Drug: Coreg

Carvedilol is a nonselective β-adrenergic blocking agent with α1-blocking activity. It is (±)-1-(Carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol. Carvedilol is a racemic mixture with the following structure: COREG (carvedilol) is a white, oval, film-coated tablet containing 3.125 mg, 6.25 mg, 12.5 mg, or 25 mg of carvedilol. The 6.25 mg, 12.5 mg, and 25 mg tablets are TILTAB® tablets. Inactive ingredients consist of colloidal silicon dioxide, crospovidone, hypromellose, lactose, magnesium stearate, polyethylene glycol, polysorbate 80, povidone, sucrose, and titanium dioxide. Carvedilol is a white to off-white powder with a molecular weight of 406.5 and a molecular formula of C24H26N2O4. It is freely soluble in dimethylsulfoxide; soluble in methylene chloride and methanol; sparingly soluble in 95% ethanol and isopropanol; slightly soluble in ethyl ether; and practically insoluble in water, gastric fluid (simulated, TS, pH 1.1), and intestinal fluid (simulated, TS without pancreatin, pH 7.5).

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Clinical Studies Experience COREG (carvedilol) has been evaluated for safety in patients with heart failure (mild, moderate, and severe), in patients with left ventricular dysfunction following myocardial infarction and in hypertensive patients. The observed adverse event profile was consistent with the pharmacology of the drug and the health status of the patients in the clinical trials. Adverse events reported for each of these patient populations are provided below. Excluded are adverse events considered too general to be informative, and those not reasonably associated with the use of the drug because they were associated with the condition being treated or are very common in the treated population. Rates of adverse events were generally similar across demographic subsets (men and women, elderly and non-elderly, blacks and non-blacks). Heart Failure COREG (carvedilol) has been evaluated for safety in heart failure in more than 4,500 patients worldwide of whom more than 2,100 participated in placebo-controlled clinical trials. Approximately 60% of the total treated population in placebo-controlled clinical trials received COREG (carvedilol) for at least 6 months and 30% received COREG (carvedilol) for at least 12 months. In the COMET trial, 1,511 patients with mild-to-moderate heart failure were treated with COREG (carvedilol) for up to 5.9 years (mean 4.8 years). Both in US clinical trials in mild-to-moderate heart failure that compared COREG (carvedilol) in daily doses up to 100 mg (n = 765) to placebo (n = 437), and in a multinational clinical trial in severe heart failure (COPERNICUS) that compared COREG (carvedilol) in daily doses up to 50 mg (n = 1,156) with placebo (n = 1,133), discontinuation rates for adverse experiences were similar in carvedilol and placebo patients. In placebo-controlled clinical trials, the only cause of discontinuation > 1%, and occurring more often on carvedilol was dizziness (1.3% on carvedilol, 0.6% on placebo in the COPERNICUS trial). Table 1 shows adverse events reported in patients with mild-to-moderate heart failure enrolled in US placebo-controlled clinical trials, and with severe heart failure enrolled in the COPERNICUS trial. Shown are adverse events that occurred more frequently in drug-treated patients than placebo-treated patients with an incidence of > 3% in patients treated with carvedilol regardless of causality. Median study medication exposure was 6.3 months for both carvedilol and placebo patients in the trials of mild-to-moderate heart failure, and 10.4 months in the trial of severe heart failure patients. The adverse event profile of COREG (carvedilol) observed in the long-term COMET study was generally similar to that observed in the US Heart Failure Trials. Table 1: Adverse Events (%) Occurring More Frequently With COREG (carvedilol) Than With Placebo in Patients With Mild-to-Moderate Heart Failure (HF) Enrolled in US Heart Failure Trials or in Patients With Severe Heart Failure in the COPERNICUS Trial (Incidence > 3% in Patients Treated With Carvedilol, Regardless of Causality)
  Mild-to-Moderate HF Severe HF COREG
(n = 765) Placebo
(n = 437) COREG
(n = 1,156) Placebo
