New Inhaled Formulations for the Treatment of Asthma in Children and Adolescents

Kelly Jane Lunsford, PharmD

Disclosures

Pediatr Pharm. 2015;21(12) 

In This Article

New Drug Products

Fluticasone Furoate

On August 20, 2014, fluticasone furoate inhalation powder (Arnuity™ Ellipta®) was approved by the Food and Drug Administration (FDA) as maintenance treatment of asthma in patients aged 12 years and older. Fluticasone furoate is an inhaled corticosteroid (ICS) that is administered once daily and is available in 100 mcg and 200 mcg strengths.[3]

The starting dosage for fluticasone furoate is based upon patients' asthma severity with patients who are have not previously been on an ICS starting at 100 mcg once daily. For patients who do not respond to the 100 mcg dose after two weeks of therapy, the dose should be increased to 200 mcg once daily (the highest recommended daily dose). Maximum benefit may not be achieved for up to two weeks or longer after starting treatment.[4] Administration of fluticasone furoate requires the patient to fully open the cover of the inhaler and inhale deeply through the mouthpiece. One potential downside of this formulation is that opening and closing the cover (without inhaling the medication) will result in a lost dose that is unable to be recovered.

Approval was based on four confirmatory clinical trials in subjects with asthma aged 12 years and older. These trials evaluated the efficacy and safety of fluticasone furoate, given once daily in the evening, on lung function in subjects who had a diagnosis of asthma for ≥ 12 weeks, were maintained on a stable ICS dose for ≥ 4 weeks, had a pre-bronchodilator FEV1 of 40–90% (adjusted for ethnicity), and evening reversibility of ≥ 12% and ≥ 200 mL following albuterol/salbutamol inhalation. This last requirement presents a problem of selection bias given that patients with a positive bronchodilator response will very likely show improvement in FEV1 in such studies. In trials with placebo arms, the treatment groups did not show significant improvements in asthma control and quality of life measures as compared with placebo.

The first trial evaluated fluticasone furoate (FF) 100 mcg once daily over 24 weeks versus placebo in patients.[5] Fluticasone propionate (FP) 250 mcg was included as an active control. Three hundred forty-three subjects were randomized 1:1:1 to FF 100 mcg once-daily, placebo once-daily, or FP 250 mcg twice-daily. The primary endpoint was change from baseline in pre-dose evening FEV1 at week 24. Both FF 100 mcg and FP 250 mcg significantly improved pre-dose evening FEV1 compared to placebo at week 24 [146 mL (p = 0.009) and 145 mL (p = 0.011), respectively].

The second trial evaluated the combination of fluticasone furoate and vilanterol 100–25 mcg (FF/VI) and FF 100 mcg compared with placebo in 609 patients over a 12 week period.[6] Coprimary endpoints were change from baseline in trough FEV1 and serial (0–24 hours) weighted mean FEV1 (wmFEV1). FF/VI significantly improved trough FEV1 (+172 mL; p < 0.001) and serial wmFEV1 (+302 mL; p < 0.001) compared to placebo. FF alone also significantly improved trough FEV1 (+136 mL; p = 0.002) and serial wmFEV1 (+186 mL; p = 0.003). Improvement in FEV1 with the addition of VI to FF was not found to be significant.

In the third trial, 239 subjects were stratified by baseline FEV1 and randomized 1:1 to treatment with FF 100 mcg or 200 mcg once daily in the evening.[7] The primary endpoint was change from baseline trough FEV1 after 24 weeks. The least squares mean trough FEV1 improved from baseline by 208 mL with FF 100 mcg and 284 mL with FF 200 mcg at week 24. A numerically greater increase was observed with FF 200 mcg (77 mL; 95% CI: -39 to 192).

In the fourth trial, 586 subjects were randomized to either FF/VI 200–25 mcg, FF 200 mcg, or FP 500 mcg.[8] Co-primary endpoints were change from baseline trough FEV1 and serial (0–24 hour) wmFEV1. FF/VI significantly improved both trough FEV1 and wmFEV1 as compared to FF and FP (193 mL and 210 mL respectively; p < 0.001 for both). Adverse effects seen in clinical trials include nasopharyngitis, headache, bronchitis, influenza, upper respiratory tract infection, sinusitis, oropharyngeal pain, and pharyngitis.

Fluticasone Furoate and Vilanterol

On April 30, 2015, the FDA approved fluticasone furoate/vilanterol (Breo® Ellipta®) for the once-daily treatment of asthma in patients aged 18 years and older. GlaxoSmithKline originally submitted for approval in patients aged 12 years of age and older. The FDA issued a response letter related to the proposed use in patients aged 12 to 17 years, stating that the data submitted did not show adequate risk-benefit to support approval in this patient population. The FDA stated that additional data would be required to further demonstrate the safety and efficacy for these patients.[9] Despite the lack of FDA approval, FF/VI appears to be welltolerated in this patient population.

The efficacy and safety of fluticasone furoate and vilanterol (FF/VI) was evaluated in several studies involving subjects 12 years of age and older.[10] One such study evaluated the addition of VI to once-daily FF on the risk of severe asthma exacerbations in patients with uncontrolled asthma. In this study, 2019 subjects aged 12 years and older with asthma and at least one documented exacerbation were randomized to FF/VI 100/25 mcg or FF 100 mcg once-daily in the evening. The primary endpoint was time to first severe exacerbation. A severe exacerbation was defined as a deterioration of asthma requiring the use of systemic corticosteroids for at least 3 days, or inpatient hospitalization, or emergency department visit due to asthma requiring systemic corticosteroids. FF/VI significantly delayed the time to first severe asthma exacerbation relative to FF alone. The adjusted probability of experiencing a severe asthma exacerbation at 52 weeks was 15.9% (95% CI 13.5% to 18.2%) in the FF 100 mcg group and 12.8% (95%CI 10.7 to 14.9%) in the FF/VI 100/25 mcg group. Subjects in the FF/VI and FF groups experienced similar adverse events.

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