Carvedilol

Heart Failure

COREG is indicated for the treatment of mild-to-severe chronic heart failure of ischemic or cardiomyopathic origin, usually in addition to diuretics, ACE inhibitors, and digitalis, to increase survival and, also, to reduce the risk of hospitalization [see DRUG INTERACTIONS , Clinical Studies].

Left Ventricular Dysfunction Following Myocardial Infarction

COREG is indicated to reduce cardiovascular mortality in clinically stable patients who have survived the acute phase of a myocardial infarction and have a left ventricular ejection fraction of less than or equal to 40% (with or without symptomatic heart failure) [see Clinical Studies].

Hypertension

COREG is indicated for the management of essential hypertension [see Clinical Studies]. It can be used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics [see DRUG INTERACTIONS].

Carvedilol is a prescription medication used to treat heart failure and high blood pressure. Carvedilol belongs to a group of drugs called beta blockers. It works to decrease blood pressure, heart rate, and the workload of the heart by blocking beta receptors.

This medication comes in tablet form and is taken twice a day with food and a full glass of water.

It is also available in controlled release capsules which are to be swallowed whole once a day with food and a full glass of water.  Do not chew, divide or crush carvedilol controlled release capsules.  

Common side effects of carvedilol include low blood pressure, weight gain, and fatigue. Carvedilol can cause dizziness. Do not drive a car or operate machinery until you know how carvedilol affects you.
 

Carvedilol is part of the drug class:

• Alpha and beta blocking agents

Serious side effects have been reported with carvedilol including the following:

• Acute exacerbation of coronary artery disease upon cessation of therapy: Do not abruptly discontinue carvedilol.
• Bradycardia (slow heart rate). Tell your healthcare provider right away if you experience any new or increasing irregularities in your heart rate.
• Hypotension. Hypotension, or low blood pressure, may cause you to feel faint or dizzy. Inadequate fluid intake, excessive sweating, diarrhea, or vomiting can lead to an excessive fall in blood pressure too. Lie down if you feel faint or dizzy. Call your doctor right away.
• Worsening heart failure. Tell your healthcare provider right away if you experience any of the following symptoms:
  • sudden weight gain
  • worsening shortness of breath
  • increased swelling of your feet, legs, or abdomen
  • needing to use more pillows to go to sleep or sleeping in a recliner
  • waking from sleep to catch your breath
  • a cough that does not go away
  • new or increasing irregularities in your heart rate
• Non-allergic bronchospasm (e.g., chronic bronchitis and emphysema): Avoid using carvedilol in patients with these conditions. 
• Diabetes: Monitor glucose as carvedilol may mask symptoms of hypoglycemia or worsen hyperglycemia.

Carvedilol can cause you to feel dizzy, tired, or faint. Do not drive a car, use machinery, or do anything that needs you to be alert if you have these symptoms.

Do not take carvedilol if you:

• Have severe heart failure and are hospitalized in the intensive care unit or require certain intravenous medications that help support circulation (inotropic medications)
• Are prone to asthma or other breathing problems
• Are allergic to carvedilol or to any of its ingredients
• Have a slow heartbeat or a heart that skips a beat (irregular heartbeat)
• Have liver problems

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if carvedilol crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. Your doctor and you will decide if the benefits outweigh the risk of using carvedilol.

• Store carvedilol tablets at 20º to 25 º C (68 º to 77 ºF).
• Store carvedilol capsules at 25°C (77°F).
• Keep the tablets dry.
• Keep carvedilol and all medicines out of the reach of children.

Carvedilol is in a group of drugs called beta-blockers. Beta-blockers affect the heart and circulation (blood flow through arteries and veins).

Carvedilol is used to treat heart failure and hypertension (high blood pressure). It is also used after a heart attack that has caused your heart not to pump as well.

Carvedilol may also be used for purposes not listed in this medication guide.

Absorption

Bioavailability

Rapidly and extensively absorbed; absolute bioavailability following oral administration of immediate-release tablets is 25–35%.1 Bioavailability of carvedilol phosphate extended-release capsules is approximately 85% that of the immediate-release tablets.59

Onset

Following oral administration as immediate-release tablets, dose-dependent hypotensive effect occurs in approximately 30 minutes; maximum effect occurs in 1.5–7 hours.1 2 17

Following oral administration as immediate-release tablets, clinically important β-adrenergic blocking activity usually occurs within 1 hour and α1-adrenergic blocking effects generally occur within 30 minutes.1 2 17

Absorption of carvedilol following administration of carvedilol phosphate extended-release capsules is slower and more prolonged compared with carvedilol immediate-release tablets; peak plasma concentrations are achieved approximately 5 hours after oral administration of the extended-release capsules.59

Food

Food decreases absorption rate (i.e., increases time to peak plasma concentration), but not extent (i.e., no effect on bioavailability) of absorption of carvedilol immediate-release tablets.1 Administration with food increases the extent of absorption of carvedilol when administered as carvedilol phosphate extended-release capsules.59 When administered with food in corresponding dosages (see Dosage under Dosage and Administration), equivalent drug exposure is achieved with carvedilol immediate release tablets and carvedilol extended-release capsules.59

Administration with food may be used to decrease risk of orthostatic hypotension.1

Special Populations

Increased plasma concentrations in individuals with CYP2D6 deficiency (poor metabolizers); results in increased α-adrenergic effects (vasodilation) and increased rate of dizziness during dosage titration.1

