Interactions : אינטראקציות

4.5 Interaction with other medicinal products and other forms of interaction
Pharmacokinetic interactions:

Effects of carvedilol on the pharmacokinetics of other medicines
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 section 4.4).
Carvedilol had no effect on digoxin administered intravenously.

Ciclosporin and tacrolimus: Two studies in renal and cardiac transplant patients receiving oral ciclosporin have shown an increase in ciclosporin plasma concentration following the initiation of carvedilol. It appears that carvedilol increases exposure to oral ciclosporin by around 10 to 20%. In an attempt to maintain therapeutic ciclosporin levels, an average 10 to 20% reduction of the ciclosporin 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 ciclosporin levels, it is recommended that ciclosporin concentrations are monitored closely after initiation of carvedilol therapy and that the dose of ciclosporin be adjusted as appropriate. In case of intravenous administration of ciclosporin, no interaction with carvedilol is expected.
Furthermore, there is evidence that CYP3A4 is involved in the metabolism of carvedilol. As tacrolimus is a substrate of P-glycoprotein and CYP3A4, its pharmacokinetics may also be affected by carvedilol through these interaction mechanisms.

Effects of other medicines and substances 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 section 5.2). Some examples observed in patients or in healthy subjects are listed below but the list is not exhaustive.

Rifampicin: In a study in 12 healthy subjects, exposure to carvedilol decreased by around 60% during concomitant administration with rifampicin and a decreased 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 beta blockade activity in patients receiving concomitant administration of carvedilol and rifampicin is appropriate.

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 beta- blockade activity in patients treated with the combination carvedilol and amiodarone is advised.

Fluoxetine and Paroxetine: In a randomized, cross-over study in 10 patients with heart failure, coadministration 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-significant 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.

Alcohol: Alcohol intake is shown to have acute hypotensive effects which may augment the blood pressure reduction caused by carvedilol. As carvedilol is soluble in ethanol, the presence of alcohol could affect the rate and/or extent of intestinal absorption of carvedilol.
Also, carvedilol is partly metabolized by CYP2E1, an enzyme known to be induced and inhibited by alcohol.

Grapefruit juice: Consumption of a single dose of 300 ml grapefruit juice results in a 1.2-fold increase of the AUC of carvedilol in comparison to water. While clinical relevance is unclear, patients should avoid concomitant intake of grapefruit juice at least until a stable dose- response relationship is established.

Pharmacodynamic interactions:

Insulin or oral hypoglycaemics: Agents with beta-blocking properties may enhance the blood-sugar-reducing effect of insulin and oral hypoglyacemics. 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 section 4.4).

Catecholamine-depleting agents: Patients taking both agents with beta-blocking properties and a medicine 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.

Non-dihydropyridine calcium channel blockers, amiodarone or other antiarrhythmics: The combined use of non-dihydropyridine calcium channel blockers, amiodarone or other antiarrhythmics with carvedilol can increase the risk of AV conduction disturbances (see section 4.4). Isolated cases of conduction disturbance (rarely with haemodynamic compromise) have been observed when carvedilol is co-administered with diltiazem. As with other agents with beta-blocking properties, if carvedilol is to be administered orally with non- dihydropyridine 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 beta-blocking properties may potentiate blood pressure and heart rate lowering effects. When concomitant treatment with agents with beta-blocking properties and clonidine is to be terminated, the beta-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 beta-blocking activity, carvedilol may potentiate the effect of other concomitantly administered medicines that are anti-hypertensive in action (e.g., alpha1-receptor antagonists) or have hypotension as part of their adverse effect profile.

Anaesthetic agents: Careful attention must be paid during general anaesthesia to the synergistic negative inotropic and hypotensive effects of carvedilol and anaesthetics (see section 4.4).

Non-steroidal anti-inflammatory drugs (NSAIDs): The concurrent use of non-steroidal anti- inflammatory drugs (NSAIDs) and beta-adrenergic blockers may result in an increase in blood pressure and impairment of blood pressure control.

Beta-agonist bronchodilators: Non-cardioselective beta-blockers oppose the bronchodilator effects of beta-agonist bronchodilators. Careful monitoring of patients is recommended.