Oral isotretinoin therapy for acne vulgaris
- Cindy Owen, MD
Cindy Owen, MD
- Assistant Professor of Medicine
- University of Louisville
- Section Editors
- Robert P Dellavalle, MD, PhD, MSPH
Robert P Dellavalle, MD, PhD, MSPH
- Section Editor — General Dermatology
- Professor of Dermatology and Public Health
- University of Colorado School of Medicine
- Colorado School of Public Health
- Chief, Dermatology Service
- US Department of Veterans Affairs
- Eastern Colorado Health Care System
- Moise L Levy, MD
Moise L Levy, MD
- Section Editor — Pediatric Dermatology
- Professor of Pediatrics and Medicine (Dermatology)
- Dell Medical School, University of Texas, Austin
- Clinical Professor of Dermatology and Pediatrics
- Baylor College of Medicine
- Mark V Dahl, MD
Mark V Dahl, MD
- Section Editor — Acne and Rosacea
- Professor Emeritus
- Mayo Clinic College of Medicine
Oral isotretinoin (13-cis retinoic acid) is effective for the treatment of severe recalcitrant nodular acne. However, isotretinoin is associated with multiple adverse effects and is teratogenic. Thus, it must be used with appropriate caution in selected patients.
This topic will discuss clinical use of oral isotretinoin and related safety concerns. The pathogenesis, clinical manifestations, diagnosis, and conventional treatment of acne vulgaris are discussed separately. (See "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris" and "Hormonal therapy for women with acne vulgaris" and "Treatment of acne vulgaris".)
MECHANISM OF ACTION
Oral isotretinoin counteracts the pathogenic factors that contribute to the development of acne vulgaris [1,2]. Therapy leads to shrinkage of sebaceous glands and a marked attenuation of sebum secretion. The decrease in sebum results in the inhibition of the sebum-dependent bacterium Cutibacterium (formerly Propionibacterium) acnes, which is a key promoter of inflammation in acne vulgaris. Oral isotretinoin also inhibits comedogenesis by fostering keratinocyte differentiation and by normalizing desquamation.
Oral isotretinoin is effective for the treatment of acne vulgaris [3-10]. The first study to show the benefit of oral isotretinoin was a case series of 14 patients with treatment-resistant severe acne . After four months of treatment, 13 out of 14 patients experienced complete clearance of their disease.
Indications — In the United States, the Food and Drug Administration (FDA) approved usage of oral isotretinoin only for severe, recalcitrant, nodular acne. "Severe, recalcitrant, nodular acne" is defined as acne with many (greater than 5 mm) inflammatory nodules that is unresponsive to conventional therapy, including systemic antibiotics.
- Ward A, Brogden RN, Heel RC, et al. Isotretinoin. A review of its pharmacological properties and therapeutic efficacy in acne and other skin disorders. Drugs 1984; 28:6.
- Brelsford M, Beute TC. Preventing and managing the side effects of isotretinoin. Semin Cutan Med Surg 2008; 27:197.
- Peck GL, Olsen TG, Yoder FW, et al. Prolonged remissions of cystic and conglobate acne with 13-cis-retinoic acid. N Engl J Med 1979; 300:329.
- Jones H, Blanc D, Cunliffe WJ. 13-cis retinoic acid and acne. Lancet 1980; 2:1048.
- Farrell LN, Strauss JS, Stranieri AM. The treatment of severe cystic acne with 13-cis-retinoic acid. Evaluation of sebum production and the clinical response in a multiple-dose trial. J Am Acad Dermatol 1980; 3:602.
- Peck GL, Olsen TG, Butkus D, et al. Isotretinoin versus placebo in the treatment of cystic acne. A randomized double-blind study. J Am Acad Dermatol 1982; 6:735.
- Lehucher-Ceyrac D, Weber-Buisset MJ. Isotretinoin and acne in practice: a prospective analysis of 188 cases over 9 years. Dermatology 1993; 186:123.
- McElwee NE, Schumacher MC, Johnson SC, et al. An observational study of isotretinoin recipients treated for acne in a health maintenance organization. Arch Dermatol 1991; 127:341.
- Jones DH, King K, Miller AJ, Cunliffe WJ. A dose-response study of I3-cis-retinoic acid in acne vulgaris. Br J Dermatol 1983; 108:333.
- Strauss JS, Rapini RP, Shalita AR, et al. Isotretinoin therapy for acne: results of a multicenter dose-response study. J Am Acad Dermatol 1984; 10:490.
