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  • CLASSES

    Respiratory Long-Acting Beta-2 Agonists (LABA)

    DEA CLASS

    Rx

    DESCRIPTION

    Inhaled long-acting beta-2 agonist (LABA); given twice daily via nebulization
    Used for the maintenance treatment of COPD in adults
    Not indicated as monotherapy to treat asthma; do not use for acute bronchospasm or acute deteriorations of COPD

    COMMON BRAND NAMES

    Perforomist

    HOW SUPPLIED

    Formoterol/Formoterol Fumarate/Perforomist Respiratory (Inhalation) Sol: 2mL, 20mcg

    DOSAGE & INDICATIONS

    For the maintenance treatment of chronic obstructive pulmonary disease (COPD) (e.g., chronic bronchitis or emphysema).
    Nebulized Inhalation dosage (solution for nebulization; e.g., Perforomist)
    Adults

    20 mcg (one 2 mL unit) via nebulizer twice daily, in the morning and evening. Max: 40 mcg/day. Administer with a standard jet nebulizer connected to an air compressor. Safety and efficacy of use with non-compressor based nebulizer systems have not been established. 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.[33259] According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines for COPD, formoterol or other LABAs may be used as initial monotherapy 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.[63765]

    MAXIMUM DOSAGE

    Adults

    40 mcg/day via nebulizer.

    Geriatric

    40 mcg/day via nebulizer.

    Adolescents

    Safety and efficacy of nebulization have not been established. Previously available inhalers were approved in children as young as 5 years of age.

    Children

    Safety and efficacy of nebulization have not been established. Previously available inhalers were approved in children as young as 5 years of age.

    Infants

    Safety and efficacy of nebulization have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific information regarding the need for formoterol dosage adjustment is not available; formoterol has not been studied in patients with hepatic impairment.

    Renal Impairment

    Formoterol has not been formally studied in patients with renal impairment; no dosage adjustment guidelines are available.

    ADMINISTRATION

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

    Inhalation Administration
    Oral Inhalation Administration

    Inhalation solution for nebulization (Perforomist):
    For oral inhalation via nebulization only.
    Dilution of the solution is not necessary prior to administration.
    Open the foil pouch to remove the dose immediately prior to use. Store unused doses in the foil pouch until time of use.
    Only administer via a standard jet nebulizer connected to an air compressor with adequate airflow and a face mask or mouthpiece. Safety and efficacy of using this product with non-compressor based nebulizer systems have not been established.
    The approximate nebulization time for a single dose is 9 minutes; however, this may vary depending upon the nebulizer system used.
    Discard contents of any partially used container. Discard the container and top immediately after use because it is a choking hazard to infants.
    Compatibility, safety, and efficacy with concurrently administered nebulized drugs have not been established.

    STORAGE

    Foradil:
    - Avoid exposure to heat
    - Prior to dispensing, store in refrigerator (36 to 46 degrees F)
    - Product should always be stored in the blister and only removed immediately before use
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Perforomist:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - May be stored at room temperature not exceeding 77 degrees F for up to 3 months
    - Protect from heat
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store unused product in foil pouch

    CONTRAINDICATIONS / PRECAUTIONS

    Monotherapy treatment of asthma

    Currently marketed formoterol products are not FDA-approved for the treatment of asthma. All long-acting beta agonists (LABAs) are contraindicated for monotherapy treatment of asthma and, in patients with asthma, must be used with an asthma controller medication (i.e., inhaled corticosteroid).

    Paradoxical bronchospasm

    Paradoxical bronchospasm can occur after treatment with formoterol and can be life-threatening. If this occurs, formoterol should be discontinued immediately and supportive care provided as necessary.

