Umeclidinium Bromide And Vilanterol Trifenatate

Q: What is Umeclidinium Bromide And Vilanterol Trifenatate used for?

1 INDICATIONS AND USAGE ANORO ELLIPTA is indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). Limitations of Use ANORO ELLIPTA is NOT indicated for the relief of acute bronchospasm or for the treatment of asthma. The safety and effectiveness of ANORO ELLIPTA in asthma have not been established. ANORO ELLIPTA is a combination of umeclidinium, an anticholinergic, and vilanterol, a long-acting beta 2 -adrenergic agonist (LABA), indicated for the mai

Q: How should I take Umeclidinium Bromide And Vilanterol Trifenatate?

2 DOSAGE AND ADMINISTRATION The recommended dosage of ANORO ELLIPTA for maintenance treatment of COPD is 62.5 mcg umeclidinium and 25 mcg vilanterol (1 actuation of ANORO ELLIPTA 62.5/25 mcg) once daily by oral inhalation. • ANORO ELLIPTA should be used at the same time every day. Do not use ANORO ELLIPTA more than 1 time every 24 hours. • No dosage adjustment is required for geriatric patients, patients with renal impairment, or patients with moderate hepatic impairment [see Clinical Pharmacolo

Q: What should I know before taking Umeclidinium Bromide And Vilanterol Trifenatate?

5 WARNINGS AND PRECAUTIONS • LABA monotherapy (without an inhaled corticosteroid) for asthma increases the risk of serious asthma-related events. ( 5.1 ) • Do not initiate in acutely deteriorating COPD. Do not use to treat acute symptoms. ( 5.2 ) • Do not use in combination with additional therapy containing a LABA because of risk of overdose. ( 5.3 ) • If paradoxical bronchospasm occurs, discontinue ANORO ELLIPTA and institute alternative therapy. ( 5.5 ) • Use with caution in patients with car

Q: Is Umeclidinium Bromide And Vilanterol Trifenatate available over the counter?

Umeclidinium Bromide And Vilanterol Trifenatate is a prescription medication. You will need a valid prescription from a licensed healthcare provider.

Prescription

Nama merek: Anoro Ellipta

Bentuk Sediaan

Inhaler

Rute Pemberian

RESPIRATORY (INHALATION)

Produsen

GlaxoSmithKline LLC

About This Medication

11 DESCRIPTION ANORO ELLIPTA is an inhalation powder drug product for delivery of a combination of umeclidinium (an anticholinergic) and vilanterol (a LABA) to patients by oral inhalation. Umeclidinium bromide has the chemical name 1-[2-(benzyloxy)ethyl]-4-(hydroxydiphenylmethyl)-1-azoniabicyclo[2.2.2]octane bromide and the following chemical structure: Umeclidinium bromide is a white powder with a molecular weight of 508.5, and the empirical formula is C 29 H 34 NO 2 •Br (as a quaternary ammonium bromide compound). It is slightly soluble in water. Vilanterol trifenatate has the chemical name triphenylacetic acid-4-{(1 R )-2-[(6-{2-[(2,6-dicholorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol (1:1) and the following chemical structure: Vilanterol trifenatate is a white powder with a molecular weight of 774.8, and the empirical formula is C 24 H 33 Cl 2 NO 5 •C 20 H 16 O 2 . It is practically insoluble in water. ANORO ELLIPTA is a light grey and red plastic inhaler containing 2 foil blister strips. Each blister on one strip contains a white powder blend of micronized umeclidinium bromide (74.2 mcg equivalent to 62.5 mcg of umeclidinium), magnesium stearate (75 mcg), and lactose monohydrate (to 12.5 mg), and each blister on the other strip contains a white powder blend of micronized vilanterol trifenatate (40 mcg equivalent to 25 mcg of vilanterol), magnesium stearate (125 mcg), and lactose monohydrate (to 12.5 mg). The lactose monohydrate contains milk proteins. After the inhaler is activated, the powder within both blisters is exposed and ready for dispersion into the airstream created by the patient inhaling through the mouthpiece. Under standardized in vitro test conditions, ANORO ELLIPTA delivers 55 mcg of umeclidinium and 22 mcg of vilanterol per dose when tested at a flow rate of 60 L/min for 4 seconds. In adult subjects with obstructive lung disease and severely compromised lung function (COPD with FEV 1 /FVC <70% and FEV 1 <30% predicted or FEV 1 <50% predicted plus chronic respiratory failure), mean peak inspiratory flow through the ELLIPTA inhaler was 66.5 L/min (range: 43.5 to 81.0 L/min). The actual amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow profile. Umeclidinium bromide chemical structure Vilanterol trifenatate chemical structure

