Preclinical: Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines are administered concurrently. The clinical relevance of these findings is unknown.

Reproductive Toxicology Studies:ADVAIR DISKUS: In mice, combining 150 mcg/kg subcutaneously of fluticasone propionate (less than the MRHD on a mg/m2 basis) with 10 mg/kg orally of salmeterol (approximately 410 times the MRHD on a mg/m2 basis) produced cleft palate, fetal death, increased implantation loss, and delayed ossification. No such effects were observed at combination subcutaneous doses up to 40 mcg/kg subcutaneously of fluticasone propionate (less than the MRHD on a mg/m2 basis) and up to 1.4 mg/kg orally doses of salmeterol (approximately 55 times the MRHD on a mg/m2 basis).

In rats, combining 100 mcg/kg subcutaneously of fluticasone propionate (equivalent to the MRHD on a mg/m2 basis) and 10 mg/kg orally of salmeterol (approximately 810 times the MRHD on a mg/m2 basis) produced decreased fetal weight, umbilical hernia, delayed ossification, and changes in the occipital bone. No such effects were observed at combination doses up to 30 mcg/kg subcutaneously of fluticasone propionate (less than the MRHD on a mg/m2 basis) and up to 1 mg/kg orally of salmeterol (approximately 80 times the MRHD on a mg/m2 basis).

Fluticasone Propionate: Subcutaneous studies in the mouse and rat at 45 and 100 mcg/kg (less than and equivalent to the MRHD on a mg/m2 basis), respectively, revealed fetal toxicity characteristic of potent corticosteroid compounds, including embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification.

In the rabbit, fetal weight reduction and cleft palate were observed at a subcutaneous dose of 4 mcg/kg (less than the MRHD on a mg/m2 basis). However, no teratogenic effects were reported at oral doses up to 300 mcg/kg (approximately 5 times the MRHD on a mg/m2 basis) of fluticasone propionate. No fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration [see Clinical Pharmacology (12.3)].

Fluticasone propionate crossed the placenta following subcutaneous administration to mice and rats and oral administration to rabbits.

Salmeterol: No teratogenic effects occurred in rats at oral doses up to 2 mg/kg (approximately 160 times the MRHD on a mg/m2 basis).

In Dutch rabbits administered oral doses of 1 mg/kg and above (approximately 50 times and above the MRHD based on comparison of the AUCs), salmeterol exhibited fetal toxic effects characteristically resulting from beta-adrenoceptor stimulation. These included precocious eyelid openings, cleft palate, sternebral fusion, limb and paw flexures, and delayed ossification of the frontal cranial bones. No such effects occurred at an oral dose of 0.6 mg/kg (approximately 20 times the MRHD based on comparison of the AUCs). New Zealand White rabbits were less sensitive since only delayed ossification of the frontal bones was seen at an oral dose of 10 mg/kg (approximately 1,600 times the MRHD on a mg/m2 basis).

Salmeterol crossed the placenta following oral administration to mice and rats.