Respiratory Drug (Bronchodilator)
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 tiotropium during human pregnancy have been located. The approved indication for the drug suggests that such experience will be rare, but its use in asthmatic patients is possible. Although the animal data suggest low risk, the absence of pregnancy data prevents a full assessment of human risk. There are human pregnancy data for ipratropium, which is the preferred inhaled anticholinergic bronchodilator in pregnancy. However, because its long elimination half-life, use of tiotropium immediately before the diagnosis of an inadvertent pregnancy would most likely result in the exposure of a portion of organogenesis. Therefore, if a nonpregnant woman has shown a good response to inhaled tiotropium, it would be reasonable to continue her on this drug during pregnancy. If the maternal condition warrants starting tiotropium in pregnancy, avoidance of the 1st trimester should be considered.
FETAL RISK SUMMARY
Tiotropium is a parasympatholytic (anticholinergic), quarternary ammonium compound that has specificity for muscarinic receptors. It is formulated as capsules that contain a powder given by oral inhalation. Tiotropium is indicated for the long-term maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. As expected, the majority of the dose is deposited in the gastrointestinal tract, but oral bioavailability is poor (2%–3%). The absolute bioavailability of an inhaled dose, primarily from the lung, is about 20%. The terminal elimination half-life after inhalation is 5–6 days (1,2).
Reproduction studies have been conducted with tiotropium in experimental animals. Long-term studies in rats revealed no evidence of tumorigenicity, mutagenicity, or clastogenicity. In pregnant rats and rabbits, inhalation doses up to about 660 and 6 times, respectively, the maximum recommended human daily dose based on BSA (MRHD) revealed no evidence of structural anomalies. In rats, however, a dose about 35 times the MRHD resulted in fetal toxicity (resorptions, litter loss, decreased number of live pups at birth, decreased mean birth weight, and a delayed pup sexual maturation) and, in a fertility study, decreased number of corpora lutea and percentage of implants. In rabbits an increase in postimplantation loss was noted at about 360 times the MRHD. The no-observed-effect level (NOEL) for these toxicities in rats and rabbits was about 4 and 80 times the MRHD, respectively. However, these dose multiples may be over-estimated because of the difficulties in measuring deposited doses in animal inhalation studies (1,2).
It is not known if tiotropium crosses the placenta. The drug’s molecular weight (about 490 for the bromide monohydrate salt) is low enough to cross. The peak plasma concentrations at steady state are very low (17–19 pg/mL), thus limiting the amount of drug at the maternal–fetal interface.
BREASTFEEDING SUMMARY
No reports describing the use of tiotropium during human lactation have been located. Because of the very low amounts in plasma (steady state peak plasma levels of 17–19 pg/mL) and the poor oral bioavailability (about 2%–3%), maternal use of the drug during lactation probably would have no effect on a nursing infant. However, close monitoring of the infant for anticholinergic effects (e.g., dry mouth, constipation, urinary retention, and increased heart rate) is warranted.
References
1.Product information. Spiriva. Boehringer Ingelheim Pharmaceuticals, 2005.
2.Product information. Spiriva. Pfizer, 2005.