Dulera (mometasone furoate/formoterol fumarate)

Dulera (formoterol and mometasone furoate) is a combination of a long-acting beta-2 adrenergic agonist (LABA) bronchodilator and an anti-inflammatory corticosteroid used to treat asthma. 

In patients with asthma, the smaller airways (bronchioles) through which air moves in and out of the lungs can be narrowed by accumulation of mucus, spasm of the muscles that surround these airways, or swelling of the lining of the airways due to inflammation. 

Airway narrowing leads to symptoms of shortness of breath, wheezing, cough, and congestion. Medications used in treating asthma include those that open airways, called bronchodilators, and those that reduce inflammation. 

Beta-2 agonists are medications that attach to beta-2 receptors on the smooth muscle cells that surround the airways, causing the muscle cells to relax and open the airways. Glucocorticoid steroids have potent anti-inflammatory actions. 

In people with asthma, the suppression of inflammation within the airways reduces the swelling caused by inflammation that narrows the airways. At the same time, production of mucus is reduced. 

Common side effects of Dulera include

• hoarseness or deepened voice,
• dry mouth,
• sore throat,
• cough,
• headache,
• stuffy nose,
• sinus pain,
• changes in menstrual periods,
• dizziness,
• anxiety,
• headache,
• sleep problems (insomnia),
• muscle cramps,
• back pain,
• skin rash, and
• itching.

Serious side effects of Dulera include

• worsening asthma symptoms,
• tremors,
• chest pain,
• fast or pounding heartbeats,
• shortness of breath,
• wheezing,
• choking,
• blurred vision,
• tunnel vision,
• eye pain or redness,
• seeing halos around lights,
• oral thrush (sores or white patches in the mouth or throat, trouble swallowing),
• high blood sugar (increased thirst, increased urination, dry mouth, fruity breath odor), and
• low potassium levels (leg cramps, constipation, irregular heartbeats, fluttering in your chest, numbness or tingling, muscle weakness or limp feeling). 

Drug interactions of Dulera include the following, which may increase the levels of mometasone in the body by reducing the breakdown of mometasone by liver enzymes and thus increase the side effects of Dulera:

• ritonavir,
• atazanavir,
• clarithromycin,
• indinavir,
• itraconazole,
• ketoconazole,
• nelfinavir, and
• telithromycin.

Additional drug interactions include the following:

• Monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants may increase the effect of formoterol on the heart and blood pressure.
• Since Dulera contains formoterol, it should not be used with or within two weeks of discontinuing monoamine oxidase inhibitors or tricyclic antidepressants.
• Beta-blockers block the therapeutic effects of beta2-agonists, such as formoterol, a component of Dulera, and may produce severe bronchospasm in patients with asthma. Patients with asthma should not be treated with beta blockers. 

Use of Dulera during pregnancy has not been adequately evaluated. It is unknown if components of Dulera are secreted in breast milk. Other medications in this class are secreted into breast milk. 

It is unknown if the small amounts of Dulera components that may appear in breast milk have an effect on the infant. Consult your doctor before breastfeeding.

WARNING

• Dulera should not be used for treatment of acute asthmatic attacks.
• Use of long acting agents like formoterol, an active ingredient in Dulera, may increase the risk of asthma-related death. Therefore, Dulera should only be used in patients whose asthma is uncontrolled by other agents, including long-term asthma-controlling medications such as an inhaled corticosteroid.
• Dulera may cause bronchospasm.

LABA use may result in the following:

• Serious asthma-related events - hospitalizations, intubations, and death.
• Cardiovascular and central nervous system effects.

Systemic and local corticosteroid use may result in the following:

• Candida albicans infection
• Immunosuppression
• Hypercorticism and adrenal suppression
• Growth effects in pediatrics
• Glaucoma and cataracts

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trials Experience

• The safety data described below is based on 3 clinical trials which randomized 1913 patients 12 years of age and older with asthma, including 679 patients exposed to Dulera for 12 to 26 weeks and 271 patients exposed for 1 year.
• Dulera was studied in two placebo-and active-controlled trials (n=781 and n=728, respectively) and in a long-term 52-week safety trial (n=404).
• In the 12 to 26week clinical trials, the population was
  • 12 to 84 years of age,
  • 41% male and 59% female,
  • 73% Caucasians,
  • 27% non-Caucasians.
• Patients received two inhalations twice daily of Dulera (100 mcg/5 mcg or 200 mcg/5 mcg), mometasone furoate MDI (100 mcg or 200 mcg), formoterol MDI (5 mcg) or placebo.
• In the long-term 52-week active-comparator safety trial, the population was
  • 12 years to 75 years of age with asthma,
  • 37% male and 63% female,
  • 47% Caucasians,
  • 53% non-Caucasians and received two inhalations twice daily of Dulera 100 mcg/5 mcg or 200 mcg/5 mcg, or an active comparator.
• The incidence of treatment emergent adverse reactions associated with Dulera in Table 2 below is based upon pooled data from 2 clinical trials 12 to 26 weeks in duration in patients 12 years and older treated with two inhalations twice daily of Dulera (100 mcg/5 mcg or 200 mcg/5 mcg), mometasone furoate MDI (100 mcg or 200 mcg), formoterol MDI (5mcg) or placebo.

