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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(eye soe TRET i noyn)
Generic Available (U.S.)
No
Index Terms
Medication Guide
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Accutane®: http://www.fda.gov/downloads/Drugs/DrugSafety/ucm085812.pdf
Sotret®: http://www.fda.gov/downloads/Drugs/DrugSafety/ucm089135.pdf`
REMS Components
Elements to Assure Safe Use; Implementation System; Medication Guide
Prescribing and Access Restrictions
As a requirement of the REMS program, access to this medication is restricted. All patients (male and female), prescribers, wholesalers, and dispensing pharmacists must register and be active in the iPLEDGE™ risk management program, designed to eliminate fetal exposures to isotretinoin. This program covers all isotretinoin products (brand and generic). The iPLEDGE™ program requires that all patients meet qualification criteria and monthly program requirements (eg, pregnancy testing). Healthcare providers can only prescribe a maximum 30-day supply at each monthly visit and must counsel patients on the iPLEDGE™ program requirements and confirm counseling via the iPLEDGE™ automated system. Registration, activation, and additional information are provided at www.ipledgeprogram.com or by calling 866-495-0654.
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of severe recalcitrant nodular acne unresponsive to conventional therapy
Use: Unlabeled
Management of moderate degrees of treatment-resistant acne, management of acne that produces physical or psychological scarring; treatment of cutaneous T-cell lymphomas (mycosis fungoides and Sézary syndrome); prevention of squamous cell skin cancers (in high-risk patients); treatment of high-risk neuroblastoma in children
Pregnancy Risk Factor
X
Pregnancy Considerations
Major fetal abnormalities (both internal and external), spontaneous abortion and premature births have been reported. [U.S. Boxed Warnings]: Birth defects (facial, eye, ear, skull, central nervous system, cardiovascular, thymus and parathyroid gland abnormalities) have been noted following isotretinoin exposure during pregnancy; low IQ scores have also been reported. The risk for spontaneous abortion and premature births is increased. Because of the high likelihood of teratogenic effects, all patients (male and female), prescribers, wholesalers, and dispensing pharmacists must register and be active in the iPLEDGE™ risk management program; do not prescribe isotretinoin for women who are or who are likely to become pregnant while using the drug. This medication is contraindicated in females of childbearing potential unless they are able to comply with the guidelines of the iPLEDGE™ pregnancy prevention program. Females of childbearing potential should not become pregnant during therapy or for 1 month following discontinuation of isotretinoin. Upon discontinuation of treatment, females of childbearing potential should have a pregnancy test after their last dose and again one month after their last dose. Two forms of contraception should be continued during this time. Any pregnancies should be reported to the iPLEDGE™ program (www.ipledgeprogram.com or 866-495-0654).
Lactation
Excretion in breast milk unknown/contraindicated
Breast-Feeding Considerations
Due to the potential for adverse reactions, breast-feeding is not recommended.
Contraindications
Hypersensitivity to isotretinoin or any component of the formulation; sensitivity to parabens, vitamin A, or other retinoids; pregnancy
Warnings/Precautions
Boxed warnings:
• Pregnancy: See “Special populations” below.
• REMS program: See “Other warnings/precautions” below.
Concerns related to adverse effects:
• Auditory impairment: Hearing impairment, which can continue after therapy is discontinued, may occur. Discontinue therapy if hearing impairment or tinnitus develops.
• Decreased bone mineral density: May decrease bone mineral density; osteoporosis, osteopenia, and bone fractures have been reported with use. Use caution in patients with a genetic predisposition to bone disorders (eg, 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).
• Dermatologic effects: Rare postmarketing cases of severe skin reactions (eg, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), including fatalities, have been reported; monitor for severe skin reactions; discontinue use if severe skin reaction occurs.
• Growth effects: Skeletal hyperostosis and premature epiphyseal closure have also been reported with the use.
• Hepatic effects: Clinical hepatitis and elevated liver enzymes have been reported with use.
• Inflammatory bowel disease: Has been reported with use; discontinue treatment if abdominal pain, rectal bleeding, or severe diarrhea occurs.
• Ocular effects: Vision impairment, corneal opacities, and decreased night vision have also been reported with use.
