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Serevent Diskus

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Serevent Diskus

Serevent Diskus

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Asthma-Related Death

LABA, such as salmeterol, the active ingredient in SEREVENT DISKUS (salmeterol xinafoate) , increase the risk of asthma-related death. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA.

Because of this risk, use of SEREVENT DISKUS (salmeterol xinafoate) for the treatment of asthma without concomitant use of a long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated. Use SEREVENT DISKUS (salmeterol xinafoate) only as additional therapy for patients with asthma who are currently taking but are inadequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue SEREVENT DISKUS (salmeterol xinafoate) ) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use SEREVENT DISKUS (salmeterol xinafoate) for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.

Pediatric and Adolescent Patients: Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. For pediatric and adolescent patients with asthma who require addition of a LABA to an inhaled corticosteroid, a fixed-dose combination product containing both an inhaled corticosteroid and a LABA should ordinarily be used to ensure adherence with both drugs. In cases where use of a separate long-term asthma control medication (e.g., inhaled corticosteroid) and a LABA is clinically indicated, appropriate steps must be taken to ensure adherence with both treatment components. If adherence cannot be assured, a fixed-dose combination product containing both an inhaled corticosteroid and a LABA is recommended.

The Salmeterol Multi-center Asthma Research Trial (SMART) was a large 28-week placebo-controlled US study comparing the safety of salmeterol (SEREVENT Inhalation Aerosol) with placebo, each added to usual asthma therapy, that showed an increase in asthma-related deaths in patients receiving salmeterol [see Clinical Studies]. Given the similar basic mechanisms of action of betai-agonists, the findings seen in the SMART study are considered a class effect.

A 16-week clinical study performed in the United Kingdom, the Salmeterol Nationwide Surveillance (SNS) study, showed results similar to the SMART study. In the SNS study, the rate of asthma-related death was numerically, though not statistically significantly, greater in patients with asthma treated with salmeterol (42 mcg twice daily) than those treated with albuterol (180 mcg 4 times daily) added to usual asthma therapy.

The SNS and SMART studies enrolled patients with asthma. No studies have been conducted that were adequate to determine whether the rate of death in patients with COPD is increased by LABA.

Deterioration of Disease and Acute Episodes

SEREVENT DISKUS (salmeterol xinafoate) should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma or COPD. SEREVENT DISKUS (salmeterol xinafoate) has not been studied in patients with acutely deteriorating asthma or COPD. The initiation of SEREVENT DISKUS (salmeterol xinafoate) in this setting is not appropriate.

Serious acute respiratory events, including fatalities, have been reported when salmeterol has been initiated in patients with significantly worsening or acutely deteriorating asthma. 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, previous life-threatening acute asthma exacerbations) and in some patients with acutely deteriorating asthma (e.g., patients with significantly increasing symptoms; increasing need for inhaled, short-acting betai-agonists; decreasing response to usual medications; increasing need for systemic corticosteroids; recent emergency room visits; deteriorating lung function). However, these events have occurred in a few patients with less severe asthma as well. It was not possible from these reports to determine whether salmeterol contributed to these events.

Increasing use of inhaled, short-acting betai-agonists is a marker of deteriorating asthma. In this situation, the patient requires immediate reevaluation with reassessment of the treatment regimen, giving special consideration to the possible need for adding additional inhaled corticosteroid or initiating systemic corticosteroids. Patients should not use more than 1 inhalation twice daily (morning and evening) of SEREVENT DISKUS (salmeterol xinafoate) .

SEREVENT DISKUS (salmeterol xinafoate) should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. An inhaled, short-acting betai-agonist, not SEREVENT DISKUS (salmeterol xinafoate) , should be used to relieve acute symptoms such as shortness of breath. When prescribing SEREVENT DISKUS (salmeterol xinafoate) , the physician must also provide the patient with an inhaled, short-acting betai-agonist (e.g., albuterol) for treatment of acute symptoms.

When beginning treatment with SEREVENT DISKUS (salmeterol xinafoate) , patients who have been taking oral or inhaled, short-acting betai-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs.

SEREVENT DISKUS (salmeterol xinafoate) is Not a Substitute for Corticosteroids

There are no data demonstrating that SEREVENT DISKUS (salmeterol xinafoate) has a clinical anti-inflammatory effect such as that associated with corticosteroids. When initiating and throughout treatment with SEREVENT DISKUS (salmeterol xinafoate) in patients receiving oral or inhaled corticosteroids for treatment of asthma, patients must continue taking a suitable dosage of corticosteroids to maintain clinical stability even if they feel better as a result of initiating SEREVENT DISKUS (salmeterol xinafoate) . Any change in corticosteroid dosage should be made ONLY after clinical evaluation.

Excessive Use of SEREVENT DISKUS (salmeterol xinafoate) and Use With Other Long-Acting Beta2-Agonists

As with other inhaled beta2-adrenergic drugs, SEREVENT DISKUS (salmeterol xinafoate) should not be used more often or at higher doses than recommended, or in conjunction with other medications containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using SEREVENT DISKUS should not use an additional LABA (e.g., formoterol fumarate, arformorterol tartrate) for any reason.

