Breo Ellipta: A new fixed-dose inhalation combo for COPD patients

May 10, 2014

FDA approves a powder delivery system combining a corticosteroid and a LABA.

Kevin ChamberlinOverview

Chronic obstructive pulmonary disease (COPD), including chronic bronchitis, emphysema, or both, gained another patient-treatment option in 2013 with the approval of Breo and its delivery device, Ellipta. Breo combines two medications - fluticasone furoate, an inhaled corticosteroid, and vilanterol, a long-acting beta2-adrenergic agonist (LABA).

Approved on May 10, 2013, the fixed-dose inhalation powder composed of fluticasone furoate and vilanterol (FFVI) was a joint collaboration between GlaxoSmithKline and Theravance.

The presence of the LABA prevented an approval of FFVI for use by asthma patients, as LABAs have been associated with an increased risk of death from asthma problems.

Efficacy

Fluticasone furoate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity for inhalation. Vilanterol is a LABA with functional selectivity similar to that of salmeterol. For COPD patients with moderate to severe airflow obstruction, treatment with an inhaled LABA or anticholinergic can provide significant benefits, including the relief of symptoms, improved lung function, a decrease in the yearly number and frequency of exacerbations, and improved quality of life.

Guidelines released by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) suggest that patients with group A defined stable COPD who are not adequately controlled with a single long-acting anticholinergic or beta2-agonist alone or in combination might benefit from using the combination of a long-acting anticholinergic with a LABA. For those with group C or D classification (severe disease and frequent exacerbations), the addition of an inhaled corticosteroid (ICS) is recommended. FDA has not approved ICS monotherapy for COPD management.

Because of the timing of publication and approval of this new agent, the 2014 GOLD guidelines do not specifically list FFVI as a treatment option. However, the clinical studies that earned FDA approval for FFVI are likely to gain inclusion in the GOLD guidelines with the next revision.

Two randomized, double-blind, 24-week clinical trials evaluated lung function in more than 2,200 patients with moderate-to-severe COPD, comparing to placebo various dosing combinations administered through one inhalation daily. The patients were 70% male and 84% Caucasian, having a mean age of 64 and an average smoking history of 44 pack-years (54% of whom reported being active smokers). Serial spirometric evaluations were performed pre-dose and up to 4 hours after dosing.

Both studies showed statistically significant improved lung function via mean forced expiratory volume in one second (FEV1) at both 0-4 hours and 23-24 hours post-dose at day 169. The combination of FFVI was significantly more effective in improving lung function than flucticasone furoate alone, but not more effective than vilanterol alone.

The two year-long, randomized, double-blind studies evaluating exacerbation frequency evaluated more than 3,200 patients with moderate-to-severe COPD exacerbations. Patients were predominantly Caucasian (85%) and male (57%), were a mean age of 64, and had an average smoking history of 46 pack-years (44% of whom reported being active smokers).

All patients were treated with fluticasone propionate/salmeterol 250/50 mcg twice daily during a four-week run-in period prior to randomization to one of the following treatment groups: FFVI 100/25 mcg, FFVI 50/25 mcg, FFVI 200/25 mcg, or vilanterol 25 mcg alone.

Exacerbations in these studies were defined as worsening of two or more major symptoms (dyspnea, sputum volume, sputum purulence) or worsening of any one major symptom together with any one minor symptom (sore throat, cold characterized by nasal discharge and/or congestion, fever without other cause, increased cough or wheeze for at least 2 consecutive days).

COPD exacerbations were defined as moderate in severity if they required treatment with systemic corticosteroids and/or antibiotics, and severe if patients received hospital admission.

In both trials, patients treated with FFVI 100/25 mcg had a lower rate of moderate/severe COPD exacerbations compared to patients treated with vilanterol treatment alone.

 

Safety

FDA approved FFVI with a patient medication guide that includes information about the potential risks of taking the drug and the warning that it should not be used as a rescue therapy to treat sudden breathing problems such as acute bronchospasm.

