Medications> Dyslipidemia>

INDICATIONS

• Hypertriglyceridemia: To prevent cardiovascular disease and events (Buse)
• Mixed dyslipidemia: To prevent cardiovascular disease and events (Buse)

• Prevention of acute pancreatitis secondary to severe hypertriglyceridemia

MECHANISM

• Activation of PPAR alpha reduces the synthesis of apo AIII, an inhibitor of the action of lipoprotein lipase (van Dijk), the enzyme that breaks down circulating triglycerides. (Hertz)
• Activation of PPAR alpha also stimulates the formation of apoAV, which lowers blood levels of triglycerides. (Prieur)

USUAL ADULT DOSING

• Fenofibrate (Tricor) 48 to 145 mg daily
• Fenofibrate (Fenoglide) 20 to 120 mg daily
• Fenofibrate, micronized (Antara, Lofibra): Antara 43 to 130 mg daily; Lofibra 67 to 200 mg daily; Tripilix 45 to 135 mg daily. Administer with food.
• Gemfibrozil (Lopid) 120 mg twice daily
• Start with maximal dose in patients with triglycerides > 500 mg/dL
• In others, dose titrations are based on patient responses when assessed at the end of 4 to 6 weeks.

FORMS

*Prices represent cost per unit specified and are representative of "Average Wholesale Price" (AWP). AWP Prices were obtained and gathered by Lakshmi Vasist Pharm D using the Red Book, manufacturer's information, and the McKesson database.

^Dosage is indicated in mg unless otherwise noted.

DOSING IN SPECIAL POPULATIONS

• Contraindicated with severe renal disease (GFR < 30 mL/min) or on dialysis
• Reduce dose with moderate renal disease, GFR between 30 and 60 mL/min

• Contraindicated for active liver disease or primary biliary cirrhosis

• Category C

• Contraindicated

ADVERSE DRUG REACTIONS

• Major concern is development of severe myositis and rhabdomyolysis when used in combination with a statin.

• There are no common side effects.

• Abnormal liver function tests
• Abdominal pain
• Upset stomach
• Myositis
• Headache, dizziness

• Severe myositis, rabdomyolysis, and renal failure when used in combination with a statin.
• Gallstones
• Bone marrow suppression

DRUG INTERACTIONS

• Statins: may increase risk of rhabdomyolysis. Monitor for sign and symptoms of rhabdomyolysis. Gemfibrozil increases rosuvastatin AUC by 90% (use fenofibrate with rosuvastatin).
• Warfarin: may increase INR. Monitor closely with co-administration.
• Bile acid sequestrants can reduce fibrate absorption. Fibrates should be taken 1 hour before or 4 to 6 hours after a sequestrant.
• Glyburide: case report of increased hypoglycemic effect with glyburide and gemfibrozil co-administration. Use with close monitoring.
• Repaglinide: gemfibrozil increased repaglinide serum concentrations 8.1-fold increase; therefore, co-administration is contraindicated. No significant interaction between fenofibrate and repaglinide.
• Pioglitazone and rosiglitazine: co-administration with fibric acid derivatives may increase hypoglycemic effect. Gemfibrozil increases pioglitazone and rosiglitazone AUC by 226% and 130%, respectively.
• Ursodiol: efficacy may be decreased.

PHARMACOKINETIC

COMMENTS

• Fibrates lower triglycerides by 25 to 50% and raise HDL cholesterol by about 8%, but may raise LDL cholesterol in patients with triglycerides > 500 mg/dL.
• Severe myositis occurs most commonly when a fibrate is taken in combination with a statin.
• The risk of myositis is greater with gemfibrozil than with fenofibrate.
• When triglyceride levels are between 200 and 500 mg/dL and LDL is elevated, begin treatment with a statin. If triglycerides are still greater than 200 mg/dL, consider adding fenofibrate. The target is a non-HDL cholesterol <100 mg/dL (non HDL cholesterol = total cholesterol - HDL cholesterol. (Expert panel ...)
• Fibrates can be used as monotherapy in patients with normal LDL cholesterol and triglycerides between 200 and 500 mg/dL and in patients with triglycerides > 500 mg/dL. (Expert panel ...)
• Fenofibrate has not been shown to reduce coronary heart disease mortality or morbidity in a large trial of patients with type 2 diabetes. (Keech)
• Fenofibrate lowers the incidence of laser treatment for diabetic retinopathy. (Keech)
• Weight loss and improved glycemic control lower triglyceride levels and should always be attempted before and during treatment with a fibrate.
• Recent RCT (ACCORD) tested effect of fenofibrate added to simvastatin in 5,518 people with diabetes at high risk for cardiovascular events. LDL-cholesterol was low (about 80 mg/dl) in both fenofibrate and placebo groups, and fenofibrate had no additional benefit to simvastatin alone (Ginsberg).

REFERENCES

RELATED MODULES

• Elderly and Diabetes