Coreg®

Carvedilol

Congestive Heart Failure Agent

GlaxoSmithKline

http://www.gsk.com/index.htm

Coreg Monograph PDF download here.

 

CPS:PIS_m137200

 

 

 

Pharmacology

Carvedilol is a cardiovascular agent for the treatment of congestive heart failure (CHF) that combines beta-adrenoceptor blockade and vasodilation in a single racemic mixture. Nonselective beta-adrenoceptor blocking activity is present in the S(-) enantiomer and alpha₁ adrenoceptor blocking activity is present at equal potency in both the R(+) and S(-) enantiomers. Carvedilol has no intrinsic sympathomimetic activity. Its action on beta-receptors is 10 times stronger than on alpha₁ receptors.

     Carvedilol reduces peripheral vascular resistance by vasodilation, thereby causing a fall in systemic blood pressure after acute administration, predominantly mediated through selective alpha₁ antagonism. Beta-blockade prevents reflex tachycardia, with the net result that heart rate is unchanged or decreased. Carvedilol reduces renin release through beta-blockade.

     In 2 studies that compared the acute hemodynamic effects of carvedilol to baseline measurements in patients with CHF, there were significant reductions in systemic blood pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, and heart rate. Initial effects on cardiac output, stroke volume index and systemic vascular resistance were small and variable.

     In terms of chronic hemodynamic effects (12 to 14 weeks), carvedilol significantly reduced systemic blood pressure, pulmonary artery pressure, right atrial pressure, systemic vascular resistance and heart rate while stroke volume index was increased.

     The mechanism for the beneficial effects of carvedilol in CHF has not been established.

     In a US multicentre program, 1197 patients with stable symptomatic CHF, NYHA class II to IV, were challenged with a low dose of carvedilol (3.125 or 6.25 mg twice daily) for 2 to 4 weeks to determine tolerability. Of these patients, 1094 were then randomized to double-blind treatment with carvedilol (n=696) or placebo (n=398) and stratified to 1 of 4 studies based on baseline exercise performance, with the prestated objective to evaluate total mortality. The average duration of therapy on carvedilol was 6.5 months in this program. Patients entering the program had symptomatic CHF due to ischemic or nonischemic cardiomyopathy, with an ejection fraction ≤  35%. All patients received conventional therapy, i.e. diuretics, angiotensin-converting enzyme (ACE) inhibitors, if tolerated, with or without digoxin.

     On an intent-to-treat basis, total mortality in this program was 3.2% in the carvedilol group and 7.8% in the placebo group. Thus, a relative risk reduction of 65% (95% confidence limits 39 and 80%, p=0.001) was observed. Treatment with carvedilol was associated with a significant decrease in the relative risk of death from progressive pump failure (81%, p=0.001) and the relative risk of sudden death (56%, p=0.033). The incidence of cardiovascular hospitalizations was 13% in the carvedilol group and 21% in the placebo group, with a relative risk reduction of 36% (95% confidence limits 14 and 53%, p=0.004).

     Improved patient well-being was observed with carvedilol treatment in the US multicentre program, as indicated by a change in the NYHA class from baseline to endpoint for the 4 US phase III placebo-controlled studies. The overall between-group difference in distributions, stratified by protocol and baseline classification, was significant (p<0.001) and as also indicated by patient and physician global assessments during US Phase III trials, 78% of patients in the carvedilol group rated their condition as improved compared to 63% in the placebo group (p values over 4 studies from 0.001 to 0.032). However, exercise tolerance was not improved.

     In a large multicentre trial of carvedilol, performed in Australia and New Zealand, 443 patients with stable symptomatic CHF NYHA Class I to III, were challenged with a low dose of carvedilol (3.125 mg or 6.25 mg twice daily) for 2 to 4 weeks to determine tolerability. Of these patients, 415 were then randomized to double-blind treatment with carvedilol (n=207) or placebo (n=208). The average duration of therapy on carvedilol was 16.1 months in this study. Patients entering the program had symptomatic CHF, due to ischemic cardiomyopathy, with an ejection fraction ≤ 45%. All patients received conventional therapy, i.e. diuretics, angiotensin-converting enzyme (ACE) inhibitors, if tolerated, with or without digoxin.

     On an intent-to-treat basis, total mortality in this Australia and New Zealand trial was 10.1% in the carvedilol group and 13.9% in the placebo group, a nonstatistically significant relative risk reduction of 29% (confidence limits 24 and 59%, p=0.231). Cardiovascular hospitalizations were 31% in the carvedilol group and 40% in the placebo group, a relative risk reduction of 28% (95% confidence limits: 1 and 48%, p=0.044). Patient well-being as judged by NYHA class or Specific Activity Scale rating, as well as exercise tolerance, were no different in the carvedilol group compared to the placebo group.

     In the Copernicus trial, 2289 patients with severe heart failure were randomly assigned to treatment with placebo or carvedilol for up to 29 months. Patients had symptoms at rest or on minimal exertion and had a left ventricular ejection fraction <25% (mean 20%), despite treatment with diuretics (99%), an ACE inhibitor (89%), and digitalis (66% worldwide, 85% within Canada) for more than 2 months. Patients with cardiac impairment not related to left ventricular dysfunction were excluded as were patients with prior cardiac transplant, cardioplasty, unstable angina, myocardial infarction, destabilizing cardiac arrhythmias, or treatment within 1 month with an α -adrenoceptor antagonist (except for prostatism), a calcium channel blocker or a class I antiarrhythmic agent. The trial was followed by a data safety monitoring committee, which stopped the trial early after a median follow-up of 10.4 months because of an observed reduction in total mortality, the primary endpoint, from 19.7% per patient-year on placebo to 12.8% per patient-year on carvedilol (a relative risk reduction of 35%; hazard ratio 0.65, 95% CI 0.52 and 0.81, and a P value adjusted for interim analyses of 0.0014). The results are summarized as follows. See  Table 1 and  Figure 1.

