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  • CLASSES

    Anti-arrhythmics, Class II
    Beta-Blockers with Alpha Blockade

    DEA CLASS

    Rx

    DESCRIPTION

    Oral nonselective beta-blocker with alpha-1-blocking properties; greater ratio of beta- to alpha-1 blocking effects; lipophilic beta-blocker; lacks ISA; indicated for HTN, post-MI, and CHF (improved morbidity and mortality in CHF, cardiomyopathy, and post-MI); off-label uses chronic angina and unstable angina.

    COMMON BRAND NAMES

    Coreg, Coreg CR

    HOW SUPPLIED

    Carvedilol/Coreg CR Oral Cap ER: 10mg, 20mg, 40mg, 80mg
    Carvedilol/Coreg Oral Tab: 3.125mg, 6.25mg, 12.5mg, 25mg

    DOSAGE & INDICATIONS

    For the treatment of essential hypertension, either as a single agent or in combination with other antihypertensive agents.
    Oral dosage (regular-release tablets)
    Adults

    Initially, 6.25 mg PO twice daily, taken with food, for 7 to 14 days. Evaluate tolerability by measuring the standing systolic pressure one hour after administration. The full antihypertensive effects are achieved within 7 to 14 days. If further control of trough diastolic blood pressure is needed, the dose may be increase to 12.5 mg PO twice daily if tolerated (based on the standing systolic pressure one hour post-dose) for another 7 to 14 days. Maximum recommended dose is 25 mg PO twice daily. If the pulse rate drops below 55 beats per minute (bpm), reduce the dose. For geriatric patients, consider lower doses.

    Oral dosage (extended-release carvedilol phosphate capsules; Coreg CR)
    Adults

    Initially, 20 mg PO once daily in the morning with food. After 7 to 14 days, the dose may be increased to 40 mg PO once daily to attain target blood pressure goals; evaluate blood pressure response after 7 to 14 days. If needed, the dose may be increased up to 80 mg PO once daily. When converting from immediate-release carvedilol to Coreg CR capsules, clinicians may utilize the following dosage conversion information: 3.125 mg PO twice daily immediate-release = 10 mg PO once daily Coreg CR; 6.25 mg PO twice daily immediate-release = 20 mg PO once daily Coreg CR; 12.5 mg PO twice daily immediate-release = 40 mg PO once daily Coreg CR; 25 mg PO twice daily immediate-release = 80 mg PO once daily Coreg CR.

    Geriatric

    Consider dosage reduction (see initial adult dosage). Although not studied for Coreg CR, carvedilol plasma levels are about 50% higher in the elderly as compared to younger subjects following administration of immediate-release tablets. When switching elderly patients (>= 65 years of age) who are taking 25 mg PO twice daily (the highest recommended dose) of immediate-release carvedilol to the extended-release dosage form, a lower starting dose of 40 mg is recommended to minimize the potential for dizziness, syncope, or hypotension. If after 2 weeks patients tolerate 40 mg PO daily, the dosage may then be increased to 80 mg PO daily.

    For the treatment of heart failure (ischemic origin or cardiomyopathy).
    For mild, moderate, or severe heart failure in adult patients (ischemic origin or cardiomyopathy) as a single agent or in conjunction with digoxin, diuretics, hydralazine, or ACE inhibitor therapy.
    Oral dosage (immediate-release tablets)
    Adults

    Initially, 3.125 mg PO twice daily for 2 weeks. Increase dosage to 6.25, 12.5, and then 25 mg PO twice daily over intervals of at least 2 weeks as tolerated. A maximum dose of 50 mg PO twice daily has been given to patients weighing more than 85 kg with mild-to-moderate heart failure. Maintain patients on lower doses if higher doses are not tolerated. Reduce dose for bradycardia (heart rate less than 55 beats per minute). Guidelines recommend an evidence-based beta blocker in combination with an angiotensin-converting enzyme (ACE) inhibitor, angiotensin receptor blocker (ARB), or angiotensin receptor-neprilysin inhibitor (ARNI) and aldosterone antagonist, in select patients, for patients with chronic reduced ejection fraction heart failure (HFrEF) to reduce morbidity and mortality. The use of an evidence-based beta blocker is recommended for patients with HFrEF NHYA class I to IV. Use of a beta-blocker in patients with preserved ejection fraction heart failure (HFpEF) and hypertension is reasonable to control blood pressure.

    Oral dosage (extended-release capsules)
    Adults

    Initially, 10 mg PO once daily for 2 weeks. Increase dosage to 20, 40, and then 80 mg PO once daily over intervals of at least 2 weeks as tolerated. Maintain patients on lower doses if higher doses are not tolerated. Reduce dose for bradycardia (heart rate less than 55 beats per minute). If switching from immediate-release (IR) to extended-release (ER) formulation, use the following conversions: 6.25 mg/day IR to 10 mg ER PO once daily; 12.5 mg/day IR to 20 mg ER PO once daily; 25 mg/day IR to 40 mg ER PO once daily; and 50 mg/day IR to 80 mg ER PO once daily. Guidelines recommend an evidence-based beta blocker in combination with an angiotensin-converting enzyme (ACE) inhibitor, angiotensin receptor blocker (ARB), or angiotensin receptor-neprilysin inhibitor (ARNI) and aldosterone antagonist, in select patients, for patients with chronic reduced ejection fraction heart failure (HFrEF) to reduce morbidity and mortality. The use of an evidence-based beta blocker is recommended for patients with HFrEF NHYA class I to IV. Use of a beta-blocker in patients with preserved ejection fraction heart failure (HFpEF) and hypertension is reasonable to control blood pressure.

    Geriatric

    Initially, 10 mg PO once daily for 2 weeks. Increase dosage to 20, 40, and then 80 mg PO once daily over intervals of at least 2 weeks as tolerated. Maintain patients on lower doses if higher doses are not tolerated. Reduce dose if patients experience bradycardia (heart rate less than 55 beats per minute). If switching from immediate-release (IR) to extended-release (ER) formulation, use the following conversions: 6.25 mg/day IR to 10 mg ER PO once daily; 12.5 mg/day IR to 20 mg ER PO once daily; 25 mg/day IR to 20 or 40 mg ER PO once daily; and 50 mg/day IR to 40 or 80 mg ER PO once daily. Guidelines recommend an evidence-based beta blocker in combination with an angiotensin-converting enzyme (ACE) inhibitor, angiotensin receptor blocker (ARB), or angiotensin receptor-neprilysin inhibitor (ARNI) and aldosterone antagonist, in select patients, for patients with chronic reduced ejection fraction heart failure (HFrEF) to reduce morbidity and mortality. The use of an evidence-based beta blocker is recommended for patients with HFrEF NHYA class I to IV. Use of a beta-blocker in patients with preserved ejection fraction heart failure (HFpEF) and hypertension is reasonable to control blood pressure.

    For patients with severe heart failure (NYHA Class III/IV) and referred for cardiac transplantation†.
    Oral dosage (regular-release tablets)
    Adults

    Limited data have shown a benefit of carvedilol in patients with severe heart failure (NYHA Class III/IV) referred for cardiac transplantation. An initial dosage of 3.125 mg PO twice daily has been studied, with titration as tolerated to a target dosage of 25 mg PO twice daily. In a subsequent trial, the dosage titration protocol was: initially 6.25 mg/day PO, titrated upward every week (in dosage increments of about 25% to 50%) to the maximally tolerated dosage (up to 100 mg/day PO). The mean daily dosage for carvedilol at the end of the study period was 58 mg (+/- 31 mg) in 48 patients. After excluding patients with contraindications to beta-blockers or patients withdrawn from beta-blockers due to intolerance, patients receiving maximally tolerated doses of beta-blockers had a significantly lower mortality rate compared to patients not receiving beta-blockers during the pre-transplantation period (9% vs. 27%). The reported reduction in mortality appears to be a decrease in the sudden death rate in patients that received beta-blockers. In this study, an initial test dose of 6.25 mg PO or 12.5 mg atenolol PO was administered to patients with NYHA Class III/IV heart failure referred for cardiac transplantation. Prior to study enrollment, 25 patients did not tolerate the beta-blocker test dose as defined by a systolic blood pressure less than 90 mm Hg or heart rate less than 60 beats per minute during the 5 hour observation period. In addition, 34 patients were excluded from beta-blocker therapy due to intolerance (e.g., symptomatic hypotension or increased congestive symptoms) prior to enrollment. Close monitoring following the initial dose and up-titration of carvedilol is prudent in patients with advanced heart failure who are referred for cardiac transplantation.

    For the treatment of heart failure in pediatric patients† (ischemic origin or cardiomyopathy) usually in conjunction with digoxin, diuretics, or ACE inhibitor therapy.
    Oral dosage (immediate-release tablets)
    Infants, Children, and Adolescents

    0.04 to 0.05 mg/kg PO twice daily (Max: 3.125 mg/dose) is a commonly reported initial dosage; however, lower doses (e.g., 0.02 mg/kg) have also been used. Typically, dosages are titrated at approximately 2 week intervals as tolerated to a maximum of about 0.8 mg/kg/day (Max: 50 mg/day). Infants and children younger than 3.5 years of age have faster carvedilol clearance suggesting that a higher mg/kg dose and/or more frequent administration (3 times daily) may be necessary to achieve therapeutic response in these patients. Conflicting data are available regarding the efficacy of carvedilol for the treatment of heart failure in pediatric patients. Although several small trials and case series report improved left ventricular function, symptoms, and/or functional class in pediatric patients , no difference was found between placebo and carvedilol with regard to the improvement or worsening of heart failure in a randomized, double-blind, placebo-controlled trial (n = 161, age 2 months to 17 years).

    For reduction of cardiovascular mortality and morbidity in stable patients with left ventricular dysfunction (ejection fraction of 40% or higher) following acute myocardial infarction.
    Oral dosage (regular-release tablets)
    Adults

    Prior to drug initiation, stabilize hemodynamics and minimize fluid retention. The initial FDA-approved dosage is 6.25 mg PO twice daily, taken with food, for the first 3 to 10 days. A lower starting dose of 3.125 mg PO twice daily may be used and/or titration may be slowed if clinically indicated (e.g., due to hypotension, bradycardia, or fluid retention). Titrate the dosage upward and gradually based on patient tolerability. If tolerated (stable heart rate and blood pressure, minimal fluid retention), increase to 12.5 mg PO twice daily. Gradually titrate to the target dosage of 25 mg PO twice daily. Maximum dosage is 50 mg/day. Using a similar dosage regimen in post-MI patients with left ventricular dysfunction (ejection fraction [EF] 40% or lower), the CAPRICORN study demonstrated reduced cardiovascular mortality and recurrent, non-fatal myocardial infarctions relative to placebo. In a prior double-blind trial, 151 patients with acute myocardial infarction were randomized to placebo or carvedilol 2.5 mg IV, followed by 12.5 mg or 25 mg PO twice daily, beginning within 24 hours of onset of chest pain and continuing for 6 months. Compared with placebo, carvedilol significantly reduced the total number of post-infarction cardiac events (17 vs. 31) and improved echocardiographic assessment of diastolic relaxation. Clinical practice guidelines state oral beta blockers should be initiated in the first 24 hours in patients with STEMI who do not have signs of heart failure, evidence of low output, increased risk for cardiogenic shock, or other contraindications for beta blocker use. Therapy should be continued during and after hospitalization for all patients with no contraindications for use. In geriatric patients, consider lower doses.

    Oral dosage (extended-release carvedilol phosphate capsules; Coreg CR)
    Adults

    Initially, 20 mg PO once daily, administered in the morning with food. A lower starting dose of 10 mg PO once daily may be used and/or titration may be slowed if clinically indicated (e.g., due to hypotension, bradycardia, or fluid retention). Prior to drug initiation, stabilize hemodynamics and minimize fluid retention. Dosage should be individualized and closely monitored by a physician during titration. After 3 to 10 days, the dosage may be increased to 40 mg PO once daily. If tolerated, then increase to the target dosage of 80 mg PO once daily. When converting from immediate-release carvedilol to Coreg CR capsules, clinicians may utilize the following dosage conversion information: 3.125 mg PO twice daily immediate-release = 10 mg PO once daily Coreg CR; 6.25 mg PO twice daily immediate-release = 20 mg PO once daily Coreg CR; 12.5 mg PO twice daily immediate-release = 40 mg PO once daily Coreg CR; 25 mg PO twice daily immediate-release = 80 mg PO once daily Coreg CR.

    Geriatric

    Consider dosage reduction (see initial adult dosage). Although not studied for Coreg CR, carvedilol plasma levels are about 50% higher in geriatric patients as compared to younger subjects following administration of immediate-release tablets. When switching geriatric patients (65 years of age and older) who are taking 25 mg PO twice daily (the highest recommended dose) of immediate-release carvedilol to the extended-release dosage form, a lower starting dose of 40 mg is recommended to minimize the potential for dizziness, syncope, or hypotension. If after 2 weeks patients tolerate 40 mg PO daily, the dosage may then be increased to 80 mg PO daily.

    For the treatment of angina†.
    Chronic stable angina†.
    Oral dosage (regular-release tablets)
    Adults

    25 to 50 mg PO twice daily has been studied in patients with chronic stable angina. In comparative studies of up to 6 months duration, carvedilol 25 mg PO twice daily was shown to be at least as effective as slow-release nifedipine , verapamil , or isosorbide dinitrate plus propranolol in improving exercise capacity, and increasing time to onset of anginal pain or onset of 1-mm ST-segment depression. In a randomized, crossover trial, carvedilol 25 to 50 mg PO twice daily was more effective than 12.5 mg PO twice daily in patients with chronic stable angina. In geriatric patients, consider lower doses.

