FDA Approves Mometasone-Formoterol Combo for Asthma

Yael Waknine

June 28, 2010

June 28, 2010 — The US Food and Drug Administration (FDA) has approved Dulera (Merck & Co, Inc) inhalation aerosol containing a combination of mometasone furoate and formoterol fumarate dihydrate for treatment of asthma in patients aged 12 years and older.

The corticosteroid/long-acting beta-2 adrenergic agonist combination will be available in a pressurized metered-dose inhaler at strengths of 100 μg/5 μg and 200 μg/5 μg by the end of July 2010.

Combination mometasone furoate plus formoterol fumarate dihydrate treatment is indicated for patients whose asthma is not adequately controlled on low- or medium-dose inhaled corticosteroids, or whose disease severity clearly warrants initiation of dual therapy. Mometasone-formoterol is not approved for the treatment of acute bronchospasm.

"Despite the advances made in the treatment of asthma in recent years, many patients may still not be well-controlled on their current therapies," said Michael S. Blaiss, MD, clinical professor of pediatrics and medicine at the University of Tennessee Health Science Center, Memphis, in a company news release. "Asthma control is an important treatment goal and Dulera provides a new option for physicians to help manage this chronic condition in appropriate patients."

FDA approval was based in part on data from two phase 3 clinical trials of 1509 patients aged 12 years and older with persistent asthma uncontrolled on medium or high-dose corticosteroids. A 2- to 3-week run-in period with mometasone was used to establish a certain level of asthma control.

Results from both studies showed that both doses of mometasone-formoterol yielded significantly greater improvements in lung function from baseline (mean area under the concentration-time curve for forced expiratory volume in 1 second, measured from 0 to 12 hours [FEV1 AUC0–12h] at week 12) compared with mometasone alone (trials 1 and 2) and with placebo (trial 1). These benefits were maintained through week 26 in trial 1.

Deteriorations in asthma and reductions in lung function were assessed to evaluate the contribution of mometasone to the combination product. Events were defined as a 20% decrease in FEV1, a 30% decrease in peak expiratory flow on 2 or more consecutive days, and emergency treatment, hospitalization, or use of systemic corticosteroids or other asthma medications not allowed by the study protocol.

Compared with the 5 μg formoterol groups, fewer events were reported with use of mometasone-formoterol at the 100 μg/5 μg dose (trial 1, 30% vs 54%; trial 2, 12% vs 18%) and the 200 μg/5 μg dose (trial 2, 12% vs 18%).

The change in mean trough FEV1 from baseline to week 12 was also assessed as another endpoint to evaluate the contribution of mometasone to the combination product. A significantly greater increase in mean trough FEV1 was observed in trial 1 for 100 μg/5 μg mometasone-formoterol relative to 5 μg formoterol (Δ, 0.13 L vs 0 L). In trial 2, a greater numerical increase in mean trough FEV1 was observed for the 100 μg/5 μg dose and 200 μg/5 μg dose, compared with 200 μg mometasone alone (Δ, 0.14 L and 0.19 L vs 0.10 L).

Adverse events most commonly reported (rate ≥ 3% and greater than placebo) in study patients receiving mometasone-formoterol therapy included nasopharyngitis, sinusitis, and headache. Oral candidiasis occurred in 0.7% of patients receiving the 100 μg/5 μg dose and 0.8% of those receiving the 200 μg/5 μg dose compared with 0.5% given placebo. A similar safety profile was observed in a long-term 52-week trial, with the exception of dysphonia (100 μg/5 μg, 5%; 200 μg/5 μg, 3.8%).

The recommended dosing regimen for mometasone-formoterol is 2 oral inhalations twice daily, administered in the morning and evening and followed by rinsing of the mouth. For patients who are currently receiving medium-dose inhaled corticosteroids, the recommended initial dose is 100 μg/5 μg twice daily; those using high-dose corticosteroids should be given 200 μg/5 μg twice daily.

If an adequate response is not achieved after 2 weeks of therapy, consideration should be given to increasing the dose (maximum, 200 μg/5 μg twice daily), adding an additional inhaled corticosteroid, or initiating oral corticosteroids.

A black box warning in the prescribing information advises that formoterol and other long-acting beta-2 adrenergic agonists increase the risk for asthma-related death and may also raise the likelihood for asthma-related hospitalization in pediatric and adult patients. It remains unclear whether concomitant use of inhaled corticosteroids mitigates or eliminates such risk.

Mometasone-formoterol should be reserved for patients whose asthma is not adequately controlled on low- or medium-dose inhaled corticosteroids, or whose disease severity clearly warrants initiation of dual therapy. Once asthma control is achieved and maintained, patients should be switched to monotherapy with a controller medication such as an inhaled corticosteroid. Mometasone-formoterol is not indicated for the relief of acute bronchospasm.

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