Isotretinoin

Mechanism of Action

Isotretinoin is an orally administered systemic retinoid. Isotretinoin is an effective acne therapy at a daily dose of 0.5 to 1.0 mg/kg. While the exact mechanism of action is unknown, isotretinoin inhibits sebaceous gland function and keratinization at pharmacologic doses. The drug has been observed to reduce sebaceous gland size and sebum production. In patients with neuroblastoma (off-label use), isotretinoin has been shown to reduce cell proliferation and induce differentiation.[6][11]

Pharmacokinetics

Absorption: Isotretinoin achieves its highest plasma concentration (Tmax) around 6.4 hours after food consumption, while this peak occurs in about 2.9 hours when it is taken on an empty stomach. Food may enhance the absorption of isotretinoin. However, this variation is not considered clinically crucial, so isotretinoin can be taken with or without meals. Advances in isotretinoin formulations, including lidose encapsulation and micronization, have reduced bioavailability variability between fed and fasted states, ensuring more consistent dosing.[12]

Distribution: Isotretinoin is highly protein-bound in plasma, with over 99.9% of the drug binding to albumin.

Metabolism: Isotretinoin is primarily metabolized in the liver by the cytochrome P450 enzymes CYP2C8, CYP2C9, CYP3A4, and CYP2B6.[13] Following oral administration, isotretinoin undergoes conversion into several metabolites, including 4-oxo-isotretinoin, retinoic acid (tretinoin), and 4-oxo-retinoic acid (4-oxo-tretinoin), which are all detectable in human plasma.[14][15] These metabolites retain retinoid activity in vitro, though their clinical significance remains to be fully understood.

Elimination: The elimination half-lives of isotretinoin and its major metabolite, 4-oxo-isotretinoin, are 18 hours and 38 hours, respectively. Isotretinoin and its metabolites are predominantly excreted through feces and urine.

Administration

Available Dosage Forms and Strengths

Isotretinoin is administered orally as 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. Isotretinoin is available in oral capsule formulations in strengths of 10 mg, 20 mg, 25 mg, 30 mg, 35 mg, and 40 mg. Additionally, it is offered as a micronized capsule formulation in strengths of 8 mg, 16 mg, 20 mg, 24 mg, 28 mg, and 32 mg.

Adult Dosage

The initial dose of isotretinoin is commonly 0.5 mg/kg/d, and then it is gradually increased to 1.0 mg/kg/d, according to patient tolerance. Typical therapy requires 15-20 weeks of daily isotretinoin administration for complete, prolonged disease remission.[6][16] For adults with severe acne, including scarring and trunk involvement, an increased dosage of isotretinoin may be prescribed at 2 mg/kg/d, administered in divided doses.

Specific Patient Populations

Hepatic impairment: Liver function abnormalities occur in up to 15% of patients taking isotretinoin, although significant elevations necessitating discontinuation are uncommon. The mechanism of injury is not fully understood, but it may involve a direct toxic effect, with higher doses linked to increased frequency. These abnormalities are generally asymptomatic and transient, often resolving without discontinuation. Regular monitoring of liver tests is advised, and isotretinoin should be stopped if aminotransferase levels exceed 5 times the upper limit of normal or if symptoms like jaundice develop.[17]

Renal impairment: No dosage adjustments are provided in the product labeling. Use with caution.

Pregnancy considerations: Isotretinoin is contraindicated in pregnancy due to its potential to cause severe fetal harm, including major congenital malformations, spontaneous abortions, and premature births. Even brief exposure during pregnancy can result in life-threatening congenital disabilities, and there is no reliable method to determine prenatally if a fetus has been affected. Documented malformations include defects in the face, eyes, ears, skull, central nervous system, cardiovascular system, thymus, and parathyroid glands. Cognitive impairments, which may be suggested by IQ scores below 85, have also been reported in children exposed in utero. If a patient becomes pregnant while undergoing isotretinoin therapy, the medication must be stopped immediately, and the patient should be referred to an obstetrician/gynecologist for further evaluation and counseling. Any suspected fetal exposure must be reported to the FDA through MedWatch (1-800-FDA-1088) and the iPLEDGE pregnancy registry (1-866-495-0654 or www.ipledgeprogram.com). Isotretinoin is available only through a restricted program under a REMS, which includes a pregnancy exposure registry to monitor pregnancy outcomes in patients exposed to isotretinoin. According to the study, isotretinoin exposure during pregnancy significantly increases the risk of congenital anomalies and adverse pregnancy outcomes compared to exposure before pregnancy, which showed similar rates to the control group. Whole exome sequencing may help evaluate complex phenotypes in isotretinoin-exposed infants, but further research is needed.[18]

Breastfeeding considerations: Due to the risk of severe adverse reactions in nursing infants, breastfeeding is not recommended during isotretinoin treatment and for at least 8 days after the last dose. Topical medications less likely to be absorbed by the mother may be preferable during breastfeeding.[19]

