LIPAGIM®160

Composition: Each film coated tablet contains:
Fenofibrate. . . . . . . . . . . . . . . . . . . . . . . 160 mg
Presentation:
Cardboard box containing 3 blisters of 10 film coated tablets.
Indications:
For the treatment of primary hyperlipidaemia types IIa, IIb, III, IV and V in patients who do not respond adequately to diet.

Additional information

Dosage and administration

Dosage:
Adults: The recommended dose is 160 mg (one tablet), once daily. Initial dose should be maintain until cholesterol level returns to normal. Cholesterol levels should be checked every 3 months.
Elderly patients (≥ 65 years old): In elderly patients, without renal impairment, no dose adjustment is necessary. The usual adult dose is recommended.
Patients with renal impairment: Lipagim 160 is not recommended in patients with severe renal impairment.
Patients with liver impairment: Lipagim 160 is not recommended in patients with liver impairment.
If serum lipid levels have not been reduced significantly after 3 – 6 months of treatment, therapeutic measures should be modified (complementary or different therapeutic measures).
The safety and efficacy of fenofibrate in children and adolescents younger than 18 years has not been established. Therefore, the use of fenofibrate is not recommended in paediatric subjects under 18 years.
Administration:
Lipagim tablets should be taken with meals and combined with fat-restricted diet.

Contraindications

Hypersensitivity to any of components listed in the formula.
Severe renal impairment.
Hepatic dysfunction, including primary and persistent cholestatic cirrhosis of unknown etiology.
Gall bladder disease.
Patients with acute or chronic pancreatitis, except acute pancreatitis due to severe hypertriglyceridemia, have had photoallergy reaction during treatment with fibrates or ketoprofen.
Concurrent use with other fibrates.
Children under 10 years of age.
Pregnant and breast-feeding women.

Warnings and precautions for use

Liver and renal function tests should be performed before starting therapy with fibrates.
Liver function:
As with other lipid lowering agents, increases have been reported in transaminase levels in some patients. Periodic liver function monitoring (every 3 months) during the first 12 months of treatment. If serum aminotransferase levels (AST, ALT) increase to more than 3 times the upper limit of normal or SGPT (ALT) > 100 international units, the treatment with fenofibrate should be discontinued.
Fenofibrate should not be administered in combination with other hepatotoxic agents.
Pancreatitis, gallstones:
As with other fibric acid derivatives, fenofibrate may increase cholesterol excretion into bile, potentially leading to cholelithiasis. If the observe gallbladder is see to have gallstones, you should stop taking fenofibrate.
Biliary complications occur easily in patients with hepatobiliary cirrhosis or gallstones.
Pancreatitis in patients treated with fenofibrate or other fibric acid derivatives have been reported.
Myositis, myopathy, and/or rhabdomyolysis have been reported in patients receiving fenofibrate or other fibric acid derivatives. Rhabdomyolysis and other complications have also been reported in patients receiving concomitant fenofibrate with other lipid-lowering drugs, such as statins (HMG-CoA reductase inhibitors). Patients taking fenofibrate should be instructed to report immediately if they have unexplained muscle pain, or sensitivity to pain or muscle weakness, especially if accompanied by difficulty breathing or fever.
Periodic monitoring of creatinine kinase (CK or CPK) should be performed in patients with these side effects. Treatment with fenofibrate should be discontinued if serum CPK levels are markedly elevated or myositis or myopathy is suspected or diagnosed.
Hypothyroidism may be a predisposing factor for potential increase in fenofibrate-induced muscle problems.
Renal function:
Fenofibrate is contraindicated in severe renal impairment.
Fenofibrate should be used with caution in patients with mild to moderate renal insufficiency. Dose should be adjusted in patients whose estimated glomerular filtration rate is 30 to 59 ml/min/1.73m2.
It is recommended that creatinine is measured during the first 3 months after initiation of treatment and periodically thereafter.
Secondary causes of hyperlipidemia:
Secondary causes of hypercholesterolemia, such as uncontrolled type 2 diabetes, hypothyroidism, nephrotic syndrome, dysproteinemia, obstructive or alcoholic liver disease should be adequately treated before treatment with fenofibrate. Secondary cause of hypercholesterolemia related to pharmacological treatment can be seen with diuretics, β-blocking agents, estrogens, progesterone, combined oral contraceptives, immunosuppressive agents and protease inhibitors. In these cases, it should be ascertained whether the hyperlipidemia is of primary or secondary nature (possible elevation of lipid values caused by these therapeutic agents).
Changes in serum creatinine levels: Elevations in serum creatinine levels have been reported in patients receiving fenofibrate. These elevations tend to return to baseline after discontinuation of fenofibrate. The clinical significance of these observations is unknown. Therefore, it is recommended that creatinine is measured during the first 3 months after initiation of treatment and periodically thereafter. Creatinine should also be checked in patients on fenofibrate who are at risk for renal impairment such as the elderly and diabetic patients. Treatment should be interrupted when creatinine level is 50% above the upper limit of normal.
Paradoxical decrease in HDL Cholesterol Levels (HDL-C): There have been post-marketing and clinical trial reports of severe decreases in HDL cholesterol levels (as low as 2 mg/dL) occurring in diabetic and non-diabetic patients initiated on fibrate therapy. The decrease in HDL-C is indicated by a decrease in apolipoprotein A1. This decrease has been reported to occur within 2 weeks to years after initiation of fibrate therapy. HDL-C levels remain low until fibrate therapy has been withdrawn; the response to withdrawal of fibrate therapy is rapid and sustained. The clinical significance of this decrease in HDL-C is unknown. It is therefore recommended HDL-C level be checked within the first few months after initiating treatment with fibrates. If severely depressed HDL-C level is detected, fibrate therapy should be discontinued, HDL-C level should be monitored until it has returned to baseline, fibrate therapy should be resumed.
Hematologic changes: Moderate and mild hemoglobin, hematocrit and leukocytes decreases have been observed in patients receiving fenofibrate. However, these parameters usually return to normal during long-term treatment. Rare cases of thrombocytopenia and agranulocytosis have been reported in patients treated with fenofibrate. Periodic monitoring of red and white blood cell counts are recommended during the first 12 months of Lipagim administration
Hypersensitivity reactions: Acute hypersensitivity reactions including severe skin rashes requiring patient hospitalization and treatment with steroids have occurred very rarely during treatment with fenofibrate, including rare spontaneous reports of Stevens-Johnson syndrome, and toxic epidermal necrolysis. Urticaria and rash were reported by 1% of patients treated with fenofibrate during the double-blind, placebo-controlled trials.
If after several months of fenofibrate administration (e.g. 3 – 6 months) serum lipid levels have not been reduced satisfactorily, complementary or different therapeutic measures should be considered.
The safety and efficacy of fenofibrate in children and adolescents younger than 18 years have not been established.

