, mean plasma clearance (0.43 L/hr/kg), and mean 3-hour urine excretion (0.7%) for glycopyrrolate were also significantly different than those of controls (3.73 hr-μg/L, 1.14 L/hr/kg, and 50%, respectively). A population pharmacokinetic analysis using BEVESPI AEROSPHERE showed that formoterol systemic exposure (AUC0-12) in subjects with COPD with moderate renal impairment (45 mL/min creatinine clearance) is expected to be approximately 45% higher compared to subjects with COPD with normal renal function (94 mL/min creatinine clearance).
Drug Interactions
No pharmacokinetic interaction is expected when glycopyrrolate and formoterol fumarate are administered in combination by the inhaled route. Specific drug-drug interaction studies have not been performed with glycopyrrolate or formoterol fumarate.
13 NONCLINICAL TOXICOLOGY
13.1. Carcinogenesis, Mutagenesis, Impairment of Fertility
BEVESPI AEROSPHERE: Long-term studies in animals have not been performed to eva luate the carcinogenic potential of BEVESPI AEROSPHERE which contains glycopyrrolate and formoterol fumarate. The data described below for the individual components apply to BEVESPI AEROSPHERE.
Glycopyrrolate
Long-term studies in animals have not been performed to eva luate the carcinogenic potential of inhaled glycopyrrolate or any other formulations of glycopyrrolate.
Glycopyrrolate was not mutagenic in the bacterial reverse mutation assay, the in vitro mammalian cell micronucleus assay in TK6 cells or the in vivo micronucleus assay in rats.
In reproduction studies in rats, dietary administration of glycopyrrolate resulted in diminished rates of conception in a dose-related manner. Other studies in dogs suggest that this may be due to diminished seminal secretion which is evident at high doses of glycopyrrolate.
Formoterol Fumarate
Long-term studies were conducted in mice using oral administration and rats using inhalation administration to eva luate 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 25 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 130 mcg/kg (approximately 65 times the MRHDID on a mcg/m2 basis). No tumors were seen at 22 mcg/kg (approximately 10 times the MRHDID on a mcg/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 7600 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 7600 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 (ap |
