VA Class:RE105

AHFS Class:

• Antimuscarinics/Antispasmodics 12:08.08

Generic Name(s):

• Aclidinium Bromide

Chemical Name:

• (3 R )-3-[(Hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide

Molecular Formula:

• C₂₆H₃₀BrNO₄S₂

Aclidinium bromide, a synthetic quaternary ammonium antimuscarinic agent, is a long-acting orally inhaled bronchodilator.1,11,12,13,14

Bronchospasm

Chronic Obstructive Pulmonary Disease

Aclidinium bromide is used as a bronchodilator for the long-term maintenance treatment of reversible bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.1,4,11,12,13,14 Orally inhaled aclidinium is not indicated for the initial treatment of acute exacerbations of COPD or for relief of acute symptoms (i.e., as rescue therapy for treatment of acute episodes of bronchospasm);1 a drug with a more rapid onset of action (e.g., a short-acting β₂-adrenergic agonist) may be preferred in such cases.9

Efficacy of aclidinium has been evaluated in 3 randomized, double-blind, placebo-controlled studies of 12 or 24 weeks' duration in adults 40 years of age or older with moderate to severe COPD.1,11,12 In the Aclidinium in Chronic Obstructive Respiratory Disease I (ACCORD I) study, the primary efficacy outcome was the change from baseline in the morning predose trough forced expiratory volume in 1 second (FEV₁) (defined as the average of 2 predose FEV₁ measurements) at 12 weeks.1,11 In this study, aclidinium 400 mcg twice daily improved the change from baseline in trough FEV₁ by 124 mL compared with placebo at 12 weeks.1,11,14 In addition, the change from baseline in peak FEV₁ (i.e., the highest value observed within 3 hours of the postmorning dose) following twice-daily administration of aclidinium 400 mcg improved by 192 mL versus placebo after 12 weeks of treatment.11 In the Aclidinium to Treat Airway Obstruction in COPD Patients (ATTAIN) study, the primary efficacy outcome was the change from baseline in the morning predose trough FEV₁ at 24 weeks.1,12 In this study, aclidinium 400 mcg twice daily improved the change from baseline in trough FEV₁ by 128 mL compared with placebo at 24 weeks.1,12,14 In addition, the change from baseline in peak FEV₁ following administration of aclidinium 400 mcg twice daily improved by 209 mL versus placebo at 24 weeks.12,14 Such improvement in lung function was maintained with aclidinium throughout the 12-hour dosing interval and for treatment periods of up to 12 or 24 weeks with no evidence of tolerance.1,11,12,13

In addition to improvements in lung function, clinical studies indicate that aclidinium improves health status and reduces COPD symptoms and possibly reduces the rate of exacerbations.1,11,12,13 In some studies, treatment with aclidinium also has been associated with a reduction in the need for supplemental short-acting β₂-agonists as rescue therapy for treatment of acute bronchospasm compared with placebo.1,11,12

For additional information on the treatment of COPD, see Uses: Chronic Obstructive Pulmonary Disease, in Ipratropium Bromide 12:08.08.

General

Dosage of aclidinium bromide is expressed in terms of the salt.1 Although each actuation of the metered-dose inhaler contains 400 mcg of aclidinium bromide as an inhalation powder, the precise amount of drug delivered to the lungs with each activation of the Pressair^® device depends on factors such as the patient's inspiratory flow rate and time.1 Using standardized in vitro testing at a flow rate of 63 L/minute, the Pressair^® inhaler delivered 375 mcg of aclidinium bromide from the mouthpiece.1 The commercially available inhaler delivers 60 metered doses.1

Administration

Aclidinium bromide is administered by oral inhalation only using a specific breath-actuated, oral inhalation device (Pressair^®) that delivers powdered drug.1

Prior to use, the inhaler should be removed from the sealed pouch.1 The protective cap should be removed from the inhaler by lightly squeezing the arrows marked on each side of the cap and pulling outward.1 The patient should then hold the inhaler with the mouthpiece toward the face, but not inside the mouth, with the green button facing straight up; the inhaler should not be tilted.1 Before placing the inhaler in the mouth, the patient should completely depress and then release the green button on the inhaler and then check the colored control window to ensure that it has changed from red to green, indicating that the dose is ready for inhalation.1

Before inhaling the dose, the patient should exhale as completely as possible, being careful not to exhale into the Pressair^® device.1 The patient should then place the mouthpiece of the inhaler tightly between the lips and inhale quickly and deeply through the mouth.1 The patient should hear a click (indicating that the inhaler is being used correctly) during the inhalation and should continue inhaling.1 The green button should not be pressed or held down during the inhalation.1 After a complete inhalation, the patient should remove the inhaler from the mouth and hold their breath for as long as comfortable, then exhale slowly through the nose.1 While some patients may taste the drug delivered from the Pressair^® device, they should be instructed not to use another dose even if they do not taste the drug.1 The patient should check the control window to ensure that it has changed from green to red, indicating that the full dose has been inhaled.1 If the control window is still green, the patient should attempt to inhale through the device again.1 If the patient is unable to inhale correctly after several attempts, the patient should contact their clinician.1 After the control window has turned red, the protective cap should be pressed back onto the mouthpiece of the inhaler.1

