ARFORMOTEROL TARTRATE- arformoterol tartrate_solution

Arformoterol, the (R,R)-enantiomer of formoterol, is a selective long-acting beta 2 2 2 2 1 2 2 The pharmacologic effects of beta 2 In vitro in vitro Systemic Safety and Pharmacokinetic/Pharmacodynamic Relationships The predominant adverse effects of inhaled beta 2 Effects on Serum Potassium and Serum Glucose Levels Changes in serum potassium and serum glucose were evaluated in a dose-ranging study of twice daily (5 mcg, 15 mcg, or 25 mcg; 215 patients with COPD) and once daily (15 mcg, 25 mcg, or 50 mcg; 191 patients with COPD) arformoterol tartrate inhalation solution in COPD patients. At 2 and 6 hours post dose at week 0 (after the first dose), mean changes in serum potassium ranging from 0 to -0. 3 mEq/L were observed in the arformoterol tartrate inhalation solution groups with similar changes observed after 2 weeks of treatment. Changes in mean serum glucose levels, ranging from a decrease of 1. 2 mg/dL to an increase of 32. 8 mg/dL were observed for arformoterol tartrate inhalation solution dose groups at both 2 and 6 hours post dose, both after the first dose and 14 days of daily treatment. Electrophysiology The effect of arformoterol tartrate inhalation solution on QT interval was evaluated in a dose-ranging study following multiple doses of arformoterol tartrate inhalation solution 5 mcg, 15 mcg, or 25 mcg twice daily or 15 mcg, 25 mcg, or 50 mcg once daily for 2 weeks in patients with COPD. ECG assessments were performed at baseline, time of peak plasma concentration and throughout the dosing interval. Different methods of correcting for heart rate were employed, including a subject-specific method and the Fridericia method. Relative to placebo, the mean change in subject-specific QTc averaged over the dosing interval ranged from -1. 7 msec, indicating little effect of arformoterol tartrate inhalation solution on cardiac repolarization after 2 weeks of treatment. The maximum mean change in subject-specific QTc for the arformoterol tartrate inhalation solution 15 mcg twice daily dose was 17. 3 msec, compared with 15. 4 msec in the placebo group. No apparent correlation of QTc with arformoterol plasma concentration was observed. Electrocardiographic Monitoring in Patients with COPD The effect of different doses of arformoterol tartrate inhalation solution on cardiac rhythm was assessed using 24-hour Holter monitoring in two 12-week, double-blind, placebo-controlled studies of 1,456 patients with COPD (873 received arformoterol tartrate inhalation solution at 15 or 25 mcg twice daily or 50 mcg once daily doses; 293 received placebo; 290 received salmeterol). The 24-hour Holter monitoring occurred once at baseline, and up to 3 times during the 12-week treatment period. The rates of new-onset cardiac arrhythmias not present at baseline over the double-blind 12-week treatment period were similar (approximately 33-34%) for patients who received arformoterol tartrate inhalation solution 15 mcg twice daily to those who received placebo. There was a dose-related increase in new, treatment-emergent arrhythmias seen in patients who received arformoterol tartrate inhalation solution 25 mcg twice daily and 50 mcg once daily, 37. 1%, respectively. The frequencies of new treatment-emergent events of non-sustained (3 to 10 beat run) and sustained (>10 beat run) ventricular tachycardia were 7. 1% in arformoterol tartrate inhalation solution 15 mcg twice daily and 6. 0% in placebo. In patients who received arformoterol tartrate inhalation solution 25 mcg twice daily and 50 mcg once daily, the frequencies of non-sustained (6. 2%, respectively) and sustained ventricular tachycardia (1. 0%, respectively) were similar. Five cases of ventricular tachycardia were reported as adverse events (1 in arformoterol tartrate inhalation solution 15 mcg twice daily and 4 in placebo), with two of these events leading to discontinuation of treatment (2 in placebo). There were no baseline occurrences of atrial fibrillation/flutter observed on 24-hour Holter monitoring in patients treated with arformoterol tartrate inhalation solution 15 mcg twice daily or placebo. New, treatment-emergent atrial fibrillation/flutter occurred in 0. 4% of patients who received arformoterol tartrate inhalation solution 15 mcg twice daily and 0. 3% of patients who received placebo. There was a dose-related increase in the frequency of atrial fibrillation/flutter reported in the arformoterol tartrate inhalation solution 25 mcg twice daily and 50 mcg once daily dose groups of 0. 4%, respectively. Two cases of atrial fibrillation/flutter were reported as adverse events (1 in arformoterol tartrate inhalation solution 15 mcg twice daily and 1 in placebo). Dose-related increases in mean maximum change in heart rate in the 12 hours after dosing were also observed following 12 weeks of dosing with arformoterol tartrate inhalation solution 15 mcg twice daily (8. 8 bpm), 25 mcg twice daily (9. 