CPS:Coreg_t1Click here for Table 1

Table 1: Coreg

Results of Copernicus

 

End Point	Placebo N=1133	Carvedilol N=1156	Hazard Ratio (95% CI)	% Reduction	Nominal P Value
Mortality	190	130	0.65 (0.52–0.81)	35	0.00013
Mortality+all hospitalization	507	425	0.76 (0.67–0.87)	24	0.00004
Mortality+CV hospitalization	395	314	0.73 (0.63–0.84)	27	0.00002
Mortality+CHF hospitalization	357	271	0.69 (0.59–0.81)	31	0.000004

 

 

Figure 1:

Coreg

Survival Analysis for Copernicus (intent-to-treat)

 

 

Pharmacokinetics

Carvedilol is rapidly absorbed following oral administration, with peak plasma concentrations of carvedilol observed at 1 hour post-dose in fasting subjects. Despite being well-absorbed, absolute bioavailability is approximately 25 to 35%, due to a significant degree of first-pass metabolism.

     Plasma concentrations achieved are proportional to the oral dose administered. When administered with food, the rate of absorption is slowed, as evidenced by a delay in time to reach peak plasma concentrations (about 2.3 hours post-dose), with no significant difference in extent of bioavailability.

     Carvedilol is highly bound to plasma proteins (greater than 98%), primarily to 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.

     Following oral administration, the apparent mean terminal elimination half-life of carvedilol ranges from 7 to 10 hours. Plasma clearance ranges from 500 to 700 mL/min. Carvedilol is extensively metabolized, with less than 2% of the dose excreted unchanged in the urine. Carvedilol is metabolized mainly by glucuronidation and aromatic ring oxidation by the cytochrome P450 system (primarily CYP2D6 and CYP2C9 isozymes). The metabolites of carvedilol are excreted mainly via the bile into the feces. Elimination is mainly biliary. The primary route of excretion is via the feces. A minor part is eliminated via the kidneys in the form of various metabolites.

     Carvedilol undergoes stereoselective first-pass metabolism with plasma levels of R(+)-carvedilol approximately 2- to 3-fold higher than S(-)-carvedilol following oral administration in healthy subjects. The mean apparent terminal elimination half-life for R(+)-carvedilol ranges from 5 to 9 hours compared with 7 to 11 hours for the S(-) enantiomer.

     Carvedilol is subject to genetic polymorphism with poor metabolizers of debrisoquin (deficient in CYP2D6) exhibiting 2- to 3-fold higher plasma concentrations of the R(+)-carvedilol compared to extensive metabolizers. In contrast, plasma levels of S(-)-carvedilol are increased only about 20 to 25% in poor metabolizers, indicating that the metabolism of this enantiomer is affected to a lesser extent by CYP2D6 than R(+)-carvedilol. The pharmacokinetics of carvedilol enantiomers do not appear to be different in poor metabolizers of S-mephenytoin, i.e. deficient in CYP2C19.

     There are at least 5 pharmacologically active metabolites of carvedilol: desmethyl, 4'-hydroxyphenyl, 5'-hydroxyphenyl, 1-hydroxycarbazolyl and 8-hydroxycabazolyl metabolites. Each of these metabolites has 2 enantiomeric forms and each metabolite possesses different relative potencies with regard to α - and β -receptor blocking activities. Plasma concentrations of these metabolites are 10- to 50-fold lower than those observed for the parent compound. Therefore, even for metabolites that are more active or at least as active as carvedilol itself, they are present at such low concentrations that they would produce effects less than, or at least not greater than, the parent compound.

     In patients with cirrhotic liver disease, the absolute bioavailability of carvedilol was 4 times greater as compared to healthy subjects with median C_max and AUC values for carvedilol 4 to 7 times higher in patients with liver disease following oral administration (see Contraindications, Warnings and Precautions).

     Although carvedilol is metabolized primarily by the liver, plasma concentrations of carvedilol have been reported to be increased in patients with renal impairment. Based on AUC data, approximately 40 to 50% higher plasma concentrations of carvedilol were observed in hypertensive patients with moderate to severe renal impairment compared to a control group of hypertensive patients with normal renal function. However, the ranges of AUC values were similar for both groups. Changes in C_max data were less pronounced, approximately 12 to 26% higher in patients with impaired renal function.

     The pharmacokinetics of carvedilol are not altered by hemodialysis.

     Steady-state plasma concentrations of carvedilol and its enantiomers increased proportionally over the 6.25 to 50 mg b.i.d. dose range in patients with CHF. Compared to healthy subjects, patients with Class IV CHF had increased mean AUC and C_max values for carvedilol and its enantiomers, with up to 50 to 100% higher values than normal volunteers. The mean apparent terminal elimination half-life for carvedilol was similar to that observed in healthy subjects.

     Compared to young subjects (18 to 43 years old), AUC values for carvedilol were, on average, 38% higher in elderly (65 to 76 years old) subjects. Moreover, AUC values were 50% higher for S(-)-carvedilol and 23% for R(+)-carvedilol in the elderly compared to the young subjects. Changes in C_max values for carvedilol and its enantiomers were less pronounced, approximately 8 to 17% higher in elderly subjects with no apparent change in T_max. Although the terminal elimination half-lives of carvedilol were similar in both young and elderly subjects, the initial decline in plasma concentrations in the elderly appeared to be slower than in the young subjects, suggesting a decrease in systemic clearance of carvedilol in the elderly (see Precautions and Dosage).

 

Indications

For the treatment of mild, moderate or severe heart failure of ischemic or nonischemic origin to increase survival and also to reduce the combined risk of all-cause mortality and cardiovascular or noncardiovascular hospitalizations.

     In general, carvedilol is used in conjunction with diuretics and an ACE inhibitor, with or without digitalis.

     Carvedilol should be prescribed by a physician experienced in the treatment of heart failure.