    Acute bronchospasm, asthma-related death

    LABAs, such as formoterol, increase the risk of asthma-related death when used without ICSs; this is considered a class effect. No study adequate to determine whether the rate of asthma-related death is increased in patients treated with formoterol has been conducted. LABAs should only be used in conjunction with ICSs for asthma; studies have found that the combined use of LABA/ICS does not increase the risk for serious asthma-related events. Formoterol should not be used for the relief of acute symptoms (i.e., as rescue therapy for the treatment of acute bronchospasm) of COPD and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled short-acting beta-2 agonist (SABA). Formoterol should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD. Available data do not suggest an increased risk of death with use of LABA in patients with COPD; however, the drug has not been studied in patients with acutely deteriorating COPD. It is crucial to inform patients of this and prescribe an inhaled SABA (e.g., albuterol), for rescue treatment of an acute attack as well as to warn them that increasing inhaled SABA use is a signal of deteriorating disease. Loss of symptom control with formoterol is also a marker of deterioration of disease; in this setting a re-evaluation of the patient and the COPD treatment regimen should be undertaken at once. Increasing the daily dose of formoterol beyond the recommended dose is not appropriate in this situation. Furthermore, patients should not use formoterol more often than recommended, at higher doses than recommended, or in conjunction with other LABAs as this would be considered duplicative therapy and may lead to additive untoward effects. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs in patients with asthma.

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

    Formoterol should be used cautiously in patients with hyperthyroidism (thyrotoxicosis), diabetes mellitus, history of seizure disorder, pheochromocytoma, or other unusual responsiveness to other sympathomimetic amines. Beta-agonists may cause transient hyperglycemia. Exacerbation of diabetes mellitus has occurred when short-acting beta-2 agonists (e.g., albuterol) have been administered systemically. During long-term studies of formoterol solution for nebulization, clinically significant changes in blood glucose occurred in some patients.

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

    Formoterol, 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. Formoterol 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, formoterol 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. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Beta-adrenergic agonist therapies like formoterol 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.

    Labor, pregnancy

    The limited data with formoterol use during human pregnancy are not sufficient to inform of drug-associated risk of adverse developmental outcomes. Use during pregnancy only if the potential benefit justifies the potential risk. In animal reproduction studies, oral administration of formoterol fumarate to pregnant rats and rabbits caused increased fetal malformations (rats and rabbits), decreased fetal weight (rats), and increased neonatal mortality (rats) following administration of doses that produced exposures approximately 730 to 29,000 times the maximum recommended human dose (MRHD) on a mg/m2 or AUC basis. These adverse effects generally occurred at large multiples of the MRHD when formoterol fumarate was administered by the oral route to achieve high systemic exposures. No effects were observed in a study with rats that received formoterol fumarate by the inhalation route at an exposure approximately 300 times the MRHD. 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; however, less data are available for long-acting beta agonists (LABAs) such as formoterol vs. short-acting beta agonists (SABAs). However, most inhaled beta-2 agonists are considered acceptable for use during pregnancy because of the low bioavailability and maternal serum levels after use. 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 (ICS), are one of the preferred treatment options for the long-term control of moderate asthma during pregnancy and lactation. Although a preferred LABA is not recommended, the guideline states that more experience is available with salmeterol. Beta-2 agonists can interfere with uterine contractility during labor; do not use formoterol during labor unless the benefits outweigh the risks.

    Breast-feeding

    There are no well-controlled human studies of the use of formoterol in women who are breast-feeding. It is not known whether formoterol is excreted in human milk. Formoterol was excreted in milk in reproductive studies in rats. The amount of radioactive formoterol was less than 2% of that in the maternal plasma. However, 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 2004 guidelines of the National Asthma Education and Prevention Program (NAEPP) Asthma and Pregnancy Working Group, long-acting beta-agonists (LABA), 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. The NAEPP suggests that LABA may be used during pregnancy and lactation because the toxicologic and pharmacologic profile is similar to that of short-acting beta-2 agonists (SABAs), for which a significant amount of data is available. 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. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MAOI therapy

    Beta-2 adrenergic agonists such as formoterol should be administered with extreme caution to patients being treated with monoamine oxidase inhibitor therapy (MAOI therapy). The action of adrenergic agonists on the cardiovascular system may be potentiated by these agents.

    Geriatric

    Geriatric patients may be more sensitive to the side effects of beta-agonists, especially tremor and tachycardia. Although not clearly established, airway responsiveness to inhaled beta-agonists may also change with age. Elderly patients may also be at increased risk for QT prolongation. 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 formoterol, can cause restlessness, increased heart rate, and anxiety.

    Children, infants

    Safety and efficacy of formoterol have not been established in children and infants under the age of 5 years, and currently marketed formoterol products are not FDA-approved for the treatment of pediatric patients. Available data from clinical trials suggest that LABAs, such as formoterol, increase the risk of asthma-related hospitalization in children and adolescents.

