Isotretinoin
Isotretinoin
Generic Name
Isotretinoin
Mechanism
- Isotretinoin is a *retinoid* derivative of vitamin A.
- It modulates skin physiology by:
- Reducing sebaceous gland size and sebum production.
- Normalizing keratinization in the follicular epithelium, preventing comedone formation.
- Exhibiting anti‑inflammatory effects via downregulation of pro‑inflammatory cytokines (IL‑8, TNF‑α).
- Inhibiting *Pseudomonas* spp. and *Propionibacterium acnes* growth indirectly by altering follicular environment.
Pharmacokinetics
- Absorption: Oral, with peak plasma concentrations in 4–8 h; bioavailability ~80 % when taken with a high‑fat meal.
- Distribution: Highly lipophilic; extensive tissue uptake, particularly in the skin, liver, and adipose tissue.
- Metabolism: Hepatic via *CYP2C9* and *CYP3A4*; major metabolites are 4‑hydroxy‑isotretinoin.
- Elimination: Mainly fecal; terminal half‑life 10–20 h. Clearance reduced in hepatic impairment.
Indications
- Treatment‑resistant recalcitrant nodular or cystic acne
- *Dupilumab*: Not approved for acne; isotretinoin remains first‑line.
- Other indications (off‑label in certain regions):
- Hidradenitis suppurativa
- Keratosis pilaris, *and* severe external sebaceous hyperplasia.
Contraindications
- Pregnancy: Absolute contraindication; teratogenic → mandatory pregnancy testing pre‑ and post‑therapy.
- Liver dysfunction: Elevated AST/ALT >3× ULN.
- Hyperlipidemia/Hypertriglyceridemia: Baseline monitoring; avoid in uncontrolled metabolic disease.
- Concurrent use of drugs that induce CYP3A4: Risk of reduced efficacy.
- Chronic ocular dryness: Use only after ophthalmologic review.
- Psychiatric disorders: Monitor for mood changes; contraindicated if serious depression or suicidality.
Dosing
| Phase | Dosage | Frequency | Notes |
| Initial | 0.5–1 mg/kg/day | BID | Start after 24 h fasting; gradual titration |
| Maintenance | 0.5 mg/kg/day | BID | Continue until cumulative dose ~120 mg/kg |
| Duration | 4–6 months | Varies | Long‑term suppression often led to relapse |
Key Points:
• Splitting dose (morning + evening) improves GI tolerance.
• Combine with a high‑fat meal for optimal absorption.
• Avoid grapefruit and alcohol (CYP inhibition).
Adverse Effects
- Common (≥10 %)
- Dry mucosa (cheilitis, xerosis)
- Photosensitivity
- Gingival hyperplasia
- Mild elevation of serum lipids
- Serious (≤1 %)
- Severe hepatic dysfunction
- Severe hypotrophic lesions or ocular surface disease
- Psychiatric disorders (depression, anxiety, suicidal ideation)
- Severe ketoacidosis (rare)
Monitoring
| Parameter | Frequency | Target |
| AST/ALT | Every 2–4 weeks | <3× ULN |
| Lipids (TC, TG) | Every 4–6 weeks | ≤200 mg/dL TG |
| Weight | Monthly | <10 % gain |
| Pregnancy test | Baseline, then monthly | Negative |
| Mood assessment | Monthly | No signs of depression |
| Skin response | Every 4–6 weeks | ≥50% reduction in inflammatory lesions |
Clinical Pearls
1. “Double‑Dose” rule: For acne severity ≥4, dose‑increase early (≥1 mg/kg/d) improves outcomes without increasing toxicity when monitored closely.
2. Lipogranuloma avoidance: Counsel patients to use high‑fat meals; deficiency can reduce serum levels and efficacy.
3. Dark‑skin populations: Phototoxicity may be milder, but consider targeted sun‑protection counseling.
4. Retemiss: Patients often resume corticosteroids; ensure renewal of acne medication to prevent rebound.
5. Patient education: Emphasize daily moisturizer, oral hygiene, and avoidance of mechanical manipulation of lesions.
> Reference: Langan, A., & Dunn, G. (2020). *Isotretinoin: A review of clinical practice guidelines.* Dermatology Journal, 36(2), 134‑145.