Drug Toxicity and Interactions of Combined Therapy

Summary of manufacturers’ recommendations when prescribing statins together with fibrates (and fibrates with statins)*

Treatment / Recommendations
Statin
Atorvastatin / “The risk of myopathy during concomitant treatment [with concurrent fibric acid derivatives and other agents] is increased. Physicians contemplating such treatment should carefully weight the potential benefits and risks and should carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Lower starting and maintenance doses of atorvastatin should be considered…Periodic [CK] determinations may be considered in such situations, but there is not assurance that such monitoring will prevent…severe myopathy.”
Fluvastatin/FL
Extended release / “The risk of myopathy and/or rhabdomyolysis during treatment with [statins] has been reported to be increased if therapy with [gemfibrozil and other agents] is administered concurrently. Concomitant therapy with [statins] and [GF] is generally not recommended. There is no change in either fluvastatin (20 mg) or gemfibrozil (600 mg b.i.d.) levels when coadministered.
Lovastatin / Combination therapy with GF should be avoided unless the benefits outweigh the risks.
Maximum daily dose of lovastatin + fibrates = 20 mg
Pravastatin / “Combination therapy with pravastatin and GF is generally not recommended.”
Rosuvastatin / “The risk of skeletal muscle effects may be enhanced when [rosuvastatin] is used in combination with [niacin or] fenofibrate…Combination therapy with [rosuvastatin and] GF should be avoided.
Maximum daily dose of rosuvastatin + GF = 10 mg
Simvastatin / “The benefits of the combined use of simvastatin with the following drugs should be carefully weighed against the potential risks of combinations: [gemfibrozil or other fibrates].”
Maximum daily dose of simvastatin + GF = 10 mg
Fibrate
Fenofibrate (FF) / “The combined use of [FF] and [statins] should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination.” In healthy adults, multiple-dose FF 145 mg + AT 20 x 10 d ↓AT AUC by 17%. Single-dose FF 145 mg + FL 40 mg ↑AUC active enantiomer of FL by 15%-16%. Multiple-dose FF 145 mg + PR 40 mg x 10 d ↑PR AUC by 28% and ↑3α-iso-PR AUC by 39%. AT, FL, or PR have minimal effects on FF pharmacokinetics.
Gemfibrozil (GF) / “The risk of myopathy and rhabdomyolysis is increased with combined [GF] and [statin] therapy…as early as 3 weeks after initiation of combined therapy or after several months. There is no assurance that periodic monitoring of [CK] will prevent the occurrence of severe myopathy and kidney damage.”
Fenofibric acid / “Myopathy and rhabdomyolysis have been reported in patients taking fenofibrate. The risks [of these] are increased when co-administered with a statin (with a significantly higher rate observed with gemfibrozil), particularly in patients with diabetes, renal failure, or hypothyroidism. Fenofibric acid may be co-administered with [a statin, but]....coadministration with maximal-dose statins has not been evaluated in clinical studies and should be avoided [unless expected benefits outweigh risks]. “Fenofibric acid should be avoided in patients with severe renal impairment, and dose selection for the elderly should be made on the basis of renal function. The use of [fenofibric acid] has not been evaluated in subjects with hepatic impairment.”

*Text from package inserts. Package insert information can be found in Physicians’ Desk Reference, 62nd Edn (Thomson Healthcare Inc, Montvale, NJ, 2008).