What are the potential side effects of isotretinoin (13-cis-retinoic acid) in all genders?

Isotretinoin Side Effects Across All Genders

Mucocutaneous Side Effects (Most Common)

Mucocutaneous side effects occur in nearly all patients receiving isotretinoin and are the most predictable adverse effects due to suppression of sebaceous gland activity. 1, 2

• Dry lips (cheilitis), dry nasal passages, and dry eyes are universal and dose-dependent 1, 2
• Dry skin and mucous membranes affecting nearly 100% of patients 3
• Increased incidence of vulvovaginitis due to Candida albicans has been noted during treatment 3
• Skin fragility and increased risk of minor skin infections including folliculitis and furunculosis due to higher rates of Staphylococcus aureus colonization 3
• Combination of cheilitis and S. aureus colonization can rarely cause lip or perioral abscesses requiring prompt attention 3

These effects are managed with pretreatment counseling and concomitant moisturizing agents; dose adjustments suffice in cases of poor tolerability 1

Metabolic and Laboratory Abnormalities

Routine monitoring of serum lipid profiles and liver function studies is mandatory, as elevations occur frequently. 3

• Elevated serum triglycerides occur in approximately 25% of patients, with levels exceeding 800 mg/dL reported 4
• Decreased high-density lipoproteins develop in approximately 15% of patients 4
• Increased cholesterol levels occur in about 7% of patients 4
• Mild to moderate liver enzyme elevations observed in approximately 15% of patients 4
• Retinoids increase insulin sensitivity and can induce hypoglycemia in patients on antidiabetic medications 3

The American Academy of Dermatology recommends monitoring liver function tests, fasting lipid panel at baseline and until response to treatment is established 3. Complete blood count monitoring is not routinely recommended 3.

Musculoskeletal Effects

Musculoskeletal side effects are more common in pediatric patients and include back pain, arthralgia, and myalgia, which can sometimes be severe. 4

• Increased incidence of back pain and arthralgia in pediatric patients (ages 12-17) compared to adults 4
• Myalgia, muscle stiffness, and tenderness reported with isotretinoin 3
• Skeletal toxicity concerns including hyperostosis, though minimal skeletal hyperostosis and calcification of ligaments/tendons observed in prospective acne studies 4
• Bone mineral density changes: In a clinical trial of 217 patients, 7.9% had decreases in lumbar spine bone mineral density >4%, and 10.6% had decreases in total hip bone mineral density >5% 4
• Spontaneous reports of osteoporosis, osteopenia, bone fractures, and delayed healing have been seen, though causality not definitively established 4
• Premature epiphyseal closure reported in two isolated acne patients, though not observed in other short-term therapy studies 3, 4

Neuropsychiatric Effects

Current evidence shows no population-based causal link between isotretinoin and depression, but individual monitoring remains essential given sporadic case reports. 3

The American Academy of Dermatology states that "current evidence is insufficient to prove either an association or causal relationship" between isotretinoin and depression/mood changes 3. Multiple population-based studies show no evidence of depression from isotretinoin, and most studies demonstrate isotretinoin improves or has no negative effects on mood, memory, attention, or executive functions 3. However, isotretinoin may cause depression, psychosis, and rarely suicidal ideation, suicide attempts, suicide, and aggressive/violent behaviors 4.

• Prescribers must monitor for depression, mood disturbance, psychosis, or aggression at each visit 5, 4
• Patients should discontinue isotretinoin immediately if they develop psychiatric symptoms and contact their prescriber without waiting for the next visit 4
• The American Academy of Dermatology recommends using Patient Health Questionnaire-2 and PHQ-9 for depression screening during treatment 5
• Isotretinoin may improve quality of life and decrease symptoms of anxiety and depression in patients with moderate to severe acne 5

Neurological Effects

Benign intracranial hypertension (pseudotumor cerebri) is a rare but serious complication requiring immediate discontinuation. 3, 4

• Pseudotumor cerebri has occurred in very rare cases, sometimes associated with concurrent tetracycline or minocycline use 3, 4
• Concomitant tetracycline treatment should be avoided 4
• Early signs include papilledema, headache, nausea, vomiting, and visual disturbances 4
• Patients with severe headache, nausea, vomiting, and visual disturbance should discontinue immediately and be referred for neurological evaluation 3, 4

