Duaklir Drug Information

is a combination of aclidinium bromide (an anticholinergic) and formoterol fumarate (a LABA) indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). Limitations of Use: DUAKLIR PRESSAIR is not indicated for the relief of acute bronchospasm or for the treatment of asthma . DUAKLIR PRESSAIR is a combination of aclidinium bromide an anticholinergic, and formoterol fumarate, a long-acting beta 2 -adrenergic agonist (LABA) indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). Limitations of Use: Not indicated for the relief of acute bronchospasm or for the treatment of asthma.

• The recommended dose of DUAKLIR PRESSAIR is one oral inhalation of 400 mcg/12 mcg, twice daily (once in the morning and once in the evening). Do not take more than one inhalation twice daily.
• For oral inhalation only. ( 2 )
• 400 mcg/12 mcg, twice daily (once in the morning and once in the evening). ( 2 )

• LABAs, such as formoterol fumarate, one of the active ingredients in DUAKLIR PRESSAIR, increase the risk of asthma-related death. DUAKLIR PRESSAIR is not indicated for the treatment of asthma [see Warnings and Precautions (5.1) ] . The following adverse reactions are described in greater detail elsewhere in the labeling:
• Paradoxical bronchospasm [see Warnings and Precautions (5.4) ]
• Immediate hypersensitivity reactions [see Contraindications (4) , Warnings and Precautions (5.5) ]
• Cardiovascular effects [see Warnings and Precautions (5.6)]
• Worsening of narrow-angle glaucoma [see Warnings and Precautions (5.9) ]
• Worsening of urinary retention [see Warnings and Precautions (5.10) ] Most common adverse reactions (incidence ≥ 3% and more common than with placebo) include: upper respiratory tract infection, headache and, back pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Covis Pharma at 1-877-411-2510 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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. 24-Week Trials 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 1 ) was 54% (range: 28% to 80%) and the mean percent reversibility was 15% (range: -19% to 69%). 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. Table 1: Adverse Reactions with DUAKLIR PRESSAIR ≥3% Incidence and More Common than with Placebo in Subjects with COPD Treatment Adverse Reactions Preferred Term DUAKLIR PRESSAIR (N=720) % Aclidinium (N=722) % Formoterol (N=716) % Placebo (N=526) % Upper respiratory tract infection Includes Viral Upper Respiratory Tract Infection and Upper Respiratory Tract Infection 8.9 7.6 8.9 6.3 Headache 6.3 6.6 7.7 5.1 Back pain 3.8 3.3 3.5 3.4 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. Long-Term Safety Extension Trial 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.

• No formal drug interaction studies have been performed with DUAKLIR PRESSAIR.
• Use of other adrenergic by any route may potentiate the effect of DUAKLIR PRESSAIR. Use with caution. ( 5.3 , 7.1 )
• Xanthine derivatives, steroids, diuretics or non-potassium sparing diuretics may potentiate hypokalemia or ECG changes. Use with caution. ( 7.2 , 7.3 )
• Diuretics: Use with caution. Electrocardiographic changes and/or hypokalemia associated with non-potassium sparing diuretics may worsen with concomitant beta 2 -agonists. ( 7.3 )
• Monoamine oxidase inhibitors and tricyclic antidepressants: Use with extreme caution. May potentiate effect of formoterol fumarate on cardiovascular system. ( 7.4 )
• Beta-blockers: Use with caution and only when medically necessary. ( 7.5 )
• Anticholinergics: May interact additively with concomitantly used anticholinergic medications. Avoid administrations of DUAKLIR PRESSAIR with other anticholinergic-containing drugs. ( 7.6 ) 7.1 Adrenergic Drugs 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 [see Warnings and Precautions (5.7) ] . 7.2 Xanthine Derivatives, Steroids Concomitant treatment with xanthine derivatives, or steroids may potentiate any hypokalemic effect of beta-adrenergic agonists such as formoterol, a component of DUAKLIR PRESSAIR. 7.3 Non-Potassium Sparing Diuretics 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. 7.4 Monoamine Oxidase Inhibitors and Tricyclic Antidepressants, QTc Prolonging Drugs DUAKLIR PRESSAIR, as with other drugs containing beta 2 -agonists, should be administered with caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or other drugs known to prolong the QTc interval, because the action of adrenergic agonists on the cardiovascular system may be potentiated by these agents. Drugs that are known to prolong the QTc interval have an increased risk of ventricular arrhythmias. 7.5 Beta-Blockers 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 2 -agonists, such as formoterol, a component of DUAKLIR PRESSAIR, but may produce severe bronchospasm in COPD patients. Therefore, patients with COPD should not normally be treated with beta-blockers. However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-blockers in patients with COPD. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution. 7.6 Anticholinergics 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 [see Warnings and Precautions ( 5.3 , 5.4 ) and Adverse Reactions (6) ] .

Pregnancy Risk Summary There are no adequate and well-controlled studies of DUAKLIR PRESSAIR or its individual components, formoterol fumarate or aclidinium bromide, in pregnant women to inform drug-associated risks. No adverse developmental effects were seen with inhalation administration of aclidinium bromide to pregnant rats and rabbits during organogenesis at 15 or 20 times, respectively, the maximum recommended human daily inhaled dose (MRHDID). However, reduced pup weights were seen when pregnant rats continued inhalation administration through lactation at 5 times the MRHDID of aclidinium bromide. Adverse developmental effects occurred when rabbits were orally dosed with aclidinium bromide at approximately 1,400 times the MRHDID . Formoterol fumarate alone, administered by the oral route, was teratogenic in rats and rabbits at 1,200 and 49,000 times the MRHDID, respectively.

