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  • CLASSES

    Anti-arrhythmics, Class II
    Selective Beta-Blockers

    DEA CLASS

    Rx

    DESCRIPTION

    Oral selective beta-1 blocker with vasodilatory properties due to nitric oxide modulation; possesses antioxidant properties; lipophilic; lacks ISA; decreases vascular peripheral resistance; improves left ventricular performance; not associated with an acute decrease in cardiac output; indicated for HTN; off-label data available for heart failure.

    COMMON BRAND NAMES

    Bystolic

    HOW SUPPLIED

    Bystolic Oral Tab: 2.5mg, 5mg, 10mg, 20mg

    DOSAGE & INDICATIONS

    For the treatment of hypertension either alone or in combination with other agents.
    Oral dosage
    Adults

    The recommended starting dose is 5 mg PO once daily. If adequate blood pressure control has not been attained, the dose can be increased at 2-week intervals up to a once daily dose of 40 mg. More frequent dosing is not beneficial. For geriatric patients, consider lower doses.

    For migraine prophylaxis†.
    Oral dosage
    Adults

    5 mg PO daily. Clinical practice guidelines classify nebivolol as possibly effective for migraine prophylaxis.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    40 mg/day PO.

    Elderly

    40 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    The recommended starting dose in patients with moderate hepatic impairment (Child-Pugh Class B) is 2.5 mg PO once daily. Dose escalation should be done cautiously. Nebivolol is contraindicated in patients with severe hepatic impairment.

    Renal Impairment

    CrCl >= 30 ml/min: No dosage adjustment needed.
    CrCl < 30 ml/min: The recommended starting dose in patients with severe renal impairment is 2.5 mg PO once daily. Dose escalation should be done cautiously.
     
    Intermittent hemodialysis
    Nebivolol has not been studied in patients receiving dialysis.

    ADMINISTRATION

    Oral Administration

    May administer without regard to meals.

    STORAGE

    Bystolic:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Nebivolol is contraindicated in patients with known nebivolol hypersensitivity or hypersensitivity to any of the product excipients.

    Abrupt discontinuation, coronary artery disease

    Abrupt discontinuation of any beta-adrenergic antagonist, including nebivolol, can result in severe exacerbation of angina, myocardial infarction, or ventricular arrhythmias, particularly in patients with preexisting coronary artery disease (CAD). Ventricular arrhythmias and myocardial infarction may occur without preceding exacerbation of angina. Patients without overt CAD also should be advised against abrupt discontinuation of nebivolol therapy. If nebivolol therapy is to be discontinued, careful monitoring should occur and the patient should be advised to minimize physical activity. If possible, nebivolol should be tapered over 1—2 weeks. If coronary insufficiency or angina develops during discontinuation, nebivolol therapy should be reinitiated, at least temporarily.

    Acute heart failure, AV block, bradycardia, cardiogenic shock, sick sinus syndrome

    Because beta-blockers depress conduction through the AV node, nebivolol is contraindicated in patients with severe bradycardia, sick sinus syndrome, or advanced AV block (second or third-degree AV block) unless a functioning pacemaker is present. In general, beta-blockers are contraindicated in patients with cardiogenic shock or acute heart failure, particularly in those with severely compromised left ventricular dysfunction, because the negative inotropic effect of these drugs can further depress cardiac output. In patients with stable, chronic heart failure, however, some beta-blockers given in low doses have been documented to be beneficial. No worsening of heart failure was reported in a placebo-controlled trial of 1067 patients > 70 years with chronic heart failure receiving a maximum of nebivolol 10 mg/day PO. If heart failure worsens, discontinuation of nebivolol therapy should be considered. Beta-blockers have also been used for the treatment of hypertrophic cardiomyopathy. In the treatment of myocardial infarction, beta-blockers are contraindicated in patients with hypotension (SBP < 100 mmHg).

    Hepatic disease

    Nebivolol is contraindicated in patients with severe hepatic disease (Child-Pugh Class > B). Nebivolol is extensively metabolized by the liver, and dosage adjustments are required in patients with moderate hepatic impairment.

    Acute bronchospasm

    Although beta-1-selective beta-blockers, such as nebivolol, 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.

    Hyperthyroidism, thyrotoxicosis

    Beta-blockers, including nebivolol, should be used with caution in patients with hyperthyroidism or thyrotoxicosis because the drug 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. Beta-blockers can reduce tachycardia, tremor, and anxiety in the hyperthyroid patient.

    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. Nonselective beta-blockers can potentiate insulin-induced hypoglycemia and delay the recovery of serum glucose levels. It is not known if nebivolol has these effects. Beta-blockers also can 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 beta-2-receptors on pancreatic islet cells, which would inhibit insulin secretion. However, clinical trial data indicate that vasodilating beta-blockers (e.g., carvedilol, nebivolol) may actually improve insulin sensitivity and glycemic control. Thus, blood glucose levels should be monitored closely if a beta-blocker is used in a patient with diabetes mellitus. Nebivolol should be used cautiously in poorly controlled diabetic patients, in diabetic patients receiving insulin or oral hypoglycemic agents and in patients subject so spontaneous hypoglycemia.

