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. Clinicians have also utilized isotretinoin 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. The patient can maximize the oral absorption of isotretinoin by taking the drug with a meal. Isotretinoin should be taken with a full glass of water to avoid esophageal irritation.
Initial dosing of isotretinoin is commonly at 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 the 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 before starting the medication. Patients should also avoid any skin resurfacing procedures (waxing, dermabrasion, laser therapy) during treatment and at least six months after treatment to prevent 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 common 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.
There are also reports of acute pancreatitis 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 one month after discontinuing treatment due to the risk of embryo-fetal toxicity.
Reports also exist of episodes of depression and psychosis 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 take place prior to prescribing isotretinoin.
Pseudotumor cerebri (benign intracranial hypertension) has presented 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 is necessary, and the patient should receive a referral to a neurologist for further evaluation.
Black Box Warning
Isotretinoin was a pregnancy category X drug under the previous FDA system and is contraindicated in women who are pregnant or who may become pregnant. There have been severe, documented congenital disabilities when pregnant women have taken isotretinoin. To prescribe and receive isotretinoin, the Food and Drug Administration requires prescribers and patients to register with the iPLEDGE program. iPLEDGE ensures the fulfillment of appropriate requirements before 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 before and while taking isotretinoin.
Females of Child-Bearing Potential (FCBP)
Two negative pregnancy tests are necessary 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 five 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 should take place at 30 days following therapy completion.
Females of child-bearing potential (FCBP) must be on two 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 condoms, 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 take place prior to starting therapy.
Ongoing monitoring (All Patients)
Liver function tests (LFTs) and lipids should require monitoring at a biweekly interval until establishing a response to isotretinoin.
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.
Isotretinoin may be prescribed by any clinician, including the nurse practitioner. While the drug is effective for the treatment of acne, all prescribers should be familiar with the drug's adverse effect profile- of which one of the most serious is teratogenicity. Isotretinoin is a pregnancy category X drug and is contraindicated in women who are pregnant or who may become pregnant. There have been severe, documented congenital disabilities when pregnant women have taken isotretinoin. To prescribe and receive isotretinoin, the Food and Drug Administration requires prescribers and patients to register with the iPLEDGE program. iPLEDGE ensures the meeting of appropriate requirements before 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 before and while taking isotretinoin.
Given the nature of isotretinoin therapy, an interprofessional healthcare team approach is absolutely necessary. Pharmacists will play a vital role in working with the patient for iPLEDGE, contacting and keeping in touch with the prescriber, and coordinating with the prescriber's nursing staff to ensure therapy is administered correctly and in the proper situation, particularly in the case of female patients. Nurses also need to provide counsel, monitor for adverse events, and can collaborate with the pharmacist regarding contraceptive measures for female patients. Both the pharmacists and nurses need an open line to the prescriber so any concerns can be addressed immediately. This interprofessional team methodology applies to any medication, but is especially necessary with isotretinoin, to achieve satisfactory and safe therapeutic outcomes for the patient. [Level V]
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