(n = 1,133) Body as a Whole   Asthenia 7 7 11 9   Fatigue 24 22 — —   Digoxin level increased 5 4 2 1   Edema generalized 5 3 6 5   Edema dependent 4 2 — — Cardiovascular   Bradycardia 9 1 10 3   Hypotension 9 3 14 8   Syncope 3 3 8 5   Angina pectoris 2 3 6 4 Central Nervous System   Dizziness 32 19 24 17   Headache 8 7 5 3 Gastrointestinal   Diarrhea 12 6 5 3   Nausea 9 5 4 3   Vomiting 6 4 1 2 Metabolic   Hyperglycemia 12 8 5 3   Weight increase 10 7 12 11   BUN increased 6 5 — —   NPN increased 6 5 — —   Hypercholesterolemia 4 3 1 1   Edema peripheral 2 1 7 6 Musculoskeletal   Arthralgia 6 5 1 1 Respiratory   Cough increased 8 9 5 4   Rales 4 4 4 2 Vision   Vision abnormal 5 2 — — Cardiac failure and dyspnea were also reported in these studies, but the rates were equal or greater in patients who received placebo. The following adverse events were reported with a frequency of > 1% but ≤ 3% and more frequently with COREG (carvedilol) in either the US placebo-controlled trials in patients with mild-to-moderate heart failure, or in patients with severe heart failure in the COPERNICUS trial. Incidence > 1% to ≤ 3% Body as a Whole: Allergy, malaise, hypovolemia, fever, leg edema. Cardiovascular: Fluid overload, postural hypotension, aggravated angina pectoris, AV block, palpitation, hypertension. Central and Peripheral Nervous System: Hypesthesia, vertigo, paresthesia. Gastrointestinal: Melena, periodontitis. Liver and Biliary System: SGPT increased, SGOT increased. Metabolic and Nutritional: Hyperuricemia, hypoglycemia, hyponatremia, increased alkaline phosphatase, glycosuria, hypervolemia, diabetes mellitus, GGT increased, weight loss, hyperkalemia, creatinine increased. Musculoskeletal: Muscle cramps. Platelet, Bleeding and Clotting: Prothrombin decreased, purpura, thrombocytopenia. Psychiatric: Somnolence. Reproductive, male: Impotence. Special Senses: Blurred vision. Urinary System: Renal insufficiency, albuminuria, hematuria. Left Ventricular Dysfunction Following Myocardial Infarction COREG (carvedilol) has been evaluated for safety in survivors of an acute myocardial infarction with left ventricular dysfunction in the CAPRICORN trial which involved 969 patients who received COREG (carvedilol) and 980 who received placebo. Approximately 75% of the patients received COREG (carvedilol) for at least 6 months and 53% received COREG (carvedilol) for at least 12 months. Patients were treated for an average of 12.9 months and 12.8 months with COREG (carvedilol) and placebo, respectively. The most common adverse events reported with COREG (carvedilol) in the CAPRICORN trial were consistent with the profile of the drug in the US heart failure trials and the COPERNICUS trial. The only additional adverse events reported in CAPRICORN in > 3% of the patients and more commonly on carvedilol were dyspnea, anemia, and lung edema. The following adverse events were reported with a frequency of > 1% but ≤ 3% and more frequently with COREG (carvedilol) : Flu syndrome, cerebrovascular accident, peripheral vascular disorder, hypotonia, depression, gastrointestinal pain, arthritis, and gout. The overall rates of discontinuations due to adverse events were similar in both groups of patients. In this database, the only cause of discontinuation > 1%, and occurring more often on carvedilol was hypotension (1.5% on carvedilol, 0.2% on placebo). Hypertension COREG (carvedilol) has been evaluated for safety in hypertension in more than 2,193 patients in US clinical trials and in 2,976 patients in international clinical trials. Approximately 36% of the total treated population received COREG (carvedilol) for at least 6 months. Most adverse events reported during therapy with COREG (carvedilol) were of mild to moderate severity. In US controlled clinical trials directly comparing COREG (carvedilol) in doses up to 50 mg (n = 1,142) to placebo (n = 462), 4.9% of patients receiving COREG (carvedilol) discontinued for adverse events versus 5.2% of placebo patients. Although there was no overall difference in discontinuation rates, discontinuations were more common in the carvedilol group for postural hypotension (1% versus 0). The overall incidence of adverse events in US placebo-controlled trials increased with increasing dose of COREG (carvedilol) . For individual adverse events this could only be distinguished for dizziness, which increased in frequency from 2% to 5% as total daily dose increased from 6.25 mg to 50 mg. Table 2 shows adverse events in US placebo-controlled clinical trials for hypertension that occurred with an incidence of ≥ 1% regardless of causality, and that were more frequent in drug-treated patients than placebo-treated patients. Table 2: Adverse Events (%) Occurring in US Placebo-Controlled Hypertension Trials (Incidence ≥ 1%, Regardless of Causality)*
  COREG
(n = 1,142) Placebo