 

 

Contraindications

In patients with: decompensated cardiac failure requiring i.v. inotropic therapy with sympathomimetic agents; bronchial asthma or related bronchospastic conditions (see Precautions); second- or third-degree AV block, or sick sinus syndrome (unless a permanent pacemaker is in place); cardiogenic shock; severe hypotension (see Warnings); severe bradycardia (see Warnings); primary obstructive valvular heart disease; clinically manifest hepatic impairment (jaundice, ascites, spider angiomata, esophageal varices, etc.); mental incapacity (e.g., severe Alzheimer's, alcoholism, drug abuse), unless closely supervised by an appropriate caregiver; hypersensitivity to carvedilol or any component of the drug.

 

Warnings

Hypotension: Hypotension and postural hypotension in CHF patients occurred with a higher incidence in carvedilol-treated than in placebo-treated patients (see Adverse Effects). The risk of these events was highest during initiation of therapy and during the first 30 days of dosing, corresponding to the up-titration period. Therefore, it is of critical importance that the dosing recommendation be followed (see Dosage).

Sinus Bradycardia: Severe sinus bradycardia may occur with the use of carvedilol. In such cases, dosage should be discontinued.

     In clinical trials, patients with a resting heart rate of less than or equal to 68 beats/min prior to initiation of carvedilol were not studied.

Hepatic Injury: Hepatocellular injury, confirmed by rechallenge, has occurred rarely with carvedilol therapy.

     Hepatic injury has been reversible and has occurred after short-and/or long-term therapy with minimal clinical symptomatology. No deaths due to liver function abnormalities have been reported in association with the use of carvedilol.

     At the first symptom/sign of liver dysfunction (e.g., pruritus, dark urine, persistent anorexia, jaundice, right upper quadrant tenderness or unexplained “flu-like” symptoms), laboratory testing should be performed. If the patient has laboratory evidence of liver injury or jaundice, carvedilol should be stopped and not restarted.

Abrupt Cessation of Therapy: In patients with heart failure treated chronically with carvedilol, abrupt cessation of therapy may lead to deterioration. Therefore, discontinuation of carvedilol should be done gradually, if possible.

     Patients with ischemic heart disease should be warned against abrupt discontinuation of beta-adrenergic blocking agents. There have been reports of severe exacerbation of angina, and of myocardial infarction or ventricular arrhythmias occurring in patients with angina pectoris, following abrupt discontinuation of beta-blocker therapy.

     The last 2 complications may occur with or without preceding exacerbation of angina pectoris. Therefore, when discontinuing carvedilol in patients with angina pectoris, the dosage should be gradually reduced over a period of about 2 weeks and the patient should be carefully observed. The same frequency of administration should be maintained. In situations of greater urgency, carvedilol therapy should be discontinued stepwise and under conditions of closer observation. If angina markedly worsens or acute coronary insufficiency develops, it is recommended that treatment with the drug be re-instituted promptly, at least temporarily.

Oculomucocutaneous Syndrome: Various skin rashes and conjunctival xerosis have been reported with beta-blockers. A severe syndrome (oculomucocutaneous syndrome) whose signs include conjunctivitis sicca and psoriasiform rashes, otitis, and sclerosing serositis has occurred with the chronic use of one beta-adrenergic blocking agent (practolol). This syndrome has not been observed in association with carvedilol or any other such agent. However, physicians should be alert to the possibility of such reactions and should discontinue treatment in the event that they occur.

Uveal Binding: Animal studies have shown that carvedilol binds to the melanin of the uveal tract. The significance of this in humans is not known, but periodic ophthalmic examinations are advisable while the patient is taking carvedilol.

Hyperthyroidism: In patients with thyrotoxicosis, possible deleterious effects from long-term use of carvedilol have not been appraised. Beta-blockade, in general, may mask the clinical signs of continuing hyperthyroidism or complications, and give a false impression of improvement. Therefore, abrupt withdrawal of carvedilol may be followed by an exacerbation of the symptoms of hyperthyroidism, including thyroid storm.

Pheochromocytoma: The effect of carvedilol in patients with pheochromocytoma has not been studied. Since paradoxical hypertensive responses have been reported in a few patients with this tumor when treated with β -blockers, physicians should use caution when administering carvedilol to patients with pheochromocytoma.

 

Precautions

Cardiac Failure: Worsening cardiac failure may occur during initiation and up-titration of carvedilol. Sympathetic stimulation is a vital component supporting circulatory function in CHF, and inhibition with beta-blockade may further depress myocardial contractility.

     Cardiac failure should be controlled for at least 4 weeks before treatment with carvedilol is initiated. In clinical trials of mild to moderate heart failure, patients were required to be on stable doses of diuretics and ACE inhibitors (if tolerated) prior to the initiation of carvedilol. Despite these steps to ensure stability, a small number of patients with mild to moderate heart failure developed worsening heart failure. During the initiation of therapy (doses of 3.125 to 6.25 mg b.i.d. over 2 to 4 weeks), 6% of patients developed worsening CHF. During up-titration (12.5 to 50 mg b.i.d. over 2 to 6 weeks), worsening heart failure was reported in 5.1% of patients treated with carvedilol and in 4.1% of placebo patients.

     In a placebo-controlled trial of patients with severe heart failure (Copernicus trial), worsening heart failure occurred during up-titration although the frequency reported during the first 3 months was similar with carvedilol (15.4%) and with placebo (14.8%). 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.

     Administration of carvedilol to patients with controlled heart failure must be carried out under careful supervision. If symptoms occur, diuretics should be increased and the carvedilol dose not advanced or even lowered until clinical stability resumes (see Dosage). However, it may be necessary to discontinue carvedilol. Such episodes may not preclude subsequent successful titration of the drug or a favorable response to carvedilol.

Renal Function: Rarely, use of carvedilol in patients with CHF has resulted in acute renal failure and deterioration of renal function, likely on a pre-renal basis. Patients at risk appear to be those with low blood pressure (systolic BP<100 mmHg), 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 (see Dosage).