Bahan Aktif

Bahan	Kekuatan
Umeclidinium Bromide	-
Vilanterol Trifenatate	-

Indikasi & Penggunaan

1 INDICATIONS AND USAGE ANORO ELLIPTA is indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). Limitations of Use ANORO ELLIPTA is NOT indicated for the relief of acute bronchospasm or for the treatment of asthma. The safety and effectiveness of ANORO ELLIPTA in asthma have not been established. ANORO ELLIPTA is a combination of umeclidinium, an anticholinergic, and vilanterol, a long-acting beta 2 -adrenergic agonist (LABA), indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). ( 1 ) Limitations of Use: Not indicated for relief of acute bronchospasm or for the treatment of asthma. ( 1 , 5.2 )

Cara kerja

12.1 Mechanism of Action ANORO ELLIPTA ANORO ELLIPTA contains both umeclidinium and vilanterol. The mechanisms of action described below for the individual components apply to ANORO ELLIPTA. These drugs represent 2 different classes of medications (an anticholinergic and a LABA) each having different effects on clinical and physiological indices. Umeclidinium Umeclidinium is a long-acting muscarinic antagonist, which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of M3 receptor at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivo studies, prevention of methacholine- and acetylcholine-induced bronchoconstrictive effects was dose-dependent and lasted longer than 24 hours. The clinical relevance of these findings is unknown. The bronchodilation following inhalation of umeclidinium is predominantly a site-specific effect. Vilanterol Vilanterol is a LABA. In vitro tests have shown the functional selectivity of vilanterol was similar to salmeterol. The clinical relevance of this in vitro finding is unknown. Although beta 2 -receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta 1 -receptors are the predominant receptors in the heart, there are also beta 2 -receptors in the human heart comprising 10% to 50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective beta 2 -agonists may have cardiac effects. The pharmacologic effects of beta 2 -adrenergic agonist drugs, including vilanterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3′,5′-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

Dosis & Cara Pemberian

2 DOSAGE AND ADMINISTRATION The recommended dosage of ANORO ELLIPTA for maintenance treatment of COPD is 62.5 mcg umeclidinium and 25 mcg vilanterol (1 actuation of ANORO ELLIPTA 62.5/25 mcg) once daily by oral inhalation. • ANORO ELLIPTA should be used at the same time every day. Do not use ANORO ELLIPTA more than 1 time every 24 hours. • No dosage adjustment is required for geriatric patients, patients with renal impairment, or patients with moderate hepatic impairment [see Clinical Pharmacology ( 12.3 )] . • For oral inhalation only. ( 2 ) • Maintenance treatment of COPD: 1 actuation of ANORO ELLIPTA once daily administered by oral inhalation. ( 2 )