(n = 462) Cardiovascular   Bradycardia 2 —   Postural hypotension  2 —   Peripheral edema 1 — Central Nervous System   Dizziness 6 5   Insomnia 2 1 Gastrointestinal   Diarrhea 2 1 Hematologic   Thrombocytopenia 1 — Metabolic   Hypertriglyceridemia 1 — * Shown are events with rate > 1% rounded to nearest integer. Dyspnea and fatigue were also reported in these studies, but the rates were equal or greater in patients who received placebo. The following adverse events not described above were reported as possibly or probably related to COREG (carvedilol) in worldwide open or controlled trials with COREG (carvedilol) in patients with hypertension or heart failure. Incidence > 0.1% to ≤ 1% Cardiovascular: Peripheral ischemia, tachycardia. Central and Peripheral Nervous System: Hypokinesia. Gastrointestinal: Bilirubinemia, increased hepatic enzymes (0.2% of hypertension patients and 0.4% of heart failure patients were discontinued from therapy because of increases in hepatic enzymes). Psychiatric: Nervousness, sleep disorder, aggravated depression, impaired concentration, abnormal thinking, paroniria, emotional lability. Respiratory System: Asthma [see CONTRAINDICATIONS]. Reproductive, male: Decreased libido. Skin and Appendages: Pruritus, rash erythematous, rash maculopapular, rash psoriaform, photosensitivity reaction. Special Senses: Tinnitus. Urinary System: Micturition frequency increased. Autonomic Nervous System: Dry mouth, sweating increased. Metabolic and Nutritional: Hypokalemia, hypertriglyceridemia. Hematologic: Anemia, leukopenia. The following events were reported in ≤ 0.1% of patients and are potentially important: Complete AV block, bundle branch block, myocardial ischemia, cerebrovascular disorder, convulsions, migraine, neuralgia, paresis, anaphylactoid reaction, alopecia, exfoliative dermatitis, amnesia, GI hemorrhage, bronchospasm, pulmonary edema, decreased hearing, respiratory alkalosis, increased BUN, decreased HDL, pancytopenia, and atypical lymphocytes. Laboratory Abnormalities Reversible elevations in serum transaminases (ALT or AST) have been observed during treatment with COREG (carvedilol) . Rates of transaminase elevations (2- to 3-times the upper limit of normal) observed during controlled clinical trials have generally been similar between patients treated with COREG (carvedilol) and those treated with placebo. However, transaminase elevations, confirmed by rechallenge, have been observed with COREG (carvedilol) . In a long-term, placebo-controlled trial in severe heart failure, patients treated with COREG (carvedilol) had lower values for hepatic transaminases than patients treated with placebo, possibly because improvements in cardiac function induced by COREG (carvedilol) led to less hepatic congestion and/or improved hepatic blood flow. COREG (carvedilol) has not been associated with clinically significant changes in serum potassium, total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or creatinine. No clinically relevant changes were noted in fasting serum glucose in hypertensive patients; fasting serum glucose was not evaluated in the heart failure clinical trials. Postmarketing Experience The following adverse reactions have been identified during post-approval use of COREG (carvedilol) . Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Reports of aplastic anemia and severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme) have been rare and received only when carvedilol was administered concomitantly with other medications associated with such reactions. Rare reports of hypersensitivity reactions (e.g., anaphylactic reaction, angioedema, and urticaria) have been received for COREG (carvedilol) and COREG (carvedilol) CR®, including cases occurring after the initiation of COREG (carvedilol) CR in patients previously treated with COREG (carvedilol) . Urinary incontinence in women (which resolved upon discontinuation of the medication) and interstitial pneumonitis have been reported rarely. Read the Coreg (carvedilol) Side Effects Center for a complete guide to possible side effectsLearn More »

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COREG (carvedilol) should be taken with food to slow the rate of absorption and reduce the incidence of orthostatic effects. Heart Failure DOSAGE MUST BE INDIVIDUALIZED AND CLOSELY MONITORED BY A PHYSICIAN DURING UP-TITRATION. Prior to initiation of COREG (carvedilol) , it is recommended that fluid retention be minimized. The recommended starting dose of COREG (carvedilol) is 3.125 mg twice daily for 2 weeks. If tolerated, patients may have their dose increased to 6.25, 12.5, and 25 mg twice daily over successive intervals of at least 2 weeks. Patients should be maintained on lower doses if higher doses are not tolerated. A maximum dose of 50 mg twice daily has been administered to patients with mild-to-moderate heart failure weighing over 85 kg (187 lbs). 