FFVI is also not recommended for persons younger than 18 years of age. In addition, FFVI is contraindicated for patients with severe hypersensitivity to milk proteins because lactose monohydrate is mixed with each component for inhalation.

The most common adverse reactions (incidence >3%) reported in connection with FFVI are nasopharyngitis (9% vs. 8%, FFVI vs. placebo), upper respiratory tract infection (7% vs. 3%), headache (7% vs. 5%), and oral candidiasis (5% vs. 2%). Given the presence of fluticasone furoate, there is also concern for increased risk of decrease in bone mineral density.

Both fluticasone furoate and vilanterol are substrates of CYP3A4 and P-glycoprotein. Administration with a potent CYP3A4 inhibitor (e.g., ketoconazole) can inhibit the systemic exposure to either or both components of FFVI.

Vilanterol is like other beta2-agonists in that extreme caution should be given to patients who are already receiving or have received within two weeks of FFVI administration agents such as tricyclic antidepressants, MAOIs, or other medications that lengthen the QTc interval and increase the risk of ventricular arrhythmias.

Finally, the co-administration of FFVI with non-potassium-sparing diuretics can worsen hypokalemia and cause EKG changes.

FFVI is labeled pregnancy category C. No human studies have substantially investigated whether either component of FFVI enters breast milk. The manufacturer therefore recommends that caution be exercised if the need to administer FFVI to nursing women arises.

 

Dosing

FFVI is dispensed as a dry-powder inhaler containing two double-foil blister strips of 100 mcg of fluticasone furoate and 25 mcg of vilanterol contained in separate blisters. When the inhaler is activated, both blisters are punctured and the patient inhales their contents simultaneously through the unit’s mouthpiece. The FDA-approved dosage is one oral inhalation, once daily.

Patients should be counseled to close their lips firmly around the curved mouthpiece. Patients should take one long, steady, deep breath through their mouths, being careful not to block the air vent on the mouthpiece with their lips or fingers. Patients should hold their breath after inhaling for three to four seconds, and then exhale slowly and gently. After the inhalation is completed, patients should close the inhaler cover, rinse their mouths with water, and spit it out, to help reduce the risk of oropharyngeal candidiasis.

No dosage adjustment is required for elderly patients, or those with hepatic or renal dysfunction.

Each inhaler unit comes with 30 doses, viable for use for six weeks from the time the original packaging is opened. When the counter shows fewer than 10 doses remaining, the left half of the counter turns red as a reminder that it is time to order a medication refill.

Patients should be instructed that each time the inhaler cover is opened fully, a clicking sound is heard and the dose is ready for inhalation. The number in the dose counter will decrease by one with each opening and clicking sound. If patients open and close the cover without inhaling, the dose is lost for use.

It is not possible to accidentally take a double dose or an extra dose in one inhalation, as any missed doses such as described above are contained within the inhaler and cannot be inhaled or re-exposed to the patient. Empty inhalers may be discarded with ordinary household waste.

References

Breo Ellipta (fluticasone furoate and vilanterol inhalation powder) product information. Research Triangle Park, NC: GlaxoSmithKline; May 2013. Accessed: February 24, 2014.

FDA News Release. “FDA approves Breo Ellipta to treat chronic obstructive pulmonary disease.” http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm351664.htm. Accessed February 25, 2014.

Global Initiative for Chronic Obstructive Lung Disease. “Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease.” Updated 2014.

www.goldcopd.org. Accessed February 25, 2014.

Martinez FJ, et al. Fluticasone furoate/vilanterol (100/25; 200/25 mcg) improves lung function in COPD: a randomized trial. Respir Med. 2013;107:550–559.

Kerwin EM, et al. A randomized trial of fluticasone furoate/vilanterol (50/25 mcg; 100/25 mcg) on lung function in COPD. Respir Med. 2013;107:560–569.

Dransfield MT, et al. Once-daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of exacerbations of COPD: Two replicate double-blind, parallel-group, randomised controlled trials. The Lancet Respiratory Medicine. 2013;1(3):210–223.