CLINICAL PHARMACOLOGY
Mechanism of Action
Salmeterol is a long-acting beta2-adrenergic agonist. In vitro studies and in vivo pharmacologic studies demonstrate that salmeterol is selective for beta2-adrenoceptors compared with isoproterenol, which has approximately equal agonist activity on beta1- and beta2-adrenoceptors. In vitro studies show salmeterol to be at least 50 times more selective for beta2-adrenoceptors than albuterol. Although beta2-adrenoceptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-adrenoceptors are the predominant receptors in the heart, there are also beta2-adrenoceptors in the human heart comprising 10% to 50% of the total beta-adrenoceptors. The precise function of these is not yet established, but they raise the possibility that even highly selective beta2-agonists may have cardiac effects.
The pharmacologic effects of beta2-adrenoceptor agonist drugs, including salmeterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3′,5′-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.
In vitro tests show that salmeterol is a potent and long-lasting inhibitor of the release of mast cell mediators, such as histamine, leukotrienes, and prostaglandin D2, from human lung. Salmeterol inhibits histamine-induced plasma protein extravasation and inhibits platelet activating factor-induced eosinophil accumulation in the lungs of guinea pigs when administered by the inhaled route. In humans, single doses of salmeterol attenuate allergen-induced bronchial hyper-responsiveness.
Pharmacokinetics
Salmeterol xinafoate, an ionic salt, dissociates in solution so that the salmeterol and 1-hydroxy-2-naphthoic acid (xinafoate) moieties are absorbed, distributed, metabolized, and excreted independently. Salmeterol acts locally in the lung; therefore, plasma levels do not predict therapeutic effect.
Absorption
Because of the small therapeutic dose, systemic levels of salmeterol are low or undetectable after inhalation of recommended doses (42 mcg of salmeterol inhalation aerosol twice daily). Following chronic administration of an inhaled dose of 42 mcg twice daily, salmeterol was detected in plasma within 5 to 10 minutes in 6 patients with asthma; plasma concentrations were very low, with peak concentrations of 150 pg/mL and no accumulation with repeated doses. Larger inhaled doses gave approximately proportionally increased blood levels. In these patients, a second peak concentration of 115 pg/mL occurred at about 45 minutes, probably due to absorption of the swallowed portion of the dose (most of the dose delivered by a metered-dose inhaler is swallowed).
Distribution
Binding of salmeterol to human plasma proteins averages 96% in vitro over the concentration range of 8 to 7,722 ng of salmeterol base per milliliter, much higher than those achieved following therapeutic doses of salmeterol.
Metabolism
Salmeterol base is extensively metabolized by hydroxylation, with subsequent elimination predominantly in the feces. No significant amount of unchanged salmeterol base was detected in either urine or feces.
Excretion
In 2 healthy subjects who received 1 mg of radiolabeled salmeterol (as salmeterol xinafoate) orally, approximately 25% and 60% of the radiolabeled salmeterol was eliminated in urine and feces, respectively, over a period of 7 days. The terminal elimination half-life was about 5.5 hours (1 volunteer only).
The xinafoate moiety has no apparent pharmacologic activity. The xinafoate moiety is highly protein bound (>99%) and has a long elimination half-life of 11 days.
Special Populations
The pharmacokinetics of salmeterol base has not been studied in elderly patients or in patients with hepatic or renal impairment. Since salmeterol is predominantly cleared by hepatic metabolism, liver function impairment may lead to accumulation of salmeterol in plasma. Therefore, patients with hepatic disease should be closely monitored.
Pharmacodynamics
Inhaled salmeterol, like other beta-adrenergic agonist drugs, can in some patients produce dose-related cardiovascular effects and effects on blood glucose and/or serum potassium (see PRECAUTIONS). The cardiovascular effects (heart rate, blood pressure) associated with salmeterol occur with similar frequency, and are of similar type and severity, as those noted following albuterol administration.
The effects of rising doses of salmeterol and standard inhaled doses of albuterol were studied in volunteers and in patients with asthma. Salmeterol doses up to 84 mcg administered as inhalation aerosol resulted in heart rate increases of 3 to 16 beats/min, about the same as albuterol dosed at 180 mcg by inhalation aerosol (4 to 10 beats/min). In 2 double-blind asthma studies, patients receiving either 42 mcg of salmeterol inhalation aerosol twice daily (N = 81) or 180 mcg of albuterol inhalation aerosol 4 times daily (N = 80) underwent continuous electrocardiographic monitoring during four 24-hour periods; no clinically significant dysrhythmias were noted. Continuous electrocardiographic monitoring was also performed in 2 double-blind studies in patients with chronic obstructive pulmonary disease (COPD) (see ADVERSE REACTIONS).
Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac 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.
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CLINICAL TRIALS
Asthma
In placebo- and albuterol-controlled, single-dose clinical trials with SEREVENT Inhalation Aerosol, the time to onset of effective bronchodilatation (>15% improvement in forced expiratory volume in 1 second [FEV1]) was 10 to 20 minutes after a 42-mcg dose. Maximum improvement in FEV1 generally occurred within 180 minutes, and clinically significant improvement continued for 12 hours in most patients.
