Serevent Diskus

— THERAPEUTIC CATEGORIES —
  • Asthma/COPD
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Serevent Diskus Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Salmeterol (as xinafoate) 50mcg/inh; dry pwd for inhalation; device with drug in blisters.

    Pharmacological Class

    Long-acting beta-2 agonist (LABA).

    How Supplied

    Diskus (60 blisters)—1

    How Supplied

    Serevent Diskus is supplied as a disposable teal green plastic inhaler containing a foil blister strip with 60 blisters. The inhaler is packaged in a plastic-coated, moisture-protective foil pouch. 

    Serevent Diskus is also supplied in an institutional pack containing 28 blisters.  

    Storage

    Store at room temperature between 68°F and 77°F (20°C and 25°C); excursions permitted from 59°F to 86°F (15°C to 30°C) [See USP Controlled Room Temperature]. Store in a dry place away from direct heat or sunlight. 

    Serevent Diskus should be stored inside the unopened moisture-protective foil pouch and only removed from the pouch immediately before initial use. Discard Serevent Diskus 6 weeks after opening the foil pouch or when the counter reads “0” (after all blisters have been used), whichever comes first. The inhaler is not reusable. Do not attempt to take the inhaler apart. 

    Manufacturer

    GlaxoSmithKline

    Serevent Diskus Indications

    Indications

    As an adjunct to inhaled corticosteroid (ICS) for the treatment of asthma and in the prevention of bronchospasm in reversible obstructive airway disease (including nocturnal asthma). Prevention of exercise-induced bronchospasm (EIB). Maintenance treatment of COPD-associated bronchospasm in adults.

    Limitations of Use

    Not for relief of acute bronchospasm.

    Serevent Diskus Dosage and Administration

    Adults and Children

    Allow approx. 12hrs between doses. Asthma: ≥4yrs: 1 inh twice daily with concomitant ICS. EIB: ≥4yrs: 1 inh at least 30mins before exercise; do not use additional doses for 12hrs after administration or if already using twice daily dosing. COPD: 1 inh twice daily. Max 1 inh twice daily.

    Serevent Diskus Contraindications

    Contraindications

    Treatment of asthma without concomitant use of ICS. Primary treatment of status asthmaticus or acute episodes of asthma or COPD requiring intensive measures. Severe hypersensitivity to milk protein.

    Serevent Diskus Boxed Warnings

    Boxed Warning

    Asthma-related death.

    Serevent Diskus Warnings/Precautions

    Warnings/Precautions

    LABA monotherapy (without ICS) may increase risk of asthma-related events (death, hospitalizations, intubations). Do not use for asthma adequately controlled on low- or medium-dose ICS. Use fixed-dose combination product of an ICS and a LABA in children with asthma to ensure adherence. Do not initiate in rapidly or acutely deteriorating asthma or COPD. Salmeterol is not a substitute for steroids. Not for use with other long-acting β2-agonists. Do not exceed recommended dose. Prescribe a short-acting, inhaled β2-agonist for acute symptoms; monitor for increased need. Discontinue if paradoxical bronchospasm occurs; use alternative therapy. Cardiovascular disease (esp. coronary insufficiency, arrhythmias, hypertension). Convulsive disorders. Thyrotoxicosis. Hyperresponsiveness to sympathomimetics. Diabetes. Ketoacidosis. Hypokalemia. Hyperglycemia. Hepatic impairment; monitor. Labor & delivery. Pregnancy. Nursing mothers.

    Warnings/Precautions

    Asthma-Related Death 

    • Increased risk of asthma-related death when LABA, such as salmeterol, is used as monotherapy (without ICS).

    • Use of Serevent Diskus for the treatment of asthma without ICS is contraindicated.

    • Do not use Serevent Diskus for patients whose asthma is adequately controlled on low- or medium-dose ICS.

    • Pediatric and Adolescent Patients  

      • For patients with asthma who require the addition of a LABA to an ICS, a fixed-dose combination product containing both an ICS and a LABA should be used to ensure adherence.

      • 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. 

    Deterioration of Disease and Acute Episodes

    • Do not initiate in patients during rapidly deteriorating or potentially life-threatening episodes of asthma or COPD.

    • Not studied in patients with acutely deteriorating asthma or COPD.

    • Immediately reevaluate patients and their treatment regimen if they require an increased use of inhaled, short-acting beta2-agonists (marker of deteriorating asthma).

    • Do not use for the relief of acute symptoms (i.e., as rescue therapy for the treatment of acute episodes of bronchospasm). Prescribe inhaled, short-acting beta2-agonist to treat acute symptoms when prescribing Serevent Diskus.

    • When beginning treatment with Serevent Diskus, patients who have been taking oral or 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. 

