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Carvedilol information from DrugsUpdate  

See Available Brands of Carvedilol in India

P - Caution when used during pregnancy
L - Contraindicated in lactation

Carvedilol is a non-selective beta blocker/alpha-1 blocker indicated in the treatment of mild to moderate congestive heart failure (CHF). It works by relaxing the blood vessels, slowing down the heart, and decreasing the amount of blood it pumps out. This decreases blood pressure, helps the heart pump more efficiently, and reduces the workload on the heart.
It is used for treating high blood pressure or certain types of heart failure. It may also be used after a heart attack to improve survival in certain patients. It may be used along with other medicines.

Pharmacodynamics

Pharmacokinetics

Absorption
Rapidly and extensively absorbed. Bioavailability is approximately 25% to 35% because of first-pass metabolism. Food decreases the rate of absorption. Instruct patients to take with food.
Distribution
More than 98% protein bound, primarily to albumin. Lipophilic, with a Vd of about 115 L. Plasma Cl is 500 to 700 mL/min.
Metabolism
Undergoes first-pass metabolism. Metabolized by aromatic ring oxidation and glucuronidation; 3 active metabolites are formed, 1 of which is about 13 times more potent than carvedilol. CYP-450 enzymes are involved in carvedilol metabolism.
Elimination
The t ½ is 7 to 10 h. Less than 2% is excreted unchanged in urine. Metabolites are excreted via the bile into feces.
Special Populations
Renal Function Impairment
Plasma concentrations may be higher (40% to 50% in those with moderate to severe renal function impairment).
Hepatic Function Impairment
Cirrhotic liver disease patients have a 4- to 7-fold increase in concentrations. Use in patients with hepatic function impairment is not recommended.
Elderly
Plasma levels are about 50% higher in elderly patients.
CHF
AUC and C max are increased.

Carvedilol Indications / Carvedilol Uses

Information Not Available

Carvedilol Adverse Reactions / Carvedilol Side Effects

Bradycardia, AV block, angina pectoris, hypervolaemia, leucopenia, hypotension, peripheral oedema, allergy, malaise, fluid overload, melena, periodontitis, hyperuricaemia, hyponatraemia, increased alkaline phosphatase, glycosuria, prothrombin time, SGPT and SGOT levels, purpura, somnolence, impotence, albuminuria, hypokinesia, nervousness, sleep disorder, skin reaction, tinnitus, dry mouth, anaemia, sweating, fatigue, arthralgia, aggravation, dizziness. Diarrhoea, nausea, vomiting, insomnia, hypercholesterolaemia, weight gain, abnormal vision, rhinitis, pharyngitis and hypertriglyceridaemia.

Precautions

Cessation of Therapy
Patients with coronary artery disease, who are being treated with Carvedilol, 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 is planned, the patients should be carefully observed and advised to limit physical activity to a minimum. Carvedilol should be discontinued over 1 to 2 weeks whenever possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that Carvedilol 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 caused bradycardia in about 2% of hypertensive patients, 9% of heart failure patients, and 6.5% of myocardial infarction patients with left ventricular dysfunction. If pulse rate drops below 55 beats/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 patients receiving Carvedilol compared to 3.6% and 2.5% of placebo patients, 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 patients receiving Carvedilol, compared to 0.4% of placebo patients. 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 patients receiving Carvedilol compared to 8.7% and 2.3% of placebo patients, respectively. These events were a cause for discontinuation of therapy in 1.1% of patients receiving Carvedilol, compared to 0.8% of placebo patients.
Postural hypotension occurred in 1.8% and syncope in 0.1% of hypertensive patients, primarily following the initial dose or at the time of dose increase and was a cause for discontinuation of therapy in 1% of patients.
In the capricorn study of survivors of an acute myocardial infarction, hypotension or postural hypotension occurred in 20.2% of patients receiving Carvedilol compared to 12.6% of placebo patients. Syncope was reported in 3.9% and 1.9% of patients, respectively. These events were a cause for discontinuation of therapy in 2.5% of patients receiving Carvedilol, compared to 0.2% of placebo patients.
Starting with a low dose, administration with food, and gradual up-titration should decrease the likelihood of syncope or excessive hypotension. 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.  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 patients 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 patients 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 may be used with caution, however, in patients who do not respond to, or cannot tolerate, other antihypertensive agents. It is prudent, if Carvedilol is used, to use the smallest effective dose, so that inhibition of endogenous or exogenous β-agonists is minimized.
In clinical trials of patients with heart failure, patients 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. Studies designed to examine the effects of Carvedilol on glycemic control in patients with diabetes and heart failure have not been conducted.
In a study designed to examine the effects of Carvedilol on glycemic control in a 161 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.