Increased peak plasma concentrations and AUCs (up to 50–100%) in heart failure patients.1

Increased plasma concentrations (50%) in elderly patients compared with younger adults.1

Substantially increased plasma concentrations (about 4- to 7-fold) in patients with cirrhosis.1 17 59

Increased plasma concentrations in patients with moderate or severe renal impairment; AUCs are similar to those in patients with normal renal function.1 59

Distribution

Extent

Substantial distribution into extravascular tissues.1

Crosses the placenta and is distributed into milk in rats.1

Plasma Protein Binding

>98%.1

Elimination

Metabolism

Substantial, stereoselective first-pass metabolism.1

Extensively metabolized; phenol ring demethylation and hydroxylation produce 3 metabolites with β-adrenergic blocking activity and (weak) vasodilating activity.1 Plasma concentrations of active metabolites are about 10% those of carvedilol.1 4’-Hydroxyphenyl metabolite is 13 times more potent than carvedilol for β-adrenergic blocking activity.1

Elimination Route

Excreted principally in the feces as metabolites; <2% excreted in urine unchanged.1

Half-life

7–10 hours.1 5–9 hours for R(+)-carvedilol, and 7–11 hours for S(-)-carvedilol.1

Special Populations

In heart failure patients, mean half-life was similar to that in normal individuals.1

Excretion apparently is not substantially affected by hemodialysis.1 17 59

Cessation of Therapy

Patients with coronary artery disease, who are being treated with Carvedilol tablets, should be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and the occurrence of myocardial infarction and ventricular arrhythmias have been reported in angina patients following the abrupt discontinuation of therapy with β-blockers. The last 2 complications may occur with or without preceding exacerbation of the angina pectoris. As with other β-blockers, when discontinuation of Carvedilol tablets is planned, the patients should be carefully observed and advised to limit physical activity to a minimum. Carvedilol tablets should be discontinued over 1 to 2 weeks whenever possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that Carvedilol tablets be promptly reinstituted, at least temporarily. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue therapy with Carvedilol abruptly even in patients treated only for hypertension or heart failure.

Bradycardia

In clinical trials, Carvedilol tablets caused bradycardia in about 2% of hypertensive subjects, 9% of heart failure subjects, and 6.5% of myocardial infarction subjects with left ventricular dysfunction. If pulse rate drops below 55 beats per minute, the dosage should be reduced.

Hypotension

In clinical trials of primarily mild-to-moderate heart failure, hypotension and postural hypotension occurred in 9.7% and syncope in 3.4% of subjects receiving Carvedilol tablets compared with 3.6% and 2.5% of placebo subjects, respectively. The risk for these events was highest during the first 30 days of dosing, corresponding to the up-titration period and was a cause for discontinuation of therapy in 0.7% of subjects receiving Carvedilol tablets, compared with 0.4% of placebo subjects. In a long-term, placebo-controlled trial in severe heart failure (COPERNICUS), hypotension and postural hypotension occurred in 15.1% and syncope in 2.9% of heart failure subjects receivingCarvedilol tablets compared with 8.7% and 2.3% of placebo subjects, respectively. These events were a cause for discontinuation of therapy in 1.1% of subjects receiving Carvedilol tablets, compared with 0.8% of placebo subjects.

Postural hypotension occurred in 1.8% and syncope in 0.1% of hypertensive subjects, primarily following the initial dose or at the time of dose increase and was a cause for discontinuation of therapy in 1% of subjects.

In the CAPRICORN trial of survivors of an acute myocardial infarction, hypotension or postural hypotension occurred in 20.2% of subjects receiving Carvedilol tablets compared with 12.6% of placebo subjects. Syncope was reported in 3.9% and 1.9% of subjects, respectively. These events were a cause for discontinuation of therapy in 2.5% of subjects receiving Carvedilol tablets, compared with 0.2% of placebo subjects.

Starting with a low dose, administration with food, and gradual up-titration should decrease the likelihood of syncope or excessive hypotension [see Dosage and Administration  (2.1, 2.2, 2.3)]. During initiation of therapy, the patient should be cautioned to avoid situations such as driving or hazardous tasks, where injury could result should syncope occur.

Heart Failure/Fluid Retention

Worsening heart failure or fluid retention may occur during up-titration of Carvedilol. If such symptoms occur, diuretics should be increased and the Carvedilol dose should not be advanced until clinical stability resumes [see Dosage and Administration (2)]. Occasionally it is necessary to lower the Carvedilol dose or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of, or a favorable response to, Carvedilol. In a placebo-controlled trial of subjects with severe heart failure, worsening heart failure during the first 3 months was reported to a similar degree with Carvedilol and with placebo. When treatment was maintained beyond 3 months, worsening heart failure was reported less frequently in subjects treated with Carvedilol than with placebo. Worsening heart failure observed during long-term therapy is more likely to be related to the patients' underlying disease than to treatment with Carvedilol.

Non-allergic Bronchospasm

Patients with bronchospastic disease (e.g., chronic bronchitis and emphysema) should, in general, not receive β-blockers. Carvedilol tablets may be used with caution, however, in patients who do not respond to, or cannot tolerate, other antihypertensive agents. It is prudent, if Carvedilol tablets are used, to use the smallest effective dose, so that inhibition of endogenous or exogenous β-agonists is minimized.

In clinical trials of subjects with heart failure, subjects with bronchospastic disease were enrolled if they did not require oral or inhaled medication to treat their bronchospastic disease. In such patients, it is recommended that Carvedilol be used with caution. The dosing recommendations should be followed closely and the dose should be lowered if any evidence of bronchospasm is observed during up-titration.

