Isotretinoin - Drug Monograph

Introduction

Isotretinoin is a systemic retinoid medication primarily used for the treatment of severe recalcitrant nodular acne that has been unresponsive to conventional therapies. It is a synthetic vitamin A derivative (13-cis-retinoic acid) that represents one of the most effective treatments for severe acne, with the potential for long-term remission. Due to its teratogenic potential and significant side effect profile, isotretinoin requires careful patient selection, monitoring, and adherence to risk management programs.

Mechanism of Action

Isotretinoin exerts its therapeutic effects through multiple mechanisms:

• Sebum Suppression: Reduces sebaceous gland size and sebum production by up to 90% through inhibition of sebocyte differentiation and induction of apoptosis
• Normalization of Follicular Keratinization: Prevents hyperkeratinization of pilosebaceous ducts
• Anti-inflammatory Effects: Modulates inflammatory pathways and reduces colonization of Cutibacterium acnes
• Regulation of Cell Cycle: Influences cellular differentiation and proliferation

Indications

• Severe recalcitrant nodular acne unresponsive to conventional therapy including systemic antibiotics

• Moderate acne that is scarring or causing significant psychological distress
• Gram-negative folliculitis
• Rosacea (particularly phymatous variants)
• Hidradenitis suppurativa
• Certain keratinizing disorders
• Prevention of skin cancers in high-risk patients

Dosage and Administration

• Initial dose: 0.5-1 mg/kg/day divided into two doses
• Maintenance dose: May be adjusted based on response and tolerability
• Typical treatment duration: 15-20 weeks
• Cumulative dose: Target 120-150 mg/kg per course

• Oral administration with food (high-fat meals increase absorption by up to 2-fold)
• Usually given in two divided doses daily

• Renal impairment: Use with caution; no specific dosage adjustment recommended
• Hepatic impairment: Contraindicated in significant hepatic impairment
• Pediatric: Safety established in children ≥12 years; use weight-based dosing
• Elderly: Limited data; use lowest effective dose

Pharmacokinetics

• Bioavailability: Approximately 25% under fasting conditions, doubles with high-fat meals
• Peak plasma concentration: 3-5 hours post-dose

• Protein binding: >99.9% (primarily albumin)
• Volume of distribution: Approximately 0.3-0.6 L/kg
• Crosses placenta and is found in breast milk

• Extensive hepatic metabolism via cytochrome P450 enzymes (primarily CYP2C8, CYP2C9, CYP3A4)
• Forms multiple metabolites including 4-oxo-isotretinoin (active)

• Half-life: 10-20 hours (isotretinoin); 17-50 hours (4-oxo-isotretinoin)
• Excretion: Primarily fecal (biliary) with minimal renal excretion

Contraindications

• Pregnancy, breastfeeding, or women who may become pregnant during treatment
• Hypersensitivity to isotretinoin, other retinoids, or any component of the formulation
• Significant hepatic impairment
• Hyperlipidemia that cannot be controlled
• Concomitant use of tetracycline antibiotics (increased risk of pseudotumor cerebri)

Warnings and Precautions

• Teratogenicity: Causes severe birth defects; pregnancy must be excluded before treatment and prevented during and after therapy

• Psychiatric effects: Depression, psychosis, suicidal ideation; monitor for mood changes
• Pseudotumor cerebri: Discontinue immediately if symptoms occur
• Pancreatitis: May occur, especially with hypertriglyceridemia
• Hearing impairment: Sensorineural hearing loss reported
• Inflammatory bowel disease: Possible association; monitor for symptoms
• Skeletal abnormalities: Bone mineral density changes, premature epiphyseal closure
• Ocular effects: Dry eyes, corneal opacities, night vision impairment
• Hyperlipidemia: Monitor triglycerides and cholesterol
• Hepatic toxicity: Regular liver function tests required

Drug Interactions

• Tetracyclines: Increased risk of pseudotumor cerebri (avoid combination)
• Vitamin A supplements: Additive toxic effects (avoid concomitant use)
• Steroids: May potentiate hyperlipidemia
• Alcohol: May increase triglyceride levels

• CYP2C8/2C9/3A4 inducers (carbamazepine, phenytoin, rifampin): May decrease isotretinoin levels
• CYP2C8/2C9/3A4 inhibitors (ketoconazole, fluconazole): May increase isotretinoin levels

• Photosensitizing agents: Enhanced photosensitivity
• Microdosed progesterone preparations: Reduced contraceptive effectiveness

Adverse Effects

• Cheilitis (90%)
• Dry skin (80%)
• Dry nose/mucous membranes (80%)
• Conjunctivitis (40%)
• Increased triglycerides (25%)

• Dry eyes
• Pruritus
• Epistaxis
• Skin fragility
• Photosensitivity
• Arthralgia/myalgia
• Headache
• Hair thinning

• Teratogenicity
• Depression/suicidal ideation
• Pancreatitis
• Hepatitis
• Inflammatory bowel disease
• Pseudotumor cerebri
• Severe hypertriglyceridemia
• Hearing impairment
• Vision changes

Monitoring Parameters

• Two negative pregnancy tests (serum β-hCG)
• Lipid profile
• Liver function tests
• Complete blood count
• Psychiatric assessment

• Monthly pregnancy tests
• Lipid panel monthly until stable
• LFTs monthly for first 3 months, then as needed
• Regular assessment of mood and psychiatric symptoms
• Monitoring for headache/visual changes (pseudotumor cerebri)
• Assessment of musculoskeletal symptoms

• Continue pregnancy prevention for 1 month after discontinuation
• Follow-up for persistent side effects

Patient Education

• Absolute requirement for two forms of contraception during and for 1 month after treatment
• Immediate reporting of possible pregnancy
• Understanding of teratogenic risks
• Participation in required risk management program (iPLEDGE in US)

• Avoid pregnancy during and after treatment
• Do not donate blood during and for 1 month after treatment
• Use lip balm and moisturizers regularly
• Use sunscreen and protective clothing
• Avoid waxing procedures (skin fragility)
• Avoid excessive alcohol consumption
• Use artificial tears for dry eyes

• Signs of depression or mood changes
• Severe headache with visual changes
• Abdominal pain, nausea, vomiting (pancreatitis)
• Hearing changes or tinnitus
• Signs of infection (due to dry mucous membranes)
• Pregnancy or possible pregnancy

References

1. Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016;74(5):945-973.e33. 2. US Food and Drug Administration. Isotretinoin package insert. Revised 2020. 3. Lee JW, Yoo KH, Park KY, et al. History of isotretinoin therapy for acne vulgaris and the risk of depression: A meta-analysis. J Am Acad Dermatol. 2019;80(2):425-432. 4. Brzezinski P, Borowska K, Chiriac A, Smigielski J. Adverse effects of isotretinoin: A large, retrospective review. Dermatol Ther. 2017;30(4). 5. iPLEDGE Program. Prescriber and Patient Information. Accessed January 2024. 6. Vallerand IA, Lewinson RT, Farris MS, et al. Efficacy and adverse events of oral isotretinoin for acne: a systematic review. Br J Dermatol. 2018;178(1):76-85. 7. Tan J, Boyal S, Desai K, et al. Oral Isotretinoin: New Developments in the Management of Acne. J Cutan Med Surg. 2018;22(3):246-253.