    Serevent Diskus is Not a Substitute for 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. 

    Excessive Use of Serevent Diskus and Use with Other Long-acting Beta2-agonists 

    • Do not use more often than recommended, at higher doses than recommended, or concomitantly with other medications containing LABA.

    Paradoxical Bronchospasm and Upper Airway Symptoms

    • If paradoxical bronchospasm occurs, treat immediately with an inhaled, short-acting bronchodilator; discontinue Serevent Diskus immediately and institute alternative therapy.

    Cardiovascular and Central Nervous System Effects 

    • Use caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

    • May produce a clinically significant cardiovascular effect (uncommon); discontinue treatment if these effects occur.

    Immediate Hypersensitivity Reactions 

    • Immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur.

    • Do not use in patients with severe milk protein allergy.

    Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors 

    • Not recommended for use with strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) due to increased cardiovascular adverse effects.

    Coexisting Conditions

    • Use caution in patients with convulsive disorders, or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines.

    Hypokalemia and Hyperglycemia 

    • May produce significant hypokalemia in some patients, possibly through intracellular shunting, which may result in adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation.

    Pregnancy Considerations

    Risk Summary  

    • Available data from published epidemiological studies and case reports with use of Serevent Diskus in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

    Clinical Considerations  

    • Disease-Associated Maternal and/or Embryofetal Risk: Women with poorly or moderately controlled asthma have an increased risk of pre-eclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Severe asthma during pregnancy is associated with maternal mortality, fetal mortality, or both. Pregnant women with asthma should be monitored closely.

    • Labor and Delivery: There are no adequate and well-controlled human studies that have evaluated the effects of Serevent Diskus during labor and delivery. Restrict use during labor to patients in whom the benefits clearly outweigh the risks due to the potential for beta-agonist interference with uterine contractility.

    Nursing Mother Considerations

    Risk Summary 

    • There is no information regarding the presence of salmeterol in human milk, the effects on the breastfed child, or the effects on milk production.

    • The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Serevent Diskus and any potential adverse effects on the breastfed child from Serevent Diskus or from the underlying maternal condition.

    Geriatric Considerations

    No apparent differences in the safety of Serevent Diskus were observed when geriatric subjects were compared with younger subjects in clinical trials. Observe with special caution when using Serevent Diskus in geriatric patients who have concomitant cardiovascular disease that could be adversely affected by beta-agonists.

    No adjustment of dosage of Serevent Diskus in geriatric patients is warranted.

    Hepatic Impairment Considerations

    Monitor closely in patients with hepatic disease.

    Serevent Diskus Pharmacokinetics

    Absorption

    Because of the small therapeutic dose, systemic levels of salmeterol are low or undetectable after inhalation of recommended doses (50 mcg of salmeterol inhalation powder twice daily). Following chronic administration of an inhaled dose of 50 mcg of salmeterol inhalation powder twice daily, salmeterol was detected in plasma within 5 to 45 minutes in 7 subjects with asthma; plasma concentrations were very low, with mean peak concentrations of 167 pg/mL at 20 minutes and no accumulation with repeated doses. 

    Distribution

    The percentage of salmeterol bound to human plasma proteins averages 96% in vitro over the concentration range of 8 to 7722 ng of salmeterol base per milliliter, much higher concentrations than those achieved following therapeutic doses of salmeterol. The xinafoate moiety is highly protein bound (>99%).

    Metabolism

    Salmeterol base is extensively metabolized by hydroxylation, with subsequent elimination predominantly in the feces. No significant amount of unchanged salmeterol base was detected in either urine or feces. An in vitro study using human liver microsomes showed that salmeterol is extensively metabolized to α-hydroxysalmeterol (aliphatic oxidation) by CYP3A4. 

    Elimination

    In 2 healthy adult subjects who received 1 mg of radiolabeled salmeterol (as salmeterol xinafoate) orally, approximately 25% and 60% of the radiolabeled salmeterol was eliminated in urine and feces, respectively, over a period of 7 days. The terminal elimination half-life was about 5.5 hours (1 volunteer only). The xinafoate moiety has no apparent pharmacologic activity. The xinafoate moiety has a long elimination half-life of 11 days. 

    Serevent Diskus Interactions

    Interactions

    Concomitant strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, ritonavir, atazanavir, clarithromycin, indinavir, nefazodone, nelfinavir, saquinavir, telithromycin): not recommended. Caution during or within 2 weeks of discontinuing MAOIs or tricyclic antidepressants, β-blockers (consider cardioselective), K+-depleting diuretics.

    Serevent Diskus Adverse Reactions

    Adverse Reactions

    Headache, influenza, nasal/sinus congestion, pharyngitis, rhinitis, tracheitis/bronchitis, cough, musculoskeletal pain, throat irritation, viral respiratory infection.