• Pseudotumor cerebri: Retinoids have been associated with pseudotumor cerebri (benign intracranial hypertension), especially in children. Concurrent use of other drugs associated with this effect (eg, tetracyclines) may increase risk. Early signs and symptoms include papilledema, headache, nausea, vomiting and visual disturbances; discontinue if papilledema occurs.
• Psychiatric effects: May cause depression, psychosis, aggressive or violent behavior, and changes in mood. Rarely, suicidal thoughts and actions have been reported during isotretinoin usage. All patients should be observed closely for symptoms of depression or suicidal thoughts. Discontinuation of treatment alone may not be sufficient, further evaluation may be necessary. Use with extreme caution in patients with a history of psychiatric disorder.
Disease-related concerns:
• Diabetes: Use with caution in patients with diabetes mellitus; impaired glucose control has been reported.
• Hypertriglyceridemia: Use with caution in patients with hypertriglyceridemia; acute pancreatitis and fatal hemorrhagic pancreatitis (rare) have been reported; discontinue therapy if severe hypertriglyceridemia or symptoms of pancreatitis occurs.
Concurrent drug therapy issues:
• Tetracyclines: Pseudotumor cerebri (benign intracranial hypertension) has been reported with use of isotretinoin in combination with tetracyclines; concomitant use should be avoided.
Special populations:
• Pregnancy: [U.S. Boxed Warning]: Birth defects (facial, eye, ear, skull, central nervous system, cardiovascular, thymus and parathyroid gland abnormalities) have been noted following isotretinoin exposure during pregnancy; low IQ scores have also been reported. The risk for spontaneous abortion and premature births is increased.
Other warnings/precautions:
• Blood donation: Patients should be instructed not to donate blood during therapy and for 1 month following discontinuation of therapy due to risk of donated blood being given to a pregnant female.
• Experienced physician: This medication should only be prescribed by prescribers competent in treating severe recalcitrant nodular acne and experienced with the use of systemic retinoids.
• Long-term use: Safety of long-term use is not established and is not recommended.
• REMS program: [U.S. Boxed Warning]: Because of the high likelihood of teratogenic effects, all patients (male and female), prescribers, wholesalers, and dispensing pharmacists must register and be active in the iPLEDGE™ risk management program; do not prescribe isotretinoin for women who are or who are likely to become pregnant while using the drug (see Additional Information or Pharmacotherapy Pearls for details). Women of childbearing potential must be 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 30-day supply, and pregnancy testing and counseling should be repeated monthly.
Adverse Reactions
Frequency not always defined.
Cardiovascular: Chest pain, edema, flushing, palpitation, stroke, syncope, tachycardia, vascular thrombotic disease
Central nervous system: Aggressive behavior, depression, dizziness, drowsiness, emotional instability, fatigue, headache, insomnia, lethargy, malaise, nervousness, paresthesia, pseudotumor cerebri, psychosis, seizure, stroke, suicidal ideation, suicide attempts, suicide, violent behavior
Dermatologic: Abnormal wound healing acne fulminans, alopecia, bruising, cheilitis, cutaneous allergic reactions, dry nose, dry skin, eczema, eruptive xanthomas, facial erythema, fragility of skin, hair abnormalities, hirsutism, hyperpigmentation, hypopigmentation, increased sunburn susceptibility, nail dystrophy, paronychia, peeling of palms, peeling of soles, photoallergic reactions, photosensitizing reactions, pruritus, purpura, rash
Endocrine & metabolic: Triglycerides increased (25%), abnormal menses, blood glucose increased, cholesterol increased, HDL decreased, hyperuricemia
Gastrointestinal: Bleeding and inflammation of the gums, colitis, esophagitis, esophageal ulceration, inflammatory bowel disease, nausea, nonspecific gastrointestinal symptoms, pancreatitis, weight loss, xerostomia
Genitourinary: Nonspecific urogenital findings
Hematologic: Agranulocytosis (rare), anemia, neutropenia, pyogenic granuloma, thrombocytopenia
Hepatic: Alkaline phosphatase increased, ALT increased, AST increased, GGTP increased, hepatitis, LDH increased
Neuromuscular & skeletal: Back pain (29% in pediatric patients), arthralgia, arthritis, bone abnormalities, bone mineral density decreased, calcification of tendons and ligaments, CPK increased, myalgia, premature epiphyseal closure, skeletal hyperostosis, tendonitis, weakness
Ocular: Cataracts, color vision disorder, conjunctivitis, corneal opacities, dry eyes, eyelid inflammation, keratitis, night vision decreased, optic neuritis, photophobia, visual disturbances
Otic: Hearing impairment, tinnitus
Renal: Glomerulonephritis, hematuria, proteinuria, pyuria, vasculitis
Respiratory: Bronchospasms, epistaxis, respiratory infection, voice alteration, Wegener's granulomatosis
Miscellaneous: Allergic reactions, anaphylactic reactions, disseminated herpes simplex, diaphoresis, infection, lymphadenopathy
Postmarketing and/or case reports: Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis
Metabolism/Transport Effects
None known.
