Isotretinoin

Hearing impairment, which can continue after therapy is discontinued, may occur. Discontinue therapy if hearing impairment or tinnitus develops.

May decrease bone mineral density; osteoporosis, osteopenia, bone fractures, and delayed healing of bone fractures have been reported. Use caution in patients with a genetic predisposition for bone loss (eg, age-related osteoporosis, history of childhood osteoporosis conditions, osteomalacia or other disorders of bone metabolism); including patients diagnosed with anorexia nervosa and those on concomitant medications that may cause drug-induced osteoporosis/osteomalacia and/or affect vitamin D metabolism (eg, systemic corticosteroids, anticonvulsants). Patients may be at increased risk when participating in activities with repetitive impact (such as sports) where the risk of spondylolisthesis with and without pars fractures and hip growth plate injuries in early and late adolescence are known.

Postmarketing reports of erythema multiforme severe skin reactions (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis), including fatalities, have been reported; monitor for severe skin reactions; discontinue use if severe skin reaction occurs.

Skeletal hyperostosis and premature epiphyseal closure have also been reported with the use.

Neutropenia and rare cases of agranulocytosis have been reported; discontinue if clinically significant decreases in white cell counts occur.

Clinical hepatitis and mild to moderate elevated liver enzymes have been reported with use; liver enzymes may normalize with dosage reduction or with continued treatment. Discontinue therapy if hepatic enzymes do not normalize or if hepatitis is suspected.

Anaphylaxis and other types of allergic reactions, including cutaneous reactions and serious cases of allergic vasculitis, often with purpura of the extremities and extracutaneous involvement (including renal) have been reported. Discontinue therapy if a serious allergic reaction occurs and institute appropriate medical management.

Inflammatory bowel disease, including regional ileitis, has been reported in patients without a prior history of intestinal disorders; discontinue treatment immediately if abdominal pain, rectal bleeding, or severe diarrhea occurs. Of note, a position statement from the American Academy of Dermatology states that based on currently available data, there is insufficient evidence to prove either an association or a causal relationship between IBD and isotretinoin use (AAD 2016).

Musculoskeletal symptoms (including arthralgia) have been reported; generally symptoms were mild to moderate, but occasionally required discontinuation of therapy. Transient pain in the chest has occurred; symptoms generally cleared after discontinuation of therapy, but in some cases persisted. Rhabdomyolysis, some associated with strenuous physical activity, has been reported (rarely).

Vision impairment, corneal opacities, decreased tolerance to contact lenses (due to dry eyes), and decreased night vision have been reported with use; discontinue therapy in patients experiencing visual difficulties. Warn patients to be cautious when driving or operating machinery at night.

Acute pancreatitis may occur in patients with normal or elevated triglyceride levels; fatal hemorrhagic pancreatitis (rare) has been reported; discontinue therapy if hypertriglyceridemia cannot be controlled at an acceptable level or symptoms of pancreatitis occurs.

Avoid prolonged exposure to UV rays or sunlight.

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 immediately and refer patient to a neurologist if papilledema occurs.

May cause depression, psychosis, mood disturbance, and rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors. All patients should be observed closely for symptoms of depression or suicidal thoughts. Discontinue therapy if depression, mood disturbance, psychosis, or aggression develops. 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:

Use with caution in patients with diabetes mellitus; impaired glucose control has been reported.

Marked elevations of serum triglycerides have been reported; use with caution in patients with hypertriglyceridemia or those who may be at high risk (eg, patients with diabetes, obesity, increased alcohol intake, family history of or those with lipid metabolism disorder). The effects on triglycerides, HDL, and cholesterol have been reversible upon discontinuation of therapy. Instruct patients to avoid or limit ethanol; may increase triglyceride levels if taken in excess. Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Special populations:

[US Boxed Warnings]: Use of isotretinoin is contraindicated in females who are or may become pregnant. Birth defects (facial, eye, ear, skull, central nervous system, cardiovascular, thymus and parathyroid gland abnormalities) have been noted following isotretinoin exposure during pregnancy and the risk for severe birth defects is high, with any dose or even with short treatment duration. 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 evaluation and mitigation strategy (REMS) program; do not prescribe isotretinoin for women who are or who are likely to become pregnant while using the drug. If pregnancy occurs during therapy, isotretinoin should be discontinued immediately and the patient referred to an obstetrician-gynecologist specializing in reproductive toxicity. Dosage form specific issues:

Absorption is ~83% greater than Accutane when administered under fasting conditions; they are bioequivalent when taken with a high-fat meal. Absorica is not interchangeable with other generic isotretinoin products.

Isotretinoin and tretinoin (which is also known as all-trans retinoic acid, or ATRA) may be confused, while both products may be used in cancer treatment, they are not interchangeable; verify product prior to dispensing and administration to prevent medication errors.

Some products may contain tartrazine (FD&C yellow no. 5), which may cause allergic reactions, including bronchial asthma, in certain individuals. Allergy is frequently seen in patients who also have an aspirin hypersensitivity. Other warnings/precautions:

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.

This medication should only be prescribed by health care providers competent in treating severe recalcitrant nodular acne and experienced with the use of systemic retinoids.

Safety of long-term use is not established and is not recommended; the effect on bone loss is unknown.

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 evaluation and mitigation strategy (REMS) 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.

Avoid skin resurfacing procedures (eg, dermabrasion, laser) and wax epilation during therapy and for at least 6 months after discontinuation of isotretinoin due to the risk of scarring.