Carvedilol Tablet (Tablet 3.

125 mg)
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[ Chemical Structures]
Classification:
Autonomic Agents
Sympatholytics
Beta-blockers

Cardiovascular Agents
Antianginals
Beta-blockers

Cardiovascular Agents
Antihypertensive Agents
Beta-blockers

Description: 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) 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.[24541]
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.[24633] 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.[26808] Subsequently, the COMET trial
evaluated carvedilol vs. metoprolol in patients with chronic heart failure (NYHA Class IIIV), and
Carvedilol
Coreg CR | Coreg
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demonstrated a significantly lower all-cause mortality for carvedilol (34% vs. 40% for metoprolol).
[27561] 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.[26194] 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.[27418] 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.[33826] Carvedilol has
been marketed in Europe since the 1980s under the trade name Kredex. Extended-release carvedilol
tablets (Coreg CR) were approved by the FDA in October 2006 for the same indications approved for
regular-release carvedilol tablets (Coreg).
Mechanism of Action: Carvedilol has multiple actions that make it a useful cardiovascular drug.
Similar to labetalol, carvedilol antagonizes both alpha
1
- and beta-receptors, however the ratio of beta-to-
alpha blockade differs between the two drugs. The ratio of beta-blockade to alpha
1
-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 alpha
1
-antagonism is essentially equal for both carvedilol
enantiomers. It is thought that alpha
1
-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 alpha
1
-
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.[24810] Vasodilatory properties of carvedilol are due mainly to
alpha
1
-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.[24810] The antioxidant effects of carvedilol have been thoroughly
reviewed.[24810] During chronic therapy, carvedilol does not decrease glomerular filtration rate (GFR)
[24441] or renal blood flow (RBF) [24442], nor does it significantly alter glucose tolerance tests or
fasting and postprandial glucose levels in non-insulin-dependent diabetics without congestive heart
failure.[24443][24444] 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%.[24445]

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Patients with chronic heart failure demonstrate increased sympathetic stimulation leading to
downregulation of beta
1
-receptors, both in number and in their sensitivity to adrenergic stimuli.[24446]
The beneficial effects of carvedilol in heart failure primarily result from its blockade of beta
1
-receptors.
Beta
1
-blockade causes an up-regulation of myocardial beta
1
-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.[24447]
Pharmacokinetics: Carvedilol is administered orally. Carvedilol 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
cytochrome P450 2D6 enzyme. There are three active metabolites having beta-antagonist activity and
weak alpha-antagonist effects. One metabolite, 4'-hydroxyphenylcarvedilol, is approximately 13 times
more potent than carvedilol as a beta-blocker. Approximately 60% of the metabolites are excreted in the
bile and eliminated in the feces, and 16% are excreted in the urine. Less than 2% is excreted unchanged
in the urine. The terminal elimination half-life ranges from 711 hours for the S(-) enantiomer and 5
9 hours for the R(+) enantiomer.


Route-Specific Pharmacokinetics
Oral Route
Carvedilol immediate-release tablets: The overall oral bioavailability of the immediate-release
tablets is about 2535% due to extensive first-pass elimination. The S(-) enantiomer has an
absolute bioavailability of 15% compared with 31% for the R(+) enantiomer. Food decreases the
rate but not the extent of absorption, which helps to minimize the risk of developing orthostatic
hypotension. Peak plasma concentrations and antihypertensive effects are reached in about 12
hours and are linearly related to the dose. Accumulation does not occur with repeated
administration. Compared with labetalol, the duration of action is greater for carvedilol (i.e.,
carvedilol duration is > 15 hours).
Carvedilol extended-release capsules: Coreg CR capsules are controlled-release oral capsules
containing carvedilol phosphate immediate-release and controlled-release microparticles which
are drug-layered and coated with methacrylic acid copolymers.[32362] The extended-release
capsules have a bioavailability of about 85% relative to the immediate-release tablets. For
comparable dosage conversion (see Dosage), the systemic exposure (AUC, Cmax, and serum
trough concentrations) of extended-release capsules is considered equivalent to immediate-release
tablets when both are administered with food.[32362] The absorption of carvedilol from Coreg
CR is slower and more prolonged compared to the immediate-release tablet with peak serum
concentrations attained about 5 hours following administration. Plasma concentrations increase in
a dose-related manner over the recommended dosage range (10 to 80 mg/day). Variability (within-
subject and between-subject) for AUC and Cmax is similar for Coreg CR and immediate-release
carvedilol. Administration of Coreg CR capsules with a high-fat meal results in increased AUC
and Cmax by approximately 20% compared to administration with a standard meal. Decreases in
the AUC (27%) and Cmax (43%) are observed when Coreg CR is administered in the fasted state
compared to administration after a standard meal. Coreg CR should be taken with food. Sprinkling
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the contents of Coreg CR capsules on applesauce does not appear to significantly effect the
overall exposure (AUC) of carvedilol compared to administration of the intact capsule following a
standard meal; however Cmax is decreased by about 18%.[32362] Absorption of the Coreg CR
beads sprinkled on other foods has not been tested. Due to stereoselective first-pass metabolism,
plasma concentrations of R(+)-carvedilol are about 23 times higher than S(-)-carvedilol after
administration of Coreg CR to healthy subjects. Pharmacodynamic studies with Coreg CR
capsules in patients with chronic heart failure or left ventricular dysfunction following acute
myocardial infarction indicate that the concentration-response relationship for beta
1
-blockade
following administration of Coreg CR is equivalent ( 20%) to immediate-release tablets. In a
randomized, double-blind, placebo-controlled trial of patients with essential hypertension, the
beta
1
-blocking effect of Coreg CR (measured by heart rate response to submaximal bicycle
ergometry) has been shown to be equivalent to that observed with immediate-release tablets at
steady state.


