SALMETEROL: 1,761 Adverse Event Reports & Safety Profile

The active component of SEREVENT DISKUS is salmeterol xinafoate, a beta 2 -adrenergic bronchodilator. Salmeterol xinafoate is the racemic form of the 1-hydroxy-2-naphthoic acid salt of salmeterol. It has the chemical name 4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol, 1-hydroxy-2-naphthalenecarboxylate and the following chemical structure: Salmeterol xinafoate is a white powder with a molecular weight of 603.8, and the empirical formula is C 25 H 37 NO 4

• C 11 H 8 O 3 . It is freely soluble in methanol; slightly soluble in ethanol, chloroform, and isopropanol; and sparingly soluble in water. SEREVENT DISKUS is a teal green plastic inhaler containing a foil blister strip. Each blister on the strip contains a white powder mix of micronized salmeterol xinafoate salt (72.5 mcg, equivalent to 50 mcg of salmeterol base) in 12.5 mg of formulation containing lactose monohydrate (which contains milk proteins). After the inhaler is activated, the powder is dispersed into the airstream created by the patient inhaling through the mouthpiece. Under standardized in vitro test conditions, SEREVENT DISKUS delivers 47 mcg of salmeterol base per blister when tested at a flow rate of 60 L/min for 2 seconds. In adult subjects with obstructive lung disease and severely compromised lung function (mean FEV 1 20% to 30% of predicted), mean peak inspiratory flow (PIF) through the DISKUS inhaler was 82.4 L/min (range: 46.1 to 115.3 L/min). The actual amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow profile. Salmeterol chemical structure

AND USAGE SEREVENT DISKUS is a LABA indicated for:

• Treatment of asthma in patients aged 4 years and older with an ICS. ( 1.1 )
• Prevention of exercise-induced bronchospasm (EIB) in patients aged 4 years and older. ( 1.2 )
• Maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD). ( 1.3 ) Important limitation of use: Not indicated for relief of acute bronchospasm. ( 1.1 , 1.3 )

1.1 Treatment of Asthma SEREVENT DISKUS is indicated for the treatment of asthma and in the prevention of bronchospasm only as concomitant therapy with an ICS in patients aged 4 years and older with reversible obstructive airway disease, including patients with symptoms of nocturnal asthma. LABA, such as salmeterol, the active ingredient in SEREVENT DISKUS, as monotherapy (without ICS) increase the risk of asthma-related death <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span> . Use of SEREVENT DISKUS for the treatment of asthma without concomitant use of an ICS is contraindicated <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> . Use SEREVENT DISKUS only as additional therapy for patients with asthma who are currently taking but are inadequately controlled on an ICS. Do not use SEREVENT DISKUS for patients whose asthma is adequately controlled on low- or medium-dose ICS. Pediatric and Adolescent Patients Available data from controlled clinical trials suggest that LABA as monotherapy 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 ICS, a fixed-dose combination product containing both an ICS and a LABA should ordinarily be used to ensure adherence with both drugs. In cases where use of a separate ICS 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 ICS and a LABA is recommended.

Important

Limitation of Use SEREVENT DISKUS is NOT indicated for the relief of acute bronchospasm.

1.2 Prevention of Exercise-Induced Bronchospasm SEREVENT DISKUS is also indicated for prevention of exercise-induced bronchospasm (EIB) in patients aged 4 years and older. Use of SEREVENT DISKUS as a single agent for the prevention of EIB may be clinically indicated in patients who do not have persistent asthma. In patients with persistent asthma, use of SEREVENT DISKUS for the prevention of EIB may be clinically indicated, but the treatment of asthma should include an ICS.

1.3 Maintenance Treatment of Chronic Obstructive Pulmonary Disease SEREVENT DISKUS is indicated for the long-term twice-daily administration in the maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD) (including emphysema and chronic bronchitis).

Important

Limitation of Use SEREVENT DISKUS is NOT indicated for the relief of acute bronchospasm.

AND ADMINISTRATION SEREVENT DISKUS should be administered by the orally inhaled route only. More frequent administration or a greater number of inhalations (more than 1 inhalation twice daily) is not recommended as some patients are more likely to experience adverse effects. Patients using SEREVENT DISKUS should not use additional LABA for any reason. [See Warnings and Precautions ( 5.4 , 5.6 ).]

