Lopid/Lopid OD

Lopid/Lopid OD

gemfibrozil

Manufacturer:

Pfizer

Distributor:

Zuellig
Full Prescribing Info
Contents
Gemfibrozil.
Description
Gemfibrozil (Lopid) 600 mg: Each tablet contains 600 mg gemfibrozil.
Gemfibrozil (Lopid OD) 900 mg: Each tablet contains 900 mg gemfibrozil.
Gemfibrozil is a non-halogenated phenoxypentanoic acid.
M. W. = 250.35.
The chemical name is 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid; the empirical formula is C15H22O3.
Gemfibrozil is a white compound with a melting point of 58°C to 61°C. Its solubility is 0.0019% in water and in acid and over 1% in dilute base. Gemfibrozil is stable under ordinary conditions.
Action
Pharmacology: Pharmacodynamics: Mechanism of Action: Gemfibrozil's mechanism of action has not been definitively established. In humans, gemfibrozil inhibits peripheral lipolysis and decreases the hepatic extraction of free fatty acids. Gemfibrozil also inhibits synthesis and increases clearance of apolipoprotein B, which is a carrier of very-low-density lipoprotein (VLDL), leading to a decrease in VLDL production. Gemfibrozil increases the level of high-density lipoprotein (HDL) subfractions, HDL2 and HDL3, as well as apolipoprotein A-I and A-II. Animal studies suggest that the turnover and removal of cholesterol from the liver is increased by gemfibrozil.
Gemfibrozil is a lipid-regulating agent, which reduces total cholesterol, low-density lipoprotein (LDL) cholesterol, VLDL and triglycerides and increases HDL cholesterol.
In the Helsinki Heart Study, a large, randomized, double-blind, placebo-controlled primary prevention trial, involving subjects with serum non-HDL cholesterol over 200 mg/dL (5.2 mmol/L) and no previous history of heart disease, gemfibrozil produced a significant reduction in total plasma triglycerides, moderate reductions in total and LDL cholesterol and a significant increase in HDL cholesterol. Over the 5-year study period the gemfibrozil group experienced a 34% reduction in the overall incidence of CHD (in years 4 and 5 of the study, the reduction in CHD was greater than 50%).
There was a 37% reduction in non-fatal MI and a 26% reduction in cardiac deaths. The overall difference in the incidence of CHD was significantly lower for gemfibrozil-treated patients than for those receiving placebo (p<0.02, two-tailed).
Pharmacokinetics: Absorption: Gemfibrozil is well absorbed from the gastrointestinal tract after oral administration. Peak plasma levels occur in 1 to 2 hours with a plasma half-life of 1.5 hours following multiple doses. Plasma levels appear proportional to the dose and do not demonstrate accumulation across time following multiple doses. Gemfibrozil pharmacokinetics are affected by the timing of meals relative to the time of dosing. In one study, both the rate and extent of absorption of the drug were significantly increased when administered 0.5 hour before meals. Average AUC was reduced by 14% to 44% when gemfibrozil was administered after meals compared to 0.5 hours before meals. In a subsequent study, the rate of absorption of gemfibrozil was maximum when administered 0.5 hours before meals, with the Cmax 50% to 60% greater than when given either with meals or fasting. In this study, there were no significant effects on the AUC of timing of dose relative to meals (see Dosage & Administration).
Distribution: Gemfibrozil is highly bound to plasma proteins, and there is potential for displacement interactions with other drugs (see Precautions).
Metabolism: Gemfibrozil undergoes oxidation of a ring methyl group to form successively a hydroxymethyl and a carboxyl metabolite.
Excretion: Approximately 70% of the administered human dose is excreted in the urine, mostly as the glucuronide conjugate, with less than 2% excreted as the unchanged gemfibrozil. Six percent of the dose is accounted for in the feces.
Toxicology: Preclinical Safety Data: Carcinogenesis, Mutagenesis and Impairment of Fertility: There are no adequate, well-controlled studies in humans. Long-term studies have been conducted in rats at 0.2 and 1.3 times the human exposure (based on AUC). The incidence of benign liver nodules and liver carcinomas was significantly increased in high dose-male rats. In high-dose female rats, there was a significant increase in the combined incidence of benign and malignant liver neoplasms.
