Palovarotene is contraindicated during pregnancy. Based on the findings in animal studies and class effects of retinoids, SOHONOS can cause fetal harm when administered during pregnancy. In animal reproduction studies, oral administration of palovarotene to pregnant rats during the period of organogenesis resulted in multiple fetal malformations typical of retinoids (e.g., cleft palate, malformed skull bone, shortening of the long bones) at doses ?0.25 mg/kg/day (less than the clinical exposure). There are no available human data on palovarotene use in pregnant women. If pregnancy occurs during treatment with palovarotene, discontinue treatment immediately and refer the patient to an obstetrician/gynecologist or other specialist experienced in reproductive toxicity for further evaluation and counseling.^L47830

No clinical experience with an overdose of palovarotene has been reported. Palovarotene is a derivative of vitamin A. In case of accidental overdose, signs of hypervitaminosis A could appear, including severe headache, nausea or vomiting, drowsiness, irritability, and pruritus. Any overdose should be treated with supportive care according to the signs and symptoms exhibited by the patient. If an overdose is suspected, patients should be treated with supportive care as clinically indicated.^L47830

Long-term studies to assess the carcinogenic potential of palovarotene have not been conducted. Palovarotene and its metabolites were negative in the vitro bacterial reverse mutation (Ames) assay and an in vitro micronucleus assay in primary human lymphocyte. Palovarotene did not have any clastogenic effect in the in vivo mouse micronucleus study.^L47830

Palovarotene effects on fertility and reproductive function were assessed in male and female rats. In a female rat fertility study, palovarotene was orally administered to females for 14 days prior to mating with drug naïve males and up to GD 7 at the dose levels of 0.3, 1, and 3 mg/kg/day. Palovarotene caused prolonged periods of diestrous and reduced ovulation rate, resulting in lower numbers of implantation sites and live embryos at 3 mg/kg/day, a dose associated with maternal toxicity.^L47830

In a male rat fertility study, palovarotene was orally administered prior to mating, during mating, and up to scheduled euthanasia (approximately 11 weeks in total) at 0.3, 1, and 3 mg/kg/day. Palovarotene did not cause adverse effects on mating, fertility indices, conception rate, reproductive organ weights, or sperm parameters up to 1 mg/kg/day (less than the clinical exposure). Males did not tolerate 3 mg/kg/day, as it produced severe systemic toxicity including deaths, adverse skin and hair coat clinical signs, and substantially reduced body weight.^L47830