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13-cis retinoic acid; isotretinoin (Accutane)

Tradename: Accutane. Indications: 1) rosacea 2) acne 3) disorders of keratosis a) keratosis follicularis b) lamellar ichthyosis c) pityriasis rubra pilaris d) keratosis palmaris et plantaris 4) psoriasis 5) cutaneous T-cell lymphoma [14] Contraindications: 1) teratogen: contraindicated in pregnancy 2) females of child-bearing age should be on a reliable method of contraception for 1 month prior to, during & after therapy 3) a pregnancy test should be performed prior to initiation of therapy in all women of child-bearing age 4) the manufacturer recommends 2 reliable methods of contraception Dosage: 1) 0.5-2 mg/kg/day PO BID 2) cystic acne a) initial dose 0.5-1.0 mg/kg/day divided BID b) after 2 weeks may increase to a max of 2 mg/kg/day c) duration of therapy: 15-20 weeks or until 70% of cysts are resolved d) use lowest effective dose for shortest effective duration e) if dose is missed, do NOT increase subsequent doses 2) disorders of keratinization: a) individualize doses b) doses up to 4 mg/kg/day have been used c) take with food Low-dose: 0.1-0.2 mg/kg/day may take longer than standard dose, but fewer adverse effects Minidose: 2.5-5 mg QD up to 6 months therapy may be necessary adverse effects are minimal Capsules: 10, 20, 40 mg. Monitor: 1) serum ALT or serum AST - serum ALT at baseline & at peak dose [17] - baseline & every 1-2 weeks until response to therapy established; - thereafter every 3 months (not necessary) [17] - increases in serum ALT or serum AST may also occur with protein supplements, exercise recovery products, excess ibuprofen, or alcohol, especially in adolescent males [15] 2) lipid panel baseline & at 4 weeks - serum triglycerides at baseline & at peak dose [17] - continue frequent monitoring in patients with diabetes, alcohol use, or personal or family history of lipid disorder 3) serum glucose baseline & periodically - check more frequently in patients with diabetes 4) pregnancy test (female) [11] - periodic eye exams if oral retinoid therapy for >= 6 months 5) abnormal laboratory findings occur but are rarely problematic [15] Adverse effects: 1) common (> 10%) a) epistaxis b) burning c) erythema d) itching of eyes (xerosis) e) cheilitis f) xerostomia g) dry skin h) myalgia (more common in adolescents than adults) [6] - back pain in 1/3 of adolescents i) increased serum triglycerides (increases of 50-70%) - pancreatitis [16] 2) less common (1-10%) a) depression (cases of suicide) - no increased risk of suicide or other psychiatric disorders [18] b) skin rash c) dry eyes d) headache e) photophobia f) skin peeling on hands & soles of feet g) dyspepsia h) fatigue 3) uncommon (< 1%) - hepatitis, ulcerative colitis [12], optic neuritis, mood changes, bleeding of gums, cataracts, pseudotumor cerebri, pruritus, hair loss, anorexia, nausea/vomiting, increased ESR, anemia 4) other [2,3] - blepharitis - conjunctivitis - nail dystrophy - arthralgias - dry nose - increases VLDL & LDL - decreased HDL - lethargy - may cause new or worsening diabetes mellitus [11] - suicidal ideation, suicide attempt [13] Drug interactions: - risk of pseudotumor cerebri increased by coadministration of doxycycline Mechanism of action: 1) regulation of cell proliferation & differentiation 2) modulation of cellular immune responses 3) inhibition of sebaceous gland activity & follicular keratinization 4) mediates apoptosis of sebaceous gland cells via induction of neutrophil gelatinase-associated lipocalin (NGAL) expression [10] Notes: * Register with iPledge: [8] Prescribing physician & patients must register. Register both men & women patients. Document negative pregnancy tests & contraceptive methods for women. Men are registered to insure proper counseling on side effects? Pharmacists will access the iPledge registry to verify that the physician & the patient are registered & a negative pregnancy test is on file. Patients must pick up the Rx within 7 days of writing.