Hepatic Impairment: Since carvedilol undergoes first-pass metabolism in the liver, reduced hepatic metabolism could lead to greater systemic bioavailability of carvedilol in patients with hepatic impairment. Care should be taken in selecting an appropriate dosage regimen for these patients (see Contraindications and Dosage). Physicians should be aware of the potential for increased manifestations of vasodilation (dizziness, postural hypotension, hypotension, syncope) or beta-blockade (bradycardia, AV block) in patients with mild hepatic impairment receiving carvedilol (see Dosage).

Bronchospasm (e.g., Chronic Bronchitis and Emphysema): Patients with bronchospastic disease should, in general, not receive β -blockers (see Contraindications).

     In clinical trials of patients with CHF, 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.

Allergic Reaction: There may be increased difficulty in treating an allergic-type reaction in patients on beta-blockers. In these patients, the reaction may be more severe due to pharmacological effects of beta-blockers and problems with fluid changes. Epinephrine should be administered with caution since it may not have its usual effects in the treatment of anaphylaxis.

     On the one hand, larger doses of epinephrine may be needed to overcome the bronchospasm, while on the other, these doses can be associated with excessive alpha-adrenergic stimulation with consequent hypertension, reflex bradycardia and heart block and possible potentiation of bronchospasm. Alternatives to the use of large doses of epinephrine include vigorous supportive care such as fluids and the use of beta-agonists, including parenteral salbutamol or isoproterenol to overcome bronchospasm, and norepinephrine to overcome hypotension.

Prinzmetal's Angina: Beta-blocking agents may provoke chest pain in patients with Prinzmetal's angina. There has been no clinical experience with carvedilol in these patients. Caution should be taken in the administration of carvedilol to patients suspected of having Prinzmetal's variant angina.

Primary Regurgitative Valvular Heart Disease: Carvedilol should be used with caution in patients with primary regurgitative valvular disease as experience in this patient population is limited.

Patients with Diabetes: Carvedilol should be administered with caution to patients subject to spontaneous hypoglycemia, or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycemic agents. Beta-adrenergic blocking drugs may enhance hypoglycemia in patients prone to this condition. Also, diabetics on insulin or oral hypoglycemic medication may have an increased tendency towards hypoglycemia when treated with these drugs. It may also be necessary to adjust the dosage of oral hypoglycemics or insulin. Early signs of acute hypoglycemia, especially tachycardia, may be masked or attenuated. Regular monitoring of blood glucose is therefore recommended when carvedilol is initiated, adjusted or discontinued.

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.

Peripheral Vascular Disease: Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in such individuals.

Patients and General Surgery: Because of the synergistic negative inotropic and vasodilating effects of carvedilol and anesthetic drugs, the potential for pronounced hypotension during anesthesia exists. If treatment with carvedilol is to be continued perioperatively, particular care should be taken when anesthetic agents which depress myocardial function are used.

Contact Lens Use: Wearers of contact lenses should bear in mind the possibility of reduced lacrimation.

Geriatrics

Pharmacokinetic studies indicate that AUC and T_max values are increased in elderly patients. Plasma levels of carvedilol averaged about 38% higher in elderly compared to young subjects. Therefore, dosage adjustments should be made with particular caution (see Dosage).

 

Pregnancy

There have been no clinical studies carried out to specifically examine the use of carvedilol in pregnant women. Beta-blockers reduce placental perfusion, which may result in intrauterine fetal death, immature and premature deliveries. In addition, adverse effects (especially hypoglycemia and bradycardia) may occur in the fetus and neonate. There is an increased risk of cardiac and pulmonary complications in the neonate in the postnatal period.

     Animal reproduction studies have revealed no teratogenic potential for carvedilol. Embryotoxicity was observed only after large doses in rabbits. The relevance of these findings for humans is uncertain.

     Carvedilol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

 

Lactation

Carvedilol and/or its metabolites are excreted in breast milk. Therefore, breast-feeding is not recommended during administration of carvedilol.

 

Children

Safety and efficacy in children have not been established.

 

Drug Interactions

Antihypertensive Agents: When administered concomitantly with other drugs that are antihypertensive in action or have hypotension as part of their adverse effect profile, carvedilol may have additive effects to excessively lower blood pressure.

Catecholamine-depleting Agents: Patients taking both agents with β -blocking properties and a drug that can deplete catecholamines (e.g., reserpine and MAO inhibitors) should be observed closely for evidence of hypotension and/or marked bradycardia.

Antiarrhythmics and Calcium Channel Blockers: Isolated cases of conduction disturbance (rarely with hemodynamic compromise) have been observed when carvedilol is coadministered with antiarrhythmic agents or calcium channel blockers such as diltiazem and verapamil that can slow cardiac conduction. As with other agents with β -blocking properties, if carvedilol is to be administered orally with antiarrhythmics that slow conduction or with calcium channel blockers of the verapamil or diltiazem type, it is recommended that ECG and blood pressure be monitored.

Digoxin: Following concomitant administration of carvedilol and digoxin, peak concentration of digoxin increased by approximately 30% and steady-state trough concentrations of digoxin were increased by about 15%. Both digoxin and carvedilol slow AV conduction. Therefore, increased monitoring of digoxin levels is recommended when initiating, adjusting or discontinuing carvedilol.

Clonidine: Concomitant administration of clonidine with agents with beta-blocking properties may potentiate blood pressure and heart rate lowering effects. When concomitant treatment with agents with beta-blocking properties and clonidine is to be terminated, the beta-blocking agent should be discontinued first. Clonidine therapy can then be discontinued several days later by gradually decreasing the dosage.

Cyclosporine: Modest increases in mean trough cyclosporine concentrations were observed following initiation of carvedilol treatment in 21 renal transplant patients suffering from chronic vascular rejection. In about 30% of patients, the dose of cyclosporine had to be reduced in order to maintain cyclosporine concentrations within the therapeutic range, while in the remainder no adjustment was needed. On the average for the group, the dose of cyclosporine was reduced about 20% in these patients. Due to wide inter-individual 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.

