aclidinium/formoterol (Rx)

Brand and Other Names:Duaklir Pressair
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

aclidinium bromide/formoterol fumarate

powder for inhalation

  • (400mcg/12mcg)/actuation by breath-actuated dry powder metered-dose inhaler

Chronic Obstructive Pulmonary Disease

Indicated for maintenance treatment of chronic obstructive pulmonary disease (COPD)

1 inhalation PO BID

Not to exceed 1 inhalation BID

Dosage Modifications

Renal or hepatic impairment: Formal pharmacokinetic studies not conducted; however, based on available data, no dosage adjustment required

Dosing Considerations

Limitations of use: Not indicated for treatment of acute bronchospasm or asthma

Safety and efficacy not established

No overall differences in safety or effectiveness were observed between adults aged ≥60 yr compared with younger adults

See adult dosing

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Interactions

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            Adverse Effects

            1-10%

            Upper respiratory tract infection (8.9%)

            Headache (6.3%)

            Back pain (3.8%)

            Cough (1-3%)

            Sinusitis (1-3%)

            Influenza (1-3%)

            Tooth abscess (1-3%)

            Insomnia (1-3%)

            Dizziness (1-3%)

            Dry mouth (1-3%)

            Oropharyngeal pain (1-3%)

            Muscle spasms (1-3%)

            Musculoskeletal pain (1-3%)

            Arthralgia (1-3%)

            Pain in extremity (1-3%)

            Urinary tract infection (1-3%)

            Blood creatine phosphokinase increased (1-3%)

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            Warnings

            Contraindications

            Severe hypersensitivity to milk proteins

            Hypersensitivity to aclidinium bromide, formoterol fumarate, or any product component

            Not indicated for asthma; use of long-acting beta2-adrenergic agonists (LABAs), including formoterol fumarate, without an inhaled corticosteroid is contraindicated in patients with asthma

            Cautions

            Safety and efficacy not established for patients with asthma; not indicated for asthma; use of LABA as monotherapy (without inhaled corticosteroids) for asthma associated with increase asthma-related deaths; available data do not suggest increased risk of death with LABAs in patients with COPD

            Do not initiate in acutely deteriorating COPD, which may be a life-threatening condition; aclidinium/formoterol is intended as maintenance treatment and should not be used for relief of acute symptoms (ie, rescue therapy for acute bronchospasm)

            Instruct patients who have been taking oral or inhaled, short-acting beta2-agonists on a regular basis (eg, 4x/day) to discontinue the regular use of these drugs and use them only for symptomatic relief of acute respiratory symptoms

            As with other inhaled drugs containing beta-agonists, do not use 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

            May cause paradoxical bronchospasm, which may be life threatening; if paradoxical bronchospasm occurs, treat immediately with an inhaled short-acting bronchodilator; discontinue aclidinium/formoterol and institute alternant therapy

            Immediate hypersensitivity reactions, including anaphylaxis, angioedema, urticaria, rash, bronchospasm, or itching, reported; discontinue aclidinium/formoterol and institute alternant therapy if this occurs

            Beta-agonists can produce clinically significant cardiovascular effects as measured by increases in pulse rate, systolic or diastolic or blood pressure, or symptoms; additionally, may cause ECG changes (eg, flattening of the T wave, prolongation of the QTc interval, and ST-segment depression), although clinical significance is unknown

            Caution with using sympathomimetic amines 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 IV, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis

            Caution with narrow-angle glaucoma; monitor for signs and symptoms of acute narrow-angle glaucoma (eg, eye pain or discomfort, blurred vision, visual halos, colored images in association with red eyes from conjunctival congestion and corneal edema)

            May worsen urinary retention or bladder neck obstruction; monitor for signs and symptoms (eg, difficulty passing urine, painful urination)

            Hypokalemia and hyperglycemia

            • Beta-agonists may produce significant hypokalemia, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects; this decrease is usually transient, not requiring potassium supplementation
            • Beta-agonist medications may produce transient hyperglycemia
            • Clinical trials of aclidinium/formoterol over 24-52 weeks' duration did not show evidence of an effect on serum glucose or potassium