    Surgery

    The necessity or desirability of withdrawing beta-blockers, like nebivolol, prior to major surgery is controversial; the risks versus benefits should be evaluated in individual patients. Patients receiving beta-blockers 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. Although gradual withdrawal of beta-blockers is sometimes recommended prior to general anesthesia, the manufacturer recommends that patients should generally continue beta-blocker therapy throughout the perioperative period to limit the risk of myocardial infarction and chest pain associated with withdrawal of therapy. 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. If beta-blocker therapy is continued, it should be noted that the reduced ability of the heart to respond to beta-adrenergically mediated sympathetic reflex stimuli may augment the risks of general anesthesia and surgical procedures. 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, or dobutamine; however, these patients may then be more at risk of developing protracted severe hypotension. Vagal dominance, if it occurs, may be corrected with atropine (1—2 mg IV).

    Peripheral vascular disease

    Nebivolol should be used with caution in patients with peripheral vascular disease because reduced cardiac output and the relative increase in alpha-receptor stimulation can exacerbate symptoms.

    Pheochromocytoma

    In patients with known or suspected pheochromocytoma, nebivolol is contraindicated when used as monotherapy. If nebivolol is required, it should be given in combination with an alpha-blocker, and only after the alpha-blocker has been initiated. Administration of beta-blockers alone in the setting of pheochromocytoma has been associated with paradoxical hypertension due to attenuation of beta-mediated vasodilation.

    Renal impairment

    Nebivolol should be used with caution in patients with severe renal impairment, as the clearance of nebivolol is reduced by approximately 50% in this patient population; dosage reduction is required. Nebivolol has not been studied in patients requiring dialysis.

    Geriatric

    In clinical trials involving nebivolol, no differences in efficacy or adverse events were seen between geriatric and younger adult patients. Dosage adjustments based on age alone are 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.

    Children, infants, neonates

    The safety and efficacy of nebivolol has not been established in neonates, infants, children, or adolescents less than 18 years of age.

    Pregnancy

     There are insufficient data to determine whether there are drug-associated risks of adverse developmental outcomes. Uncontrolled hypertension during pregnancy carries risks to the mother and fetus. The use of beta-blockers during the third trimester may increase the risk of hypotension, bradycardia, hypoglycemia, and respiratory depression in the neonate. Decreased pup weights, prolonged gestation, dystocia, late fetal death, stillbirths, and reduced maternal care were all observed when nebivolol was administered to pregnant rats during the perinatal period (late gestation, parturition and lactation).

    Breast-feeding

    It is not known if nebivolol is excreted in human milk. Nebivolol is present in rat milk. The use of nebivolol is not recommended during breast-feeding due to the potential for the development of serious adverse reactions (e.g., bradycardia) to the nursing infant. Other beta-blockers for which more data are available, such as labetalol, metoprolol, and propranolol, may represent possible alternatives for some patients. The American Academy of Pediatrics regards these beta-blockers as usually compatible with breast feeding. 

    ADVERSE REACTIONS

    Severe

    bradycardia / Rapid / 0-1.0
    angioedema / Rapid / 0-1.0
    pulmonary edema / Early / Incidence not known
    AV block / Early / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    bronchospasm / Rapid / Incidence not known
    vasculitis / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known

    Moderate

    chest pain (unspecified) / Early / 0-1.0
    peripheral edema / Delayed / 1.0-1.0
    dyspnea / Early / 0-1.0
    hypercholesterolemia / Delayed / 1.0
    hypotension / Rapid / Incidence not known
    hypertriglyceridemia / Delayed / Incidence not known
    hyperuricemia / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    psoriasis / Delayed / Incidence not known
    peripheral vasoconstriction / Rapid / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    palpitations / Early / Incidence not known
    withdrawal / Early / Incidence not known
    hypertension / Early / Incidence not known
    sinus tachycardia / Rapid / Incidence not known

    Mild

    headache / Early / 6.0-9.0
    fatigue / Early / 2.0-5.0
    dizziness / Early / 2.0-4.0
    diarrhea / Early / 2.0-3.0
    nausea / Early / 1.0-3.0
    insomnia / Early / 1.0-1.0
    rash / Early / 0-1.0
    asthenia / Delayed / 1.0
    paresthesias / Delayed / 1.0
    abdominal pain / Early / 1.0
    drowsiness / Early / Incidence not known
    vertigo / Early / Incidence not known
    syncope / Early / Incidence not known
    vomiting / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    pruritus / Rapid / Incidence not known
    tremor / Early / Incidence not known
    diaphoresis / Early / Incidence not known

