CARVEDILOL (Generic for COREG)

Carvedilol is a combined alpha- and nonselective beta-blocker. Although it has some pharmacologic similarities to labetalol, the ratio of beta to alpha-1 effects is much greater for carvedilol than for labetalol. Carvedilol is a lipophilic beta-blocker, and lacks intrinsic sympathomimetic activity (ISA). Carvedilol also possesses antioxidant properties. The commercial product is a racemic mixture of two enantiomers, R(+) and S(-), both of which are important for the desired clinical effect. Carvedilol (Coreg(R)) was approved in the US in September 1995 for the treatment of hypertension, either alone or in combination with other antihypertensive agents. In comparative studies in elderly hypertensive patients, blood pressure lowering effects of carvedilol were similar to other antihypertensives. Carvedilol is appropriate therapy for treating hypertension in patients with renal disease or diabetes mellitus. A study in the treatment of heart failure was prematurely stopped in April 1995 due to early evidence of a beneficial effect on morbidity and mortality; results revealed a 65% decrease in risk of death in patients assigned to carvedilol. Only 1.6% of patients who were randomized had to discontinue carvedilol due to worsening heart failure. The FDA granted final approval for carvedilol use in mild-moderate heart failure in May 1997. An indication for use in severe heart failure received approval in November 2001 based on the COPERNICUS trial findings; carvedilol reduced mortality and hospitalization rate in patients with severe chronic heart failure. Subsequently, the COMET trial evaluated carvedilol vs. metoprolol in patients with chronic heart failure (NYHA Class II-IV), and demonstrated a significantly lower all-cause mortality for carvedilol (34% vs. 40% for metoprolol). However, the COMET study has been criticized for utilizing the immediate-release form of metoprolol (tartrate) vs. the extended-release formulation (succinate), which has been FDA-approved for heart failure based on the favorable findings of the MERIT-HF trial. The COMET trial has also been criticized for evaluating a substantially lower metoprolol target dosage (50 mg PO twice daily) than the FDA-approved target dosage for heart failure (200 mg PO once daily) supported by the MERIT-HF trial. In March 2003, carvedilol received approval for use to prevent cardiovascular mortality in stable patients with left ventricular dysfunction following acute myocardial infarction. This approval was based on the results of the CAPRICORN trial. Carvedilol has been studied in stable angina pectoris. The 2007 AHA guidelines for the management of hypertension state beta-blockers should not be used as first-line therapy for the treatment of hypertension, as several comparative clinical trials have shown beta blockers to be inferior to ACE inhibitors, angiotensin-receptor blockers, or calcium channel blockers for preventing both stroke and coronary artery disease complications. These guidelines do, however, recommend the use of beta-blockers for the treatment of hypertension in patients with angina, prior myocardial infarction, or heart failure. Carvedilol has been marketed in Europe since the 1980s under the trade name Kredex(TM). Extended-release carvedilol tablets (Coreg CR(TM)) were approved by the FDA in October 2006 for the same indications approved for regular-release carvedilol tablets (Coreg(R)).

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

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

Route-Specific Administration

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.

Adverse effects observed in pediatric patients receiving carvedilol for cardiac failure are similar to those observed in adults. The reported incidence of adverse events ranges from 21 to 54% with drug discontinuation rates of approximately 6 to 13% from limited clinical trials and manufacturer information on file. In a letter received from Glaxo SmithKline dated August 29, 2006, the manufacturer has provided the following unpublished information regarding results of a multicenter, prospective, randomized, double-blind trial which evaluated outcomes in 161 children with NYHA or Ross Class II-IV cardiac failure receiving low dose carvedilol, high dose carvedilol, or placebo for 8 months in addition to standard therapy for cardiac failure. This outcomes study included children aged 3 months to 17 years (median 3 years) who had symptomatic cardiac failure due to systemic ventricular dysfunction. In this trial, the overall discontinuation rate was 13% due to adverse events; no difference was observed between the low dose, high dose, and placebo groups. In this trial, there was no significant difference in cardiac failure outcome (defined as ''worsened', 'unchanged', or 'improved') between the combined carvedilol groups and placebo. Cardiac failure outcome was defined by a composite of death, hospitalization, NYHA or Ross classification, and global assessment. The design and a brief summary of findings for this trial have been published.

Most adverse reactions to carvedilol are associated with its pharmacological effects. When beginning treatment with carvedilol, patients may experience worsening heart failure or fluid retention/edema (4-6%) during the initial up-titration period. In these individuals, the dosage of carvedilol may need to be reduced or temporarily discontinued; subsequent increases in carvedilol dosage is not precluded in these patients. Abruptly discontinuing beta-blocker therapy in patients with coronary artery disease may result in exacerbation of angina or the development of a myocardial infarction or ventricular arrhythmia; thus, gradual discontinuance of carvedilol therapy over a 1-2 week period is recommended. Angina (2-6%) and myocardial infarctions (< 0.1%) have been reported during carvedilol clinical trials. In addition, because beta-blockers slow AV nodal conduction, hypotension (9-20.2%), sinus bradycardia (0.5-10%), as well as AV block (0.1-3%) and bundle-branch block (<= 0.1%) can occur. Orthostatic hypotension affects a significant percentage of carvedilol recipients (1.8-20.2); however, this adverse reaction is an infrequent cause of discontinuation of carvedilol therapy. Adverse events related to orthostatic hypotension include dizziness (2-32%) and syncope (0.1-8%). A post-marketing study reported that 7% of patients were withdrawn from carvedilol due to adverse reactions including vertigo, headache, bronchospastic episodes, fatigue, and rash (unspecified). During clinical trials, the frequency with which these adverse reactions occurred were: vertigo (2-3%), headache (5-8%), bronchospastic episodes (0.1%), fatigue (24%), and rash (0.1-1%). Other common adverse reactions reported with carvedilol therapy include abdominal pain (2-3%), diarrhea (1-12%), nausea (2-9%), vomiting (1-6%), somnolence (drowsiness) (2-3%), peripheral edema (1-7%), pulmonary edema (0.1-3%), and insomnia (1-2%). Palpitations, hypertension, fever, hypoesthesia, hypervolemia, hypovolemia, melena, paresthesias, and muscle cramps have also been reported (frequency > 1% and <= 3%). The profile of adverse events observed with Coreg CR capsules is generally similar to that observed with immediate-release carvedilol tablets. According to the manufacturer, differences in safety are not expected due to the similarity in plasma carvedilol concentrations for Coreg CR capsules versus immediate-release tablets. Coreg CR has been evaluated for safety in a short-term trial (two weeks of immediate-release carvedilol and two weeks of Coreg CR) which included 157 patients with chronic heart failure (stable mild, moderate, or severe) and 30 patients with left ventricular dysfunction following acute myocardial infarction. The safety profile observed with Coreg CR in this small, short-term trial was similar to that observed with immediate-release carvedilol. In addition, carvedilol phosphate extended-release capsules have been evaluated for safety in an 8-week double-blind placebo-controlled trial in 337 hypertensive patients. Adverse events occurring with Coreg CR more often than placebo and >= 1% included: pharyngitis reported as nasopharyngitis (4%), dizziness (2%), peripheral edema (2%), nasal congestion (1%), paresthesias (1%), sinus congestion (1%), diarrhea (1%), and insomnia (1%). The reported overall rates of discontinuations due to adverse events are similar between Coreg CR and placebo.

