Gemfibrozil

Article Author:
Bryan Quintanilla Rodriguez
Article Editor:
Ricardo Correa
Updated:
8/17/2019 9:20:54 PM
PubMed Link:
Gemfibrozil

Indications

Gemfibrozil is an FDA approved fibric acid agent (fibrate) for the management of 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 a 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 symptoms of subsisting coronary heart disease. Gemfibrozil also provide 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 the recommendation 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]

 Dosing form

Gemfibrozil is available in tablets of 600 mg. 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. 

 Dose modifications

 In the case of mild/moderate renal impairment, it is recommended to use this drug with caution if the baseline creatinine is higher than 2 mg/dL. It has been reported cases of deterioration of renal function in some patients.

This medication is contraindicated in patients with hepatic impairment and severe renal impairment.[4][5][6][7][8][9]

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 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 is capable of inhibiting peripheral lipolysis and of decreasing the hepatic removal of free fatty acids, consequently reducing hepatic triglyceride production. Gemfibrozil inhibits the synthesis and increases the clearance of VLDL carrier apolipoprotein B, leading to a decrease in 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.[10][11][9]

Administration

Gemfibrozil is given, orally, once a day nearly 30 minutes before breakfast or dinner.In term of pharmacodynamics, gemfibrozil is protein-bound mostly (99%). The metabolism is hepatic, and excretion is in the urine (70%) and feces (6%). The half-life of the drug is approximately 1.5 hours, with a peak serum time of roughly 1 to 2 hours.Gemfibrozil is pregnancy category C. It is suggested to use it with caution. Consider usage if benefits exceed risks. Simultaneous administration of gemfibrozil a 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.[7][11][9]

Adverse Effects

Some of the most common reported adverse effects are dyspepsia, fatigue, rash, vertigo, atrial fibrillation, eczema, abdominal pain, nausea, and 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.[12][13][9]

Contraindications

Contraindications for the use of gemfibrozil include hepatic or severe renal dysfunction (including primary biliary cirrhosis), presence of cholelithiasis, or gallbladder abnormalities, hypersensitivity, and combination therapy of gemfibrozil with the following drugs: simvastatin, repaglinide or dasabuvir. Gemfibrozil can potentially interact with other medications; it is recommended to monitor dose or frequency modifications.If the therapeutic response to gemfibrozil is incompetent after three months of treatment, it is recommended to suspend gemfibrozil. There have been cases 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. 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.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 good practice during the first 12 months of treatment with this medication. It has been reported worsening in 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 is capable of increasing 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.[12][13][9]

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.[8][13][9]

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.[8][13][9]

Enhancing Healthcare Team Outcomes

Primary care physicians, hospitalists, internists, cardiologists, and endocrinologists regularly prescribe this medication. Gemfibrozil is helpful for the management of hypertriglyceridemia and comparatively effective and safe. It is essential to enhance the knowledge of healthcare providers, including nurses and pharmacists, about this drug. They must advise the patient that the medication can potentially produce dangerous side effects like diarrhea, peripheral neuropathy, hyperkalemia, myopathy, renal failure, rhabdomyolysis. Monitoring of 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, and determining treatment efficiency, reporting any concerns to the prescribing physician. Pharmacists should verify dose regimen and also 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 co-operating beyond expectations to accomplish excellent patient outcomes and prevent complications.[8][13][9] [Level V]


References

[1] Kim K,Kleinman HK,Lee HJ,Pahan K, Safety and potential efficacy of gemfibrozil as a supportive treatment for children with late infantile neuronal ceroid lipofuscinosis and other lipid storage disorders. Orphanet journal of rare diseases. 2017 Jun 17;     [PubMed PMID: 28623936]
[2] Ghosh A,Rangasamy SB,Modi KK,Pahan K, Gemfibrozil, food and drug administration-approved lipid-lowering drug, increases longevity in mouse model of late infantile neuronal ceroid lipofuscinosis. Journal of neurochemistry. 2017 May;     [PubMed PMID: 28199020]
[3] Ghosh A,Corbett GT,Gonzalez FJ,Pahan K, Gemfibrozil and fenofibrate, Food and Drug Administration-approved lipid-lowering drugs, up-regulate tripeptidyl-peptidase 1 in brain cells via peroxisome proliferator-activated receptor α: implications for late infantile Batten disease therapy. The Journal of biological chemistry. 2012 Nov 9;     [PubMed PMID: 22989886]
[4] Lipid-lowering drugs. The Medical letter on drugs and therapeutics. 2019 Feb 11;     [PubMed PMID: 30845106]
[5] Effects of the lipid regulator drug gemfibrozil: A toxicological and behavioral perspective., Henriques JF,Almeida AR,Andrade T,Koba O,Golovko O,Soares AM,Oliveira M,Domingues I,, Aquatic toxicology (Amsterdam, Netherlands), 2015 Oct 3     [PubMed PMID: 26482382]
[6] Effect of Andrographis paniculata Extract on Triglyceride Levels of the Patients with Hypertriglyceridemia: A Randomized Controlled Trial., Phunikhom K,Khampitak K,Aromdee C,Arkaravichien T,Sattayasai J,, Journal of the Medical Association of Thailand = Chotmaihet thangphaet, 2015 Jul     [PubMed PMID: 26434249]
[7] Nonstatin Therapies for Management of Dyslipidemia: A Review., Sando KR,Knight M,, Clinical therapeutics, 2015 Oct 1     [PubMed PMID: 26412799]
[8] Fibrates for secondary prevention of cardiovascular disease and stroke., Wang D,Liu B,Tao W,Hao Z,Liu M,, The Cochrane database of systematic reviews, 2015 Oct 25     [PubMed PMID: 26497361]
[9] Ito MK, Long-chain omega-3 fatty acids, fibrates and niacin as therapeutic options in the treatment of hypertriglyceridemia: a review of the literature. Atherosclerosis. 2015 Oct;     [PubMed PMID: 26296750]
[10] Gemfibrozil disrupts the metabolism of circulating lipids in bobwhite quails., Bussière-Côté S,Omlin T,de Càssia Pinheiro E,Weber JM,, Comparative biochemistry and physiology. Toxicology & pharmacology : CBP, 2015 Sep 30     [PubMed PMID: 26432161]
[11] Hepatic Disposition of Gemfibrozil and Its Major Metabolite, Gemfibrozil 1-O-β-Glucuronide., Kimoto E,Li R,Scialis RJ,Lai Y,Varma MV,, Molecular pharmaceutics, 2015 Oct 1     [PubMed PMID: 26378985]
[12] Hypertriglyceridemia: a too long unfairly neglected major cardiovascular risk factor., Tenenbaum A,Klempfner R,Fisman EZ,, Cardiovascular diabetology, 2014 Dec 4     [PubMed PMID: 25471221]
[13] Okopień B,Buldak L,Bołdys A, Fibrates in the management of atherogenic dyslipidemia. Expert review of cardiovascular therapy. 2017 Dec;     [PubMed PMID: 29183206]