Inducers and Inhibitors of Cytochrome P450: Since carvedilol undergoes substantial oxidative metabolism, care may be required in patients receiving inducers or inhibitors of cytochrome P450, as plasma concentrations may be altered. Pretreatment with rifampin (600 mg daily for 12 days) decreased the AUC and C_max for carvedilol approximately 70% following a single oral dose of carvedilol. Coadministration of carvedilol and cimetidine (1000 mg/day) resulted in a 30% increase in median AUC for carvedilol. Despite the reduction in oral clearance, peak plasma concentrations of carvedilol were unchanged due to an apparent decrease in the rate of absorption.

Grapefruit Juice: Following simultaneous administration of a single dose of 25 mg of carvedilol with 300 mL of grapefruit juice (an inhibitor of CYP3A4 and CYP1A2), AUC for carvedilol was approximately 16% higher than following administration of carvedilol with 300 mL of water.

Nitroglycerin: The effect of carvedilol coadministration with nitroglycerin has not been studied. Carvedilol could blunt the reflex tachycardia produced by nitroglycerin through its beta-adrenergic blocking activity. When it is used with nitroglycerin in patients with angina pectoris, additional decreases in blood pressure may occur.

Insulin or Oral Hypoglycemics: Agents with beta-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.

Tricyclic Antidepressants: The effect of carvedilol coadministration with tricyclic antidepressants has not been studied. As an increased incidence of tremor has been observed with other drugs of this class upon coadministration of tricyclic antidepressants, the possibility of a drug interaction cannot be excluded.

Warfarin: Carvedilol (12.5 mg twice daily for 7 days) did not have an effect on warfarin-induced increase in steady-state prothrombin time ratios and did not alter the pharmacokinetics of both enantiomers of warfarin following concomitant administration with warfarin in healthy volunteers.

 

Adverse Effects

Mild to Moderate Heart Failure—Controlled Trials: In 6 US placebo-controlled trials, 1313 patients were challenged with carvedilol over a 2 to 4 week period. Of these patients, 1202 were randomized to double-blind treatment with carvedilol (n=765) or placebo (n=437) and 92.5% of those treated with carvedilol reported at least 1 adverse experience.

     During the double-blind phase of these trials, adverse experiences rated as serious were reported in 22.4% of patients treated with carvedilol and 31.8% in the placebo group. The most serious adverse experiences reported with carvedilol were cardiac failure (5.6%), syncope (1.8%), bradycardia (1.6%), hypotension (1.3%), myocardial infarction (0.9%), acute renal failure (0.8%) and AV block (0.7%).

     Adverse experiences rated as severe in intensity during the double-blind phase of these trials were reported in 24.3% of patients treated with carvedilol. The most frequent severe adverse experiences were cardiac failure (2.9%), fatigue (2.2%), dizziness (2.0%), dyspnea (1.8%) and syncope (1.7%).

     The most common adverse experiences reported in the double-blind phase of the US clinical trial experience (see  Table 2) with carvedilol were dizziness (32.4%), fatigue (23.9%), dyspnea (21.3%), upper respiratory infection (18.3%), cardiac failure (15.3%) and chest pain (14.4%).

     Of the 1202 patients who received randomized treatment in these trials, 5.4% of patients treated with carvedilol withdrew because of adverse experiences compared with 8.0% of placebo patients. Bradycardia, fatigue, hypotension, dizziness and dyspnea were the most commonly reported adverse experiences leading to discontinuation in patients treated with carvedilol (see  Table 2).

     Six deaths occurred in 1319 patients enrolled in the screening phase (3 to 4 weeks), 11 deaths occurred in 1313 patients challenged with carvedilol (2 to 4 weeks). There were 8 deaths (3/765 carvedilol; 5/437 placebo) during up-titration phase (2 to 6 weeks) and 47 deaths (20/765 carvedilol; 27/437 placebo) during the maintenance phase (up to 12 months) of the studies.

     Withdrawals due to worsening heart failure in US placebo- controlled trials were as follows: during challenge, 1.4% of patients (18/1313 for 2 to 4 weeks); during up-titration, 0.9% (7/765) of patients treated with carvedilol and 0% (0/437) of placebo patients (2 to 6 weeks); during the maintenance phase, 0.7% (5/765) of patients treated with carvedilol and 2.3% (10/437) of placebo patients (up to 12 months).

     Worsening renal function, including acute renal failure (see  Table 2), has been seen in some patients (carvedilol 9.5% and placebo 7.6%). Patients at greatest risk include those with pre-existing renal insufficiency, hypotension and ischemic cardiomyopathy, previous renal insufficiency due to ACE inhibitors, diffuse vascular disease or evidence of renal artery stenosis.

      Table 2 shows adverse events reported in patients with mild to moderate heart failure enrolled in US placebo-controlled clinical trials. Shown are adverse events that occurred more frequently in carvedilol-treated patients than placebo-treated patients with an incidence >1% regardless of causality. Median study medication exposure was 6.3 months for carvedilol and placebo patients.