Central nervous system (CNS) effects can occur with beta-blockers therapy. It has been proposed that lipophilic beta-blockers are more likely to be associated with CNS effects; however, this theory has been debated based on clinical experience with beta-blockers. Carvedilol is a lipophilic beta-blocker. Depression has been infrequently (0.1-3%) reported during carvedilol therapy. Other CNS adverse events reported at an incidence of 0.1-1% during carvedilol clinical trials included anxiety or nervousness, confusion, impaired cognition, abnormal thinking, paroniria or nightmares, and emotional lability. Amnesia, migraine, and convulsions or tremor have also been reported in <= 0.1% of carvedilol recipients.

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. Beta-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. In addition, nonselective beta-blockers, such as carvedilol, may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose concentrations. In studies of congestive heart failure patients, worsening of hyperglycemia occurred in 5-12% of carvedilol-treated patients. During these same studies, hypoglycemia and diabetes mellitus were reported in 2-3% of carvedilol recipients.

Beta-blockers can cause bronchospasm, dyspnea, and/or wheezing in patients with asthma or pulmonary disease. Non-selective beta-blockers such as carvedilol are more likely than selective agents to precipitate pulmonary disorders. Adverse pulmonary events reported during carvedilol clinical trials included asthma (0.1-1%), bronchospasm (<= 0.1%), cough (5-8%), dyspnea (11%), rales (4%), and respiratory alkalosis (<= 0.1%). Patients with preexisting bronchospastic disease are at greater risk. Two cases of asthma-related death have been reported in patients receiving single doses of carvedilol. Rare post-marketing reports describing interstitial pneumonitis associated with carvedilol therapy do exist.

Less frequent dermatological reactions reported during carvedilol therapy (incidence 0.1-1%, regardless of causality) include: pruritus, erythematous rash, maculopapular rash, psoriaform rash, and photosensitivity. Severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme) have been reported during post-marketing experience. Other dermatologic reactions reported in <= 0.1% of carvedilol recipients have included reversible alopecia and exfoliative dermatitis.

Hypersensitivity reactions including anaphylactoid reactions, angioedema, and urticaria have been reported in post-marketing experience for the regular-release and extended-release formulations of carvedilol, including cases occurring after the initiation of extended-release capsules in patients previously treated with the regular-release tablets.

Hyperbilirubinemia (0.1-1%) and elevated hepatic enzymes (0.1-3%) have been observed during carvedilol therapy. Generally, the elevations (2 to 3 times the upper limit of normal) occur at a similar or lower rate than placebo during clinical trials. In severe heart failure patients, the rate of elevated transaminases has been reported to be lower than placebo, possibly due to improved cardiac output and reduced hepatic congestion. Use of carvedilol is contraindicated in persons with severe hepatic impairment. If hepatic enzyme concentrations indicate hepatic injury, or there is clinical jaundice and liver function tests confirm possible liver injury, carvedilol therapy should be discontinued.

Genitourinary disorders reported following treatment with carvedilol include decreased renal function, glycosuria, proteinuria or albuminuria, hematuria (all > 1 to <= 3%), and increased urinary frequency (0.1-1%). Male patients have also experienced impotence (erectile dysfunction) (2-3%) and libido decrease (male) (0.1-1%) after receiving carvedilol. Rare post-marketing reports exist of urinary incontinence in women, which resolved upon discontinuation of carvedilol therapy.

Carvedilol therapy has been associated with hematologic adverse events. Recipients of carvedilol during clinical trials have experienced anemia (0.1-3%), leukopenia (0.1-1%), pancytopenia (<= 0.1%) and thrombocytopenia (1-3%). Additionally, decreases in prothrombin or hypoprothrombinemia (2-3%) and the development of bleeding disorders such as purpura (2-3%) and GI bleeding (<= 0.1%) have occurred following treatment with carvedilol. Aplastic anemia has also been reported rarely following administration of carvedilol during post-marketing experience.

Pain, discomfort, and generalized weakness have been reported following treatment with carvedilol. During clinical trials, recipients of carvedilol reported experiencing the following symptoms: asthenia or weakness (7-11%), arthralgia (1-6%), neuralgia or neuropathic pain (<= 0.1%), malaise (2-3%), arthritis (2-3%), gout (2-3%), periodontitis (2-3%), hypotonia (2-3%), hypokinesia or dyskinesia (0.1-1%), and paresis (<= 0.1%).

