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    Respiratory Long-Acting Beta-2 Agonists (LABA)

    BOXED WARNING

    Acute bronchospasm, asthma-related death, status asthmaticus

    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.[28467] Salmeterol is not a substitute for inhaled corticosteroid therapy (ICS) or oral corticosteroid therapy; corticosteroids should not be stopped or reduced when salmeterol is initiated. Subsequent changes to any preexisting corticosteroid regimen, such as a dose reduction, should only be made following a thorough clinical evaluation. Salmeterol, as monotherapy for asthma, increases the risk for asthma-related death.[28467] 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.[28467] 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.[28467] 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.[28467] [41230] There are no data to suggest an increased risk of death with use of LABAs in patients with COPD.[28467] 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.[62717]
     

    DEA CLASS

    Rx

    DESCRIPTION

    Orally inhaled long-acting beta-2 agonist (LABA); given twice daily
    Used in adult and pediatric patients 4 years and older for add-on asthma maintenance therapy to an asthma controller medication and for exercise-induced bronchospasm (EIB); also used for maintenance treatment of COPD in adults
    LABA monotherapy for asthma is contraindicated due to an increased risk for asthma-related death

    COMMON BRAND NAMES

    Serevent Diskus

    HOW SUPPLIED

    Serevent Diskus Respiratory (Inhalation) Inhalant: 1actuation, 50mcg

    DOSAGE & INDICATIONS

    For asthma maintenance treatment.
    Oral Inhalation dosage (inhalation powder; e.g., Serevent Diskus)
    Adults

    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 dose (Max: 100 mcg/day). Salmeterol monotherapy for asthma is contraindicated; use concurrently with a controller medication, such as an inhaled corticosteroid. Use of a fixed-dose combination product containing both salmeterol and an inhaled corticosteroid (e.g., Advair) is preferred to this product.

    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 dose (Max: 100 mcg/day). Salmeterol monotherapy for asthma is contraindicated; use concurrently with a controller medication, such as an inhaled corticosteroid. 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)
    Adults

    50 mcg (1 oral inhalation of 50 mcg/actuation) at least 30 minutes before exercise. Protection lasts up to 9 hours in adults, 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.

    Children and Adolescents 4 years and older

    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.

    For the maintenance treatment of chronic obstructive pulmonary disease (COPD) (e.g., chronic bronchitis or emphysema).
    Oral Inhalation dosage (inhalation powder; e.g., Serevent Diskus)
    Adults

    50 mcg (1 oral inhalation of 50 mcg/actuation) twice daily, morning and evening, approximately 12 hours apart is the recommended and max dosage. Not indicated to treat acute exacerbations of COPD and should not be used for the relief of acute bronchospasm; use a short-acting beta-2 agonist (SABA) for rescue therapy. According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines for COPD, salmeterol and other LABAs may be used as initial monotherapy in patients in Groups A and B. In Group C patients, long-acting muscarinic antagonists (LAMAs) are preferred as initial therapy over LABAs due to effectiveness in preventing exacerbations. In Group D patients, LABAs are used as initial therapy in combination with inhaled corticosteroids (ICS) or LAMAs. At follow-up, if the patient is still experiencing dyspnea, consider switching inhaler device and investigate for other causes of dyspnea. If the patient has exacerbations, consider triple therapy with a LAMA, a LABA, and ICS.

    For altitude sickness prophylaxis†, specifically prevention of high altitude pulmonary edema†.
    Oral inhalation dosage
    Adults

    125 mcg by oral inhalation every 12 hours starting the day before ascent and continuing for 5 days after reaching the target altitude or until descent is initiated as an adjunct to nifedipine. Prophylactic medications should only be considered for individuals with a prior history of high altitude pulmonary edema.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    100 mcg/day oral inhalation powder.

    Geriatric

    100 mcg/day oral inhalation powder.

    Adolescents

    100 mcg/day oral inhalation powder.

    Children

    4 years or older: 100 mcg/day oral inhalation powder.
    Less than 4 years: Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available. Salmeterol is predominately metabolized in the liver; hepatic impairment may lead to drug accumulation. Close monitoring is recommended.

    Renal Impairment

    No dosage adjustments are needed.

    ADMINISTRATION

    Inhalation Administration
    Oral Inhalation Administration

    NOTE: 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)
    One Diskus blister (one inhalation) contains 50 mcg of salmeterol as the xinafoate salt.
    Instruct the patient to open and prepare mouthpiece of Diskus device and slide device lever to activate the first dose (see package instructions). Do not advance the lever more than once at any one time as this will release further doses that will be wasted. Holding the Diskus mouthpiece level to, but away from, the mouth, exhale; be careful never to breathe into the Diskus inhaler. Then, put the mouthpiece to the lips and breathe in the dose quickly and deeply through the mouth. Remove the Diskus from the mouth, hold breath for at least 10 seconds, and then exhale slowly. 
    Instruct patient to close the Diskus, which will also reset the dose lever for the next scheduled dose.
    Most patients can either feel or taste the powder medication during administration; however, do not repeat the dose if it is not felt.
    Do NOT use a spacer with the Diskus inhaler.
    After administration, instruct patient to rinse mouth with water to minimize dry mouth.
    To avoid the spread of infection, the device should not be used by more than one person. 
    Storage: The Diskus device and mouthpiece should be kept dry; do not wash. Discard the Diskus device 6 weeks after opening the foil pouch or when the counter reads “0” (after all blisters have been used), whichever comes first.

