Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3649
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Sotret (Capsule, Gelatin Coated)
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Sotret should be administered with a meal (see PRECAUTIONS: Information for Patients). The recommended dosage range for Sotret is 0.5 to 1.0 mg/kg/day given in two divided doses with food for 15 to 20 weeks. In studies comparing 0.1, 0.5, and 1 mg/kg/day,it was found that all dosages provided initial clearing of disease, but there was a greater need for retreatment with the lower dosages. During treatment, the dose may be adjusted according to response of the disease and/or the appearance of clinical side effects���some of which may be dose related. Adult patients whose disease is very severe with scarring or is primarily manifested on the trunk may require dose adjustments up to 2.0 mg/kg/day, as tolerated. Failure to take Sotret with food will significantly decrease absorption. Before upward dose adjustments are made, the patients should be questioned about their compliance with food instructions. The safety of once daily dosing with Sotret has not been established. Once daily dosing is not recommended. If the total nodule count has been reduced by more than 70% prior to completing 15 to 20 weeks of treatment, the drug may be discontinued. After a period of 2 months or more off therapy, and if warranted by persistent or recurring severe nodular acne, a second course of therapy may be initiated. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth. Long-term use of Sotret, even in low doses, has not been studied, and is not recommended. It is important that Sotret be given at the recommended doses for no longer than the recommended duration. The effect of long-term use of Sotret on bone loss is unknown (see WARNINGS: Skeletal: Bone Mineral Density, Hyperostosis, and Premature Epiphyseal Closure). Contraceptive measures must be followed for any subsequent course of therapy (see PRECAUTIONS). Table 3 Sotret Dosing by Body Weight (Based on Administration With Food)
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Isotretinoin, a retinoid, is available as Sotret in 10 mg, 20 mg, 30 mg, and 40 mg soft gelatin capsules for oral administration. Each capsule contains butylated hydroxyanisole, edetate disodium, hydrogenated soybean oil, hydrogenated vegetable oil, iron oxide black, soybean oil and white wax. Gelatin capsules contain glycerin and parabens (methyl and propyl), with the following dye systems: 10 mg - iron oxide (red) and titanium dioxide; 20 mg - FD&C Red No. 3, FD&C Blue No. 1, and titanium dioxide; 30 mg - FD&C Yellow No. 6, and titanium dioxide; 40 mg - FD&C Yellow No. 6, D&C Yellow No. 10, and titanium dioxide. Chemically, isotretinoin is 13-cis-retinoic acid and is related to both retinoic acid and retinol (vitamin A). It is a yellow to orange crystalline powder with a molecular weight of 300.44. The structural formula is:
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Isotretinoin is a retinoid, which when administered in pharmacologic dosages of 0.5 to 1 mg/kg/day (see DOSAGE AND ADMINISTRATION), inhibits sebaceous gland function and keratinization. The exact mechanism of action of isotretinoin is unknown.<br/>Nodular Acne: Clinical improvement in nodular acne patients occurs in association with a reduction in sebum secretion. The decrease in sebum secretion is temporary and is related to the dose and duration of treatment with Sotret, and reflects a reduction in sebaceous gland size and an inhibition of sebaceous gland differentiation.<br/>Pharmacokinetics:<br/>Absorption: Due to its high lipophilicity, oral absorption of isotretinoin is enhanced when given with a high-fat meal. In a crossover study, 74 healthy adult subjects received a single 80 mg oral dose (2 x 40 mg capsules) of isotretinoin capsules under fasted and fed conditions. Both peak plasma concentration (C) and the total exposure (AUC) of isotretinoin were more than doubled following a standardized high-fat meal when compared with isotretinoin capsules given under fasted conditions (see Table 2). The observed elimination half-life was unchanged. This lack of change in half-life suggests that food increases the bioavailability of isotretinoin without altering its disposition. The time to peak concentration (T) was also increased with food and may be related to a longer absorption phase. Therefore, Sotret capsules should always be taken with food (see DOSAGE AND ADMINISTRATION). Clinical studies have shown that there is no difference in the pharmacokinetics of isotretinoin between patients with nodular acne and healthy subjects with normal skin. Table 2 Pharmacokinetic Parameters of Isotretinoin Mean (%CV), N=74<br/>Distribution: Isotretinoin is more than 99.9% bound to plasma proteins, primarily albumin.