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Indacaterol Maleate

Class: Selective beta-2-Adrenergic Agonists
Chemical Name: 5 - [(1R) - 2 - [(5,6 - Diethyl - 2,3 - dihydro - 1H - inden - 2 - yl)amino] - 1 - hydroxyethyl] - 8 - hydroxy - 2(1H) - quinolinone, (2Z)-2-butenedioate (1:1)
Molecular Formula: C24H28N2O3•C4 H4O4
CAS Number: 753498-25-8
Brands: Arcapta Neohaler

Warning(s)

  • Increased risk of asthma-related death with long-acting β2-adrenergic agonists.1 11 12 (See REMS and also see Asthma-related Death under Cautions.)

  • Increased risk of asthma-related death considered class effect of long-acting β2-adrenergic agonists, including indacaterol.1

  • All long-acting β2-adrenergic agonists, including indacaterol, contraindicated in patients with asthma without concomitant use of long-term asthma controller therapy.1 11 12 Safety and efficacy of indacaterol in patients with asthma not established; indacaterol not indicated for treatment of asthma.1

Introduction

Bronchodilator; a relatively selective, long-acting β2-agonist.1 14 15 16 17

Uses for Indacaterol Maleate

COPD

Long-term maintenance treatment of airflow obstruction associated with COPD, including chronic bronchitis and/or emphysema.1 3 4 5 6 7 14

Not indicated for treatment of acute deterioration of COPD or relief of acute symptoms (i.e., as rescue therapy for treatment of acute episodes of bronchospasm).1 (See Deterioration of Disease and Acute Episodes under Cautions.)

Other Uses

Not indicated for treatment of asthma; safety and efficacy in asthma not established.1

Indacaterol Maleate Dosage and Administration

General

  • When initiating indacaterol therapy, discontinue regular use of short-acting, inhaled β2-adrenergic agonists; use such agents only for symptomatic relief of acute COPD symptoms not controlled by indacaterol.1

  • Failure to respond to a previously effective dosage may indicate deterioration of disease that requires immediate reevaluation.1 Do not increase daily dosage of indacaterol beyond the recommended dosage.1 (See Deterioration of Disease and Acute Episodes under Cautions.)

Administration

Administer by oral inhalation only using a specific oral inhalation device (Neohaler) that delivers powdered drug from capsules.1

Administer once daily at the same time every day.1

Do notswallow the dry-powder capsules, as intended effects on lungs will not be obtained.1

Oral Inhalation

Pull cap off and open inhaler by holding its base and tilting the mouthpiece.2 Expose only one capsule from blister card immediately before use.2 Place capsule into chamber of inhaler; do not place capsule directly into mouthpiece.2 After loading capsule, fully close inhaler; expect to hear a click as inhaler closes.2 While holding inhaler upright, fully press both piercing buttons one time only and then release; expect to hear a click as capsule is pierced.2

Exhale fully; do not blow into mouthpiece.2 Hold inhaler device with buttons to left and right (not up and down); do not press piercing buttons again.2 Place mouthpiece between lips and inhale rapidly and steadily, as deeply as possible through inhaler; expect to hear a whirring noise.2 Remove inhaler from mouth and continue to hold the breath for as long as comfortable, then breathe out.2

Open inhaler to see if any powder remains in capsule; if so, close inhaler, breathe out completely, and inhale once again.2 Most patients are able to empty powder from capsules in 1 or 2 inhalations.2 Upon completion of inhalation(s), open mouthpiece again, tip inhaler device to remove and then discard empty capsule.2 Close inhaler and replace cap.2

If whirring noise not heard upon inhalation, capsule may be stuck in capsule cavity; open inhaler and carefully loosen capsule by tapping base of inhaler device.2 Do not press piercing buttons to loosen capsule.2

Do not wash Neohaler device; keep dry.2 Cleaning inhaler device not necessary; if desired, a clean, dry, lint-free cloth or soft brush may be used to wipe inhaler between uses.2

