BROVANA® (arformoterol tartrate)

BROVANA® (arformoterol tartrate)

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BROVANA® (arformoterol tartrate)

BROVANA (arformoterol tartrate) Inhalation Solution is a sterile, clear, colorless, aqueous solution of the tartrate salt of arformoterol, the (R,R)-enantiomer of formoterol. Arformoterol is a selective beta2-adrenergic bronchodilator. The chemical name for arformoterol tartrate is formamide, N-[2-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]-, (2R,3R)-2,3-dihydroxybutanedioate (1:1 salt).

The molecular weight of arformoterol tartrate is 494.5 g/mol, and its empirical formula is C19H24N2O4•C4H6O6 (1:1 salt). It is a white to off-white solid that is slightly soluble in water.

Arformoterol tartrate is the United States Adopted Name (USAN) for (R,R)-formoterol L-tartrate.

Indications and usage

BROVANA Inhalation Solution is a long-acting beta2-adrenergic agonist ( beta2-agonist) indicated for:

  • Long-term, twice daily (morning and evening) administration in the maintenance treatment of bronchoconstriction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.

Important limitations of use:

  • BROVANA Inhalation Solution is not indicated to treat acute deteriorations of chronic obstructive pulmonary disease.
  • BROVANA Inhalation Solution is not indicated to treat asthma.

Mechanism of Action

Arformoterol, the (R,R)-enantiomer of formoterol, is a selective long-acting beta2– adrenergic receptor agonist (beta2-agonist) that has two-fold greater potency than racemic formoterol (which contains both the (S,S) and (R,R)-enantiomers). The (S,S)-enantiomer is about 1,000-fold less potent as a beta2 -agonist than the (R,R)-enantiomer. While it is recognized that beta2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-receptors are the predominant receptors in the heart, data indicate that 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 arformoterol, 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 intracellular cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

Dosage and administration

For oral inhalation only.

  • A total daily dose of greater than 30 mcg is not recommended.
  • One 15 mcg/2 mL vial every 12 hours.
  • For use with a standard jet nebulizer (with a face mask or mouthpiece) connected to an air compressor.

Contraindications

  • BROVANA Inhalation Solution is contraindicated in patients with a history of hypersensitivity to arformoterol, racemic formoterol or to any other components of this product.
  • All LABA, including BROVANA Inhalation Solution, are contraindicated in patients with asthma without use of a long-term asthma control medication.

Drug interactions

Adrenergic Drugs: If additional adrenergic drugs are to be administered by any route, they should be used with caution because the sympathetic effects of arformoterol may be potentiated.

Xanthine Derivatives, Steroids, or Diuretics: Concomitant treatment with methylxanthine (aminophylline, theophylline), steroids, or diuretics may potentiate any hypokalemic effect of adrenergic agonists including BROVANA Inhalation Solution.

Non-potassium Sparing Diuretics: 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 beta-agonists, including BROVANA Inhalation Solution, with nonpotassium sparing diuretics.

MAO Inhibitors, Tricyclic Antidepressants, QTc Prolonging Drugs: BROVANA Inhalation Solution, as with other beta-agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTc interval because of the effect of adrenergic agonists on the cardiovascular system may be potentiated by these agents.

Beta-Blockers: Beta-adrenergic receptor antagonists (beta-blockers) and BROVANA Inhalation Solution may inhibit the effect of each other when administered concurrently. Beta-blockers not only block the therapeutic effects of beta-agonists, but may produce severe bronchospasm in COPD patients. Therefore, patients with COPD 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 COPD. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution.

Warnings and precautions

Long-acting beta2-adrenergic agonists (LABA) increase the risk of asthma-related death. A placebo-controlled study with another long-acting beta2-adrenergic agonist (salmeterol) showed an increase in asthma related deaths in patients receiving salmeterol.

The finding of an increase in the risk of asthma-related deaths with salmeterol is considered a class effect of LABA, including arformoterol, the active ingredient in BROVANA Inhalation Solution. The safety and efficacy of BROVANA Inhalation Solution in patients with asthma have not been established. All LABA, including BROVANA Inhalation Solution, are contraindicated in patients with asthma without use of a long-term asthma control medication.

