J.-M. Geiger

Teratogenic risk with etretinate and acitretin treatment

Etretinate (Tigason, Tegison) and its active metabolite acitretin (Neotigason, Soriatane) are known teratogens. Pregnancy should be avoided during treatment and until 2 years after treatment discontinuation. The question is discussed whether a dose or a blood concentration of the drug below which there is no teratogenic risk can be determined. Animal experimental and human pharmacokinetic data are reviewed. An evaluation of the outcomes of pregnancies which occurred in mothers exposed to etretinate or acitretin was performed. A threshold dose in human therapy below which there is no risk of congenital malformation cannot be determined based on animal experimental data. With regard to pharmacokinetics, there are currently no data suggesting that blood levels of the drug below the detection limit of 2 ng/ml are associated with a teratogenic risk. The most useful information is given by reports in women who were exposed to either retinoid before or during pregnancy. The data indicate that the risk of spontaneous abortion or congenital malformation is high when the drug is administered during the first trimester of pregnancy. After treatment discontinuation, the risk is low since the number of abnormalities seems not to exceed those observed in a general population. There are currently no available data which suggest that the pregnancy warnings are inappropriate in terms of duration of contraception.

Benefit of progressively increasing doses during the initial treatment with acitretin in psoriasis.

The purpose of this double-blind study was to compare the therapeutic effects of a low initial dosage of acitretin, increased at 2-week intervals (group 1: 10, 30, 50 mg/day) with a high initial dosage decreased at similar intervals (group 3: 50, 30, 10 mg/day) and with a constant dosage (group 2: 30 mg/day) in 66 patients (47 men and 19 women) with severe psoriasis. At the end of the double-blind phase, the mean percent improvement, calculated by the Psoriasis Area and Severity Index score, was as follows: 62.7% in group 1, 55.9% in group 2 and 67.1% in group 3. The double-blind phase of 6 weeks was followed by an open phase of 6 weeks, during which the patients were treated either with 10, 30 or 50 mg/day, according to the therapeutic response. At the end of treatment (12 weeks), a mean improvement of more than 80% was obtained in all three groups. Hypervitaminosis A signs and symptoms were observed in all patients. The frequency and severity of these adverse reactions were shown to be dose-dependent. This study shows that a low dose progressively increased is advisable because of similar activity and better acceptability.

Retinoids and Sebaceous Gland Activity

BACKGROUND AND OBJECTIVE The marked efficacy of isotretinoin in the treatment of acne is undoubtedly due to its potential to inhibit sebaceous gland activity. The question arises if the anti-acne effect of new oral retinoids can be predicted by using the currently available experimental models. METHODS We reviewed the effects of various oral retinoids on sebum excretion in humans and their efficacy in acne. The human data were compared to the results obtained from in vitro and animal models. RESULTS Oral retinoids such as etretinate, acitretin and the so-called arotinoids were not able to inhibit the sebum production in humans and were ineffective against acne. In various animal models (i.e. sebum production in rats, flank organ size in hamsters, ear sebaceous gland size in hamster, most of these retinoids were shown to be effective. Furthermore, in addition to isotretinoin, some retinoids were able to suppress the proliferation of human sebocytes in vitro. CONCLUSIONS The elucidation of the mechanism of action of isotretinoin on the sebocyte biology is critical for the search of more reliable models and for the discovery of new retinoids with anti-acne activity.

Efficacy of Oral Low-Dose Tretinoin (all-trans-Retinoic Acid) in Lichen planus

BACKGROUND Retinoids were shown to be effective in the treatment of both oral and cutaneous forms of lichen planus. OBJECTIVE Confirm the beneficial effect of low doses of oral tretinoin in lichen planus. METHODS Eighteen patients with lichen planus were treated in an open study for up to 19 months. Efficacy and safety data were recorded. RESULTS Complete remission was observed in 13 (72%) and marked improvement in 4 (22%) out of 18 patients. Six patients showed moderate and 12 had no side effects. CONCLUSION Tretinoin is a valuable drug when given at low doses to patients with lichen planus who failed to respond to other therapies.

Is There a Reproductive Safety Risk in Male Patients Treated with Acitretin (Neotigason®/Soriatane®)?

Review of preclinical data including genotoxicity assays and a male rat reproduction toxicology study demonstrates that acitretin (Neotigason®/Soriatane®) does not affect the reproductive outcome in naive females mated with treated males. Prospective studies of teratogenic risk or impairment of fertility cannot be ethically conducted in humans. However, it is highly unlikely that any fetal malformation could be induced by an ejaculate containing traces of acitretin. Indeed, worldwide postmarketing surveillance has not revealed any cases of retinoid embryopathy associated with paternal treatment with acitretin. Birth defects seen in pregnancies fathered by male acitretin patients were all events expected to occur in the general population at known frequencies. In conclusion, therefore, available data do not appear to indicate any reproductive safety risk due to paternal treatment with acitretin.

Oral 9-cis-Retinoic Acid versus 13-cis-Retinoic Acid in Acne Therapy

BACKGROUND 9-cis-Retinoic acid (9-cis-RA) is as active as 13-cis-retinoic acid (13-cis-RA) in inhibiting the proliferation of cultured human sebocytes and in reducing the size of sebaceous glands of hamsters. OBJECTIVE Evaluate the anti-acne effect of 9-cis-RA compared to that of 13-cis-RA in a pilot study. METHODS Four young male patients with acne were treated in an open study consecutively with 9-cis-RA and 13-cis-RA given at similar doses. RESULTS No beneficial effects were observed with 9-cis-RA in any of the patients whereas all responded favorably to 13-cis-RA. CONCLUSION For the two retinoids tested, the anti-acne effect correlates with the sebosuppressive effect in humans.