Glycemic Control in Type 2 Diabetes

In general, β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective β-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned about these possibilities.

In heart failure patients with diabetes, Carvedilol therapy may lead to worsening hyperglycemia, which responds to intensification of hypoglycemic therapy. It is recommended that blood glucose be monitored when Carvedilol dosing is initiated, adjusted, or discontinued. Trials designed to examine the effects of Carvedilol on glycemic control in patients with diabetes and heart failure have not been conducted.

In a trial designed to examine the effects of Carvedilol on glycemic control in a population with mild-to-moderate hypertension and well-controlled type 2 diabetes mellitus, Carvedilol had no adverse effect on glycemic control, based on HbA1c measurements [see Clinical Studies (14.4)].

Peripheral Vascular Disease

β-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in such individuals.

Deterioration of Renal Function

Rarely, use of Carvedilol in patients with heart failure has resulted in deterioration of renal function. Patients at risk appear to be those with low blood pressure (systolic blood pressure less than 100 mm Hg), ischemic heart disease and diffuse vascular disease, and/or underlying renal insufficiency. Renal function has returned to baseline when Carvedilol was stopped. 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.

Major Surgery

Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.

Thyrotoxicosis

β-adrenergic blockade may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of β-blockade may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate thyroid storm.

Pheochromocytoma

In patients with pheochromocytoma, an α-blocking agent should be initiated prior to the use of any β-blocking agent. Although Carvedilol has both α- and β-blocking pharmacologic activities, there has been no experience with its use in this condition. Therefore, caution should be taken in the administration of Carvedilol to patients suspected of having pheochromocytoma.

Prinzmetal’s Variant Angina

Agents with non-selective β-blocking activity may provoke chest pain in patients with Prinzmetal's variant angina. There has been no clinical experience with Carvedilol in these patients although the α-blocking activity may prevent such symptoms. However, caution should be taken in the administration of Carvedilol to patients suspected of having Prinzmetal's variant angina.

Risk of Anaphylactic Reaction

While taking β-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.

Intraoperative Floppy Iris Syndrome

Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients treated with alpha-1 blockers (Carvedilol is an alpha/beta blocker). This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The patient's ophthalmologist should be prepared for possible modifications to the surgical technique, such as utilization of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to be a benefit of stopping alpha-1 blocker therapy prior to cataract surgery.

Clinical Studies Experience

Carvedilol tablets have been evaluated for safety in subjects with heart failure (mild, moderate, and severe), in subjects with left ventricular dysfunction following myocardial infarction and in hypertensive subjects. The observed adverse event profile was consistent with the pharmacology of the drug and the health status of the subjects in the clinical trials. Adverse events reported for each of these patient populations are provided below. Excluded are adverse events considered too general to be informative, and those not reasonably associated with the use of the drug because they were associated with the condition being treated or are very common in the treated population. Rates of adverse events were generally similar across demographic subsets (men and women, elderly and non-elderly, blacks and non-blacks).

Heart Failure

Carvedilol tablets have been evaluated for safety in heart failure in more than 4,500 subjects worldwide of whom more than 2,100 participated in placebo-controlled clinical trials. Approximately 60% of the total treated population in placebo-controlled clinical trials received Carvedilol tablets for at least 6 months and 30% received Carvedilol tablets for at least 12 months. In the COMET trial, 1,511 subjects with mild-to-moderateheart failure were treated with Carvedilol tablets for up to 5.9 years (mean: 4.8 years). Both in US clinical trials in mild-to-moderate heart failure that compared Carvedilol tablets in daily doses up to 100 mg (n = 765) with placebo (n = 437), and in a multinational clinical trial in severe heart failure (COPERNICUS) that compared Carvedilol tablets in daily doses up to 50 mg (n = 1,156) with placebo (n = 1,133), discontinuation rates for adverse experiences were similar in Carvedilol and placebo subjects. In placebo-controlled clinical trials, the only cause of discontinuation greater than1%, and occurring more often on Carvedilol was dizziness (1.3% on Carvedilol, 0.6% on placebo in the COPERNICUS trial).

Table 1 shows adverse events reported in subjects with mild-to-moderate heart failure enrolled in US placebo-controlled clinical trials, and with severe heart failure enrolled in the COPERNICUS trial. Shown are adverse events that occurred more frequently in drug-treated subjects than placebo-treated subjects with an incidence of greater than 3% in subjects treated with Carvedilol regardless of causality. Median trial medication exposure was 6.3 months for both Carvedilol and placebo subjects in the trials of mild-to-moderate heart failure, and 10.4 months in the trial of severe heart failure subjects. The adverse event profile of Carvedilol tablets observed in the long-term COMET trial was generally similar to that observed in the US Heart Failure Trials.

Cardiac failure and dyspnea were also reported in these trials, but the rates were equal or greater in subjects who received placebo.

The following adverse events were reported with a frequency of greater than 1% but less than or equal to 3% and more frequently with Carvedilol in either the US placebo-controlled trials in subjects with mild-to-moderate heart failure, or in subjects with severe heart failure in the COPERNICUS trial.

Incidence greater than 1% to less than or equal to 3%

Body as a Whole

Allergy, malaise, hypovolemia, fever, leg edema.

Cardiovascular

Fluid overload, postural hypotension, aggravated angina pectoris, AV block, palpitation, hypertension.