    STORAGE

    Serevent Diskus:
    - Avoid direct heat and sunlight
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in a dry place

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Do not exceed recommended dosages of beta-agonists; fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs in patients with asthma. The exact cause of death is unknown, but cardiac arrest after an unexpected development of a severe acute asthmatic crisis and subsequent hypoxia is suspected.

    Monotherapy treatment of asthma

    Salmeterol is contraindicated for monotherapy treatment of asthma; it should not be used without an asthma controller medication (i.e. inhaled corticosteroid).

    Milk protein hypersensitivity

    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. 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.

    Acute bronchospasm, asthma-related death, status asthmaticus

    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.[28467] Salmeterol is not a substitute for inhaled corticosteroid therapy (ICS) or oral corticosteroid therapy; corticosteroids should not be stopped or reduced when salmeterol is initiated. Subsequent changes to any preexisting corticosteroid regimen, such as a dose reduction, should only be made following a thorough clinical evaluation. Salmeterol, as monotherapy for asthma, increases the risk for asthma-related death.[28467] 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.[28467] 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.[28467] 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.[28467] [41230] There are no data to suggest an increased risk of death with use of LABAs in patients with COPD.[28467] 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.[62717]
     

    Diabetes mellitus, hyperglycemia, hyperthyroidism, pheochromocytoma, seizure disorder, thyrotoxicosis

    Salmeterol should be used cautiously in patients with hyperthyroidism (thyrotoxicosis), seizure disorder, pheochromocytoma, or other unusual responsiveness to other sympathomimetic amines. High doses of systemically short-acting beta2-agonists (e.g., albuterol) have been reported to cause hyperglycemia and aggravate preexisting diabetes mellitus and ketoacidosis. Clinically significant changes in blood glucose were seen infrequently during clinical trials with salmeterol inhalation at recommended doses.

    Cardiac arrhythmias, coronary artery disease, hypertension, hypokalemia, QT prolongation, ventricular arrhythmias

    Salmeterol, like other beta2-agonists and sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency (coronary artery disease), cardiac arrhythmias, and hypertension. Salmeterol can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, and cardiac arrhythmias, such as supraventricular tachycardia and extrasystoles. If such effects occur, salmeterol inhalation may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiographic changes, such as flattening of the T wave, QT prolongation, and ST segment depression, although 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. Beta2-agonists like salmeterol may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. Clinically significant changes in serum potassium were seen infrequently during clinical trials with salmeterol inhalation at recommended doses.

    Labor, pregnancy

    There are no adequate and well-controlled trials with salmeterol in pregnant women. It is known that improved maternal and perinatal outcomes are achieved with optimal control of asthma during pregnancy. Large studies of women with asthma have confirmed the lack of relationship between the use of inhaled beta-2 agonists and adverse maternal or fetal outcomes. According to the 2004 guidelines of the National Asthma Education and Prevention Program (NAEPP) Asthma and Pregnancy Working Group, long-acting beta-agonists (LABAs) in combination with inhaled corticosteroids are one of the preferred treatment options for the long-term control of moderate persistent asthma during pregnancy and lactation. Although a preferred LABA is not recommended, the guideline states that more experience is available with salmeterol. Of note, the inclusion of LABA as an option for patients with moderate asthma was based off of efficacy data, and no safety data in pregnant or lactating women were available at the time of the report. While less data are available for LABAs such as salmeterol vs. short-acting beta agonists (SABAs), most inhaled beta-2 agonists are considered acceptable for use during pregnancy because of the low bioavailability and maternal serum levels after use. The effects of salmeterol on preterm labor or labor at term have not been studied. Because beta-2 agonists may interfere with uterine contractility, salmeterol use during labor should be restricted to those patients in whom the benefits clearly outweigh the risks.

    Breast-feeding

    There is no information regarding the presence of salmeterol in human milk, the effects on the breastfed child, or the effects on milk production. Salmeterol has been shown to be excreted in the milk of rats; however, data describing the use of salmeterol during human lactation are unavailable. Plasma concentrations of salmeterol after inhaled therapeutic doses are very low. Most inhaled bronchodilators are considered acceptable for use during the postpartum period and breast-feeding because of the low bioavailability and maternal serum levels after use. According to the National Asthma Education and Prevention Program (NAEPP) Asthma and Pregnancy Working Group, long-acting beta-2 agonists (LABAs) in combination with inhaled corticosteroids (ICSs) are one of the preferred treatment options for the long-term management of moderate persistent asthma during pregnancy and lactation. Although a preferred LABA is not recommended, the NAEPP guideline states that more experience is available with salmeterol. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition.

    Children, infants

    Safety and efficacy for salmeterol have not been established in neonates, infants, or children less than 4 years of age.

    Hepatic disease

    Salmeterol is predominately eliminated by hepatic metabolism and should be used with caution in patients who have hepatic disease or hepatic impairment as drug accumulation may occur. Salmeterol has not been studied in patients with hepatic impairment.

    Paradoxical bronchospasm

    Paradoxical bronchospasm can occur after treatment with salmeterol and can be life-threatening. If this occurs, discontinue salmeterol immediately and provide any necessary supportive care.

    MAOI therapy

    Beta-2 agonists, including salmeterol, should be administered with extreme caution to patients who have received within the previous 2 weeks or are currently being treated with tricyclic antidepressant or MAOI therapy. Concurrent use may potentiate salmeterol-induced adverse effects on the vascular system.