Paradoxical Bronchospasm and Upper Airway Symptoms

As with other inhaled medications, SEREVENT DISKUS (salmeterol xinafoate) can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with SEREVENT DISKUS (salmeterol xinafoate) , it should be treated immediately with an inhaled, short-acting bronchodilator; SEREVENT DISKUS (salmeterol xinafoate) should be discontinued immediately; and alternative therapy should be instituted. Upper airway symptoms of laryngeal spasm, irritation, or swelling, such as stridor and choking, have been reported in patients receiving SEREVENT DISKUS (salmeterol xinafoate) .

Cardiovascular and Central Nervous System Effects

Excessive beta-adrenergic stimulation has been associated with seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, palpitation, nausea, dizziness, fatigue, malaise, and insomnia [see OVERDOSAGE]. Therefore, SEREVENT DISKUS (salmeterol xinafoate) , like all products containing sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Salmeterol 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 at recommended doses, if they 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. Large doses of inhaled or oral salmeterol (12 to 20 times the recommended dose) have been associated with clinically significant prolongation of the QTc interval, which has the potential for producing ventricular arrhythmias. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.

Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions may occur after administration of SEREVENT DISKUS, as demonstrated by cases of urticaria, angioedema, rash, and bronchospasm. There have been reports of anaphylactic reactions in patients with severe milk protein allergy; therefore, patients with severe milk protein allergy should not take SEREVENT DISKUS [see CONTRAINDICATIONS].

Drug Interactions With Strong Cytochrome P450 3A4 Inhibitors

Because of the potential for drug interactions and the potential for increased risk of cardiovascular adverse events, the concomitant use of SEREVENT DISKUS (salmeterol xinafoate) with strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ketoconazole, ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) is not recommended [see DRUG INTERACTIONS].

Coexisting Conditions

SEREVENT DISKUS (salmeterol xinafoate) , like all medications containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta2-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

Hypokalemia and Hyperglycemia

Beta-adrenergic 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]. The decrease in serum potassium is usually transient, not requiring supplementation. Clinically significant and dose-related changes in blood glucose and/or serum potassium were seen infrequently during clinical studies with SEREVENT DISKUS (salmeterol xinafoate) at recommended doses.

Patient Counseling Information

See FDA-approved Medication Guide.

Asthma-Related Death

Patients should be informed that salmeterol increases the risk of asthma-related death and may increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Patients should be informed that SEREVENT DISKUS (salmeterol xinafoate) should not be the only therapy for the treatment of asthma and must only be used as additional therapy when long-term asthma control medications (e.g., inhaled corticosteroids) do not adequately control asthma symptoms. They should also be informed that currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Patients should be informed that when SEREVENT DISKUS (salmeterol xinafoate) is added to their treatment regimen they must continue to use their long-term asthma control medication.

Not for Acute Symptoms

SEREVENT DISKUS (salmeterol xinafoate) is not meant to relieve acute asthma symptoms or exacerbations of COPD and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting betai-agonist such as albuterol. The physician should provide the patient with such medication and instruct the patient in how it should be used.

Patients should be instructed to notify their physicians immediately if they experience any of the following:

  • Decreasing effectiveness of inhaled, short-acting betai-agonists
  • Need for more inhalations than usual of inhaled, short-acting betai-agonists
  • Significant decrease in lung function as outlined by the physician

Patients should not stop therapy with SEREVENT DISKUS (salmeterol xinafoate) without physician/provider guidance since symptoms may recur after discontinuation.

SEREVENT DISKUS (salmeterol xinafoate) is Not a Substitute for Corticosteroids

All patients with asthma should be advised that they must also continue regular maintenance treatment with an inhaled corticosteroid if they are taking SEREVENT DISKUS (salmeterol xinafoate) .

SEREVENT DISKUS (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 SEREVENT DISKUS (salmeterol xinafoate) .

Do Not Use Additional Long-Acting Beta2-Agonists

When patients are prescribed SEREVENT DISKUS (salmeterol xinafoate) , other LABA should not be used.

Risks Associated With Beta-Agonist Therapy

Patients should be informed of adverse effects associated with betai-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.

Treatment of Exercised-lnduced Bronchospasm

When used for the treatment of EIB, additional doses of SEREVENT should not be used for 12 hours. Patients who are receiving SEREVENT DISKUS (salmeterol xinafoate) twice daily should not use additional SEREVENT for prevention of EIB.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

In an 18-month carcinogenicity study in CD-mice, salmeterol at oral doses of 1.4 mg/kg and above (approximately 20 times the MRHD for adults and children based on comparison of the plasma AUCs) caused a dose-related increase in the incidence of smooth muscle hyperplasia, cystic glandular hyperplasia, leiomyomas of the uterus, and ovarian cysts. No tumors were seen at 0.2 mg/kg (approximately 3 times the MRHD for adults and children based on comparison of the AUCs).

