Arformoterol Tartrate

Class: Selective beta-2-Adrenergic Agonists
Chemical Name: (2R,3R) - 2,3 - dihydroxybutanedioate - N - [2 - hydroxy - 5 - [(1R) - 1 - hydroxy - 2 - [[(1R) - 2 - (4 - methoxyphenyl) - 1 - methylethyl]amino]ethyl]phenyl] - formamide
Molecular Formula: C19H24N2O4•C4H6O6
CAS Number: 200815-49-2
Brands: Brovana

Warning(s)

  • Increased risk of asthma-related death with long-acting β2-adrenergic agonists.1 14 15 16 17 18 19 (See REMS and see also Asthma-related Death under Cautions.)

  • Increased risk of asthma-related death considered class effect of long-acting β2-adrenergic agonists, including arformoterol.1 7 14 19

  • All long-acting β2-adrenergic agonists, including arformoterol, contraindicated in patients with asthma without concomitant use of long-term asthma controller therapy.1 Safety and efficacy of arformoterol in patients with asthma not established.1

Introduction

Bronchodilator; relatively selective long-acting β2-agonist.1 2 3 12 13

Uses for Arformoterol Tartrate

COPD

Long-term treatment of bronchoconstriction associated with COPD, including chronic bronchitis and emphysema.1 3 6

Long-acting β2-adrenergic agonists recommended as maintenance therapy in patients with moderate (e.g., forced expiratory volume in 1 second [FEV1] ≥50 but <80% of predicted) to very severe COPD (e.g., FEV1 <30% of predicted or <50% of predicted plus chronic respiratory failure) who have persistent symptoms not relieved by as-needed therapy with short-acting bronchodilators (e.g., ipratropium, β2-adrenergic agonist).5 9

Slideshow: COPD: Could You Be At Risk?

Regular treatment with long-acting bronchodilators more effective and convenient than treatment with short-acting bronchodilators.5 Superiority of one long-acting bronchodilator over another currently not established.11 If inadequate response, may use a combination of long-acting bronchodilators, such as a long-acting inhaled anticholinergic agent (tiotropium) and a long-acting β2-adrenergic agonist.5 9

In patients with severe (e.g., FEV1 <50% of predicted, history of repeated exacerbations) to very severe COPD, add regular treatment with an inhaled corticosteroid to long-acting bronchodilator therapy.5 9 11 If inadequate response or limiting adverse effects occur, add or substitute extended-release oral theophylline.9 11

Not to be used for immediate relief of acute exacerbations of COPD.1 6 Use short-acting inhaled β2-agonist intermittently (as needed) for acute symptoms of COPD.1 5 (See Acute Exacerbations of COPD under Cautions.) Efficacy and safety of long-acting bronchodilators, with or without inhaled corticosteroids, during acute exacerbations of COPD not established.1 5

Arformoterol Tartrate Dosage and Administration

General

  • When arformoterol therapy is initiated, discontinue regular use of short-acting, inhaled β2-adrenergic agonists, and use such agents only for relief of acute symptoms of COPD that are not controlled by arformoterol.1 2 6

  • Failure to respond to a previously effective dosage may indicate destabilization of COPD that requires reevaluation.1 Do not use extra/increased doses of arformoterol in such situations.1 2 6 (See Acute Exacerbations of COPD under Cautions.)

Administration

Oral Inhalation Solution

Administer by oral inhalation via nebulization twice daily (morning and evening) only.1 2 Do not administer inhalation solution orally.1

Using in vitro testing at a mean flow rate of 3.3 L/minute for an average of ≤6 minutes, Pari-LC Plus nebulizer connected to a Pari DURA-NEB 3000 compressor delivered approximately 27.6% of original dose at mouthpiece.1

For administration of arformoterol inhalation solution for nebulization in single-use units, open 1 vial and squeeze entire contents into nebulizer reservoir.2

Attach reservoir to mouthpiece or face mask and to compressor according to manufacturer’s instructions.2

Place mouthpiece of nebulizer in mouth or put on nebulizer face mask and turn on compressor.2 Breathe as calmly, deeply, and evenly as possible until nebulizer stops producing mist, about 5–10 minutes.2

Clean nebulizer after use according to manufacturer’s instructions.2

Safety and efficacy of arformoterol inhalation solution administered by a nebulizer other than the Pari-LC Plus nebulizer or a compressor other than Pari Dura-Neb 3000 compressor not established.1

Dosage

Commercially available as arformoterol tartrate; dosage expressed in terms of arformoterol.1

Delivery of oral inhalation solution to lungs depends on type of jet nebulizers used, performance of compressor, and other factors such patient’s inspiratory flow.1 (See Administration under Dosage and Administration.)