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 hour after dosing. During these periods, patients should avoid situations such as driving or hazardous tasks, where symptoms could result in injury. Vasodilatory symptoms often do not require treatment, but it may be useful to separate the time of dosing of COREG (carvedilol) from that of the ACE inhibitor or to reduce temporarily the dose of the ACE inhibitor. The dose of COREG (carvedilol) should not be increased until symptoms of worsening heart failure or vasodilation have been stabilized. Fluid retention (with or without transient worsening heart failure symptoms) should be treated by an increase in the dose of diuretics. The dose of COREG (carvedilol) should be reduced if patients experience bradycardia (heart rate < 55 beats/minute). Episodes of dizziness or fluid retention during initiation of COREG (carvedilol) can generally be managed without discontinuation of treatment and do not preclude subsequent successful titration of, or a favorable response to, carvedilol. Left Ventricular Dysfunction Following Myocardial Infarction DOSAGE MUST BE INDIVIDUALIZED AND MONITORED DURING UP-TITRATION. Treatment with COREG (carvedilol) may be started as an inpatient or outpatient and should be started after the patient is hemodynamically stable and fluid retention has been minimized. It is recommended that COREG (carvedilol) be started at 6.25 mg twice daily and increased after 3 to 10 days, based on tolerability, to 12.5 mg twice daily, then again to the target dose of 25 mg twice daily. A lower starting dose may be used (3.125 mg twice daily) and/or the rate of up-titration may be slowed if clinically indicated (e.g., due to low blood pressure or heart rate, or fluid retention). Patients should be maintained on lower doses if higher doses are not tolerated. The recommended dosing regimen need not be altered in patients who received treatment with an IV or oral β-blocker during the acute phase of the myocardial infarction. Hypertension DOSAGE MUST BE INDIVIDUALIZED. The recommended starting dose of COREG (carvedilol) is 6.25 mg twice daily. If this dose is tolerated, using standing systolic pressure measured about 1 hour after dosing as a guide, the dose should be maintained for 7 to 14 days, and then increased to 12.5 mg twice daily if needed, based on trough blood pressure, again using standing systolic pressure one hour after dosing as a guide for tolerance. This dose should also be maintained for 7 to 14 days and can then be adjusted upward to 25 mg twice daily if tolerated and needed. The full antihypertensive effect of COREG (carvedilol) is seen within 7 to 14 days. Total daily dose should not exceed 50 mg. Concomitant administration with a diuretic can be expected to produce additive effects and exaggerate the orthostatic component of carvedilol action. Hepatic Impairment COREG (carvedilol) should not be given to patients with severe hepatic impairment [see CONTRAINDICATIONS].

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CYP2D6 Inhibitors and Poor Metabolizers Interactions of carvedilol with potent inhibitors of CYP2D6 isoenzyme (such as quinidine, fluoxetine, paroxetine, and propafenone) have not been studied, but these drugs would be expected to increase blood levels of the R(+) enantiomer of carvedilol [see CLINICAL PHARMACOLOGY]. Retrospective analysis of side effects in clinical trials showed that poor 2D6 metabolizers had a higher rate of dizziness during up-titration, presumably resulting from vasodilating effects of the higher concentrations of the α-blocking R(+) enantiomer. Hypotensive Agents Patients taking both agents with β-blocking properties and a drug that can deplete catecholamines (e.g., reserpine and monoamine oxidase inhibitors) should be observed closely for signs of hypotension and/or severe bradycardia. Concomitant administration of clonidine with agents with β-blocking properties may potentiate blood-pressure- and heart-rate-lowering effects. When concomitant treatment with agents with β-blocking properties and clonidine is to be terminated, the β-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 interindividual variability in the dose adjustment required, it is recommended that cyclosporine concentrations be monitored closely after initiation of carvedilol therapy and that the dose of cyclosporine be adjusted as appropriate. Digitalis Glycosides Both digitalis glycosides and β-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Digoxin concentrations are increased by about 15% when digoxin and carvedilol are administered concomitantly. Therefore, increased monitoring of digoxin is recommended when initiating, adjusting, or discontinuing COREG [see CLINICAL PHARMACOLOGY]. Inducers/Inhibitors of Hepatic Metabolism Rifampin reduced plasma concentrations of carvedilol by about 70% [see CLINICAL PHARMACOLOGY]. Cimetidine increased AUC by about 30% but caused no change in Cmax [see CLINICAL PHARMACOLOGY]. Amiodarone Amiodarone, and its metabolite desethyl amiodarone, inhibitors of CYP2C9 and P-glycoprotein, increased