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Indacaterol and Glycopyrrolate

Pronunciation

(in da KA ter ol & glye koe PIR oh late)

Index Terms

  • Glycopyrrolate and Indacaterol
  • Glycopyrrolate and Indacaterol Maleate
  • Glycopyrronium and Indacaterol
  • Glycopyrronium Bromide and Indacaterol Maleate
  • Indacaterol Maleate and Glycopyrronium Bromide
  • Indacaterol/Glycopyrrolate
  • QVA149

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Inhalation:

Utibron Neohaler: Indacaterol 27.5 mcg and glycopyrrolate 15.6 mcg [contains milk protein]

Brand Names: U.S.

  • Utibron Neohaler

Pharmacologic Category

  • Anticholinergic Agent
  • Beta2 Agonist
  • Beta2-Adrenergic Agonist, Long-Acting

Pharmacology

Indacaterol: Relaxes bronchial smooth muscle by selective action on beta2-receptors with little effect on heart rate; acts locally in the lung.

Glycopyrrolate: In COPD, competitively and reversibly inhibits the action of acetylcholine at muscarinic receptor subtypes 1-3 (greater affinity for subtypes 1 and 3) in bronchial smooth muscle thereby causing bronchodilation.

Use: Labeled Indications

Chronic obstructive pulmonary disease:

Long-term maintenance treatment of airflow obstruction in chronic obstructive pulmonary disease (COPD) including chronic bronchitis and/or emphysema.

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

Contraindications

Hypersensitivity to indacaterol, glycopyrrolate, or any component of the formulation; monotherapy in patients with asthma (ie, without concurrent use of a long-term asthma control medication)

Canadian labeling: Additional contraindications (not in US labeling): Severe hypersensitivity to milk proteins

Dosing: Adult

COPD (maintenance): Oral inhalation:

US labeling: 1 capsule (indacaterol 27.5 mcg/glycopyrrolate 15.6 mcg) inhaled twice daily (maximum: 2 capsules/day)

Canadian labeling: 1 capsule (indacaterol 110 mcg/glycopyrrolate 50 mcg) inhaled once daily (maximum: 1 capsule/day)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

GFR ≥30 mL/minute/1.73 m2: No dosage adjustment necessary.

GFR <30 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.

ESRD requiring dialysis: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.

Dosing: Hepatic Impairment

Mild-to-moderate impairment: No dosage adjustment necessary.

Severe impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); use with caution.

Administration

For inhalation using Neohaler (US) or Ultibro Breezhaler (Canada) only; do not swallow capsules. Use the new inhaler included with each prescription. Do not remove capsules from blister until immediately before use. Use at the same time each day. Discard any capsules that are exposed to air and not used immediately.

Storage

Store at 15°C to 25°C (59°F to 77°F). Protect from light and moisture. Remove from blister pack immediately before use; discard capsule if not used immediately.

Drug Interactions

AbobotulinumtoxinA: Anticholinergic Agents may enhance the anticholinergic effect of AbobotulinumtoxinA. Monitor therapy

Acetylcholinesterase Inhibitors: May diminish the therapeutic effect of Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Monitor therapy

Aclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Analgesics (Opioid): Anticholinergic Agents may enhance the adverse/toxic effect of Analgesics (Opioid). Specifically, the risk for constipation and urinary retention may be increased with this combination. Monitor therapy

Anticholinergic Agents: May enhance the anticholinergic effect of Glycopyrrolate (Oral Inhalation). Avoid combination

AtoMOXetine: May enhance the tachycardic effect of Beta2-Agonists. Monitor therapy

AtoMOXetine: May enhance the hypertensive effect of Sympathomimetics. AtoMOXetine may enhance the tachycardic effect of Sympathomimetics. Monitor therapy

Atosiban: Beta2-Agonists may enhance the adverse/toxic effect of Atosiban. Specifically, there may be an increased risk for pulmonary edema and/or dyspnea. Monitor therapy

Beta-Blockers (Beta1 Selective): May diminish the bronchodilatory effect of Beta2-Agonists. Of particular concern with nonselective beta-blockers or higher doses of the beta1 selective beta-blockers. Monitor therapy

