Respiratory Agent
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Potential Toxicity
PREGNANCY SUMMARY
Zafirlukast is not teratogenic in animals, and the few adverse outcomes in humans do not demonstrate a pattern that suggests a common cause. However, the human data are limited. One source stated that zafirlukast may be safe to use during pregnancy, but this conclusion was based solely on animal studies (1). A 2000 position statement of the American College of Obstetricians and Gynecologists (ACOG) and the American College of Allergy, Asthma and Immunology (ACAAI) recommended that zafirlukast could be considered in patients with recalcitrant asthma who had shown a uniquely favorable response to the drug prior to becoming pregnant (2).
FETAL RISK SUMMARY
Zafirlukast is an oral selective peptide leukotriene receptor antagonist that is indicated for the prophylaxis and chronic treatment of asthma. It is extensively metabolized to inactive compounds that are primarily eliminated in the feces. Plasma protein binding is >99%. The mean terminal half-life is about 10 hours, but other studies have reported the plasma half-lives in the 8- to 16-hour range (3).
Reproduction studies conducted in mice and rats with oral doses ≤160 and 410 times the maximum recommended human dose based on BSA (MRHD-BSA), respectively, and in monkeys with doses resulting in exposures up to about 20 times the MRHD based on AUC of the drug plus metabolites (MRHD-AUC), did not observe any evidence of teratogenicity. The maximum doses in rats and monkeys were maternally toxic, resulting in maternal deaths in some cases (rats), fetal resorptions (rats), and spontaneous abortions (SABs) (monkeys) (3).
Zafirlukast was carcinogenic (hepatocellular adenomas) in male mice at a dose about 30 times the MRHD-BSA. Female mice at this dose had a greater incidence of whole-body histocytic sarcomas. Male and female rats at an exposure about 160 times the MRHD-AUC had an increased incidence of urinary bladder transitional cell papillomas. The no-effect doses in mice and rats were 10 times the MRHD-BSA and 140 times the MRHD-AUC, respectively. Assays for mutagenic and clastogenic effects were negative. In addition, no evidence of impaired fertility or reproduction was observed in male and female rats with doses up to about 410 times the MRHD-BSA (3).
It is not known if zafirlukast crosses the human placenta. The molecular weight (about 576) and long elimination half-life suggest that passage to the embryo and fetus should be expected. However, the extensive metabolism and protein binding should limit the exposure.
A 2007 report described the pregnancy outcomes of 96 women exposed to leukotriene receptor antagonists (montelukast and zafirlukast) (4). The women were enrolled in the Organization of Teratology Information Specialists (OTIS) Asthma Medications in Pregnancy study. Two comparison groups were formed consisting of 122 pregnant women who exclusively took short-acting β2-sympathomimetics or 346 pregnant women without asthma (control group). Among the 96 subjects, 72 took montelukast, 22 took zafirlukast, and 2 took both drugs. Most subjects (89.6%) were exposed in the 1st trimester and 50% were exposed throughout gestation. There were no differences among the three groups in terms of preterm delivery, Apgar scores at 1 and 5 minutes, birth weight and height ≤10th percentile, or ponderal index <2.2. The adjusted mean birth weight in subject infants was significantly lower than that in infants from controls without asthma (3384 vs. 3529 g) (p <0.05). There were no significant differences in pregnancy loss (SABs, ectopic pregnancies, and stillbirths), gestational diabetes, preeclampsia, and maternal weight gain. There were significantly (p <0.05) more birth defects in subjects (5.95%) compared with the control group (0.3%), but the prevalence in the control group was abnormally low. There was no significant difference in the prevalence of defects between subjects and those treated with β2-agonists (3.9%). No birth defects were reported in stillbirths, SABs, or elective abortions. Birth defects in liveborn infants of subjects (specific exposure not given) were Sturge–Weber sequence, congenital hip dislocation, bilateral club foot, neurofibromatosis type 1 (an autosomal-dominant inheritance pattern); and imperforate anus. The causes of the other four defects are either unknown or multifactorial, but no specific pattern of defects is evident (4).
BREASTFEEDING SUMMARY
The manufacturer reports that zafirlukast is excreted into breast milk (3). In healthy women taking 40 mg orally twice daily, the average steady-state concentration of zafirlukast in milk was 50 ng/mL compared with 255 ng/mL in the plasma (milk:plasma ratio 0.2). The effects in a nursing infant from exposure to the drug in milk are unknown. The manufacturer recommends against breastfeeding because of the potential for tumorigenicity noted in mice and rats, as well as the enhanced sensitivity to the adverse effects of the drug in neonatal rats and dogs (3).
References
1.Anonymous. Drugs for asthma. Med Lett Drugs Ther 2000;42:19–24.
2.Joint Committee of the American College of Obstetricians and Gynecologists (ACOG) and the American College of Allergy, Asthma and Immunology (ACAAI). The use of newer asthma and allergy medications during pregnancy. Ann Allergy Asthma Immunol 2000;84:475–80.
3.Product information. Accolate. AstraZeneca Pharmaceuticals, 2004.
4.Bakhireva LN, Jones KL, Schatz M, Klonoff-Cohen HS, Johnson D, Slymen DJ, Chambers CD., and the Organization of Teratology Information Specialists Collaborative Research Group. Safety of leukotriene receptor antagonists in pregnancy. J Allergy Clin Immunol 2007;119:618–25.