Adults

COPD
Oral Inhalation Solution

Usual dosage: 15 mcg twice daily via nebulization.1 13 Higher dosages provide no additional therapeutic benefit and increase risk of adverse effects.1 3 6 Maximum 30 mcg daily.1 2 6 13

Prescribing Limits

Adults

COPD
Oral Inhalation

Maximum 30 mcg daily.1 2 6 13

Special Populations

Hepatic Impairment

Dosage adjustment not required.1 6

Renal Impairment

Dosage adjustment not required.1 6

Geriatric Patients

Dosage adjustment not required.1 6

Patients with Deficient CYP2D6 or Uridine Disphosphoglucuronosyltransferase 1A1 Activity

No dosage adjustment required.1 (See Elimination: Special Populations, under Pharmacokinetics.)

Cautions for Arformoterol Tartrate

Contraindications

Known hypersensitivity to arformoterol, formoterol, or any ingredient in formulation.1

All long-acting β2-adrenergic agonists, including arformoterol, contraindicated in patients with asthma without concomitant use of long-term asthma controller therapy; safety and efficacy of arformoterol in patients with asthma not established.1 (See Asthma-related Death under Cautions.)

Warnings/Precautions

Warnings

Asthma-related Death

Increased risk of asthma-related death reported with long-acting β2-adrenergic agonists.1 (See REMS and also see Boxed Warning.)

All long-acting β2-adrenergic agonists, including arformoterol, contraindicated in patients with asthma without concomitant use of long-term asthma controller therapy.1 Safety and efficacy of arformoterol in patients with asthma not established.1

Data from large placebo-controlled safety study (Salmeterol Multicenter Asthma Research Trial [SMART]) showed an increase in asthma-related deaths in patients receiving salmeterol in addition to usual asthma therapy,1 14 15 16 17 which is considered class effect of long-acting β2-adrenergic agonists, including arformoterol.1 However, no adequate studies conducted to determine whether rate of asthma-related death is increased in patients receiving arformoterol.1 (See Advice to Patients.)

While data from currently available studies do not show increased risk of asthma-related death with racemic formoterol, data from small clinical studies suggest higher incidence of serious asthma exacerbations with formoterol compared with placebo.1 7

Not known whether rate of death is increased in patients with COPD receiving arformoterol.1 2 7 Data from large placebo-controlled study (TOwards a Revolution in COPD Health [TORCH]) evaluating survival in patients with COPD receiving salmeterol, fluticasone propionate, or both drugs over a 3-year period did not reveal an increased incidence of COPD-related or overall deaths in patients receiving salmeterol in addition to usual COPD therapy.22 23

Acute Exacerbations of COPD

Do not initiate therapy in patients with acutely deteriorating COPD, which may be life threatening;1 not indicated for treatment of acute episodes of bronchospasm (i.e., rescue therapy).1 6 Safety and efficacy of arformoterol for relief of acute symptoms of COPD not established.1 6

Failure to respond to a previously effective dosage of arformoterol or supplemental short-acting β2-agonist (e.g., increased need for additional short-acting β2-agonist) may indicate substantially worsening COPD.1 6 Promptly reevaluate COPD therapy.1 6 Do not use extra doses of arformoterol alone or with other long-acting, inhaled β2-adrenergic agonists (e.g., formoterol) for maintenance therapy of COPD or any other reason.1 2 6 7

Cardiovascular Effects

Possible clinically important changes in systolic and/or diastolic BP, heart rate, ECG (e.g., flattening of T wave, prolongation of QTc interval, ST-segment depression) changes, and/or cardiovascular symptoms.1 3 6 13 Such effects uncommon with recommended dosage; may require discontinuance of drug.1 6

Use with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, or hypertension.1 6

Excessive Doses

Fatalities associated with excessive use of inhaled sympathomimetic drugs.1 6 Do not use higher than recommended dosage of arformoterol.1 6

Patients receiving arformoterol should not use additional arformoterol or other long-acting β2-adrenergic agonists for maintenance treatment of COPD.1 2 6

Sensitivity Reactions

Immediate hypersensitivity reactions (e.g., anaphylactic reactions, urticaria, angioedema, rash, bronchospasm) reported.1 6

Major Toxicities

Paradoxical Bronchospasm

Possible acute, life-threatening, paradoxical bronchospasm may occur.1 6

Discontinue therapy immediately if bronchospasm occurs and institute alternative therapy.1 6

