Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The clinical program for DUAKLIR PRESSAIR included 6501 subjects with COPD in 2 placebo-controlled and 1 active-controlled 24-week lung function trials, one long-term safety extension study of 28 weeks and 2 other clinical trials. A total of 1893 subjects have received at least 1 dose of DUAKLIR PRESSAIR.

The frequency of common adverse reactions in Table 1 below is based upon pooled data from two, double-blind, placebo-controlled parallel group clinical trials (Trials 1 and 2, n=1729 and n=1669) in 3398 adult patients with moderate to severe COPD. Of these, 60% were male and 94% were Caucasian. They had a mean age of 64 years and an average smoking history of 46 pack-years, with 49% identified as current smokers. At screening, the mean post-bronchodilator percent predicted forced expiratory volume in 1 second (FEV

Table 1 shows all adverse reactions that occurred with a frequency of greater than or equal to 3% in the DUAKLIR PRESSAIR group in the two 24-week placebo-controlled trials where the rates in the DUAKLIR PRESSAIR group exceeded placebo.

Other adverse reactions reported in clinical studies with an incidence of >1% but less than 3% with DUAKLIR PRESSAIR but more common than with placebo were cough, sinusitis, influenza, tooth abscess, insomnia, dizziness, dry mouth, oropharyngeal pain, muscle spasms, musculoskeletal pain, arthralgia, pain in extremity, urinary tract infection, and blood creatine phosphokinase increased.

The adverse events reported in the 24-week active-controlled trial were consistent with those observed in 24-week placebo-controlled trials.

In a 28-week safety extension trial, 918 subjects who successfully completed Trial 2 were treated for up to an additional 28 weeks for a total treatment period of up to 52 weeks with DUAKLIR PRESSAIR, aclidinium 400 mcg, formoterol fumarate 12 mcg administered twice daily or placebo. Because the subjects continued from Trial 2 into the safety extension trial, the demographic and baseline characteristics of the long-term safety extension trial were similar to those of the placebo-controlled efficacy trials described above. The adverse reactions reported in the long-term safety trial were consistent with those observed in the 24-week placebo-controlled trials.

If additional adrenergic drugs are to be administered by any route, they should be used with caution because the sympathetic effects of formoterol, a component of DUAKLIR PRESSAIR, may be potentiated

Concomitant treatment with xanthine derivatives, or steroids may potentiate any hypokalemic effect of beta-adrenergic agonists such as formoterol, a component of DUAKLIR PRESSAIR.

The electrocardiographic changes and/or hypokalemia that may result from the administration of non-potassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of beta-agonists with non–potassium-sparing diuretics.

DUAKLIR PRESSAIR, as with other drugs containing beta

Beta-adrenergic receptor antagonists (beta-blockers) and DUAKLIR PRESSAIR may inhibit the effect of each other when administered concurrently. Beta-blockers not only block the therapeutic effects of beta

There is a potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, avoid coadministration of DUAKLIR PRESSAIR with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic effects

Dose selection for DUAKLIR PRESSAIR for COPD was primarily based on data for the individual components, aclidinium bromide and formoterol fumarate, in COPD patients.

Dose selection for aclidinium was supported by a 7-day, randomized, double-blind, active and placebo-controlled, crossover trial evaluating 3 doses of aclidinium bromide (400, 200, and 100 mcg) administered twice daily and an active control in 79 subjects with COPD. A dose ordering was observed, with the aclidinium bromide 400 mcg demonstrating larger improvements in FEV

The change from baseline in FEV

Dose selection for formoterol was supported by a randomized, double-blind, placebo and active comparator (open-label) controlled, 5-period incomplete unbalanced crossover trial evaluating 3 doses of formoterol fumarate (24, 12, and 6 mcg) administered twice daily and an open-label active comparator in 132 subjects with COPD.

