Drug Class Description

Generic Name

Drug Description

Presentation

Indications

Lopid is indicated as an adjunct to diet and other non-pharmacological treatment (e.g. exercise, weight reduction) for the following:

Treatment of dyslipidemia Mixed dyslipidaemia characterised by hypertriglyceridaemia and/or low HDL-cholesterol. Primary hypercholesterolaemia, particularly when a statin is considered inappropriate or is not tolerated.

Primary prevention Reduction of cardiovascular morbidity in males with increased non-HDL cholesterol and at high risk for a first cardiovascular event, particularly when a statin is considered inappropriate or is not tolerated

Adult Dosage

Prior to initiating gemfibrozil, other medical problems such as hypothyroidism and diabetes mellitus must be controlled as best as possible and patients should be placed on a standard lipid-lowering diet, which should be continued during treatment. Lopid should be taken orally.

Adult

The dose range is 900 mg to 1200 mg daily.

The only dose with documented effect on morbidity is 1200 mg daily.

The 1200 mg dose is taken as 600 mg twice daily, half an hour before breakfast and half an hour before the evening meal.

The 900 mg dose is taken as a single dose half an hour before the evening meal.

Renal impairment

In patients with mild to moderate renal impairment (Glomerular filtration rate 50 - 80 and 30 - < 50 ml/min/1.73 m², respectively), start treatment at 900 mg daily and assess renal function before increasing dose. Lopid should not be used in patients with severely impaired renal function.

Hepatic impairment

Gemfibrozil is contraindicated in hepatic impairment

Child Dosage

Gemfibrozil therapy has not been investigated in children. Due to the lack of data the use of Lopid in children is not recommended.

Contra Indications

Hypersensitivity to gemfibrozil or any of the excipients.

Hepatic impairment.

Severe renal impairment.

History of/or pre-existing gall bladder or biliary tract disease, including gallstones

Concomitant use of repaglinide.

Patients with previous history of photoallergy or phototoxic reaction during treatment with fibrates.

Special Precautions

Muscle disorders (myopathy/rhabdomyolysis)

There have been reports of myositis, myopathy and markedly elevated creatine

phosphokinase associated with gemfibrozil. Rhabdomyolysis has also been reported rarely.

Muscle damage must be considered in any patient presenting with diffuse myalgia, muscle tenderness and/or marked increase in muscle CPK levels ( >5x ULN); under these conditions treatment must be discontinued.

Concomitant HMG CoA reductase inhibitors

The risk of muscle damage may be increased in the event of combination with an HMG-CoA reductase inhibitor. Pharmacokinetic interactions may also be present and dosage adjustments may be necessary.

The benefit of further alterations in lipid levels by the combined use of gemfibrozil and HMG-CoA reductase inhibitors should be carefully weighed against the potential risks of such combinations and clinical monitoring is recommended.

A creatine phosphokinase (CPK) level should be measured before starting such a combination in patients with pre-disposing factors for rhabdomyolysis as follows:

• renal impairment

• hypothyroidism

• alcohol abuse

• age> 70 years

• personal or family history of hereditary muscular disorders

• previous history of muscular toxicity with another fibrate or HMG-CoA reductase inhibitor

In most subjects who have had an unsatisfactory lipid response to either drug alone, the possible benefits of combined therapy with HMG-CoA reductase inhibitors and gemfibrozil does not outweigh the risks of severe myopathy, rhabdomylosis and acute renal failure.

Use in patients with gallstone formation

Gemfibrozil may increase cholesterol excretion into the bile raising the potential for gallstone formation. Cases of cholelithiasis have been reported with gemfibrozil therapy. If cholelithiasis is suspected, gallbladder studies are indicated. Gemfibrozil therapy should be discontinued if gallstones are found.

Monitoring serum lipids

Periodic determinations of serum lipids are necessary during treatment with gemfibrozil. Sometimes a paradoxical increase of (total and LDL) cholesterol can occur in patients with hypertriglyceridaemia. If the response is insufficient after 3 months of therapy at recommended doses treatment should be discontinued and alternative treatment methods considered.

Monitoring liver function

Elevated levels of ALAT, ASAT, alkaline phosphatase, LDH, CK and bilirubin have been reported. These are usually reversible when gemfibrozil is discontinued. Therefore liver function tests should be performed periodically. Gemfibrozil therapy should be terminated if abnormalities persist.

Monitoring blood counts

Periodic blood count determinations are recommended during the first 12 months of gemfibrozil administration. Anaemia, leucopenia, thrombocytopenia, eosinophilia and bone marrow hypoplasia have been reported rarely.

Interactions with other medicinal products

Concomitant use with CYP2C8, CYP2C9, CYP2C19, CYP1A2, UGTA1 and UGTA3 substrates.

The interaction profile of gemfibrozil is complex resulting in increased exposure of many medicinal products if administered concomitantly with gemfibrozil.

Gemfibrozil potently inhibits CYP2C8, CYP2C9, CYP2C19, CYP1A2, UGTA1 and UGTA3 enzymes

Concomitant use with hypoglycaemic agents

There have been reports of hypoglycaemic reactions after concomitant use with gemfibrozil and hypoglycaemic agents (oral agents and insulin). Monitoring of glucose levels is recommended.