Recommendation for pregnancy and breastfeeding

Pregnancy: This drug should not be used during pregnancy.
Breastfeeding: There are no data on the excretion of fenofibrate and/or its metabolites into breast milk. Consequently, fenofibrate 160 mg tablets should not be used in nursing mothers because of the safety to mother and infant.

Effects on ability to drive and use machines

The influence of Lipagim 160 on the ability to drive and use machines has not been reported.

Interactions, incompatibilities of medicine

HMG CoA reductase inhibitors and other fibrates: Combination of a fibrate with HMG CoA reductase inhibitors (e.g. pravastatin, simvastatin, fluvastatin) or other fibrates significantly increases the risk of muscle injury.
Cyclosporine: Combination of fibrates with cyclosporine increases the risk of nephrotoxicity due to cyclosporine.
Oral anticoagulants: Fenofibrate enhances oral anticoagulant effect and may increase the risk of hemorrhage. That is because fenofibrate is highly protein bound, with the potential to displace warfarin from its binding protein, leading to an enhanced hypoprothrombinemic effect. The use of fenofibrate and oral anticoagulants at the same time is not recommended. If this combination is required plasma prothrombin levels should be monitored. When starting fibrate therapy, the anticoagulant dose should be reduced by one-third of the normal dose and gradually adjusted if necessary according to INR (International Normalised Ratio) monitoring and 8 days after fibrate withdrawal.
Glitazones: Some cases of reversible reductions in HDL-cholesterol have been reported during concomitant use of fenofibrate and glitazones. Therefore, it is recommended to monitor HDL- cholesterol if the two drugs are combined and discontinuation of either therapy if HDL- cholesterol be too low.
CYP2C19, CYP2A6 and CYP2C9 metabolized drugs:
In vitro studies using human liver microsomes indicate that fenofibrate and fenofibric acid are not inhibitors of cytochrome (CYP) P450 isoforms CYP3A4, CYP2D6, CYP2E1, or CYP1A2. They are weak inhibitors of CYP2C19 and CYP2A6, and mild-to-moderate inhibitors of CYP2C9 at therapeutic concentrations.
Patients co-administered fenofibrate and CYP2C19, CYP2A6, and especially CYP2C9 metabolised drugs with a narrow therapeutic index should be carefully monitored and, if necessary, dose adjustment of these drugs is recommended.
Hepatotoxic drugs (MAO inhibitors, perhexiline maleate etc.) should not be combined with fenofibrate.