Side Effects Overview

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: • Serious asthma-related events–hospitalizations, intubations, death [see Warnings and Precautions ( 5.1 )] • Paradoxical bronchospasm [see Warnings and Precautions ( 5.5 )] • Cardiovascular effects [see Warnings and Precautions ( 5.7 )] • Worsening of narrow-angle glaucoma [see Warnings and Precautions ( 5.9 )] • Worsening of urinary retention [see Warnings and Precautions ( 5.10 )] Most common adverse reactions (incidence ≥1% and more common than placebo) are pharyngitis, sinusitis, lower respiratory tract infection, constipation, diarrhea, pain in extremity, muscle spasms, neck pain, and chest pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The clinical program for ANORO ELLIPTA included 8,138 subjects with COPD in four 6‑month lung function trials, one 12-month long-term safety study, and 9 other trials of shorter duration. A total of 1,124 subjects have received at least 1 dose of ANORO ELLIPTA (umeclidinium/vilanterol 62.5/25 mcg), and 1,330 subjects have received a higher dose of umeclidinium/vilanterol (125/25 mcg). The safety data described below are based on the four 6-month and one 12-month trials. Adverse reactions observed in the other trials were similar to those observed in the confirmatory trials. 6-Month Trials The incidence of adverse reactions associated with ANORO ELLIPTA in Table 1 is based on four 6-month trials: 2 placebo-controlled trials (Trial 1 and Trial 2); N = 1,532 and N = 1,489, respectively) and 2 active-controlled trials (Trial 3 and Trial 4); N = 843 and N = 869, respectively). Of the 4,733 subjects, 68% were male and 84% were white. They had a mean age of 63 years and an average smoking history of 45 pack-years, with 50% identified as current smokers. At screening, the mean postbronchodilator percent predicted forced expiratory volume in 1 second (FEV 1 ) was 48% (range: 13% to 76%), the mean postbronchodilator FEV 1 /forced vital capacity (FVC) ratio was 0.47 (range: 0.13 to 0.78), and the mean percent reversibility was 14% (range: -45% to 109%). Subjects received 1 dose once daily of the following: ANORO ELLIPTA, umeclidinium/vilanterol 125/25 mcg, umeclidinium 62.5 mcg, umeclidinium 125 mcg, vilanterol 25 mcg, active control, or placebo. Table 1. Adverse Reactions with ANORO ELLIPTA with ≥1% Incidence and More Common than Placebo in Subjects with Chronic Obstructive Pulmonary Disease Adverse Reaction ANORO ELLIPTA (n = 842) % Umeclidinium 62.5 mcg (n = 418) % Vilanterol 25 mcg (n = 1,034) % Placebo (n = 555) % Infections and infestations Pharyngitis 2 1 2 <1 Sinusitis 1 <1 1 <1 Lower respiratory tract infection 1 <1 <1 <1 Gastrointestinal disorders Constipation 1 <1 <1 <1 Diarrhea 2 <1 2 1 Musculoskeletal and connective tissue disorders Pain in extremity 2 <1 2 1 Muscle spasms 1 <1 <1 <1 Neck pain 1 <1 <1 <1 General disorders and administration site conditions Chest pain 1 <1 <1 <1 Other adverse reactions with ANORO ELLIPTA observed with an incidence <1% but more common than placebo included the following: productive cough, dry mouth, dyspepsia, abdominal pain, gastroesophageal reflux disease, vomiting, musculoskeletal chest pain, chest discomfort, asthenia, atrial fibrillation, ventricular extrasystoles, supraventricular extrasystoles, myocardial infarction, pruritus, rash, and conjunctivitis. 12-Month Trial In a long-term safety trial (Trial 5), 335 subjects were treated for up to 12 months with umeclidinium/vilanterol 125/25 mcg or placebo. The demographic and baseline characteristics of the long-term safety trial were similar to those of the placebo-controlled efficacy trials described above. Adverse reactions observed with a frequency of ≥1% in the group receiving umeclidinium/vilanterol 125/25 mcg that exceeded that in placebo in this trial were: headache, back pain, sinusitis, cough, urinary tract infection, arthralgia, nausea, vertigo, abdominal pain, pleuritic pain, viral respiratory tract infection, toothache, and diabetes mellitus. 6.2 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postapproval use of ANORO ELLIPTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to ANORO ELLIPTA or a combination of these factors. Cardiac Disorders Palpitations. Eye Disorders Blurred vision, eye pain, glaucoma, increased intraocular pressure. Immune System Disorders Hypersensitivity reactions, including anaphylaxis, angioedema, and urticaria. Nervous System Disorders Dysgeusia, tremor. Psychiatric Disorders Anxiety. Renal and Urinary Disorders Dysuria, urinary retention. Respiratory, Thoracic, and Mediastinal Disorders Dysphonia, paradoxical bronchospasm.

