umeclidinium bromide/vilanterol inhaled/fluticasone furoate inhaled (Rx)

>10% (Asthma)

Pharyngitis/nasopharyngitis (15-17%)

1-10% (COPD)

Headache (4%)

Back pain (4%)

Diarrhea (2%)

Dysgeusia (2%)

Cough (1%)

Oropharyngeal pain (1%)

Gastroenteritis (1%)

≥1%

• Upper respiratory tract infection
• Pneumonia
• Bronchitis
• Oral candidiasis
• Arthralgia
• Influenza
• Sinusitis
• Pharyngitis
• Rhinitis
• Constipation
• Urinary tract infection
• Dysphonia

1-10% (Asthma)

Headache (5-9%)

Upper respiratory tract infection (5-7%)

Bronchitis (4-5%)

Respiratory tract infection (3-4%)

Influenza (1-4%)

Sinusitis (2-3%)

Back pain (2-3%)

Rhinitis (1-2%)

Urinary tract infection (<1 to 2%)

Dysphonia (1%)

Oropharyngeal pain (1%)

Pneumonia (<1 to 1%)

Cough (<1 to 1%)

Postmarketing Reports

Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria

Contraindications

Severe hypersensitivity to milk proteins

Hypersensitivity to fluticasone furoate, umeclidinium, vilanterol, or any of the excipients

Primary treatment of status asthmaticus or other acute episodes of COPD or asthma where intensive measures are required

Cautions

Use of long-acting beta2-adrenergic agonists (LABA) as monotherapy (without inhaled corticosteroid [ICS]) for asthma associated with increased risk of asthma-related death; data from controlled clinical trials suggest that LABA monotherapy increases risk of asthma-related hospitalization in pediatric and adolescent patients; available data from clinical trials in patients with COPD do not suggest an increased risk of death with use of LABA in patients with COPD; additionally, LABAs used in fixed-dose combination with ICS, data from large clinical trials do not show significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared with ICS alone

Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs; avoid using higher doses than recommended, or in conjunction with other medicines containing LABAs

Localized infections of the mouth and pharynx with Candida albicans reported with orally inhaled corticosteroids; when infection occurs, treat with appropriate local/systemic (ie, oral) antifungal therapy; advise the patient to rinse mouth with water without swallowing following inhalation to reduce oropharyngeal candidiasis risk

Lower respiratory tract infections, including pneumonia, reported following administration inhaled corticosteroids

Caution with ICSs in patients with active or quiescent tuberculosis infections of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex

Life-threatening paradoxical bronchospasm may occur; if this occurs, treat immediately with inhaled, short-acting bronchodilator; discontinue treatment immediately and institute alternant therapy

Hypersensitivity reactions (eg, anaphylaxis, angioedema, rash, urticaria) may occur

Use caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension; consider discontinuing therapy if such effects occur

Assess bone mineral density (BMD) prior to initiating therapy and periodically thereafter; decreases in BMD have been observed with long-term administration of products containing ICS; if significant reductions in BMD are seen and therapy is still necessary, use of medicine to treat or prevent osteoporosis should be strongly considered

Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with COPD following long-term administration of ICS or with use of inhaled anticholinergics; closely monitor patients with vision changes or with a history of increased intraocular pressure, narrow- or open-angle glaucoma, and/or cataracts

Use caution in patients with urinary retention; monitor for signs and symptoms of urinary retention (eg, difficulty passing urine, painful urination), especially in patients with prostatic hyperplasia or bladder-neck obstruction; patients should consult healthcare provider if signs or symptoms develop

Beta-adrenergic agonist medicines may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has potential to produce adverse cardiovascular effect; the decrease is usually transient, not requiring supplementation

Because of possibility of significant systemic absorption of ICS in sensitive patients, patients should be observed carefully for any evidence of systemic corticosteroid effects; important to observe patients postoperatively or during periods of stress for evidence of inadequate adrenal response; implement appropriate therapy as necessary

Hypercorticism and adrenal suppression (including adrenal crisis) may appear in small number of patients who are sensitive; if such effects occur, reduce dose of drug slowly, consistent with accepted procedures for reducing systemic corticosteroids, and consider other treatments for management of COPD or asthma symptoms

Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to children and adolescents

Transferring patients from systemic corticosteroid therapy

• During withdrawal from oral corticosteroids, some patients may experience symptoms
• During periods of stress, a severe COPD exacerbation, or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their health care practitioner for further instruction
• These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress, a severe COPD exacerbation, or a severe asthma attack
• Lung function (FEV1), beta-agonist use, and COPD or asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids
• Transfer of patients from systemic corticosteroid therapy to inhaler therapy may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy

Deterioration of disease and acute episodes

• If 100/62.5/25 mcg dose no longer controls symptoms of bronchoconstriction; patient’s inhaled, short-acting beta2-agonist becomes less effective; or the patient needs shorter-more acting beta2-agonist than usual, these may be markers of deterioration of disease; for COPD, the daily 100/62.5/25 mcg dose should not be increased

• If therapy no longer controls symptoms of bronchoconstriction, COPD may deteriorate acutely over a period of hours or chronically over several days or longer; in this setting reevaluation of patient’s COPD should be undertaken at once; increasing daily dose beyond recommended dose is not appropriate in this situation
• Avoid initiating treatment during rapidly deteriorating or potentially life-threatening episodes of COPD; therapy in patients with acutely deteriorating COPD has not been studied
• Acute symptoms should be treated with an inhaled, short-acting beta2-agonist; avoid using formulation for the relief of acute symptoms (ie, as rescue therapy for the treatment of acute episodes of bronchospasm)
• When initiating treatment, patients who have been taking oral or inhaled, short-acting beta2-agonists on a regular basis (eg, QID) should discontinue the regular use of these drugs and use them only for symptomatic relief of acute respiratory symptoms