    Milk protein hypersensitivity

    Immediate hypersensitivity reactions may occur after administration of formoterol, as demonstrated by cases of anaphylactic reactions, urticaria, angioedema, rash, and bronchospasm. If such reactions occur, stop use of the product and treat the allergy as per standard of care. Alternative treatment should be considered. Previously marketed formoterol inhalation powders contained lactose as a carrier; the product information carried a warning that patients with a severe milk protein hypersensitivity may experience an allergic reaction to these products.

    ADVERSE REACTIONS

    Severe

    angioedema / Rapid / 0-1.0
    anaphylactoid reactions / Rapid / 0-1.0
    atrial fibrillation / Early / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    bronchospasm / Rapid / Incidence not known
    asthma-related death / Delayed / Incidence not known

    Moderate

    chest pain (unspecified) / Early / 1.9-3.2
    dyspnea / Early / 2.1-2.1
    dysphonia / Delayed / 1.0-1.0
    sinus tachycardia / Rapid / Incidence not known
    hypertension / Early / Incidence not known
    palpitations / Early / Incidence not known
    supraventricular tachycardia (SVT) / Early / Incidence not known
    angina / Early / Incidence not known
    QT prolongation / Rapid / Incidence not known
    tolerance / Delayed / Incidence not known
    wheezing / Rapid / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    hypokalemia / Delayed / Incidence not known