Carvedilol treatment has been associated with ophthalmic adverse reactions. During clinical trials, visual impairment (5%), including blurred vision (2-3%), was reported in persons receiving carvedilol.

Intraoperative floppy iris syndrome (IFIS) has been observed during cataract surgery in some patients treated with alpha-1 blockers. It is not known if carvedilol, an alpha/beta blocker, is associated with this condition; however, the manufacturer of labetalol, another alpha/beta blocker, warns clinicians should be prepared for possible modifications to the surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances. The syndrome is characterized by a triad of a features that distinguish it: 1) a flaccid iris that billows in response to intraoperative irrigation currents, 2) progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and 3) potential prolapse of the iris toward the phacoemulsification incisions. There does not appear to be a benefit of stopping alpha-1 blocker therapy prior to cataract surgery.

Laboratory abnormalities have been reported during carvedilol clinical trials. These abnormalities include hypercholesterolemia (1-4%), increased BUN (0.1-6%), elevated hepatic enzymes (0.1-3%), elevated creatinine (2-3%), hyponatremia (2-3%), hyperuricemia (2-3%), hyperkalemia (2-3%), hypokalemia (0.1-1%), hypertriglyceridemia (0.1-1%), hyperbilirubinemia (0.1-1%), and decreased HDL (<= 0.1%).

Carvedilol treatment has been associated with auditory adverse reactions. Cases of tinnitus (0.1-1%), some resulting in decreased hearing (incidence <= 0.1%), were reported by patients receiving carvedilol during clinical trials.

Other adverse reactions reported by persons receiving treatment with carvedilol during clinical trials include weight gain (10-12%), weight loss (2-3%), peripheral vascular disorder (2-3%), cerebrovascular accident or stroke (0.1-3%), peripheral vasoconstriction or ischemia (0.1-1%), sinus tachycardia (0.1-1%), hyperhidrosis (sweating, 0.1-1%), and xerostomia or dry mouth (0.1-1%).

Withdrawal symptoms, including headache, diaphoresis, palpitations, sinus tachycardia, tremor, and hypertension, have been associated with abrupt discontinuation of beta-blockers in hypertensive patients. Gradual tapering and/or prolonged administration of small doses of carvedilol prior to complete cessation may prevent adverse events.

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 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.

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.

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.

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.

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.

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.

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.

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).

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.

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.

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.

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

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

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.

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.

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.

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.

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.

For the treatment of essential hypertension, either as a single agent or in combination with other antihypertensive agents:
Oral dosage (immediate-release):
Adults: 6.25 mg PO twice daily, initially. May double dose every 7 to 14 days if further control is needed. Max: 25 mg PO twice daily.
Oral dosage (extended-release, carvedilol-naive):
Adults: 20 mg PO once daily, initially. May double dose every 7 to 14 days if further control is needed. Max: 80 mg PO once daily.
Oral dosage (extended-release, transitioning from immediate-release carvedilol):
Adults: 10 mg PO once daily extended-release for 3.125 mg PO twice daily immediate-release; 20 mg PO once daily extended-release for 6.25 mg PO twice daily immediate-release; 40 mg PO once daily extended-release for 12.5 mg PO twice daily immediate-release; and 80 mg PO once daily extended-release for 25 mg PO twice daily immediate-release. May double dose after at least 14 days if further control is needed. Max: 80 mg PO once daily.
Geriatric Adults: 10 mg PO once daily extended-release for 3.125 mg PO twice daily immediate-release; 20 mg PO once daily extended-release for 6.25 mg PO twice daily immediate-release; 20 or 40 mg PO once daily extended-release for 12.5 mg PO twice daily immediate-release; and 40 mg PO once daily extended-release for 25 mg PO twice daily immediate-release. May double dose after at least 14 days if further control is needed. Max: 80 mg PO once daily.

For the treatment of heart failure (ischemic origin or cardiomyopathy):
-for the treatment of mild-to-severe chronic heart failure of ischemic or cardiomyopathy origin in adults, usually in combination with ACE inhibitors, digoxin, or diuretics:
Oral dosage (immediate-release):
Adults weighing more than 85 kg: 3.125 mg PO twice daily for 2 weeks, initially. Increase the dose after 2 weeks as tolerated to 6.25, 12.5, 25, and then 50 mg PO twice daily. 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.
Adults weighing 85 kg or less: 3.125 mg PO twice daily for 2 weeks, initially. Increase the dose after 2 weeks as tolerated to 6.25, 12.5, and then 25 mg PO twice daily. 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):
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 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):
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 patients with severe heart failure (NYHA Class III/IV) and referred for cardiac transplantation*:
Oral dosage (immediate-release):
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 angina*:
-for the treatment of chronic stable angina*:
Oral dosage (immediate-release):
Adults: 25 to 50 mg PO twice daily.
-for the treatment of unstable angina* as adjunct to standard therapy:
Oral dosage (immediate-release):
Adults: 25 mg PO twice daily.