    DRUG INTERACTIONS

    Abiraterone: (Major) Avoid the concomitant use of nebivolol and abiraterone. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as abiraterone, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible. If these drugs are coadministered, patients should be monitored for increased toxicity as well as increased therapeutic effect.
    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.
    Acetaminophen; Chlorpheniramine: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with chlorpheniramine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as chlorpheniramine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with chlorpheniramine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as chlorpheniramine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with chlorpheniramine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as chlorpheniramine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with chlorpheniramine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as chlorpheniramine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with chlorpheniramine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as chlorpheniramine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with chlorpheniramine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as chlorpheniramine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Acetaminophen; Diphenhydramine: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with diphenhydramine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as diphenhydramine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Adenosine: (Moderate) Use adenosine with caution in the presence of beta blockers due to the potential for additive or synergistic depressant effects on the sinoatrial and atrioventricular nodes.
    Albiglutide: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also 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 noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    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; Metformin: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also 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 noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Alpha-blockers: (Moderate) Orthostatic hypotension may be more likely if beta-blockers are coadministered with alpha-blockers.
    Alpha-glucosidase Inhibitors: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also 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 noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    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: (Moderate) Concomitant administration of nebivolol 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. Because amiodarone is an inhibitor of CYP2D6, decreased clearance of nebivolol, which is a CYP2D6 substrate, is also possible. Caution and close monitoring are recommended during coadministration; a dose reduction of one or both drugs may be needed based on response. 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; Celecoxib: (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; 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; Valsartan; 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.
    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) Use of beta blockers and apomorphine together can increase the hypotensive effects of apomorphine. Monitor blood pressure regularly during use of this combination.
    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.
    Artemether; Lumefantrine: (Major) Avoid the concomitant use of nebivolol and artemether; lumefantrine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as lumefantrine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible. If these drugs are coadministered, patients should be monitored for increased toxicity as well as increased therapeutic effect.
    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) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with asenapine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as asenapine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible. In addition, secondary to alpha-blockade, asenapine can produce vasodilation that may result in additive effects during concurrent use of nebivolol. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known; the nebivolol dosage may need to be adjusted. 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.
    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: (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; Caffeine; Orphenadrine: (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; Citric Acid; Sodium Bicarbonate: (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. (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with cobicistat. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as cobicistat, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    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.
    Berotralstat: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with berotralstat; adjust the nebivolol dose according to blood pressure response. Concomitant use may increase the exposure of nebivolol. Nebivolol is a CYP2D6 substrate and berotralstat is a moderate CYP2D6 inhibitor.
    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.
    Bretylium: (Moderate) Bretylium and beta-blockers may have an additive effect when used concomitantly; monitor for hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.
    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.
    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.
    Bupivacaine; Meloxicam: (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.
    Bupropion: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with bupropion. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as bupropion, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Bupropion; Naltrexone: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with bupropion. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as bupropion, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Cabergoline: (Moderate) Cabergoline should be used cautiously with antihypertensive agents, including beta-blockers. Cabergoline has been associated with hypotension. Initial doses of cabergoline higher than 1 mg may produce orthostatic hypotension. It may be advisable to monitor blood pressure.
    Canagliflozin; Metformin: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also 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 noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Carbetapentane; Chlorpheniramine: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with chlorpheniramine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as chlorpheniramine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with chlorpheniramine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as chlorpheniramine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with diphenhydramine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as diphenhydramine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    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.
    Ceritinib: (Major) Avoid coadministration of ceritinib with nebivolol if possible due to the risk of additive bradycardia. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if bradycardia occurs. Bradycardia has been reported with ceritinib treatment; nebivolol also causes bradycardia.
    Cevimeline: (Major) Cevimeline should be administered with caution to patients taking beta adrenergic antagonists, because of the possibility of conduction disturbances. Cevimeline can potentially alter cardiac conduction and/or heart rate. Patients with significant cardiovascular disease treated with beta-blockers may potentially be unable to compensate for transient changes in hemodynamics or rhythm induced by cevimeline. If use of these drugs together cannot be avoided, close monitoring of blood pressure, heart rate and cardiac function is advised.
    Chloroprocaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Chlorpheniramine: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with chlorpheniramine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as chlorpheniramine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Chlorpheniramine; Codeine: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with chlorpheniramine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as chlorpheniramine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Chlorpheniramine; Dextromethorphan: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with chlorpheniramine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as chlorpheniramine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with chlorpheniramine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as chlorpheniramine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with chlorpheniramine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as chlorpheniramine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with chlorpheniramine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as chlorpheniramine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with chlorpheniramine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as chlorpheniramine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with chlorpheniramine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as chlorpheniramine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Chlorpheniramine; Hydrocodone: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with chlorpheniramine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as chlorpheniramine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with chlorpheniramine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as chlorpheniramine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with chlorpheniramine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as chlorpheniramine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with chlorpheniramine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as chlorpheniramine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Chlorpheniramine; Phenylephrine: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with chlorpheniramine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as chlorpheniramine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with chlorpheniramine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as chlorpheniramine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Chlorpromazine: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with chlorpromazine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as chlorpromazine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    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.