• For oral inhalation only. ( 2 )
• Treatment of asthma in patients aged 4 years and older: 1 inhalation twice daily in addition to concomitant treatment with an ICS. ( 2.1 )
• EIB: 1 inhalation at least 30 minutes before exercise. ( 2.2 )
• Maintenance treatment of bronchospasm associated with COPD: 1 inhalation twice daily. ( 2.3 )

2.1 Asthma LABA, such as salmeterol, the active ingredient in SEREVENT DISKUS, as monotherapy (without ICS) increase the risk of asthma-related death <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span>. Because of this risk, use of SEREVENT DISKUS for the treatment of asthma without concomitant use of an ICS is contraindicated. Use SEREVENT DISKUS only as additional therapy for patients with asthma who are currently taking but are inadequately controlled on an ICS. Do not use SEREVENT DISKUS for patients whose asthma is adequately controlled on low- or medium-dose ICS. Pediatric and Adolescent Patients Available data from controlled clinical trials suggest that LABA as monotherapy increase the risk of asthma-related hospitalization in pediatric and adolescent patients. For patients with asthma younger than 18 years who require addition of a LABA to an ICS, a fixed-dose combination product containing both an ICS and a LABA should ordinarily be used to ensure adherence with both drugs. In cases where use of a separate ICS 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 ICS and a LABA is recommended. For bronchodilatation and prevention of symptoms of asthma, including the symptoms of nocturnal asthma, the usual dosage for adults and children aged 4 years and older is 1 inhalation (50 mcg) twice daily, approximately 12 hours apart. 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. If symptoms arise in the period between doses, an inhaled, short-acting beta 2 -agonist should be taken for immediate relief.

2.2 Exercise-Induced Bronchospasm Use of SEREVENT DISKUS as a single agent for the prevention of EIB may be clinically indicated in patients who do not have persistent asthma. In patients with persistent asthma, use of SEREVENT DISKUS for the prevention of EIB may be clinically indicated, but the treatment of asthma should include an ICS. One inhalation of SEREVENT DISKUS at least 30 minutes before exercise has been shown to protect patients against EIB. When used intermittently as needed for prevention of EIB, this protection may last up to 9 hours in adults and adolescents and up to 12 hours in patients aged 4 to 11 years. Additional doses of SEREVENT should not be used for 12 hours after the administration of this drug. Patients who are receiving SEREVENT DISKUS twice daily should not use additional SEREVENT for prevention of EIB.

2.3 Chronic Obstructive Pulmonary Disease For maintenance treatment of bronchospasm associated with COPD (including chronic bronchitis and emphysema), the dosage for adults is 1 inhalation (50 mcg) twice daily, approximately 12 hours apart.

Use of SEREVENT DISKUS for the treatment of asthma without concomitant use of an ICS is contraindicated [see Warnings and Precautions ( 5.1 )] . The use of SEREVENT DISKUS is contraindicated in the following conditions:

• Primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required [see Warnings and Precautions ( 5.2 )]
• Severe hypersensitivity to milk proteins or demonstrated hypersensitivity to salmeterol or any of the excipients [see Warnings and Precautions ( 5.7 ), Adverse Reactions ( 6.3 ), Description ( 11 )]
• Asthma: Without concomitant use of an ICS. ( 4 )
• Primary treatment of status asthmaticus or acute episodes of asthma or COPD requiring intensive measures. ( 4 )
• Severe hypersensitivity to milk proteins or demonstrated hypersensitivity to salmeterol or any of the excipients. ( 4 )

REACTIONS LABA, including salmeterol, the active ingredient in SEREVENT DISKUS, as monotherapy (without ICS) increase the risk of asthma-related death. Data from a large 28-week placebo-controlled U.S. trial that compared the safety of salmeterol or placebo added to usual asthma therapy showed an increase in asthma-related deaths in subjects receiving salmeterol. Available data from controlled clinical trials suggest that LABA as monotherapy increase the risk of asthma-related hospitalization in pediatric and adolescent patients [see Warnings and Precautions ( 5.1 ), Clinical Studies ( 14.1 )] . Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Most common adverse reactions (incidence ≥5%) are:

• Asthma: Headache, influenza, nasal/sinus congestion, pharyngitis, rhinitis, tracheitis/bronchitis. ( 6.1 )
• COPD: Cough, headache, musculoskeletal pain, throat irritation, viral respiratory infection. ( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trials Experience in Asthma Adult and Adolescent Subjects Aged 12 Years and Older Two multicenter, 12-week, placebo-controlled clinical trials evaluated twice-daily doses of SEREVENT DISKUS in subjects aged 12 years and older with asthma.

