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Isotretinoin
Isotretinoin, a retinoid, is available as Accutane in 10-mg, 20-mg and 40-mg soft gelatin capsules for oral administration. Each capsule contains beeswax, butylated hydroxyanisole, edetate disodium, hydrogenated soybean oil flakes, hydrogenated vegetable oil, and soybean oil. 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; 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. Isotretinoin is a retinoid, which when administered in pharmacologic dosages of 0.5 to 1.0 mg/kg/day (see DOSAGE AND ADMINISTRATION), inhibits sebaceous gland function and keratinization. The exact mechanism of action of isotretinoin is unknown. 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 Accutane, and reflects a reduction in sebaceous gland size and an inhibition of sebaceous gland differentiation.1 Pharmacokinetics 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 Accutane under fasted and fed conditions. Both peak plasma concentration (Cmax) and the total exposure (AUC) of isotretinoin were more than doubled following a standardized high-fat meal when compared with Accutane given under fasted conditions (see Table 2 below). 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 (Tmax) was also increased with food and may be related to a longer absorption phase. Therefore, Accutane 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.
Distribution Isotretinoin is more than 99.9% bound to plasma proteins, primarily albumin. 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 Accutane 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 (³18 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. Elimination Following oral administration of an 80 mg dose of 14C-isotretinoin as a liquid suspension, 14C-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 Accutane to 74 healthy adult subjects under fed conditions, the mean SD elimination half-lives (t1/2) 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. Special Patient Populations 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 (³18 years) who received Accutane 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.
In pediatric patients (12 to 15 years), the mean ± SD elimination half-lives (t1/2) 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. Severe Recalcitrant Nodular Acne Accutane 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,2 means "many" as opposed to "few or several" nodules. Because of significant adverse effects associated with its use, Accutane should be reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. In addition, Accutane is indicated only for those females who are not pregnant, because Accutane 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.1,3,4 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 Accutane. 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). Accutane should be administered with a meal (see PRECAUTIONS: Information for Patients and Prescribers). The recommended dosage range for Accutane 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 1.0 mg/kg/day,8 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 Accutane 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 Accutane 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 Accutane, even in low doses, has not been studied, and is not recommended. It is important that Accutane be given at the recommended doses for no longer than the recommended duration. The effect of long-term use of Accutane 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 boxed CONTRAINDICATIONS AND WARNINGS).
Soft gelatin capsules, 10 mg (light pink), imprinted ACCUTANE 10 ROCHE. Boxes
of 100 containing 10 Prescription Paks of 10 capsules (NDC 0004-0155-49).
Clinical Trials and Postmarketing Surveillance The adverse reactions listed below reflect the experience from investigational studies of Accutane, and the postmarketing experience. The relationship of some of these events to Accutane therapy is unknown. Many of the side effects and adverse reactions seen in patients receiving Accutane are similar to those described in patients taking very high doses of vitamin A (dryness of the skin and mucous membranes, eg, of the lips, nasal passage, and eyes). 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). Body as a Whole allergic reactions, including vasculitis, systemic hypersensitivity (see PRECAUTIONS: Hypersensitivity), edema, fatigue, lymphadenopathy, weight loss Cardiovascular palpitation, tachycardia, vascular thrombotic disease, stroke Endocrine/Metabolic hypertriglyceridemia (see WARNINGS: Lipids), alterations in blood sugar levels (see PRECAUTIONS: Laboratory Tests) 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 Hematologic allergic reactions (see PRECAUTIONS: Hypersensitivity), anemia, thrombocytopenia, neutropenia, rare reports of agranulocytosis (see PRECAUTIONS: Information for Patients and Prescribers). See PRECAUTIONS: Laboratory Tests for other hematological parameters. 