Continuing Education Activity

Gemfibrozil is an FDA-approved fibric acid agent (fibrate) to manage hypertriglyceridemia (particularly in type IV and V hyperlipidemia). Diet and exercise constitute the first-line treatment for mild and moderate hypertriglyceridemia. However, patients with no adequate therapeutic response to dietary measurements will benefit from the initiation of this medication. Very high levels of triglycerides represent a risk factor for the development of acute pancreatitis. Gemfibrozil is a useful medication for the reduction of triglycerides in patients with very high triglycerides serum levels. This drug is also approved for decreasing the risk of developing coronary heart disease (Type IIb), particularly in patients without a history of subsisting coronary heart disease symptoms. This activity outlines the indications, contraindications, interactions, monitoring, and other therapeutic information pertinent to members of the interprofessional healthcare team caring for patients with hyperlipidemia (particularly hypertriglyceridemia) with gemfibrozil.

Objectives:

• Identify the mechanism of action of gemfibrozil.
• Describe the adverse effects of gemfibrozil.
• Review the toxicity of gemfibrozil.
• Summarize interprofessional team strategies for improving care coordination and communication to advance gemfibrozil and improve outcomes.

Indications

Gemfibrozil is an FDA-approved fibric acid agent (fibrate) to manage hypertriglyceridemia (particularly in type IV and V hyperlipidemia). Diet and exercise constitute the first-line treatment for mild and moderate hypertriglyceridemia. However, patients with no adequate therapeutic response to dietary measurements will benefit from the initiation of this medication. Very high levels of triglycerides represent a risk factor for the development of acute pancreatitis. Gemfibrozil is a useful medication for the reduction of triglycerides in patients with very high serum triglycerides levels.

This drug is also approved for decreasing the risk of developing coronary heart disease (Type IIb), particularly in patients without a history of subsisting coronary heart disease symptoms. In addition, gemfibrozil also provides a beneficial effect on patients with an inadequate response to weight loss, dietary treatment, exercise, and other medications (such as bile acid sequestrants and nicotinic acid, well known to decrease LDL-and increase HDL-cholesterol), and in individuals with a lipid profile consisting of low HDL-cholesterol levels, elevated LDL-cholesterol and elevated triglycerides.

It is recommended to investigate and rule out secondary causes of hyperlipidemia before beginning gemfibrozil therapy. Administration for two to three months is necessary before evaluating efficacy. Treatment discontinuation is recommended if there is an inadequate response within two to three months of receiving gemfibrozil therapy.

Clinicians have also used gemfibrozil under an orphan designation for the treatment of neuronal ceroid lipofuscinoses. According to recent clinical trials, gemfibrozil can be used safely and with potential efficacy as a supportive treatment for children with late neuronal ceroid lipofuscinoses and other lipid storage diseases. It also has been reported to increase longevity in mouse models of late infantile neuronal ceroid lipofuscinoses.[1][2][3]

Mechanism of Action

The mechanism of action of gemfibrozil implies activation of the peroxisome proliferator-activated receptor-alpha (PPAR-alpha), generating changes in the lipid metabolism, consequently decreasing plasmatic triglyceride levels and increasing high-density lipoprotein (HDL). The PPAR-alpha produces up-regulation of the lipoprotein lipase (LPL) in the adipose tissue and muscle, leading to a reduction of the triglyceride levels. Gemfibrozil can inhibit peripheral lipolysis and decrease the hepatic removal of free fatty acids, consequently reducing hepatic triglyceride production. Gemfibrozil inhibits the synthesis and increases the clearance of very-low-density lipoprotein (VLDL) carrier apolipoprotein B, leading to decreased VLDL production. The reduction in VLDL can cause plasma triglyceride levels to decrease by 30% to 60%. It may also increase HDL-cholesterol by an unknown mechanism.[4][5][6]

Pharmacokinetics

Gemfibrozil is given orally, in two divided doses, nearly 30 minutes before breakfast or dinner. Gemfibrozil is mostly protein-bound (99%). It is metabolized hepatically into inactive metabolites, and it is excreted in the urine (70%) and feces (6%). The drug's half-life is approximately 1.5 hours, with a peak serum time of roughly 1 to 2 hours.

