Isotretinoin Made S.M.A.R.T. and Simple
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Isotretinoin Made S.M.A.R.T.™ and Simple Eve J. Lowenstein, MD, PhD With the introduction of oral isotretinoin 20 years sebum production and secondary Propionibacterium ago, an incredible triumph was achieved in the acnes growth and inflammation also contribute to treatment of acne vulgaris. Much has been acne’s pathogenesis.2,3 In addition, exposure to learned of the pathogenesis of acne and the moisturizers; tars; halogenated hydrocarbons; and mechanism by which isotretinoin affects acne. medications such as phenytoin, isoniazid, iodides, The teratogenicity of isotretinoin has cast a phenobarbital, lithium, ethionamide, and steroids shadow on this effective drug with recent concern may exacerbate acne.4 about the regulation of its use. The S.M.A.R.T.™ Isotretinoin is the only treatment that affects program has been implemented to address this all major etiologic factors implicated in acne.5 concern. Alleged depressive mood effects of Endogenous retinoids mediate their biologic effect isotretinoin have resulted in further controversy. through modulation of DNA transcription via The efficacy of and indications for isotretinoin use nuclear retinoic acid receptors.6 Isotretinoin does are discussed here, with elaboration on the not bind directly to retinoic acid receptors but is reported side effects. Given its established risks, thought to behave as a prodrug, converted by treatment with isotretinoin may become severely sebocytes into active species that bind retinoid curtailed if caution is not exercised. receptors.7 Isotretinoin normalizes keratinocyte mat- uration and adhesion, resulting in reduced comedo cne vulgaris is a common skin disorder affecting formation. Isotretinoin also causes a decrease in almost everyone at some point in life. Acne has sebocyte-mediated androgen synthesis6 and an 80% A been in existence at least since ancient times, reduction in sebum synthesis within a month of ini- with paleopathologic evidence of comedones demon- tiating therapy.8 Oral isotretinoin reduces the total strated in mummies dating as far back as ancient number of resistant bacterial organisms on the skin9 Egypt.1 Thousands of years have passed since these and directly reduces neutrophil chemotaxis.10,11 first documented cases, and pimples still plague Unlike other treatment modalities that merely humanity. Twenty years ago, oral isotretinoin was temporize,3 isotretinoin results in long-term acne introduced to fill the need for an effective therapy remission for 70% to 89% of treated patients, with for this scourge of the skin and has proven to be a beneficial effects persisting after its discontinua- wonder drug. Unfortunately, auspicious isotretinoin is tion.12 Most relapses occur within the first 18 months a teratogen. Controversy also has surrounded the after treatment ends.13,14 Patients failing the first psychiatric side effects allegedly attributed to this course frequently respond better to the second drug. The following is an update on the complexities course.2 Subsequent courses for nodulocystic acne involved in isotretinoin use for acne management. are rarely needed. The official indication for isotretinoin use is for Why Use Isotretinoin for Acne? patients with severe recalcitrant nodular acne that The causes of acne vulgaris are multiple. Acne is a is unresponsive to conventional therapies, includ- consequence of the disordered function of the ing topical and oral antibiotics and oral contra- pilosebaceous unit.2 Acne’s pathogenesis has been ceptive treatments.15 Many patients, however, ascribed to the formation of the microcomedo, an have inflammatory lesions that do not qualify as essential acne precursor, in the context of abnor- severe acne but can result in physical and psycho- mal follicular epithelial differentiation. Elevated logic scarring if alternative treatments are insti- tuted.13 Oral isotretinoin has been shown to From the Department of Dermatology, SUNY Health Science reduce the severity of scarring.16 An international Center at Brooklyn, New York. survey revealed that dermatologists worldwide The author has no commercial, proprietary, or financial interest (as consultant, reviewer, or evaluator) in isotretinoin. use isotretinoin for broader indications, including Reprints: Eve J. Lowenstein, MD, PhD, 450 Clarkson Ave, Box 46, moderate acne with a less than 50% response rate Brooklyn, NY 11203 (e-mail: [email protected]). to other therapies and acne that scars, induces VOLUME 70, AUGUST 2002 115 Isotretinoin Made S.M.A.R.T.