    Geriatric

    Geriatric patients may be more sensitive to the side effects of beta-agonists, especially tremor and tachycardia. As with other beta-2 agonists, special caution should be observed when using salmeterol in elderly patients who have concomitant cardiovascular disease that could be adversely affected by beta-agonists. Elderly patients may also be at increased risk for QT prolongation.   Although not clearly established, airway responsiveness to inhaled beta-agonists may also change with age. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). The OBRA guidelines caution that inhaled beta-agonists, such as salmeterol, can cause restlessness, increased heart rate, and anxiety.

    ADVERSE REACTIONS

    Severe

    laryngospasm / Rapid / Incidence not known
    bronchospasm / Rapid / Incidence not known
    asthma-related death / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known

    Moderate

    tracheitis / Delayed / 3.0-7.0
    hypertension / Early / 4.0-4.0
    migraine / Early / 1.0
    bone pain / Delayed / 1.0
    candidiasis / Delayed / 1.0
    elevated hepatic enzymes / Delayed / 1.0
    wheezing / Rapid / Incidence not known
    hypokalemia / Delayed / Incidence not known
    hypotension / Rapid / Incidence not known
    QT prolongation / Rapid / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    palpitations / Early / Incidence not known
    angina / Early / Incidence not known
    contact dermatitis / Delayed / Incidence not known
    hyperglycemia / Delayed / Incidence not known

    Mild

    headache / Early / 13.0-17.0
    musculoskeletal pain / Early / 12.0-12.0
    nasal congestion / Early / 4.0-9.0
    influenza / Delayed / 5.0-5.0
    rhinitis / Early / 4.0-5.0
    dizziness / Early / 4.0-4.0
    rash / Early / 4.0-4.0
    urticaria / Rapid / 3.0-3.0
    nausea / Early / 3.0-3.0
    vomiting / Early / 3.0-3.0
    muscle cramps / Delayed / 3.0-3.0
    pharyngitis / Delayed / 3.0
    sinusitis / Delayed / 3.0
    infection / Delayed / 3.0
    cough / Delayed / 3.0
    anxiety / Delayed / 1.0
    dyspepsia / Early / 1.0
    arthralgia / Delayed / 1.0
    xerostomia / Early / 1.0
    dental pain / Delayed / 1.0
    fatigue / Early / Incidence not known
    insomnia / Early / Incidence not known
    paresthesias / Delayed / Incidence not known
    tremor / Early / Incidence not known
    malaise / Early / Incidence not known

