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Arformoterol

Pronunciation

(ar for MOE ter ol)

Index Terms

  • (R,R)-Formoterol L-Tartrate
  • Arformoterol Tartrate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Nebulization Solution, Inhalation:

Brovana: 15 mcg/2 mL (2 mL)

Brand Names: U.S.

  • Brovana

Pharmacologic Category

  • Beta2-Adrenergic Agonist
  • Beta2-Adrenergic Agonist, Long-Acting

Pharmacology

Arformoterol, the (R,R)-enantiomer of the racemic formoterol, is a long-acting beta2-agonist that relaxes bronchial smooth muscle by selective action on beta2-receptors with little effect on cardiovascular system.

Absorption

A portion of inhaled dose is absorbed into systemic circulation

Metabolism

Hepatic via direct glucuronidation and secondarily via O-demethylation; CYP2D6 and CYP2C19 (to a lesser extent) involved in O-demethylation

Onset of Action

7-20 minutes; Peak effect: 1-3 hours

Time to Peak

0.5-3 hours

Half-Life Elimination

26 hours

Protein Binding

52% to 65%

Special Populations: Hepatic Function Impairment

The systemic exposure (Cmax and AUC) to arformoterol increased 1.3- to 2.4-fold in subjects with hepatic impairment.

Use: Labeled Indications

Chronic obstructive pulmonary disease: Long-term maintenance treatment of bronchoconstriction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema

Contraindications

Hypersensitivity to arformoterol, racemic formoterol, or to any component of the formulation; patients with asthma without use of a long-term asthma control medication.

Documentation of allergenic cross-reactivity for sympathomimetics is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Dosing: Adult

COPD: Nebulization: 15 mcg twice daily; maximum: 30 mcg daily

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

No dosage adjustment necessary.

Dosing: Hepatic Impairment

No dosage adjustment necessary. Use with caution; systemic drug exposure prolonged.

Administration

Nebulization: Remove each vial from individually sealed foil pouch immediately before use. Use with standard jet nebulizer connected to an air compressor, administer with mouthpiece or face mask. Administer vial undiluted and do not mix with other medications in nebulizer.

Storage

Prior to dispensing, store in protective foil pouch under refrigeration at 2°C to 8°C (36°F to 46°F). Protect from light and excessive heat. After dispensing, unopened foil pouches may be stored at 20°C to 25°C (68°F to 77°F) for up to 6 weeks. Only remove vial from foil pouch immediately before use.

Drug Interactions

AtoMOXetine: May enhance the tachycardic effect of Beta2-Agonists. Monitor therapy

AtoMOXetine: May enhance the hypertensive effect of Sympathomimetics. AtoMOXetine may enhance the tachycardic effect of Sympathomimetics. Monitor therapy

Atosiban: Beta2-Agonists may enhance the adverse/toxic effect of Atosiban. Specifically, there may be an increased risk for pulmonary edema and/or dyspnea. Monitor therapy

Beta-Blockers (Beta1 Selective): May diminish the bronchodilatory effect of Beta2-Agonists. Of particular concern with nonselective beta-blockers or higher doses of the beta1 selective beta-blockers. Monitor therapy

Beta-Blockers (Nonselective): May diminish the bronchodilatory effect of Beta2-Agonists. Avoid combination

Betahistine: May diminish the therapeutic effect of Beta2-Agonists. Monitor therapy

Cannabinoid-Containing Products: May enhance the tachycardic effect of Sympathomimetics. Exceptions: Cannabidiol. Monitor therapy

Cocaine: May enhance the hypertensive effect of Sympathomimetics. Management: Consider alternatives to use of this combination when possible. Monitor closely for substantially increased blood pressure or heart rate and for any evidence of myocardial ischemia with concurrent use. Consider therapy modification

Doxofylline: Sympathomimetics may enhance the adverse/toxic effect of Doxofylline. Monitor therapy

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Iobenguane I 123: Sympathomimetics may diminish the therapeutic effect of Iobenguane I 123. Avoid combination