™ relapse after withdrawal of therapy, or induces psy- acne excorea, macrocomedones, microcysts, syringo- chological stress.17 The past 20 years have seen mas, adenoma sebaceum, acne keloidalis nuchae, prescribing trends shift from treatment of severe pseudofolliculitis barbae, hidradenitis, and pilo- nodular acne in the 1980s to less severe but nidal cysts.4,29 Alternative therapeutic approaches treatment-resistant moderate acne in the 1990s.18 may be instituted as deemed appropriate, such as Thus, even in milder cases of acne, isotretinoin electrodesiccation of macrocomedones,32 acne may be the drug of choice. Another indication surgery for microcysts, and psychotherapy for that favors isotretinoin therapy is patients with excoriated acne.33 Acne fulminans, sometimes high sebum excretion rates who frequently treated effectively with isotretinoin, can be precip- respond poorly to antibiotic therapy.13 Resistance itated by isotretinoin in rare instances.28 Therapy to antibiotics by P acnes also has curtailed their should be halted in these patients, and systemic therapeutic efficacy in acne treatment.19 Oral steroids should be instituted.34 antibiotic therapy also can harbor significant side effects. Finally, oral isotretinoin has demonstrated Side Effects and Complications significant cost savings compared with other acne of Isotretinoin treatment modalities.17,20 Systemic adverse effects are rarely severe (2%) with The current dose recommendation for oral isotretinoin therapy.17 isotretinoin is a single 20-week course in the range Teratogenicity—Teratogenicity is the most of 0.5 to 2 mg/kg per day.17 Twice-daily dosing is serious adverse effect of oral isotretinoin therapy. used to increase absorption.21 Most physicians aim Although isotretinoin is a naturally occurring for a cumulative dose of at least 1 mg/kg per day.23 molecule in humans and vitamin A is required for Although isotretinoin at lower doses is effective in normal embryonic development,35 first trimester treating acne, relapse is more frequent for nodular pregnancy exposure to isotretinoin can cause retinoic acne with doses below 1 mg/kg per day.2,23 Because acid embryopathy.36 Isotretinoin is the most highly continued clinical improvement may be seen 4 to used teratogenic drug in the United States.37 Between 5 months after treatment completion, several 1982 and early 2000, the manufacturer received months may be allowed to elapse before consider- reports of 1995 exposed pregnancies.37 The number of ing re-treatment. infants born with congenital malformations after Food increases the bioavailability of isotretinoin.24 intrauterine isotretinoin exposure is not known, A new micronized formulation of isotretinoin although the manufacturer has received reports of with enhanced bioavailability allows for about a 71 infants with congenital malformations.37 Most of 50% lower dose to be taken once daily without the the exposed pregnancies were not because of contra- need for concomitant food ingestion.25 Although ceptive failure but rather failure to use contracep- micronized isotretinoin could increase compliance tion.37 Studies indicate that patient education in and offer a modest improvement in mucocutaneous pregnancy prevention is key and that physicians must side effects and lipid level changes compared with use greater caution in prescribing isotretinoin. standard isotretinoin therapy,26 this formulation has To improve pregnancy avoidance, Hoffmann- not yet received US Food and Drug Administration La Roche Inc instituted the Pregnancy Prevention (FDA) approval. Program for Women on Accutane® in 1988. Certain patients respond poorly when treated Exposed pregnancies, however, continued to occur. with isotretinoin.13 Inadequate dosing and noncom- Most recently, the FDA agreed to the continued pliance are frequent causes of relapse. Young men use of isotretinoin under the System to Manage with extensive truncal acne tend to relapse.27 Other Accutane Related Teratogenicity™ (S.M.A.R.T.) pro- causes for relapse include sinus tracts, acne of short gram, a registry designed to enhance the present duration, hemorrhagic crusted acne,28 and hyperan- pregnancy prevention risk management program.15 drogenic women.13,29 Carbamazepine, phenytoin, S.M.A.R.T. introductory packets have been mailed and valproate also can lower serum concentration to all US dermatologists. To prescribe isotretinoin and efficacy of isotretinoin.30 Staphylococcus aureus and be in compliance with the product label, colonization complicating isotretinoin therapy can dermatologists must read the S.M.A.R.T. Guide to result in “nonresponse.”31 Thus, for nonresponders Best Practices and sign and return to the manufac- with generalized dermatitis, skin culture and the turer the S.M.A.R.T. Letter of Understanding.15 The judicial institution of oral antibiotics is indicated.31 manufacturer-issued yellow qualification stickers Treatment failures also have been reported from must be applied to every isotretinoin prescription the inappropriate expectation that isotretinoin