Table 2: Treatment-Emergent Adverse Reactions in Dulera Groups Occurring at an Incidence of ≥3% and More Commonly than Placebo

• Oral candidiasis has been reported in clinical trials at an incidence of 0.7% in patients using Dulera 100 mcg/5 mcg, 0.8% in patients using Dulera 200 mcg/5 mcg and 0.5% in the placebo group.

Long-Term Clinical Trial Experience

• In a long-term safety trial in patients 12 years and older treated for 52 weeks with Dulera 100 mcg/5 mcg (n=141), Dulera 200 mcg/5 mcg (n=130) or an active comparator (n=133), safety outcomes in general were similar to those observed in the shorter 12 to 26 week controlled trials.
• No asthma-related deaths were observed. 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.
• No clinically significant changes in blood chemistry, hematology, or ECG were observed.

Postmarketing Experience

The following adverse reactions have been reported during post-approval use of Dulera or post-approval use with inhaled mometasone furoate or inhaled formoterol fumarate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Cardiac disorders: angina pectoris, cardiac arrhythmias, e.g., atrial fibrillation, ventricular extrasystoles, tachyarrhythmia Immune system disorders: immediate and delayed hypersensitivity reactions including anaphylactic reaction, angioedema, severe hypotension, rash, pruritus
• Investigations: electrocardiogram QT prolonged, blood pressure increased (including hypertension)
• Metabolism and nutrition disorders: hypokalemia, hyperglycemia
• Respiratory, thoracic and mediastinal disorders: asthma aggravation, which may include cough, dyspnea, wheezing and bronchospasm

In clinical trials, concurrent administration of Dulera and other drugs, such as short-acting beta₂-agonist and intranasal corticosteroids have not resulted in an increased frequency of adverse drug reactions. No formal drug interaction studies have been performed with Dulera. The drug interactions of the combination are expected to reflect those of the individual components.

Inhibitors Of Cytochrome P450 3A4

• The main route of metabolism of corticosteroids, including mometasone furoate, a component of Dulera, is via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4).
• After oral administration of ketoconazole, a strong inhibitor of CYP3A4, the mean plasma concentration of orally inhaled mometasone furoate increased.
• Concomitant administration of CYP3A4 inhibitors may inhibit the metabolism of, and increase the systemic exposure to, mometasone furoate.
• Caution should be exercised when considering the coadministration of Dulera with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin).

Adrenergic Agents

• If additional adrenergic drugs are to be administered by any route, they should be used with caution because the pharmacologically predictable sympathetic effects of formoterol, a component of Dulera, may be potentiated.

Xanthine Derivatives

• Concomitant treatment with xanthine derivatives may potentiate any hypokalemic effect of formoterol, a component of Dulera.

Diuretics

• Concomitant treatment with diuretics may potentiate the possible hypokalemic effect of adrenergic agonists.
• The ECG changes and/or hypokalemia that may result from the administration of non-potassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded.
• Although the clinical significance of these effects is not known, caution is advised in the coadministration of Dulera with non-potassium-sparing diuretics.

Monoamine Oxidase Inhibitors, Tricyclic Antidepressants, And Drugs Known To Prolong The QTc Interval

• Dulera should be administered with caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, macrolides, or drugs known to prolong the QTc interval or within 2 weeks of discontinuation of such agents, because the action of formoterol, a component of Dulera, on the cardiovascular system may be potentiated by these agents.
• Drugs that are known to prolong the QTc interval have an increased risk of ventricular arrhythmias.

Beta-Adrenergic Receptor Antagonists

• Beta-adrenergic receptor antagonists (beta-blockers) and formoterol may inhibit the effect of each other when administered concurrently.
• Beta-blockers not only block the therapeutic effects of beta₂-agonists, such as formoterol, a component of Dulera, but may produce severe bronchospasm in patients with asthma.
• Therefore, patients with asthma should not normally be treated with beta-blockers.
• However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-blockers in patients with asthma.
• In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution.

Halogenated Hydrocarbons

• There is an elevated risk of arrhythmias in patients receiving concomitant anesthesia with halogenated hydrocarbons.