Dosage

Available as indacaterol maleate; dosage expressed in terms of indacaterol.1

Each capsule contains 75 mcg of indacaterol as dry powder for oral inhalation.1 In vitro, each activation of Neohaler inhaler delivered about 57 mcg of indacaterol.1 Precise amount of drug delivered to lungs depends on factors such as patient's inspiratory flow rate and time.1

Adults

COPD
Oral Inhalation

75 mcg (contents of 1 capsule) once daily.1

Prescribing Limits

Adults

COPD
Oral Inhalation

Do not use more frequently than one 75-mcg dose in a 24-hour period.1 2

Special Populations

Dosage adjustment not necessary based on effect of age, gender, and weight on systemic exposure in patients with COPD.1

Hepatic Impairment

No dosage adjustment required in patients with mild or moderate hepatic impairment; data not available in patients with severe hepatic impairment.1 (See Absorption: Special Populations, under Pharmacokinetics.)

Renal Impairment

No dosage adjustment required.1 (See Renal Impairment under Cautions.)

Geriatric Patients

No dosage adjustment required.1 (See Geriatric Use under Cautions.)

Cautions for Indacaterol Maleate

Contraindications

  • All long-acting β2-adrenergic agonists, including indacaterol, contraindicated in patients with asthma without concomitant use of long-term asthma controller therapy; indacaterol not indicated for treatment of asthma.1 (See Asthma-related Death under Cautions.)

Warnings/Precautions

Warnings

Asthma-related Death

Increased risk of asthma-related death reported with long-acting β2-adrenergic agonists.1 11 12 (See REMS and also see Boxed Warning.)

All long-acting β2-adrenergic agonists, including indacaterol, contraindicated in patients with asthma without concomitant use of long-term asthma controller therapy.1 11 12 Safety and efficacy of indacaterol in patients with asthma not established; therefore, not indicated for treatment of asthma.1

Data from large placebo-controlled safety study (Salmeterol Multicenter Asthma Research Trial [SMART]) showed increased risk of asthma-related deaths in patients receiving certain long-acting β2-adrenergic agonists (e.g., salmeterol) in addition to usual asthma therapy.1 11 Increased risk of asthma-related death with salmeterol considered class effect of long-acting β2-adrenergic agonists, including indacaterol.1 However, no adequate studies conducted to determine whether rate of asthma-related death is increased in patients receiving indacaterol.1 (See Advice to Patients.)

Serious asthma-related events, including death, reported with indacaterol in clinical studies;1 8 however, data inadequate to precisely quantify differences in serious asthma exacerbation rates between treatment groups.1

Not known whether death rate is increased in patients with COPD receiving long-acting β2-adrenergic agonists, including indacaterol.1

Other Warnings/Precautions

Deterioration of Disease and Acute Episodes

Do not initiate indacaterol therapy in patients with acutely deteriorating COPD, which may be life-threatening.1 Indacaterol not studied in this patient population.1

Do not use for relief of acute symptoms (i.e., as rescue therapy for treatment of acute episodes of bronchospasm).1 Not studied for relief of acute symptoms; do not use extra doses of the drug in such situations.1 Use a short-acting, inhaled β2-agonist for treatment of acute symptoms.1

When initiating indacaterol therapy, discontinue regular use (e.g., 4 times daily) of short-acting, inhaled β2-agonists and use such agents only for symptomatic relief of acute respiratory symptoms.1

Failure to respond to a previously effective dosage of indacaterol or supplemental short-acting, inhaled β2-agonist (e.g., increased need for additional short-acting, inhaled β2-agonist) may indicate deterioration of COPD.1 Immediately reevaluate the patient and treatment regimen.1 Increasing daily dosage of indacaterol to exceed the recommended dosage not appropriate.1

Excessive Use and Use With Other Long-acting β2-Adrenergic Agonists

Do not use indacaterol more frequently or at doses higher than recommended, or concomitantly with other preparations containing long-acting β2-adrenergic agonists, since overdosage may result.1

Clinically important cardiovascular effects and fatalities associated with excessive use of inhaled sympathomimetic drugs.1 (See Cardiovascular Effects under Cautions.)