For the treatment of left ventricular dysfunction after acute myocardial infarction for reduction of cardiovascular mortality in stable persons with a left ventricular ejection fraction of 40% or less:
Oral dosage (immediate-release):
Adults: 6.25 mg PO twice daily, initially. If tolerated, increase the dose to 12.5 mg PO twice daily after 3 to 10 days and then 25 mg PO twice daily after another 3 to 10 days. A lower starting dose of 3.125 mg PO twice daily may be used and/or titration slowed if needed (e.g., due to hypotension, bradycardia, or fluid retention). Guidelines recommend initiating oral beta blockers in the first 24 hours in persons with STEMI/NSTEMI who do not have signs of heart failure, evidence of low output, increased risk for cardiogenic shock, or other contraindications for beta blocker use.
Oral dosage (extended-release, carvedilol-naive):
Adults: 20 mg PO once daily, initially. If tolerated, increase the dose to 40 mg PO once daily after 3 to 10 days and then 80 mg PO once daily after another 3 to 10 days. A lower starting dose of 10 mg PO once daily may be used and/or titration slowed if necessary (e.g., due to hypotension, bradycardia, or fluid retention).
Oral dosage (extended-release, transitioning from immediate-release carvedilol):
Adults: 10 mg PO once daily extended-release for 3.125 mg PO twice daily immediate-release; 20 mg PO once daily extended-release for 6.25 mg PO twice daily immediate-release; 40 mg PO once daily extended-release for 12.5 mg PO twice daily immediate-release; and 80 mg PO once daily extended-release for 25 mg PO twice daily immediate-release. May double dose after at least 14 days if needed. Max: 80 mg PO once daily.
Geriatric Adults: 10 mg PO once daily extended-release for 3.125 mg PO twice daily immediate-release; 20 mg PO once daily extended-release for 6.25 mg PO twice daily immediate-release; 20 or 40 mg PO once daily extended-release for 12.5 mg PO twice daily immediate-release; and 40 mg PO once daily extended-release for 25 mg PO twice daily immediate-release. May double dose after at least 14 days if needed. Max: 80 mg PO once daily.

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.

Maximum Dosage Limits:
-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.

Patients with Hepatic Impairment Dosing
Contraindicated in patients with severe hepatic impairment.

Patients with Renal Impairment Dosing
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.

*non-FDA-approved indication

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; Aspirin: (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; Aspirin; Diphenhydramine: (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.

Adagrasib: (Moderate) Monitor for signs of bradycardia or heart block if coadministration of carvedilol with adagrasib is necessary. Carvedilol is a CYP2C9 substrate and adagrasib is a CYP2C9 inhibitor. Concomitant use may enhance the beta-blocking properties of carvedilol resulting in further slowing of the heart rate or cardiac conduction.

Adenosine: (Moderate) Use adenosine with caution in the presence of beta blockers due to the potential for additive or synergistic depressant effects on the sinoatrial and atrioventricular nodes.

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: (Moderate) Monitor for signs of bradycardia or heart block if coadministration of carvedilol with amiodarone is necessary. Carvedilol is a CYP2C9 substrate and amiodarone is a CYP2C9 inhibitor. Concomitant use may enhance the beta-blocking properties of carvedilol resulting in further slowing of the heart rate or cardiac conduction.

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) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with carvedilol is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; carvedilol is a P-gp inhibitor.

Amlodipine; Benazepril: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.

Amlodipine; Celecoxib: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.

Amlodipine; Olmesartan: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.

Amlodipine; Valsartan: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.

Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.

Amobarbital: (Moderate) Although concurrent use of amobarbital with antihypertensive agents may lead to hypotension, barbiturates, as a class, can enhance the hepatic metabolism of beta-blockers that are significantly metabolized by the liver. Beta-blockers that may be affected include betaxolol, labetalol, metoprolol, pindolol, propranolol, and timolol. Clinicians should closely monitor patients blood pressure during times of coadministration.

Amyl Nitrite: (Moderate) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as antihypertensive agents or other peripheral vasodilators. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with any beta-blockers.

Antithyroid agents: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.

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%.

Apomorphine: (Moderate) Use of beta blockers and apomorphine together can increase the hypotensive effects of apomorphine. Monitor blood pressure regularly during use of this combination.

Apraclonidine: (Minor) Theoretically, additive blood pressure reductions could occur when apraclonidine is combined with antihypertensive agents.

Aripiprazole: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents. It may be advisable to monitor blood pressure when these medications are coadministered.

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.

Asciminib: (Moderate) Monitor for signs of bradycardia or heart block if coadministration of carvedilol with asciminib 200 mg twice daily is necessary. Carvedilol is a CYP2C9 substrate and asciminib 200 mg twice daily is a CYP2C9 inhibitor. Concomitant use may enhance the beta-blocking properties of carvedilol resulting in further slowing of the heart rate or cardiac conduction. An interaction is not expected with asciminib doses less than 200 mg twice daily.

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: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.

Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.

Aspirin, ASA; Carisoprodol: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.

Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.

Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.

Aspirin, ASA; Dipyridamole: (Major) Beta-blockers should generally be withheld before dipyridamole-stress testing. Monitor the heart rate carefully following the dipyridamole injection. (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.

Aspirin, ASA; Omeprazole: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.

Aspirin, ASA; Oxycodone: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.

Aspirin, ASA; Pravastatin: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.

Atazanavir: (Moderate) Atazanavir can prolong the PR interval. Coadministration with other agents that prolong the PR interval, like beta blockers, may result in elevated risk of conduction disturbances and atrioventricular block.

Atazanavir; Cobicistat: (Moderate) Atazanavir can prolong the PR interval. Coadministration with other agents that prolong the PR interval, like beta blockers, may result in elevated risk of conduction disturbances and atrioventricular block. (Moderate) 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) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with carvedilol is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; carvedilol is a P-gp inhibitor.

Atorvastatin; Ezetimibe: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with carvedilol is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; carvedilol is a P-gp inhibitor.

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.

Berotralstat: (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking carvedilol. Concurrent use may increase berotralstat exposure and the risk of adverse effects. Berotralstat is a P-gp substrate and carvedilol is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased berotralstat exposure by 69%.

Beta-agonists: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.

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.

Bretylium: (Moderate) Bretylium and beta-blockers may have an additive effect when used concomitantly; monitor for hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.

Brexpiprazole: (Moderate) Due to brexpiprazole's antagonism at alpha 1-adrenergic receptors, the drug may enhance the hypotensive effects of alpha-blockers and other antihypertensive agents.

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.

Budesonide; Glycopyrrolate; 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; Epinephrine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of bupivacaine and antihypertensive agents. Peripheral vasodilation may occur after use of bupivacaine. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Blood concentrations of local anesthetics achieved after therapeutic doses are associated with minimal change in peripheral vascular resistance. Higher blood concentrations of local anesthetics may occur due to inadvertent intravascular administration or repeated doses.

