Side Effects of Accutane (isotretinoin)

Accutane (isotretinoin) is a retinoid used to treat severe acne that is resistant to more conservative treatments such as creams, drying agents, and topical or oral antibiotics. 

Acne is caused by inflammation of the skin. It primarily affects teenagers, but it also affects adults. Severe acne causes permanent scarring of the skin. The inflammation is caused in part by an increased secretion of sebum (oily substance) from glands in the skin (sebaceous glands). The sebum provokes inflammation, and the inflammation resolves (heals) with the formation of a scar (keratinization). 

The exact mechanism of action of Accutane is not known; however, it may reduce acne by reducing the secretion of sebum. If less sebum is secreted it is likely that there will be less inflammation and keratinization.

Common side effects of Accutane include

• dry skin,
• itching,
• dry nose,
• nosebleeds,
• cracks in the corners of the mouth,
• dry mouth,
• inflammation of the whites of the eyes,
• joint aches,
• increased cholesterol,
• increased triglycerides,
• increased glucose,
• headache,
• ringing in the ears,
• insomnia,
• abnormal menstrual periods, and
• fluid retention (edema).

Serious side effects of Accutane include

• skin infections,
• peeling,
• sun-sensitivity to drugs,
• hearing impairment,
• hepatitis,
• psychiatric problems (depression, hallucinations, and suicidal behavior),
• erythema multiforme and severe skin reactions (for example, Stevens-Johnson syndrome, toxic epidermal necrolysis), and rarely,
• brain swelling (pseudotumor cerebri or intracranial hypertension), which produces nausea, vomiting, headache, and changes in vision.

Drug interactions of Accutane include vitamin A, because Accutane is closely related to vitamin A and the use of both at the same time may lead to vitamin A side effects. 

Treatment with tetracycline and Accutane should not be given at the same time since the combination has been associated with brain swelling. 

Accutane is harmful to a fetus and should not be used during pregnancy. Women of childbearing age must have two negative pregnancy test results before therapy is started, and a pregnancy test must be conducted during each month of therapy. 

Two effective forms of birth control must be used during therapy, and pregnancy should be avoided one month before, during, and at least one month after stopping Accutane. 

It is unknown if Accutane is secreted in breast milk, but because of its potentially serious side effects, it should not be used by breastfeeding mothers.

The most common side effects of isotretinoin are:

• Dry skin,
• Itching,
• Dry nose,
• Nosebleeds (epistaxis),
• Cracks in the corners of the mouth (chilitis),
• Dry mouth,
• Inflammation of the whites of the eyes.

Joint aches also are common. Patients may develop an increase in blood cholesterol and triglycerides. Psychiatric problems such as depression, hallucinations and suicidal behavior have been reported.

Other side effects include:

• Joint aches
• Increased cholesterol
• Increased triglycerides
• Increased glucose
• Headache
• Ringing in the ears
• Insomnia
• Abnormal periods
• Edema

Serious side effects include:

• Skin infections
• Peeling
• Sun-sensitivity to drugs
• Hearing impairment
• Hepatitis

Rarely, isotretinoin can cause brain swelling (pseudotumor cerebri or intracranial hypertension), which produces nausea, vomiting, headache, and changes in vision.

Erythema multiforme and severe skin reactions (for example, Stevens-Johnson syndrome, toxic epidermal necrolysis) have been associated with isotretinoin use. These events may be serious and result in life-threatening events or death, hospitalization, or disability. Patients should be monitored closely for severe skin reactions, and isotretinoin discontinued if necessary.

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.

Body as a Whole

allergic reactions, including vasculitis, systemic hypersensitivity, edema, fatigue, lymphadenopathy, weight loss

Cardiovascular

palpitation, tachycardia, vascular thrombotic disease, stroke

Endocrine/Metabolic

hypertriglyceridemia, alterations in blood sugar levels

Gastrointestinal

inflammatory bowel disease, hepatitis, pancreatitis, bleeding and inflammation of the gums, colitis, esophagitis/esophageal ulceration, ileitis, nausea, other nonspecific gastrointestinal symptoms

Hematologic

allergic reactions, anemia, thrombocytopenia, neutropenia, rare reports of agranulocytosis. See prescribing information for other hematological parameters.

Musculoskeletal

skeletal hyperostosis, calcification of tendons and ligaments, premature epiphyseal closure, decreases in bone mineral density, musculoskeletal symptoms (sometimes severe) including back pain, myalgia, and arthralgia, transient pain in the chest, arthritis, tendonitis, other types of bone abnormalities, elevations of CPK/rare reports of rhabdomyolysis.

Neurological

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, 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), abnormal wound healing (delayed healing or exuberant granulation tissue with crusting)

Special Senses

Hearing — hearing impairment, tinnitus.

Vision — corneal opacities, decreased night vision which may persist, cataracts, color vision disorder, conjunctivitis, dry eyes, eyelid inflammation, keratitis, optic neuritis, photophobia, visual disturbances

Urinary System

glomerulonephritis, nonspecific urogenital findings

Laboratory

Elevation of plasma triglycerides, decrease in serum high-density lipoprotein (HDL) levels, elevations of serum cholesterol during treatment

Increased alkaline phosphatase, SGOT (AST), SGPT (ALT), GGTP or LDH

Elevation of fasting blood sugar, elevations of CPK, hyperuricemia

Decreases in red blood cell parameters, decreases in white blood cell counts (including severe neutropenia and rare reports of agranulocytosis, 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.
• 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. 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.
• 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.
• 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.