Table

1 reports the incidence of adverse reactions in these 2 trials.

Table

1.

Adverse

Reactions with SEREVENT DISKUS with ≥3% Incidence and More Common than Placebo in Adult and Adolescent Subjects with Asthma a a Table 1 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of ≥3% in the group receiving SEREVENT DISKUS and were more common than in the placebo group.

Adverse Event

Percent of Subjects SEREVENT DISKUS 50 mcg Twice Daily (n = 149)

Albuterol Inhalation Aerosol

180 mcg 4 Times Daily (n = 150) Placebo (n = 152) Ear, nose, and throat Nasal/sinus congestion, pallor 9 8 6 Rhinitis 5 4 4 Neurological Headache 13 12 9 Respiratory Asthma 3 <1 1 Tracheitis/bronchitis 7 3 4 Influenza 5 5 2 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.

Additional Adverse

Reactions: Other adverse reactions not previously listed, whether considered drug-related or not by the investigators, that were reported more frequently by subjects with asthma treated with SEREVENT DISKUS compared with subjects treated with placebo include the following: contact dermatitis, eczema, localized aches and pains, nausea, oral mucosal abnormality, pain in joint, paresthesia, pyrexia of unknown origin, sinus headache, and sleep disturbance.

Pediatric Subjects Aged

4 to 11 Years Two multicenter, 12-week, controlled trials have evaluated twice-daily doses of SEREVENT DISKUS in subjects aged 4 to 11 years with asthma.

Table

2 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of ≥3% in the group receiving SEREVENT DISKUS and were more common than in the placebo group.

Table

2.

Adverse Reaction

Incidence in Two 12-Week Pediatric Clinical Trials in Subjects with Asthma Adverse Event Percent of Subjects SEREVENT DISKUS 50 mcg Twice Daily (n = 211)

Albuterol Inhalation Aerosol

200 mcg 4 Times Daily (n = 115) Placebo (n = 215) Ear, nose, and throat Ear signs and symptoms 4 9 3 Pharyngitis 6 3 3 Neurological Headache 17 20 14 Respiratory Asthma 4 <1 2 Skin Skin rashes 4 2 3 Urticaria 3 2 0 The following events were reported at an incidence of >1% 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. In clinical trials evaluating concurrent therapy of salmeterol with ICS, adverse events were consistent with those previously reported for salmeterol, or with events that would be expected with the use of ICS.

Laboratory Test Abnormalities

Elevation of hepatic enzymes was reported in ≥1% of subjects in clinical trials. The elevations were transient and did not lead to discontinuation from the trials. In addition, there were no clinically relevant changes noted in glucose or potassium.

6.2 Clinical Trials Experience in Chronic Obstructive Pulmonary Disease Two multicenter, 24-week, placebo-controlled U.S. trials evaluated twice-daily doses of SEREVENT DISKUS in subjects with COPD. For presentation ( Table 3 ), the placebo data from a third trial, identical in design, subject entrance criteria, and overall conduct but comparing fluticasone propionate with placebo, were integrated with the placebo data from these 2 trials (total N = 341 for salmeterol and 576 for placebo).

Table

3.

Adverse

Reactions with SEREVENT DISKUS with ≥3% Incidence in U.S.

Controlled Clinical

Trials in Subjects with Chronic Obstructive Pulmonary Disease a a Table 3 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of ≥3% in the group receiving SEREVENT DISKUS and were more common than in the placebo group.

Adverse Event

Percent of Subjects SEREVENT DISKUS 50 mcg Twice Daily (n = 341) Placebo (n = 576)

Cardiovascular Hypertension

4 2 Ear, nose, and throat Throat irritation 7 6 Nasal congestion/blockage 4 3 Sinusitis 4 2 Ear signs and symptoms 3 1 Gastrointestinal Nausea and vomiting 3 3 Lower respiratory Cough 5 4 Rhinitis 4 2 Viral respiratory infection 5 4 Musculoskeletal Musculoskeletal pain 12 10 Muscle cramps and spasms 3 1 Neurological Headache 14 11 Dizziness 4 2 Average duration of exposure (days) 138.5

