Drug interactions
Cytochrome P450 3A4 Inhibitors: In vitro and in vivo data indicate that pravastatin is
not metabolized by cytochrome P450 3A4 to a clinically significant extent. This has been
shown in studies with known cytochrome P450 3A4 inhibitors (see diltiazem and
itraconazole below). Other examples of cytochrome P450 3A4 inhibitors include
ketoconazole, mibefradil, and erythromycin.
Diltiazem: Steady-state levels of diltiazem (a known, weak inhibitor of P450 3A4) had
no effect on the pharmacokinetics of pravastatin. In this study, the AUC and Cmax of
another HMG-CoA reductase inhibitor which is known to be metabolized by cytochrome
P450 3A4 increased by factors of 3.6 and 4.3, respectively.
Itraconazole: The mean AUC and Cmax for pravastatin were increased by factors of 1.7
and 2.5, respectively, when given with itraconazole (a potent P450 3A4 inhibitor which
also inhibits p-glycoprotein transport) as compared to placebo. The mean t½ was not
affected by itraconazole, suggesting that the relatively small increases in Cmax and AUC
were due solely to increased bioavailability rather than a decrease in clearance, consistent
with inhibition of p-glycoprotein transport by itraconazole. This drug transport system is
thought to affect bioavailability and excretion of HMG-CoA reductase inhibitors,
including pravastatin. The AUC and Cmax of another HMG-CoA reductase inhibitor
which is known to be metabolized by cytochrome P450 3A4 increased by factors of 19
and 17, respectively, when given with itraconazole.
Antipyrine: Since concomitant administration of pravastatin had no effect on the
clearance of antipyrine, interactions with other drugs metabolized via the same hepatic
cytochrome isozymes are not expected.
Cholestyramine/Colestipol: Concomitant administration resulted in an approximately
40 to 50% decrease in the mean AUC of pravastatin. However, when pravastatin was
administered 1 hour before or 4 hours after cholestyramine or 1 hour before colestipol
and a standard meal, there was no clinically significant decrease in bioavailability or
therapeutic effect. (See DOSAGE AND ADMINISTRATION: Concomitant Therapy.)
Warfarin: Concomitant administration of 40 mg pravastatin had no clinically significant
effect on prothrombin time when administered in a study to normal elderly subjects who
were stabilized on warfarin.
Cimetidine: The AUC0-12hr for pravastatin when given with cimetidine was not
significantly different from the AUC for pravastatin when given alone. A significant
difference was observed between the AUC’s for pravastatin when given with cimetidine
compared to when administered with antacid.
Digoxin: In a crossover trial involving 18 healthy male subjects given 20 mg pravastatin
and 0.2 mg digoxin concurrently for 9 days, the bioavailability parameters of digoxin
were not affected. The AUC of pravastatin tended to increase, but the overall
bioavailability of pravastatin plus its metabolites SQ 31,906 and SQ 31,945 was not
altered.
Cyclosporine: Some investigators have measured cyclosporine levels in patients on
pravastatin (up to 20 mg), and to date, these results indicate no clinically meaningful
elevations in cyclosporine levels. In one single-dose study, pravastatin levels were found
to be increased in cardiac transplant patients receiving cyclosporine.
Gemfibrozil: In a crossover study in 20 healthy male volunteers given concomitant
single doses of pravastatin and gemfibrozil, there was a significant decrease in urinary
excretion and protein binding of pravastatin. In addition, there was a significant increase
in AUC, Cmax, and Tmax for the pravastatin metabolite SQ 31,906. Combination therapy
with pravastatin and gemfibrozil is generally not recommended. (See WARNING:
Skeletal Muscle.)
In interaction studies with aspirin, antacids (1 hour prior to PRAVACHOL), cimetidine,
nicotinic acid, or probucol, no statistically significant differences in bioavailability were
seen when PRAVACHOL (pravastatin sodium) was administered.
Pravachol
Cholesterol
Liver enzymes
Drug interactions
Dosage and administration
Pharmacokinetics metabolism
Skeletal muscle
Clinical pharmacology