Beta-Blockers (Nonselective): May diminish the bronchodilatory effect of Beta2-Agonists. Avoid combination

Betahistine: May diminish the therapeutic effect of Beta2-Agonists. Monitor therapy

Caffeine and Caffeine Containing Products: May enhance the adverse/toxic effect of Indacaterol. Caffeine and Caffeine Containing Products may enhance the hypokalemic effect of Indacaterol. Monitor therapy

Cannabinoid-Containing Products: May enhance the tachycardic effect of Sympathomimetics. Exceptions: Cannabidiol. Monitor therapy

Cannabinoid-Containing Products: Anticholinergic Agents may enhance the tachycardic effect of Cannabinoid-Containing Products. Exceptions: Cannabidiol. Monitor therapy

Chloral Betaine: May enhance the adverse/toxic effect of Anticholinergic Agents. Monitor therapy

Cimetropium: Anticholinergic Agents may enhance the anticholinergic effect of Cimetropium. Avoid combination

Cocaine: May enhance the hypertensive effect of Sympathomimetics. Management: Consider alternatives to use of this combination when possible. Monitor closely for substantially increased blood pressure or heart rate and for any evidence of myocardial ischemia with concurrent use. Consider therapy modification

Corticosteroids (Systemic): Indacaterol may enhance the hypokalemic effect of Corticosteroids (Systemic). Monitor therapy

Doxofylline: Sympathomimetics may enhance the adverse/toxic effect of Doxofylline. Monitor therapy

Eluxadoline: Anticholinergic Agents may enhance the constipating effect of Eluxadoline. Avoid combination

Gastrointestinal Agents (Prokinetic): Anticholinergic Agents may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Monitor therapy

Glucagon: Anticholinergic Agents may enhance the adverse/toxic effect of Glucagon. Specifically, the risk of gastrointestinal adverse effects may be increased. Avoid combination

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Iobenguane I 123: Sympathomimetics may diminish the therapeutic effect of Iobenguane I 123. Avoid combination

Ipratropium (Oral Inhalation): May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Itopride: Anticholinergic Agents may diminish the therapeutic effect of Itopride. Monitor therapy

Levosulpiride: Anticholinergic Agents may diminish the therapeutic effect of Levosulpiride. Avoid combination

Linezolid: May enhance the hypertensive effect of Sympathomimetics. Management: Reduce initial doses of sympathomimetic agents, and closely monitor for enhanced pressor response, in patients receiving linezolid. Specific dose adjustment recommendations are not presently available. Consider therapy modification

Long-Acting Beta2-Agonists: May enhance the adverse/toxic effect of other Long-Acting Beta2-Agonists. Avoid combination

Loop Diuretics: Beta2-Agonists may enhance the hypokalemic effect of Loop Diuretics. Monitor therapy

Loxapine: Agents to Treat Airway Disease may enhance the adverse/toxic effect of Loxapine. More specifically, the use of Agents to Treat Airway Disease is likely a marker of patients who are likely at a greater risk for experiencing significant bronchospasm from use of inhaled loxapine. Management: This is specific to the Adasuve brand of loxapine, which is an inhaled formulation. This does not apply to non-inhaled formulations of loxapine. Avoid combination

MAO Inhibitors: May enhance the adverse/toxic effect of Beta2-Agonists. Monitor therapy

Mianserin: May enhance the anticholinergic effect of Anticholinergic Agents. Monitor therapy

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Mirabegron: Anticholinergic Agents may enhance the adverse/toxic effect of Mirabegron. Monitor therapy

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Nitroglycerin: Anticholinergic Agents may decrease the absorption of Nitroglycerin. Specifically, anticholinergic agents may decrease the dissolution of sublingual nitroglycerin tablets, possibly impairing or slowing nitroglycerin absorption. Monitor therapy

OnabotulinumtoxinA: Anticholinergic Agents may enhance the anticholinergic effect of OnabotulinumtoxinA. Monitor therapy

Oxatomide: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Potassium Chloride: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Chloride. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium chloride. Avoid combination