<br/>Metabolism: Following oral administration of isotretinoin, at least three metabolites have been identified in human plasma: 4-oxo-isotretinoin, retinoic acid (tretinoin), and 4-oxo-retinoic acid (4-oxo-tretinoin). Retinoic acid and 13-cis-retinoic acid are geometric isomers and show reversible interconversion. The administration of one isomer will give rise to the other. Isotretinoin is also irreversibly oxidized to 4-oxo-isotretinoin, which forms its geometric isomer 4-oxo-tretinoin. After a single 80 mg oral dose of isotretinoin capsules to 74 healthy adult subjects, concurrent administration of food increased the extent of formation of all metabolites in plasma when compared to the extent of formation under fasted conditions. All of these metabolites possess retinoid activity that is in some in vitro models more than that of the parent isotretinoin. However, the clinical significance of these models is unknown. After multiple oral dose administration of isotretinoin to adult cystic acne patients (���18 years), the exposure of patients to 4-oxo-isotretinoin at steady-state under fasted and fed conditions was approximately 3.4 times higher than that of isotretinoin. In vitro studies indicate that the primary P450 isoforms involved in isotretinoin metabolism are 2C8, 2C9, 3A4, and 2B6. Isotretinoin and its metabolites are further metabolized into conjugates, which are then excreted in urine and feces.<br/>Elimination: Following oral administration of an 80 mg dose ofC-isotretinoin as a liquid suspension,C-activity in blood declined with a half-life of 90 hours. The metabolites of isotretinoin and any conjugates are ultimately excreted in the feces and urine in relatively equal amounts (total of 65% to 83%). After a single 80 mg oral dose of isotretinoin to 74 healthy adult subjects under fed conditions, the mean��SD elimination half-lives (t) of isotretinoin and 4-oxo-isotretinoin were 21.0��8.2 hours and 24.0��5.3 hours, respectively. After both single and multiple doses, the observed accumulation ratios of isotretinoin ranged from 0.90 to 5.43 in patients with cystic acne.<br/>Special Patient Populations:<br/>Pediatric Patients: The pharmacokinetics of isotretinoin were evaluated after single and multiple doses in 38 pediatric patients (12 to 15 years) and 19 adult patients (���18 years) who received isotretinoin capsules for the treatment of severe recalcitrant nodular acne. In both age groups, 4-oxo-isotretinoin was the major metabolite; tretinoin and 4-oxo-tretinoin were also observed. The dose-normalized pharmacokinetic parameters for isotretinoin following single and multiple doses are summarized in Table 3 for pediatric patients. There were no statistically significant differences in the pharmacokinetics of isotretinoin between pediatric and adult patients. Table 3. Pharmacokinetic Parameters of Isotretinoin Following Single and Multiple Dose Administration in Pediatric Patients, 12 to 15 Years of Age Mean (��SD), N = 38* In pediatric patients (12 to 15 years), the mean��SD elimination half-lives (t) of isotretinoin and 4- oxo-isotretinoin were 15.7��5.1 hours and 23.1��5.7 hours, respectively. The accumulation ratios of isotretinoin ranged from 0.46 to 3.65 for pediatric patients.
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Pregnancy: Category X.: See Boxed CONTRAINDICATIONS AND WARNINGS.<br/>Allergic Reactions: Sotret is contraindicated in patients who are hypersensitive to this medication or to any of its components. Sotret should not be given to patients who are sensitive to parabens, which are used as preservatives in the gelatin capsule (see PRECAUTIONS: Hypersensitivity).
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Soft gelatin capsules, 10 mg (light pink), imprinted���5R���. Boxes of 30 containing 3 Prescription Packs of 10 capsules (NDC 10631-584-31) Boxes of 100 containing 10 Prescription Packs of 10 capsules (NDC 10631-584-77) Soft gelatin capsules, 20 mg (maroon), imprinted���6R���. Boxes of 30 containing 3 Prescription Packs of 10 capsules (NDC 10631-585-31) Boxes of 100 containing 10 Prescription Packs of 10 capsules (NDC 10631-585-77) Soft gelatin capsules, 30 mg (golden yellow), imprinted���8R���. Boxes of 30 containing 3 Prescription Packs of 10 capsules (NDC 10631-447-31) Boxes of 100 containing 10 Prescription Packs of 10 capsules (NDC 10631-447-77) Soft gelatin capsules, 40 mg (yellow), imprinted���7R���. Boxes of 30 containing 3 Prescription Packs of 10 capsules (NDC 10631-586-31) Boxes of 100 containing 10 Prescription Packs of 10 capsules (NDC 10631-586-77) Store at 20 - 25��C (68 - 77��F). (See USP Controlled Room Temperature). Protect from light.
