SEREVENT DISKUS

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Inhalation Administration
Oral Inhalation Administration
NOTE: Patients should be instructed to never use salmeterol to treat acute bronchospasm. If any patient who uses salmeterol experiences wheezing that worsens and cannot be relieved during an acute asthma attack, they should be instructed to seek immediate medical attention.

Powder for Oral Inhalation (Serevent Diskus)
-Each device is supplied within a moisture-protective foil pouch; only open when ready to use.
-The device will be in the closed position. The patient should fill in the "Pouch opened" and "Use by" dates in the blank lines on the label. The "Use by" date for Serevent Diskus is 6 weeks from the date the pouch is opened.
-Do not use the device with a spacer or valve holding chamber (VHC) device.
-Open the device by holding it in one hand and using the thumb of the other hand to push the thumbgrip away until the mouthpiece shows and snaps into place.
-Instruct the patient to hold the device in a level, flat position with the mouthpiece towards them and to slide the lever away from them as far as it will go until it clicks.
-To avoid releasing a dose by mistake, warn the patient not to close or tilt the device, play with the lever, or slide the lever more than once.
-Before inhaling the dose, have the patient breathe out as far as they can while holding the device level and away from their mouth. They should never breathe out into the mouthpiece.
-Instruct the patient to put the mouthpiece to their lips and breathe in through the mouth quickly and deeply through the device. Remove the device from the mouth, hold breath for about 10 seconds and then breathe out slowly.
-After taking a dose, the patient should close the device by sliding the thumbgrip back towards them far as it will go. The device will click shut. The lever will automatically return to its original position.
-Most patients can either feel or taste the powder medication during administration; however, the dose should not be repeated if it is not felt.
-The counter displays how many doses are left. After 55 doses, the patient will see numbers 5 to 0 in red, warning there are only a few doses left.
-After administration, instruct patient to rinse mouth thoroughly with water to minimize dry mouth.
-Never wash the mouthpiece or any part of the device; keep it dry.
-To avoid the spread of infection, do not use the device for more than one person.
-Instruct patients to safely dispose of the device by the specified "Use by" date or when the counter reads 0, whichever comes first.

Several studies were done to determine if salmeterol administration would promote tachyphylaxis to the pulmonary effects of albuterol. Although long-term salmeterol therapy does not appear to produce tachyphylaxis to the bronchodilating effects of albuterol, tachyphylaxis to extrapulmonary effects, such as elevated blood glucose concentrations and decreased diastolic blood pressure, was observed.

Respiratory and infectious adverse reactions reported in patients receiving salmeterol during clinical trials include nasal congestion (9%), rhinitis (5%), tracheitis (7%), influenza (5%), asthma (3% to 4%), and ear signs and symptoms (4%). Adverse reactions occurring with salmeterol during clinical trials, but in a greater percentage in the placebo or control arm included pharyngitis (3% or more), sinusitis (3% or more), throat irritation (7%), upper respiratory tract infection (3% or more), cough (3% or more), conjunctivitis (1% or more), keratitis (1% or more) and lower respiratory signs and symptoms (1% or more). Upper airway symptoms of laryngospasm, irritation, or swelling, including stridor and choking, and oropharyngeal irritation have been reported with postmarketing use of salmeterol.

An increase in the need for rescue inhaler use and/or worsening wheezing may occur during therapy with salmeterol and are symptoms of acutely deteriorating asthma, a potentially life-threatening situation. Advise patients not to exceed recommended doses of this medicine, but instead, seek immediate medical attention if such symptoms occur. When long-acting beta-agonists (LABAs) are used in fixed-dose combination with inhaled corticosteroids (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. The use of a LABA as asthma monotherapy, without an ICS, is associated with an increased risk of asthma-related death. Available data from controlled clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric and adolescent patients. These findings are considered a class effect of LABA monotherapy. In most cases, serious acute respiratory events have occurred in patients with severe asthma and/or in patients in whom asthma has been acutely deteriorating, but such events have also occurred in patients with less severe asthma.

Headache was reported in 13% to 17% of pediatric patients receiving salmeterol in clinical trials. Other central nervous system (CNS) adverse events reported include migraine, dizziness, anxiety, and paresthesias. Tremor, nervousness, fatigue, malaise, and insomnia have been associated with use of other beta-agonists and may occur with salmeterol therapy, especially at high doses.

