COPD Respiratory Antimuscarinics Drug Class Monograph

Transcription

1 Line of Business: Medi-Cal Effective Date: May 17, 2017 Revision Date: May 17, 2017 COPD Respiratory Antimuscarinics Drug Class Monograph This policy has been developed through review of medical literature, consideration of medical necessity, generally accepted medical practice standards, and approved by the IEHP Pharmacy and Therapeutic Subcommittee. Drugs: Anoro Ellipta (umeclidinium/vilanterol), Bevespi Aerosphere (glycopyrronium/formeterol), Incruse Ellipta (umeclidinium bromide), Spiriva HandiHaler (tiotropium), Spiriva Respimat (tiotropium), Stiolto Respimat (olodaterol/tiotropium), Tudorza Pressair (aclidinium), Utibron Neohaler (indacaterol/glycopyrrolate) Policy/Criteria: A. Non-formulary COPD long acting muscarinic agonist inhaler Diagnosis: a. COPD Specialist: Not Applicable Criteria: a. Failure or clinically significant adverse effects to ONE formulary long acting bronchodilator: Incruse Ellipta, Stiolto Respimat, Tudorza or Serevent. B. Non-formulary COPD long acting combination muscarinic agonist and beta agonist inhaler Diagnosis: a. COPD Specialist: Not Applicable Criteria: a. Failure or clinically significant adverse effects to Stiolto Respimat

2 Clinical Justification: 2017 Global Initiative for Chronic Obstructive Lung Disease Bronchodilators in Stable COPD: Bronchodilator medications are central to symptom management in COPD Inhaled therapy is preferred. The choice between beta-agonist, anticholinergic, theophylline or combination therapy depends on availability and individual patient response in terms of symptom relief and side effects Bronchodilators are prescribed on as-needed or on a regular basis to prevent or reduce symptoms Long-acting inhaled bronchodilators are convenient and more effective at producing maintained symptom relief than short-acting bronchodilators Combining bronchodilators of different pharmacological classes may improve efficacy and decrease the risk of side effects compared to increasing the dose of a single bronchodilator Anticholinergics: Tiotropium reduces exacerbations and related hospitalizations, improves symptoms and health status (Evidence A), and improve the effectiveness of pulmonary rehabilitation (Evidence B). The long acting anticholinergics aclidinium and glycopyrronium seem to have similar action on lung function and breathlessness as tiotropium, whereas far less data are available for other outcomes. Combination Bronchodilator Therapy: Combinations of a long-acting beta2 agonist and a long-acting anticholinergic are superior compared to either medication alone in improving FEV1 and symptoms (Evidence A). Combinations of a long-acting beta2 agonist and a long-acting anticholinergic reduce exacerbations compared to monotherapy (Evidence B) or inhaled corticosteroids and long-acting beta2 agonists (Evidence B). The combined use of short or long-acting beta2-agonists and anticholinergics may be considered if symptoms are not improved with single agents. (Evidence B) Comparing tiotropium with other long-acting anticholinergics: In a small trial, a randomized, double-blind, and crossover clinical study comparing aclidinium 400mcg twice daily with tiotropium 18mcg once daily in moderate to severe COPD patients, improvements in FEV1 were superior than placebo, but not significantly different from each other.

3 In a 12-week, randomized, double-blinded clinical study, glycopyrronium 50 mcg demonstrated non-inferiority to tiotropium 18 mcg in trough FEV1 at week 12 and indicated similar effect of both treatments on lung function and clinical outcomes in patients with moderate-to-severe COPD.