9 bpm) and 50 mcg once daily (12 bpm) versus placebo (8. Tachyphylaxis/Tolerance Tolerance to the effects of inhaled beta-agonists can occur with regularly-scheduled, chronic use. In two placebo-controlled clinical trials in patients with COPD involving approximately 725 patients in each, the overall efficacy of arformoterol tartrate inhalation solution was maintained throughout the 12-week trial duration. However, tolerance to the bronchodilator effect of arformoterol tartrate inhalation solution was observed after 6 weeks of dosing, as measured by a decrease in trough FEV 1 1 1 The pharmacokinetics (PK) of arformoterol have been investigated in healthy subjects, elderly subjects, renally and hepatically impaired subjects, and COPD patients following the nebulization of the recommended therapeutic dose and doses up to 96 mcg. Absorption In COPD patients administered 15 mcg arformoterol every 12 hours for 14 days, the mean steady-state peak (R,R)-formoterol plasma concentration (C max 0-12h max Systemic exposure to (R,R)-formoterol increased linearly with dose in COPD patients following arformoterol doses of 5 mcg, 15 mcg, or 25 mcg twice daily for 2 weeks or 15 mcg, 25 mcg, or 50 mcg once daily for 2 weeks. In a crossover study in patients with COPD, when arformoterol 15 mcg inhalation solution and 12 and 24 mcg formoterol fumarate inhalation powder (Foradil registered registered 0-12h max In a study in patients with asthma, treatment with arformoterol 50 mcg with pre- and post- treatment with activated charcoal resulted in a geometric mean decrease in (R,R)-formoterol AUC 0-6h max Distribution The binding of arformoterol to human plasma proteins in vitro Metabolism In vitro in vitro Arformoterol was almost entirely metabolized following oral administration of 35 mcg of radiolabeled arformoterol in eight healthy subjects. Direct conjugation of arformoterol with glucuronic acid was the major metabolic pathway. Most of the drug-related material in plasma and urine was in the form of glucuronide or sulfate conjugates of arformoterol. O- Desmethylation and conjugates of the O-desmethyl metabolite were relatively minor metabolites accounting for less than 17% of the dose recovered in urine and feces. Elimination After administration of a single oral dose of radiolabeled arformoterol to eight healthy male subjects, 63% of the total radioactive dose was recovered in urine and 11% in feces within 48 hours. A total of 89% of the total radioactive dose was recovered within 14 days, with 67% in urine and 22% in feces. Approximately 1% of the dose was recovered as unchanged arformoterol in urine over 14 days. Renal clearance was 8. 9 L/hr for unchanged arformoterol in these subjects. In COPD patients given 15 mcg inhaled arformoterol twice a day for 14 days, the mean terminal half-life of arformoterol was 26 hours. Special Populations: Gender A population PK analysis indicated that there was no effect of gender upon the pharmacokinetics of arformoterol. Race The influence of race on arformoterol pharmacokinetics was assessed using a population PK analysis and data from healthy subjects. There was no clinically significant impact of race upon the pharmacokinetic profile of arformoterol. Geriatric The pharmacokinetic profile of arformoterol in 24 elderly subjects (aged 65 years or older) was compared to a younger cohort of 24 subjects (18 to 45 years) that were matched for body weight and gender. No significant differences in systemic exposure (AUC and C max Pediatric The pharmacokinetics of arformoterol have not been studied in pediatric subjects. Hepatic Impairment The pharmacokinetic profile of arformoterol was assessed in 24 subjects with mild, moderate, and severe hepatic impairment. The systemic exposure (C max Renal Impairment The impact of renal disease upon the pharmacokinetics of arformoterol was studied in 24 subjects with mild, moderate, or severe renal impairment. Systemic exposure (AUC and C max Drug-Drug Interaction When paroxetine, a potent inhibitor of CYP2D6, was co-administered with arformoterol tartrate inhalation solution at steady-state, exposure to either drug was not altered. Dosage adjustments of arformoterol tartrate inhalation solution are not necessary when the drug is given concomitantly with potent CYP2D6 inhibitors. Arformoterol did not inhibit CYP1A2, CYP2A6, CYP2C9/10, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, or CYP4A9/11 enzymes at >1,000-fold higher concentrations than the expected peak plasma concentrations following a therapeutic dose. Arformoterol is eliminated through the action of multiple drug metabolizing enzymes. Direct glucuronidation of arformoterol is mediated by several UGT enzymes and is the primary elimination route. O-Desmethylation is a secondary route catalyzed by the CYP enzymes CYP2D6 and CYP2C19. In otherwise healthy subjects with reduced CYP2D6 and/or UGT1A1 enzyme activity, there was no impact on systemic exposure to arformoterol compared to subjects with normal CYP2D6 and/or UGT1A1 enzyme activities.