    Unstable angina† as adjunct to standard therapy.
    Oral dosage (regular-release tablets)
    Adults

    25 mg PO twice daily; titrate slowly. The target dose of 50 mg/day PO reduces heart rate, blood pressure, and ischemic burden in patients with unstable angina pectoris. Close monitoring for bradycardia or hypotension is recommended.

    For heart rate control in patients with atrial fibrillation† or atrial flutter†.
    Oral dosage
    Adults

    3.125 to 25 mg PO twice daily. Clinical practice guidelines recommend the use of beta blockers to control the ventricular rate for patients with paroxysmal, persistent, or permanent atrial fibrillation.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    50 mg/day PO regular-release carvedilol for hypertension or post-myocardial infarction; 100 mg/day PO regular-release carvedilol for heart failure; 80 mg/day PO extended-release carvedilol phosphate capsules (Coreg CR) for hypertension, post-myocardial infarction, and heart failure.

    Geriatric

    50 mg/day PO regular-release carvedilol for hypertension or post-myocardial infarction; 100 mg/day PO regular-release carvedilol for heart failure; 80 mg/day PO extended-release carvedilol phosphate capsules (Coreg CR) for hypertension, post-myocardial infarction, and heart failure.

    Adolescents

    Safety and efficacy have not been established; however, a common maximum target dose of 0.8 to 1 mg/kg/day PO (Max: 50 mg/day) using immediate-release tablets has been studied off-label.

    Children

    Safety and efficacy have not been established; however, a common maximum target dose of 0.8 to 1 mg/kg/day PO (Max: 50 mg/day) has been studied off-label.

    Infants

    Safety and efficacy have not been established. A common maximum target dose of 0.8 to 1 mg/kg/day PO is used off-label, and up to 2 mg/kg/day has been reported in one infant.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Contraindicated in patients with severe hepatic impairment.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears no dosage adjustments are needed.
     
    Intermittent hemodialysis
    Due to its high degree of plasma protein-binding, carvedilol is not likely to be significantly removed by hemodialysis. No supplemental dosage is needed.

    ADMINISTRATION

     
    NOTE: The manufacturer of carvedilol recommends individualized dosing and close monitoring by a health care professional during upward titration.

    Oral Administration

    Administer with food to reduce the rate of absorption. This minimizes the risk of orthostatic hypotension.

    Oral Solid Formulations

    Extended-release capsules (Coreg CR): Administer once daily in the morning with food; do not crush or chew the capsules. Separate the administration of extended-release capsules from alcohol consumption (including prescription and over-the-counter medications that contain ethanol) by at least 2 hours. The capsules may be carefully opened and the beads sprinkled over a spoonful of applesauce. The applesauce should not be warm because it could affect the modified-release properties. The mixture of drug and applesauce should be consumed immediately in its entirety; do not store for future use. Absorption of the Coreg CR beads sprinkled on other foods has not been tested.

    Oral Liquid Formulations

    Oral suspension†: Shake well prior to each use. Administer with appropriate calibrated oral device to ensure accurate dosing.

    Extemporaneous Compounding-Oral

    Extemporaneous formulas for oral suspension†:
    NOTE: In a letter received from GlaxoSmithKline dated June 21, 2006, the manufacturer has provided the following information regarding extemporaneous formulations. Two methods of formulation, resulting in DIFFERENT final concentrations, are described.
    Method 1 (0.1 mg/mL suspension): An oral suspension with a final concentration of 0.1 mg/mL may be prepared in a glass amber bottle as follows (manufacturer data on file). Place one 3.125 mg carvedilol tablet in 5 ml purified water for 10 minutes, then swirl the mixture lightly for 30 seconds to allow disintegration. Add 10 mL Ora-Sweet SF and 15 mL Oral-Plus to the mixture, then cap the bottle and shake vigorously for 30 seconds for adequate mixing. The final suspension volume is 30 mL. The resulting suspension is viscous, white, and opaque with a pinkish tinge. Store the glass amber bottle at room temperature (approximately 25 degrees C or 77 degrees F) for up to 12 weeks.
    Method 2 (1.67 mg/mL suspension): An oral suspension with a final concentration of 1.67 mg/mL may be prepared in a glass amber bottle as follows (manufacturer data on file). Place two 25 mg carvedilol tablet in 5 mL purified water for 10 minutes, then swirl the mixture lightly for 30 seconds to allow disintegration. Add 10 mL Ora-Sweet SF and 15 mL Oral-Plus to the mixture, then cap the bottle and shake vigorously for 30 seconds for adequate mixing. The final suspension volume is 30 ml. The resulting suspension is viscous, white, and opaque with a pinkish tinge. Store the glass amber bottle at room temperature (approximately 25 degrees C or 77 degrees F) for up to 12 weeks.

    STORAGE

    Generic:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Coreg:
    - Protect from moisture
    - Store below 86 degrees F
    Coreg CR:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Beta-blocker hypersensitivity, history of angioedema

    Carvedilol is contraindicated in patients who have demonstrated a serious hypersensitivity reaction (e.g. Stevens-Johnson syndrome, anaphylaxis, or history of angioedema to the drug or any of the components in the commercial formulation. Do not use carvedilol in patients with known beta-blocker hypersensitivity. Cross-sensitivity between beta-blockers may occur.

    Abrupt discontinuation

    Abrupt discontinuation of any beta-adrenergic blocking agent, including carvedilol, can result in the development of myocardial ischemia, myocardial infarction, ventricular arrhythmias, or hypertension, particularly in patients with preexisting cardiac disease. If carvedilol therapy is to be discontinued, it should be gradually withdrawn over 1—2 weeks whenever possible.

    Hyperthyroidism, thyroid disease, thyrotoxicosis

    Carvedilol 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.

    Pheochromocytoma, vasospastic angina

    In patients with pheochromocytoma, an alpha-blocking agent should be initiated prior to the use of a beta-blocking agent. Although carvedilol has both alpha-blocking and beta-blocking actions, there has been no experience with its use in this condition. Carvedilol should be used cautiously in patients with pheochromocytoma. In patients with pheochromocytoma, an alpha-blocking agent should be used prior to the initiation of any beta-blocker. Beta-blocker monotherapy should also be used with caution in patients with vasospastic angina (Prinzmetal's angina) because of the risk of hypertension secondary to unopposed alpha-receptor stimulation.

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

    Because beta-blockers depress conduction through the AV node, these drugs are contraindicated in patients with severe bradycardia, sick sinus syndrome, or second- or third-degree AV block unless a functioning pacemaker is present. Although carvedilol is indicated for the treatment of patients with mild to severe chronic heart failure, it should not be used in patients with acute heart failure, particularly in those requiring IV inotropic therapy. Fluid retention due to acute left ventricular dysfunction should be treated and minimized (e.g., with the use of diuretics) prior to adding carvedilol therapy. Hypotension and orthostatic hypotension are commonly encountered during the initial dosing period; use with caution in patients predisposed to low blood pressure or receiving other medications that may lower blood pressure. Dose reduction or discontinuation may be needed to manage significant bradycardia (e.g., heart rate < 55 beats per min), hypotensive effects, or syncope. Starting with a low dose, careful monitoring of blood pressure, administration with food, and gradual titration help minimize the risk of bradycardia, hypotension, or syncope in the early dosing period. Many beta-blockers are used in the treatment of hypertrophic cardiomyopathy. Beta-blockers are generally contraindicated in patients with cardiogenic shock and should be used cautiously in patients with acute pulmonary edema or other forms of ventricular dysfunction.

    Cerebrovascular disease

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

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

    Carvedilol is a non-selective beta-blocker and, as such, should be avoided in patients with bronchial asthma (two cases of death from status asthmaticus have been reported in patients receiving single doses of carvedilol) and should generally be avoided in patients with other pulmonary disease [e.g., chronic obstructive pulmonary disease (COPD), emphysema, bronchitis] in which acute bronchospasm would put them at risk. All beta-blockers, including beta1-selective agents, should be used with caution in these patients, particularly with high-dose therapy.

    Driving or operating machinery

    Beta-blockers may be associated with dizziness or drowsiness in some patients. Patients should be cautioned to avoid driving or operating machinery until the drug response is known, especially during initial dosing titration and dosage increases of carvedilol in patients with heart failure.

    Surgery

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

    Hepatic disease

    Carvedilol is hepatically metabolized. Patients with cirrhotic hepatic disease may have significantly higher concentrations of carvedilol (approximately 4—7 fold) compared to healthy patients. According to the manufacturer, carvedilol is contraindicated in patients with severe hepatic disease. Studies of patients with cirrhosis (mean Child-Pugh score 7.4 +/- 0.5) receiving carvedilol have reported reduced portal pressure and significant hypotensive effects , with some patients not being able to tolerate a 25 mg dose of carvedilol.

    Peripheral vascular disease, renal disease, renal failure, renal impairment

    Rarely, use of carvedilol in patients with congestive heart failure has resulted in deterioration of renal function. Patients at risk appear to be those with hypotension (systolic BP < 100 mmHg), ischemic heart disease and diffuse vascular disease, and/or underlying renal disease or renal impairment; renal function has returned to baseline when carvedilol was discontinued. In patients with these risk factors it is recommended that renal function be monitored during up-titration of carvedilol and the drug discontinued or dosage reduced if worsening of renal function occurs. Patients with renal impairment or renal failure may have higher plasma levels of carvedilol; however, no dosage adjustments are needed. Because beta-blockers can produce or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease, carvedilol should be administered cautiously to these patients.

    Depression

    Beta-blockers should be used with caution in patients with major depression. It has been proposed that lipophilic beta-blockers (e.g., carvedilol) are more likely to be associated with CNS effects than hydrophilic drugs; however, this theory has been debated based on clinical experience with beta-blockers.

    Psoriasis

    Beta-blockers, such as carvedilol, may exacerbate psoriasis.

    Myasthenia gravis

    Beta-blockers, such as carvedilol, may potentiate muscle weakness and double vision in patients with myasthenia gravis.

    Geriatric

    Carvedilol plasma levels average about 50% higher in geriatric patients as compared to younger patients. Beta-blockers can be used safely in elderly patients; however, these patients may have exaggerated responses (e.g., orthostatic effects) to usual adult doses. During clinical trials of immediate-release carvedilol for hypertension, heart failure, and myocardial infarction populations, significant percentages of elderly patients were enrolled (21—48%). With the exception of dizziness in hypertensive patients (8.8% for elderly vs. 6% for younger patients), no overall differences in the safety or effectiveness of immediate-release carvedilol were seen. A randomized trial of patients >= 65 years of age with mild to moderate heart failure compared patients switched to extended-release carvedilol to those maintained on the immediate-release formulation. The combined incidence of dizziness, hypotension, or syncope was 24% in patients switched from the highest dose of immediate-release carvedilol (25 mg PO twice daily) compared to 11% in patients maintained on the immediate-release formulation. Based on these findings, the manufacturer suggests using a lower starting dose of extended-release carvedilol (40 mg/day PO) when switching elderly patients from 25 mg twice daily of the immediate-release formulation. Initial dosage reduction of immediate-release carvedilol should be considered in elderly patients; adjust further dosage based on clinical response.

    Diabetes mellitus, hypoglycemia

    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. Carvedilol should be used with caution in diabetes mellitus because the drug can mask symptoms of hypoglycemia such as tachycardia, palpitations, tremor, and anxiety. However, carvedilol usually does not mask other symptoms of hypoglycemia (sweating and hypertension). Beta-blockers may potentiate insulin-induced hypoglycemia and delay the recovery of serum glucose levels by interfering with glycogenolysis. In patients with mild to moderate hypertension and type 2 diabetes, no adverse effects on glycemic control as measured by HbA1c in patients receiving carvedilol (GEMINI). Although not systematically studied in heart failure patients with diabetes mellitus, carvedilol may lead to worsening hyperglycemia; the manufacturer recommends monitoring of blood glucose during initiation of carvedilol therapy and following dosage adjustments or drug discontinuation. Carvedilol should be used cautiously in patients receiving insulin or oral hypoglycemic agents. While beta-blockers probably should not be used in patients with brittle diabetes, they may be used cautiously in more stable patients.

    Contact lenses

    Carvedilol may cause decreased lacrimation which may make the eyes dry. Patients wearing contact lenses may have an increased awareness, or blurred vision. The use of lubricating drops may be necessary.

    Pregnancy

    Available data regarding the use of carvedilol in pregnant women are insufficient to determine whether there are drug-associated risks of adverse developmental outcomes. Uncontrolled hypertension increases risks to the mother and fetus during pregnancy. Beta-blocker use in the third trimester may increase the risk of hypotension, bradycardia, hypoglycemia, and respiratory depression in the neonate. There is no evidence of adverse developmental outcomes in animals at clinically relevant doses. At maternally toxic doses of 50 times the maximum recommended human dose (MRHD), post-implantation loss, decreased fetal body weight, and increased frequency of delayed fetal skeletal development were observed in rats. Post-implantation loss was observed when pregnant rabbits received 25 times the MRHD during organogenesis.