Drug Interactions
Alcohol (Ethyl): May enhance the adverse/toxic effect of ISOtretinoin. Specifically, the risk for elevated triglyceride concentrations may be increased. Risk C: Monitor therapy
Contraceptives (Estrogens): Retinoic Acid Derivatives may diminish the therapeutic effect of Contraceptives (Estrogens). Two forms of contraception are recommended in females of child-bearing potential during retinoic acid derivative therapy. Risk C: Monitor therapy
Contraceptives (Progestins): Retinoic Acid Derivatives may diminish the therapeutic effect of Contraceptives (Progestins). Retinoic Acid Derivatives may decrease the serum concentration of Contraceptives (Progestins). Management: Two forms of effective contraception should be used in patients receiving retinoic acid derivatives. Particularly, microdosed progesterone-only preparations may be inadequately effective. Risk D: Consider therapy modification
Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Risk C: Monitor therapy
Tetracycline Derivatives: May enhance the adverse/toxic effect of Retinoic Acid Derivatives. The development of pseudotumor cerebri is of particular concern. Risk X: Avoid combination
Vitamin A: Retinoic Acid Derivatives may enhance the adverse/toxic effect of Vitamin A. Risk X: 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.
Storage
Store at room temperature of 59°F to 86°F (15°C to 30°C). Protect from light.
Mechanism of Action
Reduces sebaceous gland size and reduces sebum production in acne treatment; in neuroblastoma, decreases cell proliferation and induces 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 1-17 years: Neuroblastoma, high-risk (unlabeled use): 160 mg/m2/day (in 2 divided doses) days 1 through 14 every 28 days for 6 cycles, beginning after continuation chemotherapy or transplantation (Matthay, 1999)
Children 12-17 years and Adults:
Acne, severe recalcitrant nodular: 0.5-1 mg/kg/day in 2 divided doses for 15-20 weeks; may discontinue earlier if the total cyst count decreases by 70%. Adults with very severe disease/scarring or primarily involves the trunk may require dosage adjustment up to 2 mg/kg/day. A second course of therapy may be initiated after a period of ≥2 months off therapy. A dose of ≤0.5 mg/kg/day may be used to minimize initial flaring (Strauss, 2007).
Acne, moderate (unlabeled use): 20 mg/day (~0.3-0.4 mg/kg/day) for 6 months (Amichai, 2006)
Dosing adjustment in renal impairment: No dosage adjustment provided in the manufacturer's labeling.
Dosing adjustment in hepatic impairment:
Hepatic impairment prior to treatment: No dosage adjustment provided in the manufacturer's labeling.
Hepatotoxicity during treatment: Liver enzymes may normalize with dosage reduction or with continued treatment; discontinue if normalization does not readily occur or if hepatitis is suspected.
Administration: Oral
Administer orally with a meal. According to the manufacturers' labeling, capsules should be swallowed whole with a full glass of liquid. For patients unable to swallow capsule whole, an oral liquid may be prepared; may irritate esophagus if contents are removed from the capsule.
Monitoring Parameters
CBC with differential and platelet count, baseline sedimentation rate, glucose, CPK; signs of depression, mood alteration, psychosis, aggression, severe skin reactions
Pregnancy test (for all female patients of childbearing potential): Two negative tests prior to beginning therapy (the second performed at least 19 days after the first test and performed during the first 5 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 all of the information on the form. 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 should be swallowed whole, however, may be opened with a large needle and contents sprinkled on applesauce or ice cream (may irritate esophagus when contents are removed from the capsule). 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; muscle aches; lethargy; visual disturbances; photosensitivity; dry mouth; nausea; dryness, redness, or itching of skin; eye irritation; or increased sensitivity to contact lenses. Report depression, suicide ideation, or severe skin reactions. Discontinue therapy and report acute vision changes, ringing in the ears or changes in hearing, rectal bleeding, abdominal cramping, or unresolved diarrhea.