    Cimetidine: (Moderate) Nebivolol is metabolized by CYP2D6 and cimetidine inhibits CYP2D6. The plasma levels of d-nebivolol were increased by 23% with the coadministration of cimetidine 400 mg twice daily. The clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible. If these drugs are coadministered, patients should be monitored for increased toxicity as well as increased therapeutic effect.
    Cinacalcet: (Major) Avoid the concomitant use of nebivolol and cinacalcet. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as cinacalcet, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible. If these drugs are coadministered, patients should be monitored for increased toxicity as well as increased therapeutic effect.
    Citalopram: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with citalopram. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as citalopram, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Clevidipine: (Moderate) Use clevidipine and nebivolol with caution due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility.
    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.
    Cobicistat: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with cobicistat. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as cobicistat, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Cocaine: (Major) Although beta-blockers are indicated to reduce cocaine-induced tachycardia, myocardial ischemia, and arrhythmias, concomitant use of cocaine and non-selective beta-adrenergic blocking agents, including ophthalmic preparations, can cause unopposed alpha-adrenergic activity, resulting in heart block, excessive bradycardia, or hypertension. In theory, the use of alpha-blocker and beta-blocker combinations or selective beta-blockers in low doses may not cause unopposed alpha stimulation in this situation. Labetalol, a beta-blocker with some alpha-blocking activity, has been used successfully to treat cocaine-induced hypertension. In addition, cocaine can reduce the therapeutic effects of beta-blockers.
    Codeine; Phenylephrine; Promethazine: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with promethazine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as promethazine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Codeine; Promethazine: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with promethazine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as promethazine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    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.
    Crizotinib: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
    Dacomitinib: (Major) Avoid the concomitant use of nebivolol and dacomitinib. If these drugs are coadministered, patients should be monitored for increased toxicity as well as increased therapeutic effect. Nebivolol is metabolized by CYP2D6; dacomitinib is a strong CYP2D6 inhibitor. An 8-fold increase in the AUC and a 3-fold increase in Cmax for d-nebivolol was seen when nebivolol was coadministered with another strong CYP2D6 inhibitor.
    Dapagliflozin; Metformin: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also 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 noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Darifenacin: (Moderate) Monitor patients closely and adjust the nebivolol dose according to blood pressure response if coadministered with darifenacin. Nebivolol plasma concentrations may be increased during concurrent use. Darifenacin is a moderate CYP2D6 inhibitor; nebivolol is a sensitive CYP2D6 substrate.
    Darunavir; Cobicistat: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with cobicistat. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as cobicistat, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with cobicistat. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as cobicistat, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Ritonavir is expected to decrease the hepatic CYP metabolism of beta-blockers like nebivolol, resulting in increased beta-blocker concentrations. Cardiac and neurologic events have been reported when ritonavir is concurrently administered with beta-blockers. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including beta-blockers) has not been evaluated. If coadministration of nebivolol and ritonavir is warranted, do so with caution and careful monitoring. Decreased beta-blocker doses may be warranted.
    Dasiglucagon: (Minor) A temporary increase in both blood pressure and pulse rate may occur following the administration of glucagon. Patients taking beta-blockers might be expected to have a greater increase in both pulse and blood pressure. Glucagon exerts positive inotropic and chronotropic effects and may, therefore, cause tachycardia and hypertension in some patients. The increase in blood pressure and pulse rate may require therapy in some patients with coronary artery disease.
    Delavirdine: (Major) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with delavirdine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as delavirdine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    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.
    Desvenlafaxine: (Major) Avoid the concomitant use of nebivolol and desvenlafaxine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as desvenlafaxine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible. The manufacturer of desvenlafaxine states no dosage adjustment of nebivolol is required when co-administered with desvenlafaxine 100 mg or lower or when desvenlafaxine is discontinued. The dose of nebivolol should be reduced by up to one-half if co-administered with desvenlafaxine 400 mg/day. Patients should be monitored for increased toxicity as well as increased therapeutic effect.
    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; Diphenhydramine; Phenylephrine: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with diphenhydramine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as diphenhydramine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Dextromethorphan; Quinidine: (Major) Quinidine may have additive effects (e.g., reduced heart rate, hypotension) on cardiovascular parameters when used together with nebivolol, a beta-blocker. Quinidine is a known inhibitor of CYP2D6 and nebivolol is metabolized by CYP2D6. Quinidine could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition. Patients should be monitored for excess beta-blockade. 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) Administer nebivolol and digoxin together cautiously. Nebivolol and digoxin slow atrioventricular conduction and decrease heart rate. Concomitant use of nebivolol and digoxin or other drugs that significantly depress AV nodal conduction can increase the risk of bradycardia and AV block. No significant changes in the pharmacokinetics of digoxin or nebivolol were seen with the concomitant administration of digoxin 0.25 mg once daily and nebivolol 10 mg once daily for 10 days in 14 healthy volunteers. No significant changes in the extent of in vitro binding of nebivolol to human plasma proteins was observed in the presence of a high digoxin concentration, and, similarly, at therapeutic digoxin concentrations, nebivolol did not significantly change the binding of digoxin to human plasma proteins.
    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) Use diltiazem and nebivolol with caution due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility.
    Dipeptidyl Peptidase-4 Inhibitors: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also 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 noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Diphenhydramine: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with diphenhydramine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as diphenhydramine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with diphenhydramine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as diphenhydramine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Diphenhydramine; Ibuprofen: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with diphenhydramine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as diphenhydramine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Diphenhydramine; Naproxen: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with diphenhydramine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as diphenhydramine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Diphenhydramine; Phenylephrine: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with diphenhydramine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as diphenhydramine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    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 nebivolol, 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) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also 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 noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Duloxetine: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with duloxetine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as duloxetine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible. In addition, orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of nebivolol and duloxetine may increase the risk of hypotension.