A comparative carcinogenicity study was also done in rats comparing three drugs in this class: fenofibrate (10 mg/kg and 60 mg/kg; 0.3 and 1.6 times the human dose), clofibrate (400 mg/kg; 1.6 times the human dose), and gemfibrozil (250 mg/kg; 1.7 times the human dose). Pancreatic acinar adenomas were increased in males and females on fenofibrate; hepatocellular carcinoma and pancreatic acinar adenomas were increased in males and hepatic neoplastic nodules in females treated with clofibrate; hepatic neoplastic nodules were increased in males and females treated with gemfibrozil, while testicular interstitial cell tumors were increased in males on all three drugs.
Long-term studies have been conducted in mice at 0.1 and 0.7 times the human exposure (based on AUC). There were no statistically significant differences from controls in the incidence of liver tumors, but the doses tested were lower than those shown to be carcinogenic with other fibrates. Administration of approximately two times the human dose (based on surface area) to male rats for 10 weeks resulted in a dose-related decrease of fertility. Subsequent studies demonstrated that this effect was reversed after a drug-free period of about 8 weeks and it was not transmitted to the offspring. Minor fetotoxicity was manifested by reduced birth weights observed at the high-dose levels.
Indications/Uses
Gemfibrozil is a lipid-regulating agent that is indicated for the following: Primary prevention of coronary heart disease (CHD) and myocardial infarction (MI) in patients with hypercholesterolemia, mixed dyslipidemia and hypertriglyceridemia, Fredrickson's classification types IIa, IIb, and IV.
Treatment of other dyslipidemias: Fredrickson types III and V; Associated with diabetes; Associated with xanthomata.
Treatment of adult patients with elevated levels of serum triglycerides (types IV and V hyperlipidemia) who present a risk of pancreatitis and do not respond adequately to a determined dietary effort to control them.
Dosage/Direction for Use
General: Lipid levels should be measured on more than one occasion, to ascertain that the levels are consistently abnormal. Before instituting therapy with gemfibrozil, every attempt should be made to control serum lipids with appropriate diet, limiting alcohol intake, exercise, and weight loss in obese patients, as well as controlling other medical problems such as diabetes mellitus or hypothyroidism which may contribute to the abnormal lipid levels. The patient should continue a standard cholesterol-lowering diet during treatment with gemfibrozil. Periodic determinations of serum lipids should be obtained during treatment with gemfibrozil. The drug should be withdrawn or additional therapy instituted if the lipid response is inadequate after 3 months.
The recommended daily dose is 900 mg to 1200 mg. The maximum daily dose is 1500 mg.
The 900 mg dose is given as a single dose one-half hour before the evening meal. The 1200 mg dose is given in two divided doses one-half hour before the morning and evening meals (see Pharmacology: Pharmacokinetics under Actions).
Use in Patients with Hepatic Dysfunction: (see Contraindications and Precautions).
Use in Patients with Renal Dysfunction: (see Contraindications and Precautions).
Use in Children: Safety and efficacy in children have not been established.
Overdosage
Overdosage has been reported with gemfibrozil. Symptoms reported with overdosage were abdominal cramps, abnormal LFTs, diarrhea, increased creatine phosphokinase (CPK), joint and muscle pain, nausea and vomiting. The patients fully recovered.
Symptomatic supportive measures should be taken should overdosage occur.
Contraindications