In a 24-month oral and inhalation carcinogenicity study in Sprague Dawley rats, salmeterol caused a dose-related increase in the incidence of mesovarian leiomyomas and ovarian cysts at doses of 0.68 mg/kg and above (approximately 55 and 25 times the MRHD for adults and children, respectively, on an mg/m2 basis). No tumors were seen at 0.21 mg/kg (approximately 15 and 8 times the MRHD for adults and children, respectively, on an 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 rats treated with salmeterol at oral doses up to 2 mg/kg (approximately 160 times the MRHD for adults on an mg/m2 basis).

Use In Specific Populations

Pregnancy

Teratoqenic Effects: Pregnancy Category C. There are no adequate and well-controlled studies with SEREVENT DISKUS (salmeterol xinafoate) in pregnant women. SEREVENT DISKUS (salmeterol xinafoate) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

No teratogenic effects occurred in rats at oral doses approximately 160 times the maximum recommended daily inhalation dose (MRHD) on an mg/m2 basis. In pregnant Dutch rabbits administered oral doses approximately 50 times the MRHD 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 such effects occurred at an oral dose approximately 20 times the MRHD based on comparison of the AUCs.

New Zealand White rabbits were less sensitive since only delayed ossification of the frontal cranial bones was seen at an oral dose approximately 1,600 times the MRHD on an 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.

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 SEREVENT DISKUS (salmeterol xinafoate) during labor should be restricted to those patients in whom the benefits clearly outweigh the risks.

Nursing Mothers

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

Pediatric Use

Available data from controlled clinical trials suggest that LAB A increase the risk of asthma-related hospitalization in pediatric and adolescent patients. For pediatric and adolescent patients with asthma who require addition of a LAB A to an inhaled corticosteroid, a fixed-dose combination product containing both an inhaled corticosteroid and a LABA should ordinarily be used to ensure adherence with both drugs [see INDICATIONS, WARNINGS AND PRECAUTIONS].

The safety and efficacy of SEREVENT DISKUS (salmeterol xinafoate) in adolescents (aged 12 years and older) has been established based on adequate and well-controlled trials conducted in adults and adolescents [see Clinical Studies]. A large 28-week placebo-controlled US study comparing salmeterol (SEREVENT Inhalation Aerosol) and placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in patients receiving salmeterol [see Clinical Studies]. Post-hoc analyses in pediatric patients aged 12 to 18 years were also performed. Pediatric patients accounted for approximately 12% of patients in each treatment arm. Respiratory-related death or life-threatening experience occurred at a similar rate in the salmeterol group (0.12% [2/1,653]) and the placebo group (0.12% [2/1,622]; relative risk: 1.0 [95% CI: 0.1, 7.2]). All-cause hospitalization, however, was increased in the salmeterol group (2% [35/1,653]) versus the placebo group ( < 1% [16/1,622]; relative risk: 2.1 [95% CI: 1.1, 3.7]).

The safety and efficacy of SEREVENT DISKUS (salmeterol xinafoate) have been evaluated in over 2,500 patients aged 4 to 11 years with asthma, 346 of whom were administered SEREVENT DISKUS (salmeterol xinafoate) for 1 year. Based on available data, no adjustment of dosage of SEREVENT DISKUS (salmeterol xinafoate) in pediatric patients is warranted for either asthma or EIB.

In 2 randomized, double-blind, controlled clinical trials of 12 weeks' duration, SEREVENT DISKUS (salmeterol xinafoate) 50 mcg was administered to 211 pediatric patients with asthma who did and who did not receive concurrent inhaled corticosteroids. The efficacy of SEREVENT DISKUS (salmeterol xinafoate) was demonstrated over the 12-week treatment period with respect to peak expiratory flow (PEF) and forced expiratory volume in 1 second (FEV1). SEREVENT DISKUS (salmeterol xinafoate) was effective in demographic subgroups (gender and age) of the population.

In 2 randomized studies in children aged 4 to 11 years with asthma and EIB, a single 50-mcg dose of SEREVENT DISKUS (salmeterol xinafoate) 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

Of the total number of adolescent and adult patients with asthma who received SEREVENT DISKUS (salmeterol xinafoate) in chronic dosing clinical trials, 209 were aged 65 years or older. Of the total number of patients with COPD who received SEREVENT DISKUS (salmeterol xinafoate) in chronic dosing clinical trials, 167 were aged 65 years or older and 45 were aged 75 years or older. No apparent differences in the safety of SEREVENT DISKUS (salmeterol xinafoate) were observed when geriatric patients were compared with younger patients in clinical trials. As with other beta2-agonists, however, special caution should be observed when using SEREVENT DISKUS (salmeterol xinafoate) in geriatric patients who have concomitant cardiovascular disease that could be adversely affected by this class of drug. Data from the trials in patients with COPD suggested a greater effect on FEV1 of SEREVENT DISKUS (salmeterol xinafoate) in the < 65 years age-group, as compared with the ≥ 65 years age-group. However, based on available data, no adjustment of dosage of SEREVENT DISKUS (salmeterol xinafoate) in geriatric patients is warranted.

Hepatic Impairment

The pharmacokinetics of salmeterol base has not been studied in patients with hepatic 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.

Last reviewed on RxList: 2/28/2011
This monograph has been modified to include the generic and brand name in many instances.

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