Central and Peripheral Nervous System

Hypesthesia, vertigo, paresthesia.

Gastrointestinal

Melena, periodontitis.

Liver and Biliary System

SGPT increased, SGOT increased.

Metabolic and Nutritional

Hyperuricemia, hypoglycemia, hyponatremia, increased alkaline phosphatase, glycosuria, hypervolemia, diabetes mellitus, GGT increased, weight loss, hyperkalemia, creatinine increased.

Musculoskeletal

Muscle cramps.

Platelet, Bleeding, and Clotting

Prothrombin decreased, purpura, thrombocytopenia.

Psychiatric

Somnolence.

Reproductive, male

Impotence.

Special Senses

Blurred vision.

Urinary System

Renal insufficiency, albuminuria, hematuria.

Left Ventricular Dysfunction following Myocardial Infarction

Carvedilol tablets have been evaluated for safety in survivors of an acute myocardial infarction with left ventricular dysfunction in the CAPRICORN trial which involved 969 subjects who received Carvedilol tablets and 980 who received placebo. Approximately 75% of the subjects received Carvedilol tablets for at least 6 months and 53% received Carvedilol tablets for at least 12 months. Subjects were treated for an average of 12.9 months and 12.8 months with Carvedilol tablets and placebo, respectively.

The most common adverse events reported with Carvedilol tablets in the CAPRICORN trial were consistent with the profile of the drug in the US heart failure trials and the COPERNICUS trial. The only additional adverse events reported in CAPRICORN in greater than 3% of the subjects and more commonly on Carvedilol were dyspnea, anemia, and lung edema. The following adverse events were reported with a frequency of greater than 1% but less than or equal to 3% and more frequently with Carvedilol tablets: flu syndrome, cerebrovascular accident, peripheral vascular disorder, hypotonia, depression, gastrointestinal pain, arthritis, and gout. The overall rates of discontinuations due to adverse events were similar in both groups of subjects. In this database, the only cause of discontinuation greater than 1%, and occurring more often on Carvedilol was hypotension (1.5% on Carvedilol, 0.2% on placebo).

Hypertension

Carvedilol tablets have been evaluated for safety in hypertension in more than 2,193 subjects in US clinical trials and in 2,976 subjects in international clinical trials. Approximately 36% of the total treated population received Carvedilol tablets for at least 6 months. Most adverse events reported during therapy with Carvedilol tablets were of mild to moderate severity. In US controlled clinical trials directly comparing Carvedilol tablets in doses up to 50 mg (n = 1,142) with placebo (n = 462), 4.9% of subjectsreceiving Carvedilol tablets discontinued for adverse events versus 5.2% of placebo subjects. Although there was no overall difference in discontinuation rates, discontinuations were more common in the Carvedilol group for postural hypotension (1% versus 0). The overall incidence of adverse events in US placebo-controlled trials increased with increasing dose of Carvedilol tablets. For individual adverse events this could only be distinguished for dizziness, which increased in frequency from 2% to 5% as total daily dose increased from 6.25 mg to 50 mg.

Table 2 shows adverse events in US placebo-controlled clinical trials for hypertension that occurred with an incidence of greater than or equal to 1% regardless of causality, and that were more frequent in drug-treated subjects than placebo-treated subjects.

Dyspnea and fatigue were also reported in these trials, but the rates were equal or greater in subjects who received placebo.

The following adverse events not described above were reported as possibly or probably related to Carvedilol tablets in worldwide open or controlled trials with Carvedilol tablets in subjects with hypertension or heart failure.

Incidence greater than 0.1% to less than or equal to 1%

Cardiovascular:

Peripheral ischemia, tachycardia.

Central and Peripheral Nervous System:

Hypokinesia.

Gastrointestinal:

Bilirubinemia, increased hepatic enzymes (0.2% of hypertension patients and 0.4% of heart failure patients were discontinued from therapy because of increases in hepatic enzymes) [see Adverse Reactions (6.2)].

Psychiatric:

Nervousness, sleep disorder, aggravated depression, impaired concentration, abnormal thinking, paroniria, emotional lability.

Respiratory System:

Asthma [see CONTRAINDICATIONS  (4)].

Reproductive, male:

Decreased libido.

Skin and Appendages:

Pruritus, rash erythematous, rash maculopapular, rash psoriaform, photosensitivity reaction.

Special Senses:

Tinnitus.

Urinary System:

Micturition frequency increased.

Autonomic Nervous System:

Dry mouth, sweating increased.

Metabolic and Nutritional:

Hypokalemia, hypertriglyceridemia.

Hematologic:

Anemia, leukopenia.

The following events were reported in less than or equal to 0.1% of subjects and are potentially important: complete AV block, bundle branch block, myocardial ischemia, cerebrovascular disorder, convulsions, migraine, neuralgia, paresis, anaphylactoid reaction, alopecia, exfoliative dermatitis, amnesia, GI hemorrhage, bronchospasm, pulmonary edema, decreased hearing, respiratory alkalosis, increased BUN, decreased HDL, pancytopenia, and atypical lymphocytes.

Laboratory Abnormalities

Reversible elevations in serum transaminases (ALT or AST) have been observed during treatment with Carvedilol tablets. Rates of transaminase elevations (2 to 3 times the upper limit of normal) observed during controlled clinical trials have generally been similar between subjects treated with Carvedilol tablets and those treated with placebo. However, transaminase elevations, confirmed by rechallenge, have been observed with Carvedilol tablets. In a long-term, placebo-controlled trial in severe heart failure, subjects treated with Carvedilol tablets had lower values for hepatic transaminases than subjects treated with placebo, possibly because improvements in cardiac function induced by Carvedilol led to less hepatic congestion and/or improved hepatic blood flow.

