5.1 Serious Asthma-Related Events-Hospitalizations, Intubations, Death

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The safety and efficacy of DUAKLIR PRESSAIR in patients with asthma have not been established. DUAKLIR PRESSAIR is not indicated for the treatment of asthma. [see Contraindications (4)].

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Use of LABA as monotherapy [without inhaled corticosteroids (ICS)] for asthma is associated with an increased risk of asthma-related death. Available data from controlled clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric and adolescent patients. These findings are considered a class effect of LABA monotherapy. When LABA are used in fixed-dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared with ICS alone.

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A 28-week, placebo-controlled, U.S. trial comparing the safety of another LABA (salmeterol) with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol (13/13,176 in subjects treated with salmeterol vs 3/13,179 in subjects treated with placebo; relative risk: 4.37 [95% CI: 1.25, 15.34]). The increased risk of asthma-related death is considered a class effect of LABAs, including formoterol fumarate, one of the active ingredients in DUAKLIR PRESSAIR.

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No trial adequate to determine whether the rate of asthma-related deaths is increased in subjects treated with DUAKLIR PRESSAIR has been conducted.

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Available data do not suggest an increased risk of death with use of LABA in patients with COPD.

5.2 Deterioration of Disease and Acute Episodes

DUAKLIR PRESSAIR should not be initiated in patients with acutely deteriorating COPD, which may be a life-threatening condition. DUAKLIR PRESSAIR has not been studied in patients with acutely deteriorating COPD. The use of DUAKLIR PRESSAIR in this setting is inappropriate.

DUAKLIR PRESSAIR is intended as twice daily maintenance treatment for COPD and should not be used for the relief of acute symptoms, i.e., as rescue therapy for treatment of acute episodes of bronchospasm. DUAKLIR PRESSAIR has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled short-acting beta2-agonist.

When beginning treatment with DUAKLIR PRESSAIR, patients who have been taking oral or inhaled, short-acting beta2-agonists on a regular basis (e.g., four times a day) should be instructed to discontinue the regular use of these drugs and use them only for symptomatic relief of acute respiratory symptoms. When prescribing DUAKLIR PRESSAIR, the healthcare provider should also prescribe an inhaled, short-acting beta2-agonist and instruct the patient on how it should be used. Increasing inhaled beta2-agonist use is a signal of deteriorating disease for which prompt medical attention is indicated.

COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If DUAKLIR PRESSAIR no longer controls symptoms of bronchoconstriction; the patient’s inhaled, short-acting beta2-agonist becomes less effective; or the patient needs more short-acting beta2-agonist than usual, these may be markers of deterioration of disease. In this setting, a re-evaluation of the patient and the COPD treatment regimen should be undertaken at once. Increasing the daily dose of DUAKLIR PRESSAIR beyond the recommended dose is not appropriate in this situation.

5.3 Excessive Use of DUAKLIR PRESSAIR and Use with Other Long-Acting Beta2 Agonists

As with other inhaled drugs containing beta-agonists, DUAKLIR PRESSAIR should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medications containing LABAs, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using DUAKLIR PRESSAIR should not use another medicine containing a LABA for any reason [see Drug Interactions (7.1)].

5.4 Paradoxical Bronchospasm

Inhaled medicines, including DUAKLIR PRESSAIR, may cause paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with DUAKLIR PRESSAIR, it should be treated immediately with an inhaled, short acting bronchodilator. DUAKLIR PRESSAIR should be discontinued immediately, and alternative therapies should be instituted.

5.5 Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions including anaphylaxis, angioedema (including swelling of the lips, tongue, or throat), urticaria, rash, bronchospasm, or itching, have occurred after administration of DUAKLIR PRESSAIR. If such a reaction occurs, therapy with DUAKLIR PRESSAIR should be stopped at once and alternative treatments should be considered.

5.6 Cardiovascular Effects

Formoterol fumarate, like other beta agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic or blood pressure, or symptoms [see Clinical Pharmacology (12.2)]. If such effects occur, DUAKLIR PRESSAIR may need to be discontinued.

In addition, beta-agonists have been reported to produce ECG changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression, although the clinical significance of these findings is unknown. Therefore, DUAKLIR PRESSAIR should be used with caution in patients with severe cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

5.7 Coexisting Conditions

DUAKLIR PRESSAIR, like other medications containing sympathomimetic amines, should be used with caution in patients with convulsive disorders, thyrotoxicosis, and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta-agonist albuterol, when administered intravenously, have been reported to aggravate pre-existing diabetes mellitus and ketoacidosis.

5.8 Hypokalemia and Hyperglycemia

Beta-agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects [see Clinical Pharmacology (12.2)]. The decrease in serum potassium is usually transient, not requiring supplementation. Beta-agonist medications may produce transient hyperglycemia in some patients. In 4 clinical trials of 24 to 52 weeks duration evaluating DUAKLIR PRESSAIR in patients with COPD, there was no evidence of a treatment effect on serum glucose or potassium.

5.9 Worsening of Narrow-Angle Glaucoma

DUAKLIR PRESSAIR should be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos, or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

5.10 Worsening of Urinary Retention

DUAKLIR PRESSAIR should be used with caution in patients with urinary retention or bladder neck obstruction. Prescribers and patients should be alert for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination), especially in patients with prostatic hyperplasia or bladder neck obstruction. Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

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 (FEV1) 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.

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.

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 beta2-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 beta2-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)].

8.1 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 [see Data].

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 [see Data].

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) [based on summed AUCs of aclidinium bromide and its metabolites at inhaled doses less than or equal to 5.0 mg/kg/day]. 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 [based on summed AUCs of aclidinium bromide and its metabolites at inhaled doses greater than or equal to 0.2 mg/kg/day]. 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 [based on summed AUCs of aclidinium bromide and its metabolites at inhaled doses less than or equal to 3.6 mg/kg/day]. 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 [based on summed AUCs of aclidinium bromide and its metabolites at oral doses greater than or equal to 150 mg/kg/day], and decreased fetal body weights were observed at approximately 2,300 times the MRHDID [based on summed AUCs of aclidinium bromide and its metabolites at oral doses greater than or equal to 300 mg/kg/day]. 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/m2 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/m2 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/m2 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/m2 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/m2 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/m2 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/m2 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/m2 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.

8.2 Lactation

Risk Summary

There are no available data on the effects of DUAKLIR PRESSAIR, aclidinium bromide, or formoterol fumarate on the breastfed child or on milk production or presence in human milk. Both aclidinium bromide and formoterol fumarate are present in rat milk [see Data]. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for DUAKLIR PRESSAIR and any potential adverse effects on the breastfed child from DUAKLIR PRESSAIR or from the underlying maternal condition.

Data

In a pharmacokinetic study, levels of radioactivity in milk and plasma in rats were measured after a single intravenous dose of 1 mg/kg of radiolabeled aclidinium bromide on approximately post-natal day 14 [see Use in Specific Populations (8.1)]. The maximum concentration of radioactivity [14C aclidinium] in milk was measured at 6 hours post-dose and was found to be 10-14 times higher than in plasma.

In the fertility and reproduction study in rats, plasma levels of formoterol were measured in pups on post-natal day 15 [see Use in Specific Populations (8.1)]. It was estimated that the maximum plasma concentration that the pups received from the maternal animal, at the highest dose of 15 mg/kg, after nursing was 4.4% (0.24 nmol/L for a litter vs. 5.5 nmol/L for the mother).

8.4 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.

8.5 Geriatric Use

Based on available data for DUAKLIR PRESSAIR or its active components, no adjustment of dosage in geriatric patients is warranted [see Clinical Pharmacology (12.3)].

Of the 720 COPD patients exposed to DUAKLIR PRESSAIR for 24 weeks in two placebo-controlled clinical trials, 238 were less than 60 years, 301 were greater than or equal to 60 to less than 70 years, and 181 were greater than or equal to 70 years of age.

No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Hepatic Impairment

Formal pharmacokinetic studies using DUAKLIR PRESSAIR have not been conducted in patients with hepatic impairment. Based on available data for aclidinium and formoterol, no adjustment of dosage in hepatically impaired subjects is warranted.

8.7 Renal Impairment

Formal pharmacokinetic studies using DUAKLIR PRESSAIR have not been conducted in patients with renal impairment. Based on available data for aclidinium and formoterol, no adjustment of dosage in renally impaired subjects is warranted.

12.1 Mechanism of Action

DUAKLIR PRESSAIR

DUAKLIR PRESSAIR contains two bronchodilators: aclidinium a long-acting muscarinic antagonist (also known as an anticholinergic) and formoterol a long-acting beta2-adrenergic agonist. Further information regarding these two substances is provided below. The mechanism of action described below for the individual components apply to DUAKLIR PRESSAIR. These drugs represent two different classes of medications (a long-acting antimuscarinic agent and a selective long-acting beta2-adrenergic receptor agonist) that have different effects on clinical and physiological indices of COPD.

Aclidinium bromide

Aclidinium bromide is a long-acting antimuscarinic agent, which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of M3 receptors at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivo studies, prevention of acetylcholine-induced bronchoconstriction effects was dose-dependent and lasted longer than 24 hours. The clinical relevance of these findings is unknown. The bronchodilation following inhalation of aclidinium bromide is predominantly a site-specific effect.

Formoterol fumarate

Formoterol fumarate is a long-acting selective beta2-adrenergic receptor agonist (LABA) (beta2-agonist). Inhaled formoterol fumarate acts locally in the lung as a bronchodilator. In-vitro studies have shown that formoterol has more than 200-fold greater agonist activity at beta2-receptors than at beta1-receptors. The in-vitro binding selectivity to beta2-over beta1-adrenoceptors is higher for formoterol than for albuterol (5 times), whereas salmeterol has a higher (3 times) beta‑selectivity ratio than formoterol.

Although beta2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-receptors are the predominant receptors in the heart, there are also beta2-receptors in the human heart comprising 10% to 50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective beta2-agonists may have cardiac effects.

The pharmacologic effects of beta2-adrenoceptor agonist drugs, including formoterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3', 5'-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

In vitro tests show that formoterol is an inhibitor of the release of mast cell mediators, such as histamine and leukotrienes, from the human lung. Formoterol also inhibits histamine-induced plasma albumin extravasation in anesthetized guinea pigs and inhibits allergen-induced eosinophil influx in dogs with airway hyper responsiveness. The relevance of these in vitro and animal findings to humans is unknown.

12.2 Pharmacodynamics

Cardiovascular effects

DUAKLIR PRESSAIR

The effect of DUAKLIR PRESSAIR on cardiac rhythm was assessed in a subset of subjects using 24-hour Holter monitoring in the 24-week placebo-controlled trials. The Holter monitoring population included 114 subjects on DUAKLIR PRESSAIR, 118 subjects on aclidinium bromide 400 mcg, 121 subjects on formoterol fumarate 12 mcg, and 81 subjects on placebo. No clinically meaningful effects on cardiac rhythm were observed.

12.3 Pharmacokinetics

Absorption

Following twice-daily oral inhalation administration of DUAKLIR PRESSAIR in COPD patients, mean maximum aclidinium and formoterol concentrations of 128 pg/mL and 17 pg/mL, respectively, occurred within 5 minutes after inhalation. Steady state was achieved within 5 days.

Distribution

Aclidinium: Aclidinium shows a volume of distribution of approximately 300 L following intravenous administration of 400 mcg in humans.

Formoterol: Over the concentration range of 10-500 nmol/L, plasma protein binding for the RR and SS enantiomers of formoterol was 46% and 58%, respectively. The concentrations of formoterol used to assess the plasma protein binding were higher than those achieved in plasma following inhalation of a single 54 mcg dose.

Elimination

Metabolism

Aclidinium: Clinical pharmacokinetics studies, including a mass balance study, indicate that the major route of metabolism of aclidinium is hydrolysis, which occurs both chemically and enzymatically by esterases.

Aclidinium is rapidly and extensively hydrolyzed in plasma to its alcohol and dithienylglycolic acid derivatives, neither of which binds to muscarinic receptors and are devoid of pharmacologic activity.

Therefore, due to the low plasma levels achieved at the clinically relevant doses, aclidinium and its metabolites are not expected to alter the disposition of drugs metabolized by the human CYP450 enzymes.

Formoterol:

Metabolism of formoterol is primarily by direct glucuronidation and by O-demethylation followed by conjugation to inactive metabolites. Secondary metabolic pathways include deformylation and sulfate conjugation. CYP2D6 and CYP2C have been identified as being primarily responsible for O-demethylation.

Excretion

Aclidinium: Total clearance was approximately 170 L/h after an intravenous dose of aclidinium bromide in young healthy volunteers with an inter-individual variability of 36%. Intravenously administered radiolabeled aclidinium bromide was administered to healthy volunteers and was extensively metabolized with 1% excreted as unchanged aclidinium. Approximately 54% to 65% of the radioactivity was excreted in urine and 20% to 33% of the dose was excreted in feces. The combined results indicated that almost the entire aclidinium bromide dose was eliminated by hydrolysis. After dry powder inhalation, urinary excretion of aclidinium is about 0.09% of the dose and the estimated effective half-life approximately 12 hours.

Formoterol: The excretion of formoterol was studied in four healthy subjects following simultaneous administration of radiolabeled formoterol via the oral and IV routes. In that study, 62% of the radiolabeled formoterol was excreted in the urine while 24% was eliminated in the feces.

Specific Populations

Geriatric Patients

The pharmacokinetic profile of aclidinium bromide and its main metabolites was assessed in 12 elderly COPD patients (aged 70 years or older) compared to a younger cohort of 12 COPD patients (40-59 years) that were administered 400 mcg aclidinium bromide once daily for 3 days via inhalation. No clinically significant differences in systemic exposure (AUC and Cmax) were observed when the two groups were compared. No dosage adjustment is necessary in elderly patients [see Use in Specific Populations (8.5)].

The pharmacokinetics of formoterol have not specifically been studied in geriatric patients.

Patients with Renal Impairment

The impact of renal disease upon the pharmacokinetics of aclidinium bromide was studied in 18 subjects with mild, moderate, or severe renal impairment. Systemic exposure (AUC and Cmax) to aclidinium and its main metabolites following single doses of 400 mcg aclidinium bromide was similar in renally impaired patients compared with 6 matched healthy control subjects. No dose adjustment is necessary in renally impaired patients [see Use in Specific Populations (8.6)]. Renal excretion of unchanged formoterol is low.

Patients with Hepatic Impairment

The effects of hepatic impairment on the pharmacokinetics of aclidinium bromide were not studied. However, hepatic insufficiency is not expected to have relevant influence on aclidinium bromide pharmacokinetics, since it is predominantly metabolized by chemical and enzymatic hydrolysis to products that do not bind to muscarinic receptors [see Use in Specific Populations (8.7)]. Specific data with formoterol is not available, but because formoterol is primarily eliminated via hepatic metabolism, an increased exposure can be expected in patients with severe liver impairment.

Drug Interactions Studies

Aclidinium: Formal drug interaction studies were not performed. In vitro studies using human liver microsomes indicated that aclidinium and its major metabolites do not inhibit CYP450, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, or 4A9/11 at concentrations up to 1,000-fold higher than the maximum plasma concentration that would be expected to be achieved at the therapeutic dose. Therefore, it is unlikely that aclidinium causes CYP450 related drug interactions [see Drug Interactions (7)].

Formoterol: Specific drug-drug interaction studies with formoterol have not been performed.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies in animals with the combination of aclidinium bromide and formoterol fumarate, to evaluate the potential for carcinogenesis, mutagenesis, or impairment of fertility, have not been performed. The data described below is from studies conducted on the individual components.

Aclidinium Bromide

Two-year inhalation studies were conducted in mice and rats to assess the carcinogenic potential of aclidinium bromide. No evidence of tumorigenicity was observed in rats and mice at aclidinium doses up to 0.20 and 2.4 mg/kg/day, respectively [approximately 10 and 80 times the Maximum Recommended Human Daily Inhalation Dose (MRHDID), respectively, based on summed AUCs of aclidinium bromide and its metabolites].

Aclidinium bromide was positive in the in vitro bacterial gene mutation assay and the in vitro thymidine locus mouse lymphoma assay. However, aclidinium bromide was negative in the in vivo mouse micronucleus assay and the in vivo/in vitro unscheduled DNA synthesis assay with rat liver.

Aclidinium bromide impaired several fertility and reproductive performance indices (increased number of days to mate, decreased conception rate, decreased number of corpora lutea, increased pre-implantation loss with consequent decreased number of implantations and live embryos) in both male and female rats administered inhaled doses greater than or equal to 0.8 mg/kg/day [approximately 15 times the MRHDID based on summed AUCs of aclidinium bromide and its metabolites]. These adverse fertility effects were observed in the presence of paternal toxicity as evidenced by mortality and decreased body weight gain. However, there were no effects on mating index and sperm number and morphology. In the separate fertility assessments (treated males mated with untreated females; treated females mated with untreated males), no effect was observed in male and female rats at inhaled doses of 1.9 and 0.8 mg/kg/day, respectively [approximately 30 and 15 times the MRHDID, respectively, based on summed AUCs of aclidinium bromide and its metabolites].

Formoterol Fumarate

Long-term studies were conducted in mice using oral administration and rats using inhalation administration to evaluate the carcinogenic potential of formoterol fumarate. In a 24-month carcinogenicity study in CD-1 mice, formoterol fumarate at oral doses of 0.1 mg/kg and above [approximately 20 times the maximum recommended human daily inhalation dose (MRHDID) on a mg/m2 basis] caused a dose-related increase in the incidence of uterine leiomyomas.

In a 24-month carcinogenicity study in Sprague-Dawley rats, an increased incidence of mesovarian leiomyoma and uterine leiomyosarcoma were observed at the inhaled dose of 0.13 mg/kg (approximately 55 times the MRHDID on a mg/m2 basis). No tumors were seen at 0.022 mg/kg (approximately 9 times the MRHDID on a mg/m2 basis). Other beta-agonist drugs have similarly demonstrated increases in leiomyomas of the genital tract in female rodents. The relevance of these findings to human use is unknown.

Formoterol fumarate was not mutagenic or clastogenic in Ames Salmonella/microsome plate test, mouse lymphoma test, chromosome aberration test in human lymphocytes, and rat micronucleus test.

A reduction in fertility and/or reproductive performance was identified in male rats treated with formoterol at an oral dose of 15 mg/kg (approximately 6,000 times the MRHDID on a mg/m2 basis). In a separate study with male rats treated with an oral dose of 15 mg/kg (approximately 6,000 times the MRHDID on a mg/m2 basis), there were findings of testicular tubular atrophy and spermatic debris in the testes and oligospermia in the epididymides. No such effect was seen at 3 mg/kg (approximately 1,200 times the MRHDID on a mg/m2 basis). No effect on fertility was detected in female rats at doses up to 15 mg/kg (approximately 6,000 times the MRHDID on a mg/m2 basis).

14.1 Dose-Ranging Trials

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

Aclidinium

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 FEV1 over 24 hours compared with aclidinium bromide 200 mcg and 100 mcg.

The change from baseline in FEV1 AUC0-12 from placebo after 7 days for the 100, 200, and 400 mcg doses were 154 mL (95% CI: 116, 192), 176 mL (95% CI: 137, 215), and 208 mL (95% CI: 170, 247), respectively. The results supported the selection of 400 mcg of aclidinium bromide twice daily in the confirmatory COPD trials.

Formoterol

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 FEV1 AUC0-12 from placebo after 7 days for the 6, 12, and 24 mcg doses were 108 mL (95% CI: 55, 161), 117 mL (95% CI: 64, 171), and 162 mL (95% CI: 107, 216), respectively. The results supported the evaluation of 12 mcg of formoterol twice daily in the confirmatory COPD trials.

14.2 Confirmatory Trials

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 FEV1 less than 80% of predicted normal values, and a ratio of FEV1/FVC of less than 0.7. The majority of these patients were male (61%) and Caucasian (94%) with a mean age of 64 years and an average smoking history of 46 pack-years (50% current smokers). During screening, mean post-bronchodilator percent predicted FEV1 was 53% (range: 10% to 86%) and mean percent reversibility was 15% (range: -33% to 121%).

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 FEV1 and change from baseline in one-hour post-dose FEV1 at Week 24 compared with formoterol fumarate 12 mcg and aclidinium 400 mcg, respectively.

In the three trials, DUAKLIR PRESSAIR demonstrated a statistically significant increase in mean change from baseline in trough FEV1 and change from baseline in one-hour post-dose FEV1 at Week 24 relative to formoterol fumarate 12 mcg and aclidinium 400 mcg, respectively (Table 2).

With the limited data available, there were consistent improvements in trough FEV1 and one-hour post-dose FEV1 with respect to age, sex, degree of airflow limitation, reversibility, GOLD stage, smoking status, or inhaled corticosteroid use.

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.

Figure 1: FEV1 profile for DUAKLIR PRESSAIR (AB/FF 400/12 mcg), aclidinium bromide 400 mcg, formoterol fumarate 12 mcg, over a 24-hour dosing interval at Day 1 (active control not shown)

Figure 2: FEV1 profile for DUAKLIR PRESSAIR (AB/FF 400/12 mcg), aclidinium bromide 400 mcg, formoterol fumarate 12 mcg, over a 24-hour dosing interval at Week 24 (active control not shown)

In Trials 1 and 2, DUAKLIR PRESSAIR displayed an increase in FEV1 compared to placebo of 0.108 L (95% CI; 0.089, 0.127) and 0.128 L (95% CI; 0.111, 0.145) within 5 minutes after the first dose, respectively.

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.

Exacerbations

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 FEV1 of 47.7% of predicted value. The majority of patients had moderate (45.1%) or severe (40.2%) airflow obstruction.

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).