Bupivacaine; Lidocaine: (Major) Drugs such as beta-blockers that decrease cardiac output reduce hepatic blood flow and thereby decrease lidocaine hepatic clearance. Also, opposing effects on conduction exist between lidocaine and beta-blockers while their effects to decrease automaticity may be additive. Propranolol has been shown to decrease lidocaine clearance and symptoms of lidocaine toxicity have been seen as a result of this interaction. This interaction is possible with other beta-blocking agents since most decrease hepatic blood flow. Monitoring of lidocaine concentrations is recommended during concomitant therapy with beta-blockers. (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of bupivacaine and antihypertensive agents. Peripheral vasodilation may occur after use of bupivacaine. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Blood concentrations of local anesthetics achieved after therapeutic doses are associated with minimal change in peripheral vascular resistance. Higher blood concentrations of local anesthetics may occur due to inadvertent intravascular administration or repeated doses.

Bupivacaine; Meloxicam: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of bupivacaine and antihypertensive agents. Peripheral vasodilation may occur after use of bupivacaine. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Blood concentrations of local anesthetics achieved after therapeutic doses are associated with minimal change in peripheral vascular resistance. Higher blood concentrations of local anesthetics may occur due to inadvertent intravascular administration or repeated doses.

Bupropion: (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: (Moderate) Cabergoline should be used cautiously with antihypertensive agents, including beta-blockers. Cabergoline has been associated with hypotension. Initial doses of cabergoline higher than 1 mg may produce orthostatic hypotension. It may be advisable to monitor blood pressure.

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.

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.

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 concomitant use of ceritinib with carvedilol if possible due to the risk of additive bradycardia. Both ceritinib and carvedilol can cause bradycardia. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if bradycardia occurs.

Cevimeline: (Major) Cevimeline should be administered with caution to patients taking beta adrenergic antagonists, because of the possibility of conduction disturbances. Cevimeline can potentially alter cardiac conduction and/or heart rate. Patients with significant cardiovascular disease treated with beta-blockers may potentially be unable to compensate for transient changes in hemodynamics or rhythm induced by cevimeline. If use of these drugs together cannot be avoided, close monitoring of blood pressure, heart rate and cardiac function is advised.

Chloroprocaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.

Chlorpromazine: (Minor) Inhibitors of the hepatic CYP450 isozyme CYP 2D6, such as chlorpromazine, may inhibit the hepatic oxidative metabolism of carvedilol.

Chlorthalidone; Clonidine: (Moderate) 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) Use clevidipine and carvedilol with caution due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility. Monitor ECG and blood pressure if diltiazem is coadministered with carvedilol.

Clonidine: (Moderate) 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.

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.

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.

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) 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.

Dasiglucagon: (Minor) A temporary increase in both blood pressure and pulse rate may occur following the administration of glucagon. Patients taking beta-blockers might be expected to have a greater increase in both pulse and blood pressure. Glucagon exerts positive inotropic and chronotropic effects and may, therefore, cause tachycardia and hypertension in some patients. The increase in blood pressure and pulse rate may require therapy in some patients with coronary artery disease.

Delavirdine: (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; 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.

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) 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 intravenously. 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. 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. Digoxin is a P-gp substrate and carvedilol is a P-gp inhibitor.

Dihydroergotamine: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.

Diltiazem: (Moderate) Use diltiazem and carvedilol with caution due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility. Monitor ECG and blood pressure if diltiazem is coadministered with carvedilol.

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; 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.

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 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 Liposomal: (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.

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.

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 Disoproxil Fumarate: (Moderate) Increased concentrations of tenofovir 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 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.

Elexacaftor; 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.

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.

Elvitegravir; 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.

Elvitegravir; Cobicistat; 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 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.

Empagliflozin; Linagliptin; Metformin: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.

Empagliflozin; Metformin: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.

Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Increased concentrations of tenofovir 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 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; 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.

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.

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) Monitor blood pressure during concomitant beta-blocker and ergotamine use. Beta-blockers may potentiate the vasoconstrictive action of ergotamine by blocking the vasodilating property of epinephrine.

Ergotamine; Caffeine: (Moderate) Monitor blood pressure during concomitant beta-blocker and ergotamine use. Beta-blockers may potentiate the vasoconstrictive action of ergotamine by blocking the vasodilating property of epinephrine.

Ertugliflozin; Metformin: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.

Escitalopram: (Moderate) Monitor for signs of bradycardia or heart block if coadministration of carvedilol with escitalopram is necessary. Carvedilol is a CYP2C9 substrate and escitalopram is a CYP2C9 inhibitor. Concomitant use may enhance the beta-blocking properties of carvedilol resulting in further slowing of the heart rate or cardiac conduction.

Estradiol Cypionate; Medroxyprogesterone: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.

Estradiol: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.

Etomidate: (Major) General anesthetics can potentiate the antihypertensive effects of beta-blockers and can produce prolonged hypotension. Beta-blockers may be continued during general anesthesia as long as the patient is monitored for cardiac depressant and hypotensive effects.

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.

Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with carvedilol is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and carvedilol is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.

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.

Ezetimibe; Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with carvedilol is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; carvedilol is a P-gp inhibitor.

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.

Fenoldopam: (Major) Avoid concomitant use of fenoldopam with beta-blockers due to the risk of hypotension. If used together, monitor blood pressure frequently. Beta-blockers may inhibit the sympathetic reflex response to fenoldopam.

Fingolimod: (Major) If possible, do not start fingolimod in a patient who is taking a drug that slows the heart rate or atrioventricular conduction such as beta-blockers. Use of these drugs during fingolimod initiation may be associated with severe bradycardia or heart block. Seek advice from the prescribing physician regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating fingolimod. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients who cannot stop taking drugs that slow the heart rate or atrioventricular conduction. Experience with fingolimod in patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular conduction is limited.

Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.

Flecainide: (Moderate) Pharmacologically, beta-blockers, like 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: (Moderate) Monitor for signs of bradycardia or heart block if coadministration of carvedilol with fluconazole is necessary. Carvedilol is a CYP2C9 substrate and fluconazole is a CYP2C9 inhibitor. Concomitant use may enhance the beta-blocking properties of carvedilol resulting in further slowing of the heart rate or cardiac conduction.

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.

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.[

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.

Hydralazine; Isosorbide Dinitrate, ISDN: (Moderate) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as antihypertensive agents or other peripheral vasodilators. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with any beta-blockers.

Icosapent ethyl: (Moderate) Beta-blockers may exacerbate hypertriglyceridemia and should be discontinued or changed to alternate therapy, if possible, prior to initiation of icosapent ethyl.

Iloperidone: (Moderate) Secondary to alpha-blockade, iloperidone can produce vasodilation that may result in additive effects during concurrent use with antihypertensive agents. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use of iloperidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.

Iloprost: (Moderate) Additive reductions in blood pressure may occur when inhaled iloprost is administered to patients receiving other antihypertensive agents.

Imatinib: (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.

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.

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 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.

Lasmiditan: (Moderate) Monitor heart rate if lasmiditan is coadministered with beta-blockers as concurrent use may increase the risk for bradycardia. Lasmiditan has been associated with lowering of heart rate. In a drug interaction study, addition of a single 200 mg dose of lasmiditan to a beta-blocker (propranolol) decreased heart rate by an additional 5 beats per minute.

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.

Lefamulin: (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with carvedilol as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate and carvedilol is a P-gp inhibitor.

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.

Levamlodipine: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.

Levodopa: (Moderate) Concomitant use of beta-blockers with levodopa can result in additive hypotensive effects.

Levothyroxine: (Minor) Because thyroid hormones cause cardiac stimulation including increased heart rate and increased contractility, the effects of beta-blockers may be reduced by thyroid hormones. The reduction of effects may be especially evident when a patient goes from a hypothyroid to a euthyroid state or when excessive amounts of thyroid hormone is given to the patient.

Levothyroxine; Liothyronine (Porcine): (Minor) Because thyroid hormones cause cardiac stimulation including increased heart rate and increased contractility, the effects of beta-blockers may be reduced by thyroid hormones. The reduction of effects may be especially evident when a patient goes from a hypothyroid to a euthyroid state or when excessive amounts of thyroid hormone is given to the patient.

Levothyroxine; Liothyronine (Synthetic): (Minor) Because thyroid hormones cause cardiac stimulation including increased heart rate and increased contractility, the effects of beta-blockers may be reduced by thyroid hormones. The reduction of effects may be especially evident when a patient goes from a hypothyroid to a euthyroid state or when excessive amounts of thyroid hormone is given to the patient.

Lidocaine: (Major) Drugs such as beta-blockers that decrease cardiac output reduce hepatic blood flow and thereby decrease lidocaine hepatic clearance. Also, opposing effects on conduction exist between lidocaine and beta-blockers while their effects to decrease automaticity may be additive. Propranolol has been shown to decrease lidocaine clearance and symptoms of lidocaine toxicity have been seen as a result of this interaction. This interaction is possible with other beta-blocking agents since most decrease hepatic blood flow. Monitoring of lidocaine concentrations is recommended during concomitant therapy with beta-blockers.

Lidocaine; Epinephrine: (Major) Drugs such as beta-blockers that decrease cardiac output reduce hepatic blood flow and thereby decrease lidocaine hepatic clearance. Also, opposing effects on conduction exist between lidocaine and beta-blockers while their effects to decrease automaticity may be additive. Propranolol has been shown to decrease lidocaine clearance and symptoms of lidocaine toxicity have been seen as a result of this interaction. This interaction is possible with other beta-blocking agents since most decrease hepatic blood flow. Monitoring of lidocaine concentrations is recommended during concomitant therapy with beta-blockers.

Lidocaine; Prilocaine: (Major) Drugs such as beta-blockers that decrease cardiac output reduce hepatic blood flow and thereby decrease lidocaine hepatic clearance. Also, opposing effects on conduction exist between lidocaine and beta-blockers while their effects to decrease automaticity may be additive. Propranolol has been shown to decrease lidocaine clearance and symptoms of lidocaine toxicity have been seen as a result of this interaction. This interaction is possible with other beta-blocking agents since most decrease hepatic blood flow. Monitoring of lidocaine concentrations is recommended during concomitant therapy with beta-blockers. (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.

Linagliptin; Metformin: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.

Linezolid: (Moderate) Linezolid is an antibiotic that is also a reversible, non-selective MAO inhibitor. Bradycardia may be worsened when MAO-inhibitors are co-administered to patients receiving beta-blockers. Use linezolid cautiously in patients receiving beta-blockers.

Liothyronine: (Minor) Because thyroid hormones cause cardiac stimulation including increased heart rate and increased contractility, the effects of beta-blockers may be reduced by thyroid hormones. The reduction of effects may be especially evident when a patient goes from a hypothyroid to a euthyroid state or when excessive amounts of thyroid hormone is given to the patient.

Liraglutide: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.

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) 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), if coadministered with carvedilol. Concurrent use may increase loperamide exposure. Loperamide is a P-gp substrate and carvedilol is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.

Loperamide; Simethicone: (Moderate) 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), if coadministered with carvedilol. Concurrent use may increase loperamide exposure. Loperamide is a P-gp substrate and carvedilol is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.

Lopinavir; 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.

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.

Mavacamten: (Moderate) Expect additive negative inotropic effects during concomitant use of mavacamten and beta-blockers. If concomitant therapy with beta-blockers is initiated, or if the dose is increased, monitor left ventricular ejection fraction closely until stable doses and clinical response have been achieved.

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.

