oxacillin and did not demonstrate antagonistic or synergistic interactions with any of the following antibacterial agents of various classes: gentamicin, vancomycin, levofloxacin, clindamycin, quinupristin/dalfopristin, linezolid, aztreonam, rifampin or daptomycin. The clinical significance of these in vitro findings is unknown. - Dalbavancin has been shown to be active against the following microorganisms, both in vitro and in clinical infections. - Staphylococcus aureus (including methicillin-resistant isolates) - Streptococcus pyogenes - Streptococcus agalactiae - Streptococcus anginosus group (including S. anginosus, S. intermedius, S. constellatus) - The following in vitro data are available, but their clinical significance is unknown. In addition, at least 90% of organisms in the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the dalbavancin susceptible breakpoint of 0.12 mcg/mL. However, the safety and efficacy of dalbavancin in treating clinical infections due to these bacteria have not been established in adequate well-controlled clinical trials. - Enterococcus faecium (vancomycin-susceptible isolates only) - Enterococcus faecalis (vancomycin-susceptible isolates only) - When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug for treatment. - Quantitative methods are used to determine minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method.1,2 When determining dalbavancin MICs, polysorbate-80 (P-80), should be added at a final concentration of 0.002% to freshly prepared or frozen microtiter trays. The MIC values should be interpreted according to the criteria provided in Table 4. - Dalbavancin disks for diffusion susceptibility testing are not available. Disk diffusion is not a reliable method for determining the in vitro activity of dalbavancin. ## Nonclinical Toxicology - Long-term studies in animals to determine the carcinogenic potential of dalbavancin have not been conducted. - Dalbavancin was not genotoxic in a mammalian HGPRT gene mutation assay, an in vitro chromosome aberration assay in Chinese Hamster Ovary cells, or an in vivo mouse micronucleus assay. - Impaired fertility in the rat was not observed at a dose of 15 mg/kg/day (1.2 times the human dose on an exposure basis). Reductions in male and female fertility and increased embryo resorptions occurred at a dose of 45 mg/kg/day (3.5 times the human dose on an exposure basis), at which signs of parental toxicity were also observed. - Increases in serum levels of liver enzymes (ALT, AST), associated with microscopic findings in the liver were noted in toxicology studies in rats and dogs where dalbavancin was administered daily for 28 to 90 days. Hepatocellular necrosis was observed in dogs dosed at ≥10 mg/kg/day for longer than 2 months, i.e., at approximately 5 to 7 times the expected human dose on an exposure basis. Histiocytic vacuolation and hepatocyte necrosis were observed in rats dosed daily at 40 and 80 mg/kg/day, respectively, for 4 weeks, (approximately 3 and 6 times the expected human dose on an exposure basis, respectively). In addition, renal toxicity characterized by increases in serum BUN and creatinine and microscopic kidney findings was observed in rats and dogs at doses 5 to 7 times the expected human dose on an exposure basis. The relationship between these findings in the animal toxicology studies after 28 and 90 consecutive days of dosing to the indicated clinical dosing of 2 doses 7 days apart are unclear. # Clinical Studies - Acute Bacterial Skin and Skin Structure Infections: Adult patients with ABSSSI were enrolled in two Phase 3, randomized, double-blind, double-dummy clinical trials of similar design (Trial 1 and Trial 2). The Intent-to-Treat (ITT) population included 1,312 randomized patients. - Patients were treated for two weeks with either a two-dose regimen of intravenous DALVANCE (1000 mg followed one week later by 500 mg) or intravenous vancomycin (1000 mg or 15 mg/kg every 12 hours, with the option to switch to oral linezolid after 3 days). DALVANCE-treated patients with creatinine clearance of less than 30 mL/min received 750 mg followed one week later by 375 mg. Approximately 5% of patients also received a protocol-specified empiric course of treatment with intravenous aztreonam for coverage of Gram-negative pathogens. - The specific infections in these trials included cellulitis (approximately 50% of patients across treatment groups), major abscess (approximately 30%), and wound infection (approximately 20%). The median lesion area at baseline was 341 cm2. In addition to local signs and symptoms of infection, patients were also required to have at least one systemic sign of disease at baseline, defined as temperature 38°C or higher (approximately 85% of patients), white blood cell count greater than 12,000 cells/mm3 (approximately 40%), or 10% or more band forms on white blood cell differential (approximately 23%). Across both trials, 59% of patients were from Eastern Europe and 36% of patients were from North America. Approximately 89% of patients were Caucasian and 58% were males. The mean age was 50 years and the mean body mass index was 29.1 kg/m2. - The primary endpoint of these two ABSSSI trials was the clinical response rate where responders were defined as patients who had no increase from baseline in lesion area 48 to 72 hours after initiation of therapy, and had a temperature consistently at or below 37.6° C upon repeated measurement. Table 6 summarizes overall clinical response rates in these two ABSSSI trials using the pre‑specified primary efficacy endpoint in the ITT population. # How Supplied - DALVANCE (dalbavancin) for injection is supplied in the following packaging configuration: - 500 mg/vial: package of 1 (NDC 57970-100-01) ## Storage - Unreconstituted DALVANCE (dalbavancin) for injection should be stored at 25ºC (77ºF); excursions permitted to 15 to 30ºC (59 to 86ºF) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be advised that allergic reactions, including serious allergic reactions, could occur, and that serious allergic reactions require immediate treatment. Patients should inform their healthcare provider about any previous hypersensitivity reactions to DALVANCE, or other glycopeptides. - Patients should be counseled that antibacterial drugs including DALVANCE should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When DALVANCE is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of treatment, and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by DALVANCE and other antibacterial drugs in the future. - Patients should be advised that diarrhea is a common problem caused by antibacterial drugs and usually resolves when the drug is discontinued. Sometimes, frequent watery or bloody diarrhea may occur and may be a sign of a more serious intestinal infection. If severe watery or bloody diarrhea develops, patients should contact their healthcare provider. # Precautions with Alcohol - Alcohol-Dalbavancin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - DALVANCE®[1] # Look-Alike Drug Names There is limited information regarding Dalbavancin Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Dalbavancin
23b4795f4ae78780350838fc30816d8aac15939b	wikidoc	Dalcetrapib	Dalcetrapib # Overview Dalcetrapib or JTT-705 is a CETP inhibitor which was being developed by Hoffmann–La Roche until May 2012. The drug was aimed at raising the blood levels of "good cholesterol" (cholesterol carried in HDL particles, aka HDL-C). Prevailing observations indicate that high HDL levels correlate with better overall cardiovascular health, though it remains unclear whether raising HDL levels consequently leads to an increase in cardiovascular health. # Development and Research A 24 week clinical trial showed that dalcetrapib did increase HDL-C levels, supporting the agent's desired effect. Further, the dal-PLAQUE phase IIb trial found evidence of plaque reduction. Plaque reduction is an anticipated observation following an increase in HDL. As of 2010 five phase II trials had started and there was no evidence of the raised blood pressure seen with torcetrapib. dal-VESSEL phase IIb trial found no evidence of flow-mediated dilatation improvement. A 17% increase of Lp-PLA2 mass level was noted. Lp-PLA2 is associated with coronary heart disease and stroke. dal-OUTCOMES phase III trial passed its first interim review in July, 2011, however, development was halted on May 7, 2012 “due to a lack of clinically meaningful efficacy”. The results of dal-OUTCOMES III were published in November, 2012.	Dalcetrapib Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2] # Overview Dalcetrapib or JTT-705 is a CETP inhibitor which was being developed by Hoffmann–La Roche until May 2012. The drug was aimed at raising the blood levels of "good cholesterol" (cholesterol carried in HDL particles, aka HDL-C). Prevailing observations indicate that high HDL levels correlate with better overall cardiovascular health, though it remains unclear whether raising HDL levels consequently leads to an increase in cardiovascular health. # Development and Research A 24 week clinical trial showed that dalcetrapib did increase HDL-C levels, supporting the agent's desired effect. Further, the dal-PLAQUE phase IIb trial found evidence of plaque reduction. Plaque reduction is an anticipated observation following an increase in HDL. As of 2010 five phase II trials had started and there was no evidence of the raised blood pressure seen with torcetrapib. dal-VESSEL phase IIb trial found no evidence of flow-mediated dilatation improvement. A 17% increase of Lp-PLA2 mass level was noted. Lp-PLA2 is associated with coronary heart disease and stroke.[1][2] dal-OUTCOMES phase III trial passed its first interim review in July, 2011, however, development was halted on May 7, 2012 “due to a lack of clinically meaningful efficacy”. The results of dal-OUTCOMES III were published in November, 2012.[3]	https://www.wikidoc.org/index.php/Dalcetrapib
cae95a57ce0d1cd525eb145b10b5b3be51b77672	wikidoc	Daratumumab	Daratumumab # 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 Daratumumab is an antineoplastic agent that is FDA approved for the treatment of multiple myeloma. Common adverse reactions include fatigue, headache, nausea, diarrhea, constipation, decreased appetite, vomiting, lymphocytopenia, neutropenia, thrombocytopenia, anemia, back pain, arthralgia, leg pain, musculoskeletal chest pain, cough, nasal congestion, dyspnea, nasopharyngitis, pneumonia, and infusion-related reaction. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Daratumumab is indicated for, in combination with lenalidomide and dexamethasone or bortezomib and dexamethasone, treatment of patients with multiple myeloma who have received at least one prior therapy; for, in combination with pomalidomide and dexamethasone, treatment of patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor; and as monotherapy, for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double refractory to a PI and an immunomodulatory agent. Dosing Information - The recommended dose of daratumumab for monotherapy and combination therapy with lenalidomide or pomalidomide and low-dose dexamethasone (4-week cycle regimens) is 16 mg/kg actual body weight administered as an intravenous infusion according to the following dosing schedule:This image is provided by the National Library of Medicine. - The recommended dose of daratumumab for combination therapy with bortezomib and dexamethasone (3-week cycle regimen) is 16 mg/kg actual body weight administered as an intravenous infusion according to the following dosing schedule:This image is provided by the National Library of Medicine. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Daratumumab in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Daratumumab in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding indications and dosing of daratumumab in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Daratumumab in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Daratumumab in pediatric patients. # Contraindications There is limited information regarding contraindications of daratumumab. # Warnings - Infusion Reactions Daratumumab can cause severe infusion reactions. Approximately half of all patients experienced a reaction, most during the first infusion. Infusion reactions can also occur with subsequent infusions. Nearly all reactions occurred during infusion or within 4 hours of completing daratumumab. Prior to the introduction of post-infusion medication in clinical trials, infusion reactions occurred up to 48 hours after infusion. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, laryngeal edema and pulmonary edema. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting and nausea. Less common symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, and hypotension. Pre-medicate patients with antihistamines, antipyretics and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt daratumumab infusion for reactions of any severity and institute medical management as needed. Permanently discontinue daratumumab therapy for life-threatening (Grade 4) reactions. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion. To reduce the risk of delayed infusion reactions, administer oral corticosteroids to all patients following daratumumab infusions. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease. - Daratumumab can cause severe infusion reactions. Approximately half of all patients experienced a reaction, most during the first infusion. Infusion reactions can also occur with subsequent infusions. Nearly all reactions occurred during infusion or within 4 hours of completing daratumumab. Prior to the introduction of post-infusion medication in clinical trials, infusion reactions occurred up to 48 hours after infusion. - Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, laryngeal edema and pulmonary edema. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting and nausea. Less common symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, and hypotension. - Pre-medicate patients with antihistamines, antipyretics and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt daratumumab infusion for reactions of any severity and institute medical management as needed. Permanently discontinue daratumumab therapy for life-threatening (Grade 4) reactions. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion. - To reduce the risk of delayed infusion reactions, administer oral corticosteroids to all patients following daratumumab infusions. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease. - Interference with serological testing Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (Indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient's serum. The determination of a patient's ABO and Rh blood type are not impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received daratumumab. Type and screen patients prior to starting daratumumab. - Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (Indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient's serum. The determination of a patient's ABO and Rh blood type are not impacted. - Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received daratumumab. Type and screen patients prior to starting daratumumab. - Neutropenia Daratumumab may increase neutropenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer's prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Daratumumab dose delay may be required to allow recovery of neutrophils. No dose reduction of daratumumab is recommended. Consider supportive care with growth factors. - Daratumumab may increase neutropenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer's prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Daratumumab dose delay may be required to allow recovery of neutrophils. No dose reduction of daratumumab is recommended. Consider supportive care with growth factors. - Thrombocytopenia Daratumumab may increase thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer's prescribing information for background therapies. Daratumumab dose delay may be required to allow recovery of platelets. No dose reduction of daratumumab is recommended. Consider supportive care with transfusions. - Daratumumab may increase thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer's prescribing information for background therapies. Daratumumab dose delay may be required to allow recovery of platelets. No dose reduction of daratumumab is recommended. Consider supportive care with transfusions. - Interference with determination of complete response Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response of disease progression in some patients with IgG kappa myeloma protein. - Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response of disease progression in some patients with IgG kappa myeloma protein. # Adverse Reactions ## Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data described below reflects exposure to daratumumab (16 mg/kg) in 820 patients with multiple myeloma including 526 patients from two Phase 3 active-controlled trials who received daratumumab in combination with either lenalidomide (DRd, n=283; Study 3) or bortezomib (DVd, n=243; Study 4) and five open-label, clinical trials in which patients received daratumumab either in combination with pomalidomide (DPd, n=103; Study 5), in combination with lenalidomide (n=35), or as monotherapy (n=156). Combination treatment with lenalidomide: Adverse reactions described in Table 4 reflect exposure to daratumumab (DRd arm) for a median treatment duration of 13.1 months (range: 0 to 20.7 months) and median treatment duration of 12.3 months (range: 0.2 to 20.1 months) for the lenalidomide group (Rd) in Study 3. The most frequent adverse reactions (≥20%) were infusion reactions, diarrhea, nausea, fatigue, pyrexia, upper respiratory tract infection, muscle spasms, cough and dyspnea. The overall incidence of serious adverse reactions was 49% for the DRd group compared with 42% for the Rd group. Serious adverse reactions with at least a 2% greater incidence in the DRd arm compared to the Rd arm were pneumonia (12% vs Rd 10%), upper respiratory tract infection (7% vs Rd 4%), influenza and pyrexia (DRd 3% vs Rd 1% for each). Adverse reactions resulted in discontinuations for 7% (n=19) of patients in the DRd arm versus 8% (n=22) in the Rd arm. Laboratory abnormalities worsening during treatment from baseline listed in Table 5. Combination treatment with Bortezomib: Adverse reactions described in Table 6 reflect exposure to daratumumab (DVd arm) for a median treatment duration of 6.5 months (range: 0 to 14.8 months) and median treatment duration of 5.2 months (range: 0.2 to 8.0 months) for the bortezomib group (Vd) in Study 4. The most frequent adverse reactions (>20%) were infusion reactions, diarrhea, peripheral edema, upper respiratory tract infection, peripheral sensory neuropathy, cough and dyspnea. The overall incidence of serious adverse reactions was 42% for the DVd group compared with 34% for the Vd group. Serious adverse reactions with at least a 2% greater incidence in the DVd arm compared to the Vd arm were upper respiratory tract infection (DVd 5% vs Vd 2%), diarrhea and atrial fibrillation (DVd 2% vs Vd 0% for each). Adverse reactions resulted in discontinuations for 7% (n=18) of patients in the DVd arm versus 9% (n=22) in the Vd arm. Laboratory abnormalities worsening during treatment are listed in Table 7. Combination treatment with Pomalidomide: Adverse reactions described in Table 8 reflect exposure to daratumumab, pomalidomide and dexamethasone (DPd) for a median treatment duration of 6 months (range: 0.03 to 16.9 months) in Study 5. The most frequent adverse reactions (>20%) were infusion reactions, diarrhea, constipation, nausea, vomiting, fatigue, pyrexia, upper respiratory tract infection, muscle spasms, back pain, arthralgia, dizziness, insomnia, cough and dyspnea. The overall incidence of serious adverse reactions was 49%. Serious adverse reactions reported in ≥5% patients included pneumonia (7%). Adverse reactions resulted in discontinuations for 13% of patients. Laboratory abnormalities worsening during treatment are listed in Table 9. Monotherapy: The safety data reflect exposure to daratumumab in 156 adult patients with relapsed and refractory multiple myeloma treated with daratumumab at 16 mg/kg in three open-label, clinical trials. The median duration of exposure was 3.3 months (range: 0.03 to 20.04 months). Serious adverse reactions were reported in 51 (33%) patients. The most frequent serious adverse reactions were pneumonia (6%), general physical health deterioration (3%), and pyrexia (3%). Adverse reactions resulted in treatment delay for 24 (15%) patients, most frequently for infections. Adverse reactions resulted in discontinuations for 6 (4%) patients. Adverse reactions occurring in at least 10% of patients are presented in Table 10. Table 11 describes Grade 3–4 laboratory abnormalities reported at a rate of ≥10%. Infusion Reactions: In clinical trials (monotherapy and combination treatment; N=820) the incidence of any grade infusion reactions was 46% with the first infusion of daratumumab, 2% with the second infusion, and 3% with subsequent infusions. Less than 1% of patients had a Grade 3 infusion reaction with second or subsequent infusions. The median time to onset of a reaction was 1.4 hours (range: 0.02 to 72.8 hours). The incidence of infusion modification due to reactions was 42%. Median durations of infusion for the 1st, 2nd and subsequent infusions were 7.0, 4.3, and 3.5 hours respectively. Severe (Grade 3) infusion reactions included bronchospasm, dyspnea, laryngeal edema, pulmonary edema, hypoxia, and hypertension. Other adverse infusion reactions (any Grade, ≥5%) were nasal congestion, cough, chills, throat irritation, vomiting and nausea. Herpes Zoster Virus Reactivation: Prophylaxis for Herpes Zoster Virus reactivation was recommended for patients in some clinical trials of daratumumab. In monotherapy studies, herpes zoster was reported in 3% of patients. In the randomized controlled combination therapy studies, herpes zoster was reported in 2% each in the DRd and Rd groups respectively (Study 3), in 5% versus 3% in the DVd and Vd groups respectively (Study 4) and in 2% of patients receiving DPd (Study 5). Infections: In patients receiving daratumumab combination therapy, Grade 3 or 4 infections were reported with daratumumab combinations and background therapies (DVd: 21%, Vd: 19%; DRd: 28%, Rd: 23%; DPd: 28%). Pneumonia was the most commonly reported severe (Grade 3 or 4) infection across studies. Discontinuations from treatment were reported in 3% versus 2% of patients in the DRd and Rd groups respectively, 4% versus 3% of patients in the DVd and Vd groups respectively and in 5% of patients receiving DPd. Fatal infections were reported in 0.8% to 2% of patients across studies, primarily due to pneumonia and sepsis. Immunogenicity: As with all therapeutic proteins, there is the potential for immunogenicity. In clinical trials of patients with multiple myeloma treated with daratumumab as monotherapy or as combination therapies, none of the 111 evaluable monotherapy patients, and 2 (0.7%) of the 298 combination therapy patients, tested positive for anti-daratumumab antibodies. One patient administered daratumumab as combination therapy, developed transient neutralizing antibodies against daratumumab. However, this assay has limitations in detecting anti-daratumumab antibodies in the presence of high concentrations of daratumumab; therefore, the incidence of antibody development might not have been reliably determined. 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 daratumumab with the incidence of antibodies to other products may be misleading. Adverse reactions by organ system: - Central Nervous System: Fatigue, headache, chills - Cardiovascular: Hypertension - Respiratory: Cough, nasal congestion, dyspnea, nasopharyngitis, pneumonia - Gastrointestinal: Nausea, diarrhea, constipation, decreased appetite, vomiting - Hematologic & oncologic: Lymphocytopenia, neutropenia, thrombocytopenia, anemia - Infection: Herpes zoster - Neuromuscular & skeletal: Back pain, arthralgia, leg pain, musculoskeletal chest pain - Miscellaneous: Infusion-related reaction, fever, physical health deterioration ## Postmarketing Experience There is limited information regarding Daratumumab Postmarketing Experience in the drug label. # Drug Interactions Daratumumab binds to CD38 on RBCs and interferes with compatibility testing, including antibody screening and cross matching. Daratumumab interference mitigation methods include treating reagent RBCs with dithiothreitol (DTT) to disrupt daratumumab binding or genotyping. Since the Kell blood group system is also sensitive to DTT treatment, K-negative units should be supplied after ruling out or identifying alloantibodies using DTT-treated RBCs.If an emergency transfusion is required, non-cross-matched ABO/RhD-compatible RBCs can be given per local blood bank practices. Daratumumab may be detected on serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for monitoring disease monoclonal immunoglobulins (M protein). This can lead to false positive SPE and IFE assay results for patients with IgG kappa myeloma protein impacting initial assessment of complete responses by International Myeloma Working Group (IMWG) criteria. In patients with persistent very good partial response, consider other methods to evaluate the depth of response. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): There are no human data to inform a risk with use of daratumumab during pregnancy. Animal studies have not been conducted. However, there are clinical considerations. Immunoglobulin G1 (IgG1) monoclonal antibodies are transferred across the placenta. Based on its mechanism of action, daratumumab may cause fetal myeloid or lymphoid-cell depletion and decreased bone density. Defer administering live vaccines to neonates and infants exposed to daratumumab in utero until a hematology evaluation is completed. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Mice that were genetically modified to eliminate all CD38 expression (CD38 knockout mice) had reduced bone density at birth that recovered by 5 months of age. In cynomolgus monkeys exposed during pregnancy to other monoclonal antibodies that affect leukocyte populations, infant monkeys had a reversible reduction in leukocytes. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Daratumumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Daratumumab during labor and delivery. ### Nursing Mothers There is no information regarding the presence of daratumumab in human milk, the effects on the breastfed infant, or the effects on milk production. Human IgG is known to be present in human milk. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for daratumumab and any potential adverse effects on the breast-fed child from daratumumab or from the underlying maternal condition. ### Pediatric Use There is no FDA guidance on the use of Daratumumab in pediatric settings. ### Geriatic Use Of the 156 patients that received daratumumab monotherapy at the recommended dose, 45% were 65 years of age or older, and 10% were 75 years of age or older. Of 664 patients that received daratumumab with various combination therapies, 41% were 65 to 75 years of age, and 9% were 75 years of age or older. No overall differences in safety or effectiveness were observed between these patients and younger patients. ### Gender There is no FDA guidance on the use of Daratumumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Daratumumab with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Daratumumab in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Daratumumab in patients with hepatic impairment. ### Females of Reproductive Potential and Males To avoid exposure to the fetus, women of reproductive potential should use effective contraception during treatment and for 3 months after cessation of daratumumab treatment. ### Immunocompromised Patients There is no FDA guidance one the use of Daratumumab in patients who are immunocompromised. # Administration and Monitoring ### Administration - Administer pre-infusion medication to reduce the risk of delayed infusion reactions to all patients 1-3 hours prior to every infusion of daratumumab as follows: Administer corticosteroids (monotherapy: methylprednisolone 100 mg, or equivalent), administered intravenously. Following the second infusion, the dose of corticosteroid may be reduced (oral or intravenous methylprednisolone 60 mg) or combination therapy: administer 20 mg dexamethasone prior to every daratumumab infusion. Dexamethasone is given intravenously prior to the first daratumumab infusion and oral administration may be considered prior to subsequent infusions). Antipyretics (oral acetaminophen 650 to 1000 mg). Antihistamine (oral or intravenous diphenhydramine 25 to 50 mg or equivalent) to reduce the risk of infusion reactions to all patients 1–3 hours prior to every infusion of daratumumab. - Administer corticosteroids (monotherapy: methylprednisolone 100 mg, or equivalent), administered intravenously. Following the second infusion, the dose of corticosteroid may be reduced (oral or intravenous methylprednisolone 60 mg) or combination therapy: administer 20 mg dexamethasone prior to every daratumumab infusion. Dexamethasone is given intravenously prior to the first daratumumab infusion and oral administration may be considered prior to subsequent infusions). - Antipyretics (oral acetaminophen 650 to 1000 mg). - Antihistamine (oral or intravenous diphenhydramine 25 to 50 mg or equivalent) to reduce the risk of infusion reactions to all patients 1–3 hours prior to every infusion of daratumumab. - Administer post-infusion medication to reduce the risk of delayed infusion reactions to all patients as follows: Monotherapy: Administer oral corticosteroid (20 mg methylprednisolone or equivalent dose of an intermediate-acting or long-acting corticosteroid in accordance with local standards) on each of the 2 days following all daratumumab infusions (beginning the day after the infusion). Combination therapy: Consider administering low-dose oral methylprednisolone (≤ 20 mg) or equivalent, the day after the daratumumab infusion. However, if a background regimen-specific corticosteroid (e.g. dexamethasone) is administered the day after the daratumumab infusion, additional post-infusion medications may not be needed. In addition, for any patients with a history of chronic obstructive pulmonary disease, consider prescribing post-infusion medications such as short and long-acting bronchodilators, and inhaled corticosteroids. Following the first four infusions, if the patient experiences no major infusion reactions, these additional inhaled post-infusion medications may be discontinued. - Monotherapy: Administer oral corticosteroid (20 mg methylprednisolone or equivalent dose of an intermediate-acting or long-acting corticosteroid in accordance with local standards) on each of the 2 days following all daratumumab infusions (beginning the day after the infusion). - Combination therapy: Consider administering low-dose oral methylprednisolone (≤ 20 mg) or equivalent, the day after the daratumumab infusion. However, if a background regimen-specific corticosteroid (e.g. dexamethasone) is administered the day after the daratumumab infusion, additional post-infusion medications may not be needed. - In addition, for any patients with a history of chronic obstructive pulmonary disease, consider prescribing post-infusion medications such as short and long-acting bronchodilators, and inhaled corticosteroids. Following the first four infusions, if the patient experiences no major infusion reactions, these additional inhaled post-infusion medications may be discontinued. - Initiate antiviral prophylaxis to prevent herpes zoster reactivation within 1 week after starting daratumumab and continue for 3 months following treatment. Administer only as an intravenous infusion after dilution in 0.9% Sodium Chloride Injection, USP. Daratumumab should be administered by a healthcare professional, with immediate access to emergency equipment and appropriate medical support to manage infusion reactions if they occur. If a planned dose of daratumumab is missed, administer the dose as soon as possible and adjust the dosing schedule accordingly, maintaining the treatment interval. Administer daratumumab infusion intravenously at the infusion rate described below. Consider incremental escalation of the infusion rate only in the absence of infusion reactions.This image is provided by the National Library of Medicine. - Administer only as an intravenous infusion after dilution in 0.9% Sodium Chloride Injection, USP. Daratumumab should be administered by a healthcare professional, with immediate access to emergency equipment and appropriate medical support to manage infusion reactions if they occur. - If a planned dose of daratumumab is missed, administer the dose as soon as possible and adjust the dosing schedule accordingly, maintaining the treatment interval. - Administer daratumumab infusion intravenously at the infusion rate described below. Consider incremental escalation of the infusion rate only in the absence of infusion reactions.This image is provided by the National Library of Medicine. - For infusion reactions of any grade/severity, immediately interrupt the daratumumab infusion and manage symptoms. Management of infusion reactions may further require reduction in the rate of infusion, or treatment discontinuation of daratumumab as outlined below: Grade 1–2 (mild to moderate): Once reaction symptoms resolve, resume the infusion at no more than half the rate at which the reaction occurred. If the patient does not experience any further reaction symptoms, infusion rate escalation may resume at increments and intervals as clinically appropriate up to the maximum rate of 200 mL/hour (Table 3). Grade 3 (severe): Once reaction symptoms resolve, consider restarting the infusion at no more than half the rate at which the reaction occurred. If the patient does not experience additional symptoms, resume infusion rate escalation at increments and intervals as outlined in Table 3. Repeat the procedure above in the event of recurrence of Grade 3 symptoms. Permanently discontinue daratumumab upon the third occurrence of a Grade 3 or greater infusion reaction. Grade 4 (life threatening): Permanently discontinue daratumumab treatment. - Grade 1–2 (mild to moderate): Once reaction symptoms resolve, resume the infusion at no more than half the rate at which the reaction occurred. If the patient does not experience any further reaction symptoms, infusion rate escalation may resume at increments and intervals as clinically appropriate up to the maximum rate of 200 mL/hour (Table 3). - Grade 3 (severe): Once reaction symptoms resolve, consider restarting the infusion at no more than half the rate at which the reaction occurred. If the patient does not experience additional symptoms, resume infusion rate escalation at increments and intervals as outlined in Table 3. Repeat the procedure above in the event of recurrence of Grade 3 symptoms. Permanently discontinue daratumumab upon the third occurrence of a Grade 3 or greater infusion reaction. - Grade 4 (life threatening): Permanently discontinue daratumumab treatment. - No dose reductions of daratumumab are recommended. Dose delay may be required to allow recovery of blood cell counts in the event of hematological toxicity. - Daratumumab is for single use only. Prepare the solution for infusion using aseptic technique as follows: Calculate the dose (mg), total volume (mL) of daratumumab solution required and the number of daratumumab vials needed based on patient actual body weight. Check that the daratumumab solution is colorless to pale yellow. Do not use if opaque particles, discoloration or other foreign particles are present. Remove a volume of 0.9% Sodium Chloride Injection, USP from the infusion bag/container that is equal to the required volume of daratumumab solution. Withdraw the necessary amount of daratumumab solution and dilute to the appropriate volume by adding to the infusion bag/container containing 0.9% Sodium Chloride Injection, USP as specified in Table 3. Infusion bags/containers must be made of either polyvinyl chloride (PVC), polypropylene (PP), polyethylene (PE) or polyolefin blend (PP+PE). Dilute under appropriate aseptic conditions. Discard any unused portion left in the vial. Gently invert the bag/container to mix the solution. Do not shake. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The diluted solution may develop very small, translucent to white proteinaceous particles, as daratumumab is a protein. Do not use if visibly opaque particles, discoloration or foreign particles are observed. Since daratumumab does not contain a preservative, administer the diluted solution immediately at room temperature 15°C–25°C (59°F–77°F) and in room light. Diluted solution may be kept at room temperature for a maximum of 15 hours (including infusion time). If not used immediately, the diluted solution can be stored prior to administration for up to 24 hours at refrigerated conditions 2°C – 8°C (36°F–46°F) and protected from light. Do not freeze. - Calculate the dose (mg), total volume (mL) of daratumumab solution required and the number of daratumumab vials needed based on patient actual body weight. - Check that the daratumumab solution is colorless to pale yellow. Do not use if opaque particles, discoloration or other foreign particles are present. - Remove a volume of 0.9% Sodium Chloride Injection, USP from the infusion bag/container that is equal to the required volume of daratumumab solution. - Withdraw the necessary amount of daratumumab solution and dilute to the appropriate volume by adding to the infusion bag/container containing 0.9% Sodium Chloride Injection, USP as specified in Table 3. Infusion bags/containers must be made of either polyvinyl chloride (PVC), polypropylene (PP), polyethylene (PE) or polyolefin blend (PP+PE). Dilute under appropriate aseptic conditions. Discard any unused portion left in the vial. - Gently invert the bag/container to mix the solution. Do not shake. - Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The diluted solution may develop very small, translucent to white proteinaceous particles, as daratumumab is a protein. Do not use if visibly opaque particles, discoloration or foreign particles are observed. - Since daratumumab does not contain a preservative, administer the diluted solution immediately at room temperature 15°C–25°C (59°F–77°F) and in room light. Diluted solution may be kept at room temperature for a maximum of 15 hours (including infusion time). - If not used immediately, the diluted solution can be stored prior to administration for up to 24 hours at refrigerated conditions 2°C – 8°C (36°F–46°F) and protected from light. Do not freeze. - Administer daratumumab as follows: If stored in the refrigerator, allow the solution to come to room temperature. Administer the diluted solution by intravenous infusion using an infusion set fitted with a flow regulator and with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) filter (pore size 0.22 or 0.2 micrometer). Administration sets must be made of either polyurethane (PU), polybutadiene (PBD), PVC, PP or PE. Do not store any unused portion of the infusion solution for reuse. Any unused product or waste material should be disposed of in accordance with local requirements. Do not infuse daratumumab concomitantly in the same intravenous line with other agents. - If stored in the refrigerator, allow the solution to come to room temperature. Administer the diluted solution by intravenous infusion using an infusion set fitted with a flow regulator and with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) filter (pore size 0.22 or 0.2 micrometer). Administration sets must be made of either polyurethane (PU), polybutadiene (PBD), PVC, PP or PE. - Do not store any unused portion of the infusion solution for reuse. Any unused product or waste material should be disposed of in accordance with local requirements. - Do not infuse daratumumab concomitantly in the same intravenous line with other agents. ### Monitoring Frequently monitor patients during the entire infusion. Interrupt daratumumab infusion for reactions of any severity and institute medical management as needed. Permanently discontinue daratumumab therapy for life-threatening (Grade 4) reactions. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion. # IV Compatibility There is limited information regarding the compatibility of Daratumumab and IV administrations. # Overdosage The dose of daratumumab at which severe toxicity occurs is not known. In the event of an overdose, monitor patients for any signs or symptoms of adverse effects and provide appropriate supportive treatment. # Pharmacology ## Mechanism of Action CD38 is a transmembrane glycoprotein (48 kDa) expressed on the surface of hematopoietic cells, including multiple myeloma and other cell types and tissues and has multiple functions, such as receptor mediated adhesion, signaling, and modulation of cyclase and hydrolase activity. Daratumumab is an IgG1κ human monoclonal antibody (mAb) that binds to CD38 and inhibits the growth of CD38 expressing tumor cells by inducing apoptosis directly through Fc mediated cross linking as well as by immune-mediated tumor cell lysis through complement dependent cytotoxicity (CDC), antibody dependent cell mediated cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP). A subset of myeloid derived suppressor cells (CD38+MDSCs), regulatory T cells (CD38+Tregs) and B cells (CD38+Bregs) are decreased by daratumumab. ## Structure There is limited information regarding Daratumumab Structure in the drug label. ## Pharmacodynamics NK cells express CD38 and are susceptible to daratumumab mediated cell lysis. Decreases in absolute counts and percentages of total NK cells (CD16+CD56+) and activated (CD16+CD56dim) NK cells in peripheral whole blood and bone marrow were observed with daratumumab treatment. Daratumumab as a large protein has a low likelihood of direct ion channel interactions. There is no evidence from non-clinical or clinical data to suggest that daratumumab has the potential to delay ventricular repolarization. ## Pharmacokinetics Over the dose range from 1 to 24 mg/kg as monotherapy or 1 to 16 mg/kg of daratumumab in combination with other treatments, increases in area under the concentration-time curve (AUC) were more than dose-proportional. Following the recommended dose of 16 mg/kg when daratumumab was administered as monotherapy or in combination therapy, the mean serum maximal concentration (Cmax) value at the end of weekly dosing, was approximately 2.7 to 3-fold higher compared to the mean serum Cmax following the first dose. The mean ± standard deviation (SD) trough serum concentration (Cmin) at the end of weekly dosing was 573 ± 332 µg/mL when daratumumab was administered as monotherapy and 502 ± 196 to 607 ± 231 µg/mL when daratumumab was administered as combination therapy. Daratumumab steady state was achieved approximately 5 months into the every 4-week dosing period (by the 21st infusion), and the mean ± SD ratio of Cmax at steady-state to Cmax after the first dose was 1.6 ± 0.5. Distribution: At the recommended dose of 16 mg/kg, the mean ± SD central volume of distribution was 4.7 ± 1.3 L when daratumumab was administered as monotherapy and 4.4 ± 1.5 L when daratumumab was administered as combination therapy. Elimination: Daratumumab clearance decreased with increasing dose and with multiple dosing. At the recommended dose of 16 mg/kg of daratumumab as monotherapy, the mean ± SD linear clearance was estimated to be 171.4 ± 95.3 mL/day. The mean ± SD estimated terminal half-life associated with linear clearance was 18 ± 9 days when daratumumab administered as monotherapy and 23 ± 12 days when daratumumab was administered as combination therapy. Specific populations: The following population characteristics have no clinically meaningful effect on the pharmacokinetics of daratumumab in patients administered daratumumab as monotherapy or as combination therapy: sex, age (31 to 84 years), mild and moderate (total bilirubin 1.5 to 3 times ULN and any ALT) hepatic impairment, or renal impairment (CLcr) 15 –89 mL/min]. The effect of severe (total bilirubin >3 times ULN and any ALT) hepatic impairment is unknown. Increasing body weight increased the central volume of distribution and clearance of daratumumab, supporting the body weight-based dosing regimen. Drug interactions: The coadministration of lenalidomide, pomalidomide or bortezomib with daratumumab did not affect the pharmacokinetics of daratumumab. The coadministration of daratumumab with bortezomib did not affect the pharmacokinetics of bortezomib. ## Nonclinical Toxicology No carcinogenicity or genotoxicity studies have been conducted with daratumumab. No animal studies have been performed to evaluate the potential effects of daratumumab on reproduction or development, or to determine potential effects on fertility in males or females. # Clinical Studies Study 3, an open-label, randomized, active-controlled Phase 3 trial, compared treatment with daratumumab 16 mg/kg in combination with lenalidomide and low-dose dexamethasone (DRd) to treatment with lenalidomide and low-dose dexamethasone (Rd) in patients with multiple myeloma who had received at least one prior therapy. Lenalidomide (25 mg once daily orally on Days 1–21 of repeated 28-day cycles) was given with low dose oral or intravenous dexamethasone 40 mg/week (or a reduced dose of 20 mg/week for patients >75 years or body mass index <18.5). On daratumumab infusion days, 20 mg of the dexamethasone dose was given as a pre-infusion medication and the remainder given the day after the infusion. For patients on a reduced dexamethasone dose, the entire 20 mg dose was given as a daratumumab pre-infusion medication. Dose adjustments for lenalidomide and dexamethasone were applied according to manufacturer's prescribing information. Treatment was continued in both arms until disease progression or unacceptable toxicity. A total of 569 patients were randomized; 286 to the DRd arm and 283 to the Rd arm. The baseline demographic and disease characteristics were similar between the daratumumab and the control arm. The median patient age was 65 years (range 34 to 89 years), 11% were ≥75 years, 59% were male; 69% Caucasian, 18% Asian, and 3% African American. Patients had received a median of 1 prior line of therapy. Sixty-three percent (63%) of patients had received prior autologous stem cell transplantation (ASCT). The majority of patients (86%) received a prior PI, 55% of patients had received a prior immunomodulatory agent, including 18% of patients who had received prior lenalidomide; and 44% of patients had received both a prior PI and immunomodulatory agent. At baseline, 27% of patients were refractory to the last line of treatment. Eighteen percent (18%) of patients were refractory to a PI only, and 21% were refractory to bortezomib. Efficacy was evaluated by progression free survival (PFS) based on International Myeloma Working Group (IMWG) criteria. Study 3 demonstrated an improvement in PFS in the DRd arm as compared to the Rd arm; the median PFS had not been reached in the DRd arm and was 18.4 months in the Rd arm (hazard ratio =0.37; 95% CI: 0.27, 0.52; p<0.0001), representing 63% reduction in the risk of disease progression or death in patients treated with DRd. Figure 1: Kaplan-Meier Curve of PFS in Study 3 Additional efficacy results from Study 3 are presented in Table 12 below. In responders, the median time to response was 1 month (range: 0.9 to 13 months) in the DRd group and 1.1 months (range: 0.9 to 10 months) in the Rd group. The median duration of response had not been reached in the DRd group (range: 1+ to 19.8+ months) and was 17.4 months (range: 1.4 to 18.5+ months) in the Rd group. With a median follow-up of 13.5 months, 75 deaths were observed; 30 in the DRd group and 45 in the Rd group. Study 4, an open-label, randomized, active-controlled Phase 3 trial, compared treatment with daratumumab 16 mg/kg in combination with bortezomib and dexamethasone (DVd), to treatment with bortezomib and dexamethasone (Vd). Bortezomib was administered by SC injection or IV infusion at a dose of 1.3 mg/m2 body surface area twice weekly for two weeks (Days 1, 4, 8, and 11) of repeated 21 day (3-week) treatment cycles, for a total of 8 cycles. Dexamethasone was administered orally at a dose of 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each of the 8 bortezomib cycles (80 mg/week for two out of three weeks of the bortezomib cycle) or a reduced dose of 20 mg/week for patients >75 years, BMI <18.5, poorly controlled diabetes mellitus or prior intolerance to steroid therapy. On the days of daratumumab infusion, 20 mg of the dexamethasone dose was administered as a pre-infusion medication. For patients on a reduced dexamethasone] dose, the entire 20 mg dose was given as a daratumumab pre-infusion medication. Bortezomib and dexamethasone were given for 8 three-week cycles in both treatment arms; whereas daratumumab was given until disease progression. However, dexamethasone 20 mg was continued as a daratumumab pre-infusion medication in the DVd arm. Dose adjustments for bortezomib and dexamethasone were applied according to manufacturer's prescribing information. A total of 498 patients were randomized; 251 to the DVd arm and 247 to the Vd arm. The baseline demographic and disease characteristics were similar between the daratumumab and the control arm. The median patient age was 64 years (range 30 to 88 years); 12% were ≥75 years, 57% were male; 87% Caucasian, 5% Asian and 4% African American. Patients had received a median of 2 prior lines of therapy and 61% of patients had received prior autologous stem cell transplantation (ASCT). Sixty-nine percent (69%) of patients had received a prior PI (66% received bortezomib) and 76% of patients received an immunomodulatory agent (42% received lenalidomide). At baseline, 32% of patients were refractory to the last line of treatment and the proportions of patients refractory to any specific prior therapy were in general well balanced between the treatment groups. Thirty-three percent (33%) of patients were refractory to an immunomodulatory agent only, with 24% patients in the DVd arm and 33% of patients in the Vd arm respectively refractory to lenalidomide. Efficacy was evaluated by progression free survival (PFS) based on International Myeloma Working Group (IMWG) criteria. Study 4 demonstrated an improvement in PFS in the DVd arm as compared to the Vd arm; the median PFS had not been reached in the DVd arm and was 7.2 months in the Vd arm (HR : 0.39 ; p-value < 0.0001), representing a 61% reduction in the risk of disease progression or death for patients treated with DVd versus Vd. Figure 2: Kaplan-Meier Curve of PFS in Study 4 Additional efficacy results from Study 4 are presented in Table 13 below. In responders, the median time to response was 0.8 months (range: 0.7 to 4 months) in the DVd group and 1.5 months (range: 0.7 to 5 months) in the Vd group. The median duration of response had not been reached in the DVd group (range: 1.4+ to 14.1+ months) and was 7.9 months (1.4+ to 12+ months) in the Vd group. With a median follow-up of 7.4 months, 65 deaths were observed; 29 in the DVd group and 36 in the Vd group were observed. Study 5 was an open-label trial in which 103 patients with multiple myeloma who had received a prior PI and an immunomodulatory agent, received 16 mg/kg daratumumab in combination with pomalidomide and low-dose dexamethasone until disease progression. Pomalidomide (4 mg once daily orally on Days 1-21 of repeated 28-day cycles) was given with low dose oral or intravenous dexamethasone 40 mg/ week (reduced dose of 20 mg/week for patients >75 years or body mass index <18.5). On daratumumab infusion days, 20 mg of the dexamethasone dose was given as a pre-infusion medication and the remainder given the day after the infusion. For patients on a reduced dexamethasone dose, the entire 20 mg dose was given as a daratumumab pre-infusion medication. The median patient age was 64 years (range: 35 to 86 years) with 8% of patients ≥75 years of age. Patients in the study had received a median of 4 prior lines of therapy. Seventy-four percent (74%) of patients had received prior ASCT. Ninety-eight percent (98%) of patients received prior bortezomib treatment, and 33% of patients received prior carfilzomib. All patients received prior lenalidomide treatment, with 98% of patients previously treated with the combination of bortezomib and lenalidomide. Eighty nine percent (89%) of patients were refractory to lenalidomide and 71% refractory to bortezomib; 64% of patients were refractory to bortezomib and lenalidomide. Efficacy results were based on overall response rate as determined by Independent Review Committee using IMWG criteria (see table 14). The median time to response was 1 month (range: 0.9 to 2.8 months). The median duration of response was 13.6 months (range: 0.9+ to 14.6+ months). Study 1, was an open-label trial evaluating daratumumab monotherapy in patients with relapsed or refractory multiple myeloma who had received at least 3 prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent or who were double-refractory to a proteasome inhibitor and an immunomodulatory agent. In 106 patients, daratumumab 16 mg/kg was administered with pre- and post-infusion medication. Treatment continued until unacceptable toxicity or disease progression. The median patient age was 63.5 years (range: 31 to 84 years), 49% were male and 79% were Caucasian. Patients had received a median of 5 prior lines of therapy. Eighty percent of patients had received prior autologous stem cell transplantation (ASCT). Prior therapies included bortezomib (99%), lenalidomide (99%), pomalidomide (63%) and carfilzomib (50%). At baseline, 97% of patients were refractory to the last line of treatment, 95% were refractory to both, a proteasome inhibitor (PI) and immunomodulatory agent, and 77% were refractory to alkylating agents. Efficacy results were based on overall response rate as determined by the Independent Review Committee assessment using IMWG criteria (see table 15). The median time to response was 1 month (range: 0.9 to 5.6 months). The median duration of response was 7.4 months (range: 1.2 to 13.1+ months). Study 2 was an open-label dose escalation trial evaluating daratumumab monotherapy in patients with relapsed or refractory multiple myeloma who had received at least 2 different cytoreductive therapies. In 42 patients, daratumumab 16 mg/kg was administered with pre- and post-infusion medication. Treatment continued until unacceptable toxicity or disease progression. The median patient age was 64 years (range: 44 to 76 years), 64% were male and 76% were Caucasian. Patients in the study had received a median of 4 prior lines of therapy. Seventy-four percent of patients had received prior ASCT. Prior therapies included bortezomib (100%), lenalidomide (95%), pomalidomide (36%) and carfilzomib (19%). At baseline, 76% of patients were refractory to the last line of treatment, 64% of patients were refractory to both, a PI and an immunomodulatory agent, and 60% of patients were refractory to alkylating agents. Overall response rate was 36% (95% CI: 21.6, 52.0%) with 1 CR and 3 VGPR. The median time to response was 1 month (range: 0.5 to 3.2 months). The median duration of response was not estimable (range: 2.2 to 13.1+ months). # How Supplied Daratumumab is a colorless to pale yellow, preservative-free solution for intravenous infusion supplied as: - NDC 57894-502-05 contains one 100 mg/5 mL single-dose vial - NDC 57894-502-20 contains one 400 mg/20 mL single-dose vial ## Storage Store in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF). Do not freeze or shake. Protect from light. This product contains no preservative. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Infusion Reactions Advise patients to seek immediate medical attention for any of the following signs and symptoms of infusion reactions: itchy, runny or blocked nose; chills, nausea, throat irritation, cough, headache, shortness of breath or difficulty breathing - Advise patients to seek immediate medical attention for any of the following signs and symptoms of infusion reactions: itchy, runny or blocked nose; chills, nausea, throat irritation, cough, headache, shortness of breath or difficulty breathing - Neutropenia Advise patients that if they have a fever, they should contact their healthcare professional. - Advise patients that if they have a fever, they should contact their healthcare professional. - Thrombocytopenia Advise patients to inform their healthcare professional if they notice signs of bruising or bleeding. - Advise patients to inform their healthcare professional if they notice signs of bruising or bleeding. - Interference with laboratory tests Advise patients to inform healthcare providers including blood transfusion centers/personnel that they are taking daratumumab, in the event of a planned transfusion. Advise patients that daratumumab can affect the results of some tests used to determine complete response in some patients and additional tests may be needed to evaluate response. - Advise patients to inform healthcare providers including blood transfusion centers/personnel that they are taking daratumumab, in the event of a planned transfusion. - Advise patients that daratumumab can affect the results of some tests used to determine complete response in some patients and additional tests may be needed to evaluate response. # Precautions with Alcohol Alcohol-Daratumumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Darzalex # Look-Alike Drug Names There is limited information regarding daratumumab Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Daratumumab Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Allison Tu [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 Daratumumab is an antineoplastic agent that is FDA approved for the treatment of multiple myeloma. Common adverse reactions include fatigue, headache, nausea, diarrhea, constipation, decreased appetite, vomiting, lymphocytopenia, neutropenia, thrombocytopenia, anemia, back pain, arthralgia, leg pain, musculoskeletal chest pain, cough, nasal congestion, dyspnea, nasopharyngitis, pneumonia, and infusion-related reaction. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Daratumumab is indicated for, in combination with lenalidomide and dexamethasone or bortezomib and dexamethasone, treatment of patients with multiple myeloma who have received at least one prior therapy; for, in combination with pomalidomide and dexamethasone, treatment of patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor; and as monotherapy, for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double refractory to a PI and an immunomodulatory agent. Dosing Information - The recommended dose of daratumumab for monotherapy and combination therapy with lenalidomide or pomalidomide and low-dose dexamethasone (4-week cycle regimens) is 16 mg/kg actual body weight administered as an intravenous infusion according to the following dosing schedule:This image is provided by the National Library of Medicine. - The recommended dose of daratumumab for combination therapy with bortezomib and dexamethasone (3-week cycle regimen) is 16 mg/kg actual body weight administered as an intravenous infusion according to the following dosing schedule:This image is provided by the National Library of Medicine. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Daratumumab in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Daratumumab in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding indications and dosing of daratumumab in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Daratumumab in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Daratumumab in pediatric patients. # Contraindications There is limited information regarding contraindications of daratumumab. # Warnings - Infusion Reactions Daratumumab can cause severe infusion reactions. Approximately half of all patients experienced a reaction, most during the first infusion. Infusion reactions can also occur with subsequent infusions. Nearly all reactions occurred during infusion or within 4 hours of completing daratumumab. Prior to the introduction of post-infusion medication in clinical trials, infusion reactions occurred up to 48 hours after infusion. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, laryngeal edema and pulmonary edema. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting and nausea. Less common symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, and hypotension. Pre-medicate patients with antihistamines, antipyretics and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt daratumumab infusion for reactions of any severity and institute medical management as needed. Permanently discontinue daratumumab therapy for life-threatening (Grade 4) reactions. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion. To reduce the risk of delayed infusion reactions, administer oral corticosteroids to all patients following daratumumab infusions. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease. - Daratumumab can cause severe infusion reactions. Approximately half of all patients experienced a reaction, most during the first infusion. Infusion reactions can also occur with subsequent infusions. Nearly all reactions occurred during infusion or within 4 hours of completing daratumumab. Prior to the introduction of post-infusion medication in clinical trials, infusion reactions occurred up to 48 hours after infusion. - Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, laryngeal edema and pulmonary edema. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting and nausea. Less common symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, and hypotension. - Pre-medicate patients with antihistamines, antipyretics and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt daratumumab infusion for reactions of any severity and institute medical management as needed. Permanently discontinue daratumumab therapy for life-threatening (Grade 4) reactions. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion. - To reduce the risk of delayed infusion reactions, administer oral corticosteroids to all patients following daratumumab infusions. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease. - Interference with serological testing Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (Indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient's serum. The determination of a patient's ABO and Rh blood type are not impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received daratumumab. Type and screen patients prior to starting daratumumab. - Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (Indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient's serum. The determination of a patient's ABO and Rh blood type are not impacted. - Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received daratumumab. Type and screen patients prior to starting daratumumab. - Neutropenia Daratumumab may increase neutropenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer's prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Daratumumab dose delay may be required to allow recovery of neutrophils. No dose reduction of daratumumab is recommended. Consider supportive care with growth factors. - Daratumumab may increase neutropenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer's prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Daratumumab dose delay may be required to allow recovery of neutrophils. No dose reduction of daratumumab is recommended. Consider supportive care with growth factors. - Thrombocytopenia Daratumumab may increase thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer's prescribing information for background therapies. Daratumumab dose delay may be required to allow recovery of platelets. No dose reduction of daratumumab is recommended. Consider supportive care with transfusions. - Daratumumab may increase thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer's prescribing information for background therapies. Daratumumab dose delay may be required to allow recovery of platelets. No dose reduction of daratumumab is recommended. Consider supportive care with transfusions. - Interference with determination of complete response Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response of disease progression in some patients with IgG kappa myeloma protein. - Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response of disease progression in some patients with IgG kappa myeloma protein. # Adverse Reactions ## Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data described below reflects exposure to daratumumab (16 mg/kg) in 820 patients with multiple myeloma including 526 patients from two Phase 3 active-controlled trials who received daratumumab in combination with either lenalidomide (DRd, n=283; Study 3) or bortezomib (DVd, n=243; Study 4) and five open-label, clinical trials in which patients received daratumumab either in combination with pomalidomide (DPd, n=103; Study 5), in combination with lenalidomide (n=35), or as monotherapy (n=156). Combination treatment with lenalidomide: Adverse reactions described in Table 4 reflect exposure to daratumumab (DRd arm) for a median treatment duration of 13.1 months (range: 0 to 20.7 months) and median treatment duration of 12.3 months (range: 0.2 to 20.1 months) for the lenalidomide group (Rd) in Study 3. The most frequent adverse reactions (≥20%) were infusion reactions, diarrhea, nausea, fatigue, pyrexia, upper respiratory tract infection, muscle spasms, cough and dyspnea. The overall incidence of serious adverse reactions was 49% for the DRd group compared with 42% for the Rd group. Serious adverse reactions with at least a 2% greater incidence in the DRd arm compared to the Rd arm were pneumonia (12% vs Rd 10%), upper respiratory tract infection (7% vs Rd 4%), influenza and pyrexia (DRd 3% vs Rd 1% for each). Adverse reactions resulted in discontinuations for 7% (n=19) of patients in the DRd arm versus 8% (n=22) in the Rd arm. Laboratory abnormalities worsening during treatment from baseline listed in Table 5. Combination treatment with Bortezomib: Adverse reactions described in Table 6 reflect exposure to daratumumab (DVd arm) for a median treatment duration of 6.5 months (range: 0 to 14.8 months) and median treatment duration of 5.2 months (range: 0.2 to 8.0 months) for the bortezomib group (Vd) in Study 4. The most frequent adverse reactions (>20%) were infusion reactions, diarrhea, peripheral edema, upper respiratory tract infection, peripheral sensory neuropathy, cough and dyspnea. The overall incidence of serious adverse reactions was 42% for the DVd group compared with 34% for the Vd group. Serious adverse reactions with at least a 2% greater incidence in the DVd arm compared to the Vd arm were upper respiratory tract infection (DVd 5% vs Vd 2%), diarrhea and atrial fibrillation (DVd 2% vs Vd 0% for each). Adverse reactions resulted in discontinuations for 7% (n=18) of patients in the DVd arm versus 9% (n=22) in the Vd arm. Laboratory abnormalities worsening during treatment are listed in Table 7. Combination treatment with Pomalidomide: Adverse reactions described in Table 8 reflect exposure to daratumumab, pomalidomide and dexamethasone (DPd) for a median treatment duration of 6 months (range: 0.03 to 16.9 months) in Study 5. The most frequent adverse reactions (>20%) were infusion reactions, diarrhea, constipation, nausea, vomiting, fatigue, pyrexia, upper respiratory tract infection, muscle spasms, back pain, arthralgia, dizziness, insomnia, cough and dyspnea. The overall incidence of serious adverse reactions was 49%. Serious adverse reactions reported in ≥5% patients included pneumonia (7%). Adverse reactions resulted in discontinuations for 13% of patients. Laboratory abnormalities worsening during treatment are listed in Table 9. Monotherapy: The safety data reflect exposure to daratumumab in 156 adult patients with relapsed and refractory multiple myeloma treated with daratumumab at 16 mg/kg in three open-label, clinical trials. The median duration of exposure was 3.3 months (range: 0.03 to 20.04 months). Serious adverse reactions were reported in 51 (33%) patients. The most frequent serious adverse reactions were pneumonia (6%), general physical health deterioration (3%), and pyrexia (3%). Adverse reactions resulted in treatment delay for 24 (15%) patients, most frequently for infections. Adverse reactions resulted in discontinuations for 6 (4%) patients. Adverse reactions occurring in at least 10% of patients are presented in Table 10. Table 11 describes Grade 3–4 laboratory abnormalities reported at a rate of ≥10%. Infusion Reactions: In clinical trials (monotherapy and combination treatment; N=820) the incidence of any grade infusion reactions was 46% with the first infusion of daratumumab, 2% with the second infusion, and 3% with subsequent infusions. Less than 1% of patients had a Grade 3 infusion reaction with second or subsequent infusions. The median time to onset of a reaction was 1.4 hours (range: 0.02 to 72.8 hours). The incidence of infusion modification due to reactions was 42%. Median durations of infusion for the 1st, 2nd and subsequent infusions were 7.0, 4.3, and 3.5 hours respectively. Severe (Grade 3) infusion reactions included bronchospasm, dyspnea, laryngeal edema, pulmonary edema, hypoxia, and hypertension. Other adverse infusion reactions (any Grade, ≥5%) were nasal congestion, cough, chills, throat irritation, vomiting and nausea. Herpes Zoster Virus Reactivation: Prophylaxis for Herpes Zoster Virus reactivation was recommended for patients in some clinical trials of daratumumab. In monotherapy studies, herpes zoster was reported in 3% of patients. In the randomized controlled combination therapy studies, herpes zoster was reported in 2% each in the DRd and Rd groups respectively (Study 3), in 5% versus 3% in the DVd and Vd groups respectively (Study 4) and in 2% of patients receiving DPd (Study 5). Infections: In patients receiving daratumumab combination therapy, Grade 3 or 4 infections were reported with daratumumab combinations and background therapies (DVd: 21%, Vd: 19%; DRd: 28%, Rd: 23%; DPd: 28%). Pneumonia was the most commonly reported severe (Grade 3 or 4) infection across studies. Discontinuations from treatment were reported in 3% versus 2% of patients in the DRd and Rd groups respectively, 4% versus 3% of patients in the DVd and Vd groups respectively and in 5% of patients receiving DPd. Fatal infections were reported in 0.8% to 2% of patients across studies, primarily due to pneumonia and sepsis. Immunogenicity: As with all therapeutic proteins, there is the potential for immunogenicity. In clinical trials of patients with multiple myeloma treated with daratumumab as monotherapy or as combination therapies, none of the 111 evaluable monotherapy patients, and 2 (0.7%) of the 298 combination therapy patients, tested positive for anti-daratumumab antibodies. One patient administered daratumumab as combination therapy, developed transient neutralizing antibodies against daratumumab. However, this assay has limitations in detecting anti-daratumumab antibodies in the presence of high concentrations of daratumumab; therefore, the incidence of antibody development might not have been reliably determined. 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 daratumumab with the incidence of antibodies to other products may be misleading. Adverse reactions by organ system: - Central Nervous System: Fatigue, headache, chills - Cardiovascular: Hypertension - Respiratory: Cough, nasal congestion, dyspnea, nasopharyngitis, pneumonia - Gastrointestinal: Nausea, diarrhea, constipation, decreased appetite, vomiting - Hematologic & oncologic: Lymphocytopenia, neutropenia, thrombocytopenia, anemia - Infection: Herpes zoster - Neuromuscular & skeletal: Back pain, arthralgia, leg pain, musculoskeletal chest pain - Miscellaneous: Infusion-related reaction, fever, physical health deterioration ## Postmarketing Experience There is limited information regarding Daratumumab Postmarketing Experience in the drug label. # Drug Interactions Daratumumab binds to CD38 on RBCs and interferes with compatibility testing, including antibody screening and cross matching. Daratumumab interference mitigation methods include treating reagent RBCs with dithiothreitol (DTT) to disrupt daratumumab binding or genotyping. Since the Kell blood group system is also sensitive to DTT treatment, K-negative units should be supplied after ruling out or identifying alloantibodies using DTT-treated RBCs.If an emergency transfusion is required, non-cross-matched ABO/RhD-compatible RBCs can be given per local blood bank practices. Daratumumab may be detected on serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for monitoring disease monoclonal immunoglobulins (M protein). This can lead to false positive SPE and IFE assay results for patients with IgG kappa myeloma protein impacting initial assessment of complete responses by International Myeloma Working Group (IMWG) criteria. In patients with persistent very good partial response, consider other methods to evaluate the depth of response. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): There are no human data to inform a risk with use of daratumumab during pregnancy. Animal studies have not been conducted. However, there are clinical considerations. Immunoglobulin G1 (IgG1) monoclonal antibodies are transferred across the placenta. Based on its mechanism of action, daratumumab may cause fetal myeloid or lymphoid-cell depletion and decreased bone density. Defer administering live vaccines to neonates and infants exposed to daratumumab in utero until a hematology evaluation is completed. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Mice that were genetically modified to eliminate all CD38 expression (CD38 knockout mice) had reduced bone density at birth that recovered by 5 months of age. In cynomolgus monkeys exposed during pregnancy to other monoclonal antibodies that affect leukocyte populations, infant monkeys had a reversible reduction in leukocytes. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Daratumumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Daratumumab during labor and delivery. ### Nursing Mothers There is no information regarding the presence of daratumumab in human milk, the effects on the breastfed infant, or the effects on milk production. Human IgG is known to be present in human milk. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for daratumumab and any potential adverse effects on the breast-fed child from daratumumab or from the underlying maternal condition. ### Pediatric Use There is no FDA guidance on the use of Daratumumab in pediatric settings. ### Geriatic Use Of the 156 patients that received daratumumab monotherapy at the recommended dose, 45% were 65 years of age or older, and 10% were 75 years of age or older. Of 664 patients that received daratumumab with various combination therapies, 41% were 65 to 75 years of age, and 9% were 75 years of age or older. No overall differences in safety or effectiveness were observed between these patients and younger patients. ### Gender There is no FDA guidance on the use of Daratumumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Daratumumab with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Daratumumab in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Daratumumab in patients with hepatic impairment. ### Females of Reproductive Potential and Males To avoid exposure to the fetus, women of reproductive potential should use effective contraception during treatment and for 3 months after cessation of daratumumab treatment. ### Immunocompromised Patients There is no FDA guidance one the use of Daratumumab in patients who are immunocompromised. # Administration and Monitoring ### Administration - Administer pre-infusion medication to reduce the risk of delayed infusion reactions to all patients 1-3 hours prior to every infusion of daratumumab as follows: Administer corticosteroids (monotherapy: methylprednisolone 100 mg, or equivalent), administered intravenously. Following the second infusion, the dose of corticosteroid may be reduced (oral or intravenous methylprednisolone 60 mg) or combination therapy: administer 20 mg dexamethasone prior to every daratumumab infusion. Dexamethasone is given intravenously prior to the first daratumumab infusion and oral administration may be considered prior to subsequent infusions). Antipyretics (oral acetaminophen 650 to 1000 mg). Antihistamine (oral or intravenous diphenhydramine 25 to 50 mg or equivalent) to reduce the risk of infusion reactions to all patients 1–3 hours prior to every infusion of daratumumab. - Administer corticosteroids (monotherapy: methylprednisolone 100 mg, or equivalent), administered intravenously. Following the second infusion, the dose of corticosteroid may be reduced (oral or intravenous methylprednisolone 60 mg) or combination therapy: administer 20 mg dexamethasone prior to every daratumumab infusion. Dexamethasone is given intravenously prior to the first daratumumab infusion and oral administration may be considered prior to subsequent infusions). - Antipyretics (oral acetaminophen 650 to 1000 mg). - Antihistamine (oral or intravenous diphenhydramine 25 to 50 mg or equivalent) to reduce the risk of infusion reactions to all patients 1–3 hours prior to every infusion of daratumumab. - Administer post-infusion medication to reduce the risk of delayed infusion reactions to all patients as follows: Monotherapy: Administer oral corticosteroid (20 mg methylprednisolone or equivalent dose of an intermediate-acting or long-acting corticosteroid in accordance with local standards) on each of the 2 days following all daratumumab infusions (beginning the day after the infusion). Combination therapy: Consider administering low-dose oral methylprednisolone (≤ 20 mg) or equivalent, the day after the daratumumab infusion. However, if a background regimen-specific corticosteroid (e.g. dexamethasone) is administered the day after the daratumumab infusion, additional post-infusion medications may not be needed. In addition, for any patients with a history of chronic obstructive pulmonary disease, consider prescribing post-infusion medications such as short and long-acting bronchodilators, and inhaled corticosteroids. Following the first four infusions, if the patient experiences no major infusion reactions, these additional inhaled post-infusion medications may be discontinued. - Monotherapy: Administer oral corticosteroid (20 mg methylprednisolone or equivalent dose of an intermediate-acting or long-acting corticosteroid in accordance with local standards) on each of the 2 days following all daratumumab infusions (beginning the day after the infusion). - Combination therapy: Consider administering low-dose oral methylprednisolone (≤ 20 mg) or equivalent, the day after the daratumumab infusion. However, if a background regimen-specific corticosteroid (e.g. dexamethasone) is administered the day after the daratumumab infusion, additional post-infusion medications may not be needed. - In addition, for any patients with a history of chronic obstructive pulmonary disease, consider prescribing post-infusion medications such as short and long-acting bronchodilators, and inhaled corticosteroids. Following the first four infusions, if the patient experiences no major infusion reactions, these additional inhaled post-infusion medications may be discontinued. - Initiate antiviral prophylaxis to prevent herpes zoster reactivation within 1 week after starting daratumumab and continue for 3 months following treatment. Administer only as an intravenous infusion after dilution in 0.9% Sodium Chloride Injection, USP. Daratumumab should be administered by a healthcare professional, with immediate access to emergency equipment and appropriate medical support to manage infusion reactions if they occur. If a planned dose of daratumumab is missed, administer the dose as soon as possible and adjust the dosing schedule accordingly, maintaining the treatment interval. Administer daratumumab infusion intravenously at the infusion rate described below. Consider incremental escalation of the infusion rate only in the absence of infusion reactions.This image is provided by the National Library of Medicine. - Administer only as an intravenous infusion after dilution in 0.9% Sodium Chloride Injection, USP. Daratumumab should be administered by a healthcare professional, with immediate access to emergency equipment and appropriate medical support to manage infusion reactions if they occur. - If a planned dose of daratumumab is missed, administer the dose as soon as possible and adjust the dosing schedule accordingly, maintaining the treatment interval. - Administer daratumumab infusion intravenously at the infusion rate described below. Consider incremental escalation of the infusion rate only in the absence of infusion reactions.This image is provided by the National Library of Medicine. - For infusion reactions of any grade/severity, immediately interrupt the daratumumab infusion and manage symptoms. Management of infusion reactions may further require reduction in the rate of infusion, or treatment discontinuation of daratumumab as outlined below: Grade 1–2 (mild to moderate): Once reaction symptoms resolve, resume the infusion at no more than half the rate at which the reaction occurred. If the patient does not experience any further reaction symptoms, infusion rate escalation may resume at increments and intervals as clinically appropriate up to the maximum rate of 200 mL/hour (Table 3). Grade 3 (severe): Once reaction symptoms resolve, consider restarting the infusion at no more than half the rate at which the reaction occurred. If the patient does not experience additional symptoms, resume infusion rate escalation at increments and intervals as outlined in Table 3. Repeat the procedure above in the event of recurrence of Grade 3 symptoms. Permanently discontinue daratumumab upon the third occurrence of a Grade 3 or greater infusion reaction. Grade 4 (life threatening): Permanently discontinue daratumumab treatment. - Grade 1–2 (mild to moderate): Once reaction symptoms resolve, resume the infusion at no more than half the rate at which the reaction occurred. If the patient does not experience any further reaction symptoms, infusion rate escalation may resume at increments and intervals as clinically appropriate up to the maximum rate of 200 mL/hour (Table 3). - Grade 3 (severe): Once reaction symptoms resolve, consider restarting the infusion at no more than half the rate at which the reaction occurred. If the patient does not experience additional symptoms, resume infusion rate escalation at increments and intervals as outlined in Table 3. Repeat the procedure above in the event of recurrence of Grade 3 symptoms. Permanently discontinue daratumumab upon the third occurrence of a Grade 3 or greater infusion reaction. - Grade 4 (life threatening): Permanently discontinue daratumumab treatment. - No dose reductions of daratumumab are recommended. Dose delay may be required to allow recovery of blood cell counts in the event of hematological toxicity. - Daratumumab is for single use only. Prepare the solution for infusion using aseptic technique as follows: Calculate the dose (mg), total volume (mL) of daratumumab solution required and the number of daratumumab vials needed based on patient actual body weight. Check that the daratumumab solution is colorless to pale yellow. Do not use if opaque particles, discoloration or other foreign particles are present. Remove a volume of 0.9% Sodium Chloride Injection, USP from the infusion bag/container that is equal to the required volume of daratumumab solution. Withdraw the necessary amount of daratumumab solution and dilute to the appropriate volume by adding to the infusion bag/container containing 0.9% Sodium Chloride Injection, USP as specified in Table 3. Infusion bags/containers must be made of either polyvinyl chloride (PVC), polypropylene (PP), polyethylene (PE) or polyolefin blend (PP+PE). Dilute under appropriate aseptic conditions. Discard any unused portion left in the vial. Gently invert the bag/container to mix the solution. Do not shake. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The diluted solution may develop very small, translucent to white proteinaceous particles, as daratumumab is a protein. Do not use if visibly opaque particles, discoloration or foreign particles are observed. Since daratumumab does not contain a preservative, administer the diluted solution immediately at room temperature 15°C–25°C (59°F–77°F) and in room light. Diluted solution may be kept at room temperature for a maximum of 15 hours (including infusion time). If not used immediately, the diluted solution can be stored prior to administration for up to 24 hours at refrigerated conditions 2°C – 8°C (36°F–46°F) and protected from light. Do not freeze. - Calculate the dose (mg), total volume (mL) of daratumumab solution required and the number of daratumumab vials needed based on patient actual body weight. - Check that the daratumumab solution is colorless to pale yellow. Do not use if opaque particles, discoloration or other foreign particles are present. - Remove a volume of 0.9% Sodium Chloride Injection, USP from the infusion bag/container that is equal to the required volume of daratumumab solution. - Withdraw the necessary amount of daratumumab solution and dilute to the appropriate volume by adding to the infusion bag/container containing 0.9% Sodium Chloride Injection, USP as specified in Table 3. Infusion bags/containers must be made of either polyvinyl chloride (PVC), polypropylene (PP), polyethylene (PE) or polyolefin blend (PP+PE). Dilute under appropriate aseptic conditions. Discard any unused portion left in the vial. - Gently invert the bag/container to mix the solution. Do not shake. - Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The diluted solution may develop very small, translucent to white proteinaceous particles, as daratumumab is a protein. Do not use if visibly opaque particles, discoloration or foreign particles are observed. - Since daratumumab does not contain a preservative, administer the diluted solution immediately at room temperature 15°C–25°C (59°F–77°F) and in room light. Diluted solution may be kept at room temperature for a maximum of 15 hours (including infusion time). - If not used immediately, the diluted solution can be stored prior to administration for up to 24 hours at refrigerated conditions 2°C – 8°C (36°F–46°F) and protected from light. Do not freeze. - Administer daratumumab as follows: If stored in the refrigerator, allow the solution to come to room temperature. Administer the diluted solution by intravenous infusion using an infusion set fitted with a flow regulator and with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) filter (pore size 0.22 or 0.2 micrometer). Administration sets must be made of either polyurethane (PU), polybutadiene (PBD), PVC, PP or PE. Do not store any unused portion of the infusion solution for reuse. Any unused product or waste material should be disposed of in accordance with local requirements. Do not infuse daratumumab concomitantly in the same intravenous line with other agents. - If stored in the refrigerator, allow the solution to come to room temperature. Administer the diluted solution by intravenous infusion using an infusion set fitted with a flow regulator and with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) filter (pore size 0.22 or 0.2 micrometer). Administration sets must be made of either polyurethane (PU), polybutadiene (PBD), PVC, PP or PE. - Do not store any unused portion of the infusion solution for reuse. Any unused product or waste material should be disposed of in accordance with local requirements. - Do not infuse daratumumab concomitantly in the same intravenous line with other agents. ### Monitoring Frequently monitor patients during the entire infusion. Interrupt daratumumab infusion for reactions of any severity and institute medical management as needed. Permanently discontinue daratumumab therapy for life-threatening (Grade 4) reactions. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion. # IV Compatibility There is limited information regarding the compatibility of Daratumumab and IV administrations. # Overdosage The dose of daratumumab at which severe toxicity occurs is not known. In the event of an overdose, monitor patients for any signs or symptoms of adverse effects and provide appropriate supportive treatment. # Pharmacology ## Mechanism of Action CD38 is a transmembrane glycoprotein (48 kDa) expressed on the surface of hematopoietic cells, including multiple myeloma and other cell types and tissues and has multiple functions, such as receptor mediated adhesion, signaling, and modulation of cyclase and hydrolase activity. Daratumumab is an IgG1κ human monoclonal antibody (mAb) that binds to CD38 and inhibits the growth of CD38 expressing tumor cells by inducing apoptosis directly through Fc mediated cross linking as well as by immune-mediated tumor cell lysis through complement dependent cytotoxicity (CDC), antibody dependent cell mediated cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP). A subset of myeloid derived suppressor cells (CD38+MDSCs), regulatory T cells (CD38+Tregs) and B cells (CD38+Bregs) are decreased by daratumumab. ## Structure There is limited information regarding Daratumumab Structure in the drug label. ## Pharmacodynamics NK cells express CD38 and are susceptible to daratumumab mediated cell lysis. Decreases in absolute counts and percentages of total NK cells (CD16+CD56+) and activated (CD16+CD56dim) NK cells in peripheral whole blood and bone marrow were observed with daratumumab treatment. Daratumumab as a large protein has a low likelihood of direct ion channel interactions. There is no evidence from non-clinical or clinical data to suggest that daratumumab has the potential to delay ventricular repolarization. ## Pharmacokinetics Over the dose range from 1 to 24 mg/kg as monotherapy or 1 to 16 mg/kg of daratumumab in combination with other treatments, increases in area under the concentration-time curve (AUC) were more than dose-proportional. Following the recommended dose of 16 mg/kg when daratumumab was administered as monotherapy or in combination therapy, the mean serum maximal concentration (Cmax) value at the end of weekly dosing, was approximately 2.7 to 3-fold higher compared to the mean serum Cmax following the first dose. The mean ± standard deviation (SD) trough serum concentration (Cmin) at the end of weekly dosing was 573 ± 332 µg/mL when daratumumab was administered as monotherapy and 502 ± 196 to 607 ± 231 µg/mL when daratumumab was administered as combination therapy. Daratumumab steady state was achieved approximately 5 months into the every 4-week dosing period (by the 21st infusion), and the mean ± SD ratio of Cmax at steady-state to Cmax after the first dose was 1.6 ± 0.5. Distribution: At the recommended dose of 16 mg/kg, the mean ± SD central volume of distribution was 4.7 ± 1.3 L when daratumumab was administered as monotherapy and 4.4 ± 1.5 L when daratumumab was administered as combination therapy. Elimination: Daratumumab clearance decreased with increasing dose and with multiple dosing. At the recommended dose of 16 mg/kg of daratumumab as monotherapy, the mean ± SD linear clearance was estimated to be 171.4 ± 95.3 mL/day. The mean ± SD estimated terminal half-life associated with linear clearance was 18 ± 9 days when daratumumab administered as monotherapy and 23 ± 12 days when daratumumab was administered as combination therapy. Specific populations: The following population characteristics have no clinically meaningful effect on the pharmacokinetics of daratumumab in patients administered daratumumab as monotherapy or as combination therapy: sex, age (31 to 84 years), mild [total bilirubin 1 to 1.5 times upper limit of normal (ULN) and any alanine transaminase (ALT)] and moderate (total bilirubin 1.5 to 3 times ULN and any ALT) hepatic impairment, or renal impairment [Creatinine clearance] (CLcr) 15 –89 mL/min]. The effect of severe (total bilirubin >3 times ULN and any ALT) hepatic impairment is unknown. Increasing body weight increased the central volume of distribution and clearance of daratumumab, supporting the body weight-based dosing regimen. Drug interactions: The coadministration of lenalidomide, pomalidomide or bortezomib with daratumumab did not affect the pharmacokinetics of daratumumab. The coadministration of daratumumab with bortezomib did not affect the pharmacokinetics of bortezomib. ## Nonclinical Toxicology No carcinogenicity or genotoxicity studies have been conducted with daratumumab. No animal studies have been performed to evaluate the potential effects of daratumumab on reproduction or development, or to determine potential effects on fertility in males or females. # Clinical Studies Study 3, an open-label, randomized, active-controlled Phase 3 trial, compared treatment with daratumumab 16 mg/kg in combination with lenalidomide and low-dose dexamethasone (DRd) to treatment with lenalidomide and low-dose dexamethasone (Rd) in patients with multiple myeloma who had received at least one prior therapy. Lenalidomide (25 mg once daily orally on Days 1–21 of repeated 28-day [4-week] cycles) was given with low dose oral or intravenous dexamethasone 40 mg/week (or a reduced dose of 20 mg/week for patients >75 years or body mass index [BMI] <18.5). On daratumumab infusion days, 20 mg of the dexamethasone dose was given as a pre-infusion medication and the remainder given the day after the infusion. For patients on a reduced dexamethasone dose, the entire 20 mg dose was given as a daratumumab pre-infusion medication. Dose adjustments for lenalidomide and dexamethasone were applied according to manufacturer's prescribing information. Treatment was continued in both arms until disease progression or unacceptable toxicity. A total of 569 patients were randomized; 286 to the DRd arm and 283 to the Rd arm. The baseline demographic and disease characteristics were similar between the daratumumab and the control arm. The median patient age was 65 years (range 34 to 89 years), 11% were ≥75 years, 59% were male; 69% Caucasian, 18% Asian, and 3% African American. Patients had received a median of 1 prior line of therapy. Sixty-three percent (63%) of patients had received prior autologous stem cell transplantation (ASCT). The majority of patients (86%) received a prior PI, 55% of patients had received a prior immunomodulatory agent, including 18% of patients who had received prior lenalidomide; and 44% of patients had received both a prior PI and immunomodulatory agent. At baseline, 27% of patients were refractory to the last line of treatment. Eighteen percent (18%) of patients were refractory to a PI only, and 21% were refractory to bortezomib. Efficacy was evaluated by progression free survival (PFS) based on International Myeloma Working Group (IMWG) criteria. Study 3 demonstrated an improvement in PFS in the DRd arm as compared to the Rd arm; the median PFS had not been reached in the DRd arm and was 18.4 months in the Rd arm (hazard ratio [HR]=0.37; 95% CI: 0.27, 0.52; p<0.0001), representing 63% reduction in the risk of disease progression or death in patients treated with DRd. Figure 1: Kaplan-Meier Curve of PFS in Study 3 Additional efficacy results from Study 3 are presented in Table 12 below. In responders, the median time to response was 1 month (range: 0.9 to 13 months) in the DRd group and 1.1 months (range: 0.9 to 10 months) in the Rd group. The median duration of response had not been reached in the DRd group (range: 1+ to 19.8+ months) and was 17.4 months (range: 1.4 to 18.5+ months) in the Rd group. With a median follow-up of 13.5 months, 75 deaths were observed; 30 in the DRd group and 45 in the Rd group. Study 4, an open-label, randomized, active-controlled Phase 3 trial, compared treatment with daratumumab 16 mg/kg in combination with bortezomib and dexamethasone (DVd), to treatment with bortezomib and dexamethasone (Vd). Bortezomib was administered by SC injection or IV infusion at a dose of 1.3 mg/m2 body surface area twice weekly for two weeks (Days 1, 4, 8, and 11) of repeated 21 day (3-week) treatment cycles, for a total of 8 cycles. Dexamethasone was administered orally at a dose of 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each of the 8 bortezomib cycles (80 mg/week for two out of three weeks of the bortezomib cycle) or a reduced dose of 20 mg/week for patients >75 years, BMI <18.5, poorly controlled diabetes mellitus or prior intolerance to steroid therapy. On the days of daratumumab infusion, 20 mg of the dexamethasone dose was administered as a pre-infusion medication. For patients on a reduced dexamethasone] dose, the entire 20 mg dose was given as a daratumumab pre-infusion medication. Bortezomib and dexamethasone were given for 8 three-week cycles in both treatment arms; whereas daratumumab was given until disease progression. However, dexamethasone 20 mg was continued as a daratumumab pre-infusion medication in the DVd arm. Dose adjustments for bortezomib and dexamethasone were applied according to manufacturer's prescribing information. A total of 498 patients were randomized; 251 to the DVd arm and 247 to the Vd arm. The baseline demographic and disease characteristics were similar between the daratumumab and the control arm. The median patient age was 64 years (range 30 to 88 years); 12% were ≥75 years, 57% were male; 87% Caucasian, 5% Asian and 4% African American. Patients had received a median of 2 prior lines of therapy and 61% of patients had received prior autologous stem cell transplantation (ASCT). Sixty-nine percent (69%) of patients had received a prior PI (66% received bortezomib) and 76% of patients received an immunomodulatory agent (42% received lenalidomide). At baseline, 32% of patients were refractory to the last line of treatment and the proportions of patients refractory to any specific prior therapy were in general well balanced between the treatment groups. Thirty-three percent (33%) of patients were refractory to an immunomodulatory agent only, with 24% patients in the DVd arm and 33% of patients in the Vd arm respectively refractory to lenalidomide. Efficacy was evaluated by progression free survival (PFS) based on International Myeloma Working Group (IMWG) criteria. Study 4 demonstrated an improvement in PFS in the DVd arm as compared to the Vd arm; the median PFS had not been reached in the DVd arm and was 7.2 months in the Vd arm (HR [95% CI]: 0.39 [0.28, 0.53]; p-value < 0.0001), representing a 61% reduction in the risk of disease progression or death for patients treated with DVd versus Vd. Figure 2: Kaplan-Meier Curve of PFS in Study 4 Additional efficacy results from Study 4 are presented in Table 13 below. In responders, the median time to response was 0.8 months (range: 0.7 to 4 months) in the DVd group and 1.5 months (range: 0.7 to 5 months) in the Vd group. The median duration of response had not been reached in the DVd group (range: 1.4+ to 14.1+ months) and was 7.9 months (1.4+ to 12+ months) in the Vd group. With a median follow-up of 7.4 months, 65 deaths were observed; 29 in the DVd group and 36 in the Vd group were observed. Study 5 was an open-label trial in which 103 patients with multiple myeloma who had received a prior PI and an immunomodulatory agent, received 16 mg/kg daratumumab in combination with pomalidomide and low-dose dexamethasone until disease progression. Pomalidomide (4 mg once daily orally on Days 1-21 of repeated 28-day [4-week] cycles) was given with low dose oral or intravenous dexamethasone 40 mg/ week (reduced dose of 20 mg/week for patients >75 years or body mass index [BMI] <18.5). On daratumumab infusion days, 20 mg of the dexamethasone dose was given as a pre-infusion medication and the remainder given the day after the infusion. For patients on a reduced dexamethasone dose, the entire 20 mg dose was given as a daratumumab pre-infusion medication. The median patient age was 64 years (range: 35 to 86 years) with 8% of patients ≥75 years of age. Patients in the study had received a median of 4 prior lines of therapy. Seventy-four percent (74%) of patients had received prior ASCT. Ninety-eight percent (98%) of patients received prior bortezomib treatment, and 33% of patients received prior carfilzomib. All patients received prior lenalidomide treatment, with 98% of patients previously treated with the combination of bortezomib and lenalidomide. Eighty nine percent (89%) of patients were refractory to lenalidomide and 71% refractory to bortezomib; 64% of patients were refractory to bortezomib and lenalidomide. Efficacy results were based on overall response rate as determined by Independent Review Committee using IMWG criteria (see table 14). The median time to response was 1 month (range: 0.9 to 2.8 months). The median duration of response was 13.6 months (range: 0.9+ to 14.6+ months). Study 1, was an open-label trial evaluating daratumumab monotherapy in patients with relapsed or refractory multiple myeloma who had received at least 3 prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent or who were double-refractory to a proteasome inhibitor and an immunomodulatory agent. In 106 patients, daratumumab 16 mg/kg was administered with pre- and post-infusion medication. Treatment continued until unacceptable toxicity or disease progression. The median patient age was 63.5 years (range: 31 to 84 years), 49% were male and 79% were Caucasian. Patients had received a median of 5 prior lines of therapy. Eighty percent of patients had received prior autologous stem cell transplantation (ASCT). Prior therapies included bortezomib (99%), lenalidomide (99%), pomalidomide (63%) and carfilzomib (50%). At baseline, 97% of patients were refractory to the last line of treatment, 95% were refractory to both, a proteasome inhibitor (PI) and immunomodulatory agent, and 77% were refractory to alkylating agents. Efficacy results were based on overall response rate as determined by the Independent Review Committee assessment using IMWG criteria (see table 15). The median time to response was 1 month (range: 0.9 to 5.6 months). The median duration of response was 7.4 months (range: 1.2 to 13.1+ months). Study 2 was an open-label dose escalation trial evaluating daratumumab monotherapy in patients with relapsed or refractory multiple myeloma who had received at least 2 different cytoreductive therapies. In 42 patients, daratumumab 16 mg/kg was administered with pre- and post-infusion medication. Treatment continued until unacceptable toxicity or disease progression. The median patient age was 64 years (range: 44 to 76 years), 64% were male and 76% were Caucasian. Patients in the study had received a median of 4 prior lines of therapy. Seventy-four percent of patients had received prior ASCT. Prior therapies included bortezomib (100%), lenalidomide (95%), pomalidomide (36%) and carfilzomib (19%). At baseline, 76% of patients were refractory to the last line of treatment, 64% of patients were refractory to both, a PI and an immunomodulatory agent, and 60% of patients were refractory to alkylating agents. Overall response rate was 36% (95% CI: 21.6, 52.0%) with 1 CR and 3 VGPR. The median time to response was 1 month (range: 0.5 to 3.2 months). The median duration of response was not estimable (range: 2.2 to 13.1+ months). # How Supplied Daratumumab is a colorless to pale yellow, preservative-free solution for intravenous infusion supplied as: - NDC 57894-502-05 contains one 100 mg/5 mL single-dose vial - NDC 57894-502-20 contains one 400 mg/20 mL single-dose vial ## Storage Store in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF). Do not freeze or shake. Protect from light. This product contains no preservative. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Infusion Reactions Advise patients to seek immediate medical attention for any of the following signs and symptoms of infusion reactions: itchy, runny or blocked nose; chills, nausea, throat irritation, cough, headache, shortness of breath or difficulty breathing - Advise patients to seek immediate medical attention for any of the following signs and symptoms of infusion reactions: itchy, runny or blocked nose; chills, nausea, throat irritation, cough, headache, shortness of breath or difficulty breathing - Neutropenia Advise patients that if they have a fever, they should contact their healthcare professional. - Advise patients that if they have a fever, they should contact their healthcare professional. - Thrombocytopenia Advise patients to inform their healthcare professional if they notice signs of bruising or bleeding. - Advise patients to inform their healthcare professional if they notice signs of bruising or bleeding. - Interference with laboratory tests Advise patients to inform healthcare providers including blood transfusion centers/personnel that they are taking daratumumab, in the event of a planned transfusion. Advise patients that daratumumab can affect the results of some tests used to determine complete response in some patients and additional tests may be needed to evaluate response. - Advise patients to inform healthcare providers including blood transfusion centers/personnel that they are taking daratumumab, in the event of a planned transfusion. - Advise patients that daratumumab can affect the results of some tests used to determine complete response in some patients and additional tests may be needed to evaluate response. # Precautions with Alcohol Alcohol-Daratumumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Darzalex # Look-Alike Drug Names There is limited information regarding daratumumab Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Daratumumab
1bfcd80b1b9c48d5b62dbe4d45547260f5273715	wikidoc	Darifenacin	Darifenacin # 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 Darifenacin is a muscarinic antagonist that is FDA approved for the {{{indicationType}}} of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency. Common adverse reactions include constipation, dry mouth, headache, dyspepsia, nausea, urinary tract infection, accidental injury, and flu symptoms. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - Enablex (darifenacin) is a muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency. - The recommended starting dose of Enablex is 7.5 mg once daily. Based upon individual response, the dose may be increased to 15 mg once daily, as early as two weeks after starting therapy. - Enablex should be taken once daily with water. Enablex may be taken with or without food, and should be swallowed whole and not chewed, divided or crushed. - For patients with moderate hepatic impairment (Child-Pugh B) or when co-administered with potent CYP3A4 inhibitors (for example, ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin and nefazadone), the daily dose of Enablex should not exceed 7.5 mg. Enablex is not recommended for use in patients with severe hepatic impairment (Child-Pugh C). ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Darifenacin in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Darifenacin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Darifenacin in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Darifenacin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Darifenacin in pediatric patients. # Contraindications - Enablex is contraindicated in patients with, or at risk for, the following conditions: - urinary retention - gastric retention, or - uncontrolled narrow-angle glaucoma. # Warnings ### Precautions - Risk of Urinary Retention - Enablex should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention. - Decreased Gastrointestinal Motility - Enablex should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention. Enablex, like other anticholinergic drugs, may decrease gastrointestinal motility and should be used with caution in patients with conditions such as severe constipation, ulcerative colitis, and myasthenia gravis. - Controlled Narrow-Angle Glaucoma - Enablex should be used with caution in patients being treated for narrow-angle glaucoma and only where the potential benefits outweigh the risks. - Angioedema - Angioedema of the face, lips, tongue, and/or larynx have been reported with darifenacin. In some cases angioedema occurred after the first dose. Angioedema associated with upper airway swelling may be life threatening. If involvement of the tongue, hypopharynx, or larynx occurs, darifenacin should be promptly discontinued and appropriate therapy and/or measures necessary to ensure a patent airway should be promptly provided. - Central Nervous System Effects - Enablex is associated with anticholinergic central nervous system (CNS) effects. A variety of CNS anticholinergic effects have been reported, including headache, confusion, hallucinations and somnolence. Patients should be monitored for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy machinery until they know how Enablex affects them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered. - Patients with Hepatic Impairment - The daily dose of Enablex should not exceed 7.5 mg for patients with moderate hepatic impairment (Child-Pugh B). Enablex has not been studied in patients with severe hepatic impairment (Child-Pugh C) and therefore is not recommended for use in this patient population. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - The safety of Enablex was evaluated in controlled clinical trials in a total of 8,830 patients, 6,001 of whom were treated with Enablex. Of this total, 1,069 patients participated in three, 12-week, randomized, placebo-controlled, fixed-dose efficacy and safety studies (Studies 1, 2 and 3). Of this total, 337 and 334 patients received Enablex 7.5 mg daily and 15 mg daily, respectively. In all long-term trials combined, 1,216 and 672 patients received treatment with Enablex for at least 24 and 52 weeks, respectively. - In Studies 1, 2 and 3 combined, the serious adverse reactions to Enablex were urinary retention and constipation. - In Studies 1, 2 and 3 combined, dry mouth leading to study discontinuation occurred in 0%, 0.9%, and 0% of patients treated with Enablex 7.5 mg daily, Enablex 15 mg daily and placebo, respectively. Constipation leading to study discontinuation occurred in 0.6%, 1.2%, and 0.3% of patients treated with Enablex 7.5 mg daily, Enablex 15 mg daily and placebo, respectively. - Table 1 lists the rates of identified adverse reactions, derived from all reported adverse events in 2% or more of patients treated with 7.5 mg or 15 mg Enablex, and greater than placebo in Studies 1, 2 and 3. In these studies, the most frequently reported adverse reactions were dry mouth and constipation. The majority of the adverse reactions were mild or moderate in severity and most occurred during the first two weeks of treatment. - Other adverse reactions reported by 1% to 2% of Enablex-treated patients include: abnormal vision, accidental injury, back pain, dry skin, flu syndrome, hypertension, vomiting, peripheral edema, weight gain, arthralgia, bronchitis, pharyngitis, rhinitis, sinusitis, rash, pruritus, urinary tract disorder and vaginitis. - Study 4 was a randomized, 12-week, placebo-controlled, dose-titration regimen study in which Enablex was administered in accordance with dosing recommendations. All patients initially received placebo or Enablex 7.5 mg daily, and after two weeks, patients and physicians were allowed to adjust upward to Enablex 15 mg if needed. In this study, the most commonly reported adverse reactions were also constipation and dry mouth. Table 2 lists the identified adverse reactions, derived from all adverse events reported in greater than 3% of patients treated with Enablex and greater than placebo. ## Postmarketing Experience - The following adverse reactions have been reported during post-approval use of Enablex extended-release tablets (darifenacin). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency or establish a causal relationship to drug exposure. - Dermatologic: erythema multiforme, interstitial granuloma annulare - General: hypersensitivity reactions, including angioedema with airway obstruction and anaphylactic reaction - Central Nervous: confusion, hallucinations and somnolence - Cardiovascular: palpitations and syncope # Drug Interactions - CYP3A4 Inhibitors - The systemic exposure of darifenacin from Enablex extended-release tablets is increased in the presence of CYP3A4 inhibitors. The daily dose of Enablex should not exceed 7.5 mg when co-administered with potent CYP3A4 inhibitors (for example, ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin and nefazadone). No dosing adjustments are recommended in the presence of moderate CYP3A4 inhibitors (for example, erythromycin, fluconazole, diltiazem and verapamil). - CYP2D6 Inhibitors - No dosing adjustments are recommended in the presence of CYP2D6 inhibitors (for example, paroxetine, fluoxetine, quinidine and duloxetine). - CYP2D6 Substrates - Caution should be taken when Enablex is used concomitantly with medications that are predominantly metabolized by CYP2D6 and which have a narrow therapeutic window (for example, flecainide, thioridazine and tricyclic antidepressants). - CYP3A4 Substrates - Darifenacin (30 mg daily) did not have a significant impact on midazolam (7.5 mg) pharmacokinetics. - Combination oral contraceptives - Darifenacin (10 mg three times daily) had no effect on the pharmacokinetics of the combination oral contraceptives containing levonorgestrel and ethinyl estradiol. - Warfarin - Darifenacin had no significant effect on prothrombin time when a single dose of warfarin 30 mg was co-administered with darifenacin (30 mg daily) at steady-state. Standard therapeutic prothrombin time monitoring for warfarin should be continued. - Digoxin - Darifenacin (30 mg daily) did not have a clinically relevant effect on the pharmacokinetics of digoxin (0.25 mg) at steady-state. Routine therapeutic drug monitoring for digoxin should be continued. - Other Anticholinergic Agents - The concomitant use of Enablex with other anticholinergic agents may increase the frequency and/or severity of dry mouth, constipation, blurred vision and other anticholinergic pharmacological effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to effects on gastrointestinal motility. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - There are no studies of darifenacin in pregnant women. - Darifenacin was not teratogenic in rats and rabbits at plasma exposures of free drug (via AUC) up to 59 times and 28 times, respectively (doses up to 50 and 30 mg/kg/day, respectively) the maximum recommended human dose of 15 mg. At approximately 59 times the MRHD in rats, there was a delay in the ossification of the sacral and caudal vertebrae which was not observed at approximately 13 times the AUC. Dystocia was observed in dams at approximately 17 times the AUC (10 mg/kg/day). Slight developmental delays were observed in pups at this dose. At five times the AUC (3 mg/kg/day), there were no effects on dams or pups. In rabbits, an exposure approximately 28 times (30 mg/kg/day) the MRHD of darifenacin was shown to increase post-implantation loss, with a no effect level at nine times (10 mg/kg/day) the AUC at the MRHD. Dilated ureter and/or kidney pelvis was also observed in offspring at this dose along with urinary bladder dilation consistent with the pharmacological action of darifenacin, with one case observed at nine times (10 mg/kg/day). No effect was observed at approximately 2.8 times (3 mg/kg/day) the AUC at the MRHD. - Because animal reproduction studies are not always predictive of human response, Enablex should be used during pregnancy only if the benefit to the mother outweighs 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 Darifenacin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Darifenacin during labor and delivery. ### Nursing Mothers - Darifenacin is excreted into the milk of rats. It is not known whether darifenacin is excreted into human milk and therefore caution should be exercised before Enablex is administered to a nursing woman. ### Pediatric Use - The safety and effectiveness of Enablex in pediatric patients have not been established. ### Geriatic Use - In the fixed-dose, placebo-controlled, clinical studies, 30% of patients treated with Enablex were over 65 years of age. No overall differences in safety or efficacy were observed between patients over 65 years (n = 207) and younger patients less than 65 years (n = 464). No dose adjustment is recommended for elderly patients. ### Gender - No dose adjustment is recommended based on gender. ### Race There is no FDA guidance on the use of Darifenacin with respect to specific racial populations. ### Renal Impairment - A study of subjects with varying degrees of renal impairment (creatinine clearance between 10 and 136 mL/min) demonstrated no clear relationship between renal function and darifenacin clearance. No dose adjustment is recommended for patients with renal impairment. ### Hepatic Impairment - Subjects with severe hepatic impairment (Child-Pugh C) have not been studied, therefore Enablex is not recommended for use in these patients. The daily dose of Enablex should not exceed 7.5 mg once daily for patients with moderate hepatic impairment (Child-Pugh B) . After adjusting for plasma protein binding, unbound darifenacin exposure was estimated to be 4.7-fold higher in subjects with moderate hepatic impairment than subjects with normal hepatic function. No dose adjustment is recommended for patients with mild hepatic impairment (Child-Pugh A). ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Darifenacin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Darifenacin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Darifenacin in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Darifenacin in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Overdosage with antimuscarinic agents, including Enablex, can result in severe antimuscarinic effects. Enablex has been administered in clinical trials at doses up to 75 mg (five times the maximum therapeutic dose) and signs of overdose were limited to abnormal vision. ### Management - Treatment should be symptomatic and supportive. In the event of overdosage,ECG monitoring is recommended. ## Chronic Overdose There is limited information regarding Chronic Overdose of Darifenacin in the drug label. # Pharmacology ## Mechanism of Action - Darifenacin is a competitive muscarinic receptor antagonist. Muscarinic receptors play an important role in several major cholinergically mediated functions, including contractions of the urinary bladder smooth muscle and stimulation of salivary secretion. - In vitro studies using human recombinantmuscarinic receptor subtypes show that darifenacin has greater affinity for the M3 receptor than for the other known muscarinic receptors (9- and 12-fold greater affinity for M3 compared to M1 and M5, respectively, and 59-fold greater affinity for M3 compared to both M2 and M4). M3 receptors are involved in contraction of human bladder and gastrointestinal smooth muscle, saliva production, and iris sphincter function. Adverse drug effects such as dry mouth, constipation and abnormal vision may be mediated through effects on M3 receptors in these organs. ## Structure - Enablex is an extended-release tablet for oral administration which contains 7.5 mg or 15 mg darifenacin as its hydrobromide salt. The active moiety, darifenacin, is a potent muscarinic receptor antagonist. - Chemically, darifenacin hydrobromide is (S)-2-{1--3-pyrrolidinyl}-2,2-diphenylacetamide hydrobromide. The empirical formula of darifenacin hydrobromide is C28H30N2O2HBr. - The structural formula is: - Darifenacin hydrobromide is a white to almost white, crystalline powder, with a molecular weight of 507.5. - Enablex is a once-a-day extended-release tablet and contains the following inactive ingredients: dibasic calcium phosphate anhydrous, hypromellose, magnesium stearate, polyethylene glycol, talc, titanium dioxide. The 15 mg tablet also contains ferric oxide red and ferric oxide yellow. ## Pharmacodynamics - In three cystometric studies performed in patients with involuntary detrusor contractions, increased bladder capacity was demonstrated by an increased volume threshold for unstable contractions and diminished frequency of unstable detrusor contractions after Enablex treatment. These findings are consistent with an antimuscarinic action on the urinary bladder. - Electrophysiology - The effect of a six-day treatment of 15 mg and 75 mg Enablex on QT/QTc interval was evaluated in a multiple-dose, double-blind, randomized, placebo- and active-controlled (moxifloxacin 400 mg) parallel-arm design study in 179 healthy adults (44% male, 56% female) aged 18 to 65. Subjects included 18% poor metabolizers (PMs) and 82% extensive metabolizers (EMs). The QT interval was measured over a 24-hour period both predosing and at steady-state. The 75 mg Enablex dose was chosen because this achieves exposure similar to that observed in CYP2D6 poor metabolizers administered the highest recommended dose (15 mg) of darifenacin in the presence of a potent CYP3A4 inhibitor. At the doses studied, Enablex did not result in QT/QTc interval prolongation at any time during the steady-state, while moxifloxacin treatment resulted in a mean increase from baseline QTcF of about 7.0 msec when compared to placebo. In this study, darifenacin 15 mg and 75 mg doses demonstrated a mean heart rate change of 3.1 and 1.3 bpm, respectively, when compared to placebo. However, in the clinical efficacy and safety studies, the change in median HR following treatment with Enablex was no different from placebo. ## Pharmacokinetics - Absorption - After oral administration of Enablex to healthy volunteers, peak plasma concentrations of darifenacin are reached approximately seven hours after multiple dosing and steady-state plasma concentrations are achieved by the sixth day of dosing. The mean (SD) steady-state time course of Enablex 7.5 mg and 15 mg extended-release tablets is depicted in Figure 1. - A summary of mean (standard deviation, SD) steady-state pharmacokinetic parameters of Enablex 7.5 mg and 15 mg extended-release tablets in EMs and PMs of CYP2D6 is provided in Table 3. - The mean oral bioavailability of Enablex in EMs at steady-state is estimated to be 15% and 19% for 7.5 mg and 15 mg tablets, respectively. - Effect of Food - Following single dose administration of Enablex with food, the AUC of darifenacin was not affected, while the Cmax was increased by 22% and Tmax was shortened by 3.3 hours. There is no effect of food on multiple-dose pharmacokinetics from Enablex. - Distribution - Darifenacin is approximately 98% bound to plasma proteins (primarily to alpha-1-acid-glycoprotein). The steady-state volume of distribution (Vss) is estimated to be 163 L. - Metabolism - Darifenacin is extensively metabolized by the liver following oral dosing. - Metabolism is mediated by cytochrome P450 enzymes CYP2D6 and CYP3A4. The three main metabolic routes are as follows: monohydroxylation in the dihydrobenzofuran ring; dihydrobenzofuran ring opening; N-dealkylation of the pyrrolidine nitrogen. - monohydroxylation in the dihydrobenzofuran ring; - dihydrobenzofuran ring opening; - N-dealkylation of the pyrrolidine nitrogen. - The initial products of the hydroxylation and N-dealkylation pathways are the major circulating metabolites but they are unlikely to contribute significantly to the overall clinical effect of darifenacin. - Variability in Metabolism - A subset of individuals (approximately 7% Caucasians and 2% African Americans) are poor metabolizers (PMs) of CYP2D6 metabolized drugs. Individuals with normal CYP2D6 activity are referred to as extensive metabolizers (EMs). The metabolism of darifenacin in PMs will be principally mediated via CYP3A4. The darifenacin ratios (PM versus EM) for Cmax and AUC following darifenacin 15 mg once daily at steady-state were 1.9 and 1.7, respectively. - Excretion - Following administration of an oral dose of 14C-darifenacin solution to healthy volunteers, approximately 60% of the radioactivity was recovered in the urine and 40% in the feces. Only a small percentage of the excreted dose was unchanged darifenacin (3%). Estimated darifenacin clearance is 40 L/h for EMs and 32 L/h for PMs. The elimination half-life of darifenacin following chronic dosing is approximately 13 to 19 hours. - Drug-Drug Interactions - Effects of Other Drugs on Darifenacin - Darifenacin metabolism is primarily mediated by the cytochrome P450 enzymes CYP2D6 and CYP3A4. Therefore, inducers of CYP3A4 or inhibitors of either of these enzymes may alter darifenacin pharmacokinetics. - CYP3A4 Inhibitors: In a drug interaction study, when a 7.5 mg once daily dose of Enablex was given to steady-state and co-administered with the potent CYP3A4 inhibitor ketoconazole 400 mg, mean darifenacin Cmax increased to 11.2 ng/mL for EMs (n = 10) and 55.4 ng/mL for one PM subject (n = 1). Mean AUC increased to 143 and 939 ngh/mL for EMs and for one PM subject, respectively. When a 15 mg daily dose of Enablex was given with ketoconazole, mean darifenacin Cmax increased to 67.6 ng/mL and 58.9 ng/mL for EMs (n = 3) and one PM subject (n = 1), respectively. Mean AUC increased to 1110 and 931 ngh/mL for EMs and for one PM subject, respectively. - The mean Cmax and AUC of darifenacin following 30 mg once daily dosing at steady-state were 128% and 95% higher, respectively, in the presence of a moderate CYP3A4 inhibitor, erythromycin. Co-administration of fluconazole, a moderate CYP3A4 inhibitor and darifenacin 30 mg once daily at steady-state increased darifenacin Cmax and AUC by 88% and 84%, respectively. - The mean Cmax and AUC of darifenacin following 30 mg once daily at steady-state were 42% and 34% higher, respectively, in the presence of cimetidine, a mixed CYP P450 enzyme inhibitor. - CYP2D6 Inhibitors: Darifenacin exposure following 30 mg once daily at steady-state was 33% higher in the presence of the potent CYP2D6 inhibitor paroxetine 20 mg. - Effects of Darifenacin on Other Drugs - In Vitro Studies: Based on in vitro human microsomal studies, Enablex is not expected to inhibit CYP1A2 or CYP2C9 at clinically relevant concentrations. - In Vivo Studies: The potential for clinical doses of Enablex to act as inhibitors of CYP2D6 or CYP3A4 substrates was investigated in specific drug interaction studies. - CYP2D6 Substrates: The mean Cmax and AUC of imipramine, a CYP2D6 substrate, were increased by 57% and 70%, respectively, in the presence of steady-state darifenacin 30 mg once daily. The mean Cmax and AUC of desipramine, the active metabolite of imipramine, were increased by 260%. - CYP3A4 Substrates: Darifenacin (30 mg daily) co-administered with a single oral dose of midazolam 7.5 mg resulted in a 17% increase in midazolam exposure. - Combination Oral Contraceptives: Darifenacin (10 mg three times daily) had no effect on the pharmacokinetics of a combination oral contraceptive containing levonorgestrel (0.15 mg) and ethinyl estradiol (0.03 mg). - Warfarin: Darifenacin had no significant effect on prothrombin time when a single dose of warfarin 30 mg was co-administered with darifenacin (30 mg daily) at steady-state]. - Digoxin: Darifenacin (30 mg daily) co-administered with digoxin (0.25 mg) at steady-state resulted in a 16% increase in digoxin exposure. - Pharmacokinetics in Special Populations - Age: A population pharmacokinetic analysis of patient data indicated a trend for clearance of darifenacin to decrease with age (6% per decade relative to a median age of 44). Following administration of Enablex 15 mg once daily, darifenacin exposure at steady-state was approximately 12% to 19% higher in volunteers between 45 and 65 years of age compared to younger volunteers aged 18 to 44 years. - Pediatric: The pharmacokinetics of Enablex has not been studied in the pediatric population. - Gender: PK parameters were calculated for 22 male and 25 female healthy volunteers. Darifenacin Cmax and AUC at steady-state were approximately 57% to 79% and 61% to 73% higher in females than in males, respectively. - Renal Impairment: A study of subjects with varying degrees of renal impairment (creatinine clearance between 10 and 136 mL/min) given Enablex 15 mg once daily to steady-state demonstrated no clear relationship between renal function and darifenacin clearance. - Hepatic Impairment: Enablex pharmacokinetics were investigated in subjects with mild (Child-Pugh A) or moderate (Child-Pugh B) impairment of hepatic function given Enablex 15 mg once daily to steady-state. Mild hepatic impairment had no effect on the pharmacokinetics of darifenacin. However, protein binding of darifenacin was affected by moderate hepatic impairment. After adjusting for plasma protein binding, unbound darifenacin exposure was estimated to be 4.7-fold higher in subjects with moderate hepatic impairment than subjects with normal hepatic function. Subjects with severe hepatic impairment (Child-Pugh C) have not been studied. ## Nonclinical Toxicology - Carcinogenicity studies with darifenacin were conducted in mice and rats. No evidence of drug-related carcinogenicity was revealed in a 24-month study in mice at dietary doses up to 100 mg/kg/day or approximately 32 times the estimated free plasma AUC reached at the maximum recommended human dose (the AUC at the MRHD) of 15 mg and in a 24-month study in rats at doses up to 15 mg/kg/day or up to approximately 12 times the AUC at the MRHD in female rats and approximately eight times the AUC at the MRHD in male rats. - Darifenacin was not genotoxic in the bacterial mutation assay (Ames test), the Chinese hamster ovary assay, the human lymphocyte assay, or the in vivo mouse bone marrow cytogenetics assay. - There was no evidence for effects on fertility in male or female rats treated at oral doses up to approximately 78 times (50 mg/kg/day) the AUC at the MRHD. # Clinical Studies - Enablex extended-release tablets were evaluated for the treatment of patients with overactive bladder with symptoms of urgency, urge urinary incontinence, and increased urinary frequency in three randomized, fixed-dose, placebo-controlled, multicenter, double-blind, 12-week studies (Studies 1, 2 and 3) and one randomized, double-blind, placebo-controlled, multicenter, dose-titration study (Study 4). For study eligibility in all four studies, patients with symptoms of overactive bladder for at least six months were required to demonstrate at least eight micturitions and at least one episode of urinary urgency per day, and at least five episodes of urge urinary incontinence per week. The majority of patients were white (94%) and female (84%), with a mean age of 58 years, range 19 to 93 years. Thirty-three percent of patients were greater than or equal to 65 years of age. These characteristics were well balanced across treatment groups. The study population was inclusive of both naïve patients who had not received prior pharmacotherapy for overactive bladder (60%) and those who had (40%). - Table 4 shows the efficacy data collected from 7- or 14-day voiding diaries in the three fixed-dose placebo-controlled studies of 1,059 patients treated with placebo, 7.5 mg or 15 mg once daily Enablex for 12 weeks. A significant decrease in the primary endpoint, change from baseline in average weekly urge urinary incontinence episodes was observed in all three studies. Data is also shown for two secondary endpoints, change from baseline in the average number of micturitions per day (urinary frequency) and change from baseline in the average volume voided per micturition. - Table 5 shows the efficacy data from the dose-titration study in 395 patients who initially received 7.5 mg Enablex or placebo daily with the option to increase to 15 mg Enablex or placebo daily after two weeks. - As seen in Figures 2 a, 2b and 2c, reductions in the number of urge incontinence episodes per week were observed within the first two weeks in patients treated with Enablex 7.5 mg and 15 mg once daily compared to placebo. Further, these effects were sustained throughout the 12-week treatment period. # How Supplied - Enablex®, 7.5 mg are round, shallow, bi-convex, white-colored tablets, and are identified with “DF” on one side and “7.5” on the reverse. - Bottle of 30........................................................................ NDC 0430-0170-15 - Bottle of 90........................................................................ NDC 0430-0170-23 - Enablex®, 15 mg are round, shallow, bi-convex, light peach-colored tablets, and are identified with “DF” on one side and “15” on the reverse. - Bottle of 30........................................................................ NDC 0430-0171-15 - Bottle of 90........................................................................ NDC 0430-0171-23 - Storage - Store at 25° C (77° F); excursions permitted to 15 to 30° C (59 to 86° F). Protect from light. - Keep this and all drugs out of the reach of children. ## Storage There is limited information regarding Darifenacin Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be informed that anticholinergic agents, such as Enablex, may produce clinically significant adverse effects related to anticholinergic pharmacological activity including constipation, urinary retention and blurred vision. Heat prostration (due to decreased sweating) can occur when anticholinergics such as Enablex are used in a hot environment. Because anticholinergics, such as Enablex, may produce dizziness or blurred vision, patients should be advised to exercise caution in decisions to engage in potentially dangerous activities until the drug’s effects have been determined. Patients should read the patient information leaflet before starting therapy with Enablex. - Patients should be informed that darifenacin may produce clinically significant angioedema that may result in airway obstruction. Patients should be advised to promptly discontinue darifenacin therapy and seek immediate medical attention if they experience edema of the tongue or laryngopharynx, or difficulty breathing. - Enablex extended-release tablets should be taken once daily with water. They may be taken with or without food, and should be swallowed whole and not chewed, divided or crushed. - Read this Patient Information leaflet about Enablex® before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking to your doctor about your medical condition or your treatment. - Enablex is a prescription medicine for adults used to treat the following symptoms due to a condition called overactive bladder: - Urge urinary incontinence: a strong need to urinate with leaking or wetting accidents - Urgency: a strong need to urinate right away - Frequency: urinating often - It is unknown if Enablex is safe and effective in children. - Do not take Enablex if you: - are not able to empty your bladder (“urinary retention”) - have delayed or slow emptying of your stomach (“gastric retention”) - have an eye problem called “uncontrolled narrow-angle glaucoma” - Before starting Enablex, tell your doctor if you: - have trouble emptying your bladder or if you have a weak urine stream - have any stomach or intestinal problems, or problems with constipation - have liver problems - have any other medical conditions - are pregnant or are planning to become pregnant. It is not known if Enablex can harm your unborn baby. - are breastfeeding or plan to breastfeed. It is not known if Enablex passes into breast milk and if it can harm your baby. Talk to your doctor about the best way to feed your baby if you take Enablex. - Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Enablex and certain other medicines may affect each other, causing side effects. - Especially tell your healthcare provider if you take a: - antifungal medicine ketoconazole (Nizoral®) or itraconazole (Sporanox®) - antibiotic medicine clarithromycin (Biaxin®) - anti-HIV medicine ritonavir (Norvir®) or nelfinavir (Viracept®) - medicine to treat depression nefazadone (Serzone®) - medicine to treat an abnormal heartbeat flecainide (Tambocor™) - antipsychotic medicine thioridazine (Mellaril®) - medicine to treat depression called a tricyclic antidepressant - Know all the medicines you take. Keep a list of them with you to show your doctor and pharmacist each time you get a new medicine. - Take Enablex exactly as prescribed. Your doctor will prescribe the dose that is right for you. Take Enablex 1 time daily with water. - Enablex should be swallowed whole. Do not chew, cut or crush Enablex tablet. - Enablex may be taken with or without food. - If you take too much Enablex call your doctor or go to the nearest hospital emergency room right away. - Enablex can cause blurred vision or dizziness. Do not drive or operate heavy machinery until you know how Enablex affects you. - Enablex may cause serious side effects including: - Serious allergic reaction. Stop taking Enablex and get medical help right away if you have: hives, skin rash or swelling severe itching swelling of your face, mouth or tongue trouble breathing - hives, skin rash or swelling - severe itching - swelling of your face, mouth or tongue - trouble breathing - The most common side effects with Enablex are: - constipation - dry mouth - headache - heartburn - nausea - urinary tract infection - blurred vision - heat exhaustion or heat-stroke. This can happen when Enablex is used in hot environments. Symptoms of heat exhaustion may include: decreased sweating dizziness tiredness nausea increase body temperature - decreased sweating - dizziness - tiredness - nausea - increase body temperature - Tell your doctor if you have any side effect that bothers you or that does not go away. - These are not all the possible side effects of Enablex. For more information, ask your doctor or pharmacist. - Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. - Store Enablex at room temperature, between 59° F to 86° F (15° C to 30° C). - Keep Enablex out of the light. - Keep Enablex and all medicines out of the reach of children. - Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Enablex for a condition for which it was not prescribed. Do not give Enablex to other people, even if they have the same symptoms you have. It may harm them. - This Patient Information leaflet summarizes the most important information about Enablex. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Enablex that is written for health professionals. - Active ingredient: darifenacin - Inactive ingredients: dibasic calcium phosphate anhydrous, hypromellose, magnesium stearate, polyethylene glycol, talc, titanium dioxide. - The 15 mg tablet also contains ferric oxide red and ferric oxide yellow. - The brands listed are the trademarks of their respective owners and are not trademarks of Warner Chilcott. # Precautions with Alcohol - Alcohol-Darifenacin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Enablex® # Look-Alike Drug Names There is limited information regarding Darifenacin Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Darifenacin 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 Darifenacin is a muscarinic antagonist that is FDA approved for the {{{indicationType}}} of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency. Common adverse reactions include constipation, dry mouth, headache, dyspepsia, nausea, urinary tract infection, accidental injury, and flu symptoms. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - Enablex (darifenacin) is a muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency. - The recommended starting dose of Enablex is 7.5 mg once daily. Based upon individual response, the dose may be increased to 15 mg once daily, as early as two weeks after starting therapy. - Enablex should be taken once daily with water. Enablex may be taken with or without food, and should be swallowed whole and not chewed, divided or crushed. - For patients with moderate hepatic impairment (Child-Pugh B) or when co-administered with potent CYP3A4 inhibitors (for example, ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin and nefazadone), the daily dose of Enablex should not exceed 7.5 mg. Enablex is not recommended for use in patients with severe hepatic impairment (Child-Pugh C). ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Darifenacin in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Darifenacin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Darifenacin in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Darifenacin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Darifenacin in pediatric patients. # Contraindications - Enablex is contraindicated in patients with, or at risk for, the following conditions: - urinary retention - gastric retention, or - uncontrolled narrow-angle glaucoma. # Warnings ### Precautions - Risk of Urinary Retention - Enablex should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention. - Decreased Gastrointestinal Motility - Enablex should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention. Enablex, like other anticholinergic drugs, may decrease gastrointestinal motility and should be used with caution in patients with conditions such as severe constipation, ulcerative colitis, and myasthenia gravis. - Controlled Narrow-Angle Glaucoma - Enablex should be used with caution in patients being treated for narrow-angle glaucoma and only where the potential benefits outweigh the risks. - Angioedema - Angioedema of the face, lips, tongue, and/or larynx have been reported with darifenacin. In some cases angioedema occurred after the first dose. Angioedema associated with upper airway swelling may be life threatening. If involvement of the tongue, hypopharynx, or larynx occurs, darifenacin should be promptly discontinued and appropriate therapy and/or measures necessary to ensure a patent airway should be promptly provided. - Central Nervous System Effects - Enablex is associated with anticholinergic central nervous system (CNS) effects. A variety of CNS anticholinergic effects have been reported, including headache, confusion, hallucinations and somnolence. Patients should be monitored for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy machinery until they know how Enablex affects them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered. - Patients with Hepatic Impairment - The daily dose of Enablex should not exceed 7.5 mg for patients with moderate hepatic impairment (Child-Pugh B). Enablex has not been studied in patients with severe hepatic impairment (Child-Pugh C) and therefore is not recommended for use in this patient population. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - The safety of Enablex was evaluated in controlled clinical trials in a total of 8,830 patients, 6,001 of whom were treated with Enablex. Of this total, 1,069 patients participated in three, 12-week, randomized, placebo-controlled, fixed-dose efficacy and safety studies (Studies 1, 2 and 3). Of this total, 337 and 334 patients received Enablex 7.5 mg daily and 15 mg daily, respectively. In all long-term trials combined, 1,216 and 672 patients received treatment with Enablex for at least 24 and 52 weeks, respectively. - In Studies 1, 2 and 3 combined, the serious adverse reactions to Enablex were urinary retention and constipation. - In Studies 1, 2 and 3 combined, dry mouth leading to study discontinuation occurred in 0%, 0.9%, and 0% of patients treated with Enablex 7.5 mg daily, Enablex 15 mg daily and placebo, respectively. Constipation leading to study discontinuation occurred in 0.6%, 1.2%, and 0.3% of patients treated with Enablex 7.5 mg daily, Enablex 15 mg daily and placebo, respectively. - Table 1 lists the rates of identified adverse reactions, derived from all reported adverse events in 2% or more of patients treated with 7.5 mg or 15 mg Enablex, and greater than placebo in Studies 1, 2 and 3. In these studies, the most frequently reported adverse reactions were dry mouth and constipation. The majority of the adverse reactions were mild or moderate in severity and most occurred during the first two weeks of treatment. - Other adverse reactions reported by 1% to 2% of Enablex-treated patients include: abnormal vision, accidental injury, back pain, dry skin, flu syndrome, hypertension, vomiting, peripheral edema, weight gain, arthralgia, bronchitis, pharyngitis, rhinitis, sinusitis, rash, pruritus, urinary tract disorder and vaginitis. - Study 4 was a randomized, 12-week, placebo-controlled, dose-titration regimen study in which Enablex was administered in accordance with dosing recommendations. All patients initially received placebo or Enablex 7.5 mg daily, and after two weeks, patients and physicians were allowed to adjust upward to Enablex 15 mg if needed. In this study, the most commonly reported adverse reactions were also constipation and dry mouth. Table 2 lists the identified adverse reactions, derived from all adverse events reported in greater than 3% of patients treated with Enablex and greater than placebo. ## Postmarketing Experience - The following adverse reactions have been reported during post-approval use of Enablex extended-release tablets (darifenacin). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency or establish a causal relationship to drug exposure. - Dermatologic: erythema multiforme, interstitial granuloma annulare - General: hypersensitivity reactions, including angioedema with airway obstruction and anaphylactic reaction - Central Nervous: confusion, hallucinations and somnolence - Cardiovascular: palpitations and syncope # Drug Interactions - CYP3A4 Inhibitors - The systemic exposure of darifenacin from Enablex extended-release tablets is increased in the presence of CYP3A4 inhibitors. The daily dose of Enablex should not exceed 7.5 mg when co-administered with potent CYP3A4 inhibitors (for example, ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin and nefazadone). No dosing adjustments are recommended in the presence of moderate CYP3A4 inhibitors (for example, erythromycin, fluconazole, diltiazem and verapamil). - CYP2D6 Inhibitors - No dosing adjustments are recommended in the presence of CYP2D6 inhibitors (for example, paroxetine, fluoxetine, quinidine and duloxetine). - CYP2D6 Substrates - Caution should be taken when Enablex is used concomitantly with medications that are predominantly metabolized by CYP2D6 and which have a narrow therapeutic window (for example, flecainide, thioridazine and tricyclic antidepressants). - CYP3A4 Substrates - Darifenacin (30 mg daily) did not have a significant impact on midazolam (7.5 mg) pharmacokinetics. - Combination oral contraceptives - Darifenacin (10 mg three times daily) had no effect on the pharmacokinetics of the combination oral contraceptives containing levonorgestrel and ethinyl estradiol. - Warfarin - Darifenacin had no significant effect on prothrombin time when a single dose of warfarin 30 mg was co-administered with darifenacin (30 mg daily) at steady-state. Standard therapeutic prothrombin time monitoring for warfarin should be continued. - Digoxin - Darifenacin (30 mg daily) did not have a clinically relevant effect on the pharmacokinetics of digoxin (0.25 mg) at steady-state. Routine therapeutic drug monitoring for digoxin should be continued. - Other Anticholinergic Agents - The concomitant use of Enablex with other anticholinergic agents may increase the frequency and/or severity of dry mouth, constipation, blurred vision and other anticholinergic pharmacological effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to effects on gastrointestinal motility. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - There are no studies of darifenacin in pregnant women. - Darifenacin was not teratogenic in rats and rabbits at plasma exposures of free drug (via AUC) up to 59 times and 28 times, respectively (doses up to 50 and 30 mg/kg/day, respectively) the maximum recommended human dose [MRHD] of 15 mg. At approximately 59 times the MRHD in rats, there was a delay in the ossification of the sacral and caudal vertebrae which was not observed at approximately 13 times the AUC. Dystocia was observed in dams at approximately 17 times the AUC (10 mg/kg/day). Slight developmental delays were observed in pups at this dose. At five times the AUC (3 mg/kg/day), there were no effects on dams or pups. In rabbits, an exposure approximately 28 times (30 mg/kg/day) the MRHD of darifenacin was shown to increase post-implantation loss, with a no effect level at nine times (10 mg/kg/day) the AUC at the MRHD. Dilated ureter and/or kidney pelvis was also observed in offspring at this dose along with urinary bladder dilation consistent with the pharmacological action of darifenacin, with one case observed at nine times (10 mg/kg/day). No effect was observed at approximately 2.8 times (3 mg/kg/day) the AUC at the MRHD. - Because animal reproduction studies are not always predictive of human response, Enablex should be used during pregnancy only if the benefit to the mother outweighs 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 Darifenacin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Darifenacin during labor and delivery. ### Nursing Mothers - Darifenacin is excreted into the milk of rats. It is not known whether darifenacin is excreted into human milk and therefore caution should be exercised before Enablex is administered to a nursing woman. ### Pediatric Use - The safety and effectiveness of Enablex in pediatric patients have not been established. ### Geriatic Use - In the fixed-dose, placebo-controlled, clinical studies, 30% of patients treated with Enablex were over 65 years of age. No overall differences in safety or efficacy were observed between patients over 65 years (n = 207) and younger patients less than 65 years (n = 464). No dose adjustment is recommended for elderly patients. ### Gender - No dose adjustment is recommended based on gender. ### Race There is no FDA guidance on the use of Darifenacin with respect to specific racial populations. ### Renal Impairment - A study of subjects with varying degrees of renal impairment (creatinine clearance between 10 and 136 mL/min) demonstrated no clear relationship between renal function and darifenacin clearance. No dose adjustment is recommended for patients with renal impairment. ### Hepatic Impairment - Subjects with severe hepatic impairment (Child-Pugh C) have not been studied, therefore Enablex is not recommended for use in these patients. The daily dose of Enablex should not exceed 7.5 mg once daily for patients with moderate hepatic impairment (Child-Pugh B) [see Dosage and Administration (2) and Warnings and Precautions (5.6)]. After adjusting for plasma protein binding, unbound darifenacin exposure was estimated to be 4.7-fold higher in subjects with moderate hepatic impairment than subjects with normal hepatic function. No dose adjustment is recommended for patients with mild hepatic impairment (Child-Pugh A). ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Darifenacin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Darifenacin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Darifenacin in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Darifenacin in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Overdosage with antimuscarinic agents, including Enablex, can result in severe antimuscarinic effects. Enablex has been administered in clinical trials at doses up to 75 mg (five times the maximum therapeutic dose) and signs of overdose were limited to abnormal vision. ### Management - Treatment should be symptomatic and supportive. In the event of overdosage,ECG monitoring is recommended. ## Chronic Overdose There is limited information regarding Chronic Overdose of Darifenacin in the drug label. # Pharmacology ## Mechanism of Action - Darifenacin is a competitive muscarinic receptor antagonist. Muscarinic receptors play an important role in several major cholinergically mediated functions, including contractions of the urinary bladder smooth muscle and stimulation of salivary secretion. - In vitro studies using human recombinantmuscarinic receptor subtypes show that darifenacin has greater affinity for the M3 receptor than for the other known muscarinic receptors (9- and 12-fold greater affinity for M3 compared to M1 and M5, respectively, and 59-fold greater affinity for M3 compared to both M2 and M4). M3 receptors are involved in contraction of human bladder and gastrointestinal smooth muscle, saliva production, and iris sphincter function. Adverse drug effects such as dry mouth, constipation and abnormal vision may be mediated through effects on M3 receptors in these organs. ## Structure - Enablex is an extended-release tablet for oral administration which contains 7.5 mg or 15 mg darifenacin as its hydrobromide salt. The active moiety, darifenacin, is a potent muscarinic receptor antagonist. - Chemically, darifenacin hydrobromide is (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide hydrobromide. The empirical formula of darifenacin hydrobromide is C28H30N2O2•HBr. - The structural formula is: - Darifenacin hydrobromide is a white to almost white, crystalline powder, with a molecular weight of 507.5. - Enablex is a once-a-day extended-release tablet and contains the following inactive ingredients: dibasic calcium phosphate anhydrous, hypromellose, magnesium stearate, polyethylene glycol, talc, titanium dioxide. The 15 mg tablet also contains ferric oxide red and ferric oxide yellow. ## Pharmacodynamics - In three cystometric studies performed in patients with involuntary detrusor contractions, increased bladder capacity was demonstrated by an increased volume threshold for unstable contractions and diminished frequency of unstable detrusor contractions after Enablex treatment. These findings are consistent with an antimuscarinic action on the urinary bladder. - Electrophysiology - The effect of a six-day treatment of 15 mg and 75 mg Enablex on QT/QTc interval was evaluated in a multiple-dose, double-blind, randomized, placebo- and active-controlled (moxifloxacin 400 mg) parallel-arm design study in 179 healthy adults (44% male, 56% female) aged 18 to 65. Subjects included 18% poor metabolizers (PMs) and 82% extensive metabolizers (EMs). The QT interval was measured over a 24-hour period both predosing and at steady-state. The 75 mg Enablex dose was chosen because this achieves exposure similar to that observed in CYP2D6 poor metabolizers administered the highest recommended dose (15 mg) of darifenacin in the presence of a potent CYP3A4 inhibitor. At the doses studied, Enablex did not result in QT/QTc interval prolongation at any time during the steady-state, while moxifloxacin treatment resulted in a mean increase from baseline QTcF of about 7.0 msec when compared to placebo. In this study, darifenacin 15 mg and 75 mg doses demonstrated a mean heart rate change of 3.1 and 1.3 bpm, respectively, when compared to placebo. However, in the clinical efficacy and safety studies, the change in median HR following treatment with Enablex was no different from placebo. ## Pharmacokinetics - Absorption - After oral administration of Enablex to healthy volunteers, peak plasma concentrations of darifenacin are reached approximately seven hours after multiple dosing and steady-state plasma concentrations are achieved by the sixth day of dosing. The mean (SD) steady-state time course of Enablex 7.5 mg and 15 mg extended-release tablets is depicted in Figure 1. - A summary of mean (standard deviation, SD) steady-state pharmacokinetic parameters of Enablex 7.5 mg and 15 mg extended-release tablets in EMs and PMs of CYP2D6 is provided in Table 3. - The mean oral bioavailability of Enablex in EMs at steady-state is estimated to be 15% and 19% for 7.5 mg and 15 mg tablets, respectively. - Effect of Food - Following single dose administration of Enablex with food, the AUC of darifenacin was not affected, while the Cmax was increased by 22% and Tmax was shortened by 3.3 hours. There is no effect of food on multiple-dose pharmacokinetics from Enablex. - Distribution - Darifenacin is approximately 98% bound to plasma proteins (primarily to alpha-1-acid-glycoprotein). The steady-state volume of distribution (Vss) is estimated to be 163 L. - Metabolism - Darifenacin is extensively metabolized by the liver following oral dosing. - Metabolism is mediated by cytochrome P450 enzymes CYP2D6 and CYP3A4. The three main metabolic routes are as follows: monohydroxylation in the dihydrobenzofuran ring; dihydrobenzofuran ring opening; N-dealkylation of the pyrrolidine nitrogen. - monohydroxylation in the dihydrobenzofuran ring; - dihydrobenzofuran ring opening; - N-dealkylation of the pyrrolidine nitrogen. - The initial products of the hydroxylation and N-dealkylation pathways are the major circulating metabolites but they are unlikely to contribute significantly to the overall clinical effect of darifenacin. - Variability in Metabolism - A subset of individuals (approximately 7% Caucasians and 2% African Americans) are poor metabolizers (PMs) of CYP2D6 metabolized drugs. Individuals with normal CYP2D6 activity are referred to as extensive metabolizers (EMs). The metabolism of darifenacin in PMs will be principally mediated via CYP3A4. The darifenacin ratios (PM versus EM) for Cmax and AUC following darifenacin 15 mg once daily at steady-state were 1.9 and 1.7, respectively. - Excretion - Following administration of an oral dose of 14C-darifenacin solution to healthy volunteers, approximately 60% of the radioactivity was recovered in the urine and 40% in the feces. Only a small percentage of the excreted dose was unchanged darifenacin (3%). Estimated darifenacin clearance is 40 L/h for EMs and 32 L/h for PMs. The elimination half-life of darifenacin following chronic dosing is approximately 13 to 19 hours. - Drug-Drug Interactions - Effects of Other Drugs on Darifenacin - Darifenacin metabolism is primarily mediated by the cytochrome P450 enzymes CYP2D6 and CYP3A4. Therefore, inducers of CYP3A4 or inhibitors of either of these enzymes may alter darifenacin pharmacokinetics. - CYP3A4 Inhibitors: In a drug interaction study, when a 7.5 mg once daily dose of Enablex was given to steady-state and co-administered with the potent CYP3A4 inhibitor ketoconazole 400 mg, mean darifenacin Cmax increased to 11.2 ng/mL for EMs (n = 10) and 55.4 ng/mL for one PM subject (n = 1). Mean AUC increased to 143 and 939 ng•h/mL for EMs and for one PM subject, respectively. When a 15 mg daily dose of Enablex was given with ketoconazole, mean darifenacin Cmax increased to 67.6 ng/mL and 58.9 ng/mL for EMs (n = 3) and one PM subject (n = 1), respectively. Mean AUC increased to 1110 and 931 ng•h/mL for EMs and for one PM subject, respectively. - The mean Cmax and AUC of darifenacin following 30 mg once daily dosing at steady-state were 128% and 95% higher, respectively, in the presence of a moderate CYP3A4 inhibitor, erythromycin. Co-administration of fluconazole, a moderate CYP3A4 inhibitor and darifenacin 30 mg once daily at steady-state increased darifenacin Cmax and AUC by 88% and 84%, respectively. - The mean Cmax and AUC of darifenacin following 30 mg once daily at steady-state were 42% and 34% higher, respectively, in the presence of cimetidine, a mixed CYP P450 enzyme inhibitor. - CYP2D6 Inhibitors: Darifenacin exposure following 30 mg once daily at steady-state was 33% higher in the presence of the potent CYP2D6 inhibitor paroxetine 20 mg. - Effects of Darifenacin on Other Drugs - In Vitro Studies: Based on in vitro human microsomal studies, Enablex is not expected to inhibit CYP1A2 or CYP2C9 at clinically relevant concentrations. - In Vivo Studies: The potential for clinical doses of Enablex to act as inhibitors of CYP2D6 or CYP3A4 substrates was investigated in specific drug interaction studies. - CYP2D6 Substrates: The mean Cmax and AUC of imipramine, a CYP2D6 substrate, were increased by 57% and 70%, respectively, in the presence of steady-state darifenacin 30 mg once daily. The mean Cmax and AUC of desipramine, the active metabolite of imipramine, were increased by 260%. - CYP3A4 Substrates: Darifenacin (30 mg daily) co-administered with a single oral dose of midazolam 7.5 mg resulted in a 17% increase in midazolam exposure. - Combination Oral Contraceptives: Darifenacin (10 mg three times daily) had no effect on the pharmacokinetics of a combination oral contraceptive containing levonorgestrel (0.15 mg) and ethinyl estradiol (0.03 mg). - Warfarin: Darifenacin had no significant effect on prothrombin time when a single dose of warfarin 30 mg was co-administered with darifenacin (30 mg daily) at steady-state]. - Digoxin: Darifenacin (30 mg daily) co-administered with digoxin (0.25 mg) at steady-state resulted in a 16% increase in digoxin exposure. - Pharmacokinetics in Special Populations - Age: A population pharmacokinetic analysis of patient data indicated a trend for clearance of darifenacin to decrease with age (6% per decade relative to a median age of 44). Following administration of Enablex 15 mg once daily, darifenacin exposure at steady-state was approximately 12% to 19% higher in volunteers between 45 and 65 years of age compared to younger volunteers aged 18 to 44 years. - Pediatric: The pharmacokinetics of Enablex has not been studied in the pediatric population. - Gender: PK parameters were calculated for 22 male and 25 female healthy volunteers. Darifenacin Cmax and AUC at steady-state were approximately 57% to 79% and 61% to 73% higher in females than in males, respectively. - Renal Impairment: A study of subjects with varying degrees of renal impairment (creatinine clearance between 10 and 136 mL/min) given Enablex 15 mg once daily to steady-state demonstrated no clear relationship between renal function and darifenacin clearance. - Hepatic Impairment: Enablex pharmacokinetics were investigated in subjects with mild (Child-Pugh A) or moderate (Child-Pugh B) impairment of hepatic function given Enablex 15 mg once daily to steady-state. Mild hepatic impairment had no effect on the pharmacokinetics of darifenacin. However, protein binding of darifenacin was affected by moderate hepatic impairment. After adjusting for plasma protein binding, unbound darifenacin exposure was estimated to be 4.7-fold higher in subjects with moderate hepatic impairment than subjects with normal hepatic function. Subjects with severe hepatic impairment (Child-Pugh C) have not been studied. ## Nonclinical Toxicology - Carcinogenicity studies with darifenacin were conducted in mice and rats. No evidence of drug-related carcinogenicity was revealed in a 24-month study in mice at dietary doses up to 100 mg/kg/day or approximately 32 times the estimated free plasma AUC reached at the maximum recommended human dose (the AUC at the MRHD) of 15 mg and in a 24-month study in rats at doses up to 15 mg/kg/day or up to approximately 12 times the AUC at the MRHD in female rats and approximately eight times the AUC at the MRHD in male rats. - Darifenacin was not genotoxic in the bacterial mutation assay (Ames test), the Chinese hamster ovary assay, the human lymphocyte assay, or the in vivo mouse bone marrow cytogenetics assay. - There was no evidence for effects on fertility in male or female rats treated at oral doses up to approximately 78 times (50 mg/kg/day) the AUC at the MRHD. # Clinical Studies - Enablex extended-release tablets were evaluated for the treatment of patients with overactive bladder with symptoms of urgency, urge urinary incontinence, and increased urinary frequency in three randomized, fixed-dose, placebo-controlled, multicenter, double-blind, 12-week studies (Studies 1, 2 and 3) and one randomized, double-blind, placebo-controlled, multicenter, dose-titration study (Study 4). For study eligibility in all four studies, patients with symptoms of overactive bladder for at least six months were required to demonstrate at least eight micturitions and at least one episode of urinary urgency per day, and at least five episodes of urge urinary incontinence per week. The majority of patients were white (94%) and female (84%), with a mean age of 58 years, range 19 to 93 years. Thirty-three percent of patients were greater than or equal to 65 years of age. These characteristics were well balanced across treatment groups. The study population was inclusive of both naïve patients who had not received prior pharmacotherapy for overactive bladder (60%) and those who had (40%). - Table 4 shows the efficacy data collected from 7- or 14-day voiding diaries in the three fixed-dose placebo-controlled studies of 1,059 patients treated with placebo, 7.5 mg or 15 mg once daily Enablex for 12 weeks. A significant decrease in the primary endpoint, change from baseline in average weekly urge urinary incontinence episodes was observed in all three studies. Data is also shown for two secondary endpoints, change from baseline in the average number of micturitions per day (urinary frequency) and change from baseline in the average volume voided per micturition. - Table 5 shows the efficacy data from the dose-titration study in 395 patients who initially received 7.5 mg Enablex or placebo daily with the option to increase to 15 mg Enablex or placebo daily after two weeks. - As seen in Figures 2 a, 2b and 2c, reductions in the number of urge incontinence episodes per week were observed within the first two weeks in patients treated with Enablex 7.5 mg and 15 mg once daily compared to placebo. Further, these effects were sustained throughout the 12-week treatment period. # How Supplied - Enablex®, 7.5 mg are round, shallow, bi-convex, white-colored tablets, and are identified with “DF” on one side and “7.5” on the reverse. - Bottle of 30........................................................................ NDC 0430-0170-15 - Bottle of 90........................................................................ NDC 0430-0170-23 - Enablex®, 15 mg are round, shallow, bi-convex, light peach-colored tablets, and are identified with “DF” on one side and “15” on the reverse. - Bottle of 30........................................................................ NDC 0430-0171-15 - Bottle of 90........................................................................ NDC 0430-0171-23 - Storage - Store at 25° C (77° F); excursions permitted to 15 to 30° C (59 to 86° F). Protect from light. - Keep this and all drugs out of the reach of children. ## Storage There is limited information regarding Darifenacin Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be informed that anticholinergic agents, such as Enablex, may produce clinically significant adverse effects related to anticholinergic pharmacological activity including constipation, urinary retention and blurred vision. Heat prostration (due to decreased sweating) can occur when anticholinergics such as Enablex are used in a hot environment. Because anticholinergics, such as Enablex, may produce dizziness or blurred vision, patients should be advised to exercise caution in decisions to engage in potentially dangerous activities until the drug’s effects have been determined. Patients should read the patient information leaflet before starting therapy with Enablex. - Patients should be informed that darifenacin may produce clinically significant angioedema that may result in airway obstruction. Patients should be advised to promptly discontinue darifenacin therapy and seek immediate medical attention if they experience edema of the tongue or laryngopharynx, or difficulty breathing. - Enablex extended-release tablets should be taken once daily with water. They may be taken with or without food, and should be swallowed whole and not chewed, divided or crushed. - Read this Patient Information leaflet about Enablex® before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking to your doctor about your medical condition or your treatment. - Enablex is a prescription medicine for adults used to treat the following symptoms due to a condition called overactive bladder: - Urge urinary incontinence: a strong need to urinate with leaking or wetting accidents - Urgency: a strong need to urinate right away - Frequency: urinating often - It is unknown if Enablex is safe and effective in children. - Do not take Enablex if you: - are not able to empty your bladder (“urinary retention”) - have delayed or slow emptying of your stomach (“gastric retention”) - have an eye problem called “uncontrolled narrow-angle glaucoma” - Before starting Enablex, tell your doctor if you: - have trouble emptying your bladder or if you have a weak urine stream - have any stomach or intestinal problems, or problems with constipation - have liver problems - have any other medical conditions - are pregnant or are planning to become pregnant. It is not known if Enablex can harm your unborn baby. - are breastfeeding or plan to breastfeed. It is not known if Enablex passes into breast milk and if it can harm your baby. Talk to your doctor about the best way to feed your baby if you take Enablex. - Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Enablex and certain other medicines may affect each other, causing side effects. - Especially tell your healthcare provider if you take a: - antifungal medicine ketoconazole (Nizoral®) or itraconazole (Sporanox®) - antibiotic medicine clarithromycin (Biaxin®) - anti-HIV medicine ritonavir (Norvir®) or nelfinavir (Viracept®) - medicine to treat depression nefazadone (Serzone®) - medicine to treat an abnormal heartbeat flecainide (Tambocor™) - antipsychotic medicine thioridazine (Mellaril®) - medicine to treat depression called a tricyclic antidepressant - Know all the medicines you take. Keep a list of them with you to show your doctor and pharmacist each time you get a new medicine. - Take Enablex exactly as prescribed. Your doctor will prescribe the dose that is right for you. Take Enablex 1 time daily with water. - Enablex should be swallowed whole. Do not chew, cut or crush Enablex tablet. - Enablex may be taken with or without food. - If you take too much Enablex call your doctor or go to the nearest hospital emergency room right away. - Enablex can cause blurred vision or dizziness. Do not drive or operate heavy machinery until you know how Enablex affects you. - Enablex may cause serious side effects including: - Serious allergic reaction. Stop taking Enablex and get medical help right away if you have: hives, skin rash or swelling severe itching swelling of your face, mouth or tongue trouble breathing - hives, skin rash or swelling - severe itching - swelling of your face, mouth or tongue - trouble breathing - The most common side effects with Enablex are: - constipation - dry mouth - headache - heartburn - nausea - urinary tract infection - blurred vision - heat exhaustion or heat-stroke. This can happen when Enablex is used in hot environments. Symptoms of heat exhaustion may include: decreased sweating dizziness tiredness nausea increase body temperature - decreased sweating - dizziness - tiredness - nausea - increase body temperature - Tell your doctor if you have any side effect that bothers you or that does not go away. - These are not all the possible side effects of Enablex. For more information, ask your doctor or pharmacist. - Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. - Store Enablex at room temperature, between 59° F to 86° F (15° C to 30° C). - Keep Enablex out of the light. - Keep Enablex and all medicines out of the reach of children. - Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Enablex for a condition for which it was not prescribed. Do not give Enablex to other people, even if they have the same symptoms you have. It may harm them. - This Patient Information leaflet summarizes the most important information about Enablex. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Enablex that is written for health professionals. - Active ingredient: darifenacin - Inactive ingredients: dibasic calcium phosphate anhydrous, hypromellose, magnesium stearate, polyethylene glycol, talc, titanium dioxide. - The 15 mg tablet also contains ferric oxide red and ferric oxide yellow. - The brands listed are the trademarks of their respective owners and are not trademarks of Warner Chilcott. # Precautions with Alcohol - Alcohol-Darifenacin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Enablex®[1] # Look-Alike Drug Names There is limited information regarding Darifenacin Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Darifenacin
