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Isotretinoin

A Review of its Pharmacological Properties and Therapeutic Efficacy in Acne and Other Skin Disorders

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Summary

Synopsis: Isotretinoin1 is a new orally active retinoic acid derivative for the treatment of severe refractory nodulocystic acne. The pharmacological profile of isotretinoin suggests that it acts primarily by reducing sebaceous gland size and sebum production, and as a result alters skin surface lipid composition. Bacterial skin microflora is reduced, probably as a result of altered sebaceous factors. Isotretinoin 1 to 2 mg/kg/day for 3 to 4 months produces 60 to 95% clearance of inflammatory lesions in patients with severe, recalcitrant nodulocystic acne, with evidence of continued healing and prolonged remissions in many patients after treatment withdrawal. Doses as low as 0.1 mg/kg/day have also proven successful in the clearance of lesions; however, with such low doses the duration of remission after discontinuation of therapy is usually shorter. Encouraging results have also been seen in small numbers of patients with rosacea, Gram-negative folliculitis, Darier’s disease, ichthyosis and pityriasis rubra pilaris, the response in keratinising disorders resembling that with the related drug etretinate. While long term follow-up studies in these patients have not been reported, prolonged remission after withdrawal of isotretinoin in disorders of keratinisation is unlikely, as with other drugs used in these conditions. Isotretinoin is only partially effective in psoriasis, in contrast to etretinate which is very effective in psoriasis but ineffective in severe acne. Some encouraging results have also been reported with isotretinoin in patients with squamous and basal cell carcinomas, but isotretinoin has proven unsuccessful in non-squamous cell epithelial and non-epithelial cancer. Side effects affecting the mucocutaneous system occur in nearly all patients receiving isotretinoin, but rarely lead to drug withdrawal. Raised serum triglyceride levels are also commonly reported. The possibility of long term spinal or skeletal bone toxicity may restrict the use of isotretinoin in severe disorders of keratinisation requiring prolonged administration. Isotretinoin is strictly contraindicated in women of childbearing potential due to its severe teratogenic properties, unless an effective form of contraception is used.

Thus, isotretinoin offers an effective advance on the treatment options available in a difficult therapeutic area — those patients with severe, nodulocystic acne not responding to ‘traditional’ therapy.

Pharmacodynamic Studies: In vivo studies in hamsters show that isotretinoin causes atrophy of the sebaceous component of the flank organ by a mechanism not involving androgen inhibition. In patients with acne, isotretinoin (0.5 to 2 mg/kg/day) for 3 to 4 months results in about 90% reduction in sebaceous gland size and sebum production, which may be maintained for prolonged periods after withdrawal of therapy. Skin surface lipid composition is altered to resemble that of a child rather than an adult. The anti-inflammatory effects of isotretinoin remain to be clarified, with preliminary in vitro studies revealing an inhibition of the release of some mediators of inflammation, but inconsistent effects on leucocytic and lymphocytic responses. Isotretinoin appears to have no intrinsic antibacterial activity; decreases seen in the epidermal bacterial population in patients with acne are probably secondary to reduced sebum production. Isotretinoin appears to increase the binding capacity of epidermal growth factor to cells. In animals, oral, subcutaneous and topical administration promotes cellular differentiation causing marked inhibition of the formation of some chemically induced tumours and the growth of transplantable tumours.

Pharmacokinetic Studies: Peak plasma concentrations of isotretinoin vary widely among individuals, but usually occur 2 to 4 hours after administration. Steady-state concentrations are also subject to considerable interindividual variation. The disposition of isotretinoin does not appear to alter during multiple-dose administration in most patients. Isotretinoin is extensively bound to albumin in the plasma. The major systemic metabolite of isotretinoin in man is 4-oxo-isotretinoin, and its plasma concentration is about 4-fold higher than that of the parent drug after multiple dosing. The elimination half-life of isotretinoin has been reported as about 10 to 20 hours in several studies in healthy subjects or patients.

Therapeutic Trials: Clinical trials with isotretinoin have included a number of studies which were of open design, although patients were said to be unresponsive to previous ‘traditional’ therapy and in that sense could be said to serve as their own controls. Double-blind techniques are of limited value with isotretinoin, due to an easily recognisable side effect profile in the great majority of patients. Therapeutic use has been limited primarily to those patients with severe treatment-resistant nodulocystic acne, and some refractory diseases of keratinisation. At a dose of 1 to 2 mg/kg/day for 3 to 4 months about 65 to 90% of inflammatory acne lesions are cleared, with tolerable side effects in most patients. There is evidence of continued improvements for prolonged periods after withdrawal of therapy, despite a return towards baseline sebaceous gland activity. Lower doses of isotretinoin (0.1 to 0.5 mg/kg/day) have produced similar rates of clearance of acne lesions; however, the duration of remission after discontinuation of therapy appears to be dose related. Rapid and extensive reductions of lesions associated with severe rosacea, and of the skin bacteria counts and lesions in Gram-negative folliculitis, are also seen with isotretinoin treatment.

