ADVAIR DISKUS ADVAIR - GlaxoSmithKline

Focal coronary arteritis occurred transiently and sporadically in Wistar rats exposed daily
to salmeterol xinafoate and fluticasone propionate combinations for 2 weeks. The lesion
was short-lived, resolving fully even with continued treatment, always being absent in
studies of 5 and 13 weeks duration. It showed both species and strain specificity, being
absent in dogs and Sprague-Dawley rats.
In 2 week inhalation studies in dogs, salmeterol-related pulse rate increases were slightly
more marked in groups given the combination compared with those given salmeterol
alone. However, there were no significant effects of the combination on ECG or on
cardiac histopathology in this species.
Reproduction
Co-administration of high-doses of oral salmeterol and subcutaneous fluticasone
propionate did not alter the incidence of any minor or major abnormality in rats or mice
compared with studies in which the drugs were administered alone. The incidence of two
variants, transposed (left) umbilical artery and incomplete ossification of the occipital
bone, were increased in rats at the highest combination dose (10 mg/kg:100 mcg/kg,
salmeterol xinafoate:fluticasone propionate).
Exposure at the no-effect dose for both variants of 1 mg/kg: 30 mcg/kg (salmeterol
xinafoate:fluticasone propionate) was approximately 12 times (salmeterol) and 4 times
(fluticasone propionate) greater than peak exposure in man after a standard 50:50 mcg
dose (salmeterol xinafoate:fluticasone propionate).
Mutagenicity
Mutagenicity studies conducted with salmeterol xinafoate or fluticasone propionate alone
did not show evidence of genotoxicity.
Genetic toxicity studies with the combination product were not conducted.
Carcinogenicity
In long-term studies, salmeterol xinafoate induced benign tumours of smooth muscle on
the mesovarium of rats and the uterus of mice. These findings in rodents are similar to
those reported previously for other beta-adrenergic agonist drugs. The relevance of these
findings to human is unknown.
No treatment-related effects were observed on the type or incidence of neoplasia in an
18 month oral (gavage) study in mice administered fluticasone propionate at dose levels
of up to 1 mg/kg/day. In a lifetime (2 years) snout-only inhalation study in rats, at dose
levels of up to 57 mcg/kg/day, there was an increase in the incidence of tumours in the
mammary gland, liver and pancreas. These were not considered as evidence of
tumorigenic effect of fluticasone propionate based on the absence of statistical support of
an increase in incidence and the historical tumour incidence data.
Salmeterol xinafoate/fluticasone propionate combination product was not tested in
carcinogenicity studies.
July 29, 2014
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