Acitretin (RO10-1670) and oral contraceptives: interaction study.

Acitretin (RO 10-1670) the main metabolite of ethylester etretinate is used in the treatment of hyperkeratoses. Since it is teratogenic it is always used in association with oral contraceptives in women of childbearing age. This study was done in order to determine whether or not acitretin interacts with and reduces the efficacy of oral contraceptives. 10 patients were given acitretin (25-40 mg/day) for at least 2 cycles in combination with 1 of 3 contraceptive regimens. 3 patients were given a normal dose combined oral contraceptive (levonorgestrel .50 mg-ethinyl estradiol .05 mg); 6 patients were given low-dose combined oral contraceptives (either levonorgestrel .15/.20 mg-ethinyl estradiol .03/.04 mg or levonorgestrel .15 mg-ethinyl estradiol .03 mg); and 1 patient was given a very low dose progestin (levonorgestrel .03 mg). By the end of the study a total of 52 cycles had been controlled for plasma progesterone levels. Only in the patient taking the very low-dose progestin (levonorgestrel .03 mg) was there a significant increase in progesterone level. It is concluded that acitretin does not interfere with antiovulatory activity of combined oral contraceptives.

Potential Risk of Birth Defects after Acitretin Discontinuation

Acitretin (Soriatane®, Neotigason®) is a synthetic retinoid for the treatment of severe forms of psoriasis and disorders of keratinisation. Like other retinoids, acitretin has a teratogenic potential since it affects cellular differentiation and proliferation. With the use of oral isotretinoin (Accutane®, Roaccutane®), malformations involving the central nervous system as well as craniofacial, cardiac and thymic structures have been reported and grouped under the term ‘retinoic acid embryopathy’ [1] which is however not easily distinguishable from certain congenital syndromes [2]. Though there is no doubt that a risk of birth defect exists when a woman becomes pregnant while using these agents, it is not clear how long she should avoid pregnancy after drug discontinuation [3]. The definition of a post-therapy contraception period is solely based on pharmacokinetic findings. Experience from reported pregnancy outcomes should also be taken into consideration for the evaluation of the teratogenic risk. The most valuable and reliable information is given by prospective cases, i.e. the pregnancy was identified prior to knowledge of the outcome. We reviewed all world-wide pregnancy data reported to the manufacturer since acitretin became available. Pregnancy information was recorded for both maternal and embryonic/fetal/neonatal outcomes. ‘Normal neonate’ indicates that the mother delivered a baby after the 36th gestational week which looks, measures and functions within normal limits. ‘Normal embryo/fetus’ indicates that the mother delivered an offspring which appears to have developed normally. Birth defects are categorised according to ICD-10 (WHO, 1992) in malformations and other abnormalities. The term ‘malformation’ indicates that a structural defect was diagnosed at birth or detected after the examination of an abortus or fetus. Other abnormalities include pregnancy-related, placental, perinatal and neonatal disorders (e.g. abnormal growth, hyperbilirubinaemia, delayed motor skills) not classified as congenital malformations. As shown in table 1, there were 88 prospective cases out of a total of 123 pregnancy reports. The majority of the pregnancies occurred during the 2-year period after therapy termination. Among the 44 infants born from women exposed to acitretin 0–2 years before conception, there was one abnormality classified as malformation (undescended testicle) and two other abnormalities (one with hypotonia and one with hypocalcaemia and icterus). All other neonates were normal. We are limited in our ability to study the teratogenic effect of acitretin in humans. The pharmacokinetic findings do not assist much since the threshold blood level for the risk is unknown. Today the recommended post-therapy contraception period is 2 years in almost all countries where acitretin is marketed. This calculation is not based on the elimination half-life of acitretin (2 days) but on that of etretinate (approx. 100 days), since acitretin is potentially esterified in vivo by ethanol into etretinate [4, 5]. Received: June 17, 1998 Accepted: July 2, 1998

Diazacholesterol-Induced Ichthyosiform Changes in Hairless Mice: Effects of Oral Etretinate and Isotretinoin

Hyperkeratotic skin changes in hairless mice can be induced by oral administration of 20,25-diazacholesterol (DZC), a hypocholesterolemic agent. This system has been reported as an animal model of ichthyosis [3] and used for the investigation of the effects of topical retinoids [2]. The aim of our pilot study was to test in this animal model two oral retinoids, etretinate and isotretinoin, both therapeutically active in ichthyotic disorders in humans [6]. Female hairless mice (Fti-Alb hr/hr), 6 8 weeks old, weighing 2 5 28 g were used. They were housed under conventional conditions and were given a DZC supplemented powder diet. The food intake was recorded daily and DZC recalculated to adjust to 60 mg/kg per day. In parallel, control animals received a normal diet, without DZC. A few hyperkeratotic skin changes were observed after 7 weeks in DZC mice. To accelerate the process, 100 mg/kg DZC, dissolved in arachis oil, was additionally administered 5 days/week by gastric tube from week 8 to the end of the study. After 14 weeks, the DZC-fed mice were divided into three parallel groups, A, B, and C. In group A, ten DZC-fed mice were additionally given orally 50 mg/kg per day etretinate (Ro 10-9359) dissolved in arachis oil on 7 days: day 1 through 5, day 8, and day 9. In group B, ten DZC mice were administered 100 mg/kg per day isotretinoin (Ro 4-3780), under similar conditions as those for group A. Group C comprised ten DZC-fed mice which did not receive retinoid treatment. In parallel, a control group D was