Coreg Information
Coreg (Carvedilol) Dosage And Administration
Coreg (Carvedilol) should be taken with food to slow the rate of absorption and reduce the incidence of orthostatic effects.
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
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.
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.
Coreg (Carvedilol) 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.
Coreg (Carvedilol) Contraindications
Coreg (Carvedilol) is contraindicated in the following conditions:
Coreg (Carvedilol) Warnings And Precautions
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.
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 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.
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.
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
Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.
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.
Coreg (Carvedilol) Adverse Reactions
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.
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.
Blood and Lymphatic System Disorders:
Immune System Disorders:
Renal and Urinary Disorders:
Respiratory, Thoracic and Mediastinal Disorders:
Skin and Subcutaneous Tissue Disorders:
Coreg (Carvedilol) Drug Interactions
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.
Coreg (Carvedilol) Use In Specific Populations
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
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) 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.
Coreg (Carvedilol) Overdosage
Overdosage may cause severe hypotension, bradycardia, cardiac insufficiency, cardiogenic shock, and cardiac arrest. Respiratory problems, bronchospasms, vomiting, lapses of consciousness, and generalized seizures may also occur.
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:
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.
Coreg (Carvedilol) Description
Carvedilol is a nonselective β-adrenergic blocking agent with α-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 CHNO. 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).
Coreg (Carvedilol) Clinical Pharmacology
Coreg (Carvedilol) is rapidly and extensively absorbed following oral administration, with absolute bioavailability of approximately 25% to 35% due to a significant degree of first-pass metabolism. Following oral administration, the apparent mean terminal elimination half-life of carvedilol generally ranges from 7 to 10 hours. 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 the time to reach peak plasma levels, with no significant difference in extent of bioavailability. Taking Coreg (Carvedilol) with food should minimize the risk of orthostatic hypotension.
Carvedilol is extensively metabolized. Following oral administration of radiolabelled carvedilol to healthy volunteers, carvedilol accounted for only about 7% of the total radioactivity in plasma as measured by area under the curve (AUC). Less than 2% of the dose was excreted unchanged in the urine. Carvedilol is metabolized primarily by aromatic ring oxidation and glucuronidation. The oxidative metabolites are further metabolized by conjugation via glucuronidation and sulfation. The metabolites of carvedilol are excreted primarily via the bile into the feces. Demethylation and hydroxylation at the phenol ring produce 3 active metabolites with β-receptor blocking activity. Based on preclinical studies, the 4'-hydroxyphenyl metabolite is approximately 13 times more potent than carvedilol for β-blockade.
Compared to carvedilol, the 3 active metabolites exhibit weak vasodilating activity. Plasma concentrations of the active metabolites are about one-tenth of those observed for carvedilol and have pharmacokinetics similar to the parent.
Carvedilol undergoes stereoselective first-pass metabolism with plasma levels of R(+)-carvedilol approximately 2 to 3 times higher than S(-)-carvedilol following oral administration in healthy subjects. The mean apparent terminal elimination half-lives for R(+)-carvedilol range from 5 to 9 hours compared with 7 to 11 hours for the S(-)-enantiomer.
The primary P450 enzymes responsible for the metabolism of both R(+) and S(-)-carvedilol in human liver microsomes were CYP2D6 and CYP2C9 and to a lesser extent CYP3A4, 2C19, 1A2, and 2E1. CYP2D6 is thought to be the major enzyme in the 4’- and 5’-hydroxylation of carvedilol, with a potential contribution from 3A4. CYP2C9 is thought to be of primary importance in the O-methylation pathway of S(-)-carvedilol.
Carvedilol is subject to the effects of genetic polymorphism with poor metabolizers of debrisoquin (a marker for cytochrome P450 2D6) exhibiting 2- to 3-fold higher plasma concentrations of R(+)-carvedilol compared to extensive metabolizers. In contrast, plasma levels of S(-)-carvedilol are increased only about 20% to 25% in poor metabolizers, indicating this enantiomer is metabolized to a lesser extent by cytochrome P450 2D6 than R(+)-carvedilol. The pharmacokinetics of carvedilol do not appear to be different in poor metabolizers of S-mephenytoin (patients deficient in cytochrome P450 2C19).
