with drugs that prolong QTc interval; adrenergic agonist effects on the cardiovascular system may be potentiated.telavancinSerious - Use Alternative (1)telavancin increases toxicity of umeclidinium bromide/vilanterol inhaled by QTc interval. Avoid or Use Alternate Drug. Exercise extreme caution when vilanterol coadministered with drugs that prolong QTc interval; adrenergic agonist effects on the cardiovascular system may be potentiated.thioridazineSerious - Use Alternative (1)thioridazine increases toxicity of umeclidinium bromide/vilanterol inhaled by QTc interval. Avoid or Use Alternate Drug. Exercise extreme caution when vilanterol coadministered with drugs that prolong QTc interval; adrenergic agonist effects on the cardiovascular system may be potentiated.thiothixeneSerious - Use Alternative (1)thiothixene increases toxicity of umeclidinium bromide/vilanterol inhaled by QTc interval. Avoid or Use Alternate Drug. Exercise extreme caution when vilanterol coadministered with drugs that prolong QTc interval; adrenergic agonist effects on the cardiovascular system may be potentiated.timololSerious - Use Alternative (1)timolol, umeclidinium bromide/vilanterol inhaled. pharmacodynamic antagonism. Avoid or Use Alternate Drug. If a beta-blocker must be used in patients with COPD taking a beta-agonist, consider using a beta-blocker that is beta-1 selective .tiotropiumContraindicated (1)tiotropium, umeclidinium bromide/vilanterol inhaled. Either increases toxicity of the other by pharmacodynamic synergism. Contraindicated. Duplicate therapy.tipranavirMonitor Closely (1)tipranavir will increase the level or effect of umeclidinium bromide/vilanterol inhaled by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Vilanterol is a CYP3A4 substrate; coadministration with potent CYP3A4 inhibitors may increase systemic exposuretoremifeneSerious - Use Alternative (1)toremifene increases toxicity of umeclidinium bromide/vilanterol inhaled by QTc interval. Avoid or Use Alternate Drug. Exercise extreme caution when vilanterol coadministered with drugs that prolong QTc interval; adrenergic agonist effects on the cardiovascular system may be potentiated.torsemideMonitor Closely (1)umeclidinium bromide/vilanterol inhaled and torsemide both decrease serum potassium. Modify Therapy/Monitor Closely. Electrocardiographic changes and/or hypokalemia associated with non?potassium-sparing diuretics may worsen with concomitant beta-agonists, particularly if recommended dose is exceededtranylcypromineSerious - Use Alternative (1)tranylcypromine and umeclidinium bromide/vilanterol inhaled both increase sympathetic (adrenergic) effects, including increased blood pressure and heart rate. Avoid or Use Alternate Drug. Exercise extreme caution if vilanterol coadministered with MAOIs or TCAs, or within 2 weeks of discontinuation of these drugs; adrenergic agonist effects on the cardiovascular system may be potentiatedtrihexyphenidylSerious - Use Alternative (1)trihexyphenidyl, umeclidinium bromide/vilanterol inhaled. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Concomitant use with other anticholinergic-containing drugs may lead to additive anticholinergic adverse effects.trimipramineSerious - Use Alternative (2)trimipramine increases toxicity of umeclidinium bromide/vilanterol inhaled by QTc interval. Avoid or Use Alternate Drug. Exercise extreme caution when vilanterol coadministered with drugs that prolong QTc interval; adrenergic agonist effects on the cardiovascular system may be potentiated. trimipramine and umeclidinium bromide/vilanterol inhaled both increase sympathetic (adrenergic) effects, including increased blood pressure and heart rate. Avoid or Use Alternate Drug. Exercise extreme caution if vilanterol coadministered with MAOIs or TCAs, or within 2 weeks of discontinuation of these drugs; adrenergic agonist effects on the cardiovascular system may be potentiatedtucatinibSerious - Use Alternative (1)tucatinib will increase the level or effect of umeclidinium bromide/vilanterol inhaled by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid concomitant use of tucatinib with CYP3A substrates, where minimal concentration changes may lead to serious or life-threatening toxicities. If unavoidable, reduce CYP3A substrate dose according to product labeling.valbenazineMonitor Closely (1)valbenazine and umeclidinium bromide/vilanterol inhaled both decrease QTc interval. Use Caution/Monitor.vandetanibSerious - Use Alternative (1)vandetanib increases toxicity of umeclidinium bromide/vilanterol inhaled by QTc interval. Avoid or Use Alternate Drug. Exercise extreme caution when vilanterol coadministered with drugs that prolong QTc interval; adrenergic agonist effects on the cardiovascular system may be potentiated.vardenafilSerious - Use Alternative (1)vardenafil increases toxicity of umeclidinium bromide/vilanterol inhaled by QTc interval. Avoid or Use Alternate Drug. Exercise extreme