Oral isotretinoin is a synthetic vitamin A analog that should be considered for all patients with moderate-or-severe recalcitrant acne, provided there are no contraindications. It is the only treatment that has an effect on all four major pathogenic factors involved in acne and is therefore, unsurprisingly, the most clinically effective anti-acne therapy available.[134–136] Since its first approval for severe treatment-resistant acne in 1982, it has revolutionized the management of acne, producing long-term remission or significant improvements in many patients.
Isotretinoin decreases the size and secretion of the sebaceous gland, normalizes follicular keratinization and prevents comedogenesis, inhibits the growth of surface and ductal P. acnes via changes of the follicular milieu, and has anti-inflammatory effects.[134,136,138–141] During treatment, isotretinoin reduces sebum production by 90% or greater (within 6 weeks) and P. acnes populations decrease substantially. However, both sebum and P. acnes levels increase upon cessation of treatment, albeit to a lesser extent.
This profound effect on sebaceous gland activity can be achieved in most patients with a dose of isotretinoin 0.5–1.0 mg/kg/day. A recent European Directive on isotretinoin prescribing has recommended a starting dose for all patients of 0.5 mg/kg/day, with the dose titrated to obtain a maximal early response offset against the development and tolerance of side effects. Being lipophilic, it should be administered with food, which has been shown by pharmokinetic studies to double absorption. A heavy alcohol intake should be avoided while on treatment as isotretinoin is metabolized by cytochrome P450 enzymes, which are induced by ethanol, resulting in reduced efficacy.
Whereas previously cumulative dosing has been advocated, it is now recommended that the duration and dose of isotretinoin should relate to the clinical response. Most cases of acne correspond to a single 4–6-month therapeutic course; 85% of patients who receive a dose of 0.5–1.0 mg/kg/day are virtually clear of all of their acne by 16 weeks. Some patients may tolerate and respond better to a longer course at a lower dose, especially mature adults with persistent and late-onset acne.[147,148] Demographic factors, such as age, sex and duration of acne, govern the rate of response and relapse. A slow response is most commonly owing to the presence of macrocomedones (70%), although other identifiable causes include associated hyperandrogenism, poor absorption of isotretinoin, colonization with Staphylococcus aureus, severe acne and unusual variants.[15,150] Differences in receptor sensitivity may also contribute to a slow response. Recurrence has been reported in up to 30% of patients and is most common in the first year after isotretinoin therapy, with patients under 16 years of age and women being at the highest risk of relapse. Maintenance with topical retinoid therapy may reduce the relapse rate by controlling microcomedo formation.
Approximately 6% of patients will experience a moderate-to-severe flare in their acne during the first few weeks of treatment. This is seen most commonly in patients with multiple macrocomedones and/or severe nodular acne. Such flares can be avoided or controlled by overlapping the initiation of isotretinoin therapy with oral erythromycin for up to 2 months. Oral tetracyclines should be avoided with isotretinoin as both can cause raised intracranial pressure. An alternative option is to start such patients at a lower isotretinoin dose (0.25 mg/kg/day) and titrate upwards over 4–6 weeks. Light cautery or hyfrecation of macrocomedones and nodules prior to initiation may also reduce the potential for flaring. If a severe flare should occur, isotretinoin should be temporarily discontinued and a 14–21-day course of prednisolone prescribed at a dose of 0.5–1.0 mg/kg/day. The dose of steroid should then be gradually reduced over 6 weeks and isotretinoin reinstituted at a lower dose.
Currently, isotretinoin is only licensed for the treatment of severe acne. However, in recent years, dermatologists have expanded their indications for isotretinoin and it is now frequently prescribed for patients with moderate inflammatory disease that has not responded to conventional therapy (topical agents and systemic antibiotics), acne that scars physically and/or psychologically and chronic acne prone to relapse. These indications remain outside the current product license. Over the years, isotretinoin has also been used 'off-license' to treat several other conditions with variable success, including severe acne rosacea, hidradenitis suppurativa, Gram-negative folliculitis and pyoderma faciale.
