Gemfibrozil

Gemfibrozil is a fibrate that lowers triglycerides by 30% to 50% and raises HDL cholesterol by 10% to 20%. It is used for severe hypertriglyceridaemia to prevent pancreatitis and for mixed dyslipidaemia. It markedly raises the levels of many statins and of repaglinide, so it is dangerous with statins and has largely been replaced by fenofibrate for combined therapy. It is widely available and cheap in East Africa.

Classification. Fibrate; PPAR alpha agonist.

Mechanism. 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. Well absorbed; food lowers absorption slightly. Half life about 1.5 hours. Metabolised to glucuronide conjugates, which inhibit statin glucuronidation and the OATP1B1 transporter. Excreted in urine (about 70%). Protein binding 95%.

Severe hypertriglyceridaemia and mixed dyslipidaemia, adult. 600 mg twice daily, taken 30 minutes before the morning and evening meals (some labels allow 900 mg once daily, 30 minutes before the evening meal); maximum 1200 mg daily.

Prevention of coronary events in men with low HDL, adult (specialist). 600 mg twice daily.

Kidney impairment. Creatinine clearance 30 to 50 mL/min: start 900 mg daily and monitor; under 30 mL/min: avoid.

Children. Not advised.

Liver impairment. Contraindicated.

Contraindications. Concurrent statins (avoid), repaglinide, dasabuvir and selexipag; severe kidney impairment (creatinine clearance under 15 mL/min); active liver disease or unexplained persistent rise in transaminases; gallbladder disease; pregnancy and breastfeeding; hypersensitivity.

Warnings. Myopathy and rhabdomyolysis (higher with statins and in kidney impairment); gallstones; pancreatitis; raised liver enzymes; anaemia and leucopenia (check the blood count); hypoglycaemia in people on repaglinide or sulphonylureas; check lipids after starting.

Adverse effects. Dyspepsia, abdominal pain, nausea, diarrhoea, rash, headache, dizziness, raised liver enzymes.

Interactions. Statins: sharply raised levels and rhabdomyolysis, so avoid (if a statin is essential, use pravastatin or low dose fluvastatin with great care). Repaglinide: contraindicated (severe hypoglycaemia). Rosuvastatin: cap at 10 mg. Warfarin: raised INR, so reduce the warfarin dose. Ezetimibe: gallstone risk. Sulphonylureas, insulin: hypoglycaemia. Colestyramine: give gemfibrozil 2 hours before or 4 hours after.

Special groups.

• Pregnancy: avoid.

• Breastfeeding: avoid.

• Patients of African ancestry: no dose change.

• Older adults: monitor for muscle symptoms and adjust for kidney function.

• Kidney impairment: avoid when creatinine clearance is under 30 mL/min.

• Liver impairment: contraindicated.

Formulations. Tablets 600 mg and 900 mg.

Administration. Oral 30 minutes before meals.

Baseline. Lipid profile, alanine aminotransferase, creatinine, full blood count, gallbladder history, creatine kinase if muscle symptoms, a full list of other medicines, pregnancy status.

Monitoring. Lipid profile at 4 to 8 weeks, then every 3 to 6 months. Alanine aminotransferase and full blood count at 3 months, then every 6 to 12 months. Creatinine yearly. Muscle symptoms.

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

Common prescribing errors. Combining with a statin; combining with repaglinide; not reducing warfarin; taking it after a meal; using it in severe kidney impairment.