concentrations of the S(-)-enantiomer of carvedilol by at least 2-fold [see CLINICAL PHARMACOLOGY]. The concomitant administration of amiodarone or other CYP2C9 inhibitors such as fluconazole with COREG may enhance the β-blocking properties of carvedilol resulting in further slowing of the heart rate or cardiac conduction. Patients should be observed for signs of bradycardia or heart block, particularly when one agent is added to pre-existing treatment with the other. Calcium Channel Blockers Conduction disturbance (rarely with hemodynamic compromise) has been observed when COREG (carvedilol) is co-administered with diltiazem. As with other agents with β-blocking properties, if COREG (carvedilol) is to be administered with calcium channel blockers of the verapamil or diltiazem type, it is recommended that ECG and blood pressure be monitored. Insulin or Oral Hypoglycemics Agents with β-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 [see WARNINGS AND PRECAUTIONS]. Read the Coreg Drug Interactions Center for a complete guide to possible interactions Learn More »

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Heart Failure COREG (carvedilol) is indicated for the treatment of mild-to-severe chronic heart failure of ischemic or cardiomyopathic origin, usually in addition to diuretics, ACE inhibitors, and digitalis, to increase survival and, also, to reduce the risk of hospitalization [see DRUG INTERACTIONS and Clinical Studies]. Left Ventricular Dysfunction Following Myocardial Infarction COREG (carvedilol) is indicated to reduce cardiovascular mortality in clinically stable patients who have survived the acute phase of a myocardial infarction and have a left ventricular ejection fraction of 40% (with or without symptomatic heart failure) [see Clinical Studies]. Hypertension COREG (carvedilol) is indicated for the management of essential hypertension [see Clinical Studies]. It can be used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics [see DRUG INTERACTIONS].

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COREG (carvedilol) is contraindicated in the following conditions:
  • Bronchial asthma or related bronchospastic conditions. Deaths from status asthmaticus have been reported following single doses of COREG (carvedilol) .
  • Second- or third-degree AV block
  • Sick sinus syndrome
  • Severe bradycardia (unless a permanent pacemaker is in place)
  • Patients with cardiogenic shock or who have decompensated heart failure requiring the use of intravenous inotropic therapy. Such patients should first be weaned from intravenous therapy before initiating COREG (carvedilol) .
  • Patients with severe hepatic impairment
  • Patients with a history of a serious hypersensitivity reaction (e.g., Stevens-Johnson syndrome, anaphylactic reaction, angioedema) to any component of this medication or other medications containing carvedilol.
Last reviewed on RxList: 2/25/2011
This monograph has been modified to include the generic and brand name in many instances.

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Overdosage may cause severe hypotension, bradycardia, cardiac insufficiency, cardiogenic shock, and cardiac arrest. Respiratory problems, bronchospasms, vomiting, lapses of consciousness, and generalized seizures may also occur. The patient should be placed in a supine position and, where necessary, kept under observation and treated under intensive-care conditions. Gastric lavage or pharmacologically induced emesis may be used shortly after ingestion. The following agents may be administered: for excessive bradycardia: Atropine, 2 mg IV. to support cardiovascular function: Glucagon, 5 to 10 mg IV rapidly over 30 seconds, followed by a continuous infusion of 5 mg/hour; sympathomimetics (dobutamine, isoprenaline, adrenaline) at doses according to body weight and effect. If peripheral vasodilation dominates, it may be necessary to administer adrenaline or noradrenaline with continuous monitoring of circulatory conditions. For therapy-resistant bradycardia, pacemaker therapy should be performed. For bronchospasm, β-sympathomimetics (as aerosol or IV) or aminophylline IV should be given. In the event of seizures, slow IV injection of diazepam or clonazepam is recommended. NOTE: In the event of severe intoxication where there are symptoms of shock, treatment with antidotes must be continued for a sufficiently long period of time consistent with the 7- to 10-hour half-life of carvedilol. Cases of overdosage with COREG (carvedilol) alone or in combination with other drugs have been reported. Quantities ingested in some cases exceeded 1,000 milligrams. Symptoms experienced included low blood pressure and heart rate. Standard supportive treatment was provided and individuals recovered.

