Isotretinoin Risk Management Program Updated - November 23, 2004

The Food and Drug Administration (FDA) has announced an update to the monitoring programs currently implemented to decrease fetal exposures to isotretinoin. The strengthened program, risk minimization action plan (RiskMAP), will include Accutane® as well as all the generic equivalents. When implemented, RiskMAP will replace the SMART program, which is managed by Roche, as well as programs supported by other isotretinoin manufacturers such as S.P.I.R.I.T.™ (Bertek Pharmaceuticals) and I.M.P.A.R.T.™ (Ranbaxy Pharmaceuticals).

RiskMAP will require all prescribers, patients, and dispensing pharmacies to register with a central clearinghouse. Specific requirements must be met prior to dispensing the first prescription and with monthly refills.

Additional details may be found on the FDA website at http://www.fda.gov/bbs/topics/ANSWERS/2004/ANS01328.html, last accessed November 29, 2004.

Prescribers will be provided with qualification stickers after they have read the details of the program and have signed (and mailed to the manufacturer) their agreement to participate. Audits of pharmacies will be conducted to monitor program compliance.

Depression, psychosis, aggressive or violent behavior, and rarely suicidal thoughts and actions have been reported during isotretinoin usage. Discontinuation of treatment alone may not be sufficient, further evaluation may be necessary. Cases of pseudotumor cerebri (benign intracranial hypertension) have been reported, some with concomitant use of tetracycline (avoid using together). Patients with papilledema, headache, nausea, vomiting, and visual disturbances should be referred to a neurologist and treatment with isotretinoin discontinued. Hearing impairment, which can continue after therapy is discontinued, may occur. Clinical hepatitis, elevated liver enzymes, inflammatory bowel disease, skeletal hyperostosis, premature epiphyseal closure, vision impairment, corneal opacities, and decreased night vision have also been reported with the use of isotretinoin. Bone mineral density may decrease; use caution in patients with a genetic predisposition to bone disorders (ie osteoporosis, osteomalacia) and with disease states or concomitant medications that can induce bone disorders. Patients may be at risk when participating in activities with repetitive impact (such as sports). Safety of long-term use is not established and is not recommended.

Cardiovascular: Palpitation, tachycardia, vascular thrombotic disease, stroke, chest pain, syncope, flushing

Central nervous system: Edema, fatigue, pseudotumor cerebri, dizziness, drowsiness, headache, insomnia, lethargy, malaise, nervousness, paresthesia, seizure, stroke, suicidal ideation, suicide attempts, suicide, depression, psychosis, aggressive or violent behavior, emotional instability

Dermatologic: Cutaneous allergic reactions, purpura, acne fulminans, alopecia, bruising, cheilitis, dry mouth, dry nose, dry skin, epistaxis, eruptive xanthomas, fragility of skin, hair abnormalities, hirsutism, hyperpigmentation, hypopigmentation, peeling of palms, peeling of soles, photoallergic reactions, photosensitizing reactions, pruritus, rash, dystrophy, paronychia, facial erythema, seborrhea, eczema, increased sunburn susceptibility, urticaria, abnormal wound healing

Endocrine & metabolic: Increased triglycerides (25%), elevated blood glucose, increased HDL, increased cholesterol, abnormal menses

Gastrointestinal: Weight loss, inflammatory bowel disease, regional ileitis, pancreatitis, bleeding and inflammation of the gums, colitis, nausea, nonspecific gastrointestinal symptoms

Genitourinary: Nonspecific urogenital findings

Hematologic: Anemia, thrombocytopenia, neutropenia, agranulocytosis, pyogenic granuloma

Hepatic: Hepatitis

Neuromuscular & skeletal: Skeletal hyperostosis, calcification of tendons and ligaments, premature epiphyseal closure, arthralgia, CPK elevations, arthritis, tendonitis, bone abnormalities, weakness, back pain (29% in pediatric patients), rhabdomyolysis (rare), bone mineral density decreased

Ocular: Corneal opacities, decreased night vision, cataracts, color vision disorder, conjunctivitis, dry eyes, eyelid inflammation, keratitis, optic neuritis, photophobia, visual disturbances

Otic: Hearing impairment, tinnitus

Renal: Vasculitis, glomerulonephritis

Respiratory: Bronchospasms, respiratory infection, voice alteration, Wegener's granulomatosis

Miscellaneous: Allergic reactions, anaphylactic reactions, lymphadenopathy, infection, disseminated herpes simplex, diaphoresis

Carbamazepine: Clearance of carbamazepine may be increased, leading to decreased levels.

Corticosteroids: Corticosteroids may cause osteoporosis. Interactive effect with isotretinoin unknown; use with caution.

Oral contraceptives: Retinoic acid derivatives may diminish the therapeutic effect of oral contraceptives. Two forms of contraception are recommended in females of childbearing potential during retinoic acid therapy.

Phenytoin: Phenytoin may cause osteomalacia. Interactive effect with isotretinoin unknown; use with caution.

Tetracycline: Cases of pseudotumor cerebri have been reported with concurrent use; avoid combination.

Ethanol: Avoid or limit ethanol (may increase triglyceride levels if taken in excess).

Food: Isotretinoin bioavailability increased if taken with food or milk.

Herb/Nutraceutical: Avoid dong quai, St John's wort (may also cause photosensitization and may decrease the effectiveness of oral contraceptives). Additional vitamin A supplements may lead to vitamin A toxicity (dry skin, irritation, arthralgias, myalgias, abdominal pain, hepatic changes); avoid use.

