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Clinical Trials and Postmarketing Surveillance

The adverse reactions listed below reflect the experience from investigational studies of Accutane (isotretinoin) , and the postmarketing experience. The relationship of some of these events to Accutane (isotretinoin) therapy is unknown. Many of the side effects and adverse reactions seen in patients receiving Accutane (isotretinoin) 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 PATIENT INFORMATION). 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, myalgia, and arthralgia (see PATIENT INFORMATION), transient pain in the chest (see PATIENT INFORMATION ), 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 erythema multiforme, 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), Stevens-Johnson syndrome, sunburn susceptibility increased, sweating, toxic epidermal necrolysis, urticaria, vasculitis (including Wegener's granulomatosis; see PRECAUTIONS: Hypersensitivity), abnormal wound healing (delayed healing or exuberant granulation tissue with crusting; see PATIENT INFORMATION)

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 PATIENT INFORMATION), 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 (isotretinoin) to vitamin A, patients should be advised against taking vitamin supplements containing vitamin A to avoid additive toxic effects.
• Tetracyclines: Concomitant treatment with Accutane (isotretinoin) and tetracyclines should be avoided because Accutane (isotretinoin) 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 (isotretinoin) therapy. Although other hormonal contraceptives are highly effective, there have been reports of pregnancy from female patients who have used combined oral contraceptives, as well as transdermal patch/injectable/implantable/vaginal ring hormonal birth control products. These reports are more frequent for female patients who use only a single method of contraception. It is not known if hormonal contraceptives differ in their effectiveness when used with Accutane (isotretinoin) . Therefore, it is critically important for female patients 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 (see PRECAUTIONS).
• Norethindrone/ethinyl estradiol: In a study of 31 premenopausal female patients with severe recalcitrant nodular acne receiving OrthoNovum® 7/7/7 Tablets as an oral contraceptive agent, Accutane (isotretinoin) at the recommended dose of 1 mg/kg/day, did not induce clinically relevant changes in the pharmacokinetics of ethinyl estradiol and norethindrone and in the serum levels of progesterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). 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.
• St. John's Wort: Accutane (isotretinoin) 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.
• Phenytoin: Accutane (isotretinoin) 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 (isotretinoin) . 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 (isotretinoin) . Therefore, caution should be exercised when using these drugs together.

Laboratory Tests

• Pregnancy Test
  • Female patients of childbearing potential must have had two negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL before receiving the initial Accutane (isotretinoin) prescription. The first test (a screening test) is obtained by the prescriber when the decision is made to pursue qualification of the patient for Accutane (isotretinoin) . The second pregnancy test (a confirmation test) must be done in a CLIA-certified laboratory. The interval between the two tests must be at least 19 days.
  • For patients with regular menstrual cycles, the second pregnancy test must be done during the first 5 days of the menstrual period immediately preceding the beginning of Accutane (isotretinoin) therapy and after the patient has used 2 forms of contraception for 1 month.
  • For patients with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding, the second pregnancy test must be done immediately preceding the beginning of Accutane (isotretinoin) therapy and after the patient has used 2 forms of contraception for 1 month.
  • Each month of therapy, patients must have a negative result from a urine or serum pregnancy test. A pregnancy test must be repeated each month, in a CLIA-certified laboratory, 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 (isotretinoin) 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 (isotretinoin) have experienced problems in the control of their blood sugar. In addition, new cases of diabetes have been diagnosed during Accutane (isotretinoin) therapy, although no causal relationship has been established.
• CPK: Some patients undergoing vigorous physical activity while on Accutane (isotretinoin) 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.

REFERENCES

7. Dicken CH, Connolly SM. Eruptive xanthomas associated with isotretinoin (13-cis-retinoic acid). Arch Dermatol 116:951-952, 1980.

Last reviewed on RxList: 1/3/2011
This monograph has been modified to include the generic and brand name in many instances.