    Serevent Diskus Clinical Trials

    Clinical Trials

    Asthma: Adult and Adolescent Subjects Aged 12 Years and Older 

    In 2 randomized, double-blind trials, the efficacy of Serevent Diskus was compared with albuterol inhalation aerosol and placebo in adolescent and adult patients with mild to moderate asthma (protocol defined as 50% to 80% predicted FEV1, actual mean of 67.7% at baseline), including those with or without conconcurrent ICS. 

    In the combined data for both trials, there was no change in effectiveness of Serevent Diskus and no gender- or age-related differences in safety or efficacy after the 12-week period. Moreover, treatment with Serevent Diskus had a change in the mean AM peak expiratory flow of +32 L/min  at week 12 from baseline compared with no change for albuterol inhalation aerosol and +2 L/min for placebo (both P <.001). The change in the mean percentage of nights with no awakenings at week 12 from baseline was +22% for the Serevent Diskus arm compared with +3% for albuterol inhalation aerosol and +3% for placebo (both P <.001). The Serevent Diskus treatment arm had a mean reduction of -2.7 inhalations per day for rescue medications at week 12 from baseline compared with -0.9 inhalations for placebo (P <.001). 

    Subjects on Concomitant Inhaled Corticosteroids: 

    • In 4 clinical trials in adult and adolescent subjects with asthma (N = 1922), the effect of adding Serevent Inhalation Aerosol to ICS therapy was evaluated over a 24-week treatment period. The trials compared the addition of salmeterol therapy to an increase (at least doubling) of the ICS dose.  

    • In 2 randomized, double-blind, controlled, parallel-group clinical trials, 997 patients 18 to 82 years of age were enrolled with persistent asthma who were previously maintained but not on adequately controlled on ICS therapy. All patients were switched to beclomethasone dipropionate (BDP) 168 mcg twice daily during a 2-week run-in period. If patients were still not adequately controlled, then they were randomly assigned to receive either the addition of Serevent Inhalation Aerosol 42 mcg twice daily or an increase of BDP to 336 mcg twice daily.

    • Both the doubling dose of BDP and the addition of Serevent Inhalation Aerosol achieved statistically significantly greater improvements in pulmonary function and asthma symptoms, and statistically significantly greater reduction in supplemental albuterol use. There was no difference between the two treatment arms for the percentage of patients who experienced asthma exacerbations.

    Additionally, in 2 randomized, double-blind, controlled, parallel-group clinical trials, 925 patients 12 to 78 years of age were enrolled with persistent asthma who were previously maintained but not adequately controlled on prior asthma therapy. All patients were switched to fluticasone propionate 88 mcg twice daily during the 2- to 4-week run-in period. If patients were still not adequately controlled, then they were randomly assigned to receive either the addition of Serevent Inhalation Aerosol 42 mcg twice daily or an increase of fluticasone propionate to 220 mcg twice daily.

    Both the increased dose of fluticasone propionate and the addition of Serevent Inhalation Aerosol achieved statistically significantly greater improvements in pulmonary function and asthma symptoms, and statistically significnatly greater reductions in supplement albuterol use. There were fewer patients treated with Serevent Inhalation Aerosol who experienced asthma exacerbations compared with the higher dose of fluticasone propionate.

     

    Pediatric Subjects

    In a randomized, double-blind, controlled trial, the efficacy of Serevent Diskus was evaluated in 449 pediatric patients with asthma who did and who did not receive concurrent ICS. Over the 12-week treatment period, results showed that treatment with Serevent Diskus 50 mcg achieved a periodic serial PEF  (36% to 39% postdose increase from baseline) and FEV1 (32% to 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 ICS.

     

    Salmeterol Multicenter Asthma Research Trial 

    The randomized, double-blind SMART trial evaluated the safety of salmeterol (Serevent Inhalation Aerosol) in LABA-naive patients with asthma (average age of 39 years; 71% Caucasian, 18% African American, 8% Hispanic). Patients were randomly assigned to receive salmeterol (Serevent Inhalation Aerosol) 42 mcg twice daily or placebo when added to usual asthma therapy over 28 weeks. 

    In an interim analysis, patients receiving salmeterol had an increased risk for fatal asthma events. In the total population, there was a higher rate of asthma-related death in patients treated with salmeterol compared with those treated with placebo (0.10% vs 0.02%, relative risk: 4.37 [95% CI, 1.25-15.34]). 

    Post hoc subpopulation analyses: 

    • In Caucasians, there was a higher rate of asthma-related death that occurred in patients treated with salmeterol compared with those treated with placebo (0.07% vs 0.01%, relative risk: 5.82 [95% CI, 0.70-48.37]). 

