Serevent

Indications : Asthma

Pregnancy Category C

FDA Class 1P (“Priority Review”)

FDA Approved 1994 Feb ; Patent Expiration 2012 Jan

DRUG CLASS : : Broncodilators

BRAND NAMES : Aeromax (Germany); Salmeter (India); Serevent (US); Serevent Inhaler and Disks (Australia); Serobid (Bahrain, Cyprus, Egypt, Iran, Iraq, Jordan, Kuwait, Lebanon, Libya, Oman, Qatar, Republic-of-Yemen, Saudi-Arabia, Syria, United-Arab-Emirates, India); Servent (US); Zamitrel (Mexico);
(International brand names outside U.S. in italics)

DESCRIPTION :

Serevent Diskus inhalation powder and Serevent inhalation aerosol contain salmeterol xinafoate as the racemic form of the 1-hydroxy-2-naphthoic acid salt of salmeterol. The active component of the formulation is salmeterol base, a highly selective beta2-adrenergic bronchodilator. The chemical name of salmeterol xinafoate is 4-hydroxy-alpha1-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol, 1 -hydroxy-2-naphthalenecarboxylate.

The molecular weight of salmeterol xinafoate is 603.8, and the empirical formula is C25H37NO4·C11H8O3. Salmeterol xinafoate is a white to off-white powder. It is freely soluble in methanol; slightly soluble in ethanol, chloroform, and isopropanol; and sparingly soluble in water.

Serevent Diskus Inhalation Powder

Serevent Diskus is a specially designed plastic device containing a double-foil blister strip of a powder formulation of salmeterol xinafoate intended for oral inhalation only. Each blister on the double-foil strip within the device contains 50 mug of salmeterol administered as the salmeterol xinafoate salt in 12.5 mg of formulation containing lactose. When a blister containing medication is opened by activating the device, the medication is dispersed into the air stream created when the patient inhales through the mouthpiece.

The amount of drug delivered to the lung will depend on patient factors such as inspiratory flow. Under standardized in vitro testing, Serevent Diskus delivers 47 mug when tested at 60 L/min flow rate for 3 seconds. In adult patients with obstructive lung disease and severely compromised lung function (mean forced expiratory volume in 1 second [FEV1] 0.65 L [range, 0.35-0.92 L], 20-30% predicted FEV1), mean peak inspiratory flow (PIF) through salmeterol xinafoate was 82.4 L/min (range, 46.1-115.3 L/min). The emitted dose of Serevent Diskus determined in an in vitro experiment modeling these patient-generated flow rates was 46 mug (range, 45-51 mug).

Servent Inhalation Aerosol

Serevent inhalation aerosol is a pressurized, metered-dose aerosol unit for oral inhalation. It contains a microcrystalline suspension of salmeterol xinafoate in a mixture of two chlorofluorocarbon propellants (trichlorofluoromethane and dichlorodifluoromethane) with lecithin. 36.25 mug of salmeterol xinafoate is equivalent to 25 mug of salmeterol base. Each actuation delivers 25 mug of salmeterol base (as salmeterol xinafoate) from the valve and 21 mug of salmeterol base (as salmeterol xinafoate) from the actuator. Each 6.5-g canister provides 60 inhalations and each 13-g canister provides 120 inhalations.

CLINICAL PHARMACOLOGY :

Mechanism of Action

Salmeterol is a long-acting beta-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 10-50% of the total beta-adrenoceptors. The precise function of these receptors has not been 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. For Salmeterol Xinafoate Inhalation Powder Only: In humans, single doses of salmeterol administered via inhalation aerosol attenuate allergen-induced bronchial hyper-responsiveness. For Salmeterol Xinafoate Inhalation Aerosol Only: In humans, single doses of salmeterol attenuate allergen-induced bronchial hyper-responsiveness.

Pharmacokinetics

Salmeterol acts locally in the lung; plasma levels therefore do not predict therapeutic effect. Because of the low therapeutic dose, systemic levels of salmeterol are low or undetectable after inhalation of the recommended doses (50 mug twice daily for salmeterol xinafoate inhalation powder, 42 mug twice daily for salmeterol xinafoate inhalation aerosol). Following chronic administration of an inhaled dose of 50 mug of salmeterol inhalation powder twice daily (42 mug of salmeterol aerosol twice daily), salmeterol was detected in plasma within 5-45 minutes in seven asthmatic patients for salmeterol xinafoate inhalation powder (5-10 minutes in six asthmatic patients for salmeterol xinafoate inhalation aerosol); plasma concentrations were very low, with mean peak concentrations of 167±75 pg/ml for salmeterol xinafoate inhalation powder and peak concentrations of 150 pg/ml for salmeterol xinafoate inhalation aerosol and no accumulation with repeated doses for either. For Salmeterol Xinafoate Inhalation Powder Only: Oral administration of 1 mg of radiolabeled salmeterol (as salmeterol xinafoate) to two healthy subjects gave peak plasma salmeterol concentrations of about 650 pg/ml at about 45 minutes; the terminal elimination half-life was about 5.5 hours (one volunteer only). For Salmeterol Xinafoate Inhalation Aerosol Only: 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).

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 base is extensively metabolized by hydroxylation, with subsequent elimination predominantly in the feces. In two 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. No significant amount of unchanged salmeterol base was detected in either urine or feces.

Salmeterol is 94-98% bound to human plasma proteins in vitro over the concentration range of 8-7722 ng of base per milliliter, much higher concentrations than those achieved following therapeutic doses of salmeterol.

The xinafoate moiety has no apparent pharmacologic activity, is highly protein bound (>99%), and has a long elimination half-life of 11 days.

The pharmacokinetics of salmeterol base has not been studied in elderly patients nor 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 cardiovascular effects (see PRECAUTIONS). The cardiovascular effects (heart rate, blood pressure) associated with salmeterol inhalation aerosol occur with similar frequency, and are of similar type and severity, as those noted following albuterol administration.

For Salmeterol Xinafoate Inhalation Powder Only : The effects of rising doses of salmeterol and standard inhaled doses of albuterol were studied in volunteers and in patients with asthma. Salmeterol doses of up to 84 mug administered as inhalation aerosol resulted in heart rate increases of 3-16 beats/min, about the same as albuterol dosed at 180 mug by inhalation aerosol (4-10 beats/min). Adolescent and adult patients receiving 50-mug doses of salmeterol powder (n=60) underwent continuous electrocardiographic monitoring during two 12-hour periods after the first dose and after 1 month of therapy, and no clinically significant dysrhythmias were noted. Also, pediatric patients receiving 50-mug doses of salmeterol inhalation powder (n=67) underwent continuous electrocardiographic monitoring during two 12-hour periods after the first dose and after 3 months of therapy, and no clinically significant dysrhythmias were noted.

For Salmeterol Xinafoate Inhalation Aerosol Only : The effects of rising inhaled doses of salmeterol and standard inhaled doses of albuterol were studied in volunteers and in patients with asthma. Salmeterol doses up to 84 mug resulted in heart rate increases of 3-16 beats/min, about the same as albuterol dosed at 180 mug by inhalation aerosol (4-10 beats/min). In two double-blind asthma studies, patients receiving either 42 mug salmeterol inhalation aerosol twice daily (n = 81) or 180 mug of albuterol inhalation aerosol four 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 two double-blind studies in COPD patients (see ADVERSE REACTIONS).

