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All about: Coreg

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Generic Name: carvedilol
Dosage Form: Tablets

1 INDICATIONS AND USAGE

1.1 Heart Failure

Coreg 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 Clinical Studies (14.1)].

1.2 Left Ventricular Dysfunction Following Myocardial Infarction

Coreg 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 (14.2)].

1.3 Hypertension

Coreg is indicated for the management of essential hypertension [see Clinical Studies (14.3, 14.4)]. It can be used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics [see Drug Interactions (7.2)].

2 DOSAGE AND ADMINISTRATION

Coreg should be taken with food to slow the rate of absorption and reduce the incidence of orthostatic effects.

2.1 Heart Failure

DOSAGE MUST BE INDIVIDUALIZED AND CLOSELY MONITORED BY A PHYSICIAN DURING UP-TITRATION. Prior to initiation of Coreg, it is recommended that fluid retention be minimized. The recommended starting dose of Coreg 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 from that of the ACE inhibitor or to reduce temporarily the dose of the ACE inhibitor. The dose of Coreg 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 should be reduced if patients experience bradycardia (heart rate <55 beats/minute).

Episodes of dizziness or fluid retention during initiation of Coreg can generally be managed without discontinuation of treatment and do not preclude subsequent successful titration of, or a favorable response to, carvedilol.

2.2 Left Ventricular Dysfunction Following Myocardial Infarction

DOSAGE MUST BE INDIVIDUALIZED AND MONITORED DURING UP-TITRATION. Treatment with Coreg 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 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.

2.3 Hypertension

DOSAGE MUST BE INDIVIDUALIZED. The recommended starting dose of Coreg 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 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.

2.4 Hepatic Impairment

Coreg should not be given to patients with severe hepatic impairment [see Contraindications (4)].

3 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.

4 CONTRAINDICATIONS

Coreg is contraindicated in the following conditions:

  • Bronchial asthma or related bronchospastic conditions. Deaths from status asthmaticus have been reported following single doses of Coreg.

  • 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

  • Patients with severe hepatic impairment

  • Patients with a history of a serious hypersensitivity reaction to carvedilol (e.g. Stevens-Johnson syndrome) (4)

5 WARNINGS AND PRECAUTIONS

5.1 Cessation of Therapy

Patients with coronary artery disease, who are being treated with Coreg, 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 is planned, the patients should be carefully observed and advised to limit physical activity to a minimum. Coreg should be discontinued over 1 to 2 weeks whenever possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that Coreg 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 abruptly even in patients treated only for hypertension or heart failure.

5.2 Bradycardia

In clinical trials, Coreg 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.

5.3 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 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, 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 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, 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 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, 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 (2.1, 2.2, 2.3)].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.

5.4 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 (2)]. 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.

5.5 Non-allergic Bronchospasm

Patients with bronchospastic disease (e.g., chronic bronchitis and emphysema) should, in general, not receive β-blockers. Coreg may be used with caution, however, in patients who do not respond to, or cannot tolerate, other antihypertensive agents. It is prudent, if Coreg 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.

5.6 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 Trials (14.4)].

5.7 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.

5.8 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.

5.9 Anesthesia and Major Surgery

If treatment with Coreg 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 (10) for information on treatment of bradycardia and hypertension].

5.10 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.

5.11 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.

5.12 Prinzmetal’s Variant Angina

Agents with non-selectiveβ-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.

5.13 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.

6 ADVERSE REACTIONS

6.1 Clinical Studies Experience

Coreg 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 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 for at least 6 months and 30% received Coreg for at least 12 months. In the COMET trial, 1,511 patients with mild-to-moderate heart failure were treated with Coreg for up to 5.9 years (mean 4.8 years). Both in US clinical trials in mild-to-moderate heart failure that compared Coreg 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 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 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 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

Placebo

Coreg

Placebo

(n = 765)

(n = 437)

(n = 1,156)

(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 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 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 and 980 who received placebo. Approximately 75% of the patients received Coreg for at least 6 months and 53% received Coreg for at least 12 months. Patients were treated for an average of 12.9 months and 12.8 months with Coreg and placebo, respectively.

The most common adverse events reported with Coreg 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: 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 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 for at least 6 months. Most adverse events reported during therapy with Coreg were of mild to moderate severity. In US controlled clinical trials directly comparing Coreg in doses up to 50 mg (n = 1,142) to placebo (n = 462), 4.9% of patients receiving Coreg 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. 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

Placebo

(n = 1,142)

(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 in worldwide open or controlled trials with Coreg 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) [see Adverse Reactions (6.2)].

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

Respiratory System: Asthma [see Contraindications (4)].

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.

6.2 Laboratory Abnormalities

Reversible elevations in serum transaminases (ALT or AST) have been observed during treatment with Coreg. 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 and those treated with placebo. However, transaminase elevations, confirmed by rechallenge, have been observed with Coreg. In a long-term, placebo-controlled trial in severe heart failure, patients treated with Coreg had lower values for hepatic transaminases than patients treated with placebo, possibly because improvements in cardiac function induced by Coreg led to less hepatic congestion and/or improved hepatic blood flow.

Coreg 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.

6.3 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Coreg. 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. Urinary incontinence in women (which resolved upon discontinuation of the medication) and interstitial pneumonitis have been reported rarely.

7 DRUG INTERACTIONS

7.1 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 (12.3)]. 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.

7.2 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.

7.3 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.

7.4 Digoxin

Digoxin concentrations are increased by about 15% when digoxin and carvedilol are administered concomitantly. Both digoxin and Coreg slow AV conduction. Therefore, increased monitoring of digoxin is recommended when initiating, adjusting, or discontinuing Coreg [see Clinical Pharmacology (12.5)].

7.5 Inducers/Inhibitors of Hepatic Metabolism

Rifampin reduced plasma concentrations of carvedilol by about 70% [see Clinical Pharmacology (12.5)]. Cimetidine increased AUC by about 30% but caused no change in Cmax[see Clinical Pharmacology (12.5)].

7.6 Calcium Channel Blockers

Conduction disturbance (rarely with hemodynamic compromise) has been observed when Coreg is co-administered with diltiazem. As with other agents with β-blocking properties, if Coreg is to be administered with calcium channel blockers of the verapamil or diltiazem type, it is recommended that ECG and blood pressure be monitored.

7.7 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 (5.6)].

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