128.9 Additional Adverse Reactions Other adverse reactions occurring in the group receiving SEREVENT DISKUS that occurred at a frequency of ≥1% and were more common than in the placebo group were as follows: anxiety; arthralgia and articular rheumatism; bone and skeletal pain; candidiasis mouth/throat; dental discomfort and pain; dyspeptic symptoms; edema and swelling; gastrointestinal infections; hyperglycemia; hyposalivation; keratitis and conjunctivitis; lower respiratory signs and symptoms; migraines; muscle pain; muscle stiffness, tightness, and rigidity; musculoskeletal inflammation; pain; and skin rashes. Adverse reactions to salmeterol are similar in nature to those seen with other selective beta 2 -adrenoceptor agonists, e.g., tachycardia; palpitations; immediate hypersensitivity reactions, including urticaria, angioedema, rash, bronchospasm; headache; tremor; nervousness; and paradoxical bronchospasm.

Laboratory Abnormalities

There were no clinically relevant changes in these trials. Specifically, no changes in potassium were noted.

6.3 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postapproval use of salmeterol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to salmeterol or a combination of these factors. In extensive U.S. and worldwide postmarketing experience with salmeterol, 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span> , but they have also occurred in a few patients with less severe asthma. It was not possible from these reports to determine whether salmeterol contributed to these events.

Cardiovascular

Arrhythmias (including atrial fibrillation, supraventricular tachycardia, extrasystoles) and anaphylaxis. Non-Site Specific Very rare anaphylactic reaction in patients with severe milk protein allergy.

Respiratory

Reports of upper airway symptoms of laryngeal spasm, irritation, or swelling such as stridor or choking; oropharyngeal irritation.

AND PRECAUTIONS

• LABA as monotherapy (without ICS) for asthma increase the risk of asthma-related death and asthma-related hospitalizations. Prescribe for asthma only as concomitant therapy with an inhaled corticosteroid. ( 5.1 )
• Do not initiate in acutely deteriorating asthma or COPD. Do not use to treat acute symptoms. ( 5.2 )
• Not a substitute for corticosteroids. Patients with asthma must take a concomitant ICS. ( 5.3 )
• Do not use in combination with an additional medicine containing a LABA because of risk of overdose. ( 5.4 )
• If paradoxical bronchospasm occurs, discontinue SEREVENT DISKUS and institute alternative therapy. ( 5.5 )
• Use with caution in patients with cardiovascular or central nervous system disorders because of beta-adrenergic stimulation. ( 5.6 )
• Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. ( 5.9 )
• Be alert to hypokalemia and hyperglycemia. ( 5.10 )

5.1 Asthma-Related Death LABA, such as salmeterol, the active ingredient in SEREVENT DISKUS, as monotherapy (without ICS) increase the risk of asthma-related death. When LABA are used in fixed - dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared with ICS alone. Use of SEREVENT DISKUS for the treatment of asthma without concomitant use of an ICS is contraindicated. Use SEREVENT DISKUS only as additional therapy for patients with asthma who are currently taking but are inadequately controlled on an ICS. Do not use SEREVENT DISKUS for patients whose asthma is adequately controlled on low- or medium-dose ICS. Pediatric and Adolescent Patients Available data from controlled clinical trials suggest that LABA as monotherapy 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 ICS, a fixed-dose combination product containing both an ICS and a LABA should ordinarily be used to ensure adherence with both drugs. In cases where use of a separate ICS 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 ICS and a LABA is recommended.

The Salmeterol Multicenter Asthma Research

Trial (SMART) was a large 28-week placebo-controlled U.S. trial 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 subjects receiving salmeterol [see Clinical Studies ( 14.1 )] . Given the similar basic mechanisms of action of beta 2 -agonists, the findings seen in the SMART trial are considered a class effect. A 16-week clinical trial performed in the United Kingdom, the Salmeterol Nationwide Surveillance (SNS) trial, showed results similar to the SMART trial. In the SNS trial, the rate of asthma-related death was numerically, though not statistically significantly, greater in subjects 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 trials enrolled subjects with asthma. Available data do not suggest an increased risk of death with use of LABA in patients with COPD.

5.2 Deterioration of Disease and Acute Episodes SEREVENT DISKUS should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma or COPD. SEREVENT DISKUS has not been studied in subjects with acutely deteriorating asthma or COPD. The initiation of SEREVENT DISKUS 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 beta 2 -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 beta 2 -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 ICS or initiating systemic corticosteroids. Patients should not use more than 1 inhalation twice daily of SEREVENT DISKUS. SEREVENT DISKUS 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 beta 2 -agonist, not SEREVENT DISKUS, should be used to relieve acute symptoms such as shortness of breath. When prescribing SEREVENT DISKUS, the healthcare provider should also prescribe an inhaled, short-acting beta 2 -agonist (e.g., albuterol) for treatment of acute symptoms. When beginning treatment with SEREVENT DISKUS, patients who have been taking oral or inhaled, short-acting beta 2 -agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs.