    DRUG INTERACTIONS

    Abarelix: (Major) Since abarelix can cause QT prolongation, abarelix should be used cautiously, if at all, with other drugs that are associated with QT prolongation. Prescribers need to weigh the potential benefits and risks of abarelix use in patients with prolonged QT syndrome or in patients taking other drugs that may prolong the QT interval. Agents associated with a lower, but possible risk for QT prolongation and torsade de pointes (TdP) based on varying levels of documentation include the beta-agonists. Beta-agonists may cause cardiovascular effects, particularly when used in high doses and/or when associated with hypokalemia.
    Acebutolol: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
    Acetaminophen; Caffeine: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
    Acetaminophen; Caffeine; Pyrilamine: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor blood pressure and heart rate during concomitant salmeterol and pseudoephedrine use. Concomitant use may potentiate sympathetic effects.
    Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Monitor blood pressure and heart rate during concomitant salmeterol and pseudoephedrine use. Concomitant use may potentiate sympathetic effects.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor blood pressure and heart rate during concomitant salmeterol and pseudoephedrine use. Concomitant use may potentiate sympathetic effects.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Acetaminophen; Pseudoephedrine: (Moderate) Monitor blood pressure and heart rate during concomitant salmeterol and pseudoephedrine use. Concomitant use may potentiate sympathetic effects.
    Aclidinium; Formoterol: (Major) Formoterol should not be used in conjunction with other medications containing a long-acting beta-2 agonist for any reason, as overdose may result. Coadministration can result in overdosage. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Acute symptoms should be treated with inhaled short-acting beta-2 agonists (SABA) such as albuterol. SABAs should not be used on a regular basis (e.g., 4 times a day) while taking formoterol. Increasing SABA use is a sign of deteriorating disease for which prompt medical attention is required. Prompt re-evaluation of the patient and their COPD treatment regimen should occur if formoterol no longer controls symptoms of bronchoconstriction, the patient's SABA rescue becomes less effective, or the patient requires more SABA rescue doses than usual. Use formoterol and drugs known to prolong the QTc interval together with extreme caution; this combination may increase the risk of cardiovascular effects and ventricular arrhythmias; this includes combination with other beta-agonists.
    Acrivastine; Pseudoephedrine: (Moderate) Monitor blood pressure and heart rate during concomitant salmeterol and pseudoephedrine use. Concomitant use may potentiate sympathetic effects.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid concomitant use of salmeterol with clarithromycin. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
    Amphetamine: (Moderate) Monitor blood pressure and heart rate during concomitant amphetamine; dextroamphetamine and salmeterol use. Concomitant use may potentiate sympathetic effects.
    Amphetamine; Dextroamphetamine Salts: (Moderate) Monitor blood pressure and heart rate during concomitant amphetamine; dextroamphetamine and salmeterol use. Concomitant use may potentiate sympathetic effects.
    Amphetamine; Dextroamphetamine: (Moderate) Monitor blood pressure and heart rate during concomitant amphetamine; dextroamphetamine and salmeterol use. Concomitant use may potentiate sympathetic effects.
    Articaine; Epinephrine: (Moderate) Monitor blood pressure and heart rate during concomitant epinephrine and salmeterol use. Concomitant use may potentiate sympathetic effects.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
    Aspirin, ASA; Caffeine: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
    Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
    Atazanavir: (Major) Avoid concomitant use of salmeterol with atazanavir. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
    Atazanavir; Cobicistat: (Major) Avoid concomitant use of salmeterol with atazanavir. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose. (Major) Avoid concomitant use of salmeterol with cobicistat. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
    Atenolol: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
    Atenolol; Chlorthalidone: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
    Bendroflumethiazide; Nadolol: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
    Benzphetamine: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Beta-adrenergic blockers: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
    Betaxolol: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
    Bisoprolol: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
    Brimonidine; Timolol: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Brompheniramine; Phenylephrine: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Brompheniramine; Pseudoephedrine: (Moderate) Monitor blood pressure and heart rate during concomitant salmeterol and pseudoephedrine use. Concomitant use may potentiate sympathetic effects.
    Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Monitor blood pressure and heart rate during concomitant salmeterol and pseudoephedrine use. Concomitant use may potentiate sympathetic effects.
    Budesonide; Formoterol: (Major) Formoterol should not be used in conjunction with other medications containing a long-acting beta-2 agonist for any reason, as overdose may result. Coadministration can result in overdosage. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Acute symptoms should be treated with inhaled short-acting beta-2 agonists (SABA) such as albuterol. SABAs should not be used on a regular basis (e.g., 4 times a day) while taking formoterol. Increasing SABA use is a sign of deteriorating disease for which prompt medical attention is required. Prompt re-evaluation of the patient and their COPD treatment regimen should occur if formoterol no longer controls symptoms of bronchoconstriction, the patient's SABA rescue becomes less effective, or the patient requires more SABA rescue doses than usual. Use formoterol and drugs known to prolong the QTc interval together with extreme caution; this combination may increase the risk of cardiovascular effects and ventricular arrhythmias; this includes combination with other beta-agonists.
    Budesonide; Glycopyrrolate; Formoterol: (Major) Formoterol should not be used in conjunction with other medications containing a long-acting beta-2 agonist for any reason, as overdose may result. Coadministration can result in overdosage. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Acute symptoms should be treated with inhaled short-acting beta-2 agonists (SABA) such as albuterol. SABAs should not be used on a regular basis (e.g., 4 times a day) while taking formoterol. Increasing SABA use is a sign of deteriorating disease for which prompt medical attention is required. Prompt re-evaluation of the patient and their COPD treatment regimen should occur if formoterol no longer controls symptoms of bronchoconstriction, the patient's SABA rescue becomes less effective, or the patient requires more SABA rescue doses than usual. Use formoterol and drugs known to prolong the QTc interval together with extreme caution; this combination may increase the risk of cardiovascular effects and ventricular arrhythmias; this includes combination with other beta-agonists.
    Bumetanide: (Moderate) Use beta-agonists and loop diuretics with caution due to risk for ECG changes and/or hypokalemia. The ECG changes and/or hypokalemia that may result from administration of loop diuretics can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded.
    Bupivacaine; Epinephrine: (Moderate) Monitor blood pressure and heart rate during concomitant epinephrine and salmeterol use. Concomitant use may potentiate sympathetic effects.
    Butalbital; Acetaminophen; Caffeine: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
    Caffeine: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
    Caffeine; Sodium Benzoate: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Carbetapentane; Phenylephrine: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Carbetapentane; Pseudoephedrine: (Moderate) Monitor blood pressure and heart rate during concomitant salmeterol and pseudoephedrine use. Concomitant use may potentiate sympathetic effects.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor blood pressure and heart rate during concomitant salmeterol and pseudoephedrine use. Concomitant use may potentiate sympathetic effects.
