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Special Alerts:

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.

Pronunciation:

(eye soe TRET i noyn)

U.S. Brand Names:

Accutane®; Amnesteem™; Claravis™; Sotret®

Synonyms:

13-cis-Retinoic Acid

Generic Available:

Yes

Canadian Brand Names:

Accutane®; Isotrex®

Use:

Treatment of severe recalcitrant nodular acne unresponsive to conventional therapy

Use - Unlabeled/Investigational:

Investigational: Treatment of children with metastatic neuroblastoma or leukemia that does not respond to conventional therapy

Restrictions:

A new program for risk minimization (RiskMAP) is being designed by the FDA and the manufacturers of isotretinoin. Details may be found on the FDA website at http://www.fda.gov/bbs/topics/ANSWERS/2004/ANS01328.html. When implemented, RiskMAP will strengthen the current prescribing and dispensing requirements. Under the current guidelines, prescriptions for isotretinoin may not be dispensed unless they are affixed with a yellow, self-adhesive, qualification sticker filled out by the prescriber. Telephone, fax, or computer-generated prescriptions are no longer valid. Prescriptions may not be written for more than a 1-month supply and must be dispensed with a patient education guide every month. In addition, prescriptions for females must be filled within 7 days of the qualification date noted on the yellow sticker; prescriptions filled after 7 days of the noted date are considered to be expired and cannot be honored. Pharmacists may call the manufacturer to confirm the prescriber's authority to write for this medication; however, this is not mandatory.

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.

Pregnancy Risk Factor:

Pregnancy Implications:

Major fetal abnormalities (both internal and external), spontaneous abortion, premature births and low IQ scores in surviving infants have been reported. This medication is contraindicated in females of childbearing potential unless they are able to comply with the guidelines of pregnancy prevention programs put in place by the FDA and the manufacturer of isotretinoin.

Lactation:

Excretion in breast milk unknown/contraindicated

Contraindications:

Hypersensitivity to isotretinoin or any component of the formulation; sensitivity to parabens, vitamin A, or other retinoids; pregnancy

Warnings/Precautions:

This medication should only be prescribed by prescribers competent in treating severe recalcitrant nodular acne, are experienced in the use of systemic retinoids, and are participating in the pregnancy prevention programs authorized by the FDA and product manufacturer. Use with caution in patients with diabetes mellitus, hypertriglyceridemia; acute pancreatitis and fatal hemorrhagic pancreatitis (rare) have been reported. Not to be used in women of childbearing potential unless woman is capable of complying with effective contraceptive measures. Patients must select and commit to two forms of contraception. Therapy is begun after two negative pregnancy tests; effective contraception must be used for at least 1 month before beginning therapy, during therapy, and for 1 month after discontinuation of therapy. Prescriptions should be written for no more than a 1-month supply, and pregnancy testing and counseling should be repeated monthly. Because of the high likelihood of teratogenic effects (~20%), do not prescribe isotretinoin for women who are or who are likely to become pregnant while using the drug (see Additional Information for details). Male and female patients must be enrolled in the manufacturer-sponsored and FDA-approved monitoring programs.

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.

Adverse Reactions:

Frequency not defined.

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

Overdosage/Toxicology:

Symptoms of overdose include headache, vomiting, flushing, abdominal pain, cheilosis, dizziness, and ataxia. All signs or symptoms have been transient. Patients should not donate blood for at least 30 days following overdose. Male patients should use a condom or avoid sexual activity for 30 days following overdose.

Drug Interactions:

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/Nutrition/Herb Interactions:

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.

Stability:

Store at room temperature and protect from light

Mechanism of Action:

Reduces sebaceous gland size and reduces sebum production; regulates cell proliferation and differentiation

Pharmacodynamics/Kinetics:

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)

Dosage:

Oral:

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

Administration:

Administer with food. Capsules can be swallowed, or chewed and swallowed. The capsule may be opened with a large needle and the contents placed on applesauce or ice cream for patients unable to swallow the capsule. Whole capsules should be swallowed with a full glass of liquid.

Monitoring Parameters:

CBC with differential and platelet count, baseline sedimentation rate, glucose, CPK

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.

Dietary Considerations:

Should be taken with food. Limit intake of vitamin A; avoid use of other vitamin A products. Some formulations may contain soybean oil.