a31d7de85f08cf280673d2632b34c283f9cb0edf	wikidoc	Data mining	Data mining Data mining can be defined as "the nontrivial extraction of implicit, previously unknown, and potentially useful information from data". Data mining may also be defined as "the science of extracting useful information from large data sets or databases". Data mining is the principle of sorting through large amounts of data and picking out relevant information. It is usually used by business intelligence organizations, and financial analysts, but it is increasingly used in the sciences to extract information from the enormous data sets generated by modern experimental and observational methods. # Discussion Metadata, or data about a given data set, are often expressed in a condensed data mine-able format, or one that facilitates the practice of data mining. Common examples include executive summaries and scientific abstracts. Although data mining is a relatively new term, the technology is not. Companies for a long time have used powerful computers to sift through volumes of data such as supermarket scanner data to produce market research reports. Continuous innovations in computer processing power, disk storage, and statistical software are dramatically increasing the accuracy and usefulness of analysis. Data mining identifies trends within data that go beyond simple analysis. Through the use of sophisticated algorithms, users have the ability to identify key attributes of business processes and target opportunities. The term data mining is often used to apply to the two separate processes of knowledge discovery and prediction. Knowledge discovery provides explicit information that has a readable form and can be understood by a user. Forecasting, or predictive modeling provides predictions of future events and may be transparent and readable in some approaches (e.g. rule based systems) and opaque in others such as neural networks. Moreover, some data mining systems such as neural networks are inherently geared towards prediction and pattern recognition, rather than knowledge discovery. # Misuse of the term The term "data mining" is often used incorrectly to apply to a variety of unrelated processes. In many cases, applications may claim to perform "data mining" by automating the creation of charts or graphs with historic trends and analysis. Although this information may be useful and timesaving, it does not fit the traditional definition of data mining, as the application performs no analysis itself and has no understanding of the underlying data. Instead, it relies on templates or pre-defined macros (created either by programmers or users) to identify trends, patterns and differences. A key defining factor for true data mining is that the application itself is performing some real analysis. In almost all cases, this analysis is guided by some degree of user interaction, but it must provide the user some insights that are not readily apparent through simple slicing and dicing. Applications that are not to some degree self-guiding are performing data analysis not data mining. # Related terms Although the term "data mining" is usually used in relation to analysis of data, like artificial intelligence, it is an umbrella term with varied meanings in a wide range of contexts. Unlike data analysis, data mining is not based or focused on an existing model which is to be tested or whose parameters are to be optimized. A promising application of Knowledge discovery is in the area of software modernization which involves understanding existing software artifacts. Usually the knowledge obtained from existing software is presented in the form of models to which specific queries can be made when necessary. An entity-relationship model is a common way to represent knowledge obtained from existing software. The Object Management Group (OMG) developed the Knowledge Discovery Metamodel (KDM), which defines an ontology for software assets and their relationships, for the purpose of performing knowledge discovery of existing code. Knowledge discovery from existing software systems, also known as software mining is closely related to data mining, since existing software artifacts contain enormous business value, key for the evolution of software systems. Knowledge Discovery from software systems addresses structure and behavior as well as the data processed by the software system. Instead of mining individual data sets, software mining focuses on metadata, such as database schemas. The OMG Knowledge Discovery Metamodel provides an integrated representation for capturing application metadata as part of a holistic existing system metamodel. Another OMG specification, the Common Warehouse Metamodel focuses entirely on mining enterprise metadata. In statistical analysis where there is no underlying theoretical model, data mining is often approximated via stepwise regression methods wherein the space of 2k possible relationships between a single outcome variable and k potential explanatory variables is smartly searched. With the advent of parallel computing, it became possible (when k is less than approximately 40) to examine all 2k models. This procedure is called all subsets or exhaustive regression. Some of the first applications of exhaustive regression involved the study of plant data. # Data dredging Data dredging or data fishing are terms one may use to criticize someone's data mining efforts when it is felt the patterns or causal relationships discovered are unfounded. In this case the pattern suffers of overfitting on the training data. Data dredging is the scanning of the data for any relationships, and then when one is found coming up with an interesting explanation. The conclusions may be suspect because data sets with large numbers of variables have by chance some "interesting" relationships. Fred Schwed said: Nevertheless, determining correlations in investment analysis has proven to be very profitable for statistical arbitrage operations (such as pairs trading strategies), and correlation analysis has shown to be very useful in risk management. Indeed, finding correlations in the financial markets, when done properly, is not the same as finding false patterns in roulette wheels. Some exploratory data work is always required in any applied statistical analysis to get a feel for the data, so sometimes the line between good statistical practice and data dredging is less than clear. Most data mining efforts are focused on developing highly detailed models of some large data set. Other researchers have described an alternate method that involves finding the minimal differences between elements in a data set, with the goal of developing simpler models that represent relevant data. When data sets contain a big set of variables, the level of statistical significance should be proportional to the patterns that were tested. For example, if we test 100 random patterns, it is expected that one of them will be "interesting" with a statistical significance at the 0.01 level. Cross validation is a common approach to evaluating the fitness of a model generated via data mining, where the data are divided into a training subset and a test subset to respectively build and then test the model. Common cross validation techniques include the holdout method, k-fold cross validation, and the leave-one-out method. # Privacy concerns There are also privacy concerns associated with data mining - specifically regarding the source of the data analyzed. Data mining government or commercial data sets for national security or law enforcement purposes has also raised privacy concerns. There are many legitimate uses of data mining. For example, a database of prescription drugs taken by a group of people could be used to find combinations of drugs exhibiting harmful interactions. Since any particular combination may occur in only 1 out of 1000 people, a great deal of data would need to be examined to discover such an interaction. A project involving pharmacies could reduce the number of drug reactions and potentially save lives. Unfortunately, there is also a huge potential for abuse of such a database. Essentially, data mining gives information that would not be available otherwise. It must be properly interpreted to be useful. When the data collected involves individual people, there are many questions concerning privacy, legality, and ethics. # Combinatorial game data mining - Data mining from combinatorial game oracles: Since the early 1960s, with the availability of oracles for certain combinatorial games, also called tablebases (e.g. for 3x3-chess) with any beginning configuration, small-board dots-and-boxes, small-board-hex, and certain endgames in chess, dots-and-boxes, and hex; a new area for data mining has been opened up. This is the extraction of human-usable strategies from these oracles. Current pattern recognition approaches do not seem to fully have the required high level of abstraction in order to be applied successfully. Instead, extensive experimentation with the tablebases combined with an intensive study of tablebase-answers to well designed problems and with knowledge of prior art i.e. pre-tablebase knowledge is used to yield insightful patterns. Berlekamp in dots-and-boxes etc. and John Nunn in chess endgames are notable examples of researchers doing this work, though they were not and are not involved in tablebase generation. # Notable uses of data mining - Data mining has been cited as the method by which the U.S. Army unit Able Danger supposedly had identified the September 11, 2001 attacks leader, Mohamed Atta, and three other 9/11 hijackers as possible members of an al Qaeda cell operating in the U.S. more than a year before the attack. See also: Able Danger, wikinews:U.S. Army intelligence had detected 9/11 terrorists year before, says officer. It has been suggested that both the Central Intelligence Agency and their Canadian counterparts, Canadian Security Intelligence Service, have put this method of interpreting data to work for them as well, although they have not said how. - See also: Able Danger, wikinews:U.S. Army intelligence had detected 9/11 terrorists year before, says officer. - It has been suggested that both the Central Intelligence Agency and their Canadian counterparts, Canadian Security Intelligence Service, have put this method of interpreting data to work for them as well, although they have not said how. # Example An example of data mining, often called the Market Basket Analysis, relates to its use in retail sales. If a clothing store records the purchases of customers, a data mining system could identify those customers who favour silk shirts over cotton ones. Although some explanations of relationships may be difficult, taking advantage of it is easier. The example deals with association rules within transaction-based data. Not all data are transaction based and logical or inexact rules may also be present within a database. In a manufacturing application, an inexact rule may state that 73% of products which have a specific defect or problem, will develop a secondary problem within the next 6 months.	Data mining Template:Cleanup Template:Cleanup-laundry Data mining can be defined as "the nontrivial extraction of implicit, previously unknown, and potentially useful information from data".[1] Data mining may also be defined as "the science of extracting useful information from large data sets or databases".[2] Data mining is the principle of sorting through large amounts of data and picking out relevant information. It is usually used by business intelligence organizations, and financial analysts, but it is increasingly used in the sciences to extract information from the enormous data sets generated by modern experimental and observational methods.[citation needed] # Discussion Template:Wiktionarypar Metadata, or data about a given data set, are often expressed in a condensed data mine-able format, or one that facilitates the practice of data mining. Common examples include executive summaries and scientific abstracts. Although data mining is a relatively new term, the technology is not. Companies for a long time have used powerful computers to sift through volumes of data such as supermarket scanner data to produce market research reports. Continuous innovations in computer processing power, disk storage, and statistical software are dramatically increasing the accuracy and usefulness of analysis. Data mining identifies trends within data that go beyond simple analysis. Through the use of sophisticated algorithms, users have the ability to identify key attributes of business processes and target opportunities. The term data mining is often used to apply to the two separate processes of knowledge discovery and prediction. Knowledge discovery provides explicit information that has a readable form and can be understood by a user. Forecasting, or predictive modeling provides predictions of future events and may be transparent and readable in some approaches (e.g. rule based systems) and opaque in others such as neural networks. Moreover, some data mining systems such as neural networks are inherently geared towards prediction and pattern recognition, rather than knowledge discovery. # Misuse of the term The term "data mining" is often used incorrectly to apply to a variety of unrelated processes. In many cases, applications may claim to perform "data mining" by automating the creation of charts or graphs with historic trends and analysis. Although this information may be useful and timesaving, it does not fit the traditional definition of data mining, as the application performs no analysis itself and has no understanding of the underlying data. Instead, it relies on templates or pre-defined macros (created either by programmers or users) to identify trends, patterns and differences. A key defining factor for true data mining is that the application itself is performing some real analysis. In almost all cases, this analysis is guided by some degree of user interaction, but it must provide the user some insights that are not readily apparent through simple slicing and dicing. Applications that are not to some degree self-guiding are performing data analysis not data mining. # Related terms Although the term "data mining" is usually used in relation to analysis of data, like artificial intelligence, it is an umbrella term with varied meanings in a wide range of contexts. Unlike data analysis, data mining is not based or focused on an existing model which is to be tested or whose parameters are to be optimized. A promising application of Knowledge discovery is in the area of software modernization which involves understanding existing software artifacts. Usually the knowledge obtained from existing software is presented in the form of models to which specific queries can be made when necessary. An entity-relationship model is a common way to represent knowledge obtained from existing software. The Object Management Group (OMG) developed the Knowledge Discovery Metamodel (KDM), which defines an ontology for software assets and their relationships, for the purpose of performing knowledge discovery of existing code. Knowledge discovery from existing software systems, also known as software mining is closely related to data mining, since existing software artifacts contain enormous business value, key for the evolution of software systems. Knowledge Discovery from software systems addresses structure and behavior as well as the data processed by the software system. Instead of mining individual data sets, software mining focuses on metadata, such as database schemas. The OMG Knowledge Discovery Metamodel provides an integrated representation for capturing application metadata as part of a holistic existing system metamodel. Another OMG specification, the Common Warehouse Metamodel focuses entirely on mining enterprise metadata. In statistical analysis where there is no underlying theoretical model, data mining is often approximated via stepwise regression methods wherein the space of 2k possible relationships between a single outcome variable and k potential explanatory variables is smartly searched. With the advent of parallel computing, it became possible (when k is less than approximately 40) to examine all 2k models. This procedure is called all subsets or exhaustive regression. Some of the first applications of exhaustive regression involved the study of plant data.[3] # Data dredging Data dredging or data fishing are terms one may use to criticize someone's data mining efforts when it is felt the patterns or causal relationships discovered are unfounded. In this case the pattern suffers of overfitting on the training data. Data dredging is the scanning of the data for any relationships, and then when one is found coming up with an interesting explanation. The conclusions may be suspect because data sets with large numbers of variables have by chance some "interesting" relationships. Fred Schwed [4] said: Nevertheless, determining correlations in investment analysis has proven to be very profitable for statistical arbitrage operations (such as pairs trading strategies), and correlation analysis has shown to be very useful in risk management. Indeed, finding correlations in the financial markets, when done properly, is not the same as finding false patterns in roulette wheels. Some exploratory data work is always required in any applied statistical analysis to get a feel for the data, so sometimes the line between good statistical practice and data dredging is less than clear. Most data mining efforts are focused on developing highly detailed models of some large data set. Other researchers have described an alternate method that involves finding the minimal differences between elements in a data set, with the goal of developing simpler models that represent relevant data. [5] When data sets contain a big set of variables, the level of statistical significance should be proportional to the patterns that were tested. For example, if we test 100 random patterns, it is expected that one of them will be "interesting" with a statistical significance at the 0.01 level. Cross validation is a common approach to evaluating the fitness of a model generated via data mining, where the data are divided into a training subset and a test subset to respectively build and then test the model. Common cross validation techniques include the holdout method, k-fold cross validation, and the leave-one-out method. # Privacy concerns There are also privacy concerns associated with data mining - specifically regarding the source of the data analyzed. Data mining government or commercial data sets for national security or law enforcement purposes has also raised privacy concerns. [6] There are many legitimate uses of data mining. For example, a database of prescription drugs taken by a group of people could be used to find combinations of drugs exhibiting harmful interactions. Since any particular combination may occur in only 1 out of 1000 people, a great deal of data would need to be examined to discover such an interaction. A project involving pharmacies could reduce the number of drug reactions and potentially save lives. Unfortunately, there is also a huge potential for abuse of such a database. Essentially, data mining gives information that would not be available otherwise. It must be properly interpreted to be useful. When the data collected involves individual people, there are many questions concerning privacy, legality, and ethics.[7] # Combinatorial game data mining - Data mining from combinatorial game oracles: Since the early 1960s, with the availability of oracles for certain combinatorial games, also called tablebases (e.g. for 3x3-chess) with any beginning configuration, small-board dots-and-boxes, small-board-hex, and certain endgames in chess, dots-and-boxes, and hex; a new area for data mining has been opened up. This is the extraction of human-usable strategies from these oracles. Current pattern recognition approaches do not seem to fully have the required high level of abstraction in order to be applied successfully. Instead, extensive experimentation with the tablebases combined with an intensive study of tablebase-answers to well designed problems and with knowledge of prior art i.e. pre-tablebase knowledge is used to yield insightful patterns. Berlekamp in dots-and-boxes etc. and John Nunn in chess endgames are notable examples of researchers doing this work, though they were not and are not involved in tablebase generation. # Notable uses of data mining - Data mining has been cited as the method by which the U.S. Army unit Able Danger supposedly had identified the September 11, 2001 attacks leader, Mohamed Atta, and three other 9/11 hijackers as possible members of an al Qaeda cell operating in the U.S. more than a year before the attack. See also: Able Danger, wikinews:U.S. Army intelligence had detected 9/11 terrorists year before, says officer. It has been suggested that both the Central Intelligence Agency and their Canadian counterparts, Canadian Security Intelligence Service, have put this method of interpreting data to work for them as well[8], although they have not said how. - See also: Able Danger, wikinews:U.S. Army intelligence had detected 9/11 terrorists year before, says officer. - It has been suggested that both the Central Intelligence Agency and their Canadian counterparts, Canadian Security Intelligence Service, have put this method of interpreting data to work for them as well[8], although they have not said how. # Example An example of data mining, often called the Market Basket Analysis, relates to its use in retail sales. If a clothing store records the purchases of customers, a data mining system could identify those customers who favour silk shirts over cotton ones. Although some explanations of relationships may be difficult, taking advantage of it is easier. The example deals with association rules within transaction-based data. Not all data are transaction based and logical or inexact rules may also be present within a database. In a manufacturing application, an inexact rule may state that 73% of products which have a specific defect or problem, will develop a secondary problem within the next 6 months.	https://www.wikidoc.org/index.php/Data_mining
ff937e4463d34d33773b38add78e2bd2bf30848c	wikidoc	Haptoglobin	Haptoglobin Haptoglobin (abbreviated as Hp) is the protein that in humans is encoded by the HP gene. In blood plasma, haptoglobin binds free hemoglobin (Hb) released from erythrocytes with high affinity and thereby inhibits its oxidative activity. The haptoglobin-hemoglobin complex will then be removed by the reticuloendothelial system (mostly the spleen). In clinical settings, the haptoglobulin assay is used to screen for and monitor intravascular hemolytic anemia. In intravascular hemolysis, free hemoglobin will be released into circulation and hence haptoglobin will bind the hemoglobin. This causes a decline in haptoglobin levels. Conversely, in extravascular hemolysis the reticuloendothelial system, especially splenic monocytes, phagocytose the erythrocytes and hemoglobin is relatively not released into circulation; however, excess hemolysis can release some hemoglobin causing haptoglobin levels to be decreased. Therefore, haptoglobin is not a reliable way to differentiate between intravascular and extravascular hemolysis. # Function This gene encodes a preproprotein that is processed to yield both alpha and beta chains, which subsequently combines as a tetramer to produce haptoglobin. Haptoglobin functions to bind free plasma hemoglobin, which allows degradative enzymes to gain access to the hemoglobin while at the same time preventing loss of iron through the kidneys and protecting the kidneys from damage by hemoglobin. For this reason, it is often referred to as the suicide protein. # Synthesis Haptoglobin is produced mostly by hepatic cells but also by other tissues such as skin, lung and kidney. In addition, the haptoglobin gene is expressed in murine and human adipose tissue. Haptoglobin had been shown to be expressed in adipose tissue of cattle as well. # Structure Haptoglobin, in its simplest form, consists of two alpha and two beta chains, connected by disulfide bridges. The chains originate from a common precursor protein, which is proteolytically cleaved during protein synthesis. Hp exists in two allelic forms in the human population, so-called Hp1 and Hp2, the latter one having arisen due to the partial duplication of Hp1 gene. Three genotypes of Hp, therefore, are found in humans: Hp1-1, Hp2-1, and Hp2-2. Hp of different genotypes have been shown to bind hemoglobin with different affinities, with Hp2-2 being the weakest binder. # In other species Hp has been found in all mammals studied so far, some birds, e.g., cormorant and ostrich but also, in its simpler form, in bony fish, e.g., zebrafish. Hp is absent in at least some amphibians (Xenopus) and neognathous birds (chicken and goose). # Clinical significance Mutations in this gene or its regulatory regions cause ahaptoglobinemia or hypohaptoglobinemia. This gene has also been linked to diabetic nephropathy, the incidence of coronary artery disease in type 1 diabetes, Crohn's disease, inflammatory disease behavior, primary sclerosing cholangitis, susceptibility to idiopathic Parkinson's disease, and a reduced incidence of Plasmodium falciparum malaria. Since the reticuloendothelial system will remove the haptoglobin-hemoglobin complex from the body, haptoglobin levels will be decreased in hemolytic anemias. In the process of binding hemoglobin, haptoglobin sequesters the iron within hemoglobin, preventing iron-utilizing bacteria from benefiting from hemolysis. It is theorized that, because of this, haptoglobin has evolved into an acute-phase protein. HP has a protective influence on the hemolytic kidney. Some studies associate certain haptoglobin phenotypes with the risk of developing schizophrenia. ## Test protocol Measuring the level of haptoglobin in a patient's blood is ordered whenever a patient exhibits symptoms of anemia, such as pallor, fatigue, or shortness of breath, along with physical signs of hemolysis, such as jaundice or dark-colored urine. The test is also commonly ordered as a hemolytic anemia battery, which also includes a reticulocyte count and a peripheral blood smear. It can also be ordered along with a direct antiglobulin test when a patient is suspected of having a transfusion reaction or symptoms of autoimmune hemolytic anemia. Also, it may be ordered in conjunction with a bilirubin. ## Interpretation A decrease in haptoglobin can support a diagnosis of hemolytic anemia, especially when correlated with a decreased red blood cell count, hemoglobin, and hematocrit, and also an increased reticulocyte count. If the reticulocyte count is increased, but the haptoglobin level is normal, this may indicate that cellular destruction is occurring in the spleen and liver, which may indicate a drug-induced hemolysis, or a red cell dysplasia. The spleen and liver recognize an error in the red cells (either drug coating the red cell membrane or a dysfunctional red cell membrane), and destroy the cell. This type of destruction does not release hemoglobin into the peripheral blood, so the haptoglobin cannot bind to it. Thus, the haptoglobin will stay normal if the hemolysis is not severe. In severe extra-vascular hemolysis, haptoglobin levels can also be low, when large amount of hemoglobin in the reticuloendothelial system leads to transfer of free hemoglobin into plasma. If there are symptoms of anemia but both the reticulocyte count and the haptoglobin level are normal, the anemia is most likely not due to hemolysis, but instead some other error in cellular production, such as aplastic anemia Haptoglobin levels that are decreased but do not accompany signs of anemia may indicate liver damage, as the liver is not producing enough haptoglobin to begin with. As haptoglobin is indeed an acute-phase protein, any inflammatory process (infection, extreme stress, burns, major crush injury, allergy, etc.) may increase the levels of plasma haptoglobin.	Haptoglobin Haptoglobin (abbreviated as Hp) is the protein that in humans is encoded by the HP gene.[1][2] In blood plasma, haptoglobin binds free hemoglobin (Hb) released from erythrocytes with high affinity and thereby inhibits its oxidative activity. The haptoglobin-hemoglobin complex will then be removed by the reticuloendothelial system (mostly the spleen). In clinical settings, the haptoglobulin assay is used to screen for and monitor intravascular hemolytic anemia. In intravascular hemolysis, free hemoglobin will be released into circulation and hence haptoglobin will bind the hemoglobin. This causes a decline in haptoglobin levels. Conversely, in extravascular hemolysis the reticuloendothelial system, especially splenic monocytes, phagocytose the erythrocytes and hemoglobin is relatively not released into circulation; however, excess hemolysis can release some hemoglobin causing haptoglobin levels to be decreased. Therefore, haptoglobin is not a reliable way to differentiate between intravascular and extravascular hemolysis. # Function This gene encodes a preproprotein that is processed to yield both alpha and beta chains, which subsequently combines as a tetramer to produce haptoglobin. Haptoglobin functions to bind free plasma hemoglobin, which allows degradative enzymes to gain access to the hemoglobin while at the same time preventing loss of iron through the kidneys and protecting the kidneys from damage by hemoglobin.[3] For this reason, it is often referred to as the suicide protein. # Synthesis Haptoglobin is produced mostly by hepatic cells but also by other tissues such as skin, lung and kidney. In addition, the haptoglobin gene is expressed in murine and human adipose tissue.[4] Haptoglobin had been shown to be expressed in adipose tissue of cattle as well.[5] # Structure Haptoglobin, in its simplest form, consists of two alpha and two beta chains, connected by disulfide bridges. The chains originate from a common precursor protein, which is proteolytically cleaved during protein synthesis. Hp exists in two allelic forms in the human population, so-called Hp1 and Hp2, the latter one having arisen due to the partial duplication of Hp1 gene. Three genotypes of Hp, therefore, are found in humans: Hp1-1, Hp2-1, and Hp2-2. Hp of different genotypes have been shown to bind hemoglobin with different affinities, with Hp2-2 being the weakest binder. # In other species Hp has been found in all mammals studied so far, some birds, e.g., cormorant and ostrich but also, in its simpler form, in bony fish, e.g., zebrafish. Hp is absent in at least some amphibians (Xenopus) and neognathous birds (chicken and goose). # Clinical significance Mutations in this gene or its regulatory regions cause ahaptoglobinemia or hypohaptoglobinemia. This gene has also been linked to diabetic nephropathy,[6] the incidence of coronary artery disease in type 1 diabetes,[7] Crohn's disease,[8] inflammatory disease behavior, primary sclerosing cholangitis, susceptibility to idiopathic Parkinson's disease,[9] and a reduced incidence of Plasmodium falciparum malaria.[10] Since the reticuloendothelial system will remove the haptoglobin-hemoglobin complex from the body, haptoglobin levels will be decreased in hemolytic anemias. In the process of binding hemoglobin, haptoglobin sequesters the iron within hemoglobin, preventing iron-utilizing bacteria from benefiting from hemolysis. It is theorized that, because of this, haptoglobin has evolved into an acute-phase protein. HP has a protective influence on the hemolytic kidney.[11][12] Some studies associate certain haptoglobin phenotypes with the risk of developing schizophrenia.[13] ## Test protocol Measuring the level of haptoglobin in a patient's blood is ordered whenever a patient exhibits symptoms of anemia, such as pallor, fatigue, or shortness of breath, along with physical signs of hemolysis, such as jaundice or dark-colored urine. The test is also commonly ordered as a hemolytic anemia battery, which also includes a reticulocyte count and a peripheral blood smear. It can also be ordered along with a direct antiglobulin test when a patient is suspected of having a transfusion reaction or symptoms of autoimmune hemolytic anemia. Also, it may be ordered in conjunction with a bilirubin. ## Interpretation A decrease in haptoglobin can support a diagnosis of hemolytic anemia, especially when correlated with a decreased red blood cell count, hemoglobin, and hematocrit, and also an increased reticulocyte count. If the reticulocyte count is increased, but the haptoglobin level is normal, this may indicate that cellular destruction is occurring in the spleen and liver, which may indicate a drug-induced hemolysis, or a red cell dysplasia. The spleen and liver recognize an error in the red cells (either drug coating the red cell membrane or a dysfunctional red cell membrane), and destroy the cell. This type of destruction does not release hemoglobin into the peripheral blood, so the haptoglobin cannot bind to it. Thus, the haptoglobin will stay normal if the hemolysis is not severe. In severe extra-vascular hemolysis, haptoglobin levels can also be low, when large amount of hemoglobin in the reticuloendothelial system leads to transfer of free hemoglobin into plasma.[14] If there are symptoms of anemia but both the reticulocyte count and the haptoglobin level are normal, the anemia is most likely not due to hemolysis, but instead some other error in cellular production, such as aplastic anemia Haptoglobin levels that are decreased but do not accompany signs of anemia may indicate liver damage, as the liver is not producing enough haptoglobin to begin with. As haptoglobin is indeed an acute-phase protein, any inflammatory process (infection, extreme stress, burns, major crush injury, allergy, etc.) may increase the levels of plasma haptoglobin.	https://www.wikidoc.org/index.php/Ddx:Haptoglobin
77d29b748750d29d9be1e3dda9fa8694e62b2f8b	wikidoc	Hypersomnia	Hypersomnia # Overview Hypersomnia is excessive amount of sleepiness. Hypersomnia is characterized by recurrent episodes of Excessive Daytime Sleepiness or prolonged nighttime sleep. Different from feeling tired due to lack of or interrupted sleep at night, persons with hypersomnia are compelled to nap repeatedly during the day, often at inappropriate times such as at work, during a meal, or in conversation. These daytime naps usually provide no relief from symptoms. Patients often have difficulty waking from a long sleep, and may feel disoriented. Other symptoms may include anxiety, increased irritation, decreased energy, restlessness, slow thinking, slow speech, loss of appetite, hallucinations, and memory difficulty. Some patients lose the ability to function in family, social, occupational, or other settings. Hypersomnia may be caused by another sleep disorder (such as narcolepsy or sleep apnea), dysfunction of the autonomic nervous system, or drug or alcohol abuse. In some cases it results from a physical problem, such as a tumor, head trauma, or injury to the central nervous system. Certain medications, or medicine withdrawal, may also cause hypersomnia. Medical conditions including multiple sclerosis, depression, encephalitis, epilepsy, or obesity may contribute to the disorder. Some people appear to have a genetic predisposition to hypersomnia; in others, there is no known cause. Hypersomnia typically affects adolescents and young adults, although the most common causes of the condition for the two age cohorts differ. # Diagnosis An adult is considered to have hypersomnia if he or she sleeps more than 10 hours per day on a regular basis for at least two weeks. # Causes Hypersomnia can be caused by genetics (heredity), brain damage, and disorders such as clinical depression, uremia and fibromyalgia. Hypersomnia can also be a symptom of other sleep disorders such as narcolepsy, sleep apnea, and restless leg syndrome. People who are overweight may be more likely to suffer from hypersomnia. This can often exacerbate weight problems as excessive sleeping decreases metabolic energy consumption, making weight loss more difficult. Another possible cause is an infection of mononucleosis, as several instances of hypersomnia have been found to arise immediately after such an infection (Dr. Givan, MD, Riley Hospital). In some instances, the cause of the hypersomnia cannot be determined; in these cases, it is considered to be idiopathic hypersomnia or if accompanied by metaphagia and hypersexual behavior may be due to Klein-Levin syndrome as a diagnosis of exclusion. # Treatment Treatment is symptomatic in nature. Stimulants, such as amphetamine, methylphenidate, and modafinil, may be prescribed. Other drugs used to treat hypersomnia include clonidine, levodopa, bromocriptine, antidepressants, and monoamine oxidase inhibitors. Changes in behavior (for example avoiding night work and social activities that delay bed time) and diet may offer some relief. Patients should avoid alcohol and caffeine.	Hypersomnia For patient information click here Template:Search infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Hypersomnia is excessive amount of sleepiness. Hypersomnia is characterized by recurrent episodes of Excessive Daytime Sleepiness or prolonged nighttime sleep. Different from feeling tired due to lack of or interrupted sleep at night, persons with hypersomnia are compelled to nap repeatedly during the day, often at inappropriate times such as at work, during a meal, or in conversation. These daytime naps usually provide no relief from symptoms. Patients often have difficulty waking from a long sleep, and may feel disoriented. Other symptoms may include anxiety, increased irritation, decreased energy, restlessness, slow thinking, slow speech, loss of appetite, hallucinations, and memory difficulty. Some patients lose the ability to function in family, social, occupational, or other settings. Hypersomnia may be caused by another sleep disorder (such as narcolepsy or sleep apnea), dysfunction of the autonomic nervous system, or drug or alcohol abuse. In some cases it results from a physical problem, such as a tumor, head trauma, or injury to the central nervous system. Certain medications, or medicine withdrawal, may also cause hypersomnia. Medical conditions including multiple sclerosis, depression, encephalitis, epilepsy, or obesity may contribute to the disorder. Some people appear to have a genetic predisposition to hypersomnia; in others, there is no known cause. Hypersomnia typically affects adolescents and young adults, although the most common causes of the condition for the two age cohorts differ. # Diagnosis An adult is considered to have hypersomnia if he or she sleeps more than 10 hours per day on a regular basis for at least two weeks. # Causes Hypersomnia can be caused by genetics (heredity), brain damage, and disorders such as clinical depression, uremia and fibromyalgia. Hypersomnia can also be a symptom of other sleep disorders such as narcolepsy, sleep apnea, and restless leg syndrome. People who are overweight may be more likely to suffer from hypersomnia. This can often exacerbate weight problems as excessive sleeping decreases metabolic energy consumption, making weight loss more difficult. Another possible cause is an infection of mononucleosis, as several instances of hypersomnia have been found to arise immediately after such an infection (Dr. Givan, MD, Riley Hospital). In some instances, the cause of the hypersomnia cannot be determined; in these cases, it is considered to be idiopathic hypersomnia or if accompanied by metaphagia and hypersexual behavior may be due to Klein-Levin syndrome as a diagnosis of exclusion. # Treatment Treatment is symptomatic in nature. Stimulants, such as amphetamine, methylphenidate, and modafinil, may be prescribed. Other drugs used to treat hypersomnia include clonidine, levodopa, bromocriptine, antidepressants, and monoamine oxidase inhibitors. Changes in behavior (for example avoiding night work and social activities that delay bed time) and diet may offer some relief. Patients should avoid alcohol and caffeine.	https://www.wikidoc.org/index.php/Ddx:Hypersomnia
20bbf49753f43d3dfaaf1d8f75ccbcae95e3673e	wikidoc	Hypovolemia	Hypovolemia Synonyms and keywords: hypovolaemia; hypovolemic. # Overview Hypovolemia is a state of decreased blood volume; more specifically, decrease in volume of blood plasma. # Causes ## Common Causes - Bleeding - Sepsis - Severe burns - Dehydration - Drugs such as diuretics or vasodilators typically used to treat hypertensive individuals ## Causes by Organ System ## Causes in Alphabetical Order # Natural History, Complications and Prognosis Severe hypovolemia may lead to hypovolemic shock which in turn can be associated with multiple organ failure, renal failure, brain damage, coma and death (desanguination).Note that in children, compensation can result in an artificially high blood pressure despite hypovolemia.This is another reason (aside from initial lower blood volume) that even the possibility of internal bleeding in children should always be treated aggressively.People can bleed to death internally without any external blood loss. # Diagnosis Clinical symptoms may not present until 10-20% of total whole-blood volume is lost. Also consider possible mechanisms of injury (especially the steering wheel and/or use/non-use of seat belt in motor vehicle accidents) that may have caused internal bleeding such as ruptured or bruised internal organs.If trained to do so and the situation permits, conduct a secondary survey and check the chest and abdominal cavities for pain, deformity, guarding or swelling.(Injuries to the pelvis and bleeding into the thigh from the femoral artery can also be life-threatening.) ## Symptoms The patient may feel : - Dizzy - Faint - Nausea - Very thirsty ## Physical Examination - Elevated pulse - Low blood pressure and the absence of perfusion - Pale skin - Reduced capillary refill assessed on forehead, lips and nail beds # Treatment Minor hypovolemia from a known cause that has been completely controlled (such as a blood transfusion from a healthy patient who is not anemic) may be countered with initial rest for up to half an hour, oral fluids including moderate sugars (apple juice is good) and the advice to the donor to eat good solid meals with proteins for the next few days.Typically, this would involve a fluid volume of less than one liter (1000 ml), although this is highly dependent on body weight.Larger people can tolerate slightly more blood loss than smaller people.More serious hypovolemia should be assessed by a nurse or doctor.When in doubt, treat hypovolemia aggressively.Note that in children, compensation can result in an artificially high blood pressure despite hypovolemia. ## First Aid External bleeding should be controlled by direct pressure. If direct pressure fails, other techniques such as elevation and pressure points should be considered. The tourniquet should be used in the case of massive hemorrhage i.e. arterial bleeds, such as the femoral artery. If a first-aider recognizes internal bleeding, the life-saving measure to take is to immediately call for emergency assistance. ## Field Care Emergency oxygen should be immediately employed to increase the efficiency of the patient's remaining blood supply.This intervention can be life-saving. The use of intravenous fluids(IVs) may help compensate for lost fluid volume, but IV fluids cannot carry oxygen in the way that blood can.See also emergency medical services for a discussion of techniques used in IV fluid management of hypovolemia. ## Hospital Treatment If the hypovolemia was caused by medication, the administration of antidotes may be appropriate but should be carefully monitored to avoid shock or the emergence of other pre-existing conditions. Blood transfusions coupled with surgical repair are the definitive treatment for hypovolemia caused by trauma.See also the discussion of shock and the importance of treating reversible shock while it can still be countered.	Hypovolemia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Aditya Govindavarjhulla, M.B.B.S. [2] Synonyms and keywords: hypovolaemia; hypovolemic. # Overview Hypovolemia is a state of decreased blood volume; more specifically, decrease in volume of blood plasma. # Causes ## Common Causes - Bleeding - Sepsis - Severe burns - Dehydration - Drugs such as diuretics or vasodilators typically used to treat hypertensive individuals ## Causes by Organ System ## Causes in Alphabetical Order # Natural History, Complications and Prognosis Severe hypovolemia may lead to hypovolemic shock which in turn can be associated with multiple organ failure, renal failure, brain damage, coma and death (desanguination).Note that in children, compensation can result in an artificially high blood pressure despite hypovolemia.This is another reason (aside from initial lower blood volume) that even the possibility of internal bleeding in children should always be treated aggressively.People can bleed to death internally without any external blood loss. # Diagnosis Clinical symptoms may not present until 10-20% of total whole-blood volume is lost. Also consider possible mechanisms of injury (especially the steering wheel and/or use/non-use of seat belt in motor vehicle accidents) that may have caused internal bleeding such as ruptured or bruised internal organs.If trained to do so and the situation permits, conduct a secondary survey and check the chest and abdominal cavities for pain, deformity, guarding or swelling.(Injuries to the pelvis and bleeding into the thigh from the femoral artery can also be life-threatening.) ## Symptoms The patient may feel : - Dizzy - Faint - Nausea - Very thirsty ## Physical Examination - Elevated pulse - Low blood pressure and the absence of perfusion - Pale skin - Reduced capillary refill assessed on forehead, lips and nail beds # Treatment Minor hypovolemia from a known cause that has been completely controlled (such as a blood transfusion from a healthy patient who is not anemic) may be countered with initial rest for up to half an hour, oral fluids including moderate sugars (apple juice is good) and the advice to the donor to eat good solid meals with proteins for the next few days.Typically, this would involve a fluid volume of less than one liter (1000 ml), although this is highly dependent on body weight.Larger people can tolerate slightly more blood loss than smaller people.More serious hypovolemia should be assessed by a nurse or doctor.When in doubt, treat hypovolemia aggressively.Note that in children, compensation can result in an artificially high blood pressure despite hypovolemia. ## First Aid External bleeding should be controlled by direct pressure. If direct pressure fails, other techniques such as elevation and pressure points should be considered. The tourniquet should be used in the case of massive hemorrhage i.e. arterial bleeds, such as the femoral artery. If a first-aider recognizes internal bleeding, the life-saving measure to take is to immediately call for emergency assistance. ## Field Care Emergency oxygen should be immediately employed to increase the efficiency of the patient's remaining blood supply.This intervention can be life-saving. The use of intravenous fluids(IVs) may help compensate for lost fluid volume, but IV fluids cannot carry oxygen in the way that blood can.See also emergency medical services for a discussion of techniques used in IV fluid management of hypovolemia. ## Hospital Treatment If the hypovolemia was caused by medication, the administration of antidotes may be appropriate but should be carefully monitored to avoid shock or the emergence of other pre-existing conditions. Blood transfusions coupled with surgical repair are the definitive treatment for hypovolemia caused by trauma.See also the discussion of shock and the importance of treating reversible shock while it can still be countered.	https://www.wikidoc.org/index.php/Ddx:Hypovolemia
8c1ba6d54d9219ce13cfa7458ef45e4cb711eae7	wikidoc	Monocytosis	Monocytosis # Overview Monocytosis is an increase in the number of circulating monocytes. In humans, 950/μL is regarded as at the upper limit of normal; monocyte counts above this level are regarded as monocytosis. Monocytes are white blood cells that give rise to macrophages and dendritic cells in the immune system. # Historical Perspective - Monocytosis was first discovered by Federica Sallusto an Italian Biologist and Immunologist and and Antonio Lanzavecchia an Italian and Swiss Immunologist in 1994 when they paved the way by formulating different culture conditions starting from monocytes. - The association between Multiple gene mutations and Clonal hematopoiesis in monocytosis was made in 2022. # Classification - monocytosis has various causes and in can be classified to reactive or clonal monocytosis. # Pathophysiology - The pathogenesis of is characterized by , , and . - The gene/Mutation in has been associated with the development of , involving the pathway. - On gross pathology, , , and are characteristic findings of . - On microscopic histopathological analysis, , , and are characteristic findings of . # Causes ## By Organ System ## In Alphabetical Order - Acute lymphocytic leukemia - Bacterial Endocarditis - Benign familial neutropenia - Brucellosis - Carcinoma - Chronic myeloid leukaemia - Chronic neutropenia - Cirrhosis - Crohn's disease - Cyclical neutropenia - Cytomegalovirus - Drugs - Gaucher's Disease - Granulocyte-macrophage colony stimulating factor - Herpes Zoster Virus - Hodgkin lymphoma - Infectious Endocarditis - Infectious hepatitis - Inflammatory bowel disease - Irritable Bowel Syndrome - Kala-azar - Kostmann syndrome - Lipid storage disease - listeriosis - Lymphoproliferative disease - Malaria - Mononeucleosis - Mycobacterium tuberculosis - Myelodysplastic syndrome - Myeloma - Myeloproliferative disease - Non-Hodgkin lymphoma - Other malignant lymphomas - Polyarteritis nodosa - Recovery from neutropenia - Relapsing fever - Rheumatoid arthritis - Rocky Mountain spotted fever - Sarcoidosis - Syphillis - Systemic lupus erythematosus - Trypanosomiasis - Tuberculosis - Ulcerative colitis - Visceral leishmaniasis - Whooping cough # Differentiating from other Diseases - must be differentiated from other diseases that cause , , and , such as: # Epidemiology and Demographics - The prevalence of is approximately per 100,000 individuals worldwide. - In , the incidence of was estimated to be cases per 100,000 individuals in . ## Age - Patients of all age groups may develop . - is more commonly observed among patients aged years old. - is more commonly observed among . ## Gender - affects men and women equally. - are more commonly affected with than . - The to ratio is approximately to 1. ## Race - There is no racial predilection for . - usually affects individuals of the race. - individuals are less likely to develop . # Risk Factors - Common risk factors in the development of are , , , and . # Natural History, Complications and Prognosis - The majority of patients with remain asymptomatic for . - Early clinical features include , , and . - If left untreated, of patients with may progress to develop , , and . - Common complications of include , , and . - Prognosis is generally , and the of patients with is approximately . # Diagnosis ## Diagnostic Criteria - The diagnosis of is made when at least of the following diagnostic criteria are met: ## Symptoms - is usually asymptomatic. - Symptoms of may include the following: ## Physical Examination - Patients with usually appear . - Physical examination may be remarkable for: ## Laboratory Findings - There are no specific laboratory findings associated with . - A is diagnostic of . - An concentration of is diagnostic of . - Other laboratory findings consistent with the diagnosis of include , , and . ## Imaging Findings - There are no findings associated with . - is the imaging modality of choice for . - On , is characterized by , , and . - may demonstrate , , and . ## Other Diagnostic Studies - may also be diagnosed using . - Findings on include , , and . # Treatment ## Medical Therapy - There is no treatment for ; the mainstay of therapy is supportive care. - The mainstay of therapy for is and . - acts by . - Response to can be monitored with every . ## Surgery - Surgery is the mainstay of therapy for . - in conjunction with is the most common approach to the treatment of . - can only be performed for patients with . ## Prevention - There are no primary preventive measures available for . - Effective measures for the primary prevention of include , , and . - Once diagnosed and successfully treated, patients with are followed-up every . Follow-up testing includes , , and .	Monocytosis Template:DiseaseDisorder infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Varun Kumar, M.B.B.S. [2] # Overview Monocytosis is an increase in the number of circulating monocytes. In humans, 950/μL is regarded as at the upper limit of normal; monocyte counts above this level are regarded as monocytosis. [1] Monocytes are white blood cells that give rise to macrophages and dendritic cells in the immune system. # Historical Perspective - Monocytosis was first discovered by Federica Sallusto an Italian Biologist and Immunologist and and Antonio Lanzavecchia an Italian and Swiss Immunologist in 1994 when they paved the way by formulating different culture conditions starting from monocytes. - The association between Multiple gene mutations and Clonal hematopoiesis in monocytosis was made in 2022. # Classification - monocytosis has various causes and in can be classified to reactive or clonal monocytosis. # Pathophysiology - The pathogenesis of [disease name] is characterized by [feature1], [feature2], and [feature3]. - The [gene name] gene/Mutation in [gene name] has been associated with the development of [disease name], involving the [molecular pathway] pathway. - On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name]. - On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name]. # Causes ## By Organ System ## In Alphabetical Order - Acute lymphocytic leukemia - Bacterial Endocarditis - Benign familial neutropenia - Brucellosis - Carcinoma - Chronic myeloid leukaemia - Chronic neutropenia - Cirrhosis - Crohn's disease - Cyclical neutropenia - Cytomegalovirus - Drugs - Gaucher's Disease - Granulocyte-macrophage colony stimulating factor - Herpes Zoster Virus - Hodgkin lymphoma - Infectious Endocarditis - Infectious hepatitis - Inflammatory bowel disease - Irritable Bowel Syndrome - Kala-azar - Kostmann syndrome - Lipid storage disease - listeriosis - Lymphoproliferative disease - Malaria - Mononeucleosis - Mycobacterium tuberculosis - Myelodysplastic syndrome - Myeloma - Myeloproliferative disease - Non-Hodgkin lymphoma - Other malignant lymphomas - Polyarteritis nodosa - Recovery from neutropenia - Relapsing fever - Rheumatoid arthritis - Rocky Mountain spotted fever - Sarcoidosis - Syphillis - Systemic lupus erythematosus - Trypanosomiasis - Tuberculosis - Ulcerative colitis - Visceral leishmaniasis - Whooping cough # Differentiating [disease name] from other Diseases - [Disease name] must be differentiated from other diseases that cause [clinical feature 1], [clinical feature 2], and [clinical feature 3], such as: - [Differential dx1] - [Differential dx2] - [Differential dx3] # Epidemiology and Demographics - The prevalence of [disease name] is approximately [number or range] per 100,000 individuals worldwide. - In [year], the incidence of [disease name] was estimated to be [number or range] cases per 100,000 individuals in [location]. ## Age - Patients of all age groups may develop [disease name]. - [Disease name] is more commonly observed among patients aged [age range] years old. - [Disease name] is more commonly observed among [elderly patients/young patients/children]. ## Gender - [Disease name] affects men and women equally. - [Gender 1] are more commonly affected with [disease name] than [gender 2]. - The [gender 1] to [Gender 2] ratio is approximately [number > 1] to 1. ## Race - There is no racial predilection for [disease name]. - [Disease name] usually affects individuals of the [race 1] race. - [Race 2] individuals are less likely to develop [disease name]. # Risk Factors - Common risk factors in the development of [disease name] are [risk factor 1], [risk factor 2], [risk factor 3], and [risk factor 4]. # Natural History, Complications and Prognosis - The majority of patients with [disease name] remain asymptomatic for [duration/years]. - Early clinical features include [manifestation 1], [manifestation 2], and [manifestation 3]. - If left untreated, [#%] of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3]. - Common complications of [disease name] include [complication 1], [complication 2], and [complication 3]. - Prognosis is generally [excellent/good/poor], and the [1/5/10year mortality/survival rate] of patients with [disease name] is approximately [#%]. # Diagnosis ## Diagnostic Criteria - The diagnosis of [disease name] is made when at least [number] of the following [number] diagnostic criteria are met: - [criterion 1] - [criterion 2] - [criterion 3] - [criterion 4] ## Symptoms - [Disease name] is usually asymptomatic. - Symptoms of [disease name] may include the following: - [symptom 1] - [symptom 2] - [symptom 3] - [symptom 4] - [symptom 5] - [symptom 6] ## Physical Examination - Patients with [disease name] usually appear [general appearance]. - Physical examination may be remarkable for: - [finding 1] - [finding 2] - [finding 3] - [finding 4] - [finding 5] - [finding 6] ## Laboratory Findings - There are no specific laboratory findings associated with [disease name]. - A [positive/negative] [test name] is diagnostic of [disease name]. - An [elevated/reduced] concentration of [serum/blood/urinary/CSF/other] [lab test] is diagnostic of [disease name]. - Other laboratory findings consistent with the diagnosis of [disease name] include [abnormal test 1], [abnormal test 2], and [abnormal test 3]. ## Imaging Findings - There are no [imaging study] findings associated with [disease name]. - [Imaging study 1] is the imaging modality of choice for [disease name]. - On [imaging study 1], [disease name] is characterized by [finding 1], [finding 2], and [finding 3]. - [Imaging study 2] may demonstrate [finding 1], [finding 2], and [finding 3]. ## Other Diagnostic Studies - [Disease name] may also be diagnosed using [diagnostic study name]. - Findings on [diagnostic study name] include [finding 1], [finding 2], and [finding 3]. # Treatment ## Medical Therapy - There is no treatment for [disease name]; the mainstay of therapy is supportive care. - The mainstay of therapy for [disease name] is [medical therapy 1] and [medical therapy 2]. - [Medical therapy 1] acts by [mechanism of action 1]. - Response to [medical therapy 1] can be monitored with [test/physical finding/imaging] every [frequency/duration]. ## Surgery - Surgery is the mainstay of therapy for [disease name]. - [Surgical procedure] in conjunction with [chemotherapy/radiation] is the most common approach to the treatment of [disease name]. - [Surgical procedure] can only be performed for patients with [disease stage] [disease name]. ## Prevention - There are no primary preventive measures available for [disease name]. - Effective measures for the primary prevention of [disease name] include [measure1], [measure2], and [measure3]. - Once diagnosed and successfully treated, patients with [disease name] are followed-up every [duration]. Follow-up testing includes [test 1], [test 2], and [test 3].	https://www.wikidoc.org/index.php/Ddx:Monocytosis
76daa60149550082b8a55947154c52f7c8a2b0da	wikidoc	Photophobia	Photophobia Synonyms and keywords: Light sensitivity; Vision-light sensitive; Eyes-sensitivity to light # Overview Photophobia (also light sensitivity) or fear of light, is a symptom of excessive sensitivity to light and the aversion to sunlight or well-lit places. In medical terms, it is not fear, but an experience of discomfort or pain to the eyes due to light exposure. # Pathophysiology Light sensitivity is usually due to too much light entering the eye, which causes over stimulation of the photoreceptors in the retina and subsequent excessive electric impulses to the optic nerve. This leads to a reflex aversion to light, and discomfort or pain. Too much light can enter the eye if it is damaged, such as with corneal abrasion and retinal damage, or if a pupil(s) is unable to normally constrict (seen with damage to the oculomotor nerve). # Causes Patients may develop photophobia as a result of several different medical conditions related to the eye or the nervous system. - Albinism - Anticholinergic drugs may cause photophobia by paralyzing the iris sphincter muscle. - Aphakia - Burns to the eye - Cataracts - Chiari malformation - Chikungunya - Conjunctivitis - Conjunctivitis - Corneal abrasion - Corneal ulcer - Cystinosis - Drugs such as Atropine, Cyclopentolate, Hydroxypropyl cellulose, Doxercalciferol, Metipranolol, Nabilone, Nilutamide, Nitisinone, Pramipexole, Travoprost, Trimethadione - Encephalitis - Encephalitis - Eye disease, injury, or infection such as chalazion, episcleritis, glaucoma, keratoconus - Hangover - Idiopathic anterior uveitis/iritis - Influenza - Iritis - Keraconjunctivitis sicca (dry eye) - Lightly pigmented eye - Meningitis - Migraines - Mydriatic use - Retinal detachment - Subarachnoid haemorrhage # Diagnosis ## Symptoms Patients with photophobia will avert their eyes from direct light (sunlight and room lights), or may seek the shelter of a dark room or wear sunglasses. - Pain in the eye - Headache - Nausea - Neck stiffness - Blurred vision - Sore or wound in eye - Redness - Itching - Swelling - Dizziness - Numbness or tingling elsewhere in the body - Changes in hearing Photophobia is also a behavior demonstrated by insects or other animals which seek to stay out of the light. ## Physical Examination ### Eye - Swelling	Photophobia For patient information, click here Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ogheneochuko Ajari, MB.BS, MS [2] Synonyms and keywords: Light sensitivity; Vision-light sensitive; Eyes-sensitivity to light # Overview Photophobia (also light sensitivity) or fear of light, is a symptom of excessive sensitivity to light and the aversion to sunlight or well-lit places. In medical terms, it is not fear, but an experience of discomfort or pain to the eyes due to light exposure. # Pathophysiology Light sensitivity is usually due to too much light entering the eye, which causes over stimulation of the photoreceptors in the retina and subsequent excessive electric impulses to the optic nerve. This leads to a reflex aversion to light, and discomfort or pain. Too much light can enter the eye if it is damaged, such as with corneal abrasion and retinal damage, or if a pupil(s) is unable to normally constrict (seen with damage to the oculomotor nerve). # Causes Patients may develop photophobia as a result of several different medical conditions related to the eye or the nervous system. - Albinism - Anticholinergic drugs may cause photophobia by paralyzing the iris sphincter muscle. - Aphakia - Burns to the eye - Cataracts - Chiari malformation - Chikungunya - Conjunctivitis - Conjunctivitis - Corneal abrasion - Corneal ulcer - Cystinosis - Drugs such as Atropine, Cyclopentolate, Hydroxypropyl cellulose, Doxercalciferol, Metipranolol, Nabilone, Nilutamide, Nitisinone, Pramipexole, Travoprost, Trimethadione - Encephalitis - Encephalitis - Eye disease, injury, or infection such as chalazion, episcleritis, glaucoma, keratoconus - Hangover - Idiopathic anterior uveitis/iritis - Influenza - Iritis - Keraconjunctivitis sicca (dry eye) - Lightly pigmented eye - Meningitis - Migraines - Mydriatic use - Retinal detachment - Subarachnoid haemorrhage # Diagnosis ## Symptoms Patients with photophobia will avert their eyes from direct light (sunlight and room lights), or may seek the shelter of a dark room or wear sunglasses. - Pain in the eye - Headache - Nausea - Neck stiffness - Blurred vision - Sore or wound in eye - Redness - Itching - Swelling - Dizziness - Numbness or tingling elsewhere in the body - Changes in hearing Photophobia is also a behavior demonstrated by insects or other animals which seek to stay out of the light. ## Physical Examination ### Eye - Swelling	https://www.wikidoc.org/index.php/Ddx:Photophobia
4b3b52acc222403326450a189261cb578b099e60	wikidoc	Plasminogen	Plasminogen 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. # Overview Plasminogen is the precurser of plasmin, converts fibrin to soluble products. # Differential Diagnosis Deficiency - Acquired - DIC - Fibrinolytic therapy - Hyperfibrinolysis - Physiologic in newborns - Severe liver damage - Hereditary Increased - Acute-phase-reaction - Diabetes Mellitus - Oral Contraceptives - Pregnancy	Plasminogen Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] 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. # Overview Plasminogen is the precurser of plasmin, converts fibrin to soluble products. [1] [2] # Differential Diagnosis Deficiency - Acquired - DIC - Fibrinolytic therapy - Hyperfibrinolysis - Physiologic in newborns - Severe liver damage - Hereditary Increased - Acute-phase-reaction - Diabetes Mellitus - Oral Contraceptives - Pregnancy	https://www.wikidoc.org/index.php/Ddx:Plasminogen
10cd405def1b3a4e2556320625b3e167f19ba07f	wikidoc	Proteinuria	Proteinuria Synonyms and keywords: Elevated urinary protein levels; Elevated urine protein To view a comprehensive algorithm of common findings of urine composition and urine output, click here # Overview Excretion of the proteins in the urine may suggest variety of medical conditions from benign to severe kidney injury. The amount of proteinuria can be used as a clue to estimate the site and the cause of proteinuria. Three factors which are involved in development of proteinuria are glomerular-capillary barrier, tubular reabsorption capability, and protein's characteristics. # Classification Proteinuria is classified based upon the site and the amount of protein in the urine. # Pathophysiology - The amount of proteins present in the urine is < 150 mg/day with an intact glomerular-capillary barrier and functioning tubules, thus increased levels of proteinuria can demonstrate kidney damage (glomerular or tubular). - Overproduction of proteins which exceeds the absorption capacity of the tubules causes proteinuria in spite of relatively normal renal function (overflow). - Normally filtration of all plasma proteins like albumin, globulins and other high-molecular-weight proteins through the glomerular-capillary wall is prevented by charge and size of the proteins and glomerular-capillary barrier . - The type and quantity of proteins in the urine may identify the etiology and site of kidney damage. - As injury to the glomerular-capillary barrier causes albuminuria, tubular damage and overflow proteinuria lead to increase loads of low-molecular-weight proteins in the urine. - The severity of protein loss in the urine depends on the mechanism of renal injury. ## Glomerular-capillary barrier - It consists of endothelial cells of capillary, glomerular basement membrane, and epithelial cells. - The endothelial cells of vessels organize a barrier with pores of 100 nm which impede the passing of the proteins from blood to the urinary space. - Glomerular basement membrane and epithelial cells (podocytes) prevent the protein passage and traps the proteins especially with the size of > 100 kDa. - The slit diaphragm acts as the most selective barrier for protein passage. - The endothelial cells, podocytes, and glomerular basement membrane impede traversal of the negative-charge proteins due to the presence of negative charges in their constitution . ## Tubular reabsorption - Almost all the proteins which are filtered through glomerulus are reabsorbed by proximal tubular cells by endocytosis. - The tubulointerstitial diseases damage the cells cause tubular proteinuria. - In circumstances where large amounts of protein is filtered, tubular proteinuria occurs as the filtered protein exceeds the reabsorption capacity of the cells. - Not all the proteins in the tubules are toxic to the cells but proximal tubule injury, light chain deposition, and tubule obstruction (cast nephropathy) due to the large amount of light chain may cause further proteinuria by the overwhelming capacity of tubular cells. ## Proteins - The size of the protein is one of the determinants of traversal through the glomerular-capillary barrier. Immunoglobulins like IgG and other high-molecular-weight proteins have the higher molecular radius, therefore, there are not able to pass over the barrier. - Low-molecular-weight proteins are the ones with < 40kDa and molecular radius < 30 Å are filtered almost completely and reabsorbed by tubular cells. - In normal physiological condition, HMW proteins do not cross the glomerular barrier. The small percentage of albumin passes the barrier which is reabsorbed completely in the proximal tubules. LMW proteins are filtered and reabsorbed completely. - Moderate alteration of permeability of glomerular barrier named as selective proteinuria, demonstrates with loss of negative-charged proteins like albumin, LMW proteins and small percentage of HMW proteins in the urine with exceeding the reabsorption capacity of tubular cells. - Severe damage to the barrier causes loss of the greater percentage of HMW proteins in the urine which is called nonselective proteinuria. - Profound damage to glomerular barrier causes severe proteinuria of all classes especially LMW and HMW. Increasing loads of protein which exceed the reabsorption capability of tubular cells causes damage to tubular cells and worsens proteinuria. (an average protein has 250 amino acids which equals molecular weight( MW) of approximately 34 kDa) # Causes For more details on the causes of glomerular proteinuria, click here. For more details on the causes of tubular proteinuria, click here. ## Causes by Organ System ## Causes in Alphabetical Order # Risk Factors The risk factors for proteinuria include: - Race and ethnicity - Obesity - Age (> 65) - Medications - Hypertension - Diabetes - Heart diseases - Family history of kidney disease # Screening - Urinalysis may be considered as a part of routine health evaluation. - Monitor of renal function and proteinuria (micro- and microalbuminuria) is recommended in individuals with systemic diseases who are at risk of proteinuria. - Isolated proteinuria (non-nephrotic), no edema or hypoalbuminemia, no clinical or serologic evidences of systemic diseases may be screened by antinuclear antibody (ANA), antineutrophil cytoplasmic antibody (ANCA), complement component C3 and C4 levels, and hepatitis serologies. # Epidemiology and Demographics - Prevalence of albuminuria is 6100 and 9700 per 100,000 in male and female population, respectively. - The estimated prevalence rate of albuminuria among diabetes population is 28,800 per 100,000 individuals. - The estimated prevalence rate of albuminuria among hypertensive population is 16,000 per 100,000 individuals. - Isolated albuminuria with normal renal function is estimated 3,300 per 100,000 adult population. # Natural History, Complications, and Prognosis ### Natural History - Proteinuria which different mechanisms causes loss of albumin, regulatory proteins, hormones and anticoagulant proteins in the urine. - Hypoalbuminemia decreases oncotic pressure and causes fluid movement from capillaries to interstitium which leads to edema. - Shift of fluids from capillaries is perceived as decreased effective vascular volume. - Activation of the renin-angiotensin system and sympathetic nervous system along with increase ADH secretion will occur which enhance salt and water reabsorption and worsen edema. - Loss of regulatory proteins change hepatic synthesis of proteins and may cause in hypercholesterolemia. - Loss of antithrombin III, proteins S and C cause platelet aggregation and thrombosis. - Loss of immunoglobulins enhances the risk of infections. ### Complications - Pulmonary edema - Renal failure - Increased risk of infections - Increased risk of thromboembolic events - Increased risk of cardiovascular disease ### Prognosis - Proteinuria is associated with left ventricular abnormalities, increased atherosclerosis, cardiovascular morbidity and mortality. - Proteinuria is an independent risk factor for developing cardiovascular disease and end stage renal disease. - Higher amounts of albuminuria, even in normal range is associated with an increased risk of cardiovascular events. - Microalbuminuria can be considered as a predictor of morbidity and mortality in patients with no significant renal diseases. - The presence of proteinuria in renal transplant patients predicts graft and patients survival. - Treatment of proteinuria in patients with chronic renal disease improves outcomes. - Increases urinary albumin to creatinine ratio in patients with different medical conditions increases mortality. - Albuminuria in any measurable levels is associated with increased risk of myocardial infarction in hypertensive patients. # Diagnosis ## Diagnostic Study of Choice ### Qualitative measures - Urine dipstick: The standard urine dipstick is sensitive to urine albumin not to the non-albumin proteins, so the positive result indicates glomerular proteinuria. The dipstick grading is semiquantitative to the amount of protein in the urine and is dependent upon urine concentration. The sensitivity of the urinary dipstick for detection of albumin in the urine ranges from 83% to 98% with a specificity of 59% to 86%. At the lower level of albuminuria, especially microalbuminuria the urine dipstick is specific but not sensitive, therefore microalbuminuria cannot be detected easily by urine dipstick unless the urine is properly concentrated. Few data suggests using specific gravity to estimate the amount of proteinuria, especially with the dipstick result of trace or 1+. Highly concentrated urine overestimates the amount of proteinuria in the urine, similarly, highly diluted urine underestimates the degree of proteinuria detected by dipstick. - The standard urine dipstick is sensitive to urine albumin not to the non-albumin proteins, so the positive result indicates glomerular proteinuria. - The dipstick grading is semiquantitative to the amount of protein in the urine and is dependent upon urine concentration. - The sensitivity of the urinary dipstick for detection of albumin in the urine ranges from 83% to 98% with a specificity of 59% to 86%. - At the lower level of albuminuria, especially microalbuminuria the urine dipstick is specific but not sensitive, therefore microalbuminuria cannot be detected easily by urine dipstick unless the urine is properly concentrated. - Few data suggests using specific gravity to estimate the amount of proteinuria, especially with the dipstick result of trace or 1+. - Highly concentrated urine overestimates the amount of proteinuria in the urine, similarly, highly diluted urine underestimates the degree of proteinuria detected by dipstick. - False-positive result: Urine PH > 8, administration of radiocontrast agents (iodinated), gross hematuria. Newer dipsticks can detect albumin-to-creatinine and total protein-to-creatinine ratios which can help to avoid errors associated with diluted or concentrated urines and non-albumin proteinuria, respectively. - False-positive result: Urine PH > 8, administration of radiocontrast agents (iodinated), gross hematuria. - Newer dipsticks can detect albumin-to-creatinine and total protein-to-creatinine ratios which can help to avoid errors associated with diluted or concentrated urines and non-albumin proteinuria, respectively. - Sulfosalicylic acid test (SSA): Use of SSA is indicated in patients with the possibility of myeloma in the presence of negative or trace dipstick with renal function impairment. Adding SSA to the urine precipitates all proteins, therefore positive dipstick with SSA demonstrates overflow or tubular proteinuria. - False-positive result: Administration of radiocontrast agents (iodinated), gross hematuria, penicillin. - False-positive result: Administration of radiocontrast agents (iodinated), gross hematuria, penicillin. Quantitative measures - 24-hour urine collection: It is the gold standard test to determine the amount of proteinuria in patients who presents with persistent proteinuria (normal value < 150 mg/day). As collecting urine for 24 is cumbersome and erroneous, spot urine of first and second morning samples with protein-creatinine ratio can be used as an estimate of total protein excretion in 24 hour. - It is the gold standard test to determine the amount of proteinuria in patients who presents with persistent proteinuria (normal value < 150 mg/day). As collecting urine for 24 is cumbersome and erroneous, spot urine of first and second morning samples with protein-creatinine ratio can be used as an estimate of total protein excretion in 24 hour. - Urine creatinine is higher in individuals with higher body muscle mass, therefore urine-protein ratio underestimates proteinuria, similarly in cachectic patients with lower muscle mass, urine-protein ratio overestimates the degree of proteinuria. - Renal biopsy: Renal biopsy is indicated in: All nephrotic range proteinuria (> 3.5 gr/day) Non-nephrotic range proteinuria with: Active urine sediment Persistent proteinuria > 1 gr/day Decreased GFR Progression of proteinuria or developing active sediment or hypertension - All nephrotic range proteinuria (> 3.5 gr/day) - Non-nephrotic range proteinuria with: Active urine sediment Persistent proteinuria > 1 gr/day Decreased GFR Progression of proteinuria or developing active sediment or hypertension - Active urine sediment - Persistent proteinuria > 1 gr/day - Decreased GFR - Progression of proteinuria or developing active sediment or hypertension ## History and Symptoms History: - Fever - Cardiac disease - Renal disease - Infections (HIV, hepatitis) - Frothy, smoky, red urine - Edema - Hypertension - Diabetes - Family history of systemic or renal disease - Hypercholesterolemia - Chronic inflammatory diseases - Medications Symptoms: - Systemic symptoms (fever, night sweats, weight loss, bone pain) - Heart diseases - Edema (ankle, periorbital, labial, scrotal) - Hypertension - Hematuria ## Physical Examination - Check for blood pressure, orthostatic and supine - Measure JVP - Weight changes - Edema - Signs of infectious diseases - Signs of heart diseases - Signs of systemic diseases - Signs for complications (thrombosis, infections) ## Laboratory Findings Laboratory investigations to be considered in proteinuria: - Fasting blood glucose, HbA1c - Hemoglobin, Hematocrit - Serum urate - Serum albumin, lipid levels - Serum electrolytes - ESR - HIV, VDRL, hepatitis serologic tests - Serum and urine protein electrophoresis - Complement C3, C4 levels - Antistreptolysin O titer - ANA - Renal ultrasound - Chest radiography # Treatment ## Medical Therapy Specific treatments of proteinuria demands proper diagnosis of the causes. For the details on the treatments of glomerular diseases, click here. For the details on the treatments of tubular diseases, click here. Non-specific treatments reduce the amount of proteinuaria and the rate of progression or address the complications of proteinuria. - Diuretics: The treatment of fluid overload in patients with moderate to severe proteinuria along with salt restriction is diuretics. For refractory cases two different class of diuretics are used if the increasing doses are not effective. Acute renal failure is the consequence of aggressive therapy with diuretics. - The treatment of fluid overload in patients with moderate to severe proteinuria along with salt restriction is diuretics. - For refractory cases two different class of diuretics are used if the increasing doses are not effective. - Acute renal failure is the consequence of aggressive therapy with diuretics. - ACE inhibitors and ARBs: These agents decrease the progression and the amount of proteinuria by decreasing the intraglomerular pressure. Inhibiting vasoconstriction of efferent arterioles, maintaining the glomerular-capillary wall and decreasing the sclerosis and fibrosis of glomerulus are the action of these drugs aside the anti-hypertensive effects. In normotensive individuals with proteinuria low dose of these drugs have the effect without evident hypotension. Adverse effects of ACE inhibitors are cough, angioedema and hyperkalemia. - These agents decrease the progression and the amount of proteinuria by decreasing the intraglomerular pressure. - Inhibiting vasoconstriction of efferent arterioles, maintaining the glomerular-capillary wall and decreasing the sclerosis and fibrosis of glomerulus are the action of these drugs aside the anti-hypertensive effects. - In normotensive individuals with proteinuria low dose of these drugs have the effect without evident hypotension. - Adverse effects of ACE inhibitors are cough, angioedema and hyperkalemia. - Mineralocorticoind receptor antagonists Adding mineralocorticoid receptor antagonists like eplerenone and spironolactone, help reducing proteinuria further but increase the rate of hyperkalemia. Eplerenone is the new drug in this category which is not associated with hyperkalemia. - Adding mineralocorticoid receptor antagonists like eplerenone and spironolactone, help reducing proteinuria further but increase the rate of hyperkalemia. - Eplerenone is the new drug in this category which is not associated with hyperkalemia. - Anticoagulants: Urinary loss of proteins in the urine especially anticoagulant proteins like antithrombin III, protein S, and protein C put the patients at the risk of thrombosis and emboli. There is no evidence supporting the use of anticoagulants as prophylaxis in nephrotic syndrome. Warfarin is recommended in patients with severe albuminuria (serum albumin < 2.5 g/dL). - Urinary loss of proteins in the urine especially anticoagulant proteins like antithrombin III, protein S, and protein C put the patients at the risk of thrombosis and emboli. - There is no evidence supporting the use of anticoagulants as prophylaxis in nephrotic syndrome. - Warfarin is recommended in patients with severe albuminuria (serum albumin < 2.5 g/dL). - Calcium-channel blockers: Diltiazem and verapamil decrease proteinuria by prevent vasoconstriction of both afferent and efferent arterioles. Other CCBs act on afferent arterioles only which worsen proteinuria. New drugs such as efonidipine and benidipine are used along with ARBs and ACE inhibitors in proteinuria. - Diltiazem and verapamil decrease proteinuria by prevent vasoconstriction of both afferent and efferent arterioles. - Other CCBs act on afferent arterioles only which worsen proteinuria. - New drugs such as efonidipine and benidipine are used along with ARBs and ACE inhibitors in proteinuria. - Vitamin D: Down-regulating gene expression and immunosuppressive characteristic of vitamin D and its analogues help decrease proteinuria by blocking the renin-angiotensin-aldosterone system. - Down-regulating gene expression and immunosuppressive characteristic of vitamin D and its analogues help decrease proteinuria by blocking the renin-angiotensin-aldosterone system. - Management of infections: Antibiotics and vaccines are indicated for the treatment and prophylaxis of infectious diseases in individuals with proteinuria due to loss of immunoglobulins, complements, and circulating blood T cells. - Antibiotics and vaccines are indicated for the treatment and prophylaxis of infectious diseases in individuals with proteinuria due to loss of immunoglobulins, complements, and circulating blood T cells. - Diet: Excessive salt consumption decreases the effect of antihypertensive medications and leads to end-stage renal failure. - Excessive salt consumption decreases the effect of antihypertensive medications and leads to end-stage renal failure. ## Primary Prevention - Primary prevention of proteinuria includes early diagnosis and treatment of diseases which lead to proteinuria. ## Secondary Prevention - Effective measures for secondary prevention of proteinuria include: - Monitor the level of proteinuria to assess the progression of the disease Monitor and treat lipid abnormalities - Monitor the level of proteinuria to assess the progression of the disease - Monitor and treat lipid abnormalities - Check for effectiveness of the therapy and medications' side effects Monitor the renal function regularly Monitor and treat the complications of proteinuria Monitor for new signs of other diseases to address the treatment properly - Check for effectiveness of the therapy and medications' side effects - Monitor the renal function regularly - Monitor and treat the complications of proteinuria - Monitor for new signs of other diseases to address the treatment properly # Related Chapters - Albuminuria - Microalbuminuria - List of terms associated with diabetes	Proteinuria Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Saeedeh Kowsarnia M.D.[2] Synonyms and keywords: Elevated urinary protein levels; Elevated urine protein To view a comprehensive algorithm of common findings of urine composition and urine output, click here # Overview Excretion of the proteins in the urine may suggest variety of medical conditions from benign to severe kidney injury. The amount of proteinuria can be used as a clue to estimate the site and the cause of proteinuria. Three factors which are involved in development of proteinuria are glomerular-capillary barrier, tubular reabsorption capability, and protein's characteristics. # Classification Proteinuria is classified based upon the site and the amount of protein in the urine.[1] # Pathophysiology - The amount of proteins present in the urine is < 150 mg/day with an intact glomerular-capillary barrier and functioning tubules, thus increased levels of proteinuria can demonstrate kidney damage (glomerular or tubular). - Overproduction of proteins which exceeds the absorption capacity of the tubules causes proteinuria in spite of relatively normal renal function (overflow). - Normally filtration of all plasma proteins like albumin, globulins and other high-molecular-weight proteins through the glomerular-capillary wall is prevented by charge and size of the proteins and glomerular-capillary barrier . - The type and quantity of proteins in the urine may identify the etiology and site of kidney damage. - As injury to the glomerular-capillary barrier causes albuminuria, tubular damage and overflow proteinuria lead to increase loads of low-molecular-weight proteins in the urine. - The severity of protein loss in the urine depends on the mechanism of renal injury. ## Glomerular-capillary barrier - It consists of endothelial cells of capillary, glomerular basement membrane, and epithelial cells. - The endothelial cells of vessels organize a barrier with pores of 100 nm which impede the passing of the proteins from blood to the urinary space. - Glomerular basement membrane and epithelial cells (podocytes) prevent the protein passage and traps the proteins especially with the size of > 100 kDa. - The slit diaphragm acts as the most selective barrier for protein passage. - The endothelial cells, podocytes, and glomerular basement membrane impede traversal of the negative-charge proteins due to the presence of negative charges in their constitution [5]. ## Tubular reabsorption - Almost all the proteins which are filtered through glomerulus are reabsorbed by proximal tubular cells by endocytosis. - The tubulointerstitial diseases damage the cells cause tubular proteinuria. - In circumstances where large amounts of protein is filtered, tubular proteinuria occurs as the filtered protein exceeds the reabsorption capacity of the cells. - Not all the proteins in the tubules are toxic to the cells but proximal tubule injury, light chain deposition, and tubule obstruction (cast nephropathy) due to the large amount of light chain may cause further proteinuria by the overwhelming capacity of tubular cells. ## Proteins - The size of the protein is one of the determinants of traversal through the glomerular-capillary barrier. Immunoglobulins like IgG and other high-molecular-weight proteins have the higher molecular radius, therefore, there are not able to pass over the barrier. - Low-molecular-weight proteins are the ones with < 40kDa and molecular radius < 30 Å are filtered almost completely and reabsorbed by tubular cells.[6] - In normal physiological condition, HMW proteins do not cross the glomerular barrier. The small percentage of albumin passes the barrier which is reabsorbed completely in the proximal tubules. LMW proteins are filtered and reabsorbed completely. [7] - Moderate alteration of permeability of glomerular barrier named as selective proteinuria, demonstrates with loss of negative-charged proteins like albumin, LMW proteins and small percentage of HMW proteins in the urine with exceeding the reabsorption capacity of tubular cells. - Severe damage to the barrier causes loss of the greater percentage of HMW proteins in the urine which is called nonselective proteinuria. - Profound damage to glomerular barrier causes severe proteinuria of all classes especially LMW and HMW. Increasing loads of protein which exceed the reabsorption capability of tubular cells causes damage to tubular cells and worsens proteinuria. (an average protein has 250 amino acids which equals molecular weight( MW) of approximately 34 kDa) # Causes For more details on the causes of glomerular proteinuria, click here. For more details on the causes of tubular proteinuria, click here. ## Causes by Organ System ## Causes in Alphabetical Order # Risk Factors The risk factors for proteinuria include: - Race and ethnicity [10] - Obesity [11] - Age (> 65) - Medications - Hypertension [12] - Diabetes [13] - Heart diseases - Family history of kidney disease # Screening - Urinalysis may be considered as a part of routine health evaluation. - Monitor of renal function and proteinuria (micro- and microalbuminuria) is recommended in individuals with systemic diseases who are at risk of proteinuria. - Isolated proteinuria (non-nephrotic), no edema or hypoalbuminemia, no clinical or serologic evidences of systemic diseases may be screened by antinuclear antibody (ANA), antineutrophil cytoplasmic antibody (ANCA), complement component C3 and C4 levels, and hepatitis serologies. # Epidemiology and Demographics - Prevalence of albuminuria is 6100 and 9700 per 100,000 in male and female population, respectively.[14] - The estimated prevalence rate of albuminuria among diabetes population is 28,800 per 100,000 individuals. - The estimated prevalence rate of albuminuria among hypertensive population is 16,000 per 100,000 individuals. - Isolated albuminuria with normal renal function is estimated 3,300 per 100,000 adult population. # Natural History, Complications, and Prognosis ### Natural History - Proteinuria which different mechanisms causes loss of albumin, regulatory proteins, hormones and anticoagulant proteins in the urine. - Hypoalbuminemia decreases oncotic pressure and causes fluid movement from capillaries to interstitium which leads to edema. - Shift of fluids from capillaries is perceived as decreased effective vascular volume. - Activation of the renin-angiotensin system and sympathetic nervous system along with increase ADH secretion will occur which enhance salt and water reabsorption and worsen edema. - Loss of regulatory proteins change hepatic synthesis of proteins and may cause in hypercholesterolemia. - Loss of antithrombin III, proteins S and C cause platelet aggregation and thrombosis. - Loss of immunoglobulins enhances the risk of infections. ### Complications - Pulmonary edema - Renal failure - Increased risk of infections - Increased risk of thromboembolic events - Increased risk of cardiovascular disease ### Prognosis - Proteinuria is associated with left ventricular abnormalities, increased atherosclerosis, cardiovascular morbidity and mortality. - Proteinuria is an independent risk factor for developing cardiovascular disease and end stage renal disease.[15] - Higher amounts of albuminuria, even in normal range is associated with an increased risk of cardiovascular events. - Microalbuminuria can be considered as a predictor of morbidity and mortality in patients with no significant renal diseases. - The presence of proteinuria in renal transplant patients predicts graft and patients survival.[16] - Treatment of proteinuria in patients with chronic renal disease improves outcomes. - Increases urinary albumin to creatinine ratio in patients with different medical conditions increases mortality. - Albuminuria in any measurable levels is associated with increased risk of myocardial infarction in hypertensive patients. # Diagnosis ## Diagnostic Study of Choice ### Qualitative measures - Urine dipstick: The standard urine dipstick is sensitive to urine albumin not to the non-albumin proteins, so the positive result indicates glomerular proteinuria. The dipstick grading is semiquantitative to the amount of protein in the urine and is dependent upon urine concentration. The sensitivity of the urinary dipstick for detection of albumin in the urine ranges from 83% to 98% with a specificity of 59% to 86%.[17] At the lower level of albuminuria, especially microalbuminuria the urine dipstick is specific but not sensitive, therefore microalbuminuria cannot be detected easily by urine dipstick unless the urine is properly concentrated. Few data suggests using specific gravity to estimate the amount of proteinuria, especially with the dipstick result of trace or 1+. Highly concentrated urine overestimates the amount of proteinuria in the urine, similarly, highly diluted urine underestimates the degree of proteinuria detected by dipstick. - The standard urine dipstick is sensitive to urine albumin not to the non-albumin proteins, so the positive result indicates glomerular proteinuria. - The dipstick grading is semiquantitative to the amount of protein in the urine and is dependent upon urine concentration. - The sensitivity of the urinary dipstick for detection of albumin in the urine ranges from 83% to 98% with a specificity of 59% to 86%.[17] - At the lower level of albuminuria, especially microalbuminuria the urine dipstick is specific but not sensitive, therefore microalbuminuria cannot be detected easily by urine dipstick unless the urine is properly concentrated. - Few data suggests using specific gravity to estimate the amount of proteinuria, especially with the dipstick result of trace or 1+. - Highly concentrated urine overestimates the amount of proteinuria in the urine, similarly, highly diluted urine underestimates the degree of proteinuria detected by dipstick. - False-positive result: Urine PH > 8, administration of radiocontrast agents (iodinated), gross hematuria. Newer dipsticks can detect albumin-to-creatinine and total protein-to-creatinine ratios which can help to avoid errors associated with diluted or concentrated urines and non-albumin proteinuria, respectively. - False-positive result: Urine PH > 8, administration of radiocontrast agents (iodinated), gross hematuria. - Newer dipsticks can detect albumin-to-creatinine and total protein-to-creatinine ratios which can help to avoid errors associated with diluted or concentrated urines and non-albumin proteinuria, respectively. - Sulfosalicylic acid test (SSA): Use of SSA is indicated in patients with the possibility of myeloma in the presence of negative or trace dipstick with renal function impairment. Adding SSA to the urine precipitates all proteins, therefore positive dipstick with SSA demonstrates overflow or tubular proteinuria. - False-positive result: Administration of radiocontrast agents (iodinated), gross hematuria, penicillin. - False-positive result: Administration of radiocontrast agents (iodinated), gross hematuria, penicillin. Quantitative measures - 24-hour urine collection: It is the gold standard test to determine the amount of proteinuria in patients who presents with persistent proteinuria (normal value < 150 mg/day). As collecting urine for 24 is cumbersome and erroneous, spot urine of first and second morning samples with protein-creatinine ratio can be used as an estimate of total protein excretion in 24 hour.[18] - It is the gold standard test to determine the amount of proteinuria in patients who presents with persistent proteinuria (normal value < 150 mg/day). As collecting urine for 24 is cumbersome and erroneous, spot urine of first and second morning samples with protein-creatinine ratio can be used as an estimate of total protein excretion in 24 hour.[18] - Urine creatinine is higher in individuals with higher body muscle mass, therefore urine-protein ratio underestimates proteinuria, similarly in cachectic patients with lower muscle mass, urine-protein ratio overestimates the degree of proteinuria. - Renal biopsy: Renal biopsy is indicated in: All nephrotic range proteinuria (> 3.5 gr/day) Non-nephrotic range proteinuria with: Active urine sediment Persistent proteinuria > 1 gr/day Decreased GFR Progression of proteinuria or developing active sediment or hypertension - All nephrotic range proteinuria (> 3.5 gr/day) - Non-nephrotic range proteinuria with: Active urine sediment Persistent proteinuria > 1 gr/day Decreased GFR Progression of proteinuria or developing active sediment or hypertension - Active urine sediment - Persistent proteinuria > 1 gr/day - Decreased GFR - Progression of proteinuria or developing active sediment or hypertension ## History and Symptoms History: - Fever - Cardiac disease - Renal disease - Infections (HIV, hepatitis) - Frothy, smoky, red urine - Edema - Hypertension - Diabetes - Family history of systemic or renal disease - Hypercholesterolemia - Chronic inflammatory diseases - Medications Symptoms: - Systemic symptoms (fever, night sweats, weight loss, bone pain) - Heart diseases - Edema (ankle, periorbital, labial, scrotal) - Hypertension - Hematuria ## Physical Examination - Check for blood pressure, orthostatic and supine - Measure JVP - Weight changes - Edema - Signs of infectious diseases - Signs of heart diseases - Signs of systemic diseases - Signs for complications (thrombosis, infections) - ## Laboratory Findings Laboratory investigations to be considered in proteinuria: - Fasting blood glucose, HbA1c - Hemoglobin, Hematocrit - Serum urate - Serum albumin, lipid levels - Serum electrolytes - ESR - HIV, VDRL, hepatitis serologic tests - Serum and urine protein electrophoresis - Complement C3, C4 levels - Antistreptolysin O titer - ANA - Renal ultrasound - Chest radiography # Treatment ## Medical Therapy Specific treatments of proteinuria demands proper diagnosis of the causes. For the details on the treatments of glomerular diseases, click here. For the details on the treatments of tubular diseases, click here. Non-specific treatments reduce the amount of proteinuaria and the rate of progression or address the complications of proteinuria. - Diuretics: The treatment of fluid overload in patients with moderate to severe proteinuria along with salt restriction is diuretics. For refractory cases two different class of diuretics are used if the increasing doses are not effective.[19] Acute renal failure is the consequence of aggressive therapy with diuretics. - The treatment of fluid overload in patients with moderate to severe proteinuria along with salt restriction is diuretics. - For refractory cases two different class of diuretics are used if the increasing doses are not effective.[19] - Acute renal failure is the consequence of aggressive therapy with diuretics. - ACE inhibitors and ARBs: These agents decrease the progression and the amount of proteinuria by decreasing the intraglomerular pressure.[20] Inhibiting vasoconstriction of efferent arterioles, maintaining the glomerular-capillary wall and decreasing the sclerosis and fibrosis of glomerulus are the action of these drugs aside the anti-hypertensive effects.[21] In normotensive individuals with proteinuria low dose of these drugs have the effect without evident hypotension.[22] Adverse effects of ACE inhibitors are cough, angioedema and hyperkalemia. - These agents decrease the progression and the amount of proteinuria by decreasing the intraglomerular pressure.[20] - Inhibiting vasoconstriction of efferent arterioles, maintaining the glomerular-capillary wall and decreasing the sclerosis and fibrosis of glomerulus are the action of these drugs aside the anti-hypertensive effects.[21] - In normotensive individuals with proteinuria low dose of these drugs have the effect without evident hypotension.[22] - Adverse effects of ACE inhibitors are cough, angioedema and hyperkalemia. - Mineralocorticoind receptor antagonists Adding mineralocorticoid receptor antagonists like eplerenone and spironolactone, help reducing proteinuria further but increase the rate of hyperkalemia. Eplerenone is the new drug in this category which is not associated with hyperkalemia. - Adding mineralocorticoid receptor antagonists like eplerenone and spironolactone, help reducing proteinuria further but increase the rate of hyperkalemia. - Eplerenone is the new drug in this category which is not associated with hyperkalemia. - Anticoagulants: Urinary loss of proteins in the urine especially anticoagulant proteins like antithrombin III, protein S, and protein C put the patients at the risk of thrombosis and emboli. There is no evidence supporting the use of anticoagulants as prophylaxis in nephrotic syndrome. Warfarin is recommended in patients with severe albuminuria (serum albumin < 2.5 g/dL). - Urinary loss of proteins in the urine especially anticoagulant proteins like antithrombin III, protein S, and protein C put the patients at the risk of thrombosis and emboli. - There is no evidence supporting the use of anticoagulants as prophylaxis in nephrotic syndrome. - Warfarin is recommended in patients with severe albuminuria (serum albumin < 2.5 g/dL). - Calcium-channel blockers: Diltiazem and verapamil decrease proteinuria by prevent vasoconstriction of both afferent and efferent arterioles. Other CCBs act on afferent arterioles only which worsen proteinuria. New drugs such as efonidipine and benidipine are used along with ARBs and ACE inhibitors in proteinuria.[23] [24] - Diltiazem and verapamil decrease proteinuria by prevent vasoconstriction of both afferent and efferent arterioles. - Other CCBs act on afferent arterioles only which worsen proteinuria. - New drugs such as efonidipine and benidipine are used along with ARBs and ACE inhibitors in proteinuria.[23] [24] - Vitamin D: Down-regulating gene expression and immunosuppressive characteristic of vitamin D and its analogues help decrease proteinuria by blocking the renin-angiotensin-aldosterone system.[25] - Down-regulating gene expression and immunosuppressive characteristic of vitamin D and its analogues help decrease proteinuria by blocking the renin-angiotensin-aldosterone system.[25] - Management of infections: Antibiotics and vaccines are indicated for the treatment and prophylaxis of infectious diseases in individuals with proteinuria due to loss of immunoglobulins, complements, and circulating blood T cells. - Antibiotics and vaccines are indicated for the treatment and prophylaxis of infectious diseases in individuals with proteinuria due to loss of immunoglobulins, complements, and circulating blood T cells. - Diet: Excessive salt consumption decreases the effect of antihypertensive medications and leads to end-stage renal failure. - Excessive salt consumption decreases the effect of antihypertensive medications and leads to end-stage renal failure. ## Primary Prevention - Primary prevention of proteinuria includes early diagnosis and treatment of diseases which lead to proteinuria. ## Secondary Prevention - Effective measures for secondary prevention of proteinuria include: - Monitor the level of proteinuria to assess the progression of the disease Monitor and treat lipid abnormalities - Monitor the level of proteinuria to assess the progression of the disease - Monitor and treat lipid abnormalities - Check for effectiveness of the therapy and medications' side effects Monitor the renal function regularly Monitor and treat the complications of proteinuria Monitor for new signs of other diseases to address the treatment properly - Check for effectiveness of the therapy and medications' side effects - Monitor the renal function regularly - Monitor and treat the complications of proteinuria - Monitor for new signs of other diseases to address the treatment properly # Related Chapters - Albuminuria - Microalbuminuria - List of terms associated with diabetes	https://www.wikidoc.org/index.php/Ddx:Proteinuria
76470ca16e6f0885324df4fd72d8aed362bd97f0	wikidoc	Vision loss	Vision loss Synonyms and keywords: Visual loss # Overview Vision loss is the absence of vision where it existed before, which can happen either acutely (i.e. abruptly) or chronically (i.e. over a long period of time). It may be caused by media opacities, retinal disease, optic nerve disease, visual pathway disorders, or functional disorders, or it may be due to an abnormality in the central nervous system. # Classification In order to gain insight into the pathophysiology of vision loss which will in turn guide treatment decisions, the signs and symptoms should be characterized: - Unilateral - Bilateral - Transient - Persistant - Sudden - Gradual - Painless - Painful # Pathophysiology ## Media Opacity Opacities of the clear refractive media of the eye such as the cornea, anterior chamber, lens, and vitreous humor may cause acute visual loss as manifested by blurry vision or reduced visual acuity. While pupillary reflexes may be affected, these conditions generally do not cause a relative afferent pupillary defect. Causes of media opacity include corneal edema, hyphema, cataract and vitreous hemorrhage. ## Retinal Disease Retinal diseases may cause sudden visual loss. Because the retina is being affected, there is usually a concomitant relative afferent pupillary defect. Conditions that affect or destroy the retina include retinal detachment; macular disease (e.g., macular degeneration); and retinal vascular occlusions, the most important of which is central retinal artery occlusion. ## Optic Nerve Disease Diseases which affect the optic nerve may cause acute visual loss. Signs include an abnormal pupillary reflex, with an afferent pupillary defect when the optic nerve disease is unilateral. The optic nerve can be affected by many diseases including optic neuritis, retrobulbar neuritis, papillitis, papilledema, glaucoma, ischemic optic neuropathy, and giant cell arteritis. ## Hypoxia The eye is very sensitive to restriction of its supply of oxygen. A dimming of vision (a brownout or greyout) accompanied by loss of peripheral perception may result from low blood pressure, shock, g-LOC (an aviation related problem) or simply standing up suddenly, especially if sick or otherwise infirm. Vision usually returns readily once the conditions restricting blood flow are lifted. ## Visual Pathway Disorder Visual pathway disorders are any problems that may impede the visual pathway. Rarely, acute visual loss is caused by homonymous hemianopia and, more rarely, cortical blindness. ## Functional Disorder The term functional disorder is now used where hysterical and malingering were historically used. This shift recognizes the inherent inability of the physician to identify the subjective experience of a patient (and thus whether that patient can truly see or not). # Causes ## Transient Vision Loss (<24 hours) - Amaurosis fugax - Vision loss is unilateral and lasts only minutes - Migrane - Vision loss lasts 10-60 minutes - Ocular ischemic syndrome (Cartoid Occlusive Disease) - Papilledema - Raised intracranial pressure - Malignant hypertension - Retinal detachment - Sudden change in blood pressure - Orthostatic hypotension - Transient acute increase in thraocular pressure - Acute Angle Closure Glaucoma - Retro-or peribulbar hemorrhage - Vertebrobasilar artery insufficiency - Vision loss is bilateral and lasts minutes - Vitreous hemorrhage - Vitreous detachment ## Vision Loss > 24 hours:Sudden, Painless - Exposure(Welder's flash) - prolonged exposure to intense light/sunlight - Ischemic optic neuropathy - To prevent permanent loss, rule out giant cell/temporal arteritis - Other retinal or central nervous system disease - Occipital lobe CVA causing cortical blindness - Optic Neuritis - Retinal artery/vein occlusion - Retinal detachment - Vitreous or aqueous hemmorrhage (hyphema) ## Vision Loss >24 hours:Gradual, Painless - Cataracts - Cerebral Neoplasm - Chronic retinopathy - Age related macular degeneration - Diabetic Retinopathy - Chronic corneal disease - Corneal dystrophy - Corneal Ulcer - Open angle Glaucoma - Optic neuropathy/atrophy - Compressive lesion - Toxic-metabolic cause - Radiation - Pseudotumor cerebri - Refractive error - Retitnitis pigmentosa ## Vision Loss >24 hours:Painful - Acute Angle Closure Glaucoma - Corneal hydrops - Keratoconus - Corneal abrasion/ulcer - Herepes simplex/zoster - Ocular onchocerciasis - "River blindness" - Onchocera volvulus worm - Optic neuritis - Orbital apex/superior orbital fissure/cavernous sinus syndrome - Uveitis ## Life-Threatening Causes ## Common Causes ## Causes by Organ System ## Causes in Alphabetical Order - 13q deletion syndrome - 2-hydroxyglutaricaciduria - 3 alpha methylglutaconicaciduria - 3-methylglutaconic aciduria - Acanthamoeba - Achromatopsia - Acromegaloid - Acute disseminated encephalomyelitis - Acute posterior multifocal placoid pigment epitheliopathy - Acute retinal necrosis - Age-related macular degeneration - Al amyloidosis - Albinism - Alezzandrini syndrome - Alpers' disease - Alport syndrome - Alström syndrome - Alveolar hydatid disease - Amaurosis congenita of leber - Amaurosis fugax - Amblyopia - Amelogenesis imperfecta - Amitriptyline - Ampola syndrome - Anencephaly - Angioid streaks - Aniridia - Anisometropia - Anophthalmia - Anophthalmos - Anterior segment mesenchymal dysgenesis - Arachnoiditis - Arteriovenous malformation - Aspartoacylase deficiency - Asthenopia - Atherosclerosis - Autoimmune uveitis - Avitaminosis - Axenfeld-rieger syndrome - Bardet-biedl syndrome - Basement membrane corneal dystrophy - Basilar artery insufficiency syndrome - Basilar artery migraine - Batten disease - Behcet's disease - Benign essential blepharospasm - Besnier-boeck-schaumann disease - Bessman-baldwin syndrome - Best vitelliform macular dystrophy - Best's disease - Bilateral occipital lobe infarct - Bilateral optic neuritis - Bilateral papilloedema - Blepharitis - Blind spot - Blindness - Blue cone monochromatism - Blue diaper syndrome - Blue-ringed octopus poisoning - Bonnet-dechaume-blanc syndrome - Bothnia retina dystrophy - Brain aneurysm - Brain tumors - Calcification of basal ganglia - Canavan leukodystrophy - Car syndrome - Carbachol - Carbamazepine - Cardiomyopathy - Carotid atherosclerosis - Carotid-cavernous fistula - Cartilaginous - Cassia stocco dos santos syndrome - Cataract - Catastrophic antiphospholipid syndrome - Celecoxib - Cenani lenz syndactylism - Central retinal artery occlusion - Central retinal vein occlusion - Central serous chorioretinopathy - Cerebral palsy - Cerebrovascular accident - Ceroid lipofuscinosis - Cesium - Chalazion - Chandler's syndrome - Charcot-marie-tooth syndrome - Charge syndrome - Chemical adverse reaction - Chemical burn - Chlorpheniramine - Chorioretinitis - Choroideremia - Choroiditis - Chromosome 11, deletion 11p - Chromosome 13, partial monosomy 13q - Chromosome 13q deletion syndrome - Chromosome 13q deletion - Chromosome 14q, partial deletion - Chromosome 17, deletion 17q23 q24 - Chromosome 2p deletion syndrome - Ciliary muscle spasm - Cinnarizine - Citrullinemia - Classic childhood ald - Clomifene - Cloudy cornea (patient information) - Cluster headache - Cobra poisoning - Coenzyme q - cytochrome c reductase - Cogan-reese syndrome - Cogan's syndrome - Cohen syndrome - Coloboma - Color blindness - Concussion - Cone dystrophy - Cone rod dystrophy - Congenital cytomegalovirus infection - Congenital disorder of glycosylation type 1g - Congenital rubella syndrome - Congenital toxoplasmosis - Congenital x-linked retinoschisis - Conversion disorder - Cornea plana 1 - Corneal dystrophy - Corneal foreign body - Corneal hypesthesia - Corneal opacity - Corneal ulcer - Cortical blindness - Cortical hyperostosis - Craniodiaphyseal dysplasia - Craniometaphyseal dysplasia - Craniosynostosis - Craniotelencephalic dysplasia - Cree leukoencephalopathy - Creutzfeldt jakob disease - Cross syndrome - Cycloplegia - Cystoid macular dystrophy - Cytomegalovirus retinitis - Cytomegalovirus - Daphne poisoning - Deferoxamine - Deletion 11p - Deletion 13q - Dermatoosteolysis - Desferrioxamine toxicity - Desipramine - Devic disease - Diabetes insipidus - Diabetic eye disease - Diabetic ketoacidosis - Diabetic retinopathy - Didmoad syndrome - Diphenhydramine - Dothiepin - Drugs - Dry eye - Dysosteosclerosis - Eales disease - Ebola - Ectodermal dysplasia - Ehlers-danlos syndrome - Emanuel syndrome - Empty sella syndrome - Encephalocele - Encephalocele anterior - Encephalocele frontal - Endophthalmitis - Enhanced s-cone syndrome - Episodic ataxia - Essential iris atrophy - Esthesioneuroblastoma - Euphorbiaceae - Eye cancer - Eye injury - Eye melanoma - Fahr's syndrome - Familial amyloid polyneuropathy - Familial infantile metachromatic leukodystrophy - Feline spongiform encephalopathy - Fetal methylmercury syndrome - Flynn-aird syndrome - Foreign body - Franceschetti-klein syndrome - Francois dyscephalic syndrome - Fuchs atrophia gyrata chorioideae et retinae - Fuchs' dystrophy - Fundus albipunctatus - Galactokinase deficiency - Gangliosidosis - Ghose-sachdev-kumar syndrome - Giant cell arteritis - Glaucoma - Glioblastoma - Goldberg–shprintzen syndrome - Graves ophthalmopathy - Gronblad-strandberg-touraine syndrome - Gustavson syndrome - Hallervorden-spatz syndrome - Hand-schuller-christian syndrome - Head injury - Heidenhain syndrome - Helminth infections - Hemianopia - Hereditary diseases - Herns syndrome - Herpes - Herpes simplex - Herpetic keratitis - Hiv - Homonymous hemianopia - Hurler syndrome - Hydranencephaly - Hydrocephalus - Hydroxyzine - Hyperopia - Hyperornithinemia - Hypertension of pregnancy - Hyphema - Hypoglycaemia - Hypophosphatemia - Hysteria - Imidazole syndrome - Incontinentia pigmenti - Increased intracranial pressure - Infant cytomegalic virus - Infantile cortical hyperostosis - Infantile neuroaxonal dystrophy - Infantile refsum disease - Inflammatory processes - Intraocular hemorrhage - Intraocular melanoma - Intraocular pressure - Iridocorneal endothelial syndrome - Iridocyclitis - Iridogoniodysgenesis - Ischemic optic neuropathy - Ivabradine - Jensen syndrome - Juvenile retinoschisis - Kallmann syndrome - Kearns–sayre syndrome - Keratitis - Keratomalacia - Krabbe leukodystrophy - Krause-kivlin syndrome - Langerhans cell histiocytosis - Lattice corneal dystrophy - Lawrence-moon syndrome - Leber's congenital amaurosis - Leber's optic atrophy - Leg absence - Lens pathology - Leprosy - Lethal congenital contracture syndrome - Leukodystrophy - Linear iga bullous dermatosis - Lithium - Lobstein disease - Lord - Lowe oculocerebrorenal syndrome - Lymphoma - Macular degeneration - Macular dystrophy - Macular edema - Macular hole - Maculopathy - Malignant hypertension - Marsden syndrome - Marshall syndrome - Mefloquine - Melanoma of the choroid - Mental retardation - Mercaptolactace-cysteine disulfiduria - Mercury poisoning - Metachromatic leukodystrophy - Metamorphopsia - Metaphyseal dysplasia - Methanol - Microcephaly - Microphthalmia - Microphthalmos - Microvascular diabetes complications - Microvascular disease - Midline craniofacial anomalies - Migraine - Minamata disease - Mitochondrial disease - Monosodium methanarsenate - Monosodium methyl arsenate - Morning glory disc anomaly - Morpholine - Mucolipidosis - Mucopolysaccharidosis - Mucormycosis - Mucosa-associated lymphoid tissue - Mucous membrane pemphigoid - Multifocal choroiditis - Multiple endocrine neoplasia type 1 - Multiple lentigines syndrome - Multiple sclerosis - Mycosis fungoides - Nalidixic acid - Nasopharyngeal carcinoma - Nasopharyngeal carcinoma - Nasopharynx cancer - Nelson syndrome - Neuroaxonal dystrophy - Neurodegeneration with brain iron accumulation - Neurodegenerative syndrome - Neurofibromatosis - Neuromyelitis optica - Neuropathic ataxia - Neuropathy - Niemann-pick disease - Night blindness - Noble-bass-sherman syndrome - Norrie syndrome - Nortriptyline - Nutritional amblyopia - Nutritional deficiencies - Nyssen-van bogaert syndrome - Obal syndrome - Occipital lobe tumours - Ocular cicatricial pemphigoid - Ocular herpes - Ocular histoplasmosis syndrome - Ocular ischemic syndrome - Ocular oncology - Ocular trauma - Oculocerebrorenal syndrome - Oculocutaneous albinism - Oguchi disease - Oligodontia - Olivopontocerebellar atrophy - Open-angle glaucoma - Ophthalmia neonatorum - Ophthalmoplegia - Optic atrophy - Optic nerve compression - Optic nerve disorder - Optic neuritis - Optic pathway glioma - Opticoacoustic nerve atrophy dementia - Orbit tumour - Orbital lymphangioma - Orbital mass - Ornithine translocase deficiency - Osteochondrodysplatic dwarfism - Osteoporosis - Pachydermoperiostosis - Pantothenate kinase-associated neurodegeneration - Panuveitis - Papilledema - Papillitis - Papilloedema - Papilloedema - Paraneoplastic cerebellar degeneration - Partial monosomy 13q - Pellagra-like syndrome - Pepper spray - Periorbital cellulitis - Peripheral type neurofibromatosis - Phacolytic glaucoma - Phenylbutazone - Phenytoin toxicity - Phosgene oxime - Photopsia - Physostigmine - Pigmentary retinopathy - Pipecolic acidemia - Pituitary adenoma - Plant poisoning - Plum syndrome - Polychondritis - Posterior column ataxia - Posterior leucoencephalopathy syndrome - Posterior vitreous detachment - Pre-eclampsia - Pregnancy toxemia - Presbyopia - Presumed ocular histoplasmosis syndrome - Prochlorperazine - Progressive multifocal leukoencephalopathy - Progressive supranuclear palsy - Protanopia - Pseudotumor cerebri - Pseudoxanthoma elasticum - Psychogenic - Pterygium - Purtscher's retinopathy - Pyle disease - Pyruvate decarboxylase - Pyruvate decarboxylase deficiency - Quinidine - Raised intraocular pressure - Ramos-arroyo syndrome - Reese-ellsworth syndrome - Refractive error - Refsum disease - Renal tubulopathy - Retinal artery occlusion - Retinal cone dystrophy - Retinal degeneration - Retinal detachment - Retinal dysplasia - Retinal migraine - Retinal tear - Retinal vein occlusion - Retinitis pigmentosa - Retinitis punctata albescens - Retinoblastoma - Retinopathy - Retinoschisis - Retrolental fibroplasia - Rhabditida - Rhabdomyosarcoma - Rhinocerebral mucormycosis - Rhinocerebral zygomycosis - Rhino-orbito-cerebral phycomycosis - Rieger syndrome - Rift valley fever - Roberts syndrome - Rofecoxib - Rollet syndrome - Roy-maroteaux-kremp syndrome - Rufous oculocutaneous albinism - Sandhoff disease - Sarcoidosis - Schindler disease - Scleritis - Sclerosteosis - Sclerostin - Secernentea - Senile macular degeneration - Senile retinoschisis - Senior-loken syndrome - Senter syndrome - Septo-optic dysplasia - Septum pellucidum - Shaken baby syndrome - Shingles - Sialidosis - Sickle cell anemia - Simell-takki syndrome - Singh-chhaparwal-dhanda syndrome - Small syndrome - Smith martin dodd syndrome - Spastic tetraplegic - Spherophakia-brachymorphia syndrome - Spinocerebellar ataxia - Stargardt disease - Stevens-johnson syndrome - Stickler syndrome - Striped blister beetle poisoning - Stroke - Subacute combined degeneration of the cord - Subacute myelo-optic neuropathy - Subacute sclerosing leukoencephalitis - Subacute sclerosing panencephalitis - Sudanophilic cerebral sclerosis - Superior orbital fissure - Syndactyly - Syphilis - Takayasu arteritis - Tapetal-like reflex - Tay-sachs disease - Temozolomide - Temporal arteritis - Thalidomide - Thallium poisoning - Thanos syndrome - Thyroid eye disease - Tolosa-hunt syndrome - Toxins - Toxoplasmosis - Trachoma - Transient ischaemic attack - Transthyretin amyloidosis - Treacher collins syndrome - Usher syndrome - Uveal diseases - Uveal melanoma - Uveitis - Vascular diseases - Vascular retinopathies - Vasculitis - Vasterbotten dystrophy - Verloes van maldergem marneffe syndrome - Vertebral artery dissection - Verteporfin - Vigabatrin - Vision impairment - Visual hallucinations - Vitamin a deficiency - Vitelliform macular dystrophy - Vitreous detachment - Vitreous floaters - Vitreous hemorrhage - Von hippel-lindau disease - Wagener syndrome - Wagner-stickler syndrome - Wagr syndrome - Wegener's granulomatosis - Wegener's granulomatosis - Weill-marchesani syndrome - Wells jankovic syndrome - Wildervanck syndrome - Wilms tumor - Winchester syndrome - Wolf-hirschhorn syndrome - Wolfram syndrome - Woods black norbury syndrome - Wrinkly skin syndrome - Wyburn-mason syndrome - Xanthomatosis cerebrotendinous - X-linked congenital stationary night blindness - X-linked intellectual disability - Ziconotide - Zunich neuroectodermal syndrome - Zygomycosis # Diagnosis ## History and Symptoms History include: - Age - Onset: - Rate of loss - Any specific trauma - Headaches - Medication - Specific medical history - Alcohol, drug and/or tabacco use ## Physical Examination ### Eyes The examination should focus on: - Acuity - Blood pressure - Color vision - Cranial exam - cranial nerve innervation - Fundus - Intraocular pressure - Ocular media opacity - Optic disc exam ## Laboratory Findings - ESR - Fasting blood glucose - HgBa1c - PPD - RPR - FTR-ABS - ACE level - Vitamin B12 - Folate ## MRI and CT - CT/MRI of head and chest # Evaluation of Monocular Transient Visual Loss Abbreviations: TVL, transient visual loss. # Treatment ## Medical Therapy - Systemic Steroids can be prescribed for the following: - Temporal arteritis - Optic neuritis - Pituitary apoplexy - Herpes zoster - Nonarteritic ischemic optic neuropathy patients - Asprin - Cavernous sinus thrombosis - Antibiotics - Anticoagulation - Corneal hydrops - Cycloplegic,hypertonic NaCl ointment ## Surgery ## Corneal Hydrops Corneal transplant ## Retinal Detachment Surgical repair ## Cataracts Surgical removal ## Temporal Arteritis Temporal biopsy and steroids. # Related Chapters - Blindness - Eye examination - Low vision - Visual acuity - Visual impairment	Vision loss For patient information, click here Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Jyostna Chouturi, M.B.B.S [2] Associate Editor(s)-in-Chief: Luke Rusowicz-Orazem, B.S. Synonyms and keywords: Visual loss # Overview Vision loss is the absence of vision where it existed before, which can happen either acutely (i.e. abruptly) or chronically (i.e. over a long period of time). It may be caused by media opacities, retinal disease, optic nerve disease, visual pathway disorders, or functional disorders, or it may be due to an abnormality in the central nervous system. # Classification In order to gain insight into the pathophysiology of vision loss which will in turn guide treatment decisions, the signs and symptoms should be characterized: - Unilateral - Bilateral - Transient - Persistant - Sudden - Gradual - Painless - Painful # Pathophysiology ## Media Opacity Opacities of the clear refractive media of the eye such as the cornea, anterior chamber, lens, and vitreous humor may cause acute visual loss as manifested by blurry vision or reduced visual acuity. While pupillary reflexes may be affected, these conditions generally do not cause a relative afferent pupillary defect. Causes of media opacity include corneal edema, hyphema, cataract and vitreous hemorrhage. ## Retinal Disease Retinal diseases may cause sudden visual loss. Because the retina is being affected, there is usually a concomitant relative afferent pupillary defect. Conditions that affect or destroy the retina include retinal detachment; macular disease (e.g., macular degeneration); and retinal vascular occlusions, the most important of which is central retinal artery occlusion. ## Optic Nerve Disease Diseases which affect the optic nerve may cause acute visual loss. Signs include an abnormal pupillary reflex, with an afferent pupillary defect when the optic nerve disease is unilateral. The optic nerve can be affected by many diseases including optic neuritis, retrobulbar neuritis, papillitis, papilledema, glaucoma, ischemic optic neuropathy, and giant cell arteritis. ## Hypoxia The eye is very sensitive to restriction of its supply of oxygen. A dimming of vision (a brownout or greyout) accompanied by loss of peripheral perception may result from low blood pressure, shock, g-LOC (an aviation related problem) or simply standing up suddenly, especially if sick or otherwise infirm. Vision usually returns readily once the conditions restricting blood flow are lifted. ## Visual Pathway Disorder Visual pathway disorders are any problems that may impede the visual pathway. Rarely, acute visual loss is caused by homonymous hemianopia and, more rarely, cortical blindness. ## Functional Disorder The term functional disorder is now used where hysterical and malingering were historically used. This shift recognizes the inherent inability of the physician to identify the subjective experience of a patient (and thus whether that patient can truly see or not). # Causes ## Transient Vision Loss (<24 hours) - Amaurosis fugax - Vision loss is unilateral and lasts only minutes - Migrane - Vision loss lasts 10-60 minutes - Ocular ischemic syndrome (Cartoid Occlusive Disease) - Papilledema - Raised intracranial pressure - Malignant hypertension - Retinal detachment - Sudden change in blood pressure - Orthostatic hypotension - Transient acute increase in thraocular pressure - Acute Angle Closure Glaucoma - Retro-or peribulbar hemorrhage - Vertebrobasilar artery insufficiency - Vision loss is bilateral and lasts minutes - Vitreous hemorrhage - Vitreous detachment ## Vision Loss > 24 hours:Sudden, Painless - Exposure(Welder's flash) - prolonged exposure to intense light/sunlight - Ischemic optic neuropathy - To prevent permanent loss, rule out giant cell/temporal arteritis - Other retinal or central nervous system disease - Occipital lobe CVA causing cortical blindness - Optic Neuritis - Retinal artery/vein occlusion - Retinal detachment - Vitreous or aqueous hemmorrhage (hyphema) ## Vision Loss >24 hours:Gradual, Painless - Cataracts - Cerebral Neoplasm - Chronic retinopathy - Age related macular degeneration - Diabetic Retinopathy - Chronic corneal disease - Corneal dystrophy - Corneal Ulcer - Open angle Glaucoma - Optic neuropathy/atrophy - Compressive lesion - Toxic-metabolic cause - Radiation - Pseudotumor cerebri - Refractive error - Retitnitis pigmentosa ## Vision Loss >24 hours:Painful - Acute Angle Closure Glaucoma - Corneal hydrops - Keratoconus - Corneal abrasion/ulcer - Herepes simplex/zoster - Ocular onchocerciasis - "River blindness" - Onchocera volvulus worm - Optic neuritis - Orbital apex/superior orbital fissure/cavernous sinus syndrome - Uveitis ## Life-Threatening Causes ## Common Causes ## Causes by Organ System ## Causes in Alphabetical Order - 13q deletion syndrome - 2-hydroxyglutaricaciduria - 3 alpha methylglutaconicaciduria - 3-methylglutaconic aciduria - Acanthamoeba - Achromatopsia - Acromegaloid - Acute disseminated encephalomyelitis - Acute posterior multifocal placoid pigment epitheliopathy - Acute retinal necrosis - Age-related macular degeneration - Al amyloidosis - Albinism - Alezzandrini syndrome - Alpers' disease - Alport syndrome - Alström syndrome - Alveolar hydatid disease - Amaurosis congenita of leber - Amaurosis fugax - Amblyopia - Amelogenesis imperfecta - Amitriptyline - Ampola syndrome - Anencephaly - Angioid streaks - Aniridia - Anisometropia - Anophthalmia - Anophthalmos - Anterior segment mesenchymal dysgenesis - Arachnoiditis - Arteriovenous malformation - Aspartoacylase deficiency - Asthenopia - Atherosclerosis - Autoimmune uveitis - Avitaminosis - Axenfeld-rieger syndrome - Bardet-biedl syndrome - Basement membrane corneal dystrophy - Basilar artery insufficiency syndrome - Basilar artery migraine - Batten disease - Behcet's disease - Benign essential blepharospasm - Besnier-boeck-schaumann disease - Bessman-baldwin syndrome - Best vitelliform macular dystrophy - Best's disease - Bilateral occipital lobe infarct - Bilateral optic neuritis - Bilateral papilloedema - Blepharitis - Blind spot - Blindness - Blue cone monochromatism - Blue diaper syndrome - Blue-ringed octopus poisoning - Bonnet-dechaume-blanc syndrome - Bothnia retina dystrophy - Brain aneurysm - Brain tumors - Calcification of basal ganglia - Canavan leukodystrophy - Car syndrome - Carbachol - Carbamazepine - Cardiomyopathy - Carotid atherosclerosis - Carotid-cavernous fistula - Cartilaginous - Cassia stocco dos santos syndrome - Cataract - Catastrophic antiphospholipid syndrome - Celecoxib - Cenani lenz syndactylism - Central retinal artery occlusion - Central retinal vein occlusion - Central serous chorioretinopathy - Cerebral palsy - Cerebrovascular accident - Ceroid lipofuscinosis - Cesium - Chalazion - Chandler's syndrome - Charcot-marie-tooth syndrome - Charge syndrome - Chemical adverse reaction - Chemical burn - Chlorpheniramine - Chorioretinitis - Choroideremia - Choroiditis - Chromosome 11, deletion 11p - Chromosome 13, partial monosomy 13q - Chromosome 13q deletion syndrome - Chromosome 13q deletion - Chromosome 14q, partial deletion - Chromosome 17, deletion 17q23 q24 - Chromosome 2p deletion syndrome - Ciliary muscle spasm - Cinnarizine - Citrullinemia - Classic childhood ald - Clomifene - Cloudy cornea (patient information) - Cluster headache - Cobra poisoning - Coenzyme q - cytochrome c reductase - Cogan-reese syndrome - Cogan's syndrome - Cohen syndrome - Coloboma - Color blindness - Concussion - Cone dystrophy - Cone rod dystrophy - Congenital cytomegalovirus infection - Congenital disorder of glycosylation type 1g - Congenital rubella syndrome - Congenital toxoplasmosis - Congenital x-linked retinoschisis - Conversion disorder - Cornea plana 1 - Corneal dystrophy - Corneal foreign body - Corneal hypesthesia - Corneal opacity - Corneal ulcer - Cortical blindness - Cortical hyperostosis - Craniodiaphyseal dysplasia - Craniometaphyseal dysplasia - Craniosynostosis - Craniotelencephalic dysplasia - Cree leukoencephalopathy - Creutzfeldt jakob disease - Cross syndrome - Cycloplegia - Cystoid macular dystrophy - Cytomegalovirus retinitis - Cytomegalovirus - Daphne poisoning - Deferoxamine - Deletion 11p - Deletion 13q - Dermatoosteolysis - Desferrioxamine toxicity - Desipramine - Devic disease - Diabetes insipidus - Diabetic eye disease - Diabetic ketoacidosis - Diabetic retinopathy - Didmoad syndrome - Diphenhydramine - Dothiepin - Drugs - Dry eye - Dysosteosclerosis - Eales disease - Ebola - Ectodermal dysplasia - Ehlers-danlos syndrome - Emanuel syndrome - Empty sella syndrome - Encephalocele - Encephalocele anterior - Encephalocele frontal - Endophthalmitis - Enhanced s-cone syndrome - Episodic ataxia - Essential iris atrophy - Esthesioneuroblastoma - Euphorbiaceae - Eye cancer - Eye injury - Eye melanoma - Fahr's syndrome - Familial amyloid polyneuropathy - Familial infantile metachromatic leukodystrophy - Feline spongiform encephalopathy - Fetal methylmercury syndrome - Flynn-aird syndrome - Foreign body - Franceschetti-klein syndrome - Francois dyscephalic syndrome - Fuchs atrophia gyrata chorioideae et retinae - Fuchs' dystrophy - Fundus albipunctatus - Galactokinase deficiency - Gangliosidosis - Ghose-sachdev-kumar syndrome - Giant cell arteritis - Glaucoma - Glioblastoma - Goldberg–shprintzen syndrome - Graves ophthalmopathy - Gronblad-strandberg-touraine syndrome - Gustavson syndrome - Hallervorden-spatz syndrome - Hand-schuller-christian syndrome - Head injury - Heidenhain syndrome - Helminth infections - Hemianopia - Hereditary diseases - Herns syndrome - Herpes - Herpes simplex - Herpetic keratitis - Hiv - Homonymous hemianopia - Hurler syndrome - Hydranencephaly - Hydrocephalus - Hydroxyzine - Hyperopia - Hyperornithinemia - Hypertension of pregnancy - Hyphema - Hypoglycaemia - Hypophosphatemia - Hysteria - Imidazole syndrome - Incontinentia pigmenti - Increased intracranial pressure - Infant cytomegalic virus - Infantile cortical hyperostosis - Infantile neuroaxonal dystrophy - Infantile refsum disease - Inflammatory processes - Intraocular hemorrhage - Intraocular melanoma - Intraocular pressure - Iridocorneal endothelial syndrome - Iridocyclitis - Iridogoniodysgenesis - Ischemic optic neuropathy - Ivabradine - Jensen syndrome - Juvenile retinoschisis - Kallmann syndrome - Kearns–sayre syndrome - Keratitis - Keratomalacia - Krabbe leukodystrophy - Krause-kivlin syndrome - Langerhans cell histiocytosis - Lattice corneal dystrophy - Lawrence-moon syndrome - Leber's congenital amaurosis - Leber's optic atrophy - Leg absence - Lens pathology - Leprosy - Lethal congenital contracture syndrome - Leukodystrophy - Linear iga bullous dermatosis - Lithium - Lobstein disease - Lord - Lowe oculocerebrorenal syndrome - Lymphoma - Macular degeneration - Macular dystrophy - Macular edema - Macular hole - Maculopathy - Malignant hypertension - Marsden syndrome - Marshall syndrome - Mefloquine - Melanoma of the choroid - Mental retardation - Mercaptolactace-cysteine disulfiduria - Mercury poisoning - Metachromatic leukodystrophy - Metamorphopsia - Metaphyseal dysplasia - Methanol - Microcephaly - Microphthalmia - Microphthalmos - Microvascular diabetes complications - Microvascular disease - Midline craniofacial anomalies - Migraine - Minamata disease - Mitochondrial disease - Monosodium methanarsenate - Monosodium methyl arsenate - Morning glory disc anomaly - Morpholine - Mucolipidosis - Mucopolysaccharidosis - Mucormycosis - Mucosa-associated lymphoid tissue - Mucous membrane pemphigoid - Multifocal choroiditis - Multiple endocrine neoplasia type 1 - Multiple lentigines syndrome - Multiple sclerosis - Mycosis fungoides - Nalidixic acid - Nasopharyngeal carcinoma - Nasopharyngeal carcinoma - Nasopharynx cancer - Nelson syndrome - Neuroaxonal dystrophy - Neurodegeneration with brain iron accumulation - Neurodegenerative syndrome - Neurofibromatosis - Neuromyelitis optica - Neuropathic ataxia - Neuropathy - Niemann-pick disease - Night blindness - Noble-bass-sherman syndrome - Norrie syndrome - Nortriptyline - Nutritional amblyopia - Nutritional deficiencies - Nyssen-van bogaert syndrome - Obal syndrome - Occipital lobe tumours - Ocular cicatricial pemphigoid - Ocular herpes - Ocular histoplasmosis syndrome - Ocular ischemic syndrome - Ocular oncology - Ocular trauma - Oculocerebrorenal syndrome - Oculocutaneous albinism - Oguchi disease - Oligodontia - Olivopontocerebellar atrophy - Open-angle glaucoma - Ophthalmia neonatorum - Ophthalmoplegia - Optic atrophy - Optic nerve compression - Optic nerve disorder - Optic neuritis - Optic pathway glioma - Opticoacoustic nerve atrophy dementia - Orbit tumour - Orbital lymphangioma - Orbital mass - Ornithine translocase deficiency - Osteochondrodysplatic dwarfism - Osteoporosis - Pachydermoperiostosis - Pantothenate kinase-associated neurodegeneration - Panuveitis - Papilledema - Papillitis - Papilloedema - Papilloedema - Paraneoplastic cerebellar degeneration - Partial monosomy 13q - Pellagra-like syndrome - Pepper spray - Periorbital cellulitis - Peripheral type neurofibromatosis - Phacolytic glaucoma - Phenylbutazone - Phenytoin toxicity - Phosgene oxime - Photopsia - Physostigmine - Pigmentary retinopathy - Pipecolic acidemia - Pituitary adenoma - Plant poisoning - Plum syndrome - Polychondritis - Posterior column ataxia - Posterior leucoencephalopathy syndrome - Posterior vitreous detachment - Pre-eclampsia - Pregnancy toxemia - Presbyopia - Presumed ocular histoplasmosis syndrome - Prochlorperazine - Progressive multifocal leukoencephalopathy - Progressive supranuclear palsy - Protanopia - Pseudotumor cerebri - Pseudoxanthoma elasticum - Psychogenic - Pterygium - Purtscher's retinopathy - Pyle disease - Pyruvate decarboxylase - Pyruvate decarboxylase deficiency - Quinidine - Raised intraocular pressure - Ramos-arroyo syndrome - Reese-ellsworth syndrome - Refractive error - Refsum disease - Renal tubulopathy - Retinal artery occlusion - Retinal cone dystrophy - Retinal degeneration - Retinal detachment - Retinal dysplasia - Retinal migraine - Retinal tear - Retinal vein occlusion - Retinitis pigmentosa - Retinitis punctata albescens - Retinoblastoma - Retinopathy - Retinoschisis - Retrolental fibroplasia - Rhabditida - Rhabdomyosarcoma - Rhinocerebral mucormycosis - Rhinocerebral zygomycosis - Rhino-orbito-cerebral phycomycosis - Rieger syndrome - Rift valley fever - Roberts syndrome - Rofecoxib - Rollet syndrome - Roy-maroteaux-kremp syndrome - Rufous oculocutaneous albinism - Sandhoff disease - Sarcoidosis - Schindler disease - Scleritis - Sclerosteosis - Sclerostin - Secernentea - Senile macular degeneration - Senile retinoschisis - Senior-loken syndrome - Senter syndrome - Septo-optic dysplasia - Septum pellucidum - Shaken baby syndrome - Shingles - Sialidosis - Sickle cell anemia - Simell-takki syndrome - Singh-chhaparwal-dhanda syndrome - Small syndrome - Smith martin dodd syndrome - Spastic tetraplegic - Spherophakia-brachymorphia syndrome - Spinocerebellar ataxia - Stargardt disease - Stevens-johnson syndrome - Stickler syndrome - Striped blister beetle poisoning - Stroke - Subacute combined degeneration of the cord - Subacute myelo-optic neuropathy - Subacute sclerosing leukoencephalitis - Subacute sclerosing panencephalitis - Sudanophilic cerebral sclerosis - Superior orbital fissure - Syndactyly - Syphilis - Takayasu arteritis - Tapetal-like reflex - Tay-sachs disease - Temozolomide - Temporal arteritis - Thalidomide - Thallium poisoning - Thanos syndrome - Thyroid eye disease - Tolosa-hunt syndrome - Toxins - Toxoplasmosis - Trachoma - Transient ischaemic attack - Transthyretin amyloidosis - Treacher collins syndrome - Usher syndrome - Uveal diseases - Uveal melanoma - Uveitis - Vascular diseases - Vascular retinopathies - Vasculitis - Vasterbotten dystrophy - Verloes van maldergem marneffe syndrome - Vertebral artery dissection - Verteporfin - Vigabatrin - Vision impairment - Visual hallucinations - Vitamin a deficiency - Vitelliform macular dystrophy - Vitreous detachment - Vitreous floaters - Vitreous hemorrhage - Von hippel-lindau disease - Wagener syndrome - Wagner-stickler syndrome - Wagr syndrome - Wegener's granulomatosis - Wegener's granulomatosis - Weill-marchesani syndrome - Wells jankovic syndrome - Wildervanck syndrome - Wilms tumor - Winchester syndrome - Wolf-hirschhorn syndrome - Wolfram syndrome - Woods black norbury syndrome - Wrinkly skin syndrome - Wyburn-mason syndrome - Xanthomatosis cerebrotendinous - X-linked congenital stationary night blindness - X-linked intellectual disability - Ziconotide - Zunich neuroectodermal syndrome - Zygomycosis # Diagnosis ## History and Symptoms History include: - Age - Onset: - Rate of loss - Any specific trauma - Headaches - Medication - Specific medical history - Alcohol, drug and/or tabacco use ## Physical Examination ### Eyes The examination should focus on: - Acuity - Blood pressure - Color vision - Cranial exam - cranial nerve innervation - Fundus - Intraocular pressure - Ocular media opacity - Optic disc exam ## Laboratory Findings - ESR - Fasting blood glucose - HgBa1c - PPD - RPR - FTR-ABS - ACE level - Vitamin B12 - Folate ## MRI and CT - CT/MRI of head and chest # Evaluation of Monocular Transient Visual Loss Abbreviations: TVL, transient visual loss. # Treatment ## Medical Therapy - Systemic Steroids can be prescribed for the following: - Temporal arteritis - Optic neuritis - Pituitary apoplexy - Herpes zoster - Nonarteritic ischemic optic neuropathy patients - Asprin - Cavernous sinus thrombosis - Antibiotics - Anticoagulation - Corneal hydrops - Cycloplegic,hypertonic NaCl ointment ## Surgery ## Corneal Hydrops Corneal transplant ## Retinal Detachment Surgical repair ## Cataracts Surgical removal ## Temporal Arteritis Temporal biopsy and steroids. # Related Chapters - Blindness - Eye examination - Low vision - Visual acuity - Visual impairment	https://www.wikidoc.org/index.php/Ddx:Vision_Loss