    Breast-feeding

     There are no data on the presence of carvedilol in human milk, the effects on the breastfed infant, or the effects on milk production. Carvedilol is present in the milk of lactating rats. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for carvedilol and any potential adverse effects on the breastfed infant for carvedilol or for the underlying maternal condition. Previous American Academy of Pediatrics recommendations did not evaluate the use of carvedilol in breast-feeding mothers. However, the AAP regarded other beta-blockers, such as labetalol, metoprolol, nadolol, propranolol, sotalol, and timolol as usually compatible with breast-feeding; these agents may represent preferable alternatives in some patients.

    Children, infants, neonates

    The safety and efficacy of carvedilol in neonates, infants, children, and adolescents have not been established according to the manufacturer. Limited data exist for off-label use in pediatric patients with heart failure. Although improved heart failure outcomes have not been demonstrated in one randomized placebo-controlled clinical trial, limited clinical trials have shown improved left ventricular function, symptoms, and/or functional class in pediatric patients with heart failure including patients with dilated cardiomyopathy.

    ADVERSE REACTIONS

    Severe

    bradycardia / Rapid / 0.5-10.0
    visual impairment / Early / 5.0-5.0
    pulmonary edema / Early / 0.1-3.0
    AV block / Early / 0.1-3.0
    proteinuria / Delayed / 2.0-3.0
    hyperkalemia / Delayed / 2.0-3.0
    stroke / Early / 0.1-3.0
    myocardial infarction / Delayed / 0-0.1
    bronchospasm / Rapid / 0-0.1
    exfoliative dermatitis / Delayed / 0-0.1
    pancytopenia / Delayed / 0-0.1
    GI bleeding / Delayed / 0-0.1
    heart failure / Delayed / Incidence not known
    asthma-related death / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    aplastic anemia / Delayed / Incidence not known

    Moderate

    orthostatic hypotension / Delayed / 1.8-20.2
    hypotension / Rapid / 9.0-20.2
    hyperglycemia / Delayed / 5.0-12.0
    dyspnea / Early / 11.0-11.0
    peripheral edema / Delayed / 1.0-7.0
    angina / Early / 2.0-6.0
    edema / Delayed / 4.0-6.0
    hypercholesterolemia / Delayed / 1.0-4.0
    hypervolemia / Delayed / 2.0-3.0
    hypovolemia / Early / 2.0-3.0
    melena / Delayed / 2.0-3.0
    palpitations / Early / 2.0-3.0
    hypertension / Early / 2.0-3.0
    depression / Delayed / 0.1-3.0
    hypoglycemia / Early / 2.0-3.0
    diabetes mellitus / Delayed / 2.0-3.0
    elevated hepatic enzymes / Delayed / 0.1-3.0
    glycosuria / Early / 2.0-3.0
    impotence (erectile dysfunction) / Delayed / 2.0-3.0
    hematuria / Delayed / 2.0-3.0
    thrombocytopenia / Delayed / 1.0-3.0
    anemia / Delayed / 0.1-3.0
    hypoprothrombinemia / Delayed / 2.0-3.0
    hypotonia / Delayed / 2.0-3.0
    gout / Delayed / 2.0-3.0
    blurred vision / Early / 2.0-3.0
    hyperuricemia / Delayed / 2.0-3.0
    hyponatremia / Delayed / 2.0-3.0
    impaired cognition / Early / 0.1-1.0
    confusion / Early / 0.1-1.0
    erythema / Early / 0.1-1.0
    psoriaform rash / Delayed / 0.1-1.0
    hyperbilirubinemia / Delayed / 0.1-1.0
    leukopenia / Delayed / 0.1-1.0
    dyskinesia / Delayed / 0.1-1.0
    hypertriglyceridemia / Delayed / 0.1-1.0
    hypokalemia / Delayed / 0.1-1.0
    peripheral vasoconstriction / Rapid / 0.1-1.0
    sinus tachycardia / Rapid / 0.1-1.0
    bundle-branch block / Early / 0-0.1
    migraine / Early / 0-0.1
    amnesia / Delayed / 0-0.1
    neuropathic pain / Delayed / 0-0.1
    paresis / Delayed / 0-0.1
    wheezing / Rapid / Incidence not known
    pneumonitis / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    urinary incontinence / Early / Incidence not known
    floppy iris syndrome / Delayed / Incidence not known
    withdrawal / Early / Incidence not known