Like other sympathomimetics, salmeterol can cause various adverse cardiovascular effects including hypertension or hypotension, angina, sinus tachycardia, and palpitations. Arrhythmia exacerbation or precipitation, such as atrial fibrillation, supraventricular tachycardia (SVT), and extrasystole have been reported with salmeterol use. In addition, beta-agonists have been reported to produce ECG changes, ST-T wave changes (e.g., flattening of the T wave, ST segment depression) and QT prolongation. Cardiac effects may be related to sympathomimetic effects and/or beta-agonist-induced hypokalemia. Stimulation of beta-2 receptors results in gluconeogenesis and intracellular movement of potassium, which may cause hyperglycemia and hypokalemia. Clinically significant effects are uncommon after administration of salmeterol at recommended doses.

Anaphylactoid reactions have been reported in patients taking salmeterol. Immediate hypersensitivity reactions may occur, as demonstrated by cases of anaphylaxis, angioedema, bronchospasm, rash, and urticaria. Paradoxical bronchospasm can also occur and can be life threatening. If this occurs, salmeterol should be discontinued immediately. Rash (unspecified) (4%), urticaria (3%), and photodermatitis (greater than 1%) were reported in children receiving salmeterol in clinical trials. Contact dermatitis and eczema have also been reported with salmeterol use.

Transiently elevated hepatic enzymes were reported in 1% or more of pediatric patients during clinical trials. Nausea, vomiting, oropharyngeal candidiasis, oral mucosal abnormality, hyposalivation, dyspepsia, dental discomfort, and gastrointestinal infections were also reported with salmeterol use in clinical trials.

Arthralgia and articular rheumatism (1% or more) were reported in pediatric patients receiving salmeterol in clinical trials. Other adverse events reported with salmeterol use include bone pain, fever of unknown origin, musculoskeletal pain, muscle cramps, muscle spasms, and muscle stiffness, tightness, and rigidity.

Use of salmeterol for monotherapy treatment of asthma is contraindicated. Salmeterol should only be used as add-on maintenance therapy in patients who are inadequately controlled on a long-term asthma control medication (e.g., inhaled corticosteroid [ICS]). Salmeterol is not a substitute for inhaled corticosteroids (ICS) or oral corticosteroid therapy; corticosteroids should not be stopped or reduced when salmeterol is initiated. Pediatric patients who require the addition of a long-acting beta-agonist (LABA) to corticosteroid therapy may benefit from an inhaled fixed-dose combination product to ensure adherence to proper therapy. Salmeterol should not be used in higher than recommended doses, more frequently than every 12 hours, or in conjunction with another LABA due to the risk of significant cardiovascular effects and fatality. Salmeterol, as monotherapy for asthma, increases the risk for asthma-related death. Available data from controlled clinical trials also suggest that LABA monotherapy for asthma increases the risk of asthma-related hospitalization in pediatric and adolescent patients. When LABA are used in fixed-dose combination with an ICS to control lung inflammation, 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. The Salmeterol Multicenter Asthma Research Trial (SMART) was a large 28-week placebo-controlled U.S. trial comparing the safety of salmeterol inhalation aerosol) with placebo, each added to usual asthma therapy, that showed an increase in asthma-related deaths in subjects receiving salmeterol. Given the similar basic mechanisms of action of long-acting beta-2 agonists (LABAs), 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 only with asthma. In December 2017, the FDA announced that there is no increase in risk of serious asthma outcomes with long-acting beta-agonists (LABAs) when used in combination with an inhaled corticosteroid (ICS); the results of all trials showed that the use of LABA in combination with ICS does not significantly increase the risk of serious asthma outcomes compared to ICS alone. The trials showed that ICS/LABA combination medicines were more effective in decreasing asthma attacks (e.g., the need to use oral corticosteroids) compared to ICS alone. Three trials were conducted in patients 12 years and older and the fourth trial included pediatric patients 4 to 11 years.

Salmeterol should not be used in patients who have demonstrated a hypersensitivity reaction to salmeterol or to any of the components in the commercial product. Serevent Diskus contains lactose and milk protein; use of this formulation is contraindicated in patients with a severe milk protein hypersensitivity. Very rarely, there have been reports of anaphylaxis in patients with severe milk protein allergy. Other immediate hypersensitivity reactions may also occur after administration of salmeterol, as demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm, and hypotension.