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Dosage Forms And Strengths The white, oval, film-coated tablets are available in the following strengths: 3.125 mg– engraved with 39 and SB, 6.25 mg–engraved with 4140 and SB, 12.5 mg–engraved with 4141 and SB, and 25 mg–engraved with 4142 and SB. Storage And Handling The white, oval, film-coated tablets are available in the following strengths: 3.125 mg– engraved with 39 and SB, in bottles of 100; 6.25 mg–engraved with 4140 and SB, in bottles of 100; 12.5 mg–engraved with 4141 and SB, in bottles of 100; 25 mg–engraved with 4142 and SB, in bottles of 100. The 6.25 mg, 12.5 mg, and 25 mg tablets are TILTAB tablets.
  • 3.125 mg 100's: NDC 0007-4139-20
  • 6.25 mg 100's: NDC 0007-4140-20
  • 12.5 mg 100's: NDC 0007-4141-20
  • 25 mg 100's: NDC 0007-4142-20
Store below 30°C (86°F). Protect from moisture. Dispense in a tight, light-resistant container. Manufactured for : GlaxoSmithKline, Research Triangle Park, NC 27709. Manufactured by: Patheon Puerto Rico, Inc., Manati, PR 00674 USALast reviewed on RxList: 2/25/2011
This monograph has been modified to include the generic and brand name in many instances.

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Cessation of Therapy Patients with coronary artery disease, who are being treated with COREG (carvedilol) , should be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and the occurrence of myocardial infarction and ventricular arrhythmias have been reported in angina patients following the abrupt discontinuation of therapy with β-blockers. The last 2 complications may occur with or without preceding exacerbation of the angina pectoris. As with other β-blockers, when discontinuation of COREG (carvedilol) is planned, the patients should be carefully observed and advised to limit physical activity to a minimum. COREG (carvedilol) should be discontinued over 1 to 2 weeks whenever possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that COREG (carvedilol) be promptly reinstituted, at least temporarily. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue therapy with COREG (carvedilol) abruptly even in patients treated only for hypertension or heart failure. Bradycardia In clinical trials, COREG (carvedilol) caused bradycardia in about 2% of hypertensive patients, 9% of heart failure patients, and 6.5% of myocardial infarction patients with left ventricular dysfunction. If pulse rate drops below 55 beats/minute, the dosage should be reduced. Hypotension In clinical trials of primarily mild-to-moderate heart failure, hypotension and postural hypotension occurred in 9.7% and syncope in 3.4% of patients receiving COREG (carvedilol) compared to 3.6% and 2.5% of placebo patients, respectively. The risk for these events was highest during the first 30 days of dosing, corresponding to the up-titration period and was a cause for discontinuation of therapy in 0.7% of patients receiving COREG (carvedilol) , compared to 0.4% of placebo patients. In a long-term, placebo-controlled trial in severe heart failure (COPERNICUS), hypotension and postural hypotension occurred in 15.1% and syncope in 2.9% of heart failure patients receiving COREG (carvedilol) compared to 8.7% and 2.3% of placebo patients, respectively. These events were a cause for discontinuation of therapy in 1.1% of patients receiving COREG (carvedilol) , compared to 0.8% of placebo patients. Postural hypotension occurred in 1.8% and syncope in 0.1% of hypertensive patients, primarily following the initial dose or at the time of dose increase and was a cause for discontinuation of therapy in 1% of patients. In the CAPRICORN study of survivors of an acute myocardial infarction, hypotension or postural hypotension occurred in 20.2% of patients receiving COREG (carvedilol) compared to 12.6% of placebo patients. Syncope was reported in 3.9% and 1.9% of patients, respectively. These events were a cause for discontinuation of therapy in 2.5% of patients receiving COREG (carvedilol) , compared to 0.2% of placebo patients. Starting with a low dose, administration with food, and gradual up-titration should decrease the likelihood of syncope or excessive hypotension [see DOSAGE AND ADMINISTRATION]. During initiation of therapy, the patient should be cautioned to avoid situations such as driving or hazardous tasks, where injury could result should syncope occur. Heart Failure/Fluid Retention Worsening heart failure or fluid retention may occur during up-titration of carvedilol. If such symptoms occur, diuretics should be increased and the carvedilol dose should not be advanced until clinical stability resumes [see DOSAGE AND ADMINISTRATION]. Occasionally it is necessary to lower the carvedilol dose or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of, or a favorable response to, carvedilol. In a placebo-controlled trial of patients with severe heart failure, worsening heart failure during the first 3 months was reported to a similar degree with carvedilol and with placebo. When treatment was maintained beyond 3 months, worsening heart failure was reported less frequently in patients treated with carvedilol than with placebo. Worsening heart failure observed during long-term therapy is more likely to be related to the patients' underlying disease than to