Deterioration of Disease and Acute Episodes: BROVANA Inhalation Solution should not be initiated in patients with acutely deteriorating COPD, which may be a life-threatening condition. The use of BROVANA Inhalation Solution in this setting is inappropriate.

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BROVANA Inhalation Solution is not indicated for the treatment of acute episodes of bronchospasm, i.e., as rescue therapy and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled short-acting beta2 -agonist

Excessive Use of BROVANA Inhalation Solution and Use with Other Long-Acting Beta2-Agonists: Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. As with other inhaled beta2-adrenergic drugs, BROVANA Inhalation Solution should not be used more often, at higher doses than recommended, or in conjunction with other medications containing long-acting beta2-agonists.

Paradoxical Bronchospasm: As with other inhaled beta2-agonists, BROVANA Inhalation Solution can produce paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs, BROVANA Inhalation Solution should be discontinued immediately and alternative therapy instituted.

Cardiovascular Effects: BROVANA Inhalation Solution, like other beta2-agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic and/or diastolic blood pressure, and/or symptoms. If such effects occur, the drug may need to be discontinued.

Coexisting Conditions: BROVANA Inhalation Solution, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension; in patients with convulsive disorders or thyrotoxicosis, and in patients who are unusually responsive to sympathomimetic amines.

Hypokalemia and Hyperglycemia: Beta-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. Beta-agonist medications may produce transient hyperglycemia in some patients.

Immediate Hypersensitivity Reactions: Immediate hypersensitivity reactions may occur after administration of BROVANA Inhalation Solution as demonstrated by cases of anaphylactic reaction, urticaria, angioedema, rash and bronchospasm.

Adverse reactions

Most common adverse reactions (≥2% incidence and more common than placebo) are pain, chest pain, back pain, diarrhea, sinusitis, leg cramps, dyspnea, rash, flu syndrome, peripheral edema and lung disorder.

Use in specific populations

Pregnancy: Pregnancy Category C.There are no adequate and well-controlled studies of BROVANA Inhalation Solution in pregnant women. Arformoterol has been shown to be teratogenic in rats and rabbits.

Labor and Delivery: There are no human studies that have investigated the effects of BROVANA Inhalation Solution on preterm labor or labor at term. Because beta-agonists may potentially interfere with uterine contractility, BROVANA Inhalation Solution should be used during labor and delivery only if the potential benefit justifies the potential risk.

Nursing Mothers: In reproductive studies in rats, arformoterol was excreted in the milk. It is not known whether arformoterol is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when BROVANA Inhalation Solution is administered to a nursing woman.

Pediatric Use: BROVANA Inhalation Solution is approved for use in the long-term maintenance treatment of bronchoconstriction associated with chronic obstructive pulmonary disease, including chronic bronchitis and emphysema. This disease does not occur in children. The safety and efficacy of BROVANA Inhalation Solution in pediatric patients have not been established.

Overdosage

Signs and symptoms may include angina, hypertension or hypotension, tachycardia, with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, muscle cramps, nausea, dizziness, fatigue, malaise, hypokalemia, hyperglycemia, metabolic acidosis and insomnia. As with all inhaled sympathomimetic medications, cardiac arrest and even death may be associated with an overdose of BROVANA Inhalation Solution.

Treatment of overdosage consists of discontinuation of BROVANA Inhalation Solution together with institution of appropriate symptomatic and/or supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of BROVANA Inhalation Solution. Cardiac monitoring is recommended in cases of overdosage.

Storage and Handling

Store BROVANA Inhalation Solution in the protective foil pouch under refrigeration at 36°-46°F (2°-8°C).

Protect from light and excessive heat.

After opening the pouch, unused unit-dose vials should be returned to, and stored in, the pouch. An opened unit-dose vial should be used right away. Discard any unit-dose vial if the solution is not colorless. Unopened foil pouches of BROVANA Inhalation Solution can also be stored at room temperature 68°-77°F (20°-25°C) for up to 6 weeks. If stored at room temperature, discard if not used after 6 weeks or if past the expiration date, whichever is sooner.

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