4 Monotherapy Anticholinergic Bronchodilator Drugs Atrovent HFA (ipratropium) Spiriva HandiHaler (tiotropium) Spiriva Respimat (tiotropium) MOA Short-acting anticholinergic agent that blocks acetylcholine at parasympathetic site in bronchial smooth muscle causing bronchodilation Long-acting anticholinergic agent that competitively and reversibly inhibits acetylcholine at M3 receptors in bronchial smooth muscle causing bronchodilation; affinity for muscarinic subtypes M1 through M5 Usual Dosing 2 inhalations four 2 inhalations of one 2 inhalations once daily times daily, not to exceed 12 inhalations in 24 hours capsule once daily FDA Indication COPD COPD COPD Asthma, maintenance therapy Pediatric Indication Not approved for children under 12 years of age Not indicated for use in children; efficacy and safety not established Asthma, maintenance therapy for 6 years and older Administration Use HFA canister with provided mouthpiece; wash mouthpiece with warm water only at least once a week for 30 seconds and air-dry completely. Prime HFA canister against mouthpiece 2 times before first use and if canister has not been used for more than 3 days; it is not necessary to shake the canister Capsules are for oral inhalation only with the HandiHaler inhalation device and must not be swallowed. Store capsules in blister packaging and remove immediately before use. If capsules are exposed to air, they should be discarded Insert capsule into center of HandiHaler device chamber; hold device with mouthpiece upwards and press the green button once to pierce the capsule. Clean HandiHaler device with warm water once a month and allow to dry for 24 hours Exhale completely then breathe in slowly and Prior to first use, insert cartridge into inhaler unit and actuate inhaler towards ground until aerosol cloud appears, then repeat 3 times to prime unit. If the inhaler is not used for more than 3 days, actuate the device 1 time to prime for use. If it is not used for more than 21 days, repeat the initial priming process

5 PK/PD Absorption: within 15 minutes; not readily absorbed into systemic circulation Peak effect: 1-2 hours Distribution: 15% of dose reaches lower airways Protein binding: 9% Metabolism: partially metabolized to inactive ester hydrolysis products Half-life: 2 hours Excretion: urine (50%) Contraindications Hypersensitivity to atropine or its derivatives Hypersensitivity to ipratropium bromide or any component of the product Warnings Not indicated for the initial treatment of acute episodes of bronchospasm where rescue therapy is required for rapid response Hypersensitivity reactions, including anaphylaxis: discontinue medication Glaucoma: use with caution in narrow-angle glaucoma Paradoxical bronchospasm: discontinue medication and institute alternative therapy Urinary retention: may deeply at a rate enough to hear or feel the capsule vibrate and hold breath as long as is comfortable. If the inhaler is not used for more than 3 days, actuate the device 1 time to prime for use. If not used more than 21 days, repeat initial priming process Absorption: poorly absorbed from GI tract, systemic absorption may occur from lung Peak effect: 7 minutes Distribution: 32 L/kg Protein binding: 72% Metabolism: hepatic (minimal), via CYP2D6 and CYP3A4 Half-life: ~25 hours Excretion: urine (7% of an inhaled dose) Hypersensitivity to tiotropium, ipratropium, or any component of the product Absorption: 5 to 7 minutes Peak: 1.5 to 3 hours Bioavailability: 33% Distribution: 32 L/kg Protein binding: 72% Metabolism: 25% via CYP2D6 and CYP3A4 oxidation with subsequent glutathione conjugation Half-life: 25 hours Excretion: urine (18.6% of an inhaled dose) Hypersensitivity to tiotropium, ipratropium, or any component of the product Not for acute use or as rescue medication Hypersensitivity reactions, including anaphylaxis: discontinue medication Glaucoma: use with caution in narrow-angle glaucoma Paradoxical bronchospasm: discontinue medication and institute alternative therapy Urinary retention: may worsen symptoms, leading to painful urination or difficulty passing urine

6 Drug-drug interaction Common Side effects worsen symptoms, leading to painful urination or difficulty passing urine Anticholinergics: Avoid coadministration due to additive effects Bronchitis, COPD exacerbation, Dyspnea, and Headache Upper respiratory tract infection, Dry mouth, Sinusitis, Pharyngitis, Nonspecific chest pain, Urinary tract infection, Dyspepsia, and Rhinits Pharyngitis, Cough, Dry mouth, Sinusitis Monitoring Pulmonary function tests, proper inhalation technique Pregnancy Category B. No teratogenic effects seen in animal studies Lactation It is not known if ipratropium is excreted in breast milk. The US labeling recommends that caution be exercised when administering to breastfeeding women. Storage and stability Store at 20-25ºC (68-77ºF), excursion permitted between 15 and 30ºC (59 and 86ºF). Do not puncture the canister or use or store near heat or open flame. Bursting may occur at temperatures above 120 ºF. Discard canister when indicator displays zero How supplied 17 mcg/actuation with 200 actuations per 12.9g canister FEV1, peak flow, other pulmonary function tests, reduction in COPD exacerbation; anticholinergic adverse reactions; signs and symptoms of narrow angle glaucoma and urinary retention Category C. Adverse effects seen in animal studies It is not known if tiotropium is excreted in breast milk. The US labeling recommends that caution be exercised when administering to breast-feeding women Store at 25ºC (77ºF), excursions permitted between 15 and 30ºC (59 and 86ºF). Do not expose capsules to extreme temperature or moisture. Do not store capsules in HandiHaler device Store at 25 C (77 F), excursions are permitted between 15 C and 30 C (59 F and 86 F). Avoid freezing 18 mcg/capsule COPD: 2.5 mcg/actuation Asthma: 1.25mcg/actuation