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 and arthralgia (see PRECAUTIONS: Information for Patients and Prescribers), transient pain in the chest (see PRECAUTIONS: Information for Patients and Prescribers), arthritis, tendonitis, other types of bone abnormalities, elevations of CPK/rare reports of rhabdomyolysis (see PRECAUTIONS: Laboratory Tests). Neurological pseudotumor cerebri (see WARNINGS: Pseudotumor Cerebri), dizziness, drowsiness, headache, insomnia, lethargy, malaise, nervousness, paresthesias, seizures, stroke, syncope, weakness 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. Reproductive System abnormal menses Respiratory bronchospasms (with or without a history of asthma), respiratory infection, voice alteration Skin and Appendages acne fulminans, alopecia (which in some cases persists), bruising, cheilitis (dry lips), dry mouth, dry nose, dry skin, epistaxis, eruptive xanthomas,7 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 and Prescribers) Special Senses Hearing hearing impairment (see WARNINGS: Hearing Impairment), tinnitus. Vision corneal opacities (see WARNINGS: Corneal Opacities), decreased night vision which may persist (see WARNINGS: Decreased Night Vision), cataracts, color vision disorder, conjunctivitis, dry eyes, eyelid inflammation, keratitis, optic neuritis, photophobia, visual disturbances Urinary System glomerulonephritis (see PRECAUTIONS: Hypersensitivity), nonspecific urogenital findings (see PRECAUTIONS: Laboratory Tests for other urological parameters) 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 and Prescribers), elevated sedimentation rates, elevated platelet counts, thrombocytopenia White cells in the urine, proteinuria, microscopic or gross hematuria · Vitamin A: Because of the relationship of Accutane to vitamin A, patients should be advised against taking vitamin supplements containing vitamin A to avoid additive toxic effects. · Tetracyclines: Concomitant treatment with Accutane and tetracyclines should be avoided because Accutane use has been associated with a number of cases of pseudotumor cerebri (benign intracranial hypertension), some of which involved concomitant use of tetracyclines. · Micro-dosed Progesterone Preparations: Micro-dosed progesterone preparations ("minipills" that do not contain an estrogen) may be an inadequate method of contraception during Accutane therapy. Although other hormonal contraceptives are highly effective, there have been reports of pregnancy from women who have used combined oral contraceptives, as well as topical/injectable/implantable/insertable hormonal birth control products. These reports are more frequent for women who use only a single method of contraception. It is not known if hormonal contraceptives differ in their effectiveness when used with Accutane. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of effective contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method, or the patient has undergone a hysterectomy (see boxed CONTRAINDICATIONS AND WARNINGS). · Phenytoin: Accutane has not been shown to alter the pharmacokinetics of phenytoin in a study in seven healthy volunteers. These results are consistent with the in vitro finding that neither isotretinoin nor its metabolites induce or inhibit the activity of the CYP 2C9 human hepatic P450 enzyme. Phenytoin is known to cause osteomalacia. No formal clinical studies have been conducted to assess if there is an interactive effect on bone loss between phenytoin and Accutane. Therefore, caution should be exercised when using these drugs together. · Systemic Corticosteroids: Systemic corticosteroids are known to cause osteoporosis. No formal clinical studies have been conducted to assess if there is an interactive effect on bone loss between systemic corticosteroids and Accutane. Therefore, caution should be exercised when using these drugs together. Prescribers are advised to consult the package insert of medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products. Accutane use is associated with depression in some patients (see WARNINGS: Psychiatric Disorders and ADVERSE REACTIONS: Psychiatric). 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. Laboratory Tests Pregnancy Test Female patients of childbearing potential must have negative results from 2 urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL before receiving the initial Accutane prescription. The first test is obtained by the prescriber when the decision is made to pursue qualification of the patient for Accutane (a screening test). The second pregnancy test (a confirmation test) should be done during the first 5 days of the menstrual period immediately preceding the beginning of Accutane therapy. For patients with amenorrhea, the second test should be done at least 11 days after the last act of unprotected sexual intercourse (without using 2 effective forms of contraception). Each month of therapy, the patient must have a negative result from a urine or serum pregnancy test. A pregnancy test must be repeated each month prior to the female patient receiving each prescription. · Lipids: Pretreatment and follow-up blood lipids should be obtained under fasting conditions. After consumption of alcohol, at least 36 hours should elapse before these determinations are made. It is recommended that these tests be performed at weekly or biweekly intervals until the lipid response to Accutane is established. The incidence of hypertriglyceridemia is 1 patient in 4 on Accutane therapy (see WARNINGS: Lipids). · Liver Function Tests: Since elevations of liver enzymes have been observed during clinical trials, and hepatitis has been reported, pretreatment and follow-up liver function tests should be performed at weekly or biweekly intervals until the response to Accutane has been established (see WARNINGS: Hepatotoxicity). · Glucose: Some patients receiving Accutane have experienced problems in the control of their blood sugar. In addition, new cases of diabetes have been diagnosed during Accutane therapy, although no causal relationship has been established. · CPK: Some patients undergoing vigorous physical activity while on Accutane therapy have experienced elevated CPK levels; however, the clinical significance is unknown. There have been rare postmarketing reports of rhabdomyolysis, some associated with strenuous physical activity. In a clinical trial of 217 pediatric patients (12 to 17 years) with severe recalcitrant nodular acne, transient elevations in CPK were observed in 12% of patients, including those undergoing strenuous physical activity in association with reported musculoskeletal adverse events such as back pain, arthralgia, limb injury, or muscle sprain. In these patients, approximately half of the CPK elevations returned to normal within 2 weeks and half returned to normal within 4 weeks. No cases of rhabdomyolysis were reported in this trial. Psychiatric Disorders Accutane may cause depression, psychosis and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors. Discontinuation of Accutane therapy may be insufficient; further evaluation may be necessary. 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 Accutaneâ (isotretinoin). Pseudotumor Cerebri Accutane 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 Accutane immediately and be referred to a neurologist for further diagnosis and care (see ADVERSE REACTIONS: Neurological). 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. Accutane should be stopped if hypertriglyceridemia cannot be controlled at an acceptable level or if symptoms of pancreatitis occur. Lipids Elevations of serum triglycerides in excess of 800 mg/dL have been reported in patients treated with Accutane. Marked elevations of serum triglycerides were reported in approximately 25% of patients receiving Accutane 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 Accutane 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 Accutane.5 Blood lipid determinations should be performed before Accutane is given and then at intervals until the lipid response to Accutane 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 Accutane therapy (patients with diabetes, obesity, increased alcohol intake, lipid metabolism disorder or familial history of lipid metabolism disorder). If Accutane 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 Accutane 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). Hearing Impairment Impaired hearing has been reported in patients taking Accutane; 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 Accutane treatment and be referred for specialized care for further evaluation (see ADVERSE REACTIONS: Special Senses). Hepatotoxicity Clinical hepatitis considered to be possibly or probably related to Accutane 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 Accutane, the drug should be discontinued and the etiology further investigated. Inflammatory Bowel Disease Accutane has 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 Accutane treatment has been stopped. Patients experiencing abdominal pain, rectal bleeding or severe diarrhea should discontinue Accutane immediately (see ADVERSE REACTIONS: Gastrointestinal). Skeletal Bone Mineral Density Effects of multiple courses of Accutane 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 Accutane 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 13-18 years, who started a second course of Accutane 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 Accutane population. While causality to Accutane has not been established, an effect cannot be ruled out. Longer term effects have not been studied. It is important that Accutane be given at the recommended doses for no longer than the recommended duration. 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.6 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 Accutane 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 Accutane given in two divided doses. Hyperostosis may require a longer time frame to appear. The clinical course and significance remain unknown. Premature Epiphyseal Closure There are spontaneous reports of premature epiphyseal closure in acne patients receiving recommended doses of Accutane. The effect of multiple courses of Accutane on epiphyseal closure is unknown. Vision Impairment Visual problems should be carefully monitored. All Accutane patients experiencing visual difficulties should discontinue Accutane treatment and have an ophthalmological examination (see ADVERSE REACTIONS: Special Senses). Corneal Opacities Corneal opacities have occurred in patients receiving Accutane 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 Accutane have either completely resolved or were resolving at follow-up 6 to 7 weeks after discontinuation of the drug (see ADVERSE REACTIONS: Special Senses). Decreased Night Vision Decreased night vision has been reported during Accutane 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. The Accutane Pregnancy Prevention and Risk Management Programs consist of the System to Manage Accutane Related Teratogenicity (S.M.A.R.T.) and the Accutane Pregnancy Prevention Program (PPP). S.M.A.R.T. should be followed for prescribing Accutane with the goal of preventing fetal exposure to isotretinoin. It consists of: 