Potassium Citrate: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Citrate. Avoid combination

Pramlintide: May enhance the anticholinergic effect of Anticholinergic Agents. These effects are specific to the GI tract. Consider therapy modification

Ramosetron: Anticholinergic Agents may enhance the constipating effect of Ramosetron. Monitor therapy

RimabotulinumtoxinB: Anticholinergic Agents may enhance the anticholinergic effect of RimabotulinumtoxinB. Monitor therapy

Secretin: Anticholinergic Agents may diminish the therapeutic effect of Secretin. Management: Avoid using drugs with substantial anticholinergic effects in patients receiving secretin whenever possible. If such agents must be used in combination, monitor closely for a diminished response to secretin. Consider therapy modification

Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. Monitor therapy

Tedizolid: May enhance the hypertensive effect of Sympathomimetics. Tedizolid may enhance the tachycardic effect of Sympathomimetics. Monitor therapy

Theophylline Derivatives: May enhance the adverse/toxic effect of Indacaterol. Theophylline Derivatives may enhance the hypokalemic effect of Indacaterol. Monitor therapy

Thiazide and Thiazide-Like Diuretics: Beta2-Agonists may enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Thiazide and Thiazide-Like Diuretics: Anticholinergic Agents may increase the serum concentration of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Tiotropium: Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium. Avoid combination

Topiramate: Anticholinergic Agents may enhance the adverse/toxic effect of Topiramate. Monitor therapy

Umeclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Adverse Reactions

Also see indacaterol monograph. Frequency not always defined.

>10%

Respiratory: Nasopharyngitis (4% to >10%)

1% to 10%

Cardiovascular: Chest pain (2%), hypertension (2%), cardiac arrhythmia

Central nervous system: Headache (2% to 3%), dizziness (2%)

Endocrine & metabolic: Hyperglycemia (≥2%)

Gastrointestinal: Gastroenteritis (3%), xerostomia (≤3%), diarrhea (≥2%), gastroesophageal reflux disease (≥2%), dyspepsia (1% to 2%)

Genitourinary: Urinary tract infection (2% to 4%), dysuria (1%)

Neuromuscular & skeletal: Back pain (2%), musculoskeletal pain (1% to 2%)

Respiratory: Cough (6%), pneumonia (2% to 4%), lower respiratory tract infection (>2%), oropharyngeal pain (2%), sinusitis (2%), rhinitis (1% to 2%), paradoxical bronchospasm, upper respiratory tract infection

Miscellaneous: Fever (2%)

<1% (Limited to important or life-threatening): Atrial fibrillation, bladder outflow obstruction, cystitis, dental caries, diabetes mellitus, glaucoma, hypersensitivity reaction, ischemic heart disease, peripheral edema, tachycardia

ALERT: U.S. Boxed Warning

Asthma-related death:

Long-acting beta2-adrenergic agonists (LABAs) increase the risk of asthma-related death. Data from a large placebo-controlled US study that compared the safety of another LABA (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol is considered a class effect of all LABAs, including indacaterol.

The safety and efficacy in patients with asthma have not been established. Indacaterol/glycopyrrolate is not indicated for the treatment of asthma.

Warnings/Precautions

Concerns related to adverse effects:

• Asthma-related deaths: [US Boxed Warning]: Long-acting beta2-agonists (LABAs) increase the risk of asthma-related death. The safety and efficacy of indacaterol/glycopyrrolate in patients with asthma have not been established. Indacaterol/glycopyrrolate is not indicated for the treatment of asthma. In a large, randomized, placebo-controlled US clinical trial (SMART 2006), salmeterol was associated with an increase in asthma-related deaths (when added to usual asthma therapy); risk is considered a class effect among all LABAs. Data are not available to determine if the addition of an inhaled corticosteroid lessens this increased risk of death associated with LABA use; however, current guidelines recommend the use of an inhaled corticosteroid before adding a LABA (GINA 2015; NIH/NHLBI 2007). In a more recent multicenter, randomized, double-blinded trial, the use of salmeterol and an inhaled corticosteroid (ie, fluticasone) combined in a single inhaler in a large number of children, adolescent, and adult patients with persistent asthma (non-life threatening and stable) did not increase the risk of serious asthma-related events compared with fluticasone alone; in addition, patients receiving fluticasone/salmeterol had fewer severe asthma exacerbations compared with patients receiving fluticasone alone (Peters 2016; Stempel 2016a; Stempel 2016b). Data are not available to determine if LABA use increases the risk of death in patients with COPD.