Carvedilol tablets have not been associated with clinically significant changes in serum potassium, total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or creatinine. No clinically relevant changes were noted in fasting serum glucose in hypertensive patients; fasting serum glucose was not evaluated in the heart failure clinical trials.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Carvedilol tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System Disorders

Aplastic anemia.

Immune System Disorders

Hypersensitivity (e.g., anaphylactic reactions, angioedema, urticaria).

Renal and Urinary Disorders

Urinary incontinence.

Respiratory, Thoracic, and Mediastinal Disorders

Interstitial pneumonitis.

Skin and Subcutaneous Tissue Disorders

Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme.

Overdosage may cause severe hypotension, bradycardia, cardiac insufficiency, cardiogenic shock, and cardiac arrest. Respiratory problems, bronchospasms, vomiting, lapses of consciousness, and generalized seizures may also occur.

The patient should be placed in a supine position and, where necessary, kept under observation and treated under intensive-care conditions. The following agents may be administered:

For excessive bradycardia: Atropine, 2 mg IV.

To support cardiovascular function: Glucagon, 5 to 10 mg IV rapidly over 30 seconds, followed by a continuous infusion of 5 mg per hour; sympathomimetics (dobutamine, isoprenaline, adrenaline) at doses according to body weight and effect.

If peripheral vasodilation dominates, it may be necessary to administer adrenaline or noradrenaline with continuous monitoring of circulatory conditions. For therapy-resistant bradycardia, pacemaker therapy should be performed. For bronchospasm, β-sympathomimetics (as aerosol or IV) or aminophylline IV should be given. In the event of seizures, slow IV injection of diazepam or clonazepam is recommended.

NOTE: In the event of severe intoxication where there are symptoms of shock, treatment with antidotes must be continued for a sufficiently long period of time consistent with the 7- to 10-hour half-life of Carvedilol.

Cases of overdosage with Carvedilol tablets alone or in combination with other drugs have been reported. Quantities ingested in some cases exceeded 1,000 milligrams. Symptoms experienced included low blood pressure and heart rate. Standard supportive treatment was provided and individuals recovered.

NDC 68382-092-01 in bottle of 100 Tablets

Carvedilol Tablets USP, 3.125 mg

Rx only

100 Tablets

ZYDUS

NDC 68382-093-01 in bottle of 100 Tablets

Carvedilol Tablets USP, 6.25 mg

Rx only

100 Tablets

ZYDUS

NDC 68382-094-01 in bottle of 100 Tablets

Carvedilol Tablets USP, 12.5 mg

Rx only

100 Tablets

ZYDUS

NDC 68382-095-01 in bottle of 100 Tablets

Carvedilol Tablets USP, 25 mg

Rx only

100 Tablets

ZYDUS

Plasma levels are about 50% higher

Reduce dosage if heart rate drops to <55 beats/minute.

Hypertension: Oral:

Immediate release: 6.25 mg twice daily; if tolerated, dose should be maintained for 1 to 2 weeks, then increased to 12.5 mg twice daily. If necessary, dosage may be increased to a maximum of 25 mg twice daily after 1 to 2 weeks. Usual dosage range (ASH/ISH [Weber, 2014]): 6.25 to 25 mg twice daily.

Extended release: Initial: 20 mg once daily, if tolerated, dose should be maintained for 1 to 2 weeks then increased to 40 mg once daily if necessary; if this dose is tolerated, maintain for 1 to 2 weeks then, if necessary, increase to 80 mg once daily; maximum dose: 80 mg once daily

Heart failure: Oral: Note: Initiate only in stable patients or hospitalized patients after volume status has been optimized and IV diuretics, vasodilators, and inotropic agents have all been successfully discontinued. Caution should be used when initiating in patients who required inotropes during their hospital course. Increase dose gradually and monitor for congestive signs and symptoms of HF making every effort to achieve target dose shown to be effective (HFSA [Lindenfeld, 2010]; Packer, 1996; ACCF/AHA [Yancy, 2013])

Immediate release: 3.125 mg twice daily for 2 weeks; if this dose is tolerated, may increase to 6.25 mg twice daily. Double the dose every 2 weeks to the highest dose tolerated by patient. (Prior to initiating therapy, other heart failure medications should be stabilized and fluid retention minimized.)

Maximum recommended dose:

Mild-to-moderate heart failure:

<85 kg: 25 mg twice daily

>85 kg: 50 mg twice daily

Severe heart failure: 25 mg twice daily (Packer, 2001)

Extended release: Initial: 10 mg once daily for 2 weeks; if the dose is tolerated, increase dose to 20 mg, 40 mg, and 80 mg over successive intervals of at least 2 weeks. Maintain on lower dose if higher dose is not tolerated. Note: The 2013 ACCF/AHA heart failure guidelines recommend a maximum dose of 80 mg once daily (Yancy, 2013).

Left ventricular dysfunction following MI: Oral: Note: Should be initiated only after patient is hemodynamically stable and fluid retention has been minimized.