Patient Education:

A patient information/consent form must be signed before this medication is prescribed. Do not sign (and do not take this medication) if you do not understand any information on the form. Use exactly as directed; do not take more than recommended. Prescriptions will be written for a 1-month supply and must be filled within 7 days; they will not be honored if filled after that time or if they do not have the appropriate yellow qualification sticker attached. Capsule can be chewed and swallowed, swallowed, or opened with a large needle and contents sprinkled on applesauce or ice cream. Whole capsules should be swallowed with a full glass of liquid. Do not take any other vitamin A products, limit vitamin A intake, and increase exercise during therapy. Limit or avoid alcohol intake. Exacerbations of acne may occur during first weeks of therapy. You may experience headache, loss of night vision, lethargy, or visual disturbances (use caution when driving or engaging in tasks requiring alertness until response to drug is known); photosensitivity (use sunscreen, wear protective clothing and eyewear, and avoid direct sunlight); dry mouth or nausea (small, frequent meals, sucking hard candy, or chewing gum may may help); or dryness, redness, or itching of skin, eye irritation, or increased sensitivity to contact lenses (wear regular glasses). Discontinue therapy and report acute vision changes, ringing in the ears or changes in hearing, rectal bleeding, abdominal cramping, or unresolved diarrhea. Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant. Do not get pregnant 1 month before, during, or for 1 month following therapy. This drug may cause severe fetal defects. Two forms of contraception and monthly tests to rule out pregnancy are required during therapy. It is important to note that any type of contraception may fail, it is the responsibility of the patient to be compliant with contraceptive therapy. Do not donate blood during or for 1 month following therapy (same reason). Do not breast-feed.

Additional Information:

Females of childbearing potential must receive oral and written information reviewing the hazards of therapy and the effects that isotretinoin can have on a fetus. Therapy should not begin without two negative pregnancy tests, one to be performed in the physician's office when qualifying the patient for treatment, the second test performed on the second day of the next normal menstrual period or 11 days after the last unprotected intercourse, whichever is last. Two forms of contraception (a primary and secondary form as described in the pregnancy prevention program materials) must be used during treatment and limitations to their use must be explained. Prescriptions should be written for no more than a 1-month supply, and pregnancy testing and counseling should be repeated monthly. Urine pregnancy test kits (for monthly pregnancy testing) and a Pregnancy Prevention Program kit (to be given to the patient prior to therapy) are provided by the manufacturer. Any cases of accidental pregnancy should be reported to the manufacturer or the FDA MedWatch Program. All patients (male and female) must read and sign the informed consent material provided in the pregnancy prevention program. Prescriptions will not be honored unless they have the yellow qualification sticker affixed.

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).

Dental Health: Effects on Dental Treatment:

Key adverse event(s) related to dental treatment: Xerostomia and changes in salivation (normal salivary flow resumes upon discontinuation).

Dental Health: Vasoconstrictor/Local Anesthetic Precautions:

No information available to require special precautions

Mental Health: Effects on Mental Status:

May cause depression, psychosis; may rarely cause suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors

Mental Health: Effects on Psychiatric Treatment:

May increase the clearance of carbamazepine, leading to decreased levels; monitor. Avoid dong quai and St John's wort (may cause photosensitization).

Dosage Forms:

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]

International Brand Names:

Accure® (AU); Accutane® (CA); Accutin® (DK); Acnetane® (ZA); Aknefug ISO® (DE); Aknenormin® (DE); Curacné® (FR); Curatane® (IL); Dermaoral® (DK); Geldermic® (AR); Isoacne® (BR); Isocutan® (AT); Isodern® (DE); Isoface® (CO); Isoroc-Mepha® (CH); Isotret-Hexal® (DE); Isotretinoin Alpharma® (DK); Isotretinoin Cross Pharma® (DK); Isotretinoin® (GB); Isotretinoin-Isis® (DE); Isotretinoin-Mepha® (CH); Isotretinoin ratiopharm® (AT, DE, DK, FI); Isotretinoin Stada® (DE); Isotrex® (AR, AT, AU, CA, CL, CO, CR, DE, DK, DO, EG, ES, FR, GB, GT, HN, HU, IE, IL, IT, JO, KW, LB, LU, MX, NZ, PA, PL, SG, SV, SY, TH, ZA); Istret® (CH); Liderma® (CH); Meditretin® (DE); Nimegen® (SG); Oratane® (AU, NZ, SG, ZA); Procuta® (FR); Roaccutan® (AR, AT, CH, CO, DE, DK, FI, HU, IT, MX, PT, RO); Roaccutane® (AU, BD, BE, CR, CZ, DO, FR, GB, GT, HK, HN, HR, IE, IL, LU, NL, NZ, PA, PL, RU, SG, SI, SV, TH, TR, YU, ZA); Roacnetan® (CL); Roacutan® (AR, BR, CZ); Roacutan Roche® (ES); Tretinac® (CH)

References

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.

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