Arformoterol tartrate inhalation solution is a long-acting beta 2 2 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 Important limitations of use: Arformoterol tartrate inhalation solution is not indicated to treat acute deteriorations of chronic obstructive pulmonary disease. 2 Arformoterol tartrate inhalation solution is not indicated to treat asthma. 2 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. 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.

The recommended dose of arformoterol tartrate inhalation solution is one 15 mcg unit-dose vial 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 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 registered trademark For oral inhalation only. A total daily dose of greater than 30 mcg is not recommended. ( 2 One 15 mcg/2 mL vial every 12 hours. ( 2 For use with a standard jet nebulizer (with a face mask or mouthpiece) connected to an air compressor.

=1% and greater than placebo). The rate of COPD exacerbations was also comparable between the arformoterol tartrate inhalation solution 15 mcg twice daily and placebo groups, 12. 1%, respectively. Adults with COPD in Long-Term (52-week) Safety Trial Arformoterol tartrate inhalation solution was evaluated in one 52 week double-blind, randomized, placebo-controlled, safety trial conducted in patients with moderate to severe COPD. The primary endpoint was time to either respiratory death or first COPD exacerbation-related hospitalization, whichever occurred first. The event had to be a death or hospitalization for which the patient's respiratory status was predominant and/or inciting contributor, as determined by the clinical investigator. The objective of the trial was to demonstrate that the risk of respiratory death or COPD exacerbation-related hospitalization for patients treated with arformoterol tartrate inhalation solution was not greater than 40% more than the risk for patient treated with placebo. A total of 841 patients (479 males and 361 females, ages 41 to 94 years old) with COPD were randomized: 420 to arformoterol tartrate inhalation solution 15 mcg twice daily and 421 to placebo. Of the randomized patients, 255 (61%) in the arformoterol tartrate inhalation solution group and 211 (50%) in the placebo group, completed one year of treatment. The trial objective was met demonstrating that COPD patients treated with arformoterol tartrate inhalation solution are not at an increased risk of respiratory death or COPD exacerbation-related hospitalizations compared to placebo.">Long-acting beta 2 [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. 2 To report SUSPECTED ADVERSE REACTIONS, contact Ingenus Pharmaceuticals, LLC at 1-877-748-1970 or FDA at 1-800-FDA-1088 or www. gov/medwatch. Adverse reactions to arformoterol tartrate inhalation solution are expected to be similar in nature to other beta 2 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 Arformoterol Tartrate Inhalation Solution 15 mcg 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 Reported terms coded to "Lung Disorder" were predominantly pulmonary or chest congestion. 7 (2) 2 (1) 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: Cardiovascular Digestive: Metabolic and Nutritional Disorders: Musculoskeletal: Nervous: Respiratory: Skin and Appendages: Special Senses: Urogenital: In these trials, the overall frequency of all cardiovascular adverse events was 6. 9% in arformoterol tartrate inhalation solution 15 mcg twice daily and 13. 3% in the placebo group. There were no frequently occurring specific cardiovascular adverse events for arformoterol tartrate inhalation solution (frequency >=1% and greater than placebo). The rate of COPD exacerbations was also comparable between the arformoterol tartrate inhalation solution 15 mcg twice daily and placebo groups, 12. 1%, respectively. Adults with COPD in Long-Term (52-week) Safety Trial Arformoterol tartrate inhalation solution was evaluated in one 52 week double-blind, randomized, placebo-controlled, safety trial conducted in patients with moderate to severe COPD. The primary endpoint was time to either respiratory death or first COPD exacerbation-related hospitalization, whichever occurred first. The event had to be a death or hospitalization for which the patient's respiratory status was predominant and/or inciting contributor, as determined by the clinical investigator. The objective of the trial was to demonstrate that the risk of respiratory death or COPD exacerbation-related hospitalization for patients treated with arformoterol tartrate inhalation solution was not greater than 40% more than the risk for patient treated with placebo. A total of 841 patients (479 males and 361 females, ages 41 to 94 years old) with COPD were randomized: 420 to arformoterol tartrate inhalation solution 15 mcg twice daily and 421 to placebo. Of the randomized patients, 255 (61%) in the arformoterol tartrate inhalation solution group and 211 (50%) in the placebo group, completed one year of treatment. The trial objective was met demonstrating that COPD patients treated with arformoterol tartrate inhalation solution are not at an increased risk of respiratory death or COPD exacerbation-related hospitalizations compared to placebo.