treatment with carvedilol. Non-allergic Bronchospasm Patients with bronchospastic disease (e.g., chronic bronchitis and emphysema) should, in general, not receive β-blockers. COREG (carvedilol) may be used with caution, however, in patients who do not respond to, or cannot tolerate, other antihypertensive agents. It is prudent, if COREG (carvedilol) is used, to use the smallest effective dose, so that inhibition of endogenous or exogenous β-agonists is minimized. In clinical trials of patients with heart failure, patients with bronchospastic disease were enrolled if they did not require oral or inhaled medication to treat their bronchospastic disease. In such patients, it is recommended that carvedilol be used with caution. The dosing recommendations should be followed closely and the dose should be lowered if any evidence of bronchospasm is observed during up-titration. Glycemic Control in Type 2 Diabetes In general, β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective β-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned about these possibilities. In heart failure patients with diabetes, carvedilol therapy may lead to worsening hyperglycemia, which responds to intensification of hypoglycemic therapy. It is recommended that blood glucose be monitored when carvedilol dosing is initiated, adjusted, or discontinued. Studies designed to examine the effects of carvedilol on glycemic control in patients with diabetes and heart failure have not been conducted. In a study designed to examine the effects of carvedilol on glycemic control in a population with mild-to-moderate hypertension and well-controlled type 2 diabetes mellitus, carvedilol had no adverse effect on glycemic control, based on HbA1c measurements [see Clinical Studies]. Peripheral Vascular Disease β-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in such individuals. Deterioration of Renal Function Rarely, use of carvedilol in patients with heart failure has resulted in deterioration of renal function. Patients at risk appear to be those with low blood pressure (systolic blood pressure < 100 mm Hg), ischemic heart disease and diffuse vascular disease, and/or underlying renal insufficiency. Renal function has returned to baseline when carvedilol was stopped. In patients with these risk factors it is recommended that renal function be monitored during up-titration of carvedilol and the drug discontinued or dosage reduced if worsening of renal function occurs. Anesthesia and Major Surgery If treatment with COREG (carvedilol) is to be continued perioperatively, particular care should be taken when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used [see OVERDOSAGE for information on treatment of bradycardia and hypertension]. Thyrotoxicosis β-adrenergic blockade may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of β-blockade may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate thyroid storm. Pheochromocytoma In patients with pheochromocytoma, an α-blocking agent should be initiated prior to the use of any β-blocking agent. Although carvedilol has both α- and β-blocking pharmacologic activities, there has been no experience with its use in this condition. Therefore, caution should be taken in the administration of carvedilol to patients suspected of having pheochromocytoma. Prinzmetal's Variant Angina Agents with non-selective β-blocking activity may provoke chest pain in patients with Prinzmetal's variant angina. There has been no clinical experience with carvedilol in these patients although the α-blocking activity may prevent such symptoms. However, caution should be taken in the administration of carvedilol to patients suspected of having Prinzmetal's variant angina. Risk of Anaphylactic Reaction While taking β-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction. Intraoperative Floppy Iris Syndrome Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients treated with alpha-1 blockers (COREG (carvedilol) is an alpha/beta blocker). This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The patient's ophthalmologist should be prepared for possible modifications to the surgical technique, such as utilization of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to be a benefit of stopping alpha-1 blocker therapy prior to cataract surgery. Patient Counseling Information See FDA-Approved Patient Labeling. Patient Advice Patients taking COREG (carvedilol) should be advised of the following: Patients should take COREG (carvedilol) with food.
  • Patients should not interrupt or discontinue using COREG (carvedilol) without a physician's advice.
  • Patients with heart failure should consult their physician if they experience signs or symptoms of worsening heart failure such as weight gain or increasing shortness of breath.
  • Patients may experience a drop in blood pressure when standing, resulting in dizziness and, rarely, fainting. Patients should sit or lie down when these symptoms of lowered blood pressure occur.
  • If experiencing dizziness or fatigue, patients should avoid driving or hazardous tasks.
  • Patients should consult a physician if they experience dizziness or faintness, in case the dosage should be adjusted.
  • Diabetic patients should report any changes in blood sugar levels to their physician.
