Gemfibrozil

Gemfibrozil is a Fibric acid derivative belonging to Antilipemic Agent.

Gemfibrozil is a lipid regulator that is used in the reduction of serum triglyceride levels in high-risk patients with hyperlipidemia.

Gemfibrozil is rapidly and completely absorbed from the GI tract. The bioavailability of Gemfibrozil is approximately 100%. The time to peak plasma concentration is within 1-2 hours. Gemfibrozil is 99% protein bound. It is 98.6% bound to serum albumin, 0.8% bound to erythrocytes, and 0.8% unbound. There is negligible binding to alpha-1-acid glycoprotein. The volume of distribution of gemfibrozil is estimated to be 0.8L/kg. Gemfibrozil is highly metabolized in the liver via oxidation into hydroxymethyl and carboxyl metabolites undergo enterohepatic recirculation. Gemfibrozil is mainly excreted via urine (approximately 70%, mainly as glucuronide conjugates and metabolites); feces (6%). The elimination half-life is about 1.5 hours.

Gemfibrozil shows common side effects like Headache, dizziness, diarrhea, sore throat, runny nose, sneezing, joint pain, etc.

Gemfibrozil is available in the form of an Oral Tablet.

Gemfibrozil is available in India, the US, the UK, Singapore, Canada, Russia, Japan, China, and Australia.

Gemfibrozil belongs to the Antilipemic Agent and acts as a Fibric acid derivative.

The exact mechanism of action of gemfibrozil is unknown, however, several theories exist regarding the VLDL effect; it can inhibit lipolysis and decrease subsequent hepatic fatty acid uptake as well as inhibit hepatic secretion of VLDL; together these actions decrease serum VLDL levels; increases HDL-cholesterol; the mechanism behind HDL elevation is currently unknown.

The Data on the onset of action of Gemfibrozil is not available.

The duration of action of Gemfibrozil is about 4-6 hours.

The Tmax of Gemfibrozil is approximately 1-2 hours.

Gemfibrozil is available in the form of Oral Tablet.

Gemfibrozil Tablet is taken orally, usually twice a day.

Gemfibrozil is used to reduce the level of bad cholesterol in the body. It is also used to lower the risk of complications of heart disease. Monitoring of cholesterol levels is necessary while receiving Gemfibrozil. Maintaining a proper diet and adopting lifestyle changes will provide an additive effect.

Gemfibrozil is a Fibric acid derivative belonging to Antilipemic Agent.

Gemfibrozil is a fibric acid derivative that decreases serum triglycerides and VLDL and increases HDL cholesterol. The exact mechanism of its action has not been fully established, but it has been shown to inhibit lipolysis of fat in adipose tissue and decrease hepatic fatty acid reuptake. It also inhibits the synthesis and increases the clearance of apolipoprotein B, a carrier molecule of VLDL.

Gemfibrozil is approved for use in the following clinical indications:

• Hyperlipidemia

Gemfibrozil is indicated to treat patients with Types IV and V hyperlipidemia who have elevated serum triglycerides (usually above 2000mg/dL), elevated VLDL cholesterol, fasting chylomicrons, are at risk of developing pancreatitis, and do not adequately respond to dietary restrictions. Gemfibrozil is also indicated to reduce the risk of developing coronary heart disease in patients with Type IIb hyperlipidemia without a history or symptoms of coronary heart disease; who do not adequately respond to weight loss, diet, exercise, and other medications; and who have low HDL, raised LDL, and raised triglycerides.

• Hyperlipidemia

Oral: 600 mg twice daily 30 minutes before breakfast and dinner.

Gemfibrozil is available in various strengths as 600mg.

Gemfibrozil is available in the form of an Oral Tablet.

• Dosage Adjustment in Kidney Patient

CrCl ≥60 mL/minute: No dosage adjustment is necessary.

CrCl 30 to <60 mL/minute: No dosage adjustment is likely necessary based on pharmacokinetic data; however, gemfibrozil is poorly tolerated in patients with CKD (eg, significantly more GI-related adverse effects) and increases in SCr have been reported. Monitor patients closely.

