Zocor is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it is not expected to affect the plasma
concentrations of other drugs metabolized by CYP3A4. Potent inhibitors of CYP3A4 (below) increase the risk of myopathy by reducing
the elimination of simvastatin.
HIV protease inhibitors
Large quantities of grapefruit juice (>1 quart daily)
Interactions with lipid-lowering drugs that can cause myopathy when given alone
The risk of myopathy is increased by gemfibrozil and to a lesser extent by other fibrates and niacin (nicotinic acid) (1 g/day).
Other drug interactions
Danazol: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of danazol particularly with higher doses of
Amiodarone or Verapamil: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of amiodarone or verapamil
with higher doses of simvastatin
Propranolol: In healthy male volunteers there was a significant decrease in mean Cmax, but no change in AUC, for simvastatin total
and active inhibitors with concomitant administration of single doses of ZOCOR and propranolol. The clinical relevance of this
finding is unclear. The pharmacokinetics of the enantiomers of propranolol were not affected.
Digoxin: Concomitant administration of a single dose of digoxin in healthy male volunteers receiving simvastatin resulted in a slight
elevation (less than 0.3 ng/mL) in digoxin concentrations in plasma (as measured by a radioimmunoassay) compared to concomitant
administration of placebo and digoxin. Patients taking digoxin should be monitored appropriately when simvastatin is initiated.
Warfarin: In two clinical studies, one in normal volunteers and the other in hypercholesterolemic patients, 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 the volunteer and patient studies, respectively. With other reductase
inhibitors, clinically evident bleeding and/or increased prothrombin time has been reported in a few patients taking coumarin
anticoagulants concomitantly. In such patients, prothrombin time should be determined before starting simvastatin and frequently
enough during early therapy to ensure that 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 on coumarin anticoagulants. If
the dose of simvastatin is changed or discontinued, the same procedure should be repeated. Zocor therapy has not been associated
with bleeding or with changes in prothrombin time in patients not taking anticoagulants.