Peringatan & Tindakan Pencegahan

5 WARNINGS AND PRECAUTIONS • LABA monotherapy (without an inhaled corticosteroid) for asthma increases the risk of serious asthma-related events. ( 5.1 ) • Do not initiate in acutely deteriorating COPD. Do not use to treat acute symptoms. ( 5.2 ) • Do not use in combination with additional therapy containing a LABA because of risk of overdose. ( 5.3 ) • If paradoxical bronchospasm occurs, discontinue ANORO ELLIPTA and institute alternative therapy. ( 5.5 ) • Use with caution in patients with cardiovascular disorders because of beta-adrenergic stimulation. ( 5.7 ) • Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. ( 5.8 ) • Worsening of narrow-angle glaucoma may occur. Use with caution in patients with narrow-angle glaucoma and instruct patients to contact a healthcare provider immediately if symptoms occur. ( 5.9 ) • Worsening of urinary retention may occur. Use with caution in patients with prostatic hyperplasia or bladder-neck obstruction and instruct patients to contact a healthcare provider immediately if symptoms occur. ( 5.10 ) • Be alert to hypokalemia and hyperglycemia. ( 5.11 ) 5.1 Serious Asthma-Related Events – Hospitalizations, Intubations, Death The safety and effectiveness of ANORO ELLIPTA in patients with asthma have not been established. ANORO ELLIPTA is not indicated for the treatment of asthma [see Contraindications ( 4 )] . Use of LABA as monotherapy (without ICS) for asthma is associated with an increased risk of asthma-related death. Available data from controlled clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric and adolescent patients. These findings are considered a class effect of LABA monotherapy. When LABA are used in fixed-dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared with ICS alone. Salmeterol Multicenter Asthma Research Trial (SMART) A 28-week, placebo-controlled, US trial that compared the safety of another LABA (salmeterol) with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol (13/13,176 in subjects treated with salmeterol vs. 3/13,179 in subjects treated with placebo; relative risk: 4.37 [95% CI: 1.25, 15.34]). The increased risk of asthma-related death is considered a class effect of LABAs, including vilanterol, one of the active ingredients in ANORO ELLIPTA. No trial adequate to determine whether the rate of asthma-related death is increased in subjects treated with ANORO ELLIPTA has been conducted. Available data do not suggest an increased risk of death with use of LABA in patients with COPD. 5.2 Deterioration of Disease and Acute Episodes ANORO ELLIPTA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD. ANORO ELLIPTA has not been studied in subjects with acutely deteriorating COPD. The initiation of ANORO ELLIPTA in this setting is not appropriate. If ANORO ELLIPTA no longer controls symptoms of bronchoconstriction; the patient’s inhaled, short-acting beta 2 -agonist becomes less effective; or the patient needs more short-acting beta 2 -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 ANORO ELLIPTA should not be increased. Increasing use of inhaled, short-acting beta 2 -agonists is a signal of deteriorating disease. In this situation, the patient requires immediate re-evaluation 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 ANORO ELLIPTA once daily. ANORO ELLIPTA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. ANORO ELLIPTA has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta 2 -agonist. When beginning treatment with ANORO ELLIPTA, patients who have been taking oral or inhaled, short-acting beta 2 -agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs and to use them only for symptomatic relief of acute respiratory symptoms. When prescribing ANORO ELLIPTA, the healthcare provider should also prescribe an inhaled, short-acting beta 2 -agonist and instruct the patient on how it should be used. 5.3 Avoid Excessive Use of ANORO ELLIPTA and Avoid Use with Other Long-acting Beta 2 -agonists ANORO ELLIPTA should not be used more often than recommended, at higher doses than recommended, or in conjunction with other therapies containing LABAs, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using ANORO ELLIPTA should not use another therapy containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason. 5.4 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors Caution should be exercised when considering the coadministration of ANORO ELLIPTA with ketoconazole and other known strong cytochrome P450 3A4 (CYP3A4) inhibitors (including, but not limited to, ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased cardiovascular adverse effects may occur [see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )] . 5.5 Paradoxical Bronchospasm As with other inhaled therapies, ANORO ELLIPTA can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with ANORO ELLIPTA, it should be treated immediately with an inhaled, short-acting bronchodilator; ANORO ELLIPTA should be discontinued immediately; and alternative therapy should be instituted. 5.6 Hypersensitivity Reactions, including Anaphylaxis Hypersensitivity reactions such as anaphylaxis, angioedema, rash, and urticaria may occur after administration of ANORO ELLIPTA. Discontinue ANORO ELLIPTA if such reactions occur. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of other powder medications containing lactose; therefore, patients with severe milk protein allergy should not use ANORO ELLIPTA [see Contraindications ( 4 ), Adverse Reactions (6.2)] . 5.7 Cardiovascular Effects Vilanterol, like other beta 2 -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, ANORO ELLIPTA 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 [see Clinical Pharmacology (12.2)] . Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. ANORO ELLIPTA, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. In a 52-week trial of subjects with COPD, the exposure-adjusted rates for any on-treatment major adverse cardiac event, including non-fatal central nervous system hemorrhages and cerebrovascular conditions, non-fatal myocardial infarction, non-fatal acute myocardial infarction, and adjudicated on-treatment death due to cardiovascular events, was 2.2 per 100 patient-years for fluticasone furoate/umeclidinium/vilanterol 100/62.5/25 mcg (n = 4,151), 1.9 per 100 patient-years for fluticasone furoate/vilanterol 100/25 mcg (n = 4,134), and 2.2 per 100 patient-years for ANORO ELLIPTA (n = 2,070). Adjudicated on‑treatment deaths due to cardiovascular events occurred in 20 of 4,151 patients (0.54 per 100 patient-years) receiving fluticasone furoate/umeclidinium/vilanterol, 27 of 4,134 patients (0.78 per 100 patient-years) receiving fluticasone furoate/vilanterol, and 16 of 2,070 patients (0.94 per 100 patient-years) receiving ANORO ELLIPTA. 5.8 Coexisting Conditions ANORO ELLIPTA, like all therapies containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta 2 -adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. 5.9 Worsening of Narrow-Angle Glaucoma ANORO ELLIPTA should be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should also be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos, or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a healthcare provider immediately if any of these signs or symptoms develop. 5.10 Worsening of Urinary Retention ANORO ELLIPTA, like all therapies containing an anticholinergic, should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of urinary retention (e.g., 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 . 5.11 Hypokalemia and Hyperglycemia Beta-adrenergic agonist therapies may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. Beta-agonist therapies may produce transient hyperglycemia in some patients. In 4 clinical trials of 6-month duration evaluating ANORO ELLIPTA in subjects with COPD, there was no evidence of a treatment effect on serum glucose or potassium.