    Carbinoxamine; Phenylephrine: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Carbinoxamine; Pseudoephedrine: (Moderate) Monitor blood pressure and heart rate during concomitant salmeterol and pseudoephedrine use. Concomitant use may potentiate sympathetic effects.
    Carteolol: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
    Carvedilol: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
    Ceritinib: (Major) Avoid concomitant use of salmeterol with ceritinib. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and ceritinib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
    Cetirizine; Pseudoephedrine: (Moderate) Monitor blood pressure and heart rate during concomitant salmeterol and pseudoephedrine use. Concomitant use may potentiate sympathetic effects.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Monitor blood pressure and heart rate during concomitant salmeterol and pseudoephedrine use. Concomitant use may potentiate sympathetic effects.
    Chlophedianol; Guaifenesin; Phenylephrine: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Chloramphenicol: (Major) Avoid concomitant use of salmeterol with chloramphenicol. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and chloramphenicol is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor blood pressure and heart rate during concomitant salmeterol and pseudoephedrine use. Concomitant use may potentiate sympathetic effects.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Monitor blood pressure and heart rate during concomitant salmeterol and pseudoephedrine use. Concomitant use may potentiate sympathetic effects.
    Chlorpheniramine; Phenylephrine: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Monitor blood pressure and heart rate during concomitant salmeterol and pseudoephedrine use. Concomitant use may potentiate sympathetic effects.
    Cisapride: (Contraindicated) QT prolongation and ventricular arrhythmias, including torsade de pointes (TdP) and death, have been reported with cisapride. Because of the potential for TdP, use of other drugs that might increase the QT interval is contraindicated with cisapride. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Clarithromycin: (Major) Avoid concomitant use of salmeterol with clarithromycin. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
    Cobicistat: (Major) Avoid concomitant use of salmeterol with cobicistat. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
    Cocaine: (Moderate) Additive effects and increased toxicity might be observed when using cocaine with beta-agonists, which are sympathomimetic agents. The combined use of these agents may have the potential for additive adrenergic stimulation and side effects, such as nervousness, insomnia, palpitations, or adverse cardiovascular effects.
    Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Monitor blood pressure and heart rate during concomitant salmeterol and pseudoephedrine use. Concomitant use may potentiate sympathetic effects.
    Codeine; Phenylephrine; Promethazine: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Darunavir: (Major) Avoid concomitant use of salmeterol with darunavir. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
    Darunavir; Cobicistat: (Major) Avoid concomitant use of salmeterol with cobicistat. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose. (Major) Avoid concomitant use of salmeterol with darunavir. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid concomitant use of salmeterol with cobicistat. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose. (Major) Avoid concomitant use of salmeterol with darunavir. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid concomitant use of salmeterol with ritonavir. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
    Delavirdine: (Major) Avoid concomitant use of salmeterol with delavirdine. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and delavirdine is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
    Desloratadine; Pseudoephedrine: (Moderate) Monitor blood pressure and heart rate during concomitant salmeterol and pseudoephedrine use. Concomitant use may potentiate sympathetic effects.
    Dexbrompheniramine; Pseudoephedrine: (Moderate) Monitor blood pressure and heart rate during concomitant salmeterol and pseudoephedrine use. Concomitant use may potentiate sympathetic effects.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor blood pressure and heart rate during concomitant salmeterol and pseudoephedrine use. Concomitant use may potentiate sympathetic effects.
    Dextroamphetamine: (Moderate) Monitor blood pressure and heart rate during concomitant amphetamine; dextroamphetamine and salmeterol use. Concomitant use may potentiate sympathetic effects.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Monitor blood pressure and heart rate during concomitant salmeterol and pseudoephedrine use. Concomitant use may potentiate sympathetic effects.
    Diethylpropion: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Diphenhydramine; Phenylephrine: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Dobutamine: (Major) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Dopamine: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Dorzolamide; Timolol: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid concomitant use of salmeterol with cobicistat. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant use of salmeterol with cobicistat. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
    Ephedrine: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Ephedrine; Guaifenesin: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Epinephrine: (Moderate) Monitor blood pressure and heart rate during concomitant epinephrine and salmeterol use. Concomitant use may potentiate sympathetic effects.
    Ergotamine; Caffeine: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
    Esmolol: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
    Ethacrynic Acid: (Moderate) Use beta-agonists and loop diuretics with caution due to risk for ECG changes and/or hypokalemia. The ECG changes and/or hypokalemia that may result from administration of loop diuretics can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded.
    Fexofenadine; Pseudoephedrine: (Moderate) Monitor blood pressure and heart rate during concomitant salmeterol and pseudoephedrine use. Concomitant use may potentiate sympathetic effects.
    Formoterol: (Major) Formoterol should not be used in conjunction with other medications containing a long-acting beta-2 agonist for any reason, as overdose may result. Coadministration can result in overdosage. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Acute symptoms should be treated with inhaled short-acting beta-2 agonists (SABA) such as albuterol. SABAs should not be used on a regular basis (e.g., 4 times a day) while taking formoterol. Increasing SABA use is a sign of deteriorating disease for which prompt medical attention is required. Prompt re-evaluation of the patient and their COPD treatment regimen should occur if formoterol no longer controls symptoms of bronchoconstriction, the patient's SABA rescue becomes less effective, or the patient requires more SABA rescue doses than usual. Use formoterol and drugs known to prolong the QTc interval together with extreme caution; this combination may increase the risk of cardiovascular effects and ventricular arrhythmias; this includes combination with other beta-agonists.
    Formoterol; Mometasone: (Major) Formoterol should not be used in conjunction with other medications containing a long-acting beta-2 agonist for any reason, as overdose may result. Coadministration can result in overdosage. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Acute symptoms should be treated with inhaled short-acting beta-2 agonists (SABA) such as albuterol. SABAs should not be used on a regular basis (e.g., 4 times a day) while taking formoterol. Increasing SABA use is a sign of deteriorating disease for which prompt medical attention is required. Prompt re-evaluation of the patient and their COPD treatment regimen should occur if formoterol no longer controls symptoms of bronchoconstriction, the patient's SABA rescue becomes less effective, or the patient requires more SABA rescue doses than usual. Use formoterol and drugs known to prolong the QTc interval together with extreme caution; this combination may increase the risk of cardiovascular effects and ventricular arrhythmias; this includes combination with other beta-agonists.
    Fosamprenavir: (Major) Avoid concomitant use of salmeterol with fosamprenavir. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and fosamprenavir is a moderate CYP3A inhibitor.