Administration

Dosage

Gemfibrozil is available in 600 mg oral tablets. The recommended dose for hypertriglyceridemia is 600 mg orally every 12 hours. It is recommended to take the medication 30 minutes before morning and evening meals. According to the manufacturer's prescribing information maximum recommended dose for adults is 1200 mg per day. If the therapeutic response to gemfibrozil is incompetent after three months of treatment, it is recommended to suspend gemfibrozil.

Specific Patient Population

Patients with Renal Impairment or Hepatic Impairment: In mild to moderate renal impairment, it is recommended to use this drug with caution if the baseline creatinine is higher than 2 mg/dL. There were cases reported for deterioration of renal function in some patients. This medication is contraindicated in patients with hepatic impairment and severe renal impairment.[7][8][9][10][11]Pregnant Women: Gemfibrozil is pregnancy category C. It is suggested to use it with caution. Consider usage if benefits exceed risks.

Breastfeeding Women: There is no relevant literature on the use of gemfibrozil in breastfeeding women. It is unknown whether gemfibrozil is excreted in human milk, and there is a concern about disrupting infant lipid metabolism with the maternal use of gemfibrozil. Since many drugs are excreted in milk and the potential for tumorigenicity of gemfibrozil in animal trials, it should be avoided during breastfeeding. An alternate drug is preferred if a woman is planning to breastfeed especially preterm infants or newborns. If needed to continue gemfibrozil, breastfeeding should be discouraged.[12]Dose Modification: Simultaneous administration of gemfibrozil with bile acid resin binding agents reduces the body exposure to the drug after administration of a dose by roughly 30%. Gemfibrozil represses CYP2C8 enzyme action; may enhance the presentation of CYP2C8 substrates. Analyze the dose modification of these substrates when supplied with gemfibrozil. This medication can improve the concentration of OATP1B1 drug substrates when given concurrently. Analyze dose modification of the substrates when given with gemfibrozil.[4][6][10]

Adverse Effects

Dyspepsia was reported in approximately 20 percent of patients on gemfibrozil. The most common reported adverse effects are fatigue, rash, atrial fibrillation, eczema, abdominal pain, nausea, vomiting, diarrhea, vertigo, constipation, and headache. Less frequent (less than 1 percent) reported adverse effects are myalgia, rhabdomyolysis (more frequent if coadministering gemfibrozil with a statin), acute appendicitis, cholelithiasis, angioedema, hypokalemia, eosinophilia, myopathy, synovitis, taste disturbance, xerostomia, flatulence.[4][13][14]

Postmarketing surveillance data suggest some causal relationship of using gemfibrozil and cases of anemia,  decreased libido, impotence, hypoesthesia, bone marrow depression, blurred vision, cholecystitis, cholestatic jaundice,  dermatomyositis, dermatitis, depression, exfoliative dermatitis, drowsiness, dizziness, headache, and leukopenia. Also, arthralgia, laryngeal edema, myalgia, limb pain, myasthenia, paresthesia, nephrotoxicity, peripheral neuritis, polymyositis, Raynaud phenomenon, rhabdomyolysis, pruritus, urticaria, and increased levels of creatine phosphokinase, serum alkaline phosphatase, serum bilirubin, serum transaminases are probable caused adverse reactions of gemfibrozil.

Contraindications

Contraindications for using gemfibrozil include hepatic or severe renal dysfunction (including primary biliary cirrhosis), presence of cholelithiasis, gallbladder abnormalities, hypersensitivity, and combination therapy of gemfibrozil with the following drugs: simvastatin, repaglinide, or dasabuvir.

Cholelithiasis is one of the potential side effects in patients managed with gemfibrozil. This medication enhances cholesterol elimination into bile. If cholelithiasis is suspected, it is recommended to order an abdominal ultrasound and HIDA scan to rule out gallstones. Discontinuation of gemfibrozil is recommended if diagnostic studies are positive for gallstones. Unusually, it has been reported in the literature the development of severe anemia, leukopenia, thrombocytopenia, and bone marrow hypoplasia. Periodical complete blood count is a good practice during the first 12 months of treatment with this medication. It has been reported worsening renal failure, particularly in patients with a baseline creatinine greater than 2.0 mg/dL. It is suggested to use an alternative treatment in these patients.