For Salmeterol Xinafoate Inhalation Powder and Aerosol : 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.

CLINICAL STUDIES :

Salmeterol Xinafoate Inhalation Powder

During the initial treatment day in several multiple-dose clinical trials with salmeterol inhalation powder in patients with asthma, the median time to onset of clinically significant bronchodilatation (15% improvement in FEV1) ranged from 30-48 minutes after a 50-mug dose.

One hour after a single dose of 50 mug of salmeterol inhalation powder, the majority of patients had 15% improvement in FEV1. Maximum improvement in FEV1 generally occurred within 180 minutes, and clinically significant improvement continued for 12 hours in most patients.

In two large, randomized, double-blind studies, salmeterol inhalation powder was compared with albuterol inhalation aerosol and placebo in adolescent and adult patients with mild-to-moderate asthma (protocol defined as 50-80% predicted FEV1, actual mean of 67.7% at baseline), including patients who did and who did not receive concurrent inhaled corticosteroids. The efficacy of salmeterol inhalation powder was demonstrated over the 12-week period with no change in effectiveness over this time period. There were no gender- or age-related differences in safety or efficacy. No development of tachyphylaxis to the bronchodilator effect has been noted in these studies.

During daily treatment with salmeterol inhalation powder for 12 weeks in adolescent and adult patients with mild-to-moderate asthma, the treatment effects found in TABLE-1 were noted.

TABLE 1 Daily Efficacy Measurements in Two Large 12-Week Clinical Trials (Combined Data)
Parameter
Time
Placebo
Salmeterol xinafoate
Albuterol
No. of randomized subjects
152
149
148
Mean AM peak expiratory flow rate (L/min)
baseline
394
395
394
12 weeks
396
427*
394
Mean % days with no asthma symptoms
baseline
14
13
12
12 weeks
20
33
21
Mean % nights with no awakenings
baseline
70
63
68
12 weeks
73
85*
71
Rescue medications (mean no. of inhalations per day)
baseline
4.2
4.3
4.3
12 weeks
3.3
1.6
2.2
Asthma exacerbations
14%
15%
16%
* Statistically superior to placebo and albuterol (P <0.001).
Statistically superior to placebo (P <0.001).

 

Safe usage with maintenance of efficacy for periods up to 1 year has been documented.

Salmeterol inhalation powder and salmeterol aerosol were compared to placebo in two additional randomized, double-blind clinical trials in adolescent and adult patients with mild-to-moderate asthma. Salmeterol inhalation powder 50 mug administered via the drug inhalation device and salmeterol inhalation aerosol 42 mug, both administered twice daily, produced significant improvements in pulmonary function compared with placebo over the 12-week period. While no statistically significant differences were observed between the active treatments for any of the efficacy assessments or safety evaluations performed, there were some efficacy measures on which the metered-dose inhaler appeared to provide better results. Similar findings were note in two randomized, single-dose, crossover comparisons of salmeterol inhalation powder and salmeterol aerosol for the prevention of exercise-induced bronchospasm. Therefore, while salmeterol xinafoate inhalation powder was comparable to salmeterol xinafoate inhalation aerosol in clinical trials in mild-to-moderate asthmatics, it should not be assumed that the salmeterol xinafoate inhalation aerosol and salmeterol xinafoate inhalation powder drug products will produce clinically equivalent outcomes in all patients.

In a large, randomized, double-blind, controlled study (n=449), 50 mug of salmeterol inhalation powder, via the drug inhalation device, was administered twice daily to pediatric asthma patients who did and who did not receive concurrent inhaled corticosteriods. The efficacy of salmeterol inhalation powder was demonstrated over the 12-week treatment period with respect to periodic serial peak expiratory flow (36-39% postdose increase from baseline) and FEV1 (32-33% postdose increase from baseline). Salmeterol was effective in demographic subgroup analyses (gender and age) and was effective when coadministered with other inhaled asthma medications such as short-acting bronchodilators and inhaled corticosteriods. A second large, randomized, double-blind, placebo-controlled study (n=207) with 50 mug of salmeterol inhalation powder via an alternate device supported the findings of the trial with drug inhalation device.

In two randomized, single-dose, crossover studies in adolescents and adults with exercise-induced bronchospasm (EIB) (n=53), 50 mug of salmeterol inhalation powder prevented EIB when dosed 30 minutes prior to exercise. For many patients, this protective effect against EIB was still apparent up to 8.5 hours following a single dose (see TABLE 2).

TABLE 2 Results of Two Exercise-Induced Bronchospasm Studies in Adolescents and Adults
     
Placebo
Salmeterol Xinafoate
     
(n=52)
(n=52)
     
n
% Total
n
% Total
0.5 Hour postdose exercise challenge
% Fall in FEV1
<10%
15
29
31
60
=10%, <20%
3
6
11
21
=20%
34
65
10
19
Mean maximal % fall in FEV1 (SE)
-25% (1.8)
-11% (1.9)
8.5 Hour postdose exercise challenge
% Fall in FEV1
<10%
12
23
26
50
=10%, <20%
7
13
12
23
=20%
33
63
14
27
Mean maximal % fall in FEV1 (SE)
-27% (1.5)
-16% (2.0)

In two randomized studies in children 4-11 years old with asthma and EIB (n=50), a single 50-mug dose of salmeterol inhalation powder prevented EIB when dosed 30 minutes prior to exercise, with protection lasting up to 11.5 hours in repeat testing following this single dose in many patients.

Salmeterol Xinafoate Inhalation Aerosol

Asthma : In placebo- and albuterol-controlled, single-dose clinical trials with salmeterol xinafoate inhalation aerosol, the time to onset of effective bronchodilatation (>15% improvement in forced expiratory volume in 1 second [FEV1]) was 10-20 minutes after a 42-mug dose. Maximum improvement in FEV1 generally occurred within 180 minutes, and clinically significant improvement continued for 12 hours in most patients.

In two large, randomized, double-blind studies, salmeterol xinafoate 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 salmeterol xinafoate 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 TABLE 3 for both the first and last treatment days.

TABLE 3 Daily Efficacy Measurements in Two Large 12-Week Clinical Trials (Combined Data)
Parameter
Time
Placebo
Salmeterol Xinafoate
Albuterol
No. of randomized subjects
187
184
185
Mean AM Peak expiratory flow rate (L/min)
baseline
412
409
398
12 weeks
414
438*
390
Mean % days with no asthma symptoms
baseline
11
11
14
12 weeks
17
35*
24
Mean % nights with no awakenings
baseline
67
67
65
12 weeks
74
87*
74
Rescue medications (mean no. of inhalations per day)
baseline
4.4
4.1
4.0
12 weeks
3.3
1.3
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.

Exercise-Induced Bronchospasm : Protection against exercise-induced bronchospasm was examined in three controlled studies. Based on median values, patients who received salmeterol xinafoate 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 4). There were, however, some patients who were not protected from exercise-induced bronchospasm after salmeterol xinafoate inhalation aerosol administration and others in whom protection against exercise-induced bronchospasm decreased with continued administration over a period of 4 weeks.

TABLE 4 Exercise-Induced Bronchospasm Mean Percentage Fall in Postexercise FEV1
Treatment
Clinical Trials/Time After Dose
Placebo
Salmeterol Xinafoate
Albuterol
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 (COPD) : In two large randomized, double-blind studies, salmeterol xinafoate inhalation aerosol administered twice daily was compared with placebo and ipratropium bromide administered four 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-mug dose of salmeterol xinafoate inhalation aerosol, 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.

