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  • CLASSES

    Selective Beta-Blockers

    DEA CLASS

    Rx

    DESCRIPTION

    Oral beta-blocker used for HTN and CHF (not FDA-approved); beta1-receptor selective; hydrophilic; excreted by renal and non-renal routes; lacks partial agonist or membrane stabilizing activity.

    COMMON BRAND NAMES

    Zebeta

    HOW SUPPLIED

    Bisoprolol/Bisoprolol Fumarate/Zebeta Oral Tab: 5mg, 10mg

    DOSAGE & INDICATIONS

    For the treatment of hypertension.
    Oral dosage
    Adults

    Initially, 5 mg PO once daily; reduce initial dose to 2.5 mg PO once daily for patients with bronchospastic disease. Some patients respond to 2.5 mg once daily. If necessary, increase to 10 mg PO once daily. Maximum dosage is 20 mg/day.

    For the treatment of heart failure†.
    Oral dosage
    Adults

    Initially, 1.25 mg PO once daily for 48 hours, then 2.5 mg once daily for the first month, then 5 mg once daily. Up to 10 mg once daily has been tolerated as a higher dosage in patients with heart failure (CIBIS-II subgroup analysis). In a study of patients with chronic heart failure (n = 641) due to systolic dysfunction (EF < 40%), bisoprolol or placebo was administered in combination with ACE inhibitor and diuretic therapy. Compared with the placebo group, patients treated with bisoprolol required fewer hospitalizations for cardiac decompensation and had more significant improvements in NYHA functional class. Patients with nonischemic cardiomyopathy appeared to derive the greatest benefit. In a long-term follow-up study of stable heart failure patients (CIBIS-II), bisoprolol prolonged survival and reduced the incidence of hospitalization; this study did not include Class IV heart failure patients. Clinical practice guidelines recommend the use of 1 of the 3 beta blockers proven to reduce mortality (bisoprolol, carvedilol, metoprolol succinate) for all stable patients with current or prior symptoms of heart failure and reduced left ventricular ejection fraction, unless contraindicated.

    For the treatment of angina†.
    Oral dosage
    Adults

    Doses of 5 to 20 mg PO once daily have been studied. In one study, bisoprolol 10 to 20 mg once daily was significantly more effective than slow-release nifedipine in reducing transient ischemic episodes in patients with chronic stable angina. In another study, bisoprolol 10 mg once daily was as effective as atenolol 100 mg PO once daily in reducing anginal attack rate in patients with stable effort angina. When discontinuing therapy, the dosage should be gradually tapered over several weeks to avoid rebound angina and adverse cardiac events.

    For heart rate control in patients who have atrial fibrillation or atrial flutter.
    Oral dosage
    Adults

    2.5 to 10 mg PO daily. Clinical practice guidelines recommend the use of beta blockers to control the ventricular rate for patients with paroxysmal, persistent, or permanent atrial fibrillation.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    20 mg/day PO for hypertension or angina; 10 mg/day PO for heart failure.

    Elderly

    20 mg/day PO for hypertension or angina; 10 mg/day PO for heart failure.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Initiate therapy with 2.5 mg PO once daily. Cautiously titrate the dosage to attain clinical goals.

    Renal Impairment

    CrCl >= 40 mL/min: no dosage adjustment needed.
    CrCl < 40 mL/min: initiate therapy with 2.5 mg PO once daily, then cautiously titrate the dosage to attain clinical goals.
     
    Intermittent hemodialysis:
    See dosage for patients with renal impairment; no supplemental dosage is needed after dialysis. Limited data suggest that bisoprolol is not dialyzable.

    ADMINISTRATION

    Oral Administration

    Bisoprolol may be administered without regard to meals.

    STORAGE

    Zebeta:
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Abrupt discontinuation

    Abrupt discontinuation of any beta-adrenergic blocking agent, including bisoprolol, can result in the development of myocardial ischemia, myocardial infarction, ventricular arrhythmias, or severe hypertension, particularly in patients with preexisting cardiac disease. Even in patients without overt coronary artery disease, it is recommended that the dosage of bisoprolol be tapered over approximately one week.

    Depression

    The actual relationship between depression and beta-blockers has not been definitively established. Beta-blockers, including bisoprolol, should be used with caution in patients with major depression.

    Acute heart failure, AV block, bradycardia, cardiogenic shock, pulmonary edema, sick sinus syndrome, ventricular dysfunction

    Because beta-blockers depress conduction through the AV node, bisoprolol is contraindicated in patients with severe bradycardia or advanced AV block (e.g., second or third-degree AV block) unless a functioning pacemaker is present. Beta-blockers should also be avoided in patients with sick sinus syndrome unless a functioning pacemaker is present. In general, bisoprolol should be avoided in patients with acute pulmonary edema and is contraindicated in patients with cardiogenic shock or acute heart failure due to systolic ventricular dysfunction. Although beta-blockers, including bisoprolol, have been used as adjunctive therapy in patients with chronic heart failure, these agents should be used cautiously in this patient population. In the setting of congestive heart failure, sympathetic stimulation is a vital component supporting circulatory function. Beta-blockade may result in further depression of myocardial contractility and precipitate more severe failure. In patients with stable, chronic heart failure, however, some beta-blockers, including bisoprolol, have been documented to be beneficial. If bisoprolol is used in a patient with chronic heart failure, low initial doses should be used and increases in dosage should be made gradually. In one placebo-controlled study of patients with chronic heart failure due to systolic dysfunction, bisoprolol was administered in combination with ACE inhibitor and diuretic therapy. Compared with the placebo group, patients treated with bisoprolol required fewer hospitalizations for cardiac decompensation and had more significant improvements in NYHA functional class. Patients with nonischemic cardiomyopathy appeared to derive the greatest benefit. In a long-term follow-up study of stable heart failure patients (CIBIS-II), bisoprolol prolonged survival and reduced the incidence of hospitalization; this study did not include Class IV heart failure patients.

    Cerebrovascular disease

    Because of potential effects of beta-blockade on blood pressure and pulse, bisoprolol should be used with caution in patients with cerebrovascular insufficiency (cerebrovascular disease) or stroke. If signs or symptoms suggesting reduced cerebral blood flow develop following initiation of beta-blocker, alternative therapy should be considered.

    Hyperthyroidism, thyroid disease, thyrotoxicosis

    Bisoprolol should be used with caution in patients with hyperthyroidism or thyrotoxicosis because beta-blockers can mask tachycardia, which is a useful monitoring parameter in thyroid disease. Abrupt withdrawal of beta-blockers in a patient with hyperthyroidism can precipitate thyroid storm. However, beta-blockers are generally useful in the symptomatic treatment of hyperthyroid-related states, like thyrotoxicosis.

    Diabetes mellitus

    Beta-blockers have been shown to increase the risk of developing diabetes mellitus in hypertensive patients; however this risk should be evaluated relative to the proven benefits of beta-blockers in reducing cardiovascular events. Bisoprolol should be used with caution in patients with poorly controlled diabetes mellitus, particularly brittle diabetes. Beta-blockers can prolong or enhance hypoglycemia by interfering with glycogenolysis; this effect may be less pronounced with beta1-selective beta-blockers than with nonselective agents. Beta-blockers can also mask signs of hypoglycemia, especially tachycardia, palpitations, and tremors; in contrast, diaphoresis and the hypertensive response to hypoglycemia are not suppressed with beta-blockade. Beta-blockers can occasionally cause hyperglycemia. This is thought to be due to blockade of beta2-receptors on pancreatic islet cells, which would inhibit insulin secretion. Thus, blood glucose levels should be monitored closely if a beta-blocker is used in a patient with diabetes mellitus.

    Acute bronchospasm, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary disease

    Although beta1-adrenergic selective beta-blockers such as bisoprolol are preferred over nonselective agents in patients with asthma or other pulmonary disease [e.g., chronic obstructive pulmonary disease (COPD), emphysema, bronchitis] in which acute bronchospasm would put them at risk, all beta-blockers should nevertheless be used with caution in these patients, particularly with high-dose therapy. In patients with bronchospastic disease, initiate therapy with the lowest dose of bisoprolol; adjust dosage cautiously based on clinical response.

    Driving or operating machinery

    Beta-blockers may be associated with dizziness or drowsiness in some patients. Patients should be cautioned to avoid driving or operating machinery until the effects of bisoprolol are known.

    Peripheral vascular disease, pheochromocytoma, Raynaud's phenomenon, vasospastic angina

    Bisoprolol should be used with caution in patients with Raynaud's phenomenon or peripheral vascular disease because reduced cardiac output and the relative increase in alpha stimulation can exacerbate symptoms. Bisoprolol monotherapy should be used with caution in patients with a pheochromocytoma or vasospastic angina (Prinzmetal's angina); beta-blockers may increase the risk of hypertension in these patients secondary to unopposed alpha-receptor stimulation. In patients with pheochromocytoma, an alpha-blocking agent should be used prior to the initiation of any beta-blocker.

    Hepatic disease, renal disease, renal failure, renal impairment

    Bisoprolol is eliminated equally by renal and non-renal pathways; consequently, elimination of bisoprolol is significantly decreased in cirrhosis and patients with renal impairment (CrCl < 40 mL/minute). In patients with renal disease (e.g., renal failure, renal impairment) or hepatic disease, low initial doses should be used and caution is advised during dose titration.