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 < 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.

Anesthesia and Major Surgery
If treatment with Carvedilol is to be continued perioperatively, particular care should be taken when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used for information on treatment of bradycardia and hypertension].

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 ß-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.

Special Precautions

Avoid abrupt withdrawal as it may precipitate thyroid storm or exacerbate hyperthyroidism. Liver injury; vascular disease, renal failures, suspected phaeochromocytoma and prinzmetal's variable angina; worsening cardiac failure or fluid retention during increase in dosage of carvedilol; diabetic patients. Pregnancy.

Other Drug Interactions

Potentiates insulin-induced hypoglycaemic action. Concurrent use with catecholamine-depleting agents and β-receptor blockers may cause marked hypotension. Serum levels may be increased by fluoxetine. May increase serum levels of ciclosporin and digoxin.
Potentially Fatal: Rifampin pretreatment results in a decreased Cmax and AUC. Combination with verapamil can lead to severe bradycardia and myocardial depression.

Other Interactions

Food Interactions: Food reduces rate of absorption and risk of hypotension

Dosage

Oral
Hypertension
Adult: Initially, 12.5 mg once daily increased to 25 mg once daily after 2 days. Alternatively, initial dose of 6.25 mg bid increased to 12.5 mg bid after 1-2 wk, increased further if necessary to 50 mg once daily or in divided doses.
Elderly: 12.5 mg once daily.
Oral
Angina pectoris
Adult: Initially, 12.5 mg bid increased to 25 mg bid after 2 days.
Oral
Heart failure
Adult: Initially, 3.125 mg bid, doubled to 6.25 mg bid after 2 wk if tolerated, then gradually increased to the max dose the patient can tolerate at intervals of not <2 wk. Max dose: >85 kg: 50 mg bid; <85 kg: 25 mg bid.
Oral
Left ventricular dysfunction post myocardial infarction
Adult: Initially: 6.25 mg bid, if tolerated, after 3-10 days, increase to 12.5 mg bid and then to a target dose of 25 mg bid.

Food(before/after)

Should be taken with food

List of Contraindications

Carvedilol and Pregnancy

Caution when used during pregnancy.
Category C: Either studies in animals have revealed adverse effects on the foetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the foetus.
In 2nd & 3rd trimesters:
Category D: There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Carvedilol and Lactation

Contraindicated in lactation.
It is not known whether this drug is excreted in human milk. Studies in rats have shown that Carvedilol and/or its metabolites (as well as other β-blockers) cross the placental barrier and are excreted in breast milk. There was increased mortality at one week post-partum in neonates from rats treated with 60 mg/kg/day (10 times the MRHD as mg/m2) and above during the last trimester through day 22 of lactation. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from β-blockers, especially bradycardia, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. The effects of other α- and β-blocking agents have included perinatal and neonatal distress.

Carvedilol and Children

It is not known whether this drug is excreted in human milk. Studies in rats have shown that Carvedilol and/or its metabolites (as well as other β-blockers) cross the placental barrier and are excreted in breast milk. There was increased mortality at one week post-partum in neonates from rats treated with 60 mg/kg/day (10 times the MRHD as mg/m2) and above during the last trimester through day 22 of lactation. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from β-blockers, especially bradycardia, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. The effects of other α- and β-blocking agents have included perinatal and neonatal distress.

Carvedilol and Geriatic

It is not known whether this drug is excreted in human milk. Studies in rats have shown that Carvedilol and/or its metabolites (as well as other β-blockers) cross the placental barrier and are excreted in breast milk. There was increased mortality at one week post-partum in neonates from rats treated with 60 mg/kg/day (10 times the MRHD as mg/m2) and above during the last trimester through day 22 of lactation. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from β-blockers, especially bradycardia, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. The effects of other α- and β-blocking agents have included perinatal and neonatal distress.

Carvedilol and Other Contraindications

Hypersensitivity; severe chronic heart failure, bronchial asthma or related bronchospastic conditions; severe hepatic impairment. Patients with NYHA class IV cardiac failure, 2nd or 3rd ° AV block, sick sinus syndrome (unless a permanent pacemaker is in place), cardiogenic shock or severe bradycardia. Lactation.

Storage

Oral: Store below 30°C

Lab interference

Oral: Store below 30°C

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