Arformoterol tartrate inhalation solution is contraindicated in patients with a history of hypersensitivity to arformoterol, racemic formoterol or to any other components of this product. Use of a LABA, including arformoterol tartrate inhalation solution, without an inhaled cortisteroid is contraindicated in patients with asthma [ see Warnings and Precautions (5) Arformoterol tartrate inhalation solution is contraindicated in patients with a history of hypersensitivity to arformoterol, racemic formoterol or to any other components of this product. ( 4 Use of a LABA, including arformoterol tartrate inhalation solution, without an inhaled corticosteroid is contraindicated in patients with asthma.

Hepatic Impairment Use with caution in patients with hepatic impairment. 6 Risk Summary There are no adequate and well-controlled studies in pregnant women. Arformoterol tartrate inhalation solution should only be used during pregnancy if the expected benefit to the patient outweighs the potential risk to the fetus. Women should be advised to contact their physician if they become pregnant while taking arformoterol tartrate inhalation solution. In animal reproduction studies with arformoterol administered by the oral route to rats and rabbits at exposures approximately 370 and 8,400 times the adult exposure at the maximum recommended human daily inhalation dose (MRHDID) of 15 mcg every 12 hours, respectively, there were findings of structural abnormalities, embryofetal and infant mortality, and alterations of growth. These adverse effects generally occurred at large multiples of the MRHDID when arformoterol was administered by the oral route to achieve high systemic exposures. No evidence of fetal harm was observed in rabbits at an exposure approximately 4,900 times the MRHDID. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Labor or Delivery The potential effect of arformoterol tartrate inhalation solution on labor and delivery is unknown. Because of the potential for beta-agonists interference with uterine contractility, use of arformoterol tartrate inhalation solution during labor should be restricted to whom the benefits clearly outweigh the risk. Data Animal Data In an embryofetal development study in which pregnant rats received doses of 1,000, 5,000 or 10,000 mcg/kg/day from gestation days 6 to 17, arformoterol was shown to be teratogenic based upon findings of omphalocele (umbilical hernia), a malformation, in rat fetuses at exposures approximately 370 times adult exposure at the MRHDID (on an AUC basis with maternal oral doses of 1,000 mcg/kg/day and higher. Maternal toxicity was not observed in rats with exposures up to 2,400 times the MRHDID (on an AUC basis with maternal oral doses up to 10,000 mcg/kg/day). A no-observed-adverse-effect-level (NOAEL) for rat fetuses was not identified. In an embryofetal development study in which pregnant rabbits received doses of 20,000, 40,000 or 80,000 mcg/kg/day from gestation days 7 to 20, arformoterol was shown to be teratogenic based upon findings of malpositioned right kidney, a malformation, in rabbit fetuses at exposures approximately 8400 times and higher than the adult exposure at the MRHDID (on an AUC basis with maternal oral doses of 20,000 mcg/kg/day and higher). Malformations including brachydactyly, bulbous aorta, and liver cysts as well as decreased body weights were observed in rabbit fetuses at doses approximately 26,000 times and higher than the MRHDID in adults (on a mcg/m 2 2 Maternal toxicity was observed at doses approximately 26,000 times and higher than the MRHDID in adults (on a mcg/m 2 In a pre- and post-natal development study, female rats received arformoterol at oral doses of 0, 1,000, 5,000, and 10,000 mcg/kg/day from gestation day 6 through lactation day 20. Lengths of gestation for female rats receiving doses 325 times and higher than the MRHDID (on a mcg/m 2 2 2 2 2 2 Risk Summary There are no data on the presence of arformoterol or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. However, arformoterol was excreted in the milk of lactating rats. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for arformoterol tartrate inhalation solution and any potential adverse effects on the breastfed infant from arformoterol tartrate inhalation solution or from the underlying maternal condition. Data Arformoterol and its metabolites were detected in the milk of lactating rats following oral administration of a 10,000 mcg/kg dose of radiolabeled arformoterol tartrate. Arformoterol tartrate 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 arformoterol tartrate inhalation solution in pediatric patients have not been established. Of the 873 patients who received arformoterol tartrate inhalation solution in two placebo-controlled clinical studies in adults with COPD, 391 (45%) were 65 years of age or older while 96 (11%) were 75 years of age or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Among subjects age 65 years and older, 129 (33%) received arformoterol tartrate inhalation solution at the recommended dose of 15 mcg twice daily, while the remainder received higher doses. ECG alerts for ventricular ectopy in patients 65 to <=75 years of age were comparable among patients receiving 15 mcg twice daily, 25 mcg twice daily, and placebo (3. 1%, respectively). A higher frequency (12. 4%) was observed when arformoterol tartrate inhalation solution was dosed at 50 mcg once daily. The clinical significance of this finding is not known. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Arformoterol tartrate inhalation solution should be used cautiously in patients with hepatic impairment due to increased systemic exposure in these patients [ see Clinical Pharmacology (12. 3) The systemic exposure to arformoterol was similar to renally impaired patients compared with demographically matched healthy control subjects [ see Clinical Pharmacology (12.