eb62d70f388e87f0157e3cbee96466ba5d2eaf94	wikidoc	Weight loss	Weight loss Synonyms and keywords: weight reduction, elderly, malignancy, infection, dietary supplements, nutrition. # Overview Weight loss, in the context of medicine or health or physical fitness, is a reduction of the total body weight. An individual may lose weight due to a mean loss of fluid, body fat or adipose tissue and/or lean mass, namely bone mineral deposits, muscle, tendon and other connective tissue. Weight loss is a product of negative energy balance and can be unintentional or intentional. It can be a side effect of therapeutic drugs. The most common cause among the elderly is cancer. A thorough history with nutritional assessment, calorie count, patient's living conditions, neurocognitive dysfunction, appropriate labs and imaging findings are necessary. Until a diagnosis is made, nutritional supplementation should not be delayed in the interest of a patient's health. Treating the underlying cause, regular follow-up, and patient counseling are important components of weight loss management. # Classification - Weight loss is a product of negative energy balance. When the human body spends more energy in work and heat than it is gaining from food or other dietary supplements, it will catabolize stored reserves of fat or muscle. - There is no formal classification system for weight loss. Based on the cause, we attempt to provide a general outline of the types of weight loss. ## Unintentional Weight Loss - A myriad of additional scientific considerations are applicable to weight loss, including but not limited to physiological and exercise sciences, nutrition science, behavioral sciences, and other sciences. - One area involves the science of bioenergetics including biochemical and physiological energy production and utilization systems, that is frequently evidence of diabetes, and ketone bodies, acetone particles occurring in body fluids and tissues involved in acidosis, also known as ketosis, somewhat common in severe diabetes. - Substantial, unintentional weight loss can be a symptom of an acute or chronic illness, especially if other evidence is demonstrated. - Weight loss accompanied by insatiable thirst, hunger and fatigue may indicate diabetes mellitus (DM). To read more about diabetes mellitus, click here. Diabetes characterized by an abnormal accumulation of carbohydrates in the bloodstream due to insufficient production of or tissue resistance to insulin. Poor management of insulin-dependent diabetes mellitus (IDDM), also known as diabetes mellitus type I, leads to an excessive amount of glucose and an insufficient amount of insulin in the bloodstream. It triggers the release of triglycerides from adipose tissues and catabolism of amino acids in the muscle tissue. This results in a loss of both fat and lean mass, predisposing a significant reduction in total body weight. - Infections such as HIV may alter the metabolism, leading to weight loss. * - Hormonal disruptions, such as an overactive thyroid (hyperthyroidism), may also lead to weight loss. - In addition to weight loss due to a reduction in fat and lean mass, illnesses such as diabetes, certain medications, lack of fluid intake, and other factors can trigger fluid loss. A fluid loss in addition to a reduction in fat and lean mass poses a risk for cachexia. Loss of muscle mass in cachexia is due to combined effect of decreased protein synthesis in combination with an increased protein degradation via lysosomes and ubiquitin-proteasome pathway. ## Intentional Weight Loss - Intentional weight loss may refer to the loss of total body mass in an effort to improve fitness, health, or appearance. - It is not uncommon for people who are already at a medically healthy weight to intentionally lose weight. In some cases, it is intending to improve athletic performance or to meet weight classifications in a sport. - In other cases, the goal is to attain a more attractively shaped body. On the other hand, being underweight is associated with health risks. - Health problems can include susceptibility to infections, osteoporosis, decreased muscle strength, trouble regulating body temperature, and even increased risk of death. ## Therapeutic Weight Loss Techniques - Overweight and obese individuals face a greater risk of health conditions such as type 2 diabetes, heart disease, high blood pressure, stroke, osteoarthritis, and certain types of cancers. - Therapeutic weight loss, in individuals who are overweight, can decrease the likelihood of developing diseases such as diabetes. - For healthy weight loss, a physician should be consulted to develop a weight loss plan that is tailored to the individual. The least intrusive weight loss methods and those most often recommended by physicians are lifestyle modifications. Usually, health professionals will recommend that their overweight patients combine a reduction of the caloric content of the diet with an increase in physical activity. - Other methods of losing weight include use of drugs and supplements that decrease appetite, block fat absorption, or reduce stomach volume. Surgery is another method. Bariatric surgery artificially reduces the size of the stomach, limiting the intake of food energy. Some of these treatments may have serious side-effects. # Causes ## Common Causes - Unintentional weight loss: - Nicotine and smoking (may be an intentional caue). - Drug side effects (mentioned below) - Age >65 years: Malignancies (specifically digestive and non-hematologic) Neurological disorders: Dementia, stroke, parkinson's disease Oral disorders Chronic disorders: Chronic renal failure - Malignancies (specifically digestive and non-hematologic) - Neurological disorders: Dementia, stroke, parkinson's disease - Oral disorders - Chronic disorders: Chronic renal failure - Age <65 years: Endocrine disorders (such as hyperthyroidism) Infections such as TB and HIV Psychiatric disorders such as depression, anxiety, and OCD, eating disorders Malignancies such as hematologic - Endocrine disorders (such as hyperthyroidism) - Infections such as TB and HIV - Psychiatric disorders such as depression, anxiety, and OCD, eating disorders - Malignancies such as hematologic - Intentional weight loss: Dieting, dexatrim, and aerobic exercise. ## Causes by Organ System ## Causes in Alphabetical Order - Abatacept Injection (patient information) - Achalasia - Actinomyces - Acute lymphoblastic leukemia - Acute myeloid leukemia - Acute promyelocytic leukemia - Adderall - Addison's disease - Adjustable gastric band - Adrenocorticotropic hormone deficiency - Aerobic exercise - Aggressive NK-cell leukemia - Alcoholic Hepatitis - Allopurinol (patient information) - Aminopterin - Amiodarone Oral (patient information) - Amphotericin B Injection (patient information) - Anorexia nervosa - Arsenic Poisoning - Aspergillus clavatus - Aspergillus fumigatus - Autoimmune pancreatitis - Barrett's esophagus - Basedow syndrome - Benzodiazepine withdrawal syndrome - Beriberi - Bevacizumab Injection (patient information) - Blastocystosis - Blastomycosis - Blind loop syndrome - Botulinum toxin - Bulimia nervosa - Bumetanide (patient information) - Busulfan (patient information) - Byssinosis - Calcitriol (patient information) - Calorie restriction - Cancer - Cannabis (drug) - Carboplatin (patient information) - Carmustine (patient information) - Castleman's disease - Celiac disease - Cervical cancer - Cetuximab Injection (patient information) - Chagas disease - Chlorambucil (patient information) - Cholangiocarcinoma - Chronic fatigue syndrome - Chronic Obstructive Pulmonary Disease - Chronic pancreatitis - Chronic Renal Failure - Chronic wasting disease - Churg-Strauss Syndrome - Cirrhosis - Cladosporium - Clenbuterol - Clofarabine Injection (patient information) - Cocaine - Cogan syndrome - Colorectal cancer - Congestive Heart Failure - Crohn's disease - Cystic Fibrosis - Cytarabine (patient information) - Dehydration - Dexatrim - Dexfenfluramine - Dexmethylphenidate - Dextroamphetamine - Diabetes mellitus type 1 - Diabulimia - Diaphoresis - Diarrhea - Dientamoeba fragilis - Dieting - Diphyllobothrium infection - DKA - Donepezil (patient information) - Duloxetine - Dysphagia - Eating disorder - ECA stack - Empyema Thoracis - Enfuvirtide Injection (patient information) - Entamoeba histolytica - Eosinophilic gastroenteritis - Ephedra - Eskatrol - Esophageal cancer - Esophageal candidiasis - Ethosuximide - Exenatide - Familial adenomatous polyposis - Fasciola hepatica - Felbamate (patient information) - Fluorouracil (patient information) - Fluticasone Nasal Spray (patient information) - Fluticasone Oral Inhalation (patient information) - Folate deficiency - Food intolerance - Frailty syndrome - Fucus vesiculosus L. - Fundic gland polyposis - Furosemide (patient information) - Galantamine (patient information) - Gallbladder cancer - Gastric bypass surgery - Gastric lymphoma - Gastroesophageal reflux disease - Gatifloxacin (patient information) - Gefitinib (patient information) - Giardia lamblia - Glucagonoma Syndrome - Glucose-galactose malabsorption - Graves' Disease - Hashimoto's thyroiditis - Hemangiosarcoma - Hepatitis C - HIV - Hodgkin's lymphoma - Hookworm - Hydrolyzed collagen (hydrolysate) - Hydroxycitric acid - Hypercalcemia - Hyperemesis gravidarum - Hyperthyroidism - Ileitis - Indapamide (patient information) - Inflammatory bowel disease - Interferon beta-1a Intramuscular Injection (patient information) - Interferon beta-1a Subcutaneous Injection (patient information) - Interferon Beta-1b Injection (patient information) - Interstitial nephritis - Irritable bowel syndrome - Ischemic colitis - Isosporiasis - Kaposi's sarcoma - Kikuchi disease - Krabbe disease - Leflunomide (patient information) - Leishmania infection - Leukemia - Leuprolide (patient information) - Levothyroxine - Liothyronine (patient information) - Liposarcoma - Liposuction - Lithium (patient information) - Liver Failure - Lomustine (patient information) - Lung cancer - Malabsorption - Malaria - Malassimilation - Malignancy - Malnutrition - Mantle cell lymphoma - Marasmus - Marburg virus - Mechlorethamine (patient information) - Mediastinal tumor - Melphalan (patient information) - Ménétrier's disease - Mercaptopurine (patient information) - Mesothelioma - Methsuximide Oral (patient information) - Methylphenidate - Micropolyspora faeni - Mini sleeve gastrectomy - Mitochondrial myopathy - Modafinil - Mucor stolonifer - Multiple endocrine neoplasia type 1 - Mycobacterium avium complex infection - Myxoma - Natalizumab injection (patient information) - Neuroendocrine tumors - Nevirapine (patient information) - Nicotine - Nilutamide - Non-Hodgkin lymphoma - Osteoporosis - Oxaliplatin injection (patient information) - Pancreatic cancer - Panniculitis - Parkinson's disease - Peginterferon alfa-2a (patient information) - Peginterferon alfa-2b (patient information) - Pemetrexed injection (patient information) - Pemoline (patient information) - Peptic ulcer - Phendimetrazine - Phenformin - Phenmetrazine - Phenylbutazone - Phenytoin oral (patient information) - Pheochromocytoma - Piroxicam (patient information) - Polyarteritis nodosa - Polymyalgia Rheumatica - Posaconazole (patient information) - Pott's disease - Pramipexole (patient information) - Pramlintide - Protriptyline (patient information) - Pulmonary alveolar proteinosis - Pyloric stenosis - Q Fever - Rasagiline (patient information) - Renal cell carcinoma - Ribavirin (patient information) - Rift Valley fever - Rivastigmine (patient information) - Sarcoidosis - Sargramostim - Selective serotonin reuptake inhibitor - Short bowel syndrome - Silicosis - Sitophilus granarius - Small intestine cancer - Sorafenib - Spironolactone and hydrochlorothiazide (patient information) - SSRI discontinuation syndrome - Stomach cancer - Streptobacillus - Sultiame - Sunitinib (patient information) - Synephrine - Syphilis - Systemic lupus erythematosus - Takayasu's Arteritis - Tamoxifen (patient information) - Thioguanine (patient information) - Thiotepa (patient information) - Thyroglobulin (patient information) - Tiagabine - Torsemide Injection (patient information) - Toxic multinodular goiter - Trimetrexate Glucuronate (patient information) - Tuberculosis - Tularemia - Ulcerative colitis - Vorinostat (patient information) - Waldenström's macroglobulinemia - Whipple disease - Zoledronic Acid Injection (patient information) - Zonisamide (patient information) # Diagnosis ## History - A thorough history includes past medical history to assess for any underlying diseases. For the elderly assess the living conditions, for neglect, neurocognitive deficits, dementia,stroke, and other disorders that may hamper access to food. Food, nutrition, access, swallowing, gut motility, absorption, excretion, all functions should be accessed. It is important to assess the amount of weight in the past three months and the pattern of weight loss. It may be assessed by changing the size of the clothes. ### Weight loss grading system (WLGS) - A grading system utilizes the % weight loss and BMI to grade the weight loss between 0-4. The disease prognosis and patient survival changes with the grade change usually moving from good prognosis to worse with low survival rates. - Among patients with incurable cancer, WLGS 4 was found to be independently associated with an increased symptom burden and worse prognosis. The quality of life also becomes poor with increasing grades of WLGS. ### Nutritional assessment - Children: A complete nutritional assessment includes: Medical history (includes birth history, developmental history). Nutritional history such as dietary intake. Physical examination that includes Anthropometric history, pubertal staging, bone age, and labs to assess the nutritional status. Linear growth assessment, bone densitometry, resting energy expenditure via indirect calorimetry, growth charts are some of the other methods utilized under specific circumstances. - Medical history (includes birth history, developmental history). - Nutritional history such as dietary intake. - Physical examination that includes Anthropometric history, pubertal staging, bone age, and labs to assess the nutritional status. - Linear growth assessment, bone densitometry, resting energy expenditure via indirect calorimetry, growth charts are some of the other methods utilized under specific circumstances. - Adults: A thorough history of food availability, financial status, neurocognitive disability, abuse, weight changes in the past three months should be considered. - Elderly: Mini-nutritional assessment is a vital component of geriatric evaluation. It includes: Anthropometric assessment: BMI, weight loss during the past three months. General assessment such as living conditions, mobility, neuropsychological issues, skin ], prescription drug use. Dietary assessment: Meals, servings, protein intake, water intake, and mode of feeding. Self-assessment: If the patient considers themselves having nutritional problems. - Anthropometric assessment: BMI, weight loss during the past three months. - General assessment such as living conditions, mobility, neuropsychological issues, skin ], prescription drug use. - Dietary assessment: Meals, servings, protein intake, water intake, and mode of feeding. - Self-assessment: If the patient considers themselves having nutritional problems. There are multiple variables and modifications of the nutritional assessment form. ### Caloric intake - Caloric intake record is of special importance among critically ill patients in ICU and calorie-protein intake should be within certain limits. ## Physical exam - A complete physical exam includes: Vital signs, HEENT, visual acuity, cardiovascular exam, GI exam (includes oral, abdominal, rectal exam), respiratory exam, and neurological examination. - To read more about a complete physical exam click here. ## Laboratory Findings The following laboratory studies should be considered: - CBC with differential : Include peripheral smear if anemia or other hematological pathologies suggesting RBC pathology. Infection (high WBC count), and parasite infection (eosinophilia). - ESR, CRP, LDH: If infection is suspected. - Glucose and/or HbA1c: To assess/ diagnose if diabetes is suspected. - CMP: Assess organ function, metabolism, and electrolyte imbalances. - Lipid profile: Assesses nutritional status. - TSH, free T4: To assess the thyroid functional status. - Urinalysis: Assess for UTIs, albuminuria, hemoglobinuria, diabetes, etc. - FOBT: Lower GI bleed such as in colon cancer, platelet disorders. - PTH levels - HIV test: As the disease is associated with infections, malignancies and itself weight loss. ### Electrolyte and Biomarker Studies - Morning ACTH stimulation test should be done if there is a suspicion of adrenal insufficiency. - To read more about the diagnostic test for Addison's disease please click here. ## Electrocardiogram - QRS voltage may increase with dramatic weight loss. ## X-ray - An x-ray may be helpful in the diagnosis of the primary focus of infection or malignancy. Findings on an x-ray suggestive of the lung cancer include solitary or diffuse mass. Comparing a solitary mass with the previous Xray or ordering a CT scan is usually the next step in evaluating a solitary lung mass. - Chest X-ray is usually the initial test that serves the purpose of screening for a focus. ## Echocardiography and Ultrasound - Ultrasound: May be helpful in the diagnosis of cysts and malignancy. Findings on ultrasound suggestive of malignancy include blood supply - Echocardiography: Heart failure assessment and tumors. ## CT scan - Whole body CT scan has the diagnostic yield of 33.5% for patients with unexplained weight loss. A lung CT demonstrating a cancer may have central or peripheral mass with variable borders. The characteristic help evaluate and assess the malignant potential of the mass. - CT may also be used to assess the possible metastasis of a disease with a small primary focus. ## Other Diagnostic Studies - Endoscopy or ] may be helpful in the diagnosis/ screening for the diseases that cause weight loss. - Age-appropriate screenings for cancers include: Upper GI endoscopy to assess for stomach cancer, peptic ulcer. Colonoscopy for colon cancer - Upper GI endoscopy to assess for stomach cancer, peptic ulcer. - Colonoscopy for colon cancer # Treatment Treating the underlying disease and nutritional support and/ or appetite stimulants to prevent further weight loss. ## Medical Therapy ### Acute therapies - Oropharyngeal or esophageal dysphagia: Pureed or thickened liquids. Speech therapy for oropharyngeal issues. - Pureed or thickened liquids. - Speech therapy for oropharyngeal issues. - Nutritional deficiency: Decreased dietary restrictions, increased oral intake. Dietary supplements in addition to regular meals. Nutritionist referral. - Decreased dietary restrictions, increased oral intake. - Dietary supplements in addition to regular meals. - Nutritionist referral. - Neglect: Social Services referral - Electrolyte imbalances: Severe: IV fluids to replenish electrolytes is severe cases. Specific treatments such as, hypokalemia medical therapy, hypomagnesemia medical therapy, hyponatremia medical therapy, hyperkalemia medical therapy, and hypernatremia medical therapy. Moderate/ mild: Adequate fluid intake and dietary supplements and tablets. - Severe: IV fluids to replenish electrolytes is severe cases. Specific treatments such as, hypokalemia medical therapy, hypomagnesemia medical therapy, hyponatremia medical therapy, hyperkalemia medical therapy, and hypernatremia medical therapy. - Moderate/ mild: Adequate fluid intake and dietary supplements and tablets. ### Chronic Pharmacotherapies - Malignancy: Adjuvant or non-adjuvant radiotherapy/ chemotherapy. Anorexia associated with malignancy and AIDS: Appetite stimulants such as megestrol 320 mg/day for adults and lower dosages for elderly. Dronabinol oral solution has quicker onset of action than the capsule form. Chemotherapy induced nausea and vomiting: Anti-emetics such as ondansetron and metoclopramide. - Adjuvant or non-adjuvant radiotherapy/ chemotherapy. - Anorexia associated with malignancy and AIDS: Appetite stimulants such as megestrol 320 mg/day for adults and lower dosages for elderly. Dronabinol oral solution has quicker onset of action than the capsule form. - Chemotherapy induced nausea and vomiting: Anti-emetics such as ondansetron and metoclopramide. - Malabsorption syndromes: Ulcerative colitis medical therapy, Crohn's disease medical therapy. Pancreatic enzymes for malabsorption in the pancreas. - Ulcerative colitis medical therapy, Crohn's disease medical therapy. - Pancreatic enzymes for malabsorption in the pancreas. - Depression: Refer for specialist care such as a psychotherapist and/or a psychiatrist. Mirtazapine helps stimulate hunger especially among patients of anorexia nervosa with depression. - Refer for specialist care such as a psychotherapist and/or a psychiatrist. - Mirtazapine helps stimulate hunger especially among patients of anorexia nervosa with depression. ## Surgery - Malignancy: Surgical resection. ## Cost-Effectiveness of Bariatric Surgery - A cohort study from United Kingdom described bariatric surgery as not cost-saving but cost-effective. It describes that to obese individuals, the increment in health care costs are exceeded by health benefits. - In a United States study utilizing microsimulation model, laparoscopic sleeve gastrectomy was described a most cost-effective for individuals with BMI between 35-39.9 kg/m2. # Primary Prevention - Patient and caregiver education and counseling. - Aggressive therapy with a psychiatrist or psychologist for anorexia nervosa. - Anti-emetics such as aprepitant to prevent chemotherapy-induced nausea and vomiting. # Prognosis - A 4%–5% or more of body weight loss within a year, or 10% or > over 5–10 years or longer, is associated with an increased mortality or morbidity/ both.	Weight loss Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Javaria Anwer M.D.[2] Cafer Zorkun, M.D., Ph.D. [3]; M.Umer Tariq [4]; Synonyms and keywords: weight reduction, elderly, malignancy, infection, dietary supplements, nutrition. # Overview Weight loss, in the context of medicine or health or physical fitness, is a reduction of the total body weight. An individual may lose weight due to a mean loss of fluid, body fat or adipose tissue and/or lean mass, namely bone mineral deposits, muscle, tendon and other connective tissue. Weight loss is a product of negative energy balance and can be unintentional or intentional. It can be a side effect of therapeutic drugs. The most common cause among the elderly is cancer. A thorough history with nutritional assessment, calorie count, patient's living conditions, neurocognitive dysfunction, appropriate labs and imaging findings are necessary. Until a diagnosis is made, nutritional supplementation should not be delayed in the interest of a patient's health. Treating the underlying cause, regular follow-up, and patient counseling are important components of weight loss management. # Classification - Weight loss is a product of negative energy balance. When the human body spends more energy in work and heat than it is gaining from food or other dietary supplements, it will catabolize stored reserves of fat or muscle. - There is no formal classification system for weight loss. Based on the cause, we attempt to provide a general outline of the types of weight loss.[1][2][3][4] ## Unintentional Weight Loss - A myriad of additional scientific considerations are applicable to weight loss, including but not limited to physiological and exercise sciences, nutrition science, behavioral sciences, and other sciences. - One area involves the science of bioenergetics including biochemical and physiological energy production and utilization systems, that is frequently evidence of diabetes, and ketone bodies, acetone particles occurring in body fluids and tissues involved in acidosis, also known as ketosis, somewhat common in severe diabetes. - Substantial, unintentional weight loss can be a symptom of an acute or chronic illness, especially if other evidence is demonstrated. - Weight loss accompanied by insatiable thirst, hunger and fatigue may indicate diabetes mellitus (DM). To read more about diabetes mellitus, click here. Diabetes characterized by an abnormal accumulation of carbohydrates in the bloodstream due to insufficient production of or tissue resistance to insulin.[5] Poor management of insulin-dependent diabetes mellitus (IDDM), also known as diabetes mellitus type I, leads to an excessive amount of glucose and an insufficient amount of insulin in the bloodstream. It triggers the release of triglycerides from adipose tissues and catabolism of amino acids in the muscle tissue. This results in a loss of both fat and lean mass, predisposing a significant reduction in total body weight. - Infections such as HIV may alter the metabolism, leading to weight loss.[6] * - Hormonal disruptions, such as an overactive thyroid (hyperthyroidism), may also lead to weight loss.[7] - In addition to weight loss due to a reduction in fat and lean mass, illnesses such as diabetes, certain medications, lack of fluid intake, and other factors can trigger fluid loss. A fluid loss in addition to a reduction in fat and lean mass poses a risk for cachexia. Loss of muscle mass in cachexia is due to combined effect of decreased protein synthesis in combination with an increased protein degradation via lysosomes and ubiquitin-proteasome pathway.[8] ## Intentional Weight Loss - Intentional weight loss may refer to the loss of total body mass in an effort to improve fitness, health, or appearance. - It is not uncommon for people who are already at a medically healthy weight to intentionally lose weight. In some cases, it is intending to improve athletic performance or to meet weight classifications in a sport. - In other cases, the goal is to attain a more attractively shaped body. On the other hand, being underweight is associated with health risks. - Health problems can include susceptibility to infections, osteoporosis, decreased muscle strength, trouble regulating body temperature, and even increased risk of death.[9] ## Therapeutic Weight Loss Techniques - Overweight and obese individuals face a greater risk of health conditions such as type 2 diabetes, heart disease, high blood pressure, stroke, osteoarthritis, and certain types of cancers.[10] - Therapeutic weight loss, in individuals who are overweight, can decrease the likelihood of developing diseases such as diabetes.[11] - For healthy weight loss, a physician should be consulted to develop a weight loss plan that is tailored to the individual. The least intrusive weight loss methods and those most often recommended by physicians are lifestyle modifications. Usually, health professionals will recommend that their overweight patients combine a reduction of the caloric content of the diet with an increase in physical activity.[12] - Other methods of losing weight include use of drugs and supplements that decrease appetite, block fat absorption, or reduce stomach volume. Surgery is another method. Bariatric surgery artificially reduces the size of the stomach, limiting the intake of food energy. Some of these treatments may have serious side-effects. # Causes ## Common Causes - Unintentional weight loss: - Nicotine and smoking (may be an intentional caue). - Drug side effects (mentioned below) - Age >65 years[13]: Malignancies (specifically digestive and non-hematologic) Neurological disorders: Dementia, stroke, parkinson's disease Oral disorders Chronic disorders: Chronic renal failure - Malignancies (specifically digestive and non-hematologic) - Neurological disorders: Dementia, stroke, parkinson's disease - Oral disorders - Chronic disorders: Chronic renal failure - Age <65 years[13]: Endocrine disorders (such as hyperthyroidism) Infections such as TB and HIV Psychiatric disorders such as depression, anxiety, and OCD, eating disorders Malignancies such as hematologic - Endocrine disorders (such as hyperthyroidism) - Infections such as TB and HIV - Psychiatric disorders such as depression, anxiety, and OCD, eating disorders - Malignancies such as hematologic - Intentional weight loss: Dieting, dexatrim, and aerobic exercise. ## Causes by Organ System[13][14][15] ## Causes in Alphabetical Order - Abatacept Injection (patient information) - Achalasia - Actinomyces - Acute lymphoblastic leukemia - Acute myeloid leukemia - Acute promyelocytic leukemia - Adderall - Addison's disease - Adjustable gastric band - Adrenocorticotropic hormone deficiency - Aerobic exercise - Aggressive NK-cell leukemia - Alcoholic Hepatitis - Allopurinol (patient information) - Aminopterin - Amiodarone Oral (patient information) - Amphotericin B Injection (patient information) - Anorexia nervosa - Arsenic Poisoning - Aspergillus clavatus - Aspergillus fumigatus - Autoimmune pancreatitis - Barrett's esophagus - Basedow syndrome - Benzodiazepine withdrawal syndrome - Beriberi - Bevacizumab Injection (patient information) - Blastocystosis - Blastomycosis - Blind loop syndrome - Botulinum toxin - Bulimia nervosa - Bumetanide (patient information) - Busulfan (patient information) - Byssinosis - Calcitriol (patient information) - Calorie restriction - Cancer - Cannabis (drug) - Carboplatin (patient information) - Carmustine (patient information) - Castleman's disease - Celiac disease - Cervical cancer - Cetuximab Injection (patient information) - Chagas disease - Chlorambucil (patient information) - Cholangiocarcinoma - Chronic fatigue syndrome - Chronic Obstructive Pulmonary Disease - Chronic pancreatitis - Chronic Renal Failure - Chronic wasting disease - Churg-Strauss Syndrome - Cirrhosis - Cladosporium - Clenbuterol - Clofarabine Injection (patient information) - Cocaine - Cogan syndrome - Colorectal cancer - Congestive Heart Failure - Crohn's disease - Cystic Fibrosis - Cytarabine (patient information) - Dehydration - Dexatrim - Dexfenfluramine - Dexmethylphenidate - Dextroamphetamine - Diabetes mellitus type 1 - Diabulimia - Diaphoresis - Diarrhea - Dientamoeba fragilis - Dieting - Diphyllobothrium infection - DKA - Donepezil (patient information) - Duloxetine - Dysphagia - Eating disorder - ECA stack - Empyema Thoracis - Enfuvirtide Injection (patient information) - Entamoeba histolytica - Eosinophilic gastroenteritis - Ephedra - Eskatrol - Esophageal cancer - Esophageal candidiasis - Ethosuximide - Exenatide - Familial adenomatous polyposis - Fasciola hepatica - Felbamate (patient information) - Fluorouracil (patient information) - Fluticasone Nasal Spray (patient information) - Fluticasone Oral Inhalation (patient information) - Folate deficiency - Food intolerance - Frailty syndrome - Fucus vesiculosus L. - Fundic gland polyposis - Furosemide (patient information) - Galantamine (patient information) - Gallbladder cancer - Gastric bypass surgery - Gastric lymphoma - Gastroesophageal reflux disease - Gatifloxacin (patient information) - Gefitinib (patient information) - Giardia lamblia - Glucagonoma Syndrome - Glucose-galactose malabsorption - Graves' Disease - Hashimoto's thyroiditis - Hemangiosarcoma - Hepatitis C - HIV - Hodgkin's lymphoma - Hookworm - Hydrolyzed collagen (hydrolysate) - Hydroxycitric acid - Hypercalcemia - Hyperemesis gravidarum - Hyperthyroidism - Ileitis - Indapamide (patient information) - Inflammatory bowel disease - Interferon beta-1a Intramuscular Injection (patient information) - Interferon beta-1a Subcutaneous Injection (patient information) - Interferon Beta-1b Injection (patient information) - Interstitial nephritis - Irritable bowel syndrome - Ischemic colitis - Isosporiasis - Kaposi's sarcoma - Kikuchi disease - Krabbe disease - Leflunomide (patient information) - Leishmania infection - Leukemia - Leuprolide (patient information) - Levothyroxine - Liothyronine (patient information) - Liposarcoma - Liposuction - Lithium (patient information) - Liver Failure - Lomustine (patient information) - Lung cancer - Malabsorption - Malaria - Malassimilation - Malignancy - Malnutrition - Mantle cell lymphoma - Marasmus - Marburg virus - Mechlorethamine (patient information) - Mediastinal tumor - Melphalan (patient information) - Ménétrier's disease - Mercaptopurine (patient information) - Mesothelioma - Methsuximide Oral (patient information) - Methylphenidate - Micropolyspora faeni - Mini sleeve gastrectomy - Mitochondrial myopathy - Modafinil - Mucor stolonifer - Multiple endocrine neoplasia type 1 - Mycobacterium avium complex infection - Myxoma - Natalizumab injection (patient information) - Neuroendocrine tumors - Nevirapine (patient information) - Nicotine - Nilutamide - Non-Hodgkin lymphoma - Osteoporosis - Oxaliplatin injection (patient information) - Pancreatic cancer - Panniculitis - Parkinson's disease - Peginterferon alfa-2a (patient information) - Peginterferon alfa-2b (patient information) - Pemetrexed injection (patient information) - Pemoline (patient information) - Peptic ulcer - Phendimetrazine - Phenformin - Phenmetrazine - Phenylbutazone - Phenytoin oral (patient information) - Pheochromocytoma - Piroxicam (patient information) - Polyarteritis nodosa - Polymyalgia Rheumatica - Posaconazole (patient information) - Pott's disease - Pramipexole (patient information) - Pramlintide - Protriptyline (patient information) - Pulmonary alveolar proteinosis - Pyloric stenosis - Q Fever - Rasagiline (patient information) - Renal cell carcinoma - Ribavirin (patient information) - Rift Valley fever - Rivastigmine (patient information) - Sarcoidosis - Sargramostim - Selective serotonin reuptake inhibitor - Short bowel syndrome - Silicosis - Sitophilus granarius - Small intestine cancer - Sorafenib - Spironolactone and hydrochlorothiazide (patient information) - SSRI discontinuation syndrome - Stomach cancer - Streptobacillus - Sultiame - Sunitinib (patient information) - Synephrine - Syphilis - Systemic lupus erythematosus - Takayasu's Arteritis - Tamoxifen (patient information) - Thioguanine (patient information) - Thiotepa (patient information) - Thyroglobulin (patient information) - Tiagabine - Torsemide Injection (patient information) - Toxic multinodular goiter - Trimetrexate Glucuronate (patient information) - Tuberculosis - Tularemia - Ulcerative colitis - Vorinostat (patient information) - Waldenström's macroglobulinemia - Whipple disease - Zoledronic Acid Injection (patient information) - Zonisamide (patient information) # Diagnosis ## History - A thorough history includes past medical history to assess for any underlying diseases. For the elderly assess the living conditions, for neglect, neurocognitive deficits, dementia,stroke, and other disorders that may hamper access to food. Food, nutrition, access, swallowing, gut motility, absorption, excretion, all functions should be accessed. It is important to assess the amount of weight in the past three months and the pattern of weight loss. It may be assessed by changing the size of the clothes. ### Weight loss grading system (WLGS)[15][15][15][16] - A grading system utilizes the % weight loss and BMI to grade the weight loss between 0-4. The disease prognosis and patient survival changes with the grade change usually moving from good prognosis to worse with low survival rates. - Among patients with incurable cancer, WLGS 4 was found to be independently associated with an increased symptom burden and worse prognosis. The quality of life also becomes poor with increasing grades of WLGS. ### Nutritional assessment - Children: A complete nutritional assessment includes[17]: Medical history (includes birth history, developmental history). Nutritional history such as dietary intake. Physical examination that includes Anthropometric history, pubertal staging, bone age, and labs to assess the nutritional status. Linear growth assessment, bone densitometry, resting energy expenditure via indirect calorimetry, growth charts are some of the other methods utilized under specific circumstances. - Medical history (includes birth history, developmental history). - Nutritional history such as dietary intake. - Physical examination that includes Anthropometric history, pubertal staging, bone age, and labs to assess the nutritional status. - Linear growth assessment, bone densitometry, resting energy expenditure via indirect calorimetry, growth charts are some of the other methods utilized under specific circumstances. - Adults: A thorough history of food availability, financial status, neurocognitive disability, abuse, weight changes in the past three months should be considered. - Elderly: Mini-nutritional assessment is a vital component of geriatric evaluation. It includes:[18][15] Anthropometric assessment: BMI, weight loss during the past three months. General assessment such as living conditions, mobility, neuropsychological issues, skin [ulcers]], prescription drug use. Dietary assessment: Meals, servings, protein intake, water intake, and mode of feeding. Self-assessment: If the patient considers themselves having nutritional problems. - Anthropometric assessment: BMI, weight loss during the past three months. - General assessment such as living conditions, mobility, neuropsychological issues, skin [ulcers]], prescription drug use. - Dietary assessment: Meals, servings, protein intake, water intake, and mode of feeding. - Self-assessment: If the patient considers themselves having nutritional problems. There are multiple variables and modifications of the nutritional assessment form. ### Caloric intake - Caloric intake record is of special importance among critically ill patients in ICU and calorie-protein intake should be within certain limits.[15] ## Physical exam - A complete physical exam includes: Vital signs, HEENT, visual acuity, cardiovascular exam, GI exam (includes oral, abdominal, rectal exam), respiratory exam, and neurological examination. - To read more about a complete physical exam click here. ## Laboratory Findings The following laboratory studies should be considered: - CBC with differential : Include peripheral smear if anemia or other hematological pathologies suggesting RBC pathology. Infection (high WBC count), and parasite infection (eosinophilia). - ESR, CRP, LDH: If infection is suspected. - Glucose and/or HbA1c: To assess/ diagnose if diabetes is suspected. - CMP: Assess organ function, metabolism, and electrolyte imbalances. - Lipid profile: Assesses nutritional status. - TSH, free T4: To assess the thyroid functional status. - Urinalysis: Assess for UTIs, albuminuria, hemoglobinuria, diabetes, etc. - FOBT: Lower GI bleed such as in colon cancer, platelet disorders. - PTH levels - HIV test: As the disease is associated with infections, malignancies and itself weight loss. ### Electrolyte and Biomarker Studies - Morning ACTH stimulation test should be done if there is a suspicion of adrenal insufficiency. - To read more about the diagnostic test for Addison's disease please click here. ## Electrocardiogram - QRS voltage may increase with dramatic weight loss. ## X-ray - An x-ray may be helpful in the diagnosis of the primary focus of infection or malignancy. Findings on an x-ray suggestive of the lung cancer include solitary or diffuse mass. Comparing a solitary mass with the previous Xray or ordering a CT scan is usually the next step in evaluating a solitary lung mass.[19] - Chest X-ray is usually the initial test that serves the purpose of screening for a focus. ## Echocardiography and Ultrasound - Ultrasound: May be helpful in the diagnosis of cysts and malignancy. Findings on ultrasound suggestive of malignancy include blood supply - Echocardiography: Heart failure assessment and tumors. ## CT scan - Whole body CT scan has the diagnostic yield of 33.5% for patients with unexplained weight loss.[20] A lung CT demonstrating a cancer may have central or peripheral mass with variable borders. The characteristic help evaluate and assess the malignant potential of the mass.[19] - CT may also be used to assess the possible metastasis of a disease with a small primary focus. ## Other Diagnostic Studies - Endoscopy or [colonoscopy]] may be helpful in the diagnosis/ screening for the diseases that cause weight loss. - Age-appropriate screenings for cancers include: Upper GI endoscopy to assess for stomach cancer, peptic ulcer. Colonoscopy for colon cancer - Upper GI endoscopy to assess for stomach cancer, peptic ulcer. - Colonoscopy for colon cancer # Treatment Treating the underlying disease and nutritional support and/ or appetite stimulants to prevent further weight loss. ## Medical Therapy[21] ### Acute therapies - Oropharyngeal or esophageal dysphagia: Pureed or thickened liquids. Speech therapy for oropharyngeal issues. - Pureed or thickened liquids. - Speech therapy for oropharyngeal issues. - Nutritional deficiency: Decreased dietary restrictions, increased oral intake. Dietary supplements in addition to regular meals. Nutritionist referral. - Decreased dietary restrictions, increased oral intake. - Dietary supplements in addition to regular meals. - Nutritionist referral. - Neglect: Social Services referral - Electrolyte imbalances: Severe: IV fluids to replenish electrolytes is severe cases. Specific treatments such as, hypokalemia medical therapy, hypomagnesemia medical therapy, hyponatremia medical therapy, hyperkalemia medical therapy, and hypernatremia medical therapy. Moderate/ mild: Adequate fluid intake and dietary supplements and tablets. - Severe: IV fluids to replenish electrolytes is severe cases. Specific treatments such as, hypokalemia medical therapy, hypomagnesemia medical therapy, hyponatremia medical therapy, hyperkalemia medical therapy, and hypernatremia medical therapy. - Moderate/ mild: Adequate fluid intake and dietary supplements and tablets. ### Chronic Pharmacotherapies - Malignancy: Adjuvant or non-adjuvant radiotherapy/ chemotherapy. Anorexia associated with malignancy and AIDS: Appetite stimulants such as megestrol 320 mg/day for adults and lower dosages for elderly. Dronabinol oral solution has quicker onset of action than the capsule form.[22] Chemotherapy induced nausea and vomiting: Anti-emetics such as ondansetron and metoclopramide.[23] - Adjuvant or non-adjuvant radiotherapy/ chemotherapy. - Anorexia associated with malignancy and AIDS: Appetite stimulants such as megestrol 320 mg/day for adults and lower dosages for elderly. Dronabinol oral solution has quicker onset of action than the capsule form.[22] - Chemotherapy induced nausea and vomiting: Anti-emetics such as ondansetron and metoclopramide.[23] - Malabsorption syndromes: Ulcerative colitis medical therapy, Crohn's disease medical therapy. Pancreatic enzymes for malabsorption in the pancreas. - Ulcerative colitis medical therapy, Crohn's disease medical therapy. - Pancreatic enzymes for malabsorption in the pancreas. - Depression: Refer for specialist care such as a psychotherapist and/or a psychiatrist. Mirtazapine helps stimulate hunger especially among patients of anorexia nervosa with depression.[24] - Refer for specialist care such as a psychotherapist and/or a psychiatrist. - Mirtazapine helps stimulate hunger especially among patients of anorexia nervosa with depression.[24] ## Surgery - Malignancy: Surgical resection. ## Cost-Effectiveness of Bariatric Surgery - A cohort study from United Kingdom described bariatric surgery as not cost-saving but cost-effective. It describes that to obese individuals, the increment in health care costs are exceeded by health benefits.[25] - In a United States study utilizing microsimulation model, laparoscopic sleeve gastrectomy was described a most cost-effective for individuals with BMI between 35-39.9 kg/m2.[4] # Primary Prevention - Patient and caregiver education and counseling. - Aggressive therapy with a psychiatrist or psychologist for anorexia nervosa. - Anti-emetics such as aprepitant to prevent chemotherapy-induced nausea and vomiting.[26][27] # Prognosis - A 4%–5% or more of body weight loss within a year, or 10% or > over 5–10 years or longer, is associated with an increased mortality or morbidity/ both.[28]	https://www.wikidoc.org/index.php/Ddx:Weight_Loss
431bf24c89371b2cd1cef2f988a0a47a16434901	wikidoc	Debye model	Debye model In thermodynamics and solid state physics, the Debye model is a method developed by Peter Debye in 1912 for estimating the phonon contribution to the specific heat (heat capacity) in a solid. It treats the vibrations of the atomic lattice (heat) as phonons in a box, in contrast to the Einstein model, which treats the solid as many individual, non-interacting quantum harmonic oscillators. The Debye model correctly predicts the low temperature dependence of the heat capacity, which is proportional to T^3. Just like the Einstein model, it also recovers the Dulong-Petit law at high temperatures. But due to simplifying assumptions, its accuracy suffers at intermediate temperatures. # Derivation The Debye model is a solid-state equivalent of Planck's law of black body radiation, where one treats electromagnetic radiation as a gas of photons in a box. The Debye model treats atomic vibrations as phonons in a box (the box being the solid). Most of the calculation steps are identical. Consider a cube of side L. From the particle in a box article, the resonating modes of the sonic disturbances inside the box (considering for now only those aligned with one axis) have wavelengths given by where n is an integer. The energy of a phonon is where h is Planck's constant and \nu_{n} is the frequency of the phonon. We make the approximation that the frequency is inversely proportional to the wavelength, giving: in which c_s is the speed of sound inside the solid. In three dimensions we will use: The approximation that the frequency is inversely proportional to the wavelength (giving a constant speed of sound) is good for low-energy phonons but not for high-energy phonons. (See the article on phonons.) This is one of the limitations of the Debye model. Let's now compute the total energy in the box where \bar{N}(E_n) is the number of phonons in the box with energy E_n. In other words, the total energy is equal to the sum of energy multiplied by the number of phonons with that energy (in one dimension). In 3 dimensions we have: Now, this is where Debye model and Planck's law of black body radiation differ. Unlike electromagnetic radiation in a box, there is a finite number of phonon energy states because a phonon cannot have infinite frequency. Its frequency is bound by the medium of its propagation -- the atomic lattice of the solid. Consider an illustration of a transverse phonon below. It is reasonable to assume that the minimum wavelength of a phonon is twice the atom separation, as shown in the lower figure. There are N atoms in a solid. Our solid is a cube, which means there are \sqrt{N} atoms per side. Atom separation is then given by L/\sqrt{N}, and the minimum wavelength is making the maximum mode number n (infinite for photons) This is the upper limit of the triple energy sum For slowly-varying, well-behaved functions, a sum can be replaced with an integral (also known as Thomas-Fermi approximation) So far, there has been no mention of \bar{N}(E), the number of phonons with energy E. Phonons obey Bose-Einstein statistics. Their distribution is given by the famous Bose-Einstein formula Because a phonon has three possible polarization states (one longitudinal and two transverse) which do not affect its energy, the formula above must be multiplied by 3 Substituting this into the energy integral yields The ease with which these integrals are evaluated for photons is due to the fact that light's frequency, at least semi-classically, is unbound. As the figure above illustrates, this is not true for phonons. In order to approximate this triple integral, Debye used spherical coordinates and boldly approximated the cube by an eighth of a sphere where R is the radius of this sphere, which is found by conserving the number of particles in the cube and in the eighth of a sphere. The volume of the cube is N unit-cell volumes, so we get: The substitution of integration over a sphere for the correct integral introduces another source of inaccuracy into the model. The energy integral becomes Changing the integration variable to x = {hc_sn\over 2LkT}, To simplify the look of this expression, define the Debye temperature T_D -- a shorthand for some constants and material-dependent variables. We then have the specific internal energy: where D_3(x) is the (third) Debye function. Differentiating with respect to T we get the dimensionless heat capacity: These formulae give the Debye model at all temperatures. The more elementary formulae given further down give the asymptotic behavior in the limit of low and high temperatures. # Debye's derivation Actually, Debye derived his equation somewhat differently and more simply. Using the solid mechanics of a continuous medium, he found that the number of vibrational states with a frequency less than a particular value was asymptotic to in which V is the volume and F is a factor which he calculated from elasticity coefficients and density. Combining this with the expected energy of a harmonic oscillator at temperature T (already used by Einstein in his model) would give an energy of if the vibrational frequencies continued to infinity. This form gives the T^4 behavior which is correct at low temperatures. But Debye realized that there could not be more than 3N vibrational states for N atoms. He made the assumption that in an atomic solid, the spectrum of frequencies of the vibrational states would continue to follow the above rule, up to a maximum frequency \nu_m chosen so that the total number of states is 3N: Debye knew that this assumption was not really correct (the higher frequencies are more closely spaced than assumed), but it guarantees the proper behavior at high temperature (the Dulong-Petit law). The energy is then given by: where D_3 is the function later given the name of third-order Debye function. # Low temperature limit The temperature of a Debye solid is said to be low if T \ll T_D, leading to This definite integral can be evaluated exactly: In the low temperature limit, the limitations of the Debye model mentioned above do not apply, and it gives a correct relationship between (phononic) heat capacity, temperature, the elastic coefficients, and the volume per atom (the latter quantities being contained in the Debye temperature). # High temperature limit The temperature of a Debye solid is said to be high if T >> T_D. e^x - 1\approx x if \|x\|, leads to This is the Dulong-Petit law, and is fairly accurate although it does not take into account anharmonicity, which causes the heat capacity to rise further. The total heat capacity of the solid, if it is a conductor or semiconductor, may also contain a non-negligible contribution from the electrons. # Debye versus Einstein So how closely do the Debye and Einstein models correspond to experiment? Surprisingly close, but Debye is correct at low temperatures whereas Einstein is not. How different are the models? To answer that question one would naturally plot the two on the same set of axes... except one can't. Both the Einstein model and the Debye model provide a functional form for the heat capacity. They are models, and no model is without a scale. A scale relates the model to its real-world counterpart. One can see that the scale of the Einstein model, which is given by is \epsilon/k. And the scale of the Debye model is T_D, the Debye temperature. Both are usually found by fitting the models to the experimental data. (The Debye temperature can theoretically be calculated from the speed of sound and crystal dimensions.) Because the two methods approach the problem from different directions and different geometries, Einstein and Debye scales are not the same, that is to say which means that plotting them on the same set of axes makes no sense. They are two models of the same thing, but of different scales. If one defines Einstein temperature as then one can say and, to relate the two, we must seek the ratio The Einstein solid is composed of single-frequency quantum harmonic oscillators, \epsilon = \hbar\omega = h\nu. That frequency, if it indeed existed, would be related to the speed of sound in the solid. If one imagines the propagation of sound as a sequence of atoms hitting one another, then it becomes obvious that the frequency of oscillation must correspond to the minimum wavelength sustainable by the atomic lattice, \lambda_{min}. which makes the Einstein temperature and the sought ratio is therefore Now both models can be plotted on the same graph. Note that this ratio is the cube root of the ratio of the volume of one octant of a 3-dimensional sphere to the volume of the cube that contains it, which is just the correction factor used by Debye when approximating the energy integral above. # Debye temperature table Even though the Debye model is not completely correct, it gives a good approximation for the low temperature heat capacity of insulating, crystalline solids where other contributions (such as highly mobile conduction electrons) are negligible. For metals, the electron contribution to the heat is proportional to T, which at low temperatures dominates the Debye T^3 result for lattice vibrations. In this case, the Debye model can only be said to approximate the lattice contribution to the specific heat. The following table lists Debye temperatures for several substances: (- Source for this information needs to be cited as some values are in gross conflict with other sources. For example, the values in Kittel, Charles, Introduction to Solid State Physics, 7th Ed., Wiley, (1996) do not agree with the table presented here *)	Debye model In thermodynamics and solid state physics, the Debye model is a method developed by Peter Debye in 1912[1] for estimating the phonon contribution to the specific heat (heat capacity) in a solid. It treats the vibrations of the atomic lattice (heat) as phonons in a box, in contrast to the Einstein model, which treats the solid as many individual, non-interacting quantum harmonic oscillators. The Debye model correctly predicts the low temperature dependence of the heat capacity, which is proportional to <math>T^3</math>. Just like the Einstein model, it also recovers the Dulong-Petit law at high temperatures. But due to simplifying assumptions, its accuracy suffers at intermediate temperatures. # Derivation The Debye model is a solid-state equivalent of Planck's law of black body radiation, where one treats electromagnetic radiation as a gas of photons in a box. The Debye model treats atomic vibrations as phonons in a box (the box being the solid). Most of the calculation steps are identical. Consider a cube of side <math>L</math>. From the particle in a box article, the resonating modes of the sonic disturbances inside the box (considering for now only those aligned with one axis) have wavelengths given by where <math>n</math> is an integer. The energy of a phonon is where <math>h</math> is Planck's constant and <math>\nu_{n}</math> is the frequency of the phonon. We make the approximation that the frequency is inversely proportional to the wavelength, giving: in which <math>c_s</math> is the speed of sound inside the solid. In three dimensions we will use: The approximation that the frequency is inversely proportional to the wavelength (giving a constant speed of sound) is good for low-energy phonons but not for high-energy phonons. (See the article on phonons.) This is one of the limitations of the Debye model. Let's now compute the total energy in the box where <math>\bar{N}(E_n)</math> is the number of phonons in the box with energy <math>E_n</math>. In other words, the total energy is equal to the sum of energy multiplied by the number of phonons with that energy (in one dimension). In 3 dimensions we have: Now, this is where Debye model and Planck's law of black body radiation differ. Unlike electromagnetic radiation in a box, there is a finite number of phonon energy states because a phonon cannot have infinite frequency. Its frequency is bound by the medium of its propagation -- the atomic lattice of the solid. Consider an illustration of a transverse phonon below. It is reasonable to assume that the minimum wavelength of a phonon is twice the atom separation, as shown in the lower figure. There are <math>N</math> atoms in a solid. Our solid is a cube, which means there are <math>\sqrt[3]{N}</math> atoms per side. Atom separation is then given by <math>L/\sqrt[3]{N}</math>, and the minimum wavelength is making the maximum mode number <math>n</math> (infinite for photons) This is the upper limit of the triple energy sum For slowly-varying, well-behaved functions, a sum can be replaced with an integral (also known as Thomas-Fermi approximation) So far, there has been no mention of <math>\bar{N}(E)</math>, the number of phonons with energy <math>E</math>. Phonons obey Bose-Einstein statistics. Their distribution is given by the famous Bose-Einstein formula Because a phonon has three possible polarization states (one longitudinal and two transverse) which do not affect its energy, the formula above must be multiplied by 3 Substituting this into the energy integral yields The ease with which these integrals are evaluated for photons is due to the fact that light's frequency, at least semi-classically, is unbound. As the figure above illustrates, this is not true for phonons. In order to approximate this triple integral, Debye used spherical coordinates and boldly approximated the cube by an eighth of a sphere where <math>R</math> is the radius of this sphere, which is found by conserving the number of particles in the cube and in the eighth of a sphere. The volume of the cube is <math>N</math> unit-cell volumes, so we get: The substitution of integration over a sphere for the correct integral introduces another source of inaccuracy into the model. The energy integral becomes Changing the integration variable to <math>x = {hc_sn\over 2LkT}</math>, To simplify the look of this expression, define the Debye temperature <math>T_D</math> -- a shorthand for some constants and material-dependent variables. We then have the specific internal energy: where <math>D_3(x)</math> is the (third) Debye function. Differentiating with respect to <math>T</math> we get the dimensionless heat capacity: These formulae give the Debye model at all temperatures. The more elementary formulae given further down give the asymptotic behavior in the limit of low and high temperatures. # Debye's derivation Actually, Debye derived his equation somewhat differently and more simply. Using the solid mechanics of a continuous medium, he found that the number of vibrational states with a frequency less than a particular value was asymptotic to in which <math> V </math> is the volume and <math> F </math> is a factor which he calculated from elasticity coefficients and density. Combining this with the expected energy of a harmonic oscillator at temperature T (already used by Einstein in his model) would give an energy of if the vibrational frequencies continued to infinity. This form gives the <math>T^4</math> behavior which is correct at low temperatures. But Debye realized that there could not be more than <math>3N</math> vibrational states for N atoms. He made the assumption that in an atomic solid, the spectrum of frequencies of the vibrational states would continue to follow the above rule, up to a maximum frequency <math>\nu_m</math> chosen so that the total number of states is <math>3N</math>: Debye knew that this assumption was not really correct (the higher frequencies are more closely spaced than assumed), but it guarantees the proper behavior at high temperature (the Dulong-Petit law). The energy is then given by: where <math>D_3</math> is the function later given the name of third-order Debye function. # Low temperature limit The temperature of a Debye solid is said to be low if <math>T \ll T_D</math>, leading to This definite integral can be evaluated exactly: In the low temperature limit, the limitations of the Debye model mentioned above do not apply, and it gives a correct relationship between (phononic) heat capacity, temperature, the elastic coefficients, and the volume per atom (the latter quantities being contained in the Debye temperature). # High temperature limit The temperature of a Debye solid is said to be high if <math>T >> T_D</math>. <math>e^x - 1\approx x</math> if <math>\|x\|<<1</math>, leads to This is the Dulong-Petit law, and is fairly accurate although it does not take into account anharmonicity, which causes the heat capacity to rise further. The total heat capacity of the solid, if it is a conductor or semiconductor, may also contain a non-negligible contribution from the electrons. # Debye versus Einstein So how closely do the Debye and Einstein models correspond to experiment? Surprisingly close, but Debye is correct at low temperatures whereas Einstein is not. How different are the models? To answer that question one would naturally plot the two on the same set of axes... except one can't. Both the Einstein model and the Debye model provide a functional form for the heat capacity. They are models, and no model is without a scale. A scale relates the model to its real-world counterpart. One can see that the scale of the Einstein model, which is given by is <math>\epsilon/k</math>. And the scale of the Debye model is <math>T_D</math>, the Debye temperature. Both are usually found by fitting the models to the experimental data. (The Debye temperature can theoretically be calculated from the speed of sound and crystal dimensions.) Because the two methods approach the problem from different directions and different geometries, Einstein and Debye scales are not the same, that is to say which means that plotting them on the same set of axes makes no sense. They are two models of the same thing, but of different scales. If one defines Einstein temperature as then one can say and, to relate the two, we must seek the ratio The Einstein solid is composed of single-frequency quantum harmonic oscillators, <math>\epsilon = \hbar\omega = h\nu</math>. That frequency, if it indeed existed, would be related to the speed of sound in the solid. If one imagines the propagation of sound as a sequence of atoms hitting one another, then it becomes obvious that the frequency of oscillation must correspond to the minimum wavelength sustainable by the atomic lattice, <math>\lambda_{min}</math>. which makes the Einstein temperature and the sought ratio is therefore Now both models can be plotted on the same graph. Note that this ratio is the cube root of the ratio of the volume of one octant of a 3-dimensional sphere to the volume of the cube that contains it, which is just the correction factor used by Debye when approximating the energy integral above. # Debye temperature table Even though the Debye model is not completely correct, it gives a good approximation for the low temperature heat capacity of insulating, crystalline solids where other contributions (such as highly mobile conduction electrons) are negligible. For metals, the electron contribution to the heat is proportional to <math>T</math>, which at low temperatures dominates the Debye <math>T^3</math> result for lattice vibrations. In this case, the Debye model can only be said to approximate the lattice contribution to the specific heat. The following table lists Debye temperatures for several substances: (* Source for this information needs to be cited as some values are in gross conflict with other sources. For example, the values in Kittel, Charles, Introduction to Solid State Physics, 7th Ed., Wiley, (1996) do not agree with the table presented here *)	https://www.wikidoc.org/index.php/Debye_model
1af6807ee1c6f9699f74c2f4a7d84c281e47be14	wikidoc	Decamethrin	Decamethrin # Overview Deltamethrin is a pyrethroid ester insecticide. # Usage Deltamethrin products are among the most popular and widely used insecticides in the world and have become very popular with pest control operators and individuals in the United States. This material is a member of one of the safest classes of pesticides: synthetic pyrethroids. This pesticide is highly toxic to aquatic life, particularly fish, and therefore must be used with extreme caution around water. Although generally considered safe to use around humans, it is still neurotoxic to humans. Deltamethrin is able to pass from a woman's skin through her blood and into her breast milk. There are many uses for deltamethrin, ranging from agricultural uses to home pest control. Deltamethrin has been instrumental in preventing the spread of diseases carried by tick-infested prairie dogs, rodents and other burrowing animals. It is helpful in eliminating and preventing a wide variety of household pests, especially spiders, fleas, ticks, carpenter ants, carpenter bees, cockroaches and bed bugs. Deltamethrin is also one of the primary ingredients in ant chalk. # Production Deltamethrin is a pyrethroid composed of a single stereoisomer, of a possible 8 stereoisomers, selectively prepared by the esterification of (1R,3R)- or cis-2,2-dimethyl-3-(2,2-dibromovinyl)cyclopropanecarboxylic acid with (alpha,S)- or (+)-alpha-cyano-3-phenoxybenzyl alcohol or by selective recrystallization of the racemic esters obtained by esterification of the (1R,3R)- or cis-acid with the racemic or (alpha-R, alpha-S, or alpha-R/S)- or + or − alcohol. # Malaria control Deltamethrin plays key role in controlling malaria vectors, and is used in the manufacture of long-lasting insecticidal mosquito nets. It is used as one of a battery of pyrethroid insecticides in control of malarial vectors, particularly Anopheles gambiae, and whilst being the most employed pyrethroid insecticide, can be used in conjunction with, or as an alternative to, permethrin, cypermethrin and other organophosphate-based insecticides, such as malathion and fenthion. Resistance to deltamethrin (and its counterparts) is now extremely widespread and threatens the success of worldwide vector control programmes. # Resistance to deltamethrin Resistance has been characterised in several insects, including important vectors of malaria like the mosquito Anopheles gambiae as well as non-disease carrying pests like bed bugs. ## Mosquitoes Methods of resistance include thickening of the cuticle of the insect to limit permeation of the insecticide, metabolic resistance via overexpression of metabolizing cytochrome P450 mono-oxygenases and glutathione-S-transferases, and the knockdown resistance (kdr) sodium channel mutations which render the action of insecticides ineffectual, even when co-administered with piperonyl butoxide. Characterization of the different forms of resistance among mosquitoes has become a top priority in groups studying tropical medicine due to the high mortality of those who reside in endemic areas. ## Bed bugs Two mutations, the valine to leucine mutation (V419L) and the leucine to isoleucine mutation (L925I) in voltage-gated sodium channel α-subunit gene, have been identified as responsible for knockdown resistance to deltamethrin in bed bugs. One study found that 88% of bed bug populations in the US had one, the other, or both mutations, meaning that deltamethrin resistance among bed bugs is currently making this insecticide obsolete. # Poisoning ## In humans Since deltamethrin is a neurotoxin, it temporarily attacks (in medical terms, "insults") the nervous system of any animal with which it comes into contact. Skin contact can lead to tingling or reddening of the skin local to the application. If taken in through the eyes or mouth, a common symptom is facial paraesthesia, which can feel like many different abnormal sensations, including burning, partial numbness, "pins and needles", skin crawling, etc. There are no reports indicating that chronic intoxication from pyrethroid insecticides causes motor neuron damage or motor neuron disease. Recently, in South Africa, residues of deltamethrin were found in breast milk, together with DDT, in an area that used DDT treatment for malaria control, as well as pyrethroids in small-scale agriculture. There are no antidotes, and treatment must be symptomatic, as approved by a physician. Over time, deltamethrin is metabolized, with a rapid loss of toxicity, and passed from the body. A poison control center should be contacted in the event of an accidental poisoning. ## In domestic animals Cases of toxicity have been observed in cattle following use of agricultural deltamethrin preparation in external application for tick control.	Decamethrin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Deltamethrin is a pyrethroid ester insecticide. # Usage Deltamethrin products are among the most popular and widely used insecticides in the world[citation needed] and have become very popular with pest control operators and individuals in the United States.[1] This material is a member of one of the safest classes of pesticides: synthetic pyrethroids. This pesticide is highly toxic to aquatic life, particularly fish, and therefore must be used with extreme caution around water. Although generally considered safe to use around humans, it is still neurotoxic to humans. Deltamethrin is able to pass from a woman's skin through her blood and into her breast milk.[2] There are many uses for deltamethrin, ranging from agricultural uses to home pest control. Deltamethrin has been instrumental in preventing the spread of diseases carried by tick-infested prairie dogs, rodents and other burrowing animals[citation needed]. It is helpful in eliminating and preventing a wide variety of household pests, especially spiders, fleas, ticks, carpenter ants, carpenter bees, cockroaches and bed bugs. Deltamethrin is also one of the primary ingredients in ant chalk. # Production Deltamethrin is a pyrethroid composed of a single stereoisomer, of a possible 8 stereoisomers, selectively prepared by the esterification of (1R,3R)- or cis-2,2-dimethyl-3-(2,2-dibromovinyl)cyclopropanecarboxylic acid with (alpha,S)- or (+)-alpha-cyano-3-phenoxybenzyl alcohol or by selective recrystallization of the racemic esters obtained by esterification of the (1R,3R)- or cis-acid with the racemic or (alpha-R, alpha-S, or alpha-R/S)- or + or − alcohol. # Malaria control Deltamethrin plays key role in controlling malaria vectors, and is used in the manufacture of long-lasting insecticidal mosquito nets. It is used as one of a battery of pyrethroid insecticides in control of malarial vectors, particularly Anopheles gambiae, and whilst being the most employed pyrethroid insecticide, can be used in conjunction with, or as an alternative to, permethrin, cypermethrin and other organophosphate-based insecticides, such as malathion and fenthion. Resistance to deltamethrin (and its counterparts) is now extremely widespread and threatens the success of worldwide vector control programmes. # Resistance to deltamethrin Resistance has been characterised in several insects, including important vectors of malaria like the mosquito Anopheles gambiae as well as non-disease carrying pests like bed bugs. ## Mosquitoes Methods of resistance include thickening of the cuticle of the insect to limit permeation of the insecticide, metabolic resistance via overexpression of metabolizing cytochrome P450 mono-oxygenases and glutathione-S-transferases, and the knockdown resistance (kdr) sodium channel mutations which render the action of insecticides ineffectual, even when co-administered with piperonyl butoxide. Characterization of the different forms of resistance among mosquitoes has become a top priority in groups studying tropical medicine due to the high mortality of those who reside in endemic areas.[3] ## Bed bugs Two mutations, the valine to leucine mutation (V419L) and the leucine to isoleucine mutation (L925I) in voltage-gated sodium channel α-subunit gene, have been identified as responsible for knockdown resistance to deltamethrin in bed bugs. One study found that 88% of bed bug populations in the US had one, the other, or both mutations, meaning that deltamethrin resistance among bed bugs is currently making this insecticide obsolete.[4] # Poisoning ## In humans Since deltamethrin is a neurotoxin, it temporarily attacks (in medical terms, "insults") the nervous system of any animal with which it comes into contact. Skin contact can lead to tingling or reddening of the skin local to the application. If taken in through the eyes or mouth, a common symptom is facial paraesthesia, which can feel like many different abnormal sensations, including burning, partial numbness, "pins and needles", skin crawling, etc. There are no reports indicating that chronic intoxication from pyrethroid insecticides causes motor neuron damage or motor neuron disease.[5] Recently, in South Africa, residues of deltamethrin were found in breast milk, together with DDT, in an area that used DDT treatment for malaria control, as well as pyrethroids in small-scale agriculture.[6] There are no antidotes, and treatment must be symptomatic, as approved by a physician. Over time, deltamethrin is metabolized, with a rapid loss of toxicity, and passed from the body. A poison control center should be contacted in the event of an accidental poisoning. ## In domestic animals Cases of toxicity have been observed in cattle following use of agricultural deltamethrin preparation in external application for tick control.[citation needed]	https://www.wikidoc.org/index.php/Decamethrin
3ad44cbdcd826a0cb9043b5315174780b2cda56d	wikidoc	Decay chain	Decay chain In nuclear science, the decay chain refers to the radioactive decay of different discrete radioactive decay products as a chained series of transformations. Most radioactive elements do not decay directly to a stable state, but rather undergo a series of decays until eventually a stable isotope is reached. Decay stages are referred to by their relationship to previous or subsequent stages. A parent isotope is one that undergoes decay to form a daughter isotope. The daughter isotope may be stable or it may decay to form a daughter isotope of its own. The daughter of a daughter isotope is sometimes called a granddaughter isotope. The time it takes for a single parent atom to decay to an atom of its daughter isotope can vary widely, not only for different parent-daughter chains, but also for identical pairings of parent and daughter isotopes. While the decay of a single atom occurs spontaneously, the decay of an initial population of identical atoms over time, t, follows a decaying exponential distribution, e-λt, where λ is called a decay constant. Because of this exponential nature, one of the properties of an isotope is its half-life, the time by which half of an initial number of identical parent radioisotopes have decayed to their daughters. Half-lives have been determined in laboratories for thousands of radioisotopes (or, radionuclides). These can range from nearly instantaneous to as much as 1019 years or more. The intermediate stages often emit more radioactivity than the original radioisotope: when equilibrium is achieved, a granddaughter isotope is present in proportion to its half-life; but since its activity is inversely proportional to its half-life, any nucleid in the decay chain finally contributes as much as the head of the chain. For example, natural uranium is not significantly radioactive, but samples of pitchblende, a uranium ore, are 13 times more radioactive because of the radium and other daughter isotopes they contain. Not only are unstable radium isotopes significant radioactive emitters, but they also generate gaseous radon as the next stage in the decay chain. Thus, radon is a naturally occurring radioactive gas, which is the leading cause of lung cancer in non-smokers. # Types The four most common modes of radioactive decay are: alpha decay, beta minus decay, beta plus decay (considered as both positron emission and electron capture) and isomeric transition. Of these decay processes, alpha decay changes the atomic mass number of the nucleus, and always decreases it by four. Because of this, almost any decay will result in a nucleus whose atomic mass number has the same residue mod 4, dividing all nuclides into four classes. The members of any possible decay chain must be drawn entirely from one of these classes. Three main decay chains (or families) are observed in nature, commonly called the thorium series, the radium series (not uranium series), and the actinium series, representing three of these four classes, and ending in three different, stable isotopes of lead. The mass number of every isotope in these chains can be represented as A=4n, A=4n+2 and A=4n+3, respectively. The long lived starting isotopes 232Th, 238U and 235U of these three have existed since the formation of the earth; the precursor 244Pu has also been found in minute amounts on earth. The fourth chain, the neptunium series with A=4n+1, due to quite short half life time of its starting isotope 237Np, is already extinct, except for the final rate-limiting step. The ending isotope of this chain is 205Tl. Some older sources give the final isotope as 209Bi, but it was recently discovered that 209Bi is radioactive with half-life of 1.9×1019 years. There are also many shorter chains, for example carbon-14. On the earth, most of the starting isotopes of these chains are generated by cosmic radiation. # Actinide alpha decay chains In the tables below, the minor branches of decay (with the branching ratio of less than 0.0001%) are omitted. The energy release includes the total kinetic energy of all the emitted particles (electrons, alpha particles, gamma quanta, neutrinos, Auger electrons and X-rays) and the recoil nucleus, assuming that the original nucleus was at rest. In the tables below, the historic names of the naturally occurring nuclides are also given. These names were used at the time when the decay chains were first discovered and investigated. From these names one can infer the particular chain to which the nuclide belongs. Also, the names indicate similarities: for example, Tn, Rn and An are all inert gases. # Beta decay chains Since heavy nuclei have a greater proportion of neutrons, fission product nuclei almost always start out with a neutron/proton ratio greater than what is stable for their mass range; therefore they undergo multiple beta decays in succession, each converting a neutron to a proton. The first decays tend to have higher decay energy and shorter half-life; the last decays may have low decay energy and/or long half-life. For example, uranium-235 has 92 protons and 143 neutrons. Fission takes one more neutron, then produces two or three more neutrons; assume that 92 protons and 142 neutrons are available for the two fission product nuclei. Suppose they have mass 99 with 39 protons and 60 neutrons (yttrium-99), and mass 135 with 53 protons and 82 neutrons (iodine-135); then the decay chains are: # Literature C.M. Lederer, J.M. Hollander, I. Perlman, Table of Isotopes, 6th ed., Wiley & Sons, New York 1968 - ↑ D.C . Hoffman, F. O. Lawrence, J. L. Mewheter, F. M. Rourke: Detection of Plutonium-244 in Nature. In: Nature, Nr. 34, 1971, pp. 132–134	Decay chain Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] In nuclear science, the decay chain refers to the radioactive decay of different discrete radioactive decay products as a chained series of transformations. Most radioactive elements do not decay directly to a stable state, but rather undergo a series of decays until eventually a stable isotope is reached. Decay stages are referred to by their relationship to previous or subsequent stages. A parent isotope is one that undergoes decay to form a daughter isotope. The daughter isotope may be stable or it may decay to form a daughter isotope of its own. The daughter of a daughter isotope is sometimes called a granddaughter isotope. The time it takes for a single parent atom to decay to an atom of its daughter isotope can vary widely, not only for different parent-daughter chains, but also for identical pairings of parent and daughter isotopes. While the decay of a single atom occurs spontaneously, the decay of an initial population of identical atoms over time, t, follows a decaying exponential distribution, e-λt, where λ is called a decay constant. Because of this exponential nature, one of the properties of an isotope is its half-life, the time by which half of an initial number of identical parent radioisotopes have decayed to their daughters. Half-lives have been determined in laboratories for thousands of radioisotopes (or, radionuclides). These can range from nearly instantaneous to as much as 1019 years or more. The intermediate stages often emit more radioactivity than the original radioisotope: when equilibrium is achieved, a granddaughter isotope is present in proportion to its half-life; but since its activity is inversely proportional to its half-life, any nucleid in the decay chain finally contributes as much as the head of the chain. For example, natural uranium is not significantly radioactive, but samples of pitchblende, a uranium ore, are 13 times more radioactive because of the radium and other daughter isotopes they contain. Not only are unstable radium isotopes significant radioactive emitters, but they also generate gaseous radon as the next stage in the decay chain. Thus, radon is a naturally occurring radioactive gas, which is the leading cause of lung cancer in non-smokers[2]. # Types The four most common modes of radioactive decay are: alpha decay, beta minus decay, beta plus decay (considered as both positron emission and electron capture) and isomeric transition. Of these decay processes, alpha decay changes the atomic mass number of the nucleus, and always decreases it by four. Because of this, almost any decay will result in a nucleus whose atomic mass number has the same residue mod 4, dividing all nuclides into four classes. The members of any possible decay chain must be drawn entirely from one of these classes. Three main decay chains (or families) are observed in nature, commonly called the thorium series, the radium series (not uranium series), and the actinium series, representing three of these four classes, and ending in three different, stable isotopes of lead. The mass number of every isotope in these chains can be represented as A=4n, A=4n+2 and A=4n+3, respectively. The long lived starting isotopes 232Th, 238U and 235U of these three have existed since the formation of the earth; the precursor 244Pu has also been found in minute amounts on earth[1]. The fourth chain, the neptunium series with A=4n+1, due to quite short half life time of its starting isotope 237Np, is already extinct, except for the final rate-limiting step. The ending isotope of this chain is 205Tl. Some older sources give the final isotope as 209Bi, but it was recently discovered that 209Bi is radioactive with half-life of 1.9×1019 years. There are also many shorter chains, for example carbon-14. On the earth, most of the starting isotopes of these chains are generated by cosmic radiation. # Actinide alpha decay chains In the tables below, the minor branches of decay (with the branching ratio of less than 0.0001%) are omitted. The energy release includes the total kinetic energy of all the emitted particles (electrons, alpha particles, gamma quanta, neutrinos, Auger electrons and X-rays) and the recoil nucleus, assuming that the original nucleus was at rest. In the tables below, the historic names of the naturally occurring nuclides are also given. These names were used at the time when the decay chains were first discovered and investigated. From these names one can infer the particular chain to which the nuclide belongs. Also, the names indicate similarities: for example, Tn, Rn and An are all inert gases. Template:Thorium series Template:Radium series Template:Actinium series Template:Neptunium series # Beta decay chains Since heavy nuclei have a greater proportion of neutrons, fission product nuclei almost always start out with a neutron/proton ratio greater than what is stable for their mass range; therefore they undergo multiple beta decays in succession, each converting a neutron to a proton. The first decays tend to have higher decay energy and shorter half-life; the last decays may have low decay energy and/or long half-life. For example, uranium-235 has 92 protons and 143 neutrons. Fission takes one more neutron, then produces two or three more neutrons; assume that 92 protons and 142 neutrons are available for the two fission product nuclei. Suppose they have mass 99 with 39 protons and 60 neutrons (yttrium-99), and mass 135 with 53 protons and 82 neutrons (iodine-135); then the decay chains are: # Literature C.M. Lederer, J.M. Hollander, I. Perlman, Table of Isotopes, 6th ed., Wiley & Sons, New York 1968 - ↑ D.C . Hoffman, F. O. Lawrence, J. L. Mewheter, F. M. Rourke: Detection of Plutonium-244 in Nature. In: Nature, Nr. 34, 1971, pp. 132–134 # External links - Decay chains - Uranium-238 decay chain - Government website listing isotopes and decay energies ast:Desintegración ca:Cadena de desintegració cs:Rozpadová řada de:Zerfallsreihe nl:Vervalreeks sv:Sönderfallskedja Template:WikiDoc Sources Template:Jb1	https://www.wikidoc.org/index.php/Decay_chain
5839fbdc7f43a72f6de868e30ba2a666f024d544	wikidoc	Ultraviolet	Ultraviolet Ultraviolet (UV) light is electromagnetic radiation with a wavelength shorter than that of visible light, but longer than soft X-rays. It is so named because the spectrum consists of electromagnetic waves with frequencies higher than those that humans identify as the color violet (purple). UV light is typically found as part of the radiation received by the Earth from the Sun. Most humans are aware of the effects of UV through the painful condition of sunburn. The UV spectrum has many other effects, including both beneficial and damaging changes to human health. # Discovery The discovery of UV radiation was intimately associated with the observation that silver salts darken when exposed to sunlight. In 1801 the German physicist Johann Wilhelm Ritter made the hallmark observation that invisible rays just beyond the violet end of the visible spectrum were especially effective at darkening silver chloride-soaked paper. He called them "de-oxidizing rays" to emphasize their chemical reactivity and to distinguish them from "heat rays" at the other end of the visible spectrum. The simpler term "chemical rays" was adopted shortly thereafter, and it remained popular throughout the 19th century. The terms chemical and heat rays were eventually dropped in favor of ultraviolet and infrared radiation, respectively. # Origin of term The name means "beyond violet" (from Latin ultra, "beyond"), violet being the color of the shortest wavelengths of visible light. UV light has a shorter wavelength than that of violet light. # Subtypes The electromagnetic spectrum of ultraviolet light can be subdivided in a number of ways. The draft ISO standard on determining solar irradiances (ISO-DIS-21348) describes the following ranges: In photolithography, in laser technology, etc., the term deep ultraviolet or DUV refers to wavelengths below 300 nm. "Vacuum UV" is so named because it is absorbed strongly by air and is therefore used in a vacuum. In the long-wave limit of this region, roughly 150-200 nm, the principal absorber is the oxygen in air. Work in this region can be performed in an oxygen free atmosphere, pure nitrogen being commonly used, which avoids the need for a vacuum chamber. See 1 E-7 m for a list of objects of comparable sizes. # Black light A black light, or Wood's light, is a lamp that emits long wave UV radiation and very little visible light. Commonly these are referred to as simply a "UV light". Fluorescent black lights are typically made in the same fashion as normal fluorescent lights except that only one phosphor is used and the normally clear glass envelope of the bulb may be replaced by a deep-bluish-purple glass called Wood's glass, a nickel-oxide–doped glass, which blocks almost all visible light above 400 nanometers. The color of such lamps is often referred to in the trade as "blacklight blue" or "BLB." This is to distinguish these lamps from "bug zapper" blacklight ("BL") lamps that don't have the blue Wood's glass. The phosphor typically used for a near 368 to 371 nanometer emission peak is either europium-doped strontium fluoroborate (SrB4O7F:Eu2+) or europium-doped strontium borate (SrB4O7:Eu2+) while the phosphor used to produce a peak around 350 to 353 nanometers is lead-doped barium silicate (BaSi2O5:Pb+). "Blacklight Blue" lamps peak at 365 nm. While "black lights" do produce light in the UV range, their spectrum is confined to the longwave UVA region. Unlike UVB and UVC, which are responsible for the direct DNA damage that leads to skin cancer, black light is limited to lower energy, longer waves and does not cause sunburn. However, UVA is capable of causing damage to collagen fibers and destroying vitamin A in skin. A black light may also be formed by simply using Wood's glass instead of clear glass as the envelope for a common incandescent bulb. This was the method used to create the very first black light sources. Though it remains a cheaper alternative to the fluorescent method, it is exceptionally inefficient at producing UV light (a mere few lumens per watt) owing to the black body nature of the incandescent light source. Incandescent UV bulbs, due to their inefficiency, may also become dangerously hot during use. More rarely still, high power (hundreds of watts) mercury vapor black lights can be found which use a UV emitting phosphor and an envelope of Wood's glass. These lamps are used mainly for theatrical and concert displays and also become very hot during normal use. Some UV fluorescent bulbs specifically designed to attract insects for use in bug zappers use the same near-UV emitting phosphor as normal blacklights, but use plain glass instead of the more expensive Wood's glass. Plain glass blocks less of the visible mercury emission spectrum, making them appear light blue to the naked eye. These lamps are referred to as "blacklight" or "BL" in most lighting catalogs. Ultraviolet light can be also generated by some light-emitting diodes. # Natural sources of UV The Sun emits ultraviolet radiation in the UVA, UVB, and UVC bands, but because of absorption in the atmosphere's ozone layer, 98.7% of the ultraviolet radiation that reaches the Earth's surface is UVA. (Some of the UVB and UVC radiation is responsible for the generation of the ozone layer.) Ordinary glass is partially transparent to UVA but is opaque to shorter wavelengths while Silica or quartz glass, depending on quality, can be transparent even to vacuum UV wavelengths. Ordinary window glass passes about 90% of the light above 350 nm, but blocks over 90% of the light below 300 nm. The onset of vacuum UV, 200 nm, is defined by the fact that ordinary air is opaque below this wavelength. This opacity is due to the strong absorption of light -f these wavelengths by oxygen in the air. Pure nitrogen (less than about 10 ppm oxygen) is transparent to wavelengths in the range of about 150–200 nm. This has wide practical significance now that semiconductor manufacturing processes are using wavelengths shorter than 200 nm. By working in oxygen-free gas, the equipment does not have to be built to withstand the pressure differences required to work in a vacuum. Some other scientific instruments, such as circular dichroism spectrometers, are also commonly nitrogen purged and operate in this spectral region. Extreme UV is characterized by a transition in the physics of interaction with matter: wavelengths longer than about 30 nm interact mainly with the chemical valence electrons of matter, while wavelengths shorter than that interact mainly with inner shell electrons and nuclei. The long end of the EUV/XUV spectrum is set by a prominent He+ spectral line at 30.4nm. XUV is strongly absorbed by most known materials, but it is possible to synthesize multilayer optics that reflect up to about 50% of XUV radiation at normal incidence. This technology has been used to make telescopes for solar imaging; it was pioneered by the NIXT and MSSTA sounding rockets in the 1990s; (current examples are SOHO/EIT and TRACE) and for nanolithography (printing of traces and devices on microchips). # Human health-related effects of UV radiation ## Beneficial effects The Earth's atmosphere blocks UV radiation from penetrating through the atmosphere by 98.7%. A positive effect of UVB exposure is that it induces the production of vitamin D in the skin. It has been estimated that tens of thousands of premature deaths occur in the United States annually from a range of cancers due to vitamin D deficiency. Another effect of vitamin D deficiency is osteomalacia (the adult equivalent of rickets), which can result in bone pain, difficulty in weight bearing and sometimes fractures. Other studies show most people get adequate Vitamin D through food and incidental exposure. Many countries have fortified certain foods with Vitamin D to prevent deficiency. Eating fortified foods or taking a dietary supplement pill is usually preferred to UVB exposure, due to the increased risk of skin cancer from UV radiation. Too little UVB radiation leads to a lack of Vitamin D. Too much UVB radiation leads to direct DNA damages and sunburn. An appropriate amount of UVB (What is appropriate depends on your skin colour) leads to a limited amount of direct DNA damage. This is recognized and repaired by the body. Then the melanin production is increased which leads to a long lasting tan. This tan occurs with a 2 day lag phase after irradiation, but it is much less harmful and long lasting than the one obtained from UVA. Ultraviolet radiation has other medical applications, in the treatment of skin conditions such as psoriasis and vitiligo. UVA radiation can be used in conjunction with psoralens (PUVA treatment). UVB radiation is rarely used in conjunction with psoralens. In cases of psoriasis and vitiligo, UV light with wavelength of 311 nm is most effective. ## Harmful effects An overexposure to UVB radiation can cause sunburn and some forms of skin cancer. In humans, prolonged exposure to solar UV radiation may result in acute and chronic health effects on the skin, eye, and immune system. However the most deadly form - malignant melanoma - is mostly caused by the indirect DNA damage (free radicals and oxidative stress). This can be seen from the absence of a UV-signature mutation in 92% of all melanoma. UVC rays are the highest energy, most dangerous type of ultraviolet light. Little attention has been given to UVC rays in the past since they are filtered out by the atmosphere. However, their use in equipment such as pond sterilization units may pose an exposure risk, if the lamp is switched on outside of its enclosed pond sterilization unit. ### Skin UVA, UVB and UVC can all damage collagen fibers and thereby accelerate aging of the skin. Both UVA and UVB destroy vitamin A in skin which may cause further damage. In the past UVA was considered less harmful, but today it is known, that it can contribute to skin cancer via the indirect DNA damage (free radicals and reactive oxygen species). It penetrates deeply but it does not cause sunburn. UVA does not damage DNA directly like UVB and UVC, but it can generate highly reactive chemical intermediates, such as hydroxyl and oxygen radicals, which in turn can damage DNA. Because it does not cause reddening of the skin (erythema) it cannot be measured in the SPF testing. There is no good clinical measurement of the blocking of UVA radiation, but it is important that sunscreen block both UVA and UVB. Some scientists blame the absence of UVA filters in sunscreens for the higher melanoma-risk that was found for sunscreen users. UVB light can cause direct DNA damage. The radiation excites DNA molecules in skin cells, causing covalent bonds to form between adjacent thymine bases, producing thymidine dimers. Thymidine dimers do not base pair normally, which can cause distortion of the DNA helix, stalled replication, gaps, and misincorporation. These can lead to mutations, which can result in cancerous growths. The mutations that are caused by the direct DNA damage carry a UV signature mutation. The mutagenicity of UV radiation can be easily observed in bacteria cultures. This cancer connection is one reason for concern about ozone depletion and the ozone hole. UVB causes some damage to collagen but at a very much slower rate than UVA. As a defense against UV radiation, the body tans when exposed to moderate (depending on skin type) levels of radiation. UVA gives a quick tan that last for days by oxidizing melanin that was already present and it triggers the release of the melanin from melanocytes. UVB yields a tan that takes roughly 2 days to develop because it stimulates the body to produce more melanin. The purpose of melanin is to block UV-radiation and prevent damage to the vulnerable skin tissues deeper down. The photochemical properties of melanin make it an excellent photoprotectant Sunscreen prevents the direct DNA damage which causes sunburn. Most of these products contain an SPF rating to show how well they block UVB rays. The SPF rating, however, offers no data about UVA protection. In the US, the FDA is considering adding a star rating system to show UVA protection. A similar system is already used in some European countries. Some sunscreen lotions now include compounds such as titanium dioxide which helps protect against UVA rays. Other UVA blocking compounds found in sunscreen include zinc oxide and avobenzone. Cantaloupe extract, rich in the compound superoxide dismutase (SOD), can be bound with gliadin to form glisodin, an orally-effective protectant against UVB radiation. There are also naturally occurring compounds found in rainforest plants that have been known to protect the skin from UV radiation damage, such as the fern Phlebodium aureum. The majority of doctors recommend patients protect themselves from UV radiation using sunscreen. Some scientists, however, question the safety of sunscreens that are absorbed into the skin or the bloodstream. These individuals claim these sunscreens generate free radicals under UV-illumination. (See the sunscreen article for a full discussion of this issue.) ### Eye High intensities of UVB light are hazardous to the eyes, and exposure can cause welder's flash (photokeratitis or arc eye) and may lead to cataracts, pterygium, and pinguecula formation. Protective eyewear is beneficial to those who are working with or those who might be exposed to ultraviolet radiation, particularly short wave UV. Given that light may reach the eye from the sides, full coverage eye protection is usually warranted if there is an increased risk of exposure, as in high altitude mountaineering. Mountaineers are exposed to higher than ordinary levels of UV radiation, both because there is less atmospheric filtering and because of reflection from snow and ice. Ordinary, untreated eyeglasses give some protection. Most plastic lenses give more protection than glass lenses, because, as noted above, glass is transparent to UVA and the common acrylic plastic used for lenses is less so. Some plastic lens materials, such as polycarbonate, inherently block most UV. There are protective treatments available for eyeglass lenses that need it which will give better protection. But even a treatment that completely blocks UV will not protect the eye from light that arrives around the lens. # Degradation of polymers, pigments and dyes Many polymers used in consumer products are degraded by UV light, and need addition of UV stabilizers to inhibit attack. Products include thermoplastics, such as polypropylene and polyethylene as well as speciality fibres like aramids. UV absorption leads to chain degradation and loss of strength. In addition, many pigments and dyes absorb UV and change colour, so paintings and textiles may need extra protection both from sunlight and fluorescent lamps. # Blockers and absorbers Ultraviolet Light Absorbers (UVAs) are molecules used in organic materials (polymers, paints, etc.) to absorb UV light in order to reduce the degradation (photo-oxidation) of a material. A number of different UVAs exist with different absorption properties. UVAs can disappear over time, so monitoring of UVA levels in weathered materials is necessary. In sunscreen, ingredients which absorb UVA/UVB rays, such as avobenzone and octyl methoxycinnamate, are known as absorbers. They are contrasted with physical "blockers" of UV radiation such as titanium dioxide and zinc oxide. (See sunscreen for a more complete list.) # Applications of UV ## Spectrophotometry UV/VIS spectroscopy is widely used as a technique in chemistry, to analyze chemical structure, most notably conjugated systems. UV radiation is often used in visible spectrophotometry to determine the existence of fluorescence in a given sample. ## Chemical markers UV fluorescent dyes are used in many applications (for example, biochemistry and forensics). The Green Fluorescent Protein (GFP) is often used in genetics as a marker. Many substances, such as proteins, have significant light absorption bands in the ultraviolet that are of use and interest in biochemistry and related fields. UV-capable spectrophotometers are common in such laboratories. ## Photochemotherapy Exposure to UVA light while the skin is hyper-photosensitive by taking psoralens is an effective treatment for psoriasis called PUVA. Due to psoralens potentially causing damage to the liver, PUVA may only be used a limited number of times over a patient's lifetime. ## Phototherapy Exposure to UVB light, particularly the 310 nm narrowband UVB range, is an effective long-term treatment for many skin conditions like psoriasis, vitiligo, eczema, and many others. UVB phototherapy does not require additional medications or topical preparations for the therapeutic benefit; only the light exposure is needed. However, phototherapy can be effective when used in conjunction with certain topical treatments such as anthralin, coal tar, and Vitamin A and D derivatives, or systemic treatments such as methotrexate and soriatane. Typical treatment regimes involve short exposure to UVB rays 3 to 5 times a week at a hospital or clinic, and for the best results, up to 30 or more sessions may be required. Side effects may include itching and redness of the skin due to UVB exposure, and possibly sunburn, if patients do not minimize exposure to natural UV rays during treatment days. ## Sterilization Ultraviolet lamps are used to sterilize workspaces and tools used in biology laboratories and medical facilities. Commercially-available low pressure mercury-vapor lamps emit about 86% of their light at 254 nanometers (nm) which coincides very well with one of the two peaks of the germicidal effectiveness curve (i.e., effectiveness for UV absorption by DNA). One of these peaks is at about 265 nm and the other is at about 185 nm. Although 185 nm is better absorbed by DNA, the quartz glass used in commercially-available lamps, as well as environmental media such as water, are more opaque to 185 nm than 254 nm (C. von Sonntag et al., 1992). UV light at these germicidal wavelengths causes adjacent thymine molecules on DNA to dimerize, if enough of these defects accumulate on a microorganism's DNA its replication is inhibited, thereby rendering it harmless (even though the organism may not be killed outright). However, since microorganisms can be shielded from ultraviolet light in small cracks and other shaded areas, these lamps are used only as a supplement to other sterilization techniques. ## Disinfecting drinking water UV radiation can be an effective viricide and bactericide. Disinfection using UV radiation is commonly used in wastewater treatment applications and is finding an increased usage in drinking water treatment. Many bottlers of spring water use UV disinfection equipment to sterilize their water. New York City has approved the construction of a 2 billion gallon per day ultraviolet drinking water disinfection facility. There are also several facilities under construction and several in operation that treat waste water with several stages of filters, hydrogen peroxide and UV light to bring the water up to drinking standards. One such facility exists in Orange County California. It used to be thought that UV disinfection was more effective for bacteria and viruses, which have more exposed genetic material, than for larger pathogens which have outer coatings or that form cyst states (e.g., Giardia) that shield their DNA from the UV light. However, it was recently discovered that ultraviolet radiation can be somewhat effective for treating the microorganism Cryptosporidium. The findings resulted in two US patents and the use of UV radiation as a viable method to treat drinking water. Giardia in turn has been shown to be very susceptible to UV-C when the tests were based on infectivity rather than excystation. It has been found that protists are able to survive high UV-C doses but are sterilized at low doses. A process named SODIS has been extensively researched in Switzerland and has proven ideal to treat small quantities of water using natural sunlight. Contaminated water is poured into transparent plastic bottles and exposed to full sunlight for six hours. The sunlight treats the contaminated water through two synergetic mechanisms: Radiation in the spectrum of UV-A (wavelength 320-400 nm) and increased water temperature. If the water temperatures rises above 50 °C, the disinfection process is three times faster. ## Food processing As consumer demand for fresh and "fresh-like" food products increases, the demand for nonthermal methods of food processing is likewise on the rise. In addition, public awareness regarding the dangers of food poisoning is also raising demand for improved food processing methods. Ultraviolet radiation is used in several food processes to kill unwanted microorganisms. UV light can be used to pasteurize fruit juices by flowing the juice over a high intensity ultraviolet light source. The effectiveness of such a process depends on the UV absorbance of the juice (Beer's law). ## Sun Tanning Sun tanning describes a darkening of the skin (especially of fair-skinned individuals) in a natural physiological response stimulated by exposure to ultraviolet radiation from sunshine (or a sunbed). With excess exposure to the sun, a suntanned area can also develop sunburn. ## Lasers Ultraviolet lasers have applications in industry (laser engraving), medicine (dermatology and keratectomy), free air secure communications and computing (optical storage). They can be made by applying frequency conversion to lower-frequency lasers, or from Ce:LiSAF crystals (cerium doped with lithium strontium aluminum fluoride), a process developed in the 1990s at Lawrence Livermore National Laboratory. # Evolutionary significance Evolution of early reproductive proteins and enzymes is attributed in modern models of evolutionary theory to ultraviolet light. Ultraviolet light causes thymine base pairs next to each other in genetic sequences to bond together into thymine dimers, a disruption in the strand which reproductive enzymes cannot copy (see picture above). This leads to frameshifting during genetic replication and protein synthesis, usually killing the organism. As early prokaryotes began to approach the surface of the ancient oceans, before the protective ozone layer had formed, blocking out most wavelengths of UV light, they almost invariably died out. The few that survived had developed enzymes which verified the genetic material and broke up thymine dimer bonds, known as excision repair enzymes. Many enzymes and proteins involved in modern mitosis and meiosis are extremely similar to excision repair enzymes, and are believed to be evolved modifications of the enzymes originally used to overcome UV light.	Ultraviolet Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Ultraviolet (UV) light is electromagnetic radiation with a wavelength shorter than that of visible light, but longer than soft X-rays. It is so named because the spectrum consists of electromagnetic waves with frequencies higher than those that humans identify as the color violet (purple). UV light is typically found as part of the radiation received by the Earth from the Sun. Most humans are aware of the effects of UV through the painful condition of sunburn. The UV spectrum has many other effects, including both beneficial and damaging changes to human health. # Discovery The discovery of UV radiation was intimately associated with the observation that silver salts darken when exposed to sunlight. In 1801 the German physicist Johann Wilhelm Ritter made the hallmark observation that invisible rays just beyond the violet end of the visible spectrum were especially effective at darkening silver chloride-soaked paper. He called them "de-oxidizing rays" to emphasize their chemical reactivity and to distinguish them from "heat rays" at the other end of the visible spectrum. The simpler term "chemical rays" was adopted shortly thereafter, and it remained popular throughout the 19th century. The terms chemical and heat rays were eventually dropped in favor of ultraviolet and infrared radiation, respectively.[1] # Origin of term The name means "beyond violet" (from Latin ultra, "beyond"), violet being the color of the shortest wavelengths of visible light. UV light has a shorter wavelength than that of violet light. # Subtypes The electromagnetic spectrum of ultraviolet light can be subdivided in a number of ways. The draft ISO standard on determining solar irradiances (ISO-DIS-21348)[2] describes the following ranges: In photolithography, in laser technology, etc., the term deep ultraviolet or DUV refers to wavelengths below 300 nm. "Vacuum UV" is so named because it is absorbed strongly by air and is therefore used in a vacuum. In the long-wave limit of this region, roughly 150-200 nm, the principal absorber is the oxygen in air. Work in this region can be performed in an oxygen free atmosphere, pure nitrogen being commonly used, which avoids the need for a vacuum chamber. See 1 E-7 m for a list of objects of comparable sizes. # Black light A black light, or Wood's light, is a lamp that emits long wave UV radiation and very little visible light. Commonly these are referred to as simply a "UV light". Fluorescent black lights are typically made in the same fashion as normal fluorescent lights except that only one phosphor is used and the normally clear glass envelope of the bulb may be replaced by a deep-bluish-purple glass called Wood's glass, a nickel-oxide–doped glass, which blocks almost all visible light above 400 nanometers. The color of such lamps is often referred to in the trade as "blacklight blue" or "BLB." This is to distinguish these lamps from "bug zapper" blacklight ("BL") lamps that don't have the blue Wood's glass. The phosphor typically used for a near 368 to 371 nanometer emission peak is either europium-doped strontium fluoroborate (SrB4O7F:Eu2+) or europium-doped strontium borate (SrB4O7:Eu2+) while the phosphor used to produce a peak around 350 to 353 nanometers is lead-doped barium silicate (BaSi2O5:Pb+). "Blacklight Blue" lamps peak at 365 nm. While "black lights" do produce light in the UV range, their spectrum is confined to the longwave UVA region. Unlike UVB and UVC, which are responsible for the direct DNA damage that leads to skin cancer, black light is limited to lower energy, longer waves and does not cause sunburn. However, UVA is capable of causing damage to collagen fibers and destroying vitamin A in skin. A black light may also be formed by simply using Wood's glass instead of clear glass as the envelope for a common incandescent bulb. This was the method used to create the very first black light sources. Though it remains a cheaper alternative to the fluorescent method, it is exceptionally inefficient at producing UV light (a mere few lumens per watt) owing to the black body nature of the incandescent light source. Incandescent UV bulbs, due to their inefficiency, may also become dangerously hot during use. More rarely still, high power (hundreds of watts) mercury vapor black lights can be found which use a UV emitting phosphor and an envelope of Wood's glass. These lamps are used mainly for theatrical and concert displays and also become very hot during normal use. Some UV fluorescent bulbs specifically designed to attract insects for use in bug zappers use the same near-UV emitting phosphor as normal blacklights, but use plain glass instead of the more expensive Wood's glass. Plain glass blocks less of the visible mercury emission spectrum, making them appear light blue to the naked eye. These lamps are referred to as "blacklight" or "BL" in most lighting catalogs. Ultraviolet light can be also generated by some light-emitting diodes. # Natural sources of UV The Sun emits ultraviolet radiation in the UVA, UVB, and UVC bands, but because of absorption in the atmosphere's ozone layer, 98.7% of the ultraviolet radiation that reaches the Earth's surface is UVA. (Some of the UVB and UVC radiation is responsible for the generation of the ozone layer.) Ordinary glass is partially transparent to UVA but is opaque to shorter wavelengths while Silica or quartz glass, depending on quality, can be transparent even to vacuum UV wavelengths. Ordinary window glass passes about 90% of the light above 350 nm, but blocks over 90% of the light below 300 nm.[3][4][5] The onset of vacuum UV, 200 nm, is defined by the fact that ordinary air is opaque below this wavelength. This opacity is due to the strong absorption of light of these wavelengths by oxygen in the air. Pure nitrogen (less than about 10 ppm oxygen) is transparent to wavelengths in the range of about 150–200 nm. This has wide practical significance now that semiconductor manufacturing processes are using wavelengths shorter than 200 nm. By working in oxygen-free gas, the equipment does not have to be built to withstand the pressure differences required to work in a vacuum. Some other scientific instruments, such as circular dichroism spectrometers, are also commonly nitrogen purged and operate in this spectral region. Extreme UV is characterized by a transition in the physics of interaction with matter: wavelengths longer than about 30 nm interact mainly with the chemical valence electrons of matter, while wavelengths shorter than that interact mainly with inner shell electrons and nuclei. The long end of the EUV/XUV spectrum is set by a prominent He+ spectral line at 30.4nm. XUV is strongly absorbed by most known materials, but it is possible to synthesize multilayer optics that reflect up to about 50% of XUV radiation at normal incidence. This technology has been used to make telescopes for solar imaging; it was pioneered by the NIXT and MSSTA sounding rockets in the 1990s; (current examples are SOHO/EIT and TRACE) and for nanolithography (printing of traces and devices on microchips). # Human health-related effects of UV radiation ## Beneficial effects The Earth's atmosphere blocks UV radiation from penetrating through the atmosphere by 98.7%. A positive effect of UVB exposure is that it induces the production of vitamin D in the skin. It has been estimated that tens of thousands of premature deaths occur in the United States annually from a range of cancers due to vitamin D deficiency.[6] Another effect of vitamin D deficiency is osteomalacia (the adult equivalent of rickets), which can result in bone pain, difficulty in weight bearing and sometimes fractures. Other studies show most people get adequate Vitamin D through food and incidental exposure.[7] Many countries have fortified certain foods with Vitamin D to prevent deficiency. Eating fortified foods or taking a dietary supplement pill is usually preferred to UVB exposure, due to the increased risk of skin cancer from UV radiation.[7] Too little UVB radiation leads to a lack of Vitamin D. Too much UVB radiation leads to direct DNA damages and sunburn. An appropriate amount of UVB (What is appropriate depends on your skin colour) leads to a limited amount of direct DNA damage. This is recognized and repaired by the body. Then the melanin production is increased which leads to a long lasting tan. This tan occurs with a 2 day lag phase after irradiation, but it is much less harmful and long lasting than the one obtained from UVA. Ultraviolet radiation has other medical applications, in the treatment of skin conditions such as psoriasis and vitiligo. UVA radiation can be used in conjunction with psoralens (PUVA treatment). UVB radiation is rarely used in conjunction with psoralens. In cases of psoriasis and vitiligo, UV light with wavelength of 311 nm is most effective. ## Harmful effects An overexposure to UVB radiation can cause sunburn and some forms of skin cancer. In humans, prolonged exposure to solar UV radiation may result in acute and chronic health effects on the skin, eye, and immune system.[8] However the most deadly form - malignant melanoma - is mostly caused by the indirect DNA damage (free radicals and oxidative stress). This can be seen from the absence of a UV-signature mutation in 92% of all melanoma.[9] UVC rays are the highest energy, most dangerous type of ultraviolet light. Little attention has been given to UVC rays in the past since they are filtered out by the atmosphere. However, their use in equipment such as pond sterilization units may pose an exposure risk, if the lamp is switched on outside of its enclosed pond sterilization unit. ### Skin Template:Cquote2 UVA, UVB and UVC can all damage collagen fibers and thereby accelerate aging of the skin. Both UVA and UVB destroy vitamin A in skin which may cause further damage.[10] In the past UVA was considered less harmful, but today it is known, that it can contribute to skin cancer via the indirect DNA damage (free radicals and reactive oxygen species). It penetrates deeply but it does not cause sunburn. UVA does not damage DNA directly like UVB and UVC, but it can generate highly reactive chemical intermediates, such as hydroxyl and oxygen radicals, which in turn can damage DNA. Because it does not cause reddening of the skin (erythema) it cannot be measured in the SPF testing. There is no good clinical measurement of the blocking of UVA radiation, but it is important that sunscreen block both UVA and UVB. Some scientists blame the absence of UVA filters in sunscreens for the higher melanoma-risk that was found for sunscreen users. [11] UVB light can cause direct DNA damage. The radiation excites DNA molecules in skin cells, causing covalent bonds to form between adjacent thymine bases, producing thymidine dimers. Thymidine dimers do not base pair normally, which can cause distortion of the DNA helix, stalled replication, gaps, and misincorporation. These can lead to mutations, which can result in cancerous growths. The mutations that are caused by the direct DNA damage carry a UV signature mutation. The mutagenicity of UV radiation can be easily observed in bacteria cultures. This cancer connection is one reason for concern about ozone depletion and the ozone hole. UVB causes some damage to collagen but at a very much slower rate than UVA. As a defense against UV radiation, the body tans when exposed to moderate (depending on skin type) levels of radiation. UVA gives a quick tan that last for days by oxidizing melanin that was already present and it triggers the release of the melanin from melanocytes. UVB yields a tan that takes roughly 2 days to develop because it stimulates the body to produce more melanin. The purpose of melanin is to block UV-radiation and prevent damage to the vulnerable skin tissues deeper down. The photochemical properties of melanin make it an excellent photoprotectant Sunscreen prevents the direct DNA damage which causes sunburn. Most of these products contain an SPF rating to show how well they block UVB rays. The SPF rating, however, offers no data about UVA protection. In the US, the FDA is considering adding a star rating system to show UVA protection. A similar system is already used in some European countries. Some sunscreen lotions now include compounds such as titanium dioxide which helps protect against UVA rays. Other UVA blocking compounds found in sunscreen include zinc oxide and avobenzone. Cantaloupe extract, rich in the compound superoxide dismutase (SOD), can be bound with gliadin to form glisodin, an orally-effective protectant against UVB radiation. There are also naturally occurring compounds found in rainforest plants that have been known to protect the skin from UV radiation damage, such as the fern Phlebodium aureum. The majority of doctors recommend patients protect themselves from UV radiation using sunscreen. Some scientists, however, question the safety of sunscreens that are absorbed into the skin or the bloodstream. These individuals claim these sunscreens generate free radicals under UV-illumination. [12] (See the sunscreen article for a full discussion of this issue.) ### Eye High intensities of UVB light are hazardous to the eyes, and exposure can cause welder's flash (photokeratitis or arc eye) and may lead to cataracts, pterygium,[13][14] and pinguecula formation. Protective eyewear is beneficial to those who are working with or those who might be exposed to ultraviolet radiation, particularly short wave UV. Given that light may reach the eye from the sides, full coverage eye protection is usually warranted if there is an increased risk of exposure, as in high altitude mountaineering. Mountaineers are exposed to higher than ordinary levels of UV radiation, both because there is less atmospheric filtering and because of reflection from snow and ice. Ordinary, untreated eyeglasses give some protection. Most plastic lenses give more protection than glass lenses, because, as noted above, glass is transparent to UVA and the common acrylic plastic used for lenses is less so. Some plastic lens materials, such as polycarbonate, inherently block most UV. There are protective treatments available for eyeglass lenses that need it which will give better protection. But even a treatment that completely blocks UV will not protect the eye from light that arrives around the lens. # Degradation of polymers, pigments and dyes Many polymers used in consumer products are degraded by UV light, and need addition of UV stabilizers to inhibit attack. Products include thermoplastics, such as polypropylene and polyethylene as well as speciality fibres like aramids. UV absorption leads to chain degradation and loss of strength. In addition, many pigments and dyes absorb UV and change colour, so paintings and textiles may need extra protection both from sunlight and fluorescent lamps. # Blockers and absorbers Ultraviolet Light Absorbers (UVAs) are molecules used in organic materials (polymers, paints, etc.) to absorb UV light in order to reduce the degradation (photo-oxidation) of a material. A number of different UVAs exist with different absorption properties. UVAs can disappear over time, so monitoring of UVA levels in weathered materials is necessary. In sunscreen, ingredients which absorb UVA/UVB rays, such as avobenzone and octyl methoxycinnamate, are known as absorbers. They are contrasted with physical "blockers" of UV radiation such as titanium dioxide and zinc oxide. (See sunscreen for a more complete list.) # Applications of UV ## Spectrophotometry UV/VIS spectroscopy is widely used as a technique in chemistry, to analyze chemical structure, most notably conjugated systems. UV radiation is often used in visible spectrophotometry to determine the existence of fluorescence in a given sample. ## Chemical markers UV fluorescent dyes are used in many applications (for example, biochemistry and forensics). The Green Fluorescent Protein (GFP) is often used in genetics as a marker. Many substances, such as proteins, have significant light absorption bands in the ultraviolet that are of use and interest in biochemistry and related fields. UV-capable spectrophotometers are common in such laboratories. ## Photochemotherapy Exposure to UVA light while the skin is hyper-photosensitive by taking psoralens is an effective treatment for psoriasis called PUVA. Due to psoralens potentially causing damage to the liver, PUVA may only be used a limited number of times over a patient's lifetime. ## Phototherapy Exposure to UVB light, particularly the 310 nm narrowband UVB range, is an effective long-term treatment for many skin conditions like psoriasis, vitiligo, eczema, and many others. UVB phototherapy does not require additional medications or topical preparations for the therapeutic benefit; only the light exposure is needed. However, phototherapy can be effective when used in conjunction with certain topical treatments such as anthralin, coal tar, and Vitamin A and D derivatives, or systemic treatments such as methotrexate and soriatane.[15] Typical treatment regimes involve short exposure to UVB rays 3 to 5 times a week at a hospital or clinic, and for the best results, up to 30 or more sessions may be required. Side effects may include itching and redness of the skin due to UVB exposure, and possibly sunburn, if patients do not minimize exposure to natural UV rays during treatment days. ## Sterilization Ultraviolet lamps are used to sterilize workspaces and tools used in biology laboratories and medical facilities. Commercially-available low pressure mercury-vapor lamps emit about 86% of their light at 254 nanometers (nm) which coincides very well with one of the two peaks of the germicidal effectiveness curve (i.e., effectiveness for UV absorption by DNA). One of these peaks is at about 265 nm and the other is at about 185 nm. Although 185 nm is better absorbed by DNA, the quartz glass used in commercially-available lamps, as well as environmental media such as water, are more opaque to 185 nm than 254 nm (C. von Sonntag et al., 1992). UV light at these germicidal wavelengths causes adjacent thymine molecules on DNA to dimerize, if enough of these defects accumulate on a microorganism's DNA its replication is inhibited, thereby rendering it harmless (even though the organism may not be killed outright). However, since microorganisms can be shielded from ultraviolet light in small cracks and other shaded areas, these lamps are used only as a supplement to other sterilization techniques. ## Disinfecting drinking water UV radiation can be an effective viricide and bactericide. Disinfection using UV radiation is commonly used in wastewater treatment applications and is finding an increased usage in drinking water treatment. Many bottlers of spring water use UV disinfection equipment to sterilize their water. New York City has approved the construction of a 2 billion gallon per day ultraviolet drinking water disinfection facility[16]. There are also several facilities under construction and several in operation that treat waste water with several stages of filters, hydrogen peroxide and UV light to bring the water up to drinking standards. One such facility exists in Orange County California. [17] [18] It used to be thought that UV disinfection was more effective for bacteria and viruses, which have more exposed genetic material, than for larger pathogens which have outer coatings or that form cyst states (e.g., Giardia) that shield their DNA from the UV light. However, it was recently discovered that ultraviolet radiation can be somewhat effective for treating the microorganism Cryptosporidium. The findings resulted in two US patents and the use of UV radiation as a viable method to treat drinking water. Giardia in turn has been shown to be very susceptible to UV-C when the tests were based on infectivity rather than excystation.[19] It has been found that protists are able to survive high UV-C doses but are sterilized at low doses. A process named SODIS [2] has been extensively researched in Switzerland and has proven ideal to treat small quantities of water using natural sunlight. Contaminated water is poured into transparent plastic bottles and exposed to full sunlight for six hours. The sunlight treats the contaminated water through two synergetic mechanisms: Radiation in the spectrum of UV-A (wavelength 320-400 nm) and increased water temperature. If the water temperatures rises above 50 °C, the disinfection process is three times faster. ## Food processing As consumer demand for fresh and "fresh-like" food products increases, the demand for nonthermal methods of food processing is likewise on the rise. In addition, public awareness regarding the dangers of food poisoning is also raising demand for improved food processing methods. Ultraviolet radiation is used in several food processes to kill unwanted microorganisms. UV light can be used to pasteurize fruit juices by flowing the juice over a high intensity ultraviolet light source. The effectiveness of such a process depends on the UV absorbance of the juice (Beer's law). ## Sun Tanning Sun tanning describes a darkening of the skin (especially of fair-skinned individuals) in a natural physiological response stimulated by exposure to ultraviolet radiation from sunshine (or a sunbed). With excess exposure to the sun, a suntanned area can also develop sunburn. ## Lasers Ultraviolet lasers have applications in industry (laser engraving), medicine (dermatology and keratectomy), free air secure communications and computing (optical storage). They can be made by applying frequency conversion to lower-frequency lasers, or from Ce:LiSAF crystals (cerium doped with lithium strontium aluminum fluoride), a process developed in the 1990s at Lawrence Livermore National Laboratory.[20] # Evolutionary significance Evolution of early reproductive proteins and enzymes is attributed in modern models of evolutionary theory to ultraviolet light. Ultraviolet light causes thymine base pairs next to each other in genetic sequences to bond together into thymine dimers, a disruption in the strand which reproductive enzymes cannot copy (see picture above). This leads to frameshifting during genetic replication and protein synthesis, usually killing the organism. As early prokaryotes began to approach the surface of the ancient oceans, before the protective ozone layer had formed, blocking out most wavelengths of UV light, they almost invariably died out. The few that survived had developed enzymes which verified the genetic material and broke up thymine dimer bonds, known as excision repair enzymes. Many enzymes and proteins involved in modern mitosis and meiosis are extremely similar to excision repair enzymes, and are believed to be evolved modifications of the enzymes originally used to overcome UV light.[21]	https://www.wikidoc.org/index.php/Deep_ultraviolet
207a9cdefb7615096f6b454849c6cbcc0b69dd7c	wikidoc	Deferasirox	Deferasirox # 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 Deferasirox is an iron chelator that is FDA approved for the {{{indicationType}}} of transfusional iron overload and iron overload in non-transfusion-dependent thalassemia syndromes. There is a Black Box Warning for this drug as shown here. Common adverse reactions include diarrhea, vomiting, nausea, abdominal pain, skin rashes, and increases in serum creatinine. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Exjade therapy should only be considered when a patient has evidence of chronic transfusional iron overload. The evidence should include the transfusion of at least 100 mL/kg of packed red blood cells (e.g., at least 20 units of packed red blood cells for a 40 kg person or more in individuals weighing more than 40 kg), and a serum ferritin consistently greater than 1000 mcg/L. - The recommended initial dose of Exjade for patients 2 years of age and older is 20 mg per kg body weight orally, once daily. Calculate doses (mg per kg per day) to the nearest whole tablet. - After commencing therapy, monitor serum ferritin monthly and adjust the dose of Exjade, if necessary, every 3-6 months based on serum ferritin trends. Make dose adjustments in steps of 5 or 10 mg per kg and tailor adjustments to the individual patient’s response and therapeutic goals. In patients not adequately controlled with doses of 30 mg per kg (e.g., serum ferritin levels persistently above 2500 mcg/L and not showing a decreasing trend over time), doses of up to 40 mg per kg may be considered. Doses above 40 mg per kg are not recommended. - If the serum ferritin falls consistently below 500 mcg/L, consider temporarily interrupting therapy with Exjade. - Exjade therapy should only be considered when a patient with NTDT syndrome has an LIC of at least 5 mg Fe/g dw and a serum ferritin greater than 300 mcg/L. - Initiating therapy: - The recommended initial dose of Exjade is 10 mg per kg body weight orally once daily. Calculate doses (mg per kg per day) to the nearest whole tablet. - If the baseline LIC is greater than 15 mg Fe/g dw, consider increasing the dose to 20 mg/kg/day after 4 weeks. - During therapy: - Monitor serum ferritin monthly. Interrupt treatment when serum ferritin is less than 300 mcg/L and obtain an LIC to determine whether the LIC has fallen to less than 3 mg Fe/g dw. - Monitor LIC every 6 months. - After 6 months of therapy, if the LIC remains greater than 7 mg Fe/g dw, increase the dose of deferasirox to a maximum of 20 mg/kg/day. Do not exceed a maximum of 20 mg/kg/day. - If after 6 months of therapy, the LIC is 3-7 mg Fe/g dw, continue treatment with deferasirox at no more than 10 mg/kg/day. - When the LIC is less than 3 mg Fe/g dw, interrupt treatment with deferasirox and continue to monitor the LIC. - Monitor blood counts, hepatic function, and renal function. - Restart treatment when the LIC rises again to more than 5 mg Fe/g dw. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Deferasirox in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Deferasirox in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Exjade therapy should only be considered when a patient has evidence of chronic transfusional iron overload. The evidence should include the transfusion of at least 100 mL/kg of packed red blood cells (e.g., at least 20 units of packed red blood cells for a 40 kg person or more in individuals weighing more than 40 kg), and a serum ferritin consistently greater than 1000 mcg/L. - The recommended initial dose of Exjade for patients 2 years of age and older is 20 mg per kg body weight orally, once daily. Calculate doses (mg per kg per day) to the nearest whole tablet. - After commencing therapy, monitor serum ferritin monthly and adjust the dose of Exjade, if necessary, every 3-6 months based on serum ferritin trends. Make dose adjustments in steps of 5 or 10 mg per kg and tailor adjustments to the individual patient’s response and therapeutic goals. In patients not adequately controlled with doses of 30 mg per kg (e.g., serum ferritin levels persistently above 2500 mcg/L and not showing a decreasing trend over time), doses of up to 40 mg per kg may be considered. Doses above 40 mg per kg are not recommended. - If the serum ferritin falls consistently below 500 mcg/L, consider temporarily interrupting therapy with Exjade. - Exjade therapy should only be considered when a patient with NTDT syndrome has an LIC of at least 5 mg Fe/g dw and a serum ferritin greater than 300 mcg/L. - Initiating therapy: - The recommended initial dose of Exjade is 10 mg per kg body weight orally once daily. Calculate doses (mg per kg per day) to the nearest whole tablet. - If the baseline LIC is greater than 15 mg Fe/g dw, consider increasing the dose to 20 mg/kg/day after 4 weeks. - During therapy: - Monitor serum ferritin monthly. Interrupt treatment when serum ferritin is less than 300 mcg/L and obtain an LIC to determine whether the LIC has fallen to less than 3 mg Fe/g dw. - Monitor LIC every 6 months. - After 6 months of therapy, if the LIC remains greater than 7 mg Fe/g dw, increase the dose of deferasirox to a maximum of 20 mg/kg/day. Do not exceed a maximum of 20 mg/kg/day. - If after 6 months of therapy, the LIC is 3-7 mg Fe/g dw, continue treatment with deferasirox at no more than 10 mg/kg/day. - When the LIC is less than 3 mg Fe/g dw, interrupt treatment with deferasirox and continue to monitor the LIC. - Monitor blood counts, hepatic function, and renal function. - Restart treatment when the LIC rises again to more than 5 mg Fe/g dw. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Deferasirox in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Deferasirox in pediatric patients. # Contraindications - Exjade is contraindicated in patients with: - Serum creatinine greater than 2 times the age-appropriate upper limit of normal or creatinine clearance less than 40 mL/min; - Poor performance status; - High-risk myelodysplastic syndromes; - Advanced malignancies; - Platelet counts <50 x 109/L; - Known hypersensitivity to deferasirox or any component of Exjade. # Warnings ### Precautions - Renal Toxicity, Renal Failure, and Proteinuria - Exjade can cause acute renal failure, fatal in some patients and requiring dialysis in others. Postmarketing experience showed that most fatalities occurred in patients with multiple comorbidities and who were in advanced stages of their hematological disorders. In the clinical trials, Exjade-treated patients experienced dose-dependent increases in serum creatinine. In patients with transfusional iron overload, these increases in creatinine occurred at a greater frequency compared to deferoxamine-treated patients (38% versus 14%, respectively, in Study 1 and 36% versus 22%, respectively, in Study 3). - Measure serum creatinine in duplicate (due to variations in measurements) and determine the creatinine clearance (estimated by the Cockcroft-Gault method) before initiating therapy in all patients in order to establish a reliable pretreatment baseline. Monitor serum creatinine weekly during the first month after initiation or modification of therapy and at least monthly thereafter. Monitor serum creatinine and/or creatinine clearance more frequently if creatinine levels are increasing. Dose reduction, interruption, or discontinuation based on increases in serum creatinine may be necessary. - Exjade is contraindicated in patients with creatinine clearance less than 40 mL/minute or serum creatinine greater than 2 times the age appropriate upper limit of normal. - Renal tubular damage, including Fanconi’s Syndrome, has been reported in patients treated with Exjade, most commonly in children and adolescents with beta-thalassemia and serum ferritin levels <;&lt1500 mcg/L. - Intermittent proteinuria (urine protein/creatinine ratio >0.6 mg/mg) occurred in 18.6% of Exjade-treated patients compared to 7.2% of deferoxamine-treated patients in Study 1. In clinical trials in patients with transfusional iron overload, Exjade was temporarily withheld until the urine protein/creatinine ratio fell below 0.6 mg/mg. Monthly monitoring for proteinuria is recommended. The mechanism and clinical significance of the proteinuria are uncertain. - Hepatic Toxicity and Failure - Exjade can cause hepatic injury, fatal in some patients. In Study 1, 4 patients (1.3%) discontinued Exjade because of hepatic toxicity (drug-induced hepatitis in 2 patients and increased serum transaminases in 2 additional patients). Hepatic toxicity appears to be more common in patients greater than 55 years of age. Hepatic failure was more common in patients with significant comorbidities, including liver cirrhosis and multiorgan failure. - Measure transaminases (AST and ALT) and bilirubin in all patients before the initiation of treatment and every 2 weeks during the first month and at least monthly thereafter. Consider dose modifications or interruption of treatment for severe or persistent elevations. - Avoid the use of Exjade in patients with severe (Child-Pugh C) hepatic impairment. Reduce the starting dose in patients with moderate (Child-Pugh B) hepatic impairment. Patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment may be at higher risk for hepatic toxicity. - Gastrointestinal (GI) Hemorrhage - GI hemorrhage, including deaths, has been reported, especially in elderly patients who had advanced hematologic malignancies and/or low platelet counts. Nonfatal upper GI irritation, ulceration and hemorrhage have been reported in patients, including children and adolescents, receiving Exjade. Monitor for signs and symptoms of GI ulceration and hemorrhage during Exjade therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. The risk of gastrointestinal hemorrhage may be increased when administering Exjade in combination with drugs that have ulcerogenic or hemorrhagic potential, such as nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, oral bisphosphonates, or anticoagulants. - Bone Marrow Suppression - Neutropenia, agranulocytosis, worsening anemia, and thrombocytopenia, including fatal events, have been reported in patients treated with Exjade. Preexisting hematologic disorders may increase this risk. Monitor blood counts in all patients. Interrupt treatment with Exjade in patients who develop cytopenias until the cause of the cytopenia has been determined. Exjade is contraindicated in patients with platelet counts below 50 x 109/L. - Increased Risk of Toxicity in the Elderly - Exjade has been associated with serious and fatal adverse reactions in the postmarketing setting, predominantly in elderly patients. Monitor elderly patients treated with Exjade more frequently for toxicity. - Hypersensitivity - Exjade may cause serious hypersensitivity reactions (such as anaphylaxis and angioedema), with the onset of the reaction usually occurring within the first month of treatment. If reactions are severe, discontinue Exjade and institute appropriate medical intervention. Exjade is contraindicated in patients with known hypersensitivity to Exjade. - Severe Skin Reactions - Severe skin reactions, including Stevens-Johnson syndrome (SJS) and erythema multiforme, have been reported during Exjade therapy. If SJS or erythema multiforme is suspected, discontinue Exjade and evaluate. - Skin Rash - Rashes may occur during Exjade treatment. For rashes of mild to moderate severity, Exjade may be continued without dose adjustment, since the rash often resolves spontaneously. In severe cases, interrupt treatment with Exjade. Reintroduction at a lower dose with escalation may be considered in combination with a short period of oral steroid administration. - Auditory and Ocular Abnormalities - Auditory disturbances (high frequency hearing loss, decreased hearing), and ocular disturbances (lens opacities, cataracts, elevations in intraocular pressure, and retinal disorders) were reported at a frequency of <1% with Exjade therapy in the clinical studies. Perform auditory and ophthalmic testing (including slit lamp examinations and dilated fundoscopy) before starting Exjade treatment and thereafter at regular intervals (every 12 months). If disturbances are noted, monitor more frequently. Consider dose reduction or interruption. - Overchelation - For patients with transfusional iron overload, measure serum ferritin monthly to assess for possible overchelation of iron. If the serum ferritin falls below 500 mcg/L, consider interrupting therapy with Exjade, since overchelation may increase Exjade toxicity. - For patients with NTDT, measure LIC by liver biopsy or by using an FDA-cleared or approved method for monitoring patients receiving deferasirox therapy every 6 months on treatment. Interrupt Exjade administration when the LIC is less than 3 mg Fe/g dw. Measure serum ferritin monthly, and if the serum ferritin falls below 300 mcg/L, interrupt Exjade and obtain a confirmatory LIC. # 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. - A total of 700 adult and pediatric patients were treated with Exjade (deferasirox) for 48 weeks in premarketing studies. These included 469 patients with beta-thalassemia, 99 with rare anemias, and 132 with sickle cell disease. Of these patients, 45% were male, 70% were Caucasian and 292 patients were <;&lt16 years of age. In the sickle cell disease population, 89% of patients were black. Median treatment duration among the sickle cell patients was 51 weeks. Of the 700 patients treated, 469 (403 beta-thalassemia and 66 rare anemias) were entered into extensions of the original clinical protocols. In ongoing extension studies, median durations of treatment were 88-205 weeks. - Six hundred twenty-seven patients with MDS were enrolled across 5 uncontrolled trials. These studies varied in duration from 1 to 5 years. The discontinuation rate across studies in the first year was 46% (AEs 20%, withdrawal of consent 10%, death 8%, other 4%, lab abnormalities 3%, and lack of efficacy 1%). Among 47 patients enrolled in the study of 5-year duration, 10 remained on Exjade at the completion of the study. - Table 1 displays adverse reactions occurring in >5% of Exjade-treated beta-thalassemia patients (Study 1), sickle cell disease patients (Study 3), and patients with MDS (MDS pool). Abdominal pain, nausea, vomiting, diarrhea, skin rashes, and increases in serum creatinine were the most frequent adverse reactions reported with a suspected relationship to Exjade. Gastrointestinal symptoms, increases in serum creatinine, and skin rash were dose related. - In Study 1, a total of 113 (38%) patients treated with Exjade had increases in serum creatinine >33% above baseline on 2 separate occasions (Table 2) and 25 (8%) patients required dose reductions. Increases in serum creatinine appeared to be dose related. In this study, 17 (6%) patients treated with Exjade developed elevations in SGPT/ALT levels >5 times the upper limit of normal at 2 consecutive visits. Of these, 2 patients had liver biopsy proven drug-induced hepatitis and both discontinued Exjade therapy . An additional 2 patients, who did not have elevations in SGPT/ALT >5 times the upper limit of normal, discontinued Exjade because of increased SGPT/ALT. Increases in transaminases did not appear to be dose related. Adverse reactions that led to discontinuations included abnormal liver function tests (2 patients) and drug-induced hepatitis (2 patients), skin rash, glycosuria/proteinuria, Henoch Schönlein purpura, hyperactivity/insomnia, drug fever, and cataract (1 patient each). - In Study 3, a total of 48 (36%) patients treated with Exjade had increases in serum creatinine >33% above baseline on 2 separate occasions (Table 2) . Of the patients who experienced creatinine increases in Study 3, 8 Exjade-treated patients required dose reductions. In this study, 5 patients in the Exjade group developed elevations in SGPT/ALT levels >5 times the upper limit of normal at 2 consecutive visits and 1 patient subsequently had Exjade permanently discontinued. Four additional patients discontinued Exjade due to adverse reactions with a suspected relationship to study drug, including diarrhea, pancreatitis associated with gallstones, atypical tuberculosis, and skin rash. - In the MDS pool, in the first year, a total of 229 (37%) patients treated with Exjade had increases in serum creatinine >33% above baseline on 2 consecutive occasions (Table 2) and 8 (3.5%) patients permanently discontinued. A total of 5 (0.8%) patients developed SGPT/ALT levels >5 times the upper limit of normal at 2 consecutive visits. The most frequent adverse reactions that led to discontinuation included increases in serum creatinine, diarrhea, nausea, rash, and vomiting. Death was reported in the first year in 52 (8%) of patients. - In Study 4, 110 patients with NTDT received 1 year of treatment with Exjade 5 or 10 mg/kg/day and 56 patients received placebo in a double-blind, randomized trial. In Study 5, 130 of the patients who completed Study 4 were treated with open-label Exjade at 5, 10, or 20 mg/kg/day (depending on the baseline LIC) for 1 year. Table 3 displays adverse reactions occurring in >5% in any group. The most frequent adverse reactions with a suspected relationship to study drug were nausea, rash, and diarrhea. In Study 4, 1 patient in the placebo 10 mg/kg/day group experienced an ALT increase to >5 times ULN and >2 times baseline (Table 4). Three Exjade-treated patients (all in the 10 mg/kg/day group) had 2 consecutive serum creatinine level increases >33% from baseline and >ULN. Serum creatinine returned to normal in all 3 patients (in 1 spontaneously and in the other 2 after drug interruption). Two additional cases of ALT increase and 2 additional cases of serum creatinine increase were observed in the 1-year extension of Study 4. - Proteinuria - In clinical studies, urine protein was measured monthly. Intermittent proteinuria (urine protein/creatinine ratio >0.6 mg/mg) occurred in 18.6% of Exjade-treated patients compared to 7.2% of deferoxamine-treated patients in Study 1. - Other Adverse Reactions - In the population of more than 5,000 patients with transfusional iron overload who have been treated with Exjade during clinical trials, adverse reactions occurring in 0.1% to 1% of patients included gastritis, edema, sleep disorder, pigmentation disorder, dizziness, anxiety, maculopathy, cholelithiasis, pyrexia, fatigue, pharyngolaryngeal pain, early cataract, hearing loss, gastrointestinal hemorrhage, gastric ulcer (including multiple ulcers), duodenal ulcer, and renal tubulopathy (Fanconi’s Syndrome). Adverse reactions occurring in 0.01% to 0.1% of patients included optic neuritis, esophagitis, and erythema multiforme. Adverse reactions which most frequently led to dose interruption or dose adjustment during clinical trials were rash, gastrointestinal disorders, infections, increased serum creatinine, and increased serum transaminases. ## Postmarketing Experience - The following adverse reactions have been spontaneously reported during post-approval use of Exjade in the transfusional iron overload setting. Because these reactions are reported voluntarily from a population of uncertain size, in which patients may have received concomitant medication, it is not always possible to reliably estimate frequency or establish a causal relationship to drug exposure. Stevens-Johnson syndrome (SJS), leukocytoclastic vasculitis, urticaria, alopecia Hypersensitivity reactions (including anaphylaxis and angioedema) Acute renal failure, tubulointerstitial nephritis Hepatic failure Gastrointestinal hemorrhage Worsening anemia # Drug Interactions - Aluminum Containing Antacid Preparations - The concomitant administration of Exjade and aluminum-containing antacid preparations has not been formally studied. Although deferasirox has a lower affinity for aluminum than for iron, avoid use of Exjade with aluminum-containing antacid preparations due to the mechanism of action of Exjade. - Agents Metabolized by CYP3A4 - Deferasirox may induce CYP3A4 resulting in a decrease in CYP3A4 substrate concentration when these drugs are coadministered. Closely monitor patients for signs of reduced effectiveness when deferasirox is administered with drugs metabolized by CYP3A4 (e.g., alfentanil, aprepitant, budesonide, buspirone, conivaptan, cyclosporine, darifenacin, darunavir, dasatinib, dihydroergotamine, dronedarone, eletriptan, eplerenone, ergotamine, everolimus, felodipine, fentanyl, hormonal contraceptive agents, indinavir, fluticasone, lopinavir, lovastatin, lurasidone, maraviroc, midazolam, nisoldipine, pimozide, quetiapine, quinidine, saquinavir, sildenafil, simvastatin, sirolimus, tacrolimus, tolvaptan, tipranavir, triazolam, ticagrelor, and vardenafil). - Agents Metabolized by CYP2C8 - Deferasirox inhibits CYP2C8 resulting in an increase in CYP2C8 substrate (e.g., repaglinide and paclitaxel) concentration when these drugs are coadministered. If Exjade and repaglinide are used concomitantly, consider decreasing the dose of repaglinide and perform careful monitoring of blood glucose levels. Closely monitor patients for signs of exposure related toxicity when Exjade is coadministered with other CYP2C8 substrates. - Agents Metabolized by CYP1A2 - Deferasirox inhibits CYP1A2 resulting in an increase in CYP1A2 substrate (e.g., alosetron, caffeine, duloxetine, melatonin, ramelteon, tacrine, theophylline, tizanidine) concentration when these drugs are coadministered. An increase in theophylline plasma concentrations could lead to clinically significant theophylline induced CNS or other adverse reactions. Avoid the concomitant use of theophylline or other CYP1A2 substrates with a narrow therapeutic index (e.g., tizanidine) with Exjade. Monitor theophylline concentrations and consider theophylline dose modification if you must coadminister theophylline with Exjade. Closely monitor patients for signs of exposure related toxicity when Exjade is coadministered with other drugs metabolized by CYP1A2. - Agents Inducing UDP-glucuronosyltransferase (UGT) Metabolism - Deferasirox is a substrate of UGT1A1 and to a lesser extent UGT1A3. The concomitant use of Exjade with potent UGT inducers (e.g., rifampicin, phenytoin, phenobarbital, ritonavir) may result in a decrease in Exjade efficacy due to a possible decrease in deferasirox concentration. Avoid the concomitant use of potent UGT inducers with Exjade. Consider increasing the initial dose of Exjade if you must coadminister these agents together. - Bile Acid Sequestrants - Avoid the concomitant use of bile acid sequestrants (e.g., cholestyramine, colesevelam, colestipol) with Exjade due to a possible decrease in deferasirox concentration. If you must coadminister these agents together, consider increasing the initial dose of Exjade. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - There are no adequate and well-controlled studies with Exjade in pregnant women. Administration of deferasirox to animals during pregnancy and lactation resulted in decreased offspring viability and an increase in renal anomalies in male offspring at exposures that were less than the recommended human exposure. Exjade should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - In embryofetal developmental studies, pregnant rats and rabbits received oral deferasirox during the period of organogenesis at doses up to (100 mg per kg/day in rats and 50 mg per kg/day in rabbits) 0.8 times the maximum recommended human dose (MRHD) on a mg/m2 basis. These doses resulted in maternal toxicity but no fetal harm was observed. - In a prenatal and postnatal developmental study, pregnant rats received oral deferasirox daily from organogenesis through lactation day 20 at doses (10, 30, and 90 mg per kg/day) 0.08, 0.2, and 0.7 times the MRHD on a mg/m2 basis. Maternal toxicity, loss of litters, and decreased offspring viability occurred at 0.7 times the MRHD on a mg/m2 basis, and increases in renal anomalies in male offspring occurred at 0.2 times the MRHD 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 Deferasirox in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Deferasirox during labor and delivery. ### Nursing Mothers - It is not known whether Exjade is excreted in human milk. Deferasirox and its metabolites were excreted in rat milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from deferasirox and its metabolites, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - Of the 700 patients with transfusional iron overload who received Exjade during clinical studies, 292 were pediatric patients 2-<16 years of age with various congenital and acquired anemias, including 52 patients age 2-<6 years, 121 patients age 6-<12 years and 119 patients age 12-<16 years. Seventy percent of these patients had beta-thalassemia. Children between the ages of 2-<6 years have a systemic exposure to Exjade approximately 50% of that of adults. However, the safety and efficacy of Exjade in pediatric patients was similar to that of adult patients, and younger pediatric patients responded similarly to older pediatric patients. The recommended starting dose and dosing modification are the same for children and adults. - Growth and development in patients with chronic iron overload due to blood transfusions were within normal limits in children followed for up to 5 years in clinical trials. - Sixteen pediatric patients (10 to <16 years of age) with chronic iron overload and NTDT were treated with Exjade in clinical studies. The safety and efficacy of Exjade in these children was similar to that seen in the adults. The recommended starting dose and dosing modification are the same for children and adults with chronic iron overload in NTDT. - Safety and effectiveness have not been established in pediatric patients with chronic iron overload due to blood transfusions who are less than 2 years of age or pediatric patients with chronic iron overload and NTDT who are less than 10 years of age. ### Geriatic Use - Four hundred thirty-one (431) patients ≥65 years of age were studied in clinical trials of Exjade in the transfusional iron overload setting. The majority of these patients had myelodysplastic syndrome (MDS) (n=393). In these trials, elderly patients experienced a higher frequency of adverse reactions than younger patients. Monitor elderly patients for early signs or symptoms of adverse reactions that may require a dose adjustment. Elderly patients are at increased risk for toxicity due to the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range. ### Gender There is no FDA guidance on the use of Deferasirox with respect to specific gender populations. ### Race There is no FDA guidance on the use of Deferasirox with respect to specific racial populations. ### Renal Impairment - For patients with renal impairment (ClCr 40-60 mL/min), reduce the starting dose by 50%. Exjade is contraindicated in patients with a creatinine clearance 2 times the age-appropriate upper limit of normal. - Exjade can cause renal failure. Monitor serum creatinine and calculate creatinine clearance (using Cockcroft-Gault method) during treatment in all patients. Reduce, interrupt or discontinue Exjade dosing based on increases in serum creatinine. ### Hepatic Impairment - In a single dose (20 mg/kg) study in patients with varying degrees of hepatic impairment, deferasirox exposure was increased compared to patients with normal hepatic function. The average total (free and bound) AUC of deferasirox increased 16% in 6 patients with mild (Child-Pugh A) hepatic impairment, and 76% in 6 patients with moderate (Child-Pugh B) hepatic impairment compared to 6 patients with normal hepatic function. The impact of severe (Child-Pugh C) hepatic impairment was assessed in only 1 patient. - Avoid the use of Exjade in patients with severe (Child-Pugh C) hepatic impairment. For patients with moderate (Child-Pugh B) hepatic impairment, the starting dose should be reduced by 50%. Closely monitor patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment for efficacy and adverse reactions that may require dose titration. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Deferasirox in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Deferasirox in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Deferasirox in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Deferasirox in the drug label. # Overdosage ## Acute Overdose - Cases of overdose (2-3 times the prescribed dose for several weeks) have been reported. In 1 case, this resulted in hepatitis which resolved without long-term consequences after a dose interruption. Single doses up to 80 mg per kg per day in iron overloaded beta-thalassemic patients have been tolerated with nausea and diarrhea noted. In healthy volunteers, single doses of up to 40 mg per kg per day were tolerated. There is no specific antidote for Exjade. In case of overdose, induce vomiting and employ gastric lavage. ## Chronic Overdose There is limited information regarding Chronic Overdose of Deferasirox in the drug label. # Pharmacology ## Mechanism of Action - Exjade (deferasirox) is an orally active chelator that is selective for iron (as Fe3+). It is a tridentate ligand that binds iron with high affinity in a 2:1 ratio. Although deferasirox has very low affinity for zinc and copper there are variable decreases in the serum concentration of these trace metals after the administration of deferasirox. The clinical significance of these decreases is uncertain. ## Structure - Exjade (deferasirox) is an iron chelating agent. Exjade tablets for oral suspension contain 125 mg, 250 mg, or 500 mg deferasirox. Deferasirox is designated chemically as 4--benzoic acid and its structural formula is: - Deferasirox is a white to slightly yellow powder. Its molecular formula is C21H15N3O4 and its molecular weight is 373.4. - Inactive Ingredients: Lactose monohydrate (NF), crospovidone (NF), povidone (K30) (NF), sodium lauryl sulphate (NF), microcrystalline cellulose (NF), silicon dioxide (NF), and magnesium stearate (NF). ## Pharmacodynamics - Pharmacodynamic effects tested in an iron balance metabolic study showed that deferasirox (10, 20, and 40 mg per kg per day) was able to induce a mean net iron excretion (0.119, 0.329, and 0.445 mg Fe/kg body weight per day, respectively) within the clinically relevant range (0.1-0.5 mg per kg per day). Iron excretion was predominantly fecal. ## Pharmacokinetics - Absorption - Exjade is absorbed following oral administration with median times to maximum plasma concentration (tmax) of about 1.5-4 hours. The Cmax and AUC of deferasirox increase approximately linearly with dose after both single administration and under steady-state conditions. Exposure to deferasirox increased by an accumulation factor of 1.3-2.3 after multiple doses. The absolute bioavailability (AUC) of deferasirox tablets for oral suspension is 70% compared to an intravenous dose. The bioavailability (AUC) of deferasirox was variably increased when taken with a meal. - Distribution - Deferasirox is highly (~99%) protein bound almost exclusively to serum albumin. The percentage of deferasirox confined to the blood cells was 5% in humans. The volume of distribution at steady state (Vss) of deferasirox is 14.37 ± 2.69 L in adults. - Metabolism - Glucuronidation is the main metabolic pathway for deferasirox, with subsequent biliary excretion. Deconjugation of glucuronidates in the intestine and subsequent reabsorption (enterohepatic recycling) is likely to occur. Deferasirox is mainly glucuronidated by UGT1A1 and to a lesser extent UGT1A3. CYP450-catalyzed (oxidative) metabolism of deferasirox appears to be minor in humans (about 8%). Deconjugation of glucuronide metabolites in the intestine and subsequent reabsorption (enterohepatic recycling) was confirmed in a healthy volunteer study in which the administration of cholestyramine 12 g twice daily (strongly binds to deferasirox and its conjugates) 4 and 10 hours after a single dose of deferasirox resulted in a 45% decrease in deferasirox exposure (AUC) by interfering with the enterohepatic recycling of deferasirox. - Excretion - Deferasirox and metabolites are primarily (84% of the dose) excreted in the feces. Renal excretion of deferasirox and metabolites is minimal (8% of the administered dose). The mean elimination half-life (t1/2) ranged from 8-16 hours following oral administration. - Drug Interactions - Midazolam: In healthy volunteers, the concomitant administration of Exjade and midazolam (a CYP3A4 probe substrate) resulted in a decrease of midazolam peak concentration by 23% and exposure by 17%. In the clinical setting, this effect may be more pronounced. The study was not adequately designed to conclusively assess the potential induction of CYP3A4 by deferasirox. - Repaglinide: In a healthy volunteer study, the concomitant administration of Exjade (30 mg per kg/day for 4 days) and the CYP2C8 probe substrate repaglinide (single dose of 0.5 mg) resulted in an increase in repaglinide systemic exposure (AUC) to 2.3-fold of control and an increase in Cmax of 62%. - Theophylline: In a healthy volunteer study, the concomitant administration of Exjade (repeated dose of 30 mg per kg/day) and the CYP1A2 substrate theophylline (single dose of 120 mg) resulted in an approximate doubling of the theophylline AUC and elimination half-life. The single dose Cmax was not affected, but an increase in theophylline Cmax is expected to occur with chronic dosing. - Rifampicin: In a healthy volunteer study, the concomitant administration of Exjade (single dose of 30 mg per kg) and the potent UDP-glucuronosyltransferase (UGT) inducer rifampicin (600 mg/day for 9 days) resulted in a decrease of deferasirox systemic exposure (AUC) by 44%. - Cholestyramine: The concomitant use of Exjade with bile acid sequestrants may result in a decrease in Exjade efficacy. In healthy volunteers, the administration of cholestyramine after a single dose of deferasirox resulted in a 45% decrease in deferasirox exposure (AUC). - In vitro studies: - Cytochrome P450 Enzymes: Deferasirox inhibits human CYP3A4, CYP2C8, CYP1A2, CYP2A6, CYP2D6, and CYP2C19 in vitro. - Transporter Systems: The addition of cyclosporin A (PgP/MRP1/MRP2 inhibitor) or verapamil (PgP/MRP1 inhibitor) did not influence ICL670 permeability in vitro. - Pharmacokinetics in Specific Populations - Pediatric: Following oral administration of single or multiple doses, systemic exposure of adolescents and children to deferasirox was less than in adult patients. In children <;&lt6 years of age, systemic exposure was about 50% lower than in adults. - Geriatric: The pharmacokinetics of deferasirox have not been studied in elderly patients (65 years of age or older). - Gender: Females have a moderately lower apparent clearance (by 17.5%) for deferasirox compared to males. - Renal Impairment: Compared to patients with MDS and ClCr >60 mL/min, patients with MDS and ClCr 40 to 60 mL/min (n=34) had approximately 50% higher mean deferasirox trough plasma concentrations. - QT Prolongation - The effect of 20 and 40 mg per kg per day of deferasirox on the QT interval was evaluated in a single-dose, double-blind, randomized, placebo- and active-controlled (moxifloxacin 400 mg), parallel group study in 182 healthy male and female volunteers age 18-65 years. No evidence of prolongation of the QTc interval was observed in this study. ## Nonclinical Toxicology - A 104-week oral carcinogenicity study in Wistar rats showed no evidence of carcinogenicity from deferasirox at doses up to 60 mg per kg per day (0.48 times the MRHD on a mg/m2 basis). A 26-week oral carcinogenicity study in p53 (+/-) transgenic mice has shown no evidence of carcinogenicity from deferasirox at doses up to 200 mg per kg per day (0.81 times the MRHD on a mg/m2 basis) in males and 300 mg per kg per day (1.21 times the MRHD on a mg/m2 basis) in females. - Deferasirox was negative in the Ames test and chromosome aberration test with human peripheral blood lymphocytes. It was positive in 1 of 3 in vivo oral rat micronucleus tests. - Deferasirox at oral doses up to 75 mg per kg per day (0.6 times the MRHD on a mg/m2 basis) was found to have no adverse effect on fertility and reproductive performance of male and female rats. # Clinical Studies - The primary efficacy study, Study 1, was a multicenter, open-label, randomized, active-comparator control study to compare Exjade (deferasirox) and deferoxamine in patients with beta-thalassemia and transfusional hemosiderosis. Patients ≥2 years of age were randomized in a 1:1 ratio to receive either oral Exjade at starting doses of 5, 10, 20, or 30 mg per kg once daily or subcutaneous Desferal (deferoxamine) at starting doses of 20 to 60 mg per kg for at least 5 days per week based on LIC at baseline (2-3, >3-7, >7-14, and >14 mg Fe/g dry weight). Patients randomized to deferoxamine who had LIC values <7 mg Fe/g dry weight were permitted to continue on their prior deferoxamine dose, even though the dose may have been higher than specified in the protocol. - Patients were to have a liver biopsy at baseline and end of study (after 12 months) for LIC. The primary efficacy endpoint was defined as a reduction in LIC of ≥3 mg Fe/g dry weight for baseline values ≥10 mg Fe/g dry weight, reduction of baseline values between 7 and <10 to <7 mg Fe/g dry weight, or maintenance or reduction for baseline values <7 mg Fe/g dry weight. - A total of 586 patients were randomized and treated, 296 with Exjade and 290 with deferoxamine. The mean age was 17.1 years (range, 2-53 years); 52% were females and 88% were Caucasian. The primary efficacy population consisted of 553 patients (Exjade n=276; deferoxamine n=277) who had LIC evaluated at baseline and 12 months or discontinued due to an adverse event. The percentage of patients achieving the primary endpoint was 52.9% for Exjade and 66.4% for deferoxamine. The relative efficacy of Exjade to deferoxamine cannot be determined from this study. - In patients who had an LIC at baseline and at end of study, the mean change in LIC was -2.4 mg Fe/g dry weight in patients treated with Exjade and -2.9 mg Fe/g dry weight in patients treated with deferoxamine. - Reduction of LIC and serum ferritin was observed with Exjade doses of 20 to 30 mg per kg per day. Exjade doses below 20 mg per kg per day failed to provide consistent lowering of LIC and serum ferritin levels (Figure 1). Therefore, a starting dose of 20 mg per kg per day is recommended. - Study 2 was an open-label, noncomparative trial of efficacy and safety of Exjade given for 1 year to patients with chronic anemias and transfusional hemosiderosis. Similar to Study 1, patients received 5, 10, 20, or 30 mg per kg per day of Exjade based on baseline LIC. - A total of 184 patients were treated in this study: 85 patients with beta-thalassemia and 99 patients with other congenital or acquired anemias (myelodysplastic syndromes, n=47; Diamond-Blackfan syndrome, n=30; other, n=22). 19% of patients were <16 years of age and 16% were ≥65 years of age. There was a reduction in the absolute LIC from baseline to end of study (-4.2 mg Fe/g dry weight). - Study 3 was a multicenter, open-label, randomized trial of the safety and efficacy of Exjade relative to deferoxamine given for 1 year in patients with sickle cell disease and transfusional hemosiderosis. Patients were randomized to Exjade at doses of 5, 10, 20, or 30 mg per kg per day or subcutaneous deferoxamine at doses of 20-60 mg per kg per day for 5 days per week according to baseline LIC. - A total of 195 patients were treated in this study: 132 with Exjade and 63 with deferoxamine. 44% of patients were <16 years of age and 91% were black. At end of study, the mean change in LIC (as measured by magnetic susceptometry by a superconducting quantum interference device) in the per protocol-1 (PP-1) population, which consisted of patients who had at least 1 post-baseline LIC assessment, was -1.3 mg Fe/g dry weight for patients receiving Exjade (n=113) and -0.7 mg Fe/g dry weight for patients receiving deferoxamine (n=54). - One-hundred five (105) patients with thalassemia major and cardiac iron overload were enrolled in a study assessing the change in cardiac MRI T2- value (measured in milliseconds, ms) before and after treatment with deferasirox. Cardiac T2- values at baseline ranged from 5 to <20 ms. The geometric mean of cardiac T2- in the 68 patients who completed 3 years of Exjade therapy increased from 11.98 ms at baseline to 17.12 ms at 3 years. Cardiac T2- values improved in patients with severe cardiac iron overload (<10 ms) and in those with mild to moderate cardiac iron overload (≥10 to <20 ms). The clinical significance of these observations is unknown. - Six hundred twenty-seven patients with MDS were enrolled across 5 uncontrolled trials. Two hundred thirty-nine of the 627 patients were enrolled in trials that limited enrollment to patients with IPSS Low or Intermediate 1 risk MDS and the remaining 388 patients were enrolled in trials that did not specify MDS risk stratification but required a life expectancy of greater than 1 year. Planned duration of treatment in these trials ranged from 1 year (365 patients) to 5 years (47 patients). These trials evaluated the effects of Exjade therapy on parameters of iron overload, including LIC (125 patients) and serum ferritin (627 patients). Percent of patients completing planned duration of treatment was 51% in the largest 1 year study, 52% in the 3-year study and 22% in the 5 year study. The major causes for treatment discontinuation were withdrawal of consent, adverse reaction, and death. Over 1 year of follow-up across these pooled studies, mean change in serum ferritin was -332.8 (±2615.59) mcg/L (n=593) and mean change in LIC was -5.9 (±8.32) mg Fe/g dw (n=68). Results of these pooled studies in 627 patients with MDS suggest a progressive decrease in serum ferritin and LIC beyond 1 year in those patients who are able to continue Exjade. No controlled trials have been performed to demonstrate that these reductions improve morbidity or mortality in patients with MDS. Adverse reactions with Exjade therapy occur more frequently in older patients. In elderly patients, including those with MDS, individualize the decision to remove accumulated iron based on clinical circumstances and the anticipated clinical benefit and risks of Exjade therapy. - Study 4 was a randomized, double-blind, placebo-controlled trial of treatment with Exjade for patients 10 years of age or older with NTDT syndromes and iron overload. Eligible patients had an LIC of at least 5 mg Fe/g dw measured by R2 MRI and a serum ferritin exceeding 300 mcg/L at screening (2 consecutive values at least 14 days apart from each other). A total of 166 patients were randomized, 55 to the Exjade 5 mg/kg/day dose group, 55 to the Exjade 10 mg/kg/day dose group, and 56 to placebo (28 to each matching placebo group). Doses could be increased after 6 months if the LIC exceeded 7 mg Fe/g dw and the LIC reduction from baseline was less than 15%. The patients enrolled included 89 males and 77 females. The underlying disease was beta-thalassemia intermedia in 95 (57%) patients, HbE beta-thalassemia in 49 (30%) patients, and alpha-thalassemia in 22 (13%) patients. There were 17 pediatric patients in the study. Caucasians comprised 57% of the study population and Asians comprised 42%. The median baseline LIC (range) for all patients was 12.1 (2.6-49.1) mg Fe/g dw. Follow-up was for 1 year. The primary efficacy endpoint of change in LIC from baseline to Week 52 was statistically significant in favor of both Exjade dose groups compared with placebo (p ≤0.001) (Table 5). Furthermore, a statistically significant dose effect of Exjade was observed in favor of the 10 mg/kg/day dose group (10 versus 5 mg/kg/day, p=0.009). In a descriptive analysis, the target LIC (less than 5 mg Fe/g dw) was reached by 15 (27%) of 55 patients in the 10 mg/kg/day arm, 8 (15%) of 55 patients in the 5 mg/kg/day arm and 2 (4%) of 56 patients in the combined placebo groups. - Study 5 was an open-label trial of Exjade for the treatment of patients previously enrolled on Study 4, including cross-over to active treatment for those previously treated with placebo. The starting dose of Exjade in Study 5 was assigned based on the patient’s LIC at completion of Study 4, being 20 mg/kg/day for an LIC exceeding 15 mg Fe/g dw, 10 mg/kg/day for LIC 3-15 mg Fe/g dw, and observation if the LIC was less than 3 mg Fe/g dw. Patients could continue on 5 mg/kg/day if they had previously exhibited at least a 30% reduction in LIC. Doses could be increased to a maximum of 20 mg/kg/day after 6 months if the LIC was more than 7 mg Fe/g dw and the LIC reduction from baseline was less than 15%. The primary efficacy endpoint in Study 5 was the proportion of patients achieving an LIC less than 5 mg Fe/g dw. A total of 133 patients were enrolled. Twenty patients began Study 5 with an LIC less than 5 mg Fe/g dw. Of the 113 patients with a baseline LIC of at least 5 mg Fe/g dw in Study 5, the target LIC (less than 5 mg Fe/g dw) was reached by 39 (35%). The responders included 4 (10%) of 39 patients treated at 20 mg/kg/day for a baseline LIC exceeding 15 mg Fe/g dw, and 31 (51%) of 61 patients treated at 10 mg/kg/day for a baseline LIC between 5 and 15 mg Fe/g dw. The absolute change in LIC at Week 52 by starting dose is shown in Table 5 above. # How Supplied - Exjade is provided as 125 mg, 250 mg, and 500 mg tablets for oral suspension. - 125 mg - Off-white, round, flat tablet with beveled edge and imprinted with “J” and “125” on one side and “NVR” on the other. - Bottles of 30 tablets………………………………………………………………..(NDC 0078-0468-15) - 250 mg - Off-white, round, flat tablet with beveled edge and imprinted with “J” and “250” on one side and “NVR” on the other. - Bottles of 30 tablets………………………………………………………………..(NDC 0078-0469-15) - 500 mg - Off-white, round, flat tablet with beveled edge and imprinted with “J” and “500” on one side and “NVR” on the other. - Bottles of 30 tablets………………………………………………………………..(NDC 0078-0470-15) - Store Exjade tablets at 25°C (77°F); excursions are permitted to 15°C-30°C (59°F-86°F). Protect from moisture. ## Storage There is limited information regarding Deferasirox Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise patients to take Exjade once daily on an empty stomach at least 30 minutes prior to food, preferably at the same time every day. Instruct patients to completely disperse the tablets in water, orange juice, or apple juice, and drink the resulting suspension immediately. After the suspension has been swallowed, resuspend any residue in a small volume of the liquid and swallow. - Advise patients not to chew tablets or swallow them whole. - Caution patients not to take aluminum-containing antacids and Exjade simultaneously. - Because auditory and ocular disturbances have been reported with Exjade, conduct auditory testing and ophthalmic testing before starting Exjade treatment and thereafter at regular intervals. - Caution patients experiencing dizziness to avoid driving or operating machinery. - Caution patients about the potential for the development of GI ulcers or bleeding when taking Exjade in combination with drugs that have ulcerogenic or hemorrhagic potential, such as NSAIDs, corticosteroids, oral bisphosphonates, or anticoagulants. - Caution patients about potential loss of effectiveness of drugs metabolized by CYP3A4 (e.g., cyclosporine, simvastatin, hormonal contraceptive agents) when Exjade is administered with these drugs. - Caution patients about potential loss of effectiveness of Exjade when administered with drugs that are potent UGT inducers (e.g., rifampicin, phenytoin, phenobarbital, ritonavir). Based on serum ferritin levels and clinical response, consider increases in the dose of Exjade when concomitantly used with potent UGT inducers. - Caution patients about potential loss of effectiveness of Exjade when administered with drugs that are bile acid sequestrants (e.g., cholestyramine, colesevelam, colestipol). Based on serum ferritin levels and clinical response, consider increases in the dose of Exjade when concomitantly used with bile acid sequestrants. - Perform careful monitoring of glucose levels when repaglinide is used concomitantly with Exjade. An interaction between Exjade and other CYP2C8 substrates like paclitaxel cannot be excluded. - Advise patients that blood tests will be performed because Exjade may affect your kidneys, liver, or blood cells. The blood tests will be performed every month or more frequently if you are at increased risk of complications (e.g., preexisting kidney condition, are elderly, have multiple medical conditions, or are taking medicine that affects your organs). There have been reports of severe kidney and liver problems, blood disorders, stomach hemorrhage and death in patients taking Exjade. - Skin rashes may occur during Exjade treatment and if severe, interrupt treatment. Serious allergic reactions (which include swelling of the throat) have been reported in patients taking Exjade, usually within the first month of treatment. If reactions are severe, advise patients to stop taking Exjade and contact their doctor immediately. # Precautions with Alcohol - Alcohol-Deferasirox interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - EXJADE® # Look-Alike Drug Names There is limited information regarding Deferasirox Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Deferasirox 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 Deferasirox is an iron chelator that is FDA approved for the {{{indicationType}}} of transfusional iron overload and iron overload in non-transfusion-dependent thalassemia syndromes. There is a Black Box Warning for this drug as shown here. Common adverse reactions include diarrhea, vomiting, nausea, abdominal pain, skin rashes, and increases in serum creatinine. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Exjade therapy should only be considered when a patient has evidence of chronic transfusional iron overload. The evidence should include the transfusion of at least 100 mL/kg of packed red blood cells (e.g., at least 20 units of packed red blood cells for a 40 kg person or more in individuals weighing more than 40 kg), and a serum ferritin consistently greater than 1000 mcg/L. - The recommended initial dose of Exjade for patients 2 years of age and older is 20 mg per kg body weight orally, once daily. Calculate doses (mg per kg per day) to the nearest whole tablet. - After commencing therapy, monitor serum ferritin monthly and adjust the dose of Exjade, if necessary, every 3-6 months based on serum ferritin trends. Make dose adjustments in steps of 5 or 10 mg per kg and tailor adjustments to the individual patient’s response and therapeutic goals. In patients not adequately controlled with doses of 30 mg per kg (e.g., serum ferritin levels persistently above 2500 mcg/L and not showing a decreasing trend over time), doses of up to 40 mg per kg may be considered. Doses above 40 mg per kg are not recommended. - If the serum ferritin falls consistently below 500 mcg/L, consider temporarily interrupting therapy with Exjade. - Exjade therapy should only be considered when a patient with NTDT syndrome has an LIC of at least 5 mg Fe/g dw and a serum ferritin greater than 300 mcg/L. - Initiating therapy: - The recommended initial dose of Exjade is 10 mg per kg body weight orally once daily. Calculate doses (mg per kg per day) to the nearest whole tablet. - If the baseline LIC is greater than 15 mg Fe/g dw, consider increasing the dose to 20 mg/kg/day after 4 weeks. - During therapy: - Monitor serum ferritin monthly. Interrupt treatment when serum ferritin is less than 300 mcg/L and obtain an LIC to determine whether the LIC has fallen to less than 3 mg Fe/g dw. - Monitor LIC every 6 months. - After 6 months of therapy, if the LIC remains greater than 7 mg Fe/g dw, increase the dose of deferasirox to a maximum of 20 mg/kg/day. Do not exceed a maximum of 20 mg/kg/day. - If after 6 months of therapy, the LIC is 3-7 mg Fe/g dw, continue treatment with deferasirox at no more than 10 mg/kg/day. - When the LIC is less than 3 mg Fe/g dw, interrupt treatment with deferasirox and continue to monitor the LIC. - Monitor blood counts, hepatic function, and renal function. - Restart treatment when the LIC rises again to more than 5 mg Fe/g dw. