[Withdrawn from the market. See 9th edition.]
ROFLUMILAST
Respiratory (Selective Phosphodiesterase 4 Inhibitor)
PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Moderate Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
No reports describing the use of roflumilast in human pregnancy have been located. Developmental toxicity, at doses that were ≤10 or less than the human dose, occurred in only one of three species tested, but teratogenicity was not observed. However, the lack of human pregnancy experience prevents a more complete assessment of the embryo–fetal risk. If the maternal benefit clearly outweighs the unknown risk, the drug should not be withheld but the woman should be informed of the unknown risk.
FETAL RISK SUMMARY
Roflumilast is an oral selective inhibitor of phosphodiesterase 4. It is indicated as a treatment to reduce the risk of chronic obstructive pulmonary disease (COPD) exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. The drug is metabolized to an active metabolite. Plasma protein binding of roflumilast and its active metabolite is about 99% and 97%, respectively. For the two agents, the median plasma effective half-life is about 17 and 30 hours, respectively (1).
Animal reproduction studies have been conducted in mice, rats, and rabbits. In mice, stillbirth and decreased pup viability occurred at doses that were about ≥16 times the maximum recommended human dose based on BSA (MRHD). Postimplantation loss was induced in rats at doses that were ≥10 times the MRHD. No treatment-related effects on embryo–fetal development were noted in mice, rats, and rabbits at doses that were about 12, 3, and 26 times the MRHD, respectively. However, the drug did adversely affect postnatal development of mice pups when dams were given the drug during pregnancy and lactation. At about 49 times the MRHD, pup rearing frequencies were decreased and, at about 97 times the MRHD, decreased survival and forelimb grip reflex and delayed pinna detachment were noted. Moreover, at about 16 times the MRHD, the drug disrupted the labor and delivery process in mice (1).
In long-term studies, roflumilast was carcinogenic in hamsters but not in mice. The drug was mutagenic in one assay but negative in multiple other assays. In a 3-month human study, roflumilast had no effects on semen parameters or reproductive hormones. In contrast, a dose-related effect on male rat fertility was noted with increases in the incidence of tubular atrophy, degeneration in the testis and spermiogenic granulation in the epididymides. No effect on female fertility was observed at the highest dose tested (1).
It is not known if roflumilast or its active metabolite cross the human placenta. The molecular weight of the parent drug (about 403), and the long effective half-lives of the parent drug and active metabolite suggest that both will cross to the embryo–fetus. However, the high plasma protein binding may limit the exposure.
BREASTFEEDING SUMMARY
No reports describing the use of roflumilast during human lactation have been located. The molecular weight of the parent drug (about 403), and the long effective half-lives (17 and 30 hours, respectively) of the parent drug and active metabolite suggest that both will be excreted into breast milk. However, the high plasma protein binding (99% and 97%, respectively) may limit the excretion. The effect of this exposure on a nursing infant is unknown. If a mother chooses to breastfeed while taking roflumilast, her nursing infant should be monitored for the most common (≥2%) adverse reactions observed in adults (diarrhea, weight decrease, nausea, headache, back pain, insomnia, dizziness, and decreased appetite) (1).
Reference
1.Product information. Daliresp. Forest Pharmaceuticals, 2011.