Isotretinoin, like etretinate, appears to be particularly effective in some diseases of keratinisation, particularly Darier’s disease, ichthyosis and pityriasis rubra pilaris, although its use for extended periods in such conditions may be limited by the possibility of long term toxicity. Mean doses of between 1.8 and 2.2 mg/kg/day have resulted in clear improvements in 50 to 70% of patients after 4 weeks’ therapy and in over 90% of patients with a longer duration of treatment. However, the marked clinical reductions in erythema, scaling, inflammation and induration in these disorders regress towards basal disease status upon discontinuation of isotretinoin. Some success has also been seen in a few patients with palmoplantar keratoderma. Isotretinoin is only partly effective in the treatment of psoriasis, although its efficacy is increased in combination with PUVA therapy, and in rare conditions such as x-linked ichthyosis, bullous congenital ichthyosiform erythroderma and pachyonychia congenita. Isotretinoin is ineffective in Hailey-Hailey disease, nevus comedonicus and Netherton’s syndrome. Regression of the pre-cancerous condition, leukoplakia, has been seen in about 90% of patients treated with either isotretinoin or etretinate, but rapid relapse occurs in some patients. In the treatment of carcinomas, isotretinoin has produced a partial response in about 25 to 30% of patients with squamous cell carcinomas, and shown some efficacy in basal cell carcinomas and cutaneous T-cell lymphoma. However, in other non-squamous cell epithelial carcinomas and non-epithelial tumours or malignancies, isotretinoin has been ineffective.

Side Effects: The incidence of side effects during treatment with isotretinoin is high. The nature of the side effects resembles hypervitaminosis A syndrome, involving mainly the mucocutaneous system. Cheilitis occurs in about 90% of patients at all doses, while dry mouth, facial desquamation, pruritus, epistaxis and gastrointestinal disturbances, each occur in 20 to 30% of patients at doses of 1 mg/kg/day, and at slightly lower rates with lower doses. However, these side effects rarely necessitate discontinuation of therapy. Conjunctivitis or eye irritation occur in a high proportion of patients at higher doses (about 50%) although at a much lower rate at 0.12 mg/kg/day (about 7%). Ophthalmological abnormalities are not usually seen. Hair loss, the major cause of drug discontinuation with etretinate, is uncommon with isotretinoin. Some troublesome side effects relating to spinal and skeletal bone structure and development have been reported after very prolonged therapy (several years) with isotretinoin.

Raised serum triglyceride concentrations are commonly reported, occasionally being elevated into the ‘abnormal’ range. This effect appears to be reversible and related to the dose and/or duration of therapy. Liver function tests are occasionally altered but these are rarely significant.

Dosage and Administration: The recommended initial dosage of isotretinoin is 1 to 2 mg/kg/day for 2 or more weeks, with a maximum dose of 200 mg/day in the United States, whereas in Europe and the United Kingdom the initial dose is 0.5 mg/kg/day. Thereafter the dose is individually adjusted according to response and toxicity, being reduced to the lowest effective dose. In acne, the usual duration of therapy is 15 to 20 weeks, although repeated courses may be given if necessary. Isotretinoin is highly teratogenic and is contraindicated in women of childbearing potential unless adequate contraceptive steps are taken. Isotretinoin showed no interaction with oral contraceptives in a preliminary study.

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Various sections of the manuscript reviewed by: R. Becke, Gordon, New South Wales, Australia; B. Berretti, Department of Dermatology, Polyclinique d’Aubervilliers, Aubervilliers, France; M. Binazzi, Instituto di Clinica Dermatologica e Venereologica dell’Universita di Perugia, Policlinico Monteluce, Perugia, Italy; P.M. Elias, Department of Dermatology, Veterans Administration Medical Center, San Francisco, California, USA; E.C. Gomez, Department of Dermatology, University of California, Davis, California, USA; A.M. Kligman, Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA; J.M. Marks, Department of Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne, England; R. Marks, Department of Medicine, Welsh National School of Medicine, Cardiff, Wales; R.G. Park, Wellington, New Zealand; G.L. Peck, Department of Health, Education, and Welfare, Bethesda, Maryland, USA; G. Plewig, Universitatshautklinik, Düsseldorf, West Germany; I. Racz, Clinic of Dermatology, Semmelweis Medical School, Budapest, Hungary; H.H. Roenigk, Department of Dermatology, Northwestern University, Chicago, Illinois, USA; J.S. Strauss, Department of Dermatology, University of Iowa, Iowa City, Iowa, USA; D.S. Wilkinson, The Chiltern Hospital, Great Missenden, Buckinghamshire, England.

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Ward, A., Brogden, R.N., Heel, R.C. et al. Isotretinoin. Drugs 28, 6–37 (1984). https://doi.org/10.2165/00003495-198428010-00002

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