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Deferasirox in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Deferasirox in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Exjade therapy should only be considered when a patient has evidence of chronic transfusional iron overload. The evidence should include the transfusion of at least 100 mL/kg of packed red blood cells (e.g., at least 20 units of packed red blood cells for a 40 kg person or more in individuals weighing more than 40 kg), and a serum ferritin consistently greater than 1000 mcg/L. - The recommended initial dose of Exjade for patients 2 years of age and older is 20 mg per kg body weight orally, once daily. Calculate doses (mg per kg per day) to the nearest whole tablet. - After commencing therapy, monitor serum ferritin monthly and adjust the dose of Exjade, if necessary, every 3-6 months based on serum ferritin trends. Make dose adjustments in steps of 5 or 10 mg per kg and tailor adjustments to the individual patient’s response and therapeutic goals. In patients not adequately controlled with doses of 30 mg per kg (e.g., serum ferritin levels persistently above 2500 mcg/L and not showing a decreasing trend over time), doses of up to 40 mg per kg may be considered. Doses above 40 mg per kg are not recommended. - If the serum ferritin falls consistently below 500 mcg/L, consider temporarily interrupting therapy with Exjade. - Exjade therapy should only be considered when a patient with NTDT syndrome has an LIC of at least 5 mg Fe/g dw and a serum ferritin greater than 300 mcg/L. - Initiating therapy: - The recommended initial dose of Exjade is 10 mg per kg body weight orally once daily. Calculate doses (mg per kg per day) to the nearest whole tablet. - If the baseline LIC is greater than 15 mg Fe/g dw, consider increasing the dose to 20 mg/kg/day after 4 weeks. - During therapy: - Monitor serum ferritin monthly. Interrupt treatment when serum ferritin is less than 300 mcg/L and obtain an LIC to determine whether the LIC has fallen to less than 3 mg Fe/g dw. - Monitor LIC every 6 months. - After 6 months of therapy, if the LIC remains greater than 7 mg Fe/g dw, increase the dose of deferasirox to a maximum of 20 mg/kg/day. Do not exceed a maximum of 20 mg/kg/day. - If after 6 months of therapy, the LIC is 3-7 mg Fe/g dw, continue treatment with deferasirox at no more than 10 mg/kg/day. - When the LIC is less than 3 mg Fe/g dw, interrupt treatment with deferasirox and continue to monitor the LIC. - Monitor blood counts, hepatic function, and renal function. - Restart treatment when the LIC rises again to more than 5 mg Fe/g dw. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Deferasirox in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Deferasirox in pediatric patients. # Contraindications - Exjade is contraindicated in patients with: - Serum creatinine greater than 2 times the age-appropriate upper limit of normal or creatinine clearance less than 40 mL/min; - Poor performance status; - High-risk myelodysplastic syndromes; - Advanced malignancies; - Platelet counts <50 x 109/L; - Known hypersensitivity to deferasirox or any component of Exjade. # Warnings ### Precautions - Renal Toxicity, Renal Failure, and Proteinuria - Exjade can cause acute renal failure, fatal in some patients and requiring dialysis in others. Postmarketing experience showed that most fatalities occurred in patients with multiple comorbidities and who were in advanced stages of their hematological disorders. In the clinical trials, Exjade-treated patients experienced dose-dependent increases in serum creatinine. In patients with transfusional iron overload, these increases in creatinine occurred at a greater frequency compared to deferoxamine-treated patients (38% versus 14%, respectively, in Study 1 and 36% versus 22%, respectively, in Study 3). - Measure serum creatinine in duplicate (due to variations in measurements) and determine the creatinine clearance (estimated by the Cockcroft-Gault method) before initiating therapy in all patients in order to establish a reliable pretreatment baseline. Monitor serum creatinine weekly during the first month after initiation or modification of therapy and at least monthly thereafter. Monitor serum creatinine and/or creatinine clearance more frequently if creatinine levels are increasing. Dose reduction, interruption, or discontinuation based on increases in serum creatinine may be necessary. - Exjade is contraindicated in patients with creatinine clearance less than 40 mL/minute or serum creatinine greater than 2 times the age appropriate upper limit of normal. - Renal tubular damage, including Fanconi’s Syndrome, has been reported in patients treated with Exjade, most commonly in children and adolescents with beta-thalassemia and serum ferritin levels <;&lt1500 mcg/L. - Intermittent proteinuria (urine protein/creatinine ratio >0.6 mg/mg) occurred in 18.6% of Exjade-treated patients compared to 7.2% of deferoxamine-treated patients in Study 1. In clinical trials in patients with transfusional iron overload, Exjade was temporarily withheld until the urine protein/creatinine ratio fell below 0.6 mg/mg. Monthly monitoring for proteinuria is recommended. The mechanism and clinical significance of the proteinuria are uncertain. - Hepatic Toxicity and Failure - Exjade can cause hepatic injury, fatal in some patients. In Study 1, 4 patients (1.3%) discontinued Exjade because of hepatic toxicity (drug-induced hepatitis in 2 patients and increased serum transaminases in 2 additional patients). Hepatic toxicity appears to be more common in patients greater than 55 years of age. Hepatic failure was more common in patients with significant comorbidities, including liver cirrhosis and multiorgan failure. - Measure transaminases (AST and ALT) and bilirubin in all patients before the initiation of treatment and every 2 weeks during the first month and at least monthly thereafter. Consider dose modifications or interruption of treatment for severe or persistent elevations. - Avoid the use of Exjade in patients with severe (Child-Pugh C) hepatic impairment. Reduce the starting dose in patients with moderate (Child-Pugh B) hepatic impairment. Patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment may be at higher risk for hepatic toxicity. - Gastrointestinal (GI) Hemorrhage - GI hemorrhage, including deaths, has been reported, especially in elderly patients who had advanced hematologic malignancies and/or low platelet counts. Nonfatal upper GI irritation, ulceration and hemorrhage have been reported in patients, including children and adolescents, receiving Exjade. Monitor for signs and symptoms of GI ulceration and hemorrhage during Exjade therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. The risk of gastrointestinal hemorrhage may be increased when administering Exjade in combination with drugs that have ulcerogenic or hemorrhagic potential, such as nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, oral bisphosphonates, or anticoagulants. - Bone Marrow Suppression - Neutropenia, agranulocytosis, worsening anemia, and thrombocytopenia, including fatal events, have been reported in patients treated with Exjade. Preexisting hematologic disorders may increase this risk. Monitor blood counts in all patients. Interrupt treatment with Exjade in patients who develop cytopenias until the cause of the cytopenia has been determined. Exjade is contraindicated in patients with platelet counts below 50 x 109/L. - Increased Risk of Toxicity in the Elderly - Exjade has been associated with serious and fatal adverse reactions in the postmarketing setting, predominantly in elderly patients. Monitor elderly patients treated with Exjade more frequently for toxicity. - Hypersensitivity - Exjade may cause serious hypersensitivity reactions (such as anaphylaxis and angioedema), with the onset of the reaction usually occurring within the first month of treatment. If reactions are severe, discontinue Exjade and institute appropriate medical intervention. Exjade is contraindicated in patients with known hypersensitivity to Exjade. - Severe Skin Reactions - Severe skin reactions, including Stevens-Johnson syndrome (SJS) and erythema multiforme, have been reported during Exjade therapy. If SJS or erythema multiforme is suspected, discontinue Exjade and evaluate. - Skin Rash - Rashes may occur during Exjade treatment. For rashes of mild to moderate severity, Exjade may be continued without dose adjustment, since the rash often resolves spontaneously. In severe cases, interrupt treatment with Exjade. Reintroduction at a lower dose with escalation may be considered in combination with a short period of oral steroid administration. - Auditory and Ocular Abnormalities - Auditory disturbances (high frequency hearing loss, decreased hearing), and ocular disturbances (lens opacities, cataracts, elevations in intraocular pressure, and retinal disorders) were reported at a frequency of <1% with Exjade therapy in the clinical studies. Perform auditory and ophthalmic testing (including slit lamp examinations and dilated fundoscopy) before starting Exjade treatment and thereafter at regular intervals (every 12 months). If disturbances are noted, monitor more frequently. Consider dose reduction or interruption. - Overchelation - For patients with transfusional iron overload, measure serum ferritin monthly to assess for possible overchelation of iron. If the serum ferritin falls below 500 mcg/L, consider interrupting therapy with Exjade, since overchelation may increase Exjade toxicity. - For patients with NTDT, measure LIC by liver biopsy or by using an FDA-cleared or approved method for monitoring patients receiving deferasirox therapy every 6 months on treatment. Interrupt Exjade administration when the LIC is less than 3 mg Fe/g dw. Measure serum ferritin monthly, and if the serum ferritin falls below 300 mcg/L, interrupt Exjade and obtain a confirmatory LIC. # 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. - A total of 700 adult and pediatric patients were treated with Exjade (deferasirox) for 48 weeks in premarketing studies. These included 469 patients with beta-thalassemia, 99 with rare anemias, and 132 with sickle cell disease. Of these patients, 45% were male, 70% were Caucasian and 292 patients were <;&lt16 years of age. In the sickle cell disease population, 89% of patients were black. Median treatment duration among the sickle cell patients was 51 weeks. Of the 700 patients treated, 469 (403 beta-thalassemia and 66 rare anemias) were entered into extensions of the original clinical protocols. In ongoing extension studies, median durations of treatment were 88-205 weeks. - Six hundred twenty-seven patients with MDS were enrolled across 5 uncontrolled trials. These studies varied in duration from 1 to 5 years. The discontinuation rate across studies in the first year was 46% (AEs 20%, withdrawal of consent 10%, death 8%, other 4%, lab abnormalities 3%, and lack of efficacy 1%). Among 47 patients enrolled in the study of 5-year duration, 10 remained on Exjade at the completion of the study. - Table 1 displays adverse reactions occurring in >5% of Exjade-treated beta-thalassemia patients (Study 1), sickle cell disease patients (Study 3), and patients with MDS (MDS pool). Abdominal pain, nausea, vomiting, diarrhea, skin rashes, and increases in serum creatinine were the most frequent adverse reactions reported with a suspected relationship to Exjade. Gastrointestinal symptoms, increases in serum creatinine, and skin rash were dose related. - In Study 1, a total of 113 (38%) patients treated with Exjade had increases in serum creatinine >33% above baseline on 2 separate occasions (Table 2) and 25 (8%) patients required dose reductions. Increases in serum creatinine appeared to be dose related. In this study, 17 (6%) patients treated with Exjade developed elevations in SGPT/ALT levels >5 times the upper limit of normal at 2 consecutive visits. Of these, 2 patients had liver biopsy proven drug-induced hepatitis and both discontinued Exjade therapy [see Warnings and Precautions (5.2)]. An additional 2 patients, who did not have elevations in SGPT/ALT >5 times the upper limit of normal, discontinued Exjade because of increased SGPT/ALT. Increases in transaminases did not appear to be dose related. Adverse reactions that led to discontinuations included abnormal liver function tests (2 patients) and drug-induced hepatitis (2 patients), skin rash, glycosuria/proteinuria, Henoch Schönlein purpura, hyperactivity/insomnia, drug fever, and cataract (1 patient each). - In Study 3, a total of 48 (36%) patients treated with Exjade had increases in serum creatinine >33% above baseline on 2 separate occasions (Table 2) [see Warnings and Precautions (5.1)]. Of the patients who experienced creatinine increases in Study 3, 8 Exjade-treated patients required dose reductions. In this study, 5 patients in the Exjade group developed elevations in SGPT/ALT levels >5 times the upper limit of normal at 2 consecutive visits and 1 patient subsequently had Exjade permanently discontinued. Four additional patients discontinued Exjade due to adverse reactions with a suspected relationship to study drug, including diarrhea, pancreatitis associated with gallstones, atypical tuberculosis, and skin rash. - In the MDS pool, in the first year, a total of 229 (37%) patients treated with Exjade had increases in serum creatinine >33% above baseline on 2 consecutive occasions (Table 2) and 8 (3.5%) patients permanently discontinued. A total of 5 (0.8%) patients developed SGPT/ALT levels >5 times the upper limit of normal at 2 consecutive visits. The most frequent adverse reactions that led to discontinuation included increases in serum creatinine, diarrhea, nausea, rash, and vomiting. Death was reported in the first year in 52 (8%) of patients. - In Study 4, 110 patients with NTDT received 1 year of treatment with Exjade 5 or 10 mg/kg/day and 56 patients received placebo in a double-blind, randomized trial. In Study 5, 130 of the patients who completed Study 4 were treated with open-label Exjade at 5, 10, or 20 mg/kg/day (depending on the baseline LIC) for 1 year. Table 3 displays adverse reactions occurring in >5% in any group. The most frequent adverse reactions with a suspected relationship to study drug were nausea, rash, and diarrhea. In Study 4, 1 patient in the placebo 10 mg/kg/day group experienced an ALT increase to >5 times ULN and >2 times baseline (Table 4). Three Exjade-treated patients (all in the 10 mg/kg/day group) had 2 consecutive serum creatinine level increases >33% from baseline and >ULN. Serum creatinine returned to normal in all 3 patients (in 1 spontaneously and in the other 2 after drug interruption). Two additional cases of ALT increase and 2 additional cases of serum creatinine increase were observed in the 1-year extension of Study 4. - Proteinuria - In clinical studies, urine protein was measured monthly. Intermittent proteinuria (urine protein/creatinine ratio >0.6 mg/mg) occurred in 18.6% of Exjade-treated patients compared to 7.2% of deferoxamine-treated patients in Study 1. - Other Adverse Reactions - In the population of more than 5,000 patients with transfusional iron overload who have been treated with Exjade during clinical trials, adverse reactions occurring in 0.1% to 1% of patients included gastritis, edema, sleep disorder, pigmentation disorder, dizziness, anxiety, maculopathy, cholelithiasis, pyrexia, fatigue, pharyngolaryngeal pain, early cataract, hearing loss, gastrointestinal hemorrhage, gastric ulcer (including multiple ulcers), duodenal ulcer, and renal tubulopathy (Fanconi’s Syndrome). Adverse reactions occurring in 0.01% to 0.1% of patients included optic neuritis, esophagitis, and erythema multiforme. Adverse reactions which most frequently led to dose interruption or dose adjustment during clinical trials were rash, gastrointestinal disorders, infections, increased serum creatinine, and increased serum transaminases. ## Postmarketing Experience - The following adverse reactions have been spontaneously reported during post-approval use of Exjade in the transfusional iron overload setting. Because these reactions are reported voluntarily from a population of uncertain size, in which patients may have received concomitant medication, it is not always possible to reliably estimate frequency or establish a causal relationship to drug exposure. Stevens-Johnson syndrome (SJS), leukocytoclastic vasculitis, urticaria, alopecia Hypersensitivity reactions (including anaphylaxis and angioedema) Acute renal failure, tubulointerstitial nephritis Hepatic failure Gastrointestinal hemorrhage Worsening anemia # Drug Interactions - Aluminum Containing Antacid Preparations - The concomitant administration of Exjade and aluminum-containing antacid preparations has not been formally studied. Although deferasirox has a lower affinity for aluminum than for iron, avoid use of Exjade with aluminum-containing antacid preparations due to the mechanism of action of Exjade. - Agents Metabolized by CYP3A4 - Deferasirox may induce CYP3A4 resulting in a decrease in CYP3A4 substrate concentration when these drugs are coadministered. Closely monitor patients for signs of reduced effectiveness when deferasirox is administered with drugs metabolized by CYP3A4 (e.g., alfentanil, aprepitant, budesonide, buspirone, conivaptan, cyclosporine, darifenacin, darunavir, dasatinib, dihydroergotamine, dronedarone, eletriptan, eplerenone, ergotamine, everolimus, felodipine, fentanyl, hormonal contraceptive agents, indinavir, fluticasone, lopinavir, lovastatin, lurasidone, maraviroc, midazolam, nisoldipine, pimozide, quetiapine, quinidine, saquinavir, sildenafil, simvastatin, sirolimus, tacrolimus, tolvaptan, tipranavir, triazolam, ticagrelor, and vardenafil). - Agents Metabolized by CYP2C8 - Deferasirox inhibits CYP2C8 resulting in an increase in CYP2C8 substrate (e.g., repaglinide and paclitaxel) concentration when these drugs are coadministered. If Exjade and repaglinide are used concomitantly, consider decreasing the dose of repaglinide and perform careful monitoring of blood glucose levels. Closely monitor patients for signs of exposure related toxicity when Exjade is coadministered with other CYP2C8 substrates. - Agents Metabolized by CYP1A2 - Deferasirox inhibits CYP1A2 resulting in an increase in CYP1A2 substrate (e.g., alosetron, caffeine, duloxetine, melatonin, ramelteon, tacrine, theophylline, tizanidine) concentration when these drugs are coadministered. An increase in theophylline plasma concentrations could lead to clinically significant theophylline induced CNS or other adverse reactions. Avoid the concomitant use of theophylline or other CYP1A2 substrates with a narrow therapeutic index (e.g., tizanidine) with Exjade. Monitor theophylline concentrations and consider theophylline dose modification if you must coadminister theophylline with Exjade. Closely monitor patients for signs of exposure related toxicity when Exjade is coadministered with other drugs metabolized by CYP1A2. - Agents Inducing UDP-glucuronosyltransferase (UGT) Metabolism - Deferasirox is a substrate of UGT1A1 and to a lesser extent UGT1A3. The concomitant use of Exjade with potent UGT inducers (e.g., rifampicin, phenytoin, phenobarbital, ritonavir) may result in a decrease in Exjade efficacy due to a possible decrease in deferasirox concentration. Avoid the concomitant use of potent UGT inducers with Exjade. Consider increasing the initial dose of Exjade if you must coadminister these agents together. - Bile Acid Sequestrants - Avoid the concomitant use of bile acid sequestrants (e.g., cholestyramine, colesevelam, colestipol) with Exjade due to a possible decrease in deferasirox concentration. If you must coadminister these agents together, consider increasing the initial dose of Exjade. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - There are no adequate and well-controlled studies with Exjade in pregnant women. Administration of deferasirox to animals during pregnancy and lactation resulted in decreased offspring viability and an increase in renal anomalies in male offspring at exposures that were less than the recommended human exposure. Exjade should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - In embryofetal developmental studies, pregnant rats and rabbits received oral deferasirox during the period of organogenesis at doses up to (100 mg per kg/day in rats and 50 mg per kg/day in rabbits) 0.8 times the maximum recommended human dose (MRHD) on a mg/m2 basis. These doses resulted in maternal toxicity but no fetal harm was observed. - In a prenatal and postnatal developmental study, pregnant rats received oral deferasirox daily from organogenesis through lactation day 20 at doses (10, 30, and 90 mg per kg/day) 0.08, 0.2, and 0.7 times the MRHD on a mg/m2 basis. Maternal toxicity, loss of litters, and decreased offspring viability occurred at 0.7 times the MRHD on a mg/m2 basis, and increases in renal anomalies in male offspring occurred at 0.2 times the MRHD 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 Deferasirox in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Deferasirox during labor and delivery. ### Nursing Mothers - It is not known whether Exjade is excreted in human milk. Deferasirox and its metabolites were excreted in rat milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from deferasirox and its metabolites, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - Of the 700 patients with transfusional iron overload who received Exjade during clinical studies, 292 were pediatric patients 2-<16 years of age with various congenital and acquired anemias, including 52 patients age 2-<6 years, 121 patients age 6-<12 years and 119 patients age 12-<16 years. Seventy percent of these patients had beta-thalassemia. Children between the ages of 2-<6 years have a systemic exposure to Exjade approximately 50% of that of adults. However, the safety and efficacy of Exjade in pediatric patients was similar to that of adult patients, and younger pediatric patients responded similarly to older pediatric patients. The recommended starting dose and dosing modification are the same for children and adults. - Growth and development in patients with chronic iron overload due to blood transfusions were within normal limits in children followed for up to 5 years in clinical trials. - Sixteen pediatric patients (10 to <16 years of age) with chronic iron overload and NTDT were treated with Exjade in clinical studies. The safety and efficacy of Exjade in these children was similar to that seen in the adults. The recommended starting dose and dosing modification are the same for children and adults with chronic iron overload in NTDT. - Safety and effectiveness have not been established in pediatric patients with chronic iron overload due to blood transfusions who are less than 2 years of age or pediatric patients with chronic iron overload and NTDT who are less than 10 years of age. ### Geriatic Use - Four hundred thirty-one (431) patients ≥65 years of age were studied in clinical trials of Exjade in the transfusional iron overload setting. The majority of these patients had myelodysplastic syndrome (MDS) (n=393). In these trials, elderly patients experienced a higher frequency of adverse reactions than younger patients. Monitor elderly patients for early signs or symptoms of adverse reactions that may require a dose adjustment. Elderly patients are at increased risk for toxicity due to the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range. ### Gender There is no FDA guidance on the use of Deferasirox with respect to specific gender populations. ### Race There is no FDA guidance on the use of Deferasirox with respect to specific racial populations. ### Renal Impairment - For patients with renal impairment (ClCr 40-60 mL/min), reduce the starting dose by 50%. Exjade is contraindicated in patients with a creatinine clearance <;&lt40 mL/min or serum creatinine >2 times the age-appropriate upper limit of normal. - Exjade can cause renal failure. Monitor serum creatinine and calculate creatinine clearance (using Cockcroft-Gault method) during treatment in all patients. Reduce, interrupt or discontinue Exjade dosing based on increases in serum creatinine. ### Hepatic Impairment - In a single dose (20 mg/kg) study in patients with varying degrees of hepatic impairment, deferasirox exposure was increased compared to patients with normal hepatic function. The average total (free and bound) AUC of deferasirox increased 16% in 6 patients with mild (Child-Pugh A) hepatic impairment, and 76% in 6 patients with moderate (Child-Pugh B) hepatic impairment compared to 6 patients with normal hepatic function. The impact of severe (Child-Pugh C) hepatic impairment was assessed in only 1 patient. - Avoid the use of Exjade in patients with severe (Child-Pugh C) hepatic impairment. For patients with moderate (Child-Pugh B) hepatic impairment, the starting dose should be reduced by 50%. Closely monitor patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment for efficacy and adverse reactions that may require dose titration. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Deferasirox in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Deferasirox in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Deferasirox in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Deferasirox in the drug label. # Overdosage ## Acute Overdose - Cases of overdose (2-3 times the prescribed dose for several weeks) have been reported. In 1 case, this resulted in hepatitis which resolved without long-term consequences after a dose interruption. Single doses up to 80 mg per kg per day in iron overloaded beta-thalassemic patients have been tolerated with nausea and diarrhea noted. In healthy volunteers, single doses of up to 40 mg per kg per day were tolerated. There is no specific antidote for Exjade. In case of overdose, induce vomiting and employ gastric lavage. ## Chronic Overdose There is limited information regarding Chronic Overdose of Deferasirox in the drug label. # Pharmacology ## Mechanism of Action - Exjade (deferasirox) is an orally active chelator that is selective for iron (as Fe3+). It is a tridentate ligand that binds iron with high affinity in a 2:1 ratio. Although deferasirox has very low affinity for zinc and copper there are variable decreases in the serum concentration of these trace metals after the administration of deferasirox. The clinical significance of these decreases is uncertain. ## Structure - Exjade (deferasirox) is an iron chelating agent. Exjade tablets for oral suspension contain 125 mg, 250 mg, or 500 mg deferasirox. Deferasirox is designated chemically as 4-[3,5-Bis (2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]-benzoic acid and its structural formula is: - Deferasirox is a white to slightly yellow powder. Its molecular formula is C21H15N3O4 and its molecular weight is 373.4. - Inactive Ingredients: Lactose monohydrate (NF), crospovidone (NF), povidone (K30) (NF), sodium lauryl sulphate (NF), microcrystalline cellulose (NF), silicon dioxide (NF), and magnesium stearate (NF). ## Pharmacodynamics - Pharmacodynamic effects tested in an iron balance metabolic study showed that deferasirox (10, 20, and 40 mg per kg per day) was able to induce a mean net iron excretion (0.119, 0.329, and 0.445 mg Fe/kg body weight per day, respectively) within the clinically relevant range (0.1-0.5 mg per kg per day). Iron excretion was predominantly fecal. ## Pharmacokinetics - Absorption - Exjade is absorbed following oral administration with median times to maximum plasma concentration (tmax) of about 1.5-4 hours. The Cmax and AUC of deferasirox increase approximately linearly with dose after both single administration and under steady-state conditions. Exposure to deferasirox increased by an accumulation factor of 1.3-2.3 after multiple doses. The absolute bioavailability (AUC) of deferasirox tablets for oral suspension is 70% compared to an intravenous dose. The bioavailability (AUC) of deferasirox was variably increased when taken with a meal. - Distribution - Deferasirox is highly (~99%) protein bound almost exclusively to serum albumin. The percentage of deferasirox confined to the blood cells was 5% in humans. The volume of distribution at steady state (Vss) of deferasirox is 14.37 ± 2.69 L in adults. - Metabolism - Glucuronidation is the main metabolic pathway for deferasirox, with subsequent biliary excretion. Deconjugation of glucuronidates in the intestine and subsequent reabsorption (enterohepatic recycling) is likely to occur. Deferasirox is mainly glucuronidated by UGT1A1 and to a lesser extent UGT1A3. CYP450-catalyzed (oxidative) metabolism of deferasirox appears to be minor in humans (about 8%). Deconjugation of glucuronide metabolites in the intestine and subsequent reabsorption (enterohepatic recycling) was confirmed in a healthy volunteer study in which the administration of cholestyramine 12 g twice daily (strongly binds to deferasirox and its conjugates) 4 and 10 hours after a single dose of deferasirox resulted in a 45% decrease in deferasirox exposure (AUC) by interfering with the enterohepatic recycling of deferasirox. - Excretion - Deferasirox and metabolites are primarily (84% of the dose) excreted in the feces. Renal excretion of deferasirox and metabolites is minimal (8% of the administered dose). The mean elimination half-life (t1/2) ranged from 8-16 hours following oral administration. - Drug Interactions - Midazolam: In healthy volunteers, the concomitant administration of Exjade and midazolam (a CYP3A4 probe substrate) resulted in a decrease of midazolam peak concentration by 23% and exposure by 17%. In the clinical setting, this effect may be more pronounced. The study was not adequately designed to conclusively assess the potential induction of CYP3A4 by deferasirox. - Repaglinide: In a healthy volunteer study, the concomitant administration of Exjade (30 mg per kg/day for 4 days) and the CYP2C8 probe substrate repaglinide (single dose of 0.5 mg) resulted in an increase in repaglinide systemic exposure (AUC) to 2.3-fold of control and an increase in Cmax of 62%. - Theophylline: In a healthy volunteer study, the concomitant administration of Exjade (repeated dose of 30 mg per kg/day) and the CYP1A2 substrate theophylline (single dose of 120 mg) resulted in an approximate doubling of the theophylline AUC and elimination half-life. The single dose Cmax was not affected, but an increase in theophylline Cmax is expected to occur with chronic dosing. - Rifampicin: In a healthy volunteer study, the concomitant administration of Exjade (single dose of 30 mg per kg) and the potent UDP-glucuronosyltransferase (UGT) inducer rifampicin (600 mg/day for 9 days) resulted in a decrease of deferasirox systemic exposure (AUC) by 44%. - Cholestyramine: The concomitant use of Exjade with bile acid sequestrants may result in a decrease in Exjade efficacy. In healthy volunteers, the administration of cholestyramine after a single dose of deferasirox resulted in a 45% decrease in deferasirox exposure (AUC). - In vitro studies: - Cytochrome P450 Enzymes: Deferasirox inhibits human CYP3A4, CYP2C8, CYP1A2, CYP2A6, CYP2D6, and CYP2C19 in vitro. - Transporter Systems: The addition of cyclosporin A (PgP/MRP1/MRP2 inhibitor) or verapamil (PgP/MRP1 inhibitor) did not influence ICL670 permeability in vitro. - Pharmacokinetics in Specific Populations - Pediatric: Following oral administration of single or multiple doses, systemic exposure of adolescents and children to deferasirox was less than in adult patients. In children <;&lt6 years of age, systemic exposure was about 50% lower than in adults. - Geriatric: The pharmacokinetics of deferasirox have not been studied in elderly patients (65 years of age or older). - Gender: Females have a moderately lower apparent clearance (by 17.5%) for deferasirox compared to males. - Renal Impairment: Compared to patients with MDS and ClCr >60 mL/min, patients with MDS and ClCr 40 to 60 mL/min (n=34) had approximately 50% higher mean deferasirox trough plasma concentrations. - QT Prolongation - The effect of 20 and 40 mg per kg per day of deferasirox on the QT interval was evaluated in a single-dose, double-blind, randomized, placebo- and active-controlled (moxifloxacin 400 mg), parallel group study in 182 healthy male and female volunteers age 18-65 years. No evidence of prolongation of the QTc interval was observed in this study. ## Nonclinical Toxicology - A 104-week oral carcinogenicity study in Wistar rats showed no evidence of carcinogenicity from deferasirox at doses up to 60 mg per kg per day (0.48 times the MRHD on a mg/m2 basis). A 26-week oral carcinogenicity study in p53 (+/-) transgenic mice has shown no evidence of carcinogenicity from deferasirox at doses up to 200 mg per kg per day (0.81 times the MRHD on a mg/m2 basis) in males and 300 mg per kg per day (1.21 times the MRHD on a mg/m2 basis) in females. - Deferasirox was negative in the Ames test and chromosome aberration test with human peripheral blood lymphocytes. It was positive in 1 of 3 in vivo oral rat micronucleus tests. - Deferasirox at oral doses up to 75 mg per kg per day (0.6 times the MRHD on a mg/m2 basis) was found to have no adverse effect on fertility and reproductive performance of male and female rats. # Clinical Studies - The primary efficacy study, Study 1, was a multicenter, open-label, randomized, active-comparator control study to compare Exjade (deferasirox) and deferoxamine in patients with beta-thalassemia and transfusional hemosiderosis. Patients ≥2 years of age were randomized in a 1:1 ratio to receive either oral Exjade at starting doses of 5, 10, 20, or 30 mg per kg once daily or subcutaneous Desferal (deferoxamine) at starting doses of 20 to 60 mg per kg for at least 5 days per week based on LIC at baseline (2-3, >3-7, >7-14, and >14 mg Fe/g dry weight). Patients randomized to deferoxamine who had LIC values <7 mg Fe/g dry weight were permitted to continue on their prior deferoxamine dose, even though the dose may have been higher than specified in the protocol. - Patients were to have a liver biopsy at baseline and end of study (after 12 months) for LIC. The primary efficacy endpoint was defined as a reduction in LIC of ≥3 mg Fe/g dry weight for baseline values ≥10 mg Fe/g dry weight, reduction of baseline values between 7 and <10 to <7 mg Fe/g dry weight, or maintenance or reduction for baseline values <7 mg Fe/g dry weight. - A total of 586 patients were randomized and treated, 296 with Exjade and 290 with deferoxamine. The mean age was 17.1 years (range, 2-53 years); 52% were females and 88% were Caucasian. The primary efficacy population consisted of 553 patients (Exjade n=276; deferoxamine n=277) who had LIC evaluated at baseline and 12 months or discontinued due to an adverse event. The percentage of patients achieving the primary endpoint was 52.9% for Exjade and 66.4% for deferoxamine. The relative efficacy of Exjade to deferoxamine cannot be determined from this study. - In patients who had an LIC at baseline and at end of study, the mean change in LIC was -2.4 mg Fe/g dry weight in patients treated with Exjade and -2.9 mg Fe/g dry weight in patients treated with deferoxamine. - Reduction of LIC and serum ferritin was observed with Exjade doses of 20 to 30 mg per kg per day. Exjade doses below 20 mg per kg per day failed to provide consistent lowering of LIC and serum ferritin levels (Figure 1). Therefore, a starting dose of 20 mg per kg per day is recommended. - Study 2 was an open-label, noncomparative trial of efficacy and safety of Exjade given for 1 year to patients with chronic anemias and transfusional hemosiderosis. Similar to Study 1, patients received 5, 10, 20, or 30 mg per kg per day of Exjade based on baseline LIC. - A total of 184 patients were treated in this study: 85 patients with beta-thalassemia and 99 patients with other congenital or acquired anemias (myelodysplastic syndromes, n=47; Diamond-Blackfan syndrome, n=30; other, n=22). 19% of patients were <16 years of age and 16% were ≥65 years of age. There was a reduction in the absolute LIC from baseline to end of study (-4.2 mg Fe/g dry weight). - Study 3 was a multicenter, open-label, randomized trial of the safety and efficacy of Exjade relative to deferoxamine given for 1 year in patients with sickle cell disease and transfusional hemosiderosis. Patients were randomized to Exjade at doses of 5, 10, 20, or 30 mg per kg per day or subcutaneous deferoxamine at doses of 20-60 mg per kg per day for 5 days per week according to baseline LIC. - A total of 195 patients were treated in this study: 132 with Exjade and 63 with deferoxamine. 44% of patients were <16 years of age and 91% were black. At end of study, the mean change in LIC (as measured by magnetic susceptometry by a superconducting quantum interference device) in the per protocol-1 (PP-1) population, which consisted of patients who had at least 1 post-baseline LIC assessment, was -1.3 mg Fe/g dry weight for patients receiving Exjade (n=113) and -0.7 mg Fe/g dry weight for patients receiving deferoxamine (n=54). - One-hundred five (105) patients with thalassemia major and cardiac iron overload were enrolled in a study assessing the change in cardiac MRI T2* value (measured in milliseconds, ms) before and after treatment with deferasirox. Cardiac T2* values at baseline ranged from 5 to <20 ms. The geometric mean of cardiac T2* in the 68 patients who completed 3 years of Exjade therapy increased from 11.98 ms at baseline to 17.12 ms at 3 years. Cardiac T2* values improved in patients with severe cardiac iron overload (<10 ms) and in those with mild to moderate cardiac iron overload (≥10 to <20 ms). The clinical significance of these observations is unknown. - Six hundred twenty-seven patients with MDS were enrolled across 5 uncontrolled trials. Two hundred thirty-nine of the 627 patients were enrolled in trials that limited enrollment to patients with IPSS Low or Intermediate 1 risk MDS and the remaining 388 patients were enrolled in trials that did not specify MDS risk stratification but required a life expectancy of greater than 1 year. Planned duration of treatment in these trials ranged from 1 year (365 patients) to 5 years (47 patients). These trials evaluated the effects of Exjade therapy on parameters of iron overload, including LIC (125 patients) and serum ferritin (627 patients). Percent of patients completing planned duration of treatment was 51% in the largest 1 year study, 52% in the 3-year study and 22% in the 5 year study. The major causes for treatment discontinuation were withdrawal of consent, adverse reaction, and death. Over 1 year of follow-up across these pooled studies, mean change in serum ferritin was -332.8 (±2615.59) mcg/L (n=593) and mean change in LIC was -5.9 (±8.32) mg Fe/g dw (n=68). Results of these pooled studies in 627 patients with MDS suggest a progressive decrease in serum ferritin and LIC beyond 1 year in those patients who are able to continue Exjade. No controlled trials have been performed to demonstrate that these reductions improve morbidity or mortality in patients with MDS. Adverse reactions with Exjade therapy occur more frequently in older patients. In elderly patients, including those with MDS, individualize the decision to remove accumulated iron based on clinical circumstances and the anticipated clinical benefit and risks of Exjade therapy. - Study 4 was a randomized, double-blind, placebo-controlled trial of treatment with Exjade for patients 10 years of age or older with NTDT syndromes and iron overload. Eligible patients had an LIC of at least 5 mg Fe/g dw measured by R2 MRI and a serum ferritin exceeding 300 mcg/L at screening (2 consecutive values at least 14 days apart from each other). A total of 166 patients were randomized, 55 to the Exjade 5 mg/kg/day dose group, 55 to the Exjade 10 mg/kg/day dose group, and 56 to placebo (28 to each matching placebo group). Doses could be increased after 6 months if the LIC exceeded 7 mg Fe/g dw and the LIC reduction from baseline was less than 15%. The patients enrolled included 89 males and 77 females. The underlying disease was beta-thalassemia intermedia in 95 (57%) patients, HbE beta-thalassemia in 49 (30%) patients, and alpha-thalassemia in 22 (13%) patients. There were 17 pediatric patients in the study. Caucasians comprised 57% of the study population and Asians comprised 42%. The median baseline LIC (range) for all patients was 12.1 (2.6-49.1) mg Fe/g dw. Follow-up was for 1 year. The primary efficacy endpoint of change in LIC from baseline to Week 52 was statistically significant in favor of both Exjade dose groups compared with placebo (p ≤0.001) (Table 5). Furthermore, a statistically significant dose effect of Exjade was observed in favor of the 10 mg/kg/day dose group (10 versus 5 mg/kg/day, p=0.009). In a descriptive analysis, the target LIC (less than 5 mg Fe/g dw) was reached by 15 (27%) of 55 patients in the 10 mg/kg/day arm, 8 (15%) of 55 patients in the 5 mg/kg/day arm and 2 (4%) of 56 patients in the combined placebo groups. - Study 5 was an open-label trial of Exjade for the treatment of patients previously enrolled on Study 4, including cross-over to active treatment for those previously treated with placebo. The starting dose of Exjade in Study 5 was assigned based on the patient’s LIC at completion of Study 4, being 20 mg/kg/day for an LIC exceeding 15 mg Fe/g dw, 10 mg/kg/day for LIC 3-15 mg Fe/g dw, and observation if the LIC was less than 3 mg Fe/g dw. Patients could continue on 5 mg/kg/day if they had previously exhibited at least a 30% reduction in LIC. Doses could be increased to a maximum of 20 mg/kg/day after 6 months if the LIC was more than 7 mg Fe/g dw and the LIC reduction from baseline was less than 15%. The primary efficacy endpoint in Study 5 was the proportion of patients achieving an LIC less than 5 mg Fe/g dw. A total of 133 patients were enrolled. Twenty patients began Study 5 with an LIC less than 5 mg Fe/g dw. Of the 113 patients with a baseline LIC of at least 5 mg Fe/g dw in Study 5, the target LIC (less than 5 mg Fe/g dw) was reached by 39 (35%). The responders included 4 (10%) of 39 patients treated at 20 mg/kg/day for a baseline LIC exceeding 15 mg Fe/g dw, and 31 (51%) of 61 patients treated at 10 mg/kg/day for a baseline LIC between 5 and 15 mg Fe/g dw. The absolute change in LIC at Week 52 by starting dose is shown in Table 5 above. # How Supplied - Exjade is provided as 125 mg, 250 mg, and 500 mg tablets for oral suspension. - 125 mg - Off-white, round, flat tablet with beveled edge and imprinted with “J” and “125” on one side and “NVR” on the other. - Bottles of 30 tablets………………………………………………………………..(NDC 0078-0468-15) - 250 mg - Off-white, round, flat tablet with beveled edge and imprinted with “J” and “250” on one side and “NVR” on the other. - Bottles of 30 tablets………………………………………………………………..(NDC 0078-0469-15) - 500 mg - Off-white, round, flat tablet with beveled edge and imprinted with “J” and “500” on one side and “NVR” on the other. - Bottles of 30 tablets………………………………………………………………..(NDC 0078-0470-15) - Store Exjade tablets at 25°C (77°F); excursions are permitted to 15°C-30°C (59°F-86°F). Protect from moisture. ## Storage There is limited information regarding Deferasirox Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise patients to take Exjade once daily on an empty stomach at least 30 minutes prior to food, preferably at the same time every day. Instruct patients to completely disperse the tablets in water, orange juice, or apple juice, and drink the resulting suspension immediately. After the suspension has been swallowed, resuspend any residue in a small volume of the liquid and swallow. - Advise patients not to chew tablets or swallow them whole. - Caution patients not to take aluminum-containing antacids and Exjade simultaneously. - Because auditory and ocular disturbances have been reported with Exjade, conduct auditory testing and ophthalmic testing before starting Exjade treatment and thereafter at regular intervals. - Caution patients experiencing dizziness to avoid driving or operating machinery. - Caution patients about the potential for the development of GI ulcers or bleeding when taking Exjade in combination with drugs that have ulcerogenic or hemorrhagic potential, such as NSAIDs, corticosteroids, oral bisphosphonates, or anticoagulants. - Caution patients about potential loss of effectiveness of drugs metabolized by CYP3A4 (e.g., cyclosporine, simvastatin, hormonal contraceptive agents) when Exjade is administered with these drugs. - Caution patients about potential loss of effectiveness of Exjade when administered with drugs that are potent UGT inducers (e.g., rifampicin, phenytoin, phenobarbital, ritonavir). Based on serum ferritin levels and clinical response, consider increases in the dose of Exjade when concomitantly used with potent UGT inducers. - Caution patients about potential loss of effectiveness of Exjade when administered with drugs that are bile acid sequestrants (e.g., cholestyramine, colesevelam, colestipol). Based on serum ferritin levels and clinical response, consider increases in the dose of Exjade when concomitantly used with bile acid sequestrants. - Perform careful monitoring of glucose levels when repaglinide is used concomitantly with Exjade. An interaction between Exjade and other CYP2C8 substrates like paclitaxel cannot be excluded. - Advise patients that blood tests will be performed because Exjade may affect your kidneys, liver, or blood cells. The blood tests will be performed every month or more frequently if you are at increased risk of complications (e.g., preexisting kidney condition, are elderly, have multiple medical conditions, or are taking medicine that affects your organs). There have been reports of severe kidney and liver problems, blood disorders, stomach hemorrhage and death in patients taking Exjade. - Skin rashes may occur during Exjade treatment and if severe, interrupt treatment. Serious allergic reactions (which include swelling of the throat) have been reported in patients taking Exjade, usually within the first month of treatment. If reactions are severe, advise patients to stop taking Exjade and contact their doctor immediately. # Precautions with Alcohol - Alcohol-Deferasirox interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - EXJADE®[1] # Look-Alike Drug Names There is limited information regarding Deferasirox Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Defarasirox
8a34d57f19fca9e0d6fa86fff50693931bfc475b	wikidoc	Deferiprone	Deferiprone # 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 Deferiprone is a heavy metal chelator that is FDA approved for the treatment of patients with transfusional iron overload due to thalassemia syndromes when current chelation therapy is inadequate. There is a Black Box Warning for this drug as shown here. Common adverse reactions include urine discoloration, nausea, vomiting and abdominal pain, alanine aminotransferase increased, arthralgia and neutropenia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Deferiprone is indicated for the treatment of patients with transfusional iron overload due to thalassemia syndromes when current chelation therapy is inadequate. - Initial dose is 25 mg/kg, orally, three times per day for a total of 75 mg/kg/day. - The maximum dose is 33 mg/kg, three times per day for a total of 99 mg/kg/day. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Deferiprone in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Deferiprone in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and efficacy has not been established in pediatric patients ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Deferiprone in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Deferiprone in pediatric patients. # Contraindications Deferiprone is contraindicated in patients with known hypersensitivity to deferiprone or to any of the excipients in the formulation. The following reactions have been reported in association with the administration of deferiprone: Henoch-Schönlein purpura; urticaria; and periorbital edema with skin rash # Warnings - Fatal agranulocytosis can occur with deferiprone use. Deferiprone can also cause neutropenia, which may foreshadow agranulocytosis. Measure the absolute neutrophil count (ANC) before starting deferiprone therapy and monitor the ANC weekly on therapy. - Interrupt deferiprone therapy if neutropenia develops (ANC < 1.5 x 109/L). - Interrupt deferiprone if infection develops, and monitor the ANC more frequently. - Advise patients taking deferiprone to immediately interrupt therapy and report to their physician if they experience any symptoms indicative of infection. - In pooled clinical trials, the incidence of agranulocytosis was 1.7% of patients. The mechanism of deferiprone-associated agranulocytosis is unknown. Agranulocytosis and neutropenia usually resolve upon discontinuation of deferiprone, but there have been reports of agranulocytosis leading to death. - Implement a plan to monitor for and to manage agranulocytosis/neutropenia prior to initiating deferiprone treatment. - Instruct the patient to immediately discontinue deferiprone and all other medications with a potential to cause neutropenia. - Obtain a complete blood cell (CBC) count, including a white blood cell (WBC) count corrected for the presence of nucleated red blood cells, an absolute neutrophil count (ANC), and a platelet count daily until recovery (ANC ≥ 1.5 x 109/L). - Consider hospitalization and other management as clinically appropriate. - Do not resume deferiprone in patients who have developed agranulocytosis unless potential benefits outweigh potential risks. Do not rechallenge patients who develop neutropenia with deferiprone unless potential benefits outweigh potential risks. - A thorough QT study has not been conducted with deferiprone. One patient with a history of QT prolongation experienced Torsades de Pointes during therapy with deferiprone. Administer deferiprone with caution to patients who may be at increased risk of prolongation of the cardiac QT interval (e.g., those with congestive heart failure, bradycardia, use of a diuretic, cardiac hypertrophy, hypokalemia or hypomagnesemia). Instruct any patient taking deferiprone who experiences symptoms suggestive of an arrhythmia (such as palpitations, dizziness, lightheadedness, syncope, or seizures) to seek medical attention immediately. - Based on evidence of genotoxicity and developmental toxicity in animal studies, deferiprone can cause fetal harm when administered to a pregnant woman. In animal studies, administration of deferiprone during the period of organogenesis resulted in embryofetal death and malformations at doses lower than equivalent human clinical doses. If deferiprone is used during pregnancy or if the patient becomes pregnant while taking deferiprone, the patient should be apprised of the potential hazard to the fetus. Women of reproductive potential should be advised to avoid pregnancy when taking deferiprone. - In clinical studies, 7.5% of 642 subjects treated with deferiprone developed increased ALT values. Four (0.62%) deferiprone-treated subjects discontinued the drug due to increased serum ALT levels and 1 (0.16%) due to an increase in both ALT and AST. - Monitor serum ALT values monthly during therapy with deferiprone, and consider interruption of therapy if there is a persistent increase in the serum transaminase levels. - Decreased plasma zinc concentrations have been observed on deferiprone therapy. Monitor plasma zinc, and supplement in the event of a deficiency. # 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. - Adverse reaction information for deferiprone represents the pooled data collected from 642 patients who participated in single arm or active-controlled clinical studies. - The most serious adverse reaction reported in clinical trials with deferiprone was agranulocytosis. - The most common adverse reactions reported during clinical trials were chromaturia, nausea, vomiting, abdominal pain, alanine aminotransferase increased, arthralgia and neutropenia. - The table below lists the adverse drug reactions that occurred in at least 1% of patients treated with deferiprone in clinical trials. - Gastrointestinal symptoms such as nausea, vomiting, and abdominal pain were the most frequent adverse reactions reported by patients participating in clinical trials and led to the discontinuation of deferiprone therapy in 1.6% of patients. - Chromaturia (reddish-brown discoloration of the urine) is a result of the excretion of the iron in the urine. ## Postmarketing Experience The following additional adverse reactions have been reported in patients receiving deferiprone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to drug exposure. - Blood and lymphatic system disorders: thrombocytosis, pancytopenia. - Cardiac disorders: atrial fibrillation, cardiac failure. - Congenital, familial and genetic disorders: hypospadias. - Eye disorders: diplopia, papilledema, retinal toxicity. - Gastrointestinal disorders: enterocolitis, rectal hemorrhage, gastric ulcer, pancreatitis, parotid gland enlargement. - General disorders and administration site conditions: chills, pyrexia, edema peripheral, multi-organ failure. - Hepatobiliary disorders: jaundice, hepatomegaly. - Immune system disorders: anaphylactic shock, hypersensitivity. - Infections and infestations: cryptococcal cutaneous infection, enteroviral encephalitis, pharyngitis, pneumonia, sepsis, furuncle, infection hepatitis, rash pustular, subcutaneous abscess. - Investigations: blood bilirubin increased, blood creatinine phosphokinase increased. - Metabolism and nutrition disorders: metabolic acidosis, dehydration. - Musculoskeletal and connective tissue disorders: myositis, chondropathy, trismus. - Nervous system disorders: cerebellar syndrome, cerebral hemorrhage, convulsion, gait disturbance, intracranial pressure increased, psychomotor skills impaired, pyramidal tract syndrome, somnolence. - Psychiatric disorders: bruxism, depression, obsessive-compulsive disorder. - Renal disorders: glycosuria, hemoglobinuria. - Respiratory, thoracic and mediastinal disorders: acute respiratory distress syndrome, epistaxis, hemoptysis, pulmonary embolism. - Skin, subcutaneous tissue disorders: hyperhidrosis, periorbital edema, photosensitivity reaction, pruritis, urticaria, rash, Henoch-Schönlein purpura. - Vascular disorders: hypotension, hypertension. # Drug Interactions Allow at least a 4-hour interval between deferiprone and other medications or supplements containing polyvalent cations such as iron, aluminum, and zinc Avoid concomitant use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis; however, if this is not possible, closely monitor the absolute neutrophil count. Deferiprone is primarily eliminated via metabolism to the 3-O-glucuronide. In vitro studies suggest that UDP glucuronosyltransferase (UGT) 1A6 is primarily responsible for the glucuronidation of deferiprone which can be reduced up to 78% in the presence of the UGT1A6 inhibitor phenylbutazone. However, the clinical significance of coadministration of deferiprone with a UGT1A6 inhibitor (e.g. diclofenac, probenecid, or silymarin (milk thistle)) on the systemic exposure of deferiprone has not been determined. Closely monitor patients for adverse reactions that may require downward dose titration or interruption when deferiprone is concomitantly administered with a UGT1A6 inhibitor. Concurrent use of deferiprone with foods, mineral supplements, and antacids that contain polyvalent cations has not been studied. However, since deferiprone has the potential to bind polyvalent cations (e.g., iron, aluminum, and zinc), allow at least a 4-hour interval between deferiprone and other medications (e.g., antacids), or supplements containing these polyvalent cations. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D Based on evidence of genotoxicity and developmental toxicity in animal studies, deferiprone can cause fetal harm when administered to a pregnant woman. In animal studies, administration of deferiprone during the period of organogenesis resulted in embryofetal death and malformations at doses lower than equivalent human clinical doses. There are no studies in pregnant women, and available human data are limited. If deferiprone is used during pregnancy or if the patient becomes pregnant while taking deferiprone, the patient should be apprised of the potential hazard to the fetus. Skeletal and soft tissue malformations occurred in offspring of rats and rabbits that received deferiprone orally during organogenesis at the lowest doses tested (25 mg/kg per day in rats; 10 mg/kg per day in rabbits). These doses were equivalent to 3% to 4% of the maximum recommended human dose (MRHD) based on body surface area. No maternal toxicity was evident at these doses. Embryofetal lethality and maternal toxicity occurred in pregnant rabbits given 100 mg/kg/day deferiprone orally during the period of organogenesis. This dose is equivalent to 32% of the MRHD based on body surface area. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Deferiprone in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Deferiprone during labor and delivery. ### Nursing Mothers It is not known whether deferiprone is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from deferiprone, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use The safety and effectiveness of deferiprone tablets for oral use in pediatric patients have not been established. ### Geriatic Use Safety and effectiveness in elderly individuals have not been established. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ### Gender the influence of gender has not been established. ### Race the influence of race has not been established. ### Renal Impairment Deferiprone has not been evaluated in patients with renal impairment. ### Hepatic Impairment Deferiprone has not been conclusively evaluated in patients with hepatic impairment. ### Females of Reproductive Potential and Males A fertility and early embryonic development study of deferiprone was conducted in rats. Sperm counts, motility and morphology were unaffected by treatment with deferiprone. There were no effects observed on male or female fertility or reproductive function at the highest dose which was 25% of the MRHD based on body surface area. ### Immunocompromised Patients There is no FDA guidance one the use of Deferiprone in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring There is limited information regarding Deferiprone Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Deferiprone and IV administrations. # Overdosage No cases of acute overdose have been reported. There is no specific antidote to deferiprone overdose. Neurological disorders such as cerebellar symptoms, diplopia, lateral nystagmus, psychomotor slowdown, hand movements and axial hypotonia have been observed in children treated with 2.5 to 3 times the recommended dose for more than one year. The neurological disorders progressively regressed after deferiprone discontinuation. # Pharmacology ## Mechanism of Action Deferiprone is a chelating agent with an affinity for ferric ion (iron III). Deferiprone binds with ferric ions to form neutral 3:1 (deferiprone:iron) complexes that are stable over a wide range of pH values. Deferiprone has a lower binding affinity for other metals such as copper, aluminum and zinc than for iron. ## Structure Deferiprone has the following structural formula: ## Pharmacodynamics No clinical studies were performed to assess the relationship between the dose of deferiprone and the amount of iron eliminated from the body. No clinical studies of the effects of deferiprone on the cardiac QT interval have been performed in human subjects ## Pharmacokinetics Deferiprone is rapidly absorbed from the upper part of the gastrointestinal tract, appearing in the blood within 5 to 10 minutes of oral administration. Peak serum concentrations occur approximately 1 hour after a single dose in fasted healthy subjects and patients, and up to 2 hours after a single dose in the fed state. Administration with food decreased the Cmax of deferiprone by 38% and the AUC by 10%. While a food effect cannot be ruled out, the magnitude of the exposure change does not warrant dose adjustment. In healthy subjects, the mean maximum concentration (Cmax) of deferiprone in serum was 20 mcg/mL, and the mean total area under the concentration-time curve (AUC) was 53 mcg∙h/mL following oral administration of a 1,500 mg dose of deferiprone tablets in the fasting state. Dose proportionality over the labeled dosage range of 25 to 33 mg/kg three times per day (75 to 99 mg/kg per day) has not been studied. The elimination half life (t1/2) of deferiprone was 1.9 hours. The accumulation of deferiprone and its glucuronide metabolite at the highest approved dosage level of 33 mg/kg three times per day has not been studied. The volume of distribution of deferiprone is 1.6 L/kg in thalassemia patients, and approximately 1 L/kg in healthy subjects. The plasma protein binding of deferiprone in humans is less than 10%. In humans, the majority of the deferiprone is metabolized, primarily by UGT1A6. The contribution of extrahepatic (e.g., renal) UGT1A6 is unknown. The major metabolite of deferiprone is the 3-O-glucuronide, which lacks iron binding capability. Peak serum concentration of the glucuronide occurs 2 to 4 hours after administration of deferiprone in fasting subjects. More than 90% of deferiprone is eliminated from plasma within 5 to 6 hours of ingestion. Following oral administration, 75% to 90% is recovered in the urine in the first 24 hours, primarily as metabolite. ## Nonclinical Toxicology Carcinogenicity studies have not been conducted with deferiprone. However, in view of the genotoxicity results, and the findings of mammary gland hyperplasia and mammary gland tumors in rats treated with deferiprone in the 52-week toxicology study, tumor formation in carcinogenicity studies must be regarded as likely. Deferiprone was positive in a mouse lymphoma cell assay in vitro. Deferiprone was clastogenic in an in vitro chromosomal aberration test in mice and in a chromosomal aberration test in Chinese Hamster Ovary cells. Deferiprone given orally or intraperitoneally was clastogenic in a bone marrow micronucleus assay in non-iron-loaded mice. A micronucleus test was also positive when mice predosed with iron dextran were treated with deferiprone. Deferiprone was not mutagenic in the Ames bacterial reverse mutation test. # Clinical Studies In a prospective, planned, pooled analysis of patients from several studies, the efficacy of deferiprone was assessed in transfusion-dependent iron overload patients in whom previous iron chelation therapy had failed or was considered inadequate due to poor tolerance. The main criterion for chelation failure was serum ferritin >2,500 mcg/L before treatment with deferiprone. deferiprone therapy (35-99 mg/kg/day) was considered successful in individual patients who experienced a ≥20% decline in serum ferritin within one year of starting therapy. Data from a total of 236 patients were analyzed. Of the 224 patients with thalassemia who received deferiprone monotherapy and were eligible for serum ferritin analysis, 105 (47%) were male and 119 (53%) were female. The mean age of these patients was 18.2 years. For the patients in the analysis, the endpoint of at least a 20% reduction in serum ferritin was met in 50% (of 236 subjects), with a 95% confidence interval of 43% to 57%. A small number of patients with thalassemia and iron overload were assessed by measuring the change in the number of milliseconds (ms) in the cardiac MRI T2- value before and after treatment with deferiprone for one year. There was an increase in cardiac MRI T2- from a mean at baseline of 11.8 ± 4.9 ms to a mean of 15.1 ± 7.0 ms after approximately one year of treatment. The clinical significance of this observation is not known. # How Supplied - Deferiprone 500 mg tablets - 100 tablets (NDC 52609-0006-1) ## Storage Store at 20º to 25ºC (68º to 77ºF) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Inform patients of the risks of developing agranulocytosis and instruct them to immediately interrupt therapy and report to their physician if they experience any symptoms of infection such as fever, sore throat or flu-like symptoms. - Advise patients that the amount of deferiprone prescribed is based on body weight and on the therapeutic goal (reduction or stabilization of the body iron load). - Advise patients to take the first dose of deferiprone in the morning, the second dose at midday, and the third dose in the evening. Clinical experience suggests that taking deferiprone with meals may reduce nausea. If a dose of this medicine has been missed, take as soon as possible. However, if it is almost time for the next dose, skip the missed dose and go back to the regular dosing schedule. Do not catch-up or double doses. - Advise patients to contact their physician in the event of overdose. - Inform patients that their urine might show a reddish/brown discoloration due to the excretion of the iron-deferiprone complex. This is a very common sign of the desired effect of deferiprone, and it is not harmful. - Counsel women of reproductive potential to avoid pregnancy while taking deferiprone. Advise patients to immediately notify their physician if they become pregnant, or if they plan to become pregnant during therapy. - Inform patients that they should not breast feed while taking deferiprone. - Inform patients that if they experience palpitations, dizziness, lightheadedness, syncope, or seizures to immediately seek medical attention. # Precautions with Alcohol Alcohol-Deferiprone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Ferriprox # Look-Alike Drug Names There is limited information regarding Deferiprone Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Deferiprone Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [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 Deferiprone is a heavy metal chelator that is FDA approved for the treatment of patients with transfusional iron overload due to thalassemia syndromes when current chelation therapy is inadequate. There is a Black Box Warning for this drug as shown here. Common adverse reactions include urine discoloration, nausea, vomiting and abdominal pain, alanine aminotransferase increased, arthralgia and neutropenia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Deferiprone is indicated for the treatment of patients with transfusional iron overload due to thalassemia syndromes when current chelation therapy is inadequate. - Initial dose is 25 mg/kg, orally, three times per day for a total of 75 mg/kg/day. - The maximum dose is 33 mg/kg, three times per day for a total of 99 mg/kg/day. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Deferiprone in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Deferiprone in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and efficacy has not been established in pediatric patients ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Deferiprone in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Deferiprone in pediatric patients. # Contraindications Deferiprone is contraindicated in patients with known hypersensitivity to deferiprone or to any of the excipients in the formulation. The following reactions have been reported in association with the administration of deferiprone: Henoch-Schönlein purpura; urticaria; and periorbital edema with skin rash # Warnings - Fatal agranulocytosis can occur with deferiprone use. Deferiprone can also cause neutropenia, which may foreshadow agranulocytosis. Measure the absolute neutrophil count (ANC) before starting deferiprone therapy and monitor the ANC weekly on therapy. - Interrupt deferiprone therapy if neutropenia develops (ANC < 1.5 x 109/L). - Interrupt deferiprone if infection develops, and monitor the ANC more frequently. - Advise patients taking deferiprone to immediately interrupt therapy and report to their physician if they experience any symptoms indicative of infection. - In pooled clinical trials, the incidence of agranulocytosis was 1.7% of patients. The mechanism of deferiprone-associated agranulocytosis is unknown. Agranulocytosis and neutropenia usually resolve upon discontinuation of deferiprone, but there have been reports of agranulocytosis leading to death. - Implement a plan to monitor for and to manage agranulocytosis/neutropenia prior to initiating deferiprone treatment. - Instruct the patient to immediately discontinue deferiprone and all other medications with a potential to cause neutropenia. - Obtain a complete blood cell (CBC) count, including a white blood cell (WBC) count corrected for the presence of nucleated red blood cells, an absolute neutrophil count (ANC), and a platelet count daily until recovery (ANC ≥ 1.5 x 109/L). - Consider hospitalization and other management as clinically appropriate. - Do not resume deferiprone in patients who have developed agranulocytosis unless potential benefits outweigh potential risks. Do not rechallenge patients who develop neutropenia with deferiprone unless potential benefits outweigh potential risks. - A thorough QT study has not been conducted with deferiprone. One patient with a history of QT prolongation experienced Torsades de Pointes during therapy with deferiprone. Administer deferiprone with caution to patients who may be at increased risk of prolongation of the cardiac QT interval (e.g., those with congestive heart failure, bradycardia, use of a diuretic, cardiac hypertrophy, hypokalemia or hypomagnesemia). Instruct any patient taking deferiprone who experiences symptoms suggestive of an arrhythmia (such as palpitations, dizziness, lightheadedness, syncope, or seizures) to seek medical attention immediately. - Based on evidence of genotoxicity and developmental toxicity in animal studies, deferiprone can cause fetal harm when administered to a pregnant woman. In animal studies, administration of deferiprone during the period of organogenesis resulted in embryofetal death and malformations at doses lower than equivalent human clinical doses. If deferiprone is used during pregnancy or if the patient becomes pregnant while taking deferiprone, the patient should be apprised of the potential hazard to the fetus. Women of reproductive potential should be advised to avoid pregnancy when taking deferiprone. - In clinical studies, 7.5% of 642 subjects treated with deferiprone developed increased ALT values. Four (0.62%) deferiprone-treated subjects discontinued the drug due to increased serum ALT levels and 1 (0.16%) due to an increase in both ALT and AST. - Monitor serum ALT values monthly during therapy with deferiprone, and consider interruption of therapy if there is a persistent increase in the serum transaminase levels. - Decreased plasma zinc concentrations have been observed on deferiprone therapy. Monitor plasma zinc, and supplement in the event of a deficiency. # 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. - Adverse reaction information for deferiprone represents the pooled data collected from 642 patients who participated in single arm or active-controlled clinical studies. - The most serious adverse reaction reported in clinical trials with deferiprone was agranulocytosis. - The most common adverse reactions reported during clinical trials were chromaturia, nausea, vomiting, abdominal pain, alanine aminotransferase increased, arthralgia and neutropenia. - The table below lists the adverse drug reactions that occurred in at least 1% of patients treated with deferiprone in clinical trials. - Gastrointestinal symptoms such as nausea, vomiting, and abdominal pain were the most frequent adverse reactions reported by patients participating in clinical trials and led to the discontinuation of deferiprone therapy in 1.6% of patients. - Chromaturia (reddish-brown discoloration of the urine) is a result of the excretion of the iron in the urine. ## Postmarketing Experience The following additional adverse reactions have been reported in patients receiving deferiprone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to drug exposure. - Blood and lymphatic system disorders: thrombocytosis, pancytopenia. - Cardiac disorders: atrial fibrillation, cardiac failure. - Congenital, familial and genetic disorders: hypospadias. - Eye disorders: diplopia, papilledema, retinal toxicity. - Gastrointestinal disorders: enterocolitis, rectal hemorrhage, gastric ulcer, pancreatitis, parotid gland enlargement. - General disorders and administration site conditions: chills, pyrexia, edema peripheral, multi-organ failure. - Hepatobiliary disorders: jaundice, hepatomegaly. - Immune system disorders: anaphylactic shock, hypersensitivity. - Infections and infestations: cryptococcal cutaneous infection, enteroviral encephalitis, pharyngitis, pneumonia, sepsis, furuncle, infection hepatitis, rash pustular, subcutaneous abscess. - Investigations: blood bilirubin increased, blood creatinine phosphokinase increased. - Metabolism and nutrition disorders: metabolic acidosis, dehydration. - Musculoskeletal and connective tissue disorders: myositis, chondropathy, trismus. - Nervous system disorders: cerebellar syndrome, cerebral hemorrhage, convulsion, gait disturbance, intracranial pressure increased, psychomotor skills impaired, pyramidal tract syndrome, somnolence. - Psychiatric disorders: bruxism, depression, obsessive-compulsive disorder. - Renal disorders: glycosuria, hemoglobinuria. - Respiratory, thoracic and mediastinal disorders: acute respiratory distress syndrome, epistaxis, hemoptysis, pulmonary embolism. - Skin, subcutaneous tissue disorders: hyperhidrosis, periorbital edema, photosensitivity reaction, pruritis, urticaria, rash, Henoch-Schönlein purpura. - Vascular disorders: hypotension, hypertension. # Drug Interactions Allow at least a 4-hour interval between deferiprone and other medications or supplements containing polyvalent cations such as iron, aluminum, and zinc Avoid concomitant use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis; however, if this is not possible, closely monitor the absolute neutrophil count. Deferiprone is primarily eliminated via metabolism to the 3-O-glucuronide. In vitro studies suggest that UDP glucuronosyltransferase (UGT) 1A6 is primarily responsible for the glucuronidation of deferiprone which can be reduced up to 78% in the presence of the UGT1A6 inhibitor phenylbutazone. However, the clinical significance of coadministration of deferiprone with a UGT1A6 inhibitor (e.g. diclofenac, probenecid, or silymarin (milk thistle)) on the systemic exposure of deferiprone has not been determined. Closely monitor patients for adverse reactions that may require downward dose titration or interruption when deferiprone is concomitantly administered with a UGT1A6 inhibitor. Concurrent use of deferiprone with foods, mineral supplements, and antacids that contain polyvalent cations has not been studied. However, since deferiprone has the potential to bind polyvalent cations (e.g., iron, aluminum, and zinc), allow at least a 4-hour interval between deferiprone and other medications (e.g., antacids), or supplements containing these polyvalent cations. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D Based on evidence of genotoxicity and developmental toxicity in animal studies, deferiprone can cause fetal harm when administered to a pregnant woman. In animal studies, administration of deferiprone during the period of organogenesis resulted in embryofetal death and malformations at doses lower than equivalent human clinical doses. There are no studies in pregnant women, and available human data are limited. If deferiprone is used during pregnancy or if the patient becomes pregnant while taking deferiprone, the patient should be apprised of the potential hazard to the fetus. Skeletal and soft tissue malformations occurred in offspring of rats and rabbits that received deferiprone orally during organogenesis at the lowest doses tested (25 mg/kg per day in rats; 10 mg/kg per day in rabbits). These doses were equivalent to 3% to 4% of the maximum recommended human dose (MRHD) based on body surface area. No maternal toxicity was evident at these doses. Embryofetal lethality and maternal toxicity occurred in pregnant rabbits given 100 mg/kg/day deferiprone orally during the period of organogenesis. This dose is equivalent to 32% of the MRHD based on body surface area. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Deferiprone in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Deferiprone during labor and delivery. ### Nursing Mothers It is not known whether deferiprone is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from deferiprone, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use The safety and effectiveness of deferiprone tablets for oral use in pediatric patients have not been established. ### Geriatic Use Safety and effectiveness in elderly individuals have not been established. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ### Gender the influence of gender has not been established. ### Race the influence of race has not been established. ### Renal Impairment Deferiprone has not been evaluated in patients with renal impairment. ### Hepatic Impairment Deferiprone has not been conclusively evaluated in patients with hepatic impairment. ### Females of Reproductive Potential and Males A fertility and early embryonic development study of deferiprone was conducted in rats. Sperm counts, motility and morphology were unaffected by treatment with deferiprone. There were no effects observed on male or female fertility or reproductive function at the highest dose which was 25% of the MRHD based on body surface area. ### Immunocompromised Patients There is no FDA guidance one the use of Deferiprone in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring There is limited information regarding Deferiprone Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Deferiprone and IV administrations. # Overdosage No cases of acute overdose have been reported. There is no specific antidote to deferiprone overdose. Neurological disorders such as cerebellar symptoms, diplopia, lateral nystagmus, psychomotor slowdown, hand movements and axial hypotonia have been observed in children treated with 2.5 to 3 times the recommended dose for more than one year. The neurological disorders progressively regressed after deferiprone discontinuation. # Pharmacology ## Mechanism of Action Deferiprone is a chelating agent with an affinity for ferric ion (iron III). Deferiprone binds with ferric ions to form neutral 3:1 (deferiprone:iron) complexes that are stable over a wide range of pH values. Deferiprone has a lower binding affinity for other metals such as copper, aluminum and zinc than for iron. ## Structure Deferiprone has the following structural formula: ## Pharmacodynamics No clinical studies were performed to assess the relationship between the dose of deferiprone and the amount of iron eliminated from the body. No clinical studies of the effects of deferiprone on the cardiac QT interval have been performed in human subjects ## Pharmacokinetics Deferiprone is rapidly absorbed from the upper part of the gastrointestinal tract, appearing in the blood within 5 to 10 minutes of oral administration. Peak serum concentrations occur approximately 1 hour after a single dose in fasted healthy subjects and patients, and up to 2 hours after a single dose in the fed state. Administration with food decreased the Cmax of deferiprone by 38% and the AUC by 10%. While a food effect cannot be ruled out, the magnitude of the exposure change does not warrant dose adjustment. In healthy subjects, the mean maximum concentration (Cmax) of deferiprone in serum was 20 mcg/mL, and the mean total area under the concentration-time curve (AUC) was 53 mcg∙h/mL following oral administration of a 1,500 mg dose of deferiprone tablets in the fasting state. Dose proportionality over the labeled dosage range of 25 to 33 mg/kg three times per day (75 to 99 mg/kg per day) has not been studied. The elimination half life (t1/2) of deferiprone was 1.9 hours. The accumulation of deferiprone and its glucuronide metabolite at the highest approved dosage level of 33 mg/kg three times per day has not been studied. The volume of distribution of deferiprone is 1.6 L/kg in thalassemia patients, and approximately 1 L/kg in healthy subjects. The plasma protein binding of deferiprone in humans is less than 10%. In humans, the majority of the deferiprone is metabolized, primarily by UGT1A6. The contribution of extrahepatic (e.g., renal) UGT1A6 is unknown. The major metabolite of deferiprone is the 3-O-glucuronide, which lacks iron binding capability. Peak serum concentration of the glucuronide occurs 2 to 4 hours after administration of deferiprone in fasting subjects. More than 90% of deferiprone is eliminated from plasma within 5 to 6 hours of ingestion. Following oral administration, 75% to 90% is recovered in the urine in the first 24 hours, primarily as metabolite. ## Nonclinical Toxicology Carcinogenicity studies have not been conducted with deferiprone. However, in view of the genotoxicity results, and the findings of mammary gland hyperplasia and mammary gland tumors in rats treated with deferiprone in the 52-week toxicology study, tumor formation in carcinogenicity studies must be regarded as likely. Deferiprone was positive in a mouse lymphoma cell assay in vitro. Deferiprone was clastogenic in an in vitro chromosomal aberration test in mice and in a chromosomal aberration test in Chinese Hamster Ovary cells. Deferiprone given orally or intraperitoneally was clastogenic in a bone marrow micronucleus assay in non-iron-loaded mice. A micronucleus test was also positive when mice predosed with iron dextran were treated with deferiprone. Deferiprone was not mutagenic in the Ames bacterial reverse mutation test. # Clinical Studies In a prospective, planned, pooled analysis of patients from several studies, the efficacy of deferiprone was assessed in transfusion-dependent iron overload patients in whom previous iron chelation therapy had failed or was considered inadequate due to poor tolerance. The main criterion for chelation failure was serum ferritin >2,500 mcg/L before treatment with deferiprone. deferiprone therapy (35-99 mg/kg/day) was considered successful in individual patients who experienced a ≥20% decline in serum ferritin within one year of starting therapy. Data from a total of 236 patients were analyzed. Of the 224 patients with thalassemia who received deferiprone monotherapy and were eligible for serum ferritin analysis, 105 (47%) were male and 119 (53%) were female. The mean age of these patients was 18.2 years. For the patients in the analysis, the endpoint of at least a 20% reduction in serum ferritin was met in 50% (of 236 subjects), with a 95% confidence interval of 43% to 57%. A small number of patients with thalassemia and iron overload were assessed by measuring the change in the number of milliseconds (ms) in the cardiac MRI T2* value before and after treatment with deferiprone for one year. There was an increase in cardiac MRI T2* from a mean at baseline of 11.8 ± 4.9 ms to a mean of 15.1 ± 7.0 ms after approximately one year of treatment. The clinical significance of this observation is not known. # How Supplied - Deferiprone 500 mg tablets - 100 tablets (NDC 52609-0006-1) ## Storage Store at 20º to 25ºC (68º to 77ºF) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Inform patients of the risks of developing agranulocytosis and instruct them to immediately interrupt therapy and report to their physician if they experience any symptoms of infection such as fever, sore throat or flu-like symptoms. - Advise patients that the amount of deferiprone prescribed is based on body weight and on the therapeutic goal (reduction or stabilization of the body iron load). - Advise patients to take the first dose of deferiprone in the morning, the second dose at midday, and the third dose in the evening. Clinical experience suggests that taking deferiprone with meals may reduce nausea. If a dose of this medicine has been missed, take as soon as possible. However, if it is almost time for the next dose, skip the missed dose and go back to the regular dosing schedule. Do not catch-up or double doses. - Advise patients to contact their physician in the event of overdose. - Inform patients that their urine might show a reddish/brown discoloration due to the excretion of the iron-deferiprone complex. This is a very common sign of the desired effect of deferiprone, and it is not harmful. - Counsel women of reproductive potential to avoid pregnancy while taking deferiprone. Advise patients to immediately notify their physician if they become pregnant, or if they plan to become pregnant during therapy. - Inform patients that they should not breast feed while taking deferiprone. - Inform patients that if they experience palpitations, dizziness, lightheadedness, syncope, or seizures to immediately seek medical attention. # Precautions with Alcohol Alcohol-Deferiprone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Ferriprox [1] # Look-Alike Drug Names There is limited information regarding Deferiprone Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Deferiprone
fb2647dc75af7089b30a95fbe14fd42a38345152	wikidoc	Defibrotide	Defibrotide # 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 Defibrotide is an oligonucleotide mixture with profibrinolytic properties that is FDA approved for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT). Common adverse reactions include hypotension, diarrhea, vomiting, nausea, and epistaxis (≥10%). # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Defibrotide is indicated for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT). The recommended dosage of Defibrotide for adult and pediatric patients is 6.25 mg/kg every 6 hours given as a 2‑hour intravenous infusion. The dose should be based on patient’s baseline body weight, defined as the patient’s weight prior to the preparative regimen for HSCT. Administer Defibrotide for a minimum of 21 days. If after 21 days signs and symptoms of hepatic VOD have not resolved, continue Defibrotide until resolution of VOD or up to a maximum of 60 days. - Treatment Modification Treatment modification, including temporary or permanent discontinuation of Defibrotide, should follow the recommendations in Table 1. - Table 1: Treatment Modifications for Toxicity or Invasive Procedures DEFITELIO: Defibrotide's Brand name ## Off-Label Use and Dosage (Adult) # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Defibrotide is indicated for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT). The recommended dosage of Defibrotide for adult and pediatric patients is 6.25 mg/kg every 6 hours given as a 2‑hour intravenous infusion. The dose should be based on patient’s baseline body weight, defined as the patient’s weight prior to the preparative regimen for HSCT. Administer Defibrotide for a minimum of 21 days. If after 21 days signs and symptoms of hepatic VOD have not resolved, continue Defibrotide until resolution of VOD or up to a maximum of 60 days. - Treatment Modification Treatment modification, including temporary or permanent discontinuation of Defibrotide, should follow the recommendations in Table 1. ## Off-Label Use and Dosage (Pediatric) # Contraindications The use of Defibrotide is contraindicated in the following conditions: # Warnings - Hemorrhage Defibrotide increased the activity of fibrinolytic enzymes in vitro, and it may increase the risk of bleeding in patients with VOD after hematopoietic stem-cell transplantation (HSCT). Do not initiate Defibrotide in patients with active bleeding. Monitor patients for signs of bleeding. If patients on Defibrotide develop bleeding, discontinue Defibrotide, treat the underlying cause, and provide supportive care until the bleeding has stopped. Concomitant use of Defibrotide and a systemic anticoagulant or fibrinolytic therapy (not including use for routine maintenance or reopening of central venous lines) may increase the risk of bleeding. Discontinue anticoagulants and fibrinolytic agents prior to Defibrotide treatment, and consider delaying the start of Defibrotide administration until the effects of the anticoagulant have abated. - Hypersensitivity Reactions Hypersensitivity reactions have occurred in less than 2% of patients treated with Defibrotide. These reactions include rash, urticaria and angioedema. One case of an anaphylactic reaction was reported in a patient who had previously received Defibrotide. Monitor patients for hypersensitivity reactions, especially if there is a history of previous exposure. If a severe hypersensitivity reaction occurs, discontinue Defibrotide, treat according to the standard of care, and monitor until symptoms resolve. # Adverse Reactions ## Clinical Trials Experience The following adverse reactions are discussed in greater detail in other sections of the labeling: - Hemorrhage - Hypersensitivity Reactions 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 Defibrotide was determined in 176 adult and pediatric patients with hepatic VOD with pulmonary and/or renal dysfunction following HSCT who were treated with Defibrotide 6.25 mg/kg every 6 hours. Patients were excluded from these trials if at time of study entry they had significant acute bleeding, active grades B-D graft-versus-host disease, or a requirement for multiple vasopressors to provide blood pressure support. For the purposes of adverse event recording in the clinical trials, events were not required to be reported if they were related to the hepatic VOD, or if they were expected to occur after hematopoietic stem-cell transplantation (HSCT), unless they were serious or Grade 4-5. The median age of the safety population was 25 years (range: 1 month to 72 years), and 63% were ≥17 years of age. A total of 60% of patients were male, 78% were white, 89% had undergone allogeneic HSCT, and the underlying diagnosis was acute leukemia for 43%. At study entry, 13% were dialysis dependent and 18% were ventilator dependent. Defibrotide was administered for a median of 21 days (range: 1 to 83 days). Information about adverse reactions resulting in permanent discontinuation of Defibrotide was available for 102 patients, and 35 (34%) of these patients had an adverse reaction with permanent discontinuation. Adverse reactions leading to permanent discontinuation included pulmonary alveolar hemorrhage in 5 (5%) patients; pulmonary hemorrhage, hypotension, catheter site hemorrhage, and multi-organ failure, each in 3 (3%) patients; and cerebral hemorrhage and sepsis, each in 2 (2%) patients. Information about adverse reactions of any grade was available for all 176 patients. The most common adverse reactions (incidence ≥10% and independent of causality) were hypotension, diarrhea, vomiting, nausea, and epistaxis. The most common serious adverse reactions (incidence ≥5% and independent of causality) were hypotension (11%) and pulmonary alveolar hemorrhage (7%). Hemorrhage events of any type and any grade were reported for 104 (59%) of the patients, and the events were grade 4-5 in 35 (20%). Table 2 presents adverse reactions independent of causality ≥10% any grade or Grade 4/5 ≥2% reported in patients treated with Defibrotide. - Table 2: Adverse Reactions(a) ≥10% or Grade 4-5 Adverse Reactions ≥2% DEFITELIO: Defibrotide's Brand name ## Postmarketing Experience There is limited information regarding Defibrotide Postmarketing Experience in the drug label. # Drug Interactions - Antithrombotic Agents Defibrotide may enhance the pharmacodynamic activity of antithrombotic/fibrinolytic drugs such as heparin or alteplase. Concomitant use of Defibrotide with antithrombotic or fibrinolytic drugs is contraindicated because of an increased risk of hemorrhage. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): N - Risk Summary There are no available data on Defibrotide use in pregnant women. When administered to pregnant rabbits during the period of organogenesis at doses that were comparable to the recommended human dose based on body surface area, Defibrotide sodium decreased the number of implantations and viable fetuses. Advise pregnant women of the potential risk of miscarriage. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively. - Data - Animal Data Embryo-Fetal toxicity assessment was attempted in rats and rabbits, but was not possible because of high maternal mortality, abortion, and fetal resorption at all doses. Pregnant rats were administered Defibrotide sodium from gestational day (GD) 6 to 15 at 0, 240, 1200, and 4800 mg/kg/day by continuous intravenous infusion over 24 hours or at 60, 120, and 240 mg/kg/day by 2-hour infusions 4 times per day. Pregnant rabbits were administered Defibrotide sodium at 0, 30, 60, or 120 mg/kg/day from GD 6 to 18 by 2-hour infusions 4 times per day. In another study in pregnant rabbits, 3 separate subgroups of animals were treated with doses of 80 mg/kg/day Defibrotide sodium administered by 2-hour infusions 4 times per day for 5 days each in a staggered manner during the organogenesis period. The dose of 80 mg/kg/day is approximately equivalent to the recommended clinical dose on a mg/m2 basis. Subgroup 1 was dosed from GD 6 to 10, subgroup 2 was dosed from GD 10 to 14, and subgroup 3 was dosed from GD 14 to 18. An increased incidence of unilateral implantation was observed in Defibrotide sodium-treated animals. Treatment with Defibrotide sodium resulted in a decreased number of implantations and viable fetuses. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Defibrotide in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Defibrotide during labor and delivery. ### Nursing Mothers There is no information regarding the presence of Defibrotide in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions, including bleeding in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with Defibrotide. ### Pediatric Use The safety and effectiveness of Defibrotide have been established in pediatric patients. Use of Defibrotide is supported by evidence from an adequate and well-controlled study and a dose finding study of Defibrotide in adult and pediatric patients with VOD with evidence of renal or pulmonary dysfunction following HSCT. The clinical trials enrolled 66 pediatric patients in the following age groups: 22 infants (1 month up to less than 2 years), 30 children (2 years up to less than 12 years), and 14 adolescents (12 years to less than 17 years). The efficacy and safety outcomes were consistent across pediatric and adult patients in the clinical trials. - Juvenile Animal Toxicity Data A juvenile toxicity study in 21-day-old rats was conducted with intravenous bolus administration of Defibrotide sodium at 40, 150, or 320 mg/kg/day for 4 weeks. A delayed mean age of preputial separation was observed at all doses, suggesting a delay in onset of male puberty. The dose of 40 mg/kg/day is approximately 0.4 times the clinical dose on a mg/m2 basis for a child. The relevance of this finding for the onset of male puberty in humans is unknown. ### Geriatic Use Clinical studies of Defibrotide did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. ### Gender There is no FDA guidance on the use of Defibrotide with respect to specific gender populations. ### Race There is no FDA guidance on the use of Defibrotide with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Defibrotide in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Defibrotide in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Defibrotide in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Defibrotide in patients who are immunocompromised. # Administration and Monitoring ### Administration - Administration Instructions - Defibrotide must be diluted prior to infusion. - Prior to administration of Defibrotide, confirm that the patient is not experiencing clinically significant bleeding and is hemodynamically stable on no more than one vasopressor. - Administer Defibrotide by constant intravenous infusion over a 2-hour period. - Administer the diluted Defibrotide solution using an infusion set equipped with a 0.2 micron in-line filter. Flush the intravenous administration line (peripheral or central) with 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP immediately before and after administration. - Do not co‑administer Defibrotide and other intravenous drugs concurrently within the same intravenous line. - Preparation Instructions Dilute Defibrotide in 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP to a concentration of 4 mg/mL to 20 mg/mL. Administer the diluted solution over 2 hours. Vials contain no antimicrobial preservatives and are intended for a single-patient-use only. Partially used vials should be discarded. Use the diluted Defibrotide solution within 4 hours if stored at room temperature or within 24 hours if stored under refrigeration. Up to four doses of Defibrotide solution may be prepared at one time, if refrigerated. Preparation Instructions: - Determine the dose (mg) and number of vials of Defibrotide based on the individual patient’s baseline weight (weight prior to the preparative regimen for HSCT). - Calculate the volume of Defibrotide needed, withdraw this amount from the vial(s) and add it to the infusion bag containing 0.9% Sodium Chloride Injection or 5% Dextrose Injection for each dose to make a final concentration of 4 mg/mL to 20 mg/mL. - Gently mix the solution for infusion. - Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Only clear solutions without visible particles should be used. Depending on the type and amount of diluent, the color of the diluted solution may vary from colorless to light yellow. ### Monitoring There is limited information regarding Defibrotide Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Defibrotide and IV administrations. # Overdosage There are no known cases of overdose with Defibrotide. There is no known antidote for Defibrotide, and Defibrotide is not dialyzable. If an overdose occurs, institute general supportive measures. # Pharmacology ## Mechanism of Action The mechanism of action of Defibrotide sodium has not been fully elucidated. In vitro, Defibrotide sodium enhances the enzymatic activity of plasmin to hydrolyze fibrin clots. Studies evaluating the pharmacological effects of Defibrotide sodium on endothelial cells (ECs) were conducted primarily in the human microvascular endothelial cell line. In vitro, Defibrotide sodium increased tissue plasminogen activator (t-PA) and thrombomodulin expression, and decreased von Willebrand factor (vWF) and plasminogen activator inhibitor‑1 (PAI-1) expression, thereby reducing EC activation and increasing EC‑mediated fibrinolysis. Defibrotide sodium protected ECs from damage caused by chemotherapy, tumor necrosis factor-α (TNF-α), serum starvation, and perfusion. ## Structure Defibrotide sodium is an oligonucleotide mixture with profibrinolytic properties. The chemical name of Defibrotide sodium is polydeoxyribonucleotide, sodium salt. Defibrotide sodium is a polydisperse mixture of predominantly single-stranded (ss) polydeoxyribonucleotide sodium salts derived from porcine intestinal tissue having a mean weighted molecular weight of 13-20 kDa, and a potency of 27-39 and 28-38 biological units per mg as determined by two separate assays measuring the release of a product formed by contact between Defibrotide sodium, plasmin and a plasmin substrate. The primary structure of Defibrotide sodium is shown below. Defibrotide sodium injection is a clear, light yellow to brown, sterile, preservative-free solution in a single-patient-use vial for intravenous use. Each milliliter of the injection contains 80 mg of Defibrotide sodium and 10 mg of Sodium Citrate, USP, in Water for Injection, USP. Hydrochloric Acid, NF, and/or Sodium Hydroxide, NF, may have been used to adjust pH to 6.8-7.8. ## Pharmacodynamics - Cardiac Electrophysiology At a dose 2.4 times the maximum recommended dose, Defibrotide does not prolong the QTc interval to any clinically relevant extent. - PAI-1 Inhibition Plasma concentrations of PAI-1 were assessed on an exploratory basis as a potential pharmacodynamic marker for efficacy in Study 2. PAI-1 is an inhibitor of t-PA and therefore of fibrinolysis. Mean PAI-1 levels on Days 7 and 14 were lower than those at baseline in patients with complete response (CR) and in those who were alive at Day+100, but this trend did not reach statistical significance. There were no statistically significant differences in mean PAI-1 levels by treatment or outcome. ## Pharmacokinetics - Absorption After intravenous administration, peak plasma concentrations of Defibrotide sodium occur approximately at the end of each infusion. - Distribution Defibrotide sodium is highly bound to human plasma proteins (average 93%) and has a volume of distribution of 8.1 to 9.1 L. - Elimination Metabolism followed by urinary excretion is likely the main route of elimination. The estimated total clearance was 3.4 to 6.1 L/h. The elimination half-life of Defibrotide sodium is less than 2 hours. Similar plasma concentration profiles were observed in VOD patients after initial and multiple-dose administration of 6.25 mg/kg every 6 hours for 5 days. Therefore, no accumulation is expected following multiple-dose administration. - Metabolism Though the precise pathway of Defibrotide sodium degradation in plasma in vivo is largely unknown, it has been suggested that nucleases, nucleotidases, nucleosidases, deaminases, and phosphorylases metabolize polynucleotides progressively to oligonucleotides, nucleotides, nucleosides, and then to the free 2'-deoxyribose sugar, purine and pyrimidine bases. The biotransformation of Defibrotide sodium was investigated in vitro by incubation with human hepatocytes from donors of different ages and showed that Defibrotide sodium does not undergo appreciable metabolism by human hepatocyte cells. - Excretion After administration of 6.25 mg/kg to 15 mg/kg doses of Defibrotide as 2-hour infusions, approximately 5-15% of the total dose was excreted in urine as Defibrotide sodium, with the majority excreted during the first 4 hours. - Specific Populations - Age: Pediatric Population Insufficient PK data were collected in pediatric patients to draw conclusions. - Renal Impairment The safety, tolerability, and pharmacokinetics of 6.25 mg/kg as 2-hour intravenous infusions of Defibrotide were evaluated in patients with Hemodialysis-dependent End Stage Renal Disease (ESRD) during hemodialysis and on days off dialysis, and in patients with severe renal disease or ESRD not requiring dialysis. Defibrotide sodium was not removed by hemodialysis, which had no notable effect on plasma clearance of Defibrotide sodium. Terminal half-lives were consistently less than 2 hours, and there was no accumulation of Defibrotide sodium following repeated dosing. Defibrotide sodium exposure (AUC) in patients with severe renal impairment or ESRD was 50% to 60% higher than that observed in matched healthy subjects. Peak concentration (Cmax) was 35% to 37% higher following single- and multiple-dose administration of Defibrotide sodium. - Drug Interactions Pharmacokinetic drug-drug interactions are unlikely at therapeutic dose. Data from in vitro studies using human biomaterial demonstrate that Defibrotide sodium does not induce (CYP1A2, CYP2B6, CYP3A4, UGT1A1) or inhibit (CYP1A2, CYP2B6, CYP3A4, CYP2C8, CYP2C9, CYP2C19, CYP2D6, UGT1A1, UGT2B7) the major drug metabolizing enzymes and is not a substrate or inhibitor of the major drug uptake transporters (OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3) or efflux transporters (P-gp and BCRP). There is some evidence (animal studies, ex vivo human plasma, and healthy volunteers) that Defibrotide sodium may enhance the pharmacodynamic activity of heparin and alteplase. ## Nonclinical Toxicology No carcinogenicity studies have been conducted with intravenous administration of Defibrotide sodium. Defibrotide sodium was not mutagenic in vitro in a bacterial reverse mutation assay (Ames assay). Defibrotide sodium was not clastogenic in an in vitro chromosomal aberrations assay in Chinese hamster ovary cells or an in vivo micronucleus assay conducted in bone marrow from rats administered Defibrotide sodium by intravenous infusion. Studies of fertility were not conducted with Defibrotide sodium administered by the intravenous route. In repeat dose general toxicology studies, when Defibrotide sodium was administered intravenously to rats and dogs for up to 13 weeks, there were no effects on male or female reproductive organs. In the 13-week toxicity studies in rats and dogs, intravenous administration of Defibrotide sodium transiently prolonged activated partial thromboplastin time (APTT) at 1200 and 4800 mg/kg/day administered as a continuous infusion in rats and at 300 and 1600 mg/kg/day administered in 2-hour infusions 4 times daily in dogs. Prothrombin time (PT) was also transiently increased at 4800 mg/kg/day in rats. These findings were observed at doses at least 6 times higher on a mg/m2 basis than the clinical dose of 25 mg/kg/day. The effects on APTT and PT may be due to direct effects on coagulation based on the dose-dependent response observed. # Clinical Studies The efficacy of Defibrotide was investigated in three studies: two prospective clinical trials (Study 1 and Study 2), and an expanded access study (Study 3). Study 1 enrolled 102 adult and pediatric patients in the Defibrotide treatment group with a diagnosis of VOD according to the following criteria (bilirubin of at least 2 mg/dL and at least two of the following findings: hepatomegaly, ascites, and weight gain greater than 5% by Day+21 post-HSCT) with an associated diagnosis of multi-organ dysfunction (pulmonary, renal, or both) by Day+28 post-HSCT. Defibrotide was administered to the treatment group at a dose of 6.25 mg/kg infused every 6 hours for a minimum of 21 days and continued until patient was discharged from the hospital. Patients enrolled in the Defibrotide treatment group were not permitted to receive concomitant medications such as heparin, warfarin, or alteplase because of an increased risk of bleeding. Study 2 included adult and pediatric patients with a diagnosis of hepatic VOD and multi-organ dysfunction following HSCT, with 75 patients treated with Defibrotide at a dose of 6.25 mg/kg infused every 6 hours. The planned minimum duration of treatment was 14 days. The treatment could be continued until signs of hepatic VOD resolved. Study 3 is an expanded access program for Defibrotide for the treatment of adult and pediatric patients with hepatic VOD. The efficacy of Defibrotide was evaluated in 351 patients who had received a HSCT and developed hepatic VOD with renal or pulmonary dysfunction. All patients received Defibrotide at a dose of 6.25 mg/kg infused every 6 hours. Baseline demographic information and details for patients treated in these studies are provided below in Table 3. - Table 3: Baseline Demographics of Patients Treated with Defibrotide at 6.25 mg/kg Every 6 Hours The efficacy of Defibrotide was based on survival at Day + 100 after HSCT. In Study 1, the survival rate was 38% (95% CI: 29%, 48%) at 100 days after transplantation. In Study 2 the survival rate was 44% (95% CI: 33%, 55%) at 100 days after transplantation. In Study 3, the Day + 100 survival was 45% (95% CI: 40%, 51%). Based on published reports and analyses of patient level data for individuals with hepatic VOD with renal or pulmonary dysfunction who received supportive care or interventions other than Defibrotide, the expected Day +100 survival rates are 21% to 31%. # How Supplied Defibrotide sodium injection is supplied in a single-patient-use, clear glass vial as a clear, light yellow to brown, sterile, preservative-free solution for intravenous infusion. Each vial (NDC 68727-800-01) contains 200 mg/2.5 mL (at a concentration of 80 mg/mL) of Defibrotide sodium. Each carton of Defibrotide sodium injection (NDC 68727-800-02) contains 10 vials. ## Storage Store Defibrotide sodium injection at 20°C-25°C (68°F-77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Hemorrhage: Advise patients and caregivers that Defibrotide may increase the risk of bleeding (hemorrhage). Instruct patients to immediately report any signs or symptoms suggestive of hemorrhage (unusual bleeding, easy bruising, blood in urine or stool, headache, confusion, slurred speech, or altered vision). - Hypersensitivity Reactions: Ask patients if they have been treated with Defibrotide sodium previously. Instruct patients on the risk of allergic reactions, including anaphylaxis. Describe the symptoms of allergic reactions, including anaphylaxis, and instruct the patient to seek medical attention immediately if they experience such symptoms. # Precautions with Alcohol Alcohol-Defibrotide interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names DEFITELIO® # Look-Alike Drug Names There is limited information regarding Defibrotide Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Defibrotide 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 Defibrotide is an oligonucleotide mixture with profibrinolytic properties that is FDA approved for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT). Common adverse reactions include hypotension, diarrhea, vomiting, nausea, and epistaxis (≥10%). # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Defibrotide is indicated for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT). The recommended dosage of Defibrotide for adult and pediatric patients is 6.25 mg/kg every 6 hours given as a 2‑hour intravenous infusion. The dose should be based on patient’s baseline body weight, defined as the patient’s weight prior to the preparative regimen for HSCT. Administer Defibrotide for a minimum of 21 days. If after 21 days signs and symptoms of hepatic VOD have not resolved, continue Defibrotide until resolution of VOD or up to a maximum of 60 days. - Treatment Modification Treatment modification, including temporary or permanent discontinuation of Defibrotide, should follow the recommendations in Table 1. - Table 1: Treatment Modifications for Toxicity or Invasive Procedures DEFITELIO: Defibrotide's Brand name ## Off-Label Use and Dosage (Adult) # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Defibrotide is indicated for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT). The recommended dosage of Defibrotide for adult and pediatric patients is 6.25 mg/kg every 6 hours given as a 2‑hour intravenous infusion. The dose should be based on patient’s baseline body weight, defined as the patient’s weight prior to the preparative regimen for HSCT. Administer Defibrotide for a minimum of 21 days. If after 21 days signs and symptoms of hepatic VOD have not resolved, continue Defibrotide until resolution of VOD or up to a maximum of 60 days. - Treatment Modification Treatment modification, including temporary or permanent discontinuation of Defibrotide, should follow the recommendations in Table 1. ## Off-Label Use and Dosage (Pediatric) # Contraindications The use of Defibrotide is contraindicated in the following conditions: # Warnings - Hemorrhage Defibrotide increased the activity of fibrinolytic enzymes in vitro, and it may increase the risk of bleeding in patients with VOD after hematopoietic stem-cell transplantation (HSCT). Do not initiate Defibrotide in patients with active bleeding. Monitor patients for signs of bleeding. If patients on Defibrotide develop bleeding, discontinue Defibrotide, treat the underlying cause, and provide supportive care until the bleeding has stopped. Concomitant use of Defibrotide and a systemic anticoagulant or fibrinolytic therapy (not including use for routine maintenance or reopening of central venous lines) may increase the risk of bleeding. Discontinue anticoagulants and fibrinolytic agents prior to Defibrotide treatment, and consider delaying the start of Defibrotide administration until the effects of the anticoagulant have abated. - Hypersensitivity Reactions Hypersensitivity reactions have occurred in less than 2% of patients treated with Defibrotide. These reactions include rash, urticaria and angioedema. One case of an anaphylactic reaction was reported in a patient who had previously received Defibrotide. Monitor patients for hypersensitivity reactions, especially if there is a history of previous exposure. If a severe hypersensitivity reaction occurs, discontinue Defibrotide, treat according to the standard of care, and monitor until symptoms resolve. # Adverse Reactions ## Clinical Trials Experience The following adverse reactions are discussed in greater detail in other sections of the labeling: - Hemorrhage - Hypersensitivity Reactions 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 Defibrotide was determined in 176 adult and pediatric patients with hepatic VOD with pulmonary and/or renal dysfunction following HSCT who were treated with Defibrotide 6.25 mg/kg every 6 hours. Patients were excluded from these trials if at time of study entry they had significant acute bleeding, active grades B-D graft-versus-host disease, or a requirement for multiple vasopressors to provide blood pressure support. For the purposes of adverse event recording in the clinical trials, events were not required to be reported if they were related to the hepatic VOD, or if they were expected to occur after hematopoietic stem-cell transplantation (HSCT), unless they were serious or Grade 4-5. The median age of the safety population was 25 years (range: 1 month to 72 years), and 63% were ≥17 years of age. A total of 60% of patients were male, 78% were white, 89% had undergone allogeneic HSCT, and the underlying diagnosis was acute leukemia for 43%. At study entry, 13% were dialysis dependent and 18% were ventilator dependent. Defibrotide was administered for a median of 21 days (range: 1 to 83 days). Information about adverse reactions resulting in permanent discontinuation of Defibrotide was available for 102 patients, and 35 (34%) of these patients had an adverse reaction with permanent discontinuation. Adverse reactions leading to permanent discontinuation included pulmonary alveolar hemorrhage in 5 (5%) patients; pulmonary hemorrhage, hypotension, catheter site hemorrhage, and multi-organ failure, each in 3 (3%) patients; and cerebral hemorrhage and sepsis, each in 2 (2%) patients. Information about adverse reactions of any grade was available for all 176 patients. The most common adverse reactions (incidence ≥10% and independent of causality) were hypotension, diarrhea, vomiting, nausea, and epistaxis. The most common serious adverse reactions (incidence ≥5% and independent of causality) were hypotension (11%) and pulmonary alveolar hemorrhage (7%). Hemorrhage events of any type and any grade were reported for 104 (59%) of the patients, and the events were grade 4-5 in 35 (20%). Table 2 presents adverse reactions independent of causality ≥10% any grade or Grade 4/5 ≥2% reported in patients treated with Defibrotide. - Table 2: Adverse Reactions(a) ≥10% or Grade 4-5 Adverse Reactions ≥2% DEFITELIO: Defibrotide's Brand name ## Postmarketing Experience There is limited information regarding Defibrotide Postmarketing Experience in the drug label. # Drug Interactions - Antithrombotic Agents Defibrotide may enhance the pharmacodynamic activity of antithrombotic/fibrinolytic drugs such as heparin or alteplase. Concomitant use of Defibrotide with antithrombotic or fibrinolytic drugs is contraindicated because of an increased risk of hemorrhage. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): N - Risk Summary There are no available data on Defibrotide use in pregnant women. When administered to pregnant rabbits during the period of organogenesis at doses that were comparable to the recommended human dose based on body surface area, Defibrotide sodium decreased the number of implantations and viable fetuses. Advise pregnant women of the potential risk of miscarriage. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively. - Data - Animal Data Embryo-Fetal toxicity assessment was attempted in rats and rabbits, but was not possible because of high maternal mortality, abortion, and fetal resorption at all doses. Pregnant rats were administered Defibrotide sodium from gestational day (GD) 6 to 15 at 0, 240, 1200, and 4800 mg/kg/day by continuous intravenous infusion over 24 hours or at 60, 120, and 240 mg/kg/day by 2-hour infusions 4 times per day. Pregnant rabbits were administered Defibrotide sodium at 0, 30, 60, or 120 mg/kg/day from GD 6 to 18 by 2-hour infusions 4 times per day. In another study in pregnant rabbits, 3 separate subgroups of animals were treated with doses of 80 mg/kg/day Defibrotide sodium administered by 2-hour infusions 4 times per day for 5 days each in a staggered manner during the organogenesis period. The dose of 80 mg/kg/day is approximately equivalent to the recommended clinical dose on a mg/m2 basis. Subgroup 1 was dosed from GD 6 to 10, subgroup 2 was dosed from GD 10 to 14, and subgroup 3 was dosed from GD 14 to 18. An increased incidence of unilateral implantation was observed in Defibrotide sodium-treated animals. Treatment with Defibrotide sodium resulted in a decreased number of implantations and viable fetuses. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Defibrotide in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Defibrotide during labor and delivery. ### Nursing Mothers There is no information regarding the presence of Defibrotide in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions, including bleeding in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with Defibrotide. ### Pediatric Use The safety and effectiveness of Defibrotide have been established in pediatric patients. Use of Defibrotide is supported by evidence from an adequate and well-controlled study and a dose finding study of Defibrotide in adult and pediatric patients with VOD with evidence of renal or pulmonary dysfunction following HSCT. The clinical trials enrolled 66 pediatric patients in the following age groups: 22 infants (1 month up to less than 2 years), 30 children (2 years up to less than 12 years), and 14 adolescents (12 years to less than 17 years). The efficacy and safety outcomes were consistent across pediatric and adult patients in the clinical trials. - Juvenile Animal Toxicity Data A juvenile toxicity study in 21-day-old rats was conducted with intravenous bolus administration of Defibrotide sodium at 40, 150, or 320 mg/kg/day for 4 weeks. A delayed mean age of preputial separation was observed at all doses, suggesting a delay in onset of male puberty. The dose of 40 mg/kg/day is approximately 0.4 times the clinical dose on a mg/m2 basis for a child. The relevance of this finding for the onset of male puberty in humans is unknown. ### Geriatic Use Clinical studies of Defibrotide did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. ### Gender There is no FDA guidance on the use of Defibrotide with respect to specific gender populations. ### Race There is no FDA guidance on the use of Defibrotide with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Defibrotide in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Defibrotide in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Defibrotide in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Defibrotide in patients who are immunocompromised. # Administration and Monitoring ### Administration - Administration Instructions - Defibrotide must be diluted prior to infusion. - Prior to administration of Defibrotide, confirm that the patient is not experiencing clinically significant bleeding and is hemodynamically stable on no more than one vasopressor. - Administer Defibrotide by constant intravenous infusion over a 2-hour period. - Administer the diluted Defibrotide solution using an infusion set equipped with a 0.2 micron in-line filter. Flush the intravenous administration line (peripheral or central) with 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP immediately before and after administration. - Do not co‑administer Defibrotide and other intravenous drugs concurrently within the same intravenous line. - Preparation Instructions Dilute Defibrotide in 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP to a concentration of 4 mg/mL to 20 mg/mL. Administer the diluted solution over 2 hours. Vials contain no antimicrobial preservatives and are intended for a single-patient-use only. Partially used vials should be discarded. Use the diluted Defibrotide solution within 4 hours if stored at room temperature or within 24 hours if stored under refrigeration. Up to four doses of Defibrotide solution may be prepared at one time, if refrigerated. Preparation Instructions: - Determine the dose (mg) and number of vials of Defibrotide based on the individual patient’s baseline weight (weight prior to the preparative regimen for HSCT). - Calculate the volume of Defibrotide needed, withdraw this amount from the vial(s) and add it to the infusion bag containing 0.9% Sodium Chloride Injection or 5% Dextrose Injection for each dose to make a final concentration of 4 mg/mL to 20 mg/mL. - Gently mix the solution for infusion. - Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Only clear solutions without visible particles should be used. Depending on the type and amount of diluent, the color of the diluted solution may vary from colorless to light yellow. ### Monitoring There is limited information regarding Defibrotide Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Defibrotide and IV administrations. # Overdosage There are no known cases of overdose with Defibrotide. There is no known antidote for Defibrotide, and Defibrotide is not dialyzable. If an overdose occurs, institute general supportive measures. # Pharmacology ## Mechanism of Action The mechanism of action of Defibrotide sodium has not been fully elucidated. In vitro, Defibrotide sodium enhances the enzymatic activity of plasmin to hydrolyze fibrin clots. Studies evaluating the pharmacological effects of Defibrotide sodium on endothelial cells (ECs) were conducted primarily in the human microvascular endothelial cell line. In vitro, Defibrotide sodium increased tissue plasminogen activator (t-PA) and thrombomodulin expression, and decreased von Willebrand factor (vWF) and plasminogen activator inhibitor‑1 (PAI-1) expression, thereby reducing EC activation and increasing EC‑mediated fibrinolysis. Defibrotide sodium protected ECs from damage caused by chemotherapy, tumor necrosis factor-α (TNF-α), serum starvation, and perfusion. ## Structure Defibrotide sodium is an oligonucleotide mixture with profibrinolytic properties. The chemical name of Defibrotide sodium is polydeoxyribonucleotide, sodium salt. Defibrotide sodium is a polydisperse mixture of predominantly single-stranded (ss) polydeoxyribonucleotide sodium salts derived from porcine intestinal tissue having a mean weighted molecular weight of 13-20 kDa, and a potency of 27-39 and 28-38 biological units per mg as determined by two separate assays measuring the release of a product formed by contact between Defibrotide sodium, plasmin and a plasmin substrate. The primary structure of Defibrotide sodium is shown below. Defibrotide sodium injection is a clear, light yellow to brown, sterile, preservative-free solution in a single-patient-use vial for intravenous use. Each milliliter of the injection contains 80 mg of Defibrotide sodium and 10 mg of Sodium Citrate, USP, in Water for Injection, USP. Hydrochloric Acid, NF, and/or Sodium Hydroxide, NF, may have been used to adjust pH to 6.8-7.8. ## Pharmacodynamics - Cardiac Electrophysiology At a dose 2.4 times the maximum recommended dose, Defibrotide does not prolong the QTc interval to any clinically relevant extent. - PAI-1 Inhibition Plasma concentrations of PAI-1 were assessed on an exploratory basis as a potential pharmacodynamic marker for efficacy in Study 2. PAI-1 is an inhibitor of t-PA and therefore of fibrinolysis. Mean PAI-1 levels on Days 7 and 14 were lower than those at baseline in patients with complete response (CR) and in those who were alive at Day+100, but this trend did not reach statistical significance. There were no statistically significant differences in mean PAI-1 levels by treatment or outcome. ## Pharmacokinetics - Absorption After intravenous administration, peak plasma concentrations of Defibrotide sodium occur approximately at the end of each infusion. - Distribution Defibrotide sodium is highly bound to human plasma proteins (average 93%) and has a volume of distribution of 8.1 to 9.1 L. - Elimination Metabolism followed by urinary excretion is likely the main route of elimination. The estimated total clearance was 3.4 to 6.1 L/h. The elimination half-life of Defibrotide sodium is less than 2 hours. Similar plasma concentration profiles were observed in VOD patients after initial and multiple-dose administration of 6.25 mg/kg every 6 hours for 5 days. Therefore, no accumulation is expected following multiple-dose administration. - Metabolism Though the precise pathway of Defibrotide sodium degradation in plasma in vivo is largely unknown, it has been suggested that nucleases, nucleotidases, nucleosidases, deaminases, and phosphorylases metabolize polynucleotides progressively to oligonucleotides, nucleotides, nucleosides, and then to the free 2'-deoxyribose sugar, purine and pyrimidine bases. The biotransformation of Defibrotide sodium was investigated in vitro by incubation with human hepatocytes from donors of different ages and showed that Defibrotide sodium does not undergo appreciable metabolism by human hepatocyte cells. - Excretion After administration of 6.25 mg/kg to 15 mg/kg doses of Defibrotide as 2-hour infusions, approximately 5-15% of the total dose was excreted in urine as Defibrotide sodium, with the majority excreted during the first 4 hours. - Specific Populations - Age: Pediatric Population Insufficient PK data were collected in pediatric patients to draw conclusions. - Renal Impairment The safety, tolerability, and pharmacokinetics of 6.25 mg/kg as 2-hour intravenous infusions of Defibrotide were evaluated in patients with Hemodialysis-dependent End Stage Renal Disease (ESRD) during hemodialysis and on days off dialysis, and in patients with severe renal disease or ESRD not requiring dialysis. Defibrotide sodium was not removed by hemodialysis, which had no notable effect on plasma clearance of Defibrotide sodium. Terminal half-lives were consistently less than 2 hours, and there was no accumulation of Defibrotide sodium following repeated dosing. Defibrotide sodium exposure (AUC) in patients with severe renal impairment or ESRD was 50% to 60% higher than that observed in matched healthy subjects. Peak concentration (Cmax) was 35% to 37% higher following single- and multiple-dose administration of Defibrotide sodium. - Drug Interactions Pharmacokinetic drug-drug interactions are unlikely at therapeutic dose. Data from in vitro studies using human biomaterial demonstrate that Defibrotide sodium does not induce (CYP1A2, CYP2B6, CYP3A4, UGT1A1) or inhibit (CYP1A2, CYP2B6, CYP3A4, CYP2C8, CYP2C9, CYP2C19, CYP2D6, UGT1A1, UGT2B7) the major drug metabolizing enzymes and is not a substrate or inhibitor of the major drug uptake transporters (OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3) or efflux transporters (P-gp and BCRP). There is some evidence (animal studies, ex vivo human plasma, and healthy volunteers) that Defibrotide sodium may enhance the pharmacodynamic activity of heparin and alteplase. ## Nonclinical Toxicology No carcinogenicity studies have been conducted with intravenous administration of Defibrotide sodium. Defibrotide sodium was not mutagenic in vitro in a bacterial reverse mutation assay (Ames assay). Defibrotide sodium was not clastogenic in an in vitro chromosomal aberrations assay in Chinese hamster ovary cells or an in vivo micronucleus assay conducted in bone marrow from rats administered Defibrotide sodium by intravenous infusion. Studies of fertility were not conducted with Defibrotide sodium administered by the intravenous route. In repeat dose general toxicology studies, when Defibrotide sodium was administered intravenously to rats and dogs for up to 13 weeks, there were no effects on male or female reproductive organs. In the 13-week toxicity studies in rats and dogs, intravenous administration of Defibrotide sodium transiently prolonged activated partial thromboplastin time (APTT) at 1200 and 4800 mg/kg/day administered as a continuous infusion in rats and at 300 and 1600 mg/kg/day administered in 2-hour infusions 4 times daily in dogs. Prothrombin time (PT) was also transiently increased at 4800 mg/kg/day in rats. These findings were observed at doses at least 6 times higher on a mg/m2 basis than the clinical dose of 25 mg/kg/day. The effects on APTT and PT may be due to direct effects on coagulation based on the dose-dependent response observed. # Clinical Studies The efficacy of Defibrotide was investigated in three studies: two prospective clinical trials (Study 1 and Study 2), and an expanded access study (Study 3). Study 1 enrolled 102 adult and pediatric patients in the Defibrotide treatment group with a diagnosis of VOD according to the following criteria (bilirubin of at least 2 mg/dL and at least two of the following findings: hepatomegaly, ascites, and weight gain greater than 5% by Day+21 post-HSCT) with an associated diagnosis of multi-organ dysfunction (pulmonary, renal, or both) by Day+28 post-HSCT. Defibrotide was administered to the treatment group at a dose of 6.25 mg/kg infused every 6 hours for a minimum of 21 days and continued until patient was discharged from the hospital. Patients enrolled in the Defibrotide treatment group were not permitted to receive concomitant medications such as heparin, warfarin, or alteplase because of an increased risk of bleeding. Study 2 included adult and pediatric patients with a diagnosis of hepatic VOD and multi-organ dysfunction following HSCT, with 75 patients treated with Defibrotide at a dose of 6.25 mg/kg infused every 6 hours. The planned minimum duration of treatment was 14 days. The treatment could be continued until signs of hepatic VOD resolved. Study 3 is an expanded access program for Defibrotide for the treatment of adult and pediatric patients with hepatic VOD. The efficacy of Defibrotide was evaluated in 351 patients who had received a HSCT and developed hepatic VOD with renal or pulmonary dysfunction. All patients received Defibrotide at a dose of 6.25 mg/kg infused every 6 hours. Baseline demographic information and details for patients treated in these studies are provided below in Table 3. - Table 3: Baseline Demographics of Patients Treated with Defibrotide at 6.25 mg/kg Every 6 Hours The efficacy of Defibrotide was based on survival at Day + 100 after HSCT. In Study 1, the survival rate was 38% (95% CI: 29%, 48%) at 100 days after transplantation. In Study 2 the survival rate was 44% (95% CI: 33%, 55%) at 100 days after transplantation. In Study 3, the Day + 100 survival was 45% (95% CI: 40%, 51%). Based on published reports and analyses of patient level data for individuals with hepatic VOD with renal or pulmonary dysfunction who received supportive care or interventions other than Defibrotide, the expected Day +100 survival rates are 21% to 31%. # How Supplied Defibrotide sodium injection is supplied in a single-patient-use, clear glass vial as a clear, light yellow to brown, sterile, preservative-free solution for intravenous infusion. Each vial (NDC 68727-800-01) contains 200 mg/2.5 mL (at a concentration of 80 mg/mL) of Defibrotide sodium. Each carton of Defibrotide sodium injection (NDC 68727-800-02) contains 10 vials. ## Storage Store Defibrotide sodium injection at 20°C-25°C (68°F-77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Hemorrhage: Advise patients and caregivers that Defibrotide may increase the risk of bleeding (hemorrhage). Instruct patients to immediately report any signs or symptoms suggestive of hemorrhage (unusual bleeding, easy bruising, blood in urine or stool, headache, confusion, slurred speech, or altered vision). - Hypersensitivity Reactions: Ask patients if they have been treated with Defibrotide sodium previously. Instruct patients on the risk of allergic reactions, including anaphylaxis. Describe the symptoms of allergic reactions, including anaphylaxis, and instruct the patient to seek medical attention immediately if they experience such symptoms. # Precautions with Alcohol Alcohol-Defibrotide interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names DEFITELIO® # Look-Alike Drug Names There is limited information regarding Defibrotide Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Defibrotide
3ef5084a0151ab27072aa4c18759444be224577b	wikidoc	Deflazacort	Deflazacort # 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 Deflazacort is a corticosteroid that is FDA approved for the treatment of Duchenne muscular dystrophy (DMD) in patients 5 years of age and older. Common adverse reactions include cushingoid appearance, weight increased, increased appetite, upper respiratory tract infection, cough, pollakiuria, hirsutism, central obesity, and nasopharyngitis. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Deflazacort is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients 5 years of age and older. - The recommended oral dosage of deflazacort is approximately 0.9 mg/kg/day once daily. If tablets are used, round up to the nearest possible dose. Any combination of the four deflazacort tablet strengths can be used to achieve this dose. If the oral suspension is used, round up to the nearest tenth of a milliliter (mL). CYP3A4 Inhibitors - Give one third of the recommended dosage when deflazacort is administered with moderate or strong CYP3A4 inhibitors. For example, a 36 mg per day dose would be reduced to a 12 mg per day dose when used with moderate or strong CYP3A4 inhibitors. CYP3A4 Inducers - Avoid use with moderate or strong CYP3A4 inducers with deflazacort. - Tablets - 6 mg: White and round with “6” debossed on one side - 18 mg: White and round with “18” debossed on one side - 30 mg: White and oval with “30” debossed on one side - 36 mg: White and oval with “36” debossed on one side - Oral Suspension - 22.75 mg/mL: Whitish suspension ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding deflazacort Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding deflazacort Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Deflazacort is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients 5 years of age and older. - The recommended oral dosage of deflazacort is approximately 0.9 mg/kg/day once daily. If tablets are used, round up to the nearest possible dose. Any combination of the four deflazacort tablet strengths can be used to achieve this dose. If the oral suspension is used, round up to the nearest tenth of a milliliter (mL). CYP3A4 Inhibitors - Give one third of the recommended dosage when deflazacort is administered with moderate or strong CYP3A4 inhibitors. For example, a 36 mg per day dose would be reduced to a 12 mg per day dose when used with moderate or strong CYP3A4 inhibitors. CYP3A4 Inducers - Avoid use with moderate or strong CYP3A4 inducers with deflazacort. - Tablets - 6 mg: White and round with “6” debossed on one side - 18 mg: White and round with “18” debossed on one side - 30 mg: White and oval with “30” debossed on one side - 36 mg: White and oval with “36” debossed on one side - Oral Suspension - 22.75 mg/mL: Whitish suspension ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding deflazacort Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding deflazacort Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications - Deflazacort is contraindicated in patients with known hypersensitivity to deflazacort or to any of the inactive ingredients. Instances of hypersensitivity, including anaphylaxis, have occurred in patients receiving corticosteroid therapy # Warnings ## Alterations in Endocrine Function - Corticosteroids, such as deflazacort, can cause serious and life-threatening alterations in endocrine function, especially with chronic use. Monitor patients receiving deflazacort for Cushing’s syndrome, hyperglycemia, and adrenal insufficiency after deflazacort withdrawal. In addition, patients with hypopituitarism, primary adrenal insufficiency or congenital adrenal hyperplasia, altered thyroid function, or pheochromocytoma may be at increased risk for adverse endocrine events. ### Risk of Adrenal Insufficiency Following Corticosteroid Withdrawal - Corticosteroids produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, with the potential for the development of secondary adrenal insufficiency after withdrawal of corticosteroid treatment. Acute adrenal insufficiency can occur if corticosteroids are withdrawn abruptly, and can be fatal. The degree and duration of adrenocortical insufficiency produced is variable among patients and depends on the dose, frequency, and duration of corticosteroid therapy. The risk is reduced by gradually tapering the corticosteroid dose when withdrawing treatment. This insufficiency may persist, however, for months after discontinuation of prolonged therapy; therefore, in any situation of stress occurring during that period of discontinuation, corticosteroid therapy should be reinstituted. For patients already taking corticosteroids during times of stress, the dosage may need to be increased. - A steroid “withdrawal syndrome”, seemingly unrelated to adrenocortical insufficiency, may also occur following abrupt discontinuance of corticosteroids. This syndrome includes symptoms such as anorexia, nausea, vomiting, lethargy, headache, fever, joint pain, desquamation, myalgia, and/or weight loss. These effects are thought to be due to the sudden change in corticosteroid concentration rather than to low corticosteroid levels. ### Cushing’s Syndrome - Cushing’s syndrome (hypercortisolism) occurs with prolonged exposure to exogenous corticosteroids, including deflazacort. Symptoms include hypertension, truncal obesity and thinning of the limbs, purple striae, facial rounding, facial plethora, muscle weakness, easy and frequent bruising with thin fragile skin, posterior neck fat deposition, osteopenia, acne, amenorrhea, hirsutism and psychiatric abnormalities. ### Hyperglycemia - Corticosteroids can increase blood glucose, worsen pre-existing diabetes, predispose those on long-term therapy to diabetes mellitus, and may reduce the effect of anti-diabetic drugs. Monitor blood glucose at regular intervals. For patients with hyperglycemia, anti-diabetic treatment should be initiated or adjusted accordingly. ### Considerations for Use in Patients with Altered Thyroid Function - Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients. Changes in thyroid status of the patient may necessitate a dose adjustment of the corticosteroid. When concomitant administration of corticosteroids and levothyroxine is required, administration of corticosteroid should precede the initiation of levothyroxine therapy to reduce the risk of adrenal crisis. ### Pheochromocytoma crisis - There have been reports of pheochromocytoma crisis, which can be fatal, after administration of systemic corticosteroids. In patients with suspected or identified pheochromocytoma, consider the risk of pheochromocytoma crisis prior to administering corticosteroids. ## Immunosuppression and Increased Risk of Infection - Corticosteroids, including deflazacort, suppress the immune system and increase the risk of infection with any pathogen, including viral, bacterial, fungal, protozoan, or helminthic. Corticosteroids reduce resistance to new infections, exacerbate existing infections, increase the risk of disseminated infections, increase the risk of reactivation or exacerbation of latent infections, and mask some signs of infection. These infections can be severe, and at times fatal. The degree to which the dose, route, and duration of corticosteroid administration correlates with the specific risks of infection is not well characterized; however, the rate of occurrence of infectious complications increases with increasing doses of corticosteroids. - Monitor for the development of infection and consider withdrawal of corticosteroids or reduction of the dose of corticosteroids as needed. ### Varicella Zoster and Measles Viral Infections - Chickenpox caused by Varicella Zoster virus and measles can have a serious or even fatal course in non-immune children or adults on corticosteroids, including deflazacort. In children or adults who have not had these diseases, particular care should be taken to avoid exposure. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with immunoglobulin (IG) may be indicated. If chickenpox develops, treatment with antiviral agents may be considered. ### Hepatitis B Virus Reactivation - Hepatitis B virus reactivation can occur in patients who are hepatitis B carriers undergoing treatment with immunosuppressive drugs including corticosteroids. Reactivation can also occur in patients who appear to have resolved hepatitis B infection. ### Fungal Infections - Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections. For patients on corticosteroids who develop systemic fungal infections, withdrawal of corticosteroids or reduction of the dose of corticosteroids is recommended. ### Amebiasis - Corticosteroids may activate latent amebiasis. Therefore, it is recommended that latent amebiasis or active amebiasis be ruled out before initiating corticosteroid therapy in any patient who has spent time in the tropics, or any patient with unexplained diarrhea. ### Strongyloides Infestation - In patients with known or suspected Strongyloides (threadworm) infestation, corticosteroid-induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia. For patients on corticosteroids who develop known or suspected Strongyloides (threadworm) infestation, withdrawal of corticosteroids or reduction of the dose of corticosteroids is recommended. ## Alterations in Cardiovascular/Renal Function - Corticosteroids, including deflazacort, can cause elevation of blood pressure, salt, and water retention, and increased excretion of potassium and calcium. Monitor blood pressure and assess for signs and symptoms of volume overload. Monitor serum potassium levels. Dietary salt restriction and potassium supplementation may be necessary. deflazacort should be used with caution in patients with congestive heart failure, hypertension, or renal insufficiency. - Literature reports suggest an association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with deflazacort should be used with great caution in these patients. ## Gastrointestinal Perforation - There is an increased risk of gastrointestinal perforation during corticosteroid use in patients with certain gastrointestinal disorders such as active or latent peptic ulcers, diverticulitis, fresh intestinal anastomoses, and non-specific ulcerative colitis. Signs of gastrointestinal perforation, such as peritoneal irritation, may be masked in patients receiving corticosteroids. - Avoid corticosteroids if there is a probability of impending perforation, abscess, or other pyogenic infections; diverticulitis; fresh intestinal anastomoses; or active or latent peptic ulcer. ## Behavioral and Mood Disturbances - Potentially severe psychiatric adverse reactions may occur with systemic corticosteroids, including deflazacort. Symptoms typically emerge within a few days or weeks of starting treatment and may be dose-related. These reactions may improve after either dose reduction or withdrawal, although pharmacologic treatment may be necessary. Psychiatric adverse reactions usually involve hypomanic or manic symptoms (e.g., euphoria, insomnia, mood swings) during treatment and depressive episodes after discontinuation of treatment. Inform patients or caregivers of the potential for behavioral and mood changes and encourage them to seek medical attention if psychiatric symptoms develop, especially if depressed mood or suicidal ideation is suspected. ## Effects on Bones ### Decreased Bone Mineral Density - Corticosteroids, including deflazacort, decrease bone formation and increase bone resorption both through their effect on calcium regulation (i.e., decreasing absorption and increasing excretion) and inhibition of osteoblast function. This, together with a decrease in the protein matrix of the bone secondary to an increase in protein catabolism and reduced sex hormone production, may lead to inhibition of bone growth in pediatric patients and the development of bone loss at any age. Bone loss can predispose patients to vertebral and long bone fractures. Consider a patient’s risk of osteoporosis before initiating corticosteroid therapy. Monitor bone mineral density in patients on long-term treatment with deflazacort. ### Avascular Necrosis - Corticosteroids, including deflazacort, may cause avascular necrosis. ## Ophthalmic Effects - Use of corticosteroids, including deflazacort, may produce posterior subcapsular cataracts. Corticosteroids may also cause glaucoma with possible damage to the optic nerves, and may increase the risk of secondary ocular infections caused by bacteria, fungi, or viruses. Corticosteroids are not recommended for patients with active ocular herpes simplex. - Intraocular pressure may become elevated in some patients taking corticosteroids. If treatment with deflazacort is continued for more than 6 weeks, monitor intraocular pressure. ## Vaccination - Administration of live or live attenuated vaccines is not recommended in patients receiving immunosuppressive doses of corticosteroids, including deflazacort. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. - Killed or inactivated vaccines may be administered during corticosteroid therapy; however, the response to such vaccines cannot be predicted. - Patients on corticosteroid therapy, including deflazacort, may exhibit a diminished response to toxoids and live or inactivated vaccines because of inhibition of antibody response. ## Serious Skin Rashes - Toxic epidermal necrolysis has been reported with the use of deflazacort with symptoms beginning within 8 weeks of starting treatment. Discontinue at the first sign of rash, unless the rash is clearly not drug related. ## Effects on Growth and Development - Long-term use of corticosteroids, including deflazacort, can have negative effects on growth and development in children. ## Myopathy - Patients receiving corticosteroids, including deflazacort, and concomitant therapy with neuromuscular blocking agents (e.g., pancuronium) or patients with disorders of neuromuscular transmission (e.g., myasthenia gravis) may be at increased risk of developing acute myopathy. This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years. ## Kaposi’s Sarcoma - Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement. ## Risk of Serious Adverse Reactions in Infants because of Benzyl Alcohol Preservative - Deflazacort Oral Suspension contains benzyl alcohol and is not approved for use in pediatric patients less than 5 years of age. Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low birth weight infants treated with benzyl alcohol-preserved drugs. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known (Deflazacort Oral Suspension contains 10.45 mg of benzyl alcohol per mL; deflazacort Tablets do not contain benzyl alcohol). ## Thromboembolic Events - Observational studies have shown an increased risk of thromboembolism (including venous thromboembolism) particularly with higher cumulative doses of corticosteroids. It is unclear if risk differs by daily dose or duration of use. Use deflazacort with caution in patients who have or may be predisposed to thromboembolic disorders. ## Anaphylaxis - Rare instances of anaphylaxis have occurred in patients receiving corticosteroid therapy, including deflazacort. # 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 Study 1, the adverse reactions that were associated with deflazacort treatment discontinuation, in decreasing order of frequency, were weight increased, obesity, cataract, and sleep disorder. ## Most Common Adverse Reactions in Clinical Studies - TABLE 1 lists the adverse reactions that occurred in ≥ 5% of patients in the 0.9 mg/kg/day deflazacort-treated group and that occurred more frequently than in placebo patients in Study 1, which included patients with DMD between the ages of 5 and 15 years. - Common adverse reactions (≥ 5% of deflazacort-treated patients) that occurred over 52 weeks of exposure to deflazacort 0.9 mg/kg/day in Study 1 and at a higher rate than deflazacort 0.9 mg/kg/day in the 12-week placebo-controlled phase of the trial include Cushingoid appearance (60%), hirsutism (35%), weight increased (28%), erythema (28%), central obesity (25%), abdominal pain/abdominal pain upper (18% combined), pollakiuria (15%), constipation (10%), irritability (10%), abnormal behavior (9%), pyrexia (9%), back pain (7%), rash (7%), contusion (6%), nausea (6%), psychomotor hyperactivity (6%), epistaxis (6%), and skin striae (6%). - Study 1 also evaluated a higher dosage of deflazacort (1.2 mg/kg/day). Compared with the 0.9 mg/kg/day dosage, deflazacort 1.2 mg/kg/day over 52 weeks was associated with a higher incidence of certain adverse reactions, including Cushingoid appearance (69%), erythema (49%), hirsutism (37%), headache (34%), weight increased (32%), constipation (15%), abdominal pain upper (14%), skin striae (11%), acne (11%), and abdominal discomfort (8%). As there was no additional benefit with the 1.2 mg/kg/day dose of deflazacort, use of deflazacort 1.2 mg/kg/day is not recommended for the treatment of DMD. - In an additional clinical study of two years duration with extended follow-up (Study 2), many of the same adverse reactions were observed. In addition, musculoskeletal events associated with long-term steroid use were also observed, including muscle weakness, tendon disorder, and osteopenia. ## Less Common Adverse Reactions Observed in Clinical Studies - Other adverse reactions (≥ 1% frequency in any deflazacort treatment group and greater than placebo) that were observed during the 12-week placebo-controlled phase of Study 1 are shown below. - Eye Disorders: Lacrimation increased - Gastrointestinal Disorders: Dyspepsia, nausea, gastrointestinal disorder - General Disorders and Administration Site Conditions: Thirst - Infections: Hordeolum, impetigo, influenza, otitis externa, pharyngitis, tooth abscess, urinary tract infection, viral infection - Injury, Poisoning and Procedural Complications: Back injury, contusion, face injury, fibula fracture, greenstick fracture, heat exhaustion - Investigations: Glucose urine present, heart rate irregular - Musculoskeletal and Connective Tissue Disorders: Back pain, muscle spasms, myalgia, neck mass, neck pain, pain in extremity - Nervous System Disorders: Dizziness, psychomotor hyperactivity - Psychiatric Disorders: Affect lability, aggression, depression, emotional disorder, middle insomnia, mood altered, mood swings, sleep disorder - Renal and Urinary Disorders: Chromaturia, dysuria, hypertonic bladder - Reproductive System and Breast Disorders: Testicular pain - Respiratory, Thoracic, and Mediastinal Disorders: Hypoventilation, rhinorrhea - Skin and Subcutaneous Tissue Disorders: Acne, alopecia, dermatitis acneiform - Vascular Disorders: Hot flush ## Postmarketing Experience - The following adverse reactions have been reported during post-approval use of deflazacort worldwide or during post-approval use of other corticosteroids. These reactions are reported voluntarily from a population of uncertain size; therefore, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure. - Blood and Lymphatic System Disorders: Leukocytosis - Cardiac Disorder: Heart failure - Eye Disorders: Chorioretinopathy, corneal or scleral thinning - Gastrointestinal Disorders: Acute pancreatitis (especially in children), hemorrhage, peptic ulceration, perforation of peptic ulcer - General Disorders and Administration Site Conditions: Edema, impaired healing - Immune System Disorders: Hypersensitivity including anaphylaxis - Metabolism and Nutrition Disorders: Impaired carbohydrate tolerance with increased requirement for anti-diabetic therapy, negative protein and calcium balance, potassium loss and hypokalemic alkalosis when co-administered with beta 2-agonist and xanthines - Musculoskeletal and Connective Tissue Disorders: Avascular necrosis, muscle wasting, negative nitrogen balance, tendonitis and tendon rupture when co-administered with quinolones, vertebral and long bone fractures - Nervous System Disorders: Aggravation of epilepsy, increased intra-cranial pressure with papilledema in children (pseudotumor cerebri) usually after treatment withdrawal, vertigo - Psychiatric Disorders: Anxiety, cognitive dysfunction including confusion and amnesia, delusions, hallucinations, mania, suicidal thoughts - Skin and Subcutaneous Tissue Disorders: Toxic epidermal necrolysis - Vascular Disorders: Thromboembolism, in particular in patients with underlying conditions associated with increased thrombotic tendency, benign intracranial hypertension # Drug Interactions - CYP3A4 Inhibitors and Inducers - Neuromuscular Blockers Moderate or Strong CYP3A4 Inhibitors: - The active metabolite of deflazacort, 21-desDFZ, is a substrate of CYP3A4. Co-administration of deflazacort with clarithromycin, a strong CYP3A4 inhibitor, increased total exposure to 21-desDFZ by about 3-fold. Therefore, give one third the recommended dosage of deflazacort when moderate or strong CYP3A4 inhibitors (e.g., clarithromycin, fluconazole, diltiazem, verapamil, grapefruit juice) are used concomitantly with deflazacort. Moderate or Strong CYP3A4 Inducers: - Co-administration of deflazacort with rifampin, a strong CYP3A4 inducer, significantly decreased the exposure of 21-desDFZ. Avoid concomitant use of strong (e.g., efavirenz) or moderate (e.g., carbamazepine, phenytoin) CYP3A4 inducers with deflazacort. - Patients receiving corticosteroids, including deflazacort, and concomitant therapy with neuromuscular blocking drugs (e.g., pancuronium) may be at increased risk of developing an acute myopathy. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Infants born to mothers who have received substantial doses of corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism. There are no adequate and well-controlled studies with deflazacort in pregnant women to inform drug-associated risks. - Corticosteroids, including deflazacort, readily cross the placenta. Adverse developmental outcomes, including orofacial clefts (cleft lip, with or without cleft palate) and intrauterine growth restriction, and decreased birth weight, have been reported with maternal use of corticosteroids, including deflazacort, during pregnancy. Some epidemiologic studies report an increased risk of orofacial clefts from about 1 per 1000 infants to 3 to 5 per 1000 infants; however, a risk for orofacial clefts has not been observed in all studies. Intrauterine growth restriction and decreased birth weight appear to be dose-related; however, the underlying maternal condition may also contribute to these risks. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. - Animal reproduction studies have not been conducted with deflazacort. Animal reproduction studies conducted with other corticosteroids in pregnant mice, rats, hamsters, and rabbits using clinically relevant doses have shown an increased incidence of cleft palate. An increase in embryofetal death, intrauterine growth retardation, and constriction of the ductus arteriosus were observed in some animal species. - Multiple cohort and case-controlled studies in humans suggest that maternal corticosteroid use during the first trimester increases the rate of cleft lip, with or without cleft palate, from about 1/1000 infants to 3-5/1000 infants. Two prospective case-controlled studies showed decreased birth weight in infants exposed to maternal corticosteroids in utero. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Deflazacort in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Deflazacort during labor and delivery. ### Nursing Mothers - Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for deflazacort and any potential adverse effects on the breastfed infant from deflazacort. There are no data on the effects on milk production. ### Pediatric Use - The safety and effectiveness of deflazacort for the treatment of DMD have been established in patients 5 years of age and older. Use of deflazacort in pediatric patients is supported by a multicenter, randomized, double-blind, placebo- and active-controlled study in 196 males. - Safety and effectiveness of deflazacort have not been established in pediatric patients less than 5 years of age. - Deflazacort Oral Suspension contains benzyl alcohol and is not approved for use in pediatric patients less than 5 years of age. Serious adverse reactions including fatal reactions and “gasping syndrome” occurred in premature neonates and low birth weight infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known (Deflazacort Oral Suspension contains 10.45 mg of benzyl alcohol per mL; deflazacort Tablets do not contain benzyl alcohol) - Oral administration of deflazacort (0, 0.1, 0.3, and 1.0 mg/kg/day) to juvenile rats from postnatal day (PND) 21 to 80 resulted in decreased body weight gain and adverse effects on skeletal development (including decreased cellularity of growth plate and altered bone distribution) and on lymphoid tissue (decreased cellularity). A no-effect dose was not identified. In addition, neurological and neurobehavioral abnormalities were observed at the mid and/or high dose. Plasma 21-desDFZ exposure (AUC) at the lowest dose tested (0.1 mg/kg/day) was lower than that in humans at the recommended human dose of deflazacort (0.9 mg/kg/day). ### Geriatic Use - DMD is largely a disease of children and young adults; therefore, there is no geriatric experience with deflazacort. ### Gender There is no FDA guidance on the use of Deflazacort with respect to specific gender populations. ### Race There is no FDA guidance on the use of Deflazacort with respect to specific racial populations. ### Renal Impairment - No dose adjustment is required in patients with mild, moderate or severe renal impairment ### Hepatic Impairment - No dose adjustment is required in patients with mild or moderate hepatic impairment. There is no clinical experience in patients with severe hepatic impairment, and a dosing recommendation can not be provided for patients with severe hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Deflazacort in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Deflazacort in patients who are immunocompromised. # Administration and Monitoring ### Administration - Deflazacort Tablets and Oral Suspension can be taken with or without food. Deflazacort Tablets - Deflazacort Tablets can be administered whole or crushed and taken immediately after mixing with applesauce. Deflazacort Oral Suspension - Shake deflazacort Oral Suspension well before administration. - Use only the oral dispenser provided with the product. After withdrawing the appropriate dose into the oral dispenser, slowly add the deflazacort Oral Suspension into 3 to 4 ounces of juice or milk and mix well. The dose should then be administered immediately. Do not administer deflazacort with grapefruit juice. - Discard any unused deflazacort Oral Suspension remaining after 1 month of first opening the bottle. - Dosage of deflazacort must be decreased gradually if the drug has been administered for more than a few days. ### Monitoring - Improvement in signs and symptoms of Duchenne muscular dystrophy indicates efficacy. - Blood glucose: Regularly during treatment and for hyperglycemia after treatment withdrawal. - Serum potassium levels. - Cushing syndrome and adrenal insufficiency: After treatment withdrawal. - Development of infection. - Blood pressure and signs and symptoms of volume overload. - Bone mineral density testing, in patients on long-term treatment. - Intraocular pressure, in patients on treatment for more than 6 weeks. # IV Compatibility There is limited information regarding the compatibility of Deflazacort and IV administrations. # Overdosage - Treatment of acute overdosage is by immediate gastric lavage or emesis followed by supportive and symptomatic therapy. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage of deflazacort may be reduced temporarily, or alternate day treatment may be introduced. # Pharmacology ## Mechanism of Action - Deflazacort is a corticosteroid prodrug, whose active metabolite, 21-desDFZ, acts through the glucocorticoid receptor to exert anti-inflammatory and immunosuppressive effects. The precise mechanism by which deflazacort exerts its therapeutic effects in patients with DMD is unknown. ## Structure ## Pharmacodynamics There is limited information regarding Deflazacort Pharmacodynamics in the drug label. ## Pharmacokinetics - After oral administration in the fasted state, the median Tmax with deflazacort tablets or suspension is about 1 hour (range 0.25 to 2 hours). Food Effect - Co-administration of deflazacort tablets with a high-fat meal reduced Cmax by about 30% and delayed Tmax by one hour, relative to administration under fasting conditions, but there was no effect on the overall systemic absorption as measured by AUC. The bioavailability of deflazacort tablets was similar to that of the oral suspension. The administration of deflazacort with food or crushed in applesauce did not affect the absorption and bioavailability of deflazacort. - The protein binding of the active metabolite of deflazacort is about 40%. Metabolism - Deflazacort is rapidly converted to the active metabolite 21-desDFZ by esterases after oral administration. 21-desDFZ is further metabolized by CYP3A4 to several other inactive metabolites. Excretion - Urinary excretion is the predominant route of deflazacort elimination (about 68% of the dose), and the elimination is almost completed by 24 hours post dose. 21-desDFZ accounts for 18% of the eliminated drug in the urine. Pediatric Patients - The Cmax values (Geometric mean, %CV) of 21-desDFZ in children (ages 5-11, N=16) and adolescents (ages 12-16, N=8) was 206 ng/mL (95.6%) and 381 ng/mL (37.7%), respectively, on Day 1 after administration of 0.9 mg/kg deflazacort. The AUCinf (Geometric mean, %CV) of 21-desDFZ in children (ages 5-11, N=16) and adolescents (ages 12-16, N=8) was 400 ngh/mL (87.5%) and 655 ngh/mL (58.1%) on Day 1 after administration of 0.9 mg/kg deflazacort. Male and Female Patients - There are no differences in the pharmacokinetics of 21-desDFZ between males and females. Racial or Ethnic Groups - There are no differences in the pharmacokinetics of 21-desDFZ between Caucasians and non-Caucasians. Patients with Renal Impairment - In a study (N=16) comparing subjects with end stage renal disease (creatinine clearance less than 15 mL/min) with healthy matched controls, 21-desDFZ exposure was similar between the groups. Patients with Hepatic Impairment - In a study (N=16) comparing subjects with moderate hepatic impairment (Child-Pugh Class B) with healthy matched controls, 21-desDFZ exposure was similar between the groups. There is no experience in patients with severe hepatic impairment. In Vivo Assessment of Drug Interactions - Compared to administration of deflazacort alone, administration of deflazacort following multiple doses of a strong CYP3A4 and Pgp inhibitor (clarithromycin) resulted in markedly higher Cmax, AUClast, and AUCinf values of 21-desDFZ. Geometric mean exposure (Cmax, AUClast, and AUCinf) of 21-desDFZ ranged from 2.3-fold to 3.4-fold higher following administration of clarithromycin. - Compared to administration of deflazacort alone, administration of deflazacort following multiple doses of a strong CYP3A4 inducer (rifampicin) resulted in markedly lower Cmax, AUClast,and AUCinf values of 21-desDFZ. Geometric mean exposures (Cmax, AUClast, and AUCinf) of 21-desDFZ were approximately 95% lower following administration of rifampin. In Vitro Assessment of Drug Interactions - 21-desDFZ at concentrations up to 100 μM did not inhibit CYP1A2, 2C9, 2C19, 3A4, UGT1A1, UGT1A4, UGT1A6, UGT1A9, or UGT2B7 and exhibited weak and not likely clinically meaningful inhibition for 2B6, 2C8, 2D6, and 3A4, UGT1A3 and UGT2B15. - Deflazacort at concentrations up to 10 μM caused no significant induction response for CYP1A2, 2B6, or 3A4. - Both deflazacort and 21-desDFZ are substrates of Pgp. 21-desDFZ is not a substrate for BCRP. Neither deflazacort nor 21-desDFZ inhibited Pgp or BCRP in vitro. 