FDA Approves Dulera

FDA Approves Merck's Dulera (mometasone furoate and formoterol fumarate dihydrate) Inhalation Aerosol for the Treatment of Asthma in Patients 12 Years of Age and Older

WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Jun 24, 2010 - Merck today announced that the U.S. Food and Drug Administration (FDA) has approved Dulera (mometasone furoate and formoterol fumarate dihydrate) Inhalation Aerosol, a new fixed-dose combination asthma treatment for patients 12 years of age and older. Dulera is not indicated for the relief of acute bronchospasm. Dulera combines an inhaled corticosteroid (mometasone furoate) with a long-acting beta2-agonist (formoterol fumarate). The approval of Dulera is based, in part, on Phase III studies that evaluated the safety and efficacy of Dulera in patients 12 years of age and older with persistent asthma.

"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, M.D., clinical professor of pediatrics and medicine at the University of Tennessee Health Science Center, Memphis, Tennessee. "Asthma control is an important treatment goal and Dulera provides a new option for physicians to help manage this chronic condition in appropriate patients."

Dulera is indicated for the treatment of asthma in patients 12 years of age and older. Dulera is not indicated for the relief of acute bronchospasm.

Long-acting beta2-adrenergic agonists (LABA), such as formoterol, one of the active ingredients in Dulera, increase the risk of asthma-related death. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Therefore, when treating patients with asthma, Dulera should only be used for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue Dulera) if possible without loss of asthma control, and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use Dulera for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids.

"As a leader in researching and developing new treatments for respiratory diseases, including asthma, Merck is committed to bringing forth medicines that help meet the needs of healthcare professionals and their patients," said James E. Fish, M.D., executive director, Global Scientific Affairs, Merck Research Laboratories. "Dulera represents an important part of this ongoing commitment."

Dulera is a pressurized metered-dose inhaler with a built-in numeric counter that shows the number of remaining doses. Dulera will be available for patients 12 years of age and older in two strengths: Dulera 100 mcg/5 mcg and Dulera 200 mcg/5 mcg. Each inhalation contains 5 mcg of formoterol fumarate and either 100 mcg or 200 mcg of mometasone furoate. The recommended starting dose is based on prior asthma therapy. The maximum daily recommended dose is two inhalations of Dulera 200 mcg/5 mcg twice daily every day in the morning and evening. Dulera is expected to be available in retail pharmacies nationwide by the end of July 2010.

Clinical Trials - Lung Function Measures

The approval of Dulera is supported, in part, by two randomized clinical trials (Trial 1, Trial 2) lasting 12 to 26 weeks in duration. These trials involved a total of 1,509 patients 12 years of age and older with persistent asthma uncontrolled on medium or high dose inhaled corticosteroids. These studies included a 2 to 3-week run-in period with mometasone furoate to establish a certain level of asthma control.

Trial 1 compared Dulera 100 mcg/5 mcg (n=191) to its individual components, mometasone furoate 100 mcg (n=192) and formoterol 5 mcg (n=202), and placebo (n=196). Trial 2 compared Dulera 200 mcg/5 mcg (n=255) with Dulera 100 mcg/5 mcg (n=233) and mometasone furoate 200 mcg (n=240). All medications were given as two inhalations twice daily by metered dose inhalers.

Results from both clinical trials showed patients receiving Dulera (100 mcg/5 mcg or 200 mcg/5 mcg) experienced significant improvement from baseline in lung function (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, a primary efficacy endpoint in the trials, compared to mometasone furoate (Trial 1 and 2) and placebo (Trial 1). In Trial 1, these differences were maintained through week 26.

The change in mean trough FEV1 from baseline to week 12 was assessed as another endpoint in both trials. In Trial 1, a significantly greater increase in the mean trough FEV1 was observed for Dulera 100 mcg/5 mcg compared to formoterol 5 mcg (the primary treatment comparison) as well as to placebo. In trial 2, a greater numerical increase in the mean trough FEV1 were was observed for Dulera 200 mcg/5 mcg compared to Dulera 100 mcg/5 mcg and mometasone furoate 200 mcg.

Clinical Trials - Clinically Judged Deteriorations in Asthma or Reduction in Lung Function

Clinically judged deteriorations in asthma or reductions in lung function were assessed in Trial 1 as another primary endpoint to evaluate the contribution of mometasone furoate 100 mcg to Dulera 100 mcg/5 mcg (primary treatment comparison Dulera vs. formoterol). Deteriorations in asthma were defined as any of the following: a 20 percent decrease in FEV1; a 30 percent decrease in peak expiratory flow (PEF) on two or more consecutive days; emergency treatment, hospitalization, or treatment with systemic corticosteroids or other asthma medications not allowed per protocol. Fewer patients who received Dulera 100 mcg/5 mcg reported an event compared to patients who received formoterol 5 mcg (p<0.001).

In Trial 2, clinically judged deterioration in asthma or reduction in lung function was also assessed as an additional endpoint. Fewer patients who received Dulera 200 mcg/5 mcg or Dulera 100 mcg/5 mcg compared to mometasone furoate 200 mcg alone reported an event, using the same definition as Trial 1.