Gemfibrozil is contraindicated in patients with hepatic or severe renal dysfunction, pre-existing gallbladder disease, and in patients who are hypersensitive to gemfibrozil and to any of the inert ingredients including corn starch, polysorbate, silicon dioxide, denatured alcohol, silica, hydroxypropyl cellulose, purified water, microcrystalline cellulose, calcium stearate, methyl hydroxybenzoate, propyl hydroxybenzoate, macrogol, hypromellose, opaspray, candelilla wax, pregelatinized starch, starch sodium glycolate, magnesium stearate, opadry white, hydroxypropyl methyl cellulose, titanium dioxide, talc, polydimethyl siloxane and polyethylene glycol.
The concomitant use of gemfibrozil is contraindicated with any of the following: simvastatin; repaglinide; dasabuvir; selexipag.
See Precautions and Interactions.
Special Precautions
Cholelithiasis: Gemfibrozil may increase cholesterol excretion into the bile, raising the potential for gallstone formation. If cholelithiasis is suspected, gallbladder studies are indicated. Gemfibrozil therapy should be discontinued if gallstones are found. Cases of cholelithiasis have been reported with gemfibrozil therapy.
HMG-CoA Reductase Inhibitors: The concomitant administration of gemfibrozil with simvastatin is contraindicated. There have been reports of severe myositis with markedly elevated creatine kinase (CK) and myoglobinuria (rhabdomyolysis) when gemfibrozil and HMG-CoA reductase inhibitors were used concomitantly. In most subjects who have had an unsatisfactory lipid response to either drug alone, the possible benefit of combined therapy with HMG-CoA reductase inhibitors and gemfibrozil does not outweigh the risks of severe myopathy, rhabdomyolysis, and acute renal failure (see Contraindications and Interactions).
Anticoagulants: Caution should be exercised with concomitant use of warfarin. The dosage of warfarin should be reduced to maintain the prothrombin time at the desired level to prevent bleeding complications. Frequent prothrombin time determinations are advisable until it has been definitely determined that the prothrombin time has stabilized.
CYP2C8 Substrates: Gemfibrozil, an inhibitor of CYP2C8, may increase exposure of CYP2C8 substrates when administered concomitantly (see Contraindications and Interactions).
Laboratory Tests: Elevated liver function tests (LFTs) such as liver transaminases (aspartate transaminase [AST; serum glutamic oxaloacetic transaminase (SGOT)], and alanine aminotransferase [ALT; serum glutamic pyruvic transaminase (SGPT)]), increased alkaline phosphatase, lactate dehydrogenase (LDH), CK, and bilirubin have rarely been reported with gemfibrozil administration. These are usually reversible when gemfibrozil is discontinued. Therefore, periodic liver function studies are recommended, and gemfibrozil therapy should be terminated if abnormalities persist.
Hematopoietic: Mild decreases in hemoglobin, hematocrit and white cell have been observed occasionally on initiating gemfibrozil therapy. However, these levels stabilize during long-term administration. Rarely, severe anemia, leukopenia, thrombocytopenia, eosinophilia and bone marrow hypoplasia have been reported. Therefore, periodic blood count determinations are recommended during the first 12 months of gemfibrozil administration.
Information for the Patient: The patient should be instructed to tell the physician if she is pregnant, a nursing mother, or thinking of becoming pregnant. Patients taking gemfibrozil should be instructed about the importance of taking the drug under the prescribed regimen, about the importance of laboratory tests to monitor lipid levels and to report any experienced side effects.
Effects on Ability to Drive and Use Machines: None known.
Use In Pregnancy & Lactation
There are no adequate and well-controlled studies in pregnant women. The use of gemfibrozil in pregnancy should be reserved for those patients where the benefits clearly outweigh the risks to the patient or fetus.
Safety in nursing mothers has not been established. It is not known whether gemfibrozil is excreted in human milk. Since many drugs are excreted in human milk, the patient should discontinue nursing before beginning gemfibrozil therapy.
Adverse Reactions
In the double-blind controlled phase of the Helsinki Heart Study, 2046 patients received gemfibrozil for up to five years. In that study, the following adverse reactions were statistically more frequent in subjects in the gemfibrozil group: See Table 1.

