Gemfibrozil

Uses

Gemfibrozil is used as a hypolipidemic agent in conjunction with dietary modification. It is recommended in the treatment of type IIa, type IIb, type III, type IV and type V hyperlipoproteinemia.

Gemfibrozil is also used to associated treatment for these conditions: Coronary Heart Disease (CHD), Fredrickson classification type IV Hyperlipidemia, Fredrickson classification type V Hyperlipidemia

How Gemfibrozil works

Gemfibrozil activates peroxisome proliferator-activated receptor-α (PPARα), which alters lipid metabolism. This activation leads to increased HDL, apo AI, apo AII, lipoprotein lipase (LPL), inhibition of apo B synthesis, peripheral lipolysis, decreased removal of free fatty acids by the liver, and increased clearance of apoB.

Upregulated LPL reduces plasma triglyceride levels. Decreased hepatic removal of fatty acids decreases the production of triglycerides. The effects on apoB synthesis and clearance decrease VLDL production which also reduce plasma triglyceride levels.

Gemfibrozil's glucuronide metabolite is also an inhibitor of CYP2C8.

Dosage

Gemfibrozil dosage

The usual dose by mouth is 1.2 gm daily in 2 divided doses given 30 minutes before morning and evening meal. The dosage range may vary between 0.9-1.5 gm daily or as directed by the physician.

Side Effects

The most frequent adverse effect involves the G. I. Tract. Abdominal pain and epigastric pain or dyspepsia is common adverse G. I. effects. Other adverse reaction includes pruritus, rash, headache, dizziness, blurred vision, painful extremities and rarely myalgia.

Toxicity

The oral TDLO of gemfibrozil in humans is 18gm/kg/3Y. The oral LD₅₀ in mice is 2218mg/kg and in rats is 1414mg/kg. The intraperitoneal LD₅₀ in rats is 445mg/kg.

Patients experiencing an overdose may present with abdominal cramps, adnormal liver function tests, diarrhea, increased CPK, joint and muscle pain, nausea, and vomiting. Patients should be treated with symptomatic and supportive measures.

Precaution

Causes of secondary hyperlipidaemia such as hypothyroidism and diabetes must be treated before initiating therapy. Renal impairment; blood disorders. Periodic monitoring of the serum lipids should be done; if no adequate response after 3 mth, treatment should be withdrawn. May increase risk of cholelithiasis.

Interaction

Concomitant anticoagulant dosage may need to be reduced and frequent determinations of prothrombin carried out to confirm that the desired prothrombin level has been re-established. There have been reports of severe myositis with marked elevation of creatinine kinase and myoglobinuria when Gemfibrozil and lovastatin were used concomitantly. In most subjects who have had an unsatisfactory lipid response to either drug alone, the possible benefit of combined therapy with lovastatin and Gemfibrozil does not outweigh the risks of severe myopathy, rhabdomyolysis and acute renal failure.

Food Interaction

• Take before a meal. Take 30 minutes before meals.

Gemfibrozil Cholesterol interaction

[Major] There have been reports of severe decreases in HDL cholesterol (HDL-C) levels (as low as 2 mg

The decrease has been reported to occur within 2 weeks to years after initiation of therapy.

It is recommended that HDL-C levels be checked within the first few months after initiation therapy and if a severely depressed HDL-C level is detected, therapy with these agents should be withdrawn.

Monitor HDL-C level until it has returned to baseline, and therapy with these agents should not be re-initiated in these patients.

Gemfibrozil Drug Interaction

Major: rosuvastatin, rosuvastatinUnknown: aspirin, aspirin, duloxetine, duloxetine, omega-3 polyunsaturated fatty acids, omega-3 polyunsaturated fatty acids, pregabalin, pregabalin, metoprolol, metoprolol, metoprolol, metoprolol, cyanocobalamin, cyanocobalamin, ascorbic acid, ascorbic acid, cholecalciferol, cholecalciferol

Gemfibrozil Disease Interaction

Major: biliary cirrhosis, cholelithiasis, HDL cholesterol, rhabdomyolysis, liver disease, renal dysfunctionModerate: hematological changes

Volume of Distribution

The volume of distribution of gemfibrozil is estimated to be 0.8L/kg.

Elimination Route

Gemfibrozil is absorbed from the gastrointestinal tract.

In healthy volunteers, a 900mg oral dose of gemfibrozil has a C_max of 46±16µg/mL with a T_max of 2.2±1.1h. In patients with chronic renal failure, gemfibrozil has a C_max of 13.8±11.1µg/mL with a T_max of 2.3±1.0h. In patients with liver disease, gemfibrozil has a C_max of 23.0±10.3µg/mL with a T_max of 2.6±1.7h.

Half Life

Gemfibrozil has a plasma half-life of 1.5 hours. In patients with renal failure the half life is 2.4h and in patients with liver disease the half life is 2.1h.

Clearance

The clearance of gemfibrozil is estimated to be 6.0L/h.

Elimination Route

Approximately 70% of a dose of gemfibrozil is eliminated in the urine. The majority of a dose is eliminated as a glucuronide conjugate and 11 6% of a dose is eliminated in the feces.

In healthy volunteers, 0.02-0.15% of a dose was detected in the urine as unmetabolized gemfibrozil, with 7-14% detected as conjugated metabolites. In patients with renal failure, trace amounts of unmetabolized gemfibrozil is present in the urine, with 0.5-9.8% detected as conjugated metabolites. In patients with liver disease, 0.1-0.2% of a dose was detected in the urine as unmetabolized gemfibrozil, with 25-50% detected as conjugated metabolites.

Pregnancy & Breastfeeding use

Safe use in human pregnancy has not been established. It is not known whether gemfibrozil is secreted in human milk. Like most drugs, gemfibrozil should normally be avoided during pregnancy and lactation.

Contraindication

Hypersensitivity. Severe hepatic or renal dysfunction; gall stones; neonates, children, pregnancy, lactation.

Storage Condition

It should be stored in a dry place at room temperature.

Innovators Monograph

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