In 2006, a European Directive was implemented to harmonize generic prescribing and appropriate delivery of isotretinoin across the EU, and to minimize adverse effects including pregnancy. Recommendations within the directive can be found in Box 2. The most significant adverse event associated with the administration of isotretinoin is teratogenicity. A Pregnancy Prevention Program has been advocated for all females of child-bearing potential and includes advice on education, therapy management and control of distribution of the drug. Educational aspects advise that both the patient and prescriber should understand the implications of teratogenicity – the patient should accept detailed counseling from the prescriber before and during treatment and sign a consent form prior to initiation. Therapy management advises that medically supervised pregnancy testing is carried out prior to, throughout the month and 5 weeks after completion of treatment, and provides advice on contraception. Distribution control suggests that only 30 days of isotretinoin can be supplied to a female patient at one time and the validity of the prescription will last just 7 days.[15,143]
Documented mandatory use of two forms of contraception while taking isotretinoin is standard practice in the USA as part of the National 'iPLEDGE' Registry, but the recommendations set out by the European Directive state that physicians many exercise clinical judgment if they establish that the patient is not sexually active.[15,155] However, it is mandatory for clinicians to observe a negative pregnancy test result at each 4-weekly follow up visit, continue education, and record, as well as act upon, any change in circumstance. Pregnancy testing prior and 5 weeks after treatment cessation is mandatory. The Pregnancy Prevention Program suggests that patients should agree to use at least one, preferably two, forms of effective contraception (including a barrier method) before therapy is initiated. Teratogenicity is the most serious potential adverse effect of isotretinoin. Approximately 50% of pregnancies spontaneously miscarry, and of the remainder, half of the infants are born with cardiovascular or skeletal deformities. Patients should be warned from the outset that termination will be recommended if they become pregnant while taking isotretinoin.
Isotretinoin has many other adverse effects but most are predictable and rarely interfere with patient management. Mucocutaneous dryness is the most common problem, including chelitis, facial and irritant dermatitis, vestibulitis and blepharoconjunctivitis. These are dose dependent and rendered tolerable by modification of the dose plus symptomatic treatment (e.g., moisturizers and lip salves). Severe dermatitis should be treated with intermediate-strength steroid ointment combined with an antiseptic. Impetiginisation should be managed with oral anti-staphylococcal therapy such as flucloxacillin and/or topical 2% mupirocin ointment. Very rarely, acne fulminans, characterized by destructive hemorrhagic lesions, leucocytosis, polyarthralgia and fever can be precipitated by isotretinoin.
Adverse psychiatric events including mood changes, depression and suicidal ideation have been reported in acne patients taking isotretinoin.[159–161] Epidemiological studies performed by the US FDA in the USA found little or no increase in psychiatric disease including depression and suicide over the background prevalence in the adolescent population.[154,155] However, clinicians should be aware of a potential rare idiosyncratic reaction in some young, vulnerable patients, which could lead to mood changes and depressive symptoms during treatment with isotretinoin, based on a controlled study by Azoulay et al.. This is the first controlled case crossover study to demonstrate a statistically significant association between isotretinoin, acne and mood disturbance, with a reported relative risk of depression of 2.68 (95% CI: 1.03–3.89). It is therefore strongly advised for physicians to enquire about emotional change at each clinic visit. If significant depression is identified, referral to a psychiatrist is recommended and the drug stopped. A detailed history, including family history, of depression and suicide should be included in the pretreatment questionnaire for all patients considered for isotretinoin.
Significant systemic effects are uncommon. Headaches may uncommonly be an early feature of benign intracranial hypertension. Arthralgias may develop, particularly in those patients who participate in heavy and regular physical activity. Less common effects include gastrointestinal upset (diarrhea/colitis), paronychia, night blindness, urticaria, pyogenic granulomas and Achilles tendonitis.
There has been much debate in recent years as to the ideal serological monitoring strategy while on therapy. Elevations in lipids and liver function tests are observed in almost all patients and rapidly return to pretreatment levels after therapy has stopped. A baseline assessment is essential, and the European Directive is prescriptive in suggesting that these blood tests should be repeated 1 month into treatment and every 3 months thereafter.
Expert Rev Clin Pharmacol. 2010;13(4):563-580. © 2010 Expert Reviews Ltd.
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