Lipanthyl Supra 160/Lipanthyl Penta 145

Lipanthyl Supra 160/Lipanthyl Penta 145

fenofibrate

Manufacturer:

Abbott

Distributor:

Zuellig
/
The Glory Medicina
Full Prescribing Info
Contents
Fenofibrate.
Description
Lipanthyl Supra 160: Each film-coated tablet contains Fenofibrate (INN) 160 mg.
Excipients/Inactive Ingredients: 138.4 mg of lactose monohydrate; 0.56 mg of Soybean lecithin.
Lipanthyl Penta 145: Each film-coated tablet contains Fenofibrate (nanoparticles) 145.0 mg.
Excipients/Inactive Ingredients: Core: Sucrose, Lactose monohydrate, microcrystalline cellulose and anhydrous colloidal silica, Crospovidone, Hypromellose, Sodium lauryl sulfate, Docusate sodium, Magnesium stearate.
Coating: Polyvinyl alcohol, Titanium dioxide (E171), Talc, Soybean lecithin, Xanthan gum.
Action
Pharmacotherapeutic Group: Lipid-lowering agents/cholesterol and triglyceride lowering products/fibrates. ATC Code: C10AB05.
Pharmacology: Pharmacodynamics: Fenofibrate is a fibric acid derivative whose lipid modifying effects in humans are mediated via activation of PPARα (peroxisome proliferator activated receptor type alpha).
Activation of PPAR increases the activity of lipoprotein lipase and reduces the production of apoliprotein CIII. Via this mechanism, fenofibrate raises lipolysis and elimination of atherogenic, triglyceride-rich particles from plasma. Activation of PPARα also induces an increase in the synthesis of apoproteins AI and AII.
The above-mentioned effects of fenofibrate lead to a reduction in very-low-density and low-density lipoproteins (VLDL and LDL) containing apolipoprotein B and an increase in the high-density lipoproteins (HDL) due to increased production of apoproteins AI and AII.
Patients with an elevated CAD risk commonly express an atherogenic lipoprotein phenotype characterized by an increased fraction of small dense LDL particles. By regulating the synthesis and catabolism of VLDL, fenofibrate lowers the levels of small dense LDL and increases LDL clearance.
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%.
In hypercholesterolaemic patients, where LDL cholesterol levels are reduced by 20 to 35%, the overall effect on cholesterol results in a decrease in the ratios of total cholesterol to HDL cholesterol, LDL cholesterol to HDL cholesterol or apo B to apo AI, all of which are markers of atherogenic risk.
There is evidence that treatment with fibrates may reduce coronary heart disease events but it has not been shown to decrease all-cause mortality in the primary or secondary prevention of cardiovascular disease.
The Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial was a randomized placebo-controlled study in 5518 patients with type 2 diabetes mellitus treated with fenofibrate in addition to simvastatin. Treatment with fenofibrate plus simvastatin did not show significant differences in the composite primary endpoint of non-fatal myocardial infarction, non-fatal stroke and cardiovascular deaths compared to simvastatin monotherapy (hazard ratio [HR] 0.92; 95% CI: 0.79 to 1.08; p=0.32; absolute risk reduction: 0.74%). In the pre-specified subgroup of dyslipidemic patients, defined as those in the lowest tertile of HDL-C (≤ 34 mg/dL or 0.88 mmol/L) and highest tertile of TG (≥ 204 mg/dL or 2.3 mmol/L), fenofibrate plus simvastatin therapy demonstrated a 31% relative risk reduction compared to simvastatin monotherapy for the composite primary outcome criterion (HR 0.69; 95% CI 0.49 to 0.97; p = 0.03; absolute risk reduction: 4.95%). Another pre-specified subgroup analysis identified a statistically significant treatment-by-gender interaction (p = 0.01) indicating a possible treatment benefit of combination therapy in men (p = 0.037) but a potentially higher risk for the primary endpoint in women treated with combination therapy compared to simvastatin monotherapy (p = 0.069). This was not observed in the above-mentioned subgroup of patients with dyslipidemia, but there was also no clear evidence of benefit in dyslipidemic women treated with fenofibrate plus simvastatin, and a possible harmful effect in this subgroup could not be ruled out.
At present time, no results of long-term controlled clinical trials are available to demonstrate the efficacy of fenofibrate in the primary or secondary prevention of atherosclerotic complications.
Extravascular deposits of cholesterol (tendinous and tuberous xanthomas) may be markedly reduced or even entirely eliminated during fenofibrate therapy.