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CONTRAINDICATIONS AND WARNINGS: Sotret must not be used by female patients who are or may become pregnant. There is an extremely high risk that severe birth defects will result if pregnancy occurs while taking isotretinoin capsules in any amount, even for short periods of time. Potentially any fetus exposed during pregnancy can be affected. There are no accurate means of determining whether an exposed fetus has been affected. Birth defects which have been documented following isotretinoin exposure include abnormalities of the face, eyes, ears, skull, central nervous system, cardiovascular system, and thymus and parathyroid glands. Cases of IQ scores less than 85 with or without other abnormalities have been reported. There is an increased risk of spontaneous abortion, and premature births have been reported. Documented external abnormalities include: skull abnormality; ear abnormalities (including anotia, micropinna, small or absent external auditory canals); eye abnormalities (including microphthalmia); facial dysmorphia; cleft palate. Documented internal abnormalities include: CNS abnormalities (including cerebral abnormalities, cerebellar malformation, hydrocephalus, microcephaly, cranial nerve deficit); cardiovascular abnormalities; thymus gland abnormality; parathyroid hormone deficiency. Insome cases death has occurred with certain of the abnormalities previously noted. If pregnancy does occur during treatment of a female patient who is taking isotretinoin capsules, isotretinoin capsules must be discontinued immediately and she should be referred to an Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation and counseling. Special Prescribing Requirements Because of isotretinoin's teratogenicity and to minimize fetal exposure, Sotret is approved for marketing only under a special restricted distribution program approved by the Food and Drug Administration. This program is called iPLEDGE���. Sotret must only be prescribed by prescribers who are registered and activated with the iPLEDGE program. Sotret capsules must only be dispensed by a pharmacy registered and activated with iPLEDGE, and must only be dispensed to patients who are registered and meet all the requirements of iPLEDGE (see PRECAUTIONS). Table 1 Monthly Required iPLEDGE Interactions
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dailymed-ingredient:butylated_hydroxyanisole,
dailymed-ingredient:edetate_disodium,
dailymed-ingredient:glycerin,
dailymed-ingredient:hydrogenated_soybean_oil,
dailymed-ingredient:hydrogenated_vegetable_oil,
dailymed-ingredient:iron_oxide_(red),
dailymed-ingredient:iron_oxide_black,
dailymed-ingredient:parabens_(methyl_and_propyl),
dailymed-ingredient:soybean_oil,
dailymed-ingredient:titanium_dioxide,
dailymed-ingredient:white_wax
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Sotret must only be prescribed by prescribers who are registered and activated with the iPLEDGE program. Sotret must only be dispensed by a pharmacy registered and activated with iPLEDGE, and must only be dispensed to patients who are registered and meet all the requirements of iPLEDGE. Registered and activated pharmacies must receive isotretinoin only from wholesalers registered with iPLEDGE. iPLEDGE program requirements for wholesalers, prescribers, and pharmacists are described below:<br/>Wholesalers:: For the purpose of the iPLEDGE program, the term wholesaler refers to wholesaler, distributor, and/or chain pharmacy distributor. To distribute Sotret, wholesalers must be registered with iPLEDGE, and agree to meet all iPLEDGE requirements for wholesale distribution of isotretinoin products. Wholesalers must register with iPLEDGE by signing and returning the iPLEDGE wholesaler agreement that affirms they will comply with all iPLEDGE requirements for distribution of isotretinoin. These include:<br/>Prescribers:: To prescribe isotretinoin, the prescriber must be registered and activated with the pregnancy risk management program iPLEDGE. Prescribers can register by signing and returning the completed registration form. Prescribers can only activate their registration by affirming that they meet requirements and will comply with all iPLEDGE requirements by attesting to the following points: To prescribe isotretinoin, the prescriber must access the iPLEDGE system via the internet (www.ipledgeprogram.com) or telephone (1-866-495-0654) to: Isotretinoin must only be prescribed to female patients who are known not to be pregnant as confirmed by a negative CLIA-certified laboratory conducted pregnancy test. Isotretinoin must only be dispensed by a pharmacy registered and activated with the pregnancy risk management program iPLEDGE and only when the registered patient meets all the requirements of the iPLEDGE program. Meeting the requirements for a female patient of childbearing potential signifies that she: If the patient has unprotected heterosexual intercourse at any time 1 month before, during, or 1 month after therapy, she must: Effective forms of contraception include both primary and secondary forms of contraception: Any birth control method can fail. There have been reports of pregnancy from female patients who have used oral contraceptives, as well as transdermal patch/injectable/implantable/vaginal ring hormonal birth control products; these pregnancies occurred while these patients were taking isotretinoin capsules. These reports are more frequent for female patients who use only a single method of contraception. Therefore, it is critically important that female patients of childbearing potential use 2 effective forms of contraception simultaneously. Patients must receive written warnings about the rates of possible contraception failure (included in patient education kits). Using two forms of contraception simultaneously substantially reduces the chances that a female will become pregnant over the risk of pregnancy with either form alone. A drug interaction that decreases effectiveness of hormonal contraceptives has not been entirely ruled out for Sotret (see PRECAUTIONS: Drug Interactions). Although hormonal contraceptives are highly effective, prescribers are advised to consult the package insert of any medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products. Patients should be prospectively cautioned not to self-medicate with the herbal supplement St. John's Wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St. John's Wort. Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St. John's Wort. If a pregnancy does occur during isotretinoin treatment, isotretinoin must be discontinued immediately. The patient should be referred to an Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure during or 1 month after isotretinoin therapy must be reported immediately to the FDA via the MedWatch number 1-800-FDA- 1088 and also to the iPLEDGE pregnancy registry at 1-866-495-0654 or via the internet (www.ipledgeprogram.com).<br/>All Patients: Isotretinoin is contraindicated in female patients who are pregnant. To receive isotretinoin all patients must meet all of the following conditions:<br/>Female Patients of Childbearing Potential: Isotretinoin is contraindicated in female patients who are pregnant. In addition to the requirements for all patients described above, female patients of childbearing potential must meet the following conditions:<br/>Pharmacists:: To dispense isotretinoin, pharmacies must be registered and activated with the pregnancy risk management program iPLEDGE. The Responsible Site Pharmacist must register the pharmacy by signing and returning the completed registration form. After registration, the Responsible Site Pharmacist can only activate the pharmacy registration by affirming that they meet requirements and will comply with all iPLEDGE requirements by attesting to the following points: To dispense isotretinoin, the pharmacist must: Sotret must only be dispensed: A Sotret Medication Guide must be given to the patient each time Sotret is dispensed, as required by law. This Sotret Medication Guide is an important part of the risk management program for the patients. Sotret must not be prescribed, dispensed or otherwise obtained through the internet or any other means outside of the iPLEDGE program. Only FDA-approved Sotret products must be distributed, prescribed, dispensed, and used. Patients must fill Sotret prescriptions only at US licensed pharmacies. A description of the iPLEDGE program educational materials available with iPLEDGE is provided below. The main goal of these educational materials is to explain the iPLEDGE program requirements and to reinforce the educational messages.<br/>General: Although an effect of Sotret on bone loss is not established, physicians should use caution when prescribing Sotret to patients with a genetic predisposition for age-related osteoporosis, a history of childhood osteoporosis conditions, osteomalacia, or other disorders of bone metabolism. This would include patients diagnosed with anorexia nervosa and those who are on chronic drug therapy that causes drug induced osteoporosis/osteomalacia and/or affects vitamin D metabolism, such as systemic corticosteroids and any anticonvulsant. Patients may be at increased risk when participating in sports with repetitive impact where the risks of spondylolisthesis with and without pars fractures and hip growth plate injuries in early and late adolescence are known. There are spontaneous reports of fractures and/or delayed healing in patients while on therapy with isotretinoin or following cessation of therapy with isotretinoin while involved in these activities. While causality to Sotret has not been established, an effect must not be ruled out.<br/>Information for Patients: See PRECAUTIONS and Boxed CONTRAINDICATIONS AND WARNINGS.<br/>Hypersensitivity: Anaphylactic reactions and other allergic reactions have been reported. Cutaneous allergic reactions and serious cases of allergic vasculitis, often with purpura (bruises and red patches) of the extremities and extracutaneous involvement (including renal) have been reported. Severe allergic reaction necessitates discontinuation of therapy and appropriate medical management.<br/>Drug Interactions:<br/>Laboratory Tests:<br/>Carcinogenesis and Mutagenesis and Impairment of Fertility: In male and female Fischer 344 rats given oral isotretinoin at dosages of 8 or 32 mg/kg/day (1.3 to 5.3 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area) for greater than 18 months, there was a dose-related increased incidence of pheochromocytoma relative to controls. The incidence of adrenal medullary hyperplasia was also increased at the higher dosage in both sexes. Therelatively high level of spontaneous pheochromocytomas occurring in the male Fischer 344 rat makes it an equivocal model for study of this tumor; therefore, the relevance of this tumor to the human population is uncertain. The Ames test was conducted with isotretinoin in two laboratories. The results of the tests in one laboratory were negative while in the second laboratory a weakly positive response (less than 1.6 x background) was noted in S. typhimurium TA100 when the assay was conducted with metabolic activation. No dose-response effect was seen and all other strains were negative. Additionally, other tests designed to assess genotoxicity (Chinese hamster cell assay, mouse micronucleus test, S. cerevisiae D7 assay, in vitro clastogenesis assay with human-derived lymphocytes, and unscheduled DNA synthesis assay) were all negative. In rats, no adverse effects on gonadal function, fertility, conception rate, gestation or parturition were observed at oral dosages of isotretinoin of 2, 8, or 32 mg/kg/day (0.3, 1.3, or 5.3 