Arformoterol

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)

Pharmacology

Mechanism of Action

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.

Pharmacokinetics/Pharmacodynamics

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%

Use in Specific Populations

Special Populations: Hepatic Function Impairment

The systemic exposure (C_max 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; monotherapy (without use of a concomitant inhaled corticosteroid) in the treatment of asthma.

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.

Dosage and Administration

Dosing: Adult

Chronic obstructive pulmonary disease: Nebulization solution: 15 mcg twice daily; maximum: 30 mcg/day.

Dosing: Geriatric

Refer to adult dosing.

Administration

Oral inhalation: Nebulization solution: 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

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

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 (Topical): 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

Guanethidine: May enhance the arrhythmogenic effect of Sympathomimetics. Guanethidine may enhance the hypertensive effect of Sympathomimetics. Monitor therapy

Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. Monitor therapy

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

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

Methacholine: Beta2-Agonists (Long-Acting) may diminish the therapeutic effect of Methacholine. Management: Hold long-acting beta₂ agonists for 36 hours before methacholine use. Consider therapy modification

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

QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Solriamfetol: Sympathomimetics may enhance the hypertensive effect of Solriamfetol. 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%: 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

Warnings/Precautions

Concerns related to adverse effects:

• Asthma-related deaths: Monotherapy with a long-acting beta-2 agonist (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. When LABAs are used in a fixed-dose combination with inhaled corticosteroids, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared to inhaled corticosteroids alone. Current guidelines recommend the use of an inhaled corticosteroid before adding a LABA (GINA 2018; NIH/NHLBI 2007). 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 children, 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 (Peters 2016; Stempel 2016a; Stempel 2016b). Arformoterol is not indicated for the treatment of asthma. Available data do not suggest an increased risk of death with use of LABA in patients with chronic obstructive pulmonary disease (COPD).
• 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 or frequency or use with other medications containing LABAs; 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. Beta-2 agonists have been reported to produce ECG changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression.
• COPD: Appropriate use: Do not use for acute episodes of COPD. Do not initiate in patients with significantly worsening or acutely deteriorating COPD. Available data do not suggest an increased risk of death with use of LABA in patients with COPD.
• Diabetes: Use with caution in patients with diabetes mellitus. Beta-2 agonists may increase serum glucose and aggravate preexisting diabetes mellitus and ketoacidosis.
• Hepatic impairment: Use with caution in patients with hepatic impairment; systemic exposure is increased.
• Hyperthyroidism: Use with caution in patients with hyperthyroidism; may stimulate thyroid activity.
• Hypokalemia: Use with caution in patients with hypokalemia; beta-2 agonists may decrease serum potassium (transient).
• Seizures: Use with caution in patients with seizure disorders; beta-2 agonists may result in CNS stimulation/excitation.

Special populations:

• Pediatric: LABAs, when used as monotherapy, may increase the risk of asthma-related hospitalization in pediatric and adolescent patients. When LABAs are used in a fixed-dose combination with inhaled corticosteroids, data from large clinical trials in adolescents do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared to inhaled corticosteroids alone.

Other warnings/precautions:

• Patient information: Patients using inhaled, short-acting beta-2 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 beta-2 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 beta 2-agonist inhalers; may be marker of a deteriorating COPD condition, hypersensitivity reactions, decreased bronchodilator response (tachyphylaxis).

Pregnancy

Pregnancy Considerations

Beta-agonists may interfere with uterine contractility if administered during labor.

Patient Education

What is this drug used for?

• It is used to treat COPD (chronic obstructive pulmonary disease).
• This drug is not to be used to treat intense flare-ups of shortness of breath. Use a rescue inhaler. Talk with the doctor.

Frequently reported side effects of this drug

• Nausea
• Vomiting
• Back pain
• Flu-like signs
• Anxiety
• Dry mouth
• Tremors
• Diarrhea
• Runny nose
• Loss of strength and energy
• Trouble sleeping

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit.
• Low potassium like muscle pain or weakness, muscle cramps, or an abnormal heartbeat.
• Acidosis like confusion, fast breathing, fast heartbeat, abnormal heartbeat, severe abdominal pain, nausea, vomiting, fatigue, shortness of breath, or loss of strength and energy.
• Chest pain
• Fast heartbeat
• Abnormal heartbeat
• Severe dizziness
• Passing out
• Vision changes
• Swelling of feet or legs
• Severe headache
• Breathing problems like shortness of breath, wheezing, coughing, or breathing gets worse.
• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.