Immunologic Agent (Immunomodulator)
PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
No reports describing the use of pimecrolimus in human pregnancy have been located. The systemic absorption after topical application of the cream is minimal. Moreover, the animal reproduction data suggest low risk. Based on this information, the topical use of the drug during pregnancy appears to represent a low, if any, risk to the embryo or fetus.
FETAL RISK SUMMARY
Pimecrolimus, a selective inhibitor of inflammatory cytokine release, is an immunosuppressant that is available as a 1% cream for topical application. It is the same subclass of topical calcineurin inhibitor immunomodulators as tacrolimus. Pimecrolimus is indicated as second-line therapy for the short-term and noncontinuous chronic treatment of mild to moderate atopic dermatitis in nonimmunocompromised adults and children ≥2 years of age. Systemic absorption was minimal with blood concentrations <0.5 ng/mL in 91% of adult subjects (1244/1362) tested. The maximum blood concentration observed in these subjects was 1.4 ng/mL. Based on in vitro tests, plasma protein binding of drug reaching the systemic circulation was 99.5%. Following a single oral dose given to volunteers, pimecrolimus was extensively metabolized to inactive metabolites and primarily excreted in the feces (1). Based on oral studies in adult patients with psoriasis, the terminal elimination half-life after 28 days of therapy was 50–100 hours (2).
Reproduction studies have been conducted in rats and rabbits. No maternal or fetal toxicity was observed in these species exposed during organogenesis to dermal doses that were 0.14 times the maximum recommended human dose of the cream (MRHD) based on BSA and 0.65 times the MRHD based on AUC, respectively. A second dermal study in pregnant rats at doses up to 0.66 times the MRHD based on AUC revealed no maternal, reproductive, or embryo–fetal toxicity, including teratogenicity, attributable to the drug. When pimecrolimus was given orally to pregnant rats and rabbits, no evidence of developmental toxicity was observed at doses up to 38 and 3.9 times the MRHD based on AUC, respectively. In rabbits, an oral dose that was 12 times the MRHD based on AUC caused maternal, embryo, and fetal toxicity. No toxicity was observed at 5 times the MRHD based on AUC. Pimecrolimus crossed the placentas of rats and rabbits given oral doses (1).
In a 2-year dermal carcinogenicity study conducted in rats, a significant increase in the incidence of follicular cell adenoma of the thyroid was observed. In mice, lymphoproliferative changes, including lymphoma, were observed. A 39-week oral study in monkeys also observed dose-related and duration-related changes that could progress to lymphoma. A dose-dependent increase in opportunistic infections also was noted. No evidence of mutagenicity or clastogenicity was observed in several tests. No effect on fertility in female and male rats was observed with oral doses that were 12 and 23 times the MRHD based on AUC, respectively. In a second oral fertility study, the no effect doses were 5 and 0.7 times the MRHD based on AUC, respectively (1).
It is not known if pimecrolimus crosses the human placenta. The molecular weight (about 810) and the long elimination half-life suggest that if the drug reaches the maternal circulation, exposure of the embryo–fetus will occur. However, the minimal blood concentrations, high plasma protein binding, and extensive metabolism suggest that such exposure will be limited, if it occurs at all.
BREASTFEEDING SUMMARY
No reports describing the use of pimecrolimus during human lactation have been located. The molecular weight (about 810) and the long elimination half-life (50–100 hours after 28 days of therapy) suggest that if the drug reaches the maternal circulation, excretion into breast milk will occur. However, the minimal blood concentrations, high plasma protein binding (99.5%), and extensive metabolism to inactive metabolites suggest that such excretion will be limited, if it occurs at all. The risk to a nursing infant is unknown but does not appear to be clinically significant.
References
1.Product information. Elidel. Novartis Pharmaceuticals, 2009.
2.Scott G, Osborne SA, Greig G, Hartmann S, Ebelin ME, Burtin P, Rappersberger K, Komar M, Wolff K. Pharmacokinetics of pimecrolimus, a novel nonsteroid anti-inflammatory drug, after single and multiple oral administration. Clin Pharmacokinet 2003;42:1305–14.