    Psoriasis

    Beta-blockers such as bisoprolol may exacerbate psoriasis.

    Myasthenia gravis

    Beta-blockers may potentiate muscle weakness and double vision in patients with myasthenia gravis. Bisoprolol should be used with caution in these patients.

    Hypotension, surgery

    The necessity or desirability of withdrawing beta-blockers prior to major surgery is controversial; the risks versus benefits should be evaluated for individual patients. Patients receiving bisoprolol before or during surgery involving the use of general anesthetics with negative inotropic effects (e.g., ether, cyclopropane, or trichloroethylene) should be monitored closely for signs of heart failure. Severe, protracted hypotension and difficulty in restarting the heart have been reported after surgery in patients receiving beta-blockers. It should also be noted that because beta-blocker therapy reduces the ability of the heart to respond to beta-adrenergically mediated sympathetic reflex stimuli, the risks of general anesthesia and surgical procedures may be augmented. Although gradual withdrawal of beta-blockers is sometimes recommended prior to general anesthesia to limit the potential for hypotension and heart failure, the manufacturer does not recommend routine withdrawal of chronically-administered bisoprolol prior to major surgery. The risk of precipitating adverse cardiac events (e.g., myocardial infarction, tachycardia) following preoperative withdrawal of beta-blockers may outweigh the risks of ongoing beta-blocker therapy, particularly in patients with co-existing cardiovascular disease. Consideration should be given to the type of surgery (e.g., cardiac vs. noncardiac), anesthetic strategy, and co-existing health conditions. The anesthetic technique may be modified to reduce the risk of concurrent beta-blocker therapy. If needed, the negative inotropic effects of beta-blockers may be cautiously reversed by sufficient doses of adrenergic agonists such as isoproterenol, dopamine, dobutamine, or norepinephrine. Vagal dominance, if it occurs, may be corrected with atropine (1—2 mg IV).

    Geriatric

    Response rates for geriatric subjects and younger adults were similar in clinical hypertension studies with bisoprolol; there was a tendency for older patients to be maintained on higher dosesl. Observed reductions in heart rate were slightly greater in the geriatric adult than in the young and tended to increase with increasing dose. In general, no disparity in safety was observed between older and younger patients. Bisoprolol dose adjustment based on age alone is not necessary. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities. According to the OBRA guidelines, antihypertensive regimens should be individualized to achieve the desired outcome while minimizing adverse effects. Antihypertensives may cause dizziness, postural hypotension, fatigue, and there is an increased risk for falls. Additionally, beta-blockers are associated with depression, bronchospasm, cardiac decompensation that may require dose adjustments in those with acute heart failure, and they may mask some symptoms of hypoglycemia (e.g., tachycardia). Beta-blockers metabolized in the liver may have an increased effect or accumulate in those with hepatic impairment. There are many drug interactions that can potentiate the effects of antihypertensives. Beta-blockers may cause or exacerbate bradycardia, particularly in patients receiving other medications that affect cardiac conduction. When discontinuing, a gradual taper may be required to avoid adverse consequences caused by abrupt discontinuation.

    Pregnancy

    Bisoprolol is classified as pregnancy risk category C. There are no adequate and well-controlled studies in pregnant women. However, in rat studies, bisoprolol was fetotoxic (increased late resorptions) and maternotoxic (decreased food intake and body weight gain). When given to pregnant rabbits, bisoprolol was not teratogenic but was embryolethal at dosages of 12.5 mg/kg/day. Thus, bisoprolol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

    Breast-feeding

    It is not known if bisoprolol is excreted in human milk. Small amounts (< 2% of a dose) of bisoprolol have been detected in the milk of lactating rats. Caution should be exercised when bisoprolol is administered to a woman who is breast-feeding. The American Academy of Pediatrics regards the following beta-blockers as usually compatible with breast feeding: labetalol, metoprolol, nadolol, propranolol, sotolol, and timolol; these agents may represent alternatives for some patients.

    Children

    The safety and efficacy of bisoprolol have not been established in children.

    Beta-blocker hypersensitivity

    Bisoprolol is contraindicated in patients exhibiting hypersensitivity to the drug or any of its excipients. Do not use bisoprolol in patients with known beta-blocker hypersensitivity. Cross-sensitivity between beta-blockers may occur.

    ADVERSE REACTIONS

    Severe

    bradycardia / Rapid / 0.4-0.5
    bronchospasm / Rapid / Incidence not known
    heart failure / Delayed / Incidence not known
    AV block / Early / Incidence not known
    vasculitis / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known

    Moderate

    elevated hepatic enzymes / Delayed / 3.9-6.2
    peripheral edema / Delayed / 3.0-3.7
    chest pain (unspecified) / Early / 1.1-1.5
    angina / Early / 1.1-1.5
    dyspnea / Early / 1.1-1.5
    depression / Delayed / 0-0.2
    orthostatic hypotension / Delayed / Incidence not known
    hypoglycemia / Early / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    diabetes mellitus / Delayed / Incidence not known
    wheezing / Rapid / Incidence not known
    hypertriglyceridemia / Delayed / Incidence not known
    hallucinations / Early / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known
    peripheral vasoconstriction / Rapid / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    palpitations / Early / Incidence not known
    withdrawal / Early / Incidence not known
    hypertension / Early / Incidence not known

