Fibrates: The use of fibrates alone is occasionally associated with myopathy. An increased risk of muscle related adverse events, including rhabdomyolysis, have been reported when fibrates are co-administered with other statins. These adverse events with pravastatin cannot be excluded; therefore the combined use of pravastatin and fibrates (e.g. gemfibrozil, fenofibrate) should generally be avoided (see Precautions). If this combination is considered necessary, careful clinical and CK monitoring of patients on such regimen is required.
Colestyramine/Colestipol: Concomitant administration resulted in approximately 40 to 50% decrease in the bioavailability of pravastatin. There was no clinically significant decrease in bioavailability or therapeutic effect when pravastatin was administered one hour before or four hours after colestyramine or one hour before colestipol (see Dosage & Administration).
Ciclosporin: Concomitant administration of pravastatin and ciclosporin leads to an approximately 4-fold increase in pravastatin systemic exposure. In some patients, however, the increase in pravastatin exposure may be larger. Clinical and biochemical monitoring of patients receiving this combination is recommended (see Dosage & Administration).
Fusidic acid: The risk of myopathy including rhabdomyolysis may be increased by the concomitant administration of systemic fusidic acid with statins. The mechanism of this interaction (whether it is pharmacodynamic or pharmacokinetic, or both) is yet unknown. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination.
If treatment with systemic fusidic acid is necessary, pravastatin treatment should be discontinued throughout the duration of the fusidic acid treatment. Also see Precautions.
Vitamin K antagonists: As with other HMG-CoA reductase inhibitors, the initiation of treatment or dose up-titration of pravastatin in patients treated concomitantly with vitamin K antagonists (e.g. warfarin or another coumarin anticoagulant) may result in an increase in International Normalised Ratio (INR). Discontinuation or down-titration of pravastatin may result in a decrease in INR. In such situations, appropriate monitoring of INR is needed.
Macrolides: Macrolides have the potential to increase statin exposure while used in combination. Pravastatin should be used cautiously with macrolide antibiotics (e.g. erythromycin, clarithromycin, roxithromycin) due to potential increased risk of myopathies.
In one of two interaction studies with pravastatin and erythromycin a statistically significant increase in pravastatin AUC (70%) and Cmax (121%) was observed. In a similar study with clarithromycin a statistically significant increase in AUC (110%) and Cmax (127%) was observed. Although these changes were minor, caution should be exercised when associating pravastatin with erythromycin or clarithromycin.
Colchicine: Precaution for use: Due to the increased risk of myopathy/rhabdomyolysis, clinical and biological monitoring is advised, especially when starting association between pravastatin and colchicine.
Nicotinic acid: The risk of muscle toxicity is increased when statins are administered concomitantly with nicotinic acid. In one study, Chinese patients taking nicotinic acid plus laropiprant concomitantly with simvastatin were reported to have a higher incidence of myopathy and rhabdomyolysis compared to Caucasians.
Rifampicin: In an interaction study where pravastatin was given together with rifampicin, a nearby 3-fold increase in pravastatin AUC and Cmax was observed. Therefore, caution should be exercised when combining pravastatin to rifampicin if both are given at the same time. No interaction would be expected if their dosing is made apart at least two hours.
Lenalidomide: There is an increased risk of rhabdomyolysis when statins are combined to lenalidomide. A reinforced clinical and biological monitoring is warranted notably during the first weeks of treatment.
Products metabolised by cytochrome P450: Pravastatin is not metabolised to a clinically significant extent by the cytochrome P450 system. This is why products that are metabolised by, or inhibitors of, the cytochrome P450 system can be added to a stable regimen of pravastatin without causing significant changes in the plasma levels of pravastatin, as have been seen with other statins. The absence of a significant pharmacokinetic interaction with pravastatin has been specifically demonstrated for several products, particularly those that are substrates/inhibitors of CYP3A4, e.g. diltiazem, verapamil, itraconazole, ketoconazole, protease inhibitors, grapefruit juice and CYP2C9 inhibitors (e.g. fluconazole).
Other products: In interaction studies, no statistically significant differences in bioavailability were observed when pravastatin was administered with acetylsalicylic acid, antacids (when given one hour prior to pravastatin), nicotinic acid or probucol.