Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of tumorigenicity was observed in a 104-week inhalation study in rats at tiotropium
doses up to 0.059 mg/kg/day, in an 83-week inhalation study in female mice at doses up to
0.145 mg/kg/day, and in a 101-week inhalation study in male mice at doses up to 0.002 mg/kg/day.
These doses correspond to approximately 25, 35, and 0.5 times the recommended human daily inhalation
dose (RHDID) on a mg/m2 basis, respectively. These dose multiples may be
over-estimated due to difficulties in measuring deposited doses in animal inhalation studies.
Tiotropium bromide demonstrated no evidence of mutagenicity or clastogenicity in the following
assays: the bacterial gene mutation assay, the V79 Chinese hamster cell mutagenesis assay, the
chromosomal aberration assays in human lymphocytes in vitro and mouse micronucleus formation
in vivo, and the unscheduled DNA synthesis in primary rat hepatocytes in vitro assay.
In rats, decreases in the number of corpora lutea and the percentage of implants were noted at
inhalation tiotropium doses of 0.078 mg/kg/day or greater (approximately 35 times the RHDID on
a mg/m2 basis). No such effects were observed at 0.009 mg/kg/day
(approximately 4 times than the RHDID on a mg/m2 basis). The fertility
index, however, was not affected at inhalation doses up to 1.689 mg/kg/day (approximately 760
times the RHDID on a mg/m2 basis). These dose multiples may be over-estimated
due to difficulties in measuring deposited doses in animal inhalation studies.
Animal Toxicology and Pharmacology
Reproductive Toxicology Studies
No evidence of fetal structural alteration was observed in rats and rabbits at inhalation tiotropium
doses of up to 1.471 and 0.007 mg/kg/day, respectively. These doses correspond to approximately 660 and
6 times the RHDID on a mg/m2 basis, respectively. However, in rats, fetal
resorption, litter loss, decreases in the number of live pups at birth and the mean pup weights, and
a delay in pup sexual maturation were observed at inhalation tiotropium doses of ≥0.078 mg/kg
(approximately 35 times the RHDID on a mg/m2 basis). In rabbits, an increase
in post-implantation loss was observed at an inhalation dose of 0.4 mg/kg/day (approximately 360 times
the RHDID on a mg/m2 basis). Such effects were not observed at inhalation
doses of 0.009 and up to 0.088 mg/kg/day in rats and rabbits, respectively. These doses correspond
to approximately 4 and 80 times the RHDID on a mg/m2 basis, respectively.
These dose multiples may be over-estimated due to difficulties in measuring deposited doses in animal
inhalation studies.
