Studies in animals with the combination of aclidinium bromide and formoterol fumarate, to evaluate the potential for carcinogenesis, mutagenesis, or impairment of fertility, have not been performed. The data described below is from studies conducted on the individual components.

Aclidinium Bromide

Two-year inhalation studies were conducted in mice and rats to assess the carcinogenic potential of aclidinium bromide. No evidence of tumorigenicity was observed in rats and mice at aclidinium doses up to 0.20 and 2.4 mg/kg/day, respectively [approximately 10 and 80 times the Maximum Recommended Human Daily Inhalation Dose (MRHDID), respectively, based on summed AUCs of aclidinium bromide and its metabolites].

Aclidinium bromide was positive in the in vitro bacterial gene mutation assay and the in vitro thymidine locus mouse lymphoma assay. However, aclidinium bromide was negative in the in vivo mouse micronucleus assay and the in vivo/in vitro unscheduled DNA synthesis assay with rat liver.

Aclidinium bromide impaired several fertility and reproductive performance indices (increased number of days to mate, decreased conception rate, decreased number of corpora lutea, increased pre-implantation loss with consequent decreased number of implantations and live embryos) in both male and female rats administered inhaled doses greater than or equal to 0.8 mg/kg/day [approximately 15 times the MRHDID based on summed AUCs of aclidinium bromide and its metabolites]. These adverse fertility effects were observed in the presence of paternal toxicity as evidenced by mortality and decreased body weight gain. However, there were no effects on mating index and sperm number and morphology. In the separate fertility assessments (treated males mated with untreated females; treated females mated with untreated males), no effect was observed in male and female rats at inhaled doses of 1.9 and 0.8 mg/kg/day, respectively [approximately 30 and 15 times the MRHDID, respectively, based on summed AUCs of aclidinium bromide and its metabolites].

Formoterol Fumarate

Long-term studies were conducted in mice using oral administration and rats using inhalation administration to evaluate the carcinogenic potential of formoterol fumarate. In a 24-month carcinogenicity study in CD-1 mice, formoterol fumarate at oral doses of 0.1 mg/kg and above [approximately 20 times the maximum recommended human daily inhalation dose (MRHDID) on a mg/m2 basis] caused a dose-related increase in the incidence of uterine leiomyomas.

In a 24-month carcinogenicity study in Sprague-Dawley rats, an increased incidence of mesovarian leiomyoma and uterine leiomyosarcoma were observed at the inhaled dose of 0.13 mg/kg (approximately 55 times the MRHDID on a mg/m2 basis). No tumors were seen at 0.022 mg/kg (approximately 9 times the MRHDID on a mg/m2 basis). Other beta-agonist drugs have similarly demonstrated increases in leiomyomas of the genital tract in female rodents. The relevance of these findings to human use is unknown.

Formoterol fumarate was not mutagenic or clastogenic in Ames Salmonella/microsome plate test, mouse lymphoma test, chromosome aberration test in human lymphocytes, and rat micronucleus test.

A reduction in fertility and/or reproductive performance was identified in male rats treated with formoterol at an oral dose of 15 mg/kg (approximately 6,000 times the MRHDID on a mg/m2 basis). In a separate study with male rats treated with an oral dose of 15 mg/kg (approximately 6,000 times the MRHDID on a mg/m2 basis), there were findings of testicular tubular atrophy and spermatic debris in the testes and oligospermia in the epididymides. No such effect was seen at 3 mg/kg (approximately 1,200 times the MRHDID on a mg/m2 basis). No effect on fertility was detected in female rats at doses up to 15 mg/kg (approximately 6,000 times the MRHDID on a mg/m2 basis).