INDICATIONS AND USAGE :

Asthma

Salmeterol xinafoate is indicated for long-term, twice-daily (morning and evening) administration in the maintenance treatment of asthma and in the prevention of bronchospasm in patients 4 years of age or older with the inhalation powder and 12 years of age and older with the inhalation aerosol with reversible obstructive airway disease, including patients with symptoms of nocturnal asthma, who require regular treatment with inhaled, short-acting beta2-agonists. It is not indicated for patients whose asthma can be managed by occasional use of inhaled, short-acting beta2-agonists.

Salmeterol xinafoate is also indicated for prevention of exercise-induced bronchospasm in patients 4 years of age or older with the inhalation powder and 12 years of age with the inhalation aerosol.

Salmeterol xinafoate may be used with or without concurrent inhaled or systemic corticosteroid therapy.

For Salmeterol Xinafoate Inhalation Aerosol Only : COPD: Salmeterol xinafoate inhalation aerosol is indicated for long-term, twice daily (morning and evening) administration in the maintenance treatment of bronchospasm associated with COPD (including emphysema and chronic bronchitis).

CONTRAINDICATIONS :

Salmeterol xinafoate is contraindicated in patients with a history of hypersensitivity to salmeterol or any of its components.

WARNINGS :

IMPORTANT INFORMATION: SALMETEROL XINAFOATE SHOULD NOT BE INITIATED IN PATIENTS WITH SIGNIFICANTLY WORSENING OR ACUTELY DETERIORATING ASTHMA, WHICH MAY BE A LIFE-THREATENING CONDITION. Serious acute respiratory events, including fatalities, have been reported, both in the United States and worldwide, when salmeterol xinafoate has been initiated in this situation.

Although it is not possible from these reports to determine whether salmeterol xinafoate contributed to these adverse events or simply failed to relieve the deteriorating asthma, the use of salmeterol xinafoate in this setting is inappropriate.

SALMETEROL XINAFOATE SHOULD NOT BE USED TO TREAT ACUTE SYMPTOMS. It is crucial to inform patients of this and prescribe an inhaled, short-acting beta2-agonist for this purpose as well as warn them that increasing inhaled beta2-agonist use is a signal of deteriorating asthma.

SALMETEROL XINAFOATE IS NOT A SUBSTITUTE FOR INHALED OR ORAL CORTICOSTEROIDS. Corticosteroids should not be stopped or reduced when salmeterol xinafoate is initiated.

(See PRECAUTIONS, Information for the Patient and PATIENT PACKAGE INSERT).

Do Not Introduce Salmeterol Xinafoate as a Treatment for Acutely Deteriorating Asthma : Salmeterol xinafoate is intended for the maintenance treatment of asthma (see INDICATIONS AND USAGE) and should not be introduced in acutely deteriorating asthma, which is a potentially life-threatening condition. There are no data demonstrating that salmeterol xinafoate provides greater efficacy than or additional efficacy to inhaled, short-acting beta2-agonists in patients with worsening asthma. Serious acute respiratory events, including fatalities, have been reported, both in the United States and worldwide, in patients receiving salmeterol xinafoate. In most cases, these have occurred in patients with severe asthma (e.g., patients with a history of corticosteroid dependence, low pulmonary function, intubation, mechanical ventilation, frequent hospitalizations, or previous life-threatening acute asthma exacerbations) and/or in some patients in whom asthma has been acutely deteriorating (e.g., unresponsive to usual medications, increasing need for inhaled, short-acting beta2-agonists, increasing need for systemic corticosteroids, significant increase in symptoms, recent emergency room visits, sudden or progressive deterioration in pulmonary function). However, they have occurred in a few patients with less severe asthma as well. It was not possible from these reports to determine whether salmeterol xinafoate contributed to these events or simply failed to relieve the deteriorating asthma.

Do Not Use Salmeterol Xinafoate to Treat Acute Symptoms : An inhaled, short-acting beta2-agonist, not salmeterol xinafoate, should be used to relieve acute asthma symptoms (and COPD symptoms for the inhalation aerosol). When prescribing salmeterol xinafoate, the physician must also provide the patient with an inhaled, short-acting beta2-agonist (e.g., albuterol) for treatment of symptoms that occur acutely, despite regular twice daily (morning and evening) use of salmeterol xinafoate.

When beginning treatment with salmeterol xinafoate, patients who have been taking inhaled, short-acting beta2-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs and use them only for symptomatic relief of acute asthma symptoms (and COPD symptoms for the inhalation aerosol). (See PRECAUTIONS, Information for the Patient).

Watch for Increasing Use of Inhaled, Short-Acting Beta2-Agonists, Which is a Marker of Deteriorating Asthma : Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. If the patient’s inhaled, short-acting beta2-agonist becomes less effective or the patient needs more inhalations than usual, this may be a marker of destabilization of asthma. In this setting, the patient requires immediate reevaluation with reassessment of the treatment regimen, giving special consideration to the possible need for corticosteroids. If the patient uses 4 or more inhalations per day of an inhaled, short-acting beta2-agonist for 2 or more consecutive days, or if more than one canister (200 inhalations per canister) of inhaled, short-acting beta2-agonist is used in an 8-week period in conjunction with salmeterol xinafoate, then the patient should consult the physician for reevaluation. Increasing the daily dosage of salmeterol xinafoate in this situation is not appropriate. Salmeterol xinafoate should not be used more frequently than twice daily (morning and evening) at the recommended dose of 1 inhalation for salmeteroal xinafoate inhalation powder and 2 inhalations for salmeteroal xinafoate inhalation aerosol.

Do Not Use Salmeterol Xinafoate as a Substitute for Oral or Inhaled Corticosteroids : The use of beta-adrenergic agonist bronchodilators alone may not be adequate to control asthma in many patients. Early consideration should be given to adding anti-inflammatory agents, e.g., corticosteroids. There are no data demonstrating that salmeterol xinafoate has a clinical anti-inflammatory effect and could be expected to take the place of, or reduce the dose of, corticosteroids. Patients who already require oral or inhaled corticosteroids for treatment of asthma should be continued on a suitable dose to maintain clinical stability even if they feel better as a result of initiating salmeterol xinafoate. Any change in corticosteroid dosage should be made ONLY after clinical evaluation (see PRECAUTIONS, Information for the Patient).

Do Not Exceed Recommended Dosage : As with other inhaled beta2-adrenergic drugs, salmeterol xinafoate should not be used more often or at higher doses than recommended. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Large doses of inhaled or oral salmeterol (12-20 times the recommended dose) have been associated with clinically significant prolongation of the QTc interval, which has the potential for producing ventricular arrhythmias.

Paradoxical Bronchospasm : Inhalation of salmeterol xinafoate can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs, salmeterol xinafoate should be discontinued immediately and alternative therapy instituted. For Salmeterol Xinafoate Inhalation Aerosol Only: It should be recognized that paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs with the first use of a new canister or vial.

Immediate Hypersensitivity Reactions : Immediate hypersensitivity reactions may occur after administration of salmeterol xinafoate, as demonstrated by rare cases of urticaria, angioedema, rash, and bronchospasm.

Upper Airway Symptoms : Symptoms of laryngeal spasm, irritation, or swelling, such as stridor and choking, have been reported in patients receiving salmeterol xinafoate.

