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The use of isotretinoin in the treatment of acne vulgaris: clinical considerations and future directions.

Isotretinoin (13-cis-retinoic acid) is a non-aromatic retinoid that was approved by the United States (US) Food and Drug Administration (FDA) as an oral capsule formulation in May 1982 with an indication for treatment of severe recalcitrant nodular acne.1-3 Over time, oral isotretinoin (ISO) has proven to be a major pharmacological breakthrough for treating severe and recalcitrant cases of inflammatory acne. The continued availability of ISO has at times been challenged due to its teratogenicity warranting further emphasis on continued patient education and the introduction of a structured, traceable, and mandated risk-management program (iPLEDGE).1-5 Other challenges have included reports of potential associations with depression, suicidal ideation, and inflammatory bowel disease.1,2,6-18 However, continued pharmacovigilance has demonstrated that these alleged risks have not been definitively associated with ISO as the causative factor and are not common enough to take away the accessability of ISO to the millions of patients with severe acne who have experienced major improvements in their quality of life after ISO treatment.2,9,10,11,15,18 Continued vigilance and assessments of outcomes related to how ISO is utilized allows for frequent re-evaluation of how efficacy and safety can be optimized both in terms of clearance upon completion of the initial ISO treatment course and achieving prolonged remission without the need for retreatment. 
 
The implementation by the US FDA of the more stringent Risk Evaluation and Mitigation Strategy (REMS) program, namely iPLEDGE, was put in place to prevent as much as possible ISO pregnancy exposures in females of child-bearing potential, and to capture the frequency and outcomes of ISO pregnancy exposures.1,2,19-22 In addition, the data captured through the iPLEDGE program allow for analysis of usage patterns with ISO by patients and prescribers. Responsible prescribing of ISO by clinicians, compliant use and follow up by patients, and vigilant dispensing practices by pharmacists underscore the safe and effective usage of this agent. Despite challenges related to teratogenic properties, known potential side effects, and alleged adverse reactions, ISO remains available in the United States under the iPLEDGE program, including in females of childbearing potential, without restrictions on indication and duration of use, provided the mandated rules of the iPLEDGE program are followed by the registered prescriber, patient, and pharmacist.1,19-22-19 
 
Several million patients, including a subset of children, have been treated with ISO. Data captured through the iPLEDGE program have documented more than 1.2 million individual patients treated from December 2005 through February 2011.23 Clinical studies and global experience have shown that ISO provides complete or nearly complete remission of acne, with sustained therapeutic benefit after completion of ISO therapy found to be a consistent observation in the vast majority of treated patients.2,24-36 In addition to severe nodular acne, the use of ISO within the dermatology community for acne has included refractory cases of severe non-nodular inflammatory acne and/or in patients who exhibit a propensity for acne scarring, with effective use in recalcitrant non-nodular inflammatory acne noted in the literature.37-39 The American Academy of Dermatology (AAD) has published a Position Statement on Oral Isotretinoin, which considers the physical and psychological impact of acne in the decision-making process on ISO use.37 In all cases, proper follow up and monitoring is recommended in compliance with the iPLEDGE program.1,2,19-22 
 
Importantly, ISO remains the only therapy for acne that is capable of inducing remission after an adequate course of therapy is completed, with prolonged remissions occurring with reasonable certainty in most patients.2,24,25,29 Due to the large volume of people with severe and recalcitrant acne who have been treated with ISO globally, and with experience in the use of ISO for more than three decades, multiple publications have addressed the need for retreatment of acne with ISO or other acne therapies.24-36,40,41 The duration of remission before need for acne retreatment and the percent of patients needing retreatment after their initial course of ISO are variable and appear to correlate with several potential contributory factors.2,25,29-36,40 These contributory factors include patient age when the initial ISO course was given, cumulative dose administered over the initial course of therapy, endogenous androgen-excess (i.e., polycystic ovary syndrome), presence/persistence of macrocomedones, presence of sinus tracts, patient adherence, and the potential role of dietary factors.2,25,29-36,40-46