21-desDFZ was not a substrate for SLC transporters OATP1B1 or OATP1B3, and did not inhibit SLC transporters OATP1B1, OATP1B3, OAT1, OAT3, or OCT2. ## Nonclinical Toxicology - In a published 2-year carcinogenicity study in rats, oral administration of deflazacort (0, 0.03, 0.06, 0.12, 0.25, 0.50, or 1.0 mg/kg/day) resulted in bone tumors (osteosarcoma and osteoma) of the head at 0.25 mg/kg/day, the highest evaluable dose. Doses higher than 0.25 mg/kg/day could not be evaluated for tumors because of a marked decrease in survival. - Deflazacort and 21-desDFZ were negative in in vitro (bacterial reverse mutation and human lymphocyte chromosomal aberration) assays and deflazacort was negative in an in vivo (rat micronucleus) assay. - Fertility studies in animals were not conducted with deflazacort. No effects on the male reproductive system were observed following oral administration of deflazacort to monkeys (0, 1.0, 3.0, or 6.0 mg/kg/day) for 39 weeks or rats (0, 0.05, 0.15, or 0.5 mg/kg/day) for 26 weeks. Plasma 21-desDFZ exposures (AUC) at the highest doses tested in monkey and rat were 4 and 2 times, respectively, that in humans at the recommended human dose of deflazacort (0.9 mg/kg/day). # Clinical Studies - The effectiveness of deflazacort for the treatment of DMD was established in Study 1, a multicenter, randomized, double-blind, placebo-controlled, 52-week study conducted in the US and Canada. The study population consisted of 196 male pediatric patients 5 to 15 years of age with documented mutation of the dystrophin gene, onset of weakness before 5 years of age, and serum creatinine kinase activity at least 10 times the upper limit of normal (ULN) at some stage in their illness. Patients were randomized to therapy with deflazacort (0.9 or 1.2 mg/kg/day), an active comparator, or placebo. A comparison to placebo was made after 12 weeks of treatment. After 12 weeks, placebo patients were re-randomized to receive either deflazacort or the active comparator; all patients continued treatment for an additional 40 weeks. Baseline characteristics were comparable between the treatment arms. - In Study 1, efficacy was evaluated by assessing the change between Baseline and Week 12 in average strength of 18 muscle groups. Individual muscle strength was graded using a modified Medical Research Council (MRC) 11-point scale, with higher scores representing greater strength. - The change in average muscle strength score between Baseline and Week 12 was significantly greater for the deflazacort 0.9 mg/kg/day dose group than for the placebo group (see TABLE 2). - Compared with the deflazacort 0.9 mg/kg/day group, the deflazacort 1.2 mg/kg/day group demonstrated a small additional benefit compared to placebo at Week 12, but had a greater incidence of adverse reactions. Therefore, use of a 1.2 mg/kg/day dosage of deflazacort is not recommended. - Although not a pre-specified statistical analysis, compared with placebo, the deflazacort 0.9 mg/kg/day dose group demonstrated at Week 52 the persistence of the treatment effect observed at Week 12 and the small advantage of the 1.2 mg/kg/day dose that was observed at Week 12 was no longer present. Also not statistically controlled for multiple comparisons, results on several timed measures of patient function (i.e., time to stand from supine, time to climb 4 stairs, and time to walk or run 30 feet) numerically favored deflazacort 0.9 mg/kg/day at Week 12, in comparison with placebo. - An additional randomized, double-blind, placebo-controlled, 104-week clinical trial evaluated deflazacort in comparison to placebo (Study 2). The study population consisted of 29 male children 6 to 12 years of age with a DMD diagnosis confirmed by the documented presence of abnormal dystrophin or a confirmed mutation of the dystrophin gene. The results of the analysis of the primary endpoint of average muscle strength scores in Study 2 (graded on a 0-5 scale) at 2 years were not statistically significant, possibly because of a limited number of patients remaining in the placebo arm (subjects were discontinued from the trial when they lost ambulation). Although not statistically controlled for multiple comparisons, average muscle strength scores at Months 6 and 12, as well as the average time to loss of ambulation, numerically favored deflazacort in comparison with placebo. # How Supplied - 6 mg are white, round with “6” debossed on one side. They are supplied as follows: NDC 52856-501-01 Bottle of 100 tablets - 18 mg are white, round with “18” debossed on one side. They are supplied as follows: NDC 52856-502-03 Bottle of 30 tablets - 30 mg are white, oval with “30” debossed on one side. They are supplied as follows: NDC 52856-503-03 Bottle of 30 tablets - 36 mg are white, oval with “36” debossed on one side. They are supplied as follows: NDC 52856-504-03 Bottle of 30 tablets - 22.75 mg/mL is a whitish colored suspension. Supplied as 13 mL in a 20 mL bottle packaged with two 1 mL oral dispensers. NDC 52856-505-21 ## Storage - Store at 20°C to 25°C (68°F to 77°F). Excursion permitted between 15°C to 30°C (59°F to 86°F). - Discard any unused deflazacort Oral Suspension remaining after 1 month of first opening the bottle. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise the patients and/or caregivers to read the FDA-approved patient labeling if deflazacort Oral Suspension is prescribed. - Warn patients and/or caregivers to not stop taking deflazacort abruptly or without first checking with their healthcare providers as there may be a need for gradual dose reduction to decrease the risk of adrenal insufficiency. - Deflazacort may be taken with or without food. Tablets - Deflazacort Tablets may be taken whole or crushed and taken immediately after mixing with applesauce. Oral Suspension - Deflazacort Oral Suspension must be shaken well prior to measuring out each dose with the enclosed oral dispenser. - The deflazacort Oral Suspension dose may be placed in 3-4 ounces of juice or milk, mixed thoroughly, and immediately administered. Do not take with grapefruit juice. - Discard any unused deflazacort Oral Suspension remaining after 1 month of first opening the bottle. - Tell patients and/or caregivers to inform their healthcare provider if the patient has had recent or ongoing infections or if they have recently received a vaccine. Medical advice should be sought immediately if the patient develops fever or other signs of infection. Patients and/or caregivers should be made aware that some infections can potentially be severe and fatal. - Warn patients who are on corticosteroids to avoid exposure to chickenpox or measles and to alert their healthcare provider immediately if they are exposed. - Inform patients and/or caregivers that deflazacort can cause an increase in blood pressure and water retention. If this occurs, dietary salt restriction and potassium supplementation may be needed. - Advise patients and/or caregivers about the potential for severe behavioral and mood changes with deflazacort and encourage them to seek medical attention if psychiatric symptoms develop. - Advise patients and/or caregivers about the risk of osteoporosis with prolonged use of deflazacort, which can predispose the patient to vertebral and long bone fractures. - Inform patients and/or caregivers that deflazacort may cause cataracts or glaucoma and advise monitoring if corticosteroid therapy is continued for more than 6 weeks. - Advise patients and/or caregivers that the administration of live or live attenuated vaccines are not recommended. Inform them that killed or inactivated vaccines may be administered, but the responses cannot be predicted. - Instruct patients and/or caregivers to seek medical attention at the first sign of a rash. - Certain medications can cause an interaction with deflazacort. Advise patients and/or caregivers to inform their healthcare provider of all the medicines the patient is taking, including over-the-counter medicines (such as insulin, aspirin or other NSAIDS), dietary supplements, and herbal products. Inform patients and/or caregivers that alternate therapy, dosage adjustment, and/or special test(s) may be needed during the treatment. # Precautions with Alcohol Alcohol-Deflazacort interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names - Emflaza # Look-Alike Drug Names There is limited information regarding Deflazacort Look-Alike Drug Names in the drug label. # Drug Shortage Status Drug Shortage # Price	Deflazacort Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sonya Gelfand, Anmol Pitliya, M.B.B.S. 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 Deflazacort is a corticosteroid that is FDA approved for the treatment of Duchenne muscular dystrophy (DMD) in patients 5 years of age and older. Common adverse reactions include cushingoid appearance, weight increased, increased appetite, upper respiratory tract infection, cough, pollakiuria, hirsutism, central obesity, and nasopharyngitis. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Deflazacort is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients 5 years of age and older. - The recommended oral dosage of deflazacort is approximately 0.9 mg/kg/day once daily. If tablets are used, round up to the nearest possible dose. Any combination of the four deflazacort tablet strengths can be used to achieve this dose. If the oral suspension is used, round up to the nearest tenth of a milliliter (mL). CYP3A4 Inhibitors - Give one third of the recommended dosage when deflazacort is administered with moderate or strong CYP3A4 inhibitors. For example, a 36 mg per day dose would be reduced to a 12 mg per day dose when used with moderate or strong CYP3A4 inhibitors. CYP3A4 Inducers - Avoid use with moderate or strong CYP3A4 inducers with deflazacort. - Tablets - 6 mg: White and round with “6” debossed on one side - 18 mg: White and round with “18” debossed on one side - 30 mg: White and oval with “30” debossed on one side - 36 mg: White and oval with “36” debossed on one side - Oral Suspension - 22.75 mg/mL: Whitish suspension ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding deflazacort Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding deflazacort Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Deflazacort is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients 5 years of age and older. - The recommended oral dosage of deflazacort is approximately 0.9 mg/kg/day once daily. If tablets are used, round up to the nearest possible dose. Any combination of the four deflazacort tablet strengths can be used to achieve this dose. If the oral suspension is used, round up to the nearest tenth of a milliliter (mL). CYP3A4 Inhibitors - Give one third of the recommended dosage when deflazacort is administered with moderate or strong CYP3A4 inhibitors. For example, a 36 mg per day dose would be reduced to a 12 mg per day dose when used with moderate or strong CYP3A4 inhibitors. CYP3A4 Inducers - Avoid use with moderate or strong CYP3A4 inducers with deflazacort. - Tablets - 6 mg: White and round with “6” debossed on one side - 18 mg: White and round with “18” debossed on one side - 30 mg: White and oval with “30” debossed on one side - 36 mg: White and oval with “36” debossed on one side - Oral Suspension - 22.75 mg/mL: Whitish suspension ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding deflazacort Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding deflazacort Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications - Deflazacort is contraindicated in patients with known hypersensitivity to deflazacort or to any of the inactive ingredients. Instances of hypersensitivity, including anaphylaxis, have occurred in patients receiving corticosteroid therapy # Warnings ## Alterations in Endocrine Function - Corticosteroids, such as deflazacort, can cause serious and life-threatening alterations in endocrine function, especially with chronic use. Monitor patients receiving deflazacort for Cushing’s syndrome, hyperglycemia, and adrenal insufficiency after deflazacort withdrawal. In addition, patients with hypopituitarism, primary adrenal insufficiency or congenital adrenal hyperplasia, altered thyroid function, or pheochromocytoma may be at increased risk for adverse endocrine events. ### Risk of Adrenal Insufficiency Following Corticosteroid Withdrawal - Corticosteroids produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, with the potential for the development of secondary adrenal insufficiency after withdrawal of corticosteroid treatment. Acute adrenal insufficiency can occur if corticosteroids are withdrawn abruptly, and can be fatal. The degree and duration of adrenocortical insufficiency produced is variable among patients and depends on the dose, frequency, and duration of corticosteroid therapy. The risk is reduced by gradually tapering the corticosteroid dose when withdrawing treatment. This insufficiency may persist, however, for months after discontinuation of prolonged therapy; therefore, in any situation of stress occurring during that period of discontinuation, corticosteroid therapy should be reinstituted. For patients already taking corticosteroids during times of stress, the dosage may need to be increased. - A steroid “withdrawal syndrome”, seemingly unrelated to adrenocortical insufficiency, may also occur following abrupt discontinuance of corticosteroids. This syndrome includes symptoms such as anorexia, nausea, vomiting, lethargy, headache, fever, joint pain, desquamation, myalgia, and/or weight loss. These effects are thought to be due to the sudden change in corticosteroid concentration rather than to low corticosteroid levels. ### Cushing’s Syndrome - Cushing’s syndrome (hypercortisolism) occurs with prolonged exposure to exogenous corticosteroids, including deflazacort. Symptoms include hypertension, truncal obesity and thinning of the limbs, purple striae, facial rounding, facial plethora, muscle weakness, easy and frequent bruising with thin fragile skin, posterior neck fat deposition, osteopenia, acne, amenorrhea, hirsutism and psychiatric abnormalities. ### Hyperglycemia - Corticosteroids can increase blood glucose, worsen pre-existing diabetes, predispose those on long-term therapy to diabetes mellitus, and may reduce the effect of anti-diabetic drugs. Monitor blood glucose at regular intervals. For patients with hyperglycemia, anti-diabetic treatment should be initiated or adjusted accordingly. ### Considerations for Use in Patients with Altered Thyroid Function - Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients. Changes in thyroid status of the patient may necessitate a dose adjustment of the corticosteroid. When concomitant administration of corticosteroids and levothyroxine is required, administration of corticosteroid should precede the initiation of levothyroxine therapy to reduce the risk of adrenal crisis. ### Pheochromocytoma crisis - There have been reports of pheochromocytoma crisis, which can be fatal, after administration of systemic corticosteroids. In patients with suspected or identified pheochromocytoma, consider the risk of pheochromocytoma crisis prior to administering corticosteroids. ## Immunosuppression and Increased Risk of Infection - Corticosteroids, including deflazacort, suppress the immune system and increase the risk of infection with any pathogen, including viral, bacterial, fungal, protozoan, or helminthic. Corticosteroids reduce resistance to new infections, exacerbate existing infections, increase the risk of disseminated infections, increase the risk of reactivation or exacerbation of latent infections, and mask some signs of infection. These infections can be severe, and at times fatal. The degree to which the dose, route, and duration of corticosteroid administration correlates with the specific risks of infection is not well characterized; however, the rate of occurrence of infectious complications increases with increasing doses of corticosteroids. - Monitor for the development of infection and consider withdrawal of corticosteroids or reduction of the dose of corticosteroids as needed. ### Varicella Zoster and Measles Viral Infections - Chickenpox caused by Varicella Zoster virus and measles can have a serious or even fatal course in non-immune children or adults on corticosteroids, including deflazacort. In children or adults who have not had these diseases, particular care should be taken to avoid exposure. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with immunoglobulin (IG) may be indicated. If chickenpox develops, treatment with antiviral agents may be considered. ### Hepatitis B Virus Reactivation - Hepatitis B virus reactivation can occur in patients who are hepatitis B carriers undergoing treatment with immunosuppressive drugs including corticosteroids. Reactivation can also occur in patients who appear to have resolved hepatitis B infection. ### Fungal Infections - Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections. For patients on corticosteroids who develop systemic fungal infections, withdrawal of corticosteroids or reduction of the dose of corticosteroids is recommended. ### Amebiasis - Corticosteroids may activate latent amebiasis. Therefore, it is recommended that latent amebiasis or active amebiasis be ruled out before initiating corticosteroid therapy in any patient who has spent time in the tropics, or any patient with unexplained diarrhea. ### Strongyloides Infestation - In patients with known or suspected Strongyloides (threadworm) infestation, corticosteroid-induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia. For patients on corticosteroids who develop known or suspected Strongyloides (threadworm) infestation, withdrawal of corticosteroids or reduction of the dose of corticosteroids is recommended. ## Alterations in Cardiovascular/Renal Function - Corticosteroids, including deflazacort, can cause elevation of blood pressure, salt, and water retention, and increased excretion of potassium and calcium. Monitor blood pressure and assess for signs and symptoms of volume overload. Monitor serum potassium levels. Dietary salt restriction and potassium supplementation may be necessary. deflazacort should be used with caution in patients with congestive heart failure, hypertension, or renal insufficiency. - Literature reports suggest an association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with deflazacort should be used with great caution in these patients. ## Gastrointestinal Perforation - There is an increased risk of gastrointestinal perforation during corticosteroid use in patients with certain gastrointestinal disorders such as active or latent peptic ulcers, diverticulitis, fresh intestinal anastomoses, and non-specific ulcerative colitis. Signs of gastrointestinal perforation, such as peritoneal irritation, may be masked in patients receiving corticosteroids. - Avoid corticosteroids if there is a probability of impending perforation, abscess, or other pyogenic infections; diverticulitis; fresh intestinal anastomoses; or active or latent peptic ulcer. ## Behavioral and Mood Disturbances - Potentially severe psychiatric adverse reactions may occur with systemic corticosteroids, including deflazacort. Symptoms typically emerge within a few days or weeks of starting treatment and may be dose-related. These reactions may improve after either dose reduction or withdrawal, although pharmacologic treatment may be necessary. Psychiatric adverse reactions usually involve hypomanic or manic symptoms (e.g., euphoria, insomnia, mood swings) during treatment and depressive episodes after discontinuation of treatment. Inform patients or caregivers of the potential for behavioral and mood changes and encourage them to seek medical attention if psychiatric symptoms develop, especially if depressed mood or suicidal ideation is suspected. ## Effects on Bones ### Decreased Bone Mineral Density - Corticosteroids, including deflazacort, decrease bone formation and increase bone resorption both through their effect on calcium regulation (i.e., decreasing absorption and increasing excretion) and inhibition of osteoblast function. This, together with a decrease in the protein matrix of the bone secondary to an increase in protein catabolism and reduced sex hormone production, may lead to inhibition of bone growth in pediatric patients and the development of bone loss at any age. Bone loss can predispose patients to vertebral and long bone fractures. Consider a patient’s risk of osteoporosis before initiating corticosteroid therapy. Monitor bone mineral density in patients on long-term treatment with deflazacort. ### Avascular Necrosis - Corticosteroids, including deflazacort, may cause avascular necrosis. ## Ophthalmic Effects - Use of corticosteroids, including deflazacort, may produce posterior subcapsular cataracts. Corticosteroids may also cause glaucoma with possible damage to the optic nerves, and may increase the risk of secondary ocular infections caused by bacteria, fungi, or viruses. Corticosteroids are not recommended for patients with active ocular herpes simplex. - Intraocular pressure may become elevated in some patients taking corticosteroids. If treatment with deflazacort is continued for more than 6 weeks, monitor intraocular pressure. ## Vaccination - Administration of live or live attenuated vaccines is not recommended in patients receiving immunosuppressive doses of corticosteroids, including deflazacort. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. - Killed or inactivated vaccines may be administered during corticosteroid therapy; however, the response to such vaccines cannot be predicted. - Patients on corticosteroid therapy, including deflazacort, may exhibit a diminished response to toxoids and live or inactivated vaccines because of inhibition of antibody response. ## Serious Skin Rashes - Toxic epidermal necrolysis has been reported with the use of deflazacort with symptoms beginning within 8 weeks of starting treatment. Discontinue at the first sign of rash, unless the rash is clearly not drug related. ## Effects on Growth and Development - Long-term use of corticosteroids, including deflazacort, can have negative effects on growth and development in children. ## Myopathy - Patients receiving corticosteroids, including deflazacort, and concomitant therapy with neuromuscular blocking agents (e.g., pancuronium) or patients with disorders of neuromuscular transmission (e.g., myasthenia gravis) may be at increased risk of developing acute myopathy. This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years. ## Kaposi’s Sarcoma - Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement. ## Risk of Serious Adverse Reactions in Infants because of Benzyl Alcohol Preservative - Deflazacort Oral Suspension contains benzyl alcohol and is not approved for use in pediatric patients less than 5 years of age. Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low birth weight infants treated with benzyl alcohol-preserved drugs. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known (Deflazacort Oral Suspension contains 10.45 mg of benzyl alcohol per mL; deflazacort Tablets do not contain benzyl alcohol). ## Thromboembolic Events - Observational studies have shown an increased risk of thromboembolism (including venous thromboembolism) particularly with higher cumulative doses of corticosteroids. It is unclear if risk differs by daily dose or duration of use. Use deflazacort with caution in patients who have or may be predisposed to thromboembolic disorders. ## Anaphylaxis - Rare instances of anaphylaxis have occurred in patients receiving corticosteroid therapy, including deflazacort. # 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 Study 1, the adverse reactions that were associated with deflazacort treatment discontinuation, in decreasing order of frequency, were weight increased, obesity, cataract, and sleep disorder. ## Most Common Adverse Reactions in Clinical Studies - TABLE 1 lists the adverse reactions that occurred in ≥ 5% of patients in the 0.9 mg/kg/day deflazacort-treated group and that occurred more frequently than in placebo patients in Study 1, which included patients with DMD between the ages of 5 and 15 years. - Common adverse reactions (≥ 5% of deflazacort-treated patients) that occurred over 52 weeks of exposure to deflazacort 0.9 mg/kg/day in Study 1 and at a higher rate than deflazacort 0.9 mg/kg/day in the 12-week placebo-controlled phase of the trial include Cushingoid appearance (60%), hirsutism (35%), weight increased (28%), erythema (28%), central obesity (25%), abdominal pain/abdominal pain upper (18% combined), pollakiuria (15%), constipation (10%), irritability (10%), abnormal behavior (9%), pyrexia (9%), back pain (7%), rash (7%), contusion (6%), nausea (6%), psychomotor hyperactivity (6%), epistaxis (6%), and skin striae (6%). - Study 1 also evaluated a higher dosage of deflazacort (1.2 mg/kg/day). Compared with the 0.9 mg/kg/day dosage, deflazacort 1.2 mg/kg/day over 52 weeks was associated with a higher incidence of certain adverse reactions, including Cushingoid appearance (69%), erythema (49%), hirsutism (37%), headache (34%), weight increased (32%), constipation (15%), abdominal pain upper (14%), skin striae (11%), acne (11%), and abdominal discomfort (8%). As there was no additional benefit with the 1.2 mg/kg/day dose of deflazacort, use of deflazacort 1.2 mg/kg/day is not recommended for the treatment of DMD. - In an additional clinical study of two years duration with extended follow-up (Study 2), many of the same adverse reactions were observed. In addition, musculoskeletal events associated with long-term steroid use were also observed, including muscle weakness, tendon disorder, and osteopenia. ## Less Common Adverse Reactions Observed in Clinical Studies - Other adverse reactions (≥ 1% frequency in any deflazacort treatment group and greater than placebo) that were observed during the 12-week placebo-controlled phase of Study 1 are shown below. - Eye Disorders: Lacrimation increased - Gastrointestinal Disorders: Dyspepsia, nausea, gastrointestinal disorder - General Disorders and Administration Site Conditions: Thirst - Infections: Hordeolum, impetigo, influenza, otitis externa, pharyngitis, tooth abscess, urinary tract infection, viral infection - Injury, Poisoning and Procedural Complications: Back injury, contusion, face injury, fibula fracture, greenstick fracture, heat exhaustion - Investigations: Glucose urine present, heart rate irregular - Musculoskeletal and Connective Tissue Disorders: Back pain, muscle spasms, myalgia, neck mass, neck pain, pain in extremity - Nervous System Disorders: Dizziness, psychomotor hyperactivity - Psychiatric Disorders: Affect lability, aggression, depression, emotional disorder, middle insomnia, mood altered, mood swings, sleep disorder - Renal and Urinary Disorders: Chromaturia, dysuria, hypertonic bladder - Reproductive System and Breast Disorders: Testicular pain - Respiratory, Thoracic, and Mediastinal Disorders: Hypoventilation, rhinorrhea - Skin and Subcutaneous Tissue Disorders: Acne, alopecia, dermatitis acneiform - Vascular Disorders: Hot flush ## Postmarketing Experience - The following adverse reactions have been reported during post-approval use of deflazacort worldwide or during post-approval use of other corticosteroids. These reactions are reported voluntarily from a population of uncertain size; therefore, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure. - Blood and Lymphatic System Disorders: Leukocytosis - Cardiac Disorder: Heart failure - Eye Disorders: Chorioretinopathy, corneal or scleral thinning - Gastrointestinal Disorders: Acute pancreatitis (especially in children), hemorrhage, peptic ulceration, perforation of peptic ulcer - General Disorders and Administration Site Conditions: Edema, impaired healing - Immune System Disorders: Hypersensitivity including anaphylaxis - Metabolism and Nutrition Disorders: Impaired carbohydrate tolerance with increased requirement for anti-diabetic therapy, negative protein and calcium balance, potassium loss and hypokalemic alkalosis when co-administered with beta 2-agonist and xanthines - Musculoskeletal and Connective Tissue Disorders: Avascular necrosis, muscle wasting, negative nitrogen balance, tendonitis and tendon rupture when co-administered with quinolones, vertebral and long bone fractures - Nervous System Disorders: Aggravation of epilepsy, increased intra-cranial pressure with papilledema in children (pseudotumor cerebri) usually after treatment withdrawal, vertigo - Psychiatric Disorders: Anxiety, cognitive dysfunction including confusion and amnesia, delusions, hallucinations, mania, suicidal thoughts - Skin and Subcutaneous Tissue Disorders: Toxic epidermal necrolysis - Vascular Disorders: Thromboembolism, in particular in patients with underlying conditions associated with increased thrombotic tendency, benign intracranial hypertension # Drug Interactions - CYP3A4 Inhibitors and Inducers - Neuromuscular Blockers Moderate or Strong CYP3A4 Inhibitors: - The active metabolite of deflazacort, 21-desDFZ, is a substrate of CYP3A4. Co-administration of deflazacort with clarithromycin, a strong CYP3A4 inhibitor, increased total exposure to 21-desDFZ by about 3-fold. Therefore, give one third the recommended dosage of deflazacort when moderate or strong CYP3A4 inhibitors (e.g., clarithromycin, fluconazole, diltiazem, verapamil, grapefruit juice) are used concomitantly with deflazacort. Moderate or Strong CYP3A4 Inducers: - Co-administration of deflazacort with rifampin, a strong CYP3A4 inducer, significantly decreased the exposure of 21-desDFZ. Avoid concomitant use of strong (e.g., efavirenz) or moderate (e.g., carbamazepine, phenytoin) CYP3A4 inducers with deflazacort. - Patients receiving corticosteroids, including deflazacort, and concomitant therapy with neuromuscular blocking drugs (e.g., pancuronium) may be at increased risk of developing an acute myopathy. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Infants born to mothers who have received substantial doses of corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism. There are no adequate and well-controlled studies with deflazacort in pregnant women to inform drug-associated risks. - Corticosteroids, including deflazacort, readily cross the placenta. Adverse developmental outcomes, including orofacial clefts (cleft lip, with or without cleft palate) and intrauterine growth restriction, and decreased birth weight, have been reported with maternal use of corticosteroids, including deflazacort, during pregnancy. Some epidemiologic studies report an increased risk of orofacial clefts from about 1 per 1000 infants to 3 to 5 per 1000 infants; however, a risk for orofacial clefts has not been observed in all studies. Intrauterine growth restriction and decreased birth weight appear to be dose-related; however, the underlying maternal condition may also contribute to these risks. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. - Animal reproduction studies have not been conducted with deflazacort. Animal reproduction studies conducted with other corticosteroids in pregnant mice, rats, hamsters, and rabbits using clinically relevant doses have shown an increased incidence of cleft palate. An increase in embryofetal death, intrauterine growth retardation, and constriction of the ductus arteriosus were observed in some animal species. - Multiple cohort and case-controlled studies in humans suggest that maternal corticosteroid use during the first trimester increases the rate of cleft lip, with or without cleft palate, from about 1/1000 infants to 3-5/1000 infants. Two prospective case-controlled studies showed decreased birth weight in infants exposed to maternal corticosteroids in utero. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Deflazacort in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Deflazacort during labor and delivery. ### Nursing Mothers - Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for deflazacort and any potential adverse effects on the breastfed infant from deflazacort. There are no data on the effects on milk production. ### Pediatric Use - The safety and effectiveness of deflazacort for the treatment of DMD have been established in patients 5 years of age and older. Use of deflazacort in pediatric patients is supported by a multicenter, randomized, double-blind, placebo- and active-controlled study in 196 males. - Safety and effectiveness of deflazacort have not been established in pediatric patients less than 5 years of age. - Deflazacort Oral Suspension contains benzyl alcohol and is not approved for use in pediatric patients less than 5 years of age. Serious adverse reactions including fatal reactions and “gasping syndrome” occurred in premature neonates and low birth weight infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known (Deflazacort Oral Suspension contains 10.45 mg of benzyl alcohol per mL; deflazacort Tablets do not contain benzyl alcohol) - Oral administration of deflazacort (0, 0.1, 0.3, and 1.0 mg/kg/day) to juvenile rats from postnatal day (PND) 21 to 80 resulted in decreased body weight gain and adverse effects on skeletal development (including decreased cellularity of growth plate and altered bone distribution) and on lymphoid tissue (decreased cellularity). A no-effect dose was not identified. In addition, neurological and neurobehavioral abnormalities were observed at the mid and/or high dose. Plasma 21-desDFZ exposure (AUC) at the lowest dose tested (0.1 mg/kg/day) was lower than that in humans at the recommended human dose of deflazacort (0.9 mg/kg/day). ### Geriatic Use - DMD is largely a disease of children and young adults; therefore, there is no geriatric experience with deflazacort. ### Gender There is no FDA guidance on the use of Deflazacort with respect to specific gender populations. ### Race There is no FDA guidance on the use of Deflazacort with respect to specific racial populations. ### Renal Impairment - No dose adjustment is required in patients with mild, moderate or severe renal impairment ### Hepatic Impairment - No dose adjustment is required in patients with mild or moderate hepatic impairment. There is no clinical experience in patients with severe hepatic impairment, and a dosing recommendation can not be provided for patients with severe hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Deflazacort in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Deflazacort in patients who are immunocompromised. # Administration and Monitoring ### Administration - Deflazacort Tablets and Oral Suspension can be taken with or without food. Deflazacort Tablets - Deflazacort Tablets can be administered whole or crushed and taken immediately after mixing with applesauce. Deflazacort Oral Suspension - Shake deflazacort Oral Suspension well before administration. - Use only the oral dispenser provided with the product. After withdrawing the appropriate dose into the oral dispenser, slowly add the deflazacort Oral Suspension into 3 to 4 ounces of juice or milk and mix well. The dose should then be administered immediately. Do not administer deflazacort with grapefruit juice. - Discard any unused deflazacort Oral Suspension remaining after 1 month of first opening the bottle. - Dosage of deflazacort must be decreased gradually if the drug has been administered for more than a few days. ### Monitoring - Improvement in signs and symptoms of Duchenne muscular dystrophy indicates efficacy. - Blood glucose: Regularly during treatment and for hyperglycemia after treatment withdrawal. - Serum potassium levels. - Cushing syndrome and adrenal insufficiency: After treatment withdrawal. - Development of infection. - Blood pressure and signs and symptoms of volume overload. - Bone mineral density testing, in patients on long-term treatment. - Intraocular pressure, in patients on treatment for more than 6 weeks. # IV Compatibility There is limited information regarding the compatibility of Deflazacort and IV administrations. # Overdosage - Treatment of acute overdosage is by immediate gastric lavage or emesis followed by supportive and symptomatic therapy. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage of deflazacort may be reduced temporarily, or alternate day treatment may be introduced. # Pharmacology ## Mechanism of Action - Deflazacort is a corticosteroid prodrug, whose active metabolite, 21-desDFZ, acts through the glucocorticoid receptor to exert anti-inflammatory and immunosuppressive effects. The precise mechanism by which deflazacort exerts its therapeutic effects in patients with DMD is unknown. ## Structure ## Pharmacodynamics There is limited information regarding Deflazacort Pharmacodynamics in the drug label. ## Pharmacokinetics - After oral administration in the fasted state, the median Tmax with deflazacort tablets or suspension is about 1 hour (range 0.25 to 2 hours). Food Effect - Co-administration of deflazacort tablets with a high-fat meal reduced Cmax by about 30% and delayed Tmax by one hour, relative to administration under fasting conditions, but there was no effect on the overall systemic absorption as measured by AUC. The bioavailability of deflazacort tablets was similar to that of the oral suspension. The administration of deflazacort with food or crushed in applesauce did not affect the absorption and bioavailability of deflazacort. - The protein binding of the active metabolite of deflazacort is about 40%. Metabolism - Deflazacort is rapidly converted to the active metabolite 21-desDFZ by esterases after oral administration. 21-desDFZ is further metabolized by CYP3A4 to several other inactive metabolites. Excretion - Urinary excretion is the predominant route of deflazacort elimination (about 68% of the dose), and the elimination is almost completed by 24 hours post dose. 21-desDFZ accounts for 18% of the eliminated drug in the urine. Pediatric Patients - The Cmax values (Geometric mean, %CV) of 21-desDFZ in children (ages 5-11, N=16) and adolescents (ages 12-16, N=8) was 206 ng/mL (95.6%) and 381 ng/mL (37.7%), respectively, on Day 1 after administration of 0.9 mg/kg deflazacort. The AUCinf (Geometric mean, %CV) of 21-desDFZ in children (ages 5-11, N=16) and adolescents (ages 12-16, N=8) was 400 ng•h/mL (87.5%) and 655 ng•h/mL (58.1%) on Day 1 after administration of 0.9 mg/kg deflazacort. Male and Female Patients - There are no differences in the pharmacokinetics of 21-desDFZ between males and females. Racial or Ethnic Groups - There are no differences in the pharmacokinetics of 21-desDFZ between Caucasians and non-Caucasians. Patients with Renal Impairment - In a study (N=16) comparing subjects with end stage renal disease (creatinine clearance less than 15 mL/min) with healthy matched controls, 21-desDFZ exposure was similar between the groups. Patients with Hepatic Impairment - In a study (N=16) comparing subjects with moderate hepatic impairment (Child-Pugh Class B) with healthy matched controls, 21-desDFZ exposure was similar between the groups. There is no experience in patients with severe hepatic impairment. In Vivo Assessment of Drug Interactions - Compared to administration of deflazacort alone, administration of deflazacort following multiple doses of a strong CYP3A4 and Pgp inhibitor (clarithromycin) resulted in markedly higher Cmax, AUClast, and AUCinf values of 21-desDFZ. Geometric mean exposure (Cmax, AUClast, and AUCinf) of 21-desDFZ ranged from 2.3-fold to 3.4-fold higher following administration of clarithromycin. - Compared to administration of deflazacort alone, administration of deflazacort following multiple doses of a strong CYP3A4 inducer (rifampicin) resulted in markedly lower Cmax, AUClast,and AUCinf values of 21-desDFZ. Geometric mean exposures (Cmax, AUClast, and AUCinf) of 21-desDFZ were approximately 95% lower following administration of rifampin. In Vitro Assessment of Drug Interactions - 21-desDFZ at concentrations up to 100 μM did not inhibit CYP1A2, 2C9, 2C19, 3A4, UGT1A1, UGT1A4, UGT1A6, UGT1A9, or UGT2B7 and exhibited weak and not likely clinically meaningful inhibition for 2B6, 2C8, 2D6, and 3A4, UGT1A3 and UGT2B15. - Deflazacort at concentrations up to 10 μM caused no significant induction response for CYP1A2, 2B6, or 3A4. - Both deflazacort and 21-desDFZ are substrates of Pgp. 21-desDFZ is not a substrate for BCRP. Neither deflazacort nor 21-desDFZ inhibited Pgp or BCRP in vitro. 21-desDFZ was not a substrate for SLC transporters OATP1B1 or OATP1B3, and did not inhibit SLC transporters OATP1B1, OATP1B3, OAT1, OAT3, or OCT2. ## Nonclinical Toxicology - In a published 2-year carcinogenicity study in rats, oral administration of deflazacort (0, 0.03, 0.06, 0.12, 0.25, 0.50, or 1.0 mg/kg/day) resulted in bone tumors (osteosarcoma and osteoma) of the head at 0.25 mg/kg/day, the highest evaluable dose. Doses higher than 0.25 mg/kg/day could not be evaluated for tumors because of a marked decrease in survival. - Deflazacort and 21-desDFZ were negative in in vitro (bacterial reverse mutation and human lymphocyte chromosomal aberration) assays and deflazacort was negative in an in vivo (rat micronucleus) assay. - Fertility studies in animals were not conducted with deflazacort. No effects on the male reproductive system were observed following oral administration of deflazacort to monkeys (0, 1.0, 3.0, or 6.0 mg/kg/day) for 39 weeks or rats (0, 0.05, 0.15, or 0.5 mg/kg/day) for 26 weeks. Plasma 21-desDFZ exposures (AUC) at the highest doses tested in monkey and rat were 4 and 2 times, respectively, that in humans at the recommended human dose of deflazacort (0.9 mg/kg/day). # Clinical Studies - The effectiveness of deflazacort for the treatment of DMD was established in Study 1, a multicenter, randomized, double-blind, placebo-controlled, 52-week study conducted in the US and Canada. The study population consisted of 196 male pediatric patients 5 to 15 years of age with documented mutation of the dystrophin gene, onset of weakness before 5 years of age, and serum creatinine kinase activity at least 10 times the upper limit of normal (ULN) at some stage in their illness. Patients were randomized to therapy with deflazacort (0.9 or 1.2 mg/kg/day), an active comparator, or placebo. A comparison to placebo was made after 12 weeks of treatment. After 12 weeks, placebo patients were re-randomized to receive either deflazacort or the active comparator; all patients continued treatment for an additional 40 weeks. Baseline characteristics were comparable between the treatment arms. - In Study 1, efficacy was evaluated by assessing the change between Baseline and Week 12 in average strength of 18 muscle groups. Individual muscle strength was graded using a modified Medical Research Council (MRC) 11-point scale, with higher scores representing greater strength. - The change in average muscle strength score between Baseline and Week 12 was significantly greater for the deflazacort 0.9 mg/kg/day dose group than for the placebo group (see TABLE 2). - Compared with the deflazacort 0.9 mg/kg/day group, the deflazacort 1.2 mg/kg/day group demonstrated a small additional benefit compared to placebo at Week 12, but had a greater incidence of adverse reactions. Therefore, use of a 1.2 mg/kg/day dosage of deflazacort is not recommended. - Although not a pre-specified statistical analysis, compared with placebo, the deflazacort 0.9 mg/kg/day dose group demonstrated at Week 52 the persistence of the treatment effect observed at Week 12 and the small advantage of the 1.2 mg/kg/day dose that was observed at Week 12 was no longer present. Also not statistically controlled for multiple comparisons, results on several timed measures of patient function (i.e., time to stand from supine, time to climb 4 stairs, and time to walk or run 30 feet) numerically favored deflazacort 0.9 mg/kg/day at Week 12, in comparison with placebo. - An additional randomized, double-blind, placebo-controlled, 104-week clinical trial evaluated deflazacort in comparison to placebo (Study 2). The study population consisted of 29 male children 6 to 12 years of age with a DMD diagnosis confirmed by the documented presence of abnormal dystrophin or a confirmed mutation of the dystrophin gene. The results of the analysis of the primary endpoint of average muscle strength scores in Study 2 (graded on a 0-5 scale) at 2 years were not statistically significant, possibly because of a limited number of patients remaining in the placebo arm (subjects were discontinued from the trial when they lost ambulation). Although not statistically controlled for multiple comparisons, average muscle strength scores at Months 6 and 12, as well as the average time to loss of ambulation, numerically favored deflazacort in comparison with placebo. # How Supplied - 6 mg are white, round with “6” debossed on one side. They are supplied as follows: NDC 52856-501-01 Bottle of 100 tablets - 18 mg are white, round with “18” debossed on one side. They are supplied as follows: NDC 52856-502-03 Bottle of 30 tablets - 30 mg are white, oval with “30” debossed on one side. They are supplied as follows: NDC 52856-503-03 Bottle of 30 tablets - 36 mg are white, oval with “36” debossed on one side. They are supplied as follows: NDC 52856-504-03 Bottle of 30 tablets - 22.75 mg/mL is a whitish colored suspension. Supplied as 13 mL in a 20 mL bottle packaged with two 1 mL oral dispensers. NDC 52856-505-21 ## Storage - Store at 20°C to 25°C (68°F to 77°F). Excursion permitted between 15°C to 30°C (59°F to 86°F). - Discard any unused deflazacort Oral Suspension remaining after 1 month of first opening the bottle. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise the patients and/or caregivers to read the FDA-approved patient labeling if deflazacort Oral Suspension is prescribed. - Warn patients and/or caregivers to not stop taking deflazacort abruptly or without first checking with their healthcare providers as there may be a need for gradual dose reduction to decrease the risk of adrenal insufficiency. - Deflazacort may be taken with or without food. Tablets - Deflazacort Tablets may be taken whole or crushed and taken immediately after mixing with applesauce. Oral Suspension - Deflazacort Oral Suspension must be shaken well prior to measuring out each dose with the enclosed oral dispenser. - The deflazacort Oral Suspension dose may be placed in 3-4 ounces of juice or milk, mixed thoroughly, and immediately administered. Do not take with grapefruit juice. - Discard any unused deflazacort Oral Suspension remaining after 1 month of first opening the bottle. - Tell patients and/or caregivers to inform their healthcare provider if the patient has had recent or ongoing infections or if they have recently received a vaccine. Medical advice should be sought immediately if the patient develops fever or other signs of infection. Patients and/or caregivers should be made aware that some infections can potentially be severe and fatal. - Warn patients who are on corticosteroids to avoid exposure to chickenpox or measles and to alert their healthcare provider immediately if they are exposed. - Inform patients and/or caregivers that deflazacort can cause an increase in blood pressure and water retention. If this occurs, dietary salt restriction and potassium supplementation may be needed. - Advise patients and/or caregivers about the potential for severe behavioral and mood changes with deflazacort and encourage them to seek medical attention if psychiatric symptoms develop. - Advise patients and/or caregivers about the risk of osteoporosis with prolonged use of deflazacort, which can predispose the patient to vertebral and long bone fractures. - Inform patients and/or caregivers that deflazacort may cause cataracts or glaucoma and advise monitoring if corticosteroid therapy is continued for more than 6 weeks. - Advise patients and/or caregivers that the administration of live or live attenuated vaccines are not recommended. Inform them that killed or inactivated vaccines may be administered, but the responses cannot be predicted. - Instruct patients and/or caregivers to seek medical attention at the first sign of a rash. - Certain medications can cause an interaction with deflazacort. Advise patients and/or caregivers to inform their healthcare provider of all the medicines the patient is taking, including over-the-counter medicines (such as insulin, aspirin or other NSAIDS), dietary supplements, and herbal products. Inform patients and/or caregivers that alternate therapy, dosage adjustment, and/or special test(s) may be needed during the treatment. # Precautions with Alcohol Alcohol-Deflazacort interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names - Emflaza # Look-Alike Drug Names There is limited information regarding Deflazacort Look-Alike Drug Names in the drug label. # Drug Shortage Status Drug Shortage # Price	https://www.wikidoc.org/index.php/Deflazacort
123710820435843cfaff50d01c40138693cda7f4	wikidoc	Delavirdine	Delavirdine # 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 Delavirdine is an antiretroviral agent that is FDA approved for the treatment of HIV infection. Common adverse reactions include rash, nausea, asthenia, headache, and fatigue. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - RESCRIPTOR Tablets are indicated for the treatment of HIV-1 infection in combination with at least 2 other active antiretroviral agents when therapy is warranted. - The following should be considered before initiating therapy with RESCRIPTOR in treatment-naive patients. There are insufficient data directly comparing antiretroviral regimens containing RESCRIPTOR with currently preferred 3-drug regimens for initial treatment of HIV. In studies comparing regimens consisting of 2 nucleoside reverse transcriptase inhibitors (NRTIs) (currently considered suboptimal) to RESCRIPTOR plus 2 NRTIs, the proportion of patients receiving the regimen containing RESCRIPTOR who achieved and sustained an HIV-1 RNA level <400 copies/mL over 1 year of therapy was relatively low. - Resistant virus emerges rapidly when RESCRIPTOR is administered as monotherapy. Therefore, RESCRIPTOR should always be administered in combination with other antiretroviral agents. - The recommended dosage for RESCRIPTOR Tablets is 400 mg (four 100-mg or two 200-mg tablets) 3 times daily. RESCRIPTOR should be used in combination with other antiretroviral therapy. The complete prescribing information for other antiretroviral agents should be consulted for information on dosage and administration. - The 100-mg RESCRIPTOR Tablets may be dispersed in water prior to consumption. To prepare a dispersion, add four 100-mg RESCRIPTOR Tablets to at least 3 ounces of water, allow to stand for a few minutes, and then stir until a uniform dispersion occurs. The dispersion should be consumed promptly. The glass should be rinsed with water and the rinse swallowed to insure the entire dose is consumed. The 200-mg tablets should be taken as intact tablets, because they are not readily dispersed in water. Note: The 200-mg tablets are approximately one-third smaller in size than the 100-mg tablets. - RESCRIPTOR Tablets may be administered with or without food. Patients with achlorhydria should take RESCRIPTOR with an acidic beverage (e.g., orange or cranberry juice). However, the effect of an acidic beverage on the absorption of delavirdine in patients with achlorhydria has not been investigated. - Patients taking both RESCRIPTOR and antacids should be advised to take them at least 1 hour apart. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Delavirdine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Delavirdine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Safety and effectiveness of delavirdine in combination with other antiretroviral agents have not been established in HIV-1–infected individuals younger than 16 years of age. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Delavirdine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Delavirdine in pediatric patients. # Contraindications - RESCRIPTOR Tablets are contraindicated in patients with known hypersensitivity to any of its ingredients. Coadministration of RESCRIPTOR is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These drugs are listed in Table 5. # Warnings - ALERT: Find out about medicines that should NOT be taken with RESCRIPTOR. This statement is included on the product’s bottle label. - Drug Interactions - Because delavirdine may inhibit the metabolism of many different drugs (e.g., antiarrhythmics, calcium channel blockers, sedative hypnotics, and others), serious and/or life-threatening drug interactions could result from inappropriate coadministration of some drugs with delavirdine. In addition, some drugs may markedly reduce delavirdine plasma concentrations, resulting in suboptimal antiviral activity and subsequent emergence of drug resistance. All prescribers should become familiar with the following tables in this package insert: Table 5, Drugs That Are Contraindicated With RESCRIPTOR;Table 6, Drugs That Should Not Be Coadministered With RESCRIPTOR;and Table 7, Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction. - Concomitant use of lovastatin or simvastatin with RESCRIPTOR is not recommended. Caution should be exercised if RESCRIPTOR is used concurrently with other HMG-CoA reductase inhibitors that are also metabolized by the CYP3A4 pathway (e.g., atorvastatin or cerivastatin). The risk of myopathy including rhabdomyolysis may be increased when RESCRIPTOR is used in combination with these drugs. - Particular caution should be used when prescribing sildenafil in patients receiving RESCRIPTOR. Coadministration of sildenafil with RESCRIPTOR is expected to substantially increase sildenafil concentrations and may result in an increase in sildenafil-associated adverse events, including hypotension, visual changes, and priapism (see PRECAUTIONS: Drug Interactions and Information for Patients, and the complete prescribing information for sildenafil). - Concomitant use of St. John’s wort (Hypericum perforatum) or St. John’s wort-containing products and RESCRIPTOR is not recommended. Coadministration of St. John’s wort with NNRTIs, including RESCRIPTOR, is expected to substantially decrease NNRTI concentrations and may result in suboptimal levels of RESCRIPTOR and lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of NNRTIs. ### Precautions - General - Delavirdine is metabolized primarily by the liver. Therefore, caution should be exercised when administering RESCRIPTOR Tablets to patients with impaired hepatic function. - Immune Reconstitution Syndrome - Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including RESCRIPTOR. During the initial phase of the combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia , or tuberculosis), which may necessitate further evaluation and treatment. - Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment. - Resistance/Cross-Resistance - NNRTIs, when used alone or in combination, may confer cross-resistance to other NNRTIs. - 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. - Skin Rash - Severe rash, including rare cases of erythema multiforme and Stevens-Johnson syndrome, has been reported in patients receiving RESCRIPTOR. Erythema multiforme and Stevens-Johnson syndrome were rarely seen in clinical trials and resolved after withdrawal of RESCRIPTOR. Any patient experiencing severe rash or rash accompanied by symptoms such as fever, blistering, oral lesions, conjunctivitis, swelling, and muscle or joint aches should discontinue RESCRIPTOR and consult a physician. Two cases of Stevens-Johnson syndrome have been reported through postmarketing surveillance out of a total of 339 surveillance reports. - In Studies 21 Part II and 13C, rash (including maculopapular rash) was reported in more patients who were treated with RESCRIPTOR 400 mg 3 times daily (35% and 32%, respectively) than in those who were not treated with RESCRIPTOR (21% and 16%, respectively). The highest intensity of rash reported in these studies was severe (Grade 3), which was observed in approximately 4% of patients treated with RESCRIPTOR in each study and in none of the patients who were not treated with RESCRIPTOR. Also in Studies 21 Part II and 13C, discontinuations due to rash were reported in more patients who received RESCRIPTOR 400 mg 3 times daily (3% and 4%, respectively) than in those who did not receive RESCRIPTOR (0% and 1%, respectively). - In most cases, the duration of the rash was less than 2 weeks and did not require dose reduction or discontinuation of RESCRIPTOR. Most patients were able to resume therapy after rechallenge with RESCRIPTOR following a treatment interruption due to rash. The distribution of the rash was mainly on the upper body and proximal arms, with decreasing intensity of the lesions on the neck and face, and progressively less on the rest of the trunk and limbs. - Occurrence of a delavirdine-associated rash after 1 month is uncommon. Symptomatic relief has been obtained using diphenhydramine hydrochloride, hydroxyzine hydrochloride, and/or topical corticosteroids. # Adverse Reactions ## Clinical Trials Experience - The safety of RESCRIPTOR Tablets alone and in combination with other therapies has been studied in approximately 6,000 patients receiving RESCRIPTOR. The majority of adverse events were of mild or moderate (i.e., ACTG Grade 1 or 2) intensity. The most frequently reported drug-related adverse event (i.e., events considered by the investigator to be related to the blinded study medication or events with an unknown or missing causal relationship to the blinded medication) among patients receiving RESCRIPTOR was skin rash. - Adverse events of moderate to severe intensity reported by at least 5% of evaluable patients in any treatment group in the pivotal trials, which includes patients receiving RESCRIPTOR in combination with zidovudine and/or lamivudine in Study 21 Part II for up to 98 weeks and in combination with zidovudine and either lamivudine, didanosine, or zalcitabine in Study 13C for up to 72 weeks are summarized in Table 9. - Other Adverse Events in Phase II/III Studies - Other adverse events that occurred in patients receiving RESCRIPTOR (in combination treatment) in all Phase II and III studies, considered possibly related to treatment, and of at least ACTG Grade 2 in intensity are listed below by body system. Abdominal cramps, abdominal distention, abdominal pain (localized), abscess, allergic reaction, chills, edema (generalized or localized), epidermal cyst, fever, infection, infection viral, lip edema, malaise, Mycobacterium tuberculosis infection, neck rigidity, sebaceous cyst, and redistribution/accumulation of body fat. Abnormal cardiac rate and rhythm, cardiac insufficiency, cardiomyopathy, hypertension, migraine, pallor, peripheral vascular disorder, and postural hypotension. Anorexia, bloody stool, colitis, constipation, decreased appetite, diarrhea (Clostridium difficile), diverticulitis, dry mouth, dyspepsia, dysphagia, enteritis at all levels, eructation, fecal incontinence, flatulence, gagging, gastroenteritis, gastroesophageal reflux, gastrointestinal bleeding, gastrointestinal disorder, gingivitis, gum hemorrhage, hepatomegaly, increased appetite, increased saliva, increased thirst, jaundice, mouth or tongue inflammation or ulcers, nonspecific hepatitis, oral/enteric moniliasis, pancreatitis, rectal disorder, sialadenitis, tooth abscess, and toothache. Adenopathy, bruising, eosinophilia, granulocytosis, leukopenia, pancytopenia, purpura, spleen disorder, thrombocytopenia, and prolonged prothrombin time. Alcohol intolerance, amylase increased, bilirubinemia, hyperglycemia, hyperkalemia, hypertriglyceridemia, hyperuricemia, hypocalcemia, hyponatremia, hypophosphatemia, increased AST (SGOT), increased gamma glutamyl transpeptidase, increased lipase, increased serum alkaline phosphatase, increased serum creatinine, and weight increase or decrease. Arthralgia or arthritis of single and multiple joints, bone disorder, bone pain, myalgia, tendon disorder, tenosynovitis, tetany, and vertigo. Abnormal coordination, agitation, amnesia, change in dreams, cognitive impairment, confusion, decreased libido, disorientation, dizziness, emotional lability, euphoria, hallucination, hyperesthesia, hyperreflexia, hypertonia, hypesthesia, impaired concentration, manic symptoms, muscle cramp, nervousness, neuropathy, nystagmus, paralysis, paranoid symptoms, restlessness, sleep cycle disorder, somnolence, tingling, tremor, vertigo, and weakness. Chest congestion, dyspnea, epistaxis, hiccups, laryngismus, pneumonia, and rhinitis. Angioedema, dermal leukocytoclastic vasculitis, dermatitis, desquamation, diaphoresis, discolored skin, dry skin, erythema, erythema multiforme, folliculitis, fungal dermatitis, hair loss, herpes zoster or simplex, nail disorder, petechiae, non-application site pruritus, seborrhea, skin hypertrophy, skin disorder, skin nodule, Stevens-Johnson syndrome, urticaria, vesiculobullous rash, and wart. Blepharitis, blurred vision, conjunctivitis, diplopia, dry eyes, ear pain, parosmia, otitis media, photophobia, taste perversion, and tinnitus. Amenorrhea, breast enlargement, calculi of the kidney, chromaturia, epididymitis, hematuria, hemospermia, impaired urination, impotence, kidney pain, metrorrhagia, nocturia, polyuria, proteinuria, testicular pain, urinary tract infection, and vaginal moniliasis. ## Postmarketing Experience - Adverse event terms reported from postmarketing surveillance that were not reported in the Phase II and III trials are presented below. Hepatic failure. Hemolytic anemia. Rhabdomyolysis. Acute kidney failure. # Drug Interactions - Delavirdine is an inhibitor of CYP3A isoform and other CYP isoforms to a lesser extent including CYP2C9, CYP2D6, and CYP2C19. Coadministration of RESCRIPTOR and drugs primarily metabolized by CYP3A (e.g., HMG-CoA reductase inhibitors and sildenafil) may result in increased plasma concentrations of the coadministered drug that could increase or prolong both its therapeutic or adverse effects. - Delavirdine is metabolized primarily by CYP3A, but in vitro data suggest that delavirdine may also be metabolized by CYP2D6. Coadministration of RESCRIPTOR and drugs that induce CYP3A, such as rifampin, may decrease delavirdine plasma concentrations and reduce its therapeutic effect. Coadministration of RESCRIPTOR and drugs that inhibit CYP3A may increase delavirdine plasma concentrations. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Delavirdine has been shown to be teratogenic in rats. Delavirdine caused ventricular septal defects in rats at doses of 50, 100, and 200 mg/kg/day when administered during the period of organogenesis. The lowest dose of delavirdine that caused malformations produced systemic exposures in pregnant rats equal to or lower than the expected human exposure to RESCRIPTOR (Cmin 15 μM) at the recommended dose. Exposure in rats approximately 5-fold higher than the expected human exposure resulted in marked maternal toxicity, embryotoxicity, fetal developmental delay, and reduced pup survival. Additionally, reduced pup survival on postpartum day 0 occurred at an exposure (mean Cmin) approximately equal to the expected human exposure. Delavirdine was excreted in the milk of lactating rats at a concentration 3 to 5 times that of rat plasma. - Delavirdine at doses of 200 and 400 mg/kg/day administered during the period of organogenesis caused maternal toxicity, embryotoxicity, and abortions in rabbits. The lowest dose of delavirdine that resulted in these toxic effects produced systemic exposures in pregnant rabbits approximately 6-fold higher than the expected human exposure to RESCRIPTOR (Cmin 15 μM) at the recommended dose. The no-observed-adverse-effect dose in the pregnant rabbit was 100 mg/kg/day. Various malformations were observed at this dose, but the incidence of such malformations was not statistically significantly different from that observed in the control group. Systemic exposures in pregnant rabbits at a dose of 100 mg/kg/day were lower than those expected in humans at the recommended clinical dose. Malformations were not apparent at 200 and 400 mg/kg/day; however, only a limited number of fetuses were available for examination as a result of maternal and embryo death. - No adequate and well-controlled studies in pregnant women have been conducted. RESCRIPTOR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Of 9 pregnancies reported in premarketing clinical studies and postmarketing experience, a total of 10 infants were born (including 1 set of twins). Eight of the infants were born healthy. One infant was born HIV-positive but was otherwise healthy and with no congenital abnormalities detected, and 1 infant was born prematurely (34 to 35 weeks) with a small muscular ventricular septal defect that spontaneously resolved. The patient received approximately 6 weeks of treatment with delavirdine and zidovudine early in the course of the pregnancy. - Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to RESCRIPTOR and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling (800) 258-4263. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Delavirdine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Delavirdine during labor and delivery. ### Nursing Mothers - The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Because of both the potential for HIV transmission and any possible adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving RESCRIPTOR. ### Pediatric Use - Safety and effectiveness of delavirdine in combination with other antiretroviral agents have not been established in HIV-1–infected individuals younger than 16 years of age. ### Geriatic Use - Clinical studies of RESCRIPTOR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be taken when dosing RESCRIPTOR in elderly patients due to 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 Delavirdine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Delavirdine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Delavirdine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Delavirdine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Delavirdine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Delavirdine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Delavirdine in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Delavirdine in the drug label. # Overdosage ## Acute Overdose - Human experience of acute overdose with RESCRIPTOR is limited. - Treatment of overdosage with RESCRIPTOR should consist of general supportive measures, including monitoring of vital signs and observation of the patient’s clinical status. There is no specific antidote for overdosage with RESCRIPTOR. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage. Since delavirdine is extensively metabolized by the liver and is highly protein-bound, dialysis is unlikely to result in significant removal of the drug. ## Chronic Overdose There is limited information regarding Chronic Overdose of Delavirdine in the drug label. # Pharmacology ## Mechanism of Action - Delavirdine is an NNRTI of HIV-1. Delavirdine binds directly to reverse transcriptase (RT) and blocks RNA-dependent and DNA-dependent DNA polymerase activities. Delavirdine does not compete with template:primer or deoxynucleoside triphosphates. HIV-2 RT and human cellular DNA polymerases α, γ, or δ are not inhibited by delavirdine. In addition, HIV-1 group O, a group of highly divergent strains that are uncommon in North America, may not be inhibited by delavirdine. ## Structure - RESCRIPTOR Tablets contain delavirdine mesylate, a synthetic non-nucleoside reverse transcriptase inhibitor (NNRTI) of the human immunodeficiency virus type 1 (HIV-1). The chemical name of delavirdine mesylate is piperazine, 1--2- pyridinyl]-4--1H-indol-2-yl]carbonyl]-, monomethanesulfonate. Its molecular formula is C22H28N6O3SCH4O3S, and its molecular weight is 552.68. The structural formula is:delavirdine chemical structure - Delavirdine mesylate is an odorless white-to-tan crystalline powder. The aqueous solubility of delavirdine free base at 23°C is 2,942 mcg/mL at pH 1.0, 295 mcg/mL at pH 2.0, and 0.81 mcg/mL at pH 7.4. - Each RESCRIPTOR Tablet, for oral administration, contains 100 or 200 mg of delavirdine mesylate (henceforth referred to as delavirdine). Inactive ingredients consist of carnauba wax, colloidal silicon dioxide, croscarmellose sodium, lactose, magnesium stearate, and microcrystalline cellulose. In addition, the 100-mg tablet contains Opadry White YS-1-7000-E and the 200-mg tablet contains hypromellose and Opadry White YS-1-18202-A. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Delavirdine in the drug label. ## Pharmacokinetics - Absorption and Bioavailability: Delavirdine is rapidly absorbed following oral administration, with peak plasma concentrations occurring at approximately 1 hour. Following administration of delavirdine 400 mg 3 times daily (n = 67, HIV-1–infected patients), the mean ±SD steady-state peak plasma concentration (Cmax) was 35 ± 20 μM (range: 2 to 100 μM), systemic exposure (AUC) was 180 ± 100 μMhr (range: 5 to 515 μMhr), and trough concentration (Cmin) was 15 ± 10 μM (range: 0.1 to 45 μM). The single-dose bioavailability of delavirdine tablets relative to an oral solution was 85% ± 25% (n = 16, non-HIV–infected subjects). The single-dose bioavailability of delavirdine tablets (100-mg strength) was increased by approximately 20% when a slurry of drug was prepared by allowing delavirdine tablets to disintegrate in water before administration (n = 16, non-HIV–infected subjects). The bioavailability of the 200-mg strength delavirdine tablets has not been evaluated when administered as a slurry because they are not readily dispersed in water. - Delavirdine may be administered with or without food. In a multiple-dose, crossover study, delavirdine was administered every 8 hours with food or every 8 hours, 1 hour before or 2 hours after a meal (n = 13, HIV-1–infected patients). Patients remained on their typical diet throughout the study; meal content was not standardized. When multiple doses of delavirdine were administered with food, geometric mean Cmax was reduced by approximately 25%, but AUC and Cmin were not altered. - Distribution: Delavirdine is extensively bound (approximately 98%) to plasma proteins, primarily albumin. The percentage of delavirdine that is protein-bound is constant over a delavirdine concentration range of 0.5 to 196 μM. In 5 HIV-1–infected patients whose total daily dose of delavirdine ranged from 600 to 1,200 mg, cerebrospinal fluid concentrations of delavirdine averaged 0.4% ± 0.07% of the corresponding plasma delavirdine concentrations; this represents about 20% of the fraction not bound to plasma proteins. Steady-state delavirdine concentrations in saliva (n = 5, HIV-1–infected patients who received delavirdine 400 mg 3 times daily) and semen (n = 5 healthy volunteers who received delavirdine 300 mg 3 times daily) were about 6% and 2%, respectively, of the corresponding plasma delavirdine concentrations collected at the end of a dosing interval. - Metabolism and Elimination: Delavirdine is extensively converted to several inactive metabolites. Delavirdine is primarily metabolized by cytochrome P450 3A (CYP3A), but in vitro data suggest that delavirdine may also be metabolized by CYP2D6. The major metabolic pathways for delavirdine are N-desalkylation and pyridine hydroxylation. Delavirdine exhibits nonlinear steady-state elimination pharmacokinetics, with apparent oral clearance decreasing by about 22-fold as the total daily dose of delavirdine increases from 60 to 1,200 mg/day. In a study of 14C-delavirdine in 6 healthy volunteers who received multiple doses of delavirdine tablets 300 mg 3 times daily, approximately 44% of the radiolabeled dose was recovered in feces, and approximately 51% of the dose was excreted in urine. Less than 5% of the dose was recovered unchanged in urine. The parent plasma half-life of delavirdine increases with dose; mean half-life following 400 mg 3 times daily is 5.8 hours, with a range of 2 to 11 hours. - In vitro and in vivo studies have shown that delavirdine reduces CYP3A activity and inhibits its own metabolism. In vitro studies have also shown that delavirdine reduces CYP2C9, CYP2D6, and CYP2C19 activity. Inhibition of hepatic CYP3A activity by delavirdine is reversible within 1 week after discontinuation of drug. - Special Populations - Hepatic or Renal Impairment: The pharmacokinetics of delavirdine in patients with hepatic or renal impairment have not been investigated. - Age: The pharmacokinetics of delavirdine have not been adequately studied in patients aged 65 years. - Gender: Data from population pharmacokinetics suggest that the plasma concentrations of delavirdine tend to be higher in females than in males. However, this difference is not considered to be clinically significant. - Race: No significant differences in the mean trough delavirdine concentrations were observed between different racial or ethnic groups. - Drug Interactions - Specific drug interaction studies were performed with delavirdine and a number of drugs. Table 1 summarizes the effects of delavirdine on the geometric mean AUC, Cmax, and Cmin of coadministered drugs. Table 2 shows the effects of coadministered drugs on the geometric mean AUC, Cmax, and Cmin of delavirdine. ## Nonclinical Toxicology - Delavirdine was negative in a battery of genetic toxicology tests which included an Ames assay, an in vitro rat hepatocyte unscheduled DNA synthesis assay, an in vitro chromosome aberration assay in human peripheral lymphocytes, an in vitro mutation assay in Chinese hamster ovary cells, and an in vivo micronucleus test in mice. - Lifetime carcinogenicity studies were conducted in rats at doses of 10, 32, and 100 mg/kg/day and in mice at doses of 62.5, 250, and 500 mg/kg/day for males and 62.5, 125, and 250 mg/kg/day for females. In rats, delavirdine was noncarcinogenic at maximally tolerated doses that produced exposures (AUC) up to 12 (male rats) and 9 (female rats) times human exposure at the recommended clinical dose. In mice, delavirdine produced significant increases in the incidence of hepatocellular adenoma/adenocarcinoma in both males and females, hepatocellular adenoma in females, and mesenchymal urinary bladder tumors in males. The systemic drug exposures (AUC) in female mice were 0.5- to 3-fold and in male mice 0.2- to 4-fold of those in humans at the recommended clinical dose. Given the lack of genotoxic activity of delavirdine, the relevance of urinary bladder and hepatocellular neoplasm in delavirdine-treated mice to humans is not known. - Delavirdine at doses of 20, 100, and 200 mg/kg/day did not cause impairment of fertility in rats when males were treated for 70 days and females were treated for 14 days prior to mating. # Clinical Studies - For clinical Studies 21 Part II and 13C described below, efficacy was evaluated by the percentage of patients with a plasma HIV-1 RNA level <400 copies/mL through Week 52 as measured by the Roche Amplicor® HIV-1 Monitor (standard assay). An intent-to-treat analysis was performed where only subjects who achieved confirmed suppression and sustained it through Week 52 are regarded as responders. All other subjects (including never suppressed, discontinued, and those who rebounded after initial suppression of <400 copies/mL) are considered failures at Week 52. Results of an interim analysis of efficacy conducted for studies 21 Part II and 13C by independent Data and Safety Monitoring Boards (DSMBs) revealed that the triple-therapy arms in both studies produced significantly greater antiviral benefit than the dual-therapy arms, and early termination of the studies was recommended. - Study 21 Part II - Study 21 Part II was a double‑blind, randomized, placebo‑controlled trial comparing treatment with RESCRIPTOR (400 mg 3 times daily, zidovudine 200 mg 3 times daily, and lamivudine 150 mg twice daily versus RESCRIPTOR 400 mg 3 times daily and zidovudine 200 mg 3 times daily versus zidovudine 200 mg 3 times daily and lamivudine 150 mg twice daily in 373 HIV-1–infected patients (mean age 35 years , 87% male, and 60% Caucasian) who were antiretroviral treatment naive (84%) or had limited nucleoside experience (16%). Mean baseline CD4+ cell count was 359 cells/mm3 and mean baseline plasma HIV‑1 RNA was 4.4 log10 copies/mL. - Results showed that the mean increases from baseline in CD4 cell counts at 52 weeks were 111 cells/mL for RESCRIPTOR + zidovudine + lamivudine, 27 cells/mL for RESCRIPTOR + zidovudine, and 74 cells/mL for zidovudine + lamivudine. - The results of the intent-to-treat analysis of the percentage of patients with a plasma HIV-1 RNA level <400 copies/mL are presented in Figure 1. HIV-1 RNA status and reasons for discontinuation of randomized treatment at 52 weeks are summarized in Table 3. Subjects who were never suppressed before discontinuation were placed in the discontinuation category. - Figure 1. Percentage of Patients With HIV-1 RNA Below 400 copies/mL Standard PCR Assay Protocol 21 Part II: Intent-to–Treat Analysis - Study 13C - Study 13C was a double‑blind, randomized, placebo‑controlled trial comparing treatment with RESCRIPTOR 400 mg 3 times daily, zidovudine 200 mg 3 times daily or 300 mg twice daily, and either didanosine 200 mg twice daily, zalcitabine 0.75 mg 3 times daily, or lamivudine 150 mg twice daily versus zidovudine 200 mg 3 times daily or 300 mg twice daily and either didanosine 200 mg twice daily, zalcitabine 0.75 mg 3 times daily, or lamivudine 150 mg twice daily in 345 HIV-1–infected patients (mean age 35.8 years , 66% male, and 63% Caucasian) who were antiretroviral treatment naive (63%) or had limited antiretroviral experience (37%). Mean baseline CD4+ cell count was 210 cells/mm3 and mean baseline plasma HIV‑1 RNA was 4.9 log10 copies/mL. - Results showed that the mean increases from baseline in CD4+ cell counts at 54 weeks were 102 cells/mL for RESCRIPTOR + zidovudine + didanosine or zalcitabine or lamivudine, and 56 cells/mL for zidovudine + didanosine or zalcitabine or lamivudine. - The results of the intent‑to‑treat analysis of the percentage of patients with a plasma HIV‑1 RNA level 400 copies/mL are presented in Figure 2. HIV‑1 RNA status and reasons for discontinuation of randomized treatment at 54 weeks are summarized in Table 4. Subjects who were never suppressed before discontinuation were placed in the discontinuation category. - Figure 2. Percentage of Patients With HIV-1 RNA Below 400 copies/mL Standard PCR Assay Protocol 13C: Intent-to–Treat Analysis # How Supplied - RESCRIPTOR Tablets are available as follows: - 100-mg: white, capsule-shaped tablets marked with “U 3761” - Bottles of 360 tablets - NDC 49702-209-24. - 200-mg: white, capsule-shaped tablets marked with “RES200” - Bottles of 180 tablets - NDC 49702-225-17. - Store at controlled room temperature 20° to 25°C (68° to 77°F). Keep container tightly closed. Protect from high humidity. ## Storage There is limited information regarding Delavirdine Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - A statement to patients and healthcare providers is included on the product’s bottle label: ALERT: Find out about medicines that should NOT be taken with RESCRIPTOR. A patient package insert (PPI) for RESCRIPTOR is available for patient information. - Patients should be informed that RESCRIPTOR is not a cure for HIV‑1 infection and that patients may continue to experience illnesses associated with HIV‑1 infection, including opportunistic infections. Patients should be advised to remain under the care of a physician while taking RESCRIPTOR. - Patients should be advised to avoid doing things that can spread HIV-1 infection to others. - Do not share needles or other injection equipment. - Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades. - Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood. - Do not breastfeed. We do not know if RESCRIPTOR 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. - Patients should be instructed that the major toxicity of RESCRIPTOR is rash and should be advised to promptly notify their physician should rash occur. The majority of rashes associated with RESCRIPTOR occur within 1 to 3 weeks after initiating treatment with RESCRIPTOR. The rash normally resolves in 3 to 14 days and may be treated symptomatically while therapy with RESCRIPTOR is continued. Any patient experiencing severe rash or rash accompanied by symptoms such as fever, blistering, oral lesions, conjunctivitis, swelling, and muscle or joint aches should discontinue medication and consult a physician. - Patients should be informed 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. - Patients should be informed to take RESCRIPTOR every day as prescribed. Patients should not alter the dose of RESCRIPTOR without consulting their doctor. If a dose is missed, patients should take the next dose as soon as possible. However, if a dose is skipped, the patient should not double the next dose. - Patients with achlorhydria should take RESCRIPTOR with an acidic beverage (e.g., orange or cranberry juice). However, the effect of an acidic beverage on the absorption of delavirdine in patients with achlorhydria has not been investigated. - Patients taking both RESCRIPTOR and antacids should be advised to take them at least 1 hour apart. - Because RESCRIPTOR may interact with certain drugs, patients should be advised to report to their doctor the use of any prescription, nonprescription medication, or herbal products, particularly St. John’s wort. - Patients receiving sildenafil and RESCRIPTOR should be advised that they may be at an increased risk of sildenafil‑associated adverse events, including hypotension, visual changes, and prolonged penile erection, and should promptly report any symptoms to their doctor. # Precautions with Alcohol - Alcohol-Delavirdine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - RESCRIPTOR® # Look-Alike Drug Names There is limited information regarding Delavirdine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Delavirdine 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 Delavirdine is an antiretroviral agent that is FDA approved for the treatment of HIV infection. Common adverse reactions include rash, nausea, asthenia, headache, and fatigue. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - RESCRIPTOR Tablets are indicated for the treatment of HIV-1 infection in combination with at least 2 other active antiretroviral agents when therapy is warranted. - The following should be considered before initiating therapy with RESCRIPTOR in treatment-naive patients. There are insufficient data directly comparing antiretroviral regimens containing RESCRIPTOR with currently preferred 3-drug regimens for initial treatment of HIV. In studies comparing regimens consisting of 2 nucleoside reverse transcriptase inhibitors (NRTIs) (currently considered suboptimal) to RESCRIPTOR plus 2 NRTIs, the proportion of patients receiving the regimen containing RESCRIPTOR who achieved and sustained an HIV-1 RNA level <400 copies/mL over 1 year of therapy was relatively low. - Resistant virus emerges rapidly when RESCRIPTOR is administered as monotherapy. Therefore, RESCRIPTOR should always be administered in combination with other antiretroviral agents. - The recommended dosage for RESCRIPTOR Tablets is 400 mg (four 100-mg or two 200-mg tablets) 3 times daily. RESCRIPTOR should be used in combination with other antiretroviral therapy. The complete prescribing information for other antiretroviral agents should be consulted for information on dosage and administration. - The 100-mg RESCRIPTOR Tablets may be dispersed in water prior to consumption. To prepare a dispersion, add four 100-mg RESCRIPTOR Tablets to at least 3 ounces of water, allow to stand for a few minutes, and then stir until a uniform dispersion occurs. The dispersion should be consumed promptly. The glass should be rinsed with water and the rinse swallowed to insure the entire dose is consumed. The 200-mg tablets should be taken as intact tablets, because they are not readily dispersed in water. Note: The 200-mg tablets are approximately one-third smaller in size than the 100-mg tablets. - RESCRIPTOR Tablets may be administered with or without food. Patients with achlorhydria should take RESCRIPTOR with an acidic beverage (e.g., orange or cranberry juice). However, the effect of an acidic beverage on the absorption of delavirdine in patients with achlorhydria has not been investigated. - Patients taking both RESCRIPTOR and antacids should be advised to take them at least 1 hour apart. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Delavirdine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Delavirdine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Safety and effectiveness of delavirdine in combination with other antiretroviral agents have not been established in HIV-1–infected individuals younger than 16 years of age. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Delavirdine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Delavirdine in pediatric patients. # Contraindications - RESCRIPTOR Tablets are contraindicated in patients with known hypersensitivity to any of its ingredients. Coadministration of RESCRIPTOR is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These drugs are listed in Table 5. # Warnings - ALERT: Find out about medicines that should NOT be taken with RESCRIPTOR. This statement is included on the product’s bottle label. - Drug Interactions - Because delavirdine may inhibit the metabolism of many different drugs (e.g., antiarrhythmics, calcium channel blockers, sedative hypnotics, and others), serious and/or life-threatening drug interactions could result from inappropriate coadministration of some drugs with delavirdine. In addition, some drugs may markedly reduce delavirdine plasma concentrations, resulting in suboptimal antiviral activity and subsequent emergence of drug resistance. All prescribers should become familiar with the following tables in this package insert: Table 5, Drugs That Are Contraindicated With RESCRIPTOR;Table 6, Drugs That Should Not Be Coadministered With RESCRIPTOR;and Table 7, Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction. - Concomitant use of lovastatin or simvastatin with RESCRIPTOR is not recommended. Caution should be exercised if RESCRIPTOR is used concurrently with other HMG-CoA reductase inhibitors that are also metabolized by the CYP3A4 pathway (e.g., atorvastatin or cerivastatin). The risk of myopathy including rhabdomyolysis may be increased when RESCRIPTOR is used in combination with these drugs. - Particular caution should be used when prescribing sildenafil in patients receiving RESCRIPTOR. Coadministration of sildenafil with RESCRIPTOR is expected to substantially increase sildenafil concentrations and may result in an increase in sildenafil-associated adverse events, including hypotension, visual changes, and priapism (see PRECAUTIONS: Drug Interactions and Information for Patients, and the complete prescribing information for sildenafil). - Concomitant use of St. John’s wort (Hypericum perforatum) or St. John’s wort-containing products and RESCRIPTOR is not recommended. Coadministration of St. John’s wort with NNRTIs, including RESCRIPTOR, is expected to substantially decrease NNRTI concentrations and may result in suboptimal levels of RESCRIPTOR and lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of NNRTIs. ### Precautions - General - Delavirdine is metabolized primarily by the liver. Therefore, caution should be exercised when administering RESCRIPTOR Tablets to patients with impaired hepatic function. - Immune Reconstitution Syndrome - Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including RESCRIPTOR. During the initial phase of the combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. - Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment. - Resistance/Cross-Resistance - NNRTIs, when used alone or in combination, may confer cross-resistance to other NNRTIs. - 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. - Skin Rash - Severe rash, including rare cases of erythema multiforme and Stevens-Johnson syndrome, has been reported in patients receiving RESCRIPTOR. Erythema multiforme and Stevens-Johnson syndrome were rarely seen in clinical trials and resolved after withdrawal of RESCRIPTOR. Any patient experiencing severe rash or rash accompanied by symptoms such as fever, blistering, oral lesions, conjunctivitis, swelling, and muscle or joint aches should discontinue RESCRIPTOR and consult a physician. Two cases of Stevens-Johnson syndrome have been reported through postmarketing surveillance out of a total of 339 surveillance reports. - In Studies 21 Part II and 13C, rash (including maculopapular rash) was reported in more patients who were treated with RESCRIPTOR 400 mg 3 times daily (35% and 32%, respectively) than in those who were not treated with RESCRIPTOR (21% and 16%, respectively). The highest intensity of rash reported in these studies was severe (Grade 3), which was observed in approximately 4% of patients treated with RESCRIPTOR in each study and in none of the patients who were not treated with RESCRIPTOR. Also in Studies 21 Part II and 13C, discontinuations due to rash were reported in more patients who received RESCRIPTOR 400 mg 3 times daily (3% and 4%, respectively) than in those who did not receive RESCRIPTOR (0% and 1%, respectively). - In most cases, the duration of the rash was less than 2 weeks and did not require dose reduction or discontinuation of RESCRIPTOR. Most patients were able to resume therapy after rechallenge with RESCRIPTOR following a treatment interruption due to rash. The distribution of the rash was mainly on the upper body and proximal arms, with decreasing intensity of the lesions on the neck and face, and progressively less on the rest of the trunk and limbs. - Occurrence of a delavirdine-associated rash after 1 month is uncommon. Symptomatic relief has been obtained using diphenhydramine hydrochloride, hydroxyzine hydrochloride, and/or topical corticosteroids. # Adverse Reactions ## Clinical Trials Experience - The safety of RESCRIPTOR Tablets alone and in combination with other therapies has been studied in approximately 6,000 patients receiving RESCRIPTOR. The majority of adverse events were of mild or moderate (i.e., ACTG Grade 1 or 2) intensity. The most frequently reported drug-related adverse event (i.e., events considered by the investigator to be related to the blinded study medication or events with an unknown or missing causal relationship to the blinded medication) among patients receiving RESCRIPTOR was skin rash. - Adverse events of moderate to severe intensity reported by at least 5% of evaluable patients in any treatment group in the pivotal trials, which includes patients receiving RESCRIPTOR in combination with zidovudine and/or lamivudine in Study 21 Part II for up to 98 weeks and in combination with zidovudine and either lamivudine, didanosine, or zalcitabine in Study 13C for up to 72 weeks are summarized in Table 9. - Other Adverse Events in Phase II/III Studies - Other adverse events that occurred in patients receiving RESCRIPTOR (in combination treatment) in all Phase II and III studies, considered possibly related to treatment, and of at least ACTG Grade 2 in intensity are listed below by body system. Abdominal cramps, abdominal distention, abdominal pain (localized), abscess, allergic reaction, chills, edema (generalized or localized), epidermal cyst, fever, infection, infection viral, lip edema, malaise, Mycobacterium tuberculosis infection, neck rigidity, sebaceous cyst, and redistribution/accumulation of body fat. Abnormal cardiac rate and rhythm, cardiac insufficiency, cardiomyopathy, hypertension, migraine, pallor, peripheral vascular disorder, and postural hypotension. Anorexia, bloody stool, colitis, constipation, decreased appetite, diarrhea (Clostridium difficile), diverticulitis, dry mouth, dyspepsia, dysphagia, enteritis at all levels, eructation, fecal incontinence, flatulence, gagging, gastroenteritis, gastroesophageal reflux, gastrointestinal bleeding, gastrointestinal disorder, gingivitis, gum hemorrhage, hepatomegaly, increased appetite, increased saliva, increased thirst, jaundice, mouth or tongue inflammation or ulcers, nonspecific hepatitis, oral/enteric moniliasis, pancreatitis, rectal disorder, sialadenitis, tooth abscess, and toothache. Adenopathy, bruising, eosinophilia, granulocytosis, leukopenia, pancytopenia, purpura, spleen disorder, thrombocytopenia, and prolonged prothrombin time. Alcohol intolerance, amylase increased, bilirubinemia, hyperglycemia, hyperkalemia, hypertriglyceridemia, hyperuricemia, hypocalcemia, hyponatremia, hypophosphatemia, increased AST (SGOT), increased gamma glutamyl transpeptidase, increased lipase, increased serum alkaline phosphatase, increased serum creatinine, and weight increase or decrease. Arthralgia or arthritis of single and multiple joints, bone disorder, bone pain, myalgia, tendon disorder, tenosynovitis, tetany, and vertigo. Abnormal coordination, agitation, amnesia, change in dreams, cognitive impairment, confusion, decreased libido, disorientation, dizziness, emotional lability, euphoria, hallucination, hyperesthesia, hyperreflexia, hypertonia, hypesthesia, impaired concentration, manic symptoms, muscle cramp, nervousness, neuropathy, nystagmus, paralysis, paranoid symptoms, restlessness, sleep cycle disorder, somnolence, tingling, tremor, vertigo, and weakness. Chest congestion, dyspnea, epistaxis, hiccups, laryngismus, pneumonia, and rhinitis. Angioedema, dermal leukocytoclastic vasculitis, dermatitis, desquamation, diaphoresis, discolored skin, dry skin, erythema, erythema multiforme, folliculitis, fungal dermatitis, hair loss, herpes zoster or simplex, nail disorder, petechiae, non-application site pruritus, seborrhea, skin hypertrophy, skin disorder, skin nodule, Stevens-Johnson syndrome, urticaria, vesiculobullous rash, and wart. Blepharitis, blurred vision, conjunctivitis, diplopia, dry eyes, ear pain, parosmia, otitis media, photophobia, taste perversion, and tinnitus. Amenorrhea, breast enlargement, calculi of the kidney, chromaturia, epididymitis, hematuria, hemospermia, impaired urination, impotence, kidney pain, metrorrhagia, nocturia, polyuria, proteinuria, testicular pain, urinary tract infection, and vaginal moniliasis. ## Postmarketing Experience - Adverse event terms reported from postmarketing surveillance that were not reported in the Phase II and III trials are presented below. Hepatic failure. Hemolytic anemia. Rhabdomyolysis. Acute kidney failure. # Drug Interactions - Delavirdine is an inhibitor of CYP3A isoform and other CYP isoforms to a lesser extent including CYP2C9, CYP2D6, and CYP2C19. Coadministration of RESCRIPTOR and drugs primarily metabolized by CYP3A (e.g., HMG-CoA reductase inhibitors and sildenafil) may result in increased plasma concentrations of the coadministered drug that could increase or prolong both its therapeutic or adverse effects. - Delavirdine is metabolized primarily by CYP3A, but in vitro data suggest that delavirdine may also be metabolized by CYP2D6. Coadministration of RESCRIPTOR and drugs that induce CYP3A, such as rifampin, may decrease delavirdine plasma concentrations and reduce its therapeutic effect. Coadministration of RESCRIPTOR and drugs that inhibit CYP3A may increase delavirdine plasma concentrations. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Delavirdine has been shown to be teratogenic in rats. Delavirdine caused ventricular septal defects in rats at doses of 50, 100, and 200 mg/kg/day when administered during the period of organogenesis. The lowest dose of delavirdine that caused malformations produced systemic exposures in pregnant rats equal to or lower than the expected human exposure to RESCRIPTOR (Cmin 15 μM) at the recommended dose. Exposure in rats approximately 5-fold higher than the expected human exposure resulted in marked maternal toxicity, embryotoxicity, fetal developmental delay, and reduced pup survival. Additionally, reduced pup survival on postpartum day 0 occurred at an exposure (mean Cmin) approximately equal to the expected human exposure. Delavirdine was excreted in the milk of lactating rats at a concentration 3 to 5 times that of rat plasma. - Delavirdine at doses of 200 and 400 mg/kg/day administered during the period of organogenesis caused maternal toxicity, embryotoxicity, and abortions in rabbits. The lowest dose of delavirdine that resulted in these toxic effects produced systemic exposures in pregnant rabbits approximately 6-fold higher than the expected human exposure to RESCRIPTOR (Cmin 15 μM) at the recommended dose. The no-observed-adverse-effect dose in the pregnant rabbit was 100 mg/kg/day. Various malformations were observed at this dose, but the incidence of such malformations was not statistically significantly different from that observed in the control group. Systemic exposures in pregnant rabbits at a dose of 100 mg/kg/day were lower than those expected in humans at the recommended clinical dose. Malformations were not apparent at 200 and 400 mg/kg/day; however, only a limited number of fetuses were available for examination as a result of maternal and embryo death. - No adequate and well-controlled studies in pregnant women have been conducted. RESCRIPTOR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Of 9 pregnancies reported in premarketing clinical studies and postmarketing experience, a total of 10 infants were born (including 1 set of twins). Eight of the infants were born healthy. One infant was born HIV-positive but was otherwise healthy and with no congenital abnormalities detected, and 1 infant was born prematurely (34 to 35 weeks) with a small muscular ventricular septal defect that spontaneously resolved. The patient received approximately 6 weeks of treatment with delavirdine and zidovudine early in the course of the pregnancy. - Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to RESCRIPTOR and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling (800) 258-4263. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Delavirdine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Delavirdine during labor and delivery. ### Nursing Mothers - The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Because of both the potential for HIV transmission and any possible adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving RESCRIPTOR. ### Pediatric Use - Safety and effectiveness of delavirdine in combination with other antiretroviral agents have not been established in HIV-1–infected individuals younger than 16 years of age. ### Geriatic Use - Clinical studies of RESCRIPTOR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be taken when dosing RESCRIPTOR in elderly patients due to 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 Delavirdine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Delavirdine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Delavirdine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Delavirdine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Delavirdine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Delavirdine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Delavirdine in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Delavirdine in the drug label. # Overdosage ## Acute Overdose - Human experience of acute overdose with RESCRIPTOR is limited. - Treatment of overdosage with RESCRIPTOR should consist of general supportive measures, including monitoring of vital signs and observation of the patient’s clinical status. There is no specific antidote for overdosage with RESCRIPTOR. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage. Since delavirdine is extensively metabolized by the liver and is highly protein-bound, dialysis is unlikely to result in significant removal of the drug. ## Chronic Overdose There is limited information regarding Chronic Overdose of Delavirdine in the drug label. # Pharmacology ## Mechanism of Action - Delavirdine is an NNRTI of HIV-1. Delavirdine binds directly to reverse transcriptase (RT) and blocks RNA-dependent and DNA-dependent DNA polymerase activities. Delavirdine does not compete with template:primer or deoxynucleoside triphosphates. HIV-2 RT and human cellular DNA polymerases α, γ, or δ are not inhibited by delavirdine. In addition, HIV-1 group O, a group of highly divergent strains that are uncommon in North America, may not be inhibited by delavirdine. ## Structure - RESCRIPTOR Tablets contain delavirdine mesylate, a synthetic non-nucleoside reverse transcriptase inhibitor (NNRTI) of the human immunodeficiency virus type 1 (HIV-1). The chemical name of delavirdine mesylate is piperazine, 1-[3-[(1-methyl-ethyl)amino]-2- pyridinyl]-4-[5-[(methylsulfonyl)amino]-1H-indol-2-yl]carbonyl]-, monomethanesulfonate. Its molecular formula is C22H28N6O3S•CH4O3S, and its molecular weight is 552.68. The structural formula is:delavirdine chemical structure - Delavirdine mesylate is an odorless white-to-tan crystalline powder. The aqueous solubility of delavirdine free base at 23°C is 2,942 mcg/mL at pH 1.0, 295 mcg/mL at pH 2.0, and 0.81 mcg/mL at pH 7.4. - Each RESCRIPTOR Tablet, for oral administration, contains 100 or 200 mg of delavirdine mesylate (henceforth referred to as delavirdine). Inactive ingredients consist of carnauba wax, colloidal silicon dioxide, croscarmellose sodium, lactose, magnesium stearate, and microcrystalline cellulose. In addition, the 100-mg tablet contains Opadry White YS-1-7000-E and the 200-mg tablet contains hypromellose and Opadry White YS-1-18202-A. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Delavirdine in the drug label. ## Pharmacokinetics - Absorption and Bioavailability: Delavirdine is rapidly absorbed following oral administration, with peak plasma concentrations occurring at approximately 1 hour. Following administration of delavirdine 400 mg 3 times daily (n = 67, HIV-1–infected patients), the mean ±SD steady-state peak plasma concentration (Cmax) was 35 ± 20 μM (range: 2 to 100 μM), systemic exposure (AUC) was 180 ± 100 μM•hr (range: 5 to 515 μM•hr), and trough concentration (Cmin) was 15 ± 10 μM (range: 0.1 to 45 μM). The single-dose bioavailability of delavirdine tablets relative to an oral solution was 85% ± 25% (n = 16, non-HIV–infected subjects). The single-dose bioavailability of delavirdine tablets (100-mg strength) was increased by approximately 20% when a slurry of drug was prepared by allowing delavirdine tablets to disintegrate in water before administration (n = 16, non-HIV–infected subjects). The bioavailability of the 200-mg strength delavirdine tablets has not been evaluated when administered as a slurry because they are not readily dispersed in water. - Delavirdine may be administered with or without food. In a multiple-dose, crossover study, delavirdine was administered every 8 hours with food or every 8 hours, 1 hour before or 2 hours after a meal (n = 13, HIV-1–infected patients). Patients remained on their typical diet throughout the study; meal content was not standardized. When multiple doses of delavirdine were administered with food, geometric mean Cmax was reduced by approximately 25%, but AUC and Cmin were not altered. - Distribution: Delavirdine is extensively bound (approximately 98%) to plasma proteins, primarily albumin. The percentage of delavirdine that is protein-bound is constant over a delavirdine concentration range of 0.5 to 196 μM. In 5 HIV-1–infected patients whose total daily dose of delavirdine ranged from 600 to 1,200 mg, cerebrospinal fluid concentrations of delavirdine averaged 0.4% ± 0.07% of the corresponding plasma delavirdine concentrations; this represents about 20% of the fraction not bound to plasma proteins. Steady-state delavirdine concentrations in saliva (n = 5, HIV-1–infected patients who received delavirdine 400 mg 3 times daily) and semen (n = 5 healthy volunteers who received delavirdine 300 mg 3 times daily) were about 6% and 2%, respectively, of the corresponding plasma delavirdine concentrations collected at the end of a dosing interval. - Metabolism and Elimination: Delavirdine is extensively converted to several inactive metabolites. Delavirdine is primarily metabolized by cytochrome P450 3A (CYP3A), but in vitro data suggest that delavirdine may also be metabolized by CYP2D6. The major metabolic pathways for delavirdine are N-desalkylation and pyridine hydroxylation. Delavirdine exhibits nonlinear steady-state elimination pharmacokinetics, with apparent oral clearance decreasing by about 22-fold as the total daily dose of delavirdine increases from 60 to 1,200 mg/day. In a study of 14C-delavirdine in 6 healthy volunteers who received multiple doses of delavirdine tablets 300 mg 3 times daily, approximately 44% of the radiolabeled dose was recovered in feces, and approximately 51% of the dose was excreted in urine. Less than 5% of the dose was recovered unchanged in urine. The parent plasma half-life of delavirdine increases with dose; mean half-life following 400 mg 3 times daily is 5.8 hours, with a range of 2 to 11 hours. - In vitro and in vivo studies have shown that delavirdine reduces CYP3A activity and inhibits its own metabolism. In vitro studies have also shown that delavirdine reduces CYP2C9, CYP2D6, and CYP2C19 activity. Inhibition of hepatic CYP3A activity by delavirdine is reversible within 1 week after discontinuation of drug. - Special Populations - Hepatic or Renal Impairment: The pharmacokinetics of delavirdine in patients with hepatic or renal impairment have not been investigated. - Age: The pharmacokinetics of delavirdine have not been adequately studied in patients aged <16 years or >65 years. - Gender: Data from population pharmacokinetics suggest that the plasma concentrations of delavirdine tend to be higher in females than in males. However, this difference is not considered to be clinically significant. - Race: No significant differences in the mean trough delavirdine concentrations were observed between different racial or ethnic groups. - Drug Interactions - Specific drug interaction studies were performed with delavirdine and a number of drugs. Table 1 summarizes the effects of delavirdine on the geometric mean AUC, Cmax, and Cmin of coadministered drugs. Table 2 shows the effects of coadministered drugs on the geometric mean AUC, Cmax, and Cmin of delavirdine. ## Nonclinical Toxicology - Delavirdine was negative in a battery of genetic toxicology tests which included an Ames assay, an in vitro rat hepatocyte unscheduled DNA synthesis assay, an in vitro chromosome aberration assay in human peripheral lymphocytes, an in vitro mutation assay in Chinese hamster ovary cells, and an in vivo micronucleus test in mice. - Lifetime carcinogenicity studies were conducted in rats at doses of 10, 32, and 100 mg/kg/day and in mice at doses of 62.5, 250, and 500 mg/kg/day for males and 62.5, 125, and 250 mg/kg/day for females. In rats, delavirdine was noncarcinogenic at maximally tolerated doses that produced exposures (AUC) up to 12 (male rats) and 9 (female rats) times human exposure at the recommended clinical dose. In mice, delavirdine produced significant increases in the incidence of hepatocellular adenoma/adenocarcinoma in both males and females, hepatocellular adenoma in females, and mesenchymal urinary bladder tumors in males. The systemic drug exposures (AUC) in female mice were 0.5- to 3-fold and in male mice 0.2- to 4-fold of those in humans at the recommended clinical dose. Given the lack of genotoxic activity of delavirdine, the relevance of urinary bladder and hepatocellular neoplasm in delavirdine-treated mice to humans is not known. - Delavirdine at doses of 20, 100, and 200 mg/kg/day did not cause impairment of fertility in rats when males were treated for 70 days and females were treated for 14 days prior to mating. # Clinical Studies - For clinical Studies 21 Part II and 13C described below, efficacy was evaluated by the percentage of patients with a plasma HIV-1 RNA level <400 copies/mL through Week 52 as measured by the Roche Amplicor® HIV-1 Monitor (standard assay). An intent-to-treat analysis was performed where only subjects who achieved confirmed suppression and sustained it through Week 52 are regarded as responders. All other subjects (including never suppressed, discontinued, and those who rebounded after initial suppression of <400 copies/mL) are considered failures at Week 52. Results of an interim analysis of efficacy conducted for studies 21 Part II and 13C by independent Data and Safety Monitoring Boards (DSMBs) revealed that the triple-therapy arms in both studies produced significantly greater antiviral benefit than the dual-therapy arms, and early termination of the studies was recommended. - Study 21 Part II - Study 21 Part II was a double‑blind, randomized, placebo‑controlled trial comparing treatment with RESCRIPTOR (400 mg 3 times daily, zidovudine 200 mg 3 times daily, and lamivudine 150 mg twice daily versus RESCRIPTOR 400 mg 3 times daily and zidovudine 200 mg 3 times daily versus zidovudine 200 mg 3 times daily and lamivudine 150 mg twice daily in 373 HIV-1–infected patients (mean age 35 years [range: 17 to 67], 87% male, and 60% Caucasian) who were antiretroviral treatment naive (84%) or had limited nucleoside experience (16%). Mean baseline CD4+ cell count was 359 cells/mm3 and mean baseline plasma HIV‑1 RNA was 4.4 log10 copies/mL. - Results showed that the mean increases from baseline in CD4 cell counts at 52 weeks were 111 cells/mL for RESCRIPTOR + zidovudine + lamivudine, 27 cells/mL for RESCRIPTOR + zidovudine, and 74 cells/mL for zidovudine + lamivudine. - The results of the intent-to-treat analysis of the percentage of patients with a plasma HIV-1 RNA level <400 copies/mL are presented in Figure 1. HIV-1 RNA status and reasons for discontinuation of randomized treatment at 52 weeks are summarized in Table 3. Subjects who were never suppressed before discontinuation were placed in the discontinuation category. - Figure 1. Percentage of Patients With HIV-1 RNA Below 400 copies/mL Standard PCR Assay Protocol 21 Part II: Intent-to–Treat Analysis - Study 13C - Study 13C was a double‑blind, randomized, placebo‑controlled trial comparing treatment with RESCRIPTOR 400 mg 3 times daily, zidovudine 200 mg 3 times daily or 300 mg twice daily, and either didanosine 200 mg twice daily, zalcitabine 0.75 mg 3 times daily, or lamivudine 150 mg twice daily versus zidovudine 200 mg 3 times daily or 300 mg twice daily and either didanosine 200 mg twice daily, zalcitabine 0.75 mg 3 times daily, or lamivudine 150 mg twice daily in 345 HIV-1–infected patients (mean age 35.8 years [range: 18 to 72], 66% male, and 63% Caucasian) who were antiretroviral treatment naive (63%) or had limited antiretroviral experience (37%). Mean baseline CD4+ cell count was 210 cells/mm3 and mean baseline plasma HIV‑1 RNA was 4.9 log10 copies/mL. - Results showed that the mean increases from baseline in CD4+ cell counts at 54 weeks were 102 cells/mL for RESCRIPTOR + zidovudine + didanosine or zalcitabine or lamivudine, and 56 cells/mL for zidovudine + didanosine or zalcitabine or lamivudine. - The results of the intent‑to‑treat analysis of the percentage of patients with a plasma HIV‑1 RNA level 400 copies/mL are presented in Figure 2. HIV‑1 RNA status and reasons for discontinuation of randomized treatment at 54 weeks are summarized in Table 4. Subjects who were never suppressed before discontinuation were placed in the discontinuation category. - Figure 2. Percentage of Patients With HIV-1 RNA Below 400 copies/mL Standard PCR Assay Protocol 13C: Intent-to–Treat Analysis # How Supplied - RESCRIPTOR Tablets are available as follows: - 100-mg: white, capsule-shaped tablets marked with “U 3761” - Bottles of 360 tablets - NDC 49702-209-24. - 200-mg: white, capsule-shaped tablets marked with “RES200” - Bottles of 180 tablets - NDC 49702-225-17. - Store at controlled room temperature 20° to 25°C (68° to 77°F). Keep container tightly closed. Protect from high humidity. ## Storage There is limited information regarding Delavirdine Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - A statement to patients and healthcare providers is included on the product’s bottle label: ALERT: Find out about medicines that should NOT be taken with RESCRIPTOR. A patient package insert (PPI) for RESCRIPTOR is available for patient information. - Patients should be informed that RESCRIPTOR is not a cure for HIV‑1 infection and that patients may continue to experience illnesses associated with HIV‑1 infection, including opportunistic infections. Patients should be advised to remain under the care of a physician while taking RESCRIPTOR. - Patients should be advised to avoid doing things that can spread HIV-1 infection to others. - Do not share needles or other injection equipment. - Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades. - Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood. - Do not breastfeed. We do not know if RESCRIPTOR 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. - Patients should be instructed that the major toxicity of RESCRIPTOR is rash and should be advised to promptly notify their physician should rash occur. The majority of rashes associated with RESCRIPTOR occur within 1 to 3 weeks after initiating treatment with RESCRIPTOR. The rash normally resolves in 3 to 14 days and may be treated symptomatically while therapy with RESCRIPTOR is continued. Any patient experiencing severe rash or rash accompanied by symptoms such as fever, blistering, oral lesions, conjunctivitis, swelling, and muscle or joint aches should discontinue medication and consult a physician. - Patients should be informed 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. - Patients should be informed to take RESCRIPTOR every day as prescribed. Patients should not alter the dose of RESCRIPTOR without consulting their doctor. If a dose is missed, patients should take the next dose as soon as possible. However, if a dose is skipped, the patient should not double the next dose. - Patients with achlorhydria should take RESCRIPTOR with an acidic beverage (e.g., orange or cranberry juice). However, the effect of an acidic beverage on the absorption of delavirdine in patients with achlorhydria has not been investigated. - Patients taking both RESCRIPTOR and antacids should be advised to take them at least 1 hour apart. - Because RESCRIPTOR may interact with certain drugs, patients should be advised to report to their doctor the use of any prescription, nonprescription medication, or herbal products, particularly St. John’s wort. - Patients receiving sildenafil and RESCRIPTOR should be advised that they may be at an increased risk of sildenafil‑associated adverse events, including hypotension, visual changes, and prolonged penile erection, and should promptly report any symptoms to their doctor. # Precautions with Alcohol - Alcohol-Delavirdine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - RESCRIPTOR®[1] # Look-Alike Drug Names There is limited information regarding Delavirdine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Delavirdine
08ddd42e83eff3c7db179cd96eb73e41396ebcfe	wikidoc	Demecolcine	Demecolcine # Overview Demecolcine, also known as colcemid, is a drug used in chemotherapy.It is closely related to the natural alkaloid colchicine with the replacement of the acetyl group on the amino moiety with methyl, but it is less toxic. It depolymerises microtubules and limits microtubule formation (inactivates spindle fibre formation), thus arresting cells in metaphase and allowing cell harvest and karyotyping to be performed. During cell division Demecolcine inhibits mitosis at metaphase by inhibiting spindle formation. Medically Demecolcine has been used to improve the results of cancer radiotherapy by synchronising tumour cells at metaphase, the radiosensitive stage of the cell cycle. In animal cloning procedures Demecolcine makes an ovum eject its nucleus, creating space for insertion of a new nucleus. # Mechanism of Action Demecolcine is a microtubule-depolymerizing drug like vinblastine. It acts by two distinct mechanisms. At very low concentration it binds to microtubule plus end to suppress microtubule dynamics. Recent study has found at higher concentration colcemid can promote microtubule detachment from microtubule organizing center. Detached microtubules with unprotected minus end depolymerizes with time. Cytotoxicity of the cells seems to correlate better with microtubule detachment. Lower concentration affects microtubule dynamics and cell migration.	Demecolcine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Demecolcine, also known as colcemid, is a drug used in chemotherapy.It is closely related to the natural alkaloid colchicine with the replacement of the acetyl group on the amino moiety with methyl, but it is less toxic. It depolymerises microtubules and limits microtubule formation (inactivates spindle fibre formation), thus arresting cells in metaphase and allowing cell harvest and karyotyping to be performed. During cell division Demecolcine inhibits mitosis at metaphase by inhibiting spindle formation. Medically Demecolcine has been used to improve the results of cancer radiotherapy by synchronising tumour cells at metaphase, the radiosensitive stage of the cell cycle.[1] In animal cloning procedures Demecolcine makes an ovum eject its nucleus, creating space for insertion of a new nucleus.[2] # Mechanism of Action Demecolcine is a microtubule-depolymerizing drug like vinblastine. It acts by two distinct mechanisms. At very low concentration it binds to microtubule plus end to suppress microtubule dynamics.[3] Recent study has found at higher concentration colcemid can promote microtubule detachment from microtubule organizing center. Detached microtubules with unprotected minus end depolymerizes with time. Cytotoxicity of the cells seems to correlate better with microtubule detachment.[4] Lower concentration affects microtubule dynamics and cell migration.[4]	https://www.wikidoc.org/index.php/Demecolcine
7802d08d4de8beeafcf0a69c9d23e8a82a9fd1bb	wikidoc	Dendralenes	Dendralenes Dendralenes are discrete acyclic cross-conjugated polyenes. The simplest dendralene is butadiene (1) or dendralene followed by dendralene (2), dendralene (3) and dendralene (4) and so forth. The name dendralene is pulled together from the words dendrimer, linear and alkene. The higher dendralenes are of scientific interest because they open up a large array of new organic compounds from a relatively simple precursor especially by Diels-Alder chemistry. Their cyclic counterparts are aptly called radialenes. One synthetic route to dendralene starts from chloroprene. This compound is converted to a Grignard reagent by action of magnesium metal which is then reacted with copper(I) chloride to an organocopper intermediate which is in turn dimerized in an oxidative coupling reaction to the butadiene dimer with copper(II) chloride. # Diels-Alder reactions dendralene shows a tandem Diels-Alder reaction with the dienophile N-methyl-maleimide or NMM. Complete site selectivity is possible with the addition of the lewis acid methyldichloroaluminium. With one set of premixing and 2 equivalents of NMM the central diene group is targeted to the monoadduct 3. With another set and a larger amount of dienophile the terminal groups react and the reaction proceeds from the monoadduct to the trisadducts 2 and 2b.	Dendralenes Dendralenes are discrete acyclic cross-conjugated polyenes. The simplest dendralene is butadiene (1) or [2]dendralene followed by [3]dendralene (2), [4]dendralene (3) and [5]dendralene (4) and so forth. The name dendralene is pulled together from the words dendrimer, linear and alkene. The higher dendralenes are of scientific interest because they open up a large array of new organic compounds from a relatively simple precursor especially by Diels-Alder chemistry. Their cyclic counterparts are aptly called radialenes. One synthetic route to [4]dendralene starts from chloroprene.[1] This compound is converted to a Grignard reagent by action of magnesium metal which is then reacted with copper(I) chloride to an organocopper intermediate which is in turn dimerized in an oxidative coupling reaction to the butadiene dimer with copper(II) chloride. # Diels-Alder reactions [4]dendralene shows a tandem Diels-Alder reaction with the dienophile N-methyl-maleimide or NMM. Complete site selectivity is possible with the addition of the lewis acid methyldichloroaluminium. With one set of premixing and 2 equivalents of NMM the central diene group is targeted to the monoadduct 3. With another set and a larger amount of dienophile the terminal groups react and the reaction proceeds from the monoadduct to the trisadducts 2 and 2b.	https://www.wikidoc.org/index.php/Dendralenes
b7ee04fa3e6ad9d0d44a2141c4ba70fb714f173e	wikidoc	Dennis Bray	Dennis Bray Dr. Dennis Bray is an active emeritus professor at University of Cambridge. His group is also part of the Oxford Centre for Integrative Systems Biology. After a first career in Neurobiology, working on cell growth and movement, Dennis Bray moved in Cambridge to develop computational models of cell signaling, in particular in relation to bacterial chemotaxis. On November 3, 2006, he was awarded the Microsoft European Science Award for his work on chemotaxis of E. coli. # Books - Essential Cell Biology (2003) (with Bruce Alberts, Karen Hopkin, Alexander Jonhson, Julian Lewis, Martin Raff, Keith Roberts, Peter Walter) ISBN-10: 081533480X, ISBN-13: 978-0815334804 - Cell Movements: From Molecules to Motility (2000) ISBN-10: 0815332823, ISBN-13: 978-0815332824 - Essential Cell Biology: An Introduction to the Molecular Biology of the Cell (1997) (with Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, Peter Walter) ISBN-10: 0815329717, ISBN-13: 978-0815329718 - Molecular Biology of the Cell (1994) (with Bruce Alberts, Julian Lewis, Martin Raff, Keith Roberts, James D. Watson) ISBN-10: 0815319274, ISBN-13: 978-0815319276 - Cell Movements (1992) ISBN-10: 0815307179, ISBN-13: 978-0815307174 - Molecular Biology of the Cell (1989) (with Bruce Alberts, Keith Roberts, Julian Lewis, Martin Raff) ISBN-10: 0824036956, ISBN-13: 9780824036959	Dennis Bray Template:Infobox Scientist Dr. Dennis Bray is an active emeritus professor at University of Cambridge. His group is also part of the Oxford Centre for Integrative Systems Biology. After a first career in Neurobiology, working on cell growth and movement, Dennis Bray moved in Cambridge to develop computational models of cell signaling, in particular in relation to bacterial chemotaxis. On November 3, 2006, he was awarded the Microsoft European Science Award for his work on chemotaxis of E. coli. [1][2] # Books - Essential Cell Biology (2003) (with Bruce Alberts, Karen Hopkin, Alexander Jonhson, Julian Lewis, Martin Raff, Keith Roberts, Peter Walter) ISBN-10: 081533480X, ISBN-13: 978-0815334804 - Cell Movements: From Molecules to Motility (2000) ISBN-10: 0815332823, ISBN-13: 978-0815332824 - Essential Cell Biology: An Introduction to the Molecular Biology of the Cell (1997) (with Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, Peter Walter) ISBN-10: 0815329717, ISBN-13: 978-0815329718 - Molecular Biology of the Cell (1994) (with Bruce Alberts, Julian Lewis, Martin Raff, Keith Roberts, James D. Watson) ISBN-10: 0815319274, ISBN-13: 978-0815319276 - Cell Movements (1992) ISBN-10: 0815307179, ISBN-13: 978-0815307174 - Molecular Biology of the Cell (1989) (with Bruce Alberts, Keith Roberts, Julian Lewis, Martin Raff) ISBN-10: 0824036956, ISBN-13: 9780824036959	https://www.wikidoc.org/index.php/Dennis_Bray
b4dd7ed28ebab6221a7939b061613891e7f3f24e	wikidoc	Dental fear	Dental fear # Overview Dental fear refers to the fear of dentistry and of receiving dental care. A pathological form of this fear (specific phobia) is variously called dental phobia, odontophobia, dentophobia, dentist phobia, or dental anxiety. It is estimated that as many as 75% of US adults experiences some degree of dental fear, from mild to severe. Approximately 5 to 10 percent of U.S. adults are considered to experience dental phobia; that is, they are so fearful of receiving dental treatment that they avoid dental care at all costs. Many dentally fearful people will only seek dental care when they have a dental emergency, such as a toothache or dental abscess. People who are very fearful of dental care often experience a “cycle of avoidance,” in which they avoid dental care due to fear until they experience a dental emergency requiring invasive treatment, which can reinforce their fear of dentistry. Women tend to report more dental fear than men, and younger people tend to report being more dentally fearful than older individuals. People tend to report being more fearful of more invasive procedures, such as oral surgery, than they are of less invasive treatment, such a professional dental cleanings, or prophylaxis. # Cause Many people report that their dental fear began after a traumatic, difficult, and/or painful dental experience. Dental fear may also develop as people hear about others' traumatic experiences or negative views of dentistry. Treatments for dental fear often include a combination of behavioral and pharmacological techniques. Specialized dental fear clinics, such as those at the University of Washington in Seattle and Göteborg University in Sweden, use both psychologists and dentists to help people learn to manage and decrease their fear of dental treatment. The goal of these clinics is to provide individuals with the fear management skills necessary for them to receive regular dental care with a minimum of fear or anxiety. Although specialized clinics exist to help individuals manage and overcome their fear of dentistry, many dental providers outside of such clinics use similar behavioral and cognitive strategies to help patients reduce their fear. # Treatment Behavioral treatments include teaching individuals relaxation techniques, such as diaphragmatic breathing and progressive muscle relaxation, as well as cognitive, or thought-based techniques, such as cognitive restructuring and guided imagery. Both relaxation and cognitive strategies have been shown to significantly reduce dental fear. One example of a behavioral technique is systematic desensitization, a method used in psychology to overcome phobias and other anxiety disorders. This is also sometimes called graduated exposure therapy or gradual exposure. For example, for a patient who is fearful of dental injections, the therapist first teaches relaxation skills to the patient, then gradually introduces the feared object (in this case, the needle and/or syringe) to the patient, encouraging the patient to manage his/her fear using the relaxation skills previously taught. The patient progresses through the steps of receiving a dental injection while using the relaxation skills, until the patient is able to successfully receive a dental injection while experiencing little to no fear. This method has been shown to be effective in treating fear of dental injections. Pharmacological techniques to manage dental fear range from mild sedation to general anesthesia, and are often used by dentists in conjunction with behavioral techniques. One common anxiety-reducing medication used in dentistry is nitrous oxide (also known as “laughing gas”), which is inhaled through a mask worn on the nose and causes feelings of relaxation and dissociation. Dentists may prescribe an oral sedative, such as a benzodiazepine like alprazolam (Xanax), diazepam (Valium), or triazolam (Halcion). While these sedatives may help people feel calmer and sometimes drowsy during dental treatment, patients are still conscious and able to communicate with the dental staff. Intravenous sedation uses benzodiazepines administered directly intravenously into a patient’s arm or hand. IV sedation is often referred to as “conscious sedation” as opposed to general anesthesia (GA), In IV sedation, patients breathe on their own while their breathing and heart rate are monitored. In GA, patients are more deeply sedated. # Alternative care People who are fearful of dental care may find dentists willing to work with fearful patients through recommendations by family and friends, dental insurance companies, and medical professionals. Often, dentists will advertise in telephone directories as being “gentle” or “catering to cowards.” Individuals are encouraged to make an initial appointment with a new dentist to discuss their previous experiences, concerns, and fears, without having any treatment done at the initial appointment. Some individuals have found online dental fear support resources to be helpful.	Dental fear Editor-In-Chief: C. Michael Gibson, M.S., M.D. [16] # Overview Dental fear refers to the fear of dentistry and of receiving dental care. A pathological form of this fear (specific phobia) is variously called dental phobia, odontophobia, dentophobia, dentist phobia, or dental anxiety. It is estimated that as many as 75% of US adults experiences some degree of dental fear, from mild to severe.[1][2] [3] Approximately 5 to 10 percent of U.S. adults are considered to experience dental phobia; that is, they are so fearful of receiving dental treatment that they avoid dental care at all costs.[4] Many dentally fearful people will only seek dental care when they have a dental emergency, such as a toothache or dental abscess. People who are very fearful of dental care often experience a “cycle of avoidance,” in which they avoid dental care due to fear until they experience a dental emergency requiring invasive treatment, which can reinforce their fear of dentistry.[5] Women tend to report more dental fear than men,[6] and younger people tend to report being more dentally fearful than older individuals.[7] People tend to report being more fearful of more invasive procedures, such as oral surgery, than they are of less invasive treatment, such a professional dental cleanings, or prophylaxis.[8] # Cause Many people report that their dental fear began after a traumatic, difficult, and/or painful dental experience.[9] Dental fear may also develop as people hear about others' traumatic experiences or negative views of dentistry.[10] Treatments for dental fear often include a combination of behavioral and pharmacological techniques. Specialized dental fear clinics, such as those at the University of Washington in Seattle and Göteborg University in Sweden, use both psychologists and dentists to help people learn to manage and decrease their fear of dental treatment. The goal of these clinics is to provide individuals with the fear management skills necessary for them to receive regular dental care with a minimum of fear or anxiety. Although specialized clinics exist to help individuals manage and overcome their fear of dentistry, many dental providers outside of such clinics use similar behavioral and cognitive strategies to help patients reduce their fear. # Treatment Behavioral treatments include teaching individuals relaxation techniques, such as diaphragmatic breathing and progressive muscle relaxation, as well as cognitive, or thought-based techniques, such as cognitive restructuring and guided imagery.[3] Both relaxation and cognitive strategies have been shown to significantly reduce dental fear.[11] One example of a behavioral technique is systematic desensitization, a method used in psychology to overcome phobias and other anxiety disorders.[12] This is also sometimes called graduated exposure therapy or gradual exposure. For example, for a patient who is fearful of dental injections, the therapist first teaches relaxation skills to the patient, then gradually introduces the feared object (in this case, the needle and/or syringe) to the patient, encouraging the patient to manage his/her fear using the relaxation skills previously taught. The patient progresses through the steps of receiving a dental injection while using the relaxation skills, until the patient is able to successfully receive a dental injection while experiencing little to no fear. This method has been shown to be effective in treating fear of dental injections.[13] Pharmacological techniques to manage dental fear range from mild sedation to general anesthesia, and are often used by dentists in conjunction with behavioral techniques.[14] One common anxiety-reducing medication used in dentistry is nitrous oxide (also known as “laughing gas”), which is inhaled through a mask worn on the nose and causes feelings of relaxation and dissociation. Dentists may prescribe an oral sedative, such as a benzodiazepine like alprazolam (Xanax), diazepam (Valium), or triazolam (Halcion). While these sedatives may help people feel calmer and sometimes drowsy during dental treatment, patients are still conscious and able to communicate with the dental staff. Intravenous sedation uses benzodiazepines administered directly intravenously into a patient’s arm or hand. IV sedation is often referred to as “conscious sedation” as opposed to general anesthesia (GA), In IV sedation, patients breathe on their own while their breathing and heart rate are monitored. In GA, patients are more deeply sedated. # Alternative care People who are fearful of dental care may find dentists willing to work with fearful patients through recommendations by family and friends, dental insurance companies, and medical professionals. Often, dentists will advertise in telephone directories as being “gentle” or “catering to cowards.” Individuals are encouraged to make an initial appointment with a new dentist to discuss their previous experiences, concerns, and fears, without having any treatment done at the initial appointment. Some individuals have found online dental fear support resources to be helpful.[15]	https://www.wikidoc.org/index.php/Dental_fear
3400b53c7ba18c7b54c4699e1967401b30bc6fae	wikidoc	Dequalinium	Dequalinium # Overview Dequalinium is a quaternary ammonium cation commonly available as the dichloride salt. The bromide, iodide, acetate, and undecenoate salts are known as well. Dequalinium chloride is the active ingredient of several medications: Dequadin an antiseptic and disinfectant. It is a topical bacteriostat. It is used in wound dressings and mouth infections and may also have antifungal action. It may cause skin ulceration. Fluomizin, vaginal tablets containing 10 mg dequalinium chloride, are used for treating vaginal bacterial conditions (i.e. Bacterial Vaginosis). The dequalinium dication is symmetrical, containing two quaternary quinolinium units linked by a dodecylene chain. # Applications Dequalinium salts may be used to treat malaria. As dequalinium chloride, it can be used in lozenges to cure sore throats however while this is effective in vitro, it is not effective in cases of streptococci infections	Dequalinium Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Dequalinium is a quaternary ammonium cation commonly available as the dichloride salt. The bromide, iodide, acetate, and undecenoate salts are known as well. Dequalinium chloride is the active ingredient of several medications: Dequadin an antiseptic and disinfectant. It is a topical bacteriostat. It is used in wound dressings and mouth infections and may also have antifungal action. It may cause skin ulceration. Fluomizin, vaginal tablets containing 10 mg dequalinium chloride, are used for treating vaginal bacterial conditions (i.e. Bacterial Vaginosis). The dequalinium dication is symmetrical, containing two quaternary quinolinium units linked by a dodecylene chain. # Applications Dequalinium salts may be used to treat malaria.[1] As dequalinium chloride, it can be used in lozenges to cure sore throats however while this is effective in vitro, it is not effective in cases of streptococci infections [2]	https://www.wikidoc.org/index.php/Dequalinium
f37a68acbe09d79102111f21a59afa32496bf358	wikidoc	Dermatology	Dermatology Dermatology (from Greek δερμα, "skin") is a branch of medicine dealing with the skin and its appendages (hair, sweat glands, etc). # Scope of the field Dermatologists are physicians (Medical Doctors) specializing in the diagnosis and treatment of diseases and tumors of the skin and its appendages. There are medical and surgical sides to the specialty. Dermatologic surgeons practice skin cancer surgery (including Mohs' micrographic surgery), laser surgery, photodynamic therapy (PDT) and cosmetic procedures using botulinum toxin ('Botox'), soft tissue fillers, sclerotherapy and liposuction. Dermatopathologists interpret tissue under the microscope (histopathology). Pediatric dermatologists specialize in the diagnoses and treatment of skin disease in children. Immunodermatologists specialize in the diagnosis and management of skin diseases driven by an altered immune system including blistering (bullous) diseases like pemphigus. In addition, there is a wide range of congenital syndromes managed by dermatologists. # Subspecialties The skin is the largest organ of the body and the most visible. Although many skin diseases are isolated, some are manifestations of internal disease. Hence, a dermatologist is schooled in aspects of surgery, rheumatology (many rheumatic diseases can feature skin symptoms and signs), immunology, neurology (the "neurocuteaneous syndromes", such as neurofibromatosis and tuberous sclerosis), infectious diseases and endocrinology. The study of genetics is also becoming increasingly important. ## Venereology and phlebology Venereology, the subspecialty that diagnoses and treats sexually transmitted diseases, and phlebology, the specialty that deals with problems of the superficial venous system, are both part of a dermatologist's expertise. ## Cosmetic dermatology Cosmetic dermatology has long been an important part of the field, and dermatologists have been the primary innovators in this area. In the 1900's dermatologists employed dermabrasion to improve acne scarring and fat microtransfer was used to fill in cutaneous defects. More recently, dermatologists have been the driving force behind the development and safe and effective employment of lasers, new dermal filling agents (collagen and hyaluronic acid), botulinum toxin ("Botox"), nonabrative laser rejuvenation procedures, intense pulsed light systems, photodynamic therapy, and chemical peeling. ## Dermatologic surgery Dermatologic surgery (dermasurgery) is performed by all dermatologists. Surgery is an integral part of dermatology residency training; thus all dermatologists are well trained in cutaneous surgery. In North America specialized training through a 1 year dermatologic surgery fellowship is available upon completion of the dermatology residency, and usually focuses on training in Mohs' micrographic surgery. Most dermatologic surgeons who have a special interest in this field apply for fellowship status in the American Society for Dermatologic Surgery, a professional organization dedicated to supporting and educating these physicians. Techniques available to a dermatologic surgeon include lasers, traditional scalpel surgery, electrosurgery, cryosurgery, photodynamic therapy, liposuction, blepharoplasty (cosmetic eyelid surgery), minimally-invasive facelift surgery (e.g., the S-lift), and a variety of topical and injectable agents such as dermal fillers including fat transfer and hyaluronic acid. Some specially trained dermatologic surgeons perform Mohs' surgery, which can be an effective method for the treatment of recurrent, indistinct, or difficult skin cancers. # Diagnosis Any mole that is irregular in color or shape should be examined by a dermatologist to determine if it is a malignant melanoma, the most serious and life-threatening form of skin cancer. Following a visual examination and a dermatoscopic exam (an invaluable new instrument that illuminates a mole without reflected light), a dermatologist may biopsy a suspicious mole. If it is malignant, it will be excised in the dermatologist's office. ## Medical history The first step of any contact with a physician is the medical history. In order to classify a cutaneous eruption, the dermatologist will ask detailed questions on the duration and temporal pattern of skin problems, itching or pain, relation to food intake, sunlight, over-the-counter creams and clothing. When an underlying disease is suspected, an additional detailed history of related symptoms will be elicited (such as arthritis in a suspected case of lupus erythematosus). ## Physical examination Dermatology has the obvious benefit of having easy access to tissue for diagnosis. Physical examination is generally done under bright light and preferably involves the whole body. At this stage, the doctor may apply Wood's light, which may aid in diagnosing types of mycosis or demonstrate the extent of pigmented lesions, or use a dermatoscope which enlarges a suspected lesion and visualizes it without reflected light. The dermatoscope is helpful in differentiating a benign naevus from melanoma or a seborrheic keratosis from a mole. A morphological classification of dermatological lesions is important in the diagnosis of dermatological disorders. Dermatologic diagnosis is often dependent upon pattern recognition of lesions and symptoms. ## Microbiology Culture or Gram staining of suspected infectious lesions may identify a pathogen and help direct therapy. ## Biopsy If the diagnosis is uncertain or a cutaneous malignancy is suspected, the dermatologic surgeon may perform a small punch biopsy (using a local anesthetic) for examination under the microscope by the dermatologist who is a trained dermatopathologist. # Therapy The skin is obviously accessible to topical local therapy. Antibiotic creams can help eliminate infections, while inflammatory skin diseases (such as eczema and psoriasis) often respond to steroid creams or topical anthralin. Dermatologists are innovators of new immune enhancing treatments, like topical imiquimod for superficial cancers and injection immunotherapy for warts as discussed below. ## Topical medications Topical medications treat many dermatological diseases, but dermatologists also use oral medications. Antibiotics and immune suppressants or immune enhancing agents (injection immunotherapy or topical imiquimod) for dermatological diseases or tumors. Isotretinoin ("Accutane") is used for severe cystic acne vulgaris and often produces a lifetime remission of this disfiguring disease. Isotretinoin prescribing in the U.S. is now controlled by a cumbersome FDA governmental website called iPLEDGE. Various new modalities of treatment are in the foray; with the advent of laser technology things are quite promising. ## Photomedicine Photomedicine involves the use of ultraviolet light, often in combination with oral or topical agents, to treat skin disease (e.g., psoriasis or mycosis fungoides). ## Surgical therapies Surgical intervention by a dermatologic surgeon may be necessary, for example, to treat varicose veins or skin cancer. Varicose veins can be treated with sclerotherapy (injecting an agent that obliterates the vein) or the long-pulsed Nd:YAG laser. Skin cancers can be managed with excision (including Mohs cancer surgery), cryosurgery, x-ray, or with the recent topical immune enhancing agent imiquimod. (See above section on "Dermatologic Surgery" for more details.) ## Psychodermatology and hypnodermatology Psychodermatology and hypnodermatology involve using hypnosis in combination with other pseudo-psychological therapies to treat skin disorders. # Training programs ## Residency training program in North America A minimum of 12 years of college and post graduate training is required to become a dermatologist in the United States and Canada. This includes graduation from a 4-year college where they will take Pre-Medicine, then a 4-year medical school followed by a year of post graduate training in medicine, surgery or pediatrics (called an internship) after which a physician may apply for admission to graduate dermatology residency training. Dermatology residencies are the most competitive in terms of admission. Following the successful completion of formal residency training in dermatology (3 years) the physician is qualified to take certifying board examinations (written) by the American Board of Dermatology or the American Osteopathic College of Dermatology. Once board certified, dermatologists become Diplomates of the American Board of Dermatology or the American Osteopathic College of Dermatology AOCD. They are then eligible to apply for fellowship status in the American Academy of Dermatology. Some dermatologists undertake advanced subspecialty training in programs known as fellowships after completion of their residency training. These fellowships are either one or two years in duration. Fellowships in dermatology include pediatric dermatology, surgical dermatology including Mohs micrographic surgery, dermatopathology (pathology of skin diseases) and dermatological immunology. ## Training programme in Australia An Australian specialist dermatologist will have completed 4-6 years of medical school (depending on institution), one internship year and at least one year of general medical or surgical service in the public hospital system, prior to becoming eligible for specialist training in dermatology. The selection process is rigorous and transparent; candidates must pass science and pharmacology exams and engage in monitored and assessed practical training in all aspects of medical and surgical dermatology. At the completion of the 5 year training programme, trainees sit a national written examination held over two days. Successful candidates may then proceed to the practical viva examination, similarly held over 2 days. Successful candidates may then apply for Fellowship status with the Australasian College of Dermatologists. ## Training program in India To be a dermatologist in India, a minimum of 2 years (for diploma ) or 3 years (for MD) of training is required after graduation from medical school and internship. The period involves rigorous training in all aspects of general dermatology, cosmetic dermatology, dermatopathology, dermatosurgery, venereal diseases (including HIV) and leprosy. At the end of the training period the resident has to go through written tests and clinical exams. The postgraduate qualification awarded is DVD (Diploma in Venereology and Dermatology) and MD (dermatology, venereology and leprosy). Many specialists also go for certification by the national board (for the award of 'diplomate of national board'). The Indian Association of Dermatologists, Venereologists and Leprologists(IADVL)is one of the largest dermatolological associations in the world. # Research From the basic science of cutaneous genetics and immunology, to the practical application of new knowledge and technology in the diagnosis and management of skin disease (like psoriasis) and surgical treatment of skin cancer, dermatologists have been among the leaders in the field. The annual meeting of the American Academy of Dermatology is one of the keys for rapid dissemination of new knowledge to the practicing dermatologist and dermatologic surgeon. # Dermatological diseases - List of dermatological diseases # History The work De morbis cutaneis ("On the diseases of the skin" - 1572) by Geronimo Mercuriali from Forlì (Italy) is known as the first scientific tractation about Dermatology. Early photographic documentation of skin diseases was produced by Balmanno Squire, Dr. Alfred Hardy, Dr. A. de Montméja, Dr. Howard Franklin Damon, Dr. George Henry Fox and Dr. Oscar G. Mason in the latter 1800s. # Notes - ↑ Wu JJ, Tyring SK. ""...has been the most competitive of all specialties for at least the last 5-6 years." This is confirmed by data from the electronic residency application service (ERAS)". Retrieved 2007-06-23.CS1 maint: Uses authors parameter (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - ↑ Wu JJ, Ramirez CC, Alonso CA et al. ""Dermatology continues to be the most competitive residency to enter..." Arch Dermatol. 2006;142:845-850". Retrieved 2007-06-25.CS1 maint: Uses authors parameter (link) CS1 maint: Explicit use of et al. (link) # Further reading - Dermatology Times - a newsmagazine	Dermatology Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Dermatology (from Greek δερμα, "skin") is a branch of medicine dealing with the skin and its appendages (hair, sweat glands, etc). # Scope of the field Dermatologists are physicians (Medical Doctors) specializing in the diagnosis and treatment of diseases and tumors of the skin and its appendages. There are medical and surgical sides to the specialty. Dermatologic surgeons practice skin cancer surgery (including Mohs' micrographic surgery), laser surgery, photodynamic therapy (PDT) and cosmetic procedures using botulinum toxin ('Botox'), soft tissue fillers, sclerotherapy and liposuction. Dermatopathologists interpret tissue under the microscope (histopathology). Pediatric dermatologists specialize in the diagnoses and treatment of skin disease in children. Immunodermatologists specialize in the diagnosis and management of skin diseases driven by an altered immune system including blistering (bullous) diseases like pemphigus. In addition, there is a wide range of congenital syndromes managed by dermatologists. # Subspecialties The skin is the largest organ of the body and the most visible. Although many skin diseases are isolated, some are manifestations of internal disease. Hence, a dermatologist is schooled in aspects of surgery, rheumatology (many rheumatic diseases can feature skin symptoms and signs), immunology, neurology (the "neurocuteaneous syndromes", such as neurofibromatosis and tuberous sclerosis), infectious diseases and endocrinology. The study of genetics is also becoming increasingly important. ## Venereology and phlebology Venereology, the subspecialty that diagnoses and treats sexually transmitted diseases, and phlebology, the specialty that deals with problems of the superficial venous system, are both part of a dermatologist's expertise. ## Cosmetic dermatology Cosmetic dermatology has long been an important part of the field, and dermatologists have been the primary innovators in this area. In the 1900's dermatologists employed dermabrasion to improve acne scarring and fat microtransfer was used to fill in cutaneous defects. More recently, dermatologists have been the driving force behind the development and safe and effective employment of lasers, new dermal filling agents (collagen and hyaluronic acid), botulinum toxin ("Botox"), nonabrative laser rejuvenation procedures, intense pulsed light systems, photodynamic therapy, and chemical peeling. ## Dermatologic surgery Dermatologic surgery (dermasurgery) is performed by all dermatologists. Surgery is an integral part of dermatology residency training; thus all dermatologists are well trained in cutaneous surgery. In North America specialized training through a 1 year dermatologic surgery fellowship is available upon completion of the dermatology residency, and usually focuses on training in Mohs' micrographic surgery. Most dermatologic surgeons who have a special interest in this field apply for fellowship status in the American Society for Dermatologic Surgery, a professional organization dedicated to supporting and educating these physicians. Techniques available to a dermatologic surgeon include lasers, traditional scalpel surgery, electrosurgery, cryosurgery, photodynamic therapy, liposuction, blepharoplasty (cosmetic eyelid surgery), minimally-invasive facelift surgery (e.g., the S-lift), and a variety of topical and injectable agents such as dermal fillers including fat transfer and hyaluronic acid. Some specially trained dermatologic surgeons perform Mohs' surgery, which can be an effective method for the treatment of recurrent, indistinct, or difficult skin cancers. # Diagnosis Any mole that is irregular in color or shape should be examined by a dermatologist to determine if it is a malignant melanoma, the most serious and life-threatening form of skin cancer. Following a visual examination and a dermatoscopic exam (an invaluable new instrument that illuminates a mole without reflected light), a dermatologist may biopsy a suspicious mole. If it is malignant, it will be excised in the dermatologist's office. ## Medical history The first step of any contact with a physician is the medical history. In order to classify a cutaneous eruption, the dermatologist will ask detailed questions on the duration and temporal pattern of skin problems, itching or pain, relation to food intake, sunlight, over-the-counter creams and clothing. When an underlying disease is suspected, an additional detailed history of related symptoms will be elicited (such as arthritis in a suspected case of lupus erythematosus). ## Physical examination Dermatology has the obvious benefit of having easy access to tissue for diagnosis. Physical examination is generally done under bright light and preferably involves the whole body. At this stage, the doctor may apply Wood's light, which may aid in diagnosing types of mycosis or demonstrate the extent of pigmented lesions, or use a dermatoscope which enlarges a suspected lesion and visualizes it without reflected light. The dermatoscope is helpful in differentiating a benign naevus from melanoma or a seborrheic keratosis from a mole. A morphological classification of dermatological lesions is important in the diagnosis of dermatological disorders. Dermatologic diagnosis is often dependent upon pattern recognition of lesions and symptoms. ## Microbiology Culture or Gram staining of suspected infectious lesions may identify a pathogen and help direct therapy. ## Biopsy If the diagnosis is uncertain or a cutaneous malignancy is suspected, the dermatologic surgeon may perform a small punch biopsy (using a local anesthetic) for examination under the microscope by the dermatologist who is a trained dermatopathologist. # Therapy The skin is obviously accessible to topical local therapy. Antibiotic creams can help eliminate infections, while inflammatory skin diseases (such as eczema and psoriasis) often respond to steroid creams or topical anthralin. Dermatologists are innovators of new immune enhancing treatments, like topical imiquimod for superficial cancers and injection immunotherapy for warts as discussed below. ## Topical medications Topical medications treat many dermatological diseases, but dermatologists also use oral medications. Antibiotics and immune suppressants or immune enhancing agents (injection immunotherapy or topical imiquimod) for dermatological diseases or tumors. Isotretinoin ("Accutane") is used for severe cystic acne vulgaris and often produces a lifetime remission of this disfiguring disease. Isotretinoin prescribing in the U.S. is now controlled by a cumbersome FDA governmental website called iPLEDGE. Various new modalities of treatment are in the foray; with the advent of laser technology things are quite promising. ## Photomedicine Photomedicine involves the use of ultraviolet light, often in combination with oral or topical agents, to treat skin disease (e.g., psoriasis or mycosis fungoides). ## Surgical therapies Surgical intervention by a dermatologic surgeon may be necessary, for example, to treat varicose veins or skin cancer. Varicose veins can be treated with sclerotherapy (injecting an agent that obliterates the vein) or the long-pulsed Nd:YAG laser. Skin cancers can be managed with excision (including Mohs cancer surgery), cryosurgery, x-ray, or with the recent topical immune enhancing agent imiquimod. (See above section on "Dermatologic Surgery" for more details.) ## Psychodermatology and hypnodermatology Psychodermatology and hypnodermatology involve using hypnosis in combination with other pseudo-psychological therapies to treat skin disorders. # Training programs ## Residency training program in North America A minimum of 12 years of college and post graduate training is required to become a dermatologist in the United States and Canada. This includes graduation from a 4-year college where they will take Pre-Medicine, then a 4-year medical school followed by a year of post graduate training in medicine, surgery or pediatrics (called an internship) after which a physician may apply for admission to graduate dermatology residency training. Dermatology residencies are the most competitive in terms of admission[1][2]. Following the successful completion of formal residency training in dermatology (3 years) the physician is qualified to take certifying board examinations (written) by the American Board of Dermatology or the American Osteopathic College of Dermatology. Once board certified, dermatologists become Diplomates of the American Board of Dermatology or the American Osteopathic College of Dermatology AOCD. They are then eligible to apply for fellowship status in the American Academy of Dermatology. Some dermatologists undertake advanced subspecialty training in programs known as fellowships after completion of their residency training. These fellowships are either one or two years in duration. Fellowships in dermatology include pediatric dermatology, surgical dermatology including Mohs micrographic surgery, dermatopathology (pathology of skin diseases) and dermatological immunology. ## Training programme in Australia An Australian specialist dermatologist will have completed 4-6 years of medical school (depending on institution), one internship year and at least one year of general medical or surgical service in the public hospital system, prior to becoming eligible for specialist training in dermatology. The selection process is rigorous and transparent; candidates must pass science and pharmacology exams and engage in monitored and assessed practical training in all aspects of medical and surgical dermatology. At the completion of the 5 year training programme, trainees sit a national written examination held over two days. Successful candidates may then proceed to the practical viva examination, similarly held over 2 days. Successful candidates may then apply for Fellowship status with the Australasian College of Dermatologists. ## Training program in India To be a dermatologist in India, a minimum of 2 years (for diploma ) or 3 years (for MD) of training is required after graduation from medical school and internship. The period involves rigorous training in all aspects of general dermatology, cosmetic dermatology, dermatopathology, dermatosurgery, venereal diseases (including HIV) and leprosy. At the end of the training period the resident has to go through written tests and clinical exams. The postgraduate qualification awarded is DVD (Diploma in Venereology and Dermatology) and MD (dermatology, venereology and leprosy). Many specialists also go for certification by the national board (for the award of 'diplomate of national board'). The Indian Association of Dermatologists, Venereologists and Leprologists(IADVL)is one of the largest dermatolological associations in the world. # Research From the basic science of cutaneous genetics and immunology, to the practical application of new knowledge and technology in the diagnosis and management of skin disease (like psoriasis) and surgical treatment of skin cancer, dermatologists have been among the leaders in the field. The annual meeting of the American Academy of Dermatology is one of the keys for rapid dissemination of new knowledge to the practicing dermatologist and dermatologic surgeon. # Dermatological diseases - List of dermatological diseases # History The work De morbis cutaneis ("On the diseases of the skin" - 1572) by Geronimo Mercuriali from Forlì (Italy) is known as the first scientific tractation about Dermatology. Early photographic documentation of skin diseases was produced by Balmanno Squire, Dr. Alfred Hardy, Dr. A. de Montméja, Dr. Howard Franklin Damon, Dr. George Henry Fox and Dr. Oscar G. Mason in the latter 1800s. # Notes - ↑ Wu JJ, Tyring SK. ""...has been the most competitive of all specialties for at least the last 5-6 years." This is confirmed by data from the electronic residency application service (ERAS)". Retrieved 2007-06-23.CS1 maint: Uses authors parameter (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - ↑ Wu JJ, Ramirez CC, Alonso CA et al. ""Dermatology continues to be the most competitive residency to enter..." Arch Dermatol. 2006;142:845-850". Retrieved 2007-06-25.CS1 maint: Uses authors parameter (link) CS1 maint: Explicit use of et al. (link) # Further reading - Dermatology Times - a newsmagazine	https://www.wikidoc.org/index.php/Dermatological
ee3faa51593b8633df64c36a9b76601b8dd28a94	wikidoc	Dermorphine	Dermorphine Dermorphine is a hepta-peptide that sometimes is found in human blood and urine. It is a highly potent mu-agonist, originally isolated from the skin of the South American frog Phyllomedusa sauvaei. This peptide is quite difficult for the body to break down, and is thought to cause or worsen mental illness. Where dermorphine comes from is still a mystery, but it is clear that its source is microbial. The reason for this is that one of the amino acids in this peptide is not among the 20 encoded by DNA and cannot be produced by higher organisms. The guess is that bacteria or molds are responsible. - Structure of dermorphine: H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2 - Chemical formula: C40H50N8O10 - Molecular weight: 802.9 g/mol	Dermorphine Dermorphine is a hepta-peptide that sometimes is found in human blood and urine.[citation needed] It is a highly potent mu-agonist, originally isolated from the skin of the South American frog Phyllomedusa sauvaei. This peptide is quite difficult for the body to break down, and is thought to cause or worsen mental illness.[1] Where dermorphine comes from is still a mystery, but it is clear that its source is microbial. The reason for this is that one of the amino acids in this peptide is not among the 20 encoded by DNA and cannot be produced by higher organisms. The guess is that bacteria or molds are responsible. - Structure of dermorphine: H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2 - Chemical formula: C40H50N8O10 - Molecular weight: 802.9 g/mol	https://www.wikidoc.org/index.php/Dermorphine
1e8583ea8db96edff54bedb1de625e79013609bb	wikidoc	Desiccation	Desiccation # Overview Desiccation is the state of extreme dryness, or the process of extreme drying. A desiccant is a hygroscopic substance that induces or sustains such a state in its local vicinity in a moderately-well sealed container. # Science ## Desiccator In science, a desiccator is a heavy glass or plastic container used in practical chemistry for making or keeping small amounts of material very dry. The material is placed on a shelf, and a drying agent or desiccant, such as dry silica gel or anhydrous sodium hydroxide, is placed below the shelf. Often some sort of humidity indicator is included in the desiccator to show, by color changes, the level of humidity. These indicators are in the form of indicator plugs or indicator cards. The active chemical is cobalt chloride (CoCl2). Anhydrous cobalt chloride is blue. When it bonds with two water molecules, (CoCl22H2O), it turns purple. Further hydration results in the pink hexaaquacobalt(II) chloride complex 2+. # Biology and ecology In biology and ecology, desiccation refers to the drying out of a living organism, such as when aquatic animals are taken out of water, or when plants are exposed to sunlight or drought. Ecologists frequently study and assess various organisms' susceptibility to desiccation. # Broadcasting In broadcast engineering, a desiccator may be used to pressurize the feedline of a high-power transmitter. Because it carries very high electrical power levels from the transmitter to the antenna, the feedline must have a good dielectric. Because it must also be lightweight so as not to overload the radio tower, air is often used as the dielectric. Since moisture can condense in these lines, desiccated air or nitrogen gas is pumped in. This pressure also keeps water or other dampness from coming in the line at any point along its length.	Desiccation # Overview Desiccation is the state of extreme dryness, or the process of extreme drying. A desiccant is a hygroscopic substance that induces or sustains such a state in its local vicinity in a moderately-well sealed container. # Science ## Desiccator In science, a desiccator is a heavy glass or plastic container used in practical chemistry for making or keeping small amounts of material very dry. The material is placed on a shelf, and a drying agent or desiccant, such as dry silica gel or anhydrous sodium hydroxide, is placed below the shelf. Often some sort of humidity indicator is included in the desiccator to show, by color changes, the level of humidity. These indicators are in the form of indicator plugs or indicator cards. The active chemical is cobalt chloride (CoCl2). Anhydrous cobalt chloride is blue. When it bonds with two water molecules, (CoCl2•2H2O), it turns purple. Further hydration results in the pink hexaaquacobalt(II) chloride complex [Co(H2O)6]2+. # Biology and ecology In biology and ecology, desiccation refers to the drying out of a living organism, such as when aquatic animals are taken out of water, or when plants are exposed to sunlight or drought. Ecologists frequently study and assess various organisms' susceptibility to desiccation. # Broadcasting In broadcast engineering, a desiccator may be used to pressurize the feedline of a high-power transmitter. Because it carries very high electrical power levels from the transmitter to the antenna, the feedline must have a good dielectric. Because it must also be lightweight so as not to overload the radio tower, air is often used as the dielectric. Since moisture can condense in these lines, desiccated air or nitrogen gas is pumped in. This pressure also keeps water or other dampness from coming in the line at any point along its length.	https://www.wikidoc.org/index.php/Desiccation
