Coreg CR (Carvedilol Phosphate) - Drug Interactions, Contraindications, Overdosage

DRUG INTERACTIONS

Inhibitors of CYP2D6

poor metabolizers of debrisoquin: Interactions of carvedilol with strong inhibitors of CYP2D6 (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.

Catecholamine-depleting 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.

Clonidine

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.

Digoxin

Digoxin concentrations are increased by about 15% when digoxin and carvedilol are administered concomitantly. Both digoxin and carvedilol slow AV conduction. Therefore, increased monitoring of digoxin is recommended when initiating, adjusting, or discontinuing COREG CR.

Inducers and inhibitors of hepatic metabolism

Rifampin reduced plasma concentrations of carvedilol by about 70%. Cimetidine increased AUC by about 30% but caused no change in C_max.

Calcium channel blockers

Isolated cases of conduction disturbance (rarely with hemodynamic compromise) have been observed when carvedilol is co-administered with diltiazem. As with other agents with β-blocking properties, if COREG CR is to be administered orally 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.

OVERDOSAGE

The acute oral LD50 doses in male and female mice and male and female rats are over 8000 mg/kg. 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.

There is no experience of overdosages with COREG CR. Cases of overdosage with 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.

CONTRAINDICATIONS

COREG CR is contraindicated in patients with bronchial asthma (2 cases of death from status asthmaticus have been reported in patients receiving single doses of carvedilol) or related bronchospastic conditions, second- or third-degree AV block, sick sinus syndrome or severe bradycardia (unless a permanent pacemaker is in place), or in 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 CR.

Use of COREG CR in patients with clinically manifest hepatic impairment is not recommended.

COREG CR is contraindicated in patients with hypersensitivity to any component of the product.