ARFORMOTEROL: 1,311 Adverse Event Reports & Safety Profile

Arformoterol tartrate inhalation solution is a sterile, clear, colorless, aqueous solution of the tartrate salt of arformoterol, the (R,R)-enantiomer of formoterol. Arformoterol is a selective beta 2 -adrenergic bronchodilator. The chemical name for arformoterol tartrate is formamide, N-[2-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]-, (2R,3R)-2,3-dihydroxybutanedioate (1:1 salt), and its established structural formula is as follows: The molecular weight of arformoterol tartrate is 494.5 g/mol, and its empirical formula is C 19 H 24 N 2 O 4

• C 4 H 6 O 6 (1:1 salt). It is a white or off-white of light brown color powder that is soluble in dimethyl sulphoxide, slightly soluble in water and methanol, insoluble in ethyl acetate. Arformoterol tartrate is the United States Adopted Name (USAN) for (R,R)-formoterol L-tartrate. Arformoterol tartrate inhalation solution is supplied as 2 mL of arformoterol tartrate solution packaged in 3 mL unit-dose, low-density polyethylene (LDPE) unit-dose vials. Each unit-dose vial contains 15 mcg of arformoterol (equivalent to 22 mcg of arformoterol tartrate) in a sterile, isotonic saline solution, pH-adjusted between 4.7 and 5.3 with citric acid and trisodium citrate dihydrate. Arformoterol tartrate inhalation solution requires no dilution before administration by nebulization. Like all other nebulized treatments, the amount delivered to the lungs will depend upon patient factors, the nebulizer used, and compressor performance. Using the PARI LC ® Plus nebulizer (with mouthpiece) connected to a PARI DURA NEB ™ 3000 compressor under in vitro conditions, the mean delivered dose from the mouthpiece (% nominal) was approximately 4.1 mcg (27.6%) at a mean flow rate of 3.3 L/min. The mean nebulization time was 6 minutes or less. Arformoterol tartrate inhalation solution should be administered from a standard jet nebulizer at adequate flow rates via face mask or mouthpiece. Patients should be carefully instructed on the correct use of this drug product (please refer to the accompanying Patient Information ). arformoterol-str.jpg

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.

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 )

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 not indicated for the treatment of asthma.

• 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. ( 4 )

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 Devatis Inc. at 1-833-534-4406 or [email protected] or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch or www.devatis.com.

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

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: 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.

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&apos;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 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-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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2) ]</span>. 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.

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 co-administration 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.