    Mild

    dizziness / Early / 2.0-32.0
    fatigue / Early / 24.0-24.0
    diarrhea / Early / 1.0-12.0
    weight gain / Delayed / 10.0-12.0
    asthenia / Delayed / 7.0-11.0
    weakness / Early / 7.0-11.0
    nausea / Early / 2.0-9.0
    syncope / Early / 0.1-8.0
    headache / Early / 5.0-8.0
    cough / Delayed / 5.0-8.0
    vomiting / Early / 1.0-6.0
    arthralgia / Delayed / 1.0-6.0
    pharyngitis / Delayed / 4.0-4.0
    hypoesthesia / Delayed / 1.1-3.0
    paresthesias / Delayed / 1.0-3.0
    vertigo / Early / 2.0-3.0
    fever / Early / 2.0-3.0
    muscle cramps / Delayed / 2.0-3.0
    abdominal pain / Early / 2.0-3.0
    drowsiness / Early / 2.0-3.0
    purpura / Delayed / 2.0-3.0
    malaise / Early / 2.0-3.0
    weight loss / Delayed / 2.0-3.0
    insomnia / Early / 1.0-2.0
    nasal congestion / Early / 1.0-1.0
    rash / Early / 0.1-1.0
    nightmares / Early / 0.1-1.0
    emotional lability / Early / 0.1-1.0
    pruritus / Rapid / 0.1-1.0
    maculopapular rash / Early / 0.1-1.0
    photosensitivity / Delayed / 0.1-1.0
    libido decrease / Delayed / 0.1-1.0
    increased urinary frequency / Early / 0.1-1.0
    tinnitus / Delayed / 0.1-1.0
    hyperhidrosis / Delayed / 0.1-1.0
    xerostomia / Early / 0.1-1.0
    tremor / Early / 0-0.1
    alopecia / Delayed / 0-0.1
    anxiety / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    diaphoresis / Early / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Moderate) Increased concentrations of dolutegravir may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and dolutegravir is a P-gp substrate in vitro.
    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; Propoxyphene: (Minor) Inhibitors of the hepatic CYP450 isozyme CYP 2D6, such as propoxyphene, may inhibit the hepatic oxidative metabolism of carvedilol. The clinical significance of this pharmacokinetic interaction is unclear.
    Adenosine: (Moderate) Because the pharmacologic effects of beta-blockers include depression of AV nodal conduction and myocardial function, additive effects are possible when used in combination with adenosine. The risk of additive inhibition of AV conduction is symptomatic bradycardia with hypotension or advanced AV block; whereas additive negative inotropic effects could precipitate overt heart failure in some patients.
    Afatinib: (Moderate) If the concomitant use of carvedilol and afatinib is necessary, consider reducing the afatinib dose by 10 mg per day if the original dose is not tolerated; resume the previous dose of afatinib as tolerated after discontinuation of carvedilol. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro, and carvedilol is a weak P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration of another P-gp inhibitor, ritonavir (200 mg twice daily for 3 days), 1 hour before afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when ritonavir was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after afatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise.
    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: (Major) Amiodarone prolongs AV nodal refractory period and decreases sinus node automaticity. Because beta-blockers have similar effects, concomitant administration of beta-blockers with amiodarone may cause additive electrophysiologic effects (slow sinus rate or worsen AV block), resulting in symptomatic bradycardia, sinus arrest, and atrioventricular block. This is particularly likely in patients with preexisting partial AV block or sinus node dysfunction. In addition, amiodarone is an inhibitor of CYP2D6, CYP2C9, and P-glycoprotein. Concomitant administration of amiodarone and carvedilol increased the concentration of the S(-) enantiomer of carvedilol by at least 2-fold. Caution is advised as metoprolol, another beta-blocker metabolized by CYP2D6, in combination with amiodarone has resulted in severe sinus bradycardia. While the combination should be used cautiously and with close monitoring, it should be noted that post-hoc analysis of amiodarone therapy in patients after acute myocardial infarction in two clinical trials revealed that amiodarone in addition to a beta-blocker significantly lowered the incidence of cardiac and arrhythmic death or resuscitated cardiac arrest when compared with amiodarone or beta-blocker therapy alone. Patients receiving amiodarone concurrently with carvedilol should be monitored for bradycardia or heart block, especially when one agent is added to pre-existing treatment with the other.
    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. (Moderate) Concomitant use of carvedilol and atorvastatin may result in increased atorvastatin concentrations. Carvedilol is a P-glycoprotein (P-gp) inhibitor and atorvastatin is a P-gp substrate. Monitor serum lipid profile and for signs and symptoms of myopathy during coadministration.
    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. (Moderate) Consider separating the time of dosing of carvedilol from that of an angiotensin-converting enzyme (ACE) inhibitor or temporarily reducing the ACE inhibitor dosage if vasodilatory symptoms (e.g., dizziness, lightheadedness, syncope) occur with concomitant use.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Amlodipine; Olmesartan: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Amlodipine; Telmisartan: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Amlodipine; Valsartan: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Amobarbital: (Moderate) Although concurrent use of amobarbital with antihypertensive agents may lead to hypotension, barbiturates, as a class, can enhance the hepatic metabolism of beta-blockers that are significantly metabolized by the liver. Beta-blockers that may be affected include betaxolol, labetalol, metoprolol, pindolol, propranolol, and timolol. Clinicians should closely monitor patients blood pressure during times of coadministration.
    Amyl Nitrite: (Moderate) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as antihypertensive agents or other peripheral vasodilators. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with any beta-blockers.
    Angiotensin-converting enzyme inhibitors: (Moderate) Consider separating the time of dosing of carvedilol from that of an angiotensin-converting enzyme (ACE) inhibitor or temporarily reducing the ACE inhibitor dosage if vasodilatory symptoms (e.g., dizziness, lightheadedness, syncope) occur with concomitant use.
    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.
    Apalutamide: (Moderate) Monitor for decreased efficacy of carvedilol if coadministration with apalutamide is necessary. Carvedilol is a CYP2C9 substrate and apalutamide is a weak CYP2C9 inducer. Coadministration with a multi-enzyme inducer decreased plasma concentrations of carvedilol by about 70%.
    Apixaban: (Major) Concomitant use of carvedilol and apixaban may result in increased apixaban concentrations. Carvedilol is a P-glycoprotein (P-gp) inhibitor and apixaban is a P-gp substrate. Increased exposure to apixaban may result in increased risk of bleeding. Monitor for evidence of bleeding during concurrent use.
    Apomorphine: (Moderate) Patients receiving apomorphine may experience orthostatic hypotension, hypotension, and/or syncope. Extreme caution should be exercised if apomorphine is used concurrently with antihypertensive agents.
    Apraclonidine: (Minor) Theoretically, additive blood pressure reductions could occur when apraclonidine is combined with antihypertensive agents.
    Aripiprazole: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents. It may be advisable to monitor blood pressure when these medications are coadministered.
    Armodafinil: (Moderate) Concomitant use of carvedilol and armodafinil may result in increased armodafinil concentrations. Carvedilol is a P-glycoprotein (P-gp) inhibitor. An in vitro study indicated that and armodafinil is a P-gp substrate. Observation of the patient for increased effects from armodafinil may be needed.
    Artemether; Lumefantrine: (Moderate) Lumefantrine is an inhibitor and carvedilol is a substrate of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased carvedilol concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Articaine; Epinephrine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects.
    Asenapine: (Moderate) Secondary to alpha-blockade, asenapine can produce vasodilation that may result in additive effects during concurrent use of carvedilol. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known; the carvedilol dosage may need to be adjusted.
    Aspirin, ASA: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Aspirin, ASA; Carisoprodol: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Aspirin, ASA; Dipyridamole: (Major) Beta-blockers should generally be withheld before dipyridamole-stress testing. Monitor the heart rate carefully following the dipyridamole injection. (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Aspirin, ASA; Omeprazole: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Aspirin, ASA; Oxycodone: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Aspirin, ASA; Pravastatin: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Atazanavir: (Moderate) Atazanavir can prolong the PR interval. Coadministration with other agents that prolong the PR interval, like beta blockers, may result in elevated risk of conduction disturbances and atrioventricular block.
    Atazanavir; Cobicistat: (Moderate) Atazanavir can prolong the PR interval. Coadministration with other agents that prolong the PR interval, like beta blockers, may result in elevated risk of conduction disturbances and atrioventricular block. (Moderate) Coadministration of cobicistat (a CYP2D6 inhibitor) with beta-blockers metabolized by CYP2D6, such as carvedilol, may result in elevated beta-blocker serum concentrations. If used concurrently, close clinical monitoring with appropriate beta-blocker dose reductions are advise.
    Atorvastatin: (Moderate) Concomitant use of carvedilol and atorvastatin may result in increased atorvastatin concentrations. Carvedilol is a P-glycoprotein (P-gp) inhibitor and atorvastatin is a P-gp substrate. Monitor serum lipid profile and for signs and symptoms of myopathy during coadministration.
    Atorvastatin; Ezetimibe: (Moderate) Concomitant use of carvedilol and atorvastatin may result in increased atorvastatin concentrations. Carvedilol is a P-glycoprotein (P-gp) inhibitor and atorvastatin is a P-gp substrate. Monitor serum lipid profile and for signs and symptoms of myopathy during coadministration.
    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.
    Benazepril: (Moderate) Consider separating the time of dosing of carvedilol from that of an angiotensin-converting enzyme (ACE) inhibitor or temporarily reducing the ACE inhibitor dosage if vasodilatory symptoms (e.g., dizziness, lightheadedness, syncope) occur with concomitant use.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Consider separating the time of dosing of carvedilol from that of an angiotensin-converting enzyme (ACE) inhibitor or temporarily reducing the ACE inhibitor dosage if vasodilatory symptoms (e.g., dizziness, lightheadedness, syncope) occur with concomitant use.
    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.
    Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving carvedilol. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving carvedilol. Bleeding risk may be increased; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a substrate of P-gp; carvedilol inhibits P-gp.
    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.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering carvedilol with boceprevir due to an increased potential for carvedilol and or boceprevir-related adverse events. If carvedilol dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of carvedilol. Carvedilol is an inhibitor and substrate of the drug efflux transporter P-glycoprotein (PGP); boceprevir is an inhibitor and substrate of this efflux protein. Coadministration may result in elevated plasma concentrations of either drug.
    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: (Major) Because the pharmacologic effects of carvedilol include AV nodal conduction depression, additive effects are possible when used in combination with antiarrhythmics such as bretylium.
    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.
    Budesonide: (Minor) Increased concentrations of budesonide may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and budesonide is a P-gp substrate.
    Budesonide; Formoterol: (Minor) Increased concentrations of budesonide may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and budesonide is a P-gp substrate.
    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.
    Bupropion: (Minor) Monitor for an increased incidence of carvedilol-related adverse effects if bupropion and carvedilol are used concomitantly. Coadministration of bupropion and carvedilol may result in increased plasma concentrations of carvedilol. Bupropion and hydroxybupropion, the major active metabolite, are inhibitors of CYP2D6 in vitro. Carvedilol is a CYP2D6 substrate.
    Bupropion; Naltrexone: (Minor) Monitor for an increased incidence of carvedilol-related adverse effects if bupropion and carvedilol are used concomitantly. Coadministration of bupropion and carvedilol may result in increased plasma concentrations of carvedilol. Bupropion and hydroxybupropion, the major active metabolite, are inhibitors of CYP2D6 in vitro. Carvedilol is a CYP2D6 substrate.
    Cabergoline: (Major) Because of its potential to cause coronary vasospasm, ergot alkaloids could theoretically antagonize the therapeutic effects of beta-blockers.
    Cabozantinib: (Minor) Monitor for an increase in carvedilol-related adverse reactions if coadministration with cabozantinib is necessary. Carvedilol is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Caffeine; Ergotamine: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Canagliflozin; 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.
    Cannabidiol: (Moderate) Consider a dose reduction of carvedilol with increased monitoring for signs of bradycardia or heart block, as clinically appropriate, if adverse reactions occur when administered with cannabidiol. Increased carvedilol exposure is possible. Carvedilol is a CYP2C9 substrate. In vitro data predicts inhibition of CYP2C9 by cannabidiol potentially resulting in clinically significant interactions.
    Capecitabine: (Moderate) Use caution if coadministration of capecitabine with carvedilol is necessary, and monitor for an increase in carvedilol-related adverse reactions, including bradycardia or heart block. Carvedilol is a CYP2C9 substrate; capecitabine and/or its metabolites are thought to be inhibitors of CYP2C9. In a drug interaction study, the mean AUC of another CYP2C9 substrate, S-warfarin (single dose), significantly increased after coadministration with capecitabine; the maximum observed INR value also increased by 91%.
    Captopril: (Moderate) Consider separating the time of dosing of carvedilol from that of an angiotensin-converting enzyme (ACE) inhibitor or temporarily reducing the ACE inhibitor dosage if vasodilatory symptoms (e.g., dizziness, lightheadedness, syncope) occur with concomitant use.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Consider separating the time of dosing of carvedilol from that of an angiotensin-converting enzyme (ACE) inhibitor or temporarily reducing the ACE inhibitor dosage if vasodilatory symptoms (e.g., dizziness, lightheadedness, syncope) occur with concomitant use.
    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 carvedilol due to the risk of additive bradycardia. If coadministration is unavoidable, monitor heart rate and blood pressure regularly and watch for carvedilol-related adverse reactions. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary.
    Cevimeline: (Moderate) Cevimeline may alter cardiac conduction and/or heart rate. Conduction disturbances are possible with concurrent use of beta-blockers and cevimeline.
    Chloroprocaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Chlorpromazine: (Minor) Inhibitors of the hepatic CYP450 isozyme CYP 2D6, such as chlorpromazine, may inhibit the hepatic oxidative metabolism of carvedilol.
    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) Monitor for an increased incidence of carvedilol-related adverse effects if cimetidine and carvedilol are used concomitantly. Inhibitors of the hepatic CYP450 isozyme CYP2D6 may inhibit the hepatic oxidative metabolism of carvedilol. Cimetidine inhibits several hepatic cytochrome isozymes, including CYP2D6 and has been shown to increase carvedilol steady-state area under the plasma-concentration time curve (AUC) by 30%. Maximum serum concentrations of carvedilol are not increased. The clinical significance of this pharmacokinetic interaction is unclear.
    Cinacalcet: (Minor) Cinacalcet, a strong in vitro inhibitor of the CYP2D6 cytochrome P450 enzyme, may theoretically increase concentrations of other drugs metabolized by this enzyme, including carvedilol.
    Citalopram: (Minor) Citalopram mildly inhibits the hepatic CYP2D6 isoenzyme at therapeutic doses. This can result in increased concentrations of drugs metabolized via the same pathway, including carvedilol.
    Clevidipine: (Moderate) Calcium-channel blockers, like clevidipine, and beta-blockers frequently are used together with no adverse reactions. Patients should be monitored carefully, however, for excessive bradycardia, cardiac conduction abnormalities, or hypotension if these drugs are given together.
    Clonidine: (Major) Monitor heart rate in patients receiving concomitant clonidine and agents known to affect sinus node function or AV nodal conduction (e.g., beta-blockers). Severe bradycardia resulting in hospitalization and pacemaker insertion has been reported during combination therapy with clonidine and other sympatholytic agents. Concomitant use of clonidine with beta-blockers can also cause additive hypotension. Beta-blockers should not be substituted for clonidine when modifications are made in a patient's antihypertensive regimen because beta-blocker administration during clonidine withdrawal can augment clonidine withdrawal, which may lead to a hypertensive crisis. If a beta-blocker is to be substituted for clonidine, clonidine should be gradually tapered and the beta-blocker should be gradually increased over several days to avoid the possibility of rebound hypertension; administration of beta-blockers during withdrawal of clonidine can precipitate severe increases in blood pressure as a result of unopposed alpha stimulation.
    Clozapine: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Cobicistat: (Moderate) Coadministration of cobicistat (a CYP2D6 inhibitor) with beta-blockers metabolized by CYP2D6, such as carvedilol, may result in elevated beta-blocker serum concentrations. If used concurrently, close clinical monitoring with appropriate beta-blocker dose reductions are advise.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of cobicistat (a CYP2D6 inhibitor) with beta-blockers metabolized by CYP2D6, such as carvedilol, may result in elevated beta-blocker serum concentrations. If used concurrently, close clinical monitoring with appropriate beta-blocker dose reductions are advise.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of cobicistat (a CYP2D6 inhibitor) with beta-blockers metabolized by CYP2D6, such as carvedilol, may result in elevated beta-blocker serum concentrations. If used concurrently, close clinical monitoring with appropriate beta-blocker dose reductions are advise. (Moderate) Increased concentrations of tenofovir, pmpa may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and tenofovir is a P-gp substrate.
    Cobimetinib: (Minor) If concurrent use of cobimetinib and carvedilol is necessary, use caution and monitor for a possible increase in cobimetinib-related adverse effects. Cobimetinib is a P-glycoprotein (P-gp) substrate, and carvedilol is a weak P-gp inhibitor; coadministration may result in increased cobimetinib exposure. However, coadministration of cobimetinib with another P-gp inhibitor, vemurafenib (960 mg twice daily), did not result in clinically relevant pharmacokinetic drug interactions.
    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.