Ophthalmologic Effects

Visual problems require careful monitoring, and patients experiencing visual difficulties should discontinue treatment and have ophthalmological examination. 4

• Decreased night vision reported during therapy, with onset sometimes sudden; some cases persist after discontinuation 4
• Corneal opacities have occurred, more frequently with higher doses; typically resolve or are resolving 6-7 weeks after discontinuation 4
• Blurred or decreased night vision reported occasionally 3
• Dry eyes are common and predictable 1, 2

Gastrointestinal Effects

The American Academy of Dermatology states that current evidence is insufficient to prove either an association or causal relationship between isotretinoin use and inflammatory bowel disease. 3

While two studies showed potential relationship between isotretinoin and IBD, more recent analyses suggest no association 3. However, the FDA label states isotretinoin has been associated with inflammatory bowel disease (including regional ileitis) in patients without prior history 4.

• Patients experiencing abdominal pain, rectal bleeding, or severe diarrhea should discontinue immediately 4
• Nausea reported infrequently 3
• Acute pancreatitis reported in patients with either elevated or normal triglyceride levels; rare instances of fatal hemorrhagic pancreatitis 4
• Isotretinoin should be stopped if hypertriglyceridemia cannot be controlled or if symptoms of pancreatitis occur 4

Severe Skin Reactions

Severe skin reactions including Stevens-Johnson Syndrome and toxic epidermal necrolysis have been reported and may be life-threatening. 4

• Erythema multiforme, SJS, and TEN associated with isotretinoin use in postmarketing reports 4
• These events may result in death, life-threatening events, hospitalization, or disability 4
• Patients should be monitored closely and discontinuation considered if warranted 4

Reproductive and Teratogenic Effects (Critical for All Genders)

Isotretinoin is strictly contraindicated in pregnancy due to severe teratogenic effects and requires mandatory contraception in all females of childbearing potential. 4, 1, 2

• All patients must adhere to the iPLEDGE risk management program 3
• Females of childbearing potential must use two forms of contraception starting 4 weeks before, during, and for one month after treatment (note: acitretin requires 3 years) 3
• The American Academy of Dermatology recommends counseling regarding user-independent contraceptive methods 3
• Medically supervised negative pregnancy test required within 2 weeks prior to therapy 3
• Therapy should start on the second or third day of the next menstrual cycle 3

Male Reproductive Effects

• In studies of 66 men, no significant changes in sperm count or motility were noted 4
• In a study of 50 men (ages 17-32), no significant effects on ejaculate volume, sperm count, total sperm motility, morphology, or seminal plasma fructose 4
• In rats, no adverse effects on gonadal function, fertility, conception rate, gestation, or parturition at doses up to 5.3 times the recommended clinical dose 4
• In dogs, testicular atrophy noted at 10-30 times the recommended clinical dose, but some sperm observed in all testes examined 4

Wound Healing and Surgical Considerations

Recent evidence shows no atypical scarring with procedures in patients currently or recently on isotretinoin, though elective procedures should be delayed 6-12 months when possible. 3

• Early case series described delayed wound healing or keloid formation, leading to recommendations to delay dermabrasion or laser resurfacing 6-12 months after discontinuation 3
• Recent prospective studies did not find atypical scarring with chemical peels or manual dermabrasion in patients currently or recently on isotretinoin 3
• Retrospective studies demonstrate safety with laser hair removal, pulsed dye laser, and CO2 laser 3
• Acitretin does not significantly affect wound healing and there is no need to stop for routine surgery such as orthopedic procedures 3

Overdose

Signs of overdosage would be similar to acute vitamin A toxicity and are expected to subside on withdrawal without treatment. 3

• Symptoms include headache, nausea, vomiting, drowsiness, and vertigo 3

Monitoring Recommendations Summary

Standard monitoring includes lipid panel, liver function tests, and pregnancy testing for females of childbearing potential; complete blood count is not routinely needed. 3, 5

• Baseline and periodic monitoring until response established 3
• Psychiatric screening with PHQ-9 at each follow-up visit 5
• More frequent monitoring for patients with diabetes, alcoholism, or obesity due to increased hypertriglyceridemia risk 3
• Patients on antidiabetic medications should check capillary glucose levels more frequently in early treatment stages 3