Generic: ARFORMOTEROL TARTRATE
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 ...
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.
5 WARNINGS AND PRECAUTIONS LABA as monotherapy (without an inhaled corticosteroid) for asthma increases the risk of serious asthma-related events. ( 5.1 ) Do not initiate arformoterol tartrate inhalation solution in acutely deteriorating patients. ( 5.2 ) Do not use for relief of acute symptoms. Concomitant short-acting beta 2 -agonists can be used as needed for acute relief. ( 5.2 ) Do not exceed the recommended dose. Excessive use of arformoterol tartrate inhalation solution, or use in conjunc...
5 WARNINGS AND PRECAUTIONS LABA as monotherapy (without an inhaled corticosteroid) for asthma increases the risk of serious asthma-related events. ( 5.1 ) Do not initiate arformoterol tartrate inhalation solution in acutely deteriorating patients. ( 5.2 ) Do not use for relief of acute symptoms. Concomitant short-acting beta 2 -agonists can be used as needed for acute relief. ( 5.2 ) Do not exceed the recommended dose. Excessive use of arformoterol tartrate inhalation solution, or use in conjunction with other medications containing long-acting beta 2 -agonists, can result in clinically significant cardiovascular effects, and may be fatal. ( 5.3 , 5.5 ) Life-threatening paradoxical bronchospasm can occur. Discontinue arformoterol tartrate inhalation solution immediately. ( 5.4 ) Use with caution in patients with cardiovascular or convulsive disorders, thyrotoxicosis, or with sensitivity to sympathomimetic drugs. ( 5.6 , 5.7 ) 5.1 Serious Asthma-Related Events - Hospitalizations, Intubations, Deaths The safety and efficacy of arformoterol tartrate inhalation solution in patients with asthma have not been established. Arformoterol tartrate inhalation solution is not indicated for the treatment of asthma [see Contraindications ( 4 )] . Use of long-acting beta 2 -adrenergic agonists (LABA) as monotherapy [without inhaled corticosteroids (ICS)] for asthma is associated with an increased risk of asthma-related death. Available data from controlled clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric and adolescent patients. These findings are considered a class effect of LABA monotherapy. When LABA are used in fixed-dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, and death) compared with ICS alone. A 28-week, placebo-controlled US study comparing the safety of another LABA (salmeterol) with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in patients receiving salmeterol (13/13,176 in patients treated with salmeterol vs. 3/13,179 in patients treated with placebo; RR 4.37, 95% CI 1.25, 15.34). The increased risk of asthma-related death is considered a class effect of the LABA, including arformoterol tartrate inhalation solution. No study adequate to determine whether the rate of asthma-related death is increased in patients treated with arformoterol tartrate inhalation solution has been conducted. Clinical studies with racemic formoterol suggested a higher incidence of serious asthma exacerbations in patients who received racemic formoterol than in those who received placebo. The sizes of these studies were not adequate to precisely quantify the differences in serious asthma exacerbation rates between treatment groups. Available data do not suggest an increased risk of death with use of LABA in patients with COPD. 5.2 Deterioration of Disease and Acute Episodes Arformoterol tartrate inhalation solution should not be initiated in patients with acutely deteriorating COPD, which may be a life-threatening condition. The use of arformoterol tartrate inhalation solution in this setting is inappropriate. Arformoterol tartrate inhalation solution is not indicated for the treatment of acute episodes of bronchospasm, i.e., as rescue therapy and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled short-acting beta 2 -agonist. When beginning arformoterol tartrate inhalation solution, patients who have been taking inhaled short-acting beta 2 -agonists on a regular basis (e.g., four times a day) should be instructed to discontinue the regular use of these drugs and use them only for symptomatic relief of acute respiratory symptoms. When prescribing arformoterol tartrate inhalation solution, the healthcare provider should also prescribe an inhaled, short-acting beta 2 -agonist and instruct the patient how it should be used. Increasing inhaled beta 2 -agonist use is a signal of deteriorating disease for which prompt medical attention is indicated. COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If arformoterol tartrate inhalation solution no longer controls the symptoms of bronchoconstriction, or the patient’s inhaled, short-acting beta 2 -agonist becomes less effective or the patient needs more inhalation of short-acting beta 2 -agonist than usual, these may be markers of deterioration of disease. In this setting, a reevaluation of the patient and the COPD treatment regimen should be undertaken at once. Increasing the daily dosage of arformoterol tartrate inhalation solution beyond the recommended 15 mcg twice daily dose is not appropriate in this situation. 5.3 Excessive Use of Arformoterol Tartrate Inhalation Solution and Use with Other Long-Acting Beta 2 -Agonists Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. As with other inhaled beta 2 -adrenergic drugs, arformoterol tartrate inhalation solution should not be used more often, at higher doses than recommended, or in conjunction with other medications containing long-acting beta 2 -agonists. 5.4 Paradoxical Bronchospasm As with other inhaled beta 2 -agonists, arformoterol tartrate inhalation solution can produce paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs, arformoterol tartrate inhalation solution should be discontinued immediately and alternative therapy instituted. 5.5 Cardiovascular Effects Arformoterol tartrate inhalation solution, like other beta 2 -agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic and/or diastolic blood pressure, and/or symptoms. If such effects occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce ECG changes, such as flattening of the T-wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Arformoterol tartrate inhalation solution, as with other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. 5.6 Coexisting Conditions Arformoterol tartrate inhalation solution, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension; in patients with convulsive disorders or thyrotoxicosis, and in patients who are unusually responsive to sympathomimetic amines. In two pooled, 12-week, placebo-controlled trials investigating arformoterol tartrate inhalation solution doses of 15 mcg BID, 25 mcg BID, and 50 mcg QD, changes in mean predose and 2-hour post dose systolic and/or diastolic blood pressure were seen as a general fall of 2 to 4 mm/Hg; for pulse rate the mean of maximal increases were 8.8 to 12.0 beats/min. Over the course of a one-year study measuring serial electrocardiograms while receiving a dose of 50 mcg daily of arformoterol tartrate inhalation solution resulted in an approximately 3.0 ms increase in QT C-F compared to the active comparator, salmeterol. Doses of the related beta 2 -agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. 5.7 Hypokalemia and Hyperglycemia Beta-agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects [see Clinical Pharmacology ( 12.2 )] . The decrease in serum potassium is usually transient, not requiring supplementation. Beta-agonist medications may produce transient hyperglycemia in some patients. Clinically significant and dose-related changes in serum potassium and blood glucose were infrequent during clinical trials with long-term administration of arformoterol tartrate inhalation solution at the recommended dose. 5.8 Immediate Hypersensitivity Reactions Immediate hypersensitivity reactions may occur after administration of arformoterol tartrate inhalation solution as demonstrated by cases of anaphylactic reaction, urticaria, angioedema, rash and bronchospasm.
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, periph...
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 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, 12.2% and 15.1%, 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.
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