Undesirable effects (ADRs)

Undesirable effects are usually mild and uncommon.
Common, ADR > 1/100
Digestive: Gastrointestinal disorders (abdominal pain, constipation, nausea).
Hepatobiliary: Increased aminotransferase (related to dose).
Musculoskeletal: Back pain, increased creatin phosphokinase.
Respiratory: Respiratory illness, rhinitis.
Uncommon, 1/1000 < ADR < 1/100
Central nervous system: Headache.
Skin: Hives, urticaria, nonspecific rash.
Musculoskeletal: Muscle disorders (for example muscle pain, myositis, muscle spasms and weakness).
Blood: Increased serum creatinine.
Rarely, ADR < 1/1000
Hepatobiliary: Gallstones.
Genitourinary: Decreased libido and impotence, sperm count decreased.
Blood: Decrease in haemoglobin and leukocytes.
Immune system disorders: Hypersensitivity.
Skin and subcutaneous tissue disorders: Photosensitivity reactions.
Unknown frequency (frequency cannot be estimated from available data):
Hepatobiliary disorders: Jaundice, complications of gallstones (e.g. cholecystitis, cholangitis, gallstone attack).
Skin and subcutaneous tissue disorders: Serious skin reactions (e.g. erythematous multiforme, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN)).
Musculoskeletal, connective tissue and bone disorders: Rhabdomyolysis.
Management of ADRs: Lipagim should be temporarily discontinued.

Overdose and management

Symptoms: No case of overdosage has been reported.
Treatment: In case of suspected overdose, symptomatic treatment and appropriate supportive measures such as vomiting or gastric lavage should be applied. Fenofibrate cannot be eliminated by haemodialysis.

Pharmacodynamic properties

Fenofibrate, a fibric acid derivative, is a lipid-lowering agent, whose lipid modifying effects reported in humans are mediated via activation of Peroxisome Proliferator Activated Receptor type alpha (PPARα).
Through activation of PPARα, fenofibrate increases the lipolysis and elimination of atherogenic triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein CIII (inhibitor of lipoprotein lipase). Activation of PPARα also induces an increase in the synthesis of apoproteins AI and AII.
The above stated effects of fenofibrate on lipoproteins lead to a reduction in very low- and low density fractions (VLDL and LDL) containing apoprotein B and an increase in the high density lipoprotein fraction (HDL) containing apoprotein AI and AII.
The relationship between hypercholesterolemia and atherosclerosis has been established, and the relationship between atherosclerosis and risk of coronary artery disease. Low HDL levels are associated with a higher risk of coronary artery disease. Elevated triglyceride levels are also associated with an increased risk of cardiovascular events.
During clinical trials with fenofibrate, total cholesterol was reduced by 20 to 25%, triglycerides by 40 to 55% and HDL cholesterol was increased by 10 to 30%.
Because of important effect of fenofibrate on LDL cholesterol and triglycerides, treatment with fenofibrate should be beneficial in hypercholesterolaemic patients with or without hypertriglyceridaemia, including secondary hyperlipoproteinaemia such as type 2 diabetes mellitus.
Fenofibrate is used for the treatment of types IIa, IIb, III, IV and V hyperlipoproteinemia in addition to a diet restricted in saturated fat and cholesterol.
Fenofibrate reduces serum uric acid levels in hyperuricemic and normal individuals by increasing the urinary excretion of uric acid.

Pharmacokinetic properties

Absorption: Fenofibrate is well absorbed from the gastrointestinal tract, especially in the presence of food. The absorption of fenofibrate is increased when administered with food. Maximum plasma concentrations (Cmax) occur within 5 hours after oral administration.
Metabolism and distribution: The drug is rapidly hydrolyzed to the active metabolite, fenofibric acid which is strongly bound to plasma albumin (more than 99%).
Elimination: Fenofibric acid is excreted mainly in the urine (70% within 24 hours), mostly in the form of glucuronic conjugates. In addition, there is reduced fenofibric acid and its glucuronide conjugate. In patients with normal renal function, the plasma elimination half-life of fenofibric acid is approximately 20 hours but this time is increased significantly in patients with renal disease and fenofibric acid accumulation is significant in patients with chronic kidney disease taking fenofibrate daily. Almost all the drug is eliminated within 6 days.

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.