    Furosemide: (Moderate) Use beta-agonists and loop diuretics with caution due to risk for ECG changes and/or hypokalemia. The ECG changes and/or hypokalemia that may result from administration of loop diuretics can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded.
    Glycopyrrolate; Formoterol: (Major) Formoterol should not be used in conjunction with other medications containing a long-acting beta-2 agonist for any reason, as overdose may result. Coadministration can result in overdosage. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Acute symptoms should be treated with inhaled short-acting beta-2 agonists (SABA) such as albuterol. SABAs should not be used on a regular basis (e.g., 4 times a day) while taking formoterol. Increasing SABA use is a sign of deteriorating disease for which prompt medical attention is required. Prompt re-evaluation of the patient and their COPD treatment regimen should occur if formoterol no longer controls symptoms of bronchoconstriction, the patient's SABA rescue becomes less effective, or the patient requires more SABA rescue doses than usual. Use formoterol and drugs known to prolong the QTc interval together with extreme caution; this combination may increase the risk of cardiovascular effects and ventricular arrhythmias; this includes combination with other beta-agonists.
    Grapefruit juice: (Major) Advise patients to avoid grapefruit and grapefruit juice during salmeterol treatment due to the risk of increased salmeterol exposure and adverse reactions. Salmeterol is a CYP3A substrate and grapefruit juice is a strong CYP3A inhibitor.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Monitor blood pressure and heart rate during concomitant salmeterol and pseudoephedrine use. Concomitant use may potentiate sympathetic effects.
    Guaifenesin; Phenylephrine: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Guaifenesin; Pseudoephedrine: (Moderate) Monitor blood pressure and heart rate during concomitant salmeterol and pseudoephedrine use. Concomitant use may potentiate sympathetic effects.
    Hydrocodone; Pseudoephedrine: (Moderate) Monitor blood pressure and heart rate during concomitant salmeterol and pseudoephedrine use. Concomitant use may potentiate sympathetic effects.
    Ibuprofen; Pseudoephedrine: (Moderate) Monitor blood pressure and heart rate during concomitant salmeterol and pseudoephedrine use. Concomitant use may potentiate sympathetic effects.
    Idelalisib: (Major) Avoid concomitant use of salmeterol with idelalisib. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and idelalisib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
    Indacaterol: (Major) Indacaterol should not be used in conjunction with other medications containing a long-acting beta-2 agonist, such as salmeterol for any reason, as overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Acute symptoms should be treated with an inhaled short-acting beta-2 agonist (SABA) such as albuterol. SABAs should not be used on a regular basis (e.g., 4 times a day) while taking indacaterol. Increasing SABA use is a sign of deteriorating disease for which prompt medical attention is required. Prompt re-evaluation of the patient and their COPD treatment regimen should occur if indacaterol no longer controls symptoms of bronchoconstriction, the patient's SABA rescue becomes less effective, or the patient requires more SABA rescue doses than usual.
    Indacaterol; Glycopyrrolate: (Major) Indacaterol should not be used in conjunction with other medications containing a long-acting beta-2 agonist, such as salmeterol for any reason, as overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Acute symptoms should be treated with an inhaled short-acting beta-2 agonist (SABA) such as albuterol. SABAs should not be used on a regular basis (e.g., 4 times a day) while taking indacaterol. Increasing SABA use is a sign of deteriorating disease for which prompt medical attention is required. Prompt re-evaluation of the patient and their COPD treatment regimen should occur if indacaterol no longer controls symptoms of bronchoconstriction, the patient's SABA rescue becomes less effective, or the patient requires more SABA rescue doses than usual.
    Indinavir: (Major) Avoid concomitant use of salmeterol with indinavir. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and indinavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
    Isocarboxazid: (Moderate) Use beta-agonists with caution in patients receiving concomitant monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping treatment with MAOIs because the action of beta-agonists on the cardiovascular system may be potentiated.
    Isoproterenol: (Major) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Itraconazole: (Major) Avoid concomitant use of salmeterol with itraconazole. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and itraconazole is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
    Ketoconazole: (Major) Avoid concomitant use of salmeterol with ketoconazole. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
    Labetalol: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
    Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of salmeterol with clarithromycin. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
    Levobetaxolol: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
    Levobunolol: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
    Levoketoconazole: (Major) Avoid concomitant use of salmeterol with ketoconazole. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
    Levothyroxine: (Moderate) Monitor blood pressure and heart rate during concomitant beta-agonist and thyroid hormone use. Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
    Levothyroxine; Liothyronine (Porcine): (Moderate) Monitor blood pressure and heart rate during concomitant beta-agonist and thyroid hormone use. Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
    Levothyroxine; Liothyronine (Synthetic): (Moderate) Monitor blood pressure and heart rate during concomitant beta-agonist and thyroid hormone use. Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
    Lidocaine; Epinephrine: (Moderate) Monitor blood pressure and heart rate during concomitant epinephrine and salmeterol use. Concomitant use may potentiate sympathetic effects.
    Linezolid: (Moderate) Linezolid may enhance the hypertensive effect of beta-agonists. Closely monitor for increased blood pressure during coadministration. Linezolid is an antibiotic that is also a weak, reversible nonselective inhibitor of monoamine oxidase (MAO). Therefore, linezolid has the potential for interaction with adrenergic agents, such as the beta-agonists.
    Liothyronine: (Moderate) Monitor blood pressure and heart rate during concomitant beta-agonist and thyroid hormone use. Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
    Lisdexamfetamine: (Moderate) Monitor blood pressure and heart rate during concomitant salmeterol and lisdexamfetamine use. Concomitant use may potentiate sympathetic effects.
    Lonafarnib: (Major) Avoid concomitant use of salmeterol with lonafarnib. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and lonafarnib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
    Loop diuretics: (Moderate) Use beta-agonists and loop diuretics with caution due to risk for ECG changes and/or hypokalemia. The ECG changes and/or hypokalemia that may result from administration of loop diuretics can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded.
    Lopinavir; Ritonavir: (Major) Avoid concomitant use of salmeterol with ritonavir. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
    Loratadine; Pseudoephedrine: (Moderate) Monitor blood pressure and heart rate during concomitant salmeterol and pseudoephedrine use. Concomitant use may potentiate sympathetic effects.
    Methacholine: (Major) Discontinue use of salmeterol 36 hours before a methacholine challenge test. Beta-agonists inhibit the airway response to methacholine.
    Methamphetamine: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Metoprolol: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
    Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
    Midodrine: (Moderate) Caution and close observation should be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Mifepristone: (Major) Avoid concomitant use of salmeterol with mifepristone. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and mifepristone is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
    Monoamine oxidase inhibitors: (Moderate) Use beta-agonists with caution in patients receiving concomitant monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping treatment with MAOIs because the action of beta-agonists on the cardiovascular system may be potentiated.