Pediatric patients: Isotretinoin is approved as safe and effective for treating severe nodular acne in patients aged 12 to 17, but its use in those under 12 has not been approved. According to the American Academy of Pediatrics (AAP), the suggested starting dose of isotretinoin is 0.5 mg/kg/d for the first 4 weeks to minimize initial flare-ups, followed by an increase to 1 mg/kg/d. The panel supports this approach for treating acne in adolescents and preadolescents and agrees that isotretinoin may be considered in younger patients with severe, refractory, or scarring acne.[20]

Older patients: Acne can persist or develop in older adults, with types like persistent, premenstrual "chin acne," or sporadic acne. When it occurs, triggers such as comedogenic substances, medications, and endocrine disorders should be ruled out. Treatment in older adults emphasizes reassurance, with azelaic acid and sulfur being preferred over more irritating options like retinoids. Low-dose systemic isotretinoin may also be beneficial for some patients.[21]

Adverse Effects

Cheilitis or dry lips are the most common dose-dependent adverse effects in about 90% of patients taking isotretinoin. Dry skin (xerosis), dry mouth (xerostomia), dry nose, and photosensitivity are common adverse effects in patients taking isotretinoin. Before starting the medication, the patient should be educated on sun protection, skin moisturizers, and barriers. Patients should also avoid all skin resurfacing procedures (waxing, dermabrasion, laser therapy) during treatment and at least 6 months after treatment to prevent skin irritation and scarring.

Hypertriglyceridemia and increased erythrocyte sedimentation rate are also very common adverse effects of isotretinoin therapy. Frequent monitoring for these effects is indicated during the induction and treatment periods. A rare case report of isotretinoin-induced pericardial effusion/atrial tachycardia has been reported.[22] Isotretinoin has been implicated in rare cases of rhabdomyolysis, particularly when combined with physical exercise.[23] Although this adverse effect is uncommon, patients experiencing myalgia should be monitored for creatine phosphokinase (CPK) elevation during therapy to facilitate early detection of potential rhabdomyolysis.[24]

A systematic review examined musculoskeletal adverse effects associated with isotretinoin. Common symptoms included low back pain, myalgia, arthralgia, sacroiliitis, and tendinopathy, with most symptoms appearing within a few months of treatment. The sacroiliitis was the most significant complication. The cumulative dose of isotretinoin was associated with an increased risk of low back pain, but no significant relationship was found with HLA-B27 status. Discontinuation of isotretinoin and anti-inflammatory treatments typically resolved symptoms.[25]

A meta-analysis found weak evidence linking major adverse cardiovascular events (MACE) to isotretinoin. Case reports highlight thromboembolic events, cardiomyopathy, arrhythmias, and acute coronary syndrome, but causality remains unclear. Cardiovascular risk factors, including baseline and follow-up lipid profiles, should be assessed before and during isotretinoin therapy. If MACE occurs, isotretinoin should be discontinued, and the relationship with the drug should be evaluated individually, considering other potential causes. Further research into underlying mechanisms is needed.[26]

Other potential adverse effects include itching (pruritis), irritation, hair thinning, skin fragility, dry eyes, skin infections, rash, bone or joint pain, muscle aches, and joint pain (arthralgias) are common. Back and joint pain are most common in the pediatric population.[27] There have been controversial associations with isotretinoin in patients who are also experiencing inflammatory bowel disease or depression. However, recent meta-analyses have not shown an association between isotretinoin and these diseases; further research is needed.[28]

Potential laboratory abnormalities for patients receiving isotretinoin include 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.[29][30]

Drug-Drug Interactions

Vitamin A: Isotretinoin should not be co-administered with vitamin A supplements to avoid the risk of increased toxicity due to synergistic effects.

Phenytoin: Caution is recommended when administering isotretinoin with phenytoin, as simultaneous use of these drugs increases the risk of osteomalacia.

Tetracyclines: The concurrent administration of isotretinoin and tetracyclines is not advisable due to the risk of idiopathic intracranial hypertension (pseudotumor cerebri).[31]

Contraindications

Isotretinoin is contraindicated for patients with hypersensitivity to its components, including vitamin A and preservatives within the gel capsule.[6][32]

Box Warnings

Isotretinoin was a pregnancy category X drug under the previous FDA system and is contraindicated in pregnant women or those who may become pregnant. There have been severe, documented congenital disabilities when pregnant women have taken isotretinoin. The Food and Drug Administration requires prescribers and patients to register with the iPLEDGE program to prescribe and receive isotretinoin. iPLEDGE ensures the fulfillment of appropriate requirements before dispensing 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.

Isotretinoin is contraindicated in patients with hypersensitivity to its components, including vitamin A and preservatives within the gel capsule.

Warnings and Precautions

Blood donation: 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.

Neuropsychiatric adverse effects: 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 or violent behaviors should occur before prescribing isotretinoin.

