Respiratory Drug (Bronchodilator)
PREGNANCY RECOMMENDATION: Limited Human Data—Probably Compatible
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
One review concluded that salmeterol was safe during human pregnancy (1), but others thought it should not be a first-line drug because of the lack of published human experience (2,3). Although human data have been published and no congenital malformations attributable to salmeterol were observed, the data are too limited to assess the safety of salmeterol. Moreover, the above study lacked the sensitivity to identify minor anomalies because of the absence of standardized examinations. Late-appearing major defects may also have been missed because of the timing of the questionnaires. However, if a patient with moderate or severe asthma had demonstrated a good therapeutic response before conception, this may favor the drug’s continuation during pregnancy (2). Moreover, salmeterol is more effective than doubling the dose of inhaled corticosteroids and may have advantages over theophylline in terms of effectiveness and tolerability (2). In addition, the very low or undetectable maternal plasma levels that occur with therapeutic inhaled doses suggest that the risk to the fetus from the drug is probably minimal or nonexistent. If salmeterol is used in pregnancy, healthcare professionals are encouraged to call the toll-free number (877-311-8972) for information about patient enrollment in an Organization of Teratology Information Specialists (OTIS) study.
FETAL RISK SUMMARY
Salmeterol is a selective β2-adrenergic bronchodilator that is indicated in the management of asthma. It is administered as an aerosol or powder for oral inhalation. Because the drug acts locally in the lung, plasma levels are very low or undetectable and are a result of swallowed salmeterol.
Animal reproduction studies have been conducted in the rat and rabbit (4). In the rat, oral doses up to approximately 160 times the maximum recommended daily human inhalation dose based on BSA (MRDHID-BSA) produced no evidence of impaired fertility or teratogenic effects. In pregnant Dutch rabbits, an oral dose about 10 times the maximum recommended daily human inhalation dose based on AUC (MRDHID-AUC) produced no fetal toxicity. When the dose was increased to about 20 times the MRDHID-AUC, fetal toxicity secondary to β-adrenoceptor stimulation was observed (precocious eyelid openings, cleft palate, sternebral fusion, limb and paw flexures, and delayed ossification of the frontal cranial bones). However, New Zealand White rabbits were much less sensitive—exhibiting only delayed ossification of the frontal cranial bones at oral doses 1600 times the MRDIHD-BSA. The fetal toxicity noted in rabbits was not thought to be relevant to humans because β-agonists characteristically induce these effects in animals (4).
In a study with pregnant rats, salmeterol concentrations in mammary tissue, placenta, and fetus after oral administration were comparable to those in maternal blood up to 6 hours after a dose (5). At 24 hours, the disposition of the drug in the fetus was primarily in the gastrointestinal tract.
It is not known if salmeterol crosses the placenta to the fetus. Although the molecular weight (about 604 for salmeterol xinafoate) is low enough, plasma levels after an inhaled therapeutic dose are very low or undetectable.
A 1998 noninterventional observational cohort study described the outcomes of pregnancies in women who had been prescribed ≥1 of 34 newly marketed drugs by general practitioners in England (6). Data were obtained by questionnaires sent to the prescribing physicians 1 month after the expected or possible date of delivery. In 831 (78%) of the pregnancies, a newly marketed drug was thought to have been taken during the 1st trimester, with birth defects noted in 14 (2.5%) singleton births of the 557 newborns (10 sets of twins). In addition, two birth defects were observed in aborted fetuses. However, few of the aborted fetuses were examined. Salmeterol was taken during the 1st trimester in 65 pregnancies. The outcomes of these pregnancies included 7 spontaneous abortions, 2 ectopic pregnancies, 4 elective abortions, 5 unknown outcomes, and 47 live births (3 premature). One full-term newborn was diagnosed with Aarskog’s syndrome (a male child with short stature, and facial, digital, and genital malformations; pectus excavatum, metatarsus adductus, and joint laxity are frequent skeletal features [7]) (6). The syndrome is thought to be secondary to X-linked recessive inheritance (7).
BREASTFEEDING SUMMARY
No reports describing the use of salmeterol during human lactation have been located. The molecular weight (about 604 for salmeterol xinafoate) is low enough for excretion into breast milk, but maternal plasma levels after an inhaled therapeutic dose are very low or undetectable. Thus, it is unlikely that clinically significant amounts would be found in milk.
References
1.Anonymous. Drugs for asthma. Med Letter Drugs Ther 2000;42:19–24.
2.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. Position statement. Ann Allergy Asthma Immunol 2000;84:475–80.
3.Tan KS, Thomson NC. Asthma in pregnancy. Am J Med 2000;109:727–33.
4.Product information. Serevent. Glaxo Wellcome, 2002.
5.Manchee GR, Barrow A, Kulkarni S, Palmer E, Oxford J, Colthup PV, Maconochie JG, Tarbit MH. Disposition of salmeterol xinafoate in laboratory animals and humans. Drug Metab Dispos 1993;21:1022–8.
6.Wilton LV, Pearce GL, Martin RM, Mackay FJ, Mann RD. The outcomes of pregnancy in women exposed to newly marketed drugs in general practice in England. Br J Obstet Gynaecol 1998;105:882–9.
7.Buyse ML, editor. Birth Defects Encyclopedia. Volume 1. Cambridge, MA: Blackwell Scientific Publications, 1990:1–2.