d79a4d35b8837d968fc9ff6c7da70bc2c6e1b504	wikidoc	Desipramine	Desipramine # 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 Desipramine is a Tricyclic antidepressant that is FDA approved for the {{{indicationType}}} of depression. There is a Black Box Warning for this drug as shown here. Common adverse reactions include constipation, xerostomia, dizziness, somnolence, blurred vision, fatigue. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Depression - 100-200 mg/day PO, single or divided doses - Maximum 300 mg/day ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Desipramine in adult patients. ### Non–Guideline-Supported Use ### Attention deficit hyperactivity disorder - Safety and efficacy not established in the pediatric age group - 25 mg/day PO, maximum 5 mg/kg/day ### Diabetic neuropathy - 100-200 mg/day - There is limited information about Off-Label Non–Guideline-Supported Use of Desipramine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Desipramine 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 Desipramine in pediatric patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Desipramine in pediatric patients. # Contraindications - The use of MAOIs intended to treat psychiatric disorders with desipramine or within 14 days of stopping treatment with desipramine is contraindicated because of an increased risk of serotonin syndrome. - The use of desipramine within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated. - Starting desipramine in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome. - desipramine is contraindicated in the acute recovery period following myocardial infarction. It should not be used in those who have shown prior hypersensitivity to the drug. - Cross-sensitivity between this and other dibenzazepines is a possibility. # Warnings Clinical Worsening and Suicide Risk - Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (selective serotonin reuptake inhibitors and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18–24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. - The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. - Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo < 18 14 additional cases 18–24 5 additional cases Decreases Compared to Placebo 25–64 1 fewer case ≥65 6 fewer cases - No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. - It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. - All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. - The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. - Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. - Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for desipramine should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder - A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that desipramine is not approved for use in treating bipolar depression. Serotonin Syndrome - The development of a potentially life-threatening serotonin syndrome has been reported with serotonin norepinephrine reuptake inhibitors (SNRIs) and SSRIs, including desipramine, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). - Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. - The concomitant use of desipramine with MAOIs intended to treat psychiatric disorders is contraindicated. desipramine should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking desipramine. desipramine should be discontinued before initiating treatment with the MAOI . - If concomitant use of desipramine with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome particularly during treatment initiation and dose increases. - Treatment with desipramine and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. Extreme caution should be used when this drug is given in the following situations: - In patients with cardiovascular disease, because of the possibility of conduction defects, arrhythmias, tachycardias, strokes, and acute myocardial infarction. - In patients who have a family history of sudden death, cardiac dysrhythmias, or cardiac conduction disturbances. - In patients with a history of urinary retention or glaucoma, because of the anticholinergic properties of the drug. - In patients with thyroid disease or those taking thyroid medication, because of the possibility of cardiovascular toxicity, including arrhythmias. - In patients with a history of seizure disorder, because this drug has been shown to lower the seizure threshold. Seizures precede cardiac dysrhythmias and death in some patients. - This drug is capable of blocking the antihypertensive effect of guanethidine and similarly acting compounds. - The patient should be cautioned that this drug may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. - In patients who may use alcohol excessively, it should be borne in mind that the potentiation may increase the danger inherent in any suicide attempt or overdosage. # Adverse Reactions ## Clinical Trials Experience Central Nervous System Cardiovascular Gastrointestinal Hypersensitive Reactions Psychiatric Anticholinergic Endocrine Miscellaneous ## Postmarketing Experience There is limited information regarding Desipramine Postmarketing Experience in the drug label. # Drug Interactions - Drugs Metabolized by P450 2D6 - The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7% to 10% of Caucasians are so called "poor metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8 fold increase in plasma AUC of the TCA). - In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type IC antiarrhythmics propafenone and flecainide). While all the SSRIs, e.g., fluoxetine, sertraline, paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). - Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6. - Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with another drug known to be an inhibitor of P450 2D6. - Anticholinergic or sympathomimetic drugs. - Close supervision and careful adjustment of dosage are required when this drug is given concomitantly with anticholinergic or sympathomimetic drugs. - Alcoholic beverages - Patients should be warned that while taking this drug their response to alcoholic beverages may be exaggerated. - psychotropic agents. - If desipramine is to be combined with other psychotropic agents such as tranquilizers or sedative/hypnotics, careful consideration should be given to the pharmacology of the agents employed since the sedative effects of desipramine and benzodiazepines (e.g., chlordiazepoxide or diazepam) are additive. Both the sedative and anticholinergic effects of the major tranquilizers are also additive to those of desipramine. - MAOIs interactions. - Concomitant use of Monoamine Oxidase Inhibitors (MAOIs) and serotonergic drugs may potentially cause life threatening adverse events . # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Safe use of desipramine during pregnancy and lactation has not been established; therefore, if it is to be given to pregnant patients, nursing mothers, or women of childbearing potential, the possible benefits must be weighed against the possible hazards to mother and child. Animal reproductive studies have been inconclusive. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Desipramine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Desipramine during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Desipramine in women who are nursing. ### Pediatric Use - Safety and effectiveness in the pediatric population have not been established. Therefore, desipramine (desipramine hydrochloride) is not recommended for use in children. - Anyone considering the use of desipramine in a child or adolescent must balance the potential risks with the clinical need. ### Geriatic Use - Clinical studies of desipramine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Lower doses are recommended for elderly patients. - The ratio of 2-hydroxydesipramine to desipramine may be increased in the elderly, most likely due to decreased renal elimination with aging. - This drug is known to be substantially excreted by the kidney, and the risk of toxic 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. - desipramine use in the elderly has been associated with a proneness to falling as well as confusional states. ### Gender There is no FDA guidance on the use of Desipramine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Desipramine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Desipramine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Desipramine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Desipramine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Desipramine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Not recommended for use in children. - Lower dosages are recommended for elderly patients and adolescents. Lower dosages are also recommended for outpatients compared to hospitalized patients, who are closely supervised. Dosage should be initiated at a low level and increased according to clinical response and any evidence of intolerance. Following remission, maintenance medication may be required for a period of time and should be at the lowest dose that will maintain remission. - Usual Adult Dose The usual adult dose is 100 to 200 mg per day. In more severely ill patients, dosage may be further increased gradually to 300 mg/day if necessary. Dosages above 300 mg/day are not recommended. Dosage should be initiated at a lower level and increased according to tolerance and clinical response. Treatment of patients requiring as much as 300 mg should generally be initiated in hospitals, where regular visits by the physician, skilled nursing care, and frequent electrocardiograms (ECGs) are available. The best available evidence of impending toxicity from very high doses of desipramine is prolongation of the QRS or QT intervals on the ECG. Prolongation of the PR interval is also significant, but less closely correlated with plasma levels. Clinical symptoms of intolerance, especially drowsiness, dizziness, and postural hypotension, should also alert the physician to the need for reduction in dosage. - Initial therapy may be administered in divided doses or a single daily dose. - Maintenance therapy may be given on a once-daily schedule for patient convenience and compliance. - Adolescent and Geriatric Dose The usual adolescent and geriatric dose is 25 to 100 mg daily. Dosage should be initiated at a lower level and increased according to tolerance and clinical response to a usual maximum of 100 mg daily. In more severely ill patients, dosage may be further increased to 150 mg/day. Doses above 150 mg/day are not recommended in these age groups. - Initial therapy may be administered in divided doses or a single daily dose. - Maintenance therapy may be given on a once-daily schedule for patient convenience and compliance. - Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with desipramine. Conversely, at least 14 days should be allowed after stopping desipramine before starting an MAOI intended to treat psychiatric disorders . - Use of desipramine With Other MAOI's Such as Linezolid or Methylene Blue Do not start desipramine in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered. In some cases, a patient already receiving desipramine therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient,desipramine should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with desipramine may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue. The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with desipramine is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use. ### Monitoring There is limited information regarding Desipramine Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Desipramine and IV administrations. # Overdosage Deaths may occur from overdosage with this class of drugs. Overdose of desipramine has resulted in a higher death rate compared to overdoses of other tricyclic antidepressants. Multiple drug ingestion (including alcohol) is common in deliberate tricyclic antidepressant overdose. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic antidepressant overdose; therefore, hospital monitoring is required as soon as possible. There is no specific antidote for desipramine overdosage. - Oral LD50 The oral LD50 of desipramine is 290 mg/kg in male mice and 320 mg/kg in female rats. Manifestations of Overdosage Critical manifestations of overdose include: cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression, including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic antidepressant toxicity. Early changes in the QRS complex include a widening of the terminal 40 msec with a rightward axis in the frontal plane, recognized by the presence of a terminal S wave in Lead 1 and AVL and an R wave in AVR. Other signs of overdose may include: confusion, disturbed concentration, transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia, or any of the symptoms listed under ADVERSE REACTIONS. - Management: Aggressive supportive care and serum alkalinization are the mainstays of therapy. - General: Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient's airway, establish an intravenous line, and initiate gastric decontamination. A minimum of 6 hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary. If signs of toxicity occur at any time during this period, extended monitoring is required. Follow ECG, renal function, CPK, and arterial blood gasses as clinically indicated. There are case reports of patients succumbing to fatal dysrhythmias late after overdose; these patients had clinical evidence of significant poisoning prior to death, and most received inadequate gastrointestinal decontamination. Monitoring of plasma drug levels should not guide management of the patient. - Gastrointestinal Decontamination: Emesis is contraindicated. Activated charcoal should be administered to patients who present early after an overdose. - Cardiovascular: A maximal limb-lead QRS duration widening to greater than 100 msec is a significant indicator of toxicity, specifically for the risk of seizures and, eventually, cardiac dysrhythmias. Serum alkalinization with intravenous sodium bicarbonate and hyperventilation (as needed) should be instituted in patients manifesting significant toxicity such as QRS widening. Dysrhythmias despite adequate alkalemia may respond to overdrive pacing, beta-agonist infusions, and magnesium therapy. Type 1A and 1C antiarrhythmics are generally contraindicated (eg, quinidine, disopyramide, and procainamide). - CNS: In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines. If these are ineffective or seizures recur, other anticonvulsants (eg, phenobarbital, propofol) may be used. - Psychiatric Follow-up: Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate. - Pediatric Management: The principles of management of child and adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment. # Pharmacology ## Mechanism of Action Available evidence suggests that many depressions have a biochemical basis in the form of a relative deficiency of neurotransmitters such as norepinephrine and serotonin. Norepinephrine deficiency may be associated with relatively low urinary 3-methoxy-4-hydroxyphenyl glycol (MHPG) levels, while serotonin deficiencies may be associated with low spinal fluid levels of 5-hydroxyindoleacetic acid. While the precise mechanism of action of the tricyclic antidepressants is unknown, a leading theory suggests that they restore normal levels of neurotransmitters by blocking the re-uptake of these substances from the synapse in the central nervous system. Evidence indicates that the secondary amine tricyclic antidepressants, including desipramine, may have greater activity in blocking the re-uptake of norepinephrine. Tertiary amine tricyclic antidepressants, such as amitriptyline, may have greater effect on serotonin re-uptake. desipramine is not a monoamine oxidase inhibitor (MAOI) and does not act primarily as a central nervous system stimulant. It has been found in some studies to have a more rapid onset of action than imipramine. Earliest therapeutic effects may occasionally be seen in 2 to 5 days, but full treatment benefit usually requires 2 to 3 weeks to obtain. ## Structure ## Pharmacodynamics Tricyclic antidepressants, such as desipramine hydrochloride, are rapidly absorbed from the gastrointestinal tract. Tricyclic antidepressants or their metabolites are to some extent excreted through the gastric mucosa and reabsorbed from the gastrointestinal tract. Desipramine is metabolized in the liver, and approximately 70% is excreted in the urine. The rate of metabolism of tricyclic antidepressants varies widely from individual to individual, chiefly on a genetically determined basis. Up to a 36-fold difference in plasma level may be noted among individuals taking the same oral dose of desipramine. The ratio of 2-hydroxydesipramine to desipramine may be increased in the elderly, most likely due to decreased renal elimination with aging. Certain drugs, particularly the psychostimulants and the phenothiazines, increase plasma levels of concomitantly administered tricyclic antidepressants through competition for the same metabolic enzyme systems. Concurrent administration of cimetidine and tricyclic antidepressants can produce clinically significant increases in the plasma concentrations of the tricyclic antidepressants. Conversely, decreases in plasma levels of the tricyclic antidepressants have been reported upon discontinuation of cimetidine, which may result in the loss of the therapeutic efficacy of the tricyclic antidepressant. Other substances, particularly barbiturates and alcohol, induce liver enzyme activity and thereby reduce tricyclic antidepressant plasma levels. Similar effects have been reported with tobacco smoke. Research on the relationship of plasma level to therapeutic response with the tricyclic antidepressants has produced conflicting results. While some studies report no correlation, many studies cite therapeutic levels for most tricyclics in the range of 50 to 300 nanograms per milliliter. The therapeutic range is different for each tricyclic antidepressant. For desipramine, an optimal range of therapeutic plasma levels has not been established. ## Pharmacokinetics There is limited information regarding Desipramine Pharmacokinetics in the drug label. ## Nonclinical Toxicology There is limited information regarding Desipramine Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Desipramine Clinical Studies in the drug label. # How Supplied 10 mg blue coated tablets imprinted 68-7 NDC 0068-0007-01: bottles of 100 25 mg yellow coated tablets imprinted desipramine 25 NDC 0068-0011-01: bottles of 100 50 mg green coated tablets imprinted desipramine 50 NDC 0068-0015-01: bottles of 100 75 mg orange coated tablets imprinted desipramine 75 NDC 0068-0019-01: bottles of 100 100 mg peach coated tablets imprinted desipramine 100 NDC 0068-0020-01: bottles of 100 150 mg white coated tablets imprinted desipramine 150 NDC 0068-0021-50: bottles of 50 ## Storage Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) . Protect from excessive heat. Dispense in tight container. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with desipramine and should counsel them in its appropriate use. A patient Medication Guide about "Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions" is available for desipramine. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. - Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking desipramine. # Precautions with Alcohol - While taking this drug their response to alcoholic beverages may be exaggerated. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names There is limited information regarding Desipramine Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Desipramine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Desipramine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Pratik Bahekar, MBBS [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 Desipramine is a Tricyclic antidepressant that is FDA approved for the {{{indicationType}}} of depression. There is a Black Box Warning for this drug as shown here. Common adverse reactions include constipation, xerostomia, dizziness, somnolence, blurred vision, fatigue. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Depression - 100-200 mg/day PO, single or divided doses - Maximum 300 mg/day ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Desipramine in adult patients. ### Non–Guideline-Supported Use ### Attention deficit hyperactivity disorder - Safety and efficacy not established in the pediatric age group - 25 mg/day PO, maximum 5 mg/kg/day ### Diabetic neuropathy - 100-200 mg/day - There is limited information about Off-Label Non–Guideline-Supported Use of Desipramine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Desipramine 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 Desipramine in pediatric patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Desipramine in pediatric patients. # Contraindications - The use of MAOIs intended to treat psychiatric disorders with desipramine or within 14 days of stopping treatment with desipramine is contraindicated because of an increased risk of serotonin syndrome. - The use of desipramine within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated. - Starting desipramine in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome. - desipramine is contraindicated in the acute recovery period following myocardial infarction. It should not be used in those who have shown prior hypersensitivity to the drug. - Cross-sensitivity between this and other dibenzazepines is a possibility. # Warnings Clinical Worsening and Suicide Risk - Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (selective serotonin reuptake inhibitors [SSRIs] and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18–24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. - The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. - Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo < 18 14 additional cases 18–24 5 additional cases Decreases Compared to Placebo 25–64 1 fewer case ≥65 6 fewer cases - No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. - It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. - All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. - The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. - Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. - Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for desipramine should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder - A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that desipramine is not approved for use in treating bipolar depression. Serotonin Syndrome - The development of a potentially life-threatening serotonin syndrome has been reported with serotonin norepinephrine reuptake inhibitors (SNRIs) and SSRIs, including desipramine, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). - Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. - The concomitant use of desipramine with MAOIs intended to treat psychiatric disorders is contraindicated. desipramine should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking desipramine. desipramine should be discontinued before initiating treatment with the MAOI . - If concomitant use of desipramine with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome particularly during treatment initiation and dose increases. - Treatment with desipramine and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. Extreme caution should be used when this drug is given in the following situations: - In patients with cardiovascular disease, because of the possibility of conduction defects, arrhythmias, tachycardias, strokes, and acute myocardial infarction. - In patients who have a family history of sudden death, cardiac dysrhythmias, or cardiac conduction disturbances. - In patients with a history of urinary retention or glaucoma, because of the anticholinergic properties of the drug. - In patients with thyroid disease or those taking thyroid medication, because of the possibility of cardiovascular toxicity, including arrhythmias. - In patients with a history of seizure disorder, because this drug has been shown to lower the seizure threshold. Seizures precede cardiac dysrhythmias and death in some patients. - This drug is capable of blocking the antihypertensive effect of guanethidine and similarly acting compounds. - The patient should be cautioned that this drug may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. - In patients who may use alcohol excessively, it should be borne in mind that the potentiation may increase the danger inherent in any suicide attempt or overdosage. # Adverse Reactions ## Clinical Trials Experience Central Nervous System Cardiovascular Gastrointestinal Hypersensitive Reactions Psychiatric Anticholinergic Endocrine Miscellaneous ## Postmarketing Experience There is limited information regarding Desipramine Postmarketing Experience in the drug label. # Drug Interactions - Drugs Metabolized by P450 2D6 - The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7% to 10% of Caucasians are so called "poor metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8 fold increase in plasma AUC of the TCA). - In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type IC antiarrhythmics propafenone and flecainide). While all the SSRIs, e.g., fluoxetine, sertraline, paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). - Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6. - Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with another drug known to be an inhibitor of P450 2D6. - Anticholinergic or sympathomimetic drugs. - Close supervision and careful adjustment of dosage are required when this drug is given concomitantly with anticholinergic or sympathomimetic drugs. - Alcoholic beverages - Patients should be warned that while taking this drug their response to alcoholic beverages may be exaggerated. - psychotropic agents. - If desipramine is to be combined with other psychotropic agents such as tranquilizers or sedative/hypnotics, careful consideration should be given to the pharmacology of the agents employed since the sedative effects of desipramine and benzodiazepines (e.g., chlordiazepoxide or diazepam) are additive. Both the sedative and anticholinergic effects of the major tranquilizers are also additive to those of desipramine. - MAOIs interactions. - Concomitant use of Monoamine Oxidase Inhibitors (MAOIs) and serotonergic drugs may potentially cause life threatening adverse events . # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Safe use of desipramine during pregnancy and lactation has not been established; therefore, if it is to be given to pregnant patients, nursing mothers, or women of childbearing potential, the possible benefits must be weighed against the possible hazards to mother and child. Animal reproductive studies have been inconclusive. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Desipramine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Desipramine during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Desipramine in women who are nursing. ### Pediatric Use - Safety and effectiveness in the pediatric population have not been established. Therefore, desipramine (desipramine hydrochloride) is not recommended for use in children. - Anyone considering the use of desipramine in a child or adolescent must balance the potential risks with the clinical need. ### Geriatic Use - Clinical studies of desipramine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Lower doses are recommended for elderly patients. - The ratio of 2-hydroxydesipramine to desipramine may be increased in the elderly, most likely due to decreased renal elimination with aging. - This drug is known to be substantially excreted by the kidney, and the risk of toxic 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. - desipramine use in the elderly has been associated with a proneness to falling as well as confusional states. ### Gender There is no FDA guidance on the use of Desipramine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Desipramine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Desipramine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Desipramine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Desipramine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Desipramine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Not recommended for use in children. - Lower dosages are recommended for elderly patients and adolescents. Lower dosages are also recommended for outpatients compared to hospitalized patients, who are closely supervised. Dosage should be initiated at a low level and increased according to clinical response and any evidence of intolerance. Following remission, maintenance medication may be required for a period of time and should be at the lowest dose that will maintain remission. - Usual Adult Dose The usual adult dose is 100 to 200 mg per day. In more severely ill patients, dosage may be further increased gradually to 300 mg/day if necessary. Dosages above 300 mg/day are not recommended. Dosage should be initiated at a lower level and increased according to tolerance and clinical response. Treatment of patients requiring as much as 300 mg should generally be initiated in hospitals, where regular visits by the physician, skilled nursing care, and frequent electrocardiograms (ECGs) are available. The best available evidence of impending toxicity from very high doses of desipramine is prolongation of the QRS or QT intervals on the ECG. Prolongation of the PR interval is also significant, but less closely correlated with plasma levels. Clinical symptoms of intolerance, especially drowsiness, dizziness, and postural hypotension, should also alert the physician to the need for reduction in dosage. - Initial therapy may be administered in divided doses or a single daily dose. - Maintenance therapy may be given on a once-daily schedule for patient convenience and compliance. - Adolescent and Geriatric Dose The usual adolescent and geriatric dose is 25 to 100 mg daily. Dosage should be initiated at a lower level and increased according to tolerance and clinical response to a usual maximum of 100 mg daily. In more severely ill patients, dosage may be further increased to 150 mg/day. Doses above 150 mg/day are not recommended in these age groups. - Initial therapy may be administered in divided doses or a single daily dose. - Maintenance therapy may be given on a once-daily schedule for patient convenience and compliance. - Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with desipramine. Conversely, at least 14 days should be allowed after stopping desipramine before starting an MAOI intended to treat psychiatric disorders . - Use of desipramine With Other MAOI's Such as Linezolid or Methylene Blue Do not start desipramine in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered. In some cases, a patient already receiving desipramine therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient,desipramine should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with desipramine may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue. The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with desipramine is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use. ### Monitoring There is limited information regarding Desipramine Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Desipramine and IV administrations. # Overdosage Deaths may occur from overdosage with this class of drugs. Overdose of desipramine has resulted in a higher death rate compared to overdoses of other tricyclic antidepressants. Multiple drug ingestion (including alcohol) is common in deliberate tricyclic antidepressant overdose. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic antidepressant overdose; therefore, hospital monitoring is required as soon as possible. There is no specific antidote for desipramine overdosage. - Oral LD50 The oral LD50 of desipramine is 290 mg/kg in male mice and 320 mg/kg in female rats. Manifestations of Overdosage Critical manifestations of overdose include: cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression, including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic antidepressant toxicity. Early changes in the QRS complex include a widening of the terminal 40 msec with a rightward axis in the frontal plane, recognized by the presence of a terminal S wave in Lead 1 and AVL and an R wave in AVR. Other signs of overdose may include: confusion, disturbed concentration, transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia, or any of the symptoms listed under ADVERSE REACTIONS. - Management: Aggressive supportive care and serum alkalinization are the mainstays of therapy. - General: Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient's airway, establish an intravenous line, and initiate gastric decontamination. A minimum of 6 hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary. If signs of toxicity occur at any time during this period, extended monitoring is required. Follow ECG, renal function, CPK, and arterial blood gasses as clinically indicated. There are case reports of patients succumbing to fatal dysrhythmias late after overdose; these patients had clinical evidence of significant poisoning prior to death, and most received inadequate gastrointestinal decontamination. Monitoring of plasma drug levels should not guide management of the patient. - Gastrointestinal Decontamination: Emesis is contraindicated. Activated charcoal should be administered to patients who present early after an overdose. - Cardiovascular: A maximal limb-lead QRS duration widening to greater than 100 msec is a significant indicator of toxicity, specifically for the risk of seizures and, eventually, cardiac dysrhythmias. Serum alkalinization with intravenous sodium bicarbonate and hyperventilation (as needed) should be instituted in patients manifesting significant toxicity such as QRS widening. Dysrhythmias despite adequate alkalemia may respond to overdrive pacing, beta-agonist infusions, and magnesium therapy. Type 1A and 1C antiarrhythmics are generally contraindicated (eg, quinidine, disopyramide, and procainamide). - CNS: In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines. If these are ineffective or seizures recur, other anticonvulsants (eg, phenobarbital, propofol) may be used. - Psychiatric Follow-up: Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate. - Pediatric Management: The principles of management of child and adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment. # Pharmacology ## Mechanism of Action Available evidence suggests that many depressions have a biochemical basis in the form of a relative deficiency of neurotransmitters such as norepinephrine and serotonin. Norepinephrine deficiency may be associated with relatively low urinary 3-methoxy-4-hydroxyphenyl glycol (MHPG) levels, while serotonin deficiencies may be associated with low spinal fluid levels of 5-hydroxyindoleacetic acid. While the precise mechanism of action of the tricyclic antidepressants is unknown, a leading theory suggests that they restore normal levels of neurotransmitters by blocking the re-uptake of these substances from the synapse in the central nervous system. Evidence indicates that the secondary amine tricyclic antidepressants, including desipramine, may have greater activity in blocking the re-uptake of norepinephrine. Tertiary amine tricyclic antidepressants, such as amitriptyline, may have greater effect on serotonin re-uptake. desipramine is not a monoamine oxidase inhibitor (MAOI) and does not act primarily as a central nervous system stimulant. It has been found in some studies to have a more rapid onset of action than imipramine. Earliest therapeutic effects may occasionally be seen in 2 to 5 days, but full treatment benefit usually requires 2 to 3 weeks to obtain. ## Structure ## Pharmacodynamics Tricyclic antidepressants, such as desipramine hydrochloride, are rapidly absorbed from the gastrointestinal tract. Tricyclic antidepressants or their metabolites are to some extent excreted through the gastric mucosa and reabsorbed from the gastrointestinal tract. Desipramine is metabolized in the liver, and approximately 70% is excreted in the urine. The rate of metabolism of tricyclic antidepressants varies widely from individual to individual, chiefly on a genetically determined basis. Up to a 36-fold difference in plasma level may be noted among individuals taking the same oral dose of desipramine. The ratio of 2-hydroxydesipramine to desipramine may be increased in the elderly, most likely due to decreased renal elimination with aging. Certain drugs, particularly the psychostimulants and the phenothiazines, increase plasma levels of concomitantly administered tricyclic antidepressants through competition for the same metabolic enzyme systems. Concurrent administration of cimetidine and tricyclic antidepressants can produce clinically significant increases in the plasma concentrations of the tricyclic antidepressants. Conversely, decreases in plasma levels of the tricyclic antidepressants have been reported upon discontinuation of cimetidine, which may result in the loss of the therapeutic efficacy of the tricyclic antidepressant. Other substances, particularly barbiturates and alcohol, induce liver enzyme activity and thereby reduce tricyclic antidepressant plasma levels. Similar effects have been reported with tobacco smoke. Research on the relationship of plasma level to therapeutic response with the tricyclic antidepressants has produced conflicting results. While some studies report no correlation, many studies cite therapeutic levels for most tricyclics in the range of 50 to 300 nanograms per milliliter. The therapeutic range is different for each tricyclic antidepressant. For desipramine, an optimal range of therapeutic plasma levels has not been established. ## Pharmacokinetics There is limited information regarding Desipramine Pharmacokinetics in the drug label. ## Nonclinical Toxicology There is limited information regarding Desipramine Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Desipramine Clinical Studies in the drug label. # How Supplied 10 mg blue coated tablets imprinted 68-7 NDC 0068-0007-01: bottles of 100 25 mg yellow coated tablets imprinted desipramine 25 NDC 0068-0011-01: bottles of 100 50 mg green coated tablets imprinted desipramine 50 NDC 0068-0015-01: bottles of 100 75 mg orange coated tablets imprinted desipramine 75 NDC 0068-0019-01: bottles of 100 100 mg peach coated tablets imprinted desipramine 100 NDC 0068-0020-01: bottles of 100 150 mg white coated tablets imprinted desipramine 150 NDC 0068-0021-50: bottles of 50 ## Storage Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature]. Protect from excessive heat. Dispense in tight container. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with desipramine and should counsel them in its appropriate use. A patient Medication Guide about "Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions" is available for desipramine. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. - Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking desipramine. # Precautions with Alcohol - While taking this drug their response to alcoholic beverages may be exaggerated. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names There is limited information regarding Desipramine Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Desipramine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Desipramine
227b90a2740619ba945ec7d5c79a491ea4fb89dd	wikidoc	Desmoplakin	Desmoplakin Desmoplakin is a protein in humans that is encoded by the DSP gene. Desmoplakin is a critical component of desmosome structures in cardiac muscle and epidermal cells, which function to maintain the structural integrity at adjacent cell contacts. In cardiac muscle, desmoplakin is localized to intercalated discs which mechanically couple cardiac cells to function in a coordinated syncytial structure. Mutations in desmoplakin have been shown to play a role in dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, striate palmoplantar keratoderma, Carvajal syndrome and paraneoplastic pemphigus. # Structure Desmoplakin exists as two predominant isoforms; the first, known as "DPII", has molecular weight 260.0 kDa (2272 amino acids) and the second, known as "DPI", has molecular weight 332.0 kDa (2871 amino acids). These isoforms are identical except for the shorter rod domain in DPII. DPI is the predominant isoform expressed in cardiac muscle. The DSP gene is located on chromosome 6p24.3, containing 24 exons and spanning approximately 45 kDa of genomic DNA. Desmoplakin is a large desmosomal plaque protein that homodimerizes and adopts a dumbbell-shaped conformation. The N-terminal globular head domain of desmoplakin is composed of a series of alpha helical bundles, and is required for both the localization to the desmosome and interaction with the N-terminal region of plakophilin 1 and plakoglobin as well as desmocollin and desmoglein. This is further sub divided into a region called the "Plakin domain" made up of six spectrin repeat domains separated by SH3 domain. A crystal structure of part of the plakin domain has been resolved, while the entire plakin domain has been elucidated using small angle X-ray scattering which revealed a non-linear structure, an unexpected result considering spectrin repeats are observed in linear orientations. The C-terminal region of desmoplakin is composed of three plakin repeat domains, termed A, B and C, which are essential for coalignment and binding of intermediate filaments. Located at the most distal C-terminus of desmoplakin is a region rich in glycine–serine–arginine; it has been demonstrated that serine phosphorylation of this domain may modify desmoplakin-intermediate filament interactions. In the mid-region of desmoplakin, a coiled-coil rod domain is responsible for homodimerization. # Function Desmosomes are intercellular junctions that tightly link adjacent cells. Desmoplakin is an obligate component of functional desmosomes that anchors intermediate filaments to desmosomal plaques. In cardiomyocytes, desmoplakin forms desmosomal plaques with the intermediate filament desmin, whereas in endothelial cells cytokeratin type intermediate filaments are recruited, and vimentin in arachnoid and follicular dendritic cell types. Both types of intermediate filaments attach in a lateral fashion to desmoplakin to form the plaque. In cardiac muscle, desmoplakin is localized to desmosomes in intercalated discs. Desmoplakin isoform DPI is highly expressed and is thought to play a role in both the assembly and stabilization of desmosomes; its role is critical, as desmoplakin knockout mice display embryonic lethality. In mice overexpressing a C-terminal mutated desmoplakin protein, desmoplakin binding to desmin is disrupted in cardiac muscle and hearts display abnormal intercalated disc formation and structure. Much has been learned regarding desmoplakin function from mutations in patients with arrhythmogenic right ventricular cardiomyopathy, where mutations in specific binding domains alter desmoplakin binding to plakoglobin or desmin and result in cell death and dysfunction. # Clinical significance Mutations in this gene are the cause of several cardiomyopathies, including dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. Mutations in DSP have also been associated with striate palmoplantar keratoderma. Carvajal syndrome results from an autosomal recessive mutation of a frameshift (7901delG) in DSP that results in a combination of above conditions, including dilated cardiomyopathy, keratoderma and woolly hair. Patients with Carvajal syndrome often suffer from heart failure in teenage years. A case of compound heterozygosity for two DSP nonsense mutations resulting in lethal acantholytic epidermolysis bullosa has been reported. Autoantibodies to DSP are a hallmark of the autoimmune disease paraneoplastic pemphigus. Decreased desmoplakin expression has been found in patients with oropharyngeal cancer and breast cancer, which may alter cell-cell adhesion properties and propagate metastasis. # Interactions Desmoplakin has been shown to interact with: - Desmin, - Keratin 1, - PKP1 - PKP2, - Plakoglobin, and - Vimentin.	Desmoplakin Desmoplakin is a protein in humans that is encoded by the DSP gene.[1][2][3] Desmoplakin is a critical component of desmosome structures in cardiac muscle and epidermal cells, which function to maintain the structural integrity at adjacent cell contacts. In cardiac muscle, desmoplakin is localized to intercalated discs which mechanically couple cardiac cells to function in a coordinated syncytial structure. Mutations in desmoplakin have been shown to play a role in dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, striate palmoplantar keratoderma, Carvajal syndrome and paraneoplastic pemphigus. # Structure Desmoplakin exists as two predominant isoforms; the first, known as "DPII", has molecular weight 260.0 kDa (2272 amino acids) and the second, known as "DPI", has molecular weight 332.0 kDa (2871 amino acids).[4][5] These isoforms are identical except for the shorter rod domain in DPII. DPI is the predominant isoform expressed in cardiac muscle.[6] The DSP gene is located on chromosome 6p24.3, containing 24 exons and spanning approximately 45 kDa of genomic DNA.[7] Desmoplakin is a large desmosomal plaque protein that homodimerizes and adopts a dumbbell-shaped conformation.[7] The N-terminal globular head domain of desmoplakin is composed of a series of alpha helical bundles, and is required for both the localization to the desmosome and interaction with the N-terminal region of plakophilin 1 and plakoglobin as well as desmocollin and desmoglein.[8] This is further sub divided into a region called the "Plakin domain" made up of six spectrin repeat domains separated by SH3 domain.[9] A crystal structure of part of the plakin domain has been resolved,[10] while the entire plakin domain has been elucidated using small angle X-ray scattering which revealed a non-linear structure, an unexpected result considering spectrin repeats are observed in linear orientations.[11] The C-terminal region of desmoplakin is composed of three plakin repeat domains, termed A, B and C, which are essential for coalignment and binding of intermediate filaments.[8][12][13] Located at the most distal C-terminus of desmoplakin is a region rich in glycine–serine–arginine; it has been demonstrated that serine phosphorylation of this domain may modify desmoplakin-intermediate filament interactions.[14] In the mid-region of desmoplakin, a coiled-coil rod domain is responsible for homodimerization.[15] # Function Desmosomes are intercellular junctions that tightly link adjacent cells. Desmoplakin is an obligate component of functional desmosomes that anchors intermediate filaments to desmosomal plaques. In cardiomyocytes, desmoplakin forms desmosomal plaques with the intermediate filament desmin, whereas in endothelial cells cytokeratin type intermediate filaments are recruited, and vimentin in arachnoid and follicular dendritic cell types.[15][16] Both types of intermediate filaments attach in a lateral fashion to desmoplakin to form the plaque.[17] In cardiac muscle, desmoplakin is localized to desmosomes in intercalated discs. Desmoplakin isoform DPI is highly expressed and is thought to play a role in both the assembly and stabilization of desmosomes; its role is critical, as desmoplakin knockout mice display embryonic lethality.[18] In mice overexpressing a C-terminal mutated desmoplakin protein, desmoplakin binding to desmin is disrupted in cardiac muscle and hearts display abnormal intercalated disc formation and structure.[19] Much has been learned regarding desmoplakin function from mutations in patients with arrhythmogenic right ventricular cardiomyopathy, where mutations in specific binding domains alter desmoplakin binding to plakoglobin or desmin and result in cell death and dysfunction.[20] # Clinical significance Mutations in this gene are the cause of several cardiomyopathies, including dilated cardiomyopathy[21][22] and arrhythmogenic right ventricular cardiomyopathy.[19][23][24][25][26][11] Mutations in DSP have also been associated with striate palmoplantar keratoderma.[21][25][27][28][29] Carvajal syndrome results from an autosomal recessive mutation of a frameshift (7901delG) in DSP that results in a combination of above conditions, including dilated cardiomyopathy, keratoderma and woolly hair.[30] Patients with Carvajal syndrome often suffer from heart failure in teenage years. A case of compound heterozygosity for two DSP nonsense mutations resulting in lethal acantholytic epidermolysis bullosa has been reported.[31][32] Autoantibodies to DSP are a hallmark of the autoimmune disease paraneoplastic pemphigus.[33][34] Decreased desmoplakin expression has been found in patients with oropharyngeal cancer and breast cancer, which may alter cell-cell adhesion properties and propagate metastasis.[35][36] # Interactions Desmoplakin has been shown to interact with: - Desmin,[37] - Keratin 1,[37] - PKP1[38] - PKP2,[39] - Plakoglobin,[40][41] and - Vimentin.[37]	https://www.wikidoc.org/index.php/Desmoplakin
23fb6f1ca915c4999df899d11eebd81db33c2338	wikidoc	Desmoplasia	Desmoplasia # Overview In medicine, desmoplasia refers to the formation of adhesions or fibrosis (fibrosis refers to scar tissue) in the vascular stroma of a neoplasm. It is usually used in the description of desmoplastic small round cell tumors. # Historical Perspective Desmoplasia originates from the Greek desmos (meaning fetter or band) and plasia (meaning to form). # Pathophysiology ## Gross Pathology Usually you only see desmoplasia with malignant neoplasms, which can evoke a fibrosis response by invading healthy tissue. ## Microscopic Pathology Infiltrating metastatic ductal carcinomas of the breast often have a scirrous, stellate appearance caused by desmoplastic formations.	Desmoplasia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview In medicine, desmoplasia refers to the formation of adhesions or fibrosis (fibrosis refers to scar tissue) in the vascular stroma of a neoplasm. It is usually used in the description of desmoplastic small round cell tumors. # Historical Perspective Desmoplasia originates from the Greek desmos (meaning fetter or band) and plasia (meaning to form). # Pathophysiology ## Gross Pathology Usually you only see desmoplasia with malignant neoplasms, which can evoke a fibrosis response by invading healthy tissue. ## Microscopic Pathology Infiltrating metastatic ductal carcinomas of the breast often have a scirrous, stellate appearance caused by desmoplastic formations. Template:WH Template:WS	https://www.wikidoc.org/index.php/Desmoplasia
5a86568b002a04f352007e2b41a59fcacb00917c	wikidoc	Tolterodine	Tolterodine # 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 Tolterodine is a cholinergic muscarinic antagonist that is FDA approved for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency. Common adverse reactions include abdominal pain, constipation, xerostomia, headache. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Overactive Bladder - Dosing information - Initial recommended dose: 2 mg PO bid. - The dose may be lowered to 1 mg twice daily based on individual response and tolerability. - For patients with significantly reduced hepatic or renal function or who are currently taking drugs that are potent inhibitors of CYP3A4 - Recommended dose: 1 mg PO bid ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of tolterodine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of tolterodine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The pharmacokinetics of tolterodine have not been established in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of tolterodine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of tolterodine in pediatric patients. # Contraindications - DETROL tablets are contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma. DETROL is also contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients, or to fesoterodine fumarate extended-release tablets which, like DETROL, are metabolized to 5-hydroxymethyl tolterodine. # Warnings - Anaphylaxis and angioedema requiring hospitalization and emergency medical treatment have occurred with the first or subsequent doses of DETROL. In the event of difficulty in breathing, upper airway obstruction, or fall in blood pressure, DETROL should be discontinued and appropriate therapy promptly provided. # Adverse Reactions ## Clinical Trials Experience - The Phase 2 and 3 clinical trial program for DETROL tablets included 3071 patients who were treated with DETROL (N=2133) or placebo (N=938). The patients were treated with 1, 2, 4, or 8 mg/day for up to 12 months. No differences in the safety profile of tolterodine were identified based on age, gender, race, or metabolism. - The data described below reflect exposure to DETROL 2 mg bid in 986 patients and to placebo in 683 patients exposed for 12 weeks in five Phase 3, controlled clinical studies. 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 adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and approximating rates. Sixty-six percent of patients receiving DETROL 2 mg bid reported adverse events versus 56% of placebo patients. The most common adverse events reported by patients receiving DETROL were dry mouth, headache, constipation, vertigo/dizziness, and abdominal pain. Dry mouth, constipation, abnormal vision (accommodation abnormalities), urinary retention, and xerophthalmia are expected side effects of antimuscarinic agents. Dry mouth was the most frequently reported adverse event for patients treated with DETROL 2 mg bid in the Phase 3 clinical studies, occurring in 34.8% of patients treated with DETROL and 9.8% of placebo-treated patients. One percent of patients treated with DETROL discontinued treatment due to dry mouth. The frequency of discontinuation due to adverse events was highest during the first 4 weeks of treatment. Seven percent of patients treated with DETROL 2 mg bid discontinued treatment due to adverse events versus 6% of placebo patients. The most common adverse events leading to discontinuation of DETROL were dizziness and headache. - Three percent of patients treated with DETROL 2 mg bid reported a serious adverse event versus 4% of placebo patients. Significant ECG changes in QT and QTc have not been demonstrated in clinical-study patients treated with DETROL 2 mg bid. Table 5 lists the adverse events reported in 1% or more of the patients treated with DETROL 2 mg bid in the 12-week studies. The adverse events are reported regardless of causality. ## Postmarketing Experience - The following events have been reported in association with tolterodine use in worldwide post-marketing experience: General: anaphylaxis and angioedema; Cardiovascular: tachycardia, palpitations, peripheral edema; Central/Peripheral Nervous: confusion, disorientation, memory impairment, hallucinations. - Reports of aggravation of symptoms of dementia (e.g., confusion, disorientation, delusion) have been reported after tolterodine therapy was initiated in patients taking cholinesterase inhibitors for the treatment of dementia. - Because these spontaneously reported events are from the worldwide post-marketing experience, the frequency of events and the role of tolterodine in their causation cannot be reliably determined. # Drug Interactions ### Fluoxetine - Fluoxetine is a selective serotonin reuptake inhibitor and a potent inhibitor of CYP2D6 activity. In a study to assess the effect of fluoxetine on the pharmacokinetics of tolterodine immediate release and its metabolites, it was observed that fluoxetine significantly inhibited the metabolism of tolterodine immediate release in extensive metabolizers, resulting in a 4.8-fold increase in tolterodine AUC. There was a 52% decrease in Cmax and a 20% decrease in AUC of the 5-hydroxymethyl metabolite. Fluoxetine thus alters the pharmacokinetics in patients who would otherwise be extensive metabolizers of tolterodine immediate release to resemble the pharmacokinetic profile in poor metabolizers. The sums of unbound serum concentrations of tolterodine immediate release and the 5-hydroxymethyl metabolite are only 25% higher during the interaction. No dose adjustment is required when DETROL and fluoxetine are coadministered. ### Other Drugs Metabolized by Cytochrome P450 Isoenzymes - Tolterodine immediate release does not cause clinically significant interactions with other drugs metabolized by the major drug metabolizing CYP enzymes. In vivo drug-interaction data show that tolterodine immediate release does not result in clinically relevant inhibition of CYP1A2, 2D6, 2C9, 2C19, or 3A4 as evidenced by lack of influence on the marker drugs caffeine, debrisoquine, S-warfarin, and omeprazole. In vitro data show that tolterodine immediate release is a competitive inhibitor of CYP2D6 at high concentrations (Ki 1.05 µM), while tolterodine immediate release as well as the 5-hydroxymethyl metabolite are devoid of any significant inhibitory potential regarding the other isoenzymes. ### CYP3A4 Inhibitors - The effect of 200 mg daily dose of ketoconazole on the pharmacokinetics of tolterodine immediate release was studied in 8 healthy volunteers, all of whom were poor metabolizers (see Pharmacokinetics,Variability in Metabolism for discussion of poor metabolizers). In the presence of ketoconazole, the mean Cmax and AUC of tolterodine increased by 2 and 2.5 fold, respectively. Based on these findings, other potent CYP3A inhibitors such as other azole antifungals (eg, itraconazole, miconazole) or macrolide antibiotics (eg, erythromycin, clarithromycin) or cyclosporine or vinblastine may also lead to increases of tolterodine plasma concentrations . ### Warfarin - In healthy volunteers, co administration of tolterodine immediate release 4 mg (2 mg bid) for 7 days and a single dose of warfarin 25 mg on day 4 had no effect on prothrombin time, factor VII suppression, or on the pharmacokinetics of warfarin. ### Oral Contraceptives - Tolterodine immediate release 4 mg (2 mg bid) had no effect on the pharmacokinetics of an oral contraceptive (ethinyl estradiol 30 µg/levonorgestrel 150 µg) as evidenced by the monitoring of ethinyl estradiol and levonorgestrel over a 2-month cycle in healthy female volunteers. ### Diuretics - Co administration of tolterodine immediate release up to 8 mg (4 mg bid) for up to 12 weeks with diuretic agents, such as indapamide, hydrochlorothiazide, triamterene, bendroflumethiazide, chlorothiazide, methylchlorothiazide, or furosemide, did not cause any adverse electrocardiographic (ECG) effects. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C Pregnancy Category C - At oral doses of 20 mg/kg/day (approximately 14 times the human exposure), no anomalies or malformations were observed in mice. When given at doses of 30 to 40 mg/kg/day, tolterodine has been shown to be embryolethal, reduce fetal weight, and increase the incidence of fetal abnormalities (cleft palate, digital abnormalities, intra-abdominal hemorrhage, and various skeletal abnormalities, primarily reduced ossification) in mice. At these doses, the AUC values were about 20- to 25-fold higher than in humans. Rabbits treated subcutaneously at a dose of 0.8 mg/kg/day achieved an AUC of 100 µg∙h/L, which is about 3-fold higher than that resulting from the human dose. This dose did not result in any embryotoxicity or teratogenicity. There are no studies of tolterodine in pregnant women. Therefore, DETROL should be used during pregnancy only if the potential benefit for the mother justifies the potential risk to the fetus. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tolterodine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Tolterodine during labor and delivery. ### Nursing Mothers Tolterodine is excreted into the milk in mice. Offspring of female mice treated with tolterodine 20 mg/kg/day during the lactation period had slightly reduced body weight gain. The offspring regained the weight during the maturation phase. It is not known whether tolterodine is excreted in human milk; therefore, DETROL should not be administered during nursing. A decision should be made whether to discontinue nursing or to discontinue DETROL in nursing mothers. ### Pediatric Use Efficacy in the pediatric population has not been demonstrated. - Two pediatric phase 3 randomized, placebo-controlled, double-blind, 12-week studies were conducted using tolterodine extended release (DETROL LA) capsules. A total of 710 pediatric patients (486 on DETROL LA and 224 on placebo) aged 5–10 years with urinary frequency and urge urinary incontinence were studied. The percentage of patients with urinary tract infections was higher in patients treated with DETROL LA (6.6%) compared to patients who received placebo (4.5%). Aggressive, abnormal and hyperactive behavior and attention disorders occurred in 2.9% of children treated with DETROL LA compared to 0.9% of children treated with placebo. ### Geriatic Use - Of the 1120 patients who were treated in the four Phase 3, 12-week clinical studies of DETROL, 474 (42%) were 65 to 91 years of age. No overall differences in safety were observed between the older and younger patients. ### Gender There is no FDA guidance on the use of Tolterodine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Tolterodine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Tolterodine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Tolterodine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Tolterodine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Tolterodine in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring FDA package insert for tolterodine contains no information regarding drug monitoring. # IV Compatibility There is limited information about the IV compatibility. # Overdosage - A 27-month-old child who ingested 5 to 7 DETROL Tablets 2 mg was treated with a suspension of activated charcoal and was hospitalized overnight with symptoms of dry mouth. The child fully recovered. ### Management of Overdosage - Overdosage with DETROL can potentially result in severe central anticholinergic effects and should be treated accordingly. ECG monitoring is recommended in the event of overdosage. In dogs, changes in the QT interval (slight prolongation of 10% to 20%) were observed at a suprapharmacologic dose of 4.5 mg/kg, which is about 68 times higher than the recommended human dose. In clinical trials of normal volunteers and patients, QT interval prolongation was observed with tolterodine immediate release at doses up to 8 mg (4 mg bid) and higher doses were not evaluated # Pharmacology ## Mechanism of Action - FDA package insert for tolterodine contains no information regarding mechanism of action. ## Structure - DETROL Tablets contain tolterodine tartrate. The active moiety, tolterodine, is a muscarinic receptor antagonist. The chemical name of tolterodine tartrate is (R)-2-1-phenylpropyl]-4-methylphenol -2,3dihydroxybutanedioate (1:1) (salt). The empirical formula of tolterodine tartrate is C26H37NO7, and its molecular weight is 475.6. The structural formula of tolterodine tartrate is represented below: - Tolterodine tartrate is a white, crystalline powder. The pKa value is 9.87 and the solubility in water is 12 mg/mL. It is soluble in methanol, slightly soluble in ethanol, and practically insoluble in toluene. The partition coefficient (Log D) between n-octanol and water is 1.83 at pH 7.3. DETROL Tablets for oral administration contain 1 or 2 mg of tolterodine tartrate. The inactive ingredients are colloidal anhydrous silica, calcium hydrogen phosphate dihydrate, cellulose microcrystalline, hypromellose, magnesium stearate, sodium starch glycolate (pH 3.0 to 5.0), stearic acid, and titanium dioxide. ## Pharmacodynamics FDA package insert for tolterodine contains no information regarding pharmacodynamics. ## Pharmacokinetics ### Absorption - In a study with 14C-tolterodine solution in healthy volunteers who received a 5-mg oral dose, at least 77% of the radiolabeled dose was absorbed. Tolterodine immediate release is rapidly absorbed, and maximum serum concentrations (Cmax) typically occur within 1 to 2 hours after dose administration. Cmax and area under the concentration-time curve (AUC) determined after dosage of tolterodine immediate release are dose-proportional over the range of 1 to 4 mg. ### Effect of Food - Food intake increases the bioavailability of tolterodine (average increase 53%), but does not affect the levels of the 5-hydroxymethyl metabolite in extensive metabolizers. This change is not expected to be a safety concern and adjustment of dose is not needed. ### Distribution - Tolterodine is highly bound to plasma proteins, primarily α1-acid glycoprotein. Unbound concentrations of tolterodine average 3.7% ± 0.13% over the concentration range achieved in clinical studies. The 5-hydroxymethyl metabolite is not extensively protein bound, with unbound fraction concentrations averaging 36% ± 4.0%. The blood to serum ratio of tolterodine and the 5-hydroxymethyl metabolite averages 0.6 and 0.8, respectively, indicating that these compounds do not distribute extensively into erythrocytes. The volume of distribution of tolterodine following administration of a 1.28-mg intravenous dose is 113 ± 26.7 L. ### Metabolism - Tolterodine is extensively metabolized by the liver following oral dosing. The primary metabolic route involves the oxidation of the 5-methyl group and is mediated by the cytochrome P450 2D6 (CYP2D6) and leads to the formation of a pharmacologically active 5-hydroxymethyl metabolite. Further metabolism leads to formation of the 5-carboxylic acid and N-dealkylated 5-carboxylic acid metabolites, which account for 51% ± 14% and 29% ± 6.3% of the metabolites recovered in the urine, respectively. Variability in Metabolism - A subset (about 7%) of the population is devoid of CYP2D6, the enzyme responsible for the formation of the 5-hydroxymethyl metabolite of tolterodine. The identified pathway of metabolism for these individuals ("poor metabolizers") is dealkylation via cytochrome P450 3A4 (CYP3A4) to N-dealkylated tolterodine. The remainder of the population is referred to as "extensive metabolizers." Pharmacokinetic studies revealed that tolterodine is metabolized at a slower rate in poor metabolizers than in extensive metabolizers; this results in significantly higher serum concentrations of tolterodine and in negligible concentrations of the 5-hydroxymethyl metabolite. ### Excretion - Following administration of a 5-mg oral dose of 14C-tolterodine solution to healthy volunteers, 77% of radioactivity was recovered in urine and 17% was recovered in feces in 7 days. Less than 1% (<2.5% in poor metabolizers) of the dose was recovered as intact tolterodine, and 5% to 14% (<1% in poor metabolizers) was recovered as the active 5-hydroxymethyl metabolite. - A summary of mean (± standard deviation) pharmacokinetic parameters of tolterodine immediate release and the 5-hydroxymethyl metabolite in extensive (EM) and poor (PM) metabolizers is provided in Table 1. These data were obtained following single and multiple doses of tolterodine 4 mg administered twice daily to 16 healthy male volunteers (8 EM, 8 PM). ### Pharmacokinetics in Special Populations Age - In Phase 1, multiple-dose studies in which tolterodine immediate release 4 mg (2 mg bid) was administered, serum concentrations of tolterodine and of the 5-hydroxymethyl metabolite were similar in healthy elderly volunteers (aged 64 through 80 years) and healthy young volunteers (aged less than 40 years). In another Phase 1 study, elderly volunteers (aged 71 through 81 years) were given tolterodine immediate release 2 or 4 mg (1 or 2 mg bid). Mean serum concentrations of tolterodine and the 5-hydroxymethyl metabolite in these elderly volunteers were approximately 20% and 50% higher, respectively, than reported in young healthy volunteers. However, no overall differences were observed in safety between older and younger patients on tolterodine in Phase 3, 12-week, controlled clinical studies; therefore, no tolterodine dosage adjustment for elderly patients is recommended . Pediatric - The pharmacokinetics of tolterodine have not been established in pediatric patients. Gender - The pharmacokinetics of tolterodine immediate release and the 5-hydroxymethyl metabolite are not influenced by gender. Mean Cmax of tolterodine (1.6 µg/L in males versus 2.2 µg/L in females) and the active 5-hydroxymethyl metabolite (2.2 µg/L in males versus 2.5 µg/L in females) are similar in males and females who were administered tolterodine immediate release 2 mg. Mean AUC values of tolterodine (6.7 µg∙h/L in males versus 7.8 µg∙h/L in females) and the 5-hydroxymethyl metabolite (10 µg∙h/L in males versus 11 µg∙h/L in females) are also similar. The elimination half-life of tolterodine for both males and females is 2.4 hours, and the half-life of the 5-hydroxymethyl metabolite is 3.0 hours in females and 3.3 hours in males. Race - Pharmacokinetic differences due to race have not been established. Renal Insufficiency - Renal impairment can significantly alter the disposition of tolterodine immediate release and its metabolites. In a study conducted in patients with creatinine clearance between 10 and 30 mL/min, tolterodine immediate release and the 5-hydroxymethyl metabolite levels were approximately 2–3 fold higher in patients with renal impairment than in healthy volunteers. Exposure levels of other metabolites of tolterodine (e.g., tolterodine acid, N-dealkylated tolterodine acid, N-dealkylated tolterodine, and N-dealkylated hydroxylated tolterodine) were significantly higher (10–30 fold) in renally impaired patients as compared to the healthy volunteers. The recommended dosage for patients with significantly reduced renal function is DETROL 1 mg twice daily . Hepatic Insufficiency - Liver impairment can significantly alter the disposition of tolterodine immediate release. In a study conducted in cirrhotic patients, the elimination half-life of tolterodine immediate release was longer in cirrhotic patients (mean, 7.8 hours) than in healthy, young, and elderly volunteers (mean, 2 to 4 hours). The clearance of orally administered tolterodine was substantially lower in cirrhotic patients (1.0 ± 1.7 L/h/kg) than in the healthy volunteers (5.7 ± 3.8 L/h/kg). The recommended dose for patients with significantly reduced hepatic function is DETROL 1 mg twice daily ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility - Carcinogenicity studies with tolterodine were conducted in mice and rats. At the maximum tolerated dose in mice (30 mg/kg/day), female rats (20 mg/kg/day), and male rats (30 mg/kg/day), AUC values obtained for tolterodine were 355, 291, and 462 µg∙h/L, respectively. In comparison, the human AUC value for a 2-mg dose administered twice daily is estimated at 34 µg∙h/L. Thus, tolterodine exposure in the carcinogenicity studies was 9- to 14-fold higher than expected in humans. No increase in tumors was found in either mice or rats. - No mutagenic effects of tolterodine were detected in a battery of in vitro tests, including bacterial mutation assays (Ames test) in 4 strains of Salmonella typhimurium and in 2 strains of Escherichia coli, a gene mutation assay in L5178Y mouse lymphoma cells, and chromosomal aberration tests in human lymphocytes. Tolterodine was also negative in vivo in the bone marrow micronucleus test in the mouse. - In female mice treated for 2 weeks before mating and during gestation with 20 mg/kg/day (corresponding to AUC value of about 500 µg∙h/L), neither effects on reproductive performance or fertility were seen. Based on AUC values, the systemic exposure was about 15-fold higher in animals than in humans. In male mice, a dose of 30 mg/kg/day did not induce any adverse effects on fertility. # Clinical Studies - DETROL Tablets were evaluated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency in four randomized, double-blind, placebo-controlled, 12-week studies. A total of 853 patients received DETROL 2 mg twice daily and 685 patients received placebo. The majority of patients were Caucasian (95%) and female (78%), with a mean age of 60 years (range, 19 to 93 years). At study entry, nearly all patients perceived they had urgency and most patients had increased frequency of micturitions and urge incontinence. These characteristics were well balanced across treatment groups for the studies. The efficacy endpoints for study 007 (see Table 3) included the change from baseline for: - Number of incontinence episodes per week - Number of micturitions per 24 hours (averaged over 7 days) - Volume of urine voided per micturition (averaged over 2 days) The efficacy endpoints for studies 008, 009, and 010 (see Table 4) were identical to the above endpoints with the exception that the number of incontinence episodes was per 24 hours (averaged over 7 days). # How Supplied - DETROL Tablets 1 mg (white, round, biconvex, film-coated tablets engraved with arcs above and below the letters "TO") and DETROL Tablets 2 mg (white, round, biconvex, film-coated tablets engraved with arcs above and below the letters "DT") are supplied as follows: Bottles of 60 Bottles of 500 Unit Dose Pack of 140 ## Storage - Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) (DTL). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information # Precautions with Alcohol Alcohol-Tolterodine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Detrol - Detrol LA # Look-Alike Drug Names There is limited information about the look-alike drug names. # Drug Shortage Status # Price	Tolterodine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2], Rabin Bista, 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 Tolterodine is a cholinergic muscarinic antagonist that is FDA approved for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency. Common adverse reactions include abdominal pain, constipation, xerostomia, headache. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Overactive Bladder - Dosing information - Initial recommended dose: 2 mg PO bid. - The dose may be lowered to 1 mg twice daily based on individual response and tolerability. - For patients with significantly reduced hepatic or renal function or who are currently taking drugs that are potent inhibitors of CYP3A4 - Recommended dose: 1 mg PO bid ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of tolterodine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of tolterodine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The pharmacokinetics of tolterodine have not been established in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of tolterodine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of tolterodine in pediatric patients. # Contraindications - DETROL tablets are contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma. DETROL is also contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients, or to fesoterodine fumarate extended-release tablets which, like DETROL, are metabolized to 5-hydroxymethyl tolterodine. # Warnings - Anaphylaxis and angioedema requiring hospitalization and emergency medical treatment have occurred with the first or subsequent doses of DETROL. In the event of difficulty in breathing, upper airway obstruction, or fall in blood pressure, DETROL should be discontinued and appropriate therapy promptly provided. # Adverse Reactions ## Clinical Trials Experience - The Phase 2 and 3 clinical trial program for DETROL tablets included 3071 patients who were treated with DETROL (N=2133) or placebo (N=938). The patients were treated with 1, 2, 4, or 8 mg/day for up to 12 months. No differences in the safety profile of tolterodine were identified based on age, gender, race, or metabolism. - The data described below reflect exposure to DETROL 2 mg bid in 986 patients and to placebo in 683 patients exposed for 12 weeks in five Phase 3, controlled clinical studies. 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 adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and approximating rates. Sixty-six percent of patients receiving DETROL 2 mg bid reported adverse events versus 56% of placebo patients. The most common adverse events reported by patients receiving DETROL were dry mouth, headache, constipation, vertigo/dizziness, and abdominal pain. Dry mouth, constipation, abnormal vision (accommodation abnormalities), urinary retention, and xerophthalmia are expected side effects of antimuscarinic agents. Dry mouth was the most frequently reported adverse event for patients treated with DETROL 2 mg bid in the Phase 3 clinical studies, occurring in 34.8% of patients treated with DETROL and 9.8% of placebo-treated patients. One percent of patients treated with DETROL discontinued treatment due to dry mouth. The frequency of discontinuation due to adverse events was highest during the first 4 weeks of treatment. Seven percent of patients treated with DETROL 2 mg bid discontinued treatment due to adverse events versus 6% of placebo patients. The most common adverse events leading to discontinuation of DETROL were dizziness and headache. - Three percent of patients treated with DETROL 2 mg bid reported a serious adverse event versus 4% of placebo patients. Significant ECG changes in QT and QTc have not been demonstrated in clinical-study patients treated with DETROL 2 mg bid. Table 5 lists the adverse events reported in 1% or more of the patients treated with DETROL 2 mg bid in the 12-week studies. The adverse events are reported regardless of causality. ## Postmarketing Experience - The following events have been reported in association with tolterodine use in worldwide post-marketing experience: General: anaphylaxis and angioedema; Cardiovascular: tachycardia, palpitations, peripheral edema; Central/Peripheral Nervous: confusion, disorientation, memory impairment, hallucinations. - Reports of aggravation of symptoms of dementia (e.g., confusion, disorientation, delusion) have been reported after tolterodine therapy was initiated in patients taking cholinesterase inhibitors for the treatment of dementia. - Because these spontaneously reported events are from the worldwide post-marketing experience, the frequency of events and the role of tolterodine in their causation cannot be reliably determined. # Drug Interactions ### Fluoxetine - Fluoxetine is a selective serotonin reuptake inhibitor and a potent inhibitor of CYP2D6 activity. In a study to assess the effect of fluoxetine on the pharmacokinetics of tolterodine immediate release and its metabolites, it was observed that fluoxetine significantly inhibited the metabolism of tolterodine immediate release in extensive metabolizers, resulting in a 4.8-fold increase in tolterodine AUC. There was a 52% decrease in Cmax and a 20% decrease in AUC of the 5-hydroxymethyl metabolite. Fluoxetine thus alters the pharmacokinetics in patients who would otherwise be extensive metabolizers of tolterodine immediate release to resemble the pharmacokinetic profile in poor metabolizers. The sums of unbound serum concentrations of tolterodine immediate release and the 5-hydroxymethyl metabolite are only 25% higher during the interaction. No dose adjustment is required when DETROL and fluoxetine are coadministered. ### Other Drugs Metabolized by Cytochrome P450 Isoenzymes - Tolterodine immediate release does not cause clinically significant interactions with other drugs metabolized by the major drug metabolizing CYP enzymes. In vivo drug-interaction data show that tolterodine immediate release does not result in clinically relevant inhibition of CYP1A2, 2D6, 2C9, 2C19, or 3A4 as evidenced by lack of influence on the marker drugs caffeine, debrisoquine, S-warfarin, and omeprazole. In vitro data show that tolterodine immediate release is a competitive inhibitor of CYP2D6 at high concentrations (Ki 1.05 µM), while tolterodine immediate release as well as the 5-hydroxymethyl metabolite are devoid of any significant inhibitory potential regarding the other isoenzymes. ### CYP3A4 Inhibitors - The effect of 200 mg daily dose of ketoconazole on the pharmacokinetics of tolterodine immediate release was studied in 8 healthy volunteers, all of whom were poor metabolizers (see Pharmacokinetics,Variability in Metabolism for discussion of poor metabolizers). In the presence of ketoconazole, the mean Cmax and AUC of tolterodine increased by 2 and 2.5 fold, respectively. Based on these findings, other potent CYP3A inhibitors such as other azole antifungals (eg, itraconazole, miconazole) or macrolide antibiotics (eg, erythromycin, clarithromycin) or cyclosporine or vinblastine may also lead to increases of tolterodine plasma concentrations . ### Warfarin - In healthy volunteers, co administration of tolterodine immediate release 4 mg (2 mg bid) for 7 days and a single dose of warfarin 25 mg on day 4 had no effect on prothrombin time, factor VII suppression, or on the pharmacokinetics of warfarin. ### Oral Contraceptives - Tolterodine immediate release 4 mg (2 mg bid) had no effect on the pharmacokinetics of an oral contraceptive (ethinyl estradiol 30 µg/levonorgestrel 150 µg) as evidenced by the monitoring of ethinyl estradiol and levonorgestrel over a 2-month cycle in healthy female volunteers. ### Diuretics - Co administration of tolterodine immediate release up to 8 mg (4 mg bid) for up to 12 weeks with diuretic agents, such as indapamide, hydrochlorothiazide, triamterene, bendroflumethiazide, chlorothiazide, methylchlorothiazide, or furosemide, did not cause any adverse electrocardiographic (ECG) effects. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C Pregnancy Category C - At oral doses of 20 mg/kg/day (approximately 14 times the human exposure), no anomalies or malformations were observed in mice. When given at doses of 30 to 40 mg/kg/day, tolterodine has been shown to be embryolethal, reduce fetal weight, and increase the incidence of fetal abnormalities (cleft palate, digital abnormalities, intra-abdominal hemorrhage, and various skeletal abnormalities, primarily reduced ossification) in mice. At these doses, the AUC values were about 20- to 25-fold higher than in humans. Rabbits treated subcutaneously at a dose of 0.8 mg/kg/day achieved an AUC of 100 µg∙h/L, which is about 3-fold higher than that resulting from the human dose. This dose did not result in any embryotoxicity or teratogenicity. There are no studies of tolterodine in pregnant women. Therefore, DETROL should be used during pregnancy only if the potential benefit for the mother justifies the potential risk to the fetus. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tolterodine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Tolterodine during labor and delivery. ### Nursing Mothers Tolterodine is excreted into the milk in mice. Offspring of female mice treated with tolterodine 20 mg/kg/day during the lactation period had slightly reduced body weight gain. The offspring regained the weight during the maturation phase. It is not known whether tolterodine is excreted in human milk; therefore, DETROL should not be administered during nursing. A decision should be made whether to discontinue nursing or to discontinue DETROL in nursing mothers. ### Pediatric Use Efficacy in the pediatric population has not been demonstrated. - Two pediatric phase 3 randomized, placebo-controlled, double-blind, 12-week studies were conducted using tolterodine extended release (DETROL LA) capsules. A total of 710 pediatric patients (486 on DETROL LA and 224 on placebo) aged 5–10 years with urinary frequency and urge urinary incontinence were studied. The percentage of patients with urinary tract infections was higher in patients treated with DETROL LA (6.6%) compared to patients who received placebo (4.5%). Aggressive, abnormal and hyperactive behavior and attention disorders occurred in 2.9% of children treated with DETROL LA compared to 0.9% of children treated with placebo. ### Geriatic Use - Of the 1120 patients who were treated in the four Phase 3, 12-week clinical studies of DETROL, 474 (42%) were 65 to 91 years of age. No overall differences in safety were observed between the older and younger patients. ### Gender There is no FDA guidance on the use of Tolterodine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Tolterodine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Tolterodine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Tolterodine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Tolterodine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Tolterodine in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring FDA package insert for tolterodine contains no information regarding drug monitoring. # IV Compatibility There is limited information about the IV compatibility. # Overdosage - A 27-month-old child who ingested 5 to 7 DETROL Tablets 2 mg was treated with a suspension of activated charcoal and was hospitalized overnight with symptoms of dry mouth. The child fully recovered. ### Management of Overdosage - Overdosage with DETROL can potentially result in severe central anticholinergic effects and should be treated accordingly. ECG monitoring is recommended in the event of overdosage. In dogs, changes in the QT interval (slight prolongation of 10% to 20%) were observed at a suprapharmacologic dose of 4.5 mg/kg, which is about 68 times higher than the recommended human dose. In clinical trials of normal volunteers and patients, QT interval prolongation was observed with tolterodine immediate release at doses up to 8 mg (4 mg bid) and higher doses were not evaluated # Pharmacology ## Mechanism of Action - FDA package insert for tolterodine contains no information regarding mechanism of action. ## Structure - DETROL Tablets contain tolterodine tartrate. The active moiety, tolterodine, is a muscarinic receptor antagonist. The chemical name of tolterodine tartrate is (R)-2-[3-[bis(1-methylethyl)-amino]1-phenylpropyl]-4-methylphenol [R-(R,R)]-2,3dihydroxybutanedioate (1:1) (salt). The empirical formula of tolterodine tartrate is C26H37NO7, and its molecular weight is 475.6. The structural formula of tolterodine tartrate is represented below: - Tolterodine tartrate is a white, crystalline powder. The pKa value is 9.87 and the solubility in water is 12 mg/mL. It is soluble in methanol, slightly soluble in ethanol, and practically insoluble in toluene. The partition coefficient (Log D) between n-octanol and water is 1.83 at pH 7.3. DETROL Tablets for oral administration contain 1 or 2 mg of tolterodine tartrate. The inactive ingredients are colloidal anhydrous silica, calcium hydrogen phosphate dihydrate, cellulose microcrystalline, hypromellose, magnesium stearate, sodium starch glycolate (pH 3.0 to 5.0), stearic acid, and titanium dioxide. ## Pharmacodynamics FDA package insert for tolterodine contains no information regarding pharmacodynamics. ## Pharmacokinetics ### Absorption - In a study with 14C-tolterodine solution in healthy volunteers who received a 5-mg oral dose, at least 77% of the radiolabeled dose was absorbed. Tolterodine immediate release is rapidly absorbed, and maximum serum concentrations (Cmax) typically occur within 1 to 2 hours after dose administration. Cmax and area under the concentration-time curve (AUC) determined after dosage of tolterodine immediate release are dose-proportional over the range of 1 to 4 mg. ### Effect of Food - Food intake increases the bioavailability of tolterodine (average increase 53%), but does not affect the levels of the 5-hydroxymethyl metabolite in extensive metabolizers. This change is not expected to be a safety concern and adjustment of dose is not needed. ### Distribution - Tolterodine is highly bound to plasma proteins, primarily α1-acid glycoprotein. Unbound concentrations of tolterodine average 3.7% ± 0.13% over the concentration range achieved in clinical studies. The 5-hydroxymethyl metabolite is not extensively protein bound, with unbound fraction concentrations averaging 36% ± 4.0%. The blood to serum ratio of tolterodine and the 5-hydroxymethyl metabolite averages 0.6 and 0.8, respectively, indicating that these compounds do not distribute extensively into erythrocytes. The volume of distribution of tolterodine following administration of a 1.28-mg intravenous dose is 113 ± 26.7 L. ### Metabolism - Tolterodine is extensively metabolized by the liver following oral dosing. The primary metabolic route involves the oxidation of the 5-methyl group and is mediated by the cytochrome P450 2D6 (CYP2D6) and leads to the formation of a pharmacologically active 5-hydroxymethyl metabolite. Further metabolism leads to formation of the 5-carboxylic acid and N-dealkylated 5-carboxylic acid metabolites, which account for 51% ± 14% and 29% ± 6.3% of the metabolites recovered in the urine, respectively. Variability in Metabolism - A subset (about 7%) of the population is devoid of CYP2D6, the enzyme responsible for the formation of the 5-hydroxymethyl metabolite of tolterodine. The identified pathway of metabolism for these individuals ("poor metabolizers") is dealkylation via cytochrome P450 3A4 (CYP3A4) to N-dealkylated tolterodine. The remainder of the population is referred to as "extensive metabolizers." Pharmacokinetic studies revealed that tolterodine is metabolized at a slower rate in poor metabolizers than in extensive metabolizers; this results in significantly higher serum concentrations of tolterodine and in negligible concentrations of the 5-hydroxymethyl metabolite. ### Excretion - Following administration of a 5-mg oral dose of 14C-tolterodine solution to healthy volunteers, 77% of radioactivity was recovered in urine and 17% was recovered in feces in 7 days. Less than 1% (<2.5% in poor metabolizers) of the dose was recovered as intact tolterodine, and 5% to 14% (<1% in poor metabolizers) was recovered as the active 5-hydroxymethyl metabolite. - A summary of mean (± standard deviation) pharmacokinetic parameters of tolterodine immediate release and the 5-hydroxymethyl metabolite in extensive (EM) and poor (PM) metabolizers is provided in Table 1. These data were obtained following single and multiple doses of tolterodine 4 mg administered twice daily to 16 healthy male volunteers (8 EM, 8 PM). ### Pharmacokinetics in Special Populations Age - In Phase 1, multiple-dose studies in which tolterodine immediate release 4 mg (2 mg bid) was administered, serum concentrations of tolterodine and of the 5-hydroxymethyl metabolite were similar in healthy elderly volunteers (aged 64 through 80 years) and healthy young volunteers (aged less than 40 years). In another Phase 1 study, elderly volunteers (aged 71 through 81 years) were given tolterodine immediate release 2 or 4 mg (1 or 2 mg bid). Mean serum concentrations of tolterodine and the 5-hydroxymethyl metabolite in these elderly volunteers were approximately 20% and 50% higher, respectively, than reported in young healthy volunteers. However, no overall differences were observed in safety between older and younger patients on tolterodine in Phase 3, 12-week, controlled clinical studies; therefore, no tolterodine dosage adjustment for elderly patients is recommended . Pediatric - The pharmacokinetics of tolterodine have not been established in pediatric patients. Gender - The pharmacokinetics of tolterodine immediate release and the 5-hydroxymethyl metabolite are not influenced by gender. Mean Cmax of tolterodine (1.6 µg/L in males versus 2.2 µg/L in females) and the active 5-hydroxymethyl metabolite (2.2 µg/L in males versus 2.5 µg/L in females) are similar in males and females who were administered tolterodine immediate release 2 mg. Mean AUC values of tolterodine (6.7 µg∙h/L in males versus 7.8 µg∙h/L in females) and the 5-hydroxymethyl metabolite (10 µg∙h/L in males versus 11 µg∙h/L in females) are also similar. The elimination half-life of tolterodine for both males and females is 2.4 hours, and the half-life of the 5-hydroxymethyl metabolite is 3.0 hours in females and 3.3 hours in males. Race - Pharmacokinetic differences due to race have not been established. Renal Insufficiency - Renal impairment can significantly alter the disposition of tolterodine immediate release and its metabolites. In a study conducted in patients with creatinine clearance between 10 and 30 mL/min, tolterodine immediate release and the 5-hydroxymethyl metabolite levels were approximately 2–3 fold higher in patients with renal impairment than in healthy volunteers. Exposure levels of other metabolites of tolterodine (e.g., tolterodine acid, N-dealkylated tolterodine acid, N-dealkylated tolterodine, and N-dealkylated hydroxylated tolterodine) were significantly higher (10–30 fold) in renally impaired patients as compared to the healthy volunteers. The recommended dosage for patients with significantly reduced renal function is DETROL 1 mg twice daily . Hepatic Insufficiency - Liver impairment can significantly alter the disposition of tolterodine immediate release. In a study conducted in cirrhotic patients, the elimination half-life of tolterodine immediate release was longer in cirrhotic patients (mean, 7.8 hours) than in healthy, young, and elderly volunteers (mean, 2 to 4 hours). The clearance of orally administered tolterodine was substantially lower in cirrhotic patients (1.0 ± 1.7 L/h/kg) than in the healthy volunteers (5.7 ± 3.8 L/h/kg). The recommended dose for patients with significantly reduced hepatic function is DETROL 1 mg twice daily ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility - Carcinogenicity studies with tolterodine were conducted in mice and rats. At the maximum tolerated dose in mice (30 mg/kg/day), female rats (20 mg/kg/day), and male rats (30 mg/kg/day), AUC values obtained for tolterodine were 355, 291, and 462 µg∙h/L, respectively. In comparison, the human AUC value for a 2-mg dose administered twice daily is estimated at 34 µg∙h/L. Thus, tolterodine exposure in the carcinogenicity studies was 9- to 14-fold higher than expected in humans. No increase in tumors was found in either mice or rats. - No mutagenic effects of tolterodine were detected in a battery of in vitro tests, including bacterial mutation assays (Ames test) in 4 strains of Salmonella typhimurium and in 2 strains of Escherichia coli, a gene mutation assay in L5178Y mouse lymphoma cells, and chromosomal aberration tests in human lymphocytes. Tolterodine was also negative in vivo in the bone marrow micronucleus test in the mouse. - In female mice treated for 2 weeks before mating and during gestation with 20 mg/kg/day (corresponding to AUC value of about 500 µg∙h/L), neither effects on reproductive performance or fertility were seen. Based on AUC values, the systemic exposure was about 15-fold higher in animals than in humans. In male mice, a dose of 30 mg/kg/day did not induce any adverse effects on fertility. # Clinical Studies - DETROL Tablets were evaluated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency in four randomized, double-blind, placebo-controlled, 12-week studies. A total of 853 patients received DETROL 2 mg twice daily and 685 patients received placebo. The majority of patients were Caucasian (95%) and female (78%), with a mean age of 60 years (range, 19 to 93 years). At study entry, nearly all patients perceived they had urgency and most patients had increased frequency of micturitions and urge incontinence. These characteristics were well balanced across treatment groups for the studies. The efficacy endpoints for study 007 (see Table 3) included the change from baseline for: - Number of incontinence episodes per week - Number of micturitions per 24 hours (averaged over 7 days) - Volume of urine voided per micturition (averaged over 2 days) The efficacy endpoints for studies 008, 009, and 010 (see Table 4) were identical to the above endpoints with the exception that the number of incontinence episodes was per 24 hours (averaged over 7 days). # How Supplied - DETROL Tablets 1 mg (white, round, biconvex, film-coated tablets engraved with arcs above and below the letters "TO") and DETROL Tablets 2 mg (white, round, biconvex, film-coated tablets engraved with arcs above and below the letters "DT") are supplied as follows: Bottles of 60 Bottles of 500 Unit Dose Pack of 140 ## Storage - Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature] (DTL). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information # Precautions with Alcohol Alcohol-Tolterodine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Detrol - Detrol LA # Look-Alike Drug Names There is limited information about the look-alike drug names. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Detrol_LA
0d4fbb82101ea40eec5624c4b3116b354fa9563d	wikidoc	Dexrazoxane	Dexrazoxane # 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 Dexrazoxane is an antineopalstic agent that is FDA approved for the treatment of reducing the incidence and severity of cardiomyopathy associated with doxorubicin administration in women with metastatic breast cancer. Common adverse reactions include alopecia, Nausea, Vomiting, fatigue/Malaise, anorexia, stomatitis, fever, infection, diarrhea, Pain at injection site, sepsis, neurotoxicity, hemorrhage, extravasation, streaking/Erythema, phlebitis, esophagitis, dysphagia.. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dexrazoxane for injection is indicated for reducing the incidence and severity of cardiomyopathy associated with doxorubicin administration in women with metastatic breast cancer who have received a cumulative doxorubicin dose of 300 mg/m2 and who will continue to receive doxorubicin therapy to maintain tumor control. Do not use with the initiation of doxorubicin therapy - Administer dexrazoxane for injection by slow I.V. push or rapid drip intravenous infusion from a bag. - The recommended dosage ratio of dexrazoxane for injection to doxorubicin is 10:1 (e.g., 500 mg/m2 dexrazoxane for injection to 50 mg/m2 doxorubicin). Do not administer doxorubicin before dexrazoxane for injection. Administer doxorubicin within 30 minutes after the completion of dexrazoxane for injection infusion. - Reduce dexrazoxane for injection dosage in patients with moderate to severe renal impairment (creatinine clearance values less than 40 mL/min) by 50% (dexrazoxane for injection to doxorubicin ratio reduced to 5:1; such as 250 mg/m2 dexrazoxane for injection to 50 mg/m2 doxorubicin) . - Since a doxorubicin dose reduction is recommended in the presence of hyperbilirubinemia, reduce the dexrazoxane for injection dosage proportionately (maintaining the 10:1 ratio) in patients with hepatic impairment. - Dexrazoxane for injection must be reconstituted with 0.167 Molar (M/6) sodium lactate injection, USP, to give a concentration of 10 mg dexrazoxane for injection for each mL of sodium lactate. The reconstituted solution should be given by slow I.V. push or rapid drip intravenous infusion from a bag. After completing the infusion of dexrazoxane for injection, and prior to a total elapsed time of 30 minutes (from the beginning of the dexrazoxane for injection infusion), the intravenous injection of doxorubicin should be given. - Reconstituted dexrazoxane for injection, when transferred to an empty infusion bag, is stable for 6 hours from the time of reconstitution when stored at controlled room temperature, 20° to 25°C (68° to 77°F) or under refrigeration, 2° to 8°C (36° to 46°F). DISCARD UNUSED SOLUTIONS. - The reconstituted dexrazoxane for injection solution may be diluted with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to a concentration range of 1.3 to 5 mg/mL in intravenous infusion bags. The resultant solutions are stable for 6 hours when stored at controlled room temperature, 20° to 25°C (68° to 77°F) or under refrigeration, 2° to 8°C (36° to 46°F). DISCARD UNUSED SOLUTIONS. - Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Solutions containing a precipitate should be discarded. - Use caution when handling and preparing the reconstituted solution. The use of gloves is recommended. If dexrazoxane for injection powder or solutions contact the skin or mucosae, wash exposed area immediately and thoroughly with soap and water. Follow special handling and disposal procedures. - Do not mix dexrazoxane for injection with other drugs. - The reconstituted solution should be given by slow I.V. push or rapid drip intravenous infusion from a bag. After completing the infusion of dexrazoxane for injection, and prior to a total elapsed time of 30 minutes (from the beginning of the dexrazoxane for injection infusion), the intravenous injection of doxorubicin should be given. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Dexrazoxane in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of dexrazoxane in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Dexrazoxane 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 Dexrazoxane in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Dexrazoxane in pediatric patients. # Contraindications - Do not use dexrazoxane for injection with non-anthracycline chemotherapy regimens. # Warnings - Dexrazoxane for injection may add to the myelosuppression caused by chemotherapeutic agents. Obtain a complete blood count prior to and during each course of therapy, and administer dexrazoxane for injection and chemotherapy only when adequate hematologic parameters are met. - Only use dexrazoxane for injection in those patients who have received a cumulative doxorubicin dose of 300 mg/m2 and are continuing with doxorubicin therapy. Do not use with chemotherapy initiation as dexrazoxane for injection may interfere with the antitumor activity of the chemotherapy regimen. In a trial conducted in patients with metastatic breast cancer who were treated with fluorouracil, doxorubicin, and cyclophosphamide (FAC) with or without dexrazoxane for injection starting with their first cycle of FAC therapy, patients who were randomized to receive dexrazoxane for injection had a lower response rate (48% vs. 63%) and shorter time to progression than patients who were randomized to receive placebo. - Treatment with dexrazoxane for injection does not completely eliminate the risk of anthracycline-induced cardiac toxicity. Monitor cardiac function before and periodically during therapy to assess left ventricular ejection fraction (LVEF). In general, if test results indicate deterioration in cardiac function associated with doxorubicin, the benefit of continued therapy should be carefully evaluated against the risk of producing irreversible cardiac damage. - Secondary malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) have been reported in studies of pediatric patients who have received dexrazoxane for injection in combination with chemotherapy. Dexrazoxane for injection is not indicated for use in pediatric patients. Some adult patients who received dexrazoxane for injection in combination with anti-cancer agents known to be carcinogenic have also developed secondary malignancies, including AML and MDS. - Razoxane is the racemic mixture, of which dexrazoxane is the S(+)-enantiomer. Secondary malignancies (primarily acute myeloid leukemia) have been reported in patients treated chronically with oral razoxane. In these patients, the total cumulative dose of razoxane ranged from 26 grams to 480 grams and the duration of treatment was from 42 to 319 weeks. One case of T-cell lymphoma, one case of B-cell lymphoma, and six to eight cases of cutaneous basal cell or squamous cell carcinoma have also been reported in patients treated with razoxane. Long-term administration of razoxane to rodents was associated with the development of malignancies . - Dexrazoxane for injection can cause fetal harm when administered to pregnant women. Dexrazoxane administration during the period of organogenesis resulted in maternal toxicity, embryotoxicity and teratogenicity in rats and rabbits at doses significantly lower than the clinically recommended dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. - Advise female patients of reproductive potential to avoid becoming pregnant and to use highly effective contraception during treatment # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. - The adverse reaction profile described in this section was identified from randomized, placebo-controlled, double-blind studies in patients with metastatic breast cancer who received the combination of the FAC chemotherapy regimen with or without dexrazoxane for injection. The dose of doxorubicin was 50 mg/m2 in each of these trials. Treatment was administered every three weeks until disease progression or cardiac toxicity. - Patients in clinical trials who received FAC with dexrazoxane for injection experienced more severe leukopenia, granulocytopenia, and thrombocytopenia than patients receiving FAC without dexrazoxane for injection . - Table 1 below lists the incidence of adverse reactions for patients receiving FAC with either dexrazoxane for injection or placebo in the breast cancer studies. Adverse experiences occurring during courses 1 through 6 are displayed for patients receiving dexrazoxane for injection or placebo with FAC beginning with their first course of therapy (columns 1 and 3, respectively). Adverse experiences occurring at course 7 and beyond for patients who received placebo with FAC during the first six courses and who then received either dexrazoxane for injection or placebo with FAC are also displayed (columns 2 and 4, respectively). - The adverse reactions listed below in Table 1 demonstrate that the frequency of adverse reaction “Pain on Injection” has been greater for dexrazoxane for injection arm, as compared to placebo. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of dexrazoxane in the drug label. # Drug Interactions - No drug interactions have been identified # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D There is no FDA guidance on usage of Dexrazoxane in women who are pregnant. Pregnancy Category (AUS): - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of dexrazoxane in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of dexrazoxane during labor and delivery. ### Nursing Mothers - It is not known whether dexrazoxane or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from dexrazoxane, 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 dexrazoxane in pediatric patients have not been established . ### Geriatic Use - Clinical studies of dexrazoxane for injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.. ### Gender - Contraception - Dexrazoxane for injection can cause fetal harm when administered during pregnancy. Advise female patients of reproductive potential to use highly effective contraception during treatment. ### Race There is no FDA guidance on the use of dexrazoxane with respect to specific racial populations. ### Renal Impairment - Greater exposure to dexrazoxane may occur in patients with compromised renal function. Reduce the dexrazoxane for injection dose by 50% in patients with creatinine clearance values < 40 mL/min. ### Hepatic Impairment There is no FDA guidance on the use of dexrazoxane in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of dexrazoxane in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of dexrazoxane in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring - Dexrazoxane may increase the myelosuppresive effects of chemotherapeutic agents. Perform hematological monitoring. # IV Compatibility There is limited information regarding IV Compatibility of dexrazoxane in the drug label. # Overdosage - There are no data on overdosage in the cardioprotective trials; the maximum dose administered during the cardioprotective trials was 1000 mg/m2 every three weeks. - Disposition studies with dexrazoxane for injection have not been conducted in cancer patients undergoing dialysis, but retention of a significant dose fraction (> 0.4) of the unchanged drug in the plasma pool, minimal tissue partitioning or binding, and availability of greater than 90% of the systemic drug levels in the unbound form suggest that it could be removed using conventional peritoneal or hemodialysis. - There is no known antidote for dexrazoxane. Instances of suspected overdose should be managed with good supportive care until resolution of myelosuppression and related conditions is complete. Management of overdose should include treatment of infections, fluid regulation, and maintenance of nutritional requirements # Pharmacology ## Mechanism of Action - The mechanism by which dexrazoxane for injection exerts its cytoprotective activity is not fully understood. Dexrazoxane is a cyclic derivative of EDTA that penetrates cell membranes. Results of laboratory studies suggest that dexrazoxane is converted intracellularly to a ring-opened chelating agent that interferes with iron-mediated free radical generation thought to be responsible, in part, for \|anthracycline-induced cardiomyopathy]]. ## Structure - Dexrazoxane for injection, a cardioprotective agent for use in conjunction with doxorubicin, is a sterile, pyrogen-free lyophilizate intended for intravenous administration. Chemically, dexrazoxane is (S)-4,4'-(1-methyl-1,2-ethanediyl)bis-2,6-piperazinedione. The structural formula is as follows: - Dexrazoxane, an intracellular chelating agent, is a derivative of EDTA. Dexrazoxane is a whitish crystalline powder that melts at 191° to 197°C. It is sparingly soluble in water and 0.1 N HCl, slightly soluble in ethanol and methanol, and practically insoluble in nonpolar organic solvents. The pKa is 2.1. Dexrazoxane has an octanol/water partition coefficient of 0.025 and degrades rapidly above a pH of 7.0. - Each 250 mg vial contains dexrazoxane hydrochloride equivalent to 250 mg dexrazoxane. Hydrochloric Acid, NF is added for pH adjustment. When reconstituted as directed with the 25 mL vial of 0.167 Molar (M/6) Sodium Lactate Injection, USP diluent provided, each mL contains: 10 mg dexrazoxane. The pH of the resultant solution is 3.5 to 5.5. - Each 500 mg vial contains dexrazoxane hydrochloride equivalent to 500 mg dexrazoxane. Hydrochloric Acid, NF is added for pH adjustment. When reconstituted as directed with the 50 mL vial of 0.167 Molar (M/6) Sodium Lactate Injection, USP diluent provided, each mL contains: 10 mg dexrazoxane. The pH of the resultant solution is 3.5 to 5.5 ## Pharmacodynamics There is limited information regarding Pharmacodynamics of dexrazoxane in the drug label. ## Pharmacokinetics - The pharmacokinetics of dexrazoxane have been studied in advanced cancer patients with normal renal and hepatic function. The pharmacokinetics of dexrazoxane can be adequately described by a two-compartment open model with first-order elimination. Dexrazoxane has been administered as a 15 minute infusion over a dose range of 60 to 900 mg/m2 with 60 mg/m2 of doxorubicin, and at a fixed dose of 500 mg/m2 with 50 mg/m2 doxorubicin. The disposition kinetics of dexrazoxane are dose-independent, as shown by linear relationship between the area under plasma concentration-time curves and administered doses ranging from 60 to 900 mg/m2. The mean peak plasma concentration of dexrazoxane was 36.5 mcg/mL at 15 minute after intravenous administration of 500 mg/m2 dose of dexrazoxane for injection over 15 to 30 minutes prior to the 50 mg/m2 doxorubicin dose. - The important pharmacokinetic parameters of dexrazoxane are summarized in Table 2: - Following a rapid distributive phase (0.2 to 0.3 hours), dexrazoxane reaches post-distributive equilibrium within 2 to 4 hours. The estimated mean steady-state volume of distribution of dexrazoxane is 22.4 L/m2 after 500 mg/m2 of dexrazoxane for injection dose followed by 50 mg/m2 of doxorubicin, suggesting distribution throughout total body water (25 L/m2). - In vitro studies have shown that dexrazoxane is not bound to plasma proteins. - Qualitative metabolism studies with dexrazoxane have confirmed the presence of unchanged drug, a diacid-diamide cleavage product, and two monoacid-monoamide ring products in the urine of animals and man. The metabolite levels were not measured in the pharmacokinetic studies. - Urinary excretion plays an important role in the elimination of dexrazoxane. Forty-two percent of a 500 mg/m2 dose of dexrazoxane for injection was excreted in the urine. Renal clearance averages 3.35 L/h/m2 after the 500 mg/m2 dexrazoxane for injection dose followed by 50 mg/m2 of doxorubicin. - Pharmacokinetics following dexrazoxane for injection administration have not been evaluated in pediatric patients. - The pharmacokinetics of dexrazoxane were assessed following a single 15 minute IV infusion of 150 mg/m2 of dexrazoxane for injection. Dexrazoxane clearance was reduced in subjects with renal dysfunction. Compared with controls, the mean AUC0-inf value was 2-fold greater in subjects with moderate (CLCR 30 to 50 mL/min) to severe (CLCR 80 mL/min). - Pharmacokinetics following dexrazoxane for injection administration have not been evaluated in patients with hepatic impairment. The dexrazoxane for injection dose is dependent upon the dose of doxorubicin . - There was no significant change in the pharmacokinetics of doxorubicin (50 mg/m2) and its predominant metabolite, doxorubicin, in the presence of dexrazoxane (500 mg/m2) in a crossover study in cancer patients. ## Nonclinical Toxicology - No long-term carcinogenicity studies have been carried out with dexrazoxane in animals. Nevertheless, a study by the National Cancer Institute has reported that long-term dosing with razoxane (the racemic mixture of dexrazoxane, ICRF-187, and its enantiomer ICRF-186) is associated with the development of malignancies in rats and possibly in mice. - Dexrazoxane was not mutagenic in the bacterial reverse mutation (Ames) test, but was found to be clastogenic to human lymphocytes in vitro and to mouse bone marrow erythrocytes in vivo(micronucleus test). - Dexrazoxane for injection has the potential to impair fertility in male patients based on effects in repeat-dose toxicology studies. Testicular atrophy was seen with dexrazoxane administration at doses as low as 30 mg/kg weekly for 6 weeks in rats (1/3 the human dose on a mg/m2 basis) and as low as 20 mg/kg weekly for 13 weeks in dogs (approximately equal to the human dose on a mg/m2 basis). # Clinical Studies - The ability of dexrazoxane for injection to prevent/reduce the incidence and severity of doxorubicin-induced cardiomyopathy was evaluated in three prospectively randomized placebo-controlled studies. In these studies, patients were treated with a doxorubicin-containing regimen and either dexrazoxane for injection or placebo starting with the first course of chemotherapy. There was no restriction on the cumulative dose of doxorubicin. Cardiac function was assessed by measurement of the LVEF, utilizing resting multigated nuclear medicine (MUGA) scans, and by clinical evaluations. Patients receiving dexrazoxane for injection had significantly smaller mean decreases from baseline in LVEF and lower incidences of congestive heart failure than the control group; however, in the largest study, patients with advanced breast cancer receiving FAC with dexrazoxane for injection had a lower response rate (48% vs. 63%) and a shorter time to progression than patients who received FAC versus placebo. - In the clinical trials, patients who were initially randomized to receive placebo were allowed to receive dexrazoxane for injection after a cumulative dose of doxorubicin above 300 mg/m2. Retrospective historical analyses showed that the risk of experiencing a cardiac event (see Table 3 for definition) at a cumulative dose of doxorubicin above 300 mg/m2 was greater in the patients who did not receive dexrazoxane for injection beginning with their seventh course of FAC than in the patients who did receive dexrazoxane for injection (HR=13.08; 95% CI: 3.72, 46.03; p < 0.001). Overall, 3% of patients treated with dexrazoxane for injection developed CHF compared with 22% of patients not receiving dexrazoxane for injection. # How Supplied - Dexrazoxane for Injection is available in the following strengths as sterile, pyrogen-free lyophilizates. - NDC 67457-207-25 - 250 mg single-dose vial with a green flip-top seal, packaged in single vial packs. (This package also contains a 25 mL vial of 0.167 Molar (M/6) Sodium Lactate Injection, USP.) - NDC 67457-208-50 - 500 mg single-dose vial with a blue flip-top seal, packaged in single vial packs. (This package also contains a 50 mL vial of 0.167 Molar (M/6) Sodium Lactate Injection, USP.) - Store at 20° to 25°C (68° to 77°F). Reconstituted solutions of dexrazoxane for injection are stable for 6 hours at controlled room temperature or under refrigeration, 2° to 8°C (36° to 46°F). DISCARD UNUSED SOLUTIONS. - Follow special handling and disposal procedures. ## Storage There is limited information regarding Dexrazoxane Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Treatment with dexrazoxane for injection is associated with leukopenia, neutropenia, and thrombocytopenia. Perform hematological monitoring - Counsel patients on pregnancy planning and prevention. Advise female patients of reproductive potential that dexrazoxane for injection can cause fetal harm and to use highly effective contraception during treatment. # Precautions with Alcohol - Alcohol-dexrazoxane interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Zinecard - Totect # Look-Alike Drug Names There is limited information regarding Dexrazoxane Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Dexrazoxane 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 Dexrazoxane is an antineopalstic agent that is FDA approved for the treatment of reducing the incidence and severity of cardiomyopathy associated with doxorubicin administration in women with metastatic breast cancer. Common adverse reactions include alopecia, Nausea, Vomiting, fatigue/Malaise, anorexia, stomatitis, fever, infection, diarrhea, Pain at injection site, sepsis, neurotoxicity, hemorrhage, extravasation, streaking/Erythema, phlebitis, esophagitis, dysphagia.. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dexrazoxane for injection is indicated for reducing the incidence and severity of cardiomyopathy associated with doxorubicin administration in women with metastatic breast cancer who have received a cumulative doxorubicin dose of 300 mg/m2 and who will continue to receive doxorubicin therapy to maintain tumor control. Do not use with the initiation of doxorubicin therapy - Administer dexrazoxane for injection by slow I.V. push or rapid drip intravenous infusion from a bag. - The recommended dosage ratio of dexrazoxane for injection to doxorubicin is 10:1 (e.g., 500 mg/m2 dexrazoxane for injection to 50 mg/m2 doxorubicin). Do not administer doxorubicin before dexrazoxane for injection. Administer doxorubicin within 30 minutes after the completion of dexrazoxane for injection infusion. - Reduce dexrazoxane for injection dosage in patients with moderate to severe renal impairment (creatinine clearance values less than 40 mL/min) by 50% (dexrazoxane for injection to doxorubicin ratio reduced to 5:1; such as 250 mg/m2 dexrazoxane for injection to 50 mg/m2 doxorubicin) . - Since a doxorubicin dose reduction is recommended in the presence of hyperbilirubinemia, reduce the dexrazoxane for injection dosage proportionately (maintaining the 10:1 ratio) in patients with hepatic impairment. - Dexrazoxane for injection must be reconstituted with 0.167 Molar (M/6) sodium lactate injection, USP, to give a concentration of 10 mg dexrazoxane for injection for each mL of sodium lactate. The reconstituted solution should be given by slow I.V. push or rapid drip intravenous infusion from a bag. After completing the infusion of dexrazoxane for injection, and prior to a total elapsed time of 30 minutes (from the beginning of the dexrazoxane for injection infusion), the intravenous injection of doxorubicin should be given. - Reconstituted dexrazoxane for injection, when transferred to an empty infusion bag, is stable for 6 hours from the time of reconstitution when stored at controlled room temperature, 20° to 25°C (68° to 77°F) or under refrigeration, 2° to 8°C (36° to 46°F). DISCARD UNUSED SOLUTIONS. - The reconstituted dexrazoxane for injection solution may be diluted with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to a concentration range of 1.3 to 5 mg/mL in intravenous infusion bags. The resultant solutions are stable for 6 hours when stored at controlled room temperature, 20° to 25°C (68° to 77°F) or under refrigeration, 2° to 8°C (36° to 46°F). DISCARD UNUSED SOLUTIONS. - Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Solutions containing a precipitate should be discarded. - Use caution when handling and preparing the reconstituted solution. The use of gloves is recommended. If dexrazoxane for injection powder or solutions contact the skin or mucosae, wash exposed area immediately and thoroughly with soap and water. Follow special handling and disposal procedures. - Do not mix dexrazoxane for injection with other drugs. - The reconstituted solution should be given by slow I.V. push or rapid drip intravenous infusion from a bag. After completing the infusion of dexrazoxane for injection, and prior to a total elapsed time of 30 minutes (from the beginning of the dexrazoxane for injection infusion), the intravenous injection of doxorubicin should be given. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Dexrazoxane in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of dexrazoxane in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Dexrazoxane 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 Dexrazoxane in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Dexrazoxane in pediatric patients. # Contraindications - Do not use dexrazoxane for injection with non-anthracycline chemotherapy regimens. # Warnings - Dexrazoxane for injection may add to the myelosuppression caused by chemotherapeutic agents. Obtain a complete blood count prior to and during each course of therapy, and administer dexrazoxane for injection and chemotherapy only when adequate hematologic parameters are met. - Only use dexrazoxane for injection in those patients who have received a cumulative doxorubicin dose of 300 mg/m2 and are continuing with doxorubicin therapy. Do not use with chemotherapy initiation as dexrazoxane for injection may interfere with the antitumor activity of the chemotherapy regimen. In a trial conducted in patients with metastatic breast cancer who were treated with fluorouracil, doxorubicin, and cyclophosphamide (FAC) with or without dexrazoxane for injection starting with their first cycle of FAC therapy, patients who were randomized to receive dexrazoxane for injection had a lower response rate (48% vs. 63%) and shorter time to progression than patients who were randomized to receive placebo. - Treatment with dexrazoxane for injection does not completely eliminate the risk of anthracycline-induced cardiac toxicity. Monitor cardiac function before and periodically during therapy to assess left ventricular ejection fraction (LVEF). In general, if test results indicate deterioration in cardiac function associated with doxorubicin, the benefit of continued therapy should be carefully evaluated against the risk of producing irreversible cardiac damage. - Secondary malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) have been reported in studies of pediatric patients who have received dexrazoxane for injection in combination with chemotherapy. Dexrazoxane for injection is not indicated for use in pediatric patients. Some adult patients who received dexrazoxane for injection in combination with anti-cancer agents known to be carcinogenic have also developed secondary malignancies, including AML and MDS. - Razoxane is the racemic mixture, of which dexrazoxane is the S(+)-enantiomer. Secondary malignancies (primarily acute myeloid leukemia) have been reported in patients treated chronically with oral razoxane. In these patients, the total cumulative dose of razoxane ranged from 26 grams to 480 grams and the duration of treatment was from 42 to 319 weeks. One case of T-cell lymphoma, one case of B-cell lymphoma, and six to eight cases of cutaneous basal cell or squamous cell carcinoma have also been reported in patients treated with razoxane. Long-term administration of razoxane to rodents was associated with the development of malignancies . - Dexrazoxane for injection can cause fetal harm when administered to pregnant women. Dexrazoxane administration during the period of organogenesis resulted in maternal toxicity, embryotoxicity and teratogenicity in rats and rabbits at doses significantly lower than the clinically recommended dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. - Advise female patients of reproductive potential to avoid becoming pregnant and to use highly effective contraception during treatment # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. - The adverse reaction profile described in this section was identified from randomized, placebo-controlled, double-blind studies in patients with metastatic breast cancer who received the combination of the FAC chemotherapy regimen with or without dexrazoxane for injection. The dose of doxorubicin was 50 mg/m2 in each of these trials. Treatment was administered every three weeks until disease progression or cardiac toxicity. - Patients in clinical trials who received FAC with dexrazoxane for injection experienced more severe leukopenia, granulocytopenia, and thrombocytopenia than patients receiving FAC without dexrazoxane for injection . - Table 1 below lists the incidence of adverse reactions for patients receiving FAC with either dexrazoxane for injection or placebo in the breast cancer studies. Adverse experiences occurring during courses 1 through 6 are displayed for patients receiving dexrazoxane for injection or placebo with FAC beginning with their first course of therapy (columns 1 and 3, respectively). Adverse experiences occurring at course 7 and beyond for patients who received placebo with FAC during the first six courses and who then received either dexrazoxane for injection or placebo with FAC are also displayed (columns 2 and 4, respectively). - The adverse reactions listed below in Table 1 demonstrate that the frequency of adverse reaction “Pain on Injection” has been greater for dexrazoxane for injection arm, as compared to placebo. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of dexrazoxane in the drug label. # Drug Interactions - No drug interactions have been identified # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D There is no FDA guidance on usage of Dexrazoxane in women who are pregnant. Pregnancy Category (AUS): - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of dexrazoxane in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of dexrazoxane during labor and delivery. ### Nursing Mothers - It is not known whether dexrazoxane or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from dexrazoxane, 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 dexrazoxane in pediatric patients have not been established . ### Geriatic Use - Clinical studies of dexrazoxane for injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.. ### Gender - Contraception - Dexrazoxane for injection can cause fetal harm when administered during pregnancy. Advise female patients of reproductive potential to use highly effective contraception during treatment. ### Race There is no FDA guidance on the use of dexrazoxane with respect to specific racial populations. ### Renal Impairment - Greater exposure to dexrazoxane may occur in patients with compromised renal function. Reduce the dexrazoxane for injection dose by 50% in patients with creatinine clearance values < 40 mL/min. ### Hepatic Impairment There is no FDA guidance on the use of dexrazoxane in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of dexrazoxane in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of dexrazoxane in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring - Dexrazoxane may increase the myelosuppresive effects of chemotherapeutic agents. Perform hematological monitoring. # IV Compatibility There is limited information regarding IV Compatibility of dexrazoxane in the drug label. # Overdosage - There are no data on overdosage in the cardioprotective trials; the maximum dose administered during the cardioprotective trials was 1000 mg/m2 every three weeks. - Disposition studies with dexrazoxane for injection have not been conducted in cancer patients undergoing dialysis, but retention of a significant dose fraction (> 0.4) of the unchanged drug in the plasma pool, minimal tissue partitioning or binding, and availability of greater than 90% of the systemic drug levels in the unbound form suggest that it could be removed using conventional peritoneal or hemodialysis. - There is no known antidote for dexrazoxane. Instances of suspected overdose should be managed with good supportive care until resolution of myelosuppression and related conditions is complete. Management of overdose should include treatment of infections, fluid regulation, and maintenance of nutritional requirements # Pharmacology ## Mechanism of Action - The mechanism by which dexrazoxane for injection exerts its cytoprotective activity is not fully understood. Dexrazoxane is a cyclic derivative of EDTA that penetrates cell membranes. Results of laboratory studies suggest that dexrazoxane is converted intracellularly to a ring-opened chelating agent that interferes with iron-mediated free radical generation thought to be responsible, in part, for [[cardiomyopathy]\|anthracycline-induced cardiomyopathy]]. ## Structure - Dexrazoxane for injection, a cardioprotective agent for use in conjunction with doxorubicin, is a sterile, pyrogen-free lyophilizate intended for intravenous administration. Chemically, dexrazoxane is (S)-4,4'-(1-methyl-1,2-ethanediyl)bis-2,6-piperazinedione. The structural formula is as follows: - Dexrazoxane, an intracellular chelating agent, is a derivative of EDTA. Dexrazoxane is a whitish crystalline powder that melts at 191° to 197°C. It is sparingly soluble in water and 0.1 N HCl, slightly soluble in ethanol and methanol, and practically insoluble in nonpolar organic solvents. The pKa is 2.1. Dexrazoxane has an octanol/water partition coefficient of 0.025 and degrades rapidly above a pH of 7.0. - Each 250 mg vial contains dexrazoxane hydrochloride equivalent to 250 mg dexrazoxane. Hydrochloric Acid, NF is added for pH adjustment. When reconstituted as directed with the 25 mL vial of 0.167 Molar (M/6) Sodium Lactate Injection, USP diluent provided, each mL contains: 10 mg dexrazoxane. The pH of the resultant solution is 3.5 to 5.5. - Each 500 mg vial contains dexrazoxane hydrochloride equivalent to 500 mg dexrazoxane. Hydrochloric Acid, NF is added for pH adjustment. When reconstituted as directed with the 50 mL vial of 0.167 Molar (M/6) Sodium Lactate Injection, USP diluent provided, each mL contains: 10 mg dexrazoxane. The pH of the resultant solution is 3.5 to 5.5 ## Pharmacodynamics There is limited information regarding Pharmacodynamics of dexrazoxane in the drug label. ## Pharmacokinetics - The pharmacokinetics of dexrazoxane have been studied in advanced cancer patients with normal renal and hepatic function. The pharmacokinetics of dexrazoxane can be adequately described by a two-compartment open model with first-order elimination. Dexrazoxane has been administered as a 15 minute infusion over a dose range of 60 to 900 mg/m2 with 60 mg/m2 of doxorubicin, and at a fixed dose of 500 mg/m2 with 50 mg/m2 doxorubicin. The disposition kinetics of dexrazoxane are dose-independent, as shown by linear relationship between the area under plasma concentration-time curves and administered doses ranging from 60 to 900 mg/m2. The mean peak plasma concentration of dexrazoxane was 36.5 mcg/mL at 15 minute after intravenous administration of 500 mg/m2 dose of dexrazoxane for injection over 15 to 30 minutes prior to the 50 mg/m2 doxorubicin dose. - The important pharmacokinetic parameters of dexrazoxane are summarized in Table 2: - Following a rapid distributive phase (0.2 to 0.3 hours), dexrazoxane reaches post-distributive equilibrium within 2 to 4 hours. The estimated mean steady-state volume of distribution of dexrazoxane is 22.4 L/m2 after 500 mg/m2 of dexrazoxane for injection dose followed by 50 mg/m2 of doxorubicin, suggesting distribution throughout total body water (25 L/m2). - In vitro studies have shown that dexrazoxane is not bound to plasma proteins. - Qualitative metabolism studies with dexrazoxane have confirmed the presence of unchanged drug, a diacid-diamide cleavage product, and two monoacid-monoamide ring products in the urine of animals and man. The metabolite levels were not measured in the pharmacokinetic studies. - Urinary excretion plays an important role in the elimination of dexrazoxane. Forty-two percent of a 500 mg/m2 dose of dexrazoxane for injection was excreted in the urine. Renal clearance averages 3.35 L/h/m2 after the 500 mg/m2 dexrazoxane for injection dose followed by 50 mg/m2 of doxorubicin. - Pharmacokinetics following dexrazoxane for injection administration have not been evaluated in pediatric patients. - The pharmacokinetics of dexrazoxane were assessed following a single 15 minute IV infusion of 150 mg/m2 of dexrazoxane for injection. Dexrazoxane clearance was reduced in subjects with renal dysfunction. Compared with controls, the mean AUC0-inf value was 2-fold greater in subjects with moderate (CLCR 30 to 50 mL/min) to severe (CLCR < 30 mL/min) renal dysfunction. Modeling demonstrated that equivalent exposure (AUC-inf) could be achieved if dosing were reduced by 50% in subjects with creatinine clearance values < 40 mL/min compared with control subjects (CLCR > 80 mL/min). - Pharmacokinetics following dexrazoxane for injection administration have not been evaluated in patients with hepatic impairment. The dexrazoxane for injection dose is dependent upon the dose of doxorubicin . - There was no significant change in the pharmacokinetics of doxorubicin (50 mg/m2) and its predominant metabolite, doxorubicin, in the presence of dexrazoxane (500 mg/m2) in a crossover study in cancer patients. ## Nonclinical Toxicology - No long-term carcinogenicity studies have been carried out with dexrazoxane in animals. Nevertheless, a study by the National Cancer Institute has reported that long-term dosing with razoxane (the racemic mixture of dexrazoxane, ICRF-187, and its enantiomer ICRF-186) is associated with the development of malignancies in rats and possibly in mice. - Dexrazoxane was not mutagenic in the bacterial reverse mutation (Ames) test, but was found to be clastogenic to human lymphocytes in vitro and to mouse bone marrow erythrocytes in vivo(micronucleus test). - Dexrazoxane for injection has the potential to impair fertility in male patients based on effects in repeat-dose toxicology studies. Testicular atrophy was seen with dexrazoxane administration at doses as low as 30 mg/kg weekly for 6 weeks in rats (1/3 the human dose on a mg/m2 basis) and as low as 20 mg/kg weekly for 13 weeks in dogs (approximately equal to the human dose on a mg/m2 basis). # Clinical Studies - The ability of dexrazoxane for injection to prevent/reduce the incidence and severity of doxorubicin-induced cardiomyopathy was evaluated in three prospectively randomized placebo-controlled studies. In these studies, patients were treated with a doxorubicin-containing regimen and either dexrazoxane for injection or placebo starting with the first course of chemotherapy. There was no restriction on the cumulative dose of doxorubicin. Cardiac function was assessed by measurement of the LVEF, utilizing resting multigated nuclear medicine (MUGA) scans, and by clinical evaluations. Patients receiving dexrazoxane for injection had significantly smaller mean decreases from baseline in LVEF and lower incidences of congestive heart failure than the control group; however, in the largest study, patients with advanced breast cancer receiving FAC with dexrazoxane for injection had a lower response rate (48% vs. 63%) and a shorter time to progression than patients who received FAC versus placebo. - In the clinical trials, patients who were initially randomized to receive placebo were allowed to receive dexrazoxane for injection after a cumulative dose of doxorubicin above 300 mg/m2. Retrospective historical analyses showed that the risk of experiencing a cardiac event (see Table 3 for definition) at a cumulative dose of doxorubicin above 300 mg/m2 was greater in the patients who did not receive dexrazoxane for injection beginning with their seventh course of FAC than in the patients who did receive dexrazoxane for injection (HR=13.08; 95% CI: 3.72, 46.03; p < 0.001). Overall, 3% of patients treated with dexrazoxane for injection developed CHF compared with 22% of patients not receiving dexrazoxane for injection. # How Supplied - Dexrazoxane for Injection is available in the following strengths as sterile, pyrogen-free lyophilizates. - NDC 67457-207-25 - 250 mg single-dose vial with a green flip-top seal, packaged in single vial packs. (This package also contains a 25 mL vial of 0.167 Molar (M/6) Sodium Lactate Injection, USP.) - NDC 67457-208-50 - 500 mg single-dose vial with a blue flip-top seal, packaged in single vial packs. (This package also contains a 50 mL vial of 0.167 Molar (M/6) Sodium Lactate Injection, USP.) - Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Reconstituted solutions of dexrazoxane for injection are stable for 6 hours at controlled room temperature or under refrigeration, 2° to 8°C (36° to 46°F). DISCARD UNUSED SOLUTIONS. - Follow special handling and disposal procedures. ## Storage There is limited information regarding Dexrazoxane Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Treatment with dexrazoxane for injection is associated with leukopenia, neutropenia, and thrombocytopenia. Perform hematological monitoring - Counsel patients on pregnancy planning and prevention. Advise female patients of reproductive potential that dexrazoxane for injection can cause fetal harm and to use highly effective contraception during treatment. # Precautions with Alcohol - Alcohol-dexrazoxane interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Zinecard - Totect # Look-Alike Drug Names There is limited information regarding Dexrazoxane Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Dexrazoxane
9ae37842f831b0961680ecdce42f3a3639edd24e	wikidoc	Diabetes UK	Diabetes UK Diabetes UK is a British patient, healthcare professional and research charity dedicated to improving the lives of people with diabetes and to working towards a future without the chronic condition diabetes. Founded in 1934 as The Diabetic Association (by H. G. Wells and Dr R. D. Lawrence), the organisation has since had two name changes - in 1954 to The British Diabetic Association and again in 2000 to Diabetes UK. It also has a website that includes information about diabetes for healthcare professionals and people living with diabetes. The membership of over 180K comprises people with diabetes, their carers and healthcare professionals. Diabetes UK's first voluntary group was set up in 1939 - 350 are now spread out across the UK. There are also local offices across England and national offices in Northern Ireland, Scotland & Wales. They run conferences for their volunteers and healthcare professionals in the field of diabetes. Diabetes UK campaigns for improvements in the care and treatment of people with diabetes. The charity has been running care holidays since the 1930s for children. Families and adult holidays have been introduced since. The holidays aim to provide support and advice in a fun surrounding. In 1993, a counselling line for patients, family and friends was launched, the Careline is contactable by a lo-call number, email and post. The charity also has an internal library and provides a science enquiry service. Diabetes UK funds UK based research into the causes and treatment of diabetes and its complications. The first research grant was made in 1936. Produces a range of information booklets and various magazines, including Balance (for patients) (formerly The Diabetic Journal, first published in 1935, changing its name to Balance in 1961 and Diabetes Update (for professionals). It also via Blackwell Publishing produces the academic journal, Diabetic Medicine. Previous issues were published by John Wiley and Sons (Volume 1, 1984 to Volume 17, mid 2000).	Diabetes UK Diabetes UK is a British patient, healthcare professional and research charity dedicated to improving the lives of people with diabetes and to working towards a future without the chronic condition diabetes. Founded in 1934 as The Diabetic Association (by H. G. Wells and Dr R. D. Lawrence), the organisation has since had two name changes - in 1954 to The British Diabetic Association and again in 2000 to Diabetes UK. It also has a website that includes information about diabetes for healthcare professionals and people living with diabetes. The membership of over 180K comprises people with diabetes, their carers and healthcare professionals. Diabetes UK's first voluntary group was set up in 1939 - 350 are now spread out across the UK. There are also local offices across England and national offices in Northern Ireland, Scotland & Wales. They run conferences for their volunteers and healthcare professionals in the field of diabetes. Diabetes UK campaigns for improvements in the care and treatment of people with diabetes. The charity has been running care holidays since the 1930s for children. Families and adult holidays have been introduced since. The holidays aim to provide support and advice in a fun surrounding.[1] In 1993, a counselling line for patients, family and friends was launched, the Careline is contactable by a lo-call number, email and post.[2] [1] The charity also has an internal library and provides a science enquiry service. [2] Diabetes UK funds UK based research into the causes and treatment of diabetes and its complications. The first research grant was made in 1936.[3] Produces a range of information booklets and various magazines, including Balance (for patients) (formerly The Diabetic Journal, first published in 1935, changing its name to Balance in 1961[3] and Diabetes Update (for professionals). It also via Blackwell Publishing produces the academic journal, Diabetic Medicine. Previous issues were published by John Wiley and Sons (Volume 1, 1984 to Volume 17, mid 2000).	https://www.wikidoc.org/index.php/Diabetes_UK
e96bbc66e8509065f60d03858890f463bbf50465	wikidoc	Diabetology	Diabetology # Overview Diabetology is the clinical science of diabetes mellitus, its diagnosis, treatment and follow-up. It can be considered a specialised field of endocrinology. The term diabetologist is used in several ways. In North America over the last 40 years it is most often used for an internist who through practice and interest develops expertise in diabetes care without having formal training or board certification in endocrinology. Diabetology is not a recognized medical specialty and has no formal training programs leading to board certification. In other contexts the term diabetologist refers to any physician, including endocrinologists, whose practice and/or research efforts are concentrated mainly in diabetes care. Apart from regulating medication (e.g. insulin) dosage and timing, a diabetologist will also concern himself with the potential consequences of diabetes, e.g. retinopathy, nephropathy and peripheral neuropathy.	Diabetology Editor-In-Chief: Ajay Vasant Rotte, M.B.B.S., Consulting Diabetologist, Bindu Hospital, Chetak Horse square, Vishwabharati colony, Aurangabad[1] # Overview Diabetology is the clinical science of diabetes mellitus, its diagnosis, treatment and follow-up. It can be considered a specialised field of endocrinology. The term diabetologist is used in several ways. In North America over the last 40 years it is most often used for an internist who through practice and interest develops expertise in diabetes care without having formal training or board certification in endocrinology. Diabetology is not a recognized medical specialty and has no formal training programs leading to board certification. In other contexts the term diabetologist refers to any physician, including endocrinologists, whose practice and/or research efforts are concentrated mainly in diabetes care. Apart from regulating medication (e.g. insulin) dosage and timing, a diabetologist will also concern himself with the potential consequences of diabetes, e.g. retinopathy, nephropathy and peripheral neuropathy.	https://www.wikidoc.org/index.php/Diabetology
6217e95f052b12f94d0a6a2fc4c6ed0bf6033c67	wikidoc	Dicotyledon	Dicotyledon Magnoliopsida is the botanical name for a class of flowering plants. By definition the class will include the family Magnoliaceae, but its circumscription can otherwise vary, being more inclusive or less inclusive depending upon the classification system being discussed. # Cronquist and Takhtajan systems In the Takhtajan system and the Cronquist system the name is used for the group known as dicotyledons. ## Magnoliopsida in the Takhtajan system The Takhtajan system used this internal taxonomy: - class Magnoliopsida subclass Magnoliidae subclass Nymphaeidae subclass Nelumbonidae subclass Ranunculidae subclass Caryophyllidae subclass Hamamelididae subclass Dilleniidae subclass Rosidae subclass Cornidae subclass Asteridae subclass Lamiidae ## Magnoliopsida in the Cronquist system The Cronquist system used this internal taxonomy (in the 1981 version): - class Magnoliopsida subclass Magnoliidae subclass Hamamelidae subclass Caryophyllidae subclass Dilleniidae subclass Rosidae subclass Asteridae # Dahlgren and Thorne systems The Dahlgren system and the Thorne system (1992) use the name Magnoliopsida for the flowering plants (angiosperms). However, the Cronquist system has been very popular and there have been many versions of the system published. In some of these Cronquist-based systems the name Magnoliopsida (at the rank of class) refers to the flowering plants (the angiosperms). - class Magnoliopsida subclass Magnoliidae subclass Liliidae # Reveal system The Reveal system uses the name Magnoliopsida for a group of the primitive dicotyledons, corresponding to about half of the plants in the magnoliids: - class 1. Magnoliopsida superorder 1. Magnolianae superorder 2. Lauranae # APG systems In the APG and APG II systems botanical names are used only at the rank of order and below. Above the rank of order, these systems use their own names, such as angiosperms, eudicots, monocots, rosids, etc. These names refer to clades (unranked). This class Magnoliopsida is not defined. Note that the idea that dicotyledons could be a taxonomic unit and get a formal name is rejected by the APG: the dicots are considered to be paraphyletic. ca:Magnoliòpsid cs:Nižší dvouděložné de:Einfurchenpollen-Zweikeimblättrige et:Kaheidulehelised fa:دولپه‌ای‌ها hsb:Magnoliopsida id:Magnoliopsida it:Magnoliopsida he:דו-פסיגיים קדומים lb:Magnoliopsida lt:Magnolijainiai ms:Magnoliopsida nl:Magnoliopsida -c:Magnoliopsida qu:Ch'ulla khata sisayuq sq:Magnoliopsida scn:Magnoliopsida simple:Magnoliopsida th:พืชใบเลี้ยงคู่ to:Lautengaʻiua bat-smg:Magnolėjainē	Dicotyledon Magnoliopsida is the botanical name for a class of flowering plants. By definition the class will include the family Magnoliaceae, but its circumscription can otherwise vary, being more inclusive or less inclusive depending upon the classification system being discussed. # Cronquist and Takhtajan systems In the Takhtajan system and the Cronquist system the name is used for the group known as dicotyledons. ## Magnoliopsida in the Takhtajan system The Takhtajan system used this internal taxonomy: - class Magnoliopsida [= dicotyledons] subclass Magnoliidae subclass Nymphaeidae subclass Nelumbonidae subclass Ranunculidae subclass Caryophyllidae subclass Hamamelididae subclass Dilleniidae subclass Rosidae subclass Cornidae subclass Asteridae subclass Lamiidae ## Magnoliopsida in the Cronquist system The Cronquist system used this internal taxonomy (in the 1981 version): - class Magnoliopsida [= dicotyledons] subclass Magnoliidae subclass Hamamelidae subclass Caryophyllidae subclass Dilleniidae subclass Rosidae subclass Asteridae # Dahlgren and Thorne systems The Dahlgren system and the Thorne system (1992) use the name Magnoliopsida for the flowering plants (angiosperms). However, the Cronquist system has been very popular and there have been many versions of the system published. In some of these Cronquist-based systems the name Magnoliopsida (at the rank of class) refers to the flowering plants (the angiosperms). - class Magnoliopsida [= angiosperms] subclass Magnoliidae [= dicotyledons] subclass Liliidae [= monocotyledons] # Reveal system The Reveal system uses the name Magnoliopsida for a group of the primitive dicotyledons, corresponding to about half of the plants in the magnoliids: - class 1. Magnoliopsida superorder 1. Magnolianae superorder 2. Lauranae # APG systems In the APG and APG II systems botanical names are used only at the rank of order and below. Above the rank of order, these systems use their own names, such as angiosperms, eudicots, monocots, rosids, etc. These names refer to clades (unranked). This class Magnoliopsida is not defined. Note that the idea that dicotyledons could be a taxonomic unit and get a formal name is rejected by the APG: the dicots are considered to be paraphyletic. Template:Wikispecies ca:Magnoliòpsid cs:Nižší dvouděložné de:Einfurchenpollen-Zweikeimblättrige et:Kaheidulehelised fa:دولپه‌ای‌ها hsb:Magnoliopsida id:Magnoliopsida it:Magnoliopsida he:דו-פסיגיים קדומים lb:Magnoliopsida lt:Magnolijainiai ms:Magnoliopsida nl:Magnoliopsida oc:Magnoliopsida qu:Ch'ulla khata sisayuq sq:Magnoliopsida scn:Magnoliopsida simple:Magnoliopsida th:พืชใบเลี้ยงคู่ to:Lautengaʻiua bat-smg:Magnolėjainē Template:WH Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Dicotyledon