Salmeterol xinafoate, like all other beta-adrenergic agonists, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of salmeterol xinafoate at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiogram (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. Therefore, salmeterol xinafoate, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

PRECAUTIONS :

General

Use with Spacer or Other Devices : For Salmeterol Xinafoate Inhalation Aerosol Only: The safety and effectiveness of salmeterol xinafoate inhalation aerosol when used with a spacer or other devices have not been adequately studied.

Cardiovascular and Other Effects : No effect on the cardiovascular system is usually seen after the administration of inhaled salmeterol in recommended doses, but the cardiovascular and central nervous system effects seen with all sympathomimetic drugs (e.g., increased blood pressure, heart rate, excitement) can occur after use of salmeterol and may require discontinuation of the drug. Salmeterol, like all 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.

As has been described with other beta-adrenergic agonist bronchodilators, clinically significant changes in systolic and/or diastolic blood pressure, pulse rate, and electrocardiograms have been seen infrequently in individual patients in controlled clinical studies with salmeterol.

Metabolic Effects : Doses of the related beta2-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. No effects on glucose have been seen with salmeterol xinafoate at recommended doses. Beta-adrenergic agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation.

Clinically significant changes in blood glucose and/or serum potassium were seen rarely during clinical studies with long-term administration of salmeterol xinafoate at recommended doses.

Information for the Patient

See PATIENT PACKAGE INSERT. For Salmeterol Xinafoate Inhalation Aerosol Only: SHAKE WELL BEFORE USING.

It is important that patients understand how to use the drug inhalation device appropriately and how it should be used in relation to other asthma (or COPD for the inhalation aerosol) medications they are taking. Patients should be given the following information:

For Salmeterol Xinafoate Inhalation Powder and Aerosol :

1. Salmeterol xinafoate is not meant to relieve acute asthma symptoms (and COPD symptoms for the inhalation aerosol) and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist such as albuterol (the physician should provide the patient with such medication and instruct the patient in how it should be used).

2. The physician should be notified immediately if any of the following situations occur, which may be a sign of seriously worsening asthma:

Decreasing effectiveness of inhaled, short-acting beta2-agonists.
Need for more inhalations than usual of inhaled, short-acting beta2-agonists.
Use of 4 or more inhalations per day of a short-acting beta2-agonist for 2 or more days consecutively.
Use of more than one canister of an inhaled, short-acting beta2-agonist in an 8-week period (i.e., canister with 200 inhalations).

3. Salmeterol xinafoate should not be used as a substitute for oral or inhaled corticosteroids. The dosage of these medications should not be changed and they should not be stopped without consulting the physician, even if the patient feels better after initiating treatment with salmeterol xinafoate.

4. Patients should be cautioned regarding common adverse cardiovascular effects, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.

5. In patients receiving salmeterol xinafoate, other inhaled medications should be used only as directed by the physician.

6. If you are pregnant or nursing, contact your physician about use of salmeterol xinafoate.

For Salmeterol Xinafoate Inhalation Powder Only :


1.
The action of salmeterol xinafoate inhalation powder may last up to 12 hours or longer. The recommended dosage (one inhalation twice daily, morning and evening) should not be exceeded.2. When used for the treatment of EIB, one inhalation of salmeterol xinafoate inhalation powder should be taken 30 minutes before exercise.

Additional doses of salmeterol xinafoate should not be used for 12 hours.
Patients who are receiving salmeterol xinafoate inhalation powder twice daily should not use additional salmeterol xinafoate for prevention of EIB.

3. Salmeterol xinafoate should not be used with a spacer.

4. Effective and safe use of the drug inhalation device includes an understanding of the way that it should be used:

Never exhale into the drug inhalation device.
Always activate and use the drug inhalation device in a level, horizontal position.
Never wash the mouthpiece or any part of the drug inhalation device. KEEP IT DRY.

For Salmeterol Xinafoate Inhalation Aerosol Only :

1. Shake well before using.
2. The action of salmeterol xinafoate inhalation aerosol may last up to 12 hours or longer. The recommended dosage (2 inhalations twice daily, morning and evening) should not be exceeded.
3. Patients should not stop salmeterol xinafoate therapy for COPD without physician/provider guidance since symptoms may occur after discontinuation.
4. When using salmeterol xinafoate inhalation aerosol to prevent exercise-induced bronchospasm, patients should take the dose at least 30-60 minutes before exercise.
5. Effective and safe use of salmeterol xinafoate inhalation aerosol includes an understanding of the way that it should be administered.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

For Salmeterol Xinafoate Inhalation Powder Only : In an 18-month carcinogenicity study in CD-mice, salmeterol xinafoate at oral doses of 1.4 mg/kg and above (approximately 20 times the maximum recommended daily inhalation dose in adults and children based on comparison of the area under the plasma concentration versus time curves [AUCs]) caused a dose-related increase in the incidence of smooth muscle hyperplasia, cystic glandular hyperplasia, and leiomyomas in the uterus and cysts in the ovaries. The incidence of leiomyosarcomas was not statistically significant. No tumors were seen at 0.2 mg/kg per day (approximately three times the maximum recommended daily inhalation doses in adults and children based on comparison of the AUCs).

For Salmeterol Xinafoate Inhalation Aerosol Only : In an 18-month oral carcinogenicity study in CD-mice, salmeterol xinafoate at oral doses of 1.4 mg/kg per day and above (approximately 9 times the maximum recommended daily inhalation dose in adults based on comparison of the areas under the plasma concentration versus time curves [AUCs]) caused dose-related increases in the incidence of smooth muscle hyperplasia, cystic glandular hyperplasia, leiomyomas of the uterus, and cysts in the ovaries. The incidence of leiomyosarcomas was not statistically significant. No tumors were seen at 0.2 mg/kg (comparable to the maximum recommended human daily inhalation dose in adults based on comparison of the AUCs).

For Salmeterol Xinafoate Inhalation Powder and Aerosol : In a 24-month oral and inhalation carcinogenicity study in Sprague Dawley rats, salmeterol caused dose-related increases in the incidence of mesovarian leiomyomas and ovarian cysts at inhalation and oral doses of 0.68 mg/kg per day and above (approximately 60 times the maximum recommended daily inhalation dose in adults with the inhalation powder and 30 times the maximum recommended daily inhalation dose in children; and approximately 55 times the maximum recommended human daily inhalation dose in adults with the inhalation aerosol, on a mg/m2 basis). No tumors were seen at 0.21 mg/kg per day (approximately 20 times the maximum recommended daily inhalation dose in adults with the inhalation powder and 9 times the maximum recommended daily inhalation dose in children; and approximately 15 times the maximum recommended human daily inhalation dose with the inhalation aerosol in adults, on a mg/m2 basis). These findings in rodents are similar to those reported previously for other beta-adrenergic agonist drugs. The relevance of these findings to human use is unknown.

Salmeterol produced no detectable or reproducible increases in microbial and mammalian gene mutation in vitro. No clastogenic activity occurred in vitro in human lymphocytes or in vivo in a rat micronucleus test. No effects on fertility were identified in male and female rats treated with salmeterol at oral doses up to 2 mg/kg per day (approximately 170 times the maximum recommended daily inhalation dose with the inhalation powder and approximately 160 times the maximum recommended human daily inhalation dose in adults with the inhalation aerosol, on a mg/m2 basis).