General Precautions

Metabolic Effects

Possible hypokalemia; may increase risk of adverse cardiovascular effects.1 3 6 9 11 Hypokalemia usually transient, not requiring supplementation.1

Clinically important changes in blood glucose concentrations possible during long-term therapy at recommended dosage.1 3 6

Use with caution in patients with thyrotoxicosis.1 6

Nervous System Effects

Use with caution in patients with seizure disorders and those unusually responsive to sympathomimetic amines.1 6

Specific Populations

Pregnancy

Category C.1

Lactation

Distributed into milk in rats.1 Not known whether distributed into human milk.1 Use caution.1

Pediatric Use

Safety and efficacy not established.1 COPD does not occur in children.1

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1 Incidence of ventricular ectopy in geriatric patients 65–75 years of age with arformoterol comparable to that with placebo.1

Hepatic Impairment

Because plasma concentrations of arformoterol may be increased in patients with hepatic impairment, use with caution and monitor patients closely.1 (See Absorption under Pharmacokinetics.)

Common Adverse Effects

Pain (unspecified),1 chest pain,1 back pain,1 diarrhea,1 sinusitis,1 leg cramps,1 dyspnea,1 rash,1 flu syndrome,1 peripheral edema,1 lung disorder.1

Interactions for Arformoterol Tartrate

Minimally metabolized by CYP2D6 and CYP2C19 isoenzymes;1 does not inhibit CYP isoenzymes 1A2, 2A6, 2C9/10, 2C19, 2D6, 2E1, 3A4/5, or 4A9/11.1 6

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP2D6: Pharmacokinetic interaction unlikely; dosage adjustment not required.1

Drugs that Prolong QT Interval

Potential pharmacodynamic interaction (increased risk of ventricular arrhythmias).1 Use concomitantly with extreme caution.1 13

Specific Drugs

Drug

Interaction

Comments

β-Adrenergic blocking agents

Potential for antagonism of pulmonary effects, resulting in severe bronchospasm in COPD patients1

If concomitant therapy necessary, consider cautious use of cardioselective β-adrenergic blocker without intrinsic sympathomimetic activity (e.g., metoprolol, atenolol, esmolol)1 10

Use low dosages of cardioselective β-adrenergic blocker initially and titrate upward with caution10

Antidepressants, tricyclic

Potential for increased cardiovascular effects1 6

Use concomitantly with extreme caution1 6

Corticosteroids

Possible potentiation of hypokalemic effects1 6

Diuretics, potassium-depleting

Potential for additive hypokalemia and/or ECG changes, especially when recommended β-agonist dose exceeded1 5

Use concomitantly with caution1

MAO inhibitors

Possible potentiation of cardiovascular effects1

Use concomitantly with extreme caution1

Paroxetine

Pharmacokinetic interaction unlikely with potent CYP2D6 inhibitors (e.g., paroxetine)1

Arformoterol dosage adjustment not necessary1

Sympathomimetic agents

Potential additive pharmacologic effects1

Use caution with concomitant sympathomimetic agents administered by any route1

Xanthine derivatives

Possible potentiation of hypokalemic effects1 13

Arformoterol Tartrate Pharmacokinetics

Absorption

Bioavailability

Approximately 25% of systemic exposure from GI absorption; majority of systemic exposure from pulmonary absorption.1 12 13

Peak plasma concentration usually attained within 0.25–1 hour.1 6 13

Onset

Clinically important bronchodilation (e.g., increase in FEV1 of 15%): Median of 6.7 minutes.1 6 13

Peak effects occur within 1–3 hours.1 6

Duration

12 hours.1 6

Special Populations

In patients with mild to severe hepatic impairment, systemic exposure was 1.3- to 2.4-fold higher than in healthy individuals.1 12 (See Hepatic Impairment under Cautions.)

In patients with mild to severe renal impairment, no marked differences in extent of systemic exposure compared with that in healthy individuals.1

Distribution

Plasma Protein Binding

52–65%.1 13

Elimination

Metabolism

Extensively metabolized in liver, principally to glucuronide (by uridine disphosphoglucuronosyltransferase [UGT] isoenzymes) and sulfate conjugates.1 6 12 13 Metabolized to limited extent by CYP2D6 and CYP2C19 isoenzymes to O-desmethyl metabolite.1 12 13

Elimination Route

Excreted in urine (67%) mainly as metabolites and in feces (22%) over 14 days.1

Half-life

Averages 26 hours at steady state.1 6 12 13

Special Populations

In otherwise healthy individuals with reduced CYP2D6 and/or UGT1A1 activity, no change in systemic exposure compared with healthy individuals with normal enzyme activities.1 (See Special Populations under Dosage and Administration.)

