Dilatrend Drug Interactions

Pharmacokinetic Interactions: Effects of Carvedilol on the pharmacokinetics of other drugs: Carvedilol is a substrate as well as an inhibitor of P-glycoprotein.
Therefore the bioavailability of drugs transported by P-glycoprotein may be increased with concomitant administration of carvedilol. In addition, the bioavailability of carvedilol can be modified by inducers or inhibitors of P-glycoprotein.
Digoxin: An increased exposure of digoxin of up to 20% has been shown in some studies in healthy subjects and patients with heart failure. A significantly larger effect has been seen in male patients compared to female patients. Therefore monitoring of digoxin levels is recommended when initiating, adjusting or discontinuing carvedilol [see Precautions]. Carvedilol had no effect on digoxin administered intravenously.
Cyclosporin: Two studies in renal and cardiac transplant patients receiving oral cyclosporin have shown an increase in cyclosporin plasma concentration following the initiation of carvedilol. It appears that carvedilol increases exposure to oral cyclosporin by around 10 to 20%. In an attempt to maintain therapeutic cyclosporin levels, an average 10-20% reduction of the cyclosporin dose was necessary. The mechanism for the interaction is not known but inhibition of intestinal P-glycoprotein by carvedilol may be involved. Due to wide interindividual variability of cyclosporin levels, it is recommended that cyclosporin concentrations are monitored closely after initiation of carvedilol therapy and that the dose of cyclosporin be adjusted as appropriate. In case of IV administration of cyclosporin, no interaction with carvedilol is expected.
Effects of other drugs on the pharmacokinetics of Carvedilol: Inhibitors as well as inducers of CYP2D6 and CYP2C9 can modify the systemic and/or presystemic metabolism of carvedilol stereoselectively, leading to increased or decreased plasma concentrations of R and S-carvedilol (see Pharmacology: Pharmacokinetics: Metabolism under Actions). Some examples observed in patients or in healthy subjects are listed below but the list is not exhaustive.
Amiodarone: An in vitro study with human liver microsomes has shown that amiodarone and desethylamiodarone inhibited the oxidation of R and S-carvedilol. The trough concentration of R and S-carvedilol was significantly increased by 2.2-fold in heart failure patients receiving carvedilol and amiodarone concomitantly as compared to patients receiving carvedilol monotherapy. The effect on S-carvedilol was attributed to desethylamiodarone, a metabolite of amiodarone, which is a strong inhibitor of CYP2C9. A monitoring of the β-blockade activity in patients treated with the combination carvedilol and amiodarone is advised.
Rifampicin: In a study in 12 healthy subjects, exposure to carvedilol decreased by around 60% during concomitant administration with rifampicin and a decrease effect of carvedilol on the systolic blood pressure was observed. The mechanism for the interaction is not known but it may be due to the induction of the intestinal P-glycoprotein by rifampicin. A close monitoring of the β-blockade activity in patients receiving concomitant administration of carvedilol and rifampicin is appropriate.
Fluoxetine and Paroxetine: In a randomized, cross-over study in 10 patients with heart failure, co-administration of fluoxetine, a strong inhibitor of CYP2D6, resulted in stereoselective inhibition of carvedilol metabolism with a 77% increase in mean R(+) enantiomer's AUC, and a non-statistically 35% increase of the S(-) enantiomer's AUC as compared to the placebo group. However, no differences in adverse events, blood pressure or heart rate were noted between treatment groups. The effect of single dose paroxetine, a strong CYP2D6 inhibitor, on carvedilol pharmacokinetics was investigated in 12 healthy subjects following single oral administration. Despite significant increase in R and S-carvedilol exposure, no clinical effects were observed in these healthy subjects.
Pharmacodynamic Interactions: Insulin or oral hypoglycaemics: Agents with β-blocking properties may enhance the blood-sugar-reducing effect of insulin and oral hypoglycaemics. The signs of hypoglycaemia may be masked or attenuated (especially tachycardia). In patients taking insulin or oral hypoglycaemics, regular monitoring of blood glucose is therefore recommended (see Precautions).
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.
Digoxin: The combined use of β-blockers and digoxin may result in additive prolongation of atrioventricular (AV) conduction time (see Precautions).
Non-dihydropyridines calcium channel blockers, amiodarone or other antiarrhythmics: In combination with carvedilol can increase the risk of AV conduction disturbances. Isolated cases of conduction disturbance (rarely with haemodynamic compromise) have been observed when carvedilol is co-administered with diltiazem. As with other agents with β-blocking properties, if carvedilol is to be administered orally with non-dihydropyridines calcium channel blockers of the verapamil or diltiazem type, amiodarone or other antiarrhythmics it is recommended that ECG and blood pressure be monitored.
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.
Antihypertensives: As with other agents with β-blocking activity, carvedilol may potentiate the effect of other concomitantly administered drugs that are anti-hypertensive in action (e.g. α1-receptor antagonists) or have hypotension as part of their adverse effect profile.
Anaesthetic agents: Careful monitoring of vital signs is recommended during anaesthesia due to the synergistic negative inotropic and hypotensive effects of carvedilol and anaesthetic drugs.
NSAIDs: The concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs) and β-adrenergic blockers may result in an increase in blood pressure and impairment of blood pressure control.
Beta-agonist bronchodilators: Non-cardioselective β-blockers oppose the bronchodilator effects of β-agonist bronchodilators. Careful monitoring of patients is recommended.