    Mild

    headache / Early / 8.8-10.9
    fatigue / Early / 6.6-8.2
    rhinitis / Early / 2.9-4.0
    diarrhea / Early / 2.6-3.5
    dizziness / Early / 2.9-3.5
    arthralgia / Delayed / 2.2-2.7
    cough / Delayed / 2.5-2.5
    insomnia / Early / 1.5-2.5
    pharyngitis / Delayed / 2.2-2.3
    sinusitis / Delayed / 2.2-2.2
    nausea / Early / 1.5-2.2
    vomiting / Early / 1.1-1.5
    hypoesthesia / Delayed / 1.1-1.5
    asthenia / Delayed / 0.4-1.5
    xerostomia / Early / 0.7-1.3
    diaphoresis / Early / 0.7-1.0
    nightmares / Early / 0-1.0
    syncope / Early / Incidence not known
    libido decrease / Delayed / Incidence not known
    rash (unspecified) / Early / Incidence not known
    skin irritation / Early / Incidence not known
    pruritus / Rapid / Incidence not known
    flushing / Rapid / Incidence not known
    alopecia / Delayed / Incidence not known
    acne vulgaris / Delayed / Incidence not known
    musculoskeletal pain / Early / Incidence not known
    muscle cramps / Delayed / Incidence not known
    myalgia / Early / Incidence not known
    back pain / Delayed / Incidence not known
    tremor / Early / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Adenosine: (Moderate) Because the pharmacologic effects of beta-blockers include depression of AV nodal conduction and myocardial function, additive effects are possible when used in combination with adenosine. The risk of additive inhibition of AV conduction is symptomatic bradycardia with hypotension or advanced AV block; whereas additive negative inotropic effects could precipitate overt heart failure in some patients.
    Albiglutide: (Moderate) Beta-adrenergic blockade may prevent the appearance of certain premonitory signs and symptoms (pulse rate and pressure changes) of acute hypoglycemia. Other manifestations such as dizziness and sweating may not be significantly affected. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been associated with potentiation of insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Selective beta-blockers, such as atenolol or metoprololl, do not appear to potentiate insulin-induced hypoglycemia. Hypoglycemia has been reported in patients taking non-selective beta-blockers during fasting for preparation for surgery, after prolonged physical exertion and in patients with renal insufficiency. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Aldesleukin, IL-2: (Moderate) Beta blockers may potentiate the hypotension seen with aldesleukin, IL 2.
    Alemtuzumab: (Moderate) Alemtuzumab may cause hypotension. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients on antihypertensive agents.
    Alfentanil: (Moderate) Alfentanil may cause bradycardia. The risk of significant hypotension and/or bradycardia during therapy with alfentanil is increased in patients receiving beta-blockers.
    Alfuzosin: (Moderate) The manufacturer warns that the combination of alfuzosin with antihypertensive agents has the potential to cause hypotension in some patients. Alfuzosin (2.5 mg, immediate-release) potentiated the hypotensive effects of atenolol (100 mg) in eight healthy young male volunteers. The Cmax and AUC of alfuzosin was increased by 28% and 21%, respectively. Alfuzosin increased the Cmax and AUC of atenolol by 26% and 14%, respectively. Significant reductions in mean blood pressure and in mean heart rate were reported with the combination.
    Aliskiren; Amlodipine: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Alogliptin: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Alogliptin; Metformin: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus. (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no significant pharmacokinetic interactions between beta-blockers and antidiabetic agents have been observed, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Alogliptin; Pioglitazone: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Alpha-blockers: (Moderate) Orthostatic hypotension may be more likely if beta-blockers are coadministered with alpha-blockers.
    Alpha-glucosidase Inhibitors: (Moderate) Beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. the can prolong hypoglycemia by interfering with the mobilization of glycogen stores or can promote hyperglycemia. Also, beta-blockers can blunt some of the physiologic symptoms of hypoglycemia, such as tremors and tachycardia. Diabetic patients on beta-blockers should closely monitor their blood glucose.
    Alprostadil: (Minor) The concomitant use of systemic alprostadil injection and antihypertensive agents, such as beta-clockers, may cause additive hypotension. Caution is advised with this combination. Systemic drug interactions with the urethral suppository (MUSE) or alprostadil intracavernous injection are unlikely in most patients because low or undetectable amounts of the drug are found in the peripheral venous circulation following administration. In those men with significant corpora cavernosa venous leakage, hypotension might be more likely. Use caution with in-clinic dosing for erectile dysfunction (ED) and monitor for the effects on blood pressure. In addition, the presence of medications in the circulation that attenuate erectile function may influence the response to alprostadil. However, in clinical trials with alprostadil intracavernous injection, anti-hypertensive agents had no apparent effect on the safety and efficacy of alprostadil.
    Amifostine: (Major) Patients receiving beta-blockers should be closely monitored during amifostine infusions due to additive effects. Patients receiving amifostine at doses recommended for chemotherapy should have antihypertensive therapy interrupted 24 hours preceding administration of amifostine. If the antihypertensive cannot be stopped, patients should not receive amifostine.
    Amiodarone: (Major) Amiodarone prolongs AV nodal refractory period and decreases sinus node automaticity. Because beta-blockers have similar effects, concomitant administration of beta-blockers with amiodarone may cause additive electrophysiologic effects (slow sinus rate or worsen AV block), resulting in symptomatic bradycardia, sinus arrest, and atrioventricular block. This is particularly likely in patients with preexisting partial AV block or sinus node dysfunction. While combination amiodarone and beta-blockers should be used cautiously and with close monitoring, it should be noted that post-hoc analysis of amiodarone therapy in patients after acute myocardial infarction in two clinical trials revealed that amiodarone in addition to a beta-blocker significantly lowered the incidence of cardiac and arrhythmic death or resuscitated cardiac arrest when compared with amiodarone or beta-blocker therapy alone.
    Amlodipine: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Amlodipine; Atorvastatin: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Amlodipine; Benazepril: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Amlodipine; Olmesartan: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Amlodipine; Telmisartan: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Amlodipine; Valsartan: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Amobarbital: (Moderate) Although concurrent use of amobarbital with antihypertensive agents may lead to hypotension, barbiturates, as a class, can enhance the hepatic metabolism of beta-blockers that are significantly metabolized by the liver. Beta-blockers that may be affected include betaxolol, labetalol, metoprolol, pindolol, propranolol, and timolol. Clinicians should closely monitor patients blood pressure during times of coadministration.
    Amyl Nitrite: (Moderate) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as antihypertensive agents or other peripheral vasodilators. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with any beta-blockers.
    Antithyroid agents: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Apomorphine: (Moderate) Patients receiving apomorphine may experience orthostatic hypotension, hypotension, and/or syncope. Extreme caution should be exercised if apomorphine is used concurrently with antihypertensive agents.
    Apraclonidine: (Minor) Theoretically, additive blood pressure reductions could occur when apraclonidine is combined with antihypertensive agents.
    Aripiprazole: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents. It may be advisable to monitor blood pressure when these medications are coadministered.
    Articaine; Epinephrine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects.
    Asenapine: (Moderate) Secondary to alpha-blockade, asenapine can produce vasodilation that may result in additive effects during concurrent use of bisoprolol. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known; the bisoprolol dosage may need to be adjusted.
    Aspirin, ASA: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Aspirin, ASA; Carisoprodol: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Aspirin, ASA; Dipyridamole: (Major) Beta-blockers should generally be withheld before dipyridamole-stress testing. Monitor the heart rate carefully following the dipyridamole injection. (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Aspirin, ASA; Omeprazole: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Aspirin, ASA; Oxycodone: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Aspirin, ASA; Pravastatin: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Atazanavir: (Moderate) Atazanavir can prolong the PR interval. Coadministration with other agents that prolong the PR interval, like beta blockers, may result in elevated risk of conduction disturbances and atrioventricular block.
    Atazanavir; Cobicistat: (Moderate) Atazanavir can prolong the PR interval. Coadministration with other agents that prolong the PR interval, like beta blockers, may result in elevated risk of conduction disturbances and atrioventricular block.
    Azelaic Acid; Copper; Folic Acid; Nicotinamide; Pyridoxine; Zinc: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
    Baclofen: (Moderate) Baclofen has been associated with hypotension. Concurrent use with baclofen and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Beta-agonists: (Moderate) Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patients 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. 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.
    Bismuth Subsalicylate: (Moderate) Concurrent use of beta-blockers with bismuth subsalicylate and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Concurrent use of beta-blockers with bismuth subsalicylate and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Bosentan: (Moderate) Although no specific interactions have been documented, bosentan has vasodilatory effects and may contribute additive hypotensive effects when given with beta-blockers.
    Brexpiprazole: (Moderate) Due to brexpiprazole's antagonism at alpha 1-adrenergic receptors, the drug may enhance the hypotensive effects of alpha-blockers and other antihypertensive agents.
    Bromocriptine: (Minor) Bromocriptine has only minimal affinity for adrenergic receptors; however, hypotension can occur during bromocriptine administration. Orthostatic hypotension occurs in 6% of acromegaly patients receiving the drug. Hypotension occurred frequently (approximately 30%) in postpartum studies, which in rare cases approached a decline in supine pressure of almost 60 mmHg. It is unknown if bromocriptine is the exact cause of this effect. However, the drug should be used cautiously with other medications known to lower blood pressure such as antihypertensive agents. Monitoring of blood pressure should be considered, especially during the initial weeks of concomitant therapy.
    Bupivacaine Liposomal: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of bupivacaine and antihypertensive agents. Peripheral vasodilation may occur after use of bupivacaine. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Blood concentrations of local anesthetics achieved after therapeutic doses are associated with minimal change in peripheral vascular resistance. Higher blood concentrations of local anesthetics may occur due to inadvertent intravascular administration or repeated doses.
    Bupivacaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of bupivacaine and antihypertensive agents. Peripheral vasodilation may occur after use of bupivacaine. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Blood concentrations of local anesthetics achieved after therapeutic doses are associated with minimal change in peripheral vascular resistance. Higher blood concentrations of local anesthetics may occur due to inadvertent intravascular administration or repeated doses.
    Bupivacaine; Lidocaine: (Major) Drugs such as beta-blockers that decrease cardiac output reduce hepatic blood flow and thereby decrease lidocaine hepatic clearance. Also, opposing effects on conduction exist between lidocaine and beta-blockers while their effects to decrease automaticity may be additive. Propranolol has been shown to decrease lidocaine clearance and symptoms of lidocaine toxicity have been seen as a result of this interaction. This interaction is possible with other beta-blocking agents since most decrease hepatic blood flow. Monitoring of lidocaine concentrations is recommended during concomitant therapy with beta-blockers. (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of bupivacaine and antihypertensive agents. Peripheral vasodilation may occur after use of bupivacaine. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Blood concentrations of local anesthetics achieved after therapeutic doses are associated with minimal change in peripheral vascular resistance. Higher blood concentrations of local anesthetics may occur due to inadvertent intravascular administration or repeated doses.
    Cabergoline: (Major) Because of its potential to cause coronary vasospasm, ergot alkaloids could theoretically antagonize the therapeutic effects of beta-blockers.
    Caffeine; Ergotamine: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Canagliflozin: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Canagliflozin is a substrate of drug transporter P-glycoprotein (P-gp). Carvedilol is a P-gp inhibitor and may theoretically increase concentrations of canagliflozin. Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Canagliflozin; Metformin: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Canagliflozin is a substrate of drug transporter P-glycoprotein (P-gp). Carvedilol is a P-gp inhibitor and may theoretically increase concentrations of canagliflozin. Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus. (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no significant pharmacokinetic interactions between beta-blockers and antidiabetic agents have been observed, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Carbidopa; Levodopa: (Moderate) Concomitant use of beta-blockers with levodopa can result in additive hypotensive effects.
