Carvedilol is a racemic mixture in which nonselective •-adrenoreceptor blocking activity is present in the S(-) enantiomer and •-adrenergic blocking activity is present in both R(+) and S(-) enantiomers at equal potency. Carvedilol has no intrinsic sympathomimetic activity.

Absorption: Carvedilol is rapidly and extensively absorbed following oral administration, with absolute bioavailability of approximately 25% to 35% due to a significant degree of first-pass metabolism.

Distribution: Carvedilol is more than 98% bound to plasma proteins, primarily with albumin. The plasma-protein binding is independent of concentration over the therapeutic range. Carvedilol is a basic, lipophilic compound with a steady-state volume of distribution of approximately 115 L, indicating substantial distribution into extravascular tissues. Plasma clearance ranges from 500 to 700 mL/min.

Metabolism: The primary P450 enzymes responsible for the metabolism of both R(+) and S(-)-carvedilol in human liver microsomes were CYP2D6 and CYP2C9 and to a lesser extent CYP3A4, 2C19, 1A2, and 2E1. CYP2D6 is thought to be the major enzyme in the 4’- and 5’-hydroxylation of carvedilol, with a potential contribution from 3A4. CYP2C9 is thought to be of primary importance in the O-methylation pathway of S(-)-carvedilol.

Excretion: The metabolites of carvedilol are excreted primarily via the bile into the feces.

Indications & Usage:
Congestive Heart Failure: Carvedilol is indicated for the treatment of mild-to-severe heart failure of ischemic or cardiomyopathic origin, usually in addition to diuretics, ACE inhibitor, and digitalis, to increase survival and, also, to reduce the risk of hospitalization.
Left Ventricular Dysfunction Following Myocardial Infarction: Carvedilol 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 ­ 40% (with or without symptomatic heart failure).
Hypertension: Carvedilol is also indicated for the management of essential hypertension. It can be used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics.

Dosage And Administration:
Congestive Heart Failure: The recommended starting dose of Carvedilol is 3.125 mg, twice daily for 2 weeks. Patients who tolerate a dose of 3.125 mg twice daily may have their dose increased to 6.25, 12.5, and 25 mg twice daily over successive intervals of at least 2 weeks. Patients should be maintained on lower doses if higher doses are not tolerated.
Left Ventricular Dysfunction Following Myocardial Infarction: Dosage must be individualized and monitored during up-titration. It is recommended that Carvedilol be started at 6.25 mg twice daily and increased after 3 to 10 days, based on tolerability to 12.5 mg twice daily, then again to the target dose of 25mg twice daily. Patients should be maintained on lower doses if higher doses are not tolerated. The recommended dosing regimen need not be altered in patients who received treatment with an IV or oral •-blocker during the acute phase of the myocardial infarction.
Hypertension: DOSAGE MUST BE INDIVIDUALIZED. The recommended starting dose of Carvedilol is 6.25 mg twice daily. If this dose is tolerated, using standing systolic pressure measured about 1 hour after dosing as a guide, the dose should be maintained for 7 to 14 days, and then increased to 12.5 mg twice daily if needed, based on trough blood pressure, again using standing systolic pressure one hour after dosing as a guide for tolerance. This dose should also be maintained for 7 to 14 days and can then be adjusted upward to 25 mg twice daily if tolerated and needed. The full antihypertensive effect of Carvedilol is seen within 7 to 14 days. Total daily dose should not exceed 50 mg. Carvedilol should be taken with food to slow the rate of absorption and reduce the incidence of orthostatic effects.

Contraindications: Carvedilol is contraindicated in patients with hypersensitivity to any component of the product. Carvedilol is contraindicated in patients with bronchial asthma or related bronchospastic conditions, second- or third-degree AV block, sick sinus syndrome or severe bradycardia (unless a permanent pacemaker is in place), or in patients with cardiogenic shock or who have decompensated heart failure requiring the use of intravenous inotropic therapy. Such patients should first be weaned from intravenous therapy before initiating Carvedilol.

Adverse Effects: The following adverse events were reported with a frequency of >1% but ­3% and more frequently with Carvedilol.
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.

Warnings & Special Precautions:
Pregnancy:
Teratogenic Effects:
Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. Carvedilol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers:
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from B-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.
In Hepatic Impairment: Carvedilol should not be given to patients with severe hepatic impairment.
Renal impairment: Rarely, use of carvedilol in patients with congestive heart failure has resulted in deterioration of renal function. Patients at risk appear to be those with 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. Carvedilol should not be given to patients with severe renal impairment.

Interactions: Pharmacokinetic Drug-Drug Interactions: Since carvedilol undergoes substantial oxidative metabolism, the metabolism and pharmacokinetics of carvedilol may be affected by induction or inhibition of cytochrome P450 enzymes.
Warfarin: Carvedilol (12.5 mg twice daily) did not have an effect on the steady-state prothrombin time ratios and did not alter the pharmacokinetics of R(+)- and S(-)-warfarin following concomitant administration with warfarin in 9 healthy volunteers.
Catecholamine-depleting agents: Patients taking both agents with •-blocking properties and a drug that can deplete catecholamines (e.g., reserpine and monoamine oxidase inhibitors) should be observed closely for signs of hypotension and/or severe bradycardia.
Clonidine: Concomitant administration of clonidine with agents with •-blocking properties may potentiate blood-pressure- and heart-rate-lowering effects. When concomitant treatment with agents with •-blocking properties and clonidine is to be terminated, the •-blocking agent should be discontinued first. Clonidine therapy can then be discontinued several days later by gradually decreasing the dosage.
Cyclosporine: Due to wide interindividual variability in the dose adjustment required, it is recommended that cyclosporine concentrations be monitored closely after initiation of carvedilol therapy and that the dose of cyclosporine be adjusted as appropriate.
Digoxin: Digoxin concentrations are increased by about 15% when digoxin and carvedilol are administered concomitantly. Both digoxin and Carvedilol slow AV conduction. Therefore, increased monitoring of digoxin is recommended when initiating, adjusting, or discontinuing Carvedilol.
Calcium channel blocker As with other agents with •-blocking properties, if Carvedilol is to be administered orally with calcium channel blockers of the verapamil or diltiazem type, it is recommended that ECG and blood pressure be monitored.
Insulin or oral hypoglycemics: Agents with •-blocking properties may enhance the blood-sugar-reducing effect of insulin and oral hypoglycemics. Therefore, in patients taking insulin or oral hypoglycemics, regular monitoring of blood glucose is recommended.

Overdosage:
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. In the case of overdosage, patient should be placed in a supine position and, where necessary, kept under observation and treated under intensive-care conditions. Gastric lavage or pharmacologically induced emesis may be used shortly after ingestion.

Storage:
Store below 30°C (86°F). Protect from light, heat and moisture. Keep all medicines out of the reach of children.