Tretinoin

⛔ FDA Black Box Warning

WARNING: EMBRYO-FETAL TOXICITY and DIFFERENTIATION SYNDROME • Tretinoin capsules can cause embryo-fetal loss and malformations when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Females of reproductive potential must have a negative pregnancy test before initiating tretinoin capsules. Advise females of reproductive potential to use two effective methods of contraception during treatment with tretinoin capsules and for 1 month after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with tretinoin capsules and for 1 week after the last dose [see Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.3)] . • Differentiation Syndrome, which can be life-threatening or fatal, occurred in about 26% of patients with APL who received tretinoin capsules. At first signs or symptoms of this syndrome, immediately initiate high-dose corticosteroid therapy and hemodynamic monitoring until resolution of signs and symptoms. Consider withholding tretinoin capsules for moderate and severe Differentiation Syndrome until resolution [see Warnings and Precautions (5.2)] . WARNING: EMBRYO-FETAL TOXICITY and DIFFERENTIATION SYNDROME See full prescribing information for complete boxed warning. • Embryo-Fetal Toxicity: tretinoin capsules can cause embryo-fetal loss and malformations when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Females of reproductive potential must have a negative pregnancy test before initiating tretinoin capsules. Advise females of reproductive potential to use two effective methods of contraception during treatment with tretinoin capsules and for 1 month after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with tretinoin capsules and for 1 week after the last dose. (5.1, 8.1, 8.3) • Differentiation Syndrome, which can be

Contraindications

Contraindications: Use of the product should be discontinued if hypersensitivity to any of the ingredients is noted.

Pregnancy & Breastfeeding

Pregnancy: Teratogenic effects. Pregnancy Category C. Oral tretinoin has been shown to be teratogenic in rats, mice, hamsters, and subhuman primates. It was teratogenic and fetotoxic in Wistar rats when given orally or topically in doses greater than 1 mg/kg/day (8 times the maximum human systemic dose adjusted for total body surface area). However, variations in teratogenic doses among various strains of rats have been reported. In the cynomolgus monkey, which metabolically is closer to humans for tretinoin than the other species examined, fetal malformations were reported at doses of 10 mg/kg/day or greater, but none were observed at 5 mg/kg/day (83 times the maximum human systemic dose adjusted for total body surface area), although increased skeletal variations were observed at all doses. A dose-related increase in embryolethality and abortion was reported. Similar results have also been reported in pigtail macaques. Topical tretinoin in animal teratogenicity tests has generated equivocal results. There is evidence for teratogenicity (shortened or kinked tail) of topical tretinoin in Wistar rats at doses greater than 1 mg/kg/day (8 times the maximum human systemic dose adjusted for total body surface area). Anomalies (humerus: short 13%, bent 6%, os parietal incompletely ossified 14%) have also been reported when 10 mg/kg/day was topically applied. There are other reports in New Zealand White rabbits administered doses of greater than 0.2 mg/kg/day (3.3 times the maximum human systemic dose adjusted for total body surface area) of an increased incidence of domed head and hydrocephaly, typical of retinoid-induced fetal malformations in this species. In contrast, several well-controlled animal studies have shown that dermally applied tretinoin may be fetotoxic, but not overly teratogenic in rats and rabbits at doses of 1.0 and 0.5 mg/kg/day, respectively (8 times the maximum human systemic dose adjusted for total body surface area in both species). With widespread