Congestive Heart Failure Agent
Action And Clinical Pharmacology: Carvedilol is a cardiovascular agent for the treatment of 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 alpha 1-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 alpha 1-receptors.
Carvedilol reduces peripheral vascular resistance by vasodilation, thereby causing a fall in systemic blood pressure after acute administration, predominantly mediated through selective alpha 1-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 congestive heart failure, 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 congestive heart failure has not been established.
In a US multicenter program, 1 197 patients with stable symptomatic congestive heart failure, 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, 1 094 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 Â£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 carevedilol 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 multicenter program, as indicated by a change in the NYHA class from baseline to endpoint for the 4 US phase III placebo-controlled studies.
In a large multicenter trial of carvedilol, performed in Australia and New Zealand, 443 patients with stable symptomatic congestive heart failure 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 Â£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.
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 2D6 and 2C9 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-lives 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 cytochrome P450 2D6) 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 cytochrome P450 2D6 than R(+)-carvedilol. The pharmacokinetics of carvedilol enantiomers do not appear to be different in poor metabolizers of S-mephenytoin, i.e. deficient in cytochrome P450 CPY 2C19.
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 a- and b-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 Cmax 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 Cmax 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 congestive heart failure. Compared to healthy subjects, patients with Class IV congestive heart failure had increased mean AUC and Cmax 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 Cmax values for carvedilol and its enantiomers were less pronounced, approximately 8 to 17% higher in elderly subjects with no apparent change in Tmax. 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 And Clinical Uses: For treatment of stable symptomatic congestive heart failure (CHF) in patients with NYHA Class II and III, taking diuretics and with angiotensin converting enzyme inhibitors, with or without digoxin.
Data are limited in NYHA Class IV patients, and therefore, carvedilol is not recommended in these patients.
Carvedilol should be prescribed by a physician experienced in the treatment of heart failure.
Beta-blockers can cause worsening heart failure. Since carvedilol has beta-blocking properties, care must be taken during initiation and up-titration of the drug in heart failure patients, since worsening heart failure has been observed during this phase of treatment. In order to minimize the risk of these events, it is critical to carefully follow the recommended dosing for carvedilol in patients with congestive heart failure (see Dosage).
Contra-Indications: In patients with: decompensated cardiac failure requiring i.v. inotropic therapy with sympathomimetic agents; bronchial asthma or related bronchospastic conditions (see Pharmacology and 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.
Manufacturers’ Warnings In Clinical States: Hypotension: Hypotension and postural hypotension in congestive heart failure 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.
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 b-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 carvedilol treatment is initiated. In clinical trials, 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 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 carvedilol-treated patients and in 4.1% of placebo patients. Therefore, 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.
Renal Function: Rarely, use of carvedilol in patients with congestive heart failure has resulted in acute renal failure and deterioration of renal function, likely on a pre-renal basis.
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 b-blockers (see Contraindications).
In clinical trials of patients with congestive 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.
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.
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 carvedilol treatment 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 Tmax 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 b-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 b-blocking properties, if carvedilol is to be administered orally with antiarrhythmics that slow conduction or 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.
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 Cmax for carvedilol approximately 70% following a single oral dose of carvedilol. Coadministration of carvedilol and cimetidine (1 000 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 rate of absorption.
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.
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.
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 Reactions: In 6 US placebo controlled trials, 1 313 patients were challenged with carvedilol over a 2 to 4 week period. Of these patients, 1 202 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 I) 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 1 202 patients who received randomized treatment in these trials, 5.4% of carvedilol patients 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 carvedilol treated patients (see Table I).
Six deaths occurred in 1 319 patients enrolled in the screening phase (3 to 4 weeks), 11 deaths occurred in 1 313 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 CHF trials were as follows: during challenge 1.4% of patients (18/1 313 for 2 to 4 weeks); during up-titration 0.9% (7/765) of carvedilol patients and 0% (0/437) of placebo patients (2 to 6 weeks); during the maintenance phase 0.7% (5/765) of carvedilol patients and 2.3% (10/437) of placebo patients (up to 12 months).
Worsening renal function, including acute renal failure (see Table I), 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 I shows adverse events in US placebo-controlled clinical trials of congestive heart failure patients that occurred with an incidence of greater than 1% regardless of causality and were more frequent in drug-treated patients than placebo-treated patients. Median study medication exposure was 6.3 months for carvedilol and placebo patients.
In addition to the events in Table I, the following events occurred in more than 1% of carvedilol-treated patients 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 I. Adverse experiences related to laboratory parameters reported in Â£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 Injury), hypokalemia, hypertriglyceridemia, anemia, leukopenia.
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 Â£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 Â£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.
Symptoms And Treatment Of Overdose: Symptoms: Cases of overdosage with carvedilol alone or in combination with other drugs have been reported. Quantities ingested in some cases exceeded 1 000 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, vasopressor, norepinephrine 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 initially 1 to 10 mg i.v., then 2 to 2.5 mg/h for long-term infusion, 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 And Administration: 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, all patients shown to have benefit 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 mg twice daily. Dosing should then be doubled every 2 weeks to the highest level tolerated by the patient. At initiation of each new dose, patients should be observed for signs of dizziness or lightheadedness for 1 to 2 hours. The maximum recommended dose is 25 mg twice daily.
The risk/benefit of carvedilol therapy 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 it has not been studied in these patients (see Warnings).
Carvedilol should be taken with food to slow the rate of absorption and reduce the incidence of orthostatic effects, especially during up-titration.
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 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 congestive heart failure patients experience bradycardia (pulse rate below 55 beats/min), the dose should be reduced, or may require discontinuation.
Geriatrics: The frequency and pattern of adverse reactions in patients Â³65 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 may need to be reduced or discontinued.
Discontinuation: 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).
Availability And Storage: 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.
COREG SmithKline Beecham Carvedilol Congestive Heart Failure Agent
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