    Carbidopa; Levodopa; Entacapone: (Moderate) Concomitant use of beta-blockers with levodopa can result in additive hypotensive effects.
    Cariprazine: (Moderate) Orthostatic vital signs should be monitored in patients who are at risk for hypotension, such as those receiving cariprazine in combination with antihypertensive agents. Atypical antipsychotics may cause orthostatic hypotension and syncope, most commonly during treatment initiation and dosage increases. Patients should be informed about measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning, or rising slowly from a seated position. Consider a cariprazine dose reduction if hypotension occurs.
    Cevimeline: (Moderate) Cevimeline may alter cardiac conduction and/or heart rate. Conduction disturbances are possible with concurrent use of beta-blockers and cevimeline.
    Chloroprocaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Chlorthalidone; Clonidine: (Major) Monitor heart rate in patients receiving concomitant clonidine and agents known to affect sinus node function or AV nodal conduction (e.g., beta-blockers). Severe bradycardia resulting in hospitalization and pacemaker insertion has been reported during combination therapy with clonidine and other sympatholytic agents. Concomitant use of clonidine with beta-blockers can also cause additive hypotension. Beta-blockers should not be substituted for clonidine when modifications are made in a patient's antihypertensive regimen because beta-blocker administration during clonidine withdrawal can augment clonidine withdrawal, which may lead to a hypertensive crisis. If a beta-blocker is to be substituted for clonidine, clonidine should be gradually tapered and the beta-blocker should be gradually increased over several days to avoid the possibility of rebound hypertension; administration of beta-blockers during withdrawal of clonidine can precipitate severe increases in blood pressure as a result of unopposed alpha stimulation.
    Choline Salicylate; Magnesium Salicylate: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Clevidipine: (Moderate) Calcium-channel blockers, like clevidipine, and beta-blockers frequently are used together with no adverse reactions. Patients should be monitored carefully, however, for excessive bradycardia, cardiac conduction abnormalities, or hypotension if these drugs are given together.
    Clonidine: (Major) Monitor heart rate in patients receiving concomitant clonidine and agents known to affect sinus node function or AV nodal conduction (e.g., beta-blockers). Severe bradycardia resulting in hospitalization and pacemaker insertion has been reported during combination therapy with clonidine and other sympatholytic agents. Concomitant use of clonidine with beta-blockers can also cause additive hypotension. Beta-blockers should not be substituted for clonidine when modifications are made in a patient's antihypertensive regimen because beta-blocker administration during clonidine withdrawal can augment clonidine withdrawal, which may lead to a hypertensive crisis. If a beta-blocker is to be substituted for clonidine, clonidine should be gradually tapered and the beta-blocker should be gradually increased over several days to avoid the possibility of rebound hypertension; administration of beta-blockers during withdrawal of clonidine can precipitate severe increases in blood pressure as a result of unopposed alpha stimulation.
    Clozapine: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Cod Liver Oil: (Moderate) Fish oil supplements may cause mild, dose-dependent reductions in systolic or diastolic blood pressure in untreated hypertensive patients. Relatively high doses of fish oil are required to produce any blood pressure lowering effect. Additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents. (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Co-Enzyme Q10, Ubiquinone: (Moderate) Co-enzyme Q10, ubiquinone (CoQ10) may lower blood pressure. CoQ10 use in combination with antihypertensive agents may lead to additional reductions in blood pressure in some individuals. Patients who choose to take CoQ10 concurrently with antihypertensive medications should receive periodic blood pressure monitoring. Patients should be advised to inform their prescriber of their use of CoQ10.
    Conivaptan: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Crizotinib: (Major) Bradycardia has been reported in patients treated with crizotinib, which may be exacerbated when crizotinib is administered concomitantly with agents known to cause bradycardia, such as beta-blockers. This combination should be avoided if possible. In addition, concomitant use of crizotinib and carvedilol may result in altered concentrations of either drug. Crizotinib is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while carvedilol is a CYP3A4 inhibitor and P-gp inhibitor and substrate.
    Dapagliflozin: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Dapagliflozin; Metformin: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus. (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no significant pharmacokinetic interactions between beta-blockers and antidiabetic agents have been observed, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Dapagliflozin; Saxagliptin: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent. (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Cardiac and neurologic events have been reported when ritonavir was concurrently administered with beta-blockers.
    Desflurane: (Moderate) Concurrent use of beta-blockers with desflurane may result in exaggerated cardiovascular effects (e.g., hypotension and negative inotropic effects). Beta-blockers may be continued during general anesthesia as long as the patient is monitored for cardiac depressant and hypotensive effects. Withdrawal of a beta-blocker perioperatively may be detrimental to the patient's clinical status and is not recommended. Caution is advised if these drugs are administered together.
    Desiccated Thyroid: (Minor) Because thyroid hormones cause cardiac stimulation including increased heart rate and increased contractility, the effects of beta-blockers may be reduced by thyroid hormones. The reduction of effects may be especially evident when a patient goes from a hypothyroid to a euthyroid state or when excessive amounts of thyroid hormone is given to the patient.
    Dexmedetomidine: (Major) In general, the concomitant administration of dexmedetomidine with antihypertensive agents could lead to additive hypotensive effects. Dexmedetomidine can produce bradycardia or AV block and should be used cautiously in patients who are receiving antihypertensive drugs that lower the heart rate such as beta-blockers.
    Dextromethorphan; Quinidine: (Major) Quinidine may have additive effects (e.g., reduced heart rate, hypotension) on cardiovascular parameters when used together with beta-blockers, like pindolol. In general, patients receiving combined therapy should be monitored for potential hypotension, orthostasis, bradycardia and/or AV block and heart failure, Reduce the beta-blocker dosage if necessary.
    Diazoxide: (Moderate) Additive hypotensive effects can occur with the concomitant administration of diazoxide with other antihypertensive agent. This interaction can be therapeutically advantageous, but dosages must be adjusted accordingly. The manufacturer advises that IV diazoxide should not be administered to patients within 6 hours of receiving beta-blockers.
    Digoxin: (Moderate) Because the pharmacologic effects of bisoprolol include depression of AV nodal conduction and myocardial function, additive effects are possible when used in combination with cardiac glycosides, especially in patients with pre-existing left ventricular dysfunction. The risk of additive inhibition of AV conduction is symptomatic bradycardia with hypotension or advanced AV block; whereas additive negative inotropic effects could precipitate overt heart failure in some patients. Despite potential for interactions, digoxin sometimes is intentionally used in combination with a beta-blocker to further reduce conduction through the AV node. Nevertheless, these combinations should be used cautiously, and therapy dosages may need adjustment in some patients.
    Dihydroergotamine: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Diltiazem: (Moderate) The combination of diltiazem and a beta-blocker, like bisoprolol, is usually well tolerated; the combination is often used for their combined therapeutic benefits to reduce angina and improve exercise tolerance. However, because beta-blockers and diltiazem are negative inotropes and chronotropes, the combination of beta-blockers and diltiazem may cause heart failure, excessive bradycardia, hypotension, cardiac conduction abnormalities, or heart block.
    Dipyridamole: (Major) Beta-blockers should generally be withheld before dipyridamole-stress testing. Monitor the heart rate carefully following the dipyridamole injection.
    Disopyramide: (Major) Disopyramide and beta-blockers, like bisoprolol, have been used together for the treatment of ventricular arrhythmias; however, this combination should be used with caution due to the potential for additive AV blocking effects. In general, patients receiving combined therapy with disopyramide and beta-blockers should be monitored for potential bradycardia, AV block, and/or hypotension.
    Donepezil: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Donepezil; Memantine: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Doxazosin: (Moderate) Orthostatic hypotension may be more likely if beta-blockers are coadministered with alpha-blockers.
    Dronedarone: (Major) In dronedarone clinical trials, bradycardia was seen more frequently in patients also receiving beta blockers. If coadministration of dronedarone and a beta blocker is unavoidable, administer a low dose of the beta blocker initially and increase the dosage only after ECG verification of tolerability. Concomitant administration may decreased AV and sinus node conduction. Furthermore, dronedarone is an inhibitor of CYP2D6, and some beta blockers are substrates for CYP2D6 (e.g., metoprolol, propranolol, nebivolol, carvedilol). Coadministration of dronedarone with a single dose of propranolol and multiple doses of metoprolol increased propranolol and metoprolol exposure by 1.3- and 1.6-fold, respectively.
    Dulaglutide: (Moderate) Beta-adrenergic blockade may prevent the appearance of certain premonitory signs and symptoms (pulse rate and pressure changes) of acute hypoglycemia. Other manifestations such as dizziness and sweating may not be significantly affected. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been associated with potentiation of insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Selective beta-blockers, such as atenolol or metoprololl, do not appear to potentiate insulin-induced hypoglycemia. Hypoglycemia has been reported in patients taking non-selective beta-blockers during fasting for preparation for surgery, after prolonged physical exertion and in patients with renal insufficiency. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Duloxetine: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of bisoprolol and duloxetine may increase the risk of hypotension. It is advisable to monitor blood pressure if the combination is necessary.
    Dutasteride; Tamsulosin: (Minor) Tamsulosin did not potentiate the hypotensive effects of atenolol. However, since the symptoms of orthostasis are reported more frequently in tamsulosin-treated vs. placebo patients, there is a potential risk of enhanced hypotensive effects when co-administered with antihypertensive agents
    Empagliflozin: (Moderate) Pharmacodynamic interactions are possible between beta-blockers and antidiabetic agents. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years.Since insulin secretion is mediated via beta2-receptors, beta-blockers, particularly nonselective agents, can directly antagonize the major beneficial effect of sulfonylureas. The ability to decrease tissue sensitivity to insulin interferes with one of the therapeutic effects of metformin. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Empagliflozin; Linagliptin: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents, such as linagliptin. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus. (Moderate) Pharmacodynamic interactions are possible between beta-blockers and antidiabetic agents. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years.Since insulin secretion is mediated via beta2-receptors, beta-blockers, particularly nonselective agents, can directly antagonize the major beneficial effect of sulfonylureas. The ability to decrease tissue sensitivity to insulin interferes with one of the therapeutic effects of metformin. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Empagliflozin; Metformin: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no significant pharmacokinetic interactions between beta-blockers and antidiabetic agents have been observed, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus. (Moderate) Pharmacodynamic interactions are possible between beta-blockers and antidiabetic agents. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years.Since insulin secretion is mediated via beta2-receptors, beta-blockers, particularly nonselective agents, can directly antagonize the major beneficial effect of sulfonylureas. The ability to decrease tissue sensitivity to insulin interferes with one of the therapeutic effects of metformin. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Enalapril; Felodipine: (Moderate) Coadministration of felodipine and bisoprolol can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Encainide: (Major) Pharmacologically, beta-blockers, like bisoprolol, cause AV nodal conduction depression and additive effects are possible when used in combination with encainide. When used together, AV block can occur. Patients should be monitored closely and the dose should be adjusted according to clinical response.
    Enflurane: (Major) General anesthetics can potentiate the antihypertensive effects of beta-blockers and can produce prolonged hypotension. Beta-blockers may be continued during general anesthesia as long as the patient is monitored for cardiac depressant and hypotensive effects.
    Epoprostenol: (Moderate) Epoprostenol can have additive effects when administered with other antihypertensive agents, including beta-blockers. These effects can be used to therapeutic advantage, but dosage adjustments may be necessary.