CPS:Coreg_t2Click here for Table 2

Table 2: Coreg

Adverse Events (% Occurrence and % Withdrawal) Occurring More Frequently with Coreg than with Placebo in Patients with Mild to Moderate Heart Failure Enrolled in US Heart Failure Trials (Incidence >1%, Regardless of Causality; Withdrawal Rates due to Adverse Events)

 

	Adverse Reactions		Withdrawals
	Coreg (n=765) % occurrence	Placebo (n=437) % occurrence	Coreg (n=765) % withdrawals	Placebo (n=437) % withdrawals
Autonomic Nervous System
Sweating Increased	2.9	2.1	—	—
Body as a Whole
Fatigue	23.9	22.4	0.7	0.7
Chest Pain	14.4	14.2	0.1	—
Pain	8.6	7.6	—	0.2
Injury	5.9	5.5	—	—
Drug Level Increased	5.1	3.7	—	0.2
Edema Generalized	5.1	2.5	—	—
Edema Dependent	3.7	1.8	—	—
Fever	3.1	2.3	—	—
Edema Legs	2.2	0.2	0.1	0.2
Edema Peripheral	1.6	0.7	—	—
Allergy	1.4	0.2	—	—
Sudden Death	1.3	1.1	—	—
Malaise	1.3	0.7	—	—
Hypovolemia	1.2	0.2	—	—
Cardiovascular
Bradycardia	8.8	0.9	0.8	—
Hypotension	8.5	3.4	0.4	0.2
Syncope	3.4	2.5	0.3	0.2
Hypertension	2.9	2.5	0.1	—
AV Block	2.9	0.5	—	—
Angina Pectoris Aggravated	2.0	1.1	—	—
Fluid Overload	1.7	1.6	—	—
Postural Hypotension	1.2	0.2	—	—
CNS
Dizziness	32.4	19.2	0.4	—
Headache	8.1	7.1	0.3	—
Paresthesia	2.0	1.8	0.1	—
Hypesthesia	1.7	1.1	—	—
Vertigo	1.4	1.1	—	—
Confusion	1.3	0.9	—	—
Somnolence	1.2	0.9	—	0.2
Gastrointestinal
Diarrhea	11.8	5.9	0.3	—
Nausea	8.5	4.8	–	—
Abdominal Pain	7.2	7.1	0.3	—
Vomiting	6.3	4.3	0.1	—
Melena	1.4	1.1	—	—
Periodontitis	1.3	0.7	—	—
Hematologic
Thrombocytopenia	2.0	0.5	0.1	—
Prothrombin Decreased	1.3	1.1	—	—
Purpura	1.3	0.2	—	—
Metabolic
Hyperglycemia	12.2	7.8	0.1	—
Weight Increase	9.7	6.9	0.1	0.5
Gout	6.3	6.2	—	—
BUN Increased	6.0	4.6	0.3	0.2
NPN Increased	5.8	4.6	0.3	0.2
Hypercholesterolemia	4.1	2.5	—	—
Dehydration	2.1	1.6	—	—
Hypervolemia	2.0	0.9	—	—
Hyperuricemia	1.8	1.6	—	—
Hypoglycemia	1.6	1.4	0.1	—
ALT Increased	1.4	0.9	—	—
Hyponatremia	1.3	1.1	—	—
Alkaline Phosphatase Increased	1.2	1.1	—	—
AST Increased	1.2	0.9	—	—
Glycosuria	1.2	0.7	—	—
Musculoskeletal
Back Pain	6.9	6.6	—	—
Arthralgia	6.4	4.8	0.1	0.2
Myalgia	3.4	2.7	—	—
Resistance Mechanism
Upper Respiratory Tract Infection	18.3	17.6	—	—
Infection	2.2	0.9	—	—
Reproductive Male
Impotence	1.7	0.9	—	—
Respiratory
Sinusitis	5.4	4.3	—	—
Bronchitis	5.4	3.4	—	0.2
Pharyngitis	3.1	2.7	—	—
Urinary/Renal
Urinary Tract Infection	3.1	2.7	—	—
Hematuria	2.9	2.1	—	—
Renal Function Abnormal	1.7	1.4	0.3	—
Albuminuria	1.6	1.1	—	—
Acute Renal Failure	1.2	0.5	0.3	—
Vision
Vision Abnormal	5.0	1.8	0.1	—

Legend:BUN=blood urea nitrogen.NPN=nonprotein nitrogen.

 

     In addition to the events in  Table 2, the following events occurred in more than 1% of patients treated with carvedilol but rates were equal to, or more common in, placebo-treated patients: asthenia, cardiac failure, flatulence, anorexia, dyspepsia, palpitation, ventricular tachycardia, atrial fibrillation, extrasystoles, bilirubinemia, hyperkalemia, arthritis, angina pectoris, insomnia, depression, amnesia, anemia, viral infection, dyspnea, coughing, respiratory disorder, pneumonia, rhinitis, rash, pruritus and leg cramps.

     Adverse experiences related to laboratory parameters reported in greater than 1% of patients are in  Table 2. Adverse experiences related to laboratory parameters reported in ≤ 1% but more than 0.1% of patients included increased hepatic enzymes (0.4% of congestive heart failure patients were discontinued from therapy because of increases in hepatic enzymes; see Precautions, Hepatic Impairment), hypokalemia, hypertriglyceridemia, anemia, leukopenia.

Severe Heart Failure—Controlled Trial: In a clinical trial in severe heart failure that compared carvedilol in daily doses of 50 mg (n=1156) with placebo (n=1133), 9.4% of patients treated with carvedilol discontinued treatment for adverse experiences versus 11.2% of placebo patients.

     The most common adverse experiences reported with carvedilol were dizziness (24.1%), hypotension (13.9%) and upper respiratory infection (see  Table 3). Median study exposure was 10.4 months for both carvedilol and placebo patients.

      Table 3 shows adverse events reported in patients with severe heart failure enrolled in multinational placebo-controlled clinical trial. Shown are adverse events that occurred more frequently in carvedilol-treated patients than placebo-treated patients with an incidence >1% regardless of causality.

