Etretinate teratogenicity

Acitretin [P] Increased conversion of acitretin to etretinate (teratogenic). 

Acitretin (Soriatane), a metabolite of the aromatic retinoid etretinate, is quite effective in the treatment of psoriasis, especially pustular forms. It is given orally at a dosage of 25-50 mg/d. Adverse effects attributable to acitretin therapy are similar to those seen with isotretinoin and resemble hypervitaminosis A. Elevations in cholesterol and triglycerides may be noted with acitretin, and hepatotoxicity with liver enzyme elevations has been reported. Acitretin is more teratogenic than isotretinoin in the animal species studied to date, which is of special concern in view of the drug s prolonged elimination time (more than 3 months) after chronic administration. In cases where etretinate is formed by concomitant administration of acitretin and ethanol, etretinate may be found in plasma and subcutaneous fat for many years. 

During the 1980s, two drugs used to treat different types of skin diseases were found to be teratogenic. The drugs, generic names are isotretoin and etretinate, respectively, and they are synthetic retinoids (i.e., derivatives of vitamin A). Isotretoin (Accutane) was prescribed for the treatment of acne while etretinate was prescribed for psoriasis. 

Human birth defects have also been observed after prenatal exposure to etretinate. Of particular significance in the case of this drug is that measurable serum concentrations have been documented more than 2 years after cessation of therapy, suggesting a remarkable example of tissue sequestration. Therefore, the risk of teratogenicity may exist for an extended period of time. 

The first part of this chapter is devoted to the results of toxicologic, mutagenic, teratogenic, and carcinogenic studies with isotretinoin and etretinate when appropriate, a comparison with results for retinol and tretinoin (all-(rans-retinoic acid) is presented. The second part of this chapter is devoted to a description of clinical or human toxicity. 

Importantly, retinoids are devoid of myelosuppressive effects and, in certain instances, actually stimulate myelopoesis. This finding is of special relevance in cancer therapy. Since many drugs used for cancer treatment are myelosuppressive, retinoids may eventually be introduced into combination cancer therapy regimens. Animal reproduction studies indicate that both etretinate and isotretinoin are teratogenic. Therefore, caution must be exercised in the treatment of female patients of reproductive age. With respect to semen, no abnormalities of ejaculate volume, sperm count, motility, or morphology have been demonstrated (Schill et a/., 1981). 

The use of etretinate either alone or in combination with presently available therapies for psoriasis has been very effective, especially for the typically treatment-resistant pustular and erythrodermic varieties. Unlike isotretinoin in acne, maintenance therapy with etretinate is necessary for most psoriatic patients. This raises questions about the long-term safety and the potential for teratogenicity of this retinoid. So far, no serious toxicity has been observed in patients who have received etretinate for 6 years. 

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