times the recommended clinical dose of 1.0 mg/kg/day, respectively, after normalization for total body surface area). In dogs, testicular atrophy was noted after treatment with oral isotretinoin for approximately 30 weeks at dosages of 20 or 60 mg/kg/day (10 or 30 times the recommended clinical dose of 1.0 mg/kg/day, respectively, after normalization for total body surface area). In general, there was microscopic evidence for appreciable depression of spermatogenesis but some sperm were observed in all testes examined and in no instance were completely atrophic tubules seen. In studies of 66 men, 30 of whom were patients with nodular acne under treatment with oral isotretinoin, no significant changes were noted in the count or motility of spermatozoa in the ejaculate. In a study of 50 men (ages17 to 32 years) receiving Sotret (isotretinoin) therapy for nodular acne, no significant effects were seen on ejaculate volume, sperm count, total sperm motility, morphology or seminal plasma fructose.<br/>Pregnancy: Category X.: See Boxed CONTRAINDICATIONS AND WARNINGS.<br/>Nursing Mothers: It is not known whether this drug is excreted in human milk. Because of the potential for adverse effects, nursing mothers should not receive Sotret.<br/>Pediatric Use: The use of isotretinoin capsules in pediatric patients less than 12 years of age has not been studied. The use of isotretinoin capsules for the treatment of severe recalcitrant nodular acne in pediatric patients ages 12 to 17 years should be given careful consideration, especially for those patients where a known metabolic or structural bone disease exists (see PRECAUTIONS: General). Use of isotretinoin capsules in this age group for severe recalcitrant nodular acne is supported by evidence from a clinical study comparing 103 pediatric patients (13 to 17 years) to 197 adult patients (���18 years). Results from this study demonstrated that isotretinoin, at a dose of 1 mg/kg/day given in two divided doses, was equally effective in treating severe recalcitrant nodular acne in both pediatric and adult patients. In studies with isotretinoin capsules, adverse reactions reported in pediatric patients were similar to those described in adults except for the increased incidence of back pain and arthralgia (both of which were sometimes severe) and myalgia in pediatric patients (see ADVERSE REACTIONS). In an open-label clinical trial (N=217) of a single course of therapy with isotretinoin capsules for severe recalcitrant nodular acne, bone density measurements at several skeletal sites were not significantly decreased (lumbar spine change>-4% and total hip change>-5%) or were increased in the majority of patients. One patient had a decrease in lumbar spine bone mineral density>4% based on unadjusted data. Sixteen (7.9%) patients had decreases in lumbar spine bone mineral density>4%, and all the other patients (92%) did not have significant decreases or had increases (adjusted for body mass index). Nine patients (4.5%) had a decrease in total hip bone mineral density>5% based on unadjusted data. Twenty one (10.6%) patients had decreases in total hip bone mineral density>5%, and all the other patients (89%) did not have significant decreased bone mineral density for up to 11 months thereafter demonstrated increasing bone density in 5 patients at the lumbar spine, while the other 3 patients had lumbar spine bone density measurements below baseline values. Total hip bone mineral densities remained below baseline (range -1.6% to -7.6%) in 5 of 8 patients (62.5%). In a separate open-label extension study of 10 patients, ages 13 to 18 years, who started a second course of isotretinoin capsules 4 months after the first course, two patients showed a decrease in mean lumbar spine bone mineral density up to 3.25% (see WARNINGS: Skeletal: Bone Mineral Density).<br/>Geriatric Use: Clinical studies of isotretinoin did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Although reported clinical experience has not identified differences in responses between elderly and younger patients, effects of aging might be expected to increase some risks associated with isotretinoin therapy (see WARNINGS and PRECAUTIONS).
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The oral LDof isotretinoin is greater than 4000 mg/kg in rats and mice (>600 times the recommended clinical dose of 1.0 mg/kg/day after normalization of the rat dose for total body surface area and>300 times the recommended clinical dose of 1.0 mg/kg/day after normalization of the mouse dose for total body surface area) and is approximately 1960 mg/kg in rabbits (653 times the recommended clinical dose of 1 mg/kg/day after normalization for total body surface area). In humans, overdosage has been associated with vomiting, facial flushing, cheilosis, abdominal pain, headache, dizziness, and ataxia. These symptoms quickly resolve without apparent residual effects. Isotretinoin causes serious birth defects at any dosage (see Boxed CONTRAINDICATIONS AND WARNINGS). Female patients of childbearing potential who present with isotretinoin overdose must be evaluated for pregnancy. Patients who are pregnant should receive counseling about the risks to the fetus, as described in the boxed CONTRAINDICATIONS AND WARNINGS. Non-pregnant patients must be warned to avoid pregnancy for at least one month and receive contraceptive counseling as described in PRECAUTIONS. Educational materials for such patients can be obtained by calling the manufacturer. Because an overdose would be expected to result in higher levels of isotretinoin in semen than found during anormal treatment course, male patients should use a condom, or avoid reproductive sexual activity with a female patient who is or might become pregnant, for 1 month after the overdose. All patients with isotretinoin overdose should not donate blood for at least 1 month.