Carvedilol is more than 98% bound to plasma proteins, primarily with albumin. The plasma-protein binding is independent of concentration over the therapeutic range. Carvedilol is a basic, lipophilic compound with a steady-state volume of distribution of approximately 115 L, indicating substantial distribution into extravascular tissues. Plasma clearance ranges from 500 to 700 mL/min.
Coreg (Carvedilol) Clinical Studies
CAPRICORN was a double-blind study comparing carvedilol and placebo in 1,959 patients with a recent myocardial infarction (within 21 days) and left ventricular ejection fraction of ≤40%, with (47%) or without symptoms of heart failure. Patients given carvedilol received 6.25 mg twice daily, titrated as tolerated to 25 mg twice daily. Patients had to have a systolic blood pressure >90 mm Hg, a sitting heart rate >60 beats/minute, and no contraindication to β-blocker use. Treatment of the index infarction included aspirin (85%), IV or oral β-blockers (37%), nitrates (73%), heparin (64%), thrombolytics (40%), and acute angioplasty (12%). Background treatment included ACE inhibitors or angiotensin receptor blockers (97%), anticoagulants (20%), lipid-lowering agents (23%), and diuretics (34%). Baseline population characteristics included an average age of 63 years, 74% male, 95% Caucasian, mean blood pressure 121/74 mm Hg, 22% with diabetes, and 54% with a history of hypertension. Mean dosage achieved of carvedilol was 20 mg twice daily; mean duration of follow-up was 15 months.
All-cause mortality was 15% in the placebo group and 12% in the carvedilol group, indicating a 23% risk reduction in patients treated with carvedilol (95% CI 2-40%, p = 0.03), as shown in Figure 3. The effects on mortality in various subgroups are shown in Figure 4. Nearly all deaths were cardiovascular (which were reduced by 25% by carvedilol), and most of these deaths were sudden or related to pump failure (both types of death were reduced by carvedilol). Another study end point, total mortality and all-cause hospitalization, did not show a significant improvement.
There was also a significant 40% reduction in fatal or non-fatal myocardial infarction observed in the group treated with carvedilol (95% CI 11% to 60%, p = 0.01). A similar reduction in the risk of myocardial infarction was also observed in a meta-analysis of placebo-controlled trials of carvedilol in heart failure.
Coreg (Carvedilol) was studied in 2 placebo-controlled trials that utilized twice-daily dosing, at total daily doses of 12.5 to 50 mg. In these and other studies, the starting dose did not exceed 12.5 mg. At 50 mg/day, Coreg (Carvedilol) reduced sitting trough (12-hour) blood pressure by about 9/5.5 mm Hg; at 25 mg/day the effect was about 7.5/3.5 mm Hg. Comparisons of trough to peak blood pressure showed a trough to peak ratio for blood pressure response of about 65%. Heart rate fell by about 7.5 beats/minute at 50 mg/day. In general, as is true for other β-blockers, responses were smaller in black than non-black patients. There were no age- or gender-related differences in response.
The peak antihypertensive effect occurred 1 to 2 hours after a dose. The dose-related blood pressure response was accompanied by a dose-related increase in adverse effects .
Coreg (Carvedilol) How Supplied/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.
Store below 30°C (86°F). Protect from moisture. Dispense in a tight, light-resistant container.
Coreg (Carvedilol) Patient Counseling Information
See FDA-Approved Patient Labeling.
Patient labeling is provided as a tear-off leaflet at the end of this full prescribing information.
Coreg (Carvedilol) , Coreg (Carvedilol) CR, and TILTAB are registered trademarks of GlaxoSmithKline.
TOPROL-XL is a registered trademark of the AstraZeneca group of companies.
Manufactured for
GlaxoSmithKline
Research Triangle Park, NC 27709
Manufactured by
Patheon Puerto Rico, Inc.
Manati, PR 00674 USA
©2011, GlaxoSmithKline. All rights reserved.
July 2011
CRG:22PI
PHARMACIST-DETACH HERE AND GIVE INSTRUCTIONS TO PATIENT
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Coreg (Carvedilol)
Coreg (Carvedilol)
Coreg (Carvedilol)
Coreg (Carvedilol)
Coreg (Carvedilol)