Kontraindikasi

4 CONTRAINDICATIONS ANORO ELLIPTA is contraindicated in: • patients with severe hypersensitivity to milk proteins or who have demonstrated hypersensitivity to umeclidinium, vilanterol, or any of the excipients [see Warnings and Precautions (5.6), Description (11)] . • use of a long-acting beta 2 -adrenergic agonist (LABA), including vilanterol, one of the active ingredients in ANORO ELLIPTA, without an inhaled corticosteroid (ICS), in patients with asthma [see Warnings and Precautions (5.1)] . ANORO ELLIPTA is not indicated for the treatment of asthma. • Severe hypersensitivity to milk proteins or any ingredients. ( 4 ) • Use of a LABA, including ANORO ELLIPTA, without an inhaled corticosteroid is contraindicated in patients with asthma. ( 4 )

Farmakokinetik

12.3 Pharmacokinetics Linear pharmacokinetics was observed for umeclidinium (62.5 to 500 mcg) and vilanterol (25 to 100 mcg). Absorption Umeclidinium: Umeclidinium plasma levels may not predict therapeutic effect. Following inhaled administration of umeclidinium in healthy subjects, C max occurred at 5 to 15 minutes. Umeclidinium is mostly absorbed from the lung after inhaled doses with minimum contribution from oral absorption. Following repeat dosing of inhaled ANORO ELLIPTA, steady state was achieved within 14 days with up to 1.8-fold accumulation. Vilanterol: Vilanterol plasma levels may not predict therapeutic effect. Following inhaled administration of vilanterol in healthy subjects, C max occurred at 5 to 15 minutes. Vilanterol is mostly absorbed from the lung after inhaled doses with negligible contribution from oral absorption. Following repeat dosing of inhaled ANORO ELLIPTA, steady state was achieved within 14 days with up to 1.7-fold accumulation. Distribution Umeclidinium: Following intravenous administration to healthy subjects, the mean volume of distribution was 86 L. In vitro plasma protein binding in human plasma was on average 89%. Vilanterol: Following intravenous administration to healthy subjects, the mean volume of distribution at steady state was 165 L. In vitro plasma protein binding in human plasma was on average 94%. Elimination Metabolism: Umeclidinium: In vitro data showed that umeclidinium is primarily metabolized by the enzyme cytochrome P450 2D6 (CYP2D6) and is a substrate for the P-glycoprotein (P-gp) transporter. The primary metabolic routes for umeclidinium are oxidative (hydroxylation, O-dealkylation) followed by conjugation (e.g., glucuronidation), resulting in a range of metabolites with either reduced pharmacological activity or for which the pharmacological activity has not been established. Systemic exposure to the metabolites is low. Vilanterol: In vitro data showed that vilanterol is metabolized principally by CYP3A4 and is a substrate for the P-gp transporter. Vilanterol is metabolized to a range of metabolites with significantly reduced β 1 - and β 2 -agonist activity. Excretion: Umeclidinium: The effective half-life after once-daily oral dosing is 11 hours. Following intravenous dosing with radiolabeled umeclidinium, mass balance showed 58% of the radiolabel in the feces and 22% in the urine. The excretion of the drug-related material in the feces following intravenous dosing indicated elimination in the bile. Following oral dosing to healthy male subjects, radiolabel recovered in feces was 92% of the total dose and that in urine was <1% of the total dose, suggesting negligible oral absorption. Vilanterol: The effective half-life for vilanterol, as determined from inhalation administration of multiple doses, is 11 hours. Following oral administration of radiolabeled vilanterol, mass balance showed 70% of the radiolabel