    Cod Liver Oil: (Moderate) Fish oil supplements may cause mild, dose-dependent reductions in systolic or diastolic blood pressure in untreated hypertensive patients. Relatively high doses of fish oil are required to produce any blood pressure lowering effect. Additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents. (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Co-Enzyme Q10, Ubiquinone: (Moderate) Co-enzyme Q10, ubiquinone (CoQ10) may lower blood pressure. CoQ10 use in combination with antihypertensive agents may lead to additional reductions in blood pressure in some individuals. Patients who choose to take CoQ10 concurrently with antihypertensive medications should receive periodic blood pressure monitoring. Patients should be advised to inform their prescriber of their use of CoQ10.
    Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and carvedilol in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Carvedilol can inhibit colchicine's metabolism via P-glycoprotein (P-gp), resulting in increased colchicine exposure. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken a P-gp inhibitor like carvedilol in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day.
    Conivaptan: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    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.
    Cyclosporine: (Moderate) Modest increases in mean trough cyclosporine concentrations may occur following initiation of carvedilol treatment. It is recommended that cyclosporine serum concentrations be monitored to individualize dosage.
    Dabigatran: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with carvedilol, a P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery, avoid coadministration with P-gp inhibitors like carvedilol in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/minute), avoid coadministration with carvedilol, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Daclatasvir: (Moderate) Systemic exposure of carvedilol, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of carvedilol; monitor patients for potential adverse effects.
    Dacomitinib: (Moderate) Monitor for increased toxicity of carvedilol if coadministered with dacomitinib. Coadministration may increase serum concentrations of carvedilol. Carvedilol is a CYP2D6 substrate; dacomitinib is a 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.
    Darunavir; Cobicistat: (Moderate) Coadministration of cobicistat (a CYP2D6 inhibitor) with beta-blockers metabolized by CYP2D6, such as carvedilol, may result in elevated beta-blocker serum concentrations. If used concurrently, close clinical monitoring with appropriate beta-blocker dose reductions are advise.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Coadministration of cobicistat (a CYP2D6 inhibitor) with beta-blockers metabolized by CYP2D6, such as carvedilol, may result in elevated beta-blocker serum concentrations. If used concurrently, close clinical monitoring with appropriate beta-blocker dose reductions are advise.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of carvedilol with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of carvedilol and all 4 antiviral drugs. Carvedilol is a substrate of the hepatic isoenzyme CYP2D6 and a substrate and inhibitor of the drug transporter P-glycoprotein (P-gp). Ritonavir inhibits CYP2D6 and P-gp. In addition, dasabuvir, ombitasvir, paritaprevir, and ritonavir are all P-gp substrates. Caution and close monitoring are advised if these drugs are administered together. (Moderate) Concurrent administration of carvedilol with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of carvedilol and the components of the hepatitis C regimen. Carvedilol is a substrate of the hepatic isoenzyme CYP2D6 and a substrate and inhibitor of the drug transporter P-glycoprotein (P-gp). Ritonavir inhibits CYP2D6 and P-gp. In addition, dasabuvir, ombitasvir, paritaprevir, and ritonavir are all P-gp substrates. Caution and close monitoring are advised if these drugs are administered together. (Moderate) Inhibitors of the hepatic CYP450 isozyme CYP2D6, such as ritonavir, may inhibit the hepatic oxidative metabolism of carvedilol. In addition, both drugs are inhibitors and subtrates for P-glycoprotein (P-gp). Close monitoring of serum drug concentrations and/or therapeutic and adverse effects is required when carvedilol is coadministered with ritonavir.
    Delavirdine: (Minor) Delavirdine inhibits CYP2D6 and may increase concentrations of other drugs metabolized by this enzyme, including carvedilol.
    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.
    Dexamethasone: (Minor) Increased concentrations of dexamethasone may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and dexamethasone is a P-gp substrate.
    Dexmedetomidine: (Major) In general, the concomitant administration of dexmedetomidine with antihypertensive agents could lead to additive hypotensive effects. Dexmedetomidine can produce bradycardia or AV block and should be used cautiously in patients who are receiving antihypertensive drugs that lower the heart rate such as beta-blockers.
    Dextromethorphan; Quinidine: (Major) Quinidine may have additive effects (e.g., reduced heart rate, hypotension) on cardiovascular parameters when used together with carvedilol, a beta-blocker. Altered concentrations of quinidine and/or carvedilol may occur during coadministration. Quinidine is a CYP2D6 inhibitor and P-glycoprotein (P-gp) inhibitor and substrate. Carvedilol is a P-gp inhibitor and substrate and a substrate of CYP2D6. 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: (Major) Coadministration of orally administered digoxin and carvedilol increases the serum concentration and AUC of digoxin by 16% and 14%, respectively. No significant changes in digoxin exposure were reported when digoxin was administered intravenously (IV). Digoxin and carvedilol are both substrates for P-glycoprotein (P-gp). Measure serum digoxin concentrations before initiating carvedilol. Reduce digoxin concentrations by decreasing the oral digoxin dose by approximately 15 to 30% or by modifying the dosing frequency and continue monitoring. No dosage adjustment is required when digoxin is administered IV. In addition, coadministration of digoxin with beta-blockers may produce additive effects on AV node conduction resulting in bradycardia and advanced or complete heart block. Despite potential for interactions, digoxin sometimes is intentionally used in combination with a beta-blocker to further reduce conduction through the AV node. Nevertheless, these combinations should be used cautiously, and therapy dosages may need adjustment in some patients.
    Dihydroergotamine: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Diltiazem: (Moderate) The combination of diltiazem and a beta-blocker, like carvedilol, is usually well tolerated; the combination is often used for their combined therapeutic benefits to reduce angina and improve exercise tolerance. However, because beta-blockers and diltiazem are negative inotropes and chronotropes, the combination of beta-blockers and diltiazem may cause heart failure, excessive bradycardia, hypotension, cardiac conduction abnormalities, or heart block.
    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.
    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 carvedilol, 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.
    Docetaxel: (Major) Increased concentrations of docetaxel may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and docetaxel is a P-gp substrate.
    Dolutegravir: (Moderate) Increased concentrations of dolutegravir may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and dolutegravir is a P-gp substrate in vitro.
    Dolutegravir; Rilpivirine: (Moderate) Increased concentrations of dolutegravir may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and dolutegravir is a P-gp substrate in vitro.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Increased concentrations of tenofovir, pmpa may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and tenofovir is a P-gp substrate.
    Doxazosin: (Moderate) Orthostatic hypotension may be more likely if beta-blockers are coadministered with alpha-blockers.
    Doxorubicin: (Moderate) Increased concentrations of doxorubicin may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and doxorubicin is a P-gp substrate.
    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.
    Drospirenone; Ethinyl Estradiol: (Moderate) Increased concentrations of ethinyl estradiol may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and ethinyl estradiol is a P-gp substrate.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Increased concentrations of ethinyl estradiol may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and ethinyl estradiol is a P-gp substrate.
    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) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of carvedilol and duloxetine may increase the risk of hypotension. It is advisable to monitor blood pressure if the combination is necessary.
    Dutasteride; Tamsulosin: (Minor) Tamsulosin did not potentiate the hypotensive effects of atenolol. However, since the symptoms of orthostasis are reported more frequently in tamsulosin-treated vs. placebo patients, there is a potential risk of enhanced hypotensive effects when co-administered with antihypertensive agents
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Increased concentrations of tenofovir, pmpa may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and tenofovir is a P-gp substrate.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Increased concentrations of tenofovir, pmpa may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and tenofovir is a P-gp substrate.
    Eliglustat: (Moderate) Coadministration of carvedilol and eliglustat may result in increased plasma concentrations of carvedilol. Monitor patients closely for carvedilol-related adverse effects including dizziness and vasodilation, and consider reducing the carvedilol dosage and titrating to clinical effect. Carvedilol is a CYP2D6 and P-gp substrate; eliglustat is a CYP2D6 and P-gp inhibitor.
    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.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Increased concentrations of tenofovir, pmpa may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and tenofovir is a P-gp substrate.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Increased concentrations of tenofovir, pmpa may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and tenofovir is a P-gp substrate.
    Enalapril, Enalaprilat: (Moderate) Consider separating the time of dosing of carvedilol from that of an angiotensin-converting enzyme (ACE) inhibitor or temporarily reducing the ACE inhibitor dosage if vasodilatory symptoms (e.g., dizziness, lightheadedness, syncope) occur with concomitant use.
    Enalapril; Felodipine: (Moderate) Coadministration of felodipine and carvedilol 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. (Moderate) Consider separating the time of dosing of carvedilol from that of an angiotensin-converting enzyme (ACE) inhibitor or temporarily reducing the ACE inhibitor dosage if vasodilatory symptoms (e.g., dizziness, lightheadedness, syncope) occur with concomitant use.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Consider separating the time of dosing of carvedilol from that of an angiotensin-converting enzyme (ACE) inhibitor or temporarily reducing the ACE inhibitor dosage if vasodilatory symptoms (e.g., dizziness, lightheadedness, syncope) occur with concomitant use.
    Encainide: (Major) Pharmacologically, beta-blockers, like carvedilol, 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.
    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.
    Erythromycin: (Moderate) Increased concentrations of erythromycin may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and erythromycin is a P-gp substrate.
    Erythromycin; Sulfisoxazole: (Moderate) Increased concentrations of erythromycin may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and erythromycin is a P-gp substrate.
    Escitalopram: (Moderate) Escitalopram is a modest inhibitor of CYP2D6. This can result in increased concentrations of drugs metabolized via the same pathway, including beta-blockers such as carvedilol. In one study, concurrent use of escitalopram and the beta-blocker metoprolol resulted in a 50% increase in Cmax and 82% increase in AUC of metoprolol. It may be advisable to carefully monitor blood pressure and heart rate during coadministration of escitalopram and carvedilol, particularly during treatment initiation and dose increases.
    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.
    Ethinyl Estradiol: (Moderate) Increased concentrations of ethinyl estradiol may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and ethinyl estradiol is a P-gp substrate.
    Ethinyl Estradiol; Desogestrel: (Moderate) Increased concentrations of ethinyl estradiol may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and ethinyl estradiol is a P-gp substrate.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Moderate) Increased concentrations of ethinyl estradiol may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and ethinyl estradiol is a P-gp substrate.
    Ethinyl Estradiol; Etonogestrel: (Moderate) Increased concentrations of ethinyl estradiol may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and ethinyl estradiol is a P-gp substrate.
    Ethinyl Estradiol; Levonorgestrel: (Moderate) Increased concentrations of ethinyl estradiol may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and ethinyl estradiol is a P-gp substrate.
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Moderate) Increased concentrations of ethinyl estradiol may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and ethinyl estradiol is a P-gp substrate.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) Increased concentrations of ethinyl estradiol may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and ethinyl estradiol is a P-gp substrate.
    Ethinyl Estradiol; Norelgestromin: (Moderate) Increased concentrations of ethinyl estradiol may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and ethinyl estradiol is a P-gp substrate.
    Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Increased concentrations of ethinyl estradiol may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and ethinyl estradiol is a P-gp substrate.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Moderate) Increased concentrations of ethinyl estradiol may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and ethinyl estradiol is a P-gp substrate.
    Ethinyl Estradiol; Norethindrone: (Moderate) Increased concentrations of ethinyl estradiol may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and ethinyl estradiol is a P-gp substrate.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Moderate) Increased concentrations of ethinyl estradiol may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and ethinyl estradiol is a P-gp substrate.
    Ethinyl Estradiol; Norgestimate: (Moderate) Increased concentrations of ethinyl estradiol may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and ethinyl estradiol is a P-gp substrate.
    Ethinyl Estradiol; Norgestrel: (Moderate) Increased concentrations of ethinyl estradiol may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and ethinyl estradiol is a P-gp substrate.
    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.
    Etoposide, VP-16: (Minor) Monitor for an increased incidence of etoposide-related adverse effects if used concomitantly with carvedilol. Carvedilol is a weak inhibitor of P-glycoprotein (P-gp) and etoposide, VP-16 is a P-gp substrate. Coadministration may increase etoposide concentrations.
    Etravirine: (Moderate) Etravirine is an inhibitor of the efflux transporter P-glycoprotein (PGP). Carvedilol is a P-glycoprotein substrate. Increased concentrations of carvedilol may occur if it is coadministered with etravirine; exercise caution.
    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.
    Felodipine: (Moderate) Coadministration of felodipine and carvedilol 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.
    Fexofenadine: (Minor) Increased concentrations of fexofenadine may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and fexofenadine is a P-gp substrate.
    Fexofenadine; Pseudoephedrine: (Minor) Increased concentrations of fexofenadine may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and fexofenadine is a P-gp substrate.
    Fingolimod: (Major) If possible, do not start fingolimod in a patient who is taking a drug that slows the heart rate or atrioventricular conduction such as beta-blockers. Use of these drugs during fingolimod initiation may be associated with severe bradycardia or heart block. Seek advice from the prescribing physician regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating fingolimod. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients who cannot stop taking drugs that slow the heart rate or atrioventricular conduction. Experience with fingolimod in patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular conduction is limited.
    Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Moderate) Co-enzyme Q10, ubiquinone (CoQ10) may lower blood pressure. CoQ10 use in combination with antihypertensive agents may lead to additional reductions in blood pressure in some individuals. Patients who choose to take CoQ10 concurrently with antihypertensive medications should receive periodic blood pressure monitoring. Patients should be advised to inform their prescriber of their use of CoQ10. (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Flecainide: (Major) Pharmacologically, beta-blockers, like carvedilol, 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.
    Fluconazole: (Major) Fluconazole is a CYP2C9 inhibitor and may inhibit the metabolism of carvedilol (CYP2C9 substrate), resulting in enhanced beta-blocking properties of carvedilol (e.g., slowing of heart rate or cardiac conduction). Patients receiving fluconazole concurrently with carvedilol should be monitored for bradycardia or heart block, especially when one agent is added to pre-existing treatment with the other.
    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: (Minor) Inhibitors of the hepatic CYP450 isozyme CYP 2D6, such as fluoxetine, may inhibit the hepatic oxidative metabolism of carvedilol.
    Fluoxetine; Olanzapine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents. (Minor) Inhibitors of the hepatic CYP450 isozyme CYP 2D6, such as fluoxetine, may inhibit the hepatic oxidative metabolism of carvedilol.
    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.
    Fosamprenavir: (Moderate) Caution is advised when administering carvedilol with fosamprenavir, as concurrent use may result in elevated fosamprenavir and reduced carvedilol plasma concentrations. Carvedilol is an inhibitor and substrate for the drug transporter P-glycoprotein (P-gp). Amprenavir, the active metabolite of fosamprenavir, is a P-gp inducer and substrate.[
    Fosinopril: (Moderate) Consider separating the time of dosing of carvedilol from that of an angiotensin-converting enzyme (ACE) inhibitor or temporarily reducing the ACE inhibitor dosage if vasodilatory symptoms (e.g., dizziness, lightheadedness, syncope) occur with concomitant use.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Consider separating the time of dosing of carvedilol from that of an angiotensin-converting enzyme (ACE) inhibitor or temporarily reducing the ACE inhibitor dosage if vasodilatory symptoms (e.g., dizziness, lightheadedness, syncope) occur with concomitant use.
    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.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and carvedilol as coadministration may increase serum concentrations of both drugs and increase the risk of adverse effects. Glecaprevir and carvedilol are both substrates and inhibitors of P-glycoprotein (P-gp). (Moderate) Caution is advised with the coadministration of pibrentasvir and carvedilol as coadministration may increase serum concentrations of both drugs and increase the risk of adverse effects. Both pibrentasvir and carvedilol are substrates and inhibitors of P-glycoprotein (P-gp).
    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) Haloperidol should be used cautiously with carvedilol due to the possibility of additive hypotension. In addition, haloperidol inhibits CYP 2D6 and may increase plasma concentrations of carvedilol.