fda1eaab2e6b3d8c7ad63cfd419594cbcc8cf48a	wikidoc	Dicyclomine	Dicyclomine # 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 Dicyclomine is an antispasmodic and anticholinergic agent that is FDA approved for the treatment of functional bowel disorder or irritable bowel syndrome. Common adverse reactions include dizziness, dry mouth, blurred vision, nausea, somnolence, asthenia, and nervousness. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - Oral Dosage and Administration in Adults - The recommended initial dose is 20 mg four times a day. After one week treatment with the initial dose, the dose may be increased to 40 mg four times a day unless side effects limit dosage escalation. - If efficacy is not achieved within 2 weeks or side effects require doses below 80 mg per day, the drug should be discontinued. Documented safety data are not available for doses above 80 mg daily for periods longer than 2 weeks. - Intramuscular Dosage and Administration in Adults - BENTYL Intramuscular Injection must be administered via intramuscular route only. Do not administer by an other route. The recommended intramuscular dose is 10 mg to 20 mg four times a day. - The intramuscular injection is to be used only for 1 or 2 days when the patient cannot take oral medication. - Intramuscular injection is about twice as bioavailable as oral dosage forms. - Preparation for Intramuscular Administration - Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. - Aspirate the syringe before injecting to avoid intravascular injection, since thrombosis may occur if the drug is inadvertently injected intravascularly. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Dicyclomine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Dicyclomine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Dicyclomine in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Dicyclomine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Dicyclomine in pediatric patients. # Contraindications - BENTYL is contraindicated in infants less than 6 months of age, nursing mothers], and in patients with: - unstable cardiovascular status in acute hemorrhage - myasthenia gravis - glaucoma - obstructive uropathy - obstructive disease of the gastrointestinal tract - severe ulcerative colitis - reflux esophagitis # Warnings ### Precautions - Inadvertent Intravenous Administration - BENTYL solution is for intramuscular administration only. Do not administer by any other route. Inadvertent intravenous administration may result in thrombosis, thrombophlebitis and injection site reactions such as pain, edema, skin color change, and reflex sympathetic dystrophy syndrome. - Cardiovascular Conditions - Dicyclomine hydrochloride needs to be used with caution in conditions characterized by tachyarrhythmia such as thyrotoxicosis, congestive heart failure and in cardiac surgery, where they may further accelerate the heart rate. Investigate any tachycardia before administration of dicyclomine hydrochloride. Care is required in patients with coronary heart disease, as ischemia and infarction may be worsened, and in patients with hypertension. - Peripheral and Central Nervous System - The peripheral effects of dicyclomine hydrochloride are a consequence of their inhibitory effect on muscarinic receptors of the autonomic nervous system. They include dryness of the mouth with difficulty in swallowing and talking, thirst, reduced bronchial secretions, dilatation of the pupils (mydriasis) with loss of accommodation (cycloplegia) and photophobia, flushing and dryness of the skin, transient bradycardia followed by tachycardia, with palpitations and arrhythmias, and difficulty in micturition, as well as reduction in the tone and motility of the gastrointestinal tract leading to constipation. - In the presence of high environmental temperature heat prostration can occur with drug use (fever and heat stroke due to decreased sweating). It should also be used cautiously in patients with fever. If symptoms occur, the drug should be discontinued and supportive measures instituted. Because of the inhibitory effect on muscarinic receptors within the autonomic nervous system, caution should be taken in patients with autonomic neuropathy. - Central nervous system (CNS) signs and symptoms include confusional state, disorientation, amnesia, hallucinations, dysarthria, ataxia, coma, euphoria, fatigue, insomnia, agitation and mannerisms, and inappropriate affect. - Psychosis and delirium have been reported in sensitive individuals (such as elderly patients and/or in patients with mental illness) given anticholinergic drugs. These CNS signs and symptoms usually resolve within 12 to 24 hours after discontinuation of the drug. - BENTYL may produce drowsiness, dizziness or blurred vision. The patient should be warned not to engage in activities requiring mental alertness, such as operating a motor vehicle or other machinery or performing hazardous work while taking BENTYL. - Myasthenia Gravis - With overdosage, a curare-like action may occur (i.e., neuromuscular blockade leading to muscular weakness and possible paralysis). It should not be given to patients with myasthenia gravis except to reduce adverse muscarinic effects of an anticholinesterase. - Intestinal Obstruction - Diarrhea may be an early symptom of incomplete intestinal obstruction, especially in patients with ileostomy or colostomy. In this instance, treatment with this drug would be inappropriate and possibly harmful. - Rarely development of Ogilvie's syndrome (colonic pseudo-obstruction) has been reported. Ogilvie's syndrome is a clinical disorder with signs, symptoms, and radiographic appearance of an acute large bowel obstruction but with no evidence of distal colonic obstruction. - Toxic Dilatation of Intestine megacolon - Toxic dilatation of intestine and intestinal perforation is possible when anticholinergic agents are administered in patients with Salmonella dysentery. - Ulcerative Colitis - Caution should be taken in patients with ulcerative colitis. Large doses may suppress intestinal motility to the point of producing a paralytic ileus and the use of this drug may precipitate or aggravate the serious complication of toxic megacolon. BENTYL is contraindicated in patients with severe ulcerative colitis. - Prostatic Hypertrophy - BENTYL should be used with caution in patients with known or suspected prostatic enlargement, in whom prostatic enlargement may lead to urinary retention. - Hepatic and Renal Disease - BENTYL should be used with caution in patients with known hepatic and renal impairment. - Geriatric Population - Dicyclomine hydrochloride should be used with caution in elderly who may be more susceptible to its adverse 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. - The data described below reflect exposure in controlled clinical trials involving over 100 patients treated for functional bowel/irritable bowel syndrome with dicyclomine hydrochloride at initial doses of 160 mg daily (40 mg four times a day) - In these trials most of the side effects were typically anticholinergic in nature and were reported by 61% of the patients. Table 1 presents adverse reactions (MedDRA 13.0 preferred terms) by decreasing order of frequency in a side-by-side comparison with placebo. - Nine percent (9%) of patients were discontinued from BENTYL because of one or more of these side effects (compared with 2% in the placebo group). In 41% of the patients with side effects, side effects disappeared or were tolerated at the 160 mg daily dose without reduction. A dose reduction from 160 mg daily to an average daily dose of 90 mg was required in 46% of the patients with side effects who then continued to experience a favorable clinical response; their side effects either disappeared or were tolerated. ## Postmarketing Experience - The following adverse reactions, presented by system organ class in alphabetical order, have been identified during post approval use of BENTYL. 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. - Cases of thrombosis, thrombophlebitis and injection site reactions such as local pain, edema, skin color change and even reflex sympathetic dystrophy syndrome have been reported following inadverent IV injection of BENTYL. Fatigue, malaise Palpitations, tachyarrhythmias Abdominal distension, abdominal pain, constipation, dry mouth, dyspepsia, nausea, vomiting Suppressed lactation As with the other anti-cholinergic drugs, cases of delirium or symptoms of delirium such as amnesia (or transient global amnesia), agitation, confusional state, delusion, disorientation, hallucination (including visual hallucination) as well as mania, mood altered and pseudodementia, have been reported with the use of Dicyclomine. Nervousness and insomnia have also been reported. Dizziness, headache, somnolence, syncope Dyspnoea, nasal congestion Drug hypersensitivity including face edema, angioedema, anaphylactic shock, dermatitis allergic, erythema, rash Cycloplegia, mydriasis, blurred vision # Drug Interactions - Antiglaucoma Agents - Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Use of BENTYL in patients with glaucoma is not recommended. - Other Drugs with Anticholinergic Activity - The following agents may increase certain actions or side effects of anticholinergic drugs including BENTYL: amantadine, antiarrhythmic agents of Class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. - Other Gastrointestinal Motility Drugs - Interaction with other gastrointestinal motility drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. - Effect of Antacids - Because antacids may interfere with the absorption of anticholinergic agents including BENTYL, simultaneous use of these drugs should be avoided. - Effect on Absorption of Other Drugs - Anticholinergic agents may affect gastrointestinal absorption of various drugs by affecting gastrointestinal motility, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentration may result. - Effect on Gastric Acid Secretion - The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category B - Adequate and well-controlled studies have not been conducted with BENTYL in pregnant women at the recommended doses of 80 to 160 mg/day. However, epidemiologic studies did not show an increased risk of structural malformations amoung babies born to women who took products containing dicyclomine hydrochloride at doses up to 40 mg/day during the first trimester of pregnancy. - Reproduction studies have been performed in rats and rabbits at doses of up to 33 times the maximum recommended human dose based on 160 mg/day (3 mg/kg) and have revealed no evidence of harm to the fetus due to dicyclomine. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dicyclomine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Dicyclomine during labor and delivery. ### Nursing Mothers - BENTYL is contraindicated in women who are breastfeeding. Dicyclomine hydrochloride is excreted in human milk. Because of the potential for serious adverse reactions in breast-fed infants from BENTYL, a decision should be made whether to discontine nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. - BENTYL is contraindicated in infants less than 6 months of age. There are published cases reporting that the administration of dicyclomine hydrochloride to infants has been followed by serious respiratory symptoms (dyspnea, shortness of breath, breathlessness, respiratory collapse, apnea and asphyxia), seizures, syncope, pulse rate fluctuations, muscular hypotonia, and coma, and death, however; no causal relationship has been established. ### Geriatic Use - Clinical studies of BENTYL did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range in adults, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. - 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 Dicyclomine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Dicyclomine with respect to specific racial populations. ### Renal Impairment - Effects of renal impairment on PK, safety and efficacy of BENTYL have not been studied. BENTYL drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. BENTYL should be administered with caution in patients with renal impairment. ### Hepatic Impairment - Effects of renal impairment on PK, safety and efficacy of BENTYL have not been studied. BENTYL should be administered with caution in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Dicyclomine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Dicyclomine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral - Intramuscular ### Monitoring There is limited information regarding Monitoring of Dicyclomine in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Dicyclomine in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - In case of an overdose, patients should contact a physician, poison control centre (1-800-222-1222), or emergency room. - The signs and symptoms of overdosage include: headache; nausea; vomiting; blurred vision; dilated pupils; hot, dry skin; dizziness; dryness of the mouth; difficulty in swallowing; and CNS stimulation including convulsion. A curare-like action may occur (i.e., neuromuscular blockade leading to muscular weakness and possible paralysis). - One reported event included a 37-year-old who reported numbness on the left side, cold fingertips, blurred vision, abdominal and flank pain, decreased appetite, dry mouth, and nervousness following ingestion of 320 mg daily (four 20 mg tablets four times daily.) These events resolved after discontinuing the dicyclomine. - The acute oral LD50 of the drug is 625 mg/kg in mice. - The amount of drug in a single dose that is ordinarily associated with symptoms of overdosage or that is likely to be life-threatening, has not been defined. The maximum human oral dose recorded was 600 mg by mouth in a 10-month-old child and approximately 1500 mg in an adult, each of whom survived. In three of the infants who died following administration of dicyclomine hydrochloride, the blood concentrations of drug were 200, 220, and 505 ng/mL. - It is not know if BENTYL is dialyzable. ### Management - Treatment should consist of gastric lavage, emetics, and activated charcoal. Sedatives (e.g., short-acting barbiturates, benzodiazepines) may be used for management of overt signs of excitement. If indicated, an appropriate parenteral cholinergic agent may be used as an antidote. ## Chronic Overdose There is limited information regarding Chronic Overdose of Dicyclomine in the drug label. # Pharmacology ## Mechanism of Action - Dicyclomine relieves smooth muscle spasm of the gastrointestinal tract. Animal studies indicate that this action is achieved via a dual mechanism: - a specific anticholinergic effect (antimuscarinic) at the acetylcholine-receptor sites with approximately 1/8 the milligram potency of atropine (in vitro, guinea pig ileum); and - a direct effect upon smooth muscle (musculotropic) as evidenced by dicyclomine's antagonism of bradykinin- and histamine-induced spasms of the isolated guinea pig ileum. - Atropine did not affect responses to these two agonists. In vivo studies in cats and dogs showed dicyclomine to be equally potent against acetylcholine (ACh)- or barium chloride (BaCl2)-induced intestinal spasm while atropine was at least 200 times more potent against effects of ACh than BaCl2. Tests for mydriatic effects in mice showed that dicyclomine was approximately 1/500 as potent as atropine; antisialagogue tests in rabbits showed dicyclomine to be 1/300 as potent as atropine. ## Structure - BENTYL is an antispasmodic and anticholinergic (antimuscarinic) agent available in the following dosage forms: - BENTYL capsules for oral use contain 10 mg dicyclomine hydrochloride USP. BENTYL 10 mg capsules also contain inactive ingredients: calcium sulfate, corn starch, FD&C Blue No. 1, FD&C Red No. 40, gelatin, lactose, magnesium stearate, pregelatinized corn starch, and titanium dioxide. - BENTYL tablets for oral use contain 20 mg dicyclomine hydrochloride USP. BENTYL 20 mg tablets also contain inactive ingredients: acacia, dibasic calcium phosphate, corn starch, FD&C Blue No. 1, lactose, magnesium stearate, pregelatinized corn starch, and sucrose. - BENTYL injection is a sterile, pyrogen-free, aqueous solution for intramuscular injection (NOT FOR INTRAVENOUS USE) supplied as an ampoule containing 20 mg/2 mL (10 mg/mL). Each mL contains 10 mg dicyclomine hydrochloride USP in sterile water for injection, made isotonic with sodium chloride. - BENTYL (dicyclomine hydrochloride) is -1-carboxylic acid, 2-(diethylamino) ethyl ester, hydrochloride, with a molecular formula of C19H35NO2HCl and the following structural formula: - Dicyclomine hydrochloride occurs as a fine, white, crystalline, practically odorless powder with a bitter taste. It is soluble in water, freely soluble in alcohol and chloroform, and very slightly soluble in ether. ## Pharmacodynamics (BENTYL can inhibit the secretion of saliva and sweat, decrease gastrointestinal secretions and motility, cause drowsiness, dilate the pupils, increase heart rate, and depress motor function. ## Pharmacokinetics - Absorption and Distribution - In man, dicyclomine is rapidly absorbed after oral administration, reaching peak values within 60-90 minutes. Mean volume of distribution for a 20 mg oral dose is approximately 3.65 L/kg suggesting exentsive distribution in tissues. - Elimination - The metabolism of dicyclomine was not studied. The principal route of excretion is via the urine (79.5% of the dose). Excretion also occurs in the feces, but to a lesser extent (8.4%). Mean half-life of plasma elimination in one study was determined to be approximately 1.8 hours when plasma concentrations were measured for 9 hours after a single dose. In subsequent studies, plasma concentrations were followed for up to 24 hours after a single dose, showing a secondary phase of elimination with a somewhat longer half-life. ## Nonclinical Toxicology - Long-term animal studies have not been conducted to evaluate the carcinogenic potential of dicyclomine. In studies in rats at doses of up to 100 mg/kg/day, dicyclomine produced no deleterious effects on breeding, conception, or parturition. # Clinical Studies - In controlled clinical trials involving over 100 patients who received drug, 82% of patients treated for functional bowel/irritable bowel syndrome with dicyclomine hydrochloride at initial doses of 160 mg daily (40 mg four times daily) demonstrated a favorable clinical response compared with 55% treated with placebo (p<0.05). # How Supplied - BENTYL Capsules - 10 mg blue capsules, imprinted BENTYL 10, supplied in bottles of 100. Store at room temperature, preferably below 86°F (30°C). - NDC number: 58914-012-10. - BENTYL Tablets - 20 mg compressed, light blue, round tablets, debossed BENTYL 20, supplied in bottles of 100. To prevent fading, avoid exposure to direct sunlight. Store at room temperature, preferably below 86°F (30°C). - NDC 58914-013-10. - BENTYL Injection - 20 mg/2 mL (10 mg/mL) injection supplied in boxes of five 20 mg/2 mL ampules (10 mg/mL). Store at room temperature, preferably below 86°F (30°C). Protect from freezing. - NDC 58914-080-52. ## Storage There is limited information regarding Dicyclomine Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Inadvertent Intravenous Administration - BENTYL injection is for intramuscular administration only. Do not administer by any other route. Inadvertent administration may result in thrombosis or thrombophlebitis and injection site such as pain, edema, skin color change and even reflex sympathetic dystrophy syndrome. - Use in Infants - Inform parents and caregivers not to administer BENTYL in infants less than 6 months of age. - Use in Nursing Mothers - Advise lactating women that BENTYL should not be used while breastfeeding their infants . - Peripheral and Central Nervous System - In the presence of a high environmental temperature, heat prostration can occur with BENTYL use (fever and heat stroke due to decreased sweating). If symptoms occur, the drug should be discontinued and a physician contacted. BENTYL may produce drowsiness or blurred vision. The patient should be warned not to engage in activities requiring mental alertness, such as operating a motor vehicle or other machinery or to perform hazardous work while taking BENTYL. # Precautions with Alcohol - Alcohol-Dicyclomine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - BENTYL® # Look-Alike Drug Names There is limited information regarding Dicyclomine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Dicyclomine 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 Dicyclomine is an antispasmodic and anticholinergic agent that is FDA approved for the treatment of functional bowel disorder or irritable bowel syndrome. Common adverse reactions include dizziness, dry mouth, blurred vision, nausea, somnolence, asthenia, and nervousness. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - Oral Dosage and Administration in Adults - The recommended initial dose is 20 mg four times a day. After one week treatment with the initial dose, the dose may be increased to 40 mg four times a day unless side effects limit dosage escalation. - If efficacy is not achieved within 2 weeks or side effects require doses below 80 mg per day, the drug should be discontinued. Documented safety data are not available for doses above 80 mg daily for periods longer than 2 weeks. - Intramuscular Dosage and Administration in Adults - BENTYL Intramuscular Injection must be administered via intramuscular route only. Do not administer by an other route. The recommended intramuscular dose is 10 mg to 20 mg four times a day. - The intramuscular injection is to be used only for 1 or 2 days when the patient cannot take oral medication. - Intramuscular injection is about twice as bioavailable as oral dosage forms. - Preparation for Intramuscular Administration - Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. - Aspirate the syringe before injecting to avoid intravascular injection, since thrombosis may occur if the drug is inadvertently injected intravascularly. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Dicyclomine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Dicyclomine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Dicyclomine in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Dicyclomine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Dicyclomine in pediatric patients. # Contraindications - BENTYL is contraindicated in infants less than 6 months of age, nursing mothers], and in patients with: - unstable cardiovascular status in acute hemorrhage - myasthenia gravis - glaucoma - obstructive uropathy - obstructive disease of the gastrointestinal tract - severe ulcerative colitis - reflux esophagitis # Warnings ### Precautions - Inadvertent Intravenous Administration - BENTYL solution is for intramuscular administration only. Do not administer by any other route. Inadvertent intravenous administration may result in thrombosis, thrombophlebitis and injection site reactions such as pain, edema, skin color change, and reflex sympathetic dystrophy syndrome. - Cardiovascular Conditions - Dicyclomine hydrochloride needs to be used with caution in conditions characterized by tachyarrhythmia such as thyrotoxicosis, congestive heart failure and in cardiac surgery, where they may further accelerate the heart rate. Investigate any tachycardia before administration of dicyclomine hydrochloride. Care is required in patients with coronary heart disease, as ischemia and infarction may be worsened, and in patients with hypertension. - Peripheral and Central Nervous System - The peripheral effects of dicyclomine hydrochloride are a consequence of their inhibitory effect on muscarinic receptors of the autonomic nervous system. They include dryness of the mouth with difficulty in swallowing and talking, thirst, reduced bronchial secretions, dilatation of the pupils (mydriasis) with loss of accommodation (cycloplegia) and photophobia, flushing and dryness of the skin, transient bradycardia followed by tachycardia, with palpitations and arrhythmias, and difficulty in micturition, as well as reduction in the tone and motility of the gastrointestinal tract leading to constipation. - In the presence of high environmental temperature heat prostration can occur with drug use (fever and heat stroke due to decreased sweating). It should also be used cautiously in patients with fever. If symptoms occur, the drug should be discontinued and supportive measures instituted. Because of the inhibitory effect on muscarinic receptors within the autonomic nervous system, caution should be taken in patients with autonomic neuropathy. - Central nervous system (CNS) signs and symptoms include confusional state, disorientation, amnesia, hallucinations, dysarthria, ataxia, coma, euphoria, fatigue, insomnia, agitation and mannerisms, and inappropriate affect. - Psychosis and delirium have been reported in sensitive individuals (such as elderly patients and/or in patients with mental illness) given anticholinergic drugs. These CNS signs and symptoms usually resolve within 12 to 24 hours after discontinuation of the drug. - BENTYL may produce drowsiness, dizziness or blurred vision. The patient should be warned not to engage in activities requiring mental alertness, such as operating a motor vehicle or other machinery or performing hazardous work while taking BENTYL. - Myasthenia Gravis - With overdosage, a curare-like action may occur (i.e., neuromuscular blockade leading to muscular weakness and possible paralysis). It should not be given to patients with myasthenia gravis except to reduce adverse muscarinic effects of an anticholinesterase. - Intestinal Obstruction - Diarrhea may be an early symptom of incomplete intestinal obstruction, especially in patients with ileostomy or colostomy. In this instance, treatment with this drug would be inappropriate and possibly harmful. - Rarely development of Ogilvie's syndrome (colonic pseudo-obstruction) has been reported. Ogilvie's syndrome is a clinical disorder with signs, symptoms, and radiographic appearance of an acute large bowel obstruction but with no evidence of distal colonic obstruction. - Toxic Dilatation of Intestine megacolon - Toxic dilatation of intestine and intestinal perforation is possible when anticholinergic agents are administered in patients with Salmonella dysentery. - Ulcerative Colitis - Caution should be taken in patients with ulcerative colitis. Large doses may suppress intestinal motility to the point of producing a paralytic ileus and the use of this drug may precipitate or aggravate the serious complication of toxic megacolon. BENTYL is contraindicated in patients with severe ulcerative colitis. - Prostatic Hypertrophy - BENTYL should be used with caution in patients with known or suspected prostatic enlargement, in whom prostatic enlargement may lead to urinary retention. - Hepatic and Renal Disease - BENTYL should be used with caution in patients with known hepatic and renal impairment. - Geriatric Population - Dicyclomine hydrochloride should be used with caution in elderly who may be more susceptible to its adverse 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. - The data described below reflect exposure in controlled clinical trials involving over 100 patients treated for functional bowel/irritable bowel syndrome with dicyclomine hydrochloride at initial doses of 160 mg daily (40 mg four times a day) - In these trials most of the side effects were typically anticholinergic in nature and were reported by 61% of the patients. Table 1 presents adverse reactions (MedDRA 13.0 preferred terms) by decreasing order of frequency in a side-by-side comparison with placebo. - Nine percent (9%) of patients were discontinued from BENTYL because of one or more of these side effects (compared with 2% in the placebo group). In 41% of the patients with side effects, side effects disappeared or were tolerated at the 160 mg daily dose without reduction. A dose reduction from 160 mg daily to an average daily dose of 90 mg was required in 46% of the patients with side effects who then continued to experience a favorable clinical response; their side effects either disappeared or were tolerated. ## Postmarketing Experience - The following adverse reactions, presented by system organ class in alphabetical order, have been identified during post approval use of BENTYL. 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. - Cases of thrombosis, thrombophlebitis and injection site reactions such as local pain, edema, skin color change and even reflex sympathetic dystrophy syndrome have been reported following inadverent IV injection of BENTYL. Fatigue, malaise Palpitations, tachyarrhythmias Abdominal distension, abdominal pain, constipation, dry mouth, dyspepsia, nausea, vomiting Suppressed lactation As with the other anti-cholinergic drugs, cases of delirium or symptoms of delirium such as amnesia (or transient global amnesia), agitation, confusional state, delusion, disorientation, hallucination (including visual hallucination) as well as mania, mood altered and pseudodementia, have been reported with the use of Dicyclomine. Nervousness and insomnia have also been reported. Dizziness, headache, somnolence, syncope Dyspnoea, nasal congestion Drug hypersensitivity including face edema, angioedema, anaphylactic shock, dermatitis allergic, erythema, rash Cycloplegia, mydriasis, blurred vision # Drug Interactions - Antiglaucoma Agents - Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Use of BENTYL in patients with glaucoma is not recommended. - Other Drugs with Anticholinergic Activity - The following agents may increase certain actions or side effects of anticholinergic drugs including BENTYL: amantadine, antiarrhythmic agents of Class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. - Other Gastrointestinal Motility Drugs - Interaction with other gastrointestinal motility drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. - Effect of Antacids - Because antacids may interfere with the absorption of anticholinergic agents including BENTYL, simultaneous use of these drugs should be avoided. - Effect on Absorption of Other Drugs - Anticholinergic agents may affect gastrointestinal absorption of various drugs by affecting gastrointestinal motility, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentration may result. - Effect on Gastric Acid Secretion - The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category B - Adequate and well-controlled studies have not been conducted with BENTYL in pregnant women at the recommended doses of 80 to 160 mg/day. However, epidemiologic studies did not show an increased risk of structural malformations amoung babies born to women who took products containing dicyclomine hydrochloride at doses up to 40 mg/day during the first trimester of pregnancy. - Reproduction studies have been performed in rats and rabbits at doses of up to 33 times the maximum recommended human dose based on 160 mg/day (3 mg/kg) and have revealed no evidence of harm to the fetus due to dicyclomine. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dicyclomine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Dicyclomine during labor and delivery. ### Nursing Mothers - BENTYL is contraindicated in women who are breastfeeding. Dicyclomine hydrochloride is excreted in human milk. Because of the potential for serious adverse reactions in breast-fed infants from BENTYL, a decision should be made whether to discontine nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. - BENTYL is contraindicated in infants less than 6 months of age. There are published cases reporting that the administration of dicyclomine hydrochloride to infants has been followed by serious respiratory symptoms (dyspnea, shortness of breath, breathlessness, respiratory collapse, apnea and asphyxia), seizures, syncope, pulse rate fluctuations, muscular hypotonia, and coma, and death, however; no causal relationship has been established. ### Geriatic Use - Clinical studies of BENTYL did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range in adults, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. - 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 Dicyclomine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Dicyclomine with respect to specific racial populations. ### Renal Impairment - Effects of renal impairment on PK, safety and efficacy of BENTYL have not been studied. BENTYL drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. BENTYL should be administered with caution in patients with renal impairment. ### Hepatic Impairment - Effects of renal impairment on PK, safety and efficacy of BENTYL have not been studied. BENTYL should be administered with caution in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Dicyclomine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Dicyclomine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral - Intramuscular ### Monitoring There is limited information regarding Monitoring of Dicyclomine in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Dicyclomine in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - In case of an overdose, patients should contact a physician, poison control centre (1-800-222-1222), or emergency room. - The signs and symptoms of overdosage include: headache; nausea; vomiting; blurred vision; dilated pupils; hot, dry skin; dizziness; dryness of the mouth; difficulty in swallowing; and CNS stimulation including convulsion. A curare-like action may occur (i.e., neuromuscular blockade leading to muscular weakness and possible paralysis). - One reported event included a 37-year-old who reported numbness on the left side, cold fingertips, blurred vision, abdominal and flank pain, decreased appetite, dry mouth, and nervousness following ingestion of 320 mg daily (four 20 mg tablets four times daily.) These events resolved after discontinuing the dicyclomine. - The acute oral LD50 of the drug is 625 mg/kg in mice. - The amount of drug in a single dose that is ordinarily associated with symptoms of overdosage or that is likely to be life-threatening, has not been defined. The maximum human oral dose recorded was 600 mg by mouth in a 10-month-old child and approximately 1500 mg in an adult, each of whom survived. In three of the infants who died following administration of dicyclomine hydrochloride, the blood concentrations of drug were 200, 220, and 505 ng/mL. - It is not know if BENTYL is dialyzable. ### Management - Treatment should consist of gastric lavage, emetics, and activated charcoal. Sedatives (e.g., short-acting barbiturates, benzodiazepines) may be used for management of overt signs of excitement. If indicated, an appropriate parenteral cholinergic agent may be used as an antidote. ## Chronic Overdose There is limited information regarding Chronic Overdose of Dicyclomine in the drug label. # Pharmacology ## Mechanism of Action - Dicyclomine relieves smooth muscle spasm of the gastrointestinal tract. Animal studies indicate that this action is achieved via a dual mechanism: - a specific anticholinergic effect (antimuscarinic) at the acetylcholine-receptor sites with approximately 1/8 the milligram potency of atropine (in vitro, guinea pig ileum); and - a direct effect upon smooth muscle (musculotropic) as evidenced by dicyclomine's antagonism of bradykinin- and histamine-induced spasms of the isolated guinea pig ileum. - Atropine did not affect responses to these two agonists. In vivo studies in cats and dogs showed dicyclomine to be equally potent against acetylcholine (ACh)- or barium chloride (BaCl2)-induced intestinal spasm while atropine was at least 200 times more potent against effects of ACh than BaCl2. Tests for mydriatic effects in mice showed that dicyclomine was approximately 1/500 as potent as atropine; antisialagogue tests in rabbits showed dicyclomine to be 1/300 as potent as atropine. ## Structure - BENTYL is an antispasmodic and anticholinergic (antimuscarinic) agent available in the following dosage forms: - BENTYL capsules for oral use contain 10 mg dicyclomine hydrochloride USP. BENTYL 10 mg capsules also contain inactive ingredients: calcium sulfate, corn starch, FD&C Blue No. 1, FD&C Red No. 40, gelatin, lactose, magnesium stearate, pregelatinized corn starch, and titanium dioxide. - BENTYL tablets for oral use contain 20 mg dicyclomine hydrochloride USP. BENTYL 20 mg tablets also contain inactive ingredients: acacia, dibasic calcium phosphate, corn starch, FD&C Blue No. 1, lactose, magnesium stearate, pregelatinized corn starch, and sucrose. - BENTYL injection is a sterile, pyrogen-free, aqueous solution for intramuscular injection (NOT FOR INTRAVENOUS USE) supplied as an ampoule containing 20 mg/2 mL (10 mg/mL). Each mL contains 10 mg dicyclomine hydrochloride USP in sterile water for injection, made isotonic with sodium chloride. - BENTYL (dicyclomine hydrochloride) is [bicyclohexyl]-1-carboxylic acid, 2-(diethylamino) ethyl ester, hydrochloride, with a molecular formula of C19H35NO2•HCl and the following structural formula: - Dicyclomine hydrochloride occurs as a fine, white, crystalline, practically odorless powder with a bitter taste. It is soluble in water, freely soluble in alcohol and chloroform, and very slightly soluble in ether. ## Pharmacodynamics (BENTYL can inhibit the secretion of saliva and sweat, decrease gastrointestinal secretions and motility, cause drowsiness, dilate the pupils, increase heart rate, and depress motor function. ## Pharmacokinetics - Absorption and Distribution - In man, dicyclomine is rapidly absorbed after oral administration, reaching peak values within 60-90 minutes. Mean volume of distribution for a 20 mg oral dose is approximately 3.65 L/kg suggesting exentsive distribution in tissues. - Elimination - The metabolism of dicyclomine was not studied. The principal route of excretion is via the urine (79.5% of the dose). Excretion also occurs in the feces, but to a lesser extent (8.4%). Mean half-life of plasma elimination in one study was determined to be approximately 1.8 hours when plasma concentrations were measured for 9 hours after a single dose. In subsequent studies, plasma concentrations were followed for up to 24 hours after a single dose, showing a secondary phase of elimination with a somewhat longer half-life. ## Nonclinical Toxicology - Long-term animal studies have not been conducted to evaluate the carcinogenic potential of dicyclomine. In studies in rats at doses of up to 100 mg/kg/day, dicyclomine produced no deleterious effects on breeding, conception, or parturition. # Clinical Studies - In controlled clinical trials involving over 100 patients who received drug, 82% of patients treated for functional bowel/irritable bowel syndrome with dicyclomine hydrochloride at initial doses of 160 mg daily (40 mg four times daily) demonstrated a favorable clinical response compared with 55% treated with placebo (p<0.05). # How Supplied - BENTYL Capsules - 10 mg blue capsules, imprinted BENTYL 10, supplied in bottles of 100. Store at room temperature, preferably below 86°F (30°C). - NDC number: 58914-012-10. - BENTYL Tablets - 20 mg compressed, light blue, round tablets, debossed BENTYL 20, supplied in bottles of 100. To prevent fading, avoid exposure to direct sunlight. Store at room temperature, preferably below 86°F (30°C). - NDC 58914-013-10. - BENTYL Injection - 20 mg/2 mL (10 mg/mL) injection supplied in boxes of five 20 mg/2 mL ampules (10 mg/mL). Store at room temperature, preferably below 86°F (30°C). Protect from freezing. - NDC 58914-080-52. ## Storage There is limited information regarding Dicyclomine Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Inadvertent Intravenous Administration - BENTYL injection is for intramuscular administration only. Do not administer by any other route. Inadvertent administration may result in thrombosis or thrombophlebitis and injection site such as pain, edema, skin color change and even reflex sympathetic dystrophy syndrome. - Use in Infants - Inform parents and caregivers not to administer BENTYL in infants less than 6 months of age. - Use in Nursing Mothers - Advise lactating women that BENTYL should not be used while breastfeeding their infants . - Peripheral and Central Nervous System - In the presence of a high environmental temperature, heat prostration can occur with BENTYL use (fever and heat stroke due to decreased sweating). If symptoms occur, the drug should be discontinued and a physician contacted. BENTYL may produce drowsiness or blurred vision. The patient should be warned not to engage in activities requiring mental alertness, such as operating a motor vehicle or other machinery or to perform hazardous work while taking BENTYL. # Precautions with Alcohol - Alcohol-Dicyclomine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - BENTYL®[1] # Look-Alike Drug Names There is limited information regarding Dicyclomine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Dicyclomine
b468cec2f7b7451fa6cb4e9a437c23dca21cce74	wikidoc	Diffraction	Diffraction Diffraction refers to various phenomena associated with the bending of waves when they interact with obstacles in their path. It occurs with any type of wave, including sound waves, water waves, and electromagnetic waves such as visible light, x-rays and radio waves. As physical objects have wave-like properties, diffraction also occurs with matter and can be studied according to the principles of quantum mechanics. While diffraction always occurs when propagating waves encounter obstacles in their paths, its effects are generally most pronounced for waves where the wavelength is on the order of the size of the diffracting objects. The complex patterns resulting from the intensity of a diffracted wave are a result of interference between different parts of a wave that traveled to the observer by different paths. # Examples of diffraction in everyday life The effects of diffraction can be readily seen in everyday life. The most colorful examples of diffraction are those involving light; for example, the closely spaced tracks on a CD or DVD act as a diffraction grating to form the familiar rainbow pattern we see when looking at a disk. This principle can be extended to engineer a grating with a structure such that it will produce any diffraction pattern desired; the hologram on a credit card is an example. Diffraction in the atmosphere by small particles can cause a bright ring to be visible around a bright light source like the sun or the moon. A shadow of a solid object, using light from a compact source, shows small fringes near its edges. All these effects are a consequence of the fact that light is a wave. Diffraction can occur with any kind of wave. Ocean waves diffract around jetties and other obstacles. Sound waves can diffract around objects, this is the reason we can still hear someone calling us even if we are hiding behind a tree. Diffraction can also be a concern in some technical applications; it sets a fundamental limit to the resolution of a camera, telescope, or microscope. # History The effects of diffraction of light were first carefully observed and characterized by Francesco Maria Grimaldi, who also coined the term diffraction, from the Latin diffringere, 'to break into pieces', referring to light breaking up into different directions. The results of Grimaldi's observations were published posthumously in 1665. Isaac Newton studied these effects and attributed them to inflexion of light rays. James Gregory (1638–1675) observed the diffraction patterns caused by a bird feather, which was effectively the first diffraction grating. In 1803 Thomas Young did his famous experiment observing interference from two closely spaced slits. Explaining his results by interference of the waves emanating from the two different slits, he deduced that light must propagate as waves. Augustin-Jean Fresnel did more definitive studies and calculations of diffraction, published in 1815 and 1818, and thereby gave great support to the wave theory of light that had been advanced by Christiaan Huygens and reinvigorated by Young, against Newton's particle theory. # The mechanism of diffraction The very heart of the explanation of all diffraction phenomena is interference. When two waves combine, their displacements add, causing either a lesser or greater total displacement depending on the phase difference between the two waves. The effect of diffraction from an opaque object can be seen as interference between different parts of the wave beyond the diffraction object. The pattern formed by this interference is dependent on the wavelength of the wave, which for example gives rise to the rainbow pattern on a CD. Most diffraction phenomena can be understood in terms of a few simple concepts that are illustrated below. The most conceptually simple example of diffraction is single-slit diffraction in which the slit is narrow, that is, significantly smaller than a wavelength of the wave. After the wave passes through the slit a pattern of semicircular ripples is formed, as if there were a simple wave source at the position of the slit. This semicircular wave is a diffraction pattern. If we now consider two such narrow apertures, the two radial waves emanating from these apertures can interfere with each other. Consider for example, a water wave incident on a screen with two small openings. The total displacement of the water on the far side of the screen at any point is the sum of the displacements of the individual radial waves at that point. Now there are points in space where the wave emanating from one aperture is always in phase with the other, i.e. they both go up at that point, this is called constructive interference and results in a greater total amplitude. There are also points where one radial wave is out of phase with the other by one half of a wavelength, this would mean that when one is going up, the other is going down, the resulting total amplitude is decreased, this is called destructive interference. The result is that there are regions where there is no wave and other regions where the wave is amplified. Another conceptually simple example is diffraction of a plane wave on a large (compared to the wavelength) plane mirror. The only direction at which all electrons oscillating in the mirror are seen oscillating in phase with each other is the specular (mirror) direction – thus a typical mirror reflects at the angle which is equal to the angle of incidence of the wave. This result is called the law of reflection. Smaller and smaller mirrors diffract light over a progressively larger and larger range of angles. Slits significantly wider than a wavelength will also show diffraction which is most noticeable near their edges. The center part of the wave shows limited effects at short distances, but exhibits a stable diffraction pattern at longer distances. This pattern is most easily understood and calculated as the interference pattern of a large number of simple sources spaced closely and evenly across the width of the slit. This concept is known as the Huygens–Fresnel principle: The propagation of a wave can be visualized by considering every point on a wavefront as a point source for a secondary radial wave. The subsequent propagation and interference of all these radial waves form the new wavefront. This principle mathematically results from interference of waves along all allowed paths between the source and the detection point (that is, all paths except those that are blocked by the diffracting objects). # Qualitative observations of diffraction Several qualitative observations can be made of diffraction in general: - The angular spacing of the features in the diffraction pattern is inversely proportional to the dimensions of the object causing the diffraction, in other words: the smaller the diffracting object the 'wider' the resulting diffraction pattern and vice versa. (More precisely, this is true of the sines of the angles.) - The diffraction angles are invariant under scaling; that is, they depend only on the ratio of the wavelength to the size of the diffracting object. - When the diffracting object has a periodic structure, for example in a diffraction grating, the features generally become sharper. The third figure, for example, shows a comparison of a double-slit pattern with a pattern formed by five slits, both sets of slits having the same spacing, between the center of one slit and the next. # Quantitative description of diffraction To determine the pattern produced by diffraction we must determine the phase and amplitude of each of the Huygens wavelets at each point in space. That is, at each point in space, we must determine the distance to each of the simple sources on the incoming wavefront. If the distance to each of the simple sources differs by an integer number of wavelengths, all the wavelets will be in phase, resulting in constructive interference. If the distance to each source is an integer plus one half of a wavelength, there will be complete destructive interference. Usually it is sufficient to determine these minimums and maximums to explain the effects we see in nature. The simplest descriptions of diffraction are those in which the situation can be reduced to a 2 dimensional problem. For water waves, this is already the case, water waves propagate only on the surface of the water. For light, we can often neglect one direction if the diffracting object extends in that direction over a distance far greater than the wavelength. In the case of light shining through small circular holes we will have to take into account the full three dimensional nature of the problem. ## Diffraction from an array of narrow slits or a grating Multiple-slit arrangements can be described as multiple simple wave sources, if the slits are narrow enough. For light, a slit is an opening that is infinitely extended in one dimension, which has the effect of reducing a wave problem in 3-space to a simpler problem in 2-space. The simplest case is that of two narrow slits, spaced a distance a apart. To determine the maxima and minima in the amplitude we must determine the difference in path length to the first slit and to the second one. In the Fraunhofer approximation, with the observer far away from the slits, the difference in path length to the two slits can be seen from the image to be Maxima in the intensity occur if this path length difference is an integer number of wavelengths: where: And the corresponding minima are at path differences of an integer number plus one half of the wavelength: For an array of slits, positions of the minima and maxima are not changed, the fringes visible on a screen however do become sharper as can be seen in the image. The same is true for a surface that is only reflective along a series of parallel lines; such a surface is called a reflection grating. We see from the formula that the diffraction angle is wavelength dependent. This means that different colors of light will diffract in different directions, which allows us to separate light into its different color components. Gratings are used in spectroscopy to determine the properties of atoms and molecules, as well as stars and interstellar dust clouds by studying the spectrum of the light they emit or absorb. Another application of diffraction gratings is to produce a monochromatic light source. This can be done by placing a slit at the angle corresponding to the constructive interference condition for the desired wavelength. ## Single-slit diffraction Slits wider than a wavelength will show diffraction at their edges. The pattern is most easily understood and calculated as the interference pattern of a large number of simple sources spaced closely and evenly across the width of the slit. We can determine the minima of the resulting intensity pattern by using the following reasoning. If for a given angle a simple source located at the left edge of the slit interferes destructively with a source located at the middle of the slit, then a simple source just to the right of the left edge will interfere destructively with a simple source located just to the right of the middle. We can continue this reasoning along the entire width of the slit to conclude that the condition for destructive interference for the entire slit is the same as the condition for destructive interference between two narrow slits a distance apart that is half the width of the slit. The result is a formula that looks very similar to the one for diffraction from a grating with the important difference that it now predicts the minima of the intensity pattern. d \sin (\theta_{min}) = n \lambda \, n is now an integer greater than 0; d is the width of the slit. The same argument does not hold for the maxima. To determine the location of the maxima and the exact intensity profile, a more rigorous treatment is required; a diffraction formalism in terms of integration over all unobstructed paths is required. The intensity profile is then given by where the sinc function is given by sinc(x)=sin(x)/x. ## Multiple extended slits For an array of slits that are wider than the wavelength of the incident wave, we must take into account interference of wave from different slits as well as interference between waves from different locations in the same slit. Minima in the intensity occur if either the single slit condition or the grating condition for complete destructive interference is met. A rigorous mathematical treatment shows that the resulting intensity pattern is the product of the grating intensity function with the single slit intensity pattern. An array of N slits, each of width d and spaced a distance a apart results in the following intensity pattern: When doing experiments with gratings that have a slit width being an integer fraction of the grating spacing, this can lead to 'missing' orders. If for example the width of a single slit is half the separation between slits (i.e. the duty cycle of the grating is 50%), the first minimum of the single slit diffraction pattern will line up with the second maximum of the grating diffraction pattern. This expected diffraction peak will then not be visible. The same is true in this case for any even-numbered grating-diffraction peak. # Particle diffraction Quantum theory tells us that every particle exhibits wave properties. In particular, massive particles can interfere and therefore diffract. Diffraction of electrons and neutrons stood as one of the powerful arguments in favor of quantum mechanics. The wavelength associated with a particle is the de Broglie wavelength where h is Planck's constant and p is the momentum of the particle (mass × velocity for slow-moving particles) . For most macroscopic objects, this wavelength is so short that it is not meaningful to assign a wavelength to them. A Sodium atom traveling at about 3000 m/s would have a De Broglie wavelength of about 5 pico meters. Because the wavelength for even the smallest of macroscopic objects is extremely small, diffraction of matter waves is only visible for small particles, like electrons, neutrons, atoms and small molecules. The short wavelength of these matter waves makes them ideally suited to study the atomic crystal structure of solids and large molecules like proteins. Relatively recently, larger molecules like buckyballs, have been shown to diffract. Currently, research is underway into the diffraction of viruses, which, being huge relative to electrons and other more commonly diffracted particles, have tiny wavelengths so must be made to travel very slowly through an extremely narrow slit in order to diffract. # Bragg diffraction Diffraction from a three dimensional periodic structure such as atoms in a crystal is called Bragg diffraction. It is similar to what occurs when waves are scattered from a diffraction grating. Bragg diffraction is a consequence of interference between waves reflecting from different crystal planes. The condition of constructive interference is given by Bragg's law: where Bragg diffraction may be carried out using either light of very short wavelength like x-rays or matter waves like neutrons (and electrons) whose wavelength is on the order of (or much smaller than) the atomic spacing. The pattern produced gives information of the separations of crystallographic planes d, allowing one to deduce the crystal structure. Diffraction contrast, in electron microscopes and x-topography devices in particular, is also a powerful tool for examining individual defects and local strain fields in crystals. # Coherence The description of diffraction relies on the interference of waves emanating from the same source taking different paths to the same point on a screen. In this description, the difference in phase between waves that took different paths is only dependent on the effective path length. This does not take into account the fact that waves that arrive at the screen at the same time were emitted by the source at different times. The initial phase with which the source emits waves can change over time in an unpredictable way. This means that waves emitted by the source at times that are too far apart can no longer form a constant interference pattern since the relation between their phases is no longer time independent. The length over which the phase in a beam of light is correlated, is called the coherence length. In order for interference to occur, the path length difference must be smaller than the coherence length. This is sometimes referred to as spectral coherence as it is related to the presence of different frequency components in the wave. In the case light emitted by an atomic transition, the coherence length is related to the lifetime of the excited state from which the atom made its transition. If waves are emitted from an extended source this can lead to incoherence in the transversal direction. When looking at a cross section of a beam of light, the length over which the phase is correlated is called the transverse coherence length. In the case of Young's double slit experiment this would mean that if the transverse coherence length is smaller than the spacing between the two slits the resulting pattern on a screen would look like two single slit diffraction patterns. In the case of particles like electrons, neutrons and atoms, the coherence length is related to the spacial extent of the wave function that describes the particle. # Diffraction limit of telescopes For diffraction through a circular aperture, there is a series of concentric rings surrounding a central Airy disc. The mathematical result is similar to a radially symmetric version of the equation given above in the case of single-slit diffraction. A wave does not have to pass through an aperture to diffract; for example, a beam of light of a finite size also undergoes diffraction and spreads in diameter. This effect limits the minimum diameter d of spot of light formed at the focus of a lens, known as the diffraction limit: where λ is the wavelength of the light, f is the focal length of the lens, and a is the diameter of the beam of light, or (if the beam is filling the lens) the diameter of the lens. The diameter given is enough to contain about 70% of the light energy; it is the radius to the first null of the Airy disk, in approximate agreement with the Rayleigh criterion. Twice that diameter, the diameter to the first null of the Airy disk, within which 83.8% of the light energy is contained, is also sometimes given as the diffraction spot diameter. By use of Huygens' principle, it is possible to compute the far-field diffraction pattern of a wave from any arbitrarily shaped aperture. If the pattern is observed at a sufficient distance from the aperture, or projected onto a screen with a collimating lens, it will appear as the two-dimensional Fourier transform of the function representing the aperture.	Diffraction Diffraction refers to various phenomena associated with the bending of waves when they interact with obstacles in their path. It occurs with any type of wave, including sound waves, water waves, and electromagnetic waves such as visible light, x-rays and radio waves. As physical objects have wave-like properties, diffraction also occurs with matter and can be studied according to the principles of quantum mechanics. While diffraction always occurs when propagating waves encounter obstacles in their paths, its effects are generally most pronounced for waves where the wavelength is on the order of the size of the diffracting objects. The complex patterns resulting from the intensity of a diffracted wave are a result of interference between different parts of a wave that traveled to the observer by different paths. # Examples of diffraction in everyday life The effects of diffraction can be readily seen in everyday life. The most colorful examples of diffraction are those involving light; for example, the closely spaced tracks on a CD or DVD act as a diffraction grating to form the familiar rainbow pattern we see when looking at a disk. This principle can be extended to engineer a grating with a structure such that it will produce any diffraction pattern desired; the hologram on a credit card is an example. Diffraction in the atmosphere by small particles can cause a bright ring to be visible around a bright light source like the sun or the moon. A shadow of a solid object, using light from a compact source, shows small fringes near its edges. All these effects are a consequence of the fact that light is a wave. Diffraction can occur with any kind of wave. Ocean waves diffract around jetties and other obstacles. Sound waves can diffract around objects, this is the reason we can still hear someone calling us even if we are hiding behind a tree. Diffraction can also be a concern in some technical applications; it sets a fundamental limit to the resolution of a camera, telescope, or microscope. # History The effects of diffraction of light were first carefully observed and characterized by Francesco Maria Grimaldi, who also coined the term diffraction, from the Latin diffringere, 'to break into pieces', referring to light breaking up into different directions. The results of Grimaldi's observations were published posthumously in 1665.[2][3] Isaac Newton studied these effects and attributed them to inflexion of light rays. James Gregory (1638–1675) observed the diffraction patterns caused by a bird feather, which was effectively the first diffraction grating. In 1803 Thomas Young did his famous experiment observing interference from two closely spaced slits. Explaining his results by interference of the waves emanating from the two different slits, he deduced that light must propagate as waves. Augustin-Jean Fresnel did more definitive studies and calculations of diffraction, published in 1815 and 1818, and thereby gave great support to the wave theory of light that had been advanced by Christiaan Huygens and reinvigorated by Young, against Newton's particle theory. # The mechanism of diffraction The very heart of the explanation of all diffraction phenomena is interference. When two waves combine, their displacements add, causing either a lesser or greater total displacement depending on the phase difference between the two waves. The effect of diffraction from an opaque object can be seen as interference between different parts of the wave beyond the diffraction object. The pattern formed by this interference is dependent on the wavelength of the wave, which for example gives rise to the rainbow pattern on a CD. Most diffraction phenomena can be understood in terms of a few simple concepts that are illustrated below. The most conceptually simple example of diffraction is single-slit diffraction in which the slit is narrow, that is, significantly smaller than a wavelength of the wave. After the wave passes through the slit a pattern of semicircular ripples is formed, as if there were a simple wave source at the position of the slit. This semicircular wave is a diffraction pattern. If we now consider two such narrow apertures, the two radial waves emanating from these apertures can interfere with each other. Consider for example, a water wave incident on a screen with two small openings. The total displacement of the water on the far side of the screen at any point is the sum of the displacements of the individual radial waves at that point. Now there are points in space where the wave emanating from one aperture is always in phase with the other, i.e. they both go up at that point, this is called constructive interference and results in a greater total amplitude. There are also points where one radial wave is out of phase with the other by one half of a wavelength, this would mean that when one is going up, the other is going down, the resulting total amplitude is decreased, this is called destructive interference. The result is that there are regions where there is no wave and other regions where the wave is amplified. Another conceptually simple example is diffraction of a plane wave on a large (compared to the wavelength) plane mirror. The only direction at which all electrons oscillating in the mirror are seen oscillating in phase with each other is the specular (mirror) direction – thus a typical mirror reflects at the angle which is equal to the angle of incidence of the wave. This result is called the law of reflection. Smaller and smaller mirrors diffract light over a progressively larger and larger range of angles. Slits significantly wider than a wavelength will also show diffraction which is most noticeable near their edges. The center part of the wave shows limited effects at short distances, but exhibits a stable diffraction pattern at longer distances. This pattern is most easily understood and calculated as the interference pattern of a large number of simple sources spaced closely and evenly across the width of the slit. This concept is known as the Huygens–Fresnel principle: The propagation of a wave can be visualized by considering every point on a wavefront as a point source for a secondary radial wave. The subsequent propagation and interference of all these radial waves form the new wavefront. This principle mathematically results from interference of waves along all allowed paths between the source and the detection point (that is, all paths except those that are blocked by the diffracting objects). # Qualitative observations of diffraction Several qualitative observations can be made of diffraction in general: - The angular spacing of the features in the diffraction pattern is inversely proportional to the dimensions of the object causing the diffraction, in other words: the smaller the diffracting object the 'wider' the resulting diffraction pattern and vice versa. (More precisely, this is true of the sines of the angles.) - The diffraction angles are invariant under scaling; that is, they depend only on the ratio of the wavelength to the size of the diffracting object. - When the diffracting object has a periodic structure, for example in a diffraction grating, the features generally become sharper. The third figure, for example, shows a comparison of a double-slit pattern with a pattern formed by five slits, both sets of slits having the same spacing, between the center of one slit and the next. # Quantitative description of diffraction To determine the pattern produced by diffraction we must determine the phase and amplitude of each of the Huygens wavelets at each point in space. That is, at each point in space, we must determine the distance to each of the simple sources on the incoming wavefront. If the distance to each of the simple sources differs by an integer number of wavelengths, all the wavelets will be in phase, resulting in constructive interference. If the distance to each source is an integer plus one half of a wavelength, there will be complete destructive interference. Usually it is sufficient to determine these minimums and maximums to explain the effects we see in nature. The simplest descriptions of diffraction are those in which the situation can be reduced to a 2 dimensional problem. For water waves, this is already the case, water waves propagate only on the surface of the water. For light, we can often neglect one direction if the diffracting object extends in that direction over a distance far greater than the wavelength. In the case of light shining through small circular holes we will have to take into account the full three dimensional nature of the problem. ## Diffraction from an array of narrow slits or a grating Multiple-slit arrangements can be described as multiple simple wave sources, if the slits are narrow enough. For light, a slit is an opening that is infinitely extended in one dimension, which has the effect of reducing a wave problem in 3-space to a simpler problem in 2-space. The simplest case is that of two narrow slits, spaced a distance a apart. To determine the maxima and minima in the amplitude we must determine the difference in path length to the first slit and to the second one. In the Fraunhofer approximation, with the observer far away from the slits, the difference in path length to the two slits can be seen from the image to be Maxima in the intensity occur if this path length difference is an integer number of wavelengths: where: And the corresponding minima are at path differences of an integer number plus one half of the wavelength: For an array of slits, positions of the minima and maxima are not changed, the fringes visible on a screen however do become sharper as can be seen in the image. The same is true for a surface that is only reflective along a series of parallel lines; such a surface is called a reflection grating. We see from the formula that the diffraction angle is wavelength dependent. This means that different colors of light will diffract in different directions, which allows us to separate light into its different color components. Gratings are used in spectroscopy to determine the properties of atoms and molecules, as well as stars and interstellar dust clouds by studying the spectrum of the light they emit or absorb. Another application of diffraction gratings is to produce a monochromatic light source. This can be done by placing a slit at the angle corresponding to the constructive interference condition for the desired wavelength. ## Single-slit diffraction Slits wider than a wavelength will show diffraction at their edges. The pattern is most easily understood and calculated as the interference pattern of a large number of simple sources spaced closely and evenly across the width of the slit. We can determine the minima of the resulting intensity pattern by using the following reasoning. If for a given angle a simple source located at the left edge of the slit interferes destructively with a source located at the middle of the slit, then a simple source just to the right of the left edge will interfere destructively with a simple source located just to the right of the middle. We can continue this reasoning along the entire width of the slit to conclude that the condition for destructive interference for the entire slit is the same as the condition for destructive interference between two narrow slits a distance apart that is half the width of the slit. The result is a formula that looks very similar to the one for diffraction from a grating with the important difference that it now predicts the minima of the intensity pattern. <math>d \sin (\theta_{min}) = n \lambda \,</math> n is now an integer greater than 0; d is the width of the slit. The same argument does not hold for the maxima. To determine the location of the maxima and the exact intensity profile, a more rigorous treatment is required; a diffraction formalism in terms of integration over all unobstructed paths is required. The intensity profile is then given by where the sinc function is given by sinc(x)=sin(x)/x. ## Multiple extended slits For an array of slits that are wider than the wavelength of the incident wave, we must take into account interference of wave from different slits as well as interference between waves from different locations in the same slit. Minima in the intensity occur if either the single slit condition or the grating condition for complete destructive interference is met. A rigorous mathematical treatment shows that the resulting intensity pattern is the product of the grating intensity function with the single slit intensity pattern. An array of N slits, each of width d and spaced a distance a apart results in the following intensity pattern: When doing experiments with gratings that have a slit width being an integer fraction of the grating spacing, this can lead to 'missing' orders. If for example the width of a single slit is half the separation between slits (i.e. the duty cycle of the grating is 50%), the first minimum of the single slit diffraction pattern will line up with the second maximum of the grating diffraction pattern. This expected diffraction peak will then not be visible. The same is true in this case for any even-numbered grating-diffraction peak. # Particle diffraction Quantum theory tells us that every particle exhibits wave properties. In particular, massive particles can interfere and therefore diffract. Diffraction of electrons and neutrons stood as one of the powerful arguments in favor of quantum mechanics. The wavelength associated with a particle is the de Broglie wavelength where h is Planck's constant and p is the momentum of the particle (mass × velocity for slow-moving particles) . For most macroscopic objects, this wavelength is so short that it is not meaningful to assign a wavelength to them. A Sodium atom traveling at about 3000 m/s would have a De Broglie wavelength of about 5 pico meters. Because the wavelength for even the smallest of macroscopic objects is extremely small, diffraction of matter waves is only visible for small particles, like electrons, neutrons, atoms and small molecules. The short wavelength of these matter waves makes them ideally suited to study the atomic crystal structure of solids and large molecules like proteins. Relatively recently, larger molecules like buckyballs,[4] have been shown to diffract. Currently, research is underway into the diffraction of viruses, which, being huge relative to electrons and other more commonly diffracted particles, have tiny wavelengths so must be made to travel very slowly through an extremely narrow slit in order to diffract. # Bragg diffraction Diffraction from a three dimensional periodic structure such as atoms in a crystal is called Bragg diffraction. It is similar to what occurs when waves are scattered from a diffraction grating. Bragg diffraction is a consequence of interference between waves reflecting from different crystal planes. The condition of constructive interference is given by Bragg's law: where Bragg diffraction may be carried out using either light of very short wavelength like x-rays or matter waves like neutrons (and electrons) whose wavelength is on the order of (or much smaller than) the atomic spacing[5]. The pattern produced gives information of the separations of crystallographic planes d, allowing one to deduce the crystal structure. Diffraction contrast, in electron microscopes and x-topography devices in particular, is also a powerful tool for examining individual defects and local strain fields in crystals. # Coherence The description of diffraction relies on the interference of waves emanating from the same source taking different paths to the same point on a screen. In this description, the difference in phase between waves that took different paths is only dependent on the effective path length. This does not take into account the fact that waves that arrive at the screen at the same time were emitted by the source at different times. The initial phase with which the source emits waves can change over time in an unpredictable way. This means that waves emitted by the source at times that are too far apart can no longer form a constant interference pattern since the relation between their phases is no longer time independent. The length over which the phase in a beam of light is correlated, is called the coherence length. In order for interference to occur, the path length difference must be smaller than the coherence length. This is sometimes referred to as spectral coherence as it is related to the presence of different frequency components in the wave. In the case light emitted by an atomic transition, the coherence length is related to the lifetime of the excited state from which the atom made its transition. If waves are emitted from an extended source this can lead to incoherence in the transversal direction. When looking at a cross section of a beam of light, the length over which the phase is correlated is called the transverse coherence length. In the case of Young's double slit experiment this would mean that if the transverse coherence length is smaller than the spacing between the two slits the resulting pattern on a screen would look like two single slit diffraction patterns. In the case of particles like electrons, neutrons and atoms, the coherence length is related to the spacial extent of the wave function that describes the particle. # Diffraction limit of telescopes For diffraction through a circular aperture, there is a series of concentric rings surrounding a central Airy disc. The mathematical result is similar to a radially symmetric version of the equation given above in the case of single-slit diffraction. A wave does not have to pass through an aperture to diffract; for example, a beam of light of a finite size also undergoes diffraction and spreads in diameter. This effect limits the minimum diameter d of spot of light formed at the focus of a lens, known as the diffraction limit: where λ is the wavelength of the light, f is the focal length of the lens, and a is the diameter of the beam of light, or (if the beam is filling the lens) the diameter of the lens. The diameter given is enough to contain about 70% of the light energy; it is the radius to the first null of the Airy disk, in approximate agreement with the Rayleigh criterion. Twice that diameter, the diameter to the first null of the Airy disk, within which 83.8% of the light energy is contained, is also sometimes given as the diffraction spot diameter. By use of Huygens' principle, it is possible to compute the far-field diffraction pattern of a wave from any arbitrarily shaped aperture. If the pattern is observed at a sufficient distance from the aperture, or projected onto a screen with a collimating lens, it will appear as the two-dimensional Fourier transform of the function representing the aperture.	https://www.wikidoc.org/index.php/Diffraction
612e2f02171b6a1c0a0bfee3ec2ec8c587eeae01	wikidoc	Diflorasone	Diflorasone # 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 Diflorasone is a corticosteroid that is FDA approved for the treatment of inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. Common adverse reactions include dry skin, pruritus, burning sensation, irritation symptom. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Diflorasone diacetate cream USP, 0.05% is a high potency corticosteroid indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. - Diflorasone diacetate cream USP, 0.05% should be applied to the affected area twice daily. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Diflorasone in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Diflorasone in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Safety and effectiveness of diflorasone diacetate cream USP, 0.05% in pediatric patients have not been established. Because of a higher ratio of skin surface area to body mass, pediatric patients are at a greater risk than adults of HPA-axis suppression when they are treated with topical corticosteroids. They are, therefore, also at greater risk of glucocorticosteroid insufficiency after withdrawal of treatment and of Cushing's syndrome while on treatment. Adverse effects including striae have been reported with inappropriate use of topical corticosteroids in pediatric patients. - HPA axis suppression, Cushing's syndrome, and intracranial hypertension have been reported in pediatric patients receiving topical corticosteroids. Manifestations of adrenal suppression in pediatric patients include linear growth retardation, delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Diflorasone in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Diflorasone in pediatric patients. # Contraindications - Diflorasone diacetate cream USP is contraindicated in those patients with a history of hypersensitivity to any of the components of the preparation. # Warnings - Systemic absorption of topical corticosteroids can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment. - Manifestations of Cushing's syndrome, hyperglycemia, and glucosuria can also be produced in some patients by systemic absorption of topical corticosteroids while on treatment. - Patients receiving a large dose of a higher potency topical steroid applied to a large surface area or under an occlusive dressing should be evaluated periodically for evidence of HPA axis suppression. This may be done by using the ACTH-stimulation, A.M. plasma cortisol, and urinary free-cortisol tests. - This product has a greater ability to produce adrenal suppression than does diflorasone diacetate ointment USP, 0.05%. At 30 g per day (applied as 15 g twice daily) diflorasone diacetate cream USP, 0.05% was shown to cause inhibition of the HPA axis in one of two patients following application for one week to psoriatic skin. At 15 g per day (applied as 7.5 g twice daily) diflorasone diacetate cream USP, 0.05% was shown to cause mild inhibition of the HPA axis in one of five patients following application for one week to diseased skin (psoriasis or atopic dermatitis). These effects were reversible upon discontinuation of treatment. By comparison, diflorasone diacetate ointment USP, 0.05% did not produce significant HPA axis suppression when used in divided doses at 30 g per day for one week in patients with psoriasis or atopic dermatitis. - If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent corticosteroid. Recovery of HPA axis function is generally prompt and complete upon discontinuation of topical corticosteroids. Infrequently, signs and symptoms of glucocorticosteroid insufficiency may occur, requiring supplemental systemic corticosteroids. For information on systemic supplementation, see prescribing information for those products. - Pediatric patients may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body mass ratios. - If irritation develops, diflorasone diacetate cream USP should be discontinued and appropriate therapy instituted. Allergic contact dermatitis with corticosteroids is usually diagnosed by observing failure to heal rather than noting a clinical exacerbation as with most topical products not containing corticosteroids. Such an observation should be corroborated with appropriate diagnostic patch testing. - If concomitant skin infections are present or develop, an appropriate antifungal or antibacterial agent should be used. If a favorable response does not occur promptly, use of diflorasone diacetate cream USP should be discontinued until the infection has been adequately controlled. - Diflorasone diacetate cream USP, 0.05% should not be used in the treatment. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Clinical Trial Experience of Diflorasone in the drug label. ## Postmarketing Experience - The following local adverse reactions have been reported infrequently with other topical corticosteroids, and they may occur more frequently with the use of occlusive dressings, especially with higher potency corticosteroids. These reactions are listed in an approximate decreasing order of occurrence: burning, itching, irritation, dryness, folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infections, skin atrophy, striae, and miliaria. # Drug Interactions There is limited information regarding Diflorasone Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Some corticosteroids have been shown to be teratogenic after dermal application to laboratory animals. - Diflorasone diacetate has been shown to be teratogenic (cleft palate) in rats when applied topically at a dose of approximately 0.001 mg/kg/day to the shaven thorax of pregnant animals. This is approximately 0.3 times the human topical dose of diflorasone diacetate cream USP, 0.05%. When pregnant rats were treated topically with approximately 0.5 mg/kg/day, uterine deaths were higher in the treated animals than in control animals. - In rabbits, cleft palate was seen when diflorasone diacetate was applied in topical doses as low as 20 mg/kg/day. In addition, fetal weight was depressed and litter sizes were smaller. - There are no adequate and well-controlled studies of the teratogenic potential of diflorasone diacetate in pregnant women. Diflorasone diacetate cream USP 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 Diflorasone in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Diflorasone during labor and delivery. ### Nursing Mothers - Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when diflorasone diacetate cream USP is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness of diflorasone diacetate cream USP, 0.05% in pediatric patients have not been established. Because of a higher ratio of skin surface area to body mass, pediatric patients are at a greater risk than adults of HPA-axis suppression when they are treated with topical corticosteroids. They are, therefore, also at greater risk of glucocorticosteroid insufficiency after withdrawal of treatment and of Cushing's syndrome while on treatment. Adverse effects including striae have been reported with inappropriate use of topical corticosteroids in pediatric patients. - HPA axis suppression, Cushing's syndrome, and intracranial hypertension have been reported in pediatric patients receiving topical corticosteroids. Manifestations of adrenal suppression in pediatric patients include linear growth retardation, delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. ### Geriatic Use There is no FDA guidance on the use of Diflorasone with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Diflorasone with respect to specific gender populations. ### Race There is no FDA guidance on the use of Diflorasone with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Diflorasone in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Diflorasone in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Diflorasone in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Diflorasone in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical ### Monitoring There is limited information regarding Monitoring of Diflorasone in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Diflorasone in the drug label. # Overdosage Topically applied diflorasone diacetate cream USP, 0.05% can be absorbed in sufficient amounts to produce systemic effects # Pharmacology ## Mechanism of Action - Like other topical corticosteroids, diflorasone diacetate has anti-inflammatory, anti-pruritic, and vasoconstrictive actions. The mechanism of the anti-inflammatory activity of the topical corticosteroids, in general, is unclear. However, corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor, arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2. ## Structure - Diflorasone diacetate cream USP, 0.05% contains the active compound diflorasone diacetate, a synthetic corticosteroid for topical dermatological use. - Chemically, diflorasone diacetate is 6α, 9α-difluoro-11β,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione 17,21 diacetate, with the empirical formula C26H32F2O7, a molecular weight of 494.5, and the following structural formula: - Each gram of diflorasone diacetate cream USP, 0.05% contains 0.5 mg diflorasone diacetate in a cream base consisting of purified water, citric acid, mineral oil, lanolin alcohol, isopropyl myristate, cetyl alcohol, glyceryl stearate/PEG 100 stearate, polysorbate 60, sorbitan monostearate, polyoxyl 40 stearate, butylated hydroxytoluene, vegetable oil, propylene glycol, monobasic sodium phosphate. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Diflorasone in the drug label. ## Pharmacokinetics - The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle and the integrity of the epidermal barrier. Occlusive dressings with hydrocortisone for up to 24 hours have not been demonstrated to increase penetration; however, occlusion of hydrocortisone for 96 hours markedly enhances penetration. Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin may increase percutaneous absorption. Studies performed with diflorasone diacetate cream indicate that it is in the high range of potency as compared with other topical corticosteroids. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Diflorasone in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Diflorasone in the drug label. # How Supplied - Diflorasone diacetate cream USP, 0.05% is available in 15 g (NDC 51672-1296-1), 30 g (NDC 51672-1296-2) and 60 g (NDC 51672-1296-3) tubes. ## Storage Store at 20°-25°C (68°-77°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Diflorasone in the drug label. # Precautions with Alcohol - Alcohol-Diflorasone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - DIFLORASONE DIACETATE ® # Look-Alike Drug Names There is limited information regarding Diflorasone Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Diflorasone 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 Diflorasone is a corticosteroid that is FDA approved for the treatment of inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. Common adverse reactions include dry skin, pruritus, burning sensation, irritation symptom. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Diflorasone diacetate cream USP, 0.05% is a high potency corticosteroid indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. - Diflorasone diacetate cream USP, 0.05% should be applied to the affected area twice daily. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Diflorasone in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Diflorasone in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Safety and effectiveness of diflorasone diacetate cream USP, 0.05% in pediatric patients have not been established. Because of a higher ratio of skin surface area to body mass, pediatric patients are at a greater risk than adults of HPA-axis suppression when they are treated with topical corticosteroids. They are, therefore, also at greater risk of glucocorticosteroid insufficiency after withdrawal of treatment and of Cushing's syndrome while on treatment. Adverse effects including striae have been reported with inappropriate use of topical corticosteroids in pediatric patients. - HPA axis suppression, Cushing's syndrome, and intracranial hypertension have been reported in pediatric patients receiving topical corticosteroids. Manifestations of adrenal suppression in pediatric patients include linear growth retardation, delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Diflorasone in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Diflorasone in pediatric patients. # Contraindications - Diflorasone diacetate cream USP is contraindicated in those patients with a history of hypersensitivity to any of the components of the preparation. # Warnings - Systemic absorption of topical corticosteroids can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment. - Manifestations of Cushing's syndrome, hyperglycemia, and glucosuria can also be produced in some patients by systemic absorption of topical corticosteroids while on treatment. - Patients receiving a large dose of a higher potency topical steroid applied to a large surface area or under an occlusive dressing should be evaluated periodically for evidence of HPA axis suppression. This may be done by using the ACTH-stimulation, A.M. plasma cortisol, and urinary free-cortisol tests. - This product has a greater ability to produce adrenal suppression than does diflorasone diacetate ointment USP, 0.05%. At 30 g per day (applied as 15 g twice daily) diflorasone diacetate cream USP, 0.05% was shown to cause inhibition of the HPA axis in one of two patients following application for one week to psoriatic skin. At 15 g per day (applied as 7.5 g twice daily) diflorasone diacetate cream USP, 0.05% was shown to cause mild inhibition of the HPA axis in one of five patients following application for one week to diseased skin (psoriasis or atopic dermatitis). These effects were reversible upon discontinuation of treatment. By comparison, diflorasone diacetate ointment USP, 0.05% did not produce significant HPA axis suppression when used in divided doses at 30 g per day for one week in patients with psoriasis or atopic dermatitis. - If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent corticosteroid. Recovery of HPA axis function is generally prompt and complete upon discontinuation of topical corticosteroids. Infrequently, signs and symptoms of glucocorticosteroid insufficiency may occur, requiring supplemental systemic corticosteroids. For information on systemic supplementation, see prescribing information for those products. - Pediatric patients may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body mass ratios. - If irritation develops, diflorasone diacetate cream USP should be discontinued and appropriate therapy instituted. Allergic contact dermatitis with corticosteroids is usually diagnosed by observing failure to heal rather than noting a clinical exacerbation as with most topical products not containing corticosteroids. Such an observation should be corroborated with appropriate diagnostic patch testing. - If concomitant skin infections are present or develop, an appropriate antifungal or antibacterial agent should be used. If a favorable response does not occur promptly, use of diflorasone diacetate cream USP should be discontinued until the infection has been adequately controlled. - Diflorasone diacetate cream USP, 0.05% should not be used in the treatment. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Clinical Trial Experience of Diflorasone in the drug label. ## Postmarketing Experience - The following local adverse reactions have been reported infrequently with other topical corticosteroids, and they may occur more frequently with the use of occlusive dressings, especially with higher potency corticosteroids. These reactions are listed in an approximate decreasing order of occurrence: burning, itching, irritation, dryness, folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infections, skin atrophy, striae, and miliaria. # Drug Interactions There is limited information regarding Diflorasone Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Some corticosteroids have been shown to be teratogenic after dermal application to laboratory animals. - Diflorasone diacetate has been shown to be teratogenic (cleft palate) in rats when applied topically at a dose of approximately 0.001 mg/kg/day to the shaven thorax of pregnant animals. This is approximately 0.3 times the human topical dose of diflorasone diacetate cream USP, 0.05%. When pregnant rats were treated topically with approximately 0.5 mg/kg/day, uterine deaths were higher in the treated animals than in control animals. - In rabbits, cleft palate was seen when diflorasone diacetate was applied in topical doses as low as 20 mg/kg/day. In addition, fetal weight was depressed and litter sizes were smaller. - There are no adequate and well-controlled studies of the teratogenic potential of diflorasone diacetate in pregnant women. Diflorasone diacetate cream USP 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 Diflorasone in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Diflorasone during labor and delivery. ### Nursing Mothers - Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when diflorasone diacetate cream USP is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness of diflorasone diacetate cream USP, 0.05% in pediatric patients have not been established. Because of a higher ratio of skin surface area to body mass, pediatric patients are at a greater risk than adults of HPA-axis suppression when they are treated with topical corticosteroids. They are, therefore, also at greater risk of glucocorticosteroid insufficiency after withdrawal of treatment and of Cushing's syndrome while on treatment. Adverse effects including striae have been reported with inappropriate use of topical corticosteroids in pediatric patients. - HPA axis suppression, Cushing's syndrome, and intracranial hypertension have been reported in pediatric patients receiving topical corticosteroids. Manifestations of adrenal suppression in pediatric patients include linear growth retardation, delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. ### Geriatic Use There is no FDA guidance on the use of Diflorasone with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Diflorasone with respect to specific gender populations. ### Race There is no FDA guidance on the use of Diflorasone with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Diflorasone in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Diflorasone in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Diflorasone in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Diflorasone in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical ### Monitoring There is limited information regarding Monitoring of Diflorasone in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Diflorasone in the drug label. # Overdosage Topically applied diflorasone diacetate cream USP, 0.05% can be absorbed in sufficient amounts to produce systemic effects # Pharmacology ## Mechanism of Action - Like other topical corticosteroids, diflorasone diacetate has anti-inflammatory, anti-pruritic, and vasoconstrictive actions. The mechanism of the anti-inflammatory activity of the topical corticosteroids, in general, is unclear. However, corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor, arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2. ## Structure - Diflorasone diacetate cream USP, 0.05% contains the active compound diflorasone diacetate, a synthetic corticosteroid for topical dermatological use. - Chemically, diflorasone diacetate is 6α, 9α-difluoro-11β,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione 17,21 diacetate, with the empirical formula C26H32F2O7, a molecular weight of 494.5, and the following structural formula: - Each gram of diflorasone diacetate cream USP, 0.05% contains 0.5 mg diflorasone diacetate in a cream base consisting of purified water, citric acid, mineral oil, lanolin alcohol, isopropyl myristate, cetyl alcohol, glyceryl stearate/PEG 100 stearate, polysorbate 60, sorbitan monostearate, polyoxyl 40 stearate, butylated hydroxytoluene, vegetable oil, propylene glycol, monobasic sodium phosphate. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Diflorasone in the drug label. ## Pharmacokinetics - The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle and the integrity of the epidermal barrier. Occlusive dressings with hydrocortisone for up to 24 hours have not been demonstrated to increase penetration; however, occlusion of hydrocortisone for 96 hours markedly enhances penetration. Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin may increase percutaneous absorption. Studies performed with diflorasone diacetate cream indicate that it is in the high range of potency as compared with other topical corticosteroids. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Diflorasone in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Diflorasone in the drug label. # How Supplied - Diflorasone diacetate cream USP, 0.05% is available in 15 g (NDC 51672-1296-1), 30 g (NDC 51672-1296-2) and 60 g (NDC 51672-1296-3) tubes. ## Storage Store at 20°-25°C (68°-77°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Diflorasone in the drug label. # Precautions with Alcohol - Alcohol-Diflorasone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - DIFLORASONE DIACETATE ®[1] # Look-Alike Drug Names There is limited information regarding Diflorasone Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Diflorasone
eff00602be2fbc572bb025762449bd60f10e196e	wikidoc	Digoxigenin	Digoxigenin Digoxigenin (DIG) is a steroid found exclusively in the flowers and leaves of the plants Digitalis purpurea and Digitalis lanata. # Use in biotechnology Its small size and relative ease with which it can be attached to biological molecules, along with the availability of antibodies in order to target it, makes it a useful tool in biochemistry. Along with fluorescein, it has become the standard immunohistochemical marker for in situ hybridisation. In this case it is conjugated to a single species of RNA nucleotide triphosphate (typically Uridine), which is then incorporated into the riboprobe as it is synthesised. It may also be conjugated with sugars, allowing the incorporation of specific sugars into glycoproteins to be imaged in a similar way.	Digoxigenin Digoxigenin (DIG) is a steroid found exclusively in the flowers and leaves of the plants Digitalis purpurea and Digitalis lanata. # Use in biotechnology Its small size and relative ease with which it can be attached to biological molecules, along with the availability of antibodies in order to target it, makes it a useful tool in biochemistry. Along with fluorescein, it has become the standard immunohistochemical marker for in situ hybridisation[citation needed]. In this case it is conjugated to a single species of RNA nucleotide triphosphate (typically Uridine), which is then incorporated into the riboprobe as it is synthesised. It may also be conjugated with sugars, allowing the incorporation of specific sugars into glycoproteins to be imaged in a similar way.	https://www.wikidoc.org/index.php/Digoxigenin
2ce9a66139ea4dddfecf56528037d03f59cfa14e	wikidoc	Imidazoline	Imidazoline # Overview Imidazoline is a nitrogen-containing heterocycle derived from imidazole. The ring contains an imine bond, and the carbons at the 4 and 5 positions are singly bonded, rather than doubly bonded for the case of imidazole. Imidazolines are structurally related to guanidines and amidines. Like imidazole, imidazoline-based compounds have been used as N-heterocyclic carbene ligands on various transition metals. It is found in the commercially available second generation Grubbs' catalyst. # Biological role Many imidazolines are biologically active. Most bio-active derivatives bear a substituent (aryl or alkyl group) on the carbon between the nitrogen centers. Some brand names include oxymetazoline, xylometazoline, tetrahydrozoline, and naphazoline.	Imidazoline Template:Chembox new Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]} # Overview Imidazoline is a nitrogen-containing heterocycle derived from imidazole. The ring contains an imine bond, and the carbons at the 4 and 5 positions are singly bonded, rather than doubly bonded for the case of imidazole. Imidazolines are structurally related to guanidines and amidines. Like imidazole, imidazoline-based compounds have been used as N-heterocyclic carbene ligands on various transition metals. It is found in the commercially available second generation Grubbs' catalyst. # Biological role Many imidazolines are biologically active.[1] Most bio-active derivatives bear a substituent (aryl or alkyl group) on the carbon between the nitrogen centers. Some brand names include oxymetazoline, xylometazoline, tetrahydrozoline, and naphazoline.	https://www.wikidoc.org/index.php/Dihydroimidazole
877cc2f917a32578c0f4eb6276c3f89da55b1cdf	wikidoc	Dimethicone	Dimethicone # 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 Dimethicone is a dermatological agent that is FDA approved for the treatment of diaper dermatitis, cracked skin and lips. Common adverse reactions include burning, stinging, redness, or irritation. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - Helps treat and prevent diaper dermatitis - Protects minor skin irritation associated with diaper dermatitis and helps protect from wetness - Temporarily protects and helps relieve chapped or cracked skin and lips ### Directions - Apply as needed - Change wet and soiled diapers, garments, and linens promptly - Cleanse the affected area and allow to dry - Apply cream liberally as often as necessary with each diaper, garment or linen change; especially at bedtime or anytime when exposure to soiled diapers, garments, linens, feces, or urine may be prolonged ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Dimethicone in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Dimethicone in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Indications - Helps treat and prevent diaper dermatitis - Protects minor skin irritation associated with diaper dermatitis and helps protect from wetness - Temporarily protects and helps relieve chapped or cracked skin and lips ### Directions - Apply as needed - Change wet and soiled diapers, garments, and linens promptly - Cleanse the affected area and allow to dry - Apply cream liberally as often as necessary with each diaper, garment or linen change; especially at bedtime or anytime when exposure to soiled diapers, garments, linens, feces, or urine may be prolonged ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Dimethicone in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Dimethicone in pediatric patients. # Contraindications There is limited information regarding Dimethicone Contraindications in the drug label. # Warnings - For external use only - When using this product - do not get into eyes - Stop use and ask a doctor if - condition worsens - symptoms last more than 7 days or clear up and occur again within a few days - Do not use on - deep or puncture wounds - animal bites - serious burns - Keep out of reach of children - If swallowed, get medical help or contact a Poison Control Center immediately # Adverse Reactions ## Clinical Trials Experience - burning, stinging, redness, or irritation ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Dimethicone in the drug label. # Drug Interactions There is limited information regarding Dimethicone 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 Dimethicone in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Dimethicone during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Dimethicone with respect to nursing mothers. ### Pediatric Use There is no FDA guidance on the use of Dimethicone with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Dimethicone with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Dimethicone with respect to specific gender populations. ### Race There is no FDA guidance on the use of Dimethicone with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Dimethicone in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Dimethicone in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Dimethicone in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Dimethicone in patients who are immunocompromised. # Administration and Monitoring ### Administration - topical ### Monitoring There is limited information regarding Monitoring of Dimethicone in the drug label. - Description # IV Compatibility There is limited information regarding IV Compatibility of Dimethicone in the drug label. # Overdosage There is limited information regarding Chronic Overdose of Dimethicone in the drug label. # Pharmacology ## Mechanism of Action There is limited information regarding Dimethicone Mechanism of Action in the drug label. ## Structure - ACTIVE INGREDIENTS - Dimethicone 5% - INACTIVE INGREDIENTS - water, petrolatum, isopropyl palmitate, propylene glycol, cetyl dimethicone copolyol, hexyl laurate, polyglycerol-4 isostearate, sodium chloride, paraffin, hydrogenated castor oil, beeswax, methylparaben, disodium EDTA, propylparaben ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Dimethicone in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of Dimethicone in the drug label. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Dimethicone in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Dimethicone in the drug label. # How Supplied ## Storage There is limited information regarding Dimethicone Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel ### PRINCIPAL DISPLAY PANEL ### Ingredients and Appearance # Patient Counseling Information QUESTION OR COMMENTS? # Precautions with Alcohol - Alcohol-Dimethicone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - SECURA DIMETHICONE PROTECTANT® # Look-Alike Drug Names There is limited information regarding Dimethicone Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Dimethicone 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 Dimethicone is a dermatological agent that is FDA approved for the treatment of diaper dermatitis, cracked skin and lips. Common adverse reactions include burning, stinging, redness, or irritation. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - Helps treat and prevent diaper dermatitis - Protects minor skin irritation associated with diaper dermatitis and helps protect from wetness - Temporarily protects and helps relieve chapped or cracked skin and lips ### Directions - Apply as needed - Change wet and soiled diapers, garments, and linens promptly - Cleanse the affected area and allow to dry - Apply cream liberally as often as necessary with each diaper, garment or linen change; especially at bedtime or anytime when exposure to soiled diapers, garments, linens, feces, or urine may be prolonged ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Dimethicone in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Dimethicone in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Indications - Helps treat and prevent diaper dermatitis - Protects minor skin irritation associated with diaper dermatitis and helps protect from wetness - Temporarily protects and helps relieve chapped or cracked skin and lips ### Directions - Apply as needed - Change wet and soiled diapers, garments, and linens promptly - Cleanse the affected area and allow to dry - Apply cream liberally as often as necessary with each diaper, garment or linen change; especially at bedtime or anytime when exposure to soiled diapers, garments, linens, feces, or urine may be prolonged ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Dimethicone in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Dimethicone in pediatric patients. # Contraindications There is limited information regarding Dimethicone Contraindications in the drug label. # Warnings - For external use only - When using this product - do not get into eyes - Stop use and ask a doctor if - condition worsens - symptoms last more than 7 days or clear up and occur again within a few days - Do not use on - deep or puncture wounds - animal bites - serious burns - Keep out of reach of children - If swallowed, get medical help or contact a Poison Control Center immediately # Adverse Reactions ## Clinical Trials Experience - burning, stinging, redness, or irritation ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Dimethicone in the drug label. # Drug Interactions There is limited information regarding Dimethicone 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 Dimethicone in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Dimethicone during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Dimethicone with respect to nursing mothers. ### Pediatric Use There is no FDA guidance on the use of Dimethicone with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Dimethicone with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Dimethicone with respect to specific gender populations. ### Race There is no FDA guidance on the use of Dimethicone with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Dimethicone in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Dimethicone in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Dimethicone in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Dimethicone in patients who are immunocompromised. # Administration and Monitoring ### Administration - topical ### Monitoring There is limited information regarding Monitoring of Dimethicone in the drug label. - Description # IV Compatibility There is limited information regarding IV Compatibility of Dimethicone in the drug label. # Overdosage There is limited information regarding Chronic Overdose of Dimethicone in the drug label. # Pharmacology ## Mechanism of Action There is limited information regarding Dimethicone Mechanism of Action in the drug label. ## Structure - ACTIVE INGREDIENTS - Dimethicone 5% - INACTIVE INGREDIENTS - water, petrolatum, isopropyl palmitate, propylene glycol, cetyl dimethicone copolyol, hexyl laurate, polyglycerol-4 isostearate, sodium chloride, paraffin, hydrogenated castor oil, beeswax, methylparaben, disodium EDTA, propylparaben ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Dimethicone in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of Dimethicone in the drug label. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Dimethicone in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Dimethicone in the drug label. # How Supplied - ## Storage There is limited information regarding Dimethicone Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel ### PRINCIPAL DISPLAY PANEL ### Ingredients and Appearance # Patient Counseling Information QUESTION OR COMMENTS? 1 800 876-1261 # Precautions with Alcohol - Alcohol-Dimethicone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - SECURA DIMETHICONE PROTECTANT®[1] # Look-Alike Drug Names There is limited information regarding Dimethicone Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Dimethicone
e0e7979963ddb343d41058859596778d9508dbd2	wikidoc	Oxalic acid	Oxalic acid Oxalic acid is the chemical compound with the formula H2C2O4. This dicarboxylic acid is better described with the formula HO2CCO2H. It is a relatively strong organic acid, being about 10,000 times stronger than acetic acid. The di-anion, known as oxalate, is also a reducing agent as well as a ligand in coordination chemistry. Many metal ions form insoluble precipitates with oxalate, a prominent example being calcium oxalate, which is the primary constituent of the most common kind of kidney stone. # Preparation Although it can be readily purchased, oxalic acid can be prepared in the laboratory by oxidizing sucrose using nitric acid in the presence of a small amount of vanadium pentoxide as a catalyst. On a large scale, sodium oxalate is manufactured by absorbing carbon monoxide under pressure in hot sodium hydroxide. Typically oxalic acid is obtained as the dihydrate. This solid can be dehydrated with heat or by azeotropic distillation. Anhydrous oxalic acid exists as two polymorphs; in one the hydrogen-bonding results in a chain-like structure whereas the hydrogen bonding pattern in the other form defines a sheet-like structure. # Reactions Oxalic acid exhibits many of the reactions characteristic of other carboxylic acids. It forms esters such as dimethyloxalate (m.p. 52.5–53.5 °C).. It forms an acid chloride called oxalyl chloride. Oxalate, the conjugate base of oxalic acid, is an excellent ligand for metal ions. It usually binds as a bidentate ligand forming a 5-membered MO2C2 ring. An illustrative complex is potassium ferrioxalate, K3. The drug Oxaliplatin exhibits improved water solubility relative to older platinum-based drugs, avoiding the dose-limiting side-effect of nephrotoxicity. # Occurrence in nature Oxalic acid and oxalates are abundantly present in many plants, most notably fat hen (lamb's quarters), sour grass, and sorrel (including oxalis). The root and/or leaves of rhubarb and buckwheat are listed being high in oxalic acid. Foods that are edible but that still contain significant concentrations of oxalic acid include - in decreasing order - star fruit (carambola), black pepper, parsley, poppy seed, rhubarb stalks, amaranth, spinach, chard, beets, cocoa, chocolate, most nuts, most berries, and beans. The gritty “mouth feel” one experiences when drinking milk with a rhubarb dessert is caused by precipitation of calcium oxalate. Thus even dilute amounts of oxalic acid can readily "crack" the casein found in various dairy products. Leaves of the tea plant (Camellia sinensis) contain among the greatest measured concentrations of oxalic acid relative to other plants. However the infusion beverage typically contains only low to moderate amounts of oxalic acid per serving, due to the small mass of leaves used for brewing. ## Physiological effects The affinity of divalent metal ions is sometimes reflected in their tendency to form insoluble precipitates. Thus in the body, oxalic acid also combines with metals ions such as Ca2+, Fe2+, and Mg2+ to deposit crystals of the corresponding oxalates, which irritate the gut and kidneys. Because it binds vital nutrients such as calcium, long-term consumption of foods high in oxalic acid can be problematic. Healthy individuals can safely consume such foods in moderation, but those with kidney disorders, gout, rheumatoid arthritis, or certain forms of chronic vulvar pain (vulvodynia) are typically advised to avoid foods high in oxalic acid or oxalates. Conversely, calcium supplements taken along with foods high in oxalic acid can cause calcium oxalate to precipitate out in the gut and drastically reduce the levels of oxalate absorbed by the body (by 97% in some cases.) The calcium oxalate precipitate (better known as kidney stones) obstruct the kidney tubules. Oxalic acid is also biosynthesized via the metabolism of ethylene glycol ("antifreeze"), glyoxylic acid, and ascorbic acid (vitamin C). The latter pathway presents a potential health risk for long term "megadosers" of vitamin C supplements. An estimated 80% of kidney stones are calcium oxalate. Some Aspergillus species produce oxalic acid, which reacts with blood or tissue calcium to precipitate calcium oxalate. There is some preliminary evidence that the administration of probiotics can affect oxalic acid excretion rates (and presumably oxalic acid levels as well.) Methods to reduce the oxalate content in food are of current interest. # Other uses - In household chemical products such as Bar Keeper's Friend, some bleaches, and rustproofing treatments. - In wood restorers where the acid dissolves away a layer of dry surface wood to expose fresh material underneath. - As an additive to automotive wheel cleaners. - As a mordant in dyeing processes. - Vaporized oxalic acid, or a 6% solution of oxalic acid in sugar syrup, is used by some beekeepers as an insecticide against the parasitic Varroa mite. - As a rust remover in such applications as automotive shops and for the restoration of antiques. - As a recommended surface pretreatment for stainless steels (surface etch) before application of solid metal or polymer self-lubricating coatings. # Tests for oxalic acid Titration with potassium permanganate can reveal the presence of oxalic acid. Ascorbate interferes with this test which is based on reducing power. For this reason, a second test for strong reductants using, for example, iodine can be done.	Oxalic acid Template:Chembox new Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Oxalic acid is the chemical compound with the formula H2C2O4. This dicarboxylic acid is better described with the formula HO2CCO2H. It is a relatively strong organic acid, being about 10,000 times stronger than acetic acid. The di-anion, known as oxalate, is also a reducing agent as well as a ligand in coordination chemistry. Many metal ions form insoluble precipitates with oxalate, a prominent example being calcium oxalate, which is the primary constituent of the most common kind of kidney stone. # Preparation Although it can be readily purchased, oxalic acid can be prepared in the laboratory by oxidizing sucrose using nitric acid in the presence of a small amount of vanadium pentoxide as a catalyst.[1] On a large scale, sodium oxalate is manufactured by absorbing carbon monoxide under pressure in hot sodium hydroxide.[2] Typically oxalic acid is obtained as the dihydrate. This solid can be dehydrated with heat or by azeotropic distillation.[3] Anhydrous oxalic acid exists as two polymorphs; in one the hydrogen-bonding results in a chain-like structure whereas the hydrogen bonding pattern in the other form defines a sheet-like structure.[4] # Reactions Oxalic acid exhibits many of the reactions characteristic of other carboxylic acids. It forms esters such as dimethyloxalate (m.p. 52.5–53.5 °C).[5]. It forms an acid chloride called oxalyl chloride. Oxalate, the conjugate base of oxalic acid, is an excellent ligand for metal ions. It usually binds as a bidentate ligand forming a 5-membered MO2C2 ring. An illustrative complex is potassium ferrioxalate, K3[Fe(C2O4)3]. The drug Oxaliplatin exhibits improved water solubility relative to older platinum-based drugs, avoiding the dose-limiting side-effect of nephrotoxicity. # Occurrence in nature Oxalic acid and oxalates are abundantly present in many plants, most notably fat hen (lamb's quarters), sour grass, and sorrel (including oxalis). The root and/or leaves of rhubarb and buckwheat are listed being high in oxalic acid.[6] Foods that are edible but that still contain significant concentrations of oxalic acid include - in decreasing order - star fruit (carambola), black pepper, parsley, poppy seed, rhubarb stalks, amaranth, spinach, chard, beets, cocoa, chocolate, most nuts, most berries, and beans. The gritty “mouth feel” one experiences when drinking milk with a rhubarb dessert is caused by precipitation of calcium oxalate. Thus even dilute amounts of oxalic acid can readily "crack" the casein found in various dairy products. Leaves of the tea plant (Camellia sinensis) contain among the greatest measured concentrations of oxalic acid relative to other plants. However the infusion beverage typically contains only low to moderate amounts of oxalic acid per serving, due to the small mass of leaves used for brewing. ## Physiological effects The affinity of divalent metal ions is sometimes reflected in their tendency to form insoluble precipitates. Thus in the body, oxalic acid also combines with metals ions such as Ca2+, Fe2+, and Mg2+ to deposit crystals of the corresponding oxalates, which irritate the gut and kidneys. Because it binds vital nutrients such as calcium, long-term consumption of foods high in oxalic acid can be problematic. Healthy individuals can safely consume such foods in moderation, but those with kidney disorders, gout, rheumatoid arthritis, or certain forms of chronic vulvar pain (vulvodynia) are typically advised to avoid foods high in oxalic acid or oxalates. Conversely, calcium supplements taken along with foods high in oxalic acid can cause calcium oxalate to precipitate out in the gut and drastically reduce the levels of oxalate absorbed by the body (by 97% in some cases.)[7][8] The calcium oxalate precipitate (better known as kidney stones) obstruct the kidney tubules. Oxalic acid is also biosynthesized via the metabolism of ethylene glycol ("antifreeze"), glyoxylic acid, and ascorbic acid (vitamin C). The latter pathway presents a potential health risk for long term "megadosers" of vitamin C supplements. An estimated 80% of kidney stones are calcium oxalate.[9] Some Aspergillus species produce oxalic acid, which reacts with blood or tissue calcium to precipitate calcium oxalate.[10] There is some preliminary evidence that the administration of probiotics can affect oxalic acid excretion rates[11] (and presumably oxalic acid levels as well.) Methods to reduce the oxalate content in food are of current interest.[12] # Other uses - In household chemical products such as Bar Keeper's Friend, some bleaches, and rustproofing treatments. - In wood restorers where the acid dissolves away a layer of dry surface wood to expose fresh material underneath. - As an additive to automotive wheel cleaners. - As a mordant in dyeing processes. - Vaporized oxalic acid, or a 6% solution of oxalic acid in sugar syrup, is used by some beekeepers as an insecticide against the parasitic Varroa mite. - As a rust remover in such applications as automotive shops and for the restoration of antiques. - As a recommended surface pretreatment for stainless steels (surface etch) before application of solid metal or polymer self-lubricating coatings. # Tests for oxalic acid Titration with potassium permanganate can reveal the presence of oxalic acid. Ascorbate interferes with this test which is based on reducing power. For this reason, a second test for strong reductants using, for example, iodine can be done.	https://www.wikidoc.org/index.php/Dimethyl_oxalate
1a1c75e9a0de3a4dcaa90db7c7b758a0e07b038e	wikidoc	Dinutuximab	Dinutuximab # 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 Dinutuximab is a GD2-binding monoclonal antibody that is FDA approved for the treatment of in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2) and 13-cis-retinoic acid (RA), for the treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to prior first-line multiagent, multimodality therapy. There is a Black Box Warning for this drug as shown here. Common adverse reactions include Serious infusion reactions, pain and peripheral neuropathy, capillary leak syndrome, hypotension, infection, neurological disorders of the eye, bone marrow suppression, electrolyte abnormalities, atypical hemolytic uremic syndrome, and embryo-fetal toxicity. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) There is limited information regarding Dinutuximab FDA-Labeled Indications and Dosage (Adult) in the drug label. ## Off-Label Use and Dosage (Adult) # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Dinutuximab is indicated, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2) and 13-cis-retinoic acid (RA), for the treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to prior first-line multiagent, multimodality therapy. Verify that patients have adequate hematologic, respiratory, hepatic, and renal function prior to initiating each course of Dinutuximab. Administer required premedication and hydration prior to initiation of each Dinutuximab infusion. Recommended Dose - The recommended dose of Dinutuximab is 17.5 mg/m2/day administered as an intravenous infusion over 10 to 20 hours for 4 consecutive days for a maximum of 5 cycles (Tables 1 and 2 ). Initiate at an infusion rate of 0.875 mg/m2/hour for 30 minutes. The infusion rate can be gradually increased as tolerated to a maximum rate of 1.75 mg/m2/hour. Follow dose modification instructions for adverse reactions. Required Pre-treatment and Guidelines for Pain Management Intravenous Hydration - Administer 0.9% Sodium Chloride Injection, USP 10 mL/kg as an intravenous infusion over one hour just prior to initiating each Dinutuximab infusion. Analgesics - Administer morphine sulfate (50 mcg/kg) intravenously immediately prior to initiation of Dinutuximab and then continue as a morphine sulfate drip at an infusion rate of 20 to 50 mcg/kg/hour during and for two hours following completion of Dinutuximab. - Administer additional 25 mcg/kg to 50 mcg/kg intravenous doses of morphine sulfate as needed for pain up to once every 2 hours followed by an increase in the morphine sulfate infusion rate in clinically stable patients. - Consider using fentanyl or hydromorphone if morphine sulfate is not tolerated. - If pain is inadequately managed with opioids, consider use of gabapentin or lidocaine in conjunction with intravenous morphine. Antihistamines and Antipyretics - Administer an antihistamine such as diphenhydramine(0.5 to 1 mg/kg; maximum dose 50 mg) intravenously over 10 to 15 minutes starting 20 minutes prior to initiation of Dinutuximab and as tolerated every 4 to 6 hours during the Dinutuximab infusion. - Administer acetaminophen (10 to 15 mg/kg; maximum dose 650 mg) 20 minutes prior to each Dinutuximab infusion and every 4 to 6 hours as needed for fever or pain. Administer ibuprofen (5 to 10 mg/kg) every 6 hours as needed for control of persistent fever or pain. Dosage Modifications - Manage adverse reactions by infusion interruption, infusion rate reduction, dose reduction, or permanent discontinuation of Dinutuximab (Table 3 and Table 4) ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use None # Contraindications - History of anaphylaxis to dinutuximab. # Warnings - Capillary leak syndrome and hypotension: Administer required prehydration and monitor patients closely during treatment. Depending upon severity, manage by interruption, infusion rate reduction, or permanent discontinuation. Infection: - Interrupt until resolution of systemic infection. Neurological Disorders of the Eye: Interrupt for dilated pupil with sluggish light reflex or other visual disturbances and permanently discontinue for recurrent eye disorders or loss of vision. Bone marrow suppression: Electrolyte abnormalities: - Monitor serum electrolytes closely. Atypical hemolytic uremic syndrome: - Permanently discontinue Dinutuximab and institute supportive management. Embryo-Fetal toxicity: - May cause fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use effective contraception. # Adverse Reactions ## Clinical Trials Experience - The most common adverse drug reactions (≥ 25%) are pain, pyrexia, thrombocytopenia, lymphopenia, infusion reactions, hypotension, hyponatremia, increased alanine aminotransferase, anemia, vomiting, diarrhea, hypokalemia, capillary leak syndrome, neutropenia, urticaria, hypoalbuminemia, increased aspartate aminotransferase, and hypocalcemia. - The most common serious adverse reactions (≥ 5%) are infections, infusion reactions, hypokalemia, hypotension, pain, fever, and capillary leak syndrome. To report SUSPECTED ADVERSE REACTIONS, contact United Therapeutics Corp. at 1-866-458-6479 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. - 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 rates observed in clinical practice. - The data described below reflect exposure toDinutuximab at the recommended dose and schedule in 1021 patients with high-risk neuroblastoma enrolled in an open label, randomized (Study 1) or single arm clinical trials (Study 2 and Study 3). Prior to enrollment, patients received therapy consisting of induction combination chemotherapy, maximum feasible surgical resection, myeloablative consolidation chemotherapy followed by autologous stem cell transplant, and radiation therapy to residual soft tissue disease. Patients receivedDinutuximab in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2) and 13-cis-retinoic acid (RA). Treatment commenced within 95 days post autologous stem cell transplant in Study 1, within 210 days of autologous stem cell transplant in Study 2, and within 110 days of autologous stem cell transplant in Study 3. Study 1 - In a randomized, open label, multi-center study (Study 1), 134 patients received dinutuximab in combination with GM-CSF, IL-2 and RA (Unituxin/RA group), including 109 randomized patients and 25 patients with biopsy-proven residual disease who were non-randomly assigned to receive dinutuximab. A total of 106 randomized patients received RA alone (RA group) . Patients had a median age at enrollment of 3.8 years (range: 0.94 to 15.3 years), and were predominantly male (60%) and White (82%). In Study 1, adverse reactions of Grade 3 or greater severity were comprehensively collected, but adverse reactions of Grade 1 or 2 severity were collected sporadically and laboratory data were not comprehensively collected. - Approximately 71% of patients in theDinutuximab/RA group and 77% of patients in the RA group completed planned treatment. The most common reason for premature discontinuation of study therapy was adverse reactions in theDinutuximab/RA group (19%) and progressive disease (17%) in the RA group. - The most common adverse drug reactions (≥ 25%) in theDinutuximab/RA group were pain, pyrexia, thrombocytopenia, lymphopenia, infusion reactions, hypotension, hyponatremia, increased alanine aminotransferase, anemia, vomiting, diarrhea, hypokalemia, capillary leak syndrome, neutropenia, urticaria, hypoalbuminemia, increased aspartate aminotransferase, and hypocalcemia. The most common serious adverse reactions (≥ 5%) in theDinutuximab/RA group were infections, infusion reactions, hypokalemia, hypotension, pain, fever, and capillary leak syndrome. Table 5 lists the adverse reactions reported in at least 10% of patients in theDinutuximab/RA group for which there was a between group difference of at least 5% (all grades) or 2% (Grade 3 or greater severity). Required Pre-treatment and Guidelines for Pain Management Intravenous Hydration - Administer 0.9% Sodium Chloride Injection, USP 10 mL/kg as an intravenous infusion over one hour just prior to initiating each Dinutuximab infusion. Analgesics - Administer morphine sulfate (50 mcg/kg) intravenously immediately prior to initiation of Dinutuximab and then continue as a morphine sulfate drip at an infusion rate of 20 to 50 mcg/kg/hour during and for two hours following completion of Dinutuximab. - Administer additional 25 mcg/kg to 50 mcg/kg intravenous doses of morphine sulfate as needed for pain up to once every 2 hours followed by an increase in the morphine sulfate infusion rate in clinically stable patients. - Consider using fentanyl or hydromorphone if morphine sulfate is not tolerated. - If pain is inadequately managed with opioids, consider use of gabapentin or lidocaine in conjunction with intravenous morphine. Antihistamines and Antipyretics - Administer an antihistamine such as diphenhydramine(0.5 to 1 mg/kg; maximum dose 50 mg) intravenously over 10 to 15 minutes starting 20 minutes prior to initiation of Dinutuximab and as tolerated every 4 to 6 hours during the Dinutuximab infusion. - Administer acetaminophen (10 to 15 mg/kg; maximum dose 650 mg) 20 minutes prior to each Dinutuximab infusion and every 4 to 6 hours as needed for fever or pain. Administer ibuprofen (5 to 10 mg/kg) every 6 hours as needed for control of persistent fever or pain. Dosage Modifications - Manage adverse reactions by infusion interruption, infusion rate reduction, dose reduction, or permanent discontinuation of Dinutuximab (Table 3 and Table 4) Immunogenicity - As with all therapeutic proteins, patients treated with Dinutuximab may develop anti-drug antibodies. In clinical studies, 52 of 284 (18%) patients from Study 2 and 13 of 103 (13%) patients from Study 3 tested positive for anti-dinutuximab binding antibodies. Neutralizing antibodies were detected in 3.6% of patients who were tested for anti-dinutuximab binding antibodies in Study 2 and Study 3. However, due to the limitations of the assay, the incidence of neutralizing antibodies may not have been reliably determined. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to Dinutuximab with the incidences of antibodies to other products may be misleading. ## Postmarketing Experience There is limited information regarding Dinutuximab Postmarketing Experience in the drug label. # Drug Interactions No drug-drug interaction studies have been conducted with dinutuximab. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Risk Summary - Based on its mechanism of action, Dinutuximab may cause fetal harm when administered to a pregnant woman. There are no studies in pregnant women and no reproductive studies in animals to inform the drug-associated risk. Monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dinutuximab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Dinutuximab during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Dinutuximab in women who are nursing. ### Pediatric Use Pediatric Use - The safety and effectiveness of Dinutuximab as part of multi-agent, multimodality therapy have been established in pediatric patients with high-risk neuroblastoma based on results of an open-label, randomized (1:1) trial conducted in 226 patients aged 11 months to 15 years (median age 3.8 years) (Study 1). Prior to enrollment, patients achieved at least a partial response to prior first-line therapy for high-risk neuroblastoma consisting of induction combination chemotherapy, maximum feasible surgical resection, myeloablative consolidation chemotherapy followed by autologous stem cell transplant, and received radiation therapy to residual soft tissue disease. Patients randomized to the Dinutuximab/13-cis-retinoic acid (RA) arm (Unituxin/RA) received up to five cycles of Dinutuximab in combination with alternating cycles of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-2 (IL-2) plus RA, followed by one cycle of RA alone. Patients randomized to the RA arm received up to six cycles of RA monotherapy. Study 1 demonstrated an improvement in event-free survival and overall survival in patients in the Dinutuximab/RA arm compared to those in the RA arm. ### Geriatic Use - The safety and effectiveness ofDinutuximab in geriatric patients have not been established. ### Gender There is no FDA guidance on the use of Dinutuximab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Dinutuximab with respect to specific racial populations. ### Renal Impairment - Dinutuximab has not been studied in patients with renal impairment. ### Hepatic Impairment - Dinutuximab has not been studied in patients with hepatic impairment. ### Females of Reproductive Potential and Males Contraception Females Dinutuximab may cause fetal harm. Advise females of reproductive potential to use effective contraception during treatment and for two months after the last dose of Dinutuximab. ### Immunocompromised Patients There is no FDA guidance one the use of Dinutuximab in patients who are immunocompromised. ### Lactation Risk Summary There is no information available on the presence of dinutuximab in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. However, human IgG is present in human milk. Because of the potential for serious adverse reactions in a breastfed infant, advise a nursing woman to discontinue breastfeeding during treatment with Dinutuximab. # Administration and Monitoring ### Administration Instructions for Preparation and Administration Preparation - Store vials in a refrigerator at 2°C to 8°C (36°F to 46°F). Protect from light by storing in the outer carton. DO NOT FREEZE OR SHAKE vials. - Inspect visually for particulate matter and discoloration prior to administration. Do not administer Dinutuximab and discard the single-use vial if the solution is cloudy, has pronounced discoloration, or contains particulate matter. - Aseptically withdraw the required volume of Dinutuximab from the single-use vial and inject into a 100 mL bag of 0.9% Sodium Chloride Injection, USP. Mix by gentle inversion. Do not shake. Discard unused contents of the vial. Store the diluted Dinutuximab solution under refrigeration (2°C to 8° C). Initiate infusion within 4 hours of preparation. Discard diluted Dinutuximab solution 24 hours after preparation. Administration - Administer Dinutuximab as a diluted intravenous infusion only. Do not administer Dinutuximab as an intravenous push or bolus. ### Monitoring There is limited information regarding Dinutuximab Monitoring in the drug label. # IV Compatibility - Injection: 17.5 mg/5 mL (3.5 mg/mL) in a single-use vial. (3) # Overdosage There is limited information regarding Dinutuximab overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action Mechanism of Action - Dinutuximab binds to the glycolipid GD2. This glycolipid is expressed on neuroblastoma cells and on normal cells of neuroectodermal origin, including the central nervous system and peripheral nerves. Dinutuximab binds to cell surface GD2 and induces cell lysis of GD2-expressing cells through antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). ## Structure There is limited information regarding Dinutuximab Structure in the drug label. ## Pharmacodynamics There is limited information regarding Dinutuximab Pharmacodynamics in the drug label. ## Pharmacokinetics - The pharmacokinetics of dinutuximab was evaluated by a population pharmacokinetic analysis in a clinical study ofDinutuximab in combination with GM-CSF, IL-2, and RA. In this study, 27 children with high-risk neuroblastoma (age: 3.9±1.9 years) received up to 5 cycles ofDinutuximab at 17.5 mg/m2/day as an intravenous infusion over 10 to 20 hours for 4 consecutive days every 28 days. The observed maximum plasma dinutuximab concentration (Cmax) was 11.5 mcg/mL . The mean volume of distribution at steady state (Vdss) was 5.4 L (28%). The clearance was 0.21 L/day (62%) and increased with body size. The terminal half-life was 10 days (56%). No formal pharmacokinetic studies were conducted in patients with renal or hepatic impairment. ## Nonclinical Toxicology 'Carcinogenesis, Mutagenesis, Impairment of Fertility'Bold text - No animal studies have been conducted to evaluate the carcinogenic or mutagenic potential of dinutuximab. - Dedicated studies examining the effects of dinutuximab on fertility in animals have not been conducted. No clear effects on reproductive organs were observed in general toxicology studies conducted in rats. - Animal Toxicology and/or Pharmacology Non-clinical studies suggest that dinutuximab-induced neuropathic pain is mediated by binding of the antibody to the GD2 antigen located on the surface of peripheral nerve fibers and myelin and subsequent induction of CDC and ADCC activity. # Clinical Studies - The safety and effectiveness of Dinutuximab was evaluated in a randomized, open-label, multicenter trial conducted in pediatric patients with high-risk neuroblastoma(Study 1). All patients had received prior therapy consisting of induction combination chemotherapy, maximum feasible surgical resection, myeloablative consolidation chemotherapy followed by autologous stem cell transplant, and radiation therapy to residual soft tissue disease. Patients were randomized between Day 50 and Day 77 post-autologous stem cell transplantation. - Patients were required to have achieved at least a partial response prior to autologous stem cell transplantation, have no evidence of disease progression following completion of front-line multi-modality therapy, have adequate pulmonary function (no dyspnea at rest and peripheral arterial oxygen saturation of at least 94% on room air), adequate hepatic function (total bilirubin 30% by echocardiogram, or if shortening fraction abnormal, ejection fraction of 55% by gated radionuclide study), and adequate renal function (glomerular filtration rate at least 70 mL/min/1.73 m2). Patients with systemic infections or a requirement for concomitant systemic corticosteroids or immunosuppressant usage were not eligible for enrollment. - Patients randomized to the Dinutuximab/RA arm received up to five cycles of dinutuximab (clinical trials material) in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) (Table 8) or interleukin-2 (IL-2) (Table 9) plus 13-cis-retinoic acid (RA), followed by one cycle of RA alone. Patients randomized to the RA arm received six cycles of RA. Dinutuximab was administered at a dose of 17.5 mg/m2/day (equivalent to 25/mg/m2/day of clinical trials material) on four consecutive days. Patients in both treatment arms received six cycles of RA at a dose of 160 mg/m2/day orally (for patients weighing more than 12 kg) or 5.33 mg/kg/day. # How Supplied - Dinutuximab is supplied in a carton containing one 17.5 mg/5 mL (3.5 mg/mL) single-use vial. NDC 66302-014-01 ## Storage - Store Dinutuximab vials under refrigeration at 2°C to 8°C until time of use. Do not freeze or shake the vial. Keep the vial in the outer carton in order to protect from light. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Serious Infusion Reactions - Inform patients and caregivers of the risk of serious infusion reactions and anaphylaxis and to immediately report any signs or symptoms, such as facial or lip swelling, urticaria, difficulty breathing, lightheadedness or dizziness that occur during or within 24 hours following the infusion. Pain and Peripheral Neuropathy - Inform patients and caregivers of the risk of severe pain and peripheral sensory and motor neuropathy and to promptly report severe or worsening pain and signs and symptoms of neuropathy such as numbness, tingling, burning, or weakness. Capillary Leak Syndrome - Inform patients and caregivers of the risk of capillary leak syndrome and to immediately report any signs or symptoms. Hypotension - Inform patients and caregivers of the risk of hypotension during the infusion and to immediately report any signs or symptoms. Infection - Inform patients and caregivers of the risk of infection following treatment and to immediately report any signs or symptoms. Neurological Disorders of the Eye - Inform patients and caregivers of the risk of neurological disorders of the eye and to promptly report signs or symptoms such as blurred vision,photophobia, ptosis, diplopia, or unequal pupil size. Bone Marrow Suppression - Inform patients and caregivers of the risk of bone marrow suppression, and to promptly report signs or symptoms of anemia, thrombocytopenia, or infection. Electrolyte Abnormalities - Inform patients and caregivers of the risk of electrolyte abnormalities including hypokalemia, hyponatremia, and hypocalcemia, and to report any signs or symptoms such as seizures, heart palpitations, and muscle cramping. Atypical Hemolytic Uremic Syndrome - Inform patients and caregivers of the risk of hemolytic uremic syndrome and to report any signs or symptoms such as fatigue, dizziness, fainting, pallor, edema, decreased urine output, or hematuria. Embryo-Fetal Toxicity - Advise women of reproductive potential of the potential risk to the fetus if administered during pregnancy and the need for use of effective contraception during and for at least two months after completing therapy. # Precautions with Alcohol Alcohol-Dinutuximab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names Unituxin # Look-Alike Drug Names There is limited information regarding Dinutuximab Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Dinutuximab Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vishal Devarkonda # 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 Dinutuximab is a GD2-binding monoclonal antibody that is FDA approved for the treatment of in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2) and 13-cis-retinoic acid (RA), for the treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to prior first-line multiagent, multimodality therapy. There is a Black Box Warning for this drug as shown here. Common adverse reactions include Serious infusion reactions, pain and peripheral neuropathy, capillary leak syndrome, hypotension, infection, neurological disorders of the eye, bone marrow suppression, electrolyte abnormalities, atypical hemolytic uremic syndrome, and embryo-fetal toxicity. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) There is limited information regarding Dinutuximab FDA-Labeled Indications and Dosage (Adult) in the drug label. ## Off-Label Use and Dosage (Adult) # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Dinutuximab is indicated, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2) and 13-cis-retinoic acid (RA), for the treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to prior first-line multiagent, multimodality therapy. Verify that patients have adequate hematologic, respiratory, hepatic, and renal function prior to initiating each course of Dinutuximab. Administer required premedication and hydration prior to initiation of each Dinutuximab infusion. Recommended Dose - The recommended dose of Dinutuximab is 17.5 mg/m2/day administered as an intravenous infusion over 10 to 20 hours for 4 consecutive days for a maximum of 5 cycles (Tables 1 and 2 ). Initiate at an infusion rate of 0.875 mg/m2/hour for 30 minutes. The infusion rate can be gradually increased as tolerated to a maximum rate of 1.75 mg/m2/hour. Follow dose modification instructions for adverse reactions. Required Pre-treatment and Guidelines for Pain Management Intravenous Hydration - Administer 0.9% Sodium Chloride Injection, USP 10 mL/kg as an intravenous infusion over one hour just prior to initiating each Dinutuximab infusion. Analgesics - Administer morphine sulfate (50 mcg/kg) intravenously immediately prior to initiation of Dinutuximab and then continue as a morphine sulfate drip at an infusion rate of 20 to 50 mcg/kg/hour during and for two hours following completion of Dinutuximab. - Administer additional 25 mcg/kg to 50 mcg/kg intravenous doses of morphine sulfate as needed for pain up to once every 2 hours followed by an increase in the morphine sulfate infusion rate in clinically stable patients. - Consider using fentanyl or hydromorphone if morphine sulfate is not tolerated. - If pain is inadequately managed with opioids, consider use of gabapentin or lidocaine in conjunction with intravenous morphine. Antihistamines and Antipyretics - Administer an antihistamine such as diphenhydramine(0.5 to 1 mg/kg; maximum dose 50 mg) intravenously over 10 to 15 minutes starting 20 minutes prior to initiation of Dinutuximab and as tolerated every 4 to 6 hours during the Dinutuximab infusion. - Administer acetaminophen (10 to 15 mg/kg; maximum dose 650 mg) 20 minutes prior to each Dinutuximab infusion and every 4 to 6 hours as needed for fever or pain. Administer ibuprofen (5 to 10 mg/kg) every 6 hours as needed for control of persistent fever or pain. Dosage Modifications - Manage adverse reactions by infusion interruption, infusion rate reduction, dose reduction, or permanent discontinuation of Dinutuximab (Table 3 and Table 4) ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use None # Contraindications - History of anaphylaxis to dinutuximab. # Warnings - Capillary leak syndrome and hypotension: Administer required prehydration and monitor patients closely during treatment. Depending upon severity, manage by interruption, infusion rate reduction, or permanent discontinuation. Infection: - Interrupt until resolution of systemic infection. Neurological Disorders of the Eye: Interrupt for dilated pupil with sluggish light reflex or other visual disturbances and permanently discontinue for recurrent eye disorders or loss of vision. Bone marrow suppression: Electrolyte abnormalities: - Monitor serum electrolytes closely. Atypical hemolytic uremic syndrome: - Permanently discontinue Dinutuximab and institute supportive management. Embryo-Fetal toxicity: - May cause fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use effective contraception. # Adverse Reactions ## Clinical Trials Experience - The most common adverse drug reactions (≥ 25%) are pain, pyrexia, thrombocytopenia, lymphopenia, infusion reactions, hypotension, hyponatremia, increased alanine aminotransferase, anemia, vomiting, diarrhea, hypokalemia, capillary leak syndrome, neutropenia, urticaria, hypoalbuminemia, increased aspartate aminotransferase, and hypocalcemia. - The most common serious adverse reactions (≥ 5%) are infections, infusion reactions, hypokalemia, hypotension, pain, fever, and capillary leak syndrome. To report SUSPECTED ADVERSE REACTIONS, contact United Therapeutics Corp. at 1-866-458-6479 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. - 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 rates observed in clinical practice. - The data described below reflect exposure toDinutuximab at the recommended dose and schedule in 1021 patients with high-risk neuroblastoma enrolled in an open label, randomized (Study 1) or single arm clinical trials (Study 2 and Study 3). Prior to enrollment, patients received therapy consisting of induction combination chemotherapy, maximum feasible surgical resection, myeloablative consolidation chemotherapy followed by autologous stem cell transplant, and radiation therapy to residual soft tissue disease. Patients receivedDinutuximab in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2) and 13-cis-retinoic acid (RA). Treatment commenced within 95 days post autologous stem cell transplant in Study 1, within 210 days of autologous stem cell transplant in Study 2, and within 110 days of autologous stem cell transplant in Study 3. Study 1 - In a randomized, open label, multi-center study (Study 1), 134 patients received dinutuximab in combination with GM-CSF, IL-2 and RA (Unituxin/RA group), including 109 randomized patients and 25 patients with biopsy-proven residual disease who were non-randomly assigned to receive dinutuximab. A total of 106 randomized patients received RA alone (RA group) [see DOSAGE AND ADMINISTRATION (2) and CLINICAL STUDIES (14)]. Patients had a median age at enrollment of 3.8 years (range: 0.94 to 15.3 years), and were predominantly male (60%) and White (82%). In Study 1, adverse reactions of Grade 3 or greater severity were comprehensively collected, but adverse reactions of Grade 1 or 2 severity were collected sporadically and laboratory data were not comprehensively collected. - Approximately 71% of patients in theDinutuximab/RA group and 77% of patients in the RA group completed planned treatment. The most common reason for premature discontinuation of study therapy was adverse reactions in theDinutuximab/RA group (19%) and progressive disease (17%) in the RA group. - The most common adverse drug reactions (≥ 25%) in theDinutuximab/RA group were pain, pyrexia, thrombocytopenia, lymphopenia, infusion reactions, hypotension, hyponatremia, increased alanine aminotransferase, anemia, vomiting, diarrhea, hypokalemia, capillary leak syndrome, neutropenia, urticaria, hypoalbuminemia, increased aspartate aminotransferase, and hypocalcemia. The most common serious adverse reactions (≥ 5%) in theDinutuximab/RA group were infections, infusion reactions, hypokalemia, hypotension, pain, fever, and capillary leak syndrome. Table 5 lists the adverse reactions reported in at least 10% of patients in theDinutuximab/RA group for which there was a between group difference of at least 5% (all grades) or 2% (Grade 3 or greater severity). Required Pre-treatment and Guidelines for Pain Management Intravenous Hydration - Administer 0.9% Sodium Chloride Injection, USP 10 mL/kg as an intravenous infusion over one hour just prior to initiating each Dinutuximab infusion. Analgesics - Administer morphine sulfate (50 mcg/kg) intravenously immediately prior to initiation of Dinutuximab and then continue as a morphine sulfate drip at an infusion rate of 20 to 50 mcg/kg/hour during and for two hours following completion of Dinutuximab. - Administer additional 25 mcg/kg to 50 mcg/kg intravenous doses of morphine sulfate as needed for pain up to once every 2 hours followed by an increase in the morphine sulfate infusion rate in clinically stable patients. - Consider using fentanyl or hydromorphone if morphine sulfate is not tolerated. - If pain is inadequately managed with opioids, consider use of gabapentin or lidocaine in conjunction with intravenous morphine. Antihistamines and Antipyretics - Administer an antihistamine such as diphenhydramine(0.5 to 1 mg/kg; maximum dose 50 mg) intravenously over 10 to 15 minutes starting 20 minutes prior to initiation of Dinutuximab and as tolerated every 4 to 6 hours during the Dinutuximab infusion. - Administer acetaminophen (10 to 15 mg/kg; maximum dose 650 mg) 20 minutes prior to each Dinutuximab infusion and every 4 to 6 hours as needed for fever or pain. Administer ibuprofen (5 to 10 mg/kg) every 6 hours as needed for control of persistent fever or pain. Dosage Modifications - Manage adverse reactions by infusion interruption, infusion rate reduction, dose reduction, or permanent discontinuation of Dinutuximab (Table 3 and Table 4) Immunogenicity - As with all therapeutic proteins, patients treated with Dinutuximab may develop anti-drug antibodies. In clinical studies, 52 of 284 (18%) patients from Study 2 and 13 of 103 (13%) patients from Study 3 tested positive for anti-dinutuximab binding antibodies. Neutralizing antibodies were detected in 3.6% of patients who were tested for anti-dinutuximab binding antibodies in Study 2 and Study 3. However, due to the limitations of the assay, the incidence of neutralizing antibodies may not have been reliably determined. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to Dinutuximab with the incidences of antibodies to other products may be misleading. ## Postmarketing Experience There is limited information regarding Dinutuximab Postmarketing Experience in the drug label. # Drug Interactions No drug-drug interaction studies have been conducted with dinutuximab. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Risk Summary - Based on its mechanism of action, Dinutuximab may cause fetal harm when administered to a pregnant woman. There are no studies in pregnant women and no reproductive studies in animals to inform the drug-associated risk. Monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dinutuximab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Dinutuximab during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Dinutuximab in women who are nursing. ### Pediatric Use Pediatric Use - The safety and effectiveness of Dinutuximab as part of multi-agent, multimodality therapy have been established in pediatric patients with high-risk neuroblastoma based on results of an open-label, randomized (1:1) trial conducted in 226 patients aged 11 months to 15 years (median age 3.8 years) (Study 1). Prior to enrollment, patients achieved at least a partial response to prior first-line therapy for high-risk neuroblastoma consisting of induction combination chemotherapy, maximum feasible surgical resection, myeloablative consolidation chemotherapy followed by autologous stem cell transplant, and received radiation therapy to residual soft tissue disease. Patients randomized to the Dinutuximab/13-cis-retinoic acid (RA) arm (Unituxin/RA) received up to five cycles of Dinutuximab in combination with alternating cycles of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-2 (IL-2) plus RA, followed by one cycle of RA alone. Patients randomized to the RA arm received up to six cycles of RA monotherapy. Study 1 demonstrated an improvement in event-free survival and overall survival in patients in the Dinutuximab/RA arm compared to those in the RA arm. ### Geriatic Use - The safety and effectiveness ofDinutuximab in geriatric patients have not been established. ### Gender There is no FDA guidance on the use of Dinutuximab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Dinutuximab with respect to specific racial populations. ### Renal Impairment - Dinutuximab has not been studied in patients with renal impairment. ### Hepatic Impairment - Dinutuximab has not been studied in patients with hepatic impairment. ### Females of Reproductive Potential and Males Contraception Females Dinutuximab may cause fetal harm. Advise females of reproductive potential to use effective contraception during treatment and for two months after the last dose of Dinutuximab. ### Immunocompromised Patients There is no FDA guidance one the use of Dinutuximab in patients who are immunocompromised. ### Lactation Risk Summary There is no information available on the presence of dinutuximab in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. However, human IgG is present in human milk. Because of the potential for serious adverse reactions in a breastfed infant, advise a nursing woman to discontinue breastfeeding during treatment with Dinutuximab. # Administration and Monitoring ### Administration Instructions for Preparation and Administration Preparation - Store vials in a refrigerator at 2°C to 8°C (36°F to 46°F). Protect from light by storing in the outer carton. DO NOT FREEZE OR SHAKE vials. - Inspect visually for particulate matter and discoloration prior to administration. Do not administer Dinutuximab and discard the single-use vial if the solution is cloudy, has pronounced discoloration, or contains particulate matter. - Aseptically withdraw the required volume of Dinutuximab from the single-use vial and inject into a 100 mL bag of 0.9% Sodium Chloride Injection, USP. Mix by gentle inversion. Do not shake. Discard unused contents of the vial. Store the diluted Dinutuximab solution under refrigeration (2°C to 8° C). Initiate infusion within 4 hours of preparation. Discard diluted Dinutuximab solution 24 hours after preparation. Administration - Administer Dinutuximab as a diluted intravenous infusion only. Do not administer Dinutuximab as an intravenous push or bolus. ### Monitoring There is limited information regarding Dinutuximab Monitoring in the drug label. # IV Compatibility - Injection: 17.5 mg/5 mL (3.5 mg/mL) in a single-use vial. (3) # Overdosage There is limited information regarding Dinutuximab overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action Mechanism of Action - Dinutuximab binds to the glycolipid GD2. This glycolipid is expressed on neuroblastoma cells and on normal cells of neuroectodermal origin, including the central nervous system and peripheral nerves. Dinutuximab binds to cell surface GD2 and induces cell lysis of GD2-expressing cells through antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). ## Structure There is limited information regarding Dinutuximab Structure in the drug label. ## Pharmacodynamics There is limited information regarding Dinutuximab Pharmacodynamics in the drug label. ## Pharmacokinetics - The pharmacokinetics of dinutuximab was evaluated by a population pharmacokinetic analysis in a clinical study ofDinutuximab in combination with GM-CSF, IL-2, and RA. In this study, 27 children with high-risk neuroblastoma (age: 3.9±1.9 years) received up to 5 cycles ofDinutuximab at 17.5 mg/m2/day as an intravenous infusion over 10 to 20 hours for 4 consecutive days every 28 days. The observed maximum plasma dinutuximab concentration (Cmax) was 11.5 mcg/mL [20%, coefficient of variation (CV)]. The mean volume of distribution at steady state (Vdss) was 5.4 L (28%). The clearance was 0.21 L/day (62%) and increased with body size. The terminal half-life was 10 days (56%). No formal pharmacokinetic studies were conducted in patients with renal or hepatic impairment. ## Nonclinical Toxicology 'Carcinogenesis, Mutagenesis, Impairment of Fertility'Bold text - No animal studies have been conducted to evaluate the carcinogenic or mutagenic potential of dinutuximab. - Dedicated studies examining the effects of dinutuximab on fertility in animals have not been conducted. No clear effects on reproductive organs were observed in general toxicology studies conducted in rats. - Animal Toxicology and/or Pharmacology Non-clinical studies suggest that dinutuximab-induced neuropathic pain is mediated by binding of the antibody to the GD2 antigen located on the surface of peripheral nerve fibers and myelin and subsequent induction of CDC and ADCC activity. # Clinical Studies - The safety and effectiveness of Dinutuximab was evaluated in a randomized, open-label, multicenter trial conducted in pediatric patients with high-risk neuroblastoma(Study 1). All patients had received prior therapy consisting of induction combination chemotherapy, maximum feasible surgical resection, myeloablative consolidation chemotherapy followed by autologous stem cell transplant, and radiation therapy to residual soft tissue disease. Patients were randomized between Day 50 and Day 77 post-autologous stem cell transplantation. - Patients were required to have achieved at least a partial response prior to autologous stem cell transplantation, have no evidence of disease progression following completion of front-line multi-modality therapy, have adequate pulmonary function (no dyspnea at rest and peripheral arterial oxygen saturation of at least 94% on room air), adequate hepatic function (total bilirubin < 1.5 × the upper limit of normal and ALT < 5 × the upper limit of normal), adequate cardiac function (shortening fraction of > 30% by echocardiogram, or if shortening fraction abnormal, ejection fraction of 55% by gated radionuclide study), and adequate renal function (glomerular filtration rate at least 70 mL/min/1.73 m2). Patients with systemic infections or a requirement for concomitant systemic corticosteroids or immunosuppressant usage were not eligible for enrollment. - Patients randomized to the Dinutuximab/RA arm received up to five cycles of dinutuximab (clinical trials material) in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) (Table 8) or interleukin-2 (IL-2) (Table 9) plus 13-cis-retinoic acid (RA), followed by one cycle of RA alone. Patients randomized to the RA arm received six cycles of RA. Dinutuximab was administered at a dose of 17.5 mg/m2/day (equivalent to 25/mg/m2/day of clinical trials material) on four consecutive days. Patients in both treatment arms received six cycles of RA at a dose of 160 mg/m2/day orally (for patients weighing more than 12 kg) or 5.33 mg/kg/day. # How Supplied - Dinutuximab is supplied in a carton containing one 17.5 mg/5 mL (3.5 mg/mL) single-use vial. NDC 66302-014-01 ## Storage - Store Dinutuximab vials under refrigeration at 2°C to 8°C until time of use. Do not freeze or shake the vial. Keep the vial in the outer carton in order to protect from light. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Serious Infusion Reactions - Inform patients and caregivers of the risk of serious infusion reactions and anaphylaxis and to immediately report any signs or symptoms, such as facial or lip swelling, urticaria, difficulty breathing, lightheadedness or dizziness that occur during or within 24 hours following the infusion. Pain and Peripheral Neuropathy - Inform patients and caregivers of the risk of severe pain and peripheral sensory and motor neuropathy and to promptly report severe or worsening pain and signs and symptoms of neuropathy such as numbness, tingling, burning, or weakness. Capillary Leak Syndrome - Inform patients and caregivers of the risk of capillary leak syndrome and to immediately report any signs or symptoms. Hypotension - Inform patients and caregivers of the risk of hypotension during the infusion and to immediately report any signs or symptoms. Infection - Inform patients and caregivers of the risk of infection following treatment and to immediately report any signs or symptoms. Neurological Disorders of the Eye - Inform patients and caregivers of the risk of neurological disorders of the eye and to promptly report signs or symptoms such as blurred vision,photophobia, ptosis, diplopia, or unequal pupil size. Bone Marrow Suppression - Inform patients and caregivers of the risk of bone marrow suppression, and to promptly report signs or symptoms of anemia, thrombocytopenia, or infection. Electrolyte Abnormalities - Inform patients and caregivers of the risk of electrolyte abnormalities including hypokalemia, hyponatremia, and hypocalcemia, and to report any signs or symptoms such as seizures, heart palpitations, and muscle cramping. Atypical Hemolytic Uremic Syndrome - Inform patients and caregivers of the risk of hemolytic uremic syndrome and to report any signs or symptoms such as fatigue, dizziness, fainting, pallor, edema, decreased urine output, or hematuria. Embryo-Fetal Toxicity - Advise women of reproductive potential of the potential risk to the fetus if administered during pregnancy and the need for use of effective contraception during and for at least two months after completing therapy. # Precautions with Alcohol Alcohol-Dinutuximab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names Unituxin # Look-Alike Drug Names There is limited information regarding Dinutuximab Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Dinutuximab