Paradoxical Bronchospasm

Possible paradoxical bronchospasm, which may be life-threatening.1

If paradoxical bronchospasm occurs, immediately discontinue indacaterol and institute alternative therapy.1

Cardiovascular Effects

Possible clinically important increases in pulse rate, systolic or diastolic BP, or cardiovascular symptoms; may require discontinuance of drug.1

ECG changes (e.g., flattening of T wave, prolongation of corrected QT [QTc] interval, ST-segment depression) reported with β2-agonists; clinical importance unknown.1

Use with caution in patients with cardiovascular disorders (e.g., coronary insufficiency, cardiac arrhythmias, hypertension).1

Metabolic and Electrolyte Effects

Use with caution in patients with thyrotoxicosis.1

Inhalation of high dosages of β2-adrenergic agonists may result in increased plasma glucose.1 IV albuterol (IV preparation not commercially available in US) reported to aggravate preexisting diabetes mellitus and ketoacidosis.1

Clinically important hypokalemia or changes in blood glucose reported infrequently during studies of long-term indacaterol therapy with similar incidence in patients receiving placebo.1 Not studied in patients with inadequately controlled diabetes mellitus.1

Clinically important hypokalemia (usually transient and not requiring supplementation) may occur in some patients receiving β2-adrenergic agonists; may result in adverse cardiovascular effects.1 (See Cardiovascular Effects under Cautions.)

Nervous System Effects

Use with caution in patients with seizure disorders and in those unusually responsive to sympathomimetic amines.1

Specific Populations

Pregnancy

Category C.1

Effects on preterm labor or labor at term not known.1 May interfere with uterine contractility; restrict use of indacaterol during labor to those patients in whom benefits clearly outweigh risks.1

Lactation

Distributed into milk in rats.1 Not known whether distributed into human milk.1 Use caution.1

Pediatric Use

Not indicated for use in pediatric patients.1 Safety and efficacy not established.1

Geriatric Use

No overall differences in efficacy observed; adverse effects similar in patients ≥65 years of age compared with overall patient population.1 Dosage adjustment not required in geriatric patients.1

Hepatic Impairment

Not studied in patients with severe hepatic impairment.1 Dosage adjustment not required in patients with mild or moderate hepatic impairment.1 (See Absorption: Special Populations and Distribution: Special Populations under Pharmacokinetics.)

Renal Impairment

Not studied in patients with renal impairment because of minimal contribution of urinary excretion to total body elimination of the drug.1 Dosage adjustment not required in patients with renal impairment.1 (See Elimination under Pharmacokinetics.)

Common Adverse Effects

Cough, oropharyngeal pain, nasopharyngitis, headache, nausea.1

Interactions for Indacaterol Maleate

Metabolized via hydroxylation (mainly by CYP3A4 and, to lesser extent, by CYP1A1 and 2D6), as well as via glucuronidation by UGT1A1.1 13

Low-affinity substrate of efflux transporter P-glycoprotein (P-gp).1

Unlikely to substantially inhibit transporter proteins (e.g., multidrug resistance protein [MRP] 2, breast cancer resistance protein [BCRP], human organic cation transporters [hOCT] 1 and 2, human multidrug and toxin extrusion [hMATE] transporters 1 and 2K) in vivo; negligible potential to induce MRP2.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes and/or the P-glycoprotein Transport System

Data from studies of potent and specific inhibitors of CYP3A4 and P-gp suggest that systemic clearance of indacaterol is influenced by changes in both CYP3A4 and P-gp activities.1 However, may administer recommended indacaterol dosage (75 mcg once daily) without adjustment.1 13

Unlikely to cause metabolic interactions by inhibition or induction of CYP isoenzymes, inhibition of transporter proteins (e.g., P-gp), or induction of P-gp.1