CPS:Coreg_t3Click here for Table 3

Table 3: Coreg

Adverse Events (% Occurrence and % Withdrawals) Occurring More Frequently with Coreg than with Placebo in Patients with Severe Heart Failure (Incidence >1%, Regardless of Causality)

 

	Adverse Reactions		Withdrawals
	Coreg (n=1156) % occurrence	Placebo (n=1133) % occurrence	Coreg (n=1156) % withdrawals	Placebo (n=1133) % withdrawals
Body as a Whole
Asthenia	10.9	9.4	0.4	0.7
Infection	2.5	2.4	—	—
Back Pain	2.9	1.4	—	—
Cardiovascular
Hypotension	13.9	8.2	0.6	0.4
Bradycardia	10.3	2.7	0.6	—
Syncope	7.6	5.0	0.4	0.4
Angina Pectoris	5.5	4.1	0.1	0.1
Hypertension	2.6	2.2	—	0.1
Postural Hypotension	1.8	1.0	0.1	0.1
Sinus Bradycardia	1.7	0.4	—	—
Palpitation	1.6	1.5	—	0.1
Gastrointestinal
Diarrhea	4.8	3.1	0.3	—
Nausea	3.8	3.3	—	0.1
Gastrointestinal Disorder	1.6	1.1	0.1	0.1
Hematologic
Anemia	2.4	2.0	—	—
Metabolic and Nutritional
Weight Gain	11.7	10.7	0.1	0.1
Peripheral Edema	7.0	6.4	0.2	0.1
Generalized Edema	6.0	4.9	0.2	0.2
Hyperglycemia	4.5	3.3	0.0	0.1
Gout	3.5	2.7	—	—
Hyperkalemia	3.3	1.9	0.2	0.1
Creatinine Increased	2.9	1.4	—	0.1
Diabetes Mellitus	2.0	1.7	—	—
Weight Loss	1.4	1.1	—	—
GGT Increased	1.3	1.1	—	—
Nervous System
Dizziness	24.1	16.8	1.3	0.6
Headache	4.8	3.0	—	0.1
Paresthesia	1.7	1.4	—	—
Respiratory
Upper Respiratory Infection	13.6	12.6	0.1	—
Dyspnea	11.2	11.0	0.5	0.3
Bronchitis	5.2	4.5	0.1	—
Cough Increased	4.5	4.2	0.1	0.2
Lung Disorder	4.0	3.2	0.1	—
Sinusitis	1.6	1.1	—	—
Special Senses
Blurred Vision	2.8	2.2	0.2	0.1
Urogenital
Kidney Failure	1.6	1.3	0.1	—

 

     In addition to the events in  Table 3, when compared with placebo, carvedilol-treated patients had fewer of the following adverse events related to the cardiovascular system and occurring in or equal to 2% of patients: sudden death, atrial fibrillation, chest pain, congestive heart failure, heart failure, peripheral vascular disorder, unstable angina pectoris and ventricular tachycardia. Other adverse experiences occurring in greater or equal to 2% but reported less frequently in carvedilol-treated patients include: abdominal pain, pain in the extremity, hypokalemia, lung edema, pneumonia, abnormal kidney function and urinary tract infection.

Hypertension and Heart Failure—Open and Controlled Trials: The following adverse events were reported as possibly or probably related in worldwide open or controlled trials with carvedilol in patients with hypertension or congestive heart failure at an incidence of >0.1% to ≤  1%:

 

Cardiovascular

peripheral ischemia, tachycardia.

 

Central and Peripheral Nervous System

hypokinesia.

General

substernal chest pain, edema.

Psychiatric

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

 

Respiratory System

asthma.

Reproductive, Male

decreased libido.

 

Skin and Appendages

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

Special Senses

tinnitus.

 

Urinary System

micturition frequency.

 

Autonomic Nervous System

dry mouth, sweating increased.

 

Metabolic and Nutritional

diabetes mellitus.

     The following adverse events were reported as possibly or probably related in worldwide open or controlled trials with carvedilol in patients with hypertension or congestive heart failure at an incidence of ≤  0.1%, and are potentially important: complete AV block, bundle branch block, myocardial ischemia, cerebrovascular disorder, convulsions, migraine, neuralgia, paresis, anaphylactoid reaction, alopecia, exfoliative dermatitis, amnesia, gastrointestinal hemorrhage, bronchospasm, pulmonary edema, decreased hearing, respiratory alkalosis, decreased HDL, pancytopenia and atypical lymphocytes.

Postmarketing Experience

The following adverse reaction has been reported in postmarketing experience: reports of aplastic anemia have been rare and received only when carvedilol was administered concomitantly with other medications associated with the event.

 

Overdose

 

 

Symptoms

Cases of overdosage with carvedilol alone or in combination with other drugs have been reported. Quantities ingested in some cases exceeded 1000 mg. Clinical signs experienced included low blood pressure and heart rate. Standard supportive treatment was provided and individuals recovered.

     In the event of inadvertent or intentional overdosage with carvedilol, there may be severe hypotension, excessive bradycardia, heart failure, cardiogenic shock and cardiac arrest due to its pharmacologic activities. There may also be respiratory distress, bronchospasm, vomiting, disturbed consciousness and generalized seizures.

 

 

Treatment

Patients who have taken an overdose of carvedilol should be placed supine, with their legs raised. For removal of the drug shortly after ingestion, gastric lavage or pharmacologically induced emesis may be useful. Carvedilol is not removed by hemodialysis. In addition to these general procedures, the patient's vital signs should be monitored under intensive care conditions with continuous monitoring, if necessary.

     The following additional supportive therapies can be used: If excessive hypotension occurs, vasopressors, norepinephrine or noradrenaline should be administered with continuous monitoring of the circulatory system. Digitalis, diuretics, and if necessary, dopamine or dobutamine should be administered if cardiac failure occurs.

     For excessive bradycardia, atropine 0.5 to 2 mg should be given i.v. In addition, glucagon 1 to 10 mg given i.v. over 30 seconds initially followed by a continuous infusion of 2 to 2.5 mg/h has been shown to be effective when severe overdosage of beta-blockers causes hypotension and/or bradycardia. For therapy-resistant bradycardia, pacemaker therapy may be necessary.

     For bronchospasm, beta-sympathomimetics (as aerosol or i.v.) or i.v. aminophylline should be given.

     In the event of seizures, slow i.v. injection of diazepam or clonazepam is recommended.

