Arformoterol Tartrate

• 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 beta₂-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.

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 beta₂-agonist.

When beginning arformoterol tartrate inhalation solution, patients who have been taking inhaled short-acting beta₂-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 beta₂-agonist and instruct the patient how it should be used. Increasing inhaled beta₂-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 beta₂-agonist becomes less effective or the patient needs more inhalation of short-acting beta₂-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.

Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. As with other inhaled beta₂-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 beta₂-agonists.

As with other inhaled beta₂-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.

Arformoterol tartrate inhalation solution, like other beta₂-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.

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 μg BID, 25 μg BID, and 50 μg 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-Fcompared to the active comparator, salmeterol. Doses of the related beta₂-agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

Beta-agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects [see

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.

Immediate hypersensitivity reactions may occur after administration of arformoterol tartrate inhalation solution as demonstrated by cases of anaphylactic reaction, urticaria, angioedema, rash and bronchospasm.