Drugs Metabolized by UGT1A1

Unlikely to cause metabolic interactions by induction of UGT1A1.1

Drugs that Prolong the QT Interval

Use with extreme caution; increased risk of ventricular arrhythmias and possible potentiation of adrenergic effects on cardiovascular system.1

Specific Drugs

Drug

Interaction

Comments

β-Adrenergic blocking agents

Potential for antagonism of pulmonary effects resulting in severe bronchospasm in COPD patients1

Avoid concomitant use1

If concomitant therapy required, consider cautious use of cardioselective β-adrenergic blocking agents1

Antidepressants, tricyclic

Potential for increased cardiovascular effects1

Use with extreme caution1

Corticosteroids

Possible potentiation of any hypokalemic effect1

Diuretics

Possible potentiation of any hypokalemic effect1

Non-potassium-sparing diuretics (e.g., loop or thiazide diuretics): Potential additive hypokalemia and/or ECG changes, especially when recommended β-agonist dosage exceeded1

Non-potassium-sparing diuretics: Clinical importance unknown; use with caution1

Erythromycin

Increased AUC and peak plasma concentrations of indacaterol1

May administer recommended indacaterol dosage (75 mcg once daily) without adjustment1 13

Ketoconazole

Increased AUC and peak plasma concentrations of indacaterol1

May administer recommended indacaterol dosage (75 mcg once daily) without adjustment1 13

MAO inhibitors

Potential for increased cardiovascular effects1

Use with extreme caution1

Ritonavir

Increase in AUC (but not peak plasma concentrations) of indacaterol1

May administer recommended indacaterol dosage (75 mcg once daily) without adjustment1 13

Sympathomimetic agents

Possible potentiation of sympathetic effects1

Use caution with concomitant sympathomimetic agents administered by any route1

Verapamil

Increased AUC and peak plasma concentrations of indacaterol1

May administer recommended indacaterol dosage (75 mcg once daily) without adjustment1 13

Xanthine derivatives

Possible potentiation of any hypokalemic effect1

Indacaterol Maleate Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following inhalation;16 absolute bioavailability is 43–45%.1

Systemic exposure results from pulmonary (about 75%) and intestinal (about 25%) absorption.1 16

Peak serum concentrations attained in approximately 15 minutes following single or repeated inhaled doses.1

Steady-state serum concentrations achieved within 12–15 days.1

Onset

Produces bronchodilation within 5 minutes.16 17 18

Duration

Produces sustained bronchodilation for at least 24 hours.16 17 18

Special Populations

No clinically important changes in peak plasma concentrations or AUC observed in patients with mild or moderate hepatic impairment.1 (See Hepatic Impairment under Cautions.)

In one study in individuals with UGT1A1 (TA)7/(TA)7 genotype (low UGT1A1 expression; also referred to as UGT1A1*28/*28) and the (TA)6/(TA)6 genotype, steady-state AUC and peak plasma concentrations were 1.2-fold higher in individuals with the (TA)7/(TA)7 genotype suggesting no relevant effect of UGT1A1 genotype on indacaterol exposure.1

Distribution

Extent

Extensively distributed.1

Distributed into milk in rats.1 Not known whether distributed into human milk.1

Plasma Protein Binding

95.1–96.2%.1

Special Populations

Protein binding in patients with mild or moderate hepatic impairment similar to that in healthy individuals.1 (See Hepatic Impairment under Cautions.)

