Dilatrend Drug Interactions

Pharmacokinetic interactions: 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.
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 as follows but the list is not exhaustive.
Digoxin: Digoxin concentrations are increased by about 15% when digoxin and carvedilol are administered concomitantly. Increased monitoring of digoxin levels is recommended when initiating, adjusting or discontinuing carvedilol (see General under Precautions).
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 the absorption of cyclosporin po through inhibition of P-glycoprotein activity in the intestine. In an attempt to maintain therapeutic cyclosporin levels, an average 10-20% reduction of the cyclosporin dose was necessary. Therefore, 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.
Rifampicin: In a study in 12 health subjects, rifampicin administration decreased the carvedilol plasma levels most likely by induction of P-glycoprotein leading to a decrease of the intestinal absorption of carvedilol and a decrease of the antihypertensive effect.
Amiodarone: In patients with heart failure, amiodarone decreased the clearance of S-carvedilol likely by inhibition of CYP2C9. The mean R-carvedilol plasma concentration was not altered. Consequently, there is a potential risk of increased β-blockade caused by a raised of the plasma S-carvedilol concentration.
Fluoxetine: 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 AUC. However, no difference in adverse events, blood pressure or heart rate were noted between treatment groups.
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 General under 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 beta-blockers and digoxin may result in additive prolongation of atrioventricular (AV) conduction time (see General under Precautions).
Verapamil, diltiazem, amiodarone or other antiarrhythmics: In combination with carvedilol can increase the risk of AV conduction disturbances (see General under Precautions).
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.
Calcium channel blockers (see General under Precautions): 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 calcium channel blockers of the verapamil or diltiazem type, it is recommended that ECG and blood pressure be monitored.
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 (see General under Precautions).
NSAIDs: The concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs) and beta-adrenergic blockers may result in an increase in blood pressure and lower blood pressure control.
Beta-agonist bronchodilators: Non-cardioselective beta blockers oppose the bronchodilator effects of beta-agonist bronchodilators. Careful monitoring of patients is recommended (see General under Precautions).