In patients with elevated baseline Lp(a) or fibrinogen levels, treatment with fenofibrate produced a significant lowering of Lp(a) or fibrinogen concentrations. Other inflammatory markers such as C-reactive protein are reduced with fenofibrate treatment.
Fenofibrate produces an approximately 25% reduction of uric acid levels. This is of additional benefit in hyperuricemic patients with disorders of lipid metabolism.
In animal studies and a clinical trial, fenofibrate inhibited platelet aggregation induced by ADP, arachidonic acid and epinephrine
Pharmacokinetics: LIPANTHYL SUPRA 160 mg is a film-coated tablet containing 160 mg of micronised fenofibrate and is suprabioavailable (larger bioavailability) compared to the previous formulations.
LIPANTHYL PENTA 145 contains 145 mg of fenofibrate nanoparticles.
Absorption: Lipanthyl Supra 160: Maximum plasma concentrations (Cmax) occur within 4 to 5 hours after oral administration. Plasma concentrations are stable during continuous treatment in any given individual.
The absorption of fenofibrate is increased when administered with food.
Lipanthyl Penta 145: Maximum plasma concentrations (Cmax) occur within 2 to 4 hours after oral administration. Plasma concentrations remian constant in response to repeated administration.
Contrarily to previous fenofibrate formulations, the maximum plasma concentration and overall uptake of the nanoparticle formulation is independent from food intake. Therefore, the medicinal product may be taken without regard to meals.
A study involving administration of the 145 mg film-coated tablet formulation of fenofibrate to healthy male and female subjects under fasting conditions and with a high fat meal indicated that exposure (AUC and Cmax) to fenofibric acid is not affected by food.
Distribution: Fenofibric acid is strongly bound to plasma albumin (more than 99%).
Metabolism and Excretion: After oral administration, fenofibrate is rapidly hydrolised by esterases to the active metabolite fenofibric acid. No unchanged fenofibrate can be detected in the plasma. Fenofibrate is not a substrate for CYP 3A4. No hepatic microsomal metabolism is involved. The drug is excreted mainly in the urine. Practically all the drug is eliminated within 6 days.
Fenofibrate is mainly excreted in the form of fenofibric acid and its glucuronide conjugate. In elderly patients, the fenofibric acid apparent total plasma clearance is not modified.
Kinetic studies following the administration of a single dose and continuous treatment have demonstrated that the drug does not accumulate. Fenofibruc acid is not eliminated by haemodialysis.
The plasma elimination half-life of fenofibric acid is approximately 20 hours.
Fenofibrate is not a substrate for CYP3A4. No hepatic microsomal metabolism is involved.
The active substance is mainly eliminated by the renal route. Elimination is virtually complete within 6 days. Fenofibrate is mainly excreted in the form of fenofibric acid and its glucuronide conjugate. Plasma clearance of fenofibric acid is unchanged in the elderly population.
Pharmacokinetic studies with single and repeated dosing have shown that the active substance does not accumulate. Fenofibric acid is not eliminated by hemodialysis.
The plasma elimination half-life of fenofibric acid is approximately 20 hours.
Toxicology: Preclinical Safety Data: Chronic toxicity studies have yielded no relevant information about specific toxicity of fenofibrate.
Studies on mutagenicity of fenofibrate have been negative.
In rats and mice, liver tumors have been found at high dosages, which are attributable to peroxisome proliferation. These changes are specific to small rodents and have not been observed in other animal species. This is of no relevance to therapeutic use in humans.
Studies in mice, rats and rabbits did not reveal any teratogenic effect. Embryotoxic effects were observed at doses in the range of maternal toxicity. Prolongation of the gestation period and difficulties during delivery were observed at high doses. No sign of any effect on fertility has been detected.
Indications/Uses
Lipanthyl Supra 160: Hypercholesterolaemia and hypertriglyceridaemia alone or combined (types IIa, IIb, IV dyslipidaemias, as well as types III and V dyslipidaemias) in patients unresponsive to dietary and other non-drug therapeutic measures (e.g. weight reduction or increased physical activity), particularly when there is evidence of associated risk factors such as hypertension and smoking.