The change from baseline in FEV

The clinical development program for DUAKLIR PRESSAIR included two placebo-controlled [Trial 1 (NCT 01462942) and Trial 2 (NCT 01437397)] and one active-controlled [Trial 3 (NCT 02796677)] randomized, double-blind, parallel-group 24-week trials in subjects with moderate to very severe COPD, including chronic bronchitis and emphysema, designed to evaluate the efficacy of DUAKLIR PRESSAIR on lung function. The 24-week trials included 4,977 subjects >40 years of age that had a clinical diagnosis of COPD, with a smoking history greater than or equal to 10 pack-years, a post-albuterol FEV

Trials 1, 2, and 3 evaluated DUAKLIR PRESSAIR (aclidinium/formoterol fumarate) 400 mcg/12 mcg, aclidinium 400 mcg, and formoterol fumarate 12 mcg. Trials 1 and 2 included a placebo arm, and Trial 3 included an active, blinded, control arm.

The co-primary endpoints were change from baseline in trough FEV

In the three trials, DUAKLIR PRESSAIR demonstrated a statistically significant increase in mean change from baseline in trough FEV

With the limited data available, there were consistent improvements in trough FEV

In Trial 3, serial spirometric evaluations were performed throughout the 24-hour dosing interval in a subset of subjects (n=563) at Day 1 and Week 24. Results from Trial 3 are shown in Figures 1 and 2.

In Trials 1 and 2, DUAKLIR PRESSAIR displayed an increase in FEV

In Trials 1 and 2, patients treated with DUAKLIR PRESSAIR used less rescue medication compared to patients treated with placebo.

The St. George’s Respiratory Questionnaire (SGRQ) was assessed in Trials 1, 2, and 3. In Trial 1, the SGRQ responder rate (defined as an improvement in score of 4 or more as threshold) was 55.3%, 53.5%, 52.1%, and 53.2% for DUAKLIR PRESSAIR, aclidinium, formoterol fumarate, and placebo, respectively, with odds ratios of 1.12 (95% CI: 0.76, 1.67) for DUAKLIR PRESSAIR vs. aclidinium, 1.16 (95% CI: 0.78, 1.73) for DUAKLIR PRESSAIR vs. formoterol fumarate, and 1.12 (95% CI: 0.68, 1.84) for DUAKLIR PRESSAIR vs. placebo. In Trial 2, the SGRQ responder rate was 58.2%, 54.5%, 52.4%, and 38.7% for DUAKLIR PRESSAIR, aclidinium, formoterol fumarate, and placebo, respectively, with odds ratios of 1.03 (95% CI: 0.66, 1.62), 1.21 (95% CI: 0.77, 1.90), and 2.26 (95% CI: 1.41, 3.61), for DUAKLIR PRESSAIR vs. aclidinium, DUAKLIR PRESSAIR vs. formoterol fumarate, and DUAKLIR PRESSAIR vs. placebo, respectively. In Trial 3, the odds ratios were 0.96 (95% CI: 0.61, 1.51) and 0.97 (95% CI: 0.59, 1.58), for DUAKLIR PRESSAIR vs. aclidinium, DUAKLIR PRESSAIR vs. formoterol fumarate, respectively.

A randomized, double-blind, placebo-controlled study of up to 36 months evaluated the efficacy of aclidinium bromide 400 mcg on COPD exacerbations in patients with moderate to very severe COPD with and without a history of exacerbations. The trial enrolled 3630 COPD patients, aged between 40 and 91 years, 58.7% were male and 90.6% were Caucasian, with a mean post-bronchodilator FEV

The primary efficacy endpoint was the rate of moderate to severe exacerbations during the first year of treatment, defined as worsening of COPD symptoms (dyspnea, cough, sputum) for at least 2 consecutive days that required treatment with antibiotics and/or systemic corticosteroids or resulted in hospitalization or lead to death. Aclidinium bromide demonstrated a statistically significant reduction in the rate of on-study moderate to severe COPD exacerbations by 17% compared to placebo (rate ratio [RR] 0.83; 95% CI 0.73 to 0.94; p=0.003).