Pregnancy, Teratogenic Effects, Pregnancy Category C

No teratogenic effects occurred in rats at oral doses up to 2 mg/kg per day (approximately 170 times the maximum recommended daily inhalation dose for the inhalation powder and approximately 160 times the maximum recommended daily inhalation dose in adults with the inhalation aerosol on a mg/m2 basis). In pregnant Dutch rabbits administered oral doses of 1 mg/kg and above (approximately 50 times the maximum recommended daily inhalation dose for the inhalation powder and approximately 20 times the maximum recommended human daily inhalation dose in adults with the inhalation aerosol based on comparison of the AUCs) salmeterol exhibited fetal toxic effects characteristically resulting from beta-adrenoceptor stimulation. These included precocious eyelid openings, cleft palate, sternebral fusion, limb and paw flexures, and delayed ossification of the frontal cranial bones. No significant effects occurred at an oral dose of 0.6 mg/kg (approximately 20 times the maximum recommended daily inhalation dose in adults for the inhalation powder and approximately 10 times the maximum recommended daily inhalation dose in adults with the inhalation aerosol based on comparison of the AUCs).

New Zealand White rabbits were less sensitive since only delayed ossification of the frontal bones was seen at oral doses of 10 mg/kg (approximately 1700 times the maximum recommended human daily inhalation dose with the inhalation powder and approximately 1600 times the maximum recommended human daily inhalation dose on a mg/m2 basis). Extensive use of other beta-agonists has provided no evidence that these class effects in animals are relevant to their use in humans. There are no adequate and well-controlled studies with salmeterol xinafoate in pregnant women. Salmeterol xinafoate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labor and Delivery

There are no well-controlled human studies that have investigated effects of salmeterol on preterm labor or labor at term. Because of the potential for beta-agonist interference with uterine contractility, use of salmeterol xinafoate for relief of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risks.

Nursing Mothers

Plasma levels of salmeterol after inhaled therapeutic doses are very low. In rats, salmeterol xinafoate is excreted in milk. However, since there are no data from controlled trials on the use of salmeterol xinafoate by nursing mothers, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Caution should be exercised when salmeterol xinafoate is administered to a nursing woman.

Pediatric Use

For Salmeterol Xinafoate Inhalation Powder Only : The safety and efficacy of salmeterol inhalation powder has been evaluated in over 2500 patients aged to 4-11 years with asthma, 346 of whom were administered salmeterol inhalation powder for 1 year. Based on available data, no adjustment of salmeterol dosage in pediatric patients is warranted for either asthma or EIB (see DOSAGE AND ADMINISTRATION).

For Salmeterol Xinafoate Inhalation Aerosol Only : The safety and effectiveness of salmeterol xinafoate in children younger than 12 years of age have not been established.

In two randomized, double-blind, controlled clinical trials of 12 weeks’ duration, salmeterol 50-mug powder was administered to 211 pediatric asthma patients who did and who did not receive concurrent inhaled corticosteriods. The efficacy of salmeterol inhalation powder was demonstrated over the 12-week treatment period with respect to peak expiratory flow and FEV1. Salmeterol inhalation powder was effective in demographic subgroups (gender and age) of the population. Salmeterol was effective when coadministered with other inhaled asthma medications, such as short-acting bronchodilators and inhaled corticosteriods. Salmeterol inhalation powder was well tolerated in the pediatric population, and there were no safety issues identified specific to the administration of salmeterol inhalation powder to pediatric patients.

In two randomized studies in children 4-11 years old with asthma and EIB, a single 50-mug dose of salmeterol inhalation powder prevented EIB when dosed 30 minutes prior to exercise, with protection lasting up to 11.5 hours in repeat testing following this single-dose in many patients.

Geriatric Use

For Salmeterol Xinafoate Inhalation Powder and Aerosol : No apparent differences in the efficacy and safety of salmeterol xinafoate were observed when geriatric patients were compared with younger patients in asthma (and COPD for the inhalation aerosol) clinical trials. As with other beta2-agonists, however, special caution should be observed when using salmeterol xinafoate powder in geriatric patients who have concomitant cardiovascular disease that could be adversely affected by this class of drug. Based on available data, no adjustment of salmeterol dosage in geriatric patients is warranted.

For Salmeterol Xinafoate Inhalation Powder Only : Of the total number of patients who received salmeterol inhalation powder in adolescent and adult chronic dosing clinical trials, 209 were 65 years of age and older.

For Salmeterol Xinafoate Inhalation Aerosol Only : Of the total number of patients who received salmeterol xinafoate inhalation aerosol in all asthma clinical studies, 241 were 65 years of age and older. Geriatric patients (65 years and older) with reversible obstructive airway disease were evaluated in 4 well-controlled studies of 3 weeks’ to 3 months’ duration. Two placebo-controlled, crossover studies evaluated twice-daily dosing with salmeterol for 21-28 days in 45 patients. An additional 75 geriatric patients were treated with salmeterol for 3 months in 2 large parallel-group, multicenter studies. These 120 patients experienced increases in AM and PM peak expiratory flow rate and decreases in diurnal variation in peak expiratory flow rate similar to responses seen in the total populations of the two latter studies. The adverse event type and frequency in geriatric patients were not different from those of the total populations studied.

In two large, randomized, double-blind, placebo-controlled 3-month studies involving patients with COPD, 133 patients using salmeterol xinafoate inhalation aerosol were 65 years and older. These patients experienced similar improvements in FEV1 as observed for patients younger than 65.

DRUG INTERACTIONS :

Short-Acting Beta-Agonists

For Salmeterol Xinafoate Inhalation Powder Only : In the two 12-week, repetitive-dose adolescent and adult clinical trials (n=149), the mean daily need for additional beta2-agonist use in patients using salmeterol inhalation powder was approximately 1½ inhalations per day. Twenty-six percent of the patients in these trials used between 8 and 24 inhalations of short-acting beta-agonist per day on one or more occasions. Nine percent of the patients in these trials averaged over 4 inhalations per day over the course of the 12-week trials. No observed increase in frequency of cardiovascular events was noted among the 3 patients who used an average of 8-11 inhalations per day; however, the safety of concomitant use of more than 8 inhalations per day of short-acting beta2-agonist with salmeterol inhalation powder has not been established. In 29 patients who experienced worsening of asthma while receiving salmeterol inhalation powder during these trials, albuterol therapy administered via either nebulizer or inhalation aerosol (one dose in most cases) led to improvement in FEV1 and no increase in occurrence of cardiovascular adverse events.

For Salmeterol Xinafoate Inhalation Aerosol Only : In the two 3-month, repetitive-dose clinical asthma trials (n = 184), the mean daily need for additional beta2-agonist use was 1 to 1½ inhalations per day, but some patients used more. Eight percent of patients used at least eight inhalations per day at least on one occasion. Six percent used 9-12 inhalations at least once. There were 15 patients (8%) who averaged over four inhalations per day. Four of these used an average of 8-11 inhalations per day. In these 15 patients there was no observed increase in frequency of cardiovascular adverse events. The safety of concomitant use of more than eight inhalations per day of short-acting beta2-agonists with salmeterol xinafoate inhalation aerosol has not been established. In 15 patients who experienced worsening of asthma while receiving salmeterol xinafoate inhalation aerosol, nebulized albuterol (one dose in most) led to improvement in FEV1 and no increase in occurrence of cardiovascular adverse events.