Concomitant oral anticoagulants

Gemfibrozil may potentiate the effects of oral anticoagulants, which necessitates careful monitoring of the anticoaglant dosing. Caution should be exercised when anticoagulants are given in conjunction with gemfibrozil. The dosage of the anticoagulant may need to be reduced to maintain desired prothrombin time levels.

Interactions

The interaction profile of gemfibrozil is complex. In vivo studies indicate that gemfibrozil is a potent inhibitor of CYP2C8 (an enzyme important for the metabolism of e.g. repaglinide, rosiglitazone and paclitaxel). In vitro studies have shown that gemfibrozil is a strong inhibitor of CYP2C9 (an enzyme involved in the metabolism of e.g. warfarin and glimepiride), but also of CYP 2C19, CYP1A2 and UGTA1 and UGTA3.

Repaglinide

The combination of gemfibrozil with repaglinide is contra-indicated. Concomitant administration has resulted in 8-fold increase in repaglinide plasma concentration probably by inhibition of the CYP2C8 enzyme, resulting in hypoglycaemic reactions.

Rosiglitazone

The combination of gemfibrozil with rosiglitazone should be approached with caution. Co-administration with rosiglitazone has resulted in 2.3-fold increase in rosiglitazone systemic exposure, probably by inhibition of the CYP2C8 isozyme.

HMG CoA reductase inhibitors

The combined use of gemfibrozil and a statin should generally be avoided. The use of fibrates alone is occasionally associated with myopathy. An increased risk of muscle related adverse events, including rhabdomyolysis, has been reported when fibrates are co-administered with statins.

Gemfibrozil has also been reported to influence the pharmacokinetics of simvaststin, lovastatin, pravastatin and rosuvastatin. Gemfibrozil caused an almost 3-fold increased in AUC of simvastatin acid possibly due to inhibition of glucoronidation via UGTA1 and UGTA3, and a 3-fold increase in pravastatin AUC which may be due to interference with transport proteins. One study indicated that the co-administration of a single rosuvastatin dose of 80 mg to healthy volunteers on gemfibrozil (600 mg twice daily) resulted in a 2.2-fold increase in mean C_max and a 1.9-fold increase in mean AUC of rosuvastatin.

Oral anticoagulants

Gemfibrozil may potentiate the effects of oral anticoagulants, which necessitates careful monitoring of the anticoagulant dosing.

Bexarotene

Concomitant administration of gemfibrozil with bexarotene is not recommended. A population analysis of plasma bexarotene concentrations in patients with cutaneous T-cell lymphoma (CTCL) indicated that concomitant administration of gemfibrozil resulted in substantial increases in plasma concentrations of bexarotene.

Bile Acid – Binding Resins

Reduced bioavailability of gemfibrozil may result when given simultaneously with resin-granule drugs such as colestipol. Administration of the products two hours or more apart is recommended.

Gemfibrozil is highly bound to plasma proteins and there is potential for displacement interactions with other drugs.

Adverse Reactions

Most commonly reported adverse reactions are of gastrointestinal character and are seen in approximately 7% of the patients. These adverse reactions do not usually lead to discontinuation of the treatment.

Adverse reactions are ranked according to frequency using the following convention: Very common ( >1/10), Common ( >1/100, <1/10), Uncommon ( >1/1,000, <1/100), Rare ( >1/10,000, <1/1,000), Very rare ( <1/10,000), including isolated reports:

Platelet, bleeding and clotting disorders

Rare: thrombocytopenia.

Red blood cell disorders

Rare: severe anaemia. Self-limiting, mild haemoglobin and haematocrit decrease have been observed on initiating gemfibrozil therapy.

White cell and reticuloendothelial system disorders

Rare: leucopoenia, eosinophilia, bone marrow hypoplasia. Self-limiting, white cell decrease has been observed on initiating gemfibrozil therapy.

Central and peripheral nervous system

Common: vertigo, headache.

Rare: dizziness, somnolence, paresthesia, peripheral neuritis, depression, decreased libido.

Vision disorders

Rare: blurred vision.

Heart rate and rhythm disorders

Uncommon: atrial fibrillation.

Gastro-intestinal system disorders

Very common: dyspepsia.

Common: abdominal pain, diarrhoea, flatulence, nausea, vomiting, constipation.

Rare: pancreatitis, acute appendicitis.

Liver and biliary system disorders

Rare: cholestatic jaundice, disturbed liver function, hepatitis, cholelithiasis, cholecystitis.

Skin and appendages disorders

Common: eczema, rash.

Rare: exfoliative dermatitis, dermatitis, pruritus, alopecia.

Musculoskeletal disorders

Rare: arthralgia, synovitis, myalgia, myopathy, myasthenia, painful extremities and myositis accompanied by increase in creatine kinase (CK), rhabdomyolysis.

Urinary system disorders

Rare: impotence.

Body as a whole-general disorders

Common: fatigue.

Rare: photosensitivity, angioedema, laryngeal edema, urticaria.

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