RECENT MAJOR CHANGES
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DRUG INTERACTIONS
Other adrenergic drugs may potentiate effect. Use with caution. 1 Xanthine derivatives, steroids, diuretics, or non-potassium sparing diuretics may potentiate hypokalemia or ECG changes. 3 MAO inhibitors, tricyclic antidepressants and drugs that prolong the QTc interval may potentiate effect on the cardiovascular system. Use with extreme caution. 4 Beta-blockers may decrease effectiveness. May block bronchodilatory effects of beta-agonists. Use with caution and only when medically necessary. 5 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. 7 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. , 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. 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 co-administration of beta-agonists, including arformoterol tartrate inhalation solution, with non-potassium sparing diuretics. 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. 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. , 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.

OVERDOSAGE
The expected signs and symptoms associated with overdosage of arformoterol tartrate inhalation solution are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms listed under ADVERSE REACTIONS Treatment of overdosage consists of discontinuation of arformoterol tartrate 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 arformoterol tartrate inhalation solution. Cardiac monitoring is recommended in cases of overdosage.
NONCLINICAL TOXICOLOGY
Long-term studies were conducted in mice using oral administration and rats using inhalation administration to evaluate the carcinogenic potential of arformoterol. In a 24-month carcinogenicity study in CD-1 mice, arformoterol caused a dose-related increase in the incidence of uterine and cervical endometrial stromal polyps and stromal cell sarcoma in female mice at oral doses of 1,000 mcg/kg and above (AUC exposure approximately 70 times adult exposure at the MRHDID). In a 24-month carcinogenicity study in Sprague-Dawley rats, arformoterol caused a statistically significant increase in the incidence of thyroid gland c-cell adenoma and carcinoma in female rats at an inhalation dose of 200 mcg/kg (AUC exposure approximately 130 times adult exposure at the MRHDID). There were no tumor findings with an inhalation dose of 40 mcg/kg (AUC exposure approximately 55 times adult exposure at the MRHDID). Arformoterol was not mutagenic or clastogenic in the following tests: mutagenicity tests in bacteria, chromosome aberration analyses in mammalian cells, and micronucleus test in mice. Arformoterol had no effects on fertility and reproductive performance in rats at oral doses up to 10,000 mcg/kg (approximately 3,200 times the MRHDID in adults on a mcg/m 2 Animal Pharmacology In animal studies investigating its cardiovascular effects, arformoterol induced dose-dependent increases in heart rate and decreases in blood pressure consistent with its pharmacology as a beta-adrenergic agonist. In dogs, at systemic exposures higher than anticipated clinically, arformoterol also induced exaggerated pharmacologic effects of a beta-adrenergic agonist on cardiac function as measured by electrocardiogram (sinus tachycardia, atrial premature beats, ventricular escape beats, PVCs). Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines are administered concurrently. The clinical significance of these findings is unknown.
CLINICAL STUDIES
Arformoterol tartrate inhalation solution was studied in two identical, 12-week, double-blind, placebo- and active-controlled, randomized, multi-center, parallel group trials conducted in the United States (Clinical Trial A and Clinical Trial B). A total of 1,456 adult patients (age range: 34 to 89 years; mean age: 63 years; gender: 860 males and 596 females) with COPD who had a mean FEV 1 1 1 1 1 1 1 1 1 Figure 1 Mean Change in FEV 1 Figure 2 Mean Change in FEV 1 Arformoterol tartrate inhalation solution 15 mcg twice daily significantly improved bronchodilation compared to placebo over the 12 hours after dosing (FEV 1 0 to 12h Following the first dose of arformoterol tartrate inhalation solution 15 mcg, the median time to onset of bronchodilation, defined by an FEV 1 1 In both clinical trials, compared to placebo, patients treated with arformoterol tartrate inhalation solution demonstrated improvements in peak expiratory flow rates, supplemental ipratropium and rescue albuterol use. Image Image.

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