Special Populations
Hepatic Impairment
Oral bioavailability following administration of immediate-release carvedilol tablets is increased
significantly in patients with hepatic disease. Patients with cirrhotic liver disease have significantly
higher plasma levels of carvedilol (approximately 47 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 levels were less
pronounced (approximately 12% to 26% higher) in patients with impaired renal function. Carvedilol is
not cleared significantly by hemodialysis.[24448]

Pediatrics
The elimination half-life of carvedilol is reported to be approximately 50% shorter for children with
heart failure relative to healthy adults (2.9 vs. 5.2 hours).[32650] In this study, infants and young
children aged < 3.5 years (n=8) had a shorter half-life relative to seven older children aged 5.5 to 19.3
years (2.2 vs. 3.6 hours).

Elderly
Oral bioavailability following administration of immediate-release carvedilol tablets is increased by
about 50% in elderly patients.
References
24441. Dupont AG, Vand der Niepen P, Taeymans Y, et al. Effect of carvedilol on ambulatory blood
pressure, renal hemodynamics, and cardiac function in essential hypertension. J Cardiovasc Pharmacol
1987;10:S130-6.
24442. Dupont AG. Effects of carvedilol on renal function. Eur J Clin Pharmacol 1990;38(suppl 2):S96-
S100.
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24443. Ehmer B, van der Does R, Rudorf J. Influence of carvedilol on blood glucose and
glycohaemoglobin A1 in non-insulin-dependent diabetics. Drugs 1988;36(suppl.):136-140.
24444. Albergati F, Pateno E, Venuti RP, et al. Comparison of the effects of carvedilol and nifedipine in
patients with essential hypertension and non-insulin-dependent diabetes mellitus. J Cardiovasc
Pharmacol 1992;19(suppl 1):S86-S89.
24445. Hauf-Zachariou U, Widman L, Zulsdorf B, et al. A double-blind comparison of the effects of
carvedilol and captopril on serum lipid concentrations in patients with mild to moderate essential
hypertension and dyslipidaemia. Eur J Clin Pharmacol 1993;45:95-100.
24446. Bristow MR, Ginsburg R, Minobe W, et al. Decreased catecholamine sensitivity and beta-
adrenergic receptor density in failing human hearts. N Engl J Med 1982;307:205-11.
24447. Eichstaedt H, Schroeder RJ, Auffermann W. Regression of left ventricular hypertrophy. J
Cardiovasc Pharmacol 1992;19(suppl 1):S55-61.
24448. Morgan T. Clinical pharmacokinetics and pharmacodynamics of carvedilol. Clin Pharmacokinet
1994;26:335-46.
24541. McTavish D, Campoli-Richards D, Sorkin EM. Carvedilol: a review of its pharmacodynamic
and pharmacokinetic properties and therapeutic efficacy. Drugs 1993;45:232-58.
24633. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in
patients with chronic heart failure. N Engl J Med 1996;334:1349-55.
24810. Ruffolo RR Jr, Boyle DA, Brooks DP, et al. Carvedilol: a novel cardiovascular drug with
multiple actions. Cardiovasc Drug Rev 1992;10:127-57.
26194. Hjalmarson A, Goldstein S, Fagerberg B, et al. Effects of controlled-release metoprolol on total
mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL
Randomized Intervention Trial in congestive heart failure (MERIT-HF). MERIT-HF Study Group.
JAMA 2000;283:1295-1302.
26808. Packer M, Coats AJS, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart
failure. N Engl J Med 2001;344:1651-1658.
27418. Dargie HJ. Effect of carvedilol on outcome after myocardial infarction in patients with left-
ventricular dysfunction: the CAPRICORN randomized trial. Lancet 2001;357:1385-90.
27561. Poole-Wilson PA, Swedberg K, Cleland JG, et al. Comparison of carvedilol and metoprolol on
clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial
(COMET): randomised controlled trial. Lancet 2003;362:7-13.
32362. Nordby HK, Nesbakken R. The effect of high dose barbiturate decompression after severe head
injury. A controlled clinical trial. Acta Neurochir 1984;72:157-66.
32650. Laer S, Mir TS, Behn F, et al. Carvedilol therapy in pediatric patients with congestive heart
failure: a study investigating clinical and pharmacokinetic parameters. Am Heart J 2002;143:916-22.
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33826. Rosendorff C, Black HR, Cannon CP, et al. Treatment of Hypertension in the Prevention and
Management of Ischemic Heart Disease: A Scientific Statement from the American Heart Association
Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology
and Prevention. Circulation 2007;115:2761-88.
[ Revised 2/2/2011 4:10:00 PM ]

Drug Information Provided by
Gold Standard Inc. 2010
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