            Drug interaction overview

            • Caution with coadministration with additional adrenergic drugs, by any administration route, because additive sympathetic effects
            • Concomitant treatment with xanthine derivatives or steroids may potentiate any hypokalemic effect of beta-adrenergic agonists
            • Caution if coadministered with other drugs that cause hypokalemia (eg, loop or thiazide diuretics)
            • Caution if beta2-agonists are coadministered with MAO 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
            • Formoterol and beta-blockers may inhibit the effect of each other if coadministered; patients with COPD are not typically treated with beta-blockers; however, under certain circumstances (eg, prophylaxis after MI), there may be no acceptable alternatives to the use of beta-blockers in patients with COPD; if needed, consider cautious use of cardioselective beta-blockers
            • Avoid coadministration of other anticholinergic medications with aclidinium, owing to additive effects
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            Pregnancy

            Pregnancy

            There are no adequate and well-controlled studies of aclidinium/formoterol or its individual components in pregnant women to assess drug-associated risks

            Animal studies

            • 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)
            • 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

            Labor or delivery

            • No well-controlled human studies
            • Because of the potential for beta-agonist interference with uterine contractility, use of during labor should be restricted to those patients in whom the benefits clearly outweigh the risk

            Lactation

            There are no available data on the breastfed child or on milk production or presence in human milk

            Both aclidinium bromide and formoterol fumarate are present in rat milk; when a drug is present in animal milk, it is likely that the drug will be present in human milk

            Animal studies

            • Aclidinium bromide reduced pup weights when pregnant rats continued inhalation administration through lactation at 5 times the MRHDID
            • Formoterol fumarate increased pup loss at birth and during lactation, and decreased pup weight in rats at 85 times the MRHDID

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Aclidinium: Long-acting muscarinic antagonist (LAMA), often referred to as an anticholinergic, has specificity for muscarinic receptors with affinity for the M3 (subscript) receptor in the airways; produces bronchodilation by inhibiting acetylcholine’s effect on muscarinic receptors in the airway smooth muscle

            Formoterol: Long-acting selective beta-2 agonist (LABA); elicits bronchial smooth muscle relaxation by 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 inhibit release of mediators of immediate hypersensitivity from cells, especially from mast cells

            Absorption

            Peak plasma time: Within 5 minutes after inhalation

            Peak plasma concentration: 128 pg/mL (aclidinium); 17 pg/mL (formoterol)

            Steady-state achieved within 5 days

            Distribution

            Vd (aclidinium; 400 mcg IV): 300 L

            Protein bound (formoterol; 54 mcg inhaled): 46% (RR enantiomer); 58% (SS enantiomer)

            Metabolism

            Aclidinium

            • Major metabolic route is hydrolysis, both chemically and enzymatically by esterases
            • Rapidly and extensively hydrolyzed in plasma to alcohol and dithienylglycolic acid derivatives, neither of which binds to muscarinic receptors and are devoid of pharmacologic activity
            • Owing 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

            • 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 identified as being primarily responsible for O-demethylation

            Elimination

            Half-life: ~12 hr (aclidinium)

            Total clearance: ~170 L/hr (aclidinium IV)

            Excretion

            • Aclidinium: 54-65% urine; 20-33% feces; <1% excreted as unchanged drug
            • Formoterol: 62% urine; 24% feces
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            Administration

            Oral Inhalation Administration

            Not for relief of acute symptoms; extra doses should not be used for that purpose

            Do not use additional LABAs while taking this combination inhaler

            Breath-actuated inhaler; counsel patients with instructions and images included with inhaler

            Missed dose: Instruct patient to take the next dose at the usual time; do not take 2 doses at one time

            Storage

            Unopened: Store inside the sealed bag and only open immediately before use; discard bag and desiccant sachet

            Opened: Store in dry place at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F)

            Do not store inhaler on a vibrating surface

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            Formulary

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.