ARFORMOTEROL TARTRATE (Page 2 of 8)

5.5 Cardiovascular Effects

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.

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 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 ms increase in QTC-F compared 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.

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 beta2 -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)].

6.1 Beta2 -Agonist Adverse Reaction Profile

Adverse reactions to arformoterol tartrate inhalation solution are expected to be similar in nature to other beta2 -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:N um be r of P at ie nt s Ex per ie nc ing A dver se Eve nt s fr om Tw o 12- Wee k, D ouble- Blind , P lace bo-C ontr olle d Cl inic al Tr ials
Total Patients
Arformoterol Tartrate Inhalation Solution
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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