In separate embryofetal developmental studies, pregnant rats and rabbits received vilanterol during the period of organogenesis at doses up to approximately 13,000 and 450 times, respectively, the maximum recommended human daily inhaled dose (MRHDID) (on an mcg/m2 basis at maternal inhalation doses up to 33,700 mcg/kg/day in rats and on an AUC basis at maternal inhaled doses up to 5,740 mcg/kg/day in rabbits). No evidence of structural abnormalities was observed at any dose in rats or in rabbits up to approximately 70 times the MRHDID (on an AUC basis at maternal doses up to 591 mcg/kg/day in rabbits). However, fetal skeletal variations were observed in rabbits at approximately 450 times the MRHDID (on an AUC basis at maternal inhaled or subcutaneous doses of 5,740 or 300 mcg/kg/day, respectively). The skeletal variations included decreased or absent ossification in the cervical vertebral centrum and metacarpals.^L44461

In a perinatal and postnatal developmental study in rats, dams received vilanterol during late gestation and the lactation periods at doses up to approximately 3,900 times the MRHDID (on an mcg/m2 basis at maternal oral doses up to 10,000 mcg/kg/day). No evidence of effects on offspring development was observed.^L44461

The expected signs and symptoms with overdosage of vilanterol are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms of beta-adrenergic stimulation (e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, hyperglycemia, hypokalemia, metabolic acidosis). As with all inhaled sympathomimetic medicines, cardiac arrest, and even death may be associated with an overdose of vilanterol.^L44461

In a 2-year carcinogenicity study in mice, vilanterol caused a statistically significant increase in ovarian tubulostromal adenomas in females at an inhaled dose of 29,500 mcg/kg/day (approximately 7,800 times the MRHDID for adults on an AUC basis). No increase in tumors was seen at an inhaled dose of 615 mcg/kg/day (approximately 210 times the MRHDID for adults on an AUC basis).^L44461

In a 2-year carcinogenicity study in rats, vilanterol caused statistically significant increases in mesovarian leiomyomas in females and a shortening of the latency of pituitary tumors at inhaled doses greater than or equal to 84.4 mcg/kg/day (greater than or equal to approximately 20 times the MRHDID for adults on an AUC basis). No tumors were seen at an inhaled dose of 10.5 mcg/kg/day (approximately equal to the MRHDID for adults on an AUC basis).^L44461

These tumor findings in rodents are similar to those reported previously for other beta-adrenergic agonist drugs. The relevance of these findings to human use is unknown.^L44461

Vilanterol tested negative in the following genotoxicity assays: the in vitro Ames assay, in vivo rat bone marrow micronucleus assay, in vivo rat unscheduled DNA synthesis (UDS) assay, and in vitro Syrian hamster embryo (SHE) cell assay. Vilanterol tested equivocal in the in vitro mouse lymphoma assay.^L44461