In 2 large, randomized, double-blind studies, SEREVENT Inhalation Aerosol was compared with albuterol and placebo in patients with mild-to-moderate asthma, including both patients who did and who did not receive concomitant inhaled corticosteroids. The efficacy of SEREVENT Inhalation Aerosol was demonstrated over the 12-week period with no change in effectiveness over this period of time. There were no gender-related differences in safety or efficacy. No development of tachyphylaxis to the bronchodilator effect has been noted in these studies. FEV1 measurements (percent of predicted) from these two 12-week trials are shown in Figure 1 for both the first and last treatment days.
Figure 1. FEV1, as Percent of Predicted, From 2 Large 12-Week Clinical Trials
First Treatment Day
Last Treatment Day (Week 12)
Table 1 shows the treatment effects seen during daily treatment with SEREVENT Inhalation Aerosol for 12 weeks in patients with asthma.
Table 1. Daily Efficacy Measurements in 2 Large 12-Week Clinical Trials (Combined Data) |
Parameter
|
Time
|
Placebo
|
SEREVENT Inhalation Aerosol
|
Albuterol Inhalation Aerosol
|
|
No. of randomized subjects
| |
187
|
184
|
185
|
|
Mean AM peak expiratory flow (L/min)
|
baseline
12 weeks
|
412
414
|
409
438*
|
398
390
|
|
Mean % days with no asthma symptoms
|
baseline
12 weeks
|
11
17
|
11
35*
|
14
24
|
|
Mean % nights with no awakenings
|
baseline
12 weeks
|
67
74
|
67
87*
|
65
74
|
|
Rescue medications (mean no. of inhalations per day)
|
baseline
12 weeks
|
4.4
3.3
|
4.1
1.3†‡
|
4.0
1.9
|
|
Asthma exacerbations
| |
17%
|
11%
|
14%
|
*p<0.001 versus albuterol and placebo.
†p<0.05 versus albuterol.
‡p<0.001 versus placebo.
Safe usage with maintenance of efficacy for periods up to 1 year has been documented.
Effects in Patients With Asthma on Concomitant Inhaled Corticosteroids
In 4 clinical trials in adult and adolescent patients with asthma (N = 1,922), the effect of adding salmeterol to inhaled corticosteroid therapy was evaluated. The studies utilized the inhalation aerosol formulation of salmeterol xinafoate for a treatment period of 6 months. They compared the addition of salmeterol therapy to an increase (at least doubling) of the inhaled corticosteroid dose.
Two randomized, double-blind, parallel-group clinical trials (N = 997) enrolled patients (ages 18 to 82 years) with persistent asthma who were previously maintained but not adequately controlled on inhaled corticosteroid therapy. During the 2-week run-in period, all patients were switched to beclomethasone dipropionate 168 mcg twice daily. Patients still not adequately controlled were randomized to either the addition of SEREVENT Inhalation Aerosol 42 mcg twice daily or an increase of beclomethasone dipropionate to 336 mcg twice daily. As compared to the doubled dose of beclomethasone dipropionate, the addition of salmeterol resulted in statistically significantly greater improvements in pulmonary function and asthma symptoms, and statistically significantly greater reduction in supplemental albuterol use. The percent of patients who experienced asthma exacerbations overall was not different between groups (i.e., 16.2% in the salmeterol group versus 17.9% in the higher-dose beclomethasone dipropionate group).
Two randomized, double-blind, parallel-group clinical trials (N = 925) enrolled patients (ages 12 to 78 years) with persistent asthma who were previously maintained but not adequately controlled on prior therapy. During the 2- to 4-week run-in period, all patients were switched to fluticasone propionate 88 mcg twice daily. Patients still not adequately controlled were randomized to either the addition of SEREVENT Inhalation Aerosol 42 mcg twice daily or an increase of fluticasone propionate to 220 mcg twice daily. As compared to the increased (2.5 times) dose of fluticasone propionate, the addition of salmeterol resulted in statistically significantly greater improvements in pulmonary function and asthma symptoms, and statistically significantly greater reduction in supplemental albuterol use. Fewer patients receiving salmeterol experienced asthma exacerbations than those receiving the higher dose of fluticasone propionate (8.8% versus 13.8%).
Salmeterol Multi-center Asthma Research Trial
The Salmeterol Multi-center Asthma Research Trial (SMART) was a randomized, double-blind study that enrolled long-acting beta2-agonist−naive patients with asthma (average age of 39 years, 71% Caucasian, 18% African American, 8% Hispanic) to assess the safety of salmeterol (SEREVENT Inhalation Aerosol, 42 mcg twice daily over 28 weeks) compared to placebo when added to usual asthma therapy. The primary endpoint was the combined number of respiratory-related deaths or respiratory-related life-threatening experiences (intubation and mechanical ventilation). Secondary endpoints included combined asthma-related deaths or life-threatening experiences and asthma-related deaths. A planned interim analysis was conducted when approximately half of the intended number of patients had been enrolled (N = 26,355).