Drug interactions overview

• Electrocardiographic changes and/or hypokalemia that may result from the administration of non–potassium-sparing diuretics (eg, loop/thiazide diuretics) can be acutely worsened by beta-agonists, especially when exceeding the recommended dose of the beta-agonist
• Avoid coadministration with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects
• Use extreme caution in patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTc interval or within 2 weeks of discontinuation of such agents, because the effect of adrenergic agonists on the cardiovascular system may be potentiated by these agent

• Strong CYP3A4 inhibitors

  • Exceeding recommended dosage or coadministration with a strong cytochrome P450 3A4 (CYP3A4) inhibitor may result in HPA dysfunction
  • Caution when considering coadministration with long-term ketoconazole and other known strong CYP3A4 inhibitors (eg, ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, voriconazole) because increased systemic corticosteroid and increased cardiovascular adverse effects may occur

Pregnancy

There are insufficient data in pregnant women to inform a drug-associated risk

In women with poorly or moderately controlled asthma, there is increased risk of several perinatal outcomes such as pre-eclampsia in the mother and prematurity, low birth weight, and small for gestational age in neonate

pregnant women should be closely monitored and medication adjusted as necessary to maintain optimal control of asthma

May be used during late gestation and labor only if the potential benefit justifies the potential for risks related to beta-agonists interfering with uterine contractility

Animal data

• Umeclidinium administered via inhalation or subcutaneously to pregnant rats and rabbits not associated with adverse effect on embryofetal development at exposures approximately 40 and 150 times, respectively, the human exposure at the maximum recommended human daily inhalation doses (MRHDID)

Lactation

There is no information available on presence of fluticasone furoate, umeclidinium, or vilanterol in human milk; effects on breastfed child; or s on milk production

Umeclidinium was detected in plasma of offspring of lactating rats treated with umeclidinium, suggesting its presence in maternal milk

Consider developmental and health benefits of breastfeeding along with mother’s clinical need for treatment and any potential adverse effects on the breastfed child from fluticasone furoate, umeclidinium, or vilanterol or from the underlying maternal condition

Pregnancy 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

Fluticasone: Anti-inflammatory corticosteroid; exact mechanism of action is unknown, but agent has been shown to exhibit anti-inflammatory effect on neutrophils, eosinophils, macrophages, mast cells, lymphocytes, and mediators (histamine, leukotrienes, cytokines, eicosanoids)

Absorption

Peak plasma time: 0.5-1 hr (fluticasone); 5-15 minutes (umeclidinium, vilanterol)

Steady state: Achieved within 6 days with up to 2.6-fold (fluticasone), 1.8-fold (umeclidinium), 1.7-fold (vilanterol) accumulation

Umeclidinium

• Peak plasma time: 5-15 minutes
• Steady state: Achieved within 14 days with up to 1.8-fold accumulation

Vilanterol

• Peak plasma time: 5-15 minutes
• Steady state: Achieved within 14 days with up to 1.7-fold accumulation

Distribution

Vd: 661 L (fluticasone); 86 L (umeclidinium); 165 L (vilanterol, steady state)

Protein binding: >99% (fluticasone); 89% (umeclidinium); 94% (vilanterol, steady state)

Metabolism

Fluticasone furoate: Hepatically metabolized via CYP3A4 to metabolites with significantly reduced corticosteroid activity

Umeclidinium: Primarily metabolized by CYP2D6 enzyme and is a substrate for the P-glycoprotein (P-gp) transporter; primary metabolic routes for umeclidinium are oxidative (hydroxylation, O-dealkylation) followed by conjugation (eg, glucuronidation)

Vilanterol: Metabolized principally by CYP3A4; P-gp transporter substrate; metabolized to range of metabolites with significantly reduced β1- and β2-agonist activity

Elimination

Half-life

Fluticasone: 24 hr

Umeclidinium: 11 hr

Vilanterol: 11 hr

Excretion

• Fluticasone PO: Urine (101%); feces (~1%)
• Umeclidinium PO: Urine (92%); feces (<1%)
• Vilanterol PO: Urine (70%); feces (30%)

Oral Inhalation Preparation

Inhaler contains 30 doses (14 doses if you have a sample or institutional pack)

Do not open the cover of inhaler until ready to use it

Oral Inhalation Administration

Breathe out, inhale medicine

Do not breathe in through the nose

Do not block the air vent with fingers

Remove the inhaler from mouth and hold breath for about 3-4 seconds

Breathe out slowly and gently

Rinse mouth with water after using inhaler and spit the water out to reduce risk of oropharyngeal candidiasis; do not swallow the water

Close inhaler

Administer at the same time each day; do not use more than once/24 hr

Transferring patients from systemic corticosteroid therapy

• Wean slowly from systemic corticosteroid use after transferring to inhaler
• Transfer from systemic corticosteroids to inhaler may unmask allergic conditions previously suppressed by systemic corticosteroid therapy (eg, rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions)
• During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal (eg, joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function
• During periods of stress or a severe COPD exacerbation, instruct patients who have been withdrawn from systemic corticosteroids to resume oral corticosteroids (in large doses) immediately and to contact their physicians

Missed dose

• Missed dose: Take as soon as possible; do not take more than 1 inhalation/day
• Take next dose at the same time; do not take 2 doses at 1 time

Storage

Store at room temperature between 68-77°F (20-25°C); excursions permitted from 59-86°F (15-30°C)

Store in a dry place away from direct heat or sunlight

Keep out of reach of children

Store inside the unopened moisture-protective foil tray and only remove from the tray immediately before initial use

Discard 6 weeks from the date tray was opened