Trifarotene

Risk Summary

Available data from clinical trials with trifarotene cream use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are case reports of major birth defects similar to those seen in fetuses exposed to oral retinoids in pregnant women exposed to other topical retinoids, but these case reports do not establish a pattern or association with retinoid-related embryopathy.

In animal reproduction studies, oral doses of trifarotene administered to pregnant rats and rabbits during organogenesis that resulted in systemic exposures more than 800 times the systemic exposure at the maximum recommended human dose (MRHD) of trifarotene cream resulted in adverse fetal effects, including fetal deaths and external, visceral, and skeletal malformations (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

Oral administration of trifarotene to pregnant rats during the period of organogenesis at doses that resulted in systemic exposures greater than 1600 times those in humans at the MRHD of trifarotene cream resulted in adverse fetal effects, including fetal deaths, reduced mean fetal weight, and external, visceral, and skeletal malformations.

Oral administration of trifarotene to pregnant rabbits during the period of organogenesis at doses that resulted in systemic exposures at least 800 times those in humans at the MRHD of trifarotene cream resulted in adverse fetal effects, including defects of the tail, limbs, urogenital organs, and vertebral column.

Trifarotene administered orally to female rats from gestation Day 6 to lactation Day 20, at doses that resulted in systemic exposures up to 594 times those in humans at the MRHD of trifarotene cream, had no effect on maternal function or behavior, including gestation, delivery, pup-rearing, lactation and nursing, or survival or development of pups. There were no effects of maternal treatment on behavior, learning, memory, or reproductive function of pups.

Risk Summary

There are no data on the presence of trifarotene in human milk, the effects on the breastfed infant, or the effects on milk production. In animal studies, trifarotene was present in rat milk with oral administration of the drug. When a drug is present in animal milk, it is likely that the drug will be present in human milk. It is possible that topical administration of large amounts of trifarotene could result in sufficient systemic absorption to produce detectable quantities in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for trifarotene cream and any potential adverse effects on the breastfed infant from trifarotene cream or from the underlying maternal condition.

Clinical Considerations

To minimize potential exposure to the breastfed infant via breastmilk, use trifarotene cream on the smallest area of skin and for the shortest duration possible while breastfeeding. Advise breastfeeding women not to apply trifarotene cream directly to the nipple and areola to avoid direct infant exposure.

Trifarotene was not carcinogenic when topically applied to mice daily for up to 24 months in the vehicle of the product (trifarotene cream) at concentrations of 0.0005% or 0.001% w/w. The systemic exposures at the highest doses evaluated in mice were approximately 82 (males) and 99 (females) times higher than the human exposure at the MRHD of trifarotene cream.

Trifarotene was not carcinogenic when administered orally to rats daily for up to 24 months at doses up to 0.75 mg/kg/day in males and 0.2 mg/kg/day in females. The systemic exposures at the highest doses evaluated in rats were approximately 645 (males) and 1642 (females) times higher than the human exposure at the MRHD of trifarotene cream.

Trifarotene was negative in an in vitro bacterial reverse mutation (Ames) assay, an in vitro micronucleus assay in primary human lymphocytes, an in vitro mouse lymphoma assay with L5178Y/TK^+/- cells, and an in vivo micronucleus assay in rats.

Trifarotene was assessed for effects on fertility or general reproductive function in rats. Males received trifarotene via oral gavage for 4 weeks prior to mating, during mating, and up to scheduled termination (approximately 6 weeks in total), and females were treated via oral gavage for 2 weeks prior to mating through Day 7 of gestation. No adverse effects on fertility or reproductive parameters, including sperm motility and concentration, were observed at the highest doses evaluated, which resulted in systemic exposures approximately 1755 (males) and 1726 (females) times higher than the human exposure at the MRHD of trifarotene cream.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect rates observed in practice. In the three Phase 3 clinical trials, 1673 subjects with acne vulgaris on the face and trunk, 9 years and older were exposed to trifarotene cream. Of these, 1220 subjects were treated once daily for up to 12 weeks and 453 were treated once daily for up to 1 year.

Adverse reactions reported in the 2 randomized, double-blind, vehicle-controlled 12-week clinical trials in ≥1.0% of subjects treated with trifarotene cream (and for which the rate exceeded the rate for vehicle), as well as the corresponding rates reported in subjects treated with the vehicle cream are presented in Table 1.

Table 1. Adverse Reactions Occurring in ≥1.0% of Subjects with Acne Vulgaris of the Face and Trunk in the Two 12-week Phase 3 Clinical Trials:

Additional adverse reactions that were reported in more than one subject treated with trifarotene cream (and at a frequency <1%) included application site pain, application site dryness, application site discoloration, application site rash, application site swelling, application site erosion, acne, dermatitis allergic, and erythema.

In the one-year, open-label safety trial that included 453 subjects 9 years and older, with acne vulgaris of the face and trunk, the pattern of adverse reactions for trifarotene cream was similar to that experienced in the 12-week controlled trials. A total of 12.6% of subjects had at least one adverse reaction during the trial, and 2.9% of subjects had an adverse reaction leading to treatment discontinuation. The most common adverse reactions (≥1% of subjects) for the entire trial were application site pruritus (4.6%), application site irritation (4.2%), and sunburn (5.5%). The frequency of adverse reactions decreased over time.

Skin irritation was evaluated by active assessment of erythema, scaling, dryness, and stinging/burning and collected separately. In the two 12-week Phase 3 clinical trials, these signs/symptoms were assessed at baseline and at least one post-baseline visit, in 1214 subjects (for face) and 1202 subjects (for trunk) treated with trifarotene cream. The percentage of subjects who were assessed to have these signs and symptoms at any post baseline visit and at a severity worse than baseline are summarized in Table 2.

Table 2. Application Site Tolerability Reactions at Any Post Baseline Visit:

Local tolerability on the face in subjects treated with trifarotene cream worsened for any of the signs/symptoms compared with baseline to a score of moderate for up to 30% of subjects, or severe for up to 6% of subjects. On the trunk, the corresponding percentages were up to 19% (moderate) and up to 5% (severe). The scores reached maximum severity at Week 1 for the face, and at Week 2 to 4 of treatment for the trunk, and decreased thereafter.

In the open-label, 1-year Phase 3 trial, the local tolerability profile was comparable to that observed in the two pivotal Phase 3 trials.