Carivalan Drug Interactions

No interactions between carvedilol and ivabradine have been observed in an interaction study conducted in healthy volunteers. Information on interactions with other products that are known for the individual active substances is provided as follows.
Ivabradine is metabolized by CYP3A4 only and it is a very weak inhibitor of this cytochrome. Ivabradine was shown not to influence the metabolism and plasma concentrations of other CYP3A4 substrates (mild, moderate and strong inhibitors). CYP3A4 inhibitors and inducers are liable to interact with ivabradine and influence its metabolism and pharmacokinetics to a clinically significant extent. Drug-drug interaction studies have established that CYP3A4 inhibitors increase ivabradine plasma concentrations, while inducers decrease them. Increased plasma concentrations of ivabradine may be associated with the risk of excessive bradycardia.
Carvedilol is both a substrate and an inhibitor of P-glycoprotein. It is therefore possible that the bioavailability of medicines which are transported by P-glycoprotein will be increased if carvedilol is administered concomitantly. In addition, the bioavailability of carvedilol may be altered by inducers or inhibitors of P-glycoprotein.
Both inhibitors and inducers of the CYP2D6 and CYP2C9 isoenzymes may alter the systemic and presystemic metabolism of carvedilol in a stereoselective manner, which may reduce or elevate the plasma concentration of R- and S-carvedilol.
Some of these types of interactions which have been observed in patients or healthy subjects are listed as follows. However, this list is not exhaustive.
Concomitant use contraindicated: See Table 2.

Click on icon to see table/diagram/image

Concomitant use not recommended: See Table 3.

Click on icon to see table/diagram/image

Concomitant use with precautions: See Table 4.

Click on icon to see table/diagram/image

Concomitant use to be taken into consideration (due to carvedilol): See Table 5.

Click on icon to see table/diagram/image

Specific drug-drug interaction studies have shown no clinically significant effect of the following medicinal products on pharmacokinetics and pharmacodynamics of ivabradine: proton pump inhibitors (omeprazole, lansoprazole), sildenafil, HMG CoA reductase inhibitors (simvastatin), dihydropyridine calcium channel blockers (amlodipine, lacidipine), digoxin and warfarin. In addition, there was no clinically significant effect of ivabradine on the pharmacokinetics of simvastatin, amlodipine, lacidipine, on the pharmacokinetics and pharmacodynamics of digoxin, warfarin and on the pharmacodynamics of aspirin.
In pivotal phase III clinical trials, the following medicinal products were routinely combined with ivabradine with no evidence of safety concerns: angiotensin converting enzyme inhibitors, angiotensin II antagonists, beta-blockers, diuretics, anti-aldosterone agents, short and long acting nitrates, HMG CoA reductase inhibitors, fibrates, proton pump inhibitors, oral antidiabetics, aspirin and other anti-platelet medicinal products.
Pediatric population: Interaction studies have only been performed in adults.