    Halothane: (Major) General anesthetics can potentiate the antihypertensive effects of beta-blockers and can produce prolonged hypotension. Beta-blockers may be continued during general anesthesia as long as the patient is monitored for cardiac depressant and hypotensive effects.
    Hawthorn, Crataegus laevigata: (Moderate) Hawthorn, Crataegus laevigata (also known as C. oxyacantha) may potentially interact with antihypertensive, heart failure, or arrhythmia medications such as the beta-blockers. Following hawthorn administration, the cardiac action potential duration is increased and the refractory period is prolonged. Hawthorn may also lower peripheral vascular resistance. Patients with hypertension or heart failure should be advised to only use hawthorn with their prescribed medications after discussion with their prescriber. Patients who choose to take hawthorn should receive periodic blood pressure and heart rate monitoring.
    Hydralazine; Isosorbide Dinitrate, ISDN: (Moderate) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as antihypertensive agents or other peripheral vasodilators. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with any beta-blockers.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Moderate) Consider separating the time of dosing of carvedilol from that of an angiotensin-converting enzyme (ACE) inhibitor or temporarily reducing the ACE inhibitor dosage if vasodilatory symptoms (e.g., dizziness, lightheadedness, syncope) occur with concomitant use.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Consider separating the time of dosing of carvedilol from that of an angiotensin-converting enzyme (ACE) inhibitor or temporarily reducing the ACE inhibitor dosage if vasodilatory symptoms (e.g., dizziness, lightheadedness, syncope) occur with concomitant use.
    Hydrochlorothiazide, HCTZ; Quinapril: (Moderate) Consider separating the time of dosing of carvedilol from that of an angiotensin-converting enzyme (ACE) inhibitor or temporarily reducing the ACE inhibitor dosage if vasodilatory symptoms (e.g., dizziness, lightheadedness, syncope) occur with concomitant use.
    Hydroxychloroquine: (Minor) Inhibitors of the hepatic CYP450 isozyme CYP 2D6, such as hydroxychloroquine, may inhibit the hepatic oxidative metabolism of carvedilol. Clinicians should use these drugs cautiously in patients stabilized on carvedilol.
    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: (Minor) Imatinib is a potent inhibitor of cytochrome P450 2D6 and may increase concentrations of other drugs metabolized by this enzyme including carvedilol. Caution is recommended when administering imatinib with carvedilol.
    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) Increased concentrations of indinavir may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and indinavir is a P-gp substrate.
    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.
    Iobenguane I 131: (Major) Discontinue carvedilol for at least 5 half-lives before the administration of the dosimetry dose or a therapeutic dose of iobenguane I-131. Do not restart carvedilol until at least 7 days after each iobenguane I-131 dose. Drugs that reduce catecholamine uptake or deplete catecholamine stores, such as carvedilol, may interfere with iobenguane I-131 uptake into cells and interfere with dosimetry calculations resulting in altered iobenguane I-131 efficacy.
    Irinotecan Liposomal: (Moderate) Increased concentrations of irinotecan may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and irinotecan is a P-gp substrate. Use caution if concomitant use is necessary and monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Irinotecan: (Moderate) Increased concentrations of irinotecan may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and irinotecan is a P-gp substrate. Use caution if concomitant use is necessary and monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Isocarboxazid: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with beta-blockers. Limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers. Although the sinus bradycardia observed was not severe, until more data are available, clinicians should use MAOIs cautiously in patients receiving beta-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Isoflurane: (Major) General anesthetics can potentiate the antihypertensive effects of beta-blockers and can produce prolonged hypotension. Beta-blockers may be continued during general anesthesia as long as the patient is monitored for cardiac depressant and hypotensive effects.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Concurrent use of carvedilol and rifampin may result in decreased carvedilol concentrations and reduced beta-blocker efficacy. Dosage must be individualized to the patient's response and tolerance. Monitor for signs of altered carvedilol response. During drug interaction studies, rifampin decreased the Cmax and AUC of carvedilol by approximately 70%. Carvedilol is metabolized primarily by CYP2D6 and CYP2C9; rifampin is a known CYP450 hepatic enzyme inducer.
    Isoniazid, INH; Rifampin: (Moderate) Concurrent use of carvedilol and rifampin may result in decreased carvedilol concentrations and reduced beta-blocker efficacy. Dosage must be individualized to the patient's response and tolerance. Monitor for signs of altered carvedilol response. During drug interaction studies, rifampin decreased the Cmax and AUC of carvedilol by approximately 70%. Carvedilol is metabolized primarily by CYP2D6 and CYP2C9; rifampin is a known CYP450 hepatic enzyme inducer.
    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.
    Itraconazole: (Moderate) Altered concentrations of itraconazole and/or carvedilol may occur during coadministration. Carvedilol and itraconazole are both substrates and inhibitors of P-glycoprotein (P-gp). Use caution if concomitant use is necessary and monitor for increased side effects.
    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.
    Ivacaftor: (Moderate) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as carvedilol. Ivacaftor is an inhibitor of CYP3A, P-glycoprotein (Pgp) and a weak inhibitor of CYP2C9; carvedilol is partially metabolized by CYP3A, CYP2C9 and is a substrate of Pgp. Co-administration of ivacaftor with CYP3A, CYP2C9, and Pgp substrates,such as carvedilol, can theoretically increase carvedilol exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Ixabepilone: (Minor) Ixabepilone is a weak inhibitor of P-glycoprotein (Pgp). Carvedilol is a Pgp substrate, and concomitant use of ixabepilone with a Pgp substrate may cause an increase in carvedilol concentrations. Use caution if ixabepilone is coadministered with a Pgp substrate.
    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.
    Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Increased concentrations of tenofovir, pmpa may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and tenofovir is a P-gp substrate.
    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.
    Ledipasvir; Sofosbuvir: (Moderate) Concurrent administration of ledipasvir; sofosbuvir and carvedilol may result in elevated plasma concentrations of ledipasvir, sofosbuvir, and carvedilol. All three are substrates for the drug transporter, P-glycoprotein (P-gp), while both ledipasvir and carvedilol are also P-gp inhibitors. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effect. For carvediolol, monitor heart rate and blood pressure as per standards of care (Minor) Coadministration of sofosbuvir and carvedilol may result in elevated sofosbuvir plasma concentrations. Sofosbuvir is a substrate for the drug transporter P-glycoprotein (P-gp); carvedilol is a P-gp inhibitor. According to the manufacturer, no dosage adjustments are required when sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effect.
    Letermovir: (Moderate) Monitor for decreased carvedilol efficacy during concurrent use of letermovir. Taking these drugs together may cause a reduction in carvedilol plasma concentrations. Letermovir is a CYP2C9 inducer; carvedilol is a substrate of CYP2C9.
    Levobupivacaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Levodopa: (Moderate) Concomitant use of beta-blockers with levodopa can result in additive hypotensive effects.
    Levomilnacipran: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of beta-blockers may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Levothyroxine: (Minor) Because thyroid hormones cause cardiac stimulation including increased heart rate and increased contractility, the effects of beta-blockers may be reduced by thyroid hormones. The reduction of effects may be especially evident when a patient goes from a hypothyroid to a euthyroid state or when excessive amounts of thyroid hormone is given to the patient.
    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.
    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.
    Lisinopril: (Moderate) Consider separating the time of dosing of carvedilol from that of an angiotensin-converting enzyme (ACE) inhibitor or temporarily reducing the ACE inhibitor dosage if vasodilatory symptoms (e.g., dizziness, lightheadedness, syncope) occur with concomitant use.
    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 carvedilol 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.
    Loperamide: (Moderate) The plasma concentration of loperamide, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with carvedilol, a mild P-gp inhibitor. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Loperamide; Simethicone: (Moderate) The plasma concentration of loperamide, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with carvedilol, a mild P-gp inhibitor. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Lopinavir; Ritonavir: (Moderate) Coadministration of lopinavir with carvedilol may result in increased concentrations of carvedilol. Carvedilol is a substrate of P-glycoprotein (P-gp); lopinavir is a P-gp inhibitor. If coadministration of these drugs is warranted, do so with caution and careful monitoring. A decrease in the carvedilol dose may be warranted. (Moderate) Inhibitors of the hepatic CYP450 isozyme CYP2D6, such as ritonavir, may inhibit the hepatic oxidative metabolism of carvedilol. In addition, both drugs are inhibitors and subtrates for P-glycoprotein (P-gp). Close monitoring of serum drug concentrations and/or therapeutic and adverse effects is required when carvedilol is coadministered with ritonavir.
    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.
    Lumacaftor; Ivacaftor: (Moderate) Concomitant use of carvedilol and lumacaftor; ivacaftor may alter the therapeutic effects of carvedilol; monitor blood pressure closely until the effects of using these drugs together are known. Carvedilol is partially metabolized by CYP3A4, CYP2C9, and CYP2C19, and is a substrate of the P-glycoprotein (P-gp) drug transporter. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor; ivacaftor may induce CYP2C19, and induce and/or inhibit CYP2C9 and P-gp. Although induction of carvedilol through the CYP3A and CYP2C19 pathways may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on CYP2C9-mediated metabolism and P-gp transport is not clear. (Moderate) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as carvedilol. Ivacaftor is an inhibitor of CYP3A, P-glycoprotein (Pgp) and a weak inhibitor of CYP2C9; carvedilol is partially metabolized by CYP3A, CYP2C9 and is a substrate of Pgp. Co-administration of ivacaftor with CYP3A, CYP2C9, and Pgp substrates,such as carvedilol, can theoretically increase carvedilol exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Lumacaftor; Ivacaftor: (Moderate) Concomitant use of carvedilol and lumacaftor; ivacaftor may alter the therapeutic effects of carvedilol; monitor blood pressure closely until the effects of using these drugs together are known. Carvedilol is partially metabolized by CYP3A4, CYP2C9, and CYP2C19, and is a substrate of the P-glycoprotein (P-gp) drug transporter. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor; ivacaftor may induce CYP2C19, and induce and/or inhibit CYP2C9 and P-gp. Although induction of carvedilol through the CYP3A and CYP2C19 pathways may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on CYP2C9-mediated metabolism and P-gp transport is not clear.
    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.
    Maraviroc: (Moderate) Increased concentrations of maraviroc may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and maraviroc is a P-gp substrate.
    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.
    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; Pioglitazone: (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.
    Methadone: (Moderate) Increased concentrations of methadone may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and methadone is a P-gp substrate.
    Methohexital: (Major) General anesthetics can potentiate the antihypertensive effects of beta-blockers and can produce prolonged hypotension.
    Methylergonovine: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Methysergide: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Milnacipran: (Moderate) Milnacipran has been associated with an increase in blood pressure. The effectiveness of antihypertensive agents may be diminished during concurrent use of milnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Milrinone: (Moderate) Concurrent administration of antihypertensive agents could lead to additive hypotension when administered with milrinone. Titrate milrinone dosage according to hemodynamic response.
    Mirabegron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as carvedilol may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Mitomycin: (Moderate) Increased concentrations of mitomycin may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and mitomycin is a P-gp substrate.
    Moexipril: (Moderate) Consider separating the time of dosing of carvedilol from that of an angiotensin-converting enzyme (ACE) inhibitor or temporarily reducing the ACE inhibitor dosage if vasodilatory symptoms (e.g., dizziness, lightheadedness, syncope) occur with concomitant use.
    Morphine: (Moderate) Increased concentrations of morphine may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and morphine is a P-gp substrate.
    Morphine; Naltrexone: (Moderate) Increased concentrations of morphine may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and morphine is a P-gp substrate.
    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.
    Nelfinavir: (Moderate) Altered concentrations of nelfinavir and/or carvedilol may occur during coadministration. Carvedilol and nelfinavir are both substrates and inhibitors of P-glycoprotein (P-gp). Use caution if concomitant use is necessary and monitor for increased side effects.
    Nesiritide, BNP: (Major) The potential for hypotension may be increased when coadministering nesiritide with antihypertensive agents.
    Niacin, Niacinamide: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
    Niacin; Simvastatin: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
    Nicardipine: (Moderate) Although concomitant therapy with nicardipine and carvedilol generally is well tolerated and can even be beneficial in some cases (by inhibiting reflex tachycardia induced by nicardipine), carvedilol can induce excessive bradycardia or hypotension. This combination also can cause additive negative inotropic effects. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nicardipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nicardipine therapy can minimize or eliminate this potential interaction. Patients should be monitored carefully, however, for excessive bradycardia, cardiac conduction abnormalities, or hypotension when these drugs are given together. In general, these reactions are more likely to occur with verapamil or diltiazem than with nicardipine.
    Nifedipine: (Moderate) In general, concomitant therapy of nifedipine with beta-blockers is well tolerated and can even be beneficial in some cases (i.e., inhibition of nifedipine-induced reflex tachycardia by beta-blockade). Negative inotropic and/or chronotropic effects can be additive when these drugs are used in combination. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nifedipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nifedipine therapy may minimize or eliminate this potential interaction. Hypotension and impaired cardiac performance can occur during coadministration of nifedipine with beta-blockers, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Monitor clinical response during coadministration; adjustment of nifedipine dosage may be needed during concurrent beta-blocker therapy.
    Nimodipine: (Moderate) Nimodipine, a selective calcium-channel blocker, can enhance the antihypertensive effects of beta-blockers. Although often used together, concurrent use of calcium-channel blockers and beta-blockers may result in additive hypotensive, negative inotropic, and/or bradycardic effects in some patients.
    Nisoldipine: (Moderate) Concurrent use of nisoldipine with carvedilol can be beneficial (i.e., inhibition of vasodilation-induced reflex tachycardia by beta-blockade); however, the additive negative inotropic and/or chronotropic effects can cause adverse effects, especially in patients with compromised ventricular function or conduction defects (e.g., sinus bradycardia or AV block).
    Nitrates: (Moderate) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as antihypertensive agents or other peripheral vasodilators. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with any beta-blockers.
    Nitroglycerin: (Moderate) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as antihypertensive agents or other peripheral vasodilators. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with any beta-blockers.
    Nitroprusside: (Moderate) Additive hypotensive effects may occur when nitroprusside is used concomitantly with other antihypertensive agents. Dosages should be adjusted carefully, according to blood pressure.
    Non-Ionic Contrast Media: (Moderate) Some clinicians consider patients taking beta-blockers to be at increased risk for anaphylactoid reactions and administer prophylactic corticosteroids/antihistamines prior to the administration of radiopaque contrast agents.
    Nonsteroidal antiinflammatory drugs: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Octreotide: (Moderate) Dose adjustments in drugs such as beta-blockers and calcium-channel blockers which cause bradycardia and/or affect cardiac conduction may be necessary during octreotide therapy due to additive effects.
    Olanzapine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of carvedilol with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of carvedilol and the components of the hepatitis C regimen. Carvedilol is a substrate of the hepatic isoenzyme CYP2D6 and a substrate and inhibitor of the drug transporter P-glycoprotein (P-gp). Ritonavir inhibits CYP2D6 and P-gp. In addition, dasabuvir, ombitasvir, paritaprevir, and ritonavir are all P-gp substrates. Caution and close monitoring are advised if these drugs are administered together. (Moderate) Inhibitors of the hepatic CYP450 isozyme CYP2D6, such as ritonavir, may inhibit the hepatic oxidative metabolism of carvedilol. In addition, both drugs are inhibitors and subtrates for P-glycoprotein (P-gp). Close monitoring of serum drug concentrations and/or therapeutic and adverse effects is required when carvedilol is coadministered with ritonavir.
    Ondansetron: (Moderate) Increased concentrations of ondansetron may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and ondansetron is a P-gp substrate.
    Oritavancin: (Moderate) Carvedilol is metabolized by CYP2D6; oritavancin is a weak CYP2D6 inducer. Plasma concentrations and efficacy of carvedilol 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.
    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.
    Paroxetine: (Minor) Inhibitors of the hepatic CYP450 isozyme CYP 2D6, such as paroxetine, may inhibit the hepatic oxidative metabolism of carvedilol.
    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) Altered concentrations of pazopanib and/or carvedilol may occur during coadministration. Carvedilol and pazopanib are both substrates and inhibitors of P-glycoprotein (P-gp). Use caution if concomitant use is necessary and monitor for increased side effects.
    Peginterferon Alfa-2b: (Moderate) Monitor for adverse effects associated with increased exposure to carvedilol if peginterferon alfa-2b is coadministered. Peginterferon alfa-2b is a CYP2D6 inhibitor, while carvedilol is a CYP2D6 substrate.