    Ergonovine: (Major) Whenever possible, concomitant use of beta-blockers and ergot alkaloids should be avoided, since propranolol has been reported to potentiate the vasoconstrictive action of ergotamine. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergot alkaloids are coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Ergotamine: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Estradiol Cypionate; Medroxyprogesterone: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Estradiol: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Etomidate: (Major) General anesthetics can potentiate the antihypertensive effects of beta-blockers and can produce prolonged hypotension. Beta-blockers may be continued during general anesthesia as long as the patient is monitored for cardiac depressant and hypotensive effects.
    Exenatide: (Moderate) Beta-adrenergic blockade may prevent the appearance of certain premonitory signs and symptoms (pulse rate and pressure changes) of acute hypoglycemia. Other manifestations such as dizziness and sweating may not be significantly affected. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been associated with potentiation of insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Selective beta-blockers, such as atenolol or metoprololl, do not appear to potentiate insulin-induced hypoglycemia. Hypoglycemia has been reported in patients taking non-selective beta-blockers during fasting for preparation for surgery, after prolonged physical exertion and in patients with renal insufficiency. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Felodipine: (Moderate) Coadministration of felodipine and bisoprolol can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Fentanyl: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving beta-blockers. In addition, increased concentrations of fentanyl may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and fentanyl is a P-gp substrate. If these drugs are coadministered, the fentanyl dose may need to be very conservative, and the patient should be carefully monitored for an extended time period for signs of too much fentanyl such as oversedation, respiratory depression, and hypotension.
    Fingolimod: (Major) If possible, do not start fingolimod in a patient who is taking a drug that slows the heart rate or atrioventricular conduction such as beta-blockers. Use of these drugs during fingolimod initiation may be associated with severe bradycardia or heart block. Seek advice from the prescribing physician regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating fingolimod. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients who cannot stop taking drugs that slow the heart rate or atrioventricular conduction. Experience with fingolimod in patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular conduction is limited.
    Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Moderate) Co-enzyme Q10, ubiquinone (CoQ10) may lower blood pressure. CoQ10 use in combination with antihypertensive agents may lead to additional reductions in blood pressure in some individuals. Patients who choose to take CoQ10 concurrently with antihypertensive medications should receive periodic blood pressure monitoring. Patients should be advised to inform their prescriber of their use of CoQ10. (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Flecainide: (Major) Pharmacologically, beta-blockers, like bisoprolol, cause AV nodal conduction depression and additive effects are possible when used in combination with flecainide. When used together, AV block can occur. During flecainide clinical trials, increased adverse events have not been reported in patients receiving combination therapy with beta-blockers and flecainide. However, patients should be monitored closely and the dose should be adjusted according to clinical response.
    Fluorescein: (Moderate) Patients on beta-blockers are at an increased risk of adverse reaction when administered fluorescein injection. It is thought that beta-blockers may worsen anaphylaxis severity by exacerbating bronchospasm or by increasing the release of anaphylaxis mediators; alternately, beta-blocker therapy may make the patient more pharmacodynamically resistance to epinephrine rescue treatment.
    Fluoxetine; Olanzapine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Food: (Major) Avoid administering marijuana and beta-blockers together as concurrent use may result in decreased beta-blocker efficacy. Marijuana is known to produce significant increases in heart rate and cardiac output lasting for 2-3 hours. Further, rare case reports of myocardial infarction and cardiac arrhythmias have been associated with marijuana use. These marijuana-induced cardiovascular effects may be detrimental to patients requiring treatment with beta-blockers; thus, coadministration of beta-blockers and marijuana should be avoided.
    Fospropofol: (Major) General anesthetics can potentiate the antihypertensive effects of beta-blockers and can produce prolonged hypotension. Beta-blockers may be continued during general anesthesia as long as the patient is monitored for cardiac depressant and hypotensive effects.
    Galantamine: (Moderate) The increase in vagal tone induced by cholinesterase inhibitors, such as galantamine, may produce bradycardia or syncope. The vagotonic effect of galantamine may theoretically be increased when given with beta-blockers.
    General anesthetics: (Major) General anesthetics can potentiate the antihypertensive effects of beta-blockers and can produce prolonged hypotension. Beta-blockers may be continued during general anesthesia as long as the patient is monitored for cardiac depressant and hypotensive effects.
    Ginger, Zingiber officinale: (Minor) In vitro studies have demonstrated the positive inotropic effects of certain gingerol constituents of ginger; but it is unclear if whole ginger root exhibits these effects clinically in humans. It is theoretically possible that excessive doses of ginger could affect the action of inotropes; however, no clinical data are available.
    Glipizide; Metformin: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no significant pharmacokinetic interactions between beta-blockers and antidiabetic agents have been observed, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Glucagon: (Minor) Because beta-blockers blunt sympathomimetic-mediated hepatic gluconeogenesis, beta-blockers can inhibit the hyperglycemic actions of glucagon. In addition, intravenous administration of glucagon has been shown to have positive inotropic and chronotropic effects. A transient increase in both blood pressure and pulse rate may occur following the administration of glucagon, especially in patients taking beta-blockers. Clinicians should be aware of these opposing pharmacologic actions of glucagon and beta-blockers.
    Glyburide; Metformin: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no significant pharmacokinetic interactions between beta-blockers and antidiabetic agents have been observed, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Guanabenz: (Moderate) Guanabenz can have additive effects when administered with other antihypertensive agents, including beta-blockers. These effects can be used to therapeutic advantage, but dosage adjustments may be necessary.
    Guanfacine: (Moderate) Guanfacine can have additive effects when administered with other antihypertensive agents, including beta-blockers. These effects can be used to therapeutic advantage, but dosage adjustments may be necessary.
    Haloperidol: (Moderate) Haloperidol should be used cautiously with bisoprolol due to the possibility of additive hypotension.
    Halothane: (Major) General anesthetics can potentiate the antihypertensive effects of beta-blockers and can produce prolonged hypotension. Beta-blockers may be continued during general anesthesia as long as the patient is monitored for cardiac depressant and hypotensive effects.
    Hawthorn, Crataegus laevigata: (Moderate) Hawthorn, Crataegus laevigata (also known as C. oxyacantha) may potentially interact with antihypertensive, heart failure, or arrhythmia medications such as the beta-blockers. Following hawthorn administration, the cardiac action potential duration is increased and the refractory period is prolonged. Hawthorn may also lower peripheral vascular resistance. Patients with hypertension or heart failure should be advised to only use hawthorn with their prescribed medications after discussion with their prescriber. Patients who choose to take hawthorn should receive periodic blood pressure and heart rate monitoring.
    Hydralazine; Isosorbide Dinitrate, ISDN: (Moderate) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as antihypertensive agents or other peripheral vasodilators. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with any beta-blockers.
    Icosapent ethyl: (Moderate) Beta-blockers may exacerbate hypertriglyceridemia and should be discontinued or changed to alternate therapy, if possible, prior to initiation of icosapent ethyl.
    Iloperidone: (Moderate) Secondary to alpha-blockade, iloperidone can produce vasodilation that may result in additive effects during concurrent use with antihypertensive agents. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use of iloperidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
    Iloprost: (Moderate) Additive reductions in blood pressure may occur when inhaled iloprost is administered to patients receiving other antihypertensive agents.
    Incretin Mimetics: (Moderate) Beta-adrenergic blockade may prevent the appearance of certain premonitory signs and symptoms (pulse rate and pressure changes) of acute hypoglycemia. Other manifestations such as dizziness and sweating may not be significantly affected. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been associated with potentiation of insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Selective beta-blockers, such as atenolol or metoprololl, do not appear to potentiate insulin-induced hypoglycemia. Hypoglycemia has been reported in patients taking non-selective beta-blockers during fasting for preparation for surgery, after prolonged physical exertion and in patients with renal insufficiency. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Insulin Degludec; Liraglutide: (Moderate) Beta-adrenergic blockade may prevent the appearance of certain premonitory signs and symptoms (pulse rate and pressure changes) of acute hypoglycemia. Other manifestations such as dizziness and sweating may not be significantly affected. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been associated with potentiation of insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Selective beta-blockers, such as atenolol or metoprololl, do not appear to potentiate insulin-induced hypoglycemia. Hypoglycemia has been reported in patients taking non-selective beta-blockers during fasting for preparation for surgery, after prolonged physical exertion and in patients with renal insufficiency. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Insulin Glargine; Lixisenatide: (Moderate) Beta-adrenergic blockade may prevent the appearance of certain premonitory signs and symptoms (pulse rate and pressure changes) of acute hypoglycemia. Other manifestations such as dizziness and sweating may not be significantly affected. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been associated with potentiation of insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Selective beta-blockers, such as atenolol or metoprololl, do not appear to potentiate insulin-induced hypoglycemia. Hypoglycemia has been reported in patients taking non-selective beta-blockers during fasting for preparation for surgery, after prolonged physical exertion and in patients with renal insufficiency. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Insulins: (Moderate) Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and insulin concomitantly should be closely monitored for an inappropriate response. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Intravenous Lipid Emulsions: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Isocarboxazid: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with beta-blockers. Limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers. Although the sinus bradycardia observed was not severe, until more data are available, clinicians should use MAOIs cautiously in patients receiving beta-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Isoflurane: (Major) General anesthetics can potentiate the antihypertensive effects of beta-blockers and can produce prolonged hypotension. Beta-blockers may be continued during general anesthesia as long as the patient is monitored for cardiac depressant and hypotensive effects.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Rifamycins induce hepatic isoenzymes CYP3A4 and CYP2C8/9. Drugs metabolized by CYP3A4 and CYP2C8/9, including bisoprolol, may require dosage adjustments when administered concurrently with rifamycins.
    Isoniazid, INH; Rifampin: (Moderate) Rifamycins induce hepatic isoenzymes CYP3A4 and CYP2C8/9. Drugs metabolized by CYP3A4 and CYP2C8/9, including bisoprolol, may require dosage adjustments when administered concurrently with rifamycins.
    Isosorbide Dinitrate, ISDN: (Moderate) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as antihypertensive agents or other peripheral vasodilators. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with any beta-blockers.
    Isosorbide Mononitrate: (Moderate) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as antihypertensive agents or other peripheral vasodilators. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with any beta-blockers.
    Isradipine: (Moderate) Although concomitant therapy with beta-blockers and isradipine is generally well tolerated and can even be beneficial in some cases, coadministration of these agents can induce excessive bradycardia or hypotension. Isradipine when used in combination with beta-blockers, especially in heart failure patients, can result in additive negative inotropic effects. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly when isradipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of isradipine therapy can minimize or eliminate this potential interaction. Patients should be monitored carefully, however, for excessive bradycardia, cardiac conduction abnormalities, or hypotension when these drugs are given together. In general, these reactions are more likely to occur with other non-dihydropyridine calcium channel blockers than with isradipine.