Pseudotumor cerebri: Pseudotumor cerebri (benign intracranial hypertension) has been 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 of isotretinoin is necessary, and the patient should receive a referral to a neurologist for further evaluation.[33][34][35]

Severe cutaneous adverse reactions: Serious reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported and warrant prompt cessation of isotretinoin if they occur during therapy.[36]

Pancreatitis: Reports indicate acute pancreatitis in isotretinoin users with both normal and high triglyceride levels. Pancreatitis may also result from an idiosyncratic reaction. Discontinue therapy if pancreatitis is suspected.[37]

Hearing abnormalities: Impaired hearing, including tinnitus, has been reported in patients treated with systemic isotretinoin. In a study of 32 patients with acne vulgaris treated with 0.5 mg/kg isotretinoin for at least 4 months, audiometric tests revealed significant changes in pure-tone thresholds at 8000 Hz across various treatment periods, including during pre-treatment, the first week, first month, third month, and sixth month. A decrease in hearing thresholds was observed at 8000 Hz by the sixth month post-treatment, but these changes improved after the discontinuation of isotretinoin. This suggests that while isotretinoin can impact hearing, the effects may be reversible after treatment cessation.[38]

Ocular adverse effects: Visual disturbances, including corneal opacities, nyctalopia, and xerophthalmia, should be monitored during isotretinoin therapy.[39][40] Corneal opacities, which are more prevalent with higher dosages and in patients with keratinization disorders, typically resolve after discontinuation. Nyctalopia may persist post-therapy, and patients should be cautioned regarding nighttime driving.[41] If visual symptoms occur, isotretinoin should be discontinued, and an ophthalmologic evaluation should be conducted.

Monitoring

Females of Child-Bearing Potential (FCBP)

Isotretinoin should only be prescribed to patients confirmed not to be pregnant with a negative pregnancy test from a CILA (Clinical Laboratory Improvement Amendments)-certified laboratory. Two negative pregnancy tests are necessary before initiating isotretinoin therapy. The first pregnancy test should occur up to 30 days before 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 treatment, a final pregnancy test should be taken 30 days following therapy completion.

Females of child-bearing potential (FCBP) must be on 2 effective forms of birth control or complete abstinence while receiving isotretinoin therapy. The iPLEDGE program defines abstinence as no 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 selected 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-administration of spermicide. Natural family planning, birth control pills without estrogen, female condoms, withdrawal, and cervical shields are not acceptable forms of birth control according to the iPLEDGE program.

Pre-treatment Monitoring (All Patients)

Before initiating isotretinoin therapy, liver function tests (LFTs), a fasting lipid profile (including triglycerides), blood glucose, creatinine phosphokinase (CPK), and complete blood counts (CBC) with differential should be drawn. Patients should also be screened for mood alteration, psychosis, aggression, suicidal ideation, skin changes, and visual changes.

Ongoing Monitoring (All Patients)

Liver function tests (LFTs) and lipids should be monitored biweekly until a response to isotretinoin is established.[6] The consensus is to check alanine aminotransferase (ALT) and triglycerides at baseline and peak doses.[42]

Acne Grading Scales

Various acne grading tools like global acne severity grading and multimodal digital imaging can be used to monitor response to treatment.[43]

Toxicity

Signs and Symptoms of Overdose

Reports of acute intoxication indicate exacerbations of common, well-known isotretinoin adverse effects, including cutaneous xerosis and cheilitis, vomiting, dizziness, facial flushing, headache, abdominal pain, and ataxia.[6]

Management of Overdose

There is no commonly used antidote for isotretinoin intoxication. Isotretinoin overdose symptoms typically resolve without lasting effects. Pregnant individuals or those who can become pregnant should be evaluated for pregnancy in case of overdose. Male patients should use a condom or avoid reproductive sexual activity for 1 month post-overdose, as isotretinoin levels in semen may be higher. Patients who experience an overdose should refrain from donating blood for at least a month.

Enhancing Healthcare Team Outcomes

Isotretinoin may be prescribed by any clinician, including nurse practitioners. While the drug is effective for the treatment of acne, all prescribers should be familiar with the drug's adverse effect profile; one of the most serious is teratogenicity. Isotretinoin is a pregnancy category X drug and is contraindicated in pregnant women or those who may become pregnant. There have been severe, documented congenital disabilities when pregnant women have taken isotretinoin. The Food and Drug Administration requires prescribers and patients to register with the iPLEDGE program to prescribe and receive isotretinoin. iPLEDGE ensures the meeting of appropriate requirements before dispensing 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.[44][45]

Given the nature of isotretinoin therapy, an interprofessional healthcare team approach is necessary. Pharmacists 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 properly, particularly for female patients. Nurses should provide counseling, monitor for adverse events, and collaborate with the pharmacist regarding contraceptive measures for female patients. Pharmacists and nurses need an open line with the prescriber to address concerns immediately. Critical care physicians should stabilize the patient in overdose/toxicity. An interprofessional team approach and communication among clinicians are crucial to decreasing potential adverse effects and improving patient outcomes related to isotretinoin therapy.