7 Monotherapy Anticholinergic Bronchodilator Drugs (cont.) MOA Incruse Ellipta (umeclidinium bromide) Long-acting anticholinergic agent that competitively and reversibly inhibits acetylcholine at M3 receptors in bronchial smooth muscle causing bronchodilation Seebri Neohaler (glycopyrrolate) Long-acting anticholinergic agent than competitively and reversibly inhibits acetylcholine at muscarinic subtypes 1 to 3 in bronchial smooth muscle causing bronchodilation Tudorza Pressair (aclidinium) Long-acting anticholinergic agent that competitively and reversibly inhibits acetylcholine at M3 receptors in bronchial smooth muscle causing bronchodilation Usual Dosing 1 inhalation daily 1 capsule inhaled twice daily 1 inhalation twice daily FDA Indication Pediatric Indication COPD Efficacy and safety not established Administration PK/PD When ready for a dose, open the cover of the inhaler; a click will be heard and the counter will decrease to indicate the device is ready. Before inhaling the dose, breath our fully, then place device firmly between lips and inhale with a long, deep, steady breath through the mouth. Do not breathe in through nose or cover air vent on the inhaler. Hold breath for 3 to 4 seconds or for as long as comfortable, and exhale slowly. Opening and closing the device without an inhalation will result in a lost dose Absorption: lung, minimum contribution from oral absorption Time to Peak: 5 to 15 minutes Distribution: 86L Protein binding: 89% Administer by inhalation route using the Neohaler device at the same time every day; do not swallow capsule. Store capsules in the blister pack until immediately before use. Use the new inhaler included with each prescription. Discard any capsules that are exposed to air and not used immediately Absorption: rapid Time to Peak: 5 minutes Bioavailability: ~40% Distribution: 83L Protein binding: 38-41% Metabolism: hepatic (minimal) Half-life: hours Excretion: urine, bile Press and release the green button and then make sure the control window has changed from red to green before inhalation. Breathe out completely before forming a tight seal with lips around the mouthpiece and breathe in; there will be a clicking sound and the control window should turn red after inhalation Time to Peak: 10 minutes Bioavailability: ~6% Distribution: 300L Protein binding: 38-41% Metabolism: rapid and extensive hydrolysis via plasma esterases to inactive alcohol and acid metabolites Half-life: 5-8 hours

8 Contraindications Warnings Drug-drug interaction Common Side effects Monitoring Pregnancy Lactation Metabolism: oxidation followed by conjugation, substrate of CYP2D6 and P-gp Half-life: 11 hours Excretion: urine (<1%) and feces (92%) Severe hypersensitivity to milk proteins Hypersensitivity to any ingredient History of known hypersensitivity to glycopyrrolate or any of the ingredients Do not initiate in acutely deteriorating COPD or to treat acute symptoms Glaucoma: use with caution in narrow-angle glaucoma Paradoxical bronchospasm: discontinue medication and institute alternative therapy Urinary retention: may worsen symptoms, leading to painful urination or difficulty passing urine Anticholinergics: Avoid coadministration due to additive effects Nasopharyngitis, Upper respiratory tract infection, Cough, Arthralgia Upper respiratory tract infection and Nasopharyngitis FEV1, peak flow, other pulmonary function tests; signs and symptoms of narrow angle glaucoma and urinary retention Category C. Adverse events were not observed in animal reproduction studies. It is not known if umeclidinium is excreted into breast milk. The US labeling recommends that caution be exercised Category C It is not known if glycopyrrolate is excreted into breast milk. The US labeling recommends that caution be exercised when administering to breast-feeding women. May suppress lactation. Excretion: urine (0.09%) Severe hypersensitivity to milk proteins Hypersensitivity to any ingredient Not for acute use or as a rescue medication Glaucoma: use with caution in narrow-angle glaucoma Paradoxical bronchospasm: discontinue medication and institute alternative therapy Urinary retention: may worsen symptoms, leading to painful urination or difficulty passing urine Hypersensitivity reactions: angioedema, bronchospasm, or anaphylaxis may occur in patients with severe hypersensitivity to milk proteins Headache, Nasopharyngitis, Cough FEV1, peak flow, other pulmonary function tests; signs and symptoms of narrow angle glaucoma and urinary retention; hypersensitivity reactions in patients with prior hypersensitivity to atropine Category C. Adverse effects were observed in animal reproduction studies. Excretion of aclidinium into human milk is probable as it was observed in animal studies. The US labeling recommends that caution be exercised when administering to breast-feeding women.