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isotretinoin
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Sotret (Capsule, Gelatin Coated)
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Clinical Trials and Postmarketing Surveillance: The adverse reactions listed below reflect the experience from investigational studies of isotretinoin capsules, and the postmarketing experience. The relationship of some of these events to isotretinoin capsules therapy is unknown. Many of the side effects and adverse reactions seen in patients receiving isotretinoin capsules are similar to those described in patients taking very high doses of vitamin A (dryness of the skin and mucous membranes, e.g., of the lips, nasal passage, and eyes).<br/>Dose Relationship: Cheilitis and hypertriglyceridemia are usually dose related. Most adverse reactions reported in clinical trials were reversible when therapy was discontinued; however, some persisted after cessation of therapy (see WARNINGS and ADVERSE REACTIONS).<br/>Body as a Whole: allergic reactions, including vasculitis, systemic hypersensitivity (see PRECAUTIONS: Hypersensitivity), edema, fatigue, lymphadenopathy, weight loss<br/>Cardiovascular: palpitation, tachycardia, vascular thrombotic disease, stroke<br/>Endocrine/Metabolic: hypertriglyceridemia (see WARNINGS: Lipids), alterations in blood sugar levels (see PRECAUTIONS: Laboratory Tests)<br/>Gastrointestinal: inflammatory bowel disease (see WARNINGS: Inflammatory Bowel Disease), hepatitis (see WARNINGS: Hepatotoxicity), pancreatitis (see WARNINGS: Lipids), bleeding and inflammation of the gums, colitis, esophagitis/esophageal ulceration, ileitis, nausea, other nonspecific gastrointestinal symptoms<br/>Hematologic: allergic reactions (see PRECAUTIONS: Hypersensitivity), anemia, thrombocytopenia, neutropenia, rare reports of agranulocytosis (see PRECAUTIONS: Information for Patients). See PRECAUTIONS: Laboratory Tests for other hematological parameters.<br/>Musculoskeletal: skeletal hyperostosis, calcification of tendons and ligaments, premature epiphyseal closure, decreases in bone mineral density (see WARNINGS: Skeletal), musculoskeletal symptoms (sometimes severe) including back pain, myalgia, and arthralgia (see PRECAUTIONS: Information for Patients), transient pain in the chest (see PRECAUTIONS: Information for Patients), arthritis, tendonitis, other types of bone abnormalities, elevations of CPK/rare reports of rhabdomyolysis (see PRECAUTIONS: Laboratory Tests).<br/>Neurological: pseudotumor cerebri (see WARNINGS: Pseudotumor Cerebri), dizziness, drowsiness, headache, insomnia, lethargy, malaise, nervousness, paresthesias, seizures, stroke, syncope, weakness<br/>Psychiatric: suicidal ideation, suicide attempts, suicide, depression, psychosis, aggression, violent behaviors (see WARNINGS: Psychiatric Disorders), emotional instability of the patients reporting depression, some reported that the depression subsided with discontinuation of therapy and recurred with reinstitution of therapy.<br/>Reproductive System: abnormal menses<br/>Respiratory: bronchospasms (with or without a history of asthma ), respiratory infection, voice alteration<br/>Skin and Appendages: acne fulminans, alopecia (which in some cases persists), bruising, cheilitis (dry lips), dry mouth, dry nose, dry skin, epistaxis, eruptive xanthomas,flushing, fragility of skin, hair abnormalities, hirsutism, hyperpigmentation and hypopigmentation, infections (including disseminated herpes simplex), nail dystrophy, paronychia, peeling of palms and soles, photoallergic/photosensitizing reactions, pruritus, pyogenic granuloma, rash (including facial erythema, seborrhea, and eczema), sunburn susceptibility increased, sweating, urticaria, vasculitis (including Wegener's granulomatosis; see PRECAUTIONS: Hypersensitivity), abnormal wound healing (delayed healing or exuberant granulation tissue with crusting; see PRECAUTIONS: Information for Patients)<br/>Special Senses:<br/>Laboratory: Elevation of plasma triglycerides (see WARNINGS: Lipids), decrease in serum high-density lipoprotein (HDL) levels, elevations of serum cholesterol during treatment Increased alkaline phosphatase, SGOT (AST), SGPT (ALT), GGTP or LDH (see WARNINGS: Hepatotoxicity) Elevation of fasting blood sugar, elevations of CPK (see PRECAUTIONS: Laboratory Tests), hyperuricemia Decreases in red blood cell parameters, decreases in white blood cell counts (including severe neutropenia and rare reports of agranulocytosis; see PRECAUTIONS: Information for Patients), elevated sedimentation rates, elevated platelet counts, thrombocytopenia White cells in the urine, proteinuria, microscopic or gross hematuria
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Psychiatric Disorders: Sotret may cause depression, psychosis and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors. No mechanism of action has been established for these events (see ADVERSE REACTIONS: Psychiatric). Prescribers should read the brochure, Recognizing Psychiatric Disorders in Adolescents and Young Adults:A Guide for Prescribers of Isotretinoin. Prescribers should be alert to the warning signs of psychiatric disorders to guide patients to receive the help they need. Therefore, prior to initiation of Sotret therapy, patients and family members should be asked about any history of psychiatric disorder, and at each visit during therapy patients should be assessed for symptoms of depression, mood disturbance, psychosis, or aggression to determine if further evaluation maybe necessary. Signs and symptoms of depression, as described in the brochure (���Recognizing Psychiatric Disorders in Adolescents and Young Adults���), include sad mood, hopelessness, feelings