What are the side effects of Acitretin?

Acitretin Side Effects

Nearly all patients taking acitretin will experience mucocutaneous side effects, with the most serious concerns being severe teratogenicity requiring 3-year post-treatment contraception in women, hyperlipidemia in 25-50% of patients (which can rarely cause fatal pancreatitis), and hepatotoxicity requiring prompt discontinuation if suspected. 1

Most Common Side Effects (Affecting Nearly All Patients)

Mucocutaneous Effects

• Cheilitis (lip dryness), xerosis (dry skin), dryness of eyes/nasal/oral mucosa, epistaxis, itching or burning skin, and brittle nails occur in nearly all patients and range from mild to severe depending on individual characteristics and dose 1
• Hair loss is more common in women, especially at doses exceeding 17.5 mg per day 1, 2
• "Retinoid dermatitis" manifests as scaly, erythematous plaques with superficial fissuring (less common) 1
• Pyogenic granulomas, particularly in periungual locations, are associated with long-term therapy 1
• Peeling of palms and soles occurs frequently 3

Critical Laboratory Abnormalities Requiring Monitoring

Hyperlipidemia (Most Common Laboratory Abnormality)

• Hyperlipidemia occurs in 25% to 50% of patients and is the most common laboratory abnormality 1, 4
• Triglyceride elevations occur in 66% of patients; cholesterol elevations in 33%; decreased HDL in 40% 4
• Risk is higher in patients with obesity, diabetes mellitus, or excessive alcohol intake 1
• Hypertriglyceridemia can reach levels causing pancreatitis, which has been fatal in some patients 1
• Elevation of triglycerides >800 mg/dL is associated with fatal fulminant pancreatitis 4
• Hypertriglyceridemia and lowered HDL may increase cardiovascular risk, with postmarketing reports of acute myocardial infarction or thromboembolic events 4

Hepatotoxicity

• Elevation in transaminases occurs in 13% to 16% of patients 1
• Major increases in liver function tests are uncommon but suggest acitretin-induced toxic hepatitis requiring prompt discontinuation 1
• Treatment was discontinued in 3.8% of patients due to elevated liver function tests in clinical trials 4
• Ten patients treated with etretinate (of which acitretin is the active metabolite) developed clinical or histologic hepatitis, with reports of hepatitis-related deaths worldwide 4

Serious but Less Common Side Effects

Neurological

• Pseudotumor cerebri (benign intracranial hypertension) has occurred in very rare cases 1
• Early signs include papilledema, headache, nausea, vomiting, and visual disturbances requiring immediate discontinuation and neurological referral 1, 4
• Mood changes can occur 1

Ophthalmologic

• Dry eyes occur in 23% of patients; eye irritation in 9%; brow and lash loss in 5% 1, 4
• Decreased night and color vision occurs occasionally 1, 4
• Less common (<5%): blurred vision, conjunctivitis, corneal epithelial abnormality, various cataracts, photophobia 1, 4
• Any patient experiencing visual difficulties should discontinue the drug and undergo ophthalmologic evaluation 4

Musculoskeletal

• Minor myalgia/arthralgia can occur 1
• Diffuse idiopathic skeletal hyperostosis is a rarely reported adverse effect presenting with vertebral syndesmophytes, bone spurs, arthritis of vertebral articulations, and degenerative spondylosis 1
• In some cases, hyperostosis may be severe and debilitating 1
• Whether acitretin causes osteoporosis is controversial; risk appears highest with long-term, high-dose therapy 1
• Premature epiphyseal growth plate closure may occur in young patients (rare) 1
• In clinical trials, 15% of patients had preexisting spinal abnormalities that showed progression 4

Other Rare but Serious Effects

• Capillary leak syndrome (potential manifestation of retinoic acid syndrome) with localized/generalized edema, weight gain, fever, hypotension, rhabdomyolysis, and myalgias 4
• Exfoliative dermatitis/erythroderma requiring discontinuation 4
• Pancreatitis can occur even in the absence of hypertriglyceridemia (rare) 4

Metabolic and Endocrine Effects

• Retinoids are associated with greater insulin sensitivity and could induce hypoglycemia in patients on antidiabetic medications 1
• Patients on diabetes medications should check capillary glucose levels more frequently in early treatment stages 1
• Increased incidence of vulvovaginitis due to Candida albicans 1

Most Serious Side Effect: Teratogenicity

Pregnancy Risk

• Multiple malformations are associated with acitretin use during pregnancy, particularly between weeks 3 and 6 of gestation 1
• Abnormalities include skeletal and craniofacial bones, central nervous system, auditory, ocular, and cardiovascular systems 1
• Women must wait at least 3 years after completion of treatment before becoming pregnant 1
• Alcohol ingestion promotes conversion of acitretin to etretinate (half-life 168 days vs. 49 hours for acitretin), though the actual amount of alcohol necessary is unknown 1
• Acitretin is absolutely contraindicated in women who plan to become pregnant or who do not use sufficient contraception 1

Male Fertility

• Acitretin does not have an effect on fertility or teratogenicity when men are taking the drug (based on limited data) 1

Drug Interactions

• Tetracyclines are contraindicated with acitretin as both can cause increased intracranial pressure 1, 4
• Vitamin A supplementation increases risk of hypervitaminosis A and should be avoided 1
• May interact with glucose-lowering effect of glyburide (glibenclamide) 1
• May interfere with contraceptive effect of microdosed progestin preparations 1
• Combination with methotrexate should be done with caution due to dual hepatotoxicity risk 1
• May reduce protein binding of phenytoin 1
• Drugs interfering with cytochrome P450 pathway (e.g., cyclosporine) may affect acitretin metabolism 1

Monitoring Requirements to Detect Side Effects

• Baseline: lipid profile, CBC, liver function tests, renal function tests, pregnancy test if indicated 1
• Ongoing: LFTs and lipid profile monthly for first 3 months, then every 3 months 1
• CBC and renal function tests every 3 months 1
• Blood lipid determinations at 1-2 week intervals until lipid response is established (usually 4-8 weeks) 4
• High-risk patients (diabetes, alcoholism, obesity) need more frequent monitoring for hypertriglyceridemia 1

Common Pitfalls

• Failing to counsel women adequately about the 3-year post-treatment contraception requirement (not 2 months as previously advocated) due to potential conversion to etretinate 1
• Not monitoring lipids closely enough in high-risk patients, missing dangerous triglyceride elevations 1
• Continuing therapy when hepatotoxicity is suspected rather than promptly discontinuing 1
• Combining with tetracyclines, risking pseudotumor cerebri 1