    Mild

    infection / Delayed / 2.7-17.2
    diarrhea / Early / 4.9-4.9
    nausea / Early / 4.9-4.9
    pharyngitis / Delayed / 3.3-3.5
    xerostomia / Early / 1.2-3.3
    sinusitis / Delayed / 2.7-2.7
    insomnia / Early / 1.5-2.4
    dizziness / Early / 1.6-2.4
    vomiting / Early / 2.4-2.4
    fever / Early / 2.2-2.2
    tremor / Early / 1.9-1.9
    muscle cramps / Delayed / 1.7-1.7
    pruritus / Rapid / 1.5-1.5
    bronchial secretions / Early / 1.5-1.5
    rash / Early / 1.1-1.1
    fatigue / Early / Incidence not known
    hoarseness / Early / Incidence not known
    headache / Early / Incidence not known
    malaise / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    photosensitivity / Delayed / Incidence not known
    dyspepsia / Early / Incidence not known
    abdominal pain / Early / Incidence not known
    paresthesias / Delayed / Incidence not known
    rhinitis / 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 be used when formoterol 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 pseudoephedrine and formoterol use. Concomitant use may potentiate sympathetic effects.
    Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Caution and close observation should be used when formoterol 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 be used when formoterol 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 pseudoephedrine and formoterol use. Concomitant use may potentiate sympathetic effects.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Caution and close observation should be used when formoterol 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 pseudoephedrine and formoterol use. Concomitant use may potentiate sympathetic effects.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) Caution and close observation should be used when formoterol 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 be used when formoterol 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 pseudoephedrine and formoterol use. Concomitant use may potentiate sympathetic effects.
    Acrivastine; Pseudoephedrine: (Moderate) Monitor blood pressure and heart rate during concomitant pseudoephedrine and formoterol use. Concomitant use may potentiate sympathetic effects.
    Amphetamine: (Moderate) Monitor blood pressure and heart rate during concomitant amphetamine; dextroamphetamine and formoterol use. Concomitant use may potentiate sympathetic effects.
    Amphetamine; Dextroamphetamine Salts: (Moderate) Monitor blood pressure and heart rate during concomitant amphetamine; dextroamphetamine and formoterol use. Concomitant use may potentiate sympathetic effects.
    Amphetamine; Dextroamphetamine: (Moderate) Monitor blood pressure and heart rate during concomitant amphetamine; dextroamphetamine and formoterol use. Concomitant use may potentiate sympathetic effects.
    Arformoterol: (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.
    Articaine; Epinephrine: (Moderate) Monitor blood pressure and heart rate during concomitant epinephrine and formoterol 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.
    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 be used when formoterol 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 be used when formoterol 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 be used when formoterol 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 be used when formoterol 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 pseudoephedrine and formoterol use. Concomitant use may potentiate sympathetic effects.
    Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Monitor blood pressure and heart rate during concomitant pseudoephedrine and formoterol use. Concomitant use may potentiate sympathetic effects.
    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 formoterol 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 be used when formoterol 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 be used when formoterol 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 be used when formoterol 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 be used when formoterol 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 be used when formoterol 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 pseudoephedrine and formoterol use. Concomitant use may potentiate sympathetic effects.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor blood pressure and heart rate during concomitant pseudoephedrine and formoterol use. Concomitant use may potentiate sympathetic effects.
    Carbinoxamine; Phenylephrine: (Moderate) Caution and close observation should be used when formoterol 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 pseudoephedrine and formoterol 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.
    Cetirizine; Pseudoephedrine: (Moderate) Monitor blood pressure and heart rate during concomitant pseudoephedrine and formoterol use. Concomitant use may potentiate sympathetic effects.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Monitor blood pressure and heart rate during concomitant pseudoephedrine and formoterol use. Concomitant use may potentiate sympathetic effects.
    Chlophedianol; Guaifenesin; Phenylephrine: (Moderate) Caution and close observation should be used when formoterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Caution and close observation should be used when formoterol 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 pseudoephedrine and formoterol use. Concomitant use may potentiate sympathetic effects.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Caution and close observation should be used when formoterol 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 pseudoephedrine and formoterol use. Concomitant use may potentiate sympathetic effects.
    Chlorpheniramine; Phenylephrine: (Moderate) Caution and close observation should be used when formoterol 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 pseudoephedrine and formoterol 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.
    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 pseudoephedrine and formoterol use. Concomitant use may potentiate sympathetic effects.
    Codeine; Phenylephrine; Promethazine: (Moderate) Caution and close observation should be used when formoterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Desloratadine; Pseudoephedrine: (Moderate) Monitor blood pressure and heart rate during concomitant pseudoephedrine and formoterol use. Concomitant use may potentiate sympathetic effects.
    Dexbrompheniramine; Pseudoephedrine: (Moderate) Monitor blood pressure and heart rate during concomitant pseudoephedrine and formoterol use. Concomitant use may potentiate sympathetic effects.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor blood pressure and heart rate during concomitant pseudoephedrine and formoterol use. Concomitant use may potentiate sympathetic effects.
    Dextroamphetamine: (Moderate) Monitor blood pressure and heart rate during concomitant amphetamine; dextroamphetamine and formoterol use. Concomitant use may potentiate sympathetic effects.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Caution and close observation should be used when formoterol 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 be used when formoterol 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 pseudoephedrine and formoterol use. Concomitant use may potentiate sympathetic effects.