CrCl <30 mL/minute: Use is contraindicated in severe kidney impairment (CrCl not specified); however, if the use of gemfibrozil is deemed necessary, initiate at a dose of 600 mg once daily with close monitoring. If the response is inadequate and the risks outweigh the benefits, may consider increasing the dose with extreme caution; not exceeding 600 mg twice daily with frequent monitoring for adverse effects.

Avoid a high-fat, high-cholesterol diet.

Gemfibrozil is contraindicated in patients with

● Hepatic or severe renal dysfunction, including primary biliary cirrhosis.

● Pre-existing gallbladder disease.

● Hypersensitivity to gemfibrozil.

● Combination therapy of gemfibrozil with repaglinide.

• Muscle injury

Gemfibrozil is known to cause myopathy and elevates creatine phosphokinase levels. Any symptoms of muscle pain, tenderness, and weakness should be reported to the doctor. The treatment should be stopped if the symptoms worsen.

• Low blood cell count

Gemfibrozil is known to lower the blood cell count, especially white blood cells and red blood cells. This medicine should be used with caution in patients with existing blood disorders. Close monitoring of blood cell count is necessary during the first 12 months of the treatment.

• Myopathy/rhabdomyolysis

Has been associated with rare myositis or rhabdomyolysis; patients should be monitored closely. Patients should be instructed to report unexplained muscle pain, tenderness, weakness, or brown urine.

• Hematologic effects

May cause mild decreases in hemoglobin, hematocrit, and WBC upon initiation which usually stabilizes with long-term therapy. Anemia, leukopenia, thrombocytopenia, and bone marrow hypoplasia have rarely been reported. Periodic monitoring is recommended during the first year of therapy.

It is not known whether Gemfibrozil is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Gemfibrozil is administered to a nursing mother.

Gemfibrozil crosses the placenta. Triglyceride concentrations increase during pregnancy as required for normal fetal development. When increases are greater than expected, supervised dietary intervention should be initiated. In women who develop very severe hypertriglyceridemia and are at risk for pancreatitis, the use of gemfibrozil beginning in the second trimester is one intervention that may be considered.

Avoid a high-fat, high-cholesterol diet.

• Common Adverse effects

Dyspepsia, Abdominal pain, Atrial fibrillation, Diarrhea, Fatigue, Eczema, Rash, Vertigo, Constipation, and Headache.

• Rare Adverse effects

Myalgia, Rhabdomyolysis (especially with the admin with a statin), Acute appendicitis, Cholelithiasis, Angioedema, Hypokalemia, Eosinophilia, Myopathy, Synovitis, Taste disturbance, Xerostomia, Flatulence, Rash.

• HMG-CoA reductase inhibitors

The risk of myopathy and rhabdomyolysis is increased with combined gemfibrozil and HMG-CoA reductase inhibitor therapy. Myopathy or rhabdomyolysis with or without acute renal failure has been reported as early as three weeks after initiation of combined therapy or after several months (see WARNINGS). There is no assurance that periodic monitoring of creatine kinase will prevent the occurrence of severe myopathy and kidney damage.

• Anticoagulants

caution should be exercised when anticoagulants are given in conjunction with Gemfibrozil. the dosage of the anticoagulant should be reduced to maintain the prothrombin time at the desired level to prevent bleeding complications. frequent prothrombin determinations are advisable until it has been definitely determined that the prothrombin level has stabilized.

• Repaglinide

In healthy volunteers, co-administration with gemfibrozil increased the plasma concentration of repaglinide and prolonged its hypoglycemic effects. Coadministration of gemfibrozil and repaglinide increases the risk for severe hypoglycemia and is contraindicated.

• CYP2C8 Substrates

Gemfibrozil is a strong inhibitor of CYP2C8 and may increase the exposure of drugs mainly metabolized by CYP2C8 (e.g., dabrafenib, enzalutamide, loperamide, montelukast, paclitaxel, pioglitazone, rosiglitazone). Therefore, dosing reduction of drugs that are mainly metabolized by CYP2C8 enzyme may be required when gemfibrozil is used concomitantly

• Dasabuvir

Co-administration of gemfibrozil with dasabuvir increased dasabuvir AUC and Cmax (ratios: 11.3 and 2.01, respectively) due to CYP2C8 inhibition. Increased dasabuvir exposure may increase the risk of QT prolongation, therefore, co-administration of gemfibrozil with dasabuvir is contraindicated.