    Ivabradine: (Moderate) Monitor heart rate if ivabradine is coadministered with other negative chronotropes like beta-blockers. Most patients receiving ivabradine will receive concomitant beta-blocker therapy. Coadministration of drugs that slow heart rate increases the risk for bradycardia.
    Ketamine: (Major) General anesthetics can potentiate the antihypertensive effects of beta-blockers and can produce prolonged hypotension. Beta-blockers may be continued during general anesthesia as long as the patient is monitored for cardiac depressant and hypotensive effects.
    Lacosamide: (Moderate) Lacosamide causes PR interval prolongation in some patients. Caution is advised during coadministration of lacosamide with other drugs that cause PR prolongation, such as beta-blockers, since further PR prolongation is possible. If concurrent use is necessary, an ECG is recommended prior to initiation of lacosamide and after the drug is titrated to the maintenence dose. Patients receiving intravenous lacosamide should be closely monitored due to the potential for profound bradycardia and AV block during coadministration.
    Lanreotide: (Moderate) Concomitant administration of bradycardia-inducing drugs (e.g., beta-adrenergic blockers) may have an additive effect on the reduction of heart rate associated with lanreotide. Adjust the beta-blocker dose if necessary.
    Levobupivacaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Levodopa: (Moderate) Concomitant use of beta-blockers with levodopa can result in additive hypotensive effects.
    Levomilnacipran: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of beta-blockers may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Levothyroxine: (Minor) Because thyroid hormones cause cardiac stimulation including increased heart rate and increased contractility, the effects of beta-blockers may be reduced by thyroid hormones. The reduction of effects may be especially evident when a patient goes from a hypothyroid to a euthyroid state or when excessive amounts of thyroid hormone is given to the patient.
    Lidocaine: (Major) Drugs such as beta-blockers that decrease cardiac output reduce hepatic blood flow and thereby decrease lidocaine hepatic clearance. Also, opposing effects on conduction exist between lidocaine and beta-blockers while their effects to decrease automaticity may be additive. Propranolol has been shown to decrease lidocaine clearance and symptoms of lidocaine toxicity have been seen as a result of this interaction. This interaction is possible with other beta-blocking agents since most decrease hepatic blood flow. Monitoring of lidocaine concentrations is recommended during concomitant therapy with beta-blockers.
    Linagliptin: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents, such as linagliptin. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Linagliptin; Metformin: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents, such as linagliptin. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus. (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no significant pharmacokinetic interactions between beta-blockers and antidiabetic agents have been observed, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Linezolid: (Moderate) Linezolid is an antibiotic that is also a reversible, non-selective MAO inhibitor. Bradycardia may be worsened when MAO-inhibitors are co-administered to patients receiving beta-blockers. Use linezolid cautiously in patients receiving beta-blockers.
    Liothyronine: (Minor) Because thyroid hormones cause cardiac stimulation including increased heart rate and increased contractility, the effects of beta-blockers may be reduced by thyroid hormones. The reduction of effects may be especially evident when a patient goes from a hypothyroid to a euthyroid state or when excessive amounts of thyroid hormone is given to the patient.
    Liotrix: (Minor) Because thyroid hormones cause cardiac stimulation including increased heart rate and increased contractility, the effects of beta-blockers may be reduced by thyroid hormones. The reduction of effects may be especially evident when a patient goes from a hypothyroid to a euthyroid state or when excessive amounts of thyroid hormone is given to the patient.
    Liraglutide: (Moderate) Beta-adrenergic blockade may prevent the appearance of certain premonitory signs and symptoms (pulse rate and pressure changes) of acute hypoglycemia. Other manifestations such as dizziness and sweating may not be significantly affected. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been associated with potentiation of insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Selective beta-blockers, such as atenolol or metoprololl, do not appear to potentiate insulin-induced hypoglycemia. Hypoglycemia has been reported in patients taking non-selective beta-blockers during fasting for preparation for surgery, after prolonged physical exertion and in patients with renal insufficiency. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Lithium: (Moderate) Beta-blockers have been used to treat lithium-induced tremor. Because tremor may be a sign of lithium toxicity and may be masked by the coadministration of beta-blockers, patients should be monitored for other clinical signs of lithium toxicity if these medications are taken concurrently. Other clinical signs of toxicity include: anorexia; visual impairment; drowsiness; muscular weakness; fasciculations or myoclonia; ataxia; dysarthria or slurred speech; stupor or coma; confusion or impaired cognition; seizures; and arrhythmias. Limited data suggest that using propranolol, even in low doses, with lithium can lead to bradycardia and syncope. In addition, lithium renal clearance has been shown to be lower when propranolol was coadministered. It is not clear if these effects are unique for propranolol or hold true for all beta-blockers. Until more data are known, clinicians should use beta-blockers with caution in patients receiving lithium.
    Lixisenatide: (Moderate) Beta-adrenergic blockade may prevent the appearance of certain premonitory signs and symptoms (pulse rate and pressure changes) of acute hypoglycemia. Other manifestations such as dizziness and sweating may not be significantly affected. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been associated with potentiation of insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Selective beta-blockers, such as atenolol or metoprololl, do not appear to potentiate insulin-induced hypoglycemia. Hypoglycemia has been reported in patients taking non-selective beta-blockers during fasting for preparation for surgery, after prolonged physical exertion and in patients with renal insufficiency. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Lopinavir; Ritonavir: (Moderate) Cardiac and neurologic events have been reported when ritonavir was concurrently administered with beta-blockers.
    Lovastatin; Niacin: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
    Lurasidone: (Moderate) Due to the antagonism of lurasidone at alpha-1 adrenergic receptors, the drug may enhance the hypotensive effects of alpha-blockers and other antihypertensive agents. If concurrent use of lurasidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
    Magnesium Salicylate: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Mefloquine: (Major) Concurrent use of mefloquine and beta blockers can result in ECG abnormalities or cardiac arrest.
    Mepivacaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Peripheral vasodilation may occur after use of mepivacaine. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Blood concentrations of local anesthetics achieved after therapeutic doses are associated with minimal change in peripheral vascular resistance. Higher blood concentrations of local anesthetics may occur due to inadvertent intravascular administration or repeated doses.
    Mepivacaine; Levonordefrin: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Peripheral vasodilation may occur after use of mepivacaine. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Blood concentrations of local anesthetics achieved after therapeutic doses are associated with minimal change in peripheral vascular resistance. Higher blood concentrations of local anesthetics may occur due to inadvertent intravascular administration or repeated doses.
    Mestranol; Norethindrone: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients; monitor patients receiving concurrent therapy to confirm that the desired antihypertensive effect is being obtained.
    Metformin: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no significant pharmacokinetic interactions between beta-blockers and antidiabetic agents have been observed, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Metformin; Pioglitazone: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no significant pharmacokinetic interactions between beta-blockers and antidiabetic agents have been observed, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Metformin; Repaglinide: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no significant pharmacokinetic interactions between beta-blockers and antidiabetic agents have been observed, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus. (Moderate) Beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. They can prolong hypoglycemia by interfering with the mobilization of glycogen stores or can promote hyperglycemia. Also, beta-blockers can blunt some of the physiologic symptoms of hypoglycemia, such as tremors and tachycardia. Diabetic patients on beta-blockers should closely monitor their blood glucose.
    Metformin; Rosiglitazone: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no significant pharmacokinetic interactions between beta-blockers and antidiabetic agents have been observed, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Metformin; Saxagliptin: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent. (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no significant pharmacokinetic interactions between beta-blockers and antidiabetic agents have been observed, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Metformin; Sitagliptin: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent. (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no significant pharmacokinetic interactions between beta-blockers and antidiabetic agents have been observed, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Methohexital: (Major) General anesthetics can potentiate the antihypertensive effects of beta-blockers and can produce prolonged hypotension.
    Methylergonovine: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Methysergide: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Milnacipran: (Moderate) Milnacipran has been associated with an increase in blood pressure. The effectiveness of antihypertensive agents may be diminished during concurrent use of milnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Milrinone: (Moderate) Concurrent administration of antihypertensive agents could lead to additive hypotension when administered with milrinone. Titrate milrinone dosage according to hemodynamic response.
    Nateglinide: (Moderate) Beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. They can prolong hypoglycemia by interfering with the mobilization of glycogen stores or can promote hyperglycemia. Also, beta-blockers can blunt some of the physiologic symptoms of hypoglycemia, such as tremors and tachycardia. Diabetic patients on beta-blockers should closely monitor their blood glucose.
    Nefazodone: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Nesiritide, BNP: (Major) The potential for hypotension may be increased when coadministering nesiritide with antihypertensive agents.
    Niacin, Niacinamide: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
    Niacin; Simvastatin: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
    Nicardipine: (Moderate) Although concomitant therapy with nicardipine and bisoprolol generally is well tolerated and can even be beneficial in some cases (by inhibiting reflex tachycardia induced by nicardipine), bisoprolol can induce excessive bradycardia or hypotension. This combination also can cause additive negative inotropic effects. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nicardipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nicardipine therapy can minimize or eliminate this potential interaction. Patients should be monitored carefully, however, for excessive bradycardia, cardiac conduction abnormalities, or hypotension when these drugs are given together. In general, these reactions are more likely to occur with verapamil or diltiazem than with nicardipine.
    Nifedipine: (Moderate) In general, concomitant therapy of nifedipine with beta-blockers is well tolerated and can even be beneficial in some cases (i.e., inhibition of nifedipine-induced reflex tachycardia by beta-blockade). Negative inotropic and/or chronotropic effects can be additive when these drugs are used in combination. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nifedipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nifedipine therapy may minimize or eliminate this potential interaction. Hypotension and impaired cardiac performance can occur during coadministration of nifedipine with beta-blockers, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Monitor clinical response during coadministration; adjustment of nifedipine dosage may be needed during concurrent beta-blocker therapy.
    Nimodipine: (Moderate) Nimodipine, a selective calcium-channel blocker, can enhance the antihypertensive effects of beta-blockers. Although often used together, concurrent use of calcium-channel blockers and beta-blockers may result in additive hypotensive, negative inotropic, and/or bradycardic effects in some patients.
    Nisoldipine: (Moderate) Concurrent use of nisoldipine with bisoprolol can be beneficial (i.e., inhibition of vasodilation-induced reflex tachycardia by beta-blockade); however, the additive negative inotropic and/or chronotropic effects can cause adverse effects, especially in patients with compromised ventricular function or conduction defects (e.g., sinus bradycardia or AV block).
    Nitrates: (Moderate) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as antihypertensive agents or other peripheral vasodilators. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with any beta-blockers.
    Nitroglycerin: (Moderate) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as antihypertensive agents or other peripheral vasodilators. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with any beta-blockers.
    Nitroprusside: (Moderate) Additive hypotensive effects may occur when nitroprusside is used concomitantly with other antihypertensive agents. Dosages should be adjusted carefully, according to blood pressure.