1) reading the booklet entitled System to Manage Accutane Related Teratogenicity (S.M.A.R.T.) Guide to Best Practices, 2) signing and returning the completed S.M.A.R.T. Letter of Understanding containing the Prescriber Checklist, 3) a yellow self-adhesive Accutane Qualification Sticker to be affixed to the prescription page. In addition, the patient educational material, Be Smart, Be Safe, Be Sure, should be used with each patient. The following further describes each component: 1) The S.M.A.R.T. Guide to Best Practices includes: Accutane teratogenic potential, information on pregnancy testing, specific information about effective contraception, the limitations of contraceptive methods and behaviors associated with an increased risk of contraceptive failure and pregnancy, the methods to evaluate pregnancy risk, and the method to complete a qualified Accutane prescription. 2) The S.M.A.R.T. Letter of Understanding attests that Accutane prescribers understand that Accutane is a teratogen, have read the S.M.A.R.T. Guide to Best Practices, understand their responsibilities in preventing exposure of pregnant females to Accutane and the procedures for qualifying female patients as defined in the boxed CONTRAINDICATIONS AND WARNINGS. The Prescriber Checklist attests that Accutane prescribers know the risk and severity of injury/birth defects from Accutane; know how to diagnose and treat the various presentations of acne; know the risk factors for unplanned pregnancy and the effective measures for avoidance; will refer the patient for, or provide, detailed pregnancy prevention counseling to help the patient have knowledge and tools needed to fulfill their ultimate responsibility to avoid becoming pregnant; understand and properly use throughout the Accutane treatment course, the revised risk management procedures, including monthly pregnancy avoidance counseling, pregnancy testing, and use of qualified prescriptions with the yellow self-adhesive Accutane Qualification Sticker. 3) The yellow self-adhesive Accutane Qualification Sticker is used as documentation that the prescriber has qualified the female patient according to the qualification criteria (see boxed CONTRAINDICATIONS AND WARNINGS). 4) Accutane Pregnancy Prevention Program (PPP) is a systematic approach to comprehensive patient education about their responsibilities and includes education for contraception compliance and reinforcement of educational messages. The PPP includes information on the risks and benefits of Accutane which is linked to the Accutane Medication Guide dispensed by pharmacists with each prescription. Male and female patients are provided with separate booklets. Each booklet contains information on Accutane therapy, including precautions and warnings, an Informed Consent/Patient Agreement form, and a toll-free line which provides Accutane information in 13 languages. The booklet for male patients, Be Smart, Be Safe, Be Sure, Accutane Risk Management Program for Men, also includes information about male reproduction, a warning not to share Accutane with others or to donate blood during Accutane therapy and for 1 month following discontinuation of Accutane. The booklet for female patients, Be Smart, Be Safe, Be Sure, Accutane Pregnancy Prevention and Risk Management Program for Women, also includes a referral program that offers females free contraception counseling, reimbursed by the manufacturer, by a reproductive specialist; a second Patient Information/Consent form concerning birth defects, obtaining her consent to be treated within this agreement; an enrollment form for the Accutane Survey; and a qualification checklist affirming the conditions under which female patients may receive Accutane. In addition, there is information on the types of contraceptive methods, the selection and use of appropriate, effective contraception, and the rates of possible contraceptive failure; a toll-free contraception counseling line; and patient education videos — the video "Be Prepared, Be Protected" and the video "Be Aware: The Risk of Pregnancy While on Accutane". General Although an effect of Accutane on bone loss is not established, physicians should use caution when prescribing Accutane 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 treatment with Accutane or following cessation of treatment with Accutane while involved in these activities. While causality to Accutane has not been established, an effect cannot be ruled out. INFORMATION FOR PATIENTS AND PRESCRIBERS · Patients should be instructed to read the Medication Guide supplied as required by law when Accutane is dispensed. The complete text of the Medication Guide is reprinted at the end of this document. For additional information, patients should also read the Patient Product Information, Important Information Concerning Your Treatment with Accutaneâ (isotretinoin). All patients should sign the Informed Consent/Patient Agreement. · Females of childbearing potential should be instructed that they must not be pregnant when Accutane therapy is initiated, and that they should use 2 forms of effective contraception 1 month before starting Accutane, while taking Accutane, and for 1 month after Accutane has been stopped. They should also sign a consent form prior to beginning Accutane therapy. They should be given an opportunity to enroll in the Accutane Survey and to review the patient videotapes provided by the manufacturer