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Background: Wixela ® Inhub ® is a dry powder inhaler approved as a generic equivalent to Advair ® Diskus ® (fluticasone propionate [FP]/salmeterol fixed-dose combination) for patients with asthma or chronic obstructive pulmonary disease (COPD). This study aimed at confirming the local (lung) therapeutic equivalence of both the FP and salmeterol components of Wixela Inhub (test [T]) to Advair Diskus (reference [R]) after inhalation. Methods: This randomized, double-blind, double-dummy, placebo-controlled, parallel-group study in patients ≥18 years with mild-to-moderate persistent asthma compared the local therapeutic equivalence (using forced expiratory volume in 1 second [FEV 1 ]) of FP/salmeterol (100/50 μg) after inhaled delivery via T and R. Results: Randomized patients ( N  = 1127) received T ( n  = 512), R ( n  = 512), or placebo ( n  = 103). T and R significantly increased day 1 FEV 1 area under the effect curve over 12 hours of the change from baseline (AUC [0-12] ) and day 29 trough FEV 1 over placebo, indicating that these endpoints were sufficiently sensitive for evaluation of bioequivalence. On day 1, T and R each increased FEV 1 AUC (0-12) over placebo (3.134 L•h [T], 2.677 L•h [R]; each p  < 0.0001). Following twice-daily dosing for 28 days, T and R also each increased trough FEV 1 (measured on day 29) over placebo (235 mL [T], 215 mL [R]; each p  < 0.0001). Least-squares mean T/R ratios (90% confidence intervals) for day 1 FEV 1 AUC (0-12) and day 29 trough FEV 1 were 1.120 (1.016-1.237) and 1.069 (0.938-1.220), respectively, indicating that T and R were bioequivalent for both co-primary endpoints. FP/salmeterol was well tolerated when administered via either T or R. Conclusions: These results demonstrate that the therapeutic effects of Wixela Inhub are bioequivalent to Advair Diskus in the lung. Wixela Inhub represents a therapeutically equivalent new FP/salmeterol treatment option for use in the treatment of asthma and COPD.

Background: Wixela ® Inhub ® was developed to deliver inhaled fluticasone propionate/salmeterol (FP/S) combination as a substitutable generic equivalent to Advair ® Diskus ® . These studies aimed to confirm the pharmacokinetic bioequivalence (BE) of FP/S after single doses of Wixela Inhub (test [T]) and Advair Diskus (reference [R]). Methods: Three open-label, randomized, two-way crossover, single-dose studies in healthy subjects ( N  = 66 each) compared the systemic exposure of FP and salmeterol after inhalation from three dose strengths of FP/S (100/50, 250/50, or 500/50 μg) delivered from T and R. Primary BE endpoints were the area under the plasma concentration-time curve from time = 0 to the last measurable concentration (AUC (0-t) ) and the maximum observed plasma concentration (C max ) for both FP and S. The BE acceptance criteria specified that the 90% confidence intervals (CIs) of the geometric mean T/R ratios for AUC (0-t) and C max can be contained within 0.80-1.25 for both FP and salmeterol. Results: Wixela Inhub met the acceptance criteria for BE for FP and salmeterol at each dose strength. Estimated AUC (0-t) and C max geometric mean ratios (T/R [90% CI]) for FP were, respectively, 1.04 (1.00-1.08) and 0.92 (0.87-0.96) for 100/50 μg FP/S, 1.07 (1.02-1.13) and 1.01 (0.95-1.07) for 250/50 μg, and 0.97 (0.92, 1.00) and 0.90 (0.86-0.93) for 500/50 μg. Estimated AUC (0-t) and C max ratios for salmeterol were, respectively, 1.08 (1.04-1.11) and 1.00 (0.94-1.04) for 100/50 μg FP/S, 1.03 (0.99-1.07) and 0.93 (0.87-1.00) for 250/50 μg, and 1.00 (0.96-1.04) and 0.86 (0.81-0.91) for 500/50 μg. FP/S at all doses via both T and R was comparably well tolerated. Conclusions: Wixela Inhub was bioequivalent to Advair Diskus at all three dose strengths for both FP and S, providing direct evidence of equivalent systemic safety and indirect evidence for equivalent pulmonary deposition.