Monoamine Oxidase Inhibitors and Tricyclic Antidepressants

Salmeterol should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of salmeterol on the vascular system may be potentiated by these agents.

Corticosteroids and Cromoglycate

In clinical trials, inhaled corticosteroids and/or inhaled cromolyn sodium did not alter the safety profile of salmeterol xinafoate when administered concurrently.

Methylxanthines

The concurrent use of intravenously or orally administered methylxanthines (e.g., aminophylline, theophylline) by patients receiving salmeterol xinafoate has not been completely evaluated. In one clinical asthma trial, 87 patients receiving salmeterol xinafoate inhalation aerosol 42 mug twice daily concurrently with a theophylline product had adverse event rates similar to those in 71 patients receiving salmeterol xinafoate inhalation aerosol without theophylline. Resting heart rates were slightly higher in the patients on theophylline but were little affected by therapy with salmeterol xinafoate inhalation aerosol.

Beta-adrenergic receptor blocking agents not only block the pulmonary effect of beta-agonists, such as salmeterol xinafoate, but may produce severe bronchospasm in asthmatic patients. Therefore, patients with asthma 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-adrenergic blocking agents in patients with asthma. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution.

The ECG changes and/or hypokalemia that may result from the administration of nonpotassium-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 coadministration of beta-agonists with nonpotassium-sparing diuretics.

ADVERSE REACTIONS :

Salmeterol Xinafoate Inhalation Powder

Adverse reactions to salmeterol are similar in nature to reactions to other selective beta2-adrenoceptor agonists, i.e., tachycardia; palpitations; immediate hypersensitivity reactions, including urticaria, angioedema, rash, bronchospasm (see WARNINGS); headache; tremor; nervousness; and paradoxical bronchospasm (see WARNINGS).

Two multicenter, 12-week, controlled studies have evaluated twice-daily doses of salmeterol xinafoate inhalation powder in patients 12 years of age and older with asthma. TABLE 5 reports the incidence of adverse events in these two studies.

TABLE 5 Adverse Experience Incidence in Two Large 12-Week Adolescent and Adult Clinical Trials
Percent of Patients
Adverse Event Type
Placebo (n=152)
Salmeterol Xinafoate Inhalation Powder 50 mug twice daily (n=149)
Albuterol Inhalation Aerosol 180 mug four times daily (n=150)
Ear, nose, and throat
Nasal/sinus congestion, pallor
6
9
8
Rhinitis
4
5
4
Neurological
Headache
9
13
12
Respiratory
Asthma
1
3
<1
Tracheitis/bronchitis
4
7
3
Influenza
2
5
5

TABLE 5 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of 3% in the salmeterol xinafoate inhalation powder treatment group and were more common in the salmeterol xinafoate inhalation powder group than in the placebo group.

Pharyngitis, sinusitis, upper respiratory tract infection, and cough occurred at 3% but were more common in the placebo group. However, throat irritation has been described at rates exceeding that of placebo in other controlled clinical trials. Other events occurring in the salmeterol xinafoate inhaltion powder group at a frequency of 1-3% and at a greater rate than in placebo were as follows.

Ear, Nose, and Throat : Sinus headache.
Gastrointestina l: Nausea.
Mouth and Teeth : Oral mucosal abnormality.
Musculoskeletal : Pain in joint.
Neurological : Sleep disturbance, paresthesia.
Skin : Contact dermatitis, eczema.
Miscellaneous : Localized aches and pains, pyrexia of unknown origin.

Two multicenter, 12-week, controlled studies have evaluated twice-daily doses of salmeterol inhalation powder in patients aged 4-11 years with asthma. TABLE 6 includes all events (whether considered drug-related or non-drug related by the investigator) that occurred at a rate of 3% in the salmeterol xinafoate inhalation powder treatment group and were more common in the salmeterol xinafoate inhalation powder group than in the placebo group.

TABLE 6 Adverse Experience Incidence in Two Large 12-Week Pediatric Clinical Trials
   
Percent of Patients
Adverse Event Type
Placebo (n=215)
Salmeterol Xinafoate Inhalation Powder 50 mug twice daily (n=211)
Albuterol Powder 200 mug 4 times daily (n=115)
Ear, nose and throat
Ear signs and symptoms
3
4
9
Pharyngitis
3
6
3
Neurological
Headache
14
17
20
Respiratory
Asthma
2
4
<1
Skin
Skin rashes
3
4
2
Urticaria
0
3
2

The following events were reported at an incidence of 1-2% (3-4 patients) in the salmeterol group and with a higher incidence than in the albuterol and placebo groups: gastrointestinal signs and symptoms, lower respiratory signs and symptoms, photodermatitis, and arthralgia and articular rheumatism.

Salmeterol Xinafoate Inhalation Aerosol

Adverse reactions to salmeterol are similar in nature to reactions to other selective beta2-adrenoceptor agonists, i.e., tachycardia; palpitations; immediate hypersensitivity reactions, including urticaria, angioedema, rash, bronchospasm (see WARNINGS); headache; tremor; nervousness; and paradoxical bronchospasm (see WARNINGS).

Asthma : Two multicenter, 12-week, controlled studies have evaluated twice-daily doses of salmeterol xinafoate inhalation aerosol in patients 12 years of age and older with asthma. TABLE 7 reports the incidence of adverse events in these two studies.

TABLE 7 Adverse Experience Incidence in Two Large 12-Week Asthma Clinical Trials*
Percent of Patients
Adverse Event Type Placebo (n=187) Salmeterol Xinafoate 42 mug twice daily (n=184) Albuterol 180 mug 4 times daily (n=185)
Ear, nose, and throat
Upper respiratory tract infection 13 14 16*
Nasopharyngitis 12 14 11
Disease of nasal cavity/sinus 4 6 1
Sinus headache 2 4 <1
Gastrointestinal
Stomachache 0 4 0
Neurological
Headache 23 28 27
Tremor 2 4 3
Respiratory
Cough 6 7 3
Lower respiratory infection 2 4 2
* The only adverse experience classified as serious was one case of upper respiratory tract infection in a patient treated with albuterol.

TABLE 7 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of over 3% in the salmeterol xinafoate inhalation aerosol treatment group and were more common in the salmeterol xinafoate inhalation aerosol group than in the placebo group.

Pharyngitis, allergic rhinitis, dizziness/giddiness, and influenza occurred at 3% or more but were equally common on placebo. Other events occurring in the salmeterol xinafoate inhalation aerosol treatment group at a frequency of 1-3% were as follows:

Cardiovascular: Tachycardia, palpitations.
Ear, Nose, and Throat : Rhinitis, laryngitis.
Gastrointestinal: Nausea, viral gastroenteritis, nausea and vomiting, diarrhea, abdominal pain.
Hypersensitivity : Uticaria.
Mouth and Teeth : Dental pain.
Musculoskeletal : Pain in joint, back pain, muscle cramp/contraction, myalgia/myositis, muscular soreness.
Neurological : Nervousness, malaise/fatigue.
Respiratory : Tracheitis/bronchitis.
Skin : Rash/skin eruption.
Urogenital : Dysmenorrhea.

In small dose-response studies, tremor, nervousness, and palpitations appeared to be dose related.

COPD : Two multicenter, 12-week, controlled studies have evaluated twice-daily doses of salmeterol xinafoate inhalation aerosol in patients with COPD. TABLE 8 reports the incidence of adverse events in these two studies.

