Arformoterol

12.1 Mechanism of Action Arformoterol, the (R,R)-enantiomer of formoterol, is a selective long-acting beta 2 -adrenergic receptor agonist (beta 2 -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 beta 2 -agonist than the (R,R)-enantiomer. While it is recognized that beta 2 -receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta 1 -receptors are the predominant receptors in the heart, data indicate that there are also beta 2 -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 beta 2 -agonists may have cardiac effects. The pharmacologic effects of beta 2 -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. In vitro tests show that arformoterol is an inhibitor of the release of mast cell mediators, such as histamine and leukotrienes, from the human lung. Arformoterol also inhibits histamine-induced plasma albumin extravasation in anesthetized guinea pigs and inhibits allergen-induced eosinophil influx in dogs with airway hyper-responsiveness. The relevance of these in vitro and animal findings to humans is unknown.

1 INDICATIONS AND USAGE Arformoterol tartrate inhalation solution is a long-acting beta 2 -adrenergic agonist (beta 2 -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. ( 1.1 ) Important limitations of use: Arformoterol tartrate inhalation solution is not indicated to treat acute deteriorations of chronic obstructive pulmonary disease. ( 1.2 , 5.2 ) Arformoterol tartrate inhalation solution is not indicated to treat asthma. ( 1.2 ) 1.1 Maintenance Treatment of COPD Arformoterol tartrate inhalation solution is indicated for the long-term, twice daily (morning and evening) maintenance treatment of bronchoconstriction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. Arformoterol tartrate inhalation solution is for use by nebulization only. 1.2 Important Limitations of Use Arformoterol tartrate inhalation solution is not indicated to treat acute deteriorations of chronic obstructive pulmonary disease [see Warnings and Precautions ( 5.2 )] . Arformoterol tartrate inhalation solution is not indicated to treat asthma. The safety and effectiveness of arformoterol tartrate inhalation solution in asthma have not been established.

2 DOSAGE AND ADMINISTRATION The recommended dose of arformoterol tartrate inhalation solution is one 15 mcg unit-dose ampule administered twice daily (morning and evening) by nebulization. A total daily dose of greater than 30 mcg (15 mcg twice daily) is not recommended. Arformoterol tartrate inhalation solution should be administered by the orally inhaled route via a standard jet nebulizer connected to an air compressor (see the accompanying Patient Information ). Arformoterol tartrate inhalation solution should not be swallowed. Arformoterol tartrate inhalation solution should be stored refrigerated in foil pouches. After opening the pouch, unused unit-dose ampules should be returned to, and stored in, the pouch. An opened unit-dose ampule should be used right away. If the recommended maintenance treatment regimen fails to provide the usual response, medical advice should be sought immediately, as this is often a sign of destabilization of COPD. Under these circumstances, the therapeutic regimen should be reevaluated and additional therapeutic options should be considered. No dose adjustment is required for patients with renal or hepatic impairment. However, since the clearance of arformoterol tartrate inhalation solution is prolonged in patients with hepatic impairment, they should be monitored closely. The drug compatibility (physical and chemical), efficacy, and safety of arformoterol tartrate inhalation solution when mixed with other drugs in a nebulizer have not been established. The safety and efficacy of arformoterol tartrate inhalation solution have been established in clinical trials when administered using the PARI LC ® Plus nebulizer (with a face mask or mouthpiece) and the PARI DURA NEB™ 3000 compressor. The safety and efficacy of arformoterol tartrate inhalation solution delivered from non-compressor based nebulizer systems have not been established. For oral inhalation only. A total daily dose of greater than 30 mcg is not recommended. ( 2 ) One 15 mcg/2 mL ampule every 12 hours. ( 2 ) For use with a standard jet nebulizer (with a face mask or mouthpiece) connected to an air compressor. ( 2 )

