Use Caution/Monitor. Drugs that are known to prolong the QTc interval may have an increased the risk of ventricular arrhythmias.zotepineMonitor Closely (2)glycopyrrolate inhaled decreases levels of zotepine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor. glycopyrrolate inhaled decreases levels of zotepine by pharmacodynamic antagonism. Use Caution/Monitor. 1-10% Nasopharyngitis (4.1%) Hypertension (2%) Back pain (1.8%) Oropharyngeal pain (1.6%) Postmarketing Reports Angioedema Dysphonia Black Box Warnings 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 Safety and efficacy of indacaterol/glycopyrrolate in patients with asthma have not been established Not indicated for the treatment of asthmaContraindications Hypersensitivity All LABAs are contraindicated in patients with asthma without use of an inhaled corticosteroid; indacaterol/glycopyrrolate is not indicated for the treatment of asthma Cautions Safety and efficacy in patients with asthma not established; not indicated for asthma; monotherapy [without inhaled corticosteroids (ICS)] for asthma is associated with an increased risk of asthma-related death (see Black Box Warnings) Available data do not suggest an increased risk of death with use of LABA in patients with COPD Should not be initiated in patients with acutely deteriorating or potentially life-threatening episodes of COPD; also do not use for the relief of acute symptoms (ie, as rescue therapy) for treating acute episodes of bronchospasm 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 reported in association with excessive use of inhaled sympathomimetic drugs; patients receiving therapy should not use another medicine containing a LABA for any reason Can produce paradoxical bronchospasm that may be life-threatening Immediate hypersensitivity reactions have been reported after administration of indacaterol or glycopyrrolate; if signs suggesting allergic reactions occur, in particular, angioedema (including difficulties in breathing or swallowing, swelling of tongue, lips, and face), anaphylaxis, urticaria, or skin rash, therapy should be discontinued immediately and alternative therapy instituted; drug should be used with caution in patients with severe hypersensitivity to milk proteins LABAs can produce clinically significant cardiovascular effects, including increases in pulse rate or systolic or diastolic blood pressure Caution with convulsive disorders, thyrotoxicosis, patients who are unusually responsive to sympathomimetic amines, narrow-angle glaucoma (may worsen), or urinary retention (eg, prostatic hyperplasia, bladder-neck obstruction); instruct patients to contact their physician immediately with worsening disease symptoms Doses of the related beta2-agonist albuterol, when administered IV, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis LABAs may produce significant hypokalemia, which has the potential to produce adverse cardiovascular effect; in patients with severe COPD, hypokalemia may be potentiated by hypoxia and concomitant treatment, which may increase the susceptibility for cardiac arrhythmias Pregnancy There are no adequate and well-controlled studies with drug combination or its individual components, indacaterol and glycopyrrolate, in pregnant women; women should be advised to contact their healthcare provider if they become pregnant while receiving therapy There are no adequate and well-controlled human trials that have investigated effects of therapy during labor and delivery; because beta-agonists may potentially interfere with uterine contractility, drug should be used during labor only if potential benefit justifies potential risk Animal data Animal reproduction studies were conducted with individual components, indacaterol and glycopyrrolate. Indacaterol: In animal reproduction studies, there was no evidence of fetal harm or structural abnormalities following subcutaneous administration of indacaterol maleate to pregnant Wistar rats and New Zealand White rabbits during the period of organogenesis at exposures approximately 340 and 770 times, respectively, the maximum recommended human dose (MRHD of 55 mcg) on an exposure (AUC) basis Glycopyrrolate: In animal reproduction studies, there was no evidence of fetal harm or structural abnormalities in Wistar rats or New Zealand White rabbits at inhaled doses approximately 1400 and 530 times, respectively, the MRHD (31.2 mcg) on an AUC basis Lactation There is no data on presence of indacaterol or glycopyrrolate or their metabolites in human milk, effects on breastfed infant, or on milk production Studies of lactating rats, indacaterol and glycopyrrolate were present in the milk; the developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on breastfed child from drug or from underlying maternal condiPregnancy 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. Mechanism of Action Glycopyrronium: Long-acting muscarinic antagonist (LAMA); often referred to as an anticholinergic; produces bronchodilation by inhibiting acetylcholine’s effect on muscarinic receptors in the airway smooth muscle Indacaterol: Long-acting beta2-agonist (LABA); stimulates intracellular adenyl cyclase, causing conversion of ATP to cyclic AMP; increased cyclic AMP levels cause relaxation of bronchial smooth muscle Absorption Absolute bioavailability: 43-45% (indacaterol) Peak plasma time: 5 minutes (glycopyrrolate); 15 minutes (indacaterol) Distribution Protein bound: 38-41% (glycopyrrolate); ~95% (indacaterol) Vd: 83-376 L (glycopyrrolate); 2361-2557 L (indacaterol) Metabolism Indacaterol Metabolized by UGT1A to the phenolic O-glucuronide Also undergoes hydroxylation (predominantly by CYP3A4) Glycopyrrolate Hydroxylation of results in a variety of mono-and bishydroxylated metabolites and direct hydrolysis results in the formation of a carboxylic acid derivative (M9) M9 is hydrolyzed by multiple CYP isoenzymes Elimination Half-life: 40-56 hr (indacaterol oral); 33-53 hr (glycopyrrolate inhaled) Renal clearance: 0.46-1.2 L/hr (indacaterol) Systemic clearance: 18.8-23.3 L/hr (indacaterol) Excretion Indacaterol: 54% (unchanged) and 23% (metabolites) in feces Glycopyrrolate: 60-70% urine; 30-40% nonrenal (mostly by metabolism; also biliary) Pharmacogenomics Indacaterol The pharmacokinetics of indacaterol were prospectively investigated in subjects with the UGT1A1 (TA)7/(TA)7 genotype (low UGT1A1 expression; also referred to as *28) and the (TA)6, (TA)6 genotype Steady-state AUC and Cmax were 1.2-fold higher in the [(TA)7, (TA)7] genotype, suggesting no relevant effect of UGT1A1 genotype of indacaterol exposure Instructions For oral inhalation only Do not swallow the capsules, as the intended effects on the lungs will not be obtained Capsules should only be used with the Neohaler device Should be administered at the same time of the day, (1 capsule in the morning and 1 capsule in the evening), every day More frequent administration or a greater number of inhalations (>1 capsule BID) is not recommended Storage Store in a dry place at controlled room temperature (77°F [25°C]); excursions permitted to 59-86°F (15-30°C) Store capsules in the blister package that they are packaged in, and only remove immediately before use with the Neohaler device No images available for this drug. No images available for this drug.A Patient Handout is not currently available for this monograph.Print FormularyPatient DiscountsAdding plans allows you to compare formulary status to other drugs in the same class.To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.Create Your List of PlansAdding plans allows you to:View the formulary and any restrictions for each plan.Manage and view all your plans together – even plans in different states.Compare formulary status to other drugs in the same class.Access your plan list on any device – mobile or desktop. The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information. View explanations for tiers and restrictions Tier Description 1 This drug is available at the lowest co-pay. 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