TABLE 8 Adverse Experience Incidence in Two Large 12-Week COPD Clinical Trials
Percent of Patients
Adverse Event Type
Placebo (n=278)
Salmeterol Xinafoate 42 mug twice daily (n=267)
Ipratropium 36 mug 4 times daily (n=271)
Ear, nose, and throat
Upper respiratory tract infection
7
9
9
Sore throat
3
8
6
Nasal sinus infection
1
4
2
Gastrointestinal
Diarrhea
3
5
4
Musculoskeletal
Back pain
3
4
3
Neurological
Headache
10
12
8
Respiratory
Chest Congestion
3
4
3

TABLE 8 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of over 3% in the salmeterol xinafoate inhalation aerosol treatment group and were more common in the salmeterol xinafoate inhalation aerosol group than in the placebo group.

Common cold, rhinorrhea, bronchitis, cough, exacerbation of chest congestion, chest pain, and dizziness occurred at 3% or more but were equally common on placebo. Other events occurring in the salmeterol xinafoate inhalation aerosol treatment group at a frequency of 1-3% were as follows:

Ear, Nose, and Throat : Cold symptoms, earache, epistaxis, nasal congestion, nasal sinus congestion, sneezing.
Gastrointestinal : Nausea, dyspepsia, gastric pain, gastric upset, abdominal pain, constipation, heartburn, oral candidiasis, xerostomia, vomiting, surgical removal of tooth.
Musculoskeletal : Leg cramps, myalgia, neck pain, pain in arm, shoulder pain, muscle injury of neck.
Neurological : Insomnia, sinus headache.
Non-Site Specific : Fatigue, fever, pain in body, discomfort in chest.
Respiratory : Acute bronchitis, dyspnea, influenza, lower respiratory tract infection, pneumonia, respiratory tract infection, shortness of breath, wheezing.
Urogenital : Urinary tract infection.

Electrocardiographic Monitoring in Patients with COPD : Continuous electrocardiographic (Holter) monitoring was performed on 284 patients in two large COPD clinical trials during five 24-hour periods. No cases of sustained ventricular tachycardia were observed. At baseline, non-sustained, asymptomatic ventricular tachycardia was recorded for 7 (7.1%), 8 (9.4%), and 3 (3.0%) patients in the placebo, salmeterol xinafoate inhalation aerosol, and ipratropium groups, respectively. During treatment, nonsustained, asymptomatic ventricular tachycardia that represented a clinically significant change from baseline was reported for 11 (11.6%), 15 (18.3%), and 20 (20.8%) patients receiving placebo, salmeterol xinafoate inhlation aerosol, and ipratropium, respectively. Four of these cases of ventricular tachycardia were reported as adverse events (1 placebo, 3 salmeterol xinafoate inhlation aerosol) by one investigator based upon review of Holter data. One case of ventricular tachycardia was observed during ECG evaluation of chest pain (ipratropium) and reported as an adverse event.

For Salmeterol Xinafoate Inhalation Powder and Aerosol

Observed During Clinical Practice : In extensive United States and worldwide postmarketing experience with salmeterol xinafoate, serious exacerbations of asthma, including some that have been fatal, have been reported. In most cases, these have occurred in patients with severe asthma and/or in some patients in whom asthma has been acutely deteriorating (see WARNINGS, Do Not Introduce Salmeterol Xinafoate as a Treatment for Acutely Deteriorating Asthma), but they have also occurred in a few patients with less severe asthma as well. It was not possible from these reports to determine whether salmeterol xinafoate contributed to these events or simply failed to relieve the deteriorating asthma.

The following events have also been identified during postapproval use of salmeterol xinafoate in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to salmeterol xinafoate.

Respiratory : Reports of upper airway symptoms of laryngeal spasm, irritation, or swelling such as stridor or choking.
Cardiovascular : Cases of hypertension, arrhythmias (including atrial fibrillation, supraventricular tachycardia, extrasystoles), and for inhalation powder only: anaphylaxis.

OVERDOSAGE :

The expected signs and symptoms with overdosage of salmeterol xinafoate are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms listed in ADVERSE REACTIONS (e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, and insomnia). Overdosage with salmeterol may be expected to result in exaggeration of the pharmacologic adverse effects associated with beta-adrenoceptor agonists, including tachycardia and/or arrhythmia, tremor, headache, and muscle cramps. Overdosage with salmeterol can lead to clinically significant prolongation of the QTc interval, which can produce ventricular arrhythmias. Other signs of overdosage may include hypokalemia and hyperglycemia.

As with all sympathomimetic medications, cardiac arrest and even death may be associated with abuse of salmeterol xinafoate.

Treatment consists of discontinuation of salmeterol xinafoate together with appropriate symptomatic therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of salmeterol xinafoate. Cardiac monitoring is recommended in cases of overdosage.

No deaths were seen in rats at an inhalation dose of 2.9 mg/kg (approximately 250 times the maximum recommended daily inhalation dose in adults and approximately 120 times the dose for children with the inhalation powder, and approximately 240 times the maximum recommended human daily inhalation dose in adults for the inhalation aerosol on a mg/m2 basis) and in dogs at an inhalation dose of 0.7 mg/kg (approximately 200 times the maximum recommended daily inhalation dose in adults and approximately 95 times the maximum recommended dose for children with the inhalation powder, and approximately 190 times the maximum recommended human daily inhalation dose in adults with the inhalation aerosol on a mg/m2 basis). By the oral route, no deaths occurred in mice at 150 mg/kg (approximately 6500 times the maximum recommended daily inhalation dose in adults and 3100 times the maximum recommended daily inhalation dose in children with the inhalation powder, and approximately 6100 times the maximum recommended human daily inhalation dose in adults with the inhalation aerosol on a mg/m2 basis) and in rats at 1000 mg/kg (approximately 86,000 times the maximum recommended daily inhalation dose for adults and 41,000 times the maximum recommended daily inhalation dose for children with the inhalation powder, and approximately 81,000 times the maximum recommended daily inhalation dose in adults with the inhalation aerosol on a mg/m2 basis).

DOSAGE AND ADMINISTRATION :

Salmeterol xinafoate inhalation powder and aerosol should be administered by the orally inhaled route only (see PATIENT PACKAGE INSERT). For Salmeterol Xinafoate Inhalation Aerosol Only: It is recommended to “test spray” salmeterol xinafoate inhalation aerosol into the air 4 times before using for the first time and in cases where the aerosol has not been used for a prolonged period of time (i.e., more than 4 weeks).

Asthma

For maintenance of bronchodilatation and prevention of symptoms of asthma, including the symptoms of nocturnal asthma, the usual dosage for adults and children 4 years of age or older for salmeterol xinafoate inhalation powder, is one inhalation (50 mug) twice daily (morning and evening, approximately 12 hours apart). The usual dosage for adults and children 12 years of age or older for salmeterol xinafoate inhalation aerosol, is two inhalations (42 mug) twice daily (morning and evening, approximately 12 hours apart). Adverse effects are more likely to occur with higher doses of salmeterol, and more frequent administration or administration of a larger number of inhalations is not recommended.

To gain full therapeutic benefit, salmeterol xinafoate should be administered twice daily (morning and evening) in the treatment of reversible airway obstruction. (For Salmeterol Xinafoate Inhalation Powder Only: The patient must not exhale into the device and the device should only be activated and used in a level, horizontal position).

If a previously effective dosage regimen fails to provide the usual response, medical advice should be sought immediately as this is often a sign of destabilization of asthma. Under these circumstances, the therapeutic regimen should be reevaluated and additional therapeutic options, such as inhaled or systemic corticosteroids, should be considered. If symptoms arise in the period between doses, an inhaled, short-acting beta2-agonist should be taken for immediate relief.

Prevention of Exercise-Induced Bronchospasm (EIB)

One inhalation of the inhalation powder at least 30 minutes before exercise (2 inhalations at least 30-60 minutes before exercise for the inhalation aerosol) have been shown to protect against EIB in many patients for up to 12 hours. Additional doses of salmeterol xinafoate should not be used for 12 hours after the administration of this drug. Patients who are receiving salmeterol xinafoate twice daily (morning and evening) should not use additional salmeterol xinafoate for prevention of exercise-induced bronchospasm (EIB). If this dose is not effective, other appropriate therapy for exercise-induced bronchospasm should be considered. For Salmeterol Xinafoate Inhalation Powder Only: When used intermittenly as needed for prevention of EIB, this protection may last up to 9 hours in adolescents and adults and up to 12 hours in patients 4-11 years of age.

Geriatric Use

In studies where geriatric patients (65 years of age or older, see PRECAUTIONS) have been treated with salmeterol xinafoate, efficacy and safety of 50 mug for the inhalation powder and 42 mug for the inhalation aerosol given twice daily (morning and and evening), did not differ from that in younger patients. Consequently, no dosage adjustment is recommended.

COPD

For Salmeterol Xinafoate Inhalation Aerosol Only: For maintenance treatment of bronchospasm associated with COPD (including chronic bronchitis and emphysema), the usual dosage for adults is two inhalations (42 mug) twice daily (morning and evening, approximately 12 hours apart).

PATIENT PACKAGE INSERT :

For Salmeterol Xinafoate Inhalation Powder Only

Before using your drug inhalation device, read complete instructions carefully.

Children should use salmeterol xinafoate under adult supervision, as instructed by the patient’s doctor.

When you take salmeterol xinafoate out of the box and foil overwrap pouch, write the “Use by” date on the label in the space provided on the device (6 weeks from date of opening). The drug inhalation device will be in the closed position. The dose indicator on the top of the drug inhalation device tells you how many doses are left. After the drug inhalation device has delivered 55 doses (23 doses for the institutional or sample pack), numbers 5 to 0 will appear in red to warn you that there are only a few doses left.

1. Hold the drug inhalation device in one hand and put the thumb of your other hand on the thumbgrip. Push your thumb away from you as far as it will go until the mouthpiece appears and snaps into position.

2. Hold the drug inhalation device in a level, horizontal position with the mouthpiece towards you. Slide the lever away from you as far as it will go until it clicks. The drug inhalation device is now ready to use. Every time the lever is pushed back, a dose is made available for inhaling. This is shown by the dose counter. At this point do not close the device, play with the lever, or advance the lever more than once because this will release doses that will be wasted.

3. Holding the drug inhalation device level and away from your mouth, breathe out as far as is comfortable. (Remember, never breathe out into the drug inhalation device mouthpiece.)

4. Put the mouthpiece to your lips. Breathe in steadily and deeply through the drug inhalation device, not through your nose.

5. Remove the drug inhalation device from your mouth.

6. Hold your breath for about 10 seconds, or for as long as is comfortable. Breathe out slowly.

7. To close the drug inhalation device, put your thumb on the thumbgrip and slide the thumbgrip back towards you as far as it will go. The drug inhalation device will click shut. The lever will automatically return to its original position and will reset. The drug inhalation device is now ready for your next scheduled dose. (Repeat steps 1 through 7.)

8. Remember:

Never exhale into the drug inhalation device.
Always activate and use the drug inhalation device in a level, horizontal position.
Never wash the mouthpiece or any part of the drug inhalation device. KEEP IT DRY.

Dosage : Use only as directed by your doctor.

Warnings : Salmeterol xinafoate is different from your other asthma medications. Salmeterol xinafoate provides a relatively longer duration of effect. The bronchodilation action of salmeterol xinafoate usually lasts for at least 12 hours. Therefore, it is important that you carefully read and understand the following information.

Your inhaled, short-acting, bronchodilator becomes less effective for treatment of sudden asthma symptoms.
You need more inhalations than usual of your inhaled, short-acting bronchodilator for treatment of sudden asthma symptoms.
You are using four or more inhalations per day of your inhaled, short-acting bronchodilator for 2 or more days consecutively.
You use more than one canister of an inhaled, short-acting, bronchodilator in an 8-week period (i.e., there are 200 inhalations per canister).

5. Use other inhaled medications only as prescribed by your doctor.

6. Do no use salmeterol xinafoate as a substitute for oral or inhaled corticosteriods. If you have been prescribed corticosteriods, you should not change your dosage of these medications or stop taking these medications without talking to your doctor, even if you feel better.

Store at controlled room temperature, 20-25° C (68-77° F) in a dry place away from direct heat or sunlight. Keep out of reach of children. The drug inhalation device is not reusable and should be discarded after every blister has been used (when the dose indicator reads “0”) or 6 weeks after removal from the moisture-protective foil overwrap pouch, whichever comes first. Do not attempt to take the device apart.

Your doctor has determined that this product is likely to help your personal health. USE THIS PRODUCT AS DIRECTED, UNLESS INSTRUCTED TO DO OTHERWISE BY YOUR DOCTOR. If you have any questions about the use of salmeterol xinafoate, consult with your doctor.

HOW SUPPLIED :

Serevent Diskus Inhalation Powder

Storage : Store at controlled room temperature, 20-25°C (68-77°F) in a dry place away from direct heat or sunlight. Keep out of reach of children. The Diskus inhalation device is not reusable and should be discarded after every blister has been used (when the dose indicator reads “0”) or 6 weeks after removal from the moisture-protective foil overwrap pouch, whichever comes first. Do not attempt to take the device apart.

Serevent Inhalation Aerosol

Each actuation of Serevent Inhalation Aerosol delivers 25 mug of salmeterol base (as salmeterol xinafoate) from the valve and 21 mug of salmeterol base (as salmeterol xinafoate) from the actuator.

Serevent Inhalation Aerosol is also supplied in a pack in which each actuation delivers 25 mug of salmeterol base (as salmeterol xinafoate) from the valve and 21 mug of salmeterol base from the actuator (as salmeterol xinafoate).

For use with Serevent inhalation aerosol actuator only. The green actuator with Serevent inhalation aerosol should not be used with other aerosol medications, and actuators from other aerosol medications should not be used with a Serevent inhalation aerosol actuator.

The correct amount of medication in each inhalation cannot be assured after 120 actuations from the 13-g canister or 60 actuations from the 6.5-g canister even though the canister is not completely empty. The canister should be discarded when the labeled number of actuations has been used.

Storage : Store between 15-30°C (59-86°F). Store canister with nozzle end down. Protect from freezing temperatures and direct sunlight.

Avoid spraying in eyes. Contents under pressure. Do not puncture or incinerate. Do not store at temperatures above 120°F. Keep out of reach of children. As with most inhaled medications in aerosol canisters, the therapeutic effect of this medication may decrease when the canister is cold; for best results, the canister should be at room temperature before use. Shake well before using.