Due to its relatively prolonged onset of action, salmeterol is contraindicated for use in patients with an acute asthma attack or status asthmaticus. Salmeterol should not be initiated in patients with deterioration of asthma or used for episodes of acute bronchospasm. It is crucial to properly educate patients and prescribe an inhaled, short-acting beta-agonist (SABA), such as albuterol, for rescue treatment. If wheezing worsens and cannot be relieved during an acute asthma attack, patients should be instructed to seek immediate medical attention. Like other inhaled beta-agonists, salmeterol can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs, it should be treated immediately with an inhaled short-acting bronchodilator (e.g., albuterol); salmeterol should be discontinued immediately and alternative therapy instituted.

Salmeterol, like other sympathomimetic amines, should be used cautiously in patients with a history of seizures or seizure disorder, hyperthyroidism, thyrotoxicosis, pheochromocytoma, or unusual responsiveness to other sympathomimetic amines. Pheochromocytoma may increase the risk of prolonging the QT interval when using salmeterol.

Avoid using salmeterol in patients with congenital long QT syndrome due to the risk of torsade de pointes. Significant changes in blood pressure and heart rate have been associated with excessive beta-adrenergic stimulation. As with other beta-adrenergic agonists, salmeterol may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease is usually transient, not requiring supplementation. Correct pre-existing hypokalemia prior to beta-agonist administration. Use salmeterol with caution in patients with conditions that may increase the risk of QT prolongation including certain cardiovascular disorders (including ischemic cardiac disease, coronary artery disease, cardiac arrhythmias, hypertension), bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, people 65 years and older, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.

Use salmeterol cautiously in patients with hepatic disease as salmeterol is predominately metabolized in the liver. Closely monitor patients with hepatic disease for signs of salmeterol accumulation.

Use with caution in diabetes mellitus. Large doses of albuterol, a related beta-2 agonist, have been reported to aggravate preexisting diabetes mellitus and diabetic ketoacidosis. Clinically significant hyperglycemia has been infrequently reported in clinical trials of salmeterol.

Salmeterol is not indicated in neonates, infants, or children less than 4 years of age. Safety and efficacy are not established in these populations.

Description: Salmeterol is an inhaled long-acting inhaled beta-2 agonist (LABA) that is given twice daily. Salmeterol is indicated in pediatric patients for the maintenance treatment of asthma in combination with an asthma controller medication (i.e., inhaled corticosteroid [ICS]) and for the prevention of exercise-induced bronchospasm (EIB). Because of its delayed onset, salmeterol should never be used to treat acute bronchospasm, and it is not recommended for initial/worsening asthma treatment. Guidelines recommend ICS in combination with LABA as the preferred controller regimen in adolescents and children 6 years and older with moderate to severe asthma. NAEPP notes that an ICS-LABA combination regimen is a treatment option in selected children less than 6 years of age with moderate to severe asthma. The use of LABAs alone to treat asthma without an ICS to treat lung inflammation is associated with an increased risk of asthma-related death; therefore, LABAs are contraindicated in patients with asthma without the use of an asthma controller medication (i.e., an ICS). Combination therapy (LABA and low-dose ICS) improves lung function, decreases asthma symptoms, and reduces exacerbation in most patients to a greater extent than doubling the dose of ICS, and reduces steroid burden and reduces the risk for ICS-related adverse effects. Although salmeterol is indicated for the prevention of exercise-induced bronchospasm (EIB), the addition of salmeterol alone to an inhaled short-acting beta-2 agonist (SABA) for EIB is not recommended; LABAs may be added to ICS controller medication for concomitant treatment in select patient populations. Salmeterol is FDA-approved in pediatric patients 4 years and older.

For asthma maintenance treatment:
Oral Inhalation dosage (inhalation powder; e.g., Serevent Diskus):
Children and Adolescents 4 to 17 years: 50 mcg (1 oral inhalation of 50 mcg/actuation) twice daily, in the morning and evening, approximately 12 hours apart, is the recommended and max dosage (Max: 100 mcg/day). Salmeterol monotherapy for asthma is contraindicated; use concurrently with a controller medication, such as an inhaled corticosteroid. The use of a fixed-dose combination product containing both salmeterol and an inhaled corticosteroid (e.g., Advair) is preferred to this product.