Clinical Trials - Safety Data

The most common treatment-emergent adverse events were nasopharyngitis, sinusitis and headache. These adverse events were reported at an incidence of greater than or equal to 3.0 percent and more commonly than placebo. Oral candidiasis has been reported in clinical trials at an incidence of 0.7 percent in patients using Dulera 100 mcg/5 mcg, 0.8 percent in patients using Dulera 200 mcg/5 mcg and 0.5 percent in the placebo group. Similar safety outcomes were observed in a long-term 52-week trial of patients 12 years of age and older receiving Dulera (100 mcg/5 mcg or 200 mcg/5 mcg) or active comparator. Dysphonia was observed at a higher frequency in the longer term treatment trial at a reported incidence of 7/141 (5%) patients receiving Dulera 100 mcg/5 mcg and 5/130 (3.8%) patients receiving Dulera 200 mcg/5 mcg.

Important Safety Information about Dulera

WARNING: ASTHMA-RELATED DEATH

Long-acting beta2-adrenergic agonists (LABA), such as formoterol, one of the active ingredients in Dulera, increase the risk of asthma-related death. Data from a large placebo-controlled U.S. study that compared the safety of another LABA (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol is considered a class effect of the LABA, including formoterol. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients.

When treating patients with asthma, prescribe Dulera only for patients with asthma not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue Dulera) if possible without loss of asthma control, and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use Dulera for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids.

Dulera is contraindicated in the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required. Dulera is contraindicated in patients with known hypersensitivity to any of the ingredients in Dulera.

Dulera is NOT a rescue medication and does NOT replace fast-acting inhalers to treat acute symptoms. Increasing use of inhaled, short-acting beta2-agonists is a marker for deteriorating asthma. In this situation, the patient requires immediate re-evaluation with reassessment of the treatment regimen.

Patients using Dulera should not use additional formoterol or other long-acting inhaled beta2-agonists for any reason.

Dulera should be used with caution in patients with tuberculosis, fungal, bacterial, viral (including chicken pox or measles), or parasitic infections; or ocular herpes simplex infections because of the potential for worsening of these infections. A more serious or even fatal course of chickenpox or measles can occur in susceptible patients.

Particular care is needed for patients who are transferred from systemically active corticosteroids to Dulera. Deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids.

Mometasone furoate, a component of Dulera, will often help control asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone. Since mometasone furoate is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of Dulera in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose.

Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with Dulera should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.

It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients, particularly when mometasone furoate is administered at higher than recommended doses over prolonged periods of time. If such effects occur, the dosage of Dulera should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and for management of asthma symptoms.

Caution should be exercised when considering the coadministration of Dulera with long-term ketoconazole and other known strong CYP3A4 inhibitors, or in patients being treated with MAO inhibitors or tricyclic antidepressants.

Discontinue Dulera and institute alternative therapy if paradoxical bronchospasm occurs.

Excessive beta-adrenergic stimulation has been associated with central nervous system and cardiovascular effects. Dulera should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids, including mometasone furoate, a component of Dulera.

Inhaled corticosteroids, including Dulera, may cause a reduction in growth velocity when administered in pediatric patients.

Glaucoma, increased intraocular pressure, and cataracts have been reported following the use of long-term inhaled corticosteroids, including mometasone furoate, a component of Dulera.

Dulera, like other medications containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis; and in patients who are unusually responsive to sympathomimetic amines. Doses of the related beta2-agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

Beta2-agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. Clinically significant changes in blood glucose and/or serum potassium were seen infrequently during clinical studies with Dulera at recommended doses.

The most common treatment-emergent adverse events reported in ‰¥ three percent of patients and more common than placebo included nasopharyngitis, sinusitis, and headache.

About Asthma

Asthma is a chronic lung disease characterized by inflammation of the air passages, resulting in the temporary narrowing of the airways. Asthma symptoms can be triggered by allergens or irritants and can include difficulty breathing, wheezing, coughing, shortness of breath and chest tightness.

About Merck

Today's Merck is a global healthcare leader. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com.

Forward-Looking Statement

This news release includes "forward-looking statements" within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Such statements may include, but are not limited to, statements about the benefits of the merger between Merck and Schering-Plough, including future financial and operating results, the combined company's plans, objectives, expectations and intentions and other statements that are not historical facts. Such statements are based upon the current beliefs and expectations of Merck's management and are subject to significant risks and uncertainties. Actual results may differ from those set forth in the forward-looking statements.

The following factors, among others, could cause actual results to differ from those set forth in the forward-looking statements: the possibility that the expected synergies from the merger of Merck and Schering-Plough will not be realized, or will not be realized within the expected time period; the impact of pharmaceutical industry regulation and health care legislation; the risk that the businesses will not be integrated successfully; disruption from the merger making it more difficult to maintain business and operational relationships; Merck's ability to accurately predict future market conditions; dependence on the effectiveness of Merck's patents and other protections for innovative products; the risk of new and changing regulation and health policies in the U.S. and internationally and the exposure to litigation and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck's 2009 Annual Report on Form 10-K and the company's other filings with the Securities and Exchange Commission (SEC) available at the SEC's Internet site (www.sec.gov).

Posted: June 2010

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Dulera (mometasone furoate and formoterol fumarate) FDA Approval History

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