Mestranol; Norethindrone: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients; monitor patients receiving concurrent therapy to confirm that the desired antihypertensive effect is being obtained.

Metformin: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.

Metformin; Repaglinide: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.

Metformin; Rosiglitazone: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.

Metformin; Saxagliptin: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.

Metformin; Sitagliptin: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.

Methacholine: (Moderate) Beta-blockers may impair reversal of methacholine-induced bronchoconstriction with an inhaled rapid-acting beta-agonist.

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.

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.

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.

Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid coadministration of sirolimus with carvedilol as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and carvedilol is a P-gp inhibitor.

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.

Neuromuscular blockers: (Moderate) Concomitant use of neuromuscular blockers and beta-blockers may prolong neuromuscular blockade.

Niacin, Niacinamide: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.

Niacin; Simvastatin: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise. (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with carvedilol is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; carvedilol is a P-gp inhibitor.

Nicardipine: (Moderate) Use nicardipine and carvedilol with caution due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility. Monitor ECG and blood pressure if nicardipine is coadministered with carvedilol.

Nifedipine: (Moderate) In general, concomitant therapy of nifedipine with beta-blockers is well tolerated and can even be beneficial in some cases (i.e., inhibition of nifedipine-induced reflex tachycardia by beta-blockade). Negative inotropic and/or chronotropic effects can be additive when these drugs are used in combination. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nifedipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nifedipine therapy may minimize or eliminate this potential interaction. Hypotension and impaired cardiac performance can occur during coadministration of nifedipine with beta-blockers, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Monitor clinical response during coadministration; adjustment of nifedipine dosage may be needed during concurrent beta-blocker therapy.

Nimodipine: (Moderate) Nimodipine, a selective calcium-channel blocker, can enhance the antihypertensive effects of beta-blockers. Although often used together, concurrent use of calcium-channel blockers and beta-blockers may result in additive hypotensive, negative inotropic, and/or bradycardic effects in some patients.

Nirmatrelvir; Ritonavir: (Moderate) 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.

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) Use caution when administering non-ionic contrast media to patients taking beta-blockers. Beta-blockers lower the threshold for and increase the severity of contrast reactions and reduce the responsiveness of treatment of hypersensitivity reactions with epinephrine.

Nonsteroidal antiinflammatory drugs: (Moderate) Monitor blood pressure during concomitant beta-blocker and nonsteroidal anti-inflammatory drug (NSAID) use. The antihypertensive effect of beta-blockers may be diminished by NSAIDs.

Octreotide: (Moderate) Dose adjustments in drugs such as beta-blockers and calcium-channel blockers which cause bradycardia and/or affect cardiac conduction may be necessary during octreotide therapy due to additive effects.

Olanzapine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.

Olanzapine; Fluoxetine: (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.

Olanzapine; Samidorphan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.

Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.

Ombitasvir; Paritaprevir; Ritonavir: (Moderate) 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) 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.

Omeprazole; Amoxicillin; 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.

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.

Ozanimod: (Moderate) Ozanimod may cause bradycardia and AV-conduction delays, which may be enhanced with the concomitant use of beta-blockers. If a calcium channel blocker that slows heart rate/cardiac conduction is also prescribed with ozanimod and a beta-blocker, a cardiologist should be consulted due to the likelyhood of additive effects.

Paliperidone: (Moderate) Paliperidone may cause orthostatic hypotension, thereby enhancing the hypotensive effects of antihypertensive agents. Orthostatic vital signs should be monitored in patients receiving paliperidone and beta-adrenergic blockers who are susceptible to hypotension.

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; Amlodipine: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.

Perphenazine: (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) Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with beta-blockers. Additive hypotensive effects may be seen when phenelzine is combined with antihypertensives. 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.

Pioglitazone; Metformin: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.

Ponesimod: (Moderate) Monitor for decreases in heart rate if concomitant use of ponesimod and beta-blockers is necessary. Consider a temporary interruption in beta-blocker therapy before initiating ponesimod in patients with a resting heart rate less than or equal to 55 bpm. Beta-blocker treatment can be initiated in patients receiving stable doses of ponesimod. Concomitant use of another beta-blocker with ponesimod resulted in a mean decrease in heart rate of 12.4 bpm after the first dose of ponesimod and 7.4 bpm after beginning maintenance ponesimod.

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.

Probenecid; 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.

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: (Moderate) 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.

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.

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.

Relugolix: (Major) Avoid concomitant use of relugolix and oral carvedilol. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer carvedilol at least 6 hours after relugolix and monitor for adverse reactions. Alternatively, relugolix therapy may be interrupted for up to 14 days if a short course of carvedilol is required; if treatment is interrupted for more than 7 days, resume relugolix with a 360 mg loading dose followed by 120 mg once daily. Relugolix is a P-gp substrate and carvedilol is a P-gp inhibitor.

Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of relugolix and oral carvedilol. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer carvedilol at least 6 hours after relugolix and monitor for adverse reactions. Alternatively, relugolix therapy may be interrupted for up to 14 days if a short course of carvedilol is required; if treatment is interrupted for more than 7 days, resume relugolix with a 360 mg loading dose followed by 120 mg once daily. Relugolix is a P-gp substrate and carvedilol is a P-gp inhibitor.

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.

Rifaximin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with carvedilol is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and carvedilol is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.

Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with carvedilol; concurrent use may increase rimegepant exposure. Rimegepant is a P-gp substrate and carvedilol is a P-gp inhibitor.

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.

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.

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.

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.

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.

Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with carvedilol is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; carvedilol is a P-gp inhibitor.

Simvastatin; Sitagliptin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with carvedilol is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; carvedilol is a P-gp inhibitor.

Siponimod: (Moderate) Monitor for significant bradycardia with coadministration of siponimod and beta-blockers, as additive lowering effects on heart rate may occur; temporary interruption of beta-blocker treatment may be necessary prior to siponimod initiation. Beta-blocker treatment can be initiated in patients receiving stable doses of siponimod.