• Bronchospasm: Rarely, paradoxical, life-threatening bronchospasm may occur with use of inhaled beta2-agonists; distinguish from inadequate response and discontinue medication immediately if paradoxical bronchospasm occurs.

• CNS depression: May cause drowsiness, dizziness, and/or blurred vision; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• Hypersensitivity: Hypersensitivity reactions may occur; discontinue immediately if signs and symptoms of an allergic reaction occur; the Canadian labeling does not recommend a rechallenge.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with cardiovascular disease (arrhythmia, coronary insufficiency, hypertension, or HF); beta-agonists may cause elevation in blood pressure and heart rate. Beta2-agonists may also produce changes in the ECG (eg, T-wave flattening, QTc prolongation, ST segment depression).

• Diabetes: Use with caution in patients with diabetes mellitus; beta2-agonists may aggravate preexisting diabetes and ketoacidosis and increase serum glucose.

• Hepatic function impairment: Use with caution in severe hepatic impairment (has not been studied).

• Hyperthyroidism: Use with caution in patients with hyperthyroidism; may stimulate thyroid activity.

• Hypokalemia: Use with caution in patients with hypokalemia; beta2-agonists may decrease serum potassium.

• Narrow angle glaucoma: Use with caution in patients with narrow angle glaucoma.

• Prostatic hyperplasia/bladder neck obstruction: Use with caution in patients with prostatic hyperplasia/bladder neck obstruction; may worsen urinary retention.

• Renal function impairment: Use with caution in patients with severe renal impairment (GFR <30 mL/minute/1.73 m2) or end-stage renal disease (ESRD) on dialysis; monitor closely.

• Seizure disorders: Use with caution in patients with seizure disorders; beta2-agonists may result in CNS stimulation/excitation.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Lactose: Some products may contain lactose; allergic reactions possible in patients with severe milk protein allergy. Use with caution in patients with severe hypersensitivity to milk proteins; use of the Canadian product is contraindicated in patients with severe milk protein allergy.

Other warnings:

• Appropriate use: Do not use for acute episodes of COPD or for acute bronchospasm; always prescribe with an inhaled short-acting beta2-agonist (eg, albuterol) and educate patient on appropriate use. Upon initiation of the combination inhaler, use of short-acting beta2-agonists should be limited to treat acute symptoms. Do not initiate in patients with significantly worsening, potentially life-threatening, or acutely deteriorating COPD. Do not increase the dose or frequency beyond what is recommended.

Monitoring Parameters

FEV1, FVC, and/or other pulmonary function tests; serum potassium, serum glucose; blood pressure, heart rate; CNS stimulation. Monitor for increased use of short-acting beta2-agonist inhalers; may be marker of a deteriorating condition. Monitor for changes in risk factors (eg, environmental exposure, smoking status).

Pregnancy Risk Factor

C

Pregnancy Considerations

Animal reproduction studies have not been conducted with this combination. Refer to individual monographs.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience pharyngitis, rhinitis, rhinorrhea, or back pain. Have patient report immediately to prescriber signs of high blood sugar (confusion, feeling sleepy, more thirst, hunger, passing urine more often, flushing, fast breathing, or breath that smells like fruit), signs of low potassium (muscle pain or weakness, muscle cramps, or an abnormal heartbeat), angina, tachycardia, arrhythmia, severe headache, severe dizziness, passing out, painful urination, change in amount of urine passed, urinary retention, difficult urination, difficulty swallowing, vision changes, eye pain, severe eye irritation, red eyes, seeing halos or bright colors around lights, severe nausea, severe vomiting, difficulty breathing, wheezing, or cough (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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