The inhaler does not need to be cleaned.1 However, if desired, the outside of the mouthpiece can be wiped with a dry tissue or paper towel; water should not be used to clean the inhaler.1 The inhaler should be discarded when the dose indicator (showing the number of doses remaining in intervals of ten) reads zero, when the device locks out (i.e., the green button stays depressed), or 45 days after removal of the inhaler from the sealed pouch, whichever comes first.1 The inhaler also should be discarded if the device appears damaged or the protective cap is lost.1

Dosage

For the long-term management of reversible bronchospasm associated with chronic obstructive pulmonary disease (COPD), the usual dosage of aclidinium bromide in adults is 400 mcg (one inhalation) twice daily via the Pressair^® device.1 Orally inhaled aclidinium should not be used for the treatment of acute episodes of bronchospasm.1

Special Populations

Dosage adjustment is not necessary in geriatric patients1,3 or patients with hepatic or renal impairment.1

Contraindications

The manufacturer states that there are no known contraindications to the use of aclidinium.1

Warnings/Precautions

Sensitivity Reactions

Immediate hypersensitivity reactions may occur after administration of aclidinium.1 If such a reaction occurs, the drug should be discontinued immediately and alternative therapy considered.1 Because of the structural similarity between atropine and aclidinium, patients with a history of hypersensitivity reactions to atropine should be monitored closely for hypersensitivity to aclidinium.1 Aclidinium also should be used with caution in patients with severe hypersensitivity to milk proteins, because the commercially available formulation of aclidinium inhalation powder contains lactose monohydrate (may include milk proteins).1

Acute Bronchospasm

Aclidinium bromide oral inhalation therapy is indicated for maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD); the drug is not indicated for treatment of acute bronchospasm (i.e., as rescue therapy).1

Paradoxical Bronchospasm

As with other inhaled agents, patients may develop paradoxical bronchospasm upon inhalation of aclidinium.1

If paradoxical bronchospasm occurs, aclidinium should be discontinued immediately and alternative therapy considered.1

Ocular Effects

Aclidinium should be used with caution in patients with acute angle-closure glaucoma.1 The drug may worsen acute angle-closure glaucoma manifested by ocular pain or discomfort, blurred vision, visual halos, or colored images in association with red eyes from conjunctival congestion and corneal edema.1 Patients with such manifestations should consult a clinician immediately; miotic eye drops alone are not considered effective treatment for this condition.1

Care should be taken to avoid contact of the drug with the eyes during oral inhalation.1 (See Advice to Patients.)

Genitourinary Effects

Aclidinium should be used with caution in patients with urinary retention.1 Aclidinium may worsen symptoms and signs (e.g., urinary retention, dysuria) associated with prostatic hyperplasia or bladder neck obstruction.1 Patients who develop such manifestations should consult a clinician immediately.1

Cardiovascular Effects

In a study evaluating potential effects of aclidinium on the QT interval, effects on prolongation of the QT interval were not observed in healthy individuals.1,15 In addition, clinically important effects on cardiac rhythm (24-hour Holter monitoring) were not observed in patients with COPD receiving aclidinium in another clinical trial.1

Analysis of pooled data from clinical studies suggests that aclidinium is not associated with an increased incidence of major adverse cardiovascular events in patients receiving the drug.14 The manufacturer of aclidinium is conducting a postmarketing study to further assess cardiovascular risk of the drug.13

Specific Populations

Pregnancy

Category C.1 (See Users Guide.)

Lactation

Aclidinium is distributed into milk in rats; it is not known whether the drug is distributed into milk in humans.1 The manufacturer recommends that orally inhaled aclidinium be used with caution in nursing women.1

Pediatric Use

Safety and efficacy of oral inhalation of aclidinium have not been established in children.1 However, COPD does not generally occur in children.1

Geriatric Use

No overall differences in safety and efficacy were observed in geriatric patients relative to younger adults, but increased sensitivity cannot be ruled out.1,3 Dosage adjustment is not necessary in geriatric patients.1,3

Hepatic Impairment

Pharmacokinetics of aclidinium have not been evaluated in patients with hepatic impairment.1

Renal Impairment

Clinically important differences in pharmacokinetics of aclidinium were not observed in patients with mild, moderate, or severe renal impairment compared with patients with normal renal function.1 The manufacturer states that dosage adjustment of aclidinium in patients with renal impairment is not necessary.1

Common Adverse Effects

Adverse events occurring in at least 3% of patients receiving aclidinium and at an incidence greater than with placebo include headache,1 nasopharyngitis,1 and cough.1

No formal drug interaction studies have been performed with aclidinium to date.1 Results of in vitro studies suggest that aclidinium has limited potential to cause metabolic interactions with cytochrome P-450 (CYP) isoenzymes at plasma concentrations achieved clinically.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

In vitro studies indicate that aclidinium and its major metabolites do not inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, or 4A9/11 at concentrations up to 1000 times greater than the peak plasma concentrations achieved clinically.1 Therefore, clinically important pharmacokinetic interactions with drugs affecting or metabolized by the CYP isoenzyme system are unlikely.1

