Isotretinoin: Communication for Preventing Birth Defects and Alerting of an Uncertain Risk of Suicide

  • Ineke CrijnsEmail author


This chapter discusses the succession of pregnancy prevention programmes (PPPs) for isotretinoin, a medicine effective against acne, but with high risks for birth defects and developmental disorders in the child when exposed during pregnancy. Strengthening of PPPs over time was considered necessary by regulators to increase the compliance with these programmes, but the communication for implementing “strict” PPPs in the healthcare system has been one of the most important challenges in the pharmaceutical field, due to its rejection by some opinion leaders among dermatologists and due to differences in cultures and expectations regarding sexual behaviour of women within and between countries. In addition, isotretinoin has been investigated for possible psychiatric adverse effects including suicidal behaviour, which caused media attention and even discussions in parliaments. Moreover, the chapter reflects on the inconclusive evidence to date in this respect and the associated needs for different regulatory action and handling of communication for isotretinoin and other retinoids. The best ways of how to communicate their risks and safe use recommendations will remain subject to discussion with a view to continuous improvement in every country of the world.



The views expressed in this chapter are the author’s personal views and may not be understood or quoted as being made on behalf of or reflecting the position of her employing organisation, i.e. the Dutch Medicines Evaluation Board, or the European Medicines Agency (EMA) or any of its committees or working parties, where she serves as an expert.


