Azelastine and fluticasone propionate

No formal drug interaction studies have been performed with azelastine hydrochloride and fluticasone propionate nasal spray. The drug interactions of the combination are expected to reflect those of the individual components. • Potent inhibitors of cytochrome P450 (CYP) 3A4: May increase blood levels of fluticasone propionate. • Ritonavir: Coadministration is not recommended. ( 5.6 , 7.2 ) • Other potent CYP3A4 inhibitors, such as ketoconazole: use caution with coadministration. ( 5.6 , 7.2 )

7.1 Central Nervous System Depressants Concurrent use of azelastine hydrochloride and fluticasone propionate nasal spray with alcohol or other central nervous system depressants should be avoided because somnolence and impairment of central nervous system performance may occur [see Warnings and Precautions (5.1) ] .

7.2 Cytochrome P450 3A4 Ritonavir (a strong CYP3A4 inhibitor) significantly increased plasma fluticasone propionate exposure following administration of fluticasone propionate aqueous nasal spray, resulting in significantly reduced serum cortisol concentrations [see Clinical Pharmacology (12.3) ] . During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing syndrome and adrenal suppression.

Therefore, coadministration of fluticasone propionate and ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. Ketoconazole (also a strong CYP3A4 inhibitor), administered in multiple 200 mg doses to steady-state, increased plasma exposure of fluticasone propionate, reduced plasma cortisol AUC, but had no effect on urinary excretion of cortisol, following administration of a single 1000 mcg dose of fluticasone propionate by oral inhalation route.

Caution should be exercised when azelastine hydrochloride and fluticasone propionate nasal spray is coadministered with ketoconazole and other known strong CYP3A4 inhibitors.

8.1 Pregnancy Risk Summary Limited data from postmarketing experience with azelastine hydrochloride and fluticasone propionate nasal spray in pregnant women have not identified any drug associated risks of miscarriage, birth defects, or other adverse maternal or fetal outcomes. The individual components of azelastine hydrochloride and fluticasone propionate nasal spray have been marketed for decades. While the data regarding the use of nasal preparations of fluticasone propionate in pregnancy are limited, data from clinical studies of inhaled fluticasone propionate do not indicate an increased risk of adverse maternal or fetal outcomes.

Animal reproduction studies with azelastine hydrochloride and fluticasone propionate nasal spray are not available; however, studies are available with its individual components, azelastine hydrochloride and fluticasone propionate. In animal reproduction studies, there was no evidence of fetal harm in animals at oral doses of azelastine hydrochloride approximately 10 times the clinical daily dose.

Oral administration of azelastine hydrochloride to pregnant mice, rats, and rabbits, during the period of organogenesis, produced developmental toxicity that included structural abnormalities, decreased embryo-fetal survival, and decreased fetal body weights at doses 530 times and higher than the maximum recommended human daily nasal dose (MRHDID) of 0.548 mg. However, the relevance of these findings in animals to pregnant women was considered questionable based upon the high animal to human dose multiple.

In animal reproduction studies, fluticasone propionate administered via nose-only inhalation to rats decreased fetal body weight, but did not induce teratogenicity at a maternal toxic dose less than the MRHDID on a mcg/m 2 basis. Teratogenicity, characteristic of corticosteroids, decreased fetal body weight and/or skeletal variations, in rats, mice, and rabbits were observed with subcutaneously administered maternal toxic doses of fluticasone propionate less than the MRHDID of 200 mcg on a mcg/m 2 basis (see Data ). Experience with corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroids than humans.

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data…