For exercise-induced bronchospasm prophylaxis:
Oral Inhalation dosage (inhalation powder; e.g., Serevent Diskus):
Children and Adolescents 4 to 17 years: 50 mcg (1 oral inhalation of 50 mcg/actuation) at least 30 minutes before exercise. Protection lasts up to 12 hours in children and 9 hours in adolescents, although duration may decrease with regular use. Do not use any additional doses within 12 hours after administering initial dose. Also, do not use an additional dose to prevent exercise-induced bronchospasm (EIB) in patients receiving salmeterol twice daily for asthma maintenance therapy.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Children
Less than 4 years: Safety and efficacy have not been established.
4 years and older: 100 mcg/day via dry powder inhaler.
-Adolescents
100 mcg/day via dry powder inhaler.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed. Salmeterol is predominately metabolized in the liver; hepatic impairment may lead to drug accumulation. Close monitoring is recommended.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Salmeterol is a highly selective beta2-adrenergic agonist that stimulates the receptors of the smooth muscle in the lungs. The net result of beta2-receptor agonism results in relaxation of bronchial and tracheal smooth muscles, which in turn relieves bronchospasm, facilitates bronchodilation, increases bronchial airflow, aids in mucous drainage, and increases vital capacity.

Intracellularly, the effects of salmeterol are mediated, in part, by activation of adenyl cyclase, the enzyme responsible for the formation of cyclic-3',5'-adenosine monophosphate (cAMP). Increased cAMP leads to activation of protein kinase A, which inhibits phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in bronchial smooth muscle relaxation. Increased cAMP also inhibits the release of histamine, leukotriene, prostaglandin D2, and tumor necrosis factor alpha from mast cells. Inhibition of mediator release is believed to inhibit bronchoconstriction to exercise and cold dry air.

The extended action of salmeterol is due to its long, lipophilic side chain. This side chain appears to bind to an exosite present only near beta2-receptors. Binding to this exosite allows the active portion of the molecule to remain at the receptor site and continually engage and disengage with the receptor, therefore providing a long duration of action. Also, exosite binding contributes to salmeterol's inhibition of late-phase responses to allergens, which usually appears after the bronchodilating effects of the shorter-acting agents have resolved.

Pharmacokinetics: Salmeterol is administered by oral inhalation. Protein binding of salmeterol is approximately 96% of the serum concentration. Extensive metabolism occurs via hydroxylation. In addition, in vitro data indicate that salmeterol also undergoes aliphatic oxidation through hepatic CYP3A4, which results in the formation of alpha-hydroxysalmeterol. The elimination half-life of orally administered salmeterol was determined as approximately 5.5 hours. Excretion is primarily in the feces. No significant amount of unchanged salmeterol has been detected in either urine or feces.

Affected cytochrome P450 isoenzymes: CYP 3A4
Salmeterol is a substrate of CYP3A4. Use of a strong inhibitor of CYP3A4, ketoconazole, with salmeterol inhibited salmeterol's metabolism and resulted in significantly increased salmeterol systemic exposure.


-Route-Specific Pharmacokinetics
Inhalation Route
Salmeterol is a lipophilic compound that rapidly passes the airway epithelium and is retained by lung tissue. Salmeterol has low oral bioavailability. Because of its high first-pass metabolism, it has the potential to cause systemic adverse effects, particularly at high doses. Following inhalation of a single 50 mcg dose, peak plasma concentrations (Cmax) are minimal at 0.1-0.2 mcg/L. Following long-term administration of salmeterol inhaled powder 50 mcg twice daily in asthmatic patients, a mean Cmax of approximately 0.167 mcg/L was detected in the plasma within 5-45 minutes; accumulation did not occur with repeat doses. The onset of clinically significant bronchodilation, as measured by a >= 15% improvement in forced expiratory volume (FEV1), occurs approximately 30-45 minutes after dry powder inhalation administration. Peak effects generally occur within 3 hours and clinically significant improvement continues for 12 hours in most patients.


-Special Populations
Hepatic Impairment
Salmeterol use has not been studied in patients with hepatic impairment. However, salmeterol is predominately eliminated by hepatic metabolism, via hydroxylation and aliphatic oxidation. In vitro study has identified a hepatic isoenzyme CYP3A4-dependent pathway. Use of this medication in patients with hepatic disease or other hepatic impairment may result in drug accumulation. The manufacturer advocates close monitoring in such patients.