    Non-Ionic Contrast Media: (Moderate) Some clinicians consider patients taking beta-blockers to be at increased risk for anaphylactoid reactions and administer prophylactic corticosteroids/antihistamines prior to the administration of radiopaque contrast agents.
    Nonsteroidal antiinflammatory drugs: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Octreotide: (Moderate) Dose adjustments in drugs such as beta-blockers and calcium-channel blockers which cause bradycardia and/or affect cardiac conduction may be necessary during octreotide therapy due to additive effects.
    Olanzapine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Cardiac and neurologic events have been reported when ritonavir was concurrently administered with beta-blockers.
    Oxymetazoline: (Major) The vasoconstricting actions of oxymetazoline, an alpha adrenergic agonist, may reduce the antihypertensive effects produced by beta-blockers. If these drugs are used together, closely monitor for changes in blood pressure.
    Paliperidone: (Moderate) Paliperidone may cause orthostatic hypotension and thus enhance the hypotensive effects of antihypertensive agents. Lower initial doses of paliperidone may be necessary in patients receiving antihypertensive agents concomitantly. In addition, altered concentrations of paliperidone and/or carvedilol may occur during coadministration. Carvedilol and paliperidone are both substrates and inhibitors of P-glycoprotein (P-gp). Use caution if concomitant use is necessary and monitor for increased side effects.
    Pasireotide: (Major) Pasireotide may cause a decrease in heart rate. Closely monitor patients who are also taking drugs associated with bradycardia such as beta-blockers. Dose adjustments of beta-blockers may be necessary.
    Pentoxifylline: (Moderate) Pentoxifylline has been used concurrently with antihypertensive drugs (beta blockers, diuretics) without observed problems. Small decreases in blood pressure have been observed in some patients treated with pentoxifylline; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensives. If indicated, dosage of the antihypertensive agents should be reduced.
    Perindopril; Amlodipine: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Phenelzine: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with beta-blockers. Limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers. Although the sinus bradycardia observed was not severe, until more data are available, clinicians should use MAOIs cautiously in patients receiving beta-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Phenoxybenzamine: (Moderate) Orthostatic hypotension may be more likely if beta-blockers are coadministered with alpha-blockers.
    Phentolamine: (Moderate) Orthostatic hypotension may be more likely if beta-blockers are coadministered with alpha-blockers.
    Pilocarpine: (Moderate) Systemically administered pilocarpine (e.g., when used for the treatment of xerostomia or xerophthalmia) should be administered with caution in patients taking beta-blockers because of the possibility of cardiac conduction disturbances. The risk of conduction disturbances with beta-blockers and ophthalmically administered pilocarpine is low.
    Pramlintide: (Moderate) Beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. They can prolong hypoglycemia by interfering with the mobilization of glycogen stores or can promote hyperglycemia. Also, beta-blockers can blunt some of the physiologic symptoms of hypoglycemia, such as tremors and tachycardia. Diabetic patients on beta-blockers should closely monitor their blood glucose.
    Prazosin: (Moderate) Orthostatic hypotension may be more likely if beta-blockers are coadministered with alpha-blockers.
    Prilocaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Prilocaine; Epinephrine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Procainamide: (Major) High or toxic concentrations of procainamide may prolong AV nodal conduction time or induce AV block; these effects could be additive with the pharmacologic actions of beta-blockers, like bisoprolol. In general, patients receiving combined therapy with procainamide and beta-blockers should be monitored for potential bradycardia, AV block, and/or hypotension.
    Procaine: (Minor) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Propafenone: (Major) Pharmacologically, beta-blockers, like bisoprolol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Patients should be monitored closely and the dose should be adjusted according to clinical response.
    Propofol: (Major) General anesthetics can potentiate the antihypertensive effects of beta-blockers and can produce prolonged hypotension. Beta-blockers may be continued during general anesthesia as long as the patient is monitored for cardiac depressant and hypotensive effects.
    Quinidine: (Major) Quinidine may have additive effects (e.g., reduced heart rate, hypotension) on cardiovascular parameters when used together with beta-blockers, like pindolol. In general, patients receiving combined therapy should be monitored for potential hypotension, orthostasis, bradycardia and/or AV block and heart failure, Reduce the beta-blocker dosage if necessary.
    Rasagiline: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with beta-blockers. Limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers. Although the sinus bradycardia observed was not severe, until more data are available, clinicians should use MAOIs cautiously in patients receiving beta-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Remifentanil: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with remifentanil may be increased in patients receiving beta-blockers or calcium-channel blockers due to additive hypotensive effects.
    Repaglinide: (Moderate) Beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. They can prolong hypoglycemia by interfering with the mobilization of glycogen stores or can promote hyperglycemia. Also, beta-blockers can blunt some of the physiologic symptoms of hypoglycemia, such as tremors and tachycardia. Diabetic patients on beta-blockers should closely monitor their blood glucose.
    Reserpine: (Moderate) Reserpine may have additive orthostatic hypotensive effects when used with beta-blockers due to catecholamine depletion. Beta-blockers may also interfere with reflex tachycardia, worsening the orthostasis. Patients treated concurrently with a beta-blocker and reserpine should be monitored closely for evidence of hypotension or marked bradycardia and associated symptoms (e.g., vertigo, syncope, postural hypotension).
    Rifabutin: (Moderate) Rifamycins induce hepatic isoenzymes CYP3A4 and CYP2C8/9. Drugs metabolized by CYP3A4 and CYP2C8/9, including bisoprolol, may require dosage adjustments when administered concurrently with rifamycins.
    Rifampin: (Moderate) Rifamycins induce hepatic isoenzymes CYP3A4 and CYP2C8/9. Drugs metabolized by CYP3A4 and CYP2C8/9, including bisoprolol, may require dosage adjustments when administered concurrently with rifamycins.
    Rifamycins: (Moderate) Rifamycins induce hepatic isoenzymes CYP3A4 and CYP2C8/9. Drugs metabolized by CYP3A4 and CYP2C8/9, including bisoprolol, may require dosage adjustments when administered concurrently with rifamycins.
    Rifapentine: (Moderate) Rifamycins induce hepatic isoenzymes CYP3A4 and CYP2C8/9. Drugs metabolized by CYP3A4 and CYP2C8/9, including bisoprolol, may require dosage adjustments when administered concurrently with rifamycins.
    Risperidone: (Moderate) Risperidone may induce orthostatic hypotension and thus enhance the hypotensive effects of bisoprolol. Lower initial doses or slower dose titration of risperidone may be necessary in patients receiving bisoprolol concomitantly.
    Ritonavir: (Moderate) Cardiac and neurologic events have been reported when ritonavir was concurrently administered with beta-blockers.
    Rivastigmine: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may theoretically be increased when given with other medications known to cause bradycardia such as beta-blockers.
    Ropivacaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Salsalate: (Moderate) Concurrent use of beta-blockers with salsalate and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Saxagliptin: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Selegiline: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with beta-blockers. Limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers. Although the sinus bradycardia observed was not severe, until more data are available, clinicians should use MAOIs cautiously in patients receiving beta-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Sevoflurane: (Major) General anesthetics can potentiate the antihypertensive effects of beta-blockers and can produce prolonged hypotension. Beta-blockers may be continued during general anesthesia as long as the patient is monitored for cardiac depressant and hypotensive effects.
    Silodosin: (Moderate) During clinical trials with silodosin, the incidence of dizziness and orthostatic hypotension was higher in patients receiving concomitant antihypertensive treatment. Thus, caution is advisable when silodosin is administered with antihypertensive agents. In addition, increased concentrations of silodosin may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and silodosin is a P-gp substrate.
    Simvastatin; Sitagliptin: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Sitagliptin: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Succinylcholine: (Moderate) Beta-blockers can enhance the neuromuscular blocking activity of succinylcholine.
    Sufentanil: (Moderate) The incidence and degree of bradycardia and hypotension during induction with sufentanil may be increased in patients receiving beta-blockers.
    Sulfonylureas: (Moderate) Beta-blockers can prolong hypoglycemia or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Pharmacokinetic interactions are also possible between individual drugs. Glyburide is a substrate of drug transporter P-glycoprotein (P-gp). Carvedilol is a P-gp inhibitor and may theoretically increase concentrations of glyburide. Patients should be monitored for changes in glycemic control.
    Sympathomimetics: (Major) Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Tacrine: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope in some patients. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Tamsulosin: (Minor) Tamsulosin did not potentiate the hypotensive effects of atenolol. However, since the symptoms of orthostasis are reported more frequently in tamsulosin-treated vs. placebo patients, there is a potential risk of enhanced hypotensive effects when co-administered with antihypertensive agents
    Tasimelteon: (Major) The efficacy of tasimelteon in treating circadian rhythm disruptions may be reduced in patients receiving beta-blockers. Because the circadian rhythm of melatonin is regulated by the sympathetic nervous system, administration of beta-blockers may result in a clinically relevant blockade of melatonin secretion.
    Terazosin: (Moderate) Orthostatic hypotension may be more likely if beta-blockers are coadministered with alpha-blockers.
    Tetrabenazine: (Moderate) Tetrabenazine may induce orthostatic hypotension and thus enhance the hypotensive effects of antihypertensive agents. Lower initial doses or slower dose titration of tetrabenazine may be necessary in patients receiving antihypertensive agents concomitantly.
    Tetracaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use caution with the concomitant use of tetracaine and antihypertensive agents.
    Thalidomide: (Moderate) Thalidomide and other agents that slow cardiac conduction such as beta-blockers should be used cautiously due to the potential for additive bradycardia.
    Thiazolidinediones: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response.
    Thiopental: (Moderate) General anesthetics can potentiate the antihypertensive effects of beta-blockers and can produce prolonged hypotension. Patients receiving beta-blockers before or during surgery involving thiopental should be monitored closely for signs of heart failure.
    Thiothixene: (Moderate) Thiothixene should be used cautiously in patients receiving antihypertensive agents. Additive hypotensive effects are possible.
    Thyroid hormones: (Minor) Because thyroid hormones cause cardiac stimulation including increased heart rate and increased contractility, the effects of beta-blockers may be reduced by thyroid hormones. The reduction of effects may be especially evident when a patient goes from a hypothyroid to a euthyroid state or when excessive amounts of thyroid hormone is given to the patient.
    Tizanidine: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Trandolapril; Verapamil: (Moderate) Oral calcium-channel blockers and beta-blockers like bisoprolol are used together for their therapeutic benefits to reduce angina and improve exercise tolerance. However, concomitant administration of beta-adrenergic blocking agents and verapamil can lead to significant AV nodal blockade. This can manifest as heart block, bradycardia, cardiac conduction abnormalities and/or prolonged PR interval. Congestive heart failure or severe hypotension also can occur. The combination of beta-blockers and verapamil should be avoided in patients with poor ventricular function due to increased negative inotropic effects.
    Tranylcypromine: (Severe) The use of hypotensive agents and tranylcypromine is contraindicated by the manufacturer of tranylcypromine because the effects of hypotensive agents may be markedly potentiated. In addition, limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers.
    Trazodone: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.
    Verapamil: (Moderate) Oral calcium-channel blockers and beta-blockers like bisoprolol are used together for their therapeutic benefits to reduce angina and improve exercise tolerance. However, concomitant administration of beta-adrenergic blocking agents and verapamil can lead to significant AV nodal blockade. This can manifest as heart block, bradycardia, cardiac conduction abnormalities and/or prolonged PR interval. Congestive heart failure or severe hypotension also can occur. The combination of beta-blockers and verapamil should be avoided in patients with poor ventricular function due to increased negative inotropic effects.
    Yohimbine: (Moderate) Yohimbine can increase blood pressure and therefore can antagonize the therapeutic action of antihypertensive agents. Use with particular caution in hypertensive patients with high or uncontrolled blood pressure.
    Ziprasidone: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.