  1. Abroms L, Maibach E, Lyon-Daniel K et al (2006) What is the best approach to reducing birth defects associated with isotretinoin? PLoS Med 3:1978–1983CrossRefGoogle Scholar
  2. AlGhamdi K, Khurram H, Asiri Y, Mandil A (2011) Dermatologists’ level of compliance with the prescription guidelines of isotretinoin for females of childbearing potential. Int J Dermatol 50:1094–1098CrossRefGoogle Scholar
  3. Anwikar SR, Bandekar MS, Khopkar U, Kshirsagar NA (2010) Prescribing and dispensing of isotretinoin: a survey. Indian J Dermatol Venereol Leprol 76:412–413CrossRefGoogle Scholar
  4. Art 31 Referral Retinoid-containing medicines (2018) on EMA website.
  5. Australian Government, Department of Health (2005) Safety information for health professionals: avoiding fetal abnormalities with isotretinoin.
  6. Bhate K, Williams HC (2013) Epidemiology of acne vulgaris. Br J Dermatol 168:474–485CrossRefGoogle Scholar
  7. Bremner J, Shearer K, McCaffery P (2012) Retinoic acid and affective disorders: the evidence for an association. J Clin Psychiatry 73:37–50CrossRefGoogle Scholar
  8. Statement by Jonca Bull, MD, Deputy Office Director, Office of Drug Evaluation V, Center for Drug Evaluation and Research, US Food and Drug Administration, before the Committee of Government Reform, US House of Representatives on 5 December 2000Google Scholar
  9. Cockerell CJ, Thiboutot DM (2006) iPLEDGE: a report from the front lines of dermatologic practice. AMA J Ethics 8:524–528CrossRefGoogle Scholar
  10. Cosgrove-Mather B (2016) Suicide pilot’s mom blames Accutane.
  11. Crijns I, Straus S, Luteijn M (2011a) Implementation of the harmonized EU isotretinoin pregnancy prevention programme: a questionnaire survey among European regulatory agencies. Drug Saf 36:27–32Google Scholar
  12. Crijns H, Straus S, Gispen-de Wied C, de Jong-van den Berg L (2011b) Compliance with pregnancy prevention programmes of isotretinoin in Europe: a systematic review. Br J Dermatol 164:238–244CrossRefGoogle Scholar
  13. Crijns I, Mantel-Teeuwisse A, Bloemberg R et al (2013) Healthcare professionals surveys to investigate the implementation of the isotretinoin pregnancy prevention programme: a descriptive study. Expert Opin Drug Saf 12:29–38CrossRefGoogle Scholar
  14. Darves B (2016) Life after iPLEDGE.
  15. Das S, Reynolds RV (2014) Recent advances in acne pathogenesis: implications for therapy. Am J Clin Dermatol 15:479–488CrossRefGoogle Scholar
  16. Doshi A (2007) The cost of clear skin: balancing the social and safety costs of iPLEDGE with the efficacy of Accutane (isotretinoin). Seton Hall Law Rev 37:625PubMedGoogle Scholar
  17. Entezari-Maleki T, Hadjibabaie M, Dousti S et al (2012) Evaluation and monitoring of isotretinoin use in Iran. Arch Iran Med 15:409–412PubMedGoogle Scholar
  18. Fakour Y, Noormohammadpour P, Ameri H et al (2014) The effect of isotretinoin (Roaccutane) therapy on depression and quality of life of patients with severe acne. Iran J Psychiatry 9:237–240PubMedPubMedCentralGoogle Scholar
  19. Dermatologic and Ophthalmic drugs advisory committee FDA, meeting 18-19 September 2000 – Briefing information – Accutane.
  20. Gnanaraj P, Karthikeyan S, Narasimhan M, Rajagopalan V (2015) Decrease in “Hamilton Rating Scale for Depression” following isotretinoin therapy in acne: an open-label prospective study. Indian J Dermatol 60:461–464CrossRefGoogle Scholar
  21. Green J (2002) Babies, blemishes and FDA: a history of Accutane regulation in the United States. Harvard Law School.
  22. Halvorsen J, Stern R, Dalgard F, Thoresen F, Bjertness E, Lien L (2011) Suicidal ideation, mental health problems, and social impairment are increased in adolescents with acne: a population-based study. J Invest Dermatol 131:363–370CrossRefGoogle Scholar
  23. Isotretinoin and the effectiveness of the pregnancy prevention programme in Europe (2016)
  24. Isotretinoin and the risk of erythema multiforme. Final SPC and PL wording agreed by the PhVWP in June 2010.
  25. James A (2016) The bitter pill - category: Accutane - Roche puts Accutane profits over lives of consumers.
  26. Jick SS, Kremers HM, Vasilakis-Scaramozza C (2000) Isotretinoin use and risk of depression, psychotic symptoms, suicide, and attempted suicide. Arch Dermatol 136:1231–1236CrossRefGoogle Scholar
  27. Kasperson RE, Renn O, Slovic P, Brown HS, Emel J, Goble R et al (1988) The social amplification of risk: a conceptual framework. Risk Anal 8:177–187CrossRefGoogle Scholar
  28. Kolata G (1985) Europeans placed stiffer curbs on acne drug. New York Times 25:A1Google Scholar
  29. Kotvitwanichkanont T, Driscoll T (2018) A comparative review of the isotretinoin pregnancy risk management programs across four continents. Int J Dermatol 57:1035–1046CrossRefGoogle Scholar
  30. Lammer E, Chen D, Hoar R et al (1985) Retinoic acid embryopathy. N Engl J Med 313:837–841CrossRefGoogle Scholar
  31. Lim SH, Jang HI, Lee DY, Yoon BK, Choi DS (2016) Recent trends in contraceptive use among Korean adolescents: results from a nationwide survey from year 2013 to 2015. Obstet Gynecol Sci 59:519–524CrossRefGoogle Scholar
  32. Magin P, Adams J, Heading P et al (2005) Patients’ perceptions of isotretinoin, depression and suicide: a qualitative study. Aust. Fam. Physician 34:795–797PubMedGoogle Scholar
  33. Marwick C (1984) More cautionary labeling appears on isotretinoin. J Am Med Assoc 251:3208–3209CrossRefGoogle Scholar
  34. Mitchell S. (2016) Congressional committee finds Accutane causes suicide.
  35. Mitchell A, Van Bennekom C, Louik C (1995) A pregnancy prevention program in women of childbearing age receiving isotretinoin. N Engl J Med 333:101–106CrossRefGoogle Scholar
  36. New Zealand Datasheet – Oratane (2016)
  37. Nguyen CM, Beroukhim K, Danesh MJ, Babikian A, Koo J, Leon A (2016) The psychosocial impact of acne, vitiligo, and psoriasis: a review. Clin Cosmet Investig Dermatol 9:383–392CrossRefGoogle Scholar
  38. Nijsten T, Rombouts S, Lambert J (2007) Acne is prevalent but use of its treatments is infrequent among adolescents from the general population. J Eur Acad Dermatol Venereol 21:163–168CrossRefGoogle Scholar
  39. Ortolon K (2006) A pox on your practice: iPLEDGE program scars dermatologists. Tex Med 102:29–31PubMedGoogle Scholar
  40. Ozyurt S, Kaptanoglu AS (2015) Systemic isotretinoin treatment and pregnancy: a longitudinal cohort study form Turkey. Eurasian J Med 47:179–183CrossRefGoogle Scholar
  41. Pierson JC, Ferris LK, Schwarz EB (2015) We pledge to change iPLEDGE. JAMA Dermatol 151:701–702CrossRefGoogle Scholar
  42. Ro/Accutane action group – news update (2002).
  43. Rosa F (1983) Teratogenicity of isotretinoin. Lancet 2:513CrossRefGoogle Scholar
  44. Rowe C, Spelman L, Oziemski M et al (2014) Isotretinoin and mental health in adolescents: Australian consensus. Aust J Dermatol 55:162–167CrossRefGoogle Scholar
  45. Shin J, Cheetham T, Wong I et al (2011) The impact of the iPLEDGE program on isotretinoin fetal exposure in an integrated health care system. J Am Acad Dermatol 65:1117–1125CrossRefGoogle Scholar
  46. Skelton C (2016) Containing the impacts in New Zealand: acne and isotretinoin III.
  47. The Royal Australian College of General Practitioners (2014) GP prescribing rights for isotretinoin.
  48. Thiboutot D, Gollnick H, Bettoli V et al (2012) Oral isotretinoin and pregnancy prevention programmes. Br J Dermatol 166:466–467CrossRefGoogle Scholar
  49. Weinberg JM (2005) iPLEDGE allegiance. Cutis 76:356PubMedGoogle Scholar
  50. Woodcock J (2002) Concerns regarding Accutane (isotretinoin).
  51. Wysowski DK, Pitts M, Beitz J (2001) An analysis of reports of depression and suicide in patients treated with isotretinoin. J Am Acad Dermatol 45:515–519CrossRefGoogle Scholar
  52. Yook JH, Han JY, Choi JS et al (2012) Pregnancy outcomes and factors associated with voluntary pregnancy termination in women who had been treated for acne with isotretinoin. Clin Toxicol 50:896–899CrossRefGoogle Scholar

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© Springer Nature Singapore Pte Ltd. 2020

Authors and Affiliations

  1. 1.Dutch Medicines Evaluation BoardUtrechtThe Netherlands

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