• Selexipag

Co-administration of gemfibrozil with selexipag doubled exposure to selexipag and increased exposure to the active metabolite by approximately 11-fold. Concomitant administration of gemfibrozil with selexipag is contraindicated.

• Enzalutamide

In healthy volunteers given a single 160 mg dose of enzalutamide after gemfibrozil 600 mg twice daily, the AUC of enzalutamide plus active metabolite (N-desmethyl enzalutamide) was increased by 2.2fold and corresponding Cmax was decreased by 16%. Increased enzalutamide exposure may increase the risk of seizures. If co-administration is considered necessary, the dose of enzalutamide should be reduced.

• OATP1B1 Substrates

Gemfibrozil is an inhibitor of OATP1B1 transporter and may increase the exposure to drugs that are substrates of OATP1B1 (e.g., atrasentan, atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide, SN-38 [active metabolite of irinotecan], rosuvastatin, pitavastatin, pravastatin, rifampin, valsartan, olmesartan). Therefore, dosing reductions of drugs that are substrates of OATP1B1 may be required when gemfibrozil is used concomitantly. Combination therapy of gemfibrozil with simvastatin or with repaglinide, which is an OATP1B1 substrate, is contraindicated

The common side effects of Gemfibrozil include the following

Common

• Stomach pain, heartburn.

Rare

• Muscle pain, tenderness, weakness, blurred vision.

• Pregnancy

Pregnancy Category C

Gemfibrozil has been shown to produce adverse effects in rats and rabbits at doses between 0.5 and 3 times the human dose (based on surface area). There are no adequate and well-controlled studies on pregnant women. Gemfibrozil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Administration of Gemfibrozil to female rats at 2 times the human dose (based on surface area) before and throughout gestation caused a dose-related decrease in conception rate, an increase in stillborns, and a slight reduction in pup weight during lactation. There were also dose-related increased skeletal variations. Anophthalmia occurred, but rarely. Administration of 0.6 and 2 times the human dose (based on surface area) of Gemfibrozil to female rats from gestation day 15 through weaning caused dose-related decreases in birth weight and suppressions of pup growth during lactation. Administration of 1 and 3 times the human dose (based on surface area) of Gemfibrozil to female rabbits during organogenesis caused a dose-related decrease in litter size and, at the high dose, an increased incidence of parietal bone variations.

• Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for Gemfibrozil in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, considering the importance of the drug to the mother.

• Pediatric Use

As per FDA, the safety and efficacy in pediatric patients have not been established.

Symptoms: Abdominal pain, cramps, abnormal LFT, diarrhea, increased creatine phosphokinase (CPK), joint and muscle pain, nausea, and vomiting.

Management: Symptomatic and supportive treatment. In acute overdosage, perform gastric lavage immediately.

Pharmacodynamic

Gemfibrozil alters lipid metabolism to treat patients with hyperlipidemia. The duration of action requires twice daily dosing as the mean residence time of gemfibrozil is up to 9.6h in patients with chronic renal failure. Gemfibrozil has a wide therapeutic index as trials with twice the standard dose were not associated with severe side effects. Patients taking gemfibrozil may be at an increased risk of developing cholelithiasis and cholecystitis, as seen in patients taking clofibrate.

Pharmacokinetics

• Absorption

Gemfibrozil is rapidly and completely absorbed from the GI tract. The bioavailability of Gemfibrozil is approximately 100%. The time to peak plasma concentration within 1-2 hours.

• Distribution

Gemfibrozil is 99% protein bound. It is 98.6% bound to serum albumin, 0.8% bound to erythrocytes, and 0.8% unbound. There is negligible binding to alpha-1-acid glycoprotein. The volume of distribution of gemfibrozil is estimated to be 0.8L/kg.

• Metabolism and Excretion

Gemfibrozil is highly metabolized in the liver via oxidation into hydroxymethyl and carboxyl metabolites undergo enterohepatic recirculation. Gemfibrozil is mainly excreted via urine (approximately 70%, mainly as glucuronide conjugates and metabolites); feces (6%). The elimination half-life is about 1.5 hours.

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