Sirolimus: (Major) Avoid coadministration of sirolimus with carvedilol as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and carvedilol is a P-gp inhibitor.

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.

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: (Moderate) Monitor hemodynamic parameters and for loss of efficacy during concomitant sympathomimetic agent and beta-blocker use; dosage adjustments may be necessary. Concomitant use may antagonize the cardiovascular effects of either drug.

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: (Moderate) Advise patients to administer the beta-blocker in the morning if tasimelteon is used concomitantly. Nighttime administration of a beta-blocker may reduce the efficacy of tasimelteon by decreasing the production of melatonin via inhibition of beta1 receptors.

Telmisartan; Amlodipine: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.

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 Disoproxil Fumarate: (Moderate) Increased concentrations of tenofovir 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.

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.

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.

Tirzepatide: (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.

Tizanidine: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.

Trandolapril; Verapamil: (Moderate) Use verapamil and carvedilol with caution and close monitoring due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility. Monitor ECG and blood pressure if verapamil is coadministered with carvedilol. There have been reports of excess bradycardia and AV block, including complete heart block, when beta-blockers and verapamil have been used for the treatment of hypertension.

Tranylcypromine: (Major) Avoid concomitant use of beta-blockers and tranylcypromine due to the risk of additive hypotension and/or severe bradycardia. Potential for this interaction persists for up to 10 days after discontinuation of tranylcypromine (or 4 to 5 half-lives after discontinuation of the beta-blocker). If a medication-free interval is not feasible, initiate therapy at the lowest appropriate dose and monitor blood pressure and heart rate closely.

Trazodone: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.

Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with carvedilol. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a substrate of the P-gp drug transporter; carvedilol is a P-gp inhibitor.

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) Use verapamil and carvedilol with caution and close monitoring due to risk for additive negative effects on heart rate, AV conduction, and/or cardiac contractility. Monitor ECG and blood pressure if verapamil is coadministered with carvedilol. There have been reports of excess bradycardia and AV block, including complete heart block, when beta-blockers and verapamil have been used for the treatment of hypertension.

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.

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.

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.

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 3 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 to 11 hours for the S(-) enantiomer and 5 to 9 hours for the R(+) enantiomer.

Affected cytochrome P450 isoenzymes and drug transporters: CYP2C9, CYP3A4, CYP2C19, CYP1A2, CYP2E1, CYP2D6, 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 (a marker for CYP2D6 metabolism).


-Route-Specific Pharmacokinetics
Oral Route
Carvedilol is rapidly and extensively absorbed after oral administration; however, the absolute bioavailability is relatively low (less than 40%) due to extensive first-pass metabolism. Because the first-pass metabolism is stereoselective, plasma concentrations of R(+)-carvedilol are about 2 to 3 times higher than S(-)-carvedilol after administration to healthy subjects.

Immediate-release tablets
The overall oral bioavailability of the immediate-release tablets is about 25% to 35% due to extensive first-pass elimination. Peak plasma concentrations and antihypertensive effects are reached in about 1 to 2 hours and are linearly related to the dose. Food decreases the rate but not the extent of absorption. Administering with food may minimize the risk of developing orthostatic hypotension. Accumulation does not occur with repeated administration.

Extended-release capsules
Carvedilol extended-release 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; however, for comparable dosage conversion, 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 the extended-release capsules is slower and more prolonged compared to the immediate-release tablet with peak serum concentrations attained about 5 hours after administration. Plasma concentrations increase in a dose-related manner over the recommended dosage range. Administration of extended-release 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 extended-release carvedilol is administered in the fasted state compared to administration after a standard meal. Sprinkling the contents of extended-release carvedilol capsules on applesauce does not appear to significantly affect the overall exposure (AUC) of carvedilol compared to administration of the intact capsule after a standard meal; however, Cmax is decreased by about 18%. The concentration-response relationship for beta1-blockade after administration of extended-release carvedilol is equivalent (+/- 20%) to immediate-release tablets in patients with heart failure and left ventricular function after myocardial infarction. In a randomized, double-blind, placebo-controlled trial of adult patients with essential hypertension, the beta1-blocking effect of extended-release carvedilol (measured by heart rate response to submaximal bicycle ergometry) was equivalent to that observed with immediate-release tablets at steady state.


-Special Populations
Hepatic Impairment
Oral bioavailability after administration of immediate-release carvedilol tablets is increased significantly in patients with hepatic disease. Patients with cirrhotic liver disease have significantly higher plasma concentrations of carvedilol (approximately 4- to 7-fold) compared to healthy patients.

Renal Impairment
Plasma concentrations of carvedilol may be increased in patients with renal impairment; however, no dosage adjustments are needed. Based on mean AUC data, approximately 40% to 50% higher plasma concentrations of carvedilol were observed in hypertensive patients with moderate to severe renal impairment compared to control hypertensive patients with normal renal function. However, the ranges of AUC values were similar for both groups. The changes in mean peak plasma concentrations were less pronounced (approximately 12% to 26% higher) in patients with impaired renal function. Carvedilol is not cleared significantly by hemodialysis.

Pediatrics
Infants, Children, and Adolescents
Carvedilol is rapidly absorbed in pediatric patients with peak plasma concentrations occurring 0.5 to 2.5 hours after administration of immediate-release formulations. The elimination half-life of carvedilol has been reported to be approximately 50% shorter for pediatric patients with heart failure than that of healthy adults. Systemic exposure is lower in younger pediatric patients compared to older pediatric patients, as evidenced by increasing AUC and half-life with age. The half-life of carvedilol has been reported to be 2.2 hours in infants and children younger than 3.5 years (n = 8) and 3.6 hours in older children 5.5 to 19.3 years (n = 7).

Geriatric
Oral bioavailability after administration of immediate-release carvedilol tablets is increased by about 50% in elderly patients.