LOPIGIM®600

Composition: Each tablet contains:
Gemfibrozil. . . . . . . . . . . . . . . . . . . . . . . 600 mg
Presentation:
Box of 3 blisters x 10 tablets.
Indications:
Gemfibrozil is a lipid regulating agent, which is indicated for the following cases:
Primary prevention of coronary heart disease (CHD) and myocardial infarction (MI) in patients with hypercholesterolaemia, mixed dyslipidemia and hypertriglyceridemia, types IIa, IIb and IV according to the Fredrickson classification.
Treatment of other dyslipidemia:
– Dyslipidemia type III and type V according to the Fredrickson classification.
– Dyslipidemia in patients with diabetes mellitus.
– Dyslipidemia in patients with xanthoma.
Treatment of adult patients with very high elevations of serum triglyceride levels (Types IV and V hyperlipidemia), who present a risk of pancreatitis and who do not respond adequately to a determined dietary effort to control them.

Additional information

Dosage and administration

Adult: 1 tablet, twice daily.
Lopigim 600 should be discontinued after 3 months if serum lipoprotein levels are not significantly improved.
Elderly (over 65 years old): As for adults.
Children and adolescents: Due to the lack of data the use of Lopigim 600 in children is not recommended.
Renal impairment: In patients with mild to moderate renal impairment (glomerular filtration rate 50 – 80 and 30 – < 50ml/min/1.73 m2, respectively), start treatment at 900mg daily and assess renal function before increasing dose.
Lopigim 600 should not be used in patients with severely impaired renal function.
Hepatic impairment: Gemfibrozil is contraindicated in patients with hepatic impairment.
Administration:
Lopigim 600 is orally taken 30 minutes before breakfast and dinner.

Contraindications

Hypersensitivity to gemfibrozil and any of the excipients of this medicine.
Severe hepatic or renal dysfunction, gallbladder disease, primary biliary cirrhosis.
Alcoholism.
Photosensitivity during treatment with fibrates.
Pregnancy and children.
Lopigim 600 should not be used concurrently with repaglinide or simvastatin.

Warnings and precautions for use

Initial Therapy: Laboratory studies should be done to ascertain that the lipid levels are consistently abnormal. Before instituting gemfibrozil therapy, every attempt should be made to control serum lipids with appropriate diet, exercise, weight loss in obese patients, and control of any medical problems such as diabetes mellitus and hypothyroidism that are contributing to the lipid abnormalities.
Continued Therapy: Periodic determination of serum lipids should be obtained, and the drug withdrawn if lipid response is inadequate after three months of therapy. When gemfibrozil is discontinued, an appropriate diet to reduce serum lipid and monitoring of serum lipid should be maintained until the patient’s condition is stabilized, because serum triglyceride and cholesterol levels may increase to baseline.

Recommendation for pregnancy and breastfeeding

Pregnancy: Gemfibrozil crosses the placenta. There are no adequate and well-controlled studies in pregnant women; Gemfibrozil should not be used during pregnancy.
Lactation: It is not known whether gemfibrozil is distributed into human milk. Because gemfibrozil has the potential to cause serious side effects in breast-fed infants, breastfeeding while using this drug is not recommended.

Effects on ability to drive and use machines

No studies on the effect of gemfibrozil on the ability to drive and use machines have been performed. However, Lopigim 600 may cause drowsiness, dizziness, headache, blurred vision. If affected, caution should be considered when driving and operating machines.

Interactions, incompatibilities of medicine

Anticoagulants, coumarin derivatives or indandione: Coadministration with gemfibrozil may significantly increase the anticoagulant effect of these medicines; Anticoagulant dose should be adjusted based on routine investigation of prothrombin time.
Chenodesoxycholic acid or ursodesoxycholic acid: The effect these agents may be reduced when concomitantly used with gemfibrozil, which tends to increase biliary cholesterol saturation.
HMG CoA reductase inhibitors (Lovastatin): The risk of rhabdomyolysis is increased with combined gemfibrozil and HMG-CoA reductase inhibitor therapy: Significant increase in creatine kinase and myoglobinuria result in acute renal failure which may occur as early as three weeks after initiation of combined therapy or after several months. There is no assurance that periodic monitoring of creatine kinase will prevent the occurrence of severe myopathy and kidney damage.
Repaglinide: Patients who are taking gemfibrozil should not start to use repaglinide and vice versa because this co-administration may increase and prolong the hypoglycemic effects of repaglinide. Co-administration of Gemfibrozil and repaglinide is contraindicated.
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.
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.
Colchicine: Risk of myopathy and rhabdomyolysis may be increased with concomitant administration of colchicine and gemfibrozil. This risk may be increased in the elderly and in patients with hepatic or renal dysfunction. Clinical and biological monitoring are recommended, especially at the start of combined treatment.