- Nagler AR, Milam EC, Orlow SJ. The use of oral antibiotics before isotretinoin therapy in patients with acne. J Am Acad Dermatol 2016; 74:273.
- Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol 2016; 74:945.
- Seukeran DC, Cunliffe WJ. The treatment of acne fulminans: a review of 25 cases. Br J Dermatol 1999; 141:307.
- Karvonen SL. Acne fulminans: report of clinical findings and treatment of twenty-four patients. J Am Acad Dermatol 1993; 28:572.
- Böni R, Nehrhoff B. Treatment of gram-negative folliculitis in patients with acne. Am J Clin Dermatol 2003; 4:273.
- Neubert U, Plewig G, Ruhfus A. Treatment of gram-negative folliculitis with isotretinoin. Arch Dermatol Res 1986; 278:307.
- Amichai B, Shemer A, Grunwald MH. Low-dose isotretinoin in the treatment of acne vulgaris. J Am Acad Dermatol 2006; 54:644.
- Webster GF, Leyden JJ, Gross JA. Comparative pharmacokinetic profiles of a novel isotretinoin formulation (isotretinoin-Lidose) and the innovator isotretinoin formulation: a randomized, 4-treatment, crossover study. J Am Acad Dermatol 2013; 69:762.
- López-Vílchez MA, Vicente Villa MA, García-Fructuoso MT, et al. [Acne fulminans after the treatment with isotretinoin]. An Esp Pediatr 1999; 51:200.
- Tan BB, Lear JT, Smith AG. Acne fulminans and erythema nodosum during isotretinoin therapy responding to dapsone. Clin Exp Dermatol 1997; 22:26.
- Layton AM, Knaggs H, Taylor J, Cunliffe WJ. Isotretinoin for acne vulgaris--10 years later: a safe and successful treatment. Br J Dermatol 1993; 129:292.
- Blasiak RC, Stamey CR, Burkhart CN, et al. High-dose isotretinoin treatment and the rate of retrial, relapse, and adverse effects in patients with acne vulgaris. JAMA Dermatol 2013; 149:1392.
- Azoulay L, Oraichi D, Bérard A. Isotretinoin therapy and the incidence of acne relapse: a nested case-control study. Br J Dermatol 2007; 157:1240.
- White GM, Chen W, Yao J, Wolde-Tsadik G. Recurrence rates after the first course of isotretinoin. Arch Dermatol 1998; 134:376.
- Patton TJ, Zirwas MJ, Wolverton SE. Systemic retinoids. In: Comprehensive Dermatologic Drug Therapy, 2nd ed, Wolverton SE (Ed), Elsevier, Philadelphia 2007. p.275.
- Lee JW, Yoo KH, Park KY, et al. Effectiveness of conventional, low-dose and intermittent oral isotretinoin in the treatment of acne: a randomized, controlled comparative study. Br J Dermatol 2011; 164:1369.
- Cyrulnik AA, Viola KV, Gewirtzman AJ, Cohen SR. High-dose isotretinoin in acne vulgaris: improved treatment outcomes and quality of life. Int J Dermatol 2012; 51:1123.
- Lammer EJ, Chen DT, Hoar RM, et al. Retinoic acid embryopathy. N Engl J Med 1985; 313:837.
- Centers for Disease Control and Prevention (CDC). Accutane-exposed pregnancies--California, 1999. MMWR Morb Mortal Wkly Rep 2000; 49:28.
- Sladden MJ, Harman KE. What is the chance of a normal pregnancy in a woman whose fetus has been exposed to isotretinoin? Arch Dermatol 2007; 143:1187.
- Vastag B. More stringent rules on accutane. JAMA 2002; 287:832.
- www.ipledgeprogram.com (Accessed on April 23, 2009).
- Neudorfer M, Goldshtein I, Shamai-Lubovitz O, et al. Ocular adverse effects of systemic treatment with isotretinoin. Arch Dermatol 2012; 148:803.
- Mathers WD, Shields WJ, Sachdev MS, et al. Meibomian gland morphology and tear osmolarity: changes with Accutane therapy. Cornea 1991; 10:286.
- Leyden JJ, James WD. Staphylococcus aureus infection as a complication of isotretinoin therapy. Arch Dermatol 1987; 123:606.
- Ellis CN, Krach KJ. Uses and complications of isotretinoin therapy. J Am Acad Dermatol 2001; 45:S150.