5.3 SEREVENT DISKUS is Not a Substitute for Corticosteroids There are no data demonstrating that SEREVENT DISKUS has a clinical anti-inflammatory effect such as that associated with corticosteroids. When initiating and throughout treatment with SEREVENT DISKUS in patients receiving oral or ICS 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. Any change in corticosteroid dosage should be made ONLY after clinical evaluation.

5.4 Excessive Use of SEREVENT DISKUS and Use with Other Long-acting Beta 2 -agonists SEREVENT DISKUS should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines 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 another medicine containing a LABA (e.g., formoterol fumarate, arformoterol tartrate, indacaterol) for any reason.

5.5 Paradoxical Bronchospasm and Upper Airway Symptoms As with other inhaled medicines, SEREVENT DISKUS can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with SEREVENT DISKUS, it should be treated immediately with an inhaled, short-acting bronchodilator; SEREVENT DISKUS 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.

5.6 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 <span class="opacity-50 text-xs">[see Overdosage ( 10 )]</span> . Therefore, SEREVENT DISKUS, 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 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. 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.

5.7 Immediate Hypersensitivity Reactions Immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of SEREVENT DISKUS. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of powder products containing lactose; therefore, patients with severe milk protein allergy should not use SEREVENT DISKUS <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> .

5.8 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors The use of strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with SEREVENT DISKUS is not recommended because increased cardiovascular adverse effects may occur <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )]</span> .

5.9 Coexisting Conditions SEREVENT DISKUS, like all medicines 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 beta 2 -adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

5.10 Hypokalemia and Hyperglycemia Beta-adrenergic agonist medicines may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.2 )]</span> . The decrease in serum potassium is usually transient, not requiring supplementation. Clinically significant and dose-related changes in blood glucose and/or serum potassium were seen infrequently during clinical trials with SEREVENT DISKUS at recommended doses.

INTERACTIONS

• Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir, ketoconazole): Use not recommended. May increase risk of cardiovascular effects. ( 7.1 )
• Monoamine oxidase inhibitors and tricyclic antidepressants: Use with extreme caution. May potentiate effect of salmeterol on vascular system. ( 7.2 )
• Beta-blockers: Use with caution. May block bronchodilatory effects of beta-agonists and produce severe bronchospasm. ( 7.3 )
• Diuretics: Use with caution. Electrocardiographic changes and/or hypokalemia associated with non–potassium-sparing diuretics may worsen with concomitant beta-agonists. ( 7.4 )

7.1 Inhibitors of Cytochrome P450 3A4 Salmeterol is a substrate of CYP3A4. The use of strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with SEREVENT DISKUS is not recommended because increased cardiovascular adverse effects may occur. In a drug interaction trial in 20 healthy subjects, coadministration of inhaled salmeterol (50 mcg twice daily) and oral ketoconazole (400 mg once daily) for 7 days resulted in greater systemic exposure to salmeterol (AUC increased 16-fold and C max increased 1.4-fold). Three (3) subjects were withdrawn due to beta 2 -agonist side effects (2 with prolonged QTc and 1 with palpitations and sinus tachycardia). Although there was no statistical effect on the mean QTc, coadministration of salmeterol and ketoconazole was associated with more frequent increases in QTc duration compared with salmeterol and placebo administration.

7.2 Monoamine Oxidase Inhibitors and Tricyclic Antidepressants SEREVENT DISKUS 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.

7.3 Beta-adrenergic Receptor Blocking Agents Beta-blockers not only block the pulmonary effect of beta-agonists, such as salmeterol, but may also produce severe bronchospasm in patients with asthma or COPD. Therefore, patients with asthma or COPD should not normally be treated with beta-blockers. However, under certain circumstances, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents for these patients; cardioselective beta-blockers could be considered, although they should be administered with caution.

7.4 Non–Potassium-Sparing Diuretics The ECG changes and/or hypokalemia that may result from the administration of non–potassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of SEREVENT DISKUS with non–potassium-sparing diuretics.