Anticholinergic Agents

Potential pharmacologic interaction (additive anticholinergic effects).1 The manufacturer states that concomitant use of aclidinium with other anticholinergic agents should be avoided.1

Other Drugs

Results of clinical studies indicate that concomitant administration of aclidinium with other drugs used in the treatment of COPD such as sympathomimetic bronchodilators (i.e., short-acting β₂-agonists), methylxanthines, and oral or inhaled corticosteroids was not associated with an increased incidence of adverse effects.1

Description

Aclidinium bromide is a synthetic quaternary ammonium antimuscarinic agent for use as a long-acting, orally inhaled bronchodilator.1 The drug is a nonselective competitive antagonist at muscarinic (M₁-M₅) receptors.1,14 Aclidinium competitively and reversibly inhibits the actions of acetylcholine and other cholinergic stimuli at M₃ receptors in the smooth muscle of the respiratory tract leading to bronchodilation.1,14

Most of a dose of orally inhaled aclidinium bromide is deposited in the oropharynx and swallowed.2,14 Aclidinium is expected to be minimally absorbed into systemic circulation whether the dose is deposited in the lungs or swallowed, since the drug undergoes rapid and extensive hydrolysis that occurs both chemically and enzymatically via esterases to inactive metabolites.1,2,14 Aclidinium and its metabolites are not expected to affect drugs metabolized by cytochrome P-450 isoenzymes at plasma concentrations achieved clinically.1 Approximately 0.1% of a dose is excreted in urine following oral inhalation.1,3 The effective half-life of aclidinium bromide is 5-8 hours following oral inhalation.1

Advice to Patients

A copy of the manufacturer's patient information for aclidinium bromide should be provided to all patients each time the drug is dispensed.1 Importance of instructing patients to read the patient information prior to initiation of therapy and each time the prescription is refilled.1

Importance of informing clinician of any history of hypersensitivity reactions to atropine or severe allergy to milk proteins.1

Importance of adequate understanding of proper storage and inhalation techniques, including use of the inhalation delivery system (Pressair^®).1

Importance of advising patients that if a dose of aclidinium bromide is missed, the next dose should be taken at the regularly scheduled time; a double dose should not be administered to make up for a missed dose.1

Importance of not using aclidinium therapy to relieve acute symptoms or exacerbations of chronic obstructive pulmonary disease (COPD).1

Importance of avoiding inadvertent contact of the drug with the eyes since this may cause blurred vision and pupillary dilation.1

Importance of informing clinician immediately if eye pain or discomfort, blurred vision, visual halos, or colored images in association with red eyes from conjunctival congestion or corneal edema occur.1

Importance of discontinuing aclidinium and informing clinician if paradoxical bronchospasm occurs.1

Importance of informing clinician immediately if urinary retention or dysuria occurs.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (e.g., eye drops) and herbal supplements, as well as any concomitant illnesses (e.g., urinary retention, enlarged prostate, angle-closure glaucoma).1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Forest Pharmaceuticals, Inc. Tudorza^® Pressair^® (aclidinium bromide inhalation powder) prescribing information. St. Louis, MO; 2012 Jul.

2. Jansat JM, Lamarca R, Garcia Gil E et al. Safety and pharmacokinetics of single doses of aclidinium bromide, a novel long-acting, inhaled antimuscarinic, in healthy subjects. Int J Clin Pharmacol Ther . 2009; 47:460-8. [PubMed 19640353]

3. de la Motte S, Beier J, Schmid K et al. Pharmacokinetics and safety of aclidinium bromide in younger and elderly patients with chronic obstructive pulmonary disease. Int J Clin Pharmacol Ther . 2012; 50:403-12. [PubMed 22541745]

4. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2013. Accessed 2013 Aug 21. [Web]

9. Veterans' Health Administration, Department of Veterans' Affairs. VHA/DoD clinical practice guideline for management of outpatient chronic obstructive pulmonary disease (COPD): guideline summary. Washington, DC: Veterans' Health Administration; 2007 Jun. Available at VA website. Accessed 2013 Aug 21. [Web]

11. Kerwin EM, D'Urzo AD, Gelb AF et al. Efficacy and safety of a 12-week treatment with twice-daily aclidinium bromide in COPD patients (ACCORD COPD I). COPD . 2012; 9:90-101. [PubMed 22320148]

12. Jones PW, Singh D, Bateman ED et al. Efficacy and safety of twice-daily aclidinium bromide in COPD patients: the ATTAIN study. Eur Respir J . 2012; 40:830-6. [PubMed 22441743]

13. . Aclidium bromide (Tudorza Pressair) for COPD. Med Lett Drugs Ther . 2012; 54:99-100. [PubMed 23223246]

14. Frampton JE. Aclidinium: in chronic obstructive pulmonary disease. Drugs . 2012; 72:1999-2011. [PubMed 23046206]

15. Lasseter KC, Aubets J, Chuecos F et al. Aclidinium bromide, a long-acting antimuscarinic, does not affect QT interval in healthy subjects. J Clin Pharmacol . 2011; 51:923-32. [PubMed 20959525]