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

 

Dosage

Dosage must be individualized and patients closely monitored during initiation and up-titration by a physician experienced in the treatment of heart failure.

     All patients in whom carvedilol therapy is to be considered must be clinically stable for 4 weeks prior to initiation of carvedilol.

     Prior to initiation of carvedilol therapy, patients should be on stable doses of diuretics and angiotensin converting enzyme inhibitors, with or without digitalis. In clinical trials, patients were on the above regimen unless they were intolerant to an ACE inhibitor.

     The recommended starting dose of carvedilol is 3.125 mg twice daily for 2 weeks. If this dose is tolerated, it can then be increased to 6.25, 12.5 and 25 mg twice daily over successive intervals of at least 2 weeks. Patients should be maintained on the highest tolerated dose. The maximum recommended dose is 25 mg twice daily. The dose of carvedilol should not be increased until symptoms of worsening heart failure or vasodilation have stabilized.

     Patients should be advised that initiation of treatment and, to a lesser extent, dosage increases may be associated with transient symptoms of dizziness or lightheadedness and, rarely, syncope within the first 2 hours after dosing. During these periods, they should avoid situations such as driving or dangerous tasks where symptoms could result in injury. In addition, carvedilol should be taken with food to slow the rate of absorption and reduce the incidence of orthostatic effects, especially during up-titration. Symptoms of hypotension do not often require treatment, but it may be useful to separate the time of dosing of carvedilol from that of the ACE inhibitor, or to reduce temporarily the dose of the ACE inhibitor.

     The risk/benefit of treatment with carvedilol in clinically stable heart failure patients with a heart rate lower than 68 beats/min should be carefully considered prior to initiation of carvedilol since carvedilol has not been studied in these patients (see Warnings).

     Before each dose increase, the patient should be seen in the office and evaluated for symptoms of worsening heart failure, vasodilation (dizziness, lightheadedness, symptomatic hypotension) or bradycardia, in order to determine tolerability of carvedilol. Transient worsening of heart failure may be treated with increased doses of diuretics, lowering the dose of carvedilol or, if necessary, discontinuation of carvedilol. Symptoms of vasodilation such as dizziness, lightheadedness or decreasing blood pressure may respond to a reduction in the dose of diuretics. If these changes do not relieve symptoms, the dose of carvedilol should be decreased. If the dose of carvedilol was decreased, it should not be increased again until symptoms of worsening heart failure or vasodilation have been stabilized for 2 weeks. Initial difficulty with titration may not preclude later attempts to re-introduce or resume titration of carvedilol, however caution is required in these circumstances. If CHF patients experience bradycardia (pulse rate below 55 beats/min), the dose of carvedilol should be reduced, or may require discontinuation.

 

Geriatrics

The frequency and pattern of adverse reactions in patients ≥ 65 years was similar to that in younger patients. However, plasma levels of carvedilol are higher in older patients compared to younger patients (see Precautions). Therefore, after initiating carvedilol at the same dose in the elderly as in younger patients, up-titration should be done more cautiously in the elderly. A lower total daily dose may be reached at the end of up-titration in such patients compared to younger patients.

Hepatic Impairment

Carvedilol is contraindicated in patients with clinically manifest liver disease (see Contraindications). In patients with milder hepatic impairment, there is a potential for increased manifestations of vasodilation and beta-blockade (see Pharmacology, Pharmacokinetics and Precautions). Therefore, after initiating carvedilol at the same dose in patients with hepatic impairment as in other patients, up-titration should be done more cautiously in patients with hepatic impairment. A lower total daily dose may be reached at the end of up-titration in such patients compared to other patients.

Renal Impairment

Acute, reversible renal failure has been seen in some patients treated with carvedilol, particularly those with underlying renal impairment (see Precautions). Therefore, after initiating carvedilol at the same dose in patients with renal impairment as in other patients, up-titration should be done more cautiously in patients with renal impairment. Renal function (BUN and creatinine) should be checked in such patients as appropriate. If renal function has deteriorated, the dose of carvedilol may need to be reduced or discontinued.

Discontinuation

Carvedilol should be gradually reduced over a period of about 2 weeks, if possible, and the patient should be carefully observed (see Warnings, Abrupt Cessation of Therapy).

 

Supplied

3.125 mg

Each white, oval, film-coated tablet, imprinted with 39 and SB, contains: carvedilol 3.125 mg. Nonmedicinal ingredients: colloidal silicone dioxide, crospovidone, lactose, magnesium stearate, opadry white YS-1-7003 and Opadry clear YS-2-7013, povidone and sucrose. HDPE bottles with plastic caps of 100.

6.25 mg

Each white, oval, film-coated, Tiltab tablet, imprinted with 4140 and SB, contains: carvedilol 6.25 mg. Nonmedicinal ingredients: colloidal silicone dioxide, crospovidone, lactose, magnesium stearate, opadry white YS-1-7003 and Opadry clear YS-2-7013, povidone and sucrose. HDPE bottles with plastic caps of 100.

12.5 mg

Each white, oval, film-coated, Tiltab tablet, imprinted with 4141 and SB, contains: carvedilol 12.5 mg. Nonmedicinal ingredients: colloidal silicone dioxide, crospovidone, lactose, magnesium stearate, opadry white YS-1-7003 and Opadry clear YS-2-7013, povidone and sucrose. HDPE bottles with plastic caps of 100.

25 mg

Each white, oval, film-coated, Tiltab tablet, imprinted with 4142 and SB, contains: carvedilol 25 mg. Nonmedicinal ingredients: colloidal silicone dioxide, crospovidone, lactose, magnesium stearate, opadry white YS-1-7003 and Opadry clear YS-2-7013, povidone and sucrose. HDPE bottles with plastic caps of 100.

     Store at room temperature, between 15 to 30°C, in tightly closed containers or dispense in a tight, light-resistant container. Protect from high humidity. Since the tablets discolor when exposed to light, they should be kept in a light-resistant container.