General

oral dermatologic agent retinoic acid

Properties

MISC-INFO: elimination route LIVER KIDNEY pregnancy-category X safety in lactation -

Database Correlations

PUBCHEM correlations

References

  1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
  2. Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996, pg 1004
  3. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 166
  4. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  5. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998 Department of Veterans Affairs, VA National Formulary
  6. Prescriber's Letter 9(8):46 2002
  7. An Enhanced Risk Management Program for Isotretinoin Products Prescriber's Letter 11(4):21 2004 Detail-Document#: 200404 (subscription needed) http://www.prescribersletter.com
  8. Prescriber's Letter 12(9): 2005 Isotretinoin (Accutane) iPLEDGE Risk Management Program Detail-Document#: 210912 (subscription needed) http://www.prescribersletter.com iPledge: http://www.ipledgeprogram.com contact: (866) 495-0654
  9. FDA Medwatch http://www.fda.gov/medwatch/safety/2006/safety06.htm#Isotretinoin
  10. Nelson AM, Zhao W, Gilliland KL, Zaenglein AL, Liu W, Thiboutot DM. Neutrophil gelatinase-associated lipocalin mediates 13-cis retinoic acid-induced apoptosis of human sebaceous gland cells. J Clin Invest. 2008 Apr;118(4):1468-78. PMID: 18317594
  11. Prescriber's Letter 17(7): 2010 Recommended Lab Monitoring for Common Medications Liver Function Test Scheduling Detail-Document#: 260704 (subscription needed) http://www.prescribersletter.com
  12. Bernstein CN et al Isotretinoin is not associated with inflammatory bowel disease: A population-based case-control study. Am J Gastroenterol 2009 Nov; 104:2774. PMID: 19623167 - Shale M et al Isotretinoin and intestinal inflammation: What gastroenterologists need to know. Gut 2009 Jun; 58:737. PMID: 19433589 - Crockett SD et al. Isotretinoin use and the risk of inflammatory bowel disease: A case-control study. Am J Gastroenterol 2010 Mar 30; PMID: 20354506 http://dx.doi.org/10.1038/ajg.2010.124
  13. Physician' First Watch, Nove 12, 2009 Massachusetts Medical Society http://www.jwatch.org - Sundstrom A et al Association of suicide attempts with acne and treatment with isotretinoin: retrospective Swedish cohort study BMJ 2010; 341:c5812 PMID: 21071484 http://www.bmj.com/content/341/bmj.c5812.full
  14. Deprecated Reference
  15. Chang MW Laboratory Monitoring During Isotretinoin Therapy for Acne: Too Much, Too Often? Physician's First Watch, Dec 21, 2015 David G. Fairchild, MD, MPH, Editor-in-Chief Massachusetts Medical Society http://www.jwatch.org - Lee YH, Scharnitz TP, Muscat J et al. Laboratory monitoring during isotretinoin therapy for acne: A systematic review and meta-analysis. JAMA Dermatol 2015 Dec 2; PMID: 26630323 http://archderm.jamanetwork.com/article.aspx?articleid=2471551
  16. Opel D, Kramer ON, Chevalier M, Bigby M, Albrecht J. Not every patient needs a triglyceride check, but all can get pancreatitis: a systematic review and clinical characterization of isotretinoin-associated pancreatitis. Br J Dermatol. 2017 Oct;177(4):960-966. Epub 2017 Sep 19. Review. PMID: 27893168
  17. Brunk D Study Provides Consensus on Lab Monitoring in Patients Treated With Isotretinoin. Medscape. June 23, 2022 https://www.medscape.com/viewarticle/976116
  18. Tan NKW et al. Risk of suicide and psychiatric disorders among isotretinoin users: A meta-analysis. JAMA Dermatol 2023 Nov 29; [e-pub] PMID: 38019562 PMCID: PMC10687715 Free PMC article https://jamanetwork.com/journals/jamadermatology/fullarticle/2812525

Substructures

isoprene