DULERA® (mometasone furoate and formoterol fumarate)

DULERA® 100 mcg/5 mcg (mometasone furoate 100 mcg and formoterol fumarate dihydrate 5 mcg) Inhalation Aerosol
DULERA® 200 mcg/5 mcg (mometasone furoate 200 mcg and formoterol fumarate dihydrate 5 mcg) Inhalation Aerosol
FOR ORAL INHALATION
Initial U.S. Approval: 2010

DULERA: DULERA contains both mometasone furoate and formoterol fumarate; therefore, the mechanisms of actions described below for the individual components apply to DULERA. These drugs represent two different classes of medications (a synthetic corticosteroid and a selective long-acting beta2-adrenergic receptor agonist) that have different effects on clinical, physiological, and inflammatory indices of asthma.

Mometasone furoate: Mometasone furoate is a corticosteroid demonstrating potent anti-inflammatory activity. The precise mechanism of corticosteroid action on asthma is not known. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to have a wide range of inhibitory effects on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in inflammation and in the asthmatic response. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma.

Mometasone furoate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor, which is approximately 12 times that of dexamethasone, 7 times that of triamcinolone acetonide, 5 times that of budesonide, and 1.5 times that of fluticasone. The clinical significance of these findings is unknown.

Formoterol fumarate: Formoterol fumarate is a long-acting selective beta2-adrenergic receptor agonist (beta2-agonist). Inhaled formoterol fumarate acts locally in the lung as a bronchodilator. In vitro studies have shown that formoterol has more than 200-fold greater agonist activity at beta2-receptors than at beta1-receptors. Although beta2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-receptors are the predominant receptors in the heart, there are also beta2-receptors in the human heart comprising 10% to 50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective beta2-agonists may have cardiac effects.

The pharmacologic effects of beta2-adrenoceptor agonist drugs, including formoterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3', 5'-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

In vitro tests show that formoterol is an inhibitor of the release of mast cell mediators, such as histamine and leukotrienes, from the human lung. Formoterol also inhibits histamine-induced plasma albumin extravasation in anesthetized guinea pigs and inhibits allergen-induced eosinophil influx in dogs with airway hyper-responsiveness. The relevance of these in vitro and animal findings to humans is unknown.

Important limitations:
Not indicated for the relief of acute bronchospasm.

USE IN SPECIFIC POPULATIONS
Hepatic impairment: Monitor patients for signs of increased drug exposure.

Deterioration of disease and acute episodes: Do not initiate in acutely deteriorating asthma or to treat acute symptoms.

Use with additional long-acting beta2-agonist: Do not use in combination because of risk of overdose.

Localized infections: Candida albicans infection of the mouth and throat may occur. Monitor patients periodically for signs of adverse effects on the oral cavity. Advise patients to rinse the mouth following inhalation.

Immunosuppression: Potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infection; or ocular herpes simplex infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients. Use with caution in patients with these infections because of the potential for worsening of these infections.

Transferring patients from systemic corticosteroids: Risk of impaired adrenal function when transferring from oral steroids. Taper patients slowly from systemic corticosteroids if transferring to DULERA.

Hypercorticism and adrenal suppression: May occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue DULERA slowly.

Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir): Risk of increased systemic corticosteroid effects. Exercise caution when used with DULERA.

Paradoxical bronchospasm: Discontinue DULERA and institute alternative therapy if paradoxical bronchospasm occurs.

Patients with cardiovascular disorders: Use with caution because of beta-adrenergic stimulation.

Decreases in bone mineral density: Monitor patients with major risk factors for decreased bone mineral content.

Effects on growth: Monitor growth of pediatric patients.

Glaucoma and cataracts: Monitor patients with change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts closely.

Coexisting conditions: Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis.

Hypokalemia and hyperglycemia: Be alert to hypokalemia and hyperglycemia.

DRUG INTERACTIONS
Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir): Use with caution. May cause increased systemic corticosteroid effects.

Adrenergic agents: Use with caution. Additional adrenergic drugs may potentiate sympathetic effects.

Xanthine derivatives and diuretics: Use with caution. May potentiate ECG changes and/or hypokalemia.

MAO inhibitors, tricyclic antidepressants, and drugs that prolong QTc interval: Use with extreme caution. May potentiate effect on the cardiovascular system.

Beta-blockers: Use with caution and only when medically necessary. May decrease effectiveness and produce severe bronchospasm.