Formoterol fumarate was also embryocidal, increased pup loss at birth and during lactation, and decreased pup weight in rats at 85 times the MRHDID. These adverse effects generally occurred at large multiples of the MRHDID when formoterol fumarate was administered by the oral route to achieve high systemic exposures. No teratogenic, embryocidal, or developmental effects were seen in rats that received inhalation doses up to 280 times the MRHDID. The estimated background risk of major birth defects and miscarriage of the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations Labor or Delivery There are no well-controlled human studies that have investigated the effects of DUAKLIR PRESSAIR during labor and delivery. Because of the potential for beta-agonist interference with uterine contractility, use of DUAKLIR PRESSAIR during labor should be restricted to those patients in whom the benefits clearly outweigh the risk. Data Animal Data Aclidinium bromide In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation days 6-17, no evidence of structural alterations was observed at approximately 15 times the maximum recommended human daily inhaled dose (MRHDID). However, in a pre- and post-natal development study, decreased pup weights were observed when pregnant rats were exposed from gestation day 6 and continuing during the lactation period at approximately 5 times the MRHDID. Maternal toxicity was also observed at inhaled doses greater than or equal to 0.2 mg/kg/day.

In an embryo-fetal development study in pregnant Himalayan rabbits administered inhaled doses of aclidinium bromide during the period of organogenesis from gestation days 6-19, no evidence of structural alterations was observed at approximately 20 times the MRHDID. However, in another embryo-fetal development study in pregnant Himalayan rabbits dosed orally from gestation days 6-19, increased incidences of additional liver lobes (3-5%), as compared to 0% in the control group, were observed at approximately 1,400 times the MRHDID, and decreased fetal body weights were observed at approximately 2,300 times the MRHDID. These fetal findings were observed in the presence of maternal toxicity. Formoterol fumarate In a fertility and reproduction study, male rats were orally dosed for 9 weeks and females for 2 weeks prior to pairing and throughout the mating period. Females were either dosed up to gestation day 19 or up until weaning of their offspring.

Males were dosed up to 25 weeks. Umbilical hernia was observed in rat fetuses at oral doses 1,200 times and greater than the MRHDID (on a mg/m 2 basis at maternal oral doses of 3 mg/kg/day and higher). Brachygnathia, abnormal shortness of the mandible, was observed in rat fetuses at a dose 6,000 times the MRHDID (on a mg/m 2 basis at a maternal oral dose of 15 mg/kg/day). Pregnancy was prolonged at a dose 6,000 times the MRHDID (on a mg/m 2 basis at a maternal oral dose of 15 mg/kg/day). Fetal and pup deaths occurred at doses approximately 1,200 times the MRHDID and higher (on a mg/m 2 basis at oral doses of 3 mg/kg/day and higher) during gestation. In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation days 6-15, no teratogenic, embryocidal or developmental effects were seen at doses up to 280 times the MRHDID (on a mg/m 2 basis with maternal inhalation doses up to 0.69 mg/kg/day). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 6-18, subcapsular cysts on the liver were observed in the fetuses at a dose 49,000 times the MRHDID (on a mg/m 2 basis with a maternal oral dose of 60 mg/kg/day). No teratogenic effects were observed at doses up to 2,800 times the MRHDID (on a mg/m 2 basis at maternal oral doses up to 3.5 mg/kg/day). In a pre- and post-natal development study, pregnant female rats received formoterol at oral doses of 0, 0.21, 0.84, and 3.4 mg/kg/day from gestation day 6 through the lactation period.

Pup survival was decreased from birth to postpartum day 26 at doses 85 times the MRHDID and higher (on a mg/m 2 basis at maternal oral doses of 0.21 mg/kg/day and higher), although there was no evidence of a dose-response relationship. There were no treatment-related effects on the physical, functional, and behavioral development of rat pups.

Pediatric Use DUAKLIR PRESSAIR is not indicated for use in children. The safety and effectiveness of DUAKLIR PRESSAIR in the pediatric population have not been established.

• Use of a long-acting beta 2 -adrenergic agonist (LABA), including formoterol fumarate, one of the active ingredients in DUAKLIR PRESSAIR, without an inhaled corticosteroid is contraindicated in patients with asthma [see Warnings and Precautions (5.1) ] . DUAKLIR PRESSAIR is not indicated for the treatment of asthma. DUAKLIR PRESSAIR is contraindicated in patients with:
• Severe hypersensitivity to milk proteins [see Warnings and Precautions (5.5) ] .
• Hypersensitivity to aclidinium bromide, formoterol fumarate, or to any component of the product [see Warnings and Precautions (5.5) ] .
• Use of a long-acting beta 2 -adrenergic agonist (LABA), including formoterol fumarate, one of the active ingredients in DUAKLIR PRESSAIR, without an inhaled corticosteroid is contraindicated in patients with asthma. ( 1 , 4 )
• Hypersensitivity to aclidinium bromide or formoterol fumarate or to any component of this product. ( 4 , 5.5 )

contains both aclidinium and formoterol fumarate; therefore, the risks associated with overdosage for the individual components described below apply to DUAKLIR PRESSAIR. The most common symptoms are blurred vision, dry mouth, nausea, muscle spasms, tremor, headache, palpitations, and systolic hypertension. Treatment of overdosage consists of discontinuation of DUAKLIR PRESSAIR together with institution of appropriate symptomatic and/or supportive therapy.