Immediate release: Initial 3.125 to 6.25 mg twice daily; increase dosage incrementally (ie, from 6.25 to 12.5 mg twice daily) at intervals of 3 to 10 days, based on tolerance, to a target dose of 25 mg twice daily. Note: The 2013 ACCF/AHA heart failure guidelines recommend a maximum dose of 50 mg twice daily (Yancy, 2013].

Extended release: Initial: Extended release: Initial: 10 to 20 mg once daily; increase dosage incrementally at intervals of 3 to 10 days, based on tolerance, to a target dose of 80 mg once daily.

Angina pectoris (off-label use): Oral: Immediate release: 25 to 50 mg twice daily

Atrial fibrillation (rate control) (off-label use): Usual maintenance dose: 3.125 to 25 mg twice daily (AHA/ACC/HRS [January, 2014]). In patients with heart failure, the initial dose of 3.125 mg twice daily may be increased at 2-week intervals to a target dose of 25 mg twice daily (50 mg twice daily for patients weighing >85 kg) (Khand, 2003)

Gastroesophageal varices (off-label use): Oral: Initial: 6.25 mg once daily; may increase after 1 week to 12.5 mg once daily if heart rate ≥55 bpm (LaBrecque 2014; Tripathi 2009). Increasing doses beyond 12.5 mg daily increases unwanted adverse effects without additional benefit (Reiberger 2012).

Conversion from immediate release to extended release (Coreg CR):

Current dose immediate release tablets 3.125 mg twice daily: Convert to extended release capsules 10 mg once daily

Current dose immediate release tablets 6.25 mg twice daily: Convert to extended release capsules 20 mg once daily

Current dose immediate release tablets 12.5 mg twice daily: Convert to extended release capsules 40 mg once daily

Current dose immediate release tablets 25 mg twice daily: Convert to extended release capsules 80 mg once daily

Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Consider therapy modification

Acetylcholinesterase Inhibitors: May enhance the bradycardic effect of Beta-Blockers. Monitor therapy

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Per US labeling: reduce afatinib by 10mg if not tolerated. Per Canadian labeling: avoid combination if possible; if used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Consider therapy modification

Ajmaline: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Alpha-/Beta-Agonists (Direct-Acting): Beta-Blockers may enhance the vasopressor effect of Alpha-/Beta-Agonists (Direct-Acting). Epinephrine used as a local anesthetic for dental procedures will not likely cause clinically relevant problems. Some beta-adrenoceptor mediated effects of Alpha-/Beta-Agonists (Direct-Acting), including anti-anaphylactic effects of epinephrine, may be diminished by Beta-Blockers. Management: Cardioselective beta-blockers and lower doses of epinephrine may confer a more limited risk. Patients who may require acute subcutaneous epinephrine (e.g., bee sting kits) should probably avoid beta blockers. Exceptions: Dipivefrin. Consider therapy modification

Alpha1-Blockers: Beta-Blockers may enhance the orthostatic hypotensive effect of Alpha1-Blockers. The risk associated with ophthalmic products is probably less than systemic products. Monitor therapy

Alpha2-Agonists: May enhance the AV-blocking effect of Beta-Blockers. Sinus node dysfunction may also be enhanced. Beta-Blockers may enhance the rebound hypertensive effect of Alpha2-Agonists. This effect can occur when the Alpha2-Agonist is abruptly withdrawn. Management: Closely monitor heart rate during treatment with a beta blocker and clonidine. Withdraw beta blockers several days before clonidine withdrawal when possible, and monitor blood pressure closely. Recommendations for other alpha2-agonists are unavailable. Exceptions: Apraclonidine. Consider therapy modification

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Aminoquinolines (Antimalarial): May decrease the metabolism of Beta-Blockers. Monitor therapy

Amiodarone: May enhance the bradycardic effect of Beta-Blockers. Possibly to the point of cardiac arrest. Amiodarone may increase the serum concentration of Beta-Blockers. Monitor therapy

Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Anilidopiperidine Opioids: May enhance the bradycardic effect of Beta-Blockers. Anilidopiperidine Opioids may enhance the hypotensive effect of Beta-Blockers. Monitor therapy

Antipsychotic Agents (Phenothiazines): May enhance the hypotensive effect of Beta-Blockers. Beta-Blockers may decrease the metabolism of Antipsychotic Agents (Phenothiazines). Antipsychotic Agents (Phenothiazines) may decrease the metabolism of Beta-Blockers. Monitor therapy

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Asunaprevir: May increase the serum concentration of CYP2D6 Substrates. Consider therapy modification

Barbiturates: May decrease the serum concentration of Beta-Blockers. Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Beta2-Agonists: Beta-Blockers (Nonselective) may diminish the bronchodilatory effect of Beta2-Agonists. Avoid combination

Betrixaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Betrixaban. Management: Decrease the betrixaban dose to an initial single dose of 80 mg followed by 40 mg once daily if combined with a P-glycoprotein inhibitor. Consider therapy modification

Bilastine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bilastine. Management: Consider alternatives when possible; bilastine should be avoided in patients with moderate to severe renal insufficiency who are receiving p-glycoprotein inhibitors. Consider therapy modification

Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Monitor therapy

Brentuximab Vedotin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy

Bretylium: May enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents. Monitor therapy

Brigatinib: May diminish the antihypertensive effect of Antihypertensive Agents. Brigatinib may enhance the bradycardic effect of Antihypertensive Agents. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Bupivacaine: Beta-Blockers may increase the serum concentration of Bupivacaine. Monitor therapy