Linezolid: May enhance the hypertensive effect of Sympathomimetics. Management: Reduce initial doses of sympathomimetic agents, and closely monitor for enhanced pressor response, in patients receiving linezolid. Specific dose adjustment recommendations are not presently available. Consider therapy modification

Long-Acting Beta2-Agonists: May enhance the adverse/toxic effect of other Long-Acting Beta2-Agonists. Avoid combination

Loop Diuretics: Beta2-Agonists may enhance the hypokalemic effect of Loop Diuretics. Monitor therapy

Loxapine: Agents to Treat Airway Disease may enhance the adverse/toxic effect of Loxapine. More specifically, the use of Agents to Treat Airway Disease is likely a marker of patients who are likely at a greater risk for experiencing significant bronchospasm from use of inhaled loxapine. Management: This is specific to the Adasuve brand of loxapine, which is an inhaled formulation. This does not apply to non-inhaled formulations of loxapine. Avoid combination

MAO Inhibitors: May enhance the adverse/toxic effect of Beta2-Agonists. Monitor therapy

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. Monitor therapy

Tedizolid: May enhance the hypertensive effect of Sympathomimetics. Tedizolid may enhance the tachycardic effect of Sympathomimetics. Monitor therapy

Thiazide and Thiazide-Like Diuretics: Beta2-Agonists may enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Tricyclic Antidepressants: May enhance the adverse/toxic effect of Beta2-Agonists. Monitor therapy

Adverse Reactions

2% to 10%:

Cardiovascular: Chest pain (7%), peripheral edema (3%)

Central nervous system: Pain (8%)

Dermatologic: Skin rash (4%)

Gastrointestinal: Diarrhea (6%)

Neuromuscular & skeletal: Back pain (6%), leg cramps (4%)

Respiratory: Dyspnea (4%), sinusitis (5%), flu-like symptoms (3%), respiratory congestion (2%)

<2% (Limited to important or life-threatening): Abscess, agitation, arteriosclerosis, arthralgia, arthritis, atrial flutter, atrioventricular block, bone disease, calcium crystalluria, cardiac failure, cerebral infarction, constipation, cystitis, decreased glucose tolerance, dehydration, digitalis intoxication, drowsiness, ECG changes, edema, fever, gastritis, glaucoma, glycosuria, gout, heart block, hematuria, hernia, hyperglycemia, hyperlipidemia, hypersensitivity reaction, hypoglycemia, hypokalemia, hypokinesia, inversion T wave on ECG, lung carcinoma, melena, myocardial infarction, neck stiffness, neoplasm, nephrolithiasis, nocturia, oral candidiasis, paradoxical bronchospasm, paralysis, paresthesia (circumoral), pelvic pain, periodontal abscess, prolonged Q-T interval on ECG, prostate specific antigen increase, pyuria, rectal hemorrhage, retroperitoneal hemorrhage, rheumatoid arthritis, skin discoloration, skin hypertrophy, supraventricular tachycardia, tendinous contracture, tremor, urinary tract abnormality, urine abnormality, viral infection, visual disturbance, voice disorder, xeroderma

ALERT: U.S. Boxed Warning

Asthma-related death:

Long-acting beta-2 adrenergic agonists may increase the risk of asthma-related death. Data from a large placebo-controlled US study that compared the safety of another long-acting beta-2 adrenergic agonist (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 long-acting beta-2 agonists, including arformoterol. The safety and efficacy of arformoterol in patients with asthma have not been established. All long-acting beta-2 agonists, including arformoterol, are contraindicated in patients with asthma without use of a long-term asthma control medication.