    • In African Americans, there was also a higher rate of asthma-related death that occurred in patients treated with salmeterol compared with those treated with placebo (0.31% vs 0.04%, relative risk: 7.26 [95% CI, 0.89-58.94]). The estimate of excess deaths in patients treated with salmeterol was greater in African Americans.

    • In pediatric subjects aged 12 to 18 years, respiratory-related death or life-threatening experience occurred at a similar rate in the salmeterol and the placebo groups. All-cause hospitalization, however, was increased in the salmeterol group (2% [35/1653]) versus the placebo group (less than 1% [16/162]).

     

    Exercise-Induced Bronchospasm (EIB)  

    In 2 randomized, single-dose, crossover trials in adolescents and adults with EIB (N = 52), 50 mcg of Serevent Diskus prevented EIB when dosed 30 minutes prior to exercise. For some subjects, this protective effect against EIB was still apparent up to 8.5 hours following a single dose.

    In 2 randomized trials in children aged 4 to 11 years with asthma and EIB (N = 50), a single 50-mcg dose of Serevent Diskus 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 subjects.  

     

    Chronic Obstructive Pulmonary Disease 

    In 2 randomized, double-blind, parallel-group clinical trials, the efficacy of Serevent Diskus was evaluated in patients with chronic bronchitis with airflow limitation, with or without emphysema, for 24 weeks. Patients received either Serevent Diskus 50 mcg twice daily (n=336) or placebo (n=366). 

    Results showed that treatment with Serevent Diskus achieved greater improvements in pulmonary function endpoints compared with placebo. There were significantly greater improvements in 2-hour postdose FEV1 at Endpoint (216 mL, 20%) compared with placebo (43 mL, 5%). Improvement was observed on the first day of treatment and maintained throughout the 24 weeks of treatment. In both trials, the Serevent Diskus group did not achieve significant improvements in secondary endpoints for COPD symptoms.

    Onset of Action and Duration of Effect:

    • In a subset of 87 patients, the onset of action and duration of effect of Serevent Diskus was evaluated.

    • At 2 hours following the first 50 mcg dose, there was significant improvement in pulmonary function observed, which was the mean FEV1 increase of 12% or more and at least 200 mL.

    • The mean time to peak bronchodilator effect was 4.75 hours. The evidence of bronchodilatation was observed throughout the 12-hour period, and the bronchodilating effect was observed after 12 weeks of treatment similar to that seen after the first dose.

    • After 12 weeks of treatment, the mean time to peak bronchodilator effect was 3.27 hours.

    Serevent Diskus Note

    Not Applicable

    Serevent Diskus Patient Counseling

    Patient Counseling

    Asthma-Related Death 

    • Inform patients that salmeterol when used alone increases the risk of asthma-related death and may increase the risk of asthma-related hospitalization in pediatric and adolescent patients. 

    • Inform patients that Serevent Diskus should not be the only therapy for the treatment of asthma and must only be used as additional therapy when ICS do not adequately control asthma symptoms. 

    • Inform patients that when Serevent Diskus is added to their treatment regimen they must continue to use their ICS. 

    Not for Acute Symptoms 

    • Inform patients that Serevent Diskus is not meant to relieve acute asthma symptoms or exacerbations of COPD and extra doses should not be used for that purpose. Advise patients to treat acute symptoms with an inhaled, short-acting beta2-agonist such as albuterol. Provide patients with such medication and instruct them in how it should be used. 

    • Instruct patients to seek medical attention immediately if they experience any of the following: 

      • Decreasing effectiveness of inhaled, short-acting beta2-agonists 

      • Need for more inhalations than usual of inhaled, short-acting beta2-agonists 

      • Significant decrease in lung function as outlined by the physician 

    • Tell patients they should not stop therapy with Serevent Diskus without physician/provider guidance since symptoms may recur after discontinuation. 

    Not a Substitute for Corticosteroids 

    • Advise all patients with asthma that they must also continue regular maintenance treatment with an ICS if they are taking Serevent Diskus. 

    • Serevent Diskus 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. 

    Do Not Use Additional Long-acting Beta2-agonists 

    • Instruct patients not to use other LABA. 

    Immediate Hypersensitivity Reactions 

    • Advise patients that immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of Serevent Diskus. Patients should discontinue Serevent Diskus if such reactions occur. 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 take Serevent Diskus. 

    Risks Associated with Beta-agonist Therapy 

    • Inform patients of adverse effects associated with beta2-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness. 

    Treatment of Exercise-Induced Bronchospasm 

    • Patients using Serevent Diskus for the treatment of EIB should not use additional doses for 12 hours. Patients who are receiving Serevent Diskus twice daily should not use additional Serevent for prevention of EIB.

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