Fenofibrate

Fenofibrate is a fibrate prodrug that lowers triglycerides by 30% to 50%, raises HDL cholesterol by 5% to 20%, and lowers LDL cholesterol modestly.

It is used for severe hypertriglyceridaemia to prevent pancreatitis, and for mixed dyslipidaemia with low HDL cholesterol in people with diabetes. It has little effect on heart attacks when added to statins in most patients.

It raises serum creatinine without harming the kidney, and it interacts with warfarin. It is less likely to cause myopathy with statins than gemfibrozil is. It is available in East Africa in a few formulations.

Classification. Fibrate; PPAR alpha agonist.

Mechanism. The active fenofibric acid activates the nuclear receptor PPAR alpha, which raises lipoprotein lipase activity and lowers apolipoprotein C-III, speeding clearance of triglyceride rich particles and reducing hepatic VLDL production.

Pharmacodynamics. Triglycerides fall within 1 to 2 weeks; the full effect takes 4 to 8 weeks.

Pharmacokinetics. Absorption is much better with food. Half life about 20 hours (fenofibric acid). Excreted mainly in urine (about 60%) as glucuronides, so it builds up in kidney impairment. Protein binding 99%.

Severe hypertriglyceridaemia and mixed dyslipidaemia, adult.

• Micronised capsules 200 mg once daily with a meal.

• Or nanocrystal tablets 145 mg once daily, or 160 mg tablets once daily (with or without food).

• Maximum 200 mg micronised daily (or 145 mg or 160 mg).

Kidney impairment. Creatinine clearance 30 to 59 mL/min: micronised 67 mg once daily or nanocrystal 48 mg once daily; contraindicated when creatinine clearance is under 30 mL/min.

Children. Not advised.

Liver impairment. Contraindicated.

Contraindications. Severe kidney impairment (creatinine clearance under 30 mL/min) and dialysis; active liver disease or unexplained persistent rise in transaminases; gallbladder disease; chronic or acute pancreatitis (except pancreatitis due to severe hypertriglyceridaemia); photosensitivity or phototoxicity with ketoprofen; pregnancy and breastfeeding; hypersensitivity.

Warnings. Raised creatinine (reversible, about 10% to 15%); gallstones; pancreatitis; raised liver enzymes; myopathy and rhabdomyolysis (risk higher with statins and in kidney impairment); venous thromboembolism; raised homocysteine; check lipids after starting.

Adverse effects. Abdominal pain, nausea, diarrhoea, raised liver enzymes, raised creatinine, rash, muscle aches, headache.

Interactions. Warfarin: raised INR, so reduce the warfarin dose by about a third and check the INR weekly. Statins: raised myopathy risk, lower than with gemfibrozil; start low and use fenofibrate rather than gemfibrozil. Ciclosporin: kidney toxicity. Colestyramine: give fenofibrate at least 1 hour before or 4 to 6 hours after. Sulphonylureas and insulin: lower blood glucose. Ketoprofen: photosensitivity.

Special groups.

• Pregnancy: avoid.

• Breastfeeding: avoid.

• Patients of African ancestry: no dose change.

• Older adults: adjust for kidney function.

• Kidney impairment: creatinine clearance 30 to 59 mL/min: reduce to micronised 67 mg or nanocrystal 48 mg once daily; under 30 mL/min: contraindicated.

• Liver impairment: contraindicated.

Formulations. Micronised capsules 67, 134, 200 mg; nanocrystal tablets 48, 145 mg; tablets 160 mg.

Administration. Oral once daily. Take micronised capsules with a meal. Swallow whole.

Baseline. Lipid profile, alanine aminotransferase, creatinine, creatine kinase if on a statin, gallbladder history, INR if on warfarin, pregnancy status.

Monitoring. Lipid profile at 4 to 8 weeks, then every 3 to 6 months. Alanine aminotransferase at baseline, every 3 months in the first year, then yearly. Creatinine at baseline, at 3 months and then every 6 months. INR weekly after starting if on warfarin. Muscle symptoms.

Stopping. Stop if triglycerides do not fall after 3 months of full dose, for pancreatitis, gallstones, persistent transaminase rise above 3 times the upper limit of normal, rhabdomyolysis, or pregnancy.

Common prescribing errors. Using it when creatinine clearance is under 30 mL/min; not reducing the warfarin dose; taking micronised capsules on an empty stomach; adding to a statin at a high dose without a creatine kinase plan; confusing formulation doses.