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

1-10%

Headache (4%)

Back pain (4%)

Diarrhea (2%)

Dysgeusia (2%)

1-10%

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

Contraindications

Severe hypersensitivity to milk proteins

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

Cautions

Use of long-acting beta2-adrenergic agonists (LABA) as monotherapy (without inhaled corticosteroid [ICS]) for asthma is associated with an 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 subjects with COPD do not suggest an increased risk of death with use of LABA in patients with COPD

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 have occurred in orally inhaled drug products containing fluticasone furoate; when infection occurs, treat with appropriate local/systemic (ie, oral) antifungal therapy; advise the patient to rinse his/her mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis

Lower respiratory tract infections, including pneumonia, have been reported following the inhaled administration of corticosteroids

Patients treated with immunosuppressive drugs are more susceptible to infections than healthy individuals; inhaled corticosteroids (ICSs) should be used with caution 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 paradoxical bronchospasm occurs following treatment, it should be treated immediately with an inhaled, short-acting bronchodilator; discontinue treatment immediately, and alternative therapy should be instituted

Hypersensitivity reactions such as anaphylaxis, angioedema, rash, and urticaria may occur; see Contraindications

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

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

Transferring patients from systemic corticosteroid therapy

• Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to inhaler
• Transfer from systemic corticosteroid therapy to inhaler may unmask allergic conditions previously suppressed by the 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 (e.g., joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function
• During periods of stress or a severe COPD exacerbation, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians

Deterioration of disease and acute episodes

• 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

Pregnancy

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

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

Lactation

There is no information available on presence of drug components in human milk, effects on breastfed child; or on milk production

Umeclidinium is present in rat 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

Fluticasone

• Peak plasma time: 0.5-1 hr
• Bioavailability: 15.2%
• Steady state was achieved within 6 days with up to 2.6-fold accumulation

Umeclidinium

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

Vilanterol

• Peak plasma time: 5-15 minutes
• Steady state was 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: Data suggest that umeclidinium is 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: 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 β1- and β2-agonist activity

Elimination

Half-life: 24 hr (fluticasone); 11 hr (umeclidinium); 11 hr (vilanterol)

Excretion, fluticasone PO: Urine (101%); feces (~1%)

Excretion, umeclidinium PO: Urine (92%); feces (<1%)

Excretion, 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; do not swallow the water

Close inhaler

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