aa5efb1b703d0d7bdd82d0ed75a998a9690d1e10	wikidoc	Laser diode	Laser diode A laser diode is a laser where the active medium is a semiconductor similar to that found in a light-emitting diode. The most common and practical type of laser diode is formed from a p-n junction and powered by injected electrical current. These devices are sometimes referred to as injection laser diodes to distinguish them from (optically) pumped laser diodes, which are more easily produced in the laboratory. # Principle of operation A laser diode, like many other semiconductor devices, is formed by doping a very thin layer on the surface of a crystal wafer. The crystal is doped to produce an n-type region and a p-type region, one above the other, resulting in a p-n junction, or diode. The many, many types of diode lasers known today collectively form a subset of the larger classification of semiconductor p-n junction diodes. Just as in any semiconductor p-n junction diode, forward electrical bias causes the two species of charge carrier, holes and electrons, to be "injected" from opposite sides of the p-n junction into the depletion region, situated at its heart. Holes are injected from the p-doped, and electrons from the n-doped, semiconductor. (A depletion region, devoid of any charge carriers, forms automatically and unavoidably as a result of the difference in chemical potential between n- and p-type semiconductors wherever they are in physical contact.) As charge injection is a distinguishing feature of diode lasers as compared to all other lasers, diode lasers are traditionally and more formally called "injection lasers." (This terminology differentiates diode lasers, e.g., from flashlamp-pumped solid state lasers, such as the ruby laser. Interestingly, whereas the term "solid-state" was extremely apt in differentiating 1950s-era semiconductor electronics from earlier generations of vacuum electronics, it would not have been adequate to convey unambiguously the unique characteristics defining 1960s-era semiconductor lasers.) When an electron and a hole are present in the same region, they may recombine or "annihilate" with the result being spontaneous emission — i.e., the electron may re-occupy the energy state of the hole, emitting a photon with energy equal to the difference between the electron and hole states involved. (In a conventional semiconductor junction diode, the energy released from the recombination of electrons and holes is carried away as phonons, i.e., lattice vibrations, rather than as photons.) Spontaneous emission gives the laser diode below lasing threshold similar properties to an LED. Spontaneous emission is necessary to initiate laser oscillation, but it is one among several sources of inefficiency once the laser is oscillating. The difference between the photon-emitting semiconductor laser (or LED) and conventional phonon-emitting (non-light-emitting) semiconductor junction diodes lies in the use of a different type of semiconductor, one whose physical and atomic structure confers the possibility for photon emission. These photon-emitting semiconductors are the so-called "direct bandgap" semiconductors. It is the nature of silicon and germanium, which are single-element semiconductors, that the bandgap does not align in such as way as to be considered "direct." However, the so-called compound semiconductors, which have virtually the identical crystal structure as silicon or germanium but use alternating arrangements of two different atomic species in a checkerboard-like pattern break the symmetry and in doing so create the critical direct bandgap. Examples of compound semiconductors are gallium arsenide, indium phosphide, gallium antimonide, gallium nitride and so forth, and junction diodes fabricated from these materials emit light. In the absence of stimulated emission (e.g., lasing) conditions, electrons and holes may coexist in proximity to one another, without recombining, for a certain time (termed the "upper-state lifetime" or "recombination time," about a nanosecond for typical diode laser materials before they recombine. Then a nearby photon with energy equal to the recombination energy can cause recombination by stimulated emission. This generates another photon of the same frequency, travelling in the same direction, with the same polarization and phase as the first photon. This means that stimulated emission causes gain in an optical wave (of the correct wavelength) in the injection region, and the gain increases as the number of electrons and holes injected across the junction increases. The spontaneous and stimulated emission processes are vastly more efficient in direct bandgap semiconductors than in indirect bandgap semiconductors, thus silicon is not a common material for laser diodes. As in other lasers, the gain region is surrounded with an optical cavity to form a laser. In the simplest form of laser diode, an optical waveguide is made on that crystal surface, such that the light is confined to a relatively narrow line. The two ends of the crystal are cleaved to form perfectly smooth, parallel edges, forming a Fabry-Perot resonator. Photons emitted into a mode of the waveguide will travel along the waveguide and be reflected several times from each end face before they are emitted. As a light wave passes through the cavity, it is amplified by stimulated emission, but light is also lost due to absorption and by incomplete reflection from the end facets. Finally, if there is more amplification than loss, the diode begins to "lase". Some important properties of laser diodes are determined by the geometry of the optical cavity. Generally, in the vertical direction, the light is contained in a very thin layer, and the structure supports only a single optical mode in the direction perpendicular to the layers. In the lateral direction, if the waveguide is wide compared to the wavelength of light, then the waveguide can support multiple lateral optical modes, and the laser is known as "multi-mode". These laterally multi-mode lasers are adequate in cases where one needs a very large amount of power, but not a small diffraction-limited beam; for example in printing, activating chemicals, or pumping other types of lasers. In applications where a small focused beam is needed, the waveguide must be made narrow, on the order of the optical wavelength. This way, only a single lateral mode is supported and one ends up with a diffraction limited beam. Such single spatial mode devices are used for optical storage, laser pointers, and fiber optics. Note that these lasers may still support multiple longitudinal modes, and thus can lase at multiple wavelengths simultaneously. The wavelength emitted is a function of the band-gap of the semiconductor and the modes of the optical cavity. In general, the maximum gain will occur for photons with energy slightly above the band-gap energy, and the modes nearest the gain peak will lase most strongly. If the diode is driven strongly enough, additional side modes may also lase. Some laser diodes, such as most visible lasers, operate at a single wavelength, but that wavelength is unstable and changes due to fluctuations in current or temperature. Due to diffraction, the beam diverges (expands) rapidly after leaving the chip, typically at 30 degrees vertically by 10 degrees laterally. A lens must be used in order to form a collimated beam like that produced by a laser pointer. If a circular beam is required, cylindrical lenses and other optics are used. For single spatial mode lasers, using symmetrical lenses, the collimated beam ends up being elliptical in shape, due to the difference in the vertical and lateral divergences. This is easily observable with a red laser pointer. The simple diode described above has been heavily modified in recent years to accommodate modern technology, resulting in a variety of types of laser diodes, as described below. # Laser diode types The simple laser diode structure, described above, is extremely inefficient. Such devices require so much power that they can only achieve pulsed operation without damage. Although historically important and easy to explain, such devices are not practical. ## Double heterostructure lasers In these devices, a layer of low bandgap material is sandwiched between two high bandgap layers. One commonly-used pair of materials is gallium arsenide (GaAs) with aluminium gallium arsenide (AlxGa(1-x)As). Each of the junctions between different bandgap materials is called a heterostructure, hence the name "double heterostructure laser" or DH laser. The kind of laser diode described in the first part of the article may be referred to as a homojunction laser, for contrast with these more popular devices. The advantage of a DH laser is that the region where free electrons and holes exist simultaneously—the active region—is confined to the thin middle layer. This means that many more of the electron-hole pairs can contribute to amplification—not so many are left out in the poorly amplifying periphery. In addition, light is reflected from the heterojunction; hence, the light is confined to the region where the amplification takes place. ## Quantum well lasers If the middle layer is made thin enough, it acts as a quantum well. This means that the vertical variation of the electron's wavefunction, and thus a component of its energy, is quantised. The efficiency of a quantum well laser is greater than that of a bulk laser because the density of states function of electrons in the quantum well system has an abrupt edge that concentrates electrons in energy states that contribute to laser action. Lasers containing more than one quantum well layer are known as multiple quantum well lasers. Multiple quantum wells improve the overlap of the gain region with the optical waveguide mode. Further improvements in the laser efficiency have also been demonstrated by reducing the quantum well layer to a quantum wire or to a "sea" of quantum dots. In a quantum cascade laser, the difference between quantum well energy levels is used for the laser transition instead of the bandgap. This enables laser action at relatively long wavelengths, which can be tuned simply by altering the thickness of the layer. ## Separate confinement heterostructure lasers The problem with the simple quantum well diode described above is that the thin layer is simply too small to effectively confine the light. To compensate, another two layers are added on, outside the first three. These layers have a lower refractive index than the centre layers, and hence confine the light effectively. Such a design is called a separate confinement heterostructure (SCH) laser diode. Almost all commercial laser diodes since the 1990s have been SCH quantum well diodes. ## Distributed feedback lasers Distributed feedback lasers (DFB) are the most common transmitter type in DWDM-systems. To stabilize the lasing wavelength, a diffraction grating is etched close to the p-n junction of the diode. This grating acts like an optical filter, causing a single wavelength to be fed back to the gain region and lase. Since the grating provides the feedback that is required for lasing, reflection from the facets is not required. Thus, at least one facet of a DFB is anti-reflection coated. The DFB laser has a stable wavelength that is set during manufacturing by the pitch of the grating, and can only be tuned slightly with temperature. Such lasers are the workhorse of demanding optical communication. ## VCSELs Vertical-cavity surface-emitting lasers (VCSELs) have the optical cavity axis along the direction of current flow rather than perpendicular to the current flow as in conventional laser diodes. The active region length is very short compared with the lateral dimensions so that the radiation emerges from the surface of the cavity rather than from its edge as shown in Fig. 2. The reflectors at the ends of the cavity are dielectric mirrors made from alternating high and low refractive index quarter-wave thick multilayer. Such dielectric mirrors provide a high degree of wavelength-selective reflectance at the required free surface wavelength λ if the thicknesses of alternating layers d1 and d2 with refractive indices n1 and n2 are such that n1d1 + n2d2 = ½λ which then leads to the constructive interference of all partially reflected waves at the interfaces. But there is a disadvantage because of the high mirror reflectivities, VCSELs have lower output powers when compared to edge emitting lasers. There are several advantages to producing VCSELs when compared with the production process of edge-emitting lasers. Edge-emitters cannot be tested until the end of the production process. If the edge-emitter does not work, whether due to bad contacts or poor material growth quality, the production time and the processing materials have been wasted. Additionally, because VCSELs emit the beam perpendicular to the active region of the laser as opposed to parallel as with an edge emitter, tens of thousands of VCSELs can be processed simultaneously on a three inch Gallium Arsenide wafer. Furthermore, even though the VCSEL production process is more labor and material intensive, the yield can be controlled to a more predictable outcome. ## VECSELs Vertical external-cavity surface-emitting lasers, or VECSELs, are similar to VCSELs. In VCSELs, the mirrors are typically grown epitaxially as part of the diode structure, or grown separately and bonded directly to the semiconductor containing the active region. VECSELs are distinguished by a construction in which one of the two mirrors is external to the diode structure. As a result, the cavity includes a free-space region. A typical distance from the diode to the external mirror would be 1 cm. One of the most interesting features of any VECSEL is the thin-ness of the semiconductor gain region in the direction of propagation, less than 100 nm. In contrast, a conventional in-plane semiconductor laser entails light propagation over distances of from 250 µm upward to 2 mm or longer. The significance of the short propagation distance is that it causes the effect of "antiguiding" nonlinearities in the diode laser gain region to be minimized. The result is a large-cross-section single-mode optical beam which is not attainable from in-plane ("edge-emitting") diode lasers. Several workers demonstrated optically pumped VECSELs, and they continue to be developed for many applications including high power sources for use in industrial machining (cutting, punching, etc.) because of their unusually high power and efficiency when pumped by multi-mode diode laser bars. Electrically pumped VECSELs have also been demonstrated. Applications for electrically pumped VECSELs include projection displays, served by frequency doubling of near-IR VECSEL emitters to produce blue and green light. # Failure modes Laser diodes have the same reliability and failure issues as light emitting diodes. In addition they are subject to catastrophic optical damage (COD) when operated at higher power. Many of the advances in reliability of diode lasers in the last 20 years remain proprietary to their developers. The reliability of a laser diode can make or break a product line. Moreover, "reverse engineering" is not always able to uncover the differences between more-reliable and less-reliable diode laser products. At the edge of a diode laser, where light is emitted, a mirror is traditionally formed by cleaving the semiconductor wafer to form a specularly reflecting plane. This approach is facilitated by the weakness of the crystallographic plane in III-V semiconductor crystals (such as GaAs, InP, GaSb, etc.) compared to other planes. A scratch made at the edge of the wafer and a slight bending force causes a nearly atomically perfect mirror-like cleavage plane to form and propagate in a straight line across the wafer. But it so happens that the atomic states at the cleavage plane are altered (compared to their bulk properties within the crystal) by the termination of the perfectly periodic lattice at that plane. Surface states at the cleaved plane, have energy levels within the (otherwise forbidden) bandgap of the semiconductor. Essentially, as a result when light propagates through the cleavage plane and transits to free space from within the semiconductor crystal, a fraction of the light energy is absorbed by the surface states whence it is converted to heat by phonon-electron interactions. This heats the cleaved mirror. In addition the mirror may heat simply because the edge of the diode laser—which is electrically pumped—is in less-than-perfect contact with the mount that provides a path for heat removal. The heating of the mirror causes the bandgap of the semiconductor to shrink in the warmer areas. The bandgap shrinkage brings more electronic band-to-band transitions into alignment with the photon energy causing yet more absorption. This is thermal runaway, a form of positive feedback, and the result can be melting of the facet, known as catastrophic optical damage, or COD. In the 1970's this problem, which is particularly nettlesome for GaAs-based lasers emitting between 1 µm and 0.630 µm wavelengths (less so for InP based lasers used for long-haul telecommunications which emit between 1.3 µm and 2 µm), was identified. Michael Ettenberg, a researcher and later Vice President at RCA Laboratories' David Sarnoff Research Center in Princeton, New Jersey, devised a solution. A thin layer of aluminum oxide was deposited on the facet. If the aluminum oxide thickness is chosen correctly it functions as an anti-reflective coating, reducing reflection at the surface. This alleviated the heating and COD at the facet. Since then, various other refinements have been employed. One approach is to create a so-called non-absorbing mirror (NAM) such that the final 10 µm or so before the light emits from the cleaved facet are rendered non-absorbing at the wavelength of interest. In the very early 1990s, SDL, Inc. began supplying high power diode lasers with good reliability characteristics. CEO Donald Scifres and CTO David Welch presented new reliability performance data at, e.g., SPIE Photonics West conferences of the era. The methods used by SDL to defeat COD were considered to be highly proprietary and have still not been disclosed publicly as of June, 2006. In the mid-1990s IBM Research (Ruschlikon, Switzerland) announced that it had devised its so-called "E2 process" which conferred extraordinary resistance to COD in GaAs-based lasers. This process, too, has never been disclosed as of June, 2006. Reliability of high-power diode laser pump bars (employed to pump solid state lasers) remains a difficult problem in a variety of applications, in spite of these proprietary advances. Indeed, the physics of diode laser failure is still being worked out and research on this subject remains active, if proprietary. Extension of the lifetime of laser diodes is critical to their continued adaptation to a wide variety of applications. # Applications of laser diodes Laser diodes are numerically the most common type of laser, with 2004 sales of approximately 733 million diode lasers, as compared to 131,000 of other types of lasers. Laser diodes find wide use in telecommunication as easily modulated and easily coupled light sources for fiber optics communication. They are used in various measuring instruments, eg. rangefinders. Another common use is in barcode readers. Visible lasers, typically red but later also green, are common as laser pointers. Both low and high-power diodes are used extensively in the printing industry both as light sources for scanning (input) of images and for very high-speed and high-resolution printing plate (output) manufacturing. Infrared and red laser diodes are common in CD players, CD-ROMs and DVD technology. Violet lasers are used in HD DVD and Blu-ray technology. Diode lasers have also found many applications in laser absorption spectrometry (LAS) for high-speed, low-cost assessment or monitoring of the concentration of various species in gas phase. High-power laser diodes are used in industrial applications such as heat treating, cladding, seam welding and for pumping other lasers, such as diode pumped solid state lasers. Applications of laser diodes can be categorized in various ways. Most applications could be served by larger solid state lasers or optical parametric oscillators, but the low cost of mass-produced diode lasers makes them essential for mass-market applications. Diode lasers can be used in a great many fields; since light has many different properties (power, wavelength & spectral quality, beam quality, polarization, etc.) it is interesting to classify applications by these basic properties. Many applications of diode lasers primarily make use of the "directed energy" property of an optical beam. In this category one might include the laser printers, bar-code readers, image scanning, illuminators, designators, optical data recording, combustion ignition, laser surgery, industrial sorting, industrial machining, and directed energy weaponry. Some of these applications are emerging while others are well-established. Applications which may today or in the future make use of the coherence of diode-laser-generated light include interferometric distance measurement, holography, coherent communications, and coherent control of chemical reactions. Applications which may make use of "narrow spectral" properties of diode lasers include range-finding, telecommunications, infra-red countermeasures, spectroscopic sensing, generation of radio-frequency or terahertz waves, atomic clock state preparation, quantum key cryptography, frequency doubling and conversion, water purification (in the UV), and photodynamic therapy (where a particular wavelength of light would cause a substance such as porphyrin to become chemically active as an anti-cancer agent only where the tissue is illuminated by light). Applications where the ability to generate ultra-short pulses of light by the technique known as "mode-locking" include clock distribution for high-performance integrated circuits, high-peak-power sources for laser-induced breakdown spectroscopy sensing, arbitrary waveform generation for radio-frequency waves, photonic sampling for analog-to-digital conversion, and optical code-division-multiple-access systems for secure communication. # History The first to demonstrate coherent light emission from a semiconductor diode (the first laser diode), is widely acknowledged to have been Robert N. Hall and his team at the General Electric research center in 1962. The first visible wavelength laser diode was demonstrated by Nick Holonyak, Jr., later in 1962 Other teams at IBM, MIT Lincoln Laboratory, Texas Instruments, and RCA Laboratories were also involved in and receive credit for historic initial demonstrations of efficient light emission and lasing in semiconductor diodes in 1962 and thereafter. In the early 1960s liquid phase epitaxy (LPE) was invented by Herbert Nelson of RCA Laboratories. By layering the highest quality crystals of varying compositions, it enabled the demonstration of the highest quality heterojunction semiconductor laser materials for many years. LPE was adopted by all the leading laboratories, worldwide and used for many years. It was finally supplanted in the 1970s by molecular beam epitaxy and organometallic chemical vapor deposition. Diode lasers of that era operated with threshold current densities of 1000 Amperes per square centimeter at 77K temperatures. Such performance enabled continuous-lasing to be demonstrated in the earliest days. However, when operated at room temperature, about 300K, threshold current densities were two orders of magnitude greater, or 100,000 Amperes per square centimeter in the best devices. The dominant challenge for the remainder of the 1960s was to obtain low threshold current density at 300K and thereby to demonstrate continuous-wave lasing at room temperature from a diode laser. The first diode lasers were homojunction diodes. That is, the material (and thus the bandgap) of the waveguide core layer and that of the surrounding clad layers, were identical. It was recognized that there was an opportunity, particularly afforded by the use of liquid phase epitaxy using aluminum gallium arsenide, to introduce heterojunctions. Heterostructures consist of layers of semiconductor crystal having varying bandgap and refractive index. Heterojunctions (formed from heterostructures) had been recognized by Herbert Kroemer, while working at RCA Laboratories in the mid-1950s, as having unique advantages for several types of electronic and optoelectronic devices including diode lasers. LPE afforded the technology of making heterojunction diode lasers. The first heterojunction diode lasers were single-heterojunction lasers. These lasers utilized aluminum gallium arsenide p-type injectors situated over n-type gallium arsenide layers grown on the substrate by LPE. An admixture of aluminum replaced gallium in the semiconductor crystal and raised the bandgap of the p-type injector over that of the n-type layers beneath. It worked; the 300K threshold currents went down by 10× to 10,000 amperes per square centimeter. Unfortunately, this was still not in the needed range and these single-heterostructure diode lasers did not function in continuous wave operation at room temperature. The innovation that broke the room temperature challenge was the double heterostructure laser. The trick was to quickly move the wafer in the LPE apparatus between different "melts" of aluminum gallium arsenide (p- and n-type) and a third melt of gallium arsenide. It had to be done rapidly since the gallium arsenide core region needed to be significantly under 1 µm in thickness. This may have been the earliest true example of "nanotechnology." The first laser diode to achieve continuous wave operation was a double heterostructure demonstrated in 1970 essentially simultaneously by Zhores Alferov and collaborators (including Dmitri Z. Garbuzov) of the Soviet Union, and Morton Panish and Izuo Hayashi working in the United States. However, it is widely accepted that Zhores I. Alferov and team reached the milestone first. For their accomplishment and that of their co-workers, Alferov and Kroemer shared the 2000 Nobel Prize in Physics.	Laser diode A laser diode is a laser where the active medium is a semiconductor similar to that found in a light-emitting diode. The most common and practical type of laser diode is formed from a p-n junction and powered by injected electrical current. These devices are sometimes referred to as injection laser diodes to distinguish them from (optically) pumped laser diodes, which are more easily produced in the laboratory. # Principle of operation A laser diode, like many other semiconductor devices, is formed by doping a very thin layer on the surface of a crystal wafer. The crystal is doped to produce an n-type region and a p-type region, one above the other, resulting in a p-n junction, or diode. The many, many types of diode lasers known today collectively form a subset of the larger classification of semiconductor p-n junction diodes. Just as in any semiconductor p-n junction diode, forward electrical bias causes the two species of charge carrier, holes and electrons, to be "injected" from opposite sides of the p-n junction into the depletion region, situated at its heart. Holes are injected from the p-doped, and electrons from the n-doped, semiconductor. (A depletion region, devoid of any charge carriers, forms automatically and unavoidably as a result of the difference in chemical potential between n- and p-type semiconductors wherever they are in physical contact.) As charge injection is a distinguishing feature of diode lasers as compared to all other lasers, diode lasers are traditionally and more formally called "injection lasers." (This terminology differentiates diode lasers, e.g., from flashlamp-pumped solid state lasers, such as the ruby laser. Interestingly, whereas the term "solid-state" was extremely apt in differentiating 1950s-era semiconductor electronics from earlier generations of vacuum electronics, it would not have been adequate to convey unambiguously the unique characteristics defining 1960s-era semiconductor lasers.) When an electron and a hole are present in the same region, they may recombine or "annihilate" with the result being spontaneous emission — i.e., the electron may re-occupy the energy state of the hole, emitting a photon with energy equal to the difference between the electron and hole states involved. (In a conventional semiconductor junction diode, the energy released from the recombination of electrons and holes is carried away as phonons, i.e., lattice vibrations, rather than as photons.) Spontaneous emission gives the laser diode below lasing threshold similar properties to an LED. Spontaneous emission is necessary to initiate laser oscillation, but it is one among several sources of inefficiency once the laser is oscillating. The difference between the photon-emitting semiconductor laser (or LED) and conventional phonon-emitting (non-light-emitting) semiconductor junction diodes lies in the use of a different type of semiconductor, one whose physical and atomic structure confers the possibility for photon emission. These photon-emitting semiconductors are the so-called "direct bandgap" semiconductors. It is the nature of silicon and germanium, which are single-element semiconductors, that the bandgap does not align in such as way as to be considered "direct." However, the so-called compound semiconductors, which have virtually the identical crystal structure as silicon or germanium but use alternating arrangements of two different atomic species in a checkerboard-like pattern break the symmetry and in doing so create the critical direct bandgap. Examples of compound semiconductors are gallium arsenide, indium phosphide, gallium antimonide, gallium nitride and so forth, and junction diodes fabricated from these materials emit light. In the absence of stimulated emission (e.g., lasing) conditions, electrons and holes may coexist in proximity to one another, without recombining, for a certain time (termed the "upper-state lifetime" or "recombination time," about a nanosecond for typical diode laser materials before they recombine. Then a nearby photon with energy equal to the recombination energy can cause recombination by stimulated emission. This generates another photon of the same frequency, travelling in the same direction, with the same polarization and phase as the first photon. This means that stimulated emission causes gain in an optical wave (of the correct wavelength) in the injection region, and the gain increases as the number of electrons and holes injected across the junction increases. The spontaneous and stimulated emission processes are vastly more efficient in direct bandgap semiconductors than in indirect bandgap semiconductors, thus silicon is not a common material for laser diodes. As in other lasers, the gain region is surrounded with an optical cavity to form a laser. In the simplest form of laser diode, an optical waveguide is made on that crystal surface, such that the light is confined to a relatively narrow line. The two ends of the crystal are cleaved to form perfectly smooth, parallel edges, forming a Fabry-Perot resonator. Photons emitted into a mode of the waveguide will travel along the waveguide and be reflected several times from each end face before they are emitted. As a light wave passes through the cavity, it is amplified by stimulated emission, but light is also lost due to absorption and by incomplete reflection from the end facets. Finally, if there is more amplification than loss, the diode begins to "lase". Some important properties of laser diodes are determined by the geometry of the optical cavity. Generally, in the vertical direction, the light is contained in a very thin layer, and the structure supports only a single optical mode in the direction perpendicular to the layers. In the lateral direction, if the waveguide is wide compared to the wavelength of light, then the waveguide can support multiple lateral optical modes, and the laser is known as "multi-mode". These laterally multi-mode lasers are adequate in cases where one needs a very large amount of power, but not a small diffraction-limited beam; for example in printing, activating chemicals, or pumping other types of lasers. In applications where a small focused beam is needed, the waveguide must be made narrow, on the order of the optical wavelength. This way, only a single lateral mode is supported and one ends up with a diffraction limited beam. Such single spatial mode devices are used for optical storage, laser pointers, and fiber optics. Note that these lasers may still support multiple longitudinal modes, and thus can lase at multiple wavelengths simultaneously. The wavelength emitted is a function of the band-gap of the semiconductor and the modes of the optical cavity. In general, the maximum gain will occur for photons with energy slightly above the band-gap energy, and the modes nearest the gain peak will lase most strongly. If the diode is driven strongly enough, additional side modes may also lase. Some laser diodes, such as most visible lasers, operate at a single wavelength, but that wavelength is unstable and changes due to fluctuations in current or temperature. Due to diffraction, the beam diverges (expands) rapidly after leaving the chip, typically at 30 degrees vertically by 10 degrees laterally. A lens must be used in order to form a collimated beam like that produced by a laser pointer. If a circular beam is required, cylindrical lenses and other optics are used. For single spatial mode lasers, using symmetrical lenses, the collimated beam ends up being elliptical in shape, due to the difference in the vertical and lateral divergences. This is easily observable with a red laser pointer. The simple diode described above has been heavily modified in recent years to accommodate modern technology, resulting in a variety of types of laser diodes, as described below. # Laser diode types The simple laser diode structure, described above, is extremely inefficient. Such devices require so much power that they can only achieve pulsed operation without damage. Although historically important and easy to explain, such devices are not practical. ## Double heterostructure lasers In these devices, a layer of low bandgap material is sandwiched between two high bandgap layers. One commonly-used pair of materials is gallium arsenide (GaAs) with aluminium gallium arsenide (AlxGa(1-x)As). Each of the junctions between different bandgap materials is called a heterostructure, hence the name "double heterostructure laser" or DH laser. The kind of laser diode described in the first part of the article may be referred to as a homojunction laser, for contrast with these more popular devices. The advantage of a DH laser is that the region where free electrons and holes exist simultaneously—the active region—is confined to the thin middle layer. This means that many more of the electron-hole pairs can contribute to amplification—not so many are left out in the poorly amplifying periphery. In addition, light is reflected from the heterojunction; hence, the light is confined to the region where the amplification takes place. ## Quantum well lasers If the middle layer is made thin enough, it acts as a quantum well. This means that the vertical variation of the electron's wavefunction, and thus a component of its energy, is quantised. The efficiency of a quantum well laser is greater than that of a bulk laser because the density of states function of electrons in the quantum well system has an abrupt edge that concentrates electrons in energy states that contribute to laser action. Lasers containing more than one quantum well layer are known as multiple quantum well lasers. Multiple quantum wells improve the overlap of the gain region with the optical waveguide mode. Further improvements in the laser efficiency have also been demonstrated by reducing the quantum well layer to a quantum wire or to a "sea" of quantum dots. In a quantum cascade laser, the difference between quantum well energy levels is used for the laser transition instead of the bandgap. This enables laser action at relatively long wavelengths, which can be tuned simply by altering the thickness of the layer. ## Separate confinement heterostructure lasers The problem with the simple quantum well diode described above is that the thin layer is simply too small to effectively confine the light. To compensate, another two layers are added on, outside the first three. These layers have a lower refractive index than the centre layers, and hence confine the light effectively. Such a design is called a separate confinement heterostructure (SCH) laser diode. Almost all commercial laser diodes since the 1990s have been SCH quantum well diodes. ## Distributed feedback lasers Distributed feedback lasers (DFB) are the most common transmitter type in DWDM-systems. To stabilize the lasing wavelength, a diffraction grating is etched close to the p-n junction of the diode. This grating acts like an optical filter, causing a single wavelength to be fed back to the gain region and lase. Since the grating provides the feedback that is required for lasing, reflection from the facets is not required. Thus, at least one facet of a DFB is anti-reflection coated. The DFB laser has a stable wavelength that is set during manufacturing by the pitch of the grating, and can only be tuned slightly with temperature. Such lasers are the workhorse of demanding optical communication. ## VCSELs Vertical-cavity surface-emitting lasers (VCSELs) have the optical cavity axis along the direction of current flow rather than perpendicular to the current flow as in conventional laser diodes. The active region length is very short compared with the lateral dimensions so that the radiation emerges from the surface of the cavity rather than from its edge as shown in Fig. 2. The reflectors at the ends of the cavity are dielectric mirrors made from alternating high and low refractive index quarter-wave thick multilayer. Such dielectric mirrors provide a high degree of wavelength-selective reflectance at the required free surface wavelength λ if the thicknesses of alternating layers d1 and d2 with refractive indices n1 and n2 are such that n1d1 + n2d2 = ½λ which then leads to the constructive interference of all partially reflected waves at the interfaces. But there is a disadvantage because of the high mirror reflectivities, VCSELs have lower output powers when compared to edge emitting lasers. There are several advantages to producing VCSELs when compared with the production process of edge-emitting lasers. Edge-emitters cannot be tested until the end of the production process. If the edge-emitter does not work, whether due to bad contacts or poor material growth quality, the production time and the processing materials have been wasted. Additionally, because VCSELs emit the beam perpendicular to the active region of the laser as opposed to parallel as with an edge emitter, tens of thousands of VCSELs can be processed simultaneously on a three inch Gallium Arsenide wafer. Furthermore, even though the VCSEL production process is more labor and material intensive, the yield can be controlled to a more predictable outcome. ## VECSELs Vertical external-cavity surface-emitting lasers, or VECSELs, are similar to VCSELs. In VCSELs, the mirrors are typically grown epitaxially as part of the diode structure, or grown separately and bonded directly to the semiconductor containing the active region. VECSELs are distinguished by a construction in which one of the two mirrors is external to the diode structure. As a result, the cavity includes a free-space region. A typical distance from the diode to the external mirror would be 1 cm. One of the most interesting features of any VECSEL is the thin-ness of the semiconductor gain region in the direction of propagation, less than 100 nm. In contrast, a conventional in-plane semiconductor laser entails light propagation over distances of from 250 µm upward to 2 mm or longer. The significance of the short propagation distance is that it causes the effect of "antiguiding" nonlinearities in the diode laser gain region to be minimized. The result is a large-cross-section single-mode optical beam which is not attainable from in-plane ("edge-emitting") diode lasers. Several workers demonstrated optically pumped VECSELs, and they continue to be developed for many applications including high power sources for use in industrial machining (cutting, punching, etc.) because of their unusually high power and efficiency when pumped by multi-mode diode laser bars. Electrically pumped VECSELs have also been demonstrated. Applications for electrically pumped VECSELs include projection displays, served by frequency doubling of near-IR VECSEL emitters to produce blue and green light. # Failure modes Laser diodes have the same reliability and failure issues as light emitting diodes. In addition they are subject to catastrophic optical damage (COD) when operated at higher power. Many of the advances in reliability of diode lasers in the last 20 years remain proprietary to their developers. The reliability of a laser diode can make or break a product line. Moreover, "reverse engineering" is not always able to uncover the differences between more-reliable and less-reliable diode laser products. At the edge of a diode laser, where light is emitted, a mirror is traditionally formed by cleaving the semiconductor wafer to form a specularly reflecting plane. This approach is facilitated by the weakness of the [110] crystallographic plane in III-V semiconductor crystals (such as GaAs, InP, GaSb, etc.) compared to other planes. A scratch made at the edge of the wafer and a slight bending force causes a nearly atomically perfect mirror-like cleavage plane to form and propagate in a straight line across the wafer. But it so happens that the atomic states at the cleavage plane are altered (compared to their bulk properties within the crystal) by the termination of the perfectly periodic lattice at that plane. Surface states at the cleaved plane, have energy levels within the (otherwise forbidden) bandgap of the semiconductor. Essentially, as a result when light propagates through the cleavage plane and transits to free space from within the semiconductor crystal, a fraction of the light energy is absorbed by the surface states whence it is converted to heat by phonon-electron interactions. This heats the cleaved mirror. In addition the mirror may heat simply because the edge of the diode laser—which is electrically pumped—is in less-than-perfect contact with the mount that provides a path for heat removal. The heating of the mirror causes the bandgap of the semiconductor to shrink in the warmer areas. The bandgap shrinkage brings more electronic band-to-band transitions into alignment with the photon energy causing yet more absorption. This is thermal runaway, a form of positive feedback, and the result can be melting of the facet, known as catastrophic optical damage, or COD. In the 1970's this problem, which is particularly nettlesome for GaAs-based lasers emitting between 1 µm and 0.630 µm wavelengths (less so for InP based lasers used for long-haul telecommunications which emit between 1.3 µm and 2 µm), was identified. Michael Ettenberg, a researcher and later Vice President at RCA Laboratories' David Sarnoff Research Center in Princeton, New Jersey, devised a solution. A thin layer of aluminum oxide was deposited on the facet. If the aluminum oxide thickness is chosen correctly it functions as an anti-reflective coating, reducing reflection at the surface. This alleviated the heating and COD at the facet. Since then, various other refinements have been employed. One approach is to create a so-called non-absorbing mirror (NAM) such that the final 10 µm or so before the light emits from the cleaved facet are rendered non-absorbing at the wavelength of interest. In the very early 1990s, SDL, Inc. began supplying high power diode lasers with good reliability characteristics. CEO Donald Scifres and CTO David Welch presented new reliability performance data at, e.g., SPIE Photonics West conferences of the era. The methods used by SDL to defeat COD were considered to be highly proprietary and have still not been disclosed publicly as of June, 2006. In the mid-1990s IBM Research (Ruschlikon, Switzerland) announced that it had devised its so-called "E2 process" which conferred extraordinary resistance to COD in GaAs-based lasers. This process, too, has never been disclosed as of June, 2006. Reliability of high-power diode laser pump bars (employed to pump solid state lasers) remains a difficult problem in a variety of applications, in spite of these proprietary advances. Indeed, the physics of diode laser failure is still being worked out and research on this subject remains active, if proprietary. Extension of the lifetime of laser diodes is critical to their continued adaptation to a wide variety of applications. # Applications of laser diodes Laser diodes are numerically the most common type of laser, with 2004 sales of approximately 733 million diode lasers,[1] as compared to 131,000 of other types of lasers.[2] Laser diodes find wide use in telecommunication as easily modulated and easily coupled light sources for fiber optics communication. They are used in various measuring instruments, eg. rangefinders. Another common use is in barcode readers. Visible lasers, typically red but later also green, are common as laser pointers. Both low and high-power diodes are used extensively in the printing industry both as light sources for scanning (input) of images and for very high-speed and high-resolution printing plate (output) manufacturing. Infrared and red laser diodes are common in CD players, CD-ROMs and DVD technology. Violet lasers are used in HD DVD and Blu-ray technology. Diode lasers have also found many applications in laser absorption spectrometry (LAS) for high-speed, low-cost assessment or monitoring of the concentration of various species in gas phase. High-power laser diodes are used in industrial applications such as heat treating, cladding, seam welding and for pumping other lasers, such as diode pumped solid state lasers. Applications of laser diodes can be categorized in various ways. Most applications could be served by larger solid state lasers or optical parametric oscillators, but the low cost of mass-produced diode lasers makes them essential for mass-market applications. Diode lasers can be used in a great many fields; since light has many different properties (power, wavelength & spectral quality, beam quality, polarization, etc.) it is interesting to classify applications by these basic properties. Many applications of diode lasers primarily make use of the "directed energy" property of an optical beam. In this category one might include the laser printers, bar-code readers, image scanning, illuminators, designators, optical data recording, combustion ignition, laser surgery, industrial sorting, industrial machining, and directed energy weaponry. Some of these applications are emerging while others are well-established. Applications which may today or in the future make use of the coherence of diode-laser-generated light include interferometric distance measurement, holography, coherent communications, and coherent control of chemical reactions. Applications which may make use of "narrow spectral" properties of diode lasers include range-finding, telecommunications, infra-red countermeasures, spectroscopic sensing, generation of radio-frequency or terahertz waves, atomic clock state preparation, quantum key cryptography, frequency doubling and conversion, water purification (in the UV), and photodynamic therapy (where a particular wavelength of light would cause a substance such as porphyrin to become chemically active as an anti-cancer agent only where the tissue is illuminated by light). Applications where the ability to generate ultra-short pulses of light by the technique known as "mode-locking" include clock distribution for high-performance integrated circuits, high-peak-power sources for laser-induced breakdown spectroscopy sensing, arbitrary waveform generation for radio-frequency waves, photonic sampling for analog-to-digital conversion, and optical code-division-multiple-access systems for secure communication. # History The first to demonstrate coherent light emission from a semiconductor diode (the first laser diode), is widely acknowledged to have been Robert N. Hall and his team at the General Electric research center in 1962.[3] The first visible wavelength laser diode was demonstrated by Nick Holonyak, Jr., later in 1962[4] Other teams at IBM, MIT Lincoln Laboratory, Texas Instruments, and RCA Laboratories were also involved in and receive credit for historic initial demonstrations of efficient light emission and lasing in semiconductor diodes in 1962 and thereafter. In the early 1960s liquid phase epitaxy (LPE) was invented by Herbert Nelson of RCA Laboratories. By layering the highest quality crystals of varying compositions, it enabled the demonstration of the highest quality heterojunction semiconductor laser materials for many years. LPE was adopted by all the leading laboratories, worldwide and used for many years. It was finally supplanted in the 1970s by molecular beam epitaxy and organometallic chemical vapor deposition. Diode lasers of that era operated with threshold current densities of 1000 Amperes per square centimeter at 77K temperatures. Such performance enabled continuous-lasing to be demonstrated in the earliest days. However, when operated at room temperature, about 300K, threshold current densities were two orders of magnitude greater, or 100,000 Amperes per square centimeter in the best devices. The dominant challenge for the remainder of the 1960s was to obtain low threshold current density at 300K and thereby to demonstrate continuous-wave lasing at room temperature from a diode laser. The first diode lasers were homojunction diodes. That is, the material (and thus the bandgap) of the waveguide core layer and that of the surrounding clad layers, were identical. It was recognized that there was an opportunity, particularly afforded by the use of liquid phase epitaxy using aluminum gallium arsenide, to introduce heterojunctions. Heterostructures consist of layers of semiconductor crystal having varying bandgap and refractive index. Heterojunctions (formed from heterostructures) had been recognized by Herbert Kroemer, while working at RCA Laboratories in the mid-1950s, as having unique advantages for several types of electronic and optoelectronic devices including diode lasers. LPE afforded the technology of making heterojunction diode lasers. The first heterojunction diode lasers were single-heterojunction lasers. These lasers utilized aluminum gallium arsenide p-type injectors situated over n-type gallium arsenide layers grown on the substrate by LPE. An admixture of aluminum replaced gallium in the semiconductor crystal and raised the bandgap of the p-type injector over that of the n-type layers beneath. It worked; the 300K threshold currents went down by 10× to 10,000 amperes per square centimeter. Unfortunately, this was still not in the needed range and these single-heterostructure diode lasers did not function in continuous wave operation at room temperature. The innovation that broke the room temperature challenge was the double heterostructure laser. The trick was to quickly move the wafer in the LPE apparatus between different "melts" of aluminum gallium arsenide (p- and n-type) and a third melt of gallium arsenide. It had to be done rapidly since the gallium arsenide core region needed to be significantly under 1 µm in thickness. This may have been the earliest true example of "nanotechnology." The first laser diode to achieve continuous wave operation was a double heterostructure demonstrated in 1970 essentially simultaneously by Zhores Alferov and collaborators (including Dmitri Z. Garbuzov) of the Soviet Union, and Morton Panish and Izuo Hayashi working in the United States. However, it is widely accepted that Zhores I. Alferov and team reached the milestone first. For their accomplishment and that of their co-workers, Alferov and Kroemer shared the 2000 Nobel Prize in Physics.	https://www.wikidoc.org/index.php/Diode_laser
70ac80bfdac13e644a7ea06b1c7589679e0a7079	wikidoc	1,4-Dioxane	1,4-Dioxane # Overview 1,4-Dioxane, often just called dioxane, is a clear, colorless heterocyclic organic compound which is a liquid at room temperature and pressure. It has the molecular formula C4H8O2 and a boiling point of 101°C. It is commonly used as an aprotic solvent. 1,4-Dioxane has a weak smell similar to that of diethyl ether. There are also two other less common isomeric compounds, 1,2-dioxane and 1,3-dioxane. 1,2-Dioxane is a peroxide which forms naturally in old bottles of tetrahydrofuran. 1,4-Dioxane is classified as an ether, with each of its two oxygen atoms forming an ether functional group. It is more polar than diethyl ether, which also has four carbons, but only one ether functional group. Diethyl ether is rather insoluble in water, but 1,4-dioxane is miscible with water and is hygroscopic. Its higher polarity and slightly higher molecular mass also gives it a substantially higher boiling point than diethyl ether. When used as a solvent for a grignard reaction, Dioxane favorably affects the formation of magnesium halide salts in the Schlenk equilibrium. The name dioxane should not be confused with dioxin, which is a different compound but is also a diether (two ether functional groups). # Uses 1,4-Dioxane is primarily used in solvent applications for the manufacturing sector; however, it is also found in fumigants and automotive coolant. Additionally, the chemical is also used as a foaming agent and appears as an accidental byproduct of the ethoxylation process in cosmetics manufacturing. It may contaminate cosmetics and personal care products such as deodorants, shampoos, toothpastes and mouthwashes. It is also commonly used as an internal standard for calibrating chemical shifts in NMR, as tetramethylsilane (the compound to which all chemical shifts are ultimately referenced) is not soluble in D2O. # Safety & environmental concerns Dioxanes combine with atmospheric oxygen on standing to form explosive peroxides, similar to many other ethers. Distillation of dioxanes concentrates these peroxides increasing the danger. Appropriate precautions should be taken. 1,4-dioxane is a known eye and respiratory tract irritant. It is suspected of causing damage to the central nervous system, liver and kidneys. Accidental worker exposure to 1,4-dioxane has resulted in several deaths. Dioxane is classified by the IARC as a Group 2B carcinogen: possibly carcinogenic to humans due to the fact that it is a known carcinogen in animals. Like many solvents, 1,4-dioxane forms contamination plumes in groundwater when released to the environment. Groundwater supplies have been adversely impacted in several areas. 1,4-dioxane is highly soluble in groundwater, does not readily bind to soils, and readily leaches to groundwater. It is also resistant to naturally occurring biodegradation processes. Due to these properties, a 1,4-dioxane plume is often much larger (and further downgradient) than the associated solvent plume.	1,4-Dioxane Template:Chembox new # Overview 1,4-Dioxane, often just called dioxane, is a clear, colorless heterocyclic organic compound which is a liquid at room temperature and pressure. It has the molecular formula C4H8O2 and a boiling point of 101°C. It is commonly used as an aprotic solvent. 1,4-Dioxane has a weak smell similar to that of diethyl ether. There are also two other less common isomeric compounds, 1,2-dioxane and 1,3-dioxane. 1,2-Dioxane is a peroxide which forms naturally in old bottles of tetrahydrofuran. 1,4-Dioxane is classified as an ether, with each of its two oxygen atoms forming an ether functional group. It is more polar than diethyl ether, which also has four carbons, but only one ether functional group. Diethyl ether is rather insoluble in water, but 1,4-dioxane is miscible with water and is hygroscopic. Its higher polarity and slightly higher molecular mass also gives it a substantially higher boiling point than diethyl ether. When used as a solvent for a grignard reaction, Dioxane favorably affects the formation of magnesium halide salts in the Schlenk equilibrium. The name dioxane should not be confused with dioxin, which is a different compound but is also a diether (two ether functional groups). # Uses 1,4-Dioxane is primarily used in solvent applications for the manufacturing sector; however, it is also found in fumigants and automotive coolant. Additionally, the chemical is also used as a foaming agent and appears as an accidental byproduct of the ethoxylation[1] process in cosmetics manufacturing. It may contaminate cosmetics and personal care products such as deodorants, shampoos, toothpastes and mouthwashes.[2] It is also commonly used as an internal standard for calibrating chemical shifts in NMR, as tetramethylsilane (the compound to which all chemical shifts are ultimately referenced) is not soluble in D2O. # Safety & environmental concerns Dioxanes combine with atmospheric oxygen on standing to form explosive peroxides, similar to many other ethers. Distillation of dioxanes concentrates these peroxides increasing the danger. Appropriate precautions should be taken. 1,4-dioxane is a known eye and respiratory tract irritant. It is suspected of causing damage to the central nervous system, liver and kidneys.[3] Accidental worker exposure to 1,4-dioxane has resulted in several deaths.[4] Dioxane is classified by the IARC as a Group 2B carcinogen: possibly carcinogenic to humans due to the fact that it is a known carcinogen in animals.[5] Like many solvents, 1,4-dioxane forms contamination plumes in groundwater when released to the environment. Groundwater supplies have been adversely impacted in several areas. 1,4-dioxane is highly soluble in groundwater, does not readily bind to soils, and readily leaches to groundwater. It is also resistant to naturally occurring biodegradation processes. Due to these properties, a 1,4-dioxane plume is often much larger (and further downgradient) than the associated solvent plume.[6]	https://www.wikidoc.org/index.php/Dioxane
508067149450dd77440c0178d5f5e6e1adcf1a66	wikidoc	Dipivefrine	Dipivefrine # 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 Dipivefrine is a Ophthalmologic Agent that is FDA approved for the treatment of of intraocular pressure in chronic open-angle glaucoma. Common adverse reactions include Burning sensation in eye, injection. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - Dipivefrin hydrochloride ophthalmic solution is indicated as initial therapy for the control of intraocular pressure in chronic open-angle glaucoma. Patients responding inadequately to other antiglaucoma therapy may respond to addition of dipivefrin. - In controlled and open-label studies of glaucoma, dipivefrin demonstrated a statistically significant intraocular pressure lowering effect. Patients using dipivefrin twice daily in studies with mean durations of 76-146 days experienced mean pressure reductions ranging from 20-24%. - Therapeutic response to 0.1% dipivefrin twice daily is somewhat less than 2% epinephrine twice daily. Controlled studies showed statistically significant differences in lowering of intraocular pressure between 0.1% dipivefrin and 2% epinephrine. In controlled studies in patients with a history of epinephrine intolerance, only 3% of patients treated with dipivefrin exhibited intolerance, while 55% of those treated with epinephrine again developed intolerance. - Therapeutic response to 0.1% dipivefrin twice daily is comparable to 2% pilocarpine 4 times daily. In controlled clinical studies comparing 0.1% dipivefrin and 2% pilocarpine, there were no statistically significant differences in the maintenance of IOP levels for the two medications. - Dipivefrin does not produce miosis or accommodative spasm which cholinergic agents are known to produce. The blurred vision and night blindness often associated with miotic agents are not present with dipivefrin therapy. Patients with cataracts avoid the inability to see around lenticular opacities caused by constricted pupil. ### Dosage - The usual dosage of dipivefrin hydrochloride ophthalmic solution, 0.1%, is one drop in the eye(s) every 12 hours. - When patients are being transferred to dipivefrin from antiglaucoma agents other than epinephrine, on the first day continue the previous medication and add one drop of dipivefrin to each eye(s) every 12 hours. On the following day, discontinue the previously used antiglaucoma agent and continue with dipivefrin. - In transferring patients from conventional epinephrine therapy to dipivefrin, simply discontinue the epinephrine medication and institute the dipivefrin regimen. - When patients on other antiglaucoma agents require additional therapy, add one drop of dipivefrin every 12 hours. - For difficult to control patients, the addition of dipivefrin hydrochloride ophthalmic solution to other agents such as pilocarpine, carbachol, echothiophate iodide or acetazolamide has been shown to be effective. - Note: Not for injection. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Dipivefrine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Dipivefrine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Dipivefrine in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Dipivefrine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Dipivefrine in pediatric patients. # Contraindications - Dipivefrin hydrochloride should not be used in patients with narrow angles since any dilation of the pupil may predispose the patient to an attack of angle-closure glaucoma. This product is contraindicated in patients who are hypersensitive to any of its components. # Warnings - NOT FOR INJECTION – FOR OPHTHALMIC USE ONLY. ### Precautions - Aphakic Patients: Macular edema has been shown to occur in up to 30% of aphakic patients treated with epinephrine. Discontinuation of epinephrine generally results in reversal of the maculopathy. - To avoid contamination, do not touch tip of container to the eye, eyelid, or any surface. - Rabbit studies indicated a dose-related incidence of meibomiam gland retention cysts following topical administration of both dipivefrin and epinephrine. # Adverse Reactions ## Clinical Trials Experience - Tachycardia, arrhythmias and hypertension have been reported with ocular administration of epinephrine. - The most frequent side effects reported with dipivefrin hydrochloride alone were injection in 6.5% of patients and burning and stinging in 6%. Follicular conjunctivitis, mydriasis and allergic reactions to dipivefrin have been reported infrequently. Epinephrine therapy can lead to adrenochrome deposits in the conjunctiva and cornea. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Dipivefrine in the drug label. # Drug Interactions There is limited information regarding Dipivefrine Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - Reproduction studies have been performed in rats and rabbits at daily oral doses up to 10 mg/kg body weight (5 mg/kg in teratogenicity studies), and have revealed no evidence of impaired fertility or harm to the fetus due to dipivefrin. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dipivefrine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Dipivefrine 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 dipivefrin hydrochloride is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use There is no FDA guidance on the use of Dipivefrine with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Dipivefrine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Dipivefrine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Dipivefrine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Dipivefrine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Dipivefrine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Dipivefrine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical application ### Monitoring There is limited information regarding Monitoring of Dipivefrine in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Dipivefrine in the drug label. # Overdosage There is limited information regarding Overdose of Dipivefrine in the drug label. # Pharmacology ## Mechanism of Action - Dipivefrin is converted to epinephrine inside the human eye by enzyme hydrolysis. The liberated epinephrine, an adrenergic agonist, appears to exert its action by decreasing aqueous production and by enhancing outflow facility. ## Structure - Dipivefrin Hydrochloride Ophthalmic Solution USP, 0.1% is a sterile, isotonic solution. Dipivefrin hydrochloride is a white, crystalline powder, freely soluble in water. It is classified as a sympathomimetic agent and has the following structural formula: - Chemical Name: (±) -3, 4-Dihydroxy-a- benzyl alcohol 3, 4-dipivalate hydrochloride. - Contains: Active: Dipivefrin hydrochloride, 0.1% (1 mg/mL). Preservative: Benzalkonium chloride 0.005%. Inactive Ingredients: Edetate Disodium, Sodium Chloride, Hydrochloric Acid and/or Sodium Hydroxide (to adjust pH to 2.5 to 3.5), Purified Water. DM-00 ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Dipivefrine in the drug label. ## Pharmacokinetics - Dipivefrin hydrochloride is a member of a class of drugs known as prodrugs. Prodrugs are usually not active in themselves and require biotransformation to the parent compound before therapeutic activity is seen. These modifications are undertaken to enhance absorption, decrease side effects and enhance stability and comfort, thus making the parent compound a more useful drug. Enhanced absorption makes the prodrug a more efficient delivery system for the parent drug because less drug will be needed to produce the desired therapeutic response. - Dipivefrin is a prodrug of epinephrine formed by the diesterification of epinephrine and pivalic acid. The addition of pivaloyl groups to the epinephrine molecule enhances its lipophilic character and, as a consequence, its penetration into the anterior chamber. - Dipivefrin is converted to epinephrine inside the human eye by enzyme hydrolysis. The liberated epinephrine, an adrenergic agonist, appears to exert its action by decreasing aqueous production and by enhancing outflow facility. The dipivefrin hydrochloride prodrug delivery system is a more efficient way of delivering the therapeutic effects of epinephrine, with fewer side effects than are associated with conventional epinephrine therapy. - The onset of action with one drop of dipivefrin hydrochloride ophthalmic solution occurs about 30 minutes after treatment, with maximum effect seen at about one hour. - Using a prodrug means that less drug is needed for therapeutic effect since absorption is enhanced with the prodrug. Dipivefrin hydrochloride, 0.1% was judged less irritating than a 1% solution of epinephrine hydrochloride or bitartrate. In addition, only 8 of 455 patients (1.8%) treated with dipivefrin reported discomfort due to photophobia, glare or light sensitivity. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Dipivefrine in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Dipivefrine in the drug label. # How Supplied - Dipivefrin Hydrochloride Ophthalmic Solution USP, 0.1% is supplied sterile in opaque plastic DROP-TAINER® Dispensers as follows: ## Storage - Store at controlled room temperature 15°-30°C (59°-86°F) in a tight, light-resistant container. # Images ## Drug Images ## Package and Label Display Panel ### Ingredients and Appearance # Patient Counseling Information - To avoid contamination, do not touch tip of container to the eye, eyelid, or any surface. # Precautions with Alcohol - Alcohol-Dipivefrine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Propine® # Look-Alike Drug Names There is limited information regarding Dipivefrine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Dipivefrine 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. # Overview Dipivefrine is a Ophthalmologic Agent that is FDA approved for the treatment of of intraocular pressure in chronic open-angle glaucoma. Common adverse reactions include Burning sensation in eye, injection. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - Dipivefrin hydrochloride ophthalmic solution is indicated as initial therapy for the control of intraocular pressure in chronic open-angle glaucoma. Patients responding inadequately to other antiglaucoma therapy may respond to addition of dipivefrin. - In controlled and open-label studies of glaucoma, dipivefrin demonstrated a statistically significant intraocular pressure lowering effect. Patients using dipivefrin twice daily in studies with mean durations of 76-146 days experienced mean pressure reductions ranging from 20-24%. - Therapeutic response to 0.1% dipivefrin twice daily is somewhat less than 2% epinephrine twice daily. Controlled studies showed statistically significant differences in lowering of intraocular pressure between 0.1% dipivefrin and 2% epinephrine. In controlled studies in patients with a history of epinephrine intolerance, only 3% of patients treated with dipivefrin exhibited intolerance, while 55% of those treated with epinephrine again developed intolerance. - Therapeutic response to 0.1% dipivefrin twice daily is comparable to 2% pilocarpine 4 times daily. In controlled clinical studies comparing 0.1% dipivefrin and 2% pilocarpine, there were no statistically significant differences in the maintenance of IOP levels for the two medications. - Dipivefrin does not produce miosis or accommodative spasm which cholinergic agents are known to produce. The blurred vision and night blindness often associated with miotic agents are not present with dipivefrin therapy. Patients with cataracts avoid the inability to see around lenticular opacities caused by constricted pupil. ### Dosage - The usual dosage of dipivefrin hydrochloride ophthalmic solution, 0.1%, is one drop in the eye(s) every 12 hours. - When patients are being transferred to dipivefrin from antiglaucoma agents other than epinephrine, on the first day continue the previous medication and add one drop of dipivefrin to each eye(s) every 12 hours. On the following day, discontinue the previously used antiglaucoma agent and continue with dipivefrin. - In transferring patients from conventional epinephrine therapy to dipivefrin, simply discontinue the epinephrine medication and institute the dipivefrin regimen. - When patients on other antiglaucoma agents require additional therapy, add one drop of dipivefrin every 12 hours. - For difficult to control patients, the addition of dipivefrin hydrochloride ophthalmic solution to other agents such as pilocarpine, carbachol, echothiophate iodide or acetazolamide has been shown to be effective. - Note: Not for injection. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Dipivefrine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Dipivefrine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Dipivefrine in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Dipivefrine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Dipivefrine in pediatric patients. # Contraindications - Dipivefrin hydrochloride should not be used in patients with narrow angles since any dilation of the pupil may predispose the patient to an attack of angle-closure glaucoma. This product is contraindicated in patients who are hypersensitive to any of its components. # Warnings - NOT FOR INJECTION – FOR OPHTHALMIC USE ONLY. ### Precautions - Aphakic Patients: Macular edema has been shown to occur in up to 30% of aphakic patients treated with epinephrine. Discontinuation of epinephrine generally results in reversal of the maculopathy. - To avoid contamination, do not touch tip of container to the eye, eyelid, or any surface. - Rabbit studies indicated a dose-related incidence of meibomiam gland retention cysts following topical administration of both dipivefrin and epinephrine. # Adverse Reactions ## Clinical Trials Experience - Tachycardia, arrhythmias and hypertension have been reported with ocular administration of epinephrine. - The most frequent side effects reported with dipivefrin hydrochloride alone were injection in 6.5% of patients and burning and stinging in 6%. Follicular conjunctivitis, mydriasis and allergic reactions to dipivefrin have been reported infrequently. Epinephrine therapy can lead to adrenochrome deposits in the conjunctiva and cornea. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Dipivefrine in the drug label. # Drug Interactions There is limited information regarding Dipivefrine Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - Reproduction studies have been performed in rats and rabbits at daily oral doses up to 10 mg/kg body weight (5 mg/kg in teratogenicity studies), and have revealed no evidence of impaired fertility or harm to the fetus due to dipivefrin. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dipivefrine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Dipivefrine 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 dipivefrin hydrochloride is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use There is no FDA guidance on the use of Dipivefrine with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Dipivefrine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Dipivefrine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Dipivefrine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Dipivefrine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Dipivefrine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Dipivefrine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical application ### Monitoring There is limited information regarding Monitoring of Dipivefrine in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Dipivefrine in the drug label. # Overdosage There is limited information regarding Overdose of Dipivefrine in the drug label. # Pharmacology ## Mechanism of Action - Dipivefrin is converted to epinephrine inside the human eye by enzyme hydrolysis. The liberated epinephrine, an adrenergic agonist, appears to exert its action by decreasing aqueous production and by enhancing outflow facility. ## Structure - Dipivefrin Hydrochloride Ophthalmic Solution USP, 0.1% is a sterile, isotonic solution. Dipivefrin hydrochloride is a white, crystalline powder, freely soluble in water. It is classified as a sympathomimetic agent and has the following structural formula: - Chemical Name: (±) -3, 4-Dihydroxy-a- [(methylamino) methyl] benzyl alcohol 3, 4-dipivalate hydrochloride. - Contains: Active: Dipivefrin hydrochloride, 0.1% (1 mg/mL). Preservative: Benzalkonium chloride 0.005%. Inactive Ingredients: Edetate Disodium, Sodium Chloride, Hydrochloric Acid and/or Sodium Hydroxide (to adjust pH to 2.5 to 3.5), Purified Water. DM-00 ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Dipivefrine in the drug label. ## Pharmacokinetics - Dipivefrin hydrochloride is a member of a class of drugs known as prodrugs. Prodrugs are usually not active in themselves and require biotransformation to the parent compound before therapeutic activity is seen. These modifications are undertaken to enhance absorption, decrease side effects and enhance stability and comfort, thus making the parent compound a more useful drug. Enhanced absorption makes the prodrug a more efficient delivery system for the parent drug because less drug will be needed to produce the desired therapeutic response. - Dipivefrin is a prodrug of epinephrine formed by the diesterification of epinephrine and pivalic acid. The addition of pivaloyl groups to the epinephrine molecule enhances its lipophilic character and, as a consequence, its penetration into the anterior chamber. - Dipivefrin is converted to epinephrine inside the human eye by enzyme hydrolysis. The liberated epinephrine, an adrenergic agonist, appears to exert its action by decreasing aqueous production and by enhancing outflow facility. The dipivefrin hydrochloride prodrug delivery system is a more efficient way of delivering the therapeutic effects of epinephrine, with fewer side effects than are associated with conventional epinephrine therapy. - The onset of action with one drop of dipivefrin hydrochloride ophthalmic solution occurs about 30 minutes after treatment, with maximum effect seen at about one hour. - Using a prodrug means that less drug is needed for therapeutic effect since absorption is enhanced with the prodrug. Dipivefrin hydrochloride, 0.1% was judged less irritating than a 1% solution of epinephrine hydrochloride or bitartrate. In addition, only 8 of 455 patients (1.8%) treated with dipivefrin reported discomfort due to photophobia, glare or light sensitivity. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Dipivefrine in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Dipivefrine in the drug label. # How Supplied - Dipivefrin Hydrochloride Ophthalmic Solution USP, 0.1% is supplied sterile in opaque plastic DROP-TAINER® Dispensers as follows: ## Storage - Store at controlled room temperature 15°-30°C (59°-86°F) in a tight, light-resistant container. # Images ## Drug Images ## Package and Label Display Panel ### Ingredients and Appearance # Patient Counseling Information - To avoid contamination, do not touch tip of container to the eye, eyelid, or any surface. # Precautions with Alcohol - Alcohol-Dipivefrine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Propine®[1] # Look-Alike Drug Names There is limited information regarding Dipivefrine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Dipivefrin
f83c7503feb805c78155dcf688e5b32d51a026b5	wikidoc	Diploblasty	Diploblasty # Overview Diploblasty is a condition of the ovum in which there are two primary germ layers: the ectoderm and endoderm. Diploblastic organisms are organisms which evolve from such an ovum, and include cnidaria and ctenophores. The endoderm allows them to develop true tissue. This includes tissue associated with the gut and associated glands. The ectoderm on the other hand gives rise to the epidermis, the nervous tissue, and if present, nephridia. Simpler animals, such as sea sponges, have one germ layer and lack true tissue organisation. All the more complex animals (from flat worms to man) are triploblastic with three germ layers (a mesoderm as well as ectoderm and endoderm). The mesoderm allows them to develop true organs.	Diploblasty # Overview Diploblasty is a condition of the ovum in which there are two primary germ layers: the ectoderm and endoderm. Diploblastic organisms are organisms which evolve from such an ovum, and include cnidaria and ctenophores. The endoderm allows them to develop true tissue. This includes tissue associated with the gut and associated glands. The ectoderm on the other hand gives rise to the epidermis, the nervous tissue, and if present, nephridia. Simpler animals, such as sea sponges, have one germ layer and lack true tissue organisation. All the more complex animals (from flat worms to man) are triploblastic with three germ layers (a mesoderm as well as ectoderm and endoderm). The mesoderm allows them to develop true organs.	https://www.wikidoc.org/index.php/Diploblastic
7c5bea262a9ca61edd7de9d737aeba56755a53b1	wikidoc	Diprenorfin	Diprenorfin # Overview Diprenorphine (diprenorfin, Revivon, M5050) is an non-selective opioid antagonist, though it may have some slight partial agonist activity at the kappa-opioid receptor. It is used to reverse the effects of super-potent opioid analgesics such as etorphine and carfentanil that are used for tranquilizing large animals in veterinary medicine. Diprenorphine is the strongest opiate antagonist that is commercially available (some 100 times more potent as an antagonist than nalorphine), and is used for reversing the effects of very strong opioids for which the binding affinity is so high that naloxone does not effectively or reliably reverse the narcotic effects. These super-potent opioids, with the single exception of buprenorphine, are not used in humans because the dose for a human is so small that it would be difficult to measure properly, so there is an excessive risk of overdose leading to fatal respiratory depression. However conventional opioid derivatives are not strong enough to rapidly tranquilize large animals such as elephants and rhinos, so drugs such as etorphine or carfentanil are available for this purpose. Diprenorphine is considered the specific antagonist for etorphine and carfentanil, and is normally used to remobilise animals once veterinary procedures have been completed. Because diprenorphine also has some agonistic properties of its own, it should not be used on humans in the event that they are accidentally exposed to etorphine or carfentanil. Naloxone or naltrexone are the preferred human antagonists. In theory, diprenorphine could also be used as an antidote for treating overdose of certain opioid derivatives which are used in humans, such as buprenorphine, for which the binding affinity is so high that naloxone does not reliably reverse the narcotic effects. However, diprenorphine is not generally available in hospitals; instead a vial of diprenorphine is supplied with etorphine or carfentanil specifically for reversing the effects of these drugs, so use of diprenorphine for treating e.g. a buprenorphine overdose is not usually carried out in practice.	Diprenorfin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Diprenorphine (diprenorfin, Revivon, M5050)[1] is an non-selective opioid antagonist, though it may have some slight partial agonist activity at the kappa-opioid receptor.[2][3] It is used to reverse the effects of super-potent opioid analgesics such as etorphine and carfentanil that are used for tranquilizing large animals in veterinary medicine. Diprenorphine is the strongest opiate antagonist that is commercially available (some 100 times more potent as an antagonist than nalorphine),[4] and is used for reversing the effects of very strong opioids for which the binding affinity is so high that naloxone does not effectively or reliably reverse the narcotic effects.[5] These super-potent opioids, with the single exception of buprenorphine, are not used in humans because the dose for a human is so small that it would be difficult to measure properly, so there is an excessive risk of overdose leading to fatal respiratory depression. However conventional opioid derivatives are not strong enough to rapidly tranquilize large animals such as elephants and rhinos, so drugs such as etorphine or carfentanil are available for this purpose. Diprenorphine is considered the specific antagonist for etorphine and carfentanil,[6] and is normally used to remobilise animals once veterinary procedures have been completed.[7] Because diprenorphine also has some agonistic properties of its own, it should not be used on humans in the event that they are accidentally exposed to etorphine or carfentanil. Naloxone or naltrexone are the preferred human antagonists.[8] In theory, diprenorphine could also be used as an antidote for treating overdose of certain opioid derivatives which are used in humans, such as buprenorphine, for which the binding affinity is so high that naloxone does not reliably reverse the narcotic effects. However, diprenorphine is not generally available in hospitals; instead a vial of diprenorphine is supplied with etorphine or carfentanil specifically for reversing the effects of these drugs, so use of diprenorphine for treating e.g. a buprenorphine overdose is not usually carried out in practice.	https://www.wikidoc.org/index.php/Diprenorfin
ef46e4bda03613dd2255e3ad0c3196c1e0392e93	wikidoc	Dirlotapide	Dirlotapide # Overview Dirlotapide is a drug used to treat obesity in dogs. It is manufactured by Pfizer and marketed as Slentrol. It works as a selective microsomal triglyceride transfer protein (MTTP) inhibitor. This blocks the assembly and release of lipoproteins into the bloodstream, thereby reducing fat absorption. It also elicits a satiety signal from lipid-filled cells lining the intestine. It is supplied as an oral solution. It is not intended for use in humans, cats, or parrots. On January 5, 2007, the U.S. Food and Drug Administration (FDA) approved Slentrol, the first time the FDA has approved a drug for obese dogs. Dirlotapide is used to manage obesity in dogs and helps by reducing appetite. It should be used as part of an overall weight control program that also includes proper diet and exercise, under the supervision of a veterinarian. Side effects may include vomiting, diarrhea, lethargy, drooling, or uncoordination. Allergic reaction to the medication may include, facial swelling, hives, scratching, sudden onset of diarrhea, vomiting, shock, seizures, pale gums, cold limbs, or coma. Contact your veterinarian if you observe any of these signs. The dose of dirlotapide will need to be recalculated each month, based on your dog's weight.	Dirlotapide Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Dirlotapide is a drug used to treat obesity in dogs. It is manufactured by Pfizer and marketed as Slentrol. It works as a selective microsomal triglyceride transfer protein (MTTP) inhibitor. This blocks the assembly and release of lipoproteins into the bloodstream, thereby reducing fat absorption. It also elicits a satiety signal from lipid-filled cells lining the intestine. It is supplied as an oral solution. It is not intended for use in humans, cats, or parrots. On January 5, 2007, the U.S. Food and Drug Administration (FDA) approved Slentrol, the first time the FDA has approved a drug for obese dogs. Dirlotapide is used to manage obesity in dogs and helps by reducing appetite. It should be used as part of an overall weight control program that also includes proper diet and exercise, under the supervision of a veterinarian. Side effects may include vomiting, diarrhea, lethargy, drooling, or uncoordination. Allergic reaction to the medication may include, facial swelling, hives, scratching, sudden onset of diarrhea, vomiting, shock, seizures, pale gums, cold limbs, or coma. Contact your veterinarian if you observe any of these signs. The dose of dirlotapide will need to be recalculated each month, based on your dog's weight.	https://www.wikidoc.org/index.php/Dirlotapide
881ab915b74ed1aa7db5024230994843fc953398	wikidoc	Leukoplakia	Leukoplakia # Overview Leukoplakia is a condition of the mouth that involves the formation of white leathery spots on the mucous membranes of the tongue and inside of the mouth. It is not a specific disease entity and is diagnosed by exclusion of diseases that may cause similar white lesions like candidiasis or lichen planus. # Epidemiology and Demographics Leukoplakia affects less than one percent of the population, and is most common in adults within the 50-70 years age group. # Diagnosis ## Common Causes The cause in most cases is unknown, but many are related to tobacco use and chronic irritation. Bloodroot, otherwise known as sanguinaria, is also believed to be associated with causing leukoplakia. A small proportion of cases, particularly those involving the floor of the mouth or the undersurface of the tongue is associated with a risk of cancer. The so-called hairy leukoplakia associated with HIV infection and other diseases of severe immune deficiency does not have risks for cancer. ## Physical Examination ### Ear Nose and Throat - The white lesion is an example of leukoplakia. - Oral Hairy Leucoplakia (EBV, HIV). ### Vulvar leukoplakia - Vulvar leukoplakia. Adapted from Dermatology Atlas. - Vulvar leukoplakia. Adapted from Dermatology Atlas. # Differential diagnosis Oral leukoplakia must be differentiated from other mouth lesions such as oral candidiasis and aphthous ulcer # Treatment The treatment of leukoplakia mainly involves avoidance of predisposing factors like smoking, tobacco and betel chewing, alcohol,and removal of chronic irritants like sharp edges of teeth. In suspicious cases, a biopsy is also taken, and surgical excision done if pre-cancerous changes or frank cancer is detected.	Leukoplakia Template:DiseaseDisorder infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2] # Overview Leukoplakia is a condition of the mouth that involves the formation of white leathery spots on the mucous membranes of the tongue and inside of the mouth. It is not a specific disease entity and is diagnosed by exclusion of diseases that may cause similar white lesions like candidiasis or lichen planus. # Epidemiology and Demographics Leukoplakia affects less than one percent of the population, and is most common in adults within the 50-70 years age group. # Diagnosis ## Common Causes The cause in most cases is unknown, but many are related to tobacco use and chronic irritation. Bloodroot, otherwise known as sanguinaria, is also believed to be associated with causing leukoplakia.[1] A small proportion of cases, particularly those involving the floor of the mouth or the undersurface of the tongue is associated with a risk of cancer. The so-called hairy leukoplakia associated with HIV infection and other diseases of severe immune deficiency does not have risks for cancer. ## Physical Examination ### Ear Nose and Throat - The white lesion is an example of leukoplakia. - Oral Hairy Leucoplakia (EBV, HIV). ### Vulvar leukoplakia - Vulvar leukoplakia. Adapted from Dermatology Atlas.[2] - Vulvar leukoplakia. Adapted from Dermatology Atlas.[2] # Differential diagnosis Oral leukoplakia must be differentiated from other mouth lesions such as oral candidiasis and aphthous ulcer # Treatment The treatment of leukoplakia mainly involves avoidance of predisposing factors like smoking, tobacco and betel chewing, alcohol,and removal of chronic irritants like sharp edges of teeth. In suspicious cases, a biopsy is also taken, and surgical excision done if pre-cancerous changes or frank cancer is detected.	https://www.wikidoc.org/index.php/Discolored_tongue
bd5294039fb6c5e3d3aa58232e7543afe2b7a280	wikidoc	Mediastinum	Mediastinum # Overview The mediastinum is a non-delineated group of structures in the thorax (chest), surrounded by loose connective tissue. It is the central compartment of the thoracic cavity. It contains the heart, the great vessels of the heart, esophagus, trachea, thymus, and lymph nodes of the central chest. # Anatomy The mediastinum lies between the right and left pleura in and near the median sagittal plane of the chest. It extends from the sternum in front to the vertebral column behind, and contains all the thoracic viscera except the lungs. It may be divided for purposes of description into two parts: - an upper portion, above the upper level of the pericardium, which is named the superior mediastinum with its superior limit at the superior thoracic opening and its inferior limit at the plane from the sternal angle to the disc of T4-T5 (Plane of Ludwig); - and a lower portion, below the upper level of the pericardium. This lower portion is again subdivided into three parts, viz.: that in front of the pericardium, the anterior mediastinum; that containing the pericardium and its contents, the middle mediastinum; and that behind the pericardium, the posterior mediastinum. - that in front of the pericardium, the anterior mediastinum; - that containing the pericardium and its contents, the middle mediastinum; - and that behind the pericardium, the posterior mediastinum. It is surrounded by the chest wall anteriorly, the lungs laterally and the spine posteriorly. It is continuous with the loose connective tissue of the neck, and extends inferiorly onto the diaphragm. Note that clinical radiologists and anatomists categorize the mediastinum in slightly different ways. # Role in disease The mediastinum frequently is the site of involvement of various tumors. Mediastinitis is inflammation of the tissues in the mediastinum, usually bacterial and due to rupture of organs in the mediastinum. As the infection can progress very quickly, this is a serious condition. Pneumomediastinum is the presence of air in the mediastinum, which can lead to pneumothorax, pneumoperitoneum, and pneumopericardium if left untreated in some cases. However, that does not always happen and sometimes those conditions actually are the cause, not the result, of pneumomediastinum. These two conditions frequently accompany Boerhaave's syndrome, or spontaneous esophageal rupture. A widened mediastinum (usually found via a chest x-ray) is a classic hallmark sign of anthrax posioning. At this point, the disease is typically fatal.	Mediastinum Template:Infobox Anatomy Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview The mediastinum is a non-delineated group of structures in the thorax (chest), surrounded by loose connective tissue. It is the central compartment of the thoracic cavity. It contains the heart, the great vessels of the heart, esophagus, trachea, thymus, and lymph nodes of the central chest. # Anatomy The mediastinum lies between the right and left pleura in and near the median sagittal plane of the chest. It extends from the sternum in front to the vertebral column behind, and contains all the thoracic viscera except the lungs. It may be divided for purposes of description into two parts: - an upper portion, above the upper level of the pericardium, which is named the superior mediastinum with its superior limit at the superior thoracic opening and its inferior limit at the plane from the sternal angle to the disc of T4-T5 (Plane of Ludwig); - and a lower portion, below the upper level of the pericardium. This lower portion is again subdivided into three parts, viz.: that in front of the pericardium, the anterior mediastinum; that containing the pericardium and its contents, the middle mediastinum; and that behind the pericardium, the posterior mediastinum. - that in front of the pericardium, the anterior mediastinum; - that containing the pericardium and its contents, the middle mediastinum; - and that behind the pericardium, the posterior mediastinum. It is surrounded by the chest wall anteriorly, the lungs laterally and the spine posteriorly. It is continuous with the loose connective tissue of the neck, and extends inferiorly onto the diaphragm. Note that clinical radiologists and anatomists categorize the mediastinum in slightly different ways. # Role in disease The mediastinum frequently is the site of involvement of various tumors. Mediastinitis is inflammation of the tissues in the mediastinum, usually bacterial and due to rupture of organs in the mediastinum. As the infection can progress very quickly, this is a serious condition. Pneumomediastinum is the presence of air in the mediastinum, which can lead to pneumothorax, pneumoperitoneum, and pneumopericardium if left untreated in some cases. However, that does not always happen and sometimes those conditions actually are the cause, not the result, of pneumomediastinum. These two conditions frequently accompany Boerhaave's syndrome, or spontaneous esophageal rupture. A widened mediastinum (usually found via a chest x-ray) is a classic hallmark sign of anthrax posioning. At this point, the disease is typically fatal.	https://www.wikidoc.org/index.php/Disorders_of_the_Mediastinum
55600f332a88be0d8b109684126bf3443c28b75e	wikidoc	Distraction	Distraction # Overview Distraction is the diversion of attention of an individual or group from the chosen object of attention onto the source of distraction. Distraction is caused by one of the following: lack of ability to pay attention; lack of interest in the object of attention; greater interest in something other than the object of attention; or the great intensity, novelty or attractiveness of something other than the object of attention. Distractions come from both external sources (physical stimulus through the five senses), or internal sources (thought, emotion, daydreams, physical urges). Divided attention, as in multi-tasking could also be considered as distraction in situations requiring full attention on a single object (e.g., sports, academic tests, performance). Distraction is a major cause of procrastination. Distraction is also a television game show hosted by Jimmy Carr both in the UK and the US. # Distraction by media The media (television, reading, video games), can be a great source of distraction. In many cases, media is viewed as more entertaining than the object of attention. The brightly colored images and appealing sounds also divert attention. The case of Shawn Woolley was a very extreme case; he became particularly involved in the computer game Everquest and quit his job to dedicate up to 12 hours a day playing the game. # Distraction in wildlife, warfare, and crime - Fake targets: In open field with mass military strategy, sometimes a contingent of troops is used to distract the enemy army so their flank is exposed, or to draw them away from a key point or fortification, such as a city. Flares can be used to divert the enemy soldiers' gaze - In open field with mass military strategy, sometimes a contingent of troops is used to distract the enemy army so their flank is exposed, or to draw them away from a key point or fortification, such as a city. - Flares can be used to divert the enemy soldiers' gaze - Pickpockets and other thieves, especially those working in teams, sometimes apply distraction, such as asking a question, bumping into the victim, or deliberately dirtying the victim's clothing and then "helping" him/her to clean it. - Animals with fake eyes on their back distract their predators with the fake eyes.	Distraction Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Distraction is the diversion of attention of an individual or group from the chosen object of attention onto the source of distraction. Distraction is caused by one of the following: lack of ability to pay attention; lack of interest in the object of attention; greater interest in something other than the object of attention; or the great intensity, novelty or attractiveness of something other than the object of attention. Distractions come from both external sources (physical stimulus through the five senses), or internal sources (thought, emotion, daydreams, physical urges). Divided attention, as in multi-tasking could also be considered as distraction in situations requiring full attention on a single object (e.g., sports, academic tests, performance). Distraction is a major cause of procrastination. Distraction is also a television game show hosted by Jimmy Carr both in the UK and the US. Template:Wiktionarypar # Distraction by media The media (television, reading, video games), can be a great source of distraction. In many cases, media is viewed as more entertaining than the object of attention. The brightly colored images and appealing sounds also divert attention. The case of Shawn Woolley was a very extreme case; he became particularly involved in the computer game Everquest and quit his job to dedicate up to 12 hours a day playing the game. # Distraction in wildlife, warfare, and crime - Fake targets: In open field with mass military strategy, sometimes a contingent of troops is used to distract the enemy army so their flank is exposed, or to draw them away from a key point or fortification, such as a city. Flares can be used to divert the enemy soldiers' gaze - In open field with mass military strategy, sometimes a contingent of troops is used to distract the enemy army so their flank is exposed, or to draw them away from a key point or fortification, such as a city. - Flares can be used to divert the enemy soldiers' gaze - Pickpockets and other thieves, especially those working in teams, sometimes apply distraction, such as asking a question, bumping into the victim, or deliberately dirtying the victim's clothing and then "helping" him/her to clean it. - Animals with fake eyes on their back distract their predators with the fake eyes.	https://www.wikidoc.org/index.php/Distraction
d393fd433b8c6dfd654d2916d151b1185c5331a3	wikidoc	Dizocilpine	Dizocilpine Dizocilpine, also known as MK-801, is a non-competitive antagonist of the NMDA receptor. It binds inside the ion channel of the receptor and thus prevents the flow of ions such as calcium (Ca2+) through the channel. Dizocilpine blocks NMDA receptors in a use- and voltage-dependent manner, since the channel must open for the drug to bind inside it. The drug is an anti-convulsant. # Possible future medical uses The effects of MK-801 at NMDA receptors are clear and significant. NMDA receptors are key in the progression of excitotoxicity (a process in which an excessive amount of extracellular glutamate overexcites glutamate receptors and harms neurons). Thus NMDA receptor antagonists including MK-801 have been extensively studied for use in treatment of diseases with excitotoxic components, such as stroke, traumatic brain injury, and neurodegenerative diseases such as Huntington's, Alzheimer's, and amyotrophic lateral sclerosis. MK-801 has shown effectiveness in protecting neurons in cell culture and animal models of excitotoxic neurodegeneration. However, NMDA antagonists like MK-801 have largely failed to show safety and effectiveness in clinical trials, possibly due to inhibition of NMDA receptor function that is necessary for normal neuronal function. Since MK-801 is a particularly strong NMDA receptor antagonist, this drug is particularly likely to have psychotomimetic side effects (such as hallucinations) that result from NMDA receptor blockade. MK-801 had a promising future as a neuroprotective agent until neurotoxic-like effects, called Olney's Lesions, were seen in certain brain regions of test rats. Merck, a drug company, promptly dropped development of MK-801. # Recreational use Dizocilpine may be effective as a recreational drug, and may have an active dose in the 50-100μg range. Little is known in this context about its effects, dosage, and risks. Dizocilpine's high potency makes its dosage more difficult to accurately control when compared to other similar drugs. As a result, the chances of overdosing are high. Users tend to report that the experience is not as enjoyable as other dissociative drugs, and it is often accompanied by strong auditory hallucinations. Also, dizocilpine is much longer-lasting than similar dissociative drugs such as ketamine and phencyclidine (PCP), and causes far worse amnesia and residual deficits in thinking, which have hindered its acceptance as a recreational drug.	Dizocilpine Dizocilpine, also known as MK-801, is a non-competitive antagonist of the NMDA receptor. It binds inside the ion channel of the receptor and thus prevents the flow of ions such as calcium (Ca2+) through the channel. Dizocilpine blocks NMDA receptors in a use- and voltage-dependent manner, since the channel must open for the drug to bind inside it. The drug is an anti-convulsant. # Possible future medical uses The effects of MK-801 at NMDA receptors are clear and significant. NMDA receptors are key in the progression of excitotoxicity (a process in which an excessive amount of extracellular glutamate overexcites glutamate receptors and harms neurons). Thus NMDA receptor antagonists including MK-801 have been extensively studied for use in treatment of diseases with excitotoxic components, such as stroke, traumatic brain injury, and neurodegenerative diseases such as Huntington's, Alzheimer's, and amyotrophic lateral sclerosis. MK-801 has shown effectiveness in protecting neurons in cell culture and animal models of excitotoxic neurodegeneration.[1][2][3] However, NMDA antagonists like MK-801 have largely failed to show safety and effectiveness in clinical trials, possibly due to inhibition of NMDA receptor function that is necessary for normal neuronal function. Since MK-801 is a particularly strong NMDA receptor antagonist, this drug is particularly likely to have psychotomimetic side effects (such as hallucinations) that result from NMDA receptor blockade. MK-801 had a promising future as a neuroprotective agent until neurotoxic-like effects, called Olney's Lesions, were seen in certain brain regions of test rats.[4][5] Merck, a drug company, promptly dropped development of MK-801. # Recreational use Dizocilpine may be effective as a recreational drug, and may have an active dose in the 50-100μg range. Little is known in this context about its effects, dosage, and risks. Dizocilpine's high potency makes its dosage more difficult to accurately control when compared to other similar drugs. As a result, the chances of overdosing are high. Users tend to report that the experience is not as enjoyable as other dissociative drugs, and it is often accompanied by strong auditory hallucinations. Also, dizocilpine is much longer-lasting than similar dissociative drugs such as ketamine and phencyclidine (PCP), and causes far worse amnesia and residual deficits in thinking, which have hindered its acceptance as a recreational drug.	https://www.wikidoc.org/index.php/Dizocilpine
9a77e4101e9da9dd38aaec975c9e2124aa203f54	wikidoc	Dolorimeter	Dolorimeter A dolorimeter is an instrument used to measure pain tolerance. Dolorimetry has been defined as "the measurement of pain sensitivity or pain intensity." There are several kinds of dolorimeter that have been developed. Dolorimeters apply steady pressure, heat, or electrical stimulation to some area, or move a joint or other body part and determine what level of heat or pressure or electric current or amount of movement produces a sensation of pain. Sometimes the pressure is applied using a blunt object, or by locally increasing the air pressure on some area of the body, and sometimes by pressing a sharp instrument against the body. # Palpometer A dolorimeter known as the Sonic Palpometer was developed at the University of Victoria in British Columbia, Canada. Patents have been applied for worldwide. The Sonic Palpometer uses ultrasound and computer technology to automate the physician's technique of palpation to determine sensitivity of some part of the patient's body. The related Pressure Controlled Palpometer (PCP) uses a pressure-sensitive piece of plastic film to determine how much pressure is being applied in palpation. This technique appears to be more reliable than unaided palpation. # Algorimeter and other methods ## Techniques using lasers Svensson et al (1997) describe the use of a CO2 laser or a contact thermode to heat the skin and elicit a pain response. A laser-based dolorimeter called a Dolorimeter Analgesia meter is marketed by IITC Life Sciences. ## Techniques using heat lamps Another pain measurement device uses heat from a 500 Watt lamp which is delivered to a small area of skin. ## Other dolorimeters - Baseline Algorimeter from the Kom Kare Company. - Björnström's algesimeter measures sensitivity of the skin to pain. - Boas' algesimeter measures sensitivity over the epigastrium Other terms for similar instruments include algesiometer, algesichronometer (which also takes time into consideration), analgesia meter, algometer, algonometer, prick-algesimeter, pressure-algometer. # Dolorimeters for animals The Hot Plate analgesia meter measures response to mice and rats placed on a hot plate. The Tail Flick analgesia meter measures the movement of the animal's tail in response to a painful sensation. An intense light beam is focused on the animal's tail, and then a timer begins. When the animal flicks its tail, the timer stops and the recorded time is a measure of the pain threshold. A pressure analgesia meter uses a stepper motor to gradually increase pressure on the animal's paw. # History In 1940, James D. Hardy, Harold G. Wolff and Helen Goodell of Cornell University introduced the first dolorimeter as a method for evaluating the effectiveness of analgesic medications. They did their work at New York Hospital. They focused the light of a 100 Watt projection lamp with a lens on an area of skin that had been blackened. They found that most people expressed a pain sensation when the skin temperature reached 113 °F (45 °C). They also found that after the skin temperature reached 152 °F (67 °C), the pain sensations did not intensify even if the heat was increased. They developed a pain scale, called the "Hardy-Wolff-Goodell" scale, with 10 gradations, or 10 levels. They assigned the name of "dols" to these levels. Unfortunately, other researchers were not able to reproduce the results of Hardy, Wolff and Goodell and the device and the approach was abandoned. Harvard Medical School Professor and Massachusetts General Hospital Anaesthetist Henry K. Beecher (1957) expressed skepticism about this method of measuring pain. In 1945, Time Magazine reported that Cleveland's Dr. Lorand Julius Bela Gluzek had developed a dolorimeter that measured pain in grams. Dr. Gluzek claimed that his dolorimeter was 97% accurate.	Dolorimeter Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] A dolorimeter is an instrument used to measure pain tolerance. Dolorimetry has been defined as "the measurement of pain sensitivity or pain intensity."[1] There are several kinds of dolorimeter that have been developed. Dolorimeters apply steady pressure, heat, or electrical stimulation to some area, or move a joint or other body part and determine what level of heat or pressure or electric current or amount of movement produces a sensation of pain. Sometimes the pressure is applied using a blunt object, or by locally increasing the air pressure on some area of the body, and sometimes by pressing a sharp instrument against the body. # Palpometer A dolorimeter known as the Sonic Palpometer was developed at the University of Victoria in British Columbia, Canada. Patents have been applied for worldwide.[2] The Sonic Palpometer uses ultrasound and computer technology to automate the physician's technique of palpation to determine sensitivity of some part of the patient's body. The related Pressure Controlled Palpometer (PCP) uses a pressure-sensitive piece of plastic film to determine how much pressure is being applied in palpation. This technique appears to be more reliable than unaided palpation.[3] # Algorimeter and other methods ## Techniques using lasers Svensson et al (1997) describe the use of a CO2 laser or a contact thermode to heat the skin and elicit a pain response.[4] A laser-based dolorimeter called a Dolorimeter Analgesia meter is marketed by IITC Life Sciences. ## Techniques using heat lamps Another pain measurement device uses heat from a 500 Watt lamp which is delivered to a small area of skin. ## Other dolorimeters - Baseline Algorimeter from the Kom Kare Company.[5] - Björnström's algesimeter measures sensitivity of the skin to pain. - Boas' algesimeter measures sensitivity over the epigastrium Other terms for similar instruments include algesiometer, algesichronometer (which also takes time into consideration), analgesia meter, algometer, algonometer, prick-algesimeter, pressure-algometer. # Dolorimeters for animals The Hot Plate analgesia meter measures response to mice and rats placed on a hot plate. The Tail Flick analgesia meter measures the movement of the animal's tail in response to a painful sensation. An intense light beam is focused on the animal's tail, and then a timer begins. When the animal flicks its tail, the timer stops and the recorded time is a measure of the pain threshold. A pressure analgesia meter uses a stepper motor to gradually increase pressure on the animal's paw. # History In 1940, James D. Hardy, Harold G. Wolff and Helen Goodell of Cornell University introduced the first dolorimeter as a method for evaluating the effectiveness of analgesic medications.[6] They did their work at New York Hospital. They focused the light of a 100 Watt projection lamp with a lens on an area of skin that had been blackened. They found that most people expressed a pain sensation when the skin temperature reached 113 °F (45 °C). They also found that after the skin temperature reached 152 °F (67 °C), the pain sensations did not intensify even if the heat was increased. They developed a pain scale, called the "Hardy-Wolff-Goodell" scale, with 10 gradations, or 10 levels. They assigned the name of "dols" to these levels.[7][8] Unfortunately, other researchers were not able to reproduce the results of Hardy, Wolff and Goodell and the device and the approach was abandoned.[9] Harvard Medical School Professor and Massachusetts General Hospital Anaesthetist Henry K. Beecher (1957) expressed skepticism about this method of measuring pain.[10] In 1945, Time Magazine reported that Cleveland's Dr. Lorand Julius Bela Gluzek had developed a dolorimeter that measured pain in grams.[11][12] Dr. Gluzek claimed that his dolorimeter was 97% accurate.	https://www.wikidoc.org/index.php/Dolorimeter
257ce31e720f5f9bc01c507c2cab5e4ae6587167	wikidoc	Domperidone	Domperidone # Overview Domperidone (trade name Motilium or Motillium) is an antidopaminergic drug, developed by Janssen Pharmaceutica, and used orally, rectally or intravenously, generally to suppress nausea and vomiting. It has also been used to stimulate lactation. # Uses ## Gastrointestinal problems Domperidone is used, together with metoclopramide, cyclizine, and 5HT3 receptor antagonists (such as granisetron) in the treatment of nausea and vomiting. It is useful in patients with Parkinson's disease because, unlike metoclopramide, domperidone does not cross the blood-brain barrier. Domperidone has also been found effective in the treatment of gastroparesis, a stomach motility condition, and for paediatric Gastroesophageal reflux (infant vomiting). ## Lactation The hormone prolactin stimulates lactation in humans, and its release is inhibited by the dopamine secreted by the hypothalamus. Domperidone, by acting as an anti-dopaminergic, results in increased prolactin secretion, and thus promotes lactation. Although it has never been officially approved for use in the United States, domperidone is widely purchased from pharmacies in other countries for this purpose. Since, according to the FDA, domperidone is not approved for enhanced lactation in any country, it is still prescribed "off-label" for this use in countries besides the United States. # Controversy Janssen Pharmaceutical has brought Domperidone before the FDA several times in the last two decades, with the most recent effort in the 1990s. Numerous U.S. clinical drug trials have demonstrated its safety and efficacy in dealing with gastroparesis symptoms, but the FDA turned down Janssen's application for Domperidone, even though the FDA's division of gastrointestinal drugs had approved Domperidone. In June 2004, the United States' main regulation agency, the Food and Drug Administration (FDA), issued a letter warning women not to take domperidone, citing unknown risks to parents and infants, and warned pharmacies that domestic sale was illegal, and that import shipments from other countries would be searched and seized. Domperidone is excreted in breast milk, and no studies on its effects on breastfeeding infants have been reported in the literature. Individual incidents of problems with the drug include cardiac arrest and arrhythmia, complications with other medications, as well as complications with improper intravenous use It has been widely speculated that this action by the FDA is related to increasing drug importation from countries such as Canada. Yet prominent doctors and pharmacists have rejected the FDA's reasoning and still promote domperidone's use in increasing milk supply. Such doctors and pharmacists are confident the drug is safe in the doses given for this purpose. The American Academy of Pediatrics considers domperidone "usually compatible with breastfeeding". There is a new controversy in Britain regarding lethal levels of sodium found in children who are administered this drug. It is now subject to a medical review following a number of criminal trials. # Brand Domperidone is marketed in India by Ion healthcare under the brand name MELDOM-DT. Also conjuction with Pantoprazole as Dompan Tablets mktg by MEDLEY Pharma. Ltd.	Domperidone Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Domperidone (trade name Motilium or Motillium) is an antidopaminergic drug, developed by Janssen Pharmaceutica, and used orally, rectally or intravenously, generally to suppress nausea and vomiting. It has also been used to stimulate lactation. # Uses ## Gastrointestinal problems Domperidone is used, together with metoclopramide, cyclizine, and 5HT3 receptor antagonists (such as granisetron) in the treatment of nausea and vomiting. It is useful in patients with Parkinson's disease because, unlike metoclopramide, domperidone does not cross the blood-brain barrier. Domperidone has also been found effective in the treatment of gastroparesis,[2] a stomach motility condition, and for paediatric Gastroesophageal reflux (infant vomiting). ## Lactation The hormone prolactin stimulates lactation in humans, and its release is inhibited by the dopamine secreted by the hypothalamus. Domperidone, by acting as an anti-dopaminergic, results in increased prolactin secretion, and thus promotes lactation. Although it has never been officially approved for use in the United States, domperidone is widely purchased from pharmacies in other countries for this purpose. Since, according to the FDA, domperidone is not approved for enhanced lactation in any country,[3] it is still prescribed "off-label" for this use in countries besides the United States.[4] # Controversy Janssen Pharmaceutical has brought Domperidone before the FDA several times in the last two decades, with the most recent effort in the 1990s. Numerous U.S. clinical drug trials have demonstrated its safety and efficacy in dealing with gastroparesis symptoms, but the FDA turned down Janssen's application for Domperidone, even though the FDA's division of gastrointestinal drugs had approved Domperidone.[5] In June 2004, the United States' main regulation agency, the Food and Drug Administration (FDA), issued a letter warning women not to take domperidone, citing unknown risks to parents and infants, and warned pharmacies that domestic sale was illegal, and that import shipments from other countries would be searched and seized. Domperidone is excreted in breast milk, and no studies on its effects on breastfeeding infants have been reported in the literature. Individual incidents of problems with the drug include cardiac arrest and arrhythmia, complications with other medications, as well as complications with improper intravenous use[4] It has been widely speculated that this action by the FDA is related to increasing drug importation from countries such as Canada. Yet prominent doctors and pharmacists have rejected the FDA's reasoning and still promote domperidone's use in increasing milk supply. Such doctors and pharmacists are confident the drug is safe in the doses given for this purpose.[6] The American Academy of Pediatrics considers domperidone "usually compatible with breastfeeding".[7] There is a new controversy in Britain regarding lethal levels of sodium found in children who are administered this drug. It is now subject to a medical review following a number of criminal trials.[8] # Brand Domperidone is marketed in India by Ion healthcare under the brand name MELDOM-DT. Also conjuction with Pantoprazole as Dompan Tablets mktg by MEDLEY Pharma. Ltd.	https://www.wikidoc.org/index.php/Domperidone
b20d742771f414a337916fc8519b0d298910b7d3	wikidoc	Don Spencer	Don Spencer Don Spencer is considered the World's Fastest Hypnotist. He credits include training over 25,000 people, hypnotizing over 1,000,000 people around the globe. His professional work spans over 2 decades and includes Clinical work, Hypnotherapy Instructor, Entertainer, Author and Producer of the longest running weekly comedy hypnosis show. His main site is a plethora of hypnotic information including the #1 best selling How to Hypnotize home video ever on his site.	Don Spencer Don Spencer is considered the World's Fastest Hypnotist. He credits include training over 25,000 people, hypnotizing over 1,000,000 people around the globe. His professional work spans over 2 decades and includes Clinical work, Hypnotherapy Instructor, Entertainer, Author and Producer of the longest running weekly comedy hypnosis show. His main site http://www.sleepnow.com is a plethora of hypnotic information including the #1 best selling How to Hypnotize home video ever on his site.	https://www.wikidoc.org/index.php/Don_Spencer
38b564815f24d0ec627efce5ea9dc824e69b75b0	wikidoc	Door safety	Door safety Door safety relates to prevention of door-related accidents. Such accidents take place in various forms, and in a number of locations; ranging from car doors to garage doors. Accidents vary in severity and frequency; however within the US, governmental departments have begun legislating to reduce the number of accidents that occur in doors. According to the National Safety Council, 300,000 injuries are caused by doors every year. Because of the number of accidents taking place, there has been a surge in the number of law suits. As organisations are at risk when car doors or doors within buildings are unprotected, businesses have begun offering solutions (such as door guards) to neutralise the threat posed by doors. A closing door can exert up to 40 tons per square inch of pressure between the hinges. According to the U.S. General Services Administration, Child Care Center Design Guide, June 1998: # Door guards Door guards (also known as hinge guards , anti-finger trapping devices and / or finger guards) protect fingers in door hinges. Door guards do this by covering the gap that is created by opening doors by covering the hinges of doors with a piece of rubber that wraps from the door frame to the door. The purpose of door guards is to reduce the number of finger trapping accidents in doors, as doors pose a risk to children especially when closing.	Door safety Door safety relates to prevention of door-related accidents. Such accidents take place in various forms, and in a number of locations; ranging from car doors to garage doors. Accidents vary in severity and frequency; however within the US, governmental departments have begun legislating to reduce the number of accidents that occur in doors. According to the National Safety Council, 300,000 injuries are caused by doors every year. Because of the number of accidents taking place, there has been a surge in the number of law suits. As organisations are at risk when car doors or doors within buildings are unprotected, businesses have begun offering solutions (such as door guards) to neutralise the threat posed by doors. A closing door can exert up to 40 tons per square inch of pressure between the hinges. According to the U.S. General Services Administration, Child Care Center Design Guide, June 1998: # Door guards Door guards (also known as hinge guards , anti-finger trapping devices and / or finger guards) protect fingers in door hinges. Door guards do this by covering the gap that is created by opening doors by covering the hinges of doors with a piece of rubber that wraps from the door frame to the door. The purpose of door guards is to reduce the number of finger trapping accidents in doors, as doors pose a risk to children especially when closing.	https://www.wikidoc.org/index.php/Door_safety
7253ffb8ad6ff51f432124043e04aeff3d64936f	wikidoc	Dorzolamide	Dorzolamide # 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 Dorzolamide is a carbonic anhydrase inhibitor that is FDA approved for the {{{indicationType}}} of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma. Common adverse reactions include taste alteration, hypersensitivity reaction, punctate keratitis, and visual discomfort. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - One drop in the affected eye(s) three times daily ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Dorzolamide in adult patients. ### Non–Guideline-Supported Use - Dosing Information - One drop 1–4 hours after anterior segment laser surgery # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information - One drop in the affected eye(s) three times daily ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Dorzolamide in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Dorzolamide in pediatric patients. # Contraindications - Hypersensitivity - Dorzolamide HCl Ophthalmic Solution is contraindicated in patients who are hypersensitive to any component of this product. # Warnings - Dorzolamide HCl Ophthalmic Solution is a sulfonamide and, although administered topically, is absorbed systemically. Therefore, the same types of adverse reactions that are attributable to sulfonamides may occur with topical administration with Dorzolamide HCl Ophthalmic Solution. Fatalities have occurred, although rarely, due to severe reactions to sulfonamides including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Sensitization may recur when a sulfonamide is readministered irrespective of the route of administration. If signs of serious reactions or hypersensitivity occur, discontinue the use of this preparation. - The management of patients with acute angle-closure glaucoma requires therapeutic interventions in addition to ocular hypotensive agents. Dorzolamide HCl Ophthalmic Solution has not been studied in patients with acute angle-closure glaucoma. - Dorzolamide HCl Ophthalmic Solution has not been studied in patients with severe renal impairment (CrCl < 30 mL/min). Because Dorzolamide HCl Ophthalmic Solution and its metabolite are excreted predominantly by the kidney, Dorzolamide HCl Ophthalmic Solution is not recommended in such patients. - Dorzolamide HCl Ophthalmic Solution has not been studied in patients with hepatic impairment and should therefore be used with caution in such patients. - In clinical studies, local ocular adverse effects, primarily conjunctivitis and lid reactions, were reported with chronic administration of Dorzolamide HCl Ophthalmic Solution. Many of these reactions had the clinical appearance and course of an allergic-type reaction that resolved upon discontinuation of drug therapy. If such reactions are observed, Dorzolamide HCl Ophthalmic Solution should be discontinued and the patient evaluated before considering restarting the drug. - There is a potential for an additive effect on the known systemic effects of carbonic anhydrase inhibition in patients receiving an oral carbonic anhydrase inhibitor and Dorzolamide HCl Ophthalmic Solution. The concomitant administration of Dorzolamide HCl Ophthalmic Solution and oral carbonic anhydrase inhibitors is not recommended. - There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface. Choroidal detachment has been reported with administration of aqueous suppressant therapy (e.g., dorzolamide) after filtration procedures. - There is an increased potential for developing corneal edema in patients with low endothelial cell counts. Precautions should be used when prescribing Dorzolamide HCl Ophthalmic Solution to this group of patients. # Adverse Reactions ## Clinical Trials Experience - The most frequent adverse events associated with Dorzolamide Hydrochloride Ophthalmic Solution were ocular burning, stinging, or discomfort immediately following ocular administration (approximately one-third of patients). Approximately one-quarter of patients noted a bitter taste following administration. Superficial punctate keratitis occurred in 10-15% of patients and signs and symptoms of ocular allergic reaction in approximately 10%. Events occurring in approximately 1-5% of patients were conjunctivitis and lid reactions, blurred vision, eye redness, tearing, dryness, and photophobia. - Other ocular events and systemic events were reported infrequently, including headache, nausea, asthenia/fatigue; and, rarely, skin rashes, urolithiasis, and iridocyclitis. - In a 3-month, double-masked, active-treatment-controlled, multicenter study in pediatric patients, the adverse experience profile of Dorzolamide HCl Ophthalmic Solution was comparable to that seen in adult patients. ## Postmarketing Experience - The following adverse events have occurred either at low incidence (<1%) during clinical trials or have been reported during the use of Dorzolamide HCl Ophthalmic Solution in clinical practice where these events were reported voluntarily from a population of unknown size and frequency of occurrence cannot be determined precisely. They have been chosen for inclusion based on factors such as seriousness, frequency of reporting, possible causal connection to Dorzolamide HCl Ophthalmic Solution, or a combination of these factors: signs and symptoms of systemic allergic reactions including angioedema, bronchospasm, pruritus, and urticaria; Stevens-Johnson syndrome and toxic epidermal necrolysis; dizziness, paresthesia; ocular pain, transient myopia, choroidal detachment following filtration surgery, eyelid crusting; dyspnea; contact dermatitis, epistaxis, dry mouth and throat irritation. # Drug Interactions - Salicylate - Although acid-base and electrolyte disturbances were not reported in the clinical trials with Dorzolamide HCl Ophthalmic Solution, these disturbances have been reported with oral carbonic anhydrase inhibitors and have, in some instances, resulted in drug interactions (e.g., toxicity associated with high-dose salicylate therapy). Therefore, the potential for such drug interactions should be considered in patients receiving Dorzolamide HCl Ophthalmic Solution. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Developmental toxicity studies with dorzolamide hydrochloride in rabbits at oral doses of ≥ 2.5 mg/kg/day (31 times the recommended human ophthalmic dose) revealed malformations of the vertebral bodies. These malformations occurred at doses that caused metabolic acidosis with decreased body weight gain in dams and decreased fetal weights. No treatment-related malformations were seen at 1.0 mg/kg/day (13 times the recommended human ophthalmic dose). There are no adequate and well-controlled studies in pregnant women. Dorzolamide HCl Ophthalmic Solution 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 B3 There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dorzolamide in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Dorzolamide during labor and delivery. ### Nursing Mothers - In a study of dorzolamide hydrochloride in lactating rats, decreases in body weight gain of 5 to 7% in offspring at an oral dose of 7.5 mg/kg/day (94 times the recommended human ophthalmic dose) were seen during lactation. A slight delay in postnatal development (incisor eruption, vaginal canalization and eye openings), secondary to lower fetal body weight, was noted. - 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 Dorzolamide HCl Ophthalmic Solution, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - Safety and IOP-lowering effects of Dorzolamide HCl Ophthalmic Solution have been demonstrated in pediatric patients in a 3-month, multicenter, double-masked, active-treatment-controlled trial. ### Geriatic Use - No overall differences in safety or effectiveness have been observed between elderly and younger patients. ### Gender There is no FDA guidance on the use of Dorzolamide with respect to specific gender populations. ### Race There is no FDA guidance on the use of Dorzolamide with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Dorzolamide in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Dorzolamide in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Dorzolamide in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Dorzolamide in patients who are immunocompromised. # Administration and Monitoring ### Administration Ophthalmic ### Monitoring Serum electrolyte levels (particularly potassium) and blood pH levels should be monitored. # IV Compatibility There is limited information regarding IV Compatibility of Dorzolamide in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms Electrolyte imbalance, development of an acidotic state, and possible central nervous system effects may occur. Serum electrolyte levels (particularly potassium) and blood pH levels should be monitored. ## Chronic Overdose There is limited information regarding Chronic Overdose of Dorzolamide in the drug label. # Pharmacology ## Mechanism of Action - Carbonic anhydrase (CA) is an enzyme found in many tissues of the body including the eye. It catalyzes the reversible reaction involving the hydration of carbon dioxide and the dehydration of carbonic acid. In humans, carbonic anhydrase exists as a number of isoenzymes, the most active being carbonic anhydrase II (CA-II), found primarily in red blood cells (RBCs), but also in other tissues. Inhibition of carbonic anhydrase in the ciliary processes of the eye decreases aqueous humor secretion, presumably by slowing the formation of bicarbonate ions with subsequent reduction in sodium and fluid transport. The result is a reduction in intraocular pressure (IOP). - Dorzolamide HCl Ophthalmic Solution contains dorzolamide hydrochloride, an inhibitor of human carbonic anhydrase II. Following topical ocular administration, Dorzolamide HCl Ophthalmic Solution reduces elevated intraocular pressure. Elevated intraocular pressure is a major risk factor in the pathogenesis of optic nerve damage and glaucomatous visual field loss. ## Structure - Dorzolamide HCl Ophthalmic Solution is a carbonic anhydrase inhibitor formulated for topical ophthalmic use. - Dorzolamide hydrochloride USP is described chemically as: (4S-trans)-4-(ethylamino)-5,6-dihydro-6-methyl-4H-thienothiopyran-2-sulfonamide 7,7-dioxide monohydrochloride. Dorzolamide hydrochloride USP is optically active. Its empirical formula is C10H16N2O4S3HCl and its structural formula is: - Dorzolamide hydrochloride USP has a molecular weight of 360.9 and a melting point of about 264°C. It is a white to off-white, crystalline powder, which is soluble in water and slightly soluble in methanol and ethanol. - Dorzolamide HCl Ophthalmic Solution is supplied as a sterile, isotonic, buffered, slightly viscous, aqueous solution of dorzolamide hydrochloride USP. The pH of the solution is approximately 5.6, and the osmolarity is 260-330 mOsM. Each mL of Dorzolamide HCl Ophthalmic Solution 2% contains 20 mg dorzolamide (22.3 mg of dorzolamide hydrochloride USP). - Inactive ingredients are hydroxyethyl cellulose, mannitol, sodium citrate dihydrate, sodium hydroxide (to adjust pH) and water for injection. Benzalkonium chloride 0.0075% is added as a preservative. ## Pharmacodynamics - When topically applied, dorzolamide reaches the systemic circulation. To assess the potential for systemic carbonic anhydrase inhibition following topical administration, drug and metabolite concentrations in RBCs and plasma and carbonic anhydrase inhibition in RBCs were measured. - Dorzolamide accumulates in RBCs during chronic dosing as a result of binding to CA-II. The parent drug forms a single N-desethyl metabolite, which inhibits CA-II less potently than the parent drug but also inhibits CA-I. The metabolite also accumulates in RBCs where it binds primarily to CA-I. Plasma concentrations of dorzolamide and metabolite are generally below the assay limit of quantitation (15nM). - Dorzolamide binds moderately to plasma proteins (approximately 33%). Dorzolamide is primarily excreted unchanged in the urine; the metabolite also is excreted in urine. After dosing is stopped, dorzolamide washes out of RBCs nonlinearly, resulting in a rapid decline of drug concentration initially, followed by a slower elimination phase with a half-life of about four months. ## Pharmacokinetics - To simulate the systemic exposure after long-term topical ocular administration, dorzolamide was given orally to eight healthy subjects for up to 20 weeks. The oral dose of 2 mg b.i.d. closely approximates the amount of drug delivered by topical ocular administration of Dorzolamide HCl Ophthalmic Solution 2% t.i.d. Steady state was reached within 8 weeks. - The inhibition of CA-II and total carbonic anhydrase activities was below the degree of inhibition anticipated to be necessary for a pharmacological effect on renal function and respiration in healthy individuals. ## Nonclinical Toxicology - In a two-year study of dorzolamide hydrochloride administered orally to male and female Sprague-Dawley rats, urinary bladder papillomas were seen in male rats in the highest dosage group of 20 mg/kg/day (250 times the recommended human ophthalmic dose). Papillomas were not seen in rats given oral doses equivalent to approximately 12 times the recommended human ophthalmic dose. No treatment-related tumors were seen in a 21-month study in female and male mice given oral doses up to 75 mg/kg/day (~900 times the recommended human ophthalmic dose). - The increased incidence of urinary bladder papillomas seen in the high-dose male rats is a class effect of carbonic anhydrase inhibitors in rats. Rats are particularly prone to developing papillomas in response to foreign bodies, compounds causing crystalluria, and diverse sodium salts. - No changes in bladder urothelium were seen in dogs given oral dorzolamide hydrochloride for one year at 2 mg/kg/day (25 times the recommended human ophthalmic dose) or monkeys dosed topically to the eye at 0.4 mg/kg/day (~5 times the recommended human ophthalmic dose) for one year. - The following tests for mutagenic potential were negative: (1) in vivo (mouse) cytogenetic assay; (2) in vitro chromosomal aberration assay; (3) alkaline elution assay; (4) V-79 assay; and (5) Ames test. - In reproduction studies of dorzolamide hydrochloride in rats, there were no adverse effects on the reproductive capacity of males or females at doses up to 188 or 94 times, respectively, the recommended human ophthalmic dose. # Clinical Studies - The efficacy of Dorzolamide HCl Ophthalmic Solution was demonstrated in clinical studies in the treatment of elevated intraocular pressure in patients with glaucoma or ocular hypertension (baseline IOP ≥ 23 mmHg). The IOP-lowering effect of Dorzolamide HCl Ophthalmic Solution was approximately 3 to 5 mmHg throughout the day and this was consistent in clinical studies of up to one year duration. - The efficacy of Dorzolamide HCl Ophthalmic Solution when dosed less frequently than three times a day (alone or in combination with other products) has not been established. - In a one year clinical study, the effect of Dorzolamide HCl Ophthalmic Solution 2% t.i.d. on the corneal endothelium was compared to that of betaxolol ophthalmic solution b.i.d. and timolol maleate ophthalmic solution 0.5% b.i.d. There were no statistically significant differences between groups in corneal endothelial cell counts or in corneal thickness measurements. There was a mean loss of approximately 4% in the endothelial cell counts for each group over the one year period. # How Supplied - Dorzolamide HCl Ophthalmic Solution is a slightly opalescent, nearly colorless, slightly viscous solution. - Dorzolamide HCl Ophthalmic Solution is supplied in a white low-density polyethylene (LDPE) bottle with a controlled drop tip and orange polypropylene cap in the following sizes: - Store Dorzolamide HCl Ophthalmic Solution at 20°-25°C (68°-77°F). Protect from light. ## Storage There is limited information regarding Dorzolamide Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Dorzolamide HCl Ophthalmic Solution is a sulfonamide and although administered topically is absorbed systemically. Therefore the same types of adverse reactions that are attributable to sulfonamides may occur with topical administration. Patients should be advised that if serious or unusual reactions including severe skin reactions or signs of hypersensitivity occur, they should discontinue the use of the product. - Patients should be advised that if they develop any ocular reactions, particularly conjunctivitis and lid reactions, they should discontinue use and seek their physician's advice. - Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures. - Patients should also be instructed that ocular solutions, if handled improperly or if the tip of the dispensing container contacts the eye or surrounding structures, can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions. - Patients also should be advised that if they have ocular surgery or develop an intercurrent ocular condition (e.g., trauma or infection), they should immediately seek their physician's advice concerning the continued use of the present multidose container. - If more than one topical ophthalmic drug is being used, the drugs should be administered at least ten minutes apart. - Patients should be advised that Dorzolamide HCl Ophthalmic Solution contains benzalkonium chloride which may be absorbed by soft contact lenses. Contact lenses should be removed prior to administration of the solution. Lenses may be reinserted 15 minutes following Dorzolamide HCl Ophthalmic Solution administration. # Precautions with Alcohol Alcohol-Dorzolamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Trusopt Ocumeter # Look-Alike Drug Names N/A # Drug Shortage Status # Price	Dorzolamide Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gerald Chi # 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 Dorzolamide is a carbonic anhydrase inhibitor that is FDA approved for the {{{indicationType}}} of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma. Common adverse reactions include taste alteration, hypersensitivity reaction, punctate keratitis, and visual discomfort. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - One drop in the affected eye(s) three times daily ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Dorzolamide in adult patients. ### Non–Guideline-Supported Use - Dosing Information - One drop 1–4 hours after anterior segment laser surgery # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information - One drop in the affected eye(s) three times daily ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Dorzolamide in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Dorzolamide in pediatric patients. # Contraindications - Hypersensitivity - Dorzolamide HCl Ophthalmic Solution is contraindicated in patients who are hypersensitive to any component of this product. # Warnings - Dorzolamide HCl Ophthalmic Solution is a sulfonamide and, although administered topically, is absorbed systemically. Therefore, the same types of adverse reactions that are attributable to sulfonamides may occur with topical administration with Dorzolamide HCl Ophthalmic Solution. Fatalities have occurred, although rarely, due to severe reactions to sulfonamides including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Sensitization may recur when a sulfonamide is readministered irrespective of the route of administration. If signs of serious reactions or hypersensitivity occur, discontinue the use of this preparation. - The management of patients with acute angle-closure glaucoma requires therapeutic interventions in addition to ocular hypotensive agents. Dorzolamide HCl Ophthalmic Solution has not been studied in patients with acute angle-closure glaucoma. - Dorzolamide HCl Ophthalmic Solution has not been studied in patients with severe renal impairment (CrCl < 30 mL/min). Because Dorzolamide HCl Ophthalmic Solution and its metabolite are excreted predominantly by the kidney, Dorzolamide HCl Ophthalmic Solution is not recommended in such patients. - Dorzolamide HCl Ophthalmic Solution has not been studied in patients with hepatic impairment and should therefore be used with caution in such patients. - In clinical studies, local ocular adverse effects, primarily conjunctivitis and lid reactions, were reported with chronic administration of Dorzolamide HCl Ophthalmic Solution. Many of these reactions had the clinical appearance and course of an allergic-type reaction that resolved upon discontinuation of drug therapy. If such reactions are observed, Dorzolamide HCl Ophthalmic Solution should be discontinued and the patient evaluated before considering restarting the drug. - There is a potential for an additive effect on the known systemic effects of carbonic anhydrase inhibition in patients receiving an oral carbonic anhydrase inhibitor and Dorzolamide HCl Ophthalmic Solution. The concomitant administration of Dorzolamide HCl Ophthalmic Solution and oral carbonic anhydrase inhibitors is not recommended. - There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface. Choroidal detachment has been reported with administration of aqueous suppressant therapy (e.g., dorzolamide) after filtration procedures. - There is an increased potential for developing corneal edema in patients with low endothelial cell counts. Precautions should be used when prescribing Dorzolamide HCl Ophthalmic Solution to this group of patients. # Adverse Reactions ## Clinical Trials Experience - The most frequent adverse events associated with Dorzolamide Hydrochloride Ophthalmic Solution were ocular burning, stinging, or discomfort immediately following ocular administration (approximately one-third of patients). Approximately one-quarter of patients noted a bitter taste following administration. Superficial punctate keratitis occurred in 10-15% of patients and signs and symptoms of ocular allergic reaction in approximately 10%. Events occurring in approximately 1-5% of patients were conjunctivitis and lid reactions, blurred vision, eye redness, tearing, dryness, and photophobia. - Other ocular events and systemic events were reported infrequently, including headache, nausea, asthenia/fatigue; and, rarely, skin rashes, urolithiasis, and iridocyclitis. - In a 3-month, double-masked, active-treatment-controlled, multicenter study in pediatric patients, the adverse experience profile of Dorzolamide HCl Ophthalmic Solution was comparable to that seen in adult patients. ## Postmarketing Experience - The following adverse events have occurred either at low incidence (<1%) during clinical trials or have been reported during the use of Dorzolamide HCl Ophthalmic Solution in clinical practice where these events were reported voluntarily from a population of unknown size and frequency of occurrence cannot be determined precisely. They have been chosen for inclusion based on factors such as seriousness, frequency of reporting, possible causal connection to Dorzolamide HCl Ophthalmic Solution, or a combination of these factors: signs and symptoms of systemic allergic reactions including angioedema, bronchospasm, pruritus, and urticaria; Stevens-Johnson syndrome and toxic epidermal necrolysis; dizziness, paresthesia; ocular pain, transient myopia, choroidal detachment following filtration surgery, eyelid crusting; dyspnea; contact dermatitis, epistaxis, dry mouth and throat irritation. # Drug Interactions - Salicylate - Although acid-base and electrolyte disturbances were not reported in the clinical trials with Dorzolamide HCl Ophthalmic Solution, these disturbances have been reported with oral carbonic anhydrase inhibitors and have, in some instances, resulted in drug interactions (e.g., toxicity associated with high-dose salicylate therapy). Therefore, the potential for such drug interactions should be considered in patients receiving Dorzolamide HCl Ophthalmic Solution. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Developmental toxicity studies with dorzolamide hydrochloride in rabbits at oral doses of ≥ 2.5 mg/kg/day (31 times the recommended human ophthalmic dose) revealed malformations of the vertebral bodies. These malformations occurred at doses that caused metabolic acidosis with decreased body weight gain in dams and decreased fetal weights. No treatment-related malformations were seen at 1.0 mg/kg/day (13 times the recommended human ophthalmic dose). There are no adequate and well-controlled studies in pregnant women. Dorzolamide HCl Ophthalmic Solution 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 B3 There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dorzolamide in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Dorzolamide during labor and delivery. ### Nursing Mothers - In a study of dorzolamide hydrochloride in lactating rats, decreases in body weight gain of 5 to 7% in offspring at an oral dose of 7.5 mg/kg/day (94 times the recommended human ophthalmic dose) were seen during lactation. A slight delay in postnatal development (incisor eruption, vaginal canalization and eye openings), secondary to lower fetal body weight, was noted. - 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 Dorzolamide HCl Ophthalmic Solution, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - Safety and IOP-lowering effects of Dorzolamide HCl Ophthalmic Solution have been demonstrated in pediatric patients in a 3-month, multicenter, double-masked, active-treatment-controlled trial. ### Geriatic Use - No overall differences in safety or effectiveness have been observed between elderly and younger patients. ### Gender There is no FDA guidance on the use of Dorzolamide with respect to specific gender populations. ### Race There is no FDA guidance on the use of Dorzolamide with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Dorzolamide in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Dorzolamide in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Dorzolamide in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Dorzolamide in patients who are immunocompromised. # Administration and Monitoring ### Administration Ophthalmic ### Monitoring Serum electrolyte levels (particularly potassium) and blood pH levels should be monitored. # IV Compatibility There is limited information regarding IV Compatibility of Dorzolamide in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms Electrolyte imbalance, development of an acidotic state, and possible central nervous system effects may occur. Serum electrolyte levels (particularly potassium) and blood pH levels should be monitored. ## Chronic Overdose There is limited information regarding Chronic Overdose of Dorzolamide in the drug label. # Pharmacology ## Mechanism of Action - Carbonic anhydrase (CA) is an enzyme found in many tissues of the body including the eye. It catalyzes the reversible reaction involving the hydration of carbon dioxide and the dehydration of carbonic acid. In humans, carbonic anhydrase exists as a number of isoenzymes, the most active being carbonic anhydrase II (CA-II), found primarily in red blood cells (RBCs), but also in other tissues. Inhibition of carbonic anhydrase in the ciliary processes of the eye decreases aqueous humor secretion, presumably by slowing the formation of bicarbonate ions with subsequent reduction in sodium and fluid transport. The result is a reduction in intraocular pressure (IOP). - Dorzolamide HCl Ophthalmic Solution contains dorzolamide hydrochloride, an inhibitor of human carbonic anhydrase II. Following topical ocular administration, Dorzolamide HCl Ophthalmic Solution reduces elevated intraocular pressure. Elevated intraocular pressure is a major risk factor in the pathogenesis of optic nerve damage and glaucomatous visual field loss. ## Structure - Dorzolamide HCl Ophthalmic Solution is a carbonic anhydrase inhibitor formulated for topical ophthalmic use. - Dorzolamide hydrochloride USP is described chemically as: (4S-trans)-4-(ethylamino)-5,6-dihydro-6-methyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide monohydrochloride. Dorzolamide hydrochloride USP is optically active. Its empirical formula is C10H16N2O4S3•HCl and its structural formula is: - Dorzolamide hydrochloride USP has a molecular weight of 360.9 and a melting point of about 264°C. It is a white to off-white, crystalline powder, which is soluble in water and slightly soluble in methanol and ethanol. - Dorzolamide HCl Ophthalmic Solution is supplied as a sterile, isotonic, buffered, slightly viscous, aqueous solution of dorzolamide hydrochloride USP. The pH of the solution is approximately 5.6, and the osmolarity is 260-330 mOsM. Each mL of Dorzolamide HCl Ophthalmic Solution 2% contains 20 mg dorzolamide (22.3 mg of dorzolamide hydrochloride USP). - Inactive ingredients are hydroxyethyl cellulose, mannitol, sodium citrate dihydrate, sodium hydroxide (to adjust pH) and water for injection. Benzalkonium chloride 0.0075% is added as a preservative. ## Pharmacodynamics - When topically applied, dorzolamide reaches the systemic circulation. To assess the potential for systemic carbonic anhydrase inhibition following topical administration, drug and metabolite concentrations in RBCs and plasma and carbonic anhydrase inhibition in RBCs were measured. - Dorzolamide accumulates in RBCs during chronic dosing as a result of binding to CA-II. The parent drug forms a single N-desethyl metabolite, which inhibits CA-II less potently than the parent drug but also inhibits CA-I. The metabolite also accumulates in RBCs where it binds primarily to CA-I. Plasma concentrations of dorzolamide and metabolite are generally below the assay limit of quantitation (15nM). - Dorzolamide binds moderately to plasma proteins (approximately 33%). Dorzolamide is primarily excreted unchanged in the urine; the metabolite also is excreted in urine. After dosing is stopped, dorzolamide washes out of RBCs nonlinearly, resulting in a rapid decline of drug concentration initially, followed by a slower elimination phase with a half-life of about four months. ## Pharmacokinetics - To simulate the systemic exposure after long-term topical ocular administration, dorzolamide was given orally to eight healthy subjects for up to 20 weeks. The oral dose of 2 mg b.i.d. closely approximates the amount of drug delivered by topical ocular administration of Dorzolamide HCl Ophthalmic Solution 2% t.i.d. Steady state was reached within 8 weeks. - The inhibition of CA-II and total carbonic anhydrase activities was below the degree of inhibition anticipated to be necessary for a pharmacological effect on renal function and respiration in healthy individuals. ## Nonclinical Toxicology - In a two-year study of dorzolamide hydrochloride administered orally to male and female Sprague-Dawley rats, urinary bladder papillomas were seen in male rats in the highest dosage group of 20 mg/kg/day (250 times the recommended human ophthalmic dose). Papillomas were not seen in rats given oral doses equivalent to approximately 12 times the recommended human ophthalmic dose. No treatment-related tumors were seen in a 21-month study in female and male mice given oral doses up to 75 mg/kg/day (~900 times the recommended human ophthalmic dose). - The increased incidence of urinary bladder papillomas seen in the high-dose male rats is a class effect of carbonic anhydrase inhibitors in rats. Rats are particularly prone to developing papillomas in response to foreign bodies, compounds causing crystalluria, and diverse sodium salts. - No changes in bladder urothelium were seen in dogs given oral dorzolamide hydrochloride for one year at 2 mg/kg/day (25 times the recommended human ophthalmic dose) or monkeys dosed topically to the eye at 0.4 mg/kg/day (~5 times the recommended human ophthalmic dose) for one year. - The following tests for mutagenic potential were negative: (1) in vivo (mouse) cytogenetic assay; (2) in vitro chromosomal aberration assay; (3) alkaline elution assay; (4) V-79 assay; and (5) Ames test. - In reproduction studies of dorzolamide hydrochloride in rats, there were no adverse effects on the reproductive capacity of males or females at doses up to 188 or 94 times, respectively, the recommended human ophthalmic dose. # Clinical Studies - The efficacy of Dorzolamide HCl Ophthalmic Solution was demonstrated in clinical studies in the treatment of elevated intraocular pressure in patients with glaucoma or ocular hypertension (baseline IOP ≥ 23 mmHg). The IOP-lowering effect of Dorzolamide HCl Ophthalmic Solution was approximately 3 to 5 mmHg throughout the day and this was consistent in clinical studies of up to one year duration. - The efficacy of Dorzolamide HCl Ophthalmic Solution when dosed less frequently than three times a day (alone or in combination with other products) has not been established. - In a one year clinical study, the effect of Dorzolamide HCl Ophthalmic Solution 2% t.i.d. on the corneal endothelium was compared to that of betaxolol ophthalmic solution b.i.d. and timolol maleate ophthalmic solution 0.5% b.i.d. There were no statistically significant differences between groups in corneal endothelial cell counts or in corneal thickness measurements. There was a mean loss of approximately 4% in the endothelial cell counts for each group over the one year period. # How Supplied - Dorzolamide HCl Ophthalmic Solution is a slightly opalescent, nearly colorless, slightly viscous solution. - Dorzolamide HCl Ophthalmic Solution is supplied in a white low-density polyethylene (LDPE) bottle with a controlled drop tip and orange polypropylene cap in the following sizes: - Store Dorzolamide HCl Ophthalmic Solution at 20°-25°C (68°-77°F). Protect from light. ## Storage There is limited information regarding Dorzolamide Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Dorzolamide HCl Ophthalmic Solution is a sulfonamide and although administered topically is absorbed systemically. Therefore the same types of adverse reactions that are attributable to sulfonamides may occur with topical administration. Patients should be advised that if serious or unusual reactions including severe skin reactions or signs of hypersensitivity occur, they should discontinue the use of the product. - Patients should be advised that if they develop any ocular reactions, particularly conjunctivitis and lid reactions, they should discontinue use and seek their physician's advice. - Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures. - Patients should also be instructed that ocular solutions, if handled improperly or if the tip of the dispensing container contacts the eye or surrounding structures, can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions. - Patients also should be advised that if they have ocular surgery or develop an intercurrent ocular condition (e.g., trauma or infection), they should immediately seek their physician's advice concerning the continued use of the present multidose container. - If more than one topical ophthalmic drug is being used, the drugs should be administered at least ten minutes apart. - Patients should be advised that Dorzolamide HCl Ophthalmic Solution contains benzalkonium chloride which may be absorbed by soft contact lenses. Contact lenses should be removed prior to administration of the solution. Lenses may be reinserted 15 minutes following Dorzolamide HCl Ophthalmic Solution administration. # Precautions with Alcohol Alcohol-Dorzolamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Trusopt Ocumeter[1] # Look-Alike Drug Names N/A[2] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Dorzolamide
4aefc45c750031d7dcacd0224ac908f6433cb1c7	wikidoc	Double bind	Double bind Double bind is a communicative situation where a person receives different or contradictory messages. The term, coined by the anthropologist Gregory Bateson and his colleagues (including Don D. Jackson, Jay Haley and John H. Weakland), attempts to account for the onset of schizophrenia without simply assuming an organic brain dysfunction. Today it is more importantly understood as an example of Bateson's approach to the complexities of communication. The phenomenon itself was functionally observed in its negative sense, and utilised in a therapeutic context, by Milton H. Erickson. The double bind is based on paradox turned to contradiction. # Explanation The double bind is often misunderstood to be a simple Catch-22 situation, where the victim is trapped by two conflicting demands. While it is true that at the core of the double bind are two conflicting demands, the difference lies in how they are imposed upon the victim, what the victim's understanding of the situation is, and who imposes these demands upon the victim. Unlike the usual no-win situation, the victim is largely unaware of the exact nature of the paradoxical situation he or she is in. This is because a demand is imposed upon them by someone they regard with respect, and the demand itself is inherently impossible to fulfill. Bateson defines the double bind as follows (paraphrased): - The situation involves two or more persons, one of whom is designated, for the purposes of definition, as the "victim". The others are people who are in some way in a higher position to the victim, for example a figure of authority such as a parent whom the victim respects. - Repeated experience. The double bind is a recurrent theme in the experience of the victim and as such cannot be constituted as a single traumatic experience. - A primary injunction is imposed upon the victim by the other person in one of two forms: (a) Do "X", or I will punish you. (b) Do not do "X", or I will punish you. The punishment is assumed to be either the withdrawing of love, the expression of hate and anger, or abandonment resulting from the authority figure's expression of extreme helplessness. - A secondary injunction is imposed upon the victim that conflicts with the first at a higher and more abstract level. For example, "Do what I told you but only do it because you want to." However, it is not necessary that this injunction be expressed verbally. - If necessary, a tertiary injunction is imposed upon the victim to prevent them from escaping the dilemma. - Finally, Bateson states that the complete list of the previous requirements may be unnecessary in the event that the victim is already viewing their world in double bind patterns. Bateson goes on to give the general characteristics of such a relationship: When the victim is involved in an intense relationship; that is, a relationship in which he feels it is vitally important that he discriminate accurately what sort of message is being communicated so that he may respond appropriately. And, the victim is caught in a situation in which the other person in the relationship is expressing two orders of message and one of these denies the other. And, the victim is unable to comment on the messages being expressed to correct his discrimination of what order of message to respond to, i.e., he cannot make a metacommunicative statement. - When the victim is involved in an intense relationship; that is, a relationship in which he feels it is vitally important that he discriminate accurately what sort of message is being communicated so that he may respond appropriately. - And, the victim is caught in a situation in which the other person in the relationship is expressing two orders of message and one of these denies the other. - And, the victim is unable to comment on the messages being expressed to correct his discrimination of what order of message to respond to, i.e., he cannot make a metacommunicative statement. Thus the essence of a double-bind is two conflicting demands, neither of which can be ignored, which leave the victim torn both ways in such a way that whichever demand they try to meet, the other demand cannot be met. "I must do it but I can't do it" is a typical description of the double-bind experience. For a double bind to be effective, the victim cannot plainly see that the demand placed on them by the primary injunction is in direct conflict with the secondary injunction. In this sense the double bind differentiates itself from a simple contradictory Catch-22 to a more inexpressible internal conflict where the victim vigorously wants to meet the demands of the primary injunction but fails each time because the victim fails to see that the situation is completely incompatible with the demands of the secondary injunction. Thus victims may express feelings of extreme anxiety in such a situation as they attempt to fulfill the demands of the primary injunction, but are met with obvious contradictions in their actions. For example, a common double bind in western culture are the marriage vows taken by the bride and groom when they make an oath to love each other until death. In this situation, the primary injunction is the oath itself, and the secondary injunction is that which is imposed onto them by their society, that their love must be true. Thus a conflict arises in their relationship if either party falls out of love with the other, but attempts to fulfill their obligation to the oath. The more he or she tries to love the other, the less genuine their love is. The double bind was originally presented as a situation that could possibly lead to schizophrenia if imposed upon young children, or simply those with unstable and weak personalities. Creating a situation where the victim could not make any comment or "metacommunicative statement" about their dilemma would, in theory, escalate their state of mental anxiety. Today, it is more important as an example of Bateson's approach to the complexities of communication. The solution to a double-bind is to place the problem in a larger context, a state Bateson identified as Learning III, a step up from Learning II, which requires only learned responses to reward/consequence situations. In Learning III, the double bind is contextualized and understood as an impossible, no-win scenario. Bateson maintained that in the case of the schizophrenic, the double bind is presented continually and habitually within the family context. By the time the child is old enough to have identified the double bind situation, it has already been internalized and the child is unable to confront it. The solution, then, is to create an escape from the conflicting logical demands of the double bind in the world of the delusional system. # The Double Bind in Evolution Having proposed the double bind theory, Bateson went on to be dismayed that it was only considered in the context of psychiatry. Bateson recognized that the double bind also plays a role in evolution, for example: "Humans disagree about important things like politics and religion because if there was unanimous agreement about those important things, humans would no longer be human and humanity as we know it would become extinct." This may sound quite strange, but it is quite logical - if everything is 'good' how can 'great' become successful without making 'good' worse/obsolete? To put it another way, whatever pattern makes the fit survive is also the thing which (ultimately) must doom the pattern to extinction. # Usage in Zen Buddhism According to philosopher and theologian Alan Watts, the double bind has long been used in Zen Buddhism as a therapeutic tool. The Zen Master purposefully imposes the double bind upon his students (through various "skillful means", called upaya) in hopes that they achieve enlightenment (satori). One of the most prominent techniques used by Zen Masters (especially those of the Rinzai school) is called the koan, in which the master gives his or her students a question and instructs them to pour all their mental energies into finding the answer to it. As an example of a koan, a student can be asked to present to the master their genuine self, "Show me who you really are." According to Watts, the student will eventually realize that there's nothing they can do, and also nothing they can not do, to present their true self, and thus they truly learn the Buddhist concept of anatman (non-self) via reductio ad absurdum. # Phrase examples - Mother telling her son: "You must love me" - Zen koan: "Be genuine" or "Who are you?" - "You must be free" - Mother to son: "Show your relatives how you play" - "You should enjoy playing with the children, just like other fathers" # Criticism Gregory Bateson's double bind theory is very complex and has only been partly tested; there are gaps in the current psychological and experimental evidence that is required to establish causation. Current subjective assessments of individuals, faced with making a serious decision while exposed to conflicting messages, report feelings of anxiety. It is argued that—if the double bind theory is indeed to overturn findings that point to a genetic basis for schizophrenia—more comprehensive psychological and experimental studies are needed, with different family types and across various family contexts. The current understanding of schizophrenia takes into account a complex interaction of genetic, neurological as well as emotional stressors including family interaction. # Neuro-linguistic programming The field of neuro-linguistic programming also makes use of the double bind. Grinder and Bandler asserted that a message could be constructed with multiple messages. While the recipient of the message is given the impression of choice, both options have the same outcome at a higher level of intention. This has application in both sales and therapy. A salesperon might ask "Would you like to pay cash or by credit card?" Both outcomes presuppose that the person will make the purchase, whereas the third option, that of not buying, is intentionally excluded from the list of choices. The well known "heads I win, tails you lose" is an example of this. In selling, the double bind is commonly used for closing through the phrase. A therapist might wish to create a message similar in structure but both options have therapeutic consequences.	Double bind Double bind is a communicative situation where a person receives different or contradictory messages. The term, coined by the anthropologist Gregory Bateson and his colleagues (including Don D. Jackson, Jay Haley and John H. Weakland), attempts to account for the onset of schizophrenia without simply assuming an organic brain dysfunction.[1][2] Today it is more importantly understood as an example of Bateson's approach to the complexities of communication. The phenomenon itself was functionally observed in its negative sense, and utilised in a therapeutic context, by Milton H. Erickson. The double bind is based on paradox turned to contradiction. # Explanation The double bind is often misunderstood to be a simple Catch-22 situation, where the victim is trapped by two conflicting demands. While it is true that at the core of the double bind are two conflicting demands, the difference lies in how they are imposed upon the victim, what the victim's understanding of the situation is, and who imposes these demands upon the victim. Unlike the usual no-win situation, the victim is largely unaware of the exact nature of the paradoxical situation he or she is in. This is because a demand is imposed upon them by someone they regard with respect, and the demand itself is inherently impossible to fulfill. Bateson defines the double bind as follows (paraphrased): - The situation involves two or more persons, one of whom is designated, for the purposes of definition, as the "victim". The others are people who are in some way in a higher position to the victim, for example a figure of authority such as a parent whom the victim respects. - Repeated experience. The double bind is a recurrent theme in the experience of the victim and as such cannot be constituted as a single traumatic experience. - A primary injunction is imposed upon the victim by the other person in one of two forms: (a) Do "X", or I will punish you. (b) Do not do "X", or I will punish you. The punishment is assumed to be either the withdrawing of love, the expression of hate and anger, or abandonment resulting from the authority figure's expression of extreme helplessness. - A secondary injunction is imposed upon the victim that conflicts with the first at a higher and more abstract level. For example, "Do what I told you but only do it because you want to." However, it is not necessary that this injunction be expressed verbally. - If necessary, a tertiary injunction is imposed upon the victim to prevent them from escaping the dilemma. - Finally, Bateson states that the complete list of the previous requirements may be unnecessary in the event that the victim is already viewing their world in double bind patterns. Bateson goes on to give the general characteristics of such a relationship: When the victim is involved in an intense relationship; that is, a relationship in which he feels it is vitally important that he discriminate accurately what sort of message is being communicated so that he may respond appropriately. And, the victim is caught in a situation in which the other person in the relationship is expressing two orders of message and one of these denies the other. And, the victim is unable to comment on the messages being expressed to correct his discrimination of what order of message to respond to, i.e., he cannot make a metacommunicative statement. - When the victim is involved in an intense relationship; that is, a relationship in which he feels it is vitally important that he discriminate accurately what sort of message is being communicated so that he may respond appropriately. - And, the victim is caught in a situation in which the other person in the relationship is expressing two orders of message and one of these denies the other. - And, the victim is unable to comment on the messages being expressed to correct his discrimination of what order of message to respond to, i.e., he cannot make a metacommunicative statement. Thus the essence of a double-bind is two conflicting demands, neither of which can be ignored, which leave the victim torn both ways in such a way that whichever demand they try to meet, the other demand cannot be met. "I must do it but I can't do it" is a typical description of the double-bind experience. For a double bind to be effective, the victim cannot plainly see that the demand placed on them by the primary injunction is in direct conflict with the secondary injunction. In this sense the double bind differentiates itself from a simple contradictory Catch-22 to a more inexpressible internal conflict where the victim vigorously wants to meet the demands of the primary injunction but fails each time because the victim fails to see that the situation is completely incompatible with the demands of the secondary injunction. Thus victims may express feelings of extreme anxiety in such a situation as they attempt to fulfill the demands of the primary injunction, but are met with obvious contradictions in their actions. For example, a common double bind in western culture are the marriage vows taken by the bride and groom when they make an oath to love each other until death. In this situation, the primary injunction is the oath itself, and the secondary injunction is that which is imposed onto them by their society, that their love must be true. Thus a conflict arises in their relationship if either party falls out of love with the other, but attempts to fulfill their obligation to the oath. The more he or she tries to love the other, the less genuine their love is. The double bind was originally presented as a situation that could possibly lead to schizophrenia if imposed upon young children, or simply those with unstable and weak personalities. Creating a situation where the victim could not make any comment or "metacommunicative statement" about their dilemma would, in theory, escalate their state of mental anxiety. Today, it is more important as an example of Bateson's approach to the complexities of communication. The solution to a double-bind is to place the problem in a larger context, a state Bateson identified as Learning III, a step up from Learning II, which requires only learned responses to reward/consequence situations. In Learning III, the double bind is contextualized and understood as an impossible, no-win scenario. Bateson maintained that in the case of the schizophrenic, the double bind is presented continually and habitually within the family context. By the time the child is old enough to have identified the double bind situation, it has already been internalized and the child is unable to confront it. The solution, then, is to create an escape from the conflicting logical demands of the double bind in the world of the delusional system. # The Double Bind in Evolution Having proposed the double bind theory, Bateson went on to be dismayed that it was only considered in the context of psychiatry. Bateson recognized that the double bind also plays a role in evolution, for example: "Humans disagree about important things like politics and religion because if there was unanimous agreement about those important things, humans would no longer be human and humanity as we know it would become extinct." This may sound quite strange, but it is quite logical - if everything is 'good' how can 'great' become successful without making 'good' worse/obsolete? To put it another way, whatever pattern makes the fit survive is also the thing which (ultimately) must doom the pattern to extinction. # Usage in Zen Buddhism According to philosopher and theologian Alan Watts, the double bind has long been used in Zen Buddhism as a therapeutic tool. The Zen Master purposefully imposes the double bind upon his students (through various "skillful means", called upaya) in hopes that they achieve enlightenment (satori). One of the most prominent techniques used by Zen Masters (especially those of the Rinzai school) is called the koan, in which the master gives his or her students a question and instructs them to pour all their mental energies into finding the answer to it. As an example of a koan, a student can be asked to present to the master their genuine self, "Show me who you really are." According to Watts, the student will eventually realize that there's nothing they can do, and also nothing they can not do, to present their true self, and thus they truly learn the Buddhist concept of anatman (non-self) via reductio ad absurdum. # Phrase examples - Mother telling her son: "You must love me" - Zen koan: "Be genuine" or "Who are you?" - "You must be free" - Mother to son: "Show your relatives how you play" - "You should enjoy playing with the children, just like other fathers" # Criticism Gregory Bateson's double bind theory is very complex and has only been partly tested; there are gaps in the current psychological and experimental evidence that is required to establish causation. Current subjective assessments of individuals, faced with making a serious decision while exposed to conflicting messages, report feelings of anxiety. It is argued that—if the double bind theory is indeed to overturn findings that point to a genetic basis for schizophrenia—more comprehensive psychological and experimental studies are needed, with different family types and across various family contexts.[3] The current understanding of schizophrenia takes into account a complex interaction of genetic, neurological as well as emotional stressors including family interaction. # Neuro-linguistic programming The field of neuro-linguistic programming also makes use of the double bind. Grinder and Bandler asserted that a message could be constructed with multiple messages. While the recipient of the message is given the impression of choice, both options have the same outcome at a higher level of intention.[4] This has application in both sales and therapy. A salesperon might ask "Would you like to pay cash or by credit card?" Both outcomes presuppose that the person will make the purchase, whereas the third option, that of not buying, is intentionally excluded from the list of choices. The well known "heads I win, tails you lose" is an example of this. In selling, the double bind is commonly used for closing through the phrase. A therapist might wish to create a message similar in structure but both options have therapeutic consequences.	https://www.wikidoc.org/index.php/Double_bind

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