6 ADVERSE REACTIONS Long-acting beta 2 -adrenergic agonists, such as arformoterol tartrate, as monotherapy (without inhaled corticosteroids) for asthma increase the risk of asthma-related events. Arformoterol tartrate inhalation solution is not indicated for the treatment of asthma [see Warnings and Precautions ( 5.1 )] . 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. ( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals USA, Inc. at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Beta 2 -Agonist Adverse Reaction Profile Adverse reactions to arformoterol tartrate inhalation solution are expected to be similar in nature to other beta 2 -adrenergic receptor agonists including: angina, hypertension or hypotension, tachycardia, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, muscle cramps, nausea, dizziness, fatigue, malaise, hypokalemia, hyperglycemia, metabolic acidosis and insomnia. 6.2 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 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 clinical practice. Adults with COPD in Short-Term Trials (12 weeks) The safety data described below for adults ≥35 years of age are based on 2 clinical trials of 12 weeks. In the 2 trials of 12 weeks duration, 1456 patients (860 males and 596 females, ages 34 to 89 years old) with COPD were treated with arformoterol tartrate inhalation solution 15 mcg twice daily, 25 mcg twice daily, 50 mcg once daily, salmeterol 42 mcg twice daily, or placebo. The racial/ethnic distribution in these two trials included 1383 Caucasians, 49 Blacks, 10 Asians, and 10 Hispanics, and 4 patients classified as Other. Among the 1,456 COPD patients in two 12-week, placebo-controlled trials, 288 were treated with arformoterol tartrate inhalation solution 15 mcg twice daily and 293 were treated with placebo. Doses of 25 mcg twice daily and 50 mcg once daily were also evaluated. Table 1 shows adverse reaction rates among patients from these two trials where the frequency was greater than or equal to 2% in the arformoterol tartrate inhalation solution 15 mcg twice daily group and where the rate in the arformoterol tartrate inhalation solution 15 mcg twice daily group exceeded the rate in the placebo group. The total number and percent of patients who reported adverse events were 202 (70%) in the 15 mcg twice daily and 219 (75%) in the placebo groups. Ten adverse events demonstrated a dose relationship: asthenia, fever, bronchitis, COPD, headache, vomiting, hyperkalemia, leukocytosis, nervousness, and tremor. Table 1: Number of Patients Experiencing Adverse Events from Two 12-Week, Double-Blind, Placebo-Controlled Clinical Trials Total Patients Arformoterol Tartrate Inhalation Solution 15 mcg twice daily Placebo n (%) n (%) 288 (100) 293 (100) Pain 23 (8) 16 (5) Chest Pain 19 (7) 19 (6) Back Pain 16 (6) 6 (2) Diarrhea 16 (6) 13 (4) Sinusitis 13 (5) 11 (4) Leg Cramps 12 (4) 6 (2) Dyspnea 11 (4) 7 (2) Rash 11 (4) 5 (2) Flu Syndrome 10 (3) 4 (1) Peripheral Edema 8 (3) 7 (2) Lung Disorder* 7 (2) 2 (1) * Reported terms coded to “Lung Disorder” were predominantly pulmonary or chest congestion. Adverse events occurring in patients treated with arformoterol tartrate inhalation solution 15 mcg twice daily with a frequency of <2%, but greater than placebo, were as follows: Body as a Whole: abscess, allergic reaction, digitalis intoxication, fever, hernia, injection site pain, neck rigidity, neoplasm, pelvic pain, retroperitoneal hemorrhage Cardiovascular: arteriosclerosis, atrial flutter, AV block, congestive heart failure, heart block, myocardial infarct, QT interval prolonged, supraventricular tachycardia, inverted T-wave Digestive: constipation, gastritis, melena, oral moniliasis, periodontal abscess, rectal hemorrhage Metabolic and Nutritional Disorders: dehydration, edema, glucose tolerance decreased, gout, hyperglycemia, hyperlipemia, hypoglycemia, hypokalemia Musculoskeletal: arthralgia, arthritis, bone disorder, rheumatoid arthritis, tendinous contracture Nervous: agitation, cerebral infarct, circumoral paresthesia, hypokinesia, paralysis, somnolence, tremor Respiratory: carcinoma of the lung, respiratory disorder, voice alteration Skin and Appendages: dry skin, herpes simplex, herpes zoster, skin discoloration, skin hypertrophy Special Senses: abnormal vision, glaucoma Urogenital: breast neoplasm, calcium crystalluria, cystitis, glycosuria, hematuria, kidney calculus, nocturia, PSA increase, pyuria, urinary tract disorder, urine abnormality. In these trials, the overall frequency of all cardiovascular adverse events was 6.9% in arformoterol tartrate inhalation solut

7 DRUG INTERACTIONS Other adrenergic drugs may potentiate effect. Use with caution. ( 5.3 , 7.1 ) Xanthine derivatives, steroids, diuretics, or non-potassium sparing diuretics may potentiate hypokalemia or ECG changes. Use with caution. ( 5.7 , 7.2 , 7.3 ) MAO inhibitors, tricyclic antidepressants and drugs that prolong the QTc interval may potentiate effect on the cardiovascular system. Use with extreme caution. ( 7.4 ) Beta-blockers may decrease effectiveness. May block bronchodilatory effects of beta-agonists. Use with caution and only when medically necessary. ( 7.5 ) 7.1 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 [see Warnings and Precautions ( 5.3 , 5.5 , 5.6 , 5.7 )] . 7.2 Xanthine Derivatives, Steroids, or Diuretics Concomitant treatment with methylxanthine (aminophylline, theophylline), steroids, or diuretics may potentiate any hypokalemic effect of adrenergic agonists including arformoterol tartrate inhalation solution [see Warnings and Precautions ( 5.7 )] . The concurrent use of intravenously or orally administered methylxanthines (e.g., aminophylline, theophylline) by patients receiving arformoterol tartrate inhalation solution has not been completely evaluated. In two combined 12-week, placebo-controlled trials that included arformoterol tartrate inhalation solution doses of 15 mcg twice daily, 25 mcg twice daily, and 50 mcg once daily, 54 of 873 arformoterol tartrate inhalation solution-treated subjects received concomitant theophylline at study entry. In a 12-month controlled trial that included a 50 mcg once daily arformoterol tartrate inhalation solution dose, 30 of the 528 arformoterol tartrate inhalation solution-treated subjects received concomitant theophylline at study entry. In these trials, heart rate and systolic blood pressure were approximately 2 to 3 bpm and 6 to 8 mm Hg higher, respectively, in subjects on concomitant theophylline compared with the overall population. 7.3 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 arformoterol tartrate inhalation solution, with non-potassium sparing diuretics. 7.4 MAO Inhibitors, Tricyclic Antidepressants, QTc Prolonging Drugs Arformoterol tartrate 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. Drugs that are known to prolong the QTc interval have an increased risk of ventricular arrhythmias. 7.5 Beta-Blockers Beta-adrenergic receptor antagonists (beta-blockers) and arformoterol tartrate 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.