of guilt, worthlessness or helplessness, loss of pleasure or interest in activities, fatigue, difficulty concentrating, change in sleep pattern, change in weight or appetite, suicidal thoughts or attempts, restlessness, irritability, acting on dangerous impulses, and persistent physical symptoms unresponsive to treatment. Patients should stop Sotretand the patient or a family member should promptly contact their prescriber if the patient develops depression, mood disturbance, psychosis, or aggression, without waiting until the next visit. Discontinuation of Sotret therapy may be insufficient; further evaluation may be necessary. While such monitoring may be helpful, it may not detect all patients at risk. Patients may report mental health problems or family history of psychiatric disorders. These reports should be discussed with the patient and/or thepatient's family. A referral to a mental health professional may be necessary. The physician should consider whether Sotret therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of isotretinoin therapy.<br/>Pseudotumor Cerebri: Isotretinoin capsule use has been associated with a number of cases of pseudotumor cerebri (benign intracranial hypertension), some of which involved concomitant use of tetracyclines. Concomitant treatment with tetracyclines should therefore be avoided. Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea and vomiting, and visual disturbances. Patients with these symptoms should be screened for papilledema and, if present, they should be told to discontinue Sotret immediately and be referred to a neurologist for further diagnosis and care (see ADVERSE REACTIONS: Neurological).<br/>Pancreatitis: Acute pancreatitis has been reported in patients with either elevated or normal serum triglyceride levels. In rare instances, fatal hemorrhagic pancreatitis has been reported. Sotret should be stopped if hypertriglyceridemia cannot be controlled at an acceptable level or if symptoms of pancreatitis occur.<br/>Lipids: Elevations of serum triglycerides in excess of 800 mg/dL have been reported in patients treated with isotretinoin capsules. Marked elevations of serum triglycerides were reported in approximately 25% of patients receiving isotretinoin capsules in clinical trials. In addition, approximately 15% developed a decrease in high-density lipoproteins and about 7% showed an increase in cholesterol levels. In clinical trials, the effects on triglycerides, HDL, and cholesterol were reversible upon cessation of isotretinoin capsules therapy. Some patients have been able to reverse triglyceride elevation by reduction in weight, restriction of dietary fat and alcohol, and reduction in dose while continuing isotretinoin capsules. Blood lipid determinations should be performed before Sotret is given and then at intervals until the lipid response to Sotret is established, which usually occurs within 4 weeks. Especially careful consideration must be given to risk/benefit for patients who may be at high risk during Sotret therapy (patients with diabetes, obesity, increased alcohol intake, lipid metabolism disorder or familial history of lipid metabolism disorder). If Sotret therapy is instituted, more frequent checks of serum values for lipids and/or blood sugar are recommended (see PRECAUTIONS: Laboratory Tests). The cardiovascular consequences of hypertriglyceridemia associated with Sotret are unknown. Animal Studies: In rats given 8 or 32 mg/kg/day of isotretinoin (1.3 to 5.3 times the recommended clinical dose of 1.0 mg/kg/day after normalization for total body surface area) for 18 months or longer, the incidences of focal calcification, fibrosis and inflammation of the myocardium, calcification of coronary, pulmonary and mesenteric arteries, and metastatic calcification of the gastric mucosa were greater than in control rats of similar age. Focal endocardial and myocardial calcifications associated with calcification of the coronary arteries were observed in two dogs after approximately 6 to 7 months of treatment with isotretinoin at a dosage of 60 to 120 mg/kg/day (30 to 60 times the recommended clinical dose of 1.0 mg/kg/day, respectively, after normalization for total body surface area).<br/>Hearing Impairment: Impaired hearing has been reported in patients taking isotretinoin capsules; in some cases, the hearing impairment has been reported to persist after therapy has been discontinued. Mechanism(s) and causality for this event have not been established. Patients who experience tinnitus or hearing impairment should discontinue Sotret treatment and be referred for specializedcare for further evaluation (see ADVERSE REACTIONS: Special Senses).<br/>Hepatotoxicity: Clinical hepatitis considered to be possibly or probably related to isotretinoin capsules therapy has been reported. Additionally, mild to moderate elevations of liver enzymes have been observed in approximately 15% of individuals treated during clinical trials, some of which normalized with dosage reduction or continued administration of the drug. If normalization does not readily occur or if hepatitis is suspected during treatment with Sotret, the drug should be discontinued and the etiology further investigated.<br/>Inflammatory Bowel Disease: Isotretinoin capsules have been associated with inflammatory bowel disease (including regional ileitis) in patients without a prior history of intestinal disorders. In some instances, symptoms have been reported to persist after isotretinoin capsules treatment has been stopped. Patients experiencing abdominal pain, rectal bleeding or severe diarrhea should discontinue Sotret immediately (see ADVERSE REACTIONS: Gastrointestinal).