Background: Asthma is widely treated using inhaled corticosteroid/long-acting beta agonist (LABA) combinations, for example, fluticasone propionate/salmeterol (FPS) dry powder inhaler, marketed as Advair ® Diskus ® . Some regulators require generics to demonstrate local (lung) therapeutic equivalence (LTE) for each component of the FPS reference, ideally with a dose-response within the approved FPS dose range. We sought to develop a methacholine challenge (MeCh) LTE methodology for assessing the LABA (salmeterol) component of FPS. Methods: Forty-six patients with asthma received single doses of albuterol (active control; 90 or 180 μg), FPS (100/50 or 200/100 μg), and placebo on 5 separate study days. Spirometry and MeCh were performed 1, 6, and 10 hours after study drug inhalation. Primary endpoint was provocative concentration of methacholine producing a 20% fall in forced expiratory volume in 1 second (PC 20 ). Study entry required screening PC 20 ≤8 mg/mL, with a greater than fourfold increase (and PC 20 ≤128 mg/mL) after 180 μg albuterol. Results: Both albuterol (90 and 180 μg) and FPS (100/50 and 200/100 μg) significantly increased PC 20 compared with placebo (sustained 6 and 10 hours postdose with FPS but not albuterol). The dose-response slopes (95% confidence interval) estimated 1 hour after treatment were 0.374 (-0.068 to 0.815) and 0.310 (-0.135 to 0.754) between low and high doses of albuterol and FPS, respectively, both nonsignificant. Slopes were shallower than those available in the literature for albuterol and formoterol, but similar to those for salmeterol. Conclusions: These data confirm that the bronchoprotective effect of FPS lasts longer than that of albuterol. The shallow dose-response slope we observed for albuterol is contrary to previous reports, probably due to the measurement of PC 20 beginning at 1 hour postdose. The results suggest that use of MeCh to assess LTE for salmeterol formulations may be more difficult to accomplish than it is for albuterol and formoterol products.

Background: Asthma is widely treated using inhaled corticosteroid/long-acting beta-agonist combinations, such as fluticasone propionate/salmeterol (FPS) dry powder inhaler. Some regulators require generic medications to demonstrate local therapeutic equivalence (LTE) for each component of the FPS reference product. Fractional exhaled nitric oxide (F eNO ) was developed as a possible LTE endpoint for the fluticasone propionate (FP) component of FPS in a randomized, double-blind, crossover study in steroid-naive asthma patients with elevated F eNO (≥45 parts per billion). Methods: Thirty-four patients received three of five treatments: FPS 100/50 μg once daily (QD), FPS 100/50 μg twice daily (BID), FPS 250/50 μg BID, FPS 500/50 μg BID, or placebo, each for 2 weeks separated by 14-day washout. F eNO was measured on days 1, 2, 3, 5, 7, and 14 of each period, according to American Thoracic Society standards. Results: FPS treatments decreased F eNO compared with placebo, with the largest differentiation between doses noted on day 14; the mean decreases from days 1 to 14 ranged from -46.6% to -64.5% with FPS versus -9.1% with placebo. The dose-response plateaued at 200 μg/day (FPS 100/50 μg BID). Linear regression analysis revealed significant slopes between FPS doses, with the steepest between 100/50 μg QD and 100/50 μg BID (-0.0039, p  = 0.020). An estimated sample size (SS) of 160 or 48 patients would be required to demonstrate LTE of generic and FPS reference products (0.80-1.25 and 0.67-1.50 bioequivalence limits, respectively). However, as the slope between BID FPS doses was shallow, a larger SS may be needed if only an approved dose regimen was used. Conclusion: F eNO could be a valid endpoint to determine LTE between the FP component of generic and reference FPS products, but only if QD dosing and wide equivalence limits are included. As QD dosing is not an approved regimen, this approach is unlikely to be acceptable.