9 when administering to breast-feeding women. Storage and stability Store at 20-25ºC (68-77ºF), excursion permitted between 15 and 30ºC (59 and 86ºF). Protect from direct heat, sunlight, and moisture. Discard 6 weeks after opening or when the dose counter reads zero Store capsules in blister pack at 25ºC (77ºF), excursions permitted between 15 and 30ºC (59 and 86ºF) until immediately before use. Protect from moisture. Discard capsule if not used immediately Store under dry conditions, in the sealed ouch, at 25ºC (77ºF), excursions permitted between 15 and 30ºC (59 and 86ºF). Remove pouch immediately prior to use. Discard inhaler 45 days after removal, when the 0 marking with a red background shows in the dose indicator, or when the inhaler locks How supplied 62.5 mcg/actuation 15.6 mcg/capsule 400 mcg/actuation Combination Anticholinergic Bronchodilator Drugs Anoro Ellipta (umeclidinium/ vilanterol) MOA Stiolto Respimat (tiotropium/ olodaterol) Utibron Neohaler (glycopyrrolate/ indacaterol) Combination of a long-acting anticholinergic agent which reversibly inhibits the M3 receptor at the smooth muscle, leading to bronchodilation, and a long-acting beta-2 agonist which stimulates adenyl cyclase resulting in increased intracellular camp which triggers bronchial smooth muscle relaxation Usual Dosing 1 inhalation daily 2 inhalations once daily 1 capsule inhaled twice daily FDA Indication COPD Pediatric Efficacy and safety not established Indication Administration Administer at the For first use or if inhaler same time each day. has not been used for Do not open the more than 21 days, prime cover until ready to the unit by actuating use. Exhale fully inhaler toward the ground before taking one until aerosol cloud is long, steady, deep visible and then repeating breath through the 3 more times. If the unit mouthpiece. Hold has not been used for breath for 3 to 4 more than 3 days, actuate seconds and exhale inhaler once prior to use. slowly and gently Do not cover the air vents when administering the inhaler. Avoid contact with eyes Do not swallow capsules. Use only with Neohaler device. Administer at the same time each day, once in the morning and once in the evening. Store capsules in the blister container and only remove immediately prior to use Combivent Respimat (ipratropium/albuterol) Combination of a short-acting anticholinergic agent which blocks acetylcholine at parasympathetic sites leading to bronchodilation, and a short-acting beta2 agonist which relaxes bronchial smooth muscle 1 inhalation four times daily For first use or if inhaler has not been used for more than 21 days, prime the unit by actuating inhaler toward the ground until aerosol cloud is visible and then repeating 3 more times. If the unit has not been used for more than 3 days, actuate inhaler once prior to use. Do not cover the air vents when administering the inhaler. Avoid