    PREGNANCY AND LACTATION

    Pregnancy

    Bisoprolol is classified as pregnancy risk category C. There are no adequate and well-controlled studies in pregnant women. However, in rat studies, bisoprolol was fetotoxic (increased late resorptions) and maternotoxic (decreased food intake and body weight gain). When given to pregnant rabbits, bisoprolol was not teratogenic but was embryolethal at dosages of 12.5 mg/kg/day. Thus, bisoprolol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

    It is not known if bisoprolol is excreted in human milk. Small amounts (< 2% of a dose) of bisoprolol have been detected in the milk of lactating rats. Caution should be exercised when bisoprolol is administered to a woman who is breast-feeding. The American Academy of Pediatrics regards the following beta-blockers as usually compatible with breast feeding: labetalol, metoprolol, nadolol, propranolol, sotolol, and timolol; these agents may represent alternatives for some patients.

    MECHANISM OF ACTION

    Bisoprolol is a beta1-selective adrenoceptor blocking agent. Similar to metoprolol and atenolol, bisoprolol, in low doses, selectively blocks catecholamine stimulation of beta1-adrenergic receptors in the heart and vascular smooth muscle. The pharmacodynamic consequences of this activity include: reduction of resting and exercise heart rate (negative chronotropic effect) and, subsequently, cardiac output; reduction of both systolic and diastolic blood pressure at rest and with exercise; and possible reduction of reflex orthostatic hypotension. Electrophysiology studies have shown that bisoprolol increases sinus node recovery time, prolongs AV node refractory periods, and prolongs AV nodal conduction. With oral doses of >= 20 mg/day, bisoprolol also can competitively block beta2-adrenergic responses in the bronchial and vascular smooth muscles, potentially causing bronchospasm.

    PHARMACOKINETICS

    Bisoprolol is administered orally. About 30% of the drug is bound to serum proteins. Bisoprolol is equally eliminated by renal and non-renal pathways with about 50% of the dose appearing as unchanged drug in the urine and the remainder appearing as inactive metabolites. Less than 2% of a dose is excreted in the feces. Bisoprolol is not metabolized by cytochrome P450 2D6. The elimination half-life of bisoprolol is 9—12 hours.

    Oral Route

    Food does not affect the absorption of bisoprolol. Absolute bioavailability after an oral dose is about 80%. Peak plasma concentrations occur within 2—4 hours. Plasma concentrations are proportional to the administered dose in the range of 5—20 mg. Once daily dosing of bisoprolol results in less than two-fold intersubject variation in peak plasma concentrations.