Distribution: Crosses placenta

Protein binding: 99% to 100%; primarily albumin

Metabolism: Hepatic via CYP2B6, 2C8, 2C9, 2D6, 3A4; forms metabolites; major metabolite: 4-oxo-isotretinoin (active)

Half-life elimination: Terminal: Parent drug: 21 hours; Metabolite: 21-24 hours

Time to peak, serum: 3-5 hours

Excretion: Urine and feces (equal amounts)

Children: Maintenance therapy for neuroblastoma (investigational): 100-250 mg/m²/day in 2 divided doses

Children and Adults: Severe recalcitrant nodular acne: 0.5-2 mg/kg/day in 2 divided doses (dosages as low as 0.05 mg/kg/day have been reported to be beneficial) for 15-20 weeks or until the total cyst count decreases by 70%, whichever is sooner. A second course of therapy may be initiated after a period of 2 months off therapy.

Dosing adjustment in hepatic impairment: Dose reductions empirically are recommended in hepatitis disease

Pregnancy test (for all female patients of childbearing potential): Two negative tests with a sensitivity of at least 25 mIU/mL prior to beginning therapy (the second performed during the first five days of the menstrual period immediately preceding the start of therapy); monthly tests to rule out pregnancy prior to refilling prescription.

Lipids: Prior to treatment and at weekly or biweekly intervals until response to treatment is established. Test should not be performed <36 hours after consumption of ethanol.

Liver function tests: Prior to treatment and at weekly or biweekly intervals until response to treatment is established.

The manufacturers of isotretinoin have developed comprehensive educational programs for healthcare providers and patients. Prior to prescribing isotretinoin, healthcare providers must be registered in one of these programs. Additional information for Accutane® and the corresponding S.M.A.R.T. (System To Manage Accutane®-Related Teratogenicity) program may be obtained from Roche Laboratories. Additional information for Amnesteem™ and the S.P.I.R.I.T.™ program (System To Prevent Isotretinoin-Related Issues of Teratogenicity) program maybe obtained from Bertek Pharmaceuticals. Additional information for Sotret® and I.M.P.A.R.T.™ (Isotretinoin Medication Program: Alerting you to the Risks of Teratogenicity) may be obtained from Ranbaxy Pharmaceuticals.

Note: In November 2004, the Food and Drug Administration (FDA) announced an update to the monitoring programs currently implemented to decrease fetal exposures to isotretinoin. The strengthened program, risk minimization action plan (RiskMAP), will include Accutane® as well as all the generic equivalents. When implemented, RiskMAP will replace the SMART program, which is managed by Roche, as well as programs supported by other isotretinoin manufacturers such as S.P.I.R.I.T.™ (Bertek Pharmaceuticals) and I.M.P.A.R.T.™ (Ranbaxy Pharmaceuticals).

Capsule:

Accutane®: 10 mg, 20 mg, 40 mg [contains soybean oil and parabens]

Amnesteem™: 10 mg, 20 mg, 40 mg [contains soybean oil]

Claravis™: 10 mg, 20 mg, 40 mg

Sotret®: 10 mg, 20 mg, 30 mg, 40 mg [contains soybean oil]

American Academy of Pediatrics Committee on Drugs, "Retinoid Therapy for Severe Dermatological Disorders,"Pediatrics, 1992, 90(1 Pt 1):119-20.

Boyd AS, "An Overview of the Retinoids,"Am J Med, 1989, 86(5):568-74.

Burrows NP and Roberts SOB, "Etretinate Hepatitis,"J Dermatol Treat, 1995, 6:135.

Castleberry RP, Emanuel PD, Zuckerman KS, et al, "A Pilot Study of Isotretinoin in the Treatment of Juvenile Chronic Myelogenous Leukemia,"N Engl J Med, 1994, 331(25):1680-4.

DiGiovanna JJ and Peck GL, "Oral Synthetic Retinoid Treatment in Children,"Pediatr Dermatol, 1983, 1(1):77-88.

Hendrix CW, Jackson KA, Whitmore E, et al, "The Effect of Isotretinoin on the Pharmacokinetics and Pharmacodynamics of Ethinyl Estradiol and Norethindrone,"Clin Pharmacol Ther, 2004, 75(5):464-75.

Hepburn NC, "Deliberate Self-Poisoning With Isotretinoin,"Br J Dermatol, 1990, 122(6):840-1.

LaFontaine N, Tousignant J, Rozenfarb E, et al, "Thyroglossal Cyst and Isotretinoin,"Eur J Dermatol, 1995, 5:225-6.

Lammer EJ, Chen DT, Hoar RM, et al, "Retinoic Acid Embryopathy,"N Engl J Med, 1985, 313(14):837-41.

Lee AG, "Pseudotumor Cerebri After Treatment With Tetracycline and Isotretinoin for Acne,"Cutis, 1995, 55(3):165-8.

Lotan R, Xu XC, Lippman SM, et al, "Suppression of Retinoic Acid Receptor-Beta in Premalignant Oral Lesions and Its Up-Regulation by Isotretinoin,"N Engl J Med, 1995, 332(21):1405-10.

Mitchell AA, Van Bennekom CM, Louik C, et al, "A Pregnancy-Prevention Program in Women of Childbearing Age Receiving Isotretinoin,"N Engl J Med, 1995, 333(2):101-6.

Rappaport EB and Knapp M, "Isotretinoin Embryopathy - A Continuing Problem,"J Clin Pharmacol, 1989, 29(5):463-5.

Reynolds CP, Kane DJ, Einhorn PA, et al, "Response of Neuroblastoma to Retinoic Acid In Vitro, and In Vivo,"Prog Clin Biol Res, 1991, 366:203-11

Taillan B, Chichmanian RM, Vialla I, et al, "Paroxysmal Nocturnal Hemoglobinuria and Hemolysis Induced by Isotretinoin,"Therapie, 1994, 49(5):468.