Additional Information
All patients (male and female), must be registered in the iPLEDGE™ risk management program. 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 at least 19 days apart. Two forms of contraception (a primary and secondary form as described in the iPLEDGE™ program materials) must be used simultaneously beginning 1 month prior to treatment, during treatment, and for 1 month after therapy is discontinued; limitations to their use must be explained. Prescriptions should be written for no more than a 30-day supply, and pregnancy testing and counseling should be repeated monthly. During therapy, pregnancy tests must be conducted by a CLIA-certified laboratory. Prescriptions must be filled and picked up from the pharmacy within 7 days of specimen collection for pregnancy test for women of childbearing potential. Prescriptions for males and females of non-childbearing potential must be filled and picked up within 30 days of prescribing.
Any cases of accidental pregnancy should be reported to the iPLEDGE™ program or FDA MedWatch. All patients (male and female) must read and sign the informed consent material provided in the pregnancy prevention program.
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).
Nursing: Physical Assessment/Monitoring
Monitor patients with diabetes closely; monitor skin for unusual reactions. Observe for depression or suicide ideation.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, oral:
Claravis™: 10 mg, 20 mg, 30 mg, 40 mg [contains soybean oil]
Capsule, softgel, oral:
Amnesteem®: 10 mg, 20 mg, 40 mg [contains soybean oil]
Sotret®: 10 mg, 20 mg, 30 mg, 40 mg [contains parabens, soybean oil]
Extemporaneously Prepared
Hazardous agent: Use appropriate precautions for handling and disposal of teratogenic capsule contents.
For patients unable to swallow the capsules whole, an oral liquid may be prepared with softgel capsules (not recommended by the manufacturers) by one of the following methods:
Place capsules (softgel formulations only) in small container and add warm (~37°C [97°F]) water or milk to cover capsule(s); wait 2-3 minutes until capsule is softened and then drink the milk or water with the softened capsule, or swallow softened capsule.
Puncture capsule (softgel formulations only) with needle or cut with scissors; squeeze capsule contents into 5-10 mL of milk or tube feed formula; draw mixture up into oral syringe and administer via feeding tube; flush feeding tube with ≥30 mL additional milk or tube feeding formula.
Puncture capsule (softgel formulations only) with needle or cut with scissors and draw contents into oral syringe; add 1-5 mL of medium chain triglyceride, soybean, or safflower oil to the oral syringe; mix gently and administer via feeding tube; flush feeding tube with ≥30 mL milk or tube feeding formula.
Lam MS, "Extemporaneous Compounding of Oral Liquid Dosage Formulations and Alternative Drug Delivery Methods for Anticancer Drugs," Pharmacotherapy, 2011, 31(2):164-92.
References
American Academy of Pediatrics Committee on Drugs, “Retinoid Therapy for Severe Dermatological Disorders,” Pediatrics, 1992, 90(1 Pt 1):119-20.
Amichai B, Shemer A, and Grunwald MH, “Low-Dose Isotretinoin in the Treatment of Acne Vulgaris,” J Am Acad Dermatol, 2006, 54(4):644-6.
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.
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.
Matthay KK, Villablanca JG, Seeger RC, et al, "Treatment of High-Risk Neuroblastoma With Intensive Chemotherapy, Radiotherapy, Autologous Bone Marrow Transplantation, and 13-cis-Retinoic Acid. Children's Cancer Group," N Engl J Med, 1999, 341(16):1165-73.
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.
Strauss JS, Krowchuk DP, Leyden JJ, et al, “Guidelines of Care for Acne Vulgaris Management,” J Am Acad Dermatol, 2007, 56(4):651-63.
Yu AL, Gilman AL, Ozkaynak MF, et al, “Anti-GD2 Antibody With GM-CSF, Interleukin-2, and Isotretinoin for Neuroblastoma,” N Engl J Med, 2010, 363(14):1324-34.
Zhang C and Duvic M, “Treatment of Cutaneous T-Cell Lymphoma With Retinoids,” Dermatol Ther, 2006, 19(5):264-71.
International Brand Names
Lexi-Comp.com
Last full review/revision March 2012
Content last modified March 2012
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