Elimination

Metabolism

Metabolized via hydroxylation (mainly by CYP3A4 and, to lesser extent, by CYP1A1 and 2D6) and via glucuronidation by UGT1A1.1 13

Low-affinity substrate of efflux transporter P-gp.1

Elimination Route

Eliminated mainly (≥90%) in feces as unchanged drug (53% of dose) and hydroxylated metabolites (23% of dose).1 Renal elimination accounts for about 2–6% of systemic clearance; generally, <2% of dose eliminated in urine as unchanged drug.1

Half-life

Average terminal half-life: 45.5–126 hours.1

Average effective half-life: 40–56 hours.1

Stability

Storage

Oral Inhalation

Powder

25°C (may be exposed to 15–30°C) in a dry place; protect from light and moisture.1

Store dry-powder capsules in foil-sealed blisters until immediately before use.1 2 Do not store used or unused capsules in inhaler device.2 Remove only one capsule immediately before use or effectiveness of drug may be reduced.1 2 Discard additional capsules if opened and exposed to air (i.e., not intended for immediate use).1

Actions

  • Synthetic sympathomimetic amine.1 10

  • Relatively selective, long-acting β2-agonist.1 14 15 16 17

  • Selectivity similar to that of formoterol; indacaterol has more than 24- or 20-fold greater agonist activity at β2-adrenergic receptors compared with β1- or β3-adrenergic receptors, respectively; clinical importance unknown.1 16

  • Activates adenyl cyclase and stimulates production of cyclic adenosine-3′,5′-monophosphate (cAMP).1 14 16 Increased concentrations of cAMP relax bronchial smooth muscle.1 14 16

  • Appears to inhibit IgE-dependent release of mediators (e.g., histamine) from human lung mast cells.15

  • Does not appear to antagonize bronchorelaxant effect of short-acting, inhaled β2-agonists.16

  • Tolerance not observed with long-term administration;16 17 improvement in lung function (as measured by FEV1) observed after 4 weeks of treatment consistently maintained over 12 weeks in clinical studies.1

Advice to Patients

  • Provide a copy of the manufacturer's patient information (medication guide) to all patients each time the drug is dispensed.1 2 Importance of instructing patients to read the medication guide prior to initiation of therapy and each time the prescription is refilled.2 11 12

  • Importance of informing patients that long-acting β2-adrenergic agonists (e.g., indacaterol) increase the risk of asthma-related death and that indacaterol is not indicated for the treatment of asthma.1 11 12

  • Importance of adequate understanding of proper storage, preparation, and inhalation techniques, including use of the inhalation delivery system (Neohaler).1

  • Importance of advising patients using indacaterol not to swallow the dry-powder capsules or to use them with any capsule inhaler other than the Neohaler device.1 Importance of advising patients not to use this inhaler with any other capsules.1 Importance of advising patients to use the new inhaler device provided with each new prescription.1

  • Importance of adherence to dosing schedules, including not altering the dose or frequency of use unless otherwise instructed by a clinician.1 2

  • Importance of advising patients that if a dose is missed, to take the dose as soon as it is remembered; importance of not taking more than one dose in a 24-hour period.1 2

  • Importance of all patients being provided with and instructed in the use of a short-acting, inhaled β2-adrenergic agonist as treatment for acute COPD symptoms.1

  • Importance of discontinuing regular use of short-acting, inhaled β2-agonists when initiating indacaterol and using short-acting, inhaled β2-agonists to relieve acute symptoms.1

  • Importance of not using indacaterol to relieve acute symptoms or exacerbations of COPD.1

  • Importance of contacting a clinician immediately if symptoms worsen, the short-acting inhaled β2-agonist becomes less effective or more inhalations than usual are required, or clinically important decrease in lung function occurs.1

  • Importance of advising patients receiving indacaterol not to use additional doses of the drug or other inhaled, long-acting β2-adrenergic agonists because excessive use of sympathomimetic agents may result in substantial cardiovascular effects or death.1

  • Importance of patients not discontinuing therapy without medical supervision, since symptoms may recur after discontinuance.1

  • Importance of informing patients of adverse effects associated with β2-adrenergic agonists (e.g., palpitations, chest pain, rapid heart rate, tremor, nervousness).1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, vitamins, and herbal supplements, as well as any concomitant illnesses (e.g., cardiac disorders, hypertension, seizures, thyroid disorders, diabetes mellitus, allergies to drugs or food).1 2

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 2

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

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Indacaterol Maleate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral Inhalation

Powder for inhalation (contained in capsules)

75 mcg (of indacaterol)

Arcapta Neohaler

Novartis

AHFS DI Essentials. © Copyright 2016, Selected Revisions August 22, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Novartis Pharmaceuticals Corporation. Arcapta Neohaler (indacaterol maleate) inhalation powder prescribing information. East Hanover, NJ; 2011 Jul.