caution when vilanterol coadministered with drugs that prolong QTc interval; adrenergic agonist effects on the cardiovascular system may be potentiated.vemurafenibSerious - Use Alternative (1)vemurafenib increases toxicity of umeclidinium bromide/vilanterol inhaled by QTc interval. Avoid or Use Alternate Drug. Exercise extreme caution when vilanterol coadministered with drugs that prolong QTc interval; adrenergic agonist effects on the cardiovascular system may be potentiated.voclosporinMonitor Closely (1)voclosporin, umeclidinium bromide/vilanterol inhaled. Either increases effects of the other by QTc interval. Use Caution/Monitor.voriconazoleMonitor Closely (1)voriconazole will increase the level or effect of umeclidinium bromide/vilanterol inhaled by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Vilanterol is a CYP3A4 substrate; coadministration with potent CYP3A4 inhibitors may increase systemic exposureSerious - Use Alternative (1)voriconazole increases toxicity of umeclidinium bromide/vilanterol inhaled by QTc interval. Avoid or Use Alternate Drug. Exercise extreme caution when vilanterol coadministered with drugs that prolong QTc interval; adrenergic agonist effects on the cardiovascular system may be potentiated.vorinostatSerious - Use Alternative (1)vorinostat increases toxicity of umeclidinium bromide/vilanterol inhaled by QTc interval. Avoid or Use Alternate Drug. Exercise extreme caution when vilanterol coadministered with drugs that prolong QTc interval; adrenergic agonist effects on the cardiovascular system may be potentiated.ziprasidoneSerious - Use Alternative (1)ziprasidone increases toxicity of umeclidinium bromide/vilanterol inhaled by QTc interval. Avoid or Use Alternate Drug. Exercise extreme caution when vilanterol coadministered with drugs that prolong QTc interval; adrenergic agonist effects on the cardiovascular system may be potentiated. 1-10% Pharyngitis (2%) Diarrhea (2%) Pain in extremity (2%) Muscle spasms (1%) Neck pain (1%) Chest pain (1%) Sinusitis (1%) Lower respiratory tract infection (1%) Constipation (1%) <1% Productive cough Dry mouth Dyspepsia Abdominal pain GERD Vomiting Musculoskeletal chest pain Chest discomfort Asthenia Atrial fibrillation Ventricular extrasystoles Supraventricular extrasystoles Myocardial infarction Pruritus Rash Conjunctivitis Postmarketing reports Cardiac Disorders : Palpitations Immune System Disorders: Hypersensitivity reactions, including anaphylaxis, angioedema, and urticaria Nervous System Disorders: Dysgeusia, tremor Psychiatric Disorders: Anxiety Eye disorders: Blurred vision, glaucoma, increased intraocular pressure Renal and urinary disorders: Dysuria, urinary retention Respiratory, thoracic, and mediastinal disorders: Dysphonia, paradoxical bronchospasm Black Box Warnings Long-acting beta2-adrenergic agonists (LABAs), such as vilanterol, increase the risk for asthma-related death A placebo-controlled trial with another LABA (salmeterol) showed an increase in asthma-related deaths; this finding is considered a class effect of all LABA, including vilanterol Safety and efficacy not established in patients with asthma; NOT approved for treatment of asthmaContraindications Severe hypersensitivity to milk proteins Demonstrated hypersensitivity to umeclidinium, vilanterol, or excipients Use without an inhaled corticosteroid in the treatment of asthma Cautions Anaphylactic reactions reported in patients with severe milk protein allergy after inhalation of other powder products containing lactose (see Contraindications) Not indicated for relief of acute bronchospasm or for the treatment of asthma; data from a large placebo-controlled trial in subjects with asthma showed that LABAs may increase the risk of asthma-related death (see Black Box Warnings) Do not initiate in patients during rapidly deteriorating or potentially life-threatening episodes of COPD Do not exceed recommended dose (ie, 1 actuation once daily) or coadminister with other medicines containing a LABA; may result in overdose Fatalities reported in association with excessive use of inhaled sympathomimetic drugs Paradoxical bronchospasm reported; discontinue umeclidinium bromide/vilanterol and treat immediately with an inhaled, prompt-acting bronchodilator (eg, albuterol) Beta2-agonists should be used with caution with convulsive disorders, thyrotoxicosis, narrow-angle glaucoma, and in individuals who are unusually responsive to sympathomimetic amines; instruct patients to consult a healthcare provider immediately if any worsening of narrow-angle glaucoma develops Prescribers and patients should be alert for signs and symptoms of urinary retention (eg, difficulty passing urine, painful urination), especially in patients with prostatic hyperplasia or bladder-neck obstruction; instruct patients to consult a healthcare provider immediately if any of these signs or symptoms develop Potential for beta2-agonists to produce significant