  • Contact lens wearers may experience decreased lacrimation.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility In 2-year studies conducted in rats given carvedilol at doses up to 75 mg/kg/day (12 times the MRHD when compared on a mg/m² basis) or in mice given up to 200 mg/kg/day (16 times the MRHD on a mg/m² basis), carvedilol had no carcinogenic effect. Carvedilol was negative when tested in a battery of genotoxicity assays, including the Ames and the CHO/HGPRT assays for mutagenicity and the in vitro hamster micronucleus and in vivo human lymphocyte cell tests for clastogenicity. At doses ≥ 200 mg/kg/day ( ≥ 32 times the MRHD as mg/m²) carvedilol was toxic to adult rats (sedation, reduced weight gain) and was associated with a reduced number of successful matings, prolonged mating time, significantly fewer corpora lutea and implants per dam, and complete resorption of 18% of the litters. The no-observed-effect dose level for overt toxicity and impairment of fertility was 60 mg/kg/day (10 times the MRHD as mg/m²). Use In Specific Populations Pregnancy Pregnancy Category C Studies performed in pregnant rats and rabbits given carvedilol revealed increased post-implantation loss in rats at doses of 300 mg/kg/day (50 times the maximum recommended human dose [MRHD] as mg/m²) and in rabbits at doses of 75 mg/kg/day (25 times the MRHD as mg/m²). In the rats, there was also a decrease in fetal body weight at the maternally toxic dose of 300 mg/kg/day (50 times the MRHD as mg/m²), which was accompanied by an elevation in the frequency of fetuses with delayed skeletal development (missing or stunted 13th rib). In rats the no-observed-effect level for developmental toxicity was 60 mg/kg/day (10 times the MRHD as mg/m²); in rabbits it was 15 mg/kg/day (5 times the MRHD as mg/m²). There are no adequate and well-controlled studies in pregnant women. COREG (carvedilol) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether this drug is excreted in human milk. Studies in rats have shown that carvedilol and/or its metabolites (as well as other β-blockers) cross the placental barrier and are excreted in breast milk. There was increased mortality at one week post-partum in neonates from rats treated with 60 mg/kg/day (10 times the MRHD as mg/m²) and above during the last trimester through day 22 of lactation. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from β-blockers, especially bradycardia, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. The effects of other α- and β-blocking agents have included perinatal and neonatal distress. Pediatric Use Effectiveness of COREG (carvedilol) in patients younger than 18 years of age has not been established. In a double-blind trial, 161 children (mean age 6 years, range 2 months to 17 years; 45% less than 2 years old) with chronic heart failure [NYHA class II-IV, left ventricular ejection fraction < 40% for children with a systemic left ventricle (LV), and moderate-severe ventricular dysfunction qualitatively by echo for those with a systemic ventricle that was not an LV] who were receiving standard background treatment were randomized to placebo or to 2 dose levels of carvedilol. These dose levels produced placebo-corrected heart rate reduction of 4-6 heart beats per minute, indicative of β-blockade activity. Exposure appeared to be lower in pediatric subjects than adults. After 8 months of follow-up, there was no significant effect of treatment on clinical outcomes. Adverse reactions in this trial that occurred in greater than 10% of patients treated with COREG (carvedilol) and at twice the rate of placebo-treated patients included chest pain (17% versus 6%), dizziness (13% versus 2%), and dyspnea (11% versus 0%). Geriatric Use Of the 765 patients with heart failure randomized to COREG (carvedilol) in US clinical trials, 31% (235) were 65 years of age or older, and 7.3% (56) were 75 years of age or older. Of the 1,156 patients randomized to COREG (carvedilol) in a long-term, placebo-controlled trial in severe heart failure, 47% (547) were 65 years of age or older, and 15% (174) were 75 years of age or older. Of 3,025 patients receiving COREG (carvedilol) in heart failure trials worldwide, 42% were 65 years of age or older. Of the 975 myocardial infarction patients randomized to COREG (carvedilol) in the CAPRICORN trial, 48% (468) were 65 years of age or older, and 11% (111) were 75 years of age or older. Of the 2,065 hypertensive patients in US clinical trials of efficacy or safety who were treated with COREG (carvedilol) , 21% (436) were 65 years of age or older. Of 3,722 patients receiving COREG (carvedilol) in hypertension clinical trials conducted worldwide, 24% were 65 years of age or older. With the exception of dizziness in hypertensive patients (incidence 8.8% in the elderly versus 6% in younger patients), no overall differences in the safety or effectiveness (see Figures 2 and 4 under CLINICAL PHARMACOLOGY) were observed between the older subjects and younger subjects in each of these populations. Similarly, other reported clinical experience has not identified differences in responses between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.Last reviewed on RxList: 2/25/2011
This monograph has been modified to include the generic and brand name in many instances.

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