nhalation after oral charcoal administration, there was a 3- to 4-fold difference in the area under the concentration-timecurves between the (R)- and (S)-albuterol enantiomers, with (S)-albuterol concentrations being consistently higher.
However, without charcoal pretreatment, after either oral or inhalation administration the differences were 8- to 24-fold,suggesting that the (R)-albuterol is preferentially metabolized in the gastrointestinal tract, presumably by SULTIA3.
Excretion
The primary route of elimination of albuterol is through renal excretion (80% to 100%) of either the parent compound orthe primary metabolite. Less than 20% of the drug is detected in the feces. Following intravenous administration ofracemic albuterol, between 25% and 46% of the (R)-albuterol fraction of the dose was excreted as unchanged (R)-albuterol in the urine.
Specific Populations
Age: No pharmacokinetic studies for ProAir Digihaler have been conducted in neonates or elderly subjects. The systemicexposure in children 6 to 11 years of age is similar to that of adults following 180 mcg single dose inhalation of albuterol
sulfate MDPI.
Sex: The influence of sex on the pharmacokinetics of ProAir Digihaler has not been studied.
Race: The influence of race on the pharmacokinetics of ProAir Digihaler has not been studied.
Renal Impairment: The effect of renal impairment on the pharmacokinetics of albuterol was eva luated in 5 subjects withcreatinine clearance of 7 to 53 mL/min, and the results were compared with those from healthy volunteers. Renal diseasehad no effect on the half-life, but there was a 67% decline in albuterol clearance. Caution should be used whenadministering high doses of ProAir Digihaler to patients with renal impairment [see Use in Specific Populations (8.5)].
Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of ProAir Digihaler has not beeneva luated.
Drug Interaction Studies: In vitro and in vivo drug interaction studies have not been conducted with ProAir Digihaler.
Known clinically significant drug interactions are outlined in Drug Interactions (7).
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 2-year study in Sprague-Dawley rats, albuterol sulfate caused a dose-related increase in the incidence of benignleiomyomas of the mesovarium at and above dietary doses of 2 mg/kg (approximately 15 times and 6 times the maximumrecommended daily inhalation dose (MRHDID) for adults and children, respectively, on a mg/m2 basis). In another studythis effect was blocked by the coadministration of propranolol, a non-selective beta-adrenergic antagonist. In an 18-monthstudy in CD-1 mice, albuterol sulfate showed no evidence of tumorigenicity at dietary doses of up to 500 mg/kg(approximately 1,900 times and 740 times the MRHDID for adults and children, respectively, on a mg/m2 basis). In a22-month study in Golden Hamsters, albuterol sulfate showed no evidence of tumorigenicity at dietary doses of up to50 mg/kg (approximately 250 times and 100 times the MRHDID for adults and children, respectively, on a mg/m2 basis).
Albuterol sulfate was not mutagenic in the Ames test or a mutation test in yeast. Albuterol sulfate was not clastogenic in ahuman peripheral lymphocyte assay or in an AH1 strain mouse micronucleus assay.
Reproduction studies in rats demonstrated no evidence of impaired fertility at oral doses up to 50 mg/kg (approximately380 times the MRHDID for adu |