    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: (Moderate) Consider separating the time of dosing of carvedilol from that of an angiotensin-converting enzyme (ACE) inhibitor or temporarily reducing the ACE inhibitor dosage if vasodilatory symptoms (e.g., dizziness, lightheadedness, syncope) occur with concomitant use.
    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. (Moderate) Consider separating the time of dosing of carvedilol from that of an angiotensin-converting enzyme (ACE) inhibitor or temporarily reducing the ACE inhibitor dosage if vasodilatory symptoms (e.g., dizziness, lightheadedness, syncope) occur with concomitant use.
    Perphenazine: (Minor) Inhibitors of the hepatic CYP450 isozyme CYP 2D6, such as perphenazine, may inhibit the hepatic oxidative metabolism of carvedilol. Clinicians should use perphenazine cautiously in patients stabilized on carvedilol.
    Perphenazine; Amitriptyline: (Minor) Inhibitors of the hepatic CYP450 isozyme CYP 2D6, such as perphenazine, may inhibit the hepatic oxidative metabolism of carvedilol. Clinicians should use perphenazine cautiously in patients stabilized on carvedilol.
    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.
    Posaconazole: (Moderate) Altered concentrations of posaconazole and/or carvedilol may occur during coadministration. Carvedilol and posaconazole are both substrates and inhibitors of P-glycoprotein (P-gp). Use caution if concomitant use is necessary and monitor for increased side effects.
    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.
    Prednisone: (Minor) Increased concentrations of prednisone may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and prednisone is a P-gp substrate.
    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 carvedilol. In general, patients receiving combined therapy with procainamide and beta-blockers should be monitored for potential bradycardia, AV block, and/or hypotension.
    Procaine: (Minor) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Propafenone: (Major) Pharmacologically, beta-blockers, like carvedilol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Patients should be monitored closely and the dose should be adjusted according to clinical response.
    Propofol: (Major) General anesthetics can potentiate the antihypertensive effects of beta-blockers and can produce prolonged hypotension. Beta-blockers may be continued during general anesthesia as long as the patient is monitored for cardiac depressant and hypotensive effects.
    Propoxyphene: (Minor) Inhibitors of the hepatic CYP450 isozyme CYP 2D6, such as propoxyphene, may inhibit the hepatic oxidative metabolism of carvedilol. The clinical significance of this pharmacokinetic interaction is unclear.
    Quinapril: (Moderate) Consider separating the time of dosing of carvedilol from that of an angiotensin-converting enzyme (ACE) inhibitor or temporarily reducing the ACE inhibitor dosage if vasodilatory symptoms (e.g., dizziness, lightheadedness, syncope) occur with concomitant use.
    Quinidine: (Major) Quinidine may have additive effects (e.g., reduced heart rate, hypotension) on cardiovascular parameters when used together with carvedilol, a beta-blocker. Altered concentrations of quinidine and/or carvedilol may occur during coadministration. Quinidine is a CYP2D6 inhibitor and P-glycoprotein (P-gp) inhibitor and substrate. Carvedilol is a P-gp inhibitor and substrate and a substrate of CYP2D6. 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: (Minor) Inhibitors of the hepatic CYP450 isozyme CYP 2D6, such as quinine, may inhibit the hepatic oxidative metabolism of carvedilol. The clinical significance of this pharmacokinetic interaction is unclear.
    Ramipril: (Moderate) Consider separating the time of dosing of carvedilol from that of an angiotensin-converting enzyme (ACE) inhibitor or temporarily reducing the ACE inhibitor dosage if vasodilatory symptoms (e.g., dizziness, lightheadedness, syncope) occur with concomitant use.
    Ranolazine: (Moderate) Inhibitors of CYP2D6, like ranolazine, may inhibit the hepatic oxidative metabolism of carvedilol.
    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).
    Rifabutin: (Moderate) Serum concentrations of carvedilol may be decreased if coadministered with rifabutin. Rifabutin is a known hepatic enzyme inducer, thus, it is not possible to stagger the administration times to avoid this interaction.
    Rifampin: (Moderate) Concurrent use of carvedilol and rifampin may result in decreased carvedilol concentrations and reduced beta-blocker efficacy. Dosage must be individualized to the patient's response and tolerance. Monitor for signs of altered carvedilol response. During drug interaction studies, rifampin decreased the Cmax and AUC of carvedilol by approximately 70%. Carvedilol is metabolized primarily by CYP2D6 and CYP2C9; rifampin is a known CYP450 hepatic enzyme inducer.
    Rifapentine: (Moderate) Rifapentine induces hepatic isoenzymes CYP3A4 and CYP2C8/9. Drugs metabolized by CYP3A4 and CYP2C8/9, such as carvedilol, may require dosage adjustments when administered concurrently with rifapentine.
    Risperidone: (Moderate) Risperidone may induce orthostatic hypotension and thus enhance the hypotensive effects of carvedilol. Lower initial doses or slower dose titration of risperidone may be necessary in patients receiving carvedilol concomitantly.
    Ritonavir: (Moderate) Inhibitors of the hepatic CYP450 isozyme CYP2D6, such as ritonavir, may inhibit the hepatic oxidative metabolism of carvedilol. In addition, both drugs are inhibitors and subtrates for P-glycoprotein (P-gp). Close monitoring of serum drug concentrations and/or therapeutic and adverse effects is required when carvedilol is coadministered with ritonavir.
    Rivaroxaban: (Moderate) Altered concentrations of rivaroxaban and/or carvedilol may occur during coadministration. Carvedilol and rivaroxaban are both substrates and inhibitors of P-glycoprotein (P-gp). Use caution if concomitant use is necessary and monitor for increased side effects.
    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) Use caution if carvedilol and rolapitant are used concurrently, and monitor for carvedilol-related adverse effects. Carvedilol is a substrate of CYP2D6 and P-glycoprotein (P-gp) that is individually dose-titrated, and rolapitant is an inhibitor of CYP2D6 and P-gp. 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. When oral rolapitant was administered with another P-gp substrate, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied. When the P-gp substrate was administered with a single dose of intravenous rolapitant, no effect on AUC and a 21% increase in the Cmax of P-gp substrate was observed.
    Ropivacaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Rucaparib: (Moderate) Monitor for signs of bradycardia or heart block if coadministration of carvedilol with rucaparib is necessary. Carvedilol is a CYP2C9 substrate and rucaparib is a weak CYP2C9 inhibitor. Concomitant use may enhance the beta-blocking properties of carvedilol resulting in further slowing of the heart rate or cardiac conduction.
    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.
    Sapropterin: (Moderate) Caution is advised with the concomitant use of sapropterin and carvedilol as coadministration may result in increased systemic exposure of carvedilol. Carvedilol is a substrate for the drug transporter P-glycoprotein (P-gp); in vitro data show that sapropterin may inhibit P-gp. If these drugs are used together, closely monitor for increased side effects of carvedilol.
    Saquinavir: (Moderate) Altered concentrations of saquinavir and/or carvedilol may occur during coadministration. Carvedilol and saquinavir are both substrates and inhibitors of P-glycoprotein (P-gp). Use caution if concomitant use is necessary and monitor for increased side effects.
    Selegiline: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with beta-blockers. Limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers. Although the sinus bradycardia observed was not severe, until more data are available, clinicians should use MAOIs cautiously in patients receiving beta-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    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.
    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.
    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.
    Simeprevir: (Moderate) Concomitant use of simeprevir and carvedilol may result in increased carvedilol plasma concentrations and side effects. Carvedilol is partially metabolized by P-glycoprotein (P-gp) and simeprevir inhibits P-gp. Monitor patients for adverse events such as cardivascular events.
    Sirolimus: (Moderate) Increased concentrations of sirolimus may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and sirolimus is a P-gp substrate.
    Sofosbuvir: (Minor) Coadministration of sofosbuvir and carvedilol may result in elevated sofosbuvir plasma concentrations. Sofosbuvir is a substrate for the drug transporter P-glycoprotein (P-gp); carvedilol is a P-gp inhibitor. According to the manufacturer, no dosage adjustments are required when sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effect.
    Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with carvedilol. Taking these medications together may increase the plasma concentrations of both drugs, potentially resulting in adverse events. Both drugs are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp). (Minor) Coadministration of sofosbuvir and carvedilol may result in elevated sofosbuvir plasma concentrations. Sofosbuvir is a substrate for the drug transporter P-glycoprotein (P-gp); carvedilol is a P-gp inhibitor. According to the manufacturer, no dosage adjustments are required when sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effect.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Plasma concentrations of carvedilol, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with voxilaprevir, a P-gp inhibitor. Monitor patients for changes in blood pressure and increased side effects if these drugs are administered concurrently. (Moderate) Use caution when administering velpatasvir with carvedilol. Taking these medications together may increase the plasma concentrations of both drugs, potentially resulting in adverse events. Both drugs are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp). (Minor) Coadministration of sofosbuvir and carvedilol may result in elevated sofosbuvir plasma concentrations. Sofosbuvir is a substrate for the drug transporter P-glycoprotein (P-gp); carvedilol is a P-gp inhibitor. According to the manufacturer, no dosage adjustments are required when sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effect.
    Succinylcholine: (Moderate) Beta-blockers can enhance the neuromuscular blocking activity of succinylcholine.
    Sufentanil: (Moderate) The incidence and degree of bradycardia and hypotension during induction with sufentanil may be increased in patients receiving beta-blockers.
    Sulfonylureas: (Moderate) 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: (Major) Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Tacrine: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope in some patients. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Talazoparib: (Major) Avoid coadministration of carvedilol with talazoparib due to increased talazoparib exposure. If concomitant use is unavoidable, reduce the dose of talazoparib to 0.75 mg PO once daily. If carvedilol is discontinued, wait at least 3 to 5 half-lives of carvedilol before increasing the dose of talazoparib to the prior dose used before carvedilol therapy. Talazoparib is a P-glycoprotein (P-gp) substrate and carvedilol is a P-gp inhibitor. In clinical trials, coadministration with P-gp inhibitors, including carvedilol, increased talazoparib exposure by approximately 45% and increased the rate of talazoparib dose reduction.
    Tamsulosin: (Minor) Tamsulosin did not potentiate the hypotensive effects of atenolol. However, since the symptoms of orthostasis are reported more frequently in tamsulosin-treated vs. placebo patients, there is a potential risk of enhanced hypotensive effects when co-administered with antihypertensive agents
    Tasimelteon: (Major) The efficacy of tasimelteon in treating circadian rhythm disruptions may be reduced in patients receiving beta-blockers. Because the circadian rhythm of melatonin is regulated by the sympathetic nervous system, administration of beta-blockers may result in a clinically relevant blockade of melatonin secretion.
    Telaprevir: (Moderate) Altered concentrations of telaprevir and/or carvedilol may occur during coadministration. Carvedilol and telaprevir are both substrates and inhibitors of P-glycoprotein (P-gp). Use caution if concomitant use is necessary and monitor for increased side effects.
    Telotristat Ethyl: (Minor) Use caution if carvedilol is coadministered with telotristat ethyl, and monitor for an increase in telotristat ethyl-related adverse reactions. Telotristat, the active metabolite of telotristat ethyl, is a substrate of P-glycoprotein (P-gp) and carvedilol is a weak P-gp inhibitor. Exposure to telotristat ethyl may increase.
    Temsirolimus: (Moderate) Monitor for an increase in temsirolimus- and carvedilol-related adverse reactions if coadministration is necessary. Both drugs are P-glycoprotein (P-gp) substrates and inhibitors. Concomitant use is likely to lead to increased concentrations of carvedilol; exposure to temsirolimus may also increase.
    Teniposide: (Moderate) Increased concentrations of teniposide may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and teniposide is a P-gp substrate.
    Tenofovir Alafenamide: (Minor) Caution is advised when administering tenofovir alafenamide concurrently with carvedilol, as coadministration may result in elevated tenofovir alafenamide plasma concentrations. Inhibitors of the drug transporter P-glycoprotein (P-gp), such as carvedilol, may increase absorption of tenofovir alafenamide, a P-gp substrate. If these medications are administered together, monitor for tenofovir-associated adverse reactions. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Tenofovir, PMPA: (Moderate) Increased concentrations of tenofovir, pmpa may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and tenofovir is a P-gp substrate.
    Terazosin: (Moderate) Orthostatic hypotension may be more likely if beta-blockers are coadministered with alpha-blockers.
    Terbinafine: (Minor) Inhibitors of the hepatic CYP450 isozyme CYP 2D6, including terbinafine, may inhibit the hepatic oxidative metabolism of carvedilol.
    Testosterone: (Moderate) Altered concentrations of testosterone and/or carvedilol may occur during coadministration. Carvedilol and testosterone are both substrates and inhibitors of P-glycoprotein (P-gp). Use caution if concomitant use is necessary and monitor for increased side effects.
    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.
    Tezacaftor; Ivacaftor: (Moderate) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as carvedilol. Ivacaftor is an inhibitor of CYP3A, P-glycoprotein (Pgp) and a weak inhibitor of CYP2C9; carvedilol is partially metabolized by CYP3A, CYP2C9 and is a substrate of Pgp. Co-administration of ivacaftor with CYP3A, CYP2C9, and Pgp substrates,such as carvedilol, can theoretically increase carvedilol exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    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: (Minor) Inhibitors of the hepatic CYP450 isozyme CYP 2D6, such as thioridazine, may inhibit the hepatic oxidative metabolism of carvedilol.
    Thiothixene: (Moderate) Thiothixene should be used cautiously in patients receiving antihypertensive agents. Additive hypotensive effects are possible.
    Thyroid hormones: (Minor) Because thyroid hormones cause cardiac stimulation including increased heart rate and increased contractility, the effects of beta-blockers may be reduced by thyroid hormones. The reduction of effects may be especially evident when a patient goes from a hypothyroid to a euthyroid state or when excessive amounts of thyroid hormone is given to the patient.
    Ticagrelor: (Moderate) Altered concentrations of ticagrelor and/or carvedilol may occur during coadministration. Carvedilol and ticagrelor are both substrates and inhibitors of P-glycoprotein (P-gp). Use caution if concomitant use is necessary and monitor for increased side effects.
    Tipranavir: (Moderate) Altered concentrations of tipranavir and/or carvedilol may occur during coadministration. Carvedilol and tipranavir are both substrates and inhibitors of P-glycoprotein (P-gp). Use caution if concomitant use is necessary and monitor for increased side effects.
    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.
    Tolvaptan: (Moderate) Altered concentrations of tolvaptan and/or carvedilol may occur during coadministration. Carvedilol and tolvaptan are both substrates and inhibitors of P-glycoprotein (P-gp). Use caution if concomitant use is necessary and monitor for increased side effects.
    Trandolapril: (Moderate) Consider separating the time of dosing of carvedilol from that of an angiotensin-converting enzyme (ACE) inhibitor or temporarily reducing the ACE inhibitor dosage if vasodilatory symptoms (e.g., dizziness, lightheadedness, syncope) occur with concomitant use.
    Trandolapril; Verapamil: (Moderate) Consider separating the time of dosing of carvedilol from that of an angiotensin-converting enzyme (ACE) inhibitor or temporarily reducing the ACE inhibitor dosage if vasodilatory symptoms (e.g., dizziness, lightheadedness, syncope) occur with concomitant use. (Moderate) Oral calcium-channel blockers and beta-blockers like carvedilol are used together for their therapeutic benefits to reduce angina and improve exercise tolerance. However, concomitant administration of beta-adrenergic blocking agents and verapamil can lead to significant AV nodal blockade. This can manifest as heart block, bradycardia, cardiac conduction abnormalities and/or prolonged PR interval. Congestive heart failure or severe hypotension also can occur. The combination of beta-blockers and verapamil should be avoided in patients with poor ventricular function due to increased negative inotropic effects.
    Tranylcypromine: (Severe) The use of hypotensive agents and tranylcypromine is contraindicated by the manufacturer of tranylcypromine because the effects of hypotensive agents may be markedly potentiated. In addition, limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers.
    Trazodone: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.
    Vemurafenib: (Moderate) Altered concentrations of vemurafenib and/or carvedilol may occur during coadministration. Carvedilol and vemurafenib are both substrates and inhibitors of P-glycoprotein (P-gp). Use caution if concomitant use is necessary and monitor for increased side effects.
    Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with carvedilol due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of carvedilol. Venetoclax is a P-glycoprotein (P-gp) substrate; carvedilol is a P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Verapamil: (Moderate) Oral calcium-channel blockers and beta-blockers like carvedilol are used together for their therapeutic benefits to reduce angina and improve exercise tolerance. However, concomitant administration of beta-adrenergic blocking agents and verapamil can lead to significant AV nodal blockade. This can manifest as heart block, bradycardia, cardiac conduction abnormalities and/or prolonged PR interval. Congestive heart failure or severe hypotension also can occur. The combination of beta-blockers and verapamil should be avoided in patients with poor ventricular function due to increased negative inotropic effects.
    Vinblastine: (Moderate) Increased concentrations of vinblastine may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and vinblastine is a P-gp substrate.
    Vincristine Liposomal: (Moderate) Increased concentrations of vincristine may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and vincristine is a P-gp substrate.
    Vincristine: (Moderate) Increased concentrations of vincristine may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and vincristine is a P-gp substrate.
    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.
    Zonisamide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and carvedilol is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.