Warnings/Precautions

Concerns related to adverse effects:

• Asthma-related deaths: [US Boxed Warning]: Long-acting beta2-agonists (LABAs) increase the risk of asthma-related deaths. Monotherapy with a LABA is contraindicated in the treatment of asthma. In a large, randomized, placebo-controlled US clinical trial (SMART 2006), salmeterol was associated with an increase in asthma-related deaths (when added to usual asthma therapy); risk is considered a class effect among all LABAs. Data are not available to determine if the addition of an inhaled corticosteroid lessens this increased risk of death associated with LABA use; however, current guidelines recommend the use of an inhaled corticosteroid before adding a LABA (GINA 2015; NIH/NHLBI 2007). LABAs should not be used for acute bronchospasm. In a more recent multicenter, randomized, double-blinded trial, the use of salmeterol and an inhaled corticosteroid (ie, fluticasone) combined in a single inhaler in a large number of adolescent and adult patients with persistent asthma (non-life threatening and stable) did not increase the risk of serious asthma-related events compared with fluticasone alone; in addition, patients receiving fluticasone/salmeterol had fewer severe asthma exacerbations compared with patients receiving fluticasone alone (Stempel 2016). Safety and efficacy of arformoterol in patients with asthma have not been established.

• Bronchospasm: Paradoxical bronchospasm that may be life-threatening may occur with use of inhaled bronchodilating agents; this reaction should be distinguished from inadequate response. Discontinue immediately if paradoxical bronchospasm occurs and institute alternative therapy.

• Hypersensitivity reactions: Immediate hypersensitivity reactions (anaphylaxis, urticaria, angioedema, rash, bronchospasm) have been reported.

• Serious effects/fatalities: Do not exceed recommended dose; serious adverse events, including fatalities, have been associated with excessive use of inhaled sympathomimetics.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with cardiovascular disease (eg, arrhythmia, hypertension, HF); beta-agonists may cause elevation in blood pressure, heart rate and result in CNS stimulation/excitation. Beta2-agonists may also increase risk of arrhythmias and prolong QTc interval.

• COPD: Appropriate use: Do not use for acute episodes of COPD. Do not initiate in patients with significantly worsening or acutely deteriorating COPD. Data are not available to determine if LABA use increases the risk of death in patients with COPD.

• Diabetes: Use with caution in patients with diabetes mellitus. Beta2-agonists may increase serum glucose; the effect is usually transient.

• Hepatic impairment: Use with caution in patients with hepatic impairment; systemic clearance prolonged in hepatic dysfunction.

• Hyperthyroidism: Use with caution in patients with hyperthyroidism; may stimulate thyroid activity.

• Hypokalemia: Use with caution in patients with hypokalemia; beta2-agonists may decrease serum potassium.

• Seizure disorders: Use with caution in patients with seizure disorders; beta2-agonists may result in CNS stimulation/excitation.

Special populations:

• Pediatric: Arfomoterol is approved for COPD, which is a disease that does not occur in the pediatric population. Safety and efficacy have not been established in children.

Other warnings/precautions:

• Patient information: Patients using inhaled, short-acting beta2-agonists (eg, albuterol) should be instructed to discontinue routine use of these medications prior to beginning treatment; short-acting agents should be reserved for symptomatic relief of acute symptoms. Patients must be instructed to seek medical attention in cases where acute symptoms are not relieved or a previous level of response is diminished. The need to increase frequency of use of short-acting beta2-agonists may indicate deterioration of COPD, and medical evaluation must not be delayed.

• Tolerance/Tachyphylaxis: Tolerance to the bronchodilator effect, measured by FEV1, has been observed in studies.

Monitoring Parameters

FEV1, peak flow, and/or other pulmonary function tests; blood pressure, heart rate; CNS stimulation; serum glucose, serum potassium. Monitor for increased use of short-acting beta2-agonist inhalers; may be marker of a deteriorating COPD condition.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies. Beta-agonists may interfere with uterine contractility if administered during labor.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience back pain, diarrhea, or rhinitis. Have patient report immediately to signs of high blood sugar (confusion, fatigue, increased thirst, increased hunger, polyuria, flushing, fast breathing, or breath that smells like fruit), signs of low potassium (muscle pain or weakness, muscle cramps, or an abnormal heartbeat), angina, tachycardia, severe anxiety, severe dizziness, passing out, chills, pharyngitis, swelling of arm or leg, severe headache, severe nausea, vomiting, difficulty speaking, signs of breathing problems (shortness of breath, wheezing, coughing, or breathing gets worse) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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