in the urine and 30% in the feces. Specific Populations The effects of renal and hepatic impairment and other intrinsic factors on the pharmacokinetics of umeclidinium and vilanterol are shown in Figure 1. Population pharmacokinetic analysis showed no evidence of a clinically significant effect of age (40 to 93 years) (Figure 1), gender (69% male) (Figure 1), inhaled corticosteroid use (48%), or weight (34 to 161 kg) on systemic exposure of either umeclidinium or vilanterol. In addition, there was no evidence of a clinically significant effect of race. Figure 1. Impact of Intrinsic Factors on the Pharmacokinetics (PK) of Umeclidinium (UMEC) and Vilanterol (VI) Patients with Hepatic Impairment: The impact of hepatic impairment on the pharmacokinetics of ANORO ELLIPTA has been evaluated in subjects with moderate hepatic impairment (Child-Pugh score of 7-9). There was no evidence of an increase in systemic exposure to either umeclidinium or vilanterol (C max and AUC) (Figure 1). There was no evidence of altered protein binding in subjects with moderate hepatic impairment compared with healthy subjects. ANORO ELLIPTA has not been evaluated in subjects with severe hepatic impairment. Patients with Renal Impairment: The pharmacokinetics of ANORO ELLIPTA has been evaluated in subjects with severe renal impairment (CrCl <30 mL/min). Umeclidinium systemic exposure was not increased and vilanterol systemic exposure (AUC (0-24) ) was 56% higher in subjects with severe renal impairment compared with healthy subjects (Figure 1). There was no evidence of altered protein binding in subjects with severe renal impairment compared with healthy subjects. Drug Interaction Studies When umeclidinium and vilanterol were administered in combination by the inhaled route, the pharmacokinetic parameters for each component were similar to those observed when each active substance was administered separately. Inhibitors of Cytochrome P450 3A4: Vilanterol is a substrate of CYP3A4. A double-blind, repeat-dose, 2-way crossover drug interaction trial was conducted in healthy subjects to investigate the pharmacokinetic and pharmacodynamic effects of vilanterol 25 mcg as an inhalation powder with ketoconazole 400 mg. The plasma concentrations of vilanterol were higher after single and repeated doses when coadministered with ketoconazole than with placebo (Figure 2). The increase in vilanterol exposure was not associated with an increase in beta-agonist–related systemic effects on heart rate or blood potassium. Inhibitors of Cytochrome P450 2D6: In vitro metabolism of umeclidinium is mediated primarily by CYP2D6. However, no clinically meaningful difference in systemic exposure to umeclidinium (500 mcg) (8 times the approved dose) was observed following repeat daily inhaled dosing in CYP2D6 normal (ultrarapid, extensive, and intermediate metabolizers) and poor metabolizer subjects (Figure 1). Inhibitors of P-glycoprotein: Umeclidinium and vilanterol are both substrates of P-gp. The effect of the moderate P-gp transporter inhibitor verapamil (240 mg once daily) on the steady-state pharmacokinetics of umeclidinium and vilanterol was assessed in healthy subjects. No effect on umeclidinium or vilanterol C max was observed; however, an approximately 1.4-fold increase in umeclidinium AUC was observed with no effect on vilanterol AUC (Figure 2). Figure 2. Impact of Extrinsic Factors on the Pharmacokinetics (PK) of Umeclidinium (UMEC) and Vilanterol (VI) Figure 1. Impact of Intrinsic Factors on the Pharmacokinetics (PK) of Umeclidinium (UMEC) and Vilanterol (VI) Figure 2. Impact of Extrinsic Factors on the Pharmacokinetics (PK) of Umeclidinium (UMEC) and Vilanterol (VI)