<br/>Skeletal:<br/>Bone Mineral Density: Effects of multiple courses of Sotret on the developing musculoskeletal system are unknown. There is some evidence that long-term, high-dose, or multiple courses of therapy with isotretinoin have more of an effect than a single course of therapy on the musculoskeletal system. In an open-label clinical trial (N=217) of a single course of therapy with isotretinoin for severe recalcitrant nodular acne, bone density measurements at several skeletal sites were not significantly decreased (lumbar spine change>-4% and total hip change>-5%) or were increased in the majority of patients. One patient had a decrease in lumbar spine bone mineral density>4% based on unadjusted data. Sixteen (7.9%) patients had decreases in lumbar spine bone mineral density>4%, and all the other patients (92%) did not have significant decreases or had increases (adjusted for body mass index). Nine patients (4.5%) had a decrease in total hip bone mineral density>5% based on unadjusted data. Twenty-one (10.6%) patients had decreases in total hip bone mineral density>5%, and all the other patients (89%) did not have significant decreases or had increases (adjusted for body mass index). Follow-up studies performed in 8 of the patients with decreased bone mineral density for up to 11 months thereafter demonstrated increasing bone density in 5 patients at the lumbar spine, while the other 3 patients had lumbar spine bone density measurements below baseline values. Total hip bone mineral densities remained below baseline (range -1.6% to -7.6%) in 5 of 8 patients (62.5%). In a separate open-label extension study of 10 patients, ages 13 to 18 years, who started a second course of isotretinoin 4 months after the first course, two patients showed a decrease in mean lumbar spine bone mineral density up to 3.25% (see PRECAUTIONS: Pediatric Use). Spontaneous reports of osteoporosis, osteopenia, bone fractures, and delayed healing of bone fractures have been seen in the isotretinoin population. While causality to Sotret has not been established, an effect cannot be ruled out. Longer term effects have not been studied. It is important that Sotret be given at the recommended doses for no longer than the recommended duration.<br/>Hyperostosis: A high prevalence of skeletal hyperostosis was noted in clinical trials for disorders of keratinization with a mean dose of 2.24 mg/kg/day. Additionally, skeletal hyperostosis was noted in 6 of 8 patients in a prospective study of disorders of keratinization.Minimal skeletal hyperostosis and calcification of ligaments and tendons have also been observed by x-ray in prospective studies of nodular acne patients treated with a single course of therapy at recommended doses. The skeletal effects of multiple Sotret treatment courses for acne are unknown. In a clinical study of 217 pediatric patients (12 to 17 years) with severe recalcitrant nodular acne, hyperostosis was not observed after 16 to 20 weeks of treatment with approximately 1 mg/kg/day of isotretinoin capsules given in two divided doses. Hyperostosis may require a longer time frame to appear. The clinical course and significance remain unknown.<br/>Premature Epiphyseal Closure: There are spontaneous reports of premature epiphyseal closure in acne patients receiving recommended doses of isotretinoin capsules. The effect of multiple courses of Sotret on epiphyseal closure is unknown.<br/>Vision Impairment: Visual problems should be carefully monitored. All Sotret patients experiencing visual difficulties should discontinue Sotret treatment and have an ophthalmological examination (see ADVERSE REACTIONS: Special Senses).<br/>Corneal Opacities: Corneal opacities have occurred in patients receiving isotretinoin capsules for acne and more frequently when higher drug dosages were used in patients with disorders of keratinization. The corneal opacities that have been observed in clinical trial patients treated with isotretinoin capsules have either completely resolved or were resolving at follow-up 6 to 7 weeks after discontinuation of the drug (see ADVERSE REACTIONS: Special Senses).<br/>Decreased Night Vision: Decreased night vision has been reported during isotretinoin capsules therapy and in some instances the event has persisted after therapy was discontinued. Because the onset in some patients was sudden, patients should be advised of this potential problem and warned to be cautious when driving or operating any vehicle at night.
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Severe Recalcitrant Nodular Acne: Sotret is indicated for the treatment of severe recalcitrant nodular acne. Nodules are inflammatory lesions with a diameter of 5 mm or greater. The nodules may become suppurative or hemorrhagic.���Severe,���by definition,means���many���as opposed to���few or several���nodules. Because of significant adverse effects associated with its use, Sotret should be reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. In addition, Sotret is indicated only for those female patients who are not pregnant, because Sotret can cause severe birth defects (see Boxed CONTRAINDICATIONS AND WARNINGS). A single course of therapy for 15 to 20 weeks has been shown to result in complete and prolonged remission of disease in many patients.If a second course of therapy is needed, it should not be initiated until at least 8 weeks after completion of the first course, because experience has shown that patients may continue to improve while off isotretinoin capsules. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth (see WARNINGS: Skeletal: Bone Mineral Density, Hyperostosis, and Premature Epiphyseal Closure).
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Sotret
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