to the prescriber. The videos include information about contraception, the most common reasons that contraception fails, and the importance of using 2 forms of effective contraception when taking teratogenic drugs and comprehensive information about types of potential birth defects which could occur if a woman who is pregnant takes Accutane at any time during pregnancy. Female patients should be seen by their prescribers monthly and have a urine or serum pregnancy test performed each month during treatment to confirm negative pregnancy status before another Accutane prescription is written (see boxed CONTRAINDICATIONS AND WARNINGS). · Accutane is found in the semen of male patients taking Accutane, but the amount delivered to a female partner would be about 1 million times lower than an oral dose of 40 mg. While the no-effect limit for isotretinoin-induced embryopathy is unknown, 20 years of postmarketing reports include 4 with isolated defects compatible with features of retinoid exposed fetuses. None of these cases had the combination of malformations characteristic of retinoid exposure, and all had other possible explanations for the defects observed. · Patients may report mental health problems or family history of psychiatric disorders. These reports should be discussed with the patient and/or the patient’s family. A referral to a mental health professional may be necessary. The physician should consider whether or not Accutane therapy is appropriate in this setting (see WARNINGS: Psychiatric Disorders). · Patients should be informed that they must not share Accutane with anyone else because of the risk of birth defects and other serious adverse events. · Patients should not donate blood during therapy and for 1 month following discontinuance of the drug because the blood might be given to a pregnant woman whose fetus must not be exposed to Accutane. · Patients should be reminded to take Accutane with a meal (see DOSAGE AND ADMINISTRATION). To decrease the risk of esophageal irritation, patients should swallow the capsules with a full glass of liquid. · Patients should be informed that transient exacerbation (flare) of acne has been seen, generally during the initial period of therapy. · Wax epilation and skin resurfacing procedures (such as dermabrasion, laser) should be avoided during Accutane therapy and for at least 6 months thereafter due to the possibility of scarring (see ADVERSE REACTIONS: Skin and Appendages). · Patients should be advised to avoid prolonged exposure to UV rays or sunlight. · Patients should be informed that they may experience decreased tolerance to contact lenses during and after therapy. · Patients should be informed that approximately 16% of patients treated with Accutane in a clinical trial developed musculoskeletal symptoms (including arthralgia) during treatment. In general, these symptoms were mild to moderate, but occasionally required discontinuation of the drug. Transient pain in the chest has been reported less frequently. In the clinical trial, these symptoms generally cleared rapidly after discontinuation of Accutane, but in some cases persisted (see ADVERSE REACTIONS: Musculoskeletal). There have been rare postmarketing reports of rhabdomyolysis, some associated with strenuous physical activity (see Laboratory Tests: CPK). · Pediatric patients and their caregivers should be informed that approximately 29% (104/358) of pediatric patients treated with Accutane developed back pain. Back pain was severe in 13.5% (14/104) of the cases and occurred at a higher frequency in female than male patients. Arthralgias were experienced in 22% (79/358) of pediatric patients. Arthralgias were severe in 7.6% (6/79) of patients. Appropriate evaluation of the musculoskeletal system should be done in patients who present with these symptoms during or after a course of Accutane. Consideration should be given to discontinuation of Accutane if any significant abnormality is found. · Neutropenia and rare cases of agranulocytosis have been reported. Accutane should be discontinued if clinically significant decreases in white cell counts occur. 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. Carcinogenesis, 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 1.0 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. The relatively 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 (ages 17 to 32 years) receiving Accutane (isotretinoin) therapy for nodular acne, no significant effects were seen on ejaculate volume, sperm count, total sperm motility, morphology or seminal plasma fructose. Pregnancy: Category X. See boxed CONTRAINDICATIONS AND WARNINGS. 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 Accutane. Pediatric Use The use of Accutane in pediatric patients less than 12 years of age has not been studied. The use of Accutane 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 Accutane 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 (³18 years). Results from this study demonstrated that Accutane, 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 Accutane, 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 Accutane 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 13-18 years, who started a second course of Accutane 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). 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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