Introduction
Tretinoin is a topical and systemic retinoid medication derived from vitamin A, primarily used in dermatology and oncology. First approved by the FDA in 1971, it remains a cornerstone treatment for acne vulgaris and photodamaged skin, while the oral formulation serves as a critical component in acute promyelocytic leukemia (APL) treatment regimens.
Mechanism of Action
Tretinoin exerts its effects through binding to nuclear retinoic acid receptors (RARs), modulating gene expression and cellular differentiation. In dermatological applications, it normalizes keratinization, reduces cohesiveness of keratinocytes, and diminishes microcomedone formation. For APL, tretinoin induces differentiation of promyelocytes into mature granulocytes by targeting the PML-RARα fusion protein characteristic of this leukemia subtype.
Indications
FDA-approved indications:- Topical formulations: Acne vulgaris, photodamaging (fine wrinkles, mottled hyperpigmentation, roughness)
- Oral formulation: Induction of remission in patients with APL (French-American-British M3 classification)
- Melasma
- Post-inflammatory hyperpigmentation
- Early striae distensae
- Verruca plana
- Keratosis pilaris
Dosage and Administration
Topical formulations:- Creams: 0.025%, 0.05%, 0.1%
- Gels: 0.01%, 0.025%, 0.05%
- Apply once daily to affected area in evening
- Start with lowest concentration; increase as tolerated
- APL: 45 mg/m²/day divided into two doses
- Continue until complete remission or maximum 90 days
- Usually administered with anthracycline-based chemotherapy
- Hepatic impairment: Use with caution
- Renal impairment: No dosage adjustment needed
- Pediatrics: Safety established for topical use in children ≥12 years
- Geriatrics: Increased sensitivity possible
Pharmacokinetics
Absorption: Minimal systemic absorption with topical application (<2%); oral administration well absorbed with food Distribution: Highly protein-bound (>95%); crosses placenta and blood-brain barrier Metabolism: Hepatic via cytochrome P450 system (primarily CYP2C8, CYP2C9, CYP3A4) Elimination: Primarily biliary excretion; terminal half-life 0.5-2 hoursContraindications
- Hypersensitivity to tretinoin or any component of formulation
- Pregnancy (oral formulation - Category D)
- Concomitant use of topical preparations with keratolytic agents, abrasive cleansers, or high alcohol-content products
- Sunburn or eczematous skin conditions (topical)
Warnings and Precautions
Retinoic Acid-APL Syndrome: Oral tretinoin may cause potentially fatal leukocytosis and respiratory distress Pseudotumor cerebri: Particularly with concomitant tetracycline antibiotics Photosensitivity: Severe sunburn risk with topical application Teratogenicity: Oral form contraindicated in pregnancy; effective contraception required Hepatotoxicity: Monitor liver function during oral therapy Hyperlipidemia: Oral form may cause elevated triglycerides and cholesterolDrug Interactions
Topical interactions:- Increased irritation with benzoyl peroxide, salicylic acid, sulfur preparations
- Photosensitizing agents (thiazides, tetracyclines, fluoroquinolones)
- CYP3A4 inducers (rifampin, phenobarbital): Decreased tretinoin levels
- CYP3A4 inhibitors (ketoconazole, erythromycin): Increased tretinoin levels
- Vitamin A supplements: Increased risk of hypervitaminosis A
- Tetracyclines: Increased risk of pseudotumor cerebri
Adverse Effects
Topical:- Common: Erythema, peeling, dryness, burning, stinging (≥10%)
- Less common: Photosensitivity, hypopigmentation, hyperpigmentation
- Very common: Headache (86%), fever (83%), skin/mucous membrane dryness (77%)
- Common: Hyperlipidemia (60%), hepatotoxicity (50%), retinoic acid-APL syndrome (25%)
- Serious: Pseudotumor cerebri, thromboembolism, leukocytosis
Monitoring Parameters
For topical use:- Skin irritation and tolerance
- Clinical response at 8-12 weeks
- Sun protection adherence
- CBC with differential (daily during induction)
- Liver function tests (weekly)
- Lipid profile (weekly)
- Coagulation parameters
- Signs of retinoic acid-APL syndrome
- Intracranial pressure symptoms
Patient Education
- Apply topical product to clean, dry skin
- Use pea-sized amount for entire face
- Expect initial "retinization" period (redness, peeling) lasting 2-6 weeks
- Strict sun protection: Broad-spectrum SPF 30+ daily, protective clothing
- Avoid waxing treated areas
- Do not use during pregnancy (oral form requires two forms of contraception)
- Report severe headache, visual changes, or breathing difficulties immediately
- Oral formulation: Take with food to improve absorption
References
1. Leyden JJ, et al. J Am Acad Dermatol. 2017;76(5):958-967. 2. Tallman MS, et al. Blood. 2002;99(3):759-767. 3. Zaenglein AL, et al. J Am Acad Dermatol. 2016;74(5):945-973. 4. FDA prescribing information: Retin-A (tretinoin) topical; Vesanoid (tretinoin) oral. 5. Kang S, et al. Fitzpatrick's Dermatology, 9th ed. McGraw-Hill; 2019. 6. National Comprehensive Cancer Network. Acute Myeloid Leukemia Guidelines, Version 3.2022.