Undesirable effects (ADRs)

Generally, ADRs of Gemfibrozil are uncommon and mild, however, because of chemical, pharmacological and clinical similarity with clofibrate, gemfibrozil may cause the same ADR as clofibrate. The ADRs of gemfibrozil commonly seen in the gastrointestinal tract are sometimes severe and discontinuation of gemfibrozile is required.
Common, ADR > 1/100
Gastrointestinal: Dyspepsia, abdominal pain, diarrhoea, vomiting, nausea, constipation, acute appendicitis.
Liver: Gallstones.
Central nervous system: Fatigue, dizziness, headache.
Skin: Eczema, rash.
Uncommon, 1/1000 < ADR < 1/100
Cardiovascular: Atrial fibrillation
Central nervous system: Hyperesthesia, dizziness, drowsiness, sleepiness, depression, cerebral hemorrhage.
Gastrointestinal: Flatulence, cholecystitis.
Nervous, musculoskeletal: Paresthesia, growth retardation.
Eyes: Vision blurred, cataract.
Guidelines for ADR management
Severe side effects in gastrointestinal may require discontinuation of gemfibrozil. Patients receiving gemfibrozil and complaining of muscle pain, tenderness, or weakness should have prompt medical evaluation for myositis, including serum creatine–kinase level determination. If myositis is suspected or diagnosed, gemfibrozil therapy should be withdrawn.
Proper diagnostic tests should be performed if signs of suspicion are associated with the hepatobiliary system. Liver function tests and complete blood cell counts should be performed 3-6 months after starting gemfibrozil therapy and, then, every year. Gemfibrozil should be discontinued and not used again if the results of liver function tests increase steadily or excessively, or there are significant abnormalities; generally, the results of abnormal tests are recovered. Gemfibrozil therapy should be discontinued if gallstones are found.

Overdose and management

Symptoms of overdose: Symptoms reported with overdosage were abdominal cramps, abnormal liver function tests, diarrhea, increased creatine phosphokinase (CPK), joint and muscle pain, nausea and vomiting. These patients have recovered completely.
Treatment: Treatment of gemfibrozil overdose includes symptomatic and supportive treatment. In case of acute gemfibrozil overdose, the stomach should be emptied immediately by induction of emesis or gastric lavage.

Pharmacodynamic properties

Gemfibrozil is a non-halogenated fibric acid derivative with hypolipidemic effects.
Gemfibrozil reduces the levels of triglyceride-rich lipoproteins, such as VLDL (very low-density lipoprotein), modestly raise HDL levels (high density lipoprotein) and has variable effects on LDL levels (low density lipoprotein). The effects on VLDL levels probably result primarily from an increase in lipoprotein lipase activity, especially in muscle. This would lead to increased hydrolysis of VLDL triglyceride content and enhanced VLDL catabolism. Gemfibrozil modifies the VLDL component due to decreasing hepatic production of apoC-III, an inhibitor of lipoprotein lipase activity, and also reduces the synthesis of VLDL triglyceride in the liver.
Additon to its lipid-lowering effect, gemfibrozil also decreases platelet aggregation, thus reduces the risk of cardiovascular disease.
The clinical effects of gemfibrozil or any other fibric acid agents on lipoprotein levels depend on the starting lipoprotein profile, the presence or absence of hyperlipoproteinemia. Patients with homozygous apoE2/apoE2 hyperlipidemia best responds to gemfibrozil therapy. Elevated triglyceride and cholesterol levels may be dramatically lowered, and tuboeruptive and palmar xanthomas may regress completely. Gemofibrozil also has good effects on angina and intermittent claudication.
Gemfibrozil therapy in patients with mild hypertriglyceridaemia (e.g, triglycerides < 400mg/dl or 4.5mmol /l), usually produces a decrease in triglyceride levels of 50% or more, and increase in HDL cholesterol levels of 15% to 25%, especially in patients with familial combined hyperlipidaemia. Gemfibrozil is effective in patients with severe hypertriglyceridaemia and accompanied by chylomicronemia syndrome. Whereas starting therapy is to reduce maximally fat from the diet as possible, gemfibrozil can both increase lipoprotein lipase activity and decrease triglyceride synthesis in the liver. In these patients, maintenance therapy with gemfibrozil may keep triglyceride concentrations at levels of less than 600 to 800mg / dl (6.8-9mmol/l) to prevent pancreatitis and tuboeruptive xanthomas.

Pharmacokinetic properties

Absorption: Gemfibrozil is rapidly and well absorbed (98 ± 1% bioavailability). Maximum bioavailability is achieved when the drug is taken 30 minutes before meals. Peak plasma levels occur in one to two hours.
Distribution: Gemfibrozil is bound to plasma proteins by more than 97%. The drug is extensively distributed and the concentrations in liver, kidney and intestine are higher than that in plasma. Volume of distribution is 0.14 ± 0.03l/kg.
Metabolism: Gemfibrozil undergoes oxidation of a ring methyl group to form successively a hydroxymethyl and a carboxyl metabolite (the main metabolite). This metabolite has a low activity compared to the mother compound gemfibrozil and an elimination half-life of approximately 20 hours. Glucuronidation to gemfibrozil 1-O-β-glucuronide is another important elimination pathway for gemfibrozil in man.
Elimination: Gemfibrozil is eliminated mostly as the glucuronide conjugate; approximately 60% to 90% of the oral dose is excreted in the urine, 6% in the feces. The excretion of gemfibrozil is reduced to a lesser extent than other fenofibrates. The clearance of gemfibrozil is 1.7 ± 0.4ml/minute/kg. Elimination half-life ls 1.5 hours.

Storage conditions, shelf-life, quality specification of the medicine

Storage conditions: Protect from humidity and light, below 30 degrees C.
Shelf – life: 36 months from the manufacture date.
Quality specification: In house specification.