    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
    Eliglustat: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with eliglustat. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as eliglustat, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible. Consider reducing the dosage of nebivolol and titrating to clinical effect.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with cobicistat. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as cobicistat, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with cobicistat. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as cobicistat, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Empagliflozin; Linagliptin; Metformin: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also 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 noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Empagliflozin; Metformin: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also 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 noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Enalapril; Felodipine: (Moderate) Coadministration of felodipine and nebivolol 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 nebivolol, 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.
    Ergotamine; Caffeine: (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.
    Ertugliflozin; Metformin: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also 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 noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Escitalopram: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with escitalopram. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as escitalopram, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    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) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also 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 noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Fedratinib: (Moderate) Monitor for increased nebivolol adverse reactions including bradycardia and hypotension during coadministration of fedratinib. Fedratinib is a moderate CYP2D6 inhibitor and nebivolol is a sensitive CYP2D6 substrate.
    Felodipine: (Moderate) Coadministration of felodipine and nebivolol 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.
    Fenoldopam: (Major) Avoid concomitant use of fenoldopam with beta-blockers due to the risk of hypotension. If used together, monitor blood pressure frequently. Beta-blockers may inhibit the sympathetic reflex response to fenoldopam.
    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) 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: (Moderate) Pharmacologically, beta-blockers, like nebivolol, 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: (Major) Avoid the concomitant use of nebivolol and fluoxetine. Nebivolol is metabolized by CYP2D6; fluoxetine inhibits CYP2D6. An 8-fold increase in the AUC and a 3-fold increase in Cmax for d-nebivolol was seen when a daily dose of fluoxetine 20 mg was administered to healthy volunteers for 21 days prior to the administration of a single 10 mg dose of nebivolol. If these drugs are coadministered, patients should be monitored for increased toxicity as well as increased therapeutic effect.
    Fluphenazine: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with fluphenazine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as fluphenazine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    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.
    Givosiran: (Major) Avoid concomitant use of givosiran and nebivolol due to the risk of increased nebivolol-related adverse reactions. If use is necessary, consider decreasing the nebivolol dose. Nebivolol is a sensitive CYP2D6 substrate. Givosiran may moderately reduce hepatic CYP2D6 enzyme activity because of its pharmacological effects on the hepatic heme biosynthesis pathway.
    Glipizide; Metformin: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also 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 noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Glucagon: (Minor) A temporary increase in both blood pressure and pulse rate may occur following the administration of glucagon. Patients taking beta-blockers might be expected to have a greater increase in both pulse and blood pressure. Glucagon exerts positive inotropic and chronotropic effects and may, therefore, cause tachycardia and hypertension in some patients. The increase in blood pressure and pulse rate may require therapy in some patients with coronary artery disease.
    Glyburide; Metformin: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also 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 noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    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) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with haloperidol. Nebivolol is metabolized by CYP2D6. Although data are lacking, significant CYP2D6 inhibitors, such as haloperidol, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    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.
    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.
    Imatinib: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with imatinib, STI-571. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as imatinib, STI-571, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Incretin Mimetics: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also 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 noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Indinavir: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with indinavir. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as indinavir, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Insulin Degludec; Liraglutide: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also 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 noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Insulin Glargine; Lixisenatide: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also 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 noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Insulins: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also 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 noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    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: (Major) Avoid the concomitant use of nebivolol and rifampin. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inducers, such as rifampin, could potentially decrease nebivolol plasma concentrations via CYP2D6 induction; the clinical significance of this potential interaction is unknown, but a decrease in therapeutic effect is possible. If these drugs are coadministered, patients should be monitored for therapeutic response.
    Isoniazid, INH; Rifampin: (Major) Avoid the concomitant use of nebivolol and rifampin. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inducers, such as rifampin, could potentially decrease nebivolol plasma concentrations via CYP2D6 induction; the clinical significance of this potential interaction is unknown, but a decrease in therapeutic effect is possible. If these drugs are coadministered, patients should be monitored for therapeutic response.
    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) Use lacosamide with caution in patients taking concomitant medications that affect cardiac conduction, such as beta-blockers, because of the risk of AV block, bradycardia, or ventricular tachyarrhythmia. If use together is necessary, obtain an ECG prior to lacosamide initiation and after treatment has been titrated to steady-state. In addition, monitor patients receiving lacosamide via the intravenous route closely.
    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.
    Lasmiditan: (Moderate) Monitor heart rate if lasmiditan is coadministered with beta-blockers as concurrent use may increase the risk for bradycardia. Lasmiditan has been associated with lowering of heart rate. In a drug interaction study, addition of a single 200 mg dose of lasmiditan to a beta-blocker (propranolol) decreased heart rate by an additional 5 beats per minute.
    Levamlodipine: (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.
    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.
    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.
    Levothyroxine; Liothyronine (Porcine): (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.
    Levothyroxine; Liothyronine (Synthetic): (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.
    Lidocaine; Prilocaine: (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.
    Linagliptin; Metformin: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also 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 noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    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.