hypokalemia (possibly through intracellular shunting) and transient hyperglycemia (not observed in clinical trials) Caution with coadministration with strong CYP3A4 inhibitors because increased cardiovascular adverse effects may occur Use beta2-agonists with extreme caution in patients being treated with MAOIs, TCAs, or drugs known to prolong the QTc interval or within 2 weeks of discontinuation of such agents Cardiovascular effects Vilanterol, like other beta2-agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, and also cardiac arrhythmias, such as supraventricular tachycardia and extrasystoles; if such effects occur, therapy may need to be discontinued In addition, beta-agonists have been reported to produce electrocardiographic changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression, although the clinical significance of these findings is unknown Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs Like other sympathomimetic amines, this drug should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension Acute disease Acute symptoms should be treated with an inhaled, short-acting beta2-agonist If therapy no longer controls symptoms of bronchoconstriction; the patient’s inhaled, short-acting beta2-agonist becomes less effective; or the patient needs more short-acting beta2-agonist than usual, these may be markers of deterioration of disease; in this setting, re-evaluate the patient and the COPD treatment regimen at once; the daily dose of this drug should not be increased Increasing use of inhaled, short-acting beta2-agonists is a signal of deteriorating disease; in this situation, the patient requires immediate reevaluation with reassessment of the treatment regimen, giving special consideration to the need for additional therapeutic options; patients should not use more than 1 inhalation of this drug once daily When beginning treatment, patients who have been taking oral or inhaled, short-acting beta2-agonists on a regular basis (eg, 4 times a day) should be instructed to discontinue regular use of these drugs and to use them only for symptomatic relief of acute respiratory symptoms; when prescribing this drug, the healthcare provider should also prescribe an inhaled, short-acting beta2-agonist and instruct the patient on how it should be used Pregnancy Use during pregnancy only if potential benefit justifies potential risk to fetus; women should be advised to contact their healthcare providers if they become pregnant while receiving therapy; use during late gestation and labor only if the potential benefit justifies potential risks related to beta-agonists interfering with uterine contractility Umeclidinium: No evidence of teratogenic effects shown in rats and rabbits at approximately 50 and 200 times, respectively, the maximum recommended human daily inhaled dose (MRHDID) in adults Vilanterol: No teratogenic effects in rats and rabbits shown at approximately 13,000 and 70 times, respectively, the MRHDID in adults; however, fetal skeletal variations observed, including decreased or absent ossification in cervical vertebral centrum and metacarpal in rabbits at approximately 450 times the MRHDID in adults Labor and delivery Not studied; because beta-agonists may potentially interfere with uterine contractility, therapy should be administered during labor only if potential benefit justifies potential risk Lactation There is no information available on presence of umeclidinium or vilanterol in human milk, effects on breastfed child, or on milk production; umeclidinium was detected in plasma of offspring of lactating rats treated with umeclidinium suggesting its presence in maternal milk; 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 umeclidinium or vilanterol or from the underlying maternal conditionPregnancy 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 Umeclidinium bromide: Long-acting muscarinic antagonist (LAMA), often referred to as an anticholinergic; blocks action of acetylcholine at muscarinic receptors (M1 to M5) in the bronchial airways (M3) by preventing increase in intracellular calcium concentration, leading to relaxation of airway smooth muscle, improved lung function, and decreased mucous secretion; dissociates slowly from M3 muscarinic receptors extending its duration of action Vilanterol: Long-acting selective beta2-adrenergic agonist (LABA); stimulates intracellular adenyl cyclase resulting in increased cAMP levels causing bronchial smooth muscle relaxation; also inhibits release of mediators of immediate hypersensitivity from cells, especially from mast cells Absorption Plasma levels not predictive of therapeutic effect Peak plasma time: 5-15 minutes (umeclidinium/vilanterol) Distribution Following IV administration of each component Protein bound: 89% (umeclidinium); 94% (vilanterol) Vd: 86 L (umeclidinium); 165 L (vilanterol) Metabolism Umeclidinium Primarily metabolized by CYP2D6 and is a substrate for the