    Nadolol: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
    Naproxen; Pseudoephedrine: (Moderate) Monitor blood pressure and heart rate during concomitant salmeterol and pseudoephedrine use. Concomitant use may potentiate sympathetic effects.
    Nebivolol: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
    Nebivolol; Valsartan: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
    Nefazodone: (Major) Avoid concomitant use of salmeterol with nefazodone. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and nefazodone is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
    Nelfinavir: (Major) Avoid concomitant use of salmeterol with nelfinavir. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and nelfinavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
    Nirmatrelvir; Ritonavir: (Major) Avoid concomitant use of salmeterol with ritonavir. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose. (Major) Consider temporary discontinuation of salmeterol during treatment with ritonavir-boosted nirmatrelvir and for at least 2 to 3 days after treatment completion; if not feasible, consider alternative COVID-19 therapy. Coadministration may increase salmeterol exposure resulting in increased toxicity, including QT prolongation, palpitations, and sinus tachycardia. Salmeterol is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor.
    Norepinephrine: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid concomitant use of salmeterol with ritonavir. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
    Penbutolol: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
    Phendimetrazine: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Phenelzine: (Moderate) Use beta-agonists with caution in patients receiving concomitant monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping treatment with MAOIs because the action of beta-agonists on the cardiovascular system may be potentiated.
    Phentermine: (Moderate) Monitor blood pressure and heart rate during concomitant salmeterol and phentermine use. Concomitant use may potentiate sympathetic effects.
    Phentermine; Topiramate: (Moderate) Monitor blood pressure and heart rate during concomitant salmeterol and phentermine use. Concomitant use may potentiate sympathetic effects.
    Phenylephrine: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Pindolol: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
    Posaconazole: (Major) Avoid concomitant use of salmeterol with posaconazole. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and posaconazole is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
    Prilocaine; Epinephrine: (Moderate) Monitor blood pressure and heart rate during concomitant epinephrine and salmeterol use. Concomitant use may potentiate sympathetic effects.
    Procarbazine: (Major) Procarbazine has MAOI activity and the cardiovascular effects of beta-2 agonists may be potentiated by concomitant use of MAOIs. Although no data are available, procarbazine may interact similarly. Close observation for such effects is prudent, particularly if beta-agonists are administered within two weeks of stopping the MAOI.
    Promethazine; Phenylephrine: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Propranolol: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
    Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
    Pseudoephedrine: (Moderate) Monitor blood pressure and heart rate during concomitant salmeterol and pseudoephedrine use. Concomitant use may potentiate sympathetic effects.
    Pseudoephedrine; Triprolidine: (Moderate) Monitor blood pressure and heart rate during concomitant salmeterol and pseudoephedrine use. Concomitant use may potentiate sympathetic effects.
    Racepinephrine: (Major) Racepinephrine is a sympathomimetic drug with agonist actions at both the alpha and beta receptors. Patients using prescription beta-agonists for the treatment of asthma should generally avoid the concurrent use of racepinephrine inhalation since additive cardiovascular and nervous system adverse effects are possible, some which may be undesirable.
    Rasagiline: (Moderate) The concomitant use of rasagiline and sympathomimetic agents was not allowed in clinical studies; therefore, caution is advised during concurrent use of rasagiline and respiratory adrenergic agents (e.g., the beta-agonists). Although sympathomimetic agents are contraindicated for use with traditional non-selective monoamine oxidase inhibitors (MAOIs), hypertensive reactions generally are not expected to occur during concurrent use with rasagiline because of the selective monoamine oxidase-B (MAO-B) inhibition of rasagiline at manufacturer recommended doses. However, the cardiovascular effects of beta-2 agonists may be potentiated by concomitant use of MAOIs. At least one case of hypertension occurred in a patient with previous episodes of high blood pressure who was receiving albuterol and selegiline, a selective MAOI related to rasagiline, concurrently. Close observation for such effects is prudent, particularly if beta-2 agonists are administered during or within 2 weeks of use of an MAOI.
    Ribociclib: (Major) Avoid concomitant use of salmeterol with ribociclib. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and ribociclib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
    Ribociclib; Letrozole: (Major) Avoid concomitant use of salmeterol with ribociclib. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and ribociclib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
    Ritonavir: (Major) Avoid concomitant use of salmeterol with ritonavir. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
    Saquinavir: (Major) Avoid concomitant use of salmeterol with saquinavir. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and saquinavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
    Telithromycin: (Major) Avoid concomitant use of salmeterol with telithromycin. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and telithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
    Theophylline, Aminophylline: (Moderate) Beta-agonists are commonly used in conjunction with aminophylline or theophylline therapy. Concomitant use can cause additive CNS stimulation; some patients may experience tremor or nervousness with combined use. More serious effects are rare, but may result in additive cardiovascular effects such as increased blood pressure and heart rate. Methylxanthine derivatives, ((e.g., theophylline and aminophylline) may rarely aggravate the hypokalemic effect seen with beta-agonists. Consider checking potassium levels if clinically indicated. (Moderate) Beta-agonists are commonly used in conjunction with aminophylline or theophylline therapy. Concomitant use can cause additive CNS stimulation; some patients may experience tremor or nervousness with combined use. More serious effects are rare, but may result in additive cardiovascular effects such as increased blood pressure and heart rate. Methylxanthine derivatives, (e.g., theophylline, aminophylline) may rarely aggravate the hypokalemic effect seen with beta-agonists. Consider checking potassium levels if clinically indicated.
    Thiazide diuretics: (Minor) Hypokalemia associated with 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 unknown, use caution when coadministering beta-agonists with thiazide diuretics and monitor serum potassium as clinically indicated.
    Thyroid hormones: (Moderate) Monitor blood pressure and heart rate during concomitant beta-agonist and thyroid hormone use. Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
    Timolol: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
    Tipranavir: (Major) Avoid concomitant use of salmeterol with tipranavir. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and tipranavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
    Torsemide: (Moderate) Use beta-agonists and loop diuretics with caution due to risk for ECG changes and/or hypokalemia. The ECG changes and/or hypokalemia that may result from administration of loop diuretics can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded.
    Tranylcypromine: (Moderate) Use beta-agonists with caution in patients receiving concomitant monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping treatment with MAOIs because the action of beta-agonists on the cardiovascular system may be potentiated.
    Tucatinib: (Major) Avoid concomitant use of salmeterol with tucatinib. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
    Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of salmeterol with clarithromycin. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
    Voriconazole: (Major) Avoid concomitant use of salmeterol with voriconazole. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.