10 PK/PD Contraindicatio ns Warnings Absorption: systemic, primarily via lungs, 5 to 15 minutes Distribution: Umeclidinium: 30,200 L; vilanterol: 1,240 L Protein binding: umeclidinium: 89%; vilanterol: 94% Metabolism: hepatic via CYP2D6 (umeclidinium) and CYP3A4 (vilanterol) Half-life: 11 hours Excretion: Urine (<1% umeclidinium; 70% vilanterol); feces (92% umeclidinium; 30% vilanterol) Severe hypersensitivity to milk proteins Absorption: tiotropium: 5 to 7 minutes; olodaterol: 10 to 20 minutes Distribution: Tiotropium: 32 L/kg; olodaterol: 1,110 L Protein binding: tiotropium: 72%; olodaterol: 60% Bioavailability: tiotropium: 33%; olodaterol: 30% Metabolism: tiotropium 25% via CYP2D6 and CYP3A4; olodaterol: extensively hepatic via CYP2C9 and CYP2C8 Half-life: Tiotropium: 25 hours; olodaterol: 45 hours Excretion: tiotropium: 18.6% in urine; olodaterol: 9% renal as parent and metabolites and 84% in feces Use in the treatment of asthma without a concomitant long-term asthma control medication Hypersensitivity to tiotropium, olodaterol, or any component of the product Absorption: glycopyrrolate: 5 minutes; indacaterol: 15 minutes Distribution: glycopyrrolate: 83 L; indacaterol: L Protein binding: glycopyrrolate: 38-41%; indacaterol: 95% Bioavailability: 43-45% Metabolism: glycopyrrolate: 30-40% of total elimination via multiple CYP enzymes; indacaterol: primary site via UGT1A1 and CYP3A4 Half-life: glycopyrrolate: hours; indacaterol: hours Excretion: glycopyrrolate: 60-70% renal; indacaterol: less than 2% renally, 54% unchanged and 23% as metabolites in feces Use in the treatment of asthma without a concomitant long-term asthma control medication Boxed Warning: Long-acting beta-2 agonists increase the risk of asthma-related deaths. Do not initiate in acutely deteriorating COPD or to treat acute symptoms Cardiovascular: Increased risk for cardiovascular effects and ECG changes Diabetes: may increase serum glucose and aggravate preexisting DM and ketoacidosis Glaucoma: use with caution in narrow-angle glaucoma Hypokalemia: may decrease serum potassium Paradoxical bronchospasm: discontinue medication and institute alternative therapy Urinary retention: may worsen symptoms, leading to painful urination or contact with eyes Absorption: ipratropium: not readily absorbed into systemic circulation from lungs; albuterol: rapid Distribution: ipratropium: 15% of dose reaches lower airways Protein binding: ipratropium: 9%; albuterol: 10% Metabolism: ipratropium: partial metabolism through liver; albuterol: hepatically to an inactive sulfate Half-life: ipratropium: 2 hours; albuterol: ~4 hours Excretion: ipratropium: 50% urine; albuterol: 30% as unchanged drug in the urine and <20% in feces Hypersensitivity to atropine or any of its derivatives. Hypersensitivity to ipratropium, albuterol, or any component of the product Paradoxical bronchospasm: Discontinue immediately and treat with alternative therapy Cardiovascular: use with caution due to beta-adrenergic stimulation Ocular effects:

11 Drug-drug interaction Common Side effects difficulty passing urine. Renal impairment: monitor closely for anticholinergic adverse events Seizure disorders: Use with caution as this drug may result in CNS stimulation Thyrotoxicosis: this may be exacerbated Strong CYP3A4 inhibitors: use with caution due to cardiovascular effects MAOIs and TCAs: use with extreme caution due to cardiovascular effects Beta-blockers: use with caution due to potential for bronchospasm and decreased effectiveness Diuretics: use with caution due to ECG changes and/or hypokalemia Anticholinergics: Avoid coadministration due to additive effects Pharyngitis Sinusitis Lower respiratory tract infection Other adrenergic drugs: use with caution Xanthine derivatives, steroids, diuretics, or non-potassium sparing diuretics: us with caution due to ECG changes and hypokalemia MAOIs, TCAs, and drugs that prolong QTc interval: use with extreme caution Beta-blockers: use with caution due to potential for bronchospasm and decreased effectiveness Anticholinergics: Avoid coadministration due to additive effects Nasopharyngitis Back Pain Cough Other adrenergic drugs: use with caution Xanthine derivatives, steroids, diuretics, or non-potassium sparing diuretics: us with caution due to ECG changes and hypokalemia MAOIs, TCAs, and drugs that prolong QTc interval: use with extreme caution Beta-blockers: use with caution due to potential for bronchospasm and decreased effectiveness Anticholinergics: Avoid coadministration due to additive effects Nasopharyngitis Hypertension Avoid spraying into eyes and monitor patients with narrow-angle glaucoma Urinary retention: use with caution Anaphylaxis: Discontinue if hypersensitivity reactions seen such as urticaria, angioedema, rash, bronchospasm, or orpharyngeal edema. Use with caution in patients with convulsive disorders, hypothyroidism, or diabetes mellitus Anticholinergics: Avoid coadministration due to additive effects Beta-adrenergic agonists: Avoid coadministration due to cardiovascular effects Beta-blockers: Consider alternative therapy due its inhibition of albuterol Diuretics: Consider monitoring potassium levels due to ECG changes and/or hypokalemia MAOIs or TCAs: Consider alternative therapy Upper respiratory infection Nasopharyin gitis