Stability

Storage

Oral Inhalation Solution

2–8°C.1 Store single-use vials in protective foil pouch to protect from light until used.1 Unopened foil pouches may be kept at 20–25°C for ≤6 weeks.1 Discard such unopened foil pouches after >6 weeks or after manufacturer’s labeled expiration date (whichever comes first).1

Once foil pouch has been opened, use immediately.1 Discard vial if solution discolored.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

For information on systemic interactions resulting from concomitant use, see Interactions.

Compatible with ipratropium bromide, acetylcysteine, or budesonide oral inhalation solution when admixed extemporaneously.21 22

Actions

  • Arformoterol is the active R, R-enantiomer of racemic formoterol.1 3 6 12 Arformoterol is twice as potent as racemic formoterol.12 13

  • Stimulates β2-adrenergic receptors and apparently has little or no effect on β1-adrenergic or muscarinic receptors.1 4 7 8

  • Stimulates production of cyclic adenosine-3′, 5′-monophosphate (cAMP), which mediates numerous cellular responses, including bronchial smooth muscle relaxation and inhibition of release of proinflammatory mediators (e.g., histamine, leukotrienes) from mast cells in airways.1 5 8 11 12 13

  • Inhibits allergen-induced infiltration of eosinophils into airways and histamine-induced extravasation of plasma proteins (e.g., albumin) in animal models.1

  • Long-term maintenance therapy (e.g., >6 weeks) associated with development of tolerance to bronchodilatory effects as evidenced by some decrease in FEV1 at the end of the dosing interval.1 13 22

Advice to Patients

  • Provide patients with a copy of the manufacturer's patient information (medication guide) each time the drug is dispensed.24 Importance of instructing patients to read the medication guide prior to initiation of therapy and each time the prescription is refilled.1 2 (See REMS.)

  • Advise of increased risk of asthma-related death with long-acting β2-adrenergic agonists, such as arformoterol.1 19 Do not use any of the long-acting β2-adrenergic agonists, including arformoterol, in patients with asthma without concomitant use of long-term asthma controller therapy.1

  • Advise of potential for adverse effects, such as palpitations, rapid heart rate, tremor, nervousness, or chest pain.1 2

  • Importance of adequate understanding of proper storage, preparation, and inhalation techniques, including use of nebulizer delivery system.1 2

  • Importance of adherence to dosing schedules, including not exceeding recommended dosage or frequency of use unless otherwise instructed by clinician.1

  • Importance of advising patient that if a dose of arformoterol is missed, the next dose should be taken at the regularly scheduled time; dose should not be doubled.1 2

  • Importance of not discontinuing arformoterol therapy without medical supervision, as symptoms may worsen.2

  • Importance of all patients being provided with and instructed in use of short-acting, inhaled β2-adrenergic bronchodilator as supplemental therapy for acute COPD symptoms.1

  • Importance of discontinuing regular use of a short-acting, inhaled β-adrenergic bronchodilator when initiating maintenance therapy with arformoterol and instituting intermittent use of a short-acting bronchodilator (not arformoterol) to relieve acute symptoms of COPD.1 2

  • Importance of not using arformoterol to relieve acute symptoms or exacerbations of COPD.1

  • Importance of contacting clinician immediately if decreased effectiveness occurs and/or breathing problems worsen quickly; do not increase dose or frequency of administration or add therapy with other long-acting, inhaled β2-adrenergic agonists.1 2 6

  • Importance of contacting a clinician immediately if short-acting β2-adrenergic agonist becomes less effective (e.g., increased dosage or frequency of administration) for acute symptoms of COPD.1 2 6

  • Importance of promptly contacting a clinician if symptoms of serious allergic reaction occur, including rash, hives, breathing problems, and swelling of face, mouth, or tongue.1 2

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 2

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, vitamins, and herbal supplements, as well as any concomitant illnesses (e.g., heart problems, high BP, seizures, thyroid disorders, diabetes mellitus, liver disorders).1 2

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Arformoterol Tartrate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral Inhalation

Solution, for Nebulization

7.5 mcg (of arformoterol) per mL

Brovana

Sunovion

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions August 22, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Sunovion Pharmaceuticals, Inc. Brovana (arformoterol tartrate) inhalation solution prescribing information. Marlborough, MA; 2011 Jan.