Frequently Asked Questions

1 INDICATIONS AND USAGE ANORO ELLIPTA is indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). Limitations of Use ANORO ELLIPTA is NOT indicated for the relief of acute bronchospasm or for the treatment of asthma. The safety and effectiveness of ANORO ELLIPTA in asthma have not been established. ANORO ELLIPTA is a combination of umeclidinium, an anticholinergic, and vilanterol, a long-acting beta 2 -adrenergic agonist (LABA), indicated for the maintenance treatment of patients with chronic …

2 DOSAGE AND ADMINISTRATION The recommended dosage of ANORO ELLIPTA for maintenance treatment of COPD is 62.5 mcg umeclidinium and 25 mcg vilanterol (1 actuation of ANORO ELLIPTA 62.5/25 mcg) once daily by oral inhalation. • ANORO ELLIPTA should be used at the same time every day. Do not use ANORO ELLIPTA more than 1 time every 24 hours. • No dosage adjustment is required for geriatric patients, patients with renal impairment, or patients with moderate hepatic impairment [see Clinical …

5 WARNINGS AND PRECAUTIONS • LABA monotherapy (without an inhaled corticosteroid) for asthma increases the risk of serious asthma-related events. ( 5.1 ) • Do not initiate in acutely deteriorating COPD. Do not use to treat acute symptoms. ( 5.2 ) • Do not use in combination with additional therapy containing a LABA because of risk of overdose. ( 5.3 ) • If paradoxical bronchospasm occurs, discontinue ANORO ELLIPTA and institute alternative therapy. ( 5.5 ) • Use with caution …

4 CONTRAINDICATIONS ANORO ELLIPTA is contraindicated in: • patients with severe hypersensitivity to milk proteins or who have demonstrated hypersensitivity to umeclidinium, vilanterol, or any of the excipients [see Warnings and Precautions (5.6), Description (11)] . • use of a long-acting beta 2 -adrenergic agonist (LABA), including vilanterol, one of the active ingredients in ANORO ELLIPTA, without an inhaled corticosteroid (ICS), in patients with asthma [see Warnings and Precautions (5.1)] . ANORO ELLIPTA is not indicated for the treatment of …

Umeclidinium Bromide And Vilanterol Trifenatate is a prescription medication. You will need a valid prescription from a licensed healthcare provider.

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References & Data Sources

• DailyMed — Umeclidinium Bromide And Vilanterol Trifenatate drug label (National Library of Medicine)
• openFDA — Umeclidinium Bromide And Vilanterol Trifenatate label data (U.S. Food & Drug Administration)
• RxNorm — RXCUI 1487519 (NLM Normalized Drug Names)
• NDC Directory — Umeclidinium Bromide And Vilanterol Trifenatate (FDA National Drug Code)

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Sumber data: DailyMed (NLM), openFDA, MFDS