    Liraglutide: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also 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 noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    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) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also 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 noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Lofexidine: (Major) Because both lofexidine and nebivolol can cause hypotension and bradycardia, concurrent use should be avoided if possible. Patients being given lofexidine in an outpatient setting should be capable of and instructed on self-monitoring for hypotension, orthostasis, bradycardia, and associated symptoms. If clinically significant or symptomatic hypotension and/or bradycardia occur, the next dose of lofexidine should be reduced in amount, delayed, or skipped.
    Lopinavir; Ritonavir: (Moderate) Ritonavir is expected to decrease the hepatic CYP metabolism of beta-blockers like nebivolol, resulting in increased beta-blocker concentrations. Cardiac and neurologic events have been reported when ritonavir is concurrently administered with beta-blockers. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including beta-blockers) has not been evaluated. If coadministration of nebivolol and ritonavir is warranted, do so with caution and careful monitoring. Decreased beta-blocker doses may be warranted.
    Lorcaserin: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with lorcaserin. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as lorcaserin, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    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.
    Meglitinides: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also 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 noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Meperidine; Promethazine: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with promethazine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as promethazine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    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) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also 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 noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Metformin; Repaglinide: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also 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 noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Metformin; Rosiglitazone: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also 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 noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Metformin; Saxagliptin: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also 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 noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Metformin; Sitagliptin: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also 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 noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Methacholine: (Moderate) Beta-blockers may impair reversal of methacholine-induced bronchoconstriction with an inhaled rapid-acting beta-agonist.
    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.
    Milrinone: (Moderate) Concurrent administration of antihypertensive agents could lead to additive hypotension when administered with milrinone. Titrate milrinone dosage according to hemodynamic response.
    Mirabegron: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with mirabegron. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as mirabegron, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible. Dose adjustment may be necessary.
    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.
    Neuromuscular blockers: (Moderate) Concomitant use of neuromuscular blockers and beta-blockers may prolong neuromuscular blockade.
    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) Use nicardipine and nebivolol with caution due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility.
    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.
    Nirmatrelvir; Ritonavir: (Moderate) Ritonavir is expected to decrease the hepatic CYP metabolism of beta-blockers like nebivolol, resulting in increased beta-blocker concentrations. Cardiac and neurologic events have been reported when ritonavir is concurrently administered with beta-blockers. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including beta-blockers) has not been evaluated. If coadministration of nebivolol and ritonavir is warranted, do so with caution and careful monitoring. Decreased beta-blocker doses may be warranted.
    Nisoldipine: (Moderate) Concurrent use of nisoldipine with nebivolol 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) Use caution when administering non-ionic contrast media to patients taking beta-blockers. Beta-blockers lower the threshold for and increase the severity of contrast reactions and reduce the responsiveness of treatment of hypersensitivity reactions with epinephrine.
    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.
    Olanzapine; Fluoxetine: (Major) Avoid the concomitant use of nebivolol and fluoxetine. Nebivolol is metabolized by CYP2D6; fluoxetine inhibits CYP2D6. An 8-fold increase in the AUC and a 3-fold increase in Cmax for d-nebivolol was seen when a daily dose of fluoxetine 20 mg was administered to healthy volunteers for 21 days prior to the administration of a single 10 mg dose of nebivolol. If these drugs are coadministered, patients should be monitored for increased toxicity as well as increased therapeutic effect. (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Olanzapine; Samidorphan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Olmesartan; 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.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Ritonavir is expected to decrease the hepatic CYP metabolism of beta-blockers like nebivolol, resulting in increased beta-blocker concentrations. Cardiac and neurologic events have been reported when ritonavir is concurrently administered with beta-blockers. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including beta-blockers) has not been evaluated. If coadministration of nebivolol and ritonavir is warranted, do so with caution and careful monitoring. Decreased beta-blocker doses may be warranted.
    Oritavancin: (Moderate) Nebivolol is metabolized by CYP2D6; oritavancin is a weak CYP2D6 inducer. Plasma concentrations and efficacy of nebivolol may be reduced if these drugs are administered concurrently.
    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.
    Ozanimod: (Moderate) Ozanimod may cause bradycardia and AV-conduction delays, which may be enhanced with the concomitant use of beta-blockers. If a calcium channel blocker that slows heart rate/cardiac conduction is also prescribed with ozanimod and a beta-blocker, a cardiologist should be consulted due to the likelyhood of additive effects.
    Paliperidone: (Moderate) Paliperidone may cause orthostatic hypotension, thereby enhancing the hypotensive effects of antihypertensive agents. Orthostatic vital signs should be monitored in patients receiving paliperidone and beta-adrenergic blockers who are susceptible to hypotension.
    Panobinostat: (Major) Avoid the concomitant use of nebivolol and panobinostat. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of nebivolol toxicity. Panobinostat is a CYP2D6 inhibitor and nebivolol is a CYP2D6-sensitive substrate. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
    Paroxetine: (Major) Avoid the concomitant use of nebivolol and paroxetine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as paroxetine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible. If these drugs are coadministered, patients should be monitored for increased toxicity as well as increased therapeutic effect.
    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.
    Pazopanib: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with pazopanib. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as pazopanib, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    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.
    Perphenazine: (Major) Avoid the concomitant use of nebivolol and perphenazine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as perphenazine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible. If these drugs are coadministered, patients should be monitored for increased toxicity as well as increased therapeutic effect.
    Perphenazine; Amitriptyline: (Major) Avoid the concomitant use of nebivolol and perphenazine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as perphenazine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible. If these drugs are coadministered, patients should be monitored for increased toxicity as well as increased therapeutic effect.
    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.
    Pimozide: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with pimozide. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as pimozide, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Pioglitazone; Metformin: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also 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 noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Pirfenidone: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with pirfenidone. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as pirfenidone, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Ponesimod: (Moderate) Monitor for decreases in heart rate if concomitant use of ponesimod and beta-blockers is necessary. Consider a temporary interruption in beta-blocker therapy before initiating ponesimod in patients with a resting heart rate less than or equal to 55 bpm. Beta-blocker treatment can be initiated in patients receiving stable doses of ponesimod. Concomitant use of another beta-blocker with ponesimod resulted in a mean decrease in heart rate of 12.4 bpm after the first dose of ponesimod and 7.4 bpm after beginning maintenance ponesimod.