    Dichlorphenamide: (Moderate) Use dichlorphenamide and arformoterol or formoterol together with caution. Metabolic acidosis is listed by the manufacturers of arformoterol and formoterol as an adverse reaction seen with beta-2 agonists but would be rare with normal doses of arformoterol or formoterol. Metabolic acidosis has been reported with dichlorphenamide. Concurrent use may increase the severity of metabolic acidosis. Measure sodium bicarbonate concentrations at baseline and periodically during dichlorphenamide treatment. If metabolic acidosis occurs or persists, consider reducing the dose or discontinuing dichlorphenamide therapy.
    Diethylpropion: (Moderate) Caution and close observation should be used when formoterol 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 be used when formoterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Dobutamine: (Moderate) Caution and close observation should be used when formoterol 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 be used when formoterol 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.
    Dyphylline: (Moderate) Concomitant use of formoterol and dyphylline may potentiate the hypokalemic effect of formoterol. Tremors, insomnia, seizures, or cardiac arrhythmias are also possible. Monitor the patient appropriately and consider checking serum potassium concentrations if clinically indicated.
    Dyphylline; Guaifenesin: (Moderate) Concomitant use of formoterol and dyphylline may potentiate the hypokalemic effect of formoterol. Tremors, insomnia, seizures, or cardiac arrhythmias are also possible. Monitor the patient appropriately and consider checking serum potassium concentrations if clinically indicated.
    Ephedrine: (Moderate) Caution and close observation should be used when formoterol 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 be used when formoterol 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 formoterol 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 pseudoephedrine and formoterol use. Concomitant use may potentiate sympathetic effects.
    Fluticasone; Salmeterol: (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.
    Fluticasone; Umeclidinium; Vilanterol: (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.
    Fluticasone; Vilanterol: (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.
    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.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Monitor blood pressure and heart rate during concomitant pseudoephedrine and formoterol use. Concomitant use may potentiate sympathetic effects.
    Guaifenesin; Phenylephrine: (Moderate) Caution and close observation should be used when formoterol 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 pseudoephedrine and formoterol use. Concomitant use may potentiate sympathetic effects.
    Hydrocodone; Pseudoephedrine: (Moderate) Monitor blood pressure and heart rate during concomitant pseudoephedrine and formoterol use. Concomitant use may potentiate sympathetic effects.
    Ibuprofen; Pseudoephedrine: (Moderate) Monitor blood pressure and heart rate during concomitant pseudoephedrine and formoterol use. Concomitant use may potentiate sympathetic effects.
    Indacaterol: (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.
    Indacaterol; Glycopyrrolate: (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.
    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: (Moderate) Caution and close observation should be used when formoterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Itraconazole: (Moderate) Use itraconazole with caution in combination with beta-agonists as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Ketoconazole: (Moderate) Formoterol, as with other long-acting beta-agonists, should be administered with extreme caution to patients being treated with drugs known to prolong the QTc interval like ketoconazole because the effect of adrenergic agonists on the cardiovascular system may be potentiated. Drugs that are known to prolong the QTc interval have an increased risk of ventricular arrhythmias. Ketoconazole has been associated with prolongation of the QT interval and torsade de pointes (TdP).
    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.
    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: (Moderate) Formoterol, as with other long-acting beta-agonists, should be administered with extreme caution to patients being treated with drugs known to prolong the QTc interval like ketoconazole because the effect of adrenergic agonists on the cardiovascular system may be potentiated. Drugs that are known to prolong the QTc interval have an increased risk of ventricular arrhythmias. Ketoconazole has been associated with prolongation of the QT interval and torsade de pointes (TdP).
    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 formoterol 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.
    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.
    Loratadine; Pseudoephedrine: (Moderate) Monitor blood pressure and heart rate during concomitant pseudoephedrine and formoterol use. Concomitant use may potentiate sympathetic effects.
    Methacholine: (Major) Discontinue use of formoterol 36 hours before a methacholine challenge test. Beta-agonists inhibit the airway response to methacholine.
    Methamphetamine: (Moderate) Caution and close observation should be used when formoterol 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 formoterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    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 pseudoephedrine and formoterol 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.
    Norepinephrine: (Moderate) Caution and close observation should be used when formoterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Olodaterol: (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.
    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 be used when formoterol 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 phentermine and formoterol use. Concomitant use may potentiate sympathetic effects.
    Phentermine; Topiramate: (Moderate) Monitor blood pressure and heart rate during concomitant phentermine and formoterol use. Concomitant use may potentiate sympathetic effects.
    Phenylephrine: (Moderate) Caution and close observation should be used when formoterol 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.
    Prilocaine; Epinephrine: (Moderate) Monitor blood pressure and heart rate during concomitant epinephrine and formoterol 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 be used when formoterol 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 pseudoephedrine and formoterol use. Concomitant use may potentiate sympathetic effects.
    Pseudoephedrine; Triprolidine: (Moderate) Monitor blood pressure and heart rate during concomitant pseudoephedrine and formoterol 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: (Moderate) Due to a possible risk for QT prolongation, ribociclib and long-acting beta-agonists should be used together cautiously. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval like ribociclib. This risk may be more clinically significant with long-acting beta-agonists such as formoterol as compared to short-acting beta-agonists.
    Ribociclib; Letrozole: (Moderate) Due to a possible risk for QT prolongation, ribociclib and long-acting beta-agonists should be used together cautiously. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval like ribociclib. This risk may be more clinically significant with long-acting beta-agonists such as formoterol as compared to short-acting beta-agonists.
    Salmeterol: (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.
    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.
    Tiotropium; Olodaterol: (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.
    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.
    Umeclidinium; Vilanterol: (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.

