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Umeclidinium and Vilanterol


General


Pronunciation

(ue me kli DIN ee um & VYE lan ter ol)


Brand Names: U.S.

  • Anoro Ellipta

Indications


Use: Labeled Indications

Chronic obstructive pulmonary disease: Maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema

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


Contraindications


Hypersensitivity to umeclidinium, vilanterol, or any component of the formulation; severe hypersensitivity to milk proteins


ALERT: U.S. Boxed Warning

Asthma-related death:

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

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


Dosing and Administration


Dosing: Adult

Chronic obstructive pulmonary disease (COPD): Umeclidinium 62.5 mcg/vilanterol 25 mcg: One inhalation once daily; maximum dose: 1 inhalation/day


Dosing: Geriatric

Refer to adult dosing.


Dosing: Renal Impairment

No dosage adjustment necessary.


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).


Administration

Oral inhalation: Administer at the same time each day. After removing from foil tray, write the "Tray Opened " � and "Discard " � dates on the inhaler label. Discard device 6 weeks after it is removed from the foil tray or when the dose counter reads "0 " � (whichever comes first).


Storage

Store between 68 � �F and 77 � �F (20 � �C and 25 � �C); excursions are permitted between 59 � �F and 86 � �F (15 � �C and 30 � �C). Store in a dry place away from direct heat or sunlight. Store inside the original, unopened foil tray; remove from tray immediately prior to initial use. Discard inhaler 6 weeks after opening the foil tray or after the labeled number of inhalations have reached zero, whichever comes first.


Dosage Forms/Strengths


Dosage Forms

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

Aerosol Powder Breath Activated, Inhalation:

Anoro Ellipta: Umeclidinium 62.5 mcg and vilanterol 25 mcg per inhalation (7 dose, 30 dose) [contains milk protein]


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: Umeclidinium may enhance the anticholinergic effect of Anticholinergic Agents. 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

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

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

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

Glycopyrrolate (Oral Inhalation): Anticholinergic Agents may enhance the anticholinergic effect of Glycopyrrolate (Oral Inhalation). 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

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

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

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


Monitoring Parameters

FEV1, peak flow, and/or other pulmonary function tests; blood pressure, heart rate; CNS stimulation; ocular changes


Adverse Reactions


Percentages as reported with combination product.

1% to 10%:

Cardiovascular: Chest pain (1%)

Central Nervous System: Headache ( ≥1%), vertigo ( ≥1%)

Endocrine & Metabolic: Diabetes Mellitus ( ≥1%)

Gastrointestinal: Diarrhea (2%), abdominal pain ( ≥1%), nausea ( ≥1%), toothache ( ≥1%), constipation (1%)

Genitourinary: Urinary Tract Infection ( ≥1%)

Neuromuscular & skeletal: Limb pain (2%), arthralgia ( ≥1%), back pain ( ≥1%), muscle spasm (1%), neck pain (1%)

Respiratory: Pharyngitis (2%), cough ( ≥1%), lower respiratory tract infection ( ≥1%), pleuritic chest pain ( ≥1%), sinusitis ( ≥1%)

<1% (Limited to important or life-threatening): Atrial fibrillation, anxiety, conjunctivitis, dysgeusia, dyspepsia, gastroesophageal reflux disease, hypersensitivity reaction (including anaphylaxis, angioedema, urticaria), musculoskeletal chest pain, myocardial infarction, palpitations, pruritus, skin rash, supraventricular extrasystole, tremor, ventricular premature contractions


Warnings/Precautions


Special Populations: Renal Function Impairment

Vilanterol systemic exposure (AUC(0-24)) was 56% higher in subjects with severe renal impairment (CrCl <30 mL/minute) compared with healthy subjects.


Warnings/Precautions

Concerns related to adverse effects:

- Asthma-related deaths: [US Boxed Warning]: Long-acting beta2-adrenergic agonists (LABAs) such as vilanterol increase the risk of asthma-related death. In a large, randomized, placebo-controlled US clinical trial (Nelson, 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. A similar increase in the risk of death associated with LABAs has not been demonstrated in patients with COPD. Not indicated for treatment of asthma.

- Bronchospasm: Can produce paradoxical bronchospasm, which may be life threatening; discontinue use immediately and institute alternative therapy.

- Hypersensitivity: Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria may occur; discontinue if such reactions occur. Use is contraindicated in patients with severe milk protein allergy.

Disease-related concerns:

- Cardiovascular disease: Use with caution in patients with cardiovascular disease, especially coronary insufficiency, cardiac arrhythmias, and hypertension; beta-agonists may cause elevation in blood pressure, heart rate, and increase risk of arrhythmias; may also cause electrocardiogram (ECG) changes (eg, flattening of the T wave, QTc prolongation, ST segment depression).

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

- Glaucoma: Use with caution in patients with narrow-angle glaucoma; monitor for symptoms of acute narrow-angle glaucoma, including eye pain/discomfort, blurred vision, visual halos, or colored images.

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

- Prostatic hyperplasia/bladder neck obstruction: Umeclidinium may worsen the symptoms of prostatic hyperplasia and/or bladder neck obstruction (eg, painful urination, difficulty passing urine); use with caution.

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

- Thyrotoxicosis: Use with caution in patients with thyrotoxicosis; beta-agonists may exacerbate the condition.

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: Powder for oral inhalation contains lactose; use is contraindicated in patients with severe milk protein allergy.

Other warnings/precautions:

- Appropriate use: Do not use for acute episodes of COPD. Do not initiate in patients with significantly worsening, potentially life-threatening, or acutely deteriorating COPD. Do not exceed the recommended dose. Do not use with other long-acting beta2-agonists; clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.

- Patient information: Patients must be instructed to use short-acting beta2-agonist (eg, albuterol) for acute COPD symptoms and to seek medical attention in cases where acute symptoms are not relieved or a previous level of response is diminished. The need to increase frequency of use of inhaled short-acting beta2-agonist may indicate deterioration of COPD, and medical evaluation to assess treatment regimen must not be delayed.


Pregnancy Risk Factor

C


Pregnancy Considerations

Animal reproduction studies have not been conducted with this combination. Beta-agonists have the potential to affect uterine contractility if administered during labor.


Actions


Pharmacology

Umeclidinium, a long-acting anticholinergic, competitively and reversibly inhibits the action of acetylcholine at type 3 muscarinic (M3) receptors in bronchial smooth muscle causing bronchodilation.

Vilanterol, a long-acting beta2-agonist, relaxes bronchial smooth muscle by selective action on beta2-receptors with little effect on heart rate.


Absorption

Umeclidinium and vilanterol: Systemic, primarily via lungs


Distribution

IV: Umeclidinium: 86 L; Vilanterol: 165 L


Metabolism

Hepatic via CYP2D6 (umeclidinium) and CYP3A4 (vilanterol)


Excretion

Urine (<1% umeclidinium; 70% vilanterol); feces (92% umeclidinium; 30% vilanterol)


Half-Life Elimination

11 hours


Protein Binding

Umeclidinium: 89%; Vilanterol: 94%


Patient and Family Education


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, rhinorrhea, muscle spasms, painful extremities, constipation, diarrhea, or neck 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 anxiety, severe headache, severe dizziness, tremors, severe nausea, vomiting, vision changes, eye pain, severe eye irritation, visual halos around lights, urinary retention, change in amount of urine passed, pain with urination, 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 healthcare 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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