Vytorin Warnings & Precautions

Drug Library
Vytorin - Warnings & Precautions [ezetimibe/simvastatin]

Warfarin:

Simvastatin 20-40 mg/day modestly potentiated the effect of coumarin anticoagulants:

The prothrombin time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in a normal volunteer study and in a hypercholesterolemic patient study, respectively. With other statins, clinically evident bleeding and/or increased prothrombin time has been reported in a few patients taking coumarin anticoagulants concomitantly. In such patients, prothrombintime should be determined before starting VYTORIN and frequently enough during early therapy to insurethat no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients oncoumarin anticoagulants. If the dose of VYTORIN is changed or discontinued, the same procedure should be repeated. Simvastatin therapy has not been associated with bleeding or with changes in prothrombinn time in patients not taking anticoagulants.

Ezetimibe

Fenofibrate:

In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold.

Gemfibrozil:

In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold.

Simvastatin Propranolol:

In healthy male volunteers there was a significant decrease in mean Cmax, but no changein AUC, for simvastatin total and active inhibitors with concomitant administration of single doses of simvastatin and propranolol. The clinical relevance of this finding is unclear. The pharmacokinetics of the enantiomers of propranolol were not affected.

CNS Toxicity

Optic nerve degeneration was seen in clinically normal dogs treated with simvastatin for 14 weeks at180 mg/kg/day, a dose that produced mean plasma drug levels about 12 times higher than the mean plasma drug level in humans taking 80 mg/day. A chemically similar drug in this class also produced optic nerve degeneration (Wallerian degeneration of retino geniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, adose that produced mean plasma drug levels about 30 times higher than the mean plasma drug level inhumans taking the highest recommended dose (as measured by total enzyme inhibitory activity). This same drug also produced vestibulo cochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis in dogs treated for 14 weeks at 180 mg/kg/day, a dose that resulted in a mean plasma drug level similar to that seen with the 60 mg/kg/day dose.