To report SUSPECTED ADVERSE REACTIONS, contact Schering Corporation, a subsidiary of Merck & Co., Inc., at 1-800-526-4099 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DOSAGE AND ADMINISTRATION

2.1 General
DULERA should be administered only by the orally inhaled route (see Instructions for Using DULERA in the Medication Guide). After each dose, the patient should be advised to rinse his/her mouth with water without swallowing.

DULERA should be primed before using for the first time by releasing 4 test sprays into the air, away from the face, shaking well before each spray. In cases where the inhaler has not been used for more than 5 days, prime the inhaler again by releasing 4 test sprays into the air, away from the face, shaking well before each spray.

The DULERA canister should only be used with the DULERA actuator. The DULERA actuator should not be used with any other inhalation drug product. Actuators from other products should not be used with the DULERA canister.

2.2 Dosing
DULERA should be administered as two inhalations twice daily every day (morning and evening) by the orally inhaled route.

Shake well prior to each inhalation.

The recommended starting dosages for DULERA treatment are based on prior asthma therapy.
Table 1: Recommended Dosages for DULERA

The maximum daily recommended dose is two inhalations of DULERA 200 mcg/5 mcg twice daily. Do not use more than two inhalations twice daily of the prescribed strength of DULERA as some patients are more likely to experience adverse effects with higher doses of formoterol. If symptoms arise between doses, an inhaled short-acting beta2-agonist should be taken for immediate relief.

If a previously effective dosage regimen of DULERA fails to provide adequate control of asthma, the therapeutic regimen should be reevaluated and additional therapeutic options, e.g., replacing the current strength of DULERA with a higher strength, adding additional inhaled corticosteroid, or initiating oral corticosteroids, should be considered.

TThe maximum benefit may not be achieved for 1 week or longer after beginning treatment. Individual patients may experience a variable time to onset and degree of symptom relief. For patients ≥12 years of age who do not respond adequately after 2 weeks of therapy, higher strength may provide additional asthma control.

DULERA is available in two strengths and supplied in the following package sizes:
Package NDC
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DULERA 100 mcg/5 mcg
120 inhalations 0085-7206-01

DULERA 100 mcg/5 mcg
60 inhalations (institutional pack) 0085-7206-07

DULERA 200 mcg/5 mcg
120 inhalations 0085-4610-01

DULERA 200 mcg/5 mcg
60 inhalations (institutional pack) 0085-4610-05

Each strength is supplied as a pressurized aluminum canister that has a blue plastic actuator integrated with a dose counter and a blue dust cap. Each 120-inhalation canister has a net fill weight of 13 grams and each 60-inhalation canister has a net fill weight of 8.8 grams. Each canister is placed into a carton. Each carton contains 1 canister and a Medication Guide.

Initially the dose counter will display "64" or "124" actuations. After the initial priming with 4 actuations, the dose counter will read "60" or "120" and the inhaler is now ready for use.

Storage and Handling

The DULERA canister should only be used with the DULERA actuator. The DULERA actuator should not be used with any other inhalation drug product. Actuators from other products should not be used with the DULERA canister.

The correct amount of medication in each inhalation cannot be ensured after the labeled number of actuations from the canister has been used, even though the inhaler may not feel completely empty and may continue to operate. The inhaler should be discarded when the labeled number of actuations has been used (the dose counter will read "0").

Store at controlled room temperature 20°–25°C (68°–77°F); excursions permitted to 15°–30°C (59°–86°F) [see USP Controlled Room Temperature].

The 120-inhalation inhaler does not require specific storage orientation. For the 60-inhalation inhaler, after priming store the inhaler with the mouthpiece down or in a horizontal position.

For best results, the canister should be at room temperature before use. Shake well before using. Keep out of reach of children. Avoid spraying in eyes.

Contents Under Pressure: Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 120°F may cause bursting. Never throw container into fire or incinerator.

Manufactured by: 3M Health Care Ltd., Loughborough, United Kingdom.

Distributed by: Schering Corporation, a subsidiary of
MERCK & CO., INC., Whitehouse Station, NJ 08889, USA

Copyright © 2010 Schering Corporation, a subsidiary of Merck & Co., Inc.
All rights reserved.

U.S. Patent Nos. 6,068,832; 7,067,502; and 7,566,705.

The trademarks depicted in this piece are owned by their respective companies.

Revised: 11/2011
35217908T