Carvedilol (Page 3 of 7)

6.2 Laboratory Abnormalities

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

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.

6.3 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of 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: Aplastic anemia.

Immune System Disorders: Hypersensitivity (e.g., anaphylactic reactions, angioedema, urticaria).

Renal and Urinary Disorders: Urinary incontinence.

Respiratory, Thoracic and Mediastinal Disorders: Interstitial pneumonitis.

Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme.

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 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 carvedilol [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 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 (12.5)]. The concomitant administration of amiodarone or other CYP2C9 inhibitors such as fluconazole with carvedilol 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.

7.7 Calcium Channel Blockers

Conduction disturbance (rarely with hemodynamic compromise) has been observed when carvedilol is co-administered with diltiazem. As with other agents with β-blocking properties, if 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.

7.8 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)].

7.9 Anesthesia

If treatment with 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 (10)].

8 USE IN SPECIFIC POPULATIONS

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

8.3 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.

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