- Etminan M, Bird ST, Delaney JA, et al. Isotretinoin and risk for inflammatory bowel disease: a nested case-control study and meta-analysis of published and unpublished data. JAMA Dermatol 2013; 149:216.
- Bernstein CN, Nugent Z, Longobardi T, Blanchard JF. Isotretinoin is not associated with inflammatory bowel disease: a population-based case-control study. Am J Gastroenterol 2009; 104:2774.
- Crockett SD, Porter CQ, Martin CF, et al. Isotretinoin use and the risk of inflammatory bowel disease: a case-control study. Am J Gastroenterol 2010; 105:1986.
- Alhusayen RO, Juurlink DN, Mamdani MM, et al. Isotretinoin use and the risk of inflammatory bowel disease: a population-based cohort study. J Invest Dermatol 2013; 133:907.
- Zane LT, Leyden WA, Marqueling AL, Manos MM. A population-based analysis of laboratory abnormalities during isotretinoin therapy for acne vulgaris. Arch Dermatol 2006; 142:1016.
- Steele RG, Lugg P, Richardson M. Premature epiphyseal closure secondary to single-course vitamin A therapy. Aust N Z J Surg 1999; 69:825.
- Luthi F, Eggel Y, Theumann N. Premature epiphyseal closure in an adolescent treated by retinoids for acne: an unusual cause of anterior knee pain. Joint Bone Spine 2012; 79:314.
- Inamo Y, Suzuki T, Mugishima H. A case of growth failure caused by 13-CIS-retinoic acid administration after bone marrow transplantation for neuroblasoma. Endocr J 1999; 46 Suppl:S113.
- Milstone LM, McGuire J, Ablow RC. Premature epiphyseal closure in a child receiving oral 13-cis-retinoic acid. J Am Acad Dermatol 1982; 7:663.
- Lawson JP, McGuire J. The spectrum of skeletal changes associated with long-term administration of 13-cis-retinoic acid. Skeletal Radiol 1987; 16:91.
- Wysowski DK, Pitts M, Beitz J. An analysis of reports of depression and suicide in patients treated with isotretinoin. J Am Acad Dermatol 2001; 45:515.
- www.fda.gov/cder/drug/InfoSheets/HCP/IsotretinoinHCP.htm (Accessed on August 12, 2005).
- Marqueling AL, Zane LT. Depression and suicidal behavior in acne patients treated with isotretinoin: a systematic review. Semin Cutan Med Surg 2005; 24:92.
- Magin P, Pond D, Smith W. Isotretinoin, depression and suicide: a review of the evidence. Br J Gen Pract 2005; 55:134.
- Hull PR, D'Arcy C. Acne, depression, and suicide. Dermatol Clin 2005; 23:665.
- Bigby M. Does isotretinoin increase the risk of depression? Arch Dermatol 2008; 144:1197.
- Huang YC, Cheng YC. Isotretinoin treatment for acne and risk of depression: A systematic review and meta-analysis. J Am Acad Dermatol 2017; 76:1068.
- Halvorsen JA, Stern RS, Dalgard F, et al. Suicidal ideation, mental health problems, and social impairment are increased in adolescents with acne: a population-based study. J Invest Dermatol 2011; 131:363.
- Sundström A, Alfredsson L, Sjölin-Forsberg G, et al. Association of suicide attempts with acne and treatment with isotretinoin: retrospective Swedish cohort study. BMJ 2010; 341:c5812.
- Lee YH, Scharnitz TP, Muscat J, et al. Laboratory Monitoring During Isotretinoin Therapy for Acne: A Systematic Review and Meta-analysis. JAMA Dermatol 2016; 152:35.
- McCarter TL, Chen YK. Marked hyperlipidemia and pancreatitis associated with isotretinoin therapy. Am J Gastroenterol 1992; 87:1855.
- Rodondi N, Darioli R, Ramelet AA, et al. High risk for hyperlipidemia and the metabolic syndrome after an episode of hypertriglyceridemia during 13-cis retinoic acid therapy for acne: a pharmacogenetic study. Ann Intern Med 2002; 136:582.
- MECHANISM OF ACTION
- CLINICAL USE
- RESPONSE TO THERAPY
- Low dose isotretinoin
- High-dose isotretinoin
- ISOTRETINOIN SAFETY
- Teratogenicity and the iPLEDGE program
- Mucocutaneous side effects
- Inflammatory bowel disease
- Other side effects
- Psychiatric effects
- Monitoring and discontinuation
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS