ACLIDINIUM: 4,956 Adverse Event Reports & Safety Profile

DUAKLIR PRESSAIR consists of a dry powder formulation of aclidinium bromide and formoterol fumarate for oral inhalation only. Aclidinium bromide, is an anticholinergic with specificity for muscarinic receptors. Aclidinium bromide is a synthetic, quaternary ammonium compound, chemically described as 1-azoniabicyclo[2.2.2]octane, 3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3 R )-. The structural formula is: Aclidinium bromide is a white powder with a molecular formula of C 26 H 30 NO 4 S 2 Br and a molecular mass of 564.56. It is very slightly soluble in water and ethanol and sparingly soluble in methanol. Formoterol fumarate, a racemate, is a selective beta 2 -adrenergic agonist. Its chemical name is (±)-2-hydroxy-5-[(1RS)-1-hydroxy-2-[[(1RS)-2-(4-methoxyphenyl)-1methylethyl]-amino]ethyl]formanilide fumarate dihydrate. The structural formula is: Formoterol fumarate (as a dihydrate) has a molecular weight of 840.91, and its molecular formula is (C 19 H 24 N 2 O 4 ) 2

• C 4 H 4 O 4
• 2H 2 O. Formoterol fumarate is a white to yellowish crystalline powder, which is freely soluble in glacial acetic acid, soluble in methanol, sparingly soluble in ethanol and isopropanol, slightly soluble in water, and practically insoluble in acetone, ethyl acetate, and diethyl ether. DUAKLIR PRESSAIR is a breath-actuated multi-dose dry powder inhaler. Each actuation of DUAKLIR PRESSAIR provides a metered dose of 12 mg of the formulation which contains lactose monohydrate (which may contain milk proteins) as the carrier, 400 mcg of aclidinium bromide (equivalent to 343 mcg of aclidinium), and 12.0 mcg of formoterol fumarate (as a dihydrate, equivalent to 11.5 mcg of formoterol fumarate anhydrous and 9.8 mcg of formoterol). This results in delivery of 396 mcg of aclidinium bromide (equivalent to 340 mcg of aclidinium) and 11.8 mcg of formoterol fumarate (as a dihydrate, equivalent to 11.3 mcg of formoterol fumarate anhydrous and 9.7 mcg of formoterol) from the mouthpiece, based on in vitro testing at an average flow rate of approximately 63 L/min with constant volume of 2 L. The amount of drug delivered to the lungs will vary depending on patient factors such as inspiratory flow rate and inspiratory time. aclidinium_bromide_structural_formula formoterol_fumarate_structural_formula

AND USAGE DUAKLIR PRESSAIR 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 [see Warnings and Precautions ( 5.1 , 5.4 )] . 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). ( 1 ) Limitations of Use: Not indicated for the relief of acute bronchospasm or for the treatment of asthma. ( 1 , 5.4 )

AND ADMINISTRATION 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 )

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 )

REACTIONS The following adverse reactions are described in greater detail in other sections:

• Paradoxical bronchospasm [see Warnings and Precautions (5.2) ]
• Worsening of narrow-angle glaucoma [see Warnings and Precautions (5.3) ]
• Worsening of urinary retention [see Warnings and Precautions (5.4) ]
• Immediate hypersensitivity reactions [see Warnings and Precautions (5.5) ] Most common adverse reactions (≥3% incidence and greater than placebo) are headache, nasopharyngitis and cough. (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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 3-Month and 6-Month Trials TUDORZA PRESSAIR was studied in two 3-month (Trials B and C) and one 6-month (Trial D) placebo-controlled trials in patients with COPD. In these trials, 636 patients were treated with TUDORZA PRESSAIR at the recommended dose of 400 mcg twice daily. The population had a mean age of 64 years (ranging from 40 to 89 years), with 58% males, 94% Caucasian, and had COPD with a mean pre-bronchodilator forced expiratory volume in one second (FEV 1 ) percent predicted of 48%. Patients with unstable cardiac disease, narrow-angle glaucoma, or symptomatic prostatic hypertrophy or bladder outlet obstruction were excluded from these trials.

Table

1 shows all adverse reactions that occurred with a frequency of greater than or equal to 1% in the TUDORZA PRESSAIR group in the two 3-month and one 6-month placebo-controlled trials where the rates in the TUDORZA PRESSAIR group exceeded placebo.

Table

1: Adverse Reactions (% Patients) in Placebo-Controlled Clinical Trials Treatment Adverse Reactions TUDORZA PRESSAIR Placebo Preferred Term (N=636) (N=640) n (%) n (%)

Headache

42 (6.6) 32 (5.0)

Nasopharyngitis

35 (5.5) 25 (3.9)

Cough

19 (3.0) 14 (2.2)

Diarrhea

17 (2.7) 9 (1.4)

Sinusitis

11 (1.7) 5 (0.8)

Rhinitis

10 (1.6) 8 (1.2)

Toothache

7 (1.1) 5 (0.8)

Fall

7 (1.1) 3 (0.5)

Vomiting

7 (1.1) 3 (0.5) In addition, among the adverse reactions observed in the clinical trials with an incidence of less than 1% were diabetes mellitus, dry mouth, 1 st degree AV block, osteoarthritis, cardiac failure, and cardio-respiratory arrest. Long-term Safety Trials TUDORZA PRESSAIR was studied in three long-term safety trials, two double blind and one open label, ranging from 40 to 52 weeks in patients with moderate to severe COPD. Two of these trials were extensions of the 3-month trials, and one was a dedicated long-term safety trial. In these trials, 891 patients were treated with TUDORZA PRESSAIR at the recommended dose of 400 mcg twice daily. The demographic and baseline characteristics of the long-term safety trials were similar to those of the placebo-controlled trials. The adverse events reported in the long-term safety trials were similar to those occurring in the placebo-controlled trials of 3 to 6 months. No new safety findings were reported compared to the placebo-controlled trials. Long-Term Trial of up to 3-Years In a long-term safety trial with 3630 moderate to very severe COPD patients with previous major cardiac events or cardiovascular risk factors at baseline, the adverse reactions reported with a frequency ≥2% in the TUDORZA PRESSAIR group in which the exposure-adjusted incidence rate exceeds the placebo group were nausea, back pain, cough, hypertension, sinusitis, constipation, arthralgia, anemia, muscle spasms, cardiac failure congestive, cellulitis, and gastroesophageal reflux disease. No other new adverse reactions were identified.

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of drug TUDORZA PRESSAIR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In postmarketing experience with TUDORZA PRESSAIR, immediate hypersensitivity reactions, including anaphylaxis, angioedema (including swelling of the lips, tongue, or throat), urticaria, rash, bronchospasm, or itching have been reported. Additionally, nausea, dysphonia, blurred vision, urinary retention, tachycardia, and stomatitis have been observed.

AND PRECAUTIONS

• Asthma-related death: Long-acting beta 2 -adrenergic agonists as monotherapy (without an inhaled corticosteroid) for asthma increase the risk of serious asthma-related events. ( 5.1 )
• Do not initiate in acutely deteriorating COPD or to treat acute symptoms. ( 5.2 )
• Do not use in combination with an additional medicine containing a LABA because of risk of overdose. ( 5.3 )
• If paradoxical bronchospasm occurs, discontinue DUAKLIR PRESSAIR and institute alternative therapy. ( 5.4 )
• Use with caution in patients with cardiovascular disorders. ( 5.6 )
• Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus and ketoacidosis. ( 5.7 )
• Be alert to hypokalemia and hyperglycemia. ( 5.8 )
• Worsening of narrow-angle glaucoma may occur. Use with caution in patients with narrow-angle glaucoma and instruct patients to contact a physician immediately if symptoms occur. ( 5.9 )
• Worsening urinary retention may occur. Use with caution in patients with prostatic hyperplasia or bladder-neck obstruction and instruct patients to consult a physician immediately if symptoms occur. ( 5.10 )

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

• 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) ] .
• 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.
• 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.
• No trial adequate to determine whether the rate of asthma-related deaths is increased in subjects treated with DUAKLIR PRESSAIR has been conducted.
• 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 beta 2 -agonist. When beginning treatment with DUAKLIR PRESSAIR, patients who have been taking oral or inhaled, short-acting beta 2 -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 beta 2 -agonist and instruct the patient on how it should be used. Increasing inhaled beta 2 -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 beta 2 -agonist becomes less effective; or the patient needs more short-acting beta 2 -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 Beta 2 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 <span class="opacity-50 text-xs">[see Drug Interactions (7.1) ]</span> .

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2) ]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2) ]</span> . 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.

INTERACTIONS 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.7) ]</span> .

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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.3 , 5.4 ) and Adverse Reactions (6) ]</span> .