2. Novartis Pharmaceuticals Corporation. Arcapta Neohaler (indacaterol maleate) inhalation powder medication guide. East Hanover, NJ; 2011 Jul.

3. Donohue JF, Fogarty C, Lötvall J et al. Once-daily bronchodilators for chronic obstructive pulmonary disease: indacaterol versus tiotropium. Am J Respir Crit Care Med. 2010; 182:155-62. [PubMed 20463178]

4. Kerwin EM, Gotfried MH, Lawrence D et al. Efficacy and tolerability of indacaterol 75 mcg once daily in patients aged ≥40 years with chronic obstructive pulmonary disease: results from 2 double-blind, placebo-controlled 12-week studies. Clin Ther. 2011; 33:1974-84. [PubMed 22177371]

5. Feldman G, Siler T, Prasad N et al. Efficacy and safety of indacaterol 150 mcg once-daily in COPD: a double-blind, randomised, 12-week study. BMC Pulm Med. 2010; 10:11. [PubMed 20211002]

6. Kornmann O, Dahl R, Centanni S et al. Once-daily indacaterol versus twice-daily salmeterol for COPD: a placebo-controlled comparison. Eur Respir J. 2011; 37:273-9. [PubMed 20693243]

7. Dahl R, Chung KF, Buhl R et al. Efficacy of a new once-daily long-acting inhaled beta2-agonist indacaterol versus twice-daily formoterol in COPD. Thorax. 2010; 65:473-9. [PubMed 20522841]

8. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 022383Orig1s00: Summary review. From FDA website. Accessed 2012 Apr 5.

9. Chowdhury BA, Seymour SM, Michele TM et al. The risks and benefits of indacaterol--the FDA's review. N Engl J Med. 2011; 365:2247-9. [PubMed 22168640]

10. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 022383Orig1s00: Chemistry review. From FDA website. Accessed 2012 Apr 4.

11. Food and Drug Administration. FDA drug safety communication: New safety requirements for long-acting inhaled asthma medications called long-acting beta-agonists (LABAs). Rockville, MD; 2010 Feb 18. Available from FDA website. Accessed 2012 Mar 5.

12. Food and Drug Administration. FDA drug safety communication: Drug labels now contain updated recommendations on the appropriate use of long-acting inhaled asthma medications called long-acting beta-agonists (LABAs). Rockville, MD; 2010 Jun 2. Available from FDA website. Accessed 2012 Mar 5.

13. Novartis Pharmaceuticals Corporation, East Hanover, NJ: Personal communication.

14. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011. Accessed 2012 Mar 5.

15. Scola AM, Loxham M, Charlton SJ et al. The long-acting beta-adrenoceptor agonist, indacaterol, inhibits IgE-dependent responses of human lung mast cells. Br J Pharmacol. 2009; 158:267-76. [PubMed 19371332]

16. McKeage K. Indacaterol: a review of its use as maintenance therapy in patients with chronic obstructive pulmonary disease. Drugs. 2012; 72:543-63. [PubMed 22356291]

17. Roig J, Hernando R, Mora R. Indacaterol, a novel once daily inhaled beta2-adrenoreceptor agonist. Open Respir Med J. 2009; 3:27-30. [PubMed 19452036]

18. Beeh KM, Beier J. The short, the long, and the “ultra-long”; why duration of bronchodilator action matters in chronic obstructive pulmonary disease. Adv Ther. 2010; 27:150-9. [PubMed 20411368]

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