Due to the low rate of primary events in the study, the findings of the planned interim analysis were not conclusive. However, analyses of secondary endpoints suggested that patients receiving salmeterol may be at increased risk for some of these events compared to patients receiving placebo. The analysis for the total population showed a relative risk of 1.40 (95% CI 0.91, 2.14) for the primary endpoint in the salmeterol group relative to the placebo group (50 out of 13,176 vs. 36 out of 13,179, respectively). In the total population, a higher number of asthma-related deaths (13 vs. 3, RR 4.37, 95% CI 1.25, 15.34) and combined asthma-related deaths or life-threatening experiences (37 vs. 22, RR 1.71, 95% CI 1.01, 2.89) occurred in patients treated with salmeterol than those treated with placebo. The analysis of the African American subgroup showed a relative risk of 4.10 (95% CI 1.54, 10.90) for the primary endpoint in patients treated with salmeterol relative to those treated with placebo (20 out of 2,366 vs. 5 out of 2,319, respectively). In African Americans, a higher number of asthma-related deaths (7 vs. 1, RR 7.26, 95% CI 0.89, 58.94) and combined asthma-related deaths or life-threatening experiences (19 vs. 4, RR 4.92, 95% CI 1.68, 14.45) occurred in patients treated with salmeterol than those treated with placebo. Analysis of the Caucasian population showed a relative risk of 1.05 (95% CI 0.62, 1.76) for the primary endpoint for those treated with salmeterol relative to those treated with placebo (29 out of 9,281 vs. 28 out of 9,361, respectively). In Caucasians, a higher number of asthma-related deaths (6 vs. 1, RR 5.82, 95% CI 0.70, 48.37) occurred in patients treated with salmeterol than in patients treated with placebo. In Caucasians, the relative risk was 1.08 (17 vs. 16, 95% CI 0.55, 2.14) for combined asthma-related deaths or life-threatening experiences in patients treated with salmeterol relative to placebo. The numbers of patients from other ethnic groups were too small to draw any conclusions in these populations. Even though SMART did not reach predetermined stopping criteria for the total population, the study was stopped due to the findings in African American patients and difficulties in enrollment.
Exercise-Induced Bronchospasm
Protection against exercise-induced bronchospasm (EIB) was examined in 3 controlled studies. Based on median values, patients who received SEREVENT Inhalation Aerosol had consistently less exercise-induced fall in FEV1 than patients who received placebo, and they were protected for a longer period of time than patients who received albuterol (see Table 2). There were, however, some patients who were not protected from EIB after SEREVENT administration and others in whom protection against EIB decreased with continued administration over a period of 4 weeks.
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Clinical Trials/Time After Dose
|
Treatment
|
|
Placebo
|
SEREVENT Inhalation Aerosol
|
Albuterol Inhalation Aerosol
|
|
Study A: 1st Dose
| | | |
|
6 hours
|
37
|
9*
| |
|
12 hours
|
27
|
16*
| |
|
Study A: 4th Week
| | | |
|
6 hours
|
30
|
19
| |
|
12 hours
|
24
|
12
| |
|
Study B:
| | | |
|
1 hour
|
37
|
0*
|
2*
|
|
6 hours
|
37
|
5*†
|
27
|
|
12 hours
|
34
|
6*†
|
33
|
|
Study C:
| | | |
|
0.5 hour
|
43
|
16*
|
8*
|
|
2.5 hours
|
33
|
12*†
|
30
|
|
4.5 hours
|
--
|
12†
|
36
|
|
6.0 hours
|
--
|
19†
|
41
|
*Statistically superior to placebo (p≤0.05).
†Statistically superior to albuterol (p≤0.05).
Chronic Obstructive Pulmonary Disease
In 2 large randomized, double-blind studies, SEREVENT Inhalation Aerosol administered twice daily was compared with placebo and ipratropium bromide inhalation aerosol administered 4 times daily in patients with COPD (emphysema and chronic bronchitis), including patients who were reversible (≥12% and ≥200 mL increase in baseline FEV1 after albuterol treatment) and nonreversible to albuterol. After a single 42-mcg dose of SEREVENT, significant improvement in pulmonary function (mean FEV1 increase of 12% or more) occurred within 30 minutes, reached a peak within 4 hours on average, and persisted for 12 hours with no loss in effectiveness observed over a 12-week treatment period. Figure 2 displays serial 12-hour measurements of FEV1 from these two 12-week trials for both the first and last treatment days.
Figure 2. FEV1 From 2 Large 12-Week Clinical Trials
First Treatment Day
* Ipratropium inhalation aerosol (or matching placebo) administered immediately following hour 6 assessment.
Last Treatment Day (Week 12)
* Ipratropium inhalation aerosol (or matching placebo) administered immediately following hour 6 assessment.
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