Gemfibrozil can potentially interact with other medications; monitoring dose or modifying frequency is recommended.[4][13][14]

• HMG CoA Reductase Inhibitors: There have been case reports of rhabdomyolysis and myopathy and its susceptibility in patients with renal failure. The simultaneous usage of HMG CoA reductase inhibitors (statins) with gemfibrozil enhances the probability of developing rhabdomyolysis or myopathy. Therefore, simvastatin is contraindicated, and rosuvastatin use should be avoided while administering gemfibrozil.

• Anticoagulants: If gemfibrozil is used in patients using drugs that modify the coagulation cascade (warfarin), it is recommended to reduce the anticoagulant dose and monitor the coagulation cascade (PT, PTT, INR) until normalization of these parameters.

• Enzalutamide: Gemfibrozil can increase CYP2C8 substrates like enzalutamide levels when it is coadministered with this drug concomitantly. It can increase the risk of seizures. If simultaneous administration is required, decrease the enzalutamide dose.

• Selexipag: Concomitant administration of selexipag with gemfibrozil is contraindicated.

• OATP1B1 substrates: Gemfibrozil inhibits OATP1B1 transporter and can increase the exposure of medicines of substrates of OATP1B1 (e.g., atorvastatin, atrasentan, bosentan,  fluvastatin, ezetimibe, glyburide, pitavastatin, rosuvastatin, rifampin, pravastatin, olmesartan, or valsartan). Therefore, reduce the dose of OATP1B1 substrates when used concomitantly with gemfibrozil.

• Colchicine: Concomitant use of colchicine and gemfibrozil can potentiate the development of myopathy and rhabdomyolysis. Elderly patients and patients with renal dysfunction are at higher risk of these adverse reactions. Exercise caution when administering colchicine and gemfibrozil, especially in elderly patients or patients with renal dysfunction.

Monitoring

The recommendation is for close follow-up when initiating this medication if intolerable side effects develop; these may necessitate discontinuation of this drug, and starting a new medication must be considered. Recommendations also include monitoring for the development of rhabdomyolysis and myopathy, regardless of the presence of acute renal failure; cases have been reported when gemfibrozil is simultaneously administered with statins. There is no established evidence that recurrent monitoring of creatine kinase (CPK) will prevent the experience of severe myopathy and kidney damage.Clinicians should follow the serum lipoproteins (LDL, VLDL, HDL, triglycerides, total cholesterol) regularly to determine therapeutic response.[4][11][14]

Toxicity

Adverse drug reactions from overdose can include diarrhea, peripheral neuropathy, hyperkalemia, myopathy, renal failure, rhabdomyolysis, elevation in liver function tests, and opacities in the eye lens. The treatment is mainly supportive.[14][11] A case of overdose with 9 gm gemfibrozil is reported in a seven-year-old child followed by complete recovery.

Enhancing Healthcare Team Outcomes

Primary care providers, nurses, hospitalists, internists, cardiologists, and endocrinologists regularly prescribe this medication. Gemfibrozil helps manage hypertriglyceridemia and is comparatively effective and safe. It is essential to enhance healthcare providers' knowledge about this drug, including nurses and pharmacists. They must advise the patient that the medication can potentially produce dangerous side effects like diarrhea, peripheral neuropathy, hyperkalemia, myopathy, renal failure, rhabdomyolysis. Monitoring renal and liver parameters in patients using this drug is recommended to detect dangerous complications on time. Nursing will be on the front line monitoring for side effects, determining treatment efficiency, and reporting any concerns to the prescribing clinician. Pharmacists should verify the dose regimen, perform medication reconciliation, and report any concerns back to the prescriber. Gemfibrozil demands an interprofessional team strategy among physicians, specialists, physician assistants, specialty-trained nurses, and pharmacists, all cooperating beyond expectations to accomplish excellent patient outcomes and prevent complications.[11][14] [Level 5]