    PREGNANCY AND LACTATION

    Pregnancy

    There is no information regarding the presence of salmeterol in human milk, the effects on the breastfed child, or the effects on milk production. Salmeterol has been shown to be excreted in the milk of rats; however, data describing the use of salmeterol during human lactation are unavailable. Plasma concentrations of salmeterol after inhaled therapeutic doses are very low. Most inhaled bronchodilators are considered acceptable for use during the postpartum period and breast-feeding because of the low bioavailability and maternal serum levels after use. According to the National Asthma Education and Prevention Program (NAEPP) Asthma and Pregnancy Working Group, long-acting beta-2 agonists (LABAs) in combination with inhaled corticosteroids (ICSs) are one of the preferred treatment options for the long-term management of moderate persistent asthma during pregnancy and lactation. Although a preferred LABA is not recommended, the NAEPP guideline states that more experience is available with salmeterol. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition.

    MECHANISM OF ACTION

    Mechanism of Action: Salmeterol is an agonist at beta-2 receptors. These receptors are present in large numbers in the lungs and are located on bronchiolar smooth muscle. Stimulation of beta-2 receptors in the lung causes relaxation of bronchial smooth muscle, which produces bronchodilation and a resultant increase in bronchial airflow. These effects are believed to be mediated, in part, by increased activity of adenyl cyclase, an intracellular enzyme responsible for the formation of cyclic-3',5'-adenosine monophosphate (cAMP).Salmeterol can inhibit the bronchoconstriction produced by histamine, methacholine, and exercise. In addition, salmeterol appears to inhibit the late phase of allergen-induced bronchoconstriction, which usually appears after the bronchodilating effects of the shorter-acting agents have resolved.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 beta-2 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.

    PHARMACOKINETICS

    Salmeterol is administered by oral inhalation. Protein binding of salmeterol is approximately 94—98% 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. Use of a strong inhibitor of CYP3A4, ketoconazole, in in vitro study has been shown to inhibit metabolism and result in significantly increased salmeterol systemic exposure. The elimination half-life of orally administered salmeterol was determined as approximately 5 hours. Excretion is primarily in the feces. No significant amount of unchanged salmeterol has been detected in either urine or feces.

    Inhalation Route

    Following inhalation, a minimal amount of salmeterol is systemically absorbed to produce plasma concentrations of 0.1—0.2 mcg/L in healthy subjects. The onset of therapeutic effects, as measured by a 15% improvement in forced expiratory flow in one second (FEV1), occurs in approximately 14 minutes with salmeterol aerosol compared to 7 minutes with albuterol. Peak effects of salmeterol aerosol are observed 3—4 hours following oral inhalation. The median time to therapeutic onset with salmeterol inhalational powder is 30—50 minutes, with maximal increases in FEV1 occurring within 2 hours. Compared to albuterol, salmeterol produces similar mean peak increases in peak expiratory flow rates (PEFR) and FEV1. With salmeterol, however, the bronchodilator effects persisted at greater than half of the maximum effect for 12 hours, whereas with albuterol, PEFR and FEV1 returned to baseline within 6 hours.