    PREGNANCY AND LACTATION

    Pregnancy

    The limited data with formoterol use during human pregnancy are not sufficient to inform of drug-associated risk of adverse developmental outcomes. Use during pregnancy only if the potential benefit justifies the potential risk. In animal reproduction studies, oral administration of formoterol fumarate to pregnant rats and rabbits caused increased fetal malformations (rats and rabbits), decreased fetal weight (rats), and increased neonatal mortality (rats) following administration of doses that produced exposures approximately 730 to 29,000 times the maximum recommended human dose (MRHD) on a mg/m2 or AUC basis. These adverse effects generally occurred at large multiples of the MRHD when formoterol fumarate was administered by the oral route to achieve high systemic exposures. No effects were observed in a study with rats that received formoterol fumarate by the inhalation route at an exposure approximately 300 times the MRHD. 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; however, less data are available for long-acting beta agonists (LABAs) such as formoterol vs. short-acting beta agonists (SABAs). However, most inhaled beta-2 agonists are considered acceptable for use during pregnancy because of the low bioavailability and maternal serum levels after use. 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 (ICS), are one of the preferred treatment options for the long-term control of moderate asthma during pregnancy and lactation. Although a preferred LABA is not recommended, the guideline states that more experience is available with salmeterol. Beta-2 agonists can interfere with uterine contractility during labor; do not use formoterol during labor unless the benefits outweigh the risks.

    MECHANISM OF ACTION

    Inhaled formoterol acts locally in the lung as a bronchodilator. Similar to other beta-2 agonists, formoterol's mechanism of action involves stimulation of adenyl cyclase leading to the production of cyclic adenosine monophosphate (cAMP) via adenosine triphosphate (ATP). Increased levels of cAMP result in relaxation of the bronchial smooth muscle.
     
    Formoterol, like salmeterol, is highly lipophilic. Formoterol enters the plasma cell membrane in the form of a depot and is gradually released into the aqueous phase to react with the beta-2 receptor, resulting in a long duration of action. The aqueous phase activity, not demonstrated by salmeterol, is responsible for the rapid onset of action of formoterol.
     
    Formoterol has more than a 200-fold greater agonist activity at beta-2 receptors (primarily in the lung) than at beta-1 receptors (primarily in the heart). However, 10% to 50% of the beta receptors in the heart are beta-2 receptors and raise the possibility that even highly selective beta-2 receptor agonists may have adverse cardiovascular effects, such as tachycardia, palpitations and ischemia.
     
    As with other beta-2 agonists, formoterol may possess antiinflammatory activity, but the clinical significance of this effect is unknown. In vitro studies have demonstrated inhibition of mast cell mediators such as histamine and leukotrienes. Monotherapy with formoterol is inappropriate due to lack of proven antiinflammatory and disease-modifying properties.

    PHARMACOKINETICS

    Formoterol is administered via nebulization. Formoterol is extensively metabolized in the liver by direct glucuronidation and O-demethylation followed by glucuronide conjugation. Four cytochrome P450 isoenzymes (CYP2D6, CYP2C19, CYP2C9, and CYP2A6) are involved in the O-demethylation of formoterol. Formoterol has not been shown to inhibit CYP450 isoenzymes. About 60% of a dose is eliminated in the urine and 33% in the feces over a period of 104 hours. In the urine, roughly 10% of a dose is excreted unchanged and roughly 15% is eliminated as the direct glucuronide conjugate. The mean terminal elimination half-life is roughly 10 hours.

    Inhalation Route

    Dry powder inhalers: Following inhalation of a single 120 mcg dose (10 times the recommended dose) by healthy subjects, a minimal amount of formoterol was absorbed into plasma within 5 minutes of dosing. Some accumulation in plasma occurs with multiple doses. Most of the inhaled formoterol delivered to the bloodstream is swallowed and absorbed from the GI tract. Bronchodilation begins to occur in 1 to 3 minutes. The onset of therapeutic effects, as measured by a 15% improvement in forced expiratory flow in one second (FEV-1), occurs in approximately 15 minutes. In clinical trials, most patients experienced the maximum improvement in FEV-1 after inhalation of a 12 mcg dose within 1 to 3 hours. Significant increases in lung function and reduction in asthmatic symptoms are evident by the second week of treatment.