    Pramlintide: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also 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 noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    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 nebivolol. 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.
    Promethazine: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with promethazine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as promethazine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Promethazine; Dextromethorphan: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with promethazine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as promethazine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Promethazine; Phenylephrine: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with promethazine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as promethazine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    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 nebivolol, a beta-blocker. Quinidine is a known inhibitor of CYP2D6 and nebivolol is metabolized by CYP2D6. Quinidine could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition. Patients should be monitored for excess beta-blockade. 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.
    Quinine: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with quinine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as quinine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Ranolazine: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with ranolazine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as ranolazine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    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.
    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).
    Rifampin: (Major) Avoid the concomitant use of nebivolol and rifampin. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inducers, such as rifampin, could potentially decrease nebivolol plasma concentrations via CYP2D6 induction; the clinical significance of this potential interaction is unknown, but a decrease in therapeutic effect is possible. If these drugs are coadministered, patients should be monitored for therapeutic response.
    Risperidone: (Moderate) Risperidone may cause orthostatic hypotension and thus enhance the hypotensive effects of nebivolol. Lower initial doses or slower dose titration of risperidone may be necessary in patients receiving nebivolol.
    Ritonavir: (Moderate) Ritonavir is expected to decrease the hepatic CYP metabolism of beta-blockers like nebivolol, resulting in increased beta-blocker concentrations. Cardiac and neurologic events have been reported when ritonavir is concurrently administered with beta-blockers. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including beta-blockers) has not been evaluated. If coadministration of nebivolol and ritonavir is warranted, do so with caution and careful monitoring. Decreased beta-blocker doses may be warranted.
    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.
    Rolapitant: (Major) Avoid the concomitant use of nebivolol and rolapitant. If these drugs are coadministered, patients should be monitored and the nebivolol dose should be adjusted according to blood pressure response. Nebivolol is a CYP2D6 substrate where an increase in exposure may significantly increase adverse effects, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    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.
    Semaglutide: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also 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 noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Sertraline: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with sertraline. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as sertraline, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    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.
    SGLT2 Inhibitors: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also 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 noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Sildenafil: (Moderate) The AUC and Cmax of sildenafil were decreased by 21% and 23%, respectively, when coadministered with nebivolol. A similar decrease in the concentration of d-nebivolol (less than 20% in the AUC and Cmax) was also observed with the coadministration of sildenafil. If sildenafil and nebivolol are to be used concomitantly, patients should be monitored closely.
    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.
    Siponimod: (Moderate) Monitor for significant bradycardia with coadministration of siponimod and beta-blockers, as additive lowering effects on heart rate may occur; temporary interruption of beta-blocker treatment may be necessary prior to siponimod initiation. Beta-blocker treatment can be initiated in patients receiving stable doses of siponimod.
    Sotalol: (Contraindicated) Coadministration would be illogical as both are beta-blockers and would represent duplicate therapy; additive effects on AV nodal conduction and blood pressure would be expected.
    Sufentanil: (Moderate) The incidence and degree of bradycardia and hypotension during induction with sufentanil may be increased in patients receiving beta-blockers.
    Sulfonylureas: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also 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 noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Sympathomimetics: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. 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. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    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: (Moderate) Advise patients to administer the beta-blocker in the morning if tasimelteon is used concomitantly. Nighttime administration of a beta-blocker may reduce the efficacy of tasimelteon by decreasing the production of melatonin via inhibition of beta1 receptors.
    Telmisartan; 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.
    Terazosin: (Moderate) Orthostatic hypotension may be more likely if beta-blockers are coadministered with alpha-blockers.
    Terbinafine: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with terbinafine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as terbinafine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    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) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also 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 noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    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.
    Thioridazine: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with thioridazine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as thioridazine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Thiothixene: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with thiothixene. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as thiothixene, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is 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.
    Tipranavir: (Major) Avoid the concomitant use of nebivolol and tipranavir. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as tipranavir, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible. If these drugs are coadministered, patients should be monitored for increased toxicity as well as increased therapeutic effect.
    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) Use verapamil and nebivolol with caution and close monitoring due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility. There have been reports of excess bradycardia and AV block, including complete heart block, when beta-blockers and verapamil have been used for the treatment of hypertension.
    Tranylcypromine: (Major) Avoid concomitant use of beta-blockers and tranylcypromine due to the risk of additive hypotension and/or severe bradycardia. Potential for this interaction persists for up to 10 days after discontinuation of tranylcypromine (or 4 to 5 half-lives after discontinuation of the beta-blocker). If a medication-free interval is not feasible, initiate therapy at the lowest appropriate dose and monitor blood pressure and heart rate closely.
    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.
    Vemurafenib: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with vemurafenib. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as vemurafenib, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Verapamil: (Moderate) Use verapamil and nebivolol with caution and close monitoring due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility. There have been reports of excess bradycardia and AV block, including complete heart block, when beta-blockers and verapamil have been used for the treatment of hypertension.
    Viloxazine: (Moderate) Monitor for increased nebivolol-related adverse reactions, including bradycardia and hypotension, during coadministration with viloxazine. Concomitant use may increase nebivolol exposure and thus enhance the beta-blocking properties. Nebivolol is a CYP2D6 substrate and viloxazine is a weak CYP2D6 inhibitor.
    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