Calcium Channel Blockers (Nondihydropyridine): May enhance the hypotensive effect of Beta-Blockers. Bradycardia and signs of heart failure have also been reported. Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Beta-Blockers. Exceptions: Bepridil. Monitor therapy

Cardiac Glycosides: Beta-Blockers may enhance the bradycardic effect of Cardiac Glycosides. Monitor therapy

Celiprolol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Celiprolol. Monitor therapy

Ceritinib: Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib. Management: If this combination cannot be avoided, monitor patients for evidence of symptomatic bradycardia, and closely monitor blood pressure and heart rate during therapy. Avoid combination

Cholinergic Agonists: Beta-Blockers may enhance the adverse/toxic effect of Cholinergic Agonists. Of particular concern are the potential for cardiac conduction abnormalities and bronchoconstriction. Management: Administer these agents in combination with caution, and monitor for conduction disturbances. Avoid methacholine with any beta blocker due to the potential for additive bronchoconstriction. Monitor therapy

Cimetidine: May increase the serum concentration of Carvedilol. Monitor therapy

Cobicistat: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. Consider therapy modification

CycloSPORINE (Systemic): Carvedilol may increase the serum concentration of CycloSPORINE (Systemic). Consider therapy modification

CYP2C9 Inhibitors (Moderate): May increase the serum concentration of Carvedilol. Specifically, concentrations of the S-carvedilol enantiomer may be increased. Monitor therapy

CYP2C9 Inhibitors (Strong): May increase the serum concentration of Carvedilol. Specifically, concentrations of the S-carvedilol enantiomer may be increased. Monitor therapy

CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Monitor therapy

CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates. Consider therapy modification

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Management: Dabigatran dose reductions may be needed. Specific recommendations vary considerably according to US vs Canadian labeling, specific P-gp inhibitor, renal function, and indication for dabigatran treatment. Refer to full monograph or dabigatran labeling. Consider therapy modification

Darunavir: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Digoxin: May enhance the bradycardic effect of Carvedilol. Carvedilol may increase the serum concentration of Digoxin. Monitor therapy

Dipyridamole: May enhance the bradycardic effect of Beta-Blockers. Monitor therapy

Disopyramide: May enhance the bradycardic effect of Beta-Blockers. Beta-Blockers may enhance the negative inotropic effect of Disopyramide. Monitor therapy

DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Dronedarone: May enhance the bradycardic effect of Beta-Blockers. Dronedarone may increase the serum concentration of Beta-Blockers. This likely applies only to those agents that are metabolized by CYP2D6. Management: Use lower initial beta-blocker doses; adequate tolerance of the combination, based on ECG findings, should be confirmed prior to any increase in beta-blocker dose. Consider therapy modification

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification

Ergot Derivatives: Beta-Blockers may enhance the vasoconstricting effect of Ergot Derivatives. Exceptions: Nicergoline. Consider therapy modification

Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for patients being treated for subependymal giant cell astrocytoma or renal cell carcinoma. See prescribing information for specific dose adjustment and monitoring recommendations. Consider therapy modification

Fingolimod: Beta-Blockers may enhance the bradycardic effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and beta-blockers if possible. If coadministration is necessary, patients should have overnight continuous ECG monitoring conducted after the first dose of fingolimod. Monitor patients for bradycardia. Consider therapy modification

Floctafenine: May enhance the adverse/toxic effect of Beta-Blockers. Avoid combination

Grass Pollen Allergen Extract (5 Grass Extract): Beta-Blockers may enhance the adverse/toxic effect of Grass Pollen Allergen Extract (5 Grass Extract). More specifically, Beta-Blockers may inhibit the ability to effectively treat severe allergic reactions to Grass Pollen Allergen Extract (5 Grass Extract) with epinephrine. Some other effects of epinephrine may be unaffected or even enhanced (e.g., vasoconstriction) during treatment with Beta-Blockers. Consider therapy modification

Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Imatinib: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Insulin: Beta-Blockers may enhance the hypoglycemic effect of Insulin. Monitor therapy

Ivabradine: Bradycardia-Causing Agents may enhance the bradycardic effect of Ivabradine. Monitor therapy

Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Monitor therapy

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy

Lidocaine (Systemic): Beta-Blockers may increase the serum concentration of Lidocaine (Systemic). Monitor therapy

Lidocaine (Topical): Beta-Blockers may increase the serum concentration of Lidocaine (Topical). Monitor therapy

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Lumacaftor: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. Lumacaftor may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Lumefantrine: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Mepivacaine: Beta-Blockers may increase the serum concentration of Mepivacaine. Monitor therapy

Methacholine: Beta-Blockers may enhance the adverse/toxic effect of Methacholine. Avoid combination

Methoxyflurane: May enhance the hypotensive effect of Beta-Blockers. Monitor therapy

Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Midodrine: Beta-Blockers may enhance the bradycardic effect of Midodrine. Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Naldemedine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naldemedine. Monitor therapy

Naloxegol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol. Monitor therapy

NiCARdipine: May enhance the hypotensive effect of Carvedilol. NiCARdipine may precipitate signs of heart failure in susceptible patients on Carvedilol NiCARdipine may increase the serum concentration of Carvedilol. Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

NIFEdipine: May enhance the hypotensive effect of Beta-Blockers. NIFEdipine may enhance the negative inotropic effect of Beta-Blockers. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May diminish the antihypertensive effect of Beta-Blockers. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Panobinostat: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of sensitive CYP2D6 substrates when possible, particularly those substrates with a narrow therapeutic index. Consider therapy modification

PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Perhexiline: CYP2D6 Substrates may increase the serum concentration of Perhexiline. Perhexiline may increase the serum concentration of CYP2D6 Substrates. Monitor therapy

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

P-glycoprotein/ABCB1 Substrates: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Propafenone: May increase the serum concentration of Beta-Blockers. Propafenone possesses some independent beta blocking activity. Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Prucalopride: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

QuiNINE: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Ranolazine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ranolazine. Monitor therapy

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Regorafenib: May enhance the bradycardic effect of Beta-Blockers. Monitor therapy

Reserpine: May enhance the hypotensive effect of Beta-Blockers. Monitor therapy

Rifamycin Derivatives: May decrease the serum concentration of Beta-Blockers. Exceptions: Rifabutin. Monitor therapy

RifAXIMin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin. Monitor therapy

Rivastigmine: May enhance the bradycardic effect of Beta-Blockers. Avoid combination

Ruxolitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Management: Ruxolitinib Canadian product labeling recommends avoiding use with bradycardia-causing agents to the extent possible. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May increase the serum concentration of Beta-Blockers. Exceptions: Citalopram; Escitalopram; FluvoxaMINE. Monitor therapy

Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Avoid combination

Sulfonylureas: Beta-Blockers may enhance the hypoglycemic effect of Sulfonylureas. Cardioselective beta-blockers (eg, acebutolol, atenolol, metoprolol, and penbutolol) may be safer than nonselective beta-blockers. All beta-blockers appear to mask tachycardia as an initial symptom of hypoglycemia. Ophthalmic beta-blockers are probably associated with lower risk than systemic agents. Monitor therapy

Theophylline Derivatives: Beta-Blockers (Nonselective) may diminish the bronchodilatory effect of Theophylline Derivatives. Consider therapy modification

Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Monitor therapy

Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Avoid combination

Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations. Consider therapy modification

VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

Yohimbine: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Heart rate, blood pressure (base need for dosage increase on trough blood pressure measurements and for tolerance on standing systolic pressure 1 hour after dosing); renal studies, BUN, liver function; blood glucose in diabetics; in patients with increased risk for developing renal dysfunction, monitor during dosage titration.

Carvedilol may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Drinking alcohol can further lower your blood pressure and may increase certain side effects of carvedilol. You should especially avoid drinking alcohol within 2 hours before or after taking extended-release carvedilol (Coreg CR).

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

Other drugs may interact with carvedilol, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Immediate-release tablets:
-Initial dose: 3.125 mg orally twice a day for 2 weeks
-Titration: If tolerated, increase dosage to 6.25, 12.5, and 25 mg orally twice a day over successive intervals of at least 2 weeks
-Maximum dose: 25 mg orally twice a day in patients weighing 85 kg or less and 50 mg orally twice a day in patients weighing 85 kg or greater

Extended-release capsules:
-Initial dose: 10 mg orally once a day for 2 weeks
-Titration: If tolerated, increase dosage to 20 mg, 40 mg, and 80 mg orally once a day over successive intervals of at least 2 weeks
-Maximum dose: 80 mg orally once a day

Comments:
-This drug should be taken with food to slow the rate of absorption and reduce the incidence of orthostatic effects.
-Prior to initiation of therapy, fluid retention should be minimized.

Use: For the treatment of mild-to-severe chronic heart failure of ischemic or cardiomyopathic origin (usually in addition to diuretics, ACE inhibitors, and digitalis, to increase survival and to reduce the risk of hospitalization)

Severe hepatic impairment: Contraindicated

This drug should be used during pregnancy only if the benefit outweighs the risk. AU TGA pregnancy category: C US FDA pregnancy category: C Risk Summary: Brief statement (only if US FDA pregnancy category: Not assigned.) Comments: -Beta blockers reduce placental perfusion which may result in intrauterine fetal death and immature and premature deliveries. -Adverse reactions (e.g., hypoglycemia, hypotension, bradycardia, respiratory depression, hypothermia) may occur in the fetus and neonate. -There is an increased risk of cardiac and pulmonary complications in the neonate in the postnatal period. -If this drug is used during pregnancy, therapy should be stopped 2 to 3 days before the expected birth; if this is not possible then the newborn should be monitored for the first 2 to 3 days of life.

There are no controlled data in human pregnancy. It is not known whether this drug can cause fetal harm or adversely affect reproductive capacity in humans. AU TGA pregnancy category C: Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details. US FDA pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

This drug appears to present a low risk to the breastfed infant; however, because there is no published experience during breastfeeding, other agents may be preferred, especially while nursing a newborn or preterm infant.

A decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother. Excreted into human milk: Yes Comment: -The effects in the nursing infant are unknown; however, the possibility of the consequences of alpha and beta blockade should be considered.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include uneven heartbeats, shortness of breath, bluish-colored fingernails, dizziness, weakness, fainting, and seizure (convulsions).

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have a serious side effect such as:

• a light-headed feeling, like you might pass out;

• slow or uneven heartbeats;

• swelling, rapid weight gain, feeling short of breath (even with mild exertion);

• cold feeling or numbness in your fingers or toes;

• chest pain, dry cough, wheezing, chest tightness, trouble breathing; or

• high blood sugar (increased thirst, increased urination, hunger, dry mouth, fruity breath odor, drowsiness, dry skin, blurred vision, weight loss).

Common side effects may include:

• weakness, dizziness;

• diarrhea;

• dry eyes;

• tired feeling; or

• weight gain.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.