2. Sunovion Pharmaceuticals, Inc. Brovana (arformoterol tartrate) inhalation solution medication guide. Marlborough, MA; 2011 Jan.

3. Baumgartner RA, Hanania NA, Calhoun WJ et al. Nebulized arformoterol in patients with COPD: A 12-week, multicenter, randomized, double-blind, double-dummy, placebo- and active-controlled trial. Clin Ther. 2007; 29:261-78. [PubMed 17472819]

4. Anon. Arformoterol: (R,R)-eformoterol, (R,R)-formoterol, aformoterol tartrate, eformoterol-Sepracor, formoterol-Sepracor, R,R-eformoterol, R,R-formoterol. Drugs R&D. 2004; 5:25-7.

5. National Heart, Lung, and Blood Institute/World Health Organization. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Bethesda, MD: National Heart, Lung, and Blood Institute, Global Initiative for Chronic Obstructive Lung Disease, World Health Organization; 2006 Nov. Available from website. Accessed 2007 Jun 25.

6. Sepracor. General summary for Brovana (arformoterol tartrate) inhalation solution. Marlborough, MA; undated.

7. Schering. Foradil (formoterol fumarate) aerolizer inhalation powder prescribing information. Kenilworth, NJ; 2006 Jun.

8. Moore RH, Khan A, Dickey BF. Long-acting inhaled β2-agonists in asthma therapy. Chest. 1998; 113:1095-108. [IDIS 404630] [PubMed 9554653]

9. O’Donnell DE, Aaron S, Bourbeau J et al. Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease. 2007 update. Can Respir. 2007; 14 (Suppl. B):5B-32B.

10. Tafreshi MJ, Weinacker AB. Beta-adrenergic-blocking agents in bronchospastic diseases: a therapeutic dilemma. Pharmacotherapy. 1999; 19(8):974-8. [PubMed 10453968]

11. American Thoracic Society and European Respiratory Society. Standards for the diagnosis and management of patients with COPD. New York, NY: American Thoracic Society, European Respiratory Society; 2005 Sep 8. Available from website. Accessed 2007 Aug 2.

12. Cada DJ, Levien T, Baker DE. Arformoterol tartrate. Hosp Pharm. 2007; 42:447-54.

13. Abdelghany O, Merl MY. Arformoterol: the first nebulized long-acting beta2-adrenergic agonist. Formulary. 2007; 42:99-109.

14. Rickard KA. Dear healthcare professional letter regarding important safety information on the use of Serevent in patients with asthma. Rockville, MD: US Food and Drug Administration; 2003 Jan 23. Available from website.

15. Food and Drug Administration. Study of asthma-drug halted. FDA Talk Paper. Rockville, MD: Food and Drug Administration; 2003 Jan 23. Available from website [no longer available online].

16. Lurie P, Wolfe SM. Misleading data analyses in salmeterol (SMART) study. Lancet. 2005; 366:1261-2. [IDIS 541200] [PubMed 16214589]

17. GlaxoSmith Kline. GlaxoSmithKline clinical trial register: salmeterol studies. SLGA5011: a double-blind, randomized, placebo-controlled surveillance study of asthma event outcomes in subjects receiving either usual pharmacolotherapy of asthma or usual pharmacotherapy plus salmeterol 42 mcg twice daily. Research Triangle Park, NC. Available from website. Accessed 2007 Aug 29.

18. Food and Drug Administration. FDA drug safety communication: New safety requirements for long-acting inhaled asthma medications called long-acting beta-agonists (LABAs). Rockville, MD; 2010 Feb 18. Available from FDA website. Accessed 2010 Jul 7.

19. GlaxoWellcome. Serevent Diskus (salmeterol xinafoate) inhalation powder prescribing information. Research Triangle Park, NC; 2007 May.

20. Food and Drug Administration. Approved risk evaluation and mitigation strategies (REMS). Available from FDA website. Accessed 2011 Apr 20.

21. Bonasia P, Cook C, Cheng Y et al. Compatibility of arformoterol tartrate inhalation solution with three nebulized drugs. Curr Med Res Opin. 2007; 23:2477-83. [PubMed 17784997]

22. Sepracor, Marlborough, MA: Personal communication.

23. Calverley PMA, Anderson JA, Celli B et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007; 356:775-89. [PubMed 17314337]

24. Brovana (arformoterol tartrate) inhalation solution risk evaluation and mitigation strategy (REMS). Initial approval 2011 Feb. Revised 2011 Feb. Reference ID: 2906399. Available from FDA website. Accessed 2011 May 13.

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