Click on icon to see table/diagram/image

Adverse events reported by more than 1% of subjects, but without a significant difference between groups: See Table 2.

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Additional adverse reactions that have been reported where a causal relationship to treatment with gemfibrozil is probable are: See Table 3.

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Additional adverse reactions that have been reported included photosensitivity, alopecia, cholecystitis and cholelithiasis (see Precautions).
Drug Interactions
Anticoagulants: Caution should be exercised when warfarin is given in conjunction with gemfibrozil. The dosage of warfarin should be reduced to maintain the prothrombin time at the desired level to prevent bleeding complications. Frequent prothrombin time determinations are advisable until it has been definitely determined that the prothrombin time has stabilized.
HMG-CoA Reductase Inhibitors: The concomitant administration of gemfibrozil with simvastatin is contraindicated. There have been reports of severe myositis and myoglobinuria (rhabdomyolysis) when gemfibrozil and HMG-CoA reductase inhibitors were used concomitantly (see Contraindications and Precautions).
CYP2C8 substrates: Gemfibrozil is an inhibitor of CYP2C8 and may increase exposure of drugs mainly metabolized by CYP2C8 (e.g., dabrafenib, enzalutamide, loperamide, montelukast, paclitaxel, pioglitazone, rosiglitazone) (see Precautions). Therefore, dosing reduction of drugs that are mainly metabolized by CYP2C8 enzyme may be required when gemfibrozil is used concomitantly.
In healthy volunteers, co-administration with gemfibrozil increased the AUC and Cmax of repaglinide by 8.1 fold and 2.4 fold, respectively. In the same study, co-administration with gemfibrozil and itraconazole increased the AUC and Cmax of repaglinide by 19.4 fold and 2.8 fold, respectively. In addition, co-administration with gemfibrozil or with gemfibrozil and itraconazole prolonged its hypoglycemic effects. Therefore, co-administration of gemfibrozil and repaglinide increases the risk for severe hypoglycemia and is contraindicated (see Contraindications and Precautions).
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 (see Contraindications and Precautions).
Co-administration of gemfibrozil with selexipag doubled exposure (AUC) to selexipag and increased exposure (AUC) to the active metabolite, ACT-333679, by approximately 11-fold. Concomitant administration of gemfibrozil with selexipag is contraindicated (see Contraindications).
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 2.2 fold 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. (See Precautions).
Bile Acid-binding Resins: Reduced bioavailability of gemfibrozil may result when given simultaneously with resin-granule drugs such as colestipol. Administration of the drugs 2 hours apart or more is recommended.
Colchicine: Risk of neuromuscular toxicity 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. Symptoms usually last between 1 week and several months after colchicine withdrawal. Clinical and biological monitoring is recommended, especially at the start of combined treatment.
In-vitro studies of CYP enzymes, UGTA enzymes and OATP1B1 transporter: In-vitro studies have shown that gemfibrozil is an inhibitor of CYP1A2, CYP2C8, CYP2C9, CYP2C19, organic anion-transporting polypeptide (OATP) 1B1 and UDP-glucuronosyltransferase (UGT) 1A1 and 1A3 (see Precautions).
Storage
Gemfibrozil (Lopid) 600 mg tablet: Store at temperatures not exceeding 30°C.
Gemfibrozil (Lopid OD) 900 mg tablet: Store at temperatures not exceeding 25°C.
ATC Classification
C10AB04 - gemfibrozil ; Belongs to the class of fibrates. Used in the treatment of hyperlipidemia.
Presentation/Packing
Lopid: Tab 600 mg (white elliptical, embossed "PD 737" on one side) x 60's.
Lopid OD: FC tab 900 mg (white, oval, biconvex) x 50's.
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