     There are insufficient data to determine whether there are drug-associated risks of adverse developmental outcomes. Uncontrolled hypertension during pregnancy carries risks to the mother and fetus. The use of beta-blockers during the third trimester may increase the risk of hypotension, bradycardia, hypoglycemia, and respiratory depression in the neonate. Decreased pup weights, prolonged gestation, dystocia, late fetal death, stillbirths, and reduced maternal care were all observed when nebivolol was administered to pregnant rats during the perinatal period (late gestation, parturition and lactation).

    It is not known if nebivolol is excreted in human milk. Nebivolol is present in rat milk. The use of nebivolol is not recommended during breast-feeding due to the potential for the development of serious adverse reactions (e.g., bradycardia) to the nursing infant. Other beta-blockers for which more data are available, such as labetalol, metoprolol, and propranolol, may represent possible alternatives for some patients. The American Academy of Pediatrics regards these beta-blockers as usually compatible with breast feeding. 

    MECHANISM OF ACTION

    Mechanism of Action: Nebivolol is a beta-1 selective (cardioselective) adrenergic antagonist. Similar to atenolol, metoprolol, and propranolol, nebivolol blocks sympathetic stimulation mediated by beta-1 adrenergic receptors in the heart and vascular smooth muscle. However, unlike propranolol, which nonspecifically blocks beta-1 and beta-2 adrenoreceptors, or atenolol, which has more affinity for the beta-1 adrenoreceptor but at higher doses loses its beta-1 specificity, nebivolol has an even higher affinity for the beta-1 adrenoreceptor. In extensive metabolizers (majority of the population) and at doses less than or equal to 10 mg, nebivolol is beta-1 selective. At higher than therapeutic doses and in poor metabolizers, nebivolol inhibits both beta-1 and beta-2 receptors. At therapeutic doses, nebivolol does not possess alpha-1 adrenergic receptor blocker activity and does not exert intrinsic sympathomimetic activity. Pharmacodynamic consequences of beta-1 receptor blockade include a decrease in both resting and exercise heart rate and cardiac output, and a decrease in both systolic and diastolic blood pressure. The exact mechanism of action of nebivolol has not been fully established. Mechanisms responsible for the pharmacological activity of nebivolol include decreased heart rate, decreased myocardial contractility, diminution of tonic sympathetic outflow to the periphery from cerebral vasomotor centers, and suppression of renin activity. In addition to the beta-blocking activity, nebivolol also modulates the endogenous production of nitric oxide resulting in peripheral vasodilation. Nitric oxide regulation contributes to endothelial function and large arterial stiffness. In addition, nebivolol also possesses antioxidant properties. Unlike other beta-blocking agents, nebivolol decreases vascular peripheral resistance, improves left ventricular performance and is not associated with an acute decrease in cardiac output sometimes seen with the initiation of other beta blockers.

    PHARMACOKINETICS

    Nebivolol is administered orally. It is approximately 98% bound to plasma proteins, mostly albumin. It is metabolized primarily by direct glucuronidation and, to a lesser extent, by N-dealkylation and oxidation by cytochrome P450 2D6. The hydroxyl metabolite and glucuronides (predominant metabolites) contribute to the beta-blocking effect. There are 2 isomers for nebivolol, d-nebivolol and l-nebivolol. The active isomer, d-nebivolol, has an effective half-life of approximately 12 hours in CYP2D6 extensive metabolizers (EMs; the majority of the population) and 19 hours in poor metabolizers (PMs). Exposure to l-nebivolol is higher than to d-nebivolol, but l-nebivolol contributes little to the activity of nebivolol, as the beta receptor affinity of d-nebivolol is greater than 1000-fold the affinity of l-nebivolol. When given the same dose, PMs attain a 5-fold higher Cmax and a 10-fold higher AUC of d-nebivolol than do EMs. With repeated once-daily dosing in EMs, d-nebivolol accumulates approximately 1.5-fold. After a single oral administration of 14C-nebivolol 38% of the dose was recovered in the urine and 44% in the feces for EMs and 67% in the urine and 13% in the feces for PMs.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP2D6
    Nebivolol is metabolized by many routes including glucuronidation and hydroxylation by CYP2D6. At therapeutic concentrations, it does not inhibit any cytochrome P450 isoenzymes.

    Oral Route

    The absorption of nebivolol tablets is similar to an oral solution; the absolute bioavailability is not known. Peak concentrations are achieved in approximately 1.5—4 hours. Food has no effect on the pharmacokinetics of nebivolol.