    PREGNANCY AND LACTATION

    Pregnancy

    Available data regarding the use of carvedilol in pregnant women are insufficient to determine whether there are drug-associated risks of adverse developmental outcomes. Uncontrolled hypertension increases risks to the mother and fetus during pregnancy. Beta-blocker use in the third trimester may increase the risk of hypotension, bradycardia, hypoglycemia, and respiratory depression in the neonate. There is no evidence of adverse developmental outcomes in animals at clinically relevant doses. At maternally toxic doses of 50 times the maximum recommended human dose (MRHD), post-implantation loss, decreased fetal body weight, and increased frequency of delayed fetal skeletal development were observed in rats. Post-implantation loss was observed when pregnant rabbits received 25 times the MRHD during organogenesis.

     There are no data on the presence of carvedilol in human milk, the effects on the breastfed infant, or the effects on milk production. Carvedilol is present in the milk of lactating rats. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for carvedilol and any potential adverse effects on the breastfed infant for carvedilol or for the underlying maternal condition. Previous American Academy of Pediatrics recommendations did not evaluate the use of carvedilol in breast-feeding mothers. However, the AAP regarded other beta-blockers, such as labetalol, metoprolol, nadolol, propranolol, sotalol, and timolol as usually compatible with breast-feeding; these agents may represent preferable alternatives in some patients.

    MECHANISM OF ACTION

    Carvedilol has multiple actions that make it a useful cardiovascular drug. Similar to labetalol, carvedilol antagonizes both alpha1- and beta-receptors, however the ratio of beta-to-alpha blockade differs between the two drugs. The ratio of beta-blockade to alpha1-blockade for carvedilol is in the order of 10 to 100:1. The ratio for labetalol is 1.5:1. Beta-antagonism is due primarily to the S(-) carvedilol enantiomer, whereas alpha1-antagonism is essentially equal for both carvedilol enantiomers. It is thought that alpha1-receptor antagonism is mainly responsible for the vasodilatory actions of carvedilol but calcium channel antagonism, which appears in some vascular beds at higher doses, may also contribute. Carvedilol lowers standing blood pressure more than supine; orthostatic hypotension may occur. Reflex tachycardia does not occur due to beta-blockade. In addition, the alpha1-blocking properties offset peripheral vasoconstriction that might be expected with beta-blockade. Carvedilol has no intrinsic sympathomimetic activity.
     
    Other mechanisms might also contribute to carvedilol's beneficial cardiovascular effects. Animal data reveal that carvedilol has calcium-channel antagonist effects at higher concentrations than those necessary for beta-receptor antagonism. Vasodilatory properties of carvedilol are due mainly to alpha1-blockade but, in certain vascular beds, calcium channel antagonism may also contribute. Reflex tachycardia usually does not occur due to the drugs beta-blocking properties. Other effects include antimitogenic effects, free radical scavenging effects, and an antioxidant effect (an effect not shared by other beta-blockers). Carvedilol is a potent inhibitor of lipid peroxidation and has been shown to prevent oxygen free radical depletion of vitamin E in brain homogenates. Its antioxidant effect is greater than that of pindolol or propranolol. The antioxidant effects of carvedilol have been thoroughly reviewed. During chronic therapy, carvedilol does not decrease glomerular filtration rate (GFR) or renal blood flow (RBF) , nor does it significantly alter glucose tolerance tests or fasting and postprandial glucose levels in non-insulin-dependent diabetics without congestive heart failure. In congestive heart failure patients with diabetes mellitus, worsening of hyperglycemia has occurred in 34.1% of carvedilol-treated patients and 21.6% of placebo-treated patients. Long-term carvedilol therapy has been reported to have a beneficial effect on serum lipids by decreasing total cholesterol by 11%, LDL-C by 16%, and triglycerides by 13% and increasing HDL-C by 11%.
     
    Patients with chronic heart failure demonstrate increased sympathetic stimulation leading to downregulation of beta1-receptors, both in number and in their sensitivity to adrenergic stimuli. The beneficial effects of carvedilol in heart failure primarily result from its blockade of beta1-receptors. Beta1-blockade causes an up-regulation of myocardial beta1-receptors, which restores the response to increased sympathetic stimulation. Due to its alpha-blocking effects (vasodilation), carvedilol also counterbalances the negative inotropic effects resulting from beta-blockade.
     
    Carvedilol therapy appears to reduce left ventricular hypertrophy (LVH). The effects of carvedilol on LVH were examined in a study involving patients with elevated diastolic blood pressure and objective evidence of LVH. There was a significant reduction in the left ventricular wall thickness following 6 months of therapy with carvedilol.

    PHARMACOKINETICS

    Carvedilol is administered orally. It is a lipophilic beta-blocker and is distributed extensively to all body tissues including breast milk. Plasma protein binding is approximately 98%, with the R(+) enantiomer being more tightly bound. Concentration in red cells is about 69% of the plasma concentration. Metabolism occurs via aromatic ring oxidation and glucuronidation by the CYP2D6 enzyme. There are three active metabolites having beta-antagonist activity and weak alpha-antagonist effects. One metabolite, 4'-hydroxyphenylcarvedilol, is approximately 13 times more potent than carvedilol as a beta-blocker. Approximately 60% of the metabolites are excreted in the bile and eliminated in the feces, and 16% are excreted in the urine. Less than 2% is excreted unchanged in the urine. The terminal elimination half-life ranges from 7—11 hours for the S(-) enantiomer and 5—9 hours for the R(+) enantiomer.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP2C9, CYP3A4, CYP2C19, CYP1A2, CYP2E1, CYP2D6, P-glycoprotein (P-gp)
    Carvedilol is extensively metabolized by CYP2C9, CYP3A4, CYP2C19, CYP1A2, CYP2E1 and most significantly by CYP2D6; it is also a substrate and inhibitor of P-glycoprotein (P-gp). Carvedilol is subject to the effects of genetic polymorphism with poor metabolizers of debrisoquin (marker for CYP2D6 metabolism).

    Oral Route

    Carvedilol immediate-release tablets: The overall oral bioavailability of the immediate-release tablets is about 25—35% due to extensive first-pass elimination. The S(-) enantiomer has an absolute bioavailability of 15% compared with 31% for the R(+) enantiomer. Food decreases the rate but not the extent of absorption, which helps to minimize the risk of developing orthostatic hypotension. Peak plasma concentrations and antihypertensive effects are reached in about 1—2 hours and are linearly related to the dose. Accumulation does not occur with repeated administration. Compared with labetalol, the duration of action is greater for carvedilol (i.e., carvedilol duration is > 15 hours).
    Carvedilol extended-release capsules: Coreg CR capsules are controlled-release oral capsules containing carvedilol phosphate immediate-release and controlled-release microparticles which are drug-layered and coated with methacrylic acid copolymers. The extended-release capsules have a bioavailability of about 85% relative to the immediate-release tablets. For comparable dosage conversion (see Dosage), the systemic exposure (AUC, Cmax, and serum trough concentrations) of extended-release capsules is considered equivalent to immediate-release tablets when both are administered with food. The absorption of carvedilol from Coreg CR is slower and more prolonged compared to the immediate-release tablet with peak serum concentrations attained about 5 hours following administration. Plasma concentrations increase in a dose-related manner over the recommended dosage range (10 to 80 mg/day). Variability (within-subject and between-subject) for AUC and Cmax is similar for Coreg CR and immediate-release carvedilol. Administration of Coreg CR capsules with a high-fat meal results in increased AUC and Cmax by approximately 20% compared to administration with a standard meal. Decreases in the AUC (27%) and Cmax (43%) are observed when Coreg CR is administered in the fasted state compared to administration after a standard meal. Coreg CR should be taken with food. Sprinkling the contents of Coreg CR capsules on applesauce does not appear to significantly effect the overall exposure (AUC) of carvedilol compared to administration of the intact capsule following a standard meal; however Cmax is decreased by about 18%. Absorption of the Coreg CR beads sprinkled on other foods has not been tested. Due to stereoselective first-pass metabolism, plasma concentrations of R(+)-carvedilol are about 2—3 times higher than S(-)-carvedilol after administration of Coreg CR to healthy subjects. Pharmacodynamic studies with Coreg CR capsules in patients with chronic heart failure or left ventricular dysfunction following acute myocardial infarction indicate that the concentration-response relationship for beta1-blockade following administration of Coreg CR is equivalent (+/- 20%) to immediate-release tablets. In a randomized, double-blind, placebo-controlled trial of patients with essential hypertension, the beta1-blocking effect of Coreg CR (measured by heart rate response to submaximal bicycle ergometry) has been shown to be equivalent to that observed with immediate-release tablets at steady state.