Respiratory Drug (Corticosteroid)
PREGNANCY RECOMMENDATION: Compatible—Maternal Benefit >> Embryo–Fetal Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
No reports describing the use of ciclesonide in human pregnancy have been located. Poorly controlled asthma may result in adverse maternal, fetal, and neonatal outcomes (4,5). Maternal complications include an increased risk of preeclampsia, gestational hypertension, hyperemesis gravidarum, vaginal hemorrhage, and induced and difficult labor. Fetal and neonatal adverse effects may be an increased risk of perinatal mortality, intrauterine growth restriction (IUGR), prematurity, lower birth weight, and neonatal hypoxia (1). Moreover, a recent study reported that asthma exacerbations during the 1st trimester significantly increased the risk of congenital malformations (2). Because controlling maternal asthma can ameliorate or prevent all of these complications, the benefits of therapy outweigh the potential risks of drug-induced teratogenicity or toxicity. Pregnant women who require an inhaled corticosteroid, such as ciclesonide, for control of their asthma should be counseled as to the risks and benefits of therapy, but treatment should not be withheld because of their pregnancy.
FETAL RISK SUMMARY
Ciclesonide is a nonhalogenated glucocorticoid that is available as an inhaled aerosol and intranasal spray. It is a prodrug that is enzymatically hydrolyzed to the active drug des-ciclesonide (RM1). The oral bioavailability of ciclesonide and RM1 is negligible. RM1 has anti-inflammatory activity with an affinity for glucocorticoid receptors that is 120 times greater than that of ciclesonide and 12 times greater than that of dexamethasone. The inhaled aerosol is indicated for the maintenance treatment of asthma as a prophylactic therapy, whereas the intranasal spray is indicated for the treatment of nasal symptoms associated with perennial or seasonal allergic rhinitis (3,4). Compared with an IV 800-mcg dose, the absolute bioavailability of ciclesonide after an oral inhalation 1280-mcg dose (four times the recommended dose) was 22% and the relative systemic exposure of RM1 was 63%. Plasma protein binding for ciclesonide and RM1 was ≥99%. Following IV administration, the mean half-lives of ciclesonide and RM1 were 0.71 and 6–7 hours, respectively (1), but a review cited mean values of 0.38 and 3.5 hours, respectively (5). Only RM1 was detected in the serum after use of the intranasal spray, and then only with daily doses ≥400 mcg (4).
Reproduction studies have been conducted in rats and rabbits. There was no teratogenicity or other fetal effects in rats given oral doses that were about 10 times the maximum human daily inhalation dose based on BSA (MHDID) (3). Similarly, no adverse fetal effects were observed when rats were given doses up to about 35 times the maximum human daily intranasal dose based on BSA (MHDND) (4). When rabbits were given a SC dose that was less than either maximum human dose, fetal toxicity consisting of death, reduced weight, cleft palate, skeletal abnormalities including incomplete ossifications, and skin effects were observed (3,4). No adverse effects were observed with a dose that was one-fifth of the toxic dose.
No carcinogenicity was observed in 2-year studies in mice and rats. Ciclesonide was not mutagenic in two assays, but was clastogenic in one of three tests. Similar findings were observed with dexamethasone, the concurrent reference corticosteroid. In addition, there was no evidence of impaired fertility in male and female rats given oral doses up to about 10 times the MHDID or about 35 times the MHDND (3,4).
It is not known if ciclesonide or RM1 crosses the human placenta. The molecular weight of ciclesonide (about 541) is low enough, but the high plasma protein binding and very short half-life suggests that minimal amounts will cross the placenta. In contrast, the half-life of RM1 suggests that exposure of the embryo–fetus to amounts greater than that from ciclesonide is likely.
BREASTFEEDING SUMMARY
No reports describing the use of ciclesonide during human lactation have been located. The molecular weight of the prodrug ciclesonide (about 541) is low enough, but the high plasma protein binding and very short half-life suggests that minimal amounts will be excreted into breast milk. In contrast, the half-life of the active drug des-ciclesonide (RM1; molecular weight not specified) suggests that exposure of the nursing infant will be greater than that from ciclesonide. Although the prodrug and its active metabolite have negligible oral bioavailability (both <1%), the relatively anti-inflammatory activity of RM1 is 12 times that of dexamethasone. The effects of this exposure on a nursing infant are unknown, but, like all corticosteroids, suppression of the hypothalamic– pituitary–adrenal function is a potential complication.
References
1.Report of the Working Group on Asthma and Pregnancy, National Institutes of Health. Management of Asthma During Pregnancy. NIH Publication No. 93-3279, September 1993.
2.Blais L, Forget A. Asthma exacerbations during the first trimester of pregnancy and the risk of congenital malformations among asthmatic women. J Allergy Clin Immunol 2008;121:1379–84.
3.Product information. Alvesco. Nycomed US, 2007.
4.Product information. Omnaris. Sepracor, 2007.
5.Derendorf H. Pharmacokinetic and pharmacodynamic properties of inhaled ciclesonide. J Clin Pharmacol 2007;47:782–9.