12 Monitoring Pregnancy Lactation Storage and stability Constipation Diarrhea Pain in extremity Muscle spasms Neck pain Chest pain FEV1, peak flow, and/or other pulmonary function tests; blood pressure, heart rate; CNS stimulation; ocular changes FEV1, peak flow, and/or other pulmonary function tests; anticholinergic effects; glaucoma, and urinary retention, increased use of SABAs FEV1, FVC, and/or other pulmonary function tests; serum potassium, serum glucose; blood pressure, heart rate; CNS stimulation; increased use of SABAs Cough Bronchitis Headache Dyspnea FEV1, FVC, peak flow, and/or other pulmonary function tests; shortness of breath; serum potassium; blood pressure, heart rate Category C. Beta-agonists have the potential to affect uterine contractility if administered during labor It is not known if It is not known if It is not known if It is not known if umeclidnium or tiotropium or olodaterol is glycopyrrolate or ipratropium or albuterol vilanterol is excreted excreted in breast milk. indacaterol is excreted are excreted in breast milk. in breast milk. The The US labeling in breast milk. The US The US labeling US labeling recommends that caution labeling recommends recommends that caution recommends that be exercised when that caution be be exercised when caution be exercised administering to breastfeeding exercised when administering to breast- when administering women. administering to breastfeeding women. to breast-feeding feeding women. women. Store at 20-25ºC (68-77ºF), excursion permitted between 15 and 30ºC (59 and 86ºF). Protect from moisture, direct heat, or sunlight. Discard inhaler after 6 weeks after initially opening the foil tray or when all the blisters have been used, whichever comes first How supplied umeclidinium 62.5 mcg/vilanterol 25 mcg Store at 25ºC (77ºF), excursions permitted between 15 and 30ºC (59 and 86ºF). Protect from freezing. Discard 3 months after first use or when locking mechanism is engages, whichever comes first tiotropium 2.5 mcg/ olodaterol 2.5 mcg Store at 25ºC (77ºF), excursions permitted between 15 and 30ºC (59 and 86ºF). Store capsules in original blister to protect from light and moisture glycopyrrolate 15.6 mcg/indacaterol 27.5mcg Store at 25ºC (77ºF), excursions permitted between 15 and 30ºC (59 and 86ºF). Avoid freezing. Discard when locking mechanism is engaged or 3 months after first use, whichever comes first ipratropium 20mcg/albuterol 100 mcg

13 References: 1. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Vancouver (WA): Global Initiative for Chronic Obstructive Lung Disease (GOLD); Tudorza Pressair [package insert]. St. Louis, MO: Almirall; July Spiriva Handihaler [package insert]. Boehringer Ingelheim, October Anoro Ellipta [package insert]. Research Triangle Park, NC: GSK; December Fuhr R, Magnussen H, Sarem K, et al. Efficacy of aclidinium bromide 400 mcg twice daily compared with placebo and tiotropium in patients with moderate to severe COPD. Chest. 2012;141(3): Chapman K, Beeh K, Beier J, et al. A blinded evaluation of the efficacy and safety of glycopyrronium, a once-daily long-acting muscarinic antagonist, versus tiotropium, in patients with COPD: the GLOW5 study. BMC Pulmonary Medicine 2014, 14:4. Change Control Date Change 05/17/2017 Added Stiolto Respimat to Medi-Cal formulary Revised criteria for non-formulary COPD long acting muscarinic agonist inhaler: o Failure or clinically significant adverse effects to ONE formulary long acting bronchodilator. Revised criteria for Non-formulary COPD long acting combination muscarinic agonist and beta agonist inhaler o Failure or clinically significant adverse effects to Stiolto Respimat