Isotretinoin is an oral prescription medication that affects sebaceous glands and is used in the treatment of severe acne. The drug was approved by the US Food and Drug Administration (FDA) in 1982 for the treatment of severe, resistant, nodular acne that is unresponsive to conventional therapy including systemic antibiotics.
Non-FDA Approved Indications
Isotretinoin has been used for moderate acne, cutaneous T-cell lymphomas, neuroblastoma, and prevention of squamous cell carcinoma in high-risk patients. Isotretinoin has also been used in the treatment of rosacea, folliculitis, and pyoderma faciale.
Isotretinoin is an orally administered systemic retinoid. At a pharmacologic strength of 0.5 to 1.0 mg/kg per day, isotretinoin is an effective acne therapy. While the exact mechanism of action is unknown, at pharmacologic doses isotretinoin inhibits sebaceous gland function and keratinization. The drug has been observed to reduce both the sebaceous gland size and sebum production.
Isotretinoin is administered orally in the form of a capsule. The drug has low bioavailability and is highly lipophilic. Oral absorption of isotretinoin can be maximized by taking the drug with a meal. Isotretinoin should be taken with a full glass of water to avoid esophageal irritation.
Isotretinoin is commonly initiated at a dose of 0.5 mg/kg per day, and then gradually increased to a dose of 1.0 mg/kg per day according to patient tolerance. Typical therapy requires a 15- to 20-week course of daily isotretinoin administration to achieve complete prolonged remission of disease.
Cheilitis or dry lips are the most common dose-dependent adverse effect seen in about 90% of patients taking isotretinoin. Dry skin (xerosis), dry mouth (xerostomia), dry nose, and sun sensitivity are also very common adverse effects seen in patients taking isotretinoin. Sun protection and skin moisturizers and barriers are important patient education topics prior to starting the medication. Patients should also avoid any skin resurfacing procedures (waxing, dermabrasion, laser therapy) during treatment and at least 6 months after treatment to avoid skin irritation and scarring.
Hypertriglyceridemia and increased erythrocyte sedimentation rate are also very common side effects of isotretinoin therapy. Frequent laboratory monitoring is indicated during the induction period and throughout treatment with isotretinoin to monitor for these common adverse effects.
Other Potential Adverse Effects
Itching (pruritis), irritation, hair thinning, skin fragility, dry eyes, skin infections, rash, bone or joint pain, muscle aches, and joint pain (arthralgias); back and joint pain is most commonly seen in the pediatric population
Other Potential Laboratory Abnormalities
Decreased high-density lipoproteins (HDLs), increased liver function tests (LFTs), increased creatinine phosphokinase (CPK), decreased hemoglobin and hematocrit, decreased erythrocyte and leukocyte counts, and increased platelet counts. In the rare event that neutropenia or agranulocytosis should occur, isotretinoin should be discontinued.
There have been controversial associations with isotretinoin in patients who also suffer from inflammatory bowel disease or depression. However, recent meta-analyses have not shown an association with isotretinoin and these diseases.
Serious skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported and warrant prompt cessation of isotretinoin if they occur during therapy.
Acute pancreatitis has been reported in patients taking isotretinoin with both normal and elevated serum triglyceride levels. Therapy should be discontinued if symptoms of pancreatitis occur.
Patients taking isotretinoin should avoid blood donation while on isotretinoin and for 1 month after discontinuing treatment due to the risk of embryo-fetal toxicity.
Episodes of depression and psychosis have been reported in patients taking isotretinoin. Even though the correlation is controversial, screening for depression, suicidal ideation, past suicide attempts, and aggressive and/or violent behaviors should be performed prior to prescribing isotretinoin.
Pseudotumor cerebri (benign intracranial hypertension) has been seen in cases of patients taking isotretinoin with concomitant use of tetracyclines. For this reason, tetracyclines should not be administered with isotretinoin. If patients develop signs or symptoms of pseudotumor cerebri, prompt cessation isotretinoin should be initiated, and the patient should be referred to a neurologist for further evaluation.
Black Box Warning
Isotretinoin is a pregnancy category X drug and is contraindicated in women who are pregnant or who may become pregnant. There have been serious documented congenital disabilities when pregnant women have taken isotretinoin. To prescribe and receive isotretinoin, the Food and Drug Administration requires prescribers and patients to be registered with the iPLEDGE program. iPLEDGE ensures appropriate requirements have been met prior to the distribution of isotretinoin to prevent the use of this medication during pregnancy. These requirements include negative pregnancy tests and documented abstinence or the use of birth control prior to and while taking isotretinoin.
Females of Child-Bearing Potential (FCBP)
Two negative pregnancy tests are required before the initiation of therapy with isotretinoin. The first pregnancy test occurs up to 30 days prior to medication initiation. The second pregnancy test must occur at least 19 days after the first negative pregnancy test and within the first 5 days of the patient’s menstrual cycle. Each subsequent month the patient must have a recorded negative pregnancy test to continue therapy. After discontinuation of therapy, a final pregnancy test is performed at 30 days post-therapy completion.
FCBP must be on 2 effective forms of birth control or complete abstinence while receiving isotretinoin therapy. The iPLEDGE program defines abstinence as no sex or sexual contact with any male 24 hours a day, 7 days a week. The iPLEDGE program does not recommend abstinence as a way to prevent pregnancy while on isotretinoin. If a patient chooses birth control, one of the birth control methods must be a “primary form” which includes tubal sterilization, partner’s vasectomy, intrauterine device, or hormonal (combination birth control pills, skin patches, shots, under-the-skin implants, or vaginal rings). Secondary forms include male latex condom, diaphragm, cervical cap, or vaginal sponge all with the co-use of spermicide. Natural family planning, birth control pills without estrogen, female condoms, withdrawal, and cervical shield are not acceptable forms of birth control according to the iPLEDGE program.
Pretreatment Monitoring (All Patients)
Liver function tests (LFTs), fasting lipid profile (including triglycerides), blood glucose, creatinine phosphokinase (CPK), and complete blood counts (CBC) with differential should be drawn before initiating therapy with isotretinoin. Screening for mood alteration, psychosis, aggression, suicidal ideation, skin changes, and visual changes should also be performed prior to starting therapy.
Ongoing monitoring (All Patients)
Liver function tests (LFTs) and lipids should be monitored at a biweekly interval until a response to isotretinoin has been established.
There is no commonly used antidote to isotretinoin intoxication. Reports of acute intoxication indicate exacerbations of common, well-known isotretinoin side-effects which include cutaneous xerosis and cheilitis.