The treatment of secondary hyperlipoproteinaemias is indicated if the hyperlipoproteinaemia persists despite effective treatment of the underlying disease (e.g. dyslipidaemia in diabetes mellitus).
Dietary measures initiated before therapy should be continued.
Lipanthyl Penta 145: LIPANTHYL PENTA 145 is indicated as an adjunct to diet and other non-pharmacological treatment (e.g. exercise, weight reduction) for the following conditions: Severe hypertriglyceridemia with or without low HDL cholesterol.
Mixed hyperlipidemia when a stain is contraindicated or not tolerated.
Mixed hyperlipidemia in patients at high cardiovascular risk in addition to a statin when triglycerides and HDL cholesterol are not adequately controlled.
Dosage/Direction for Use
During treatment, diet should be continued and serum levels of total C, LDL-C and triglycerides should be determined periodically. If an adequate lipid-lowering response has not been achieved after several months of treatment with fenofibrate (e.g. 3 months), complementary or different therapeutic measures should be considered.
Posology: Adults: Lipanthyl Supra 160: The recommended dose is one tablet containing 160 mg fenofibrate daily.
Patients receiving one LIPANTHYL 200 mg capsule of micronized fenofibrate can be switched to one tablet of LIPANTHYL 160 mg film-coated tablet without any dose adjustment.
Lipanthyl Penta 145: Recommended daily dose: 1 film-coated tablet once daily (containing 145 mg fenofibrate) once daily. Patients currently taking fenofibrate 200 mg or 160 mg once daily can be changed to LIPANTHYL PENTA 145 (1 film-coated tablet daily) without further dose adjustment.
Children: Lipanthyl Supra 160: The use of the 160 mg dosage form is contraindicated.
Lipanthyl Penta 145: Safety and efficacy of fenofibrate have not been sufficiently established in children and adolescents below the age of 18. No studies are available. Therefore, the use of fenofibrate in children and adolescents below the age of 18 is not recommended.
Elderly patients: In elderly patients, without renal impairment, the usual adult dose is recommended.
Patients with renal impairment: A dosage reduction is recommended in patients with renal impairment. The use of other forms containing a lower dose of the active substance (67 mg of micronized fenofibrate in capsules or 100 mg of standard fenofibrate in capsules) is recommended in these patients.
Patients with hepatic impairment:
This disease has not been evaluated in clinical studies.
The dietary measures initiated before treatment must be continued.
If the serum lipid levels have not sufficiently decreased after several months (e.g. 3 months) of treatment, complementary or different therapeutic measures should be considered.
Method of administration: Lipanthyl Supra 160: Tablets should be swallowed whole during a meal.
Lipanthyl Penta 145: The film-coated tablet should be swallowed whole with a glass of water. It may be taken at any time of the day, with or without food (see Pharmacology: Pharmacokinetics under Actions).
Overdosage
Only isolated reports of fenofibrate overdose have been received. In the majority of cases no overdose symptoms were reported. No case of overdose has been reported. No specific antidote is known. If an overdose is suspected, treat symptomatically ad institute appropriate supportive measures as required. Fenofibrate cannot be eliminated by haemodialysis.
Contraindications
Contra-indicated in children, during pregnancy or lactation, in patients with liver insufficiency (including biliary cirrhosis and unexplained persistent liver function abnormality e.g. persistent elevations in serum transaminases), severe chronic kidney disease, in patients hypersensitive to fenofibrate and/or excipients, known photoallergy or phototoxic reaction during treatment with fibrates or ketoprofen, chronic or acute pancreatitis with the exception of acute pancreatitis due to severe hypertriglyceridemia, known gallbladder disease. LIPANTHYL PENTA 145/LIPANTHYL SUPRA 160 mg should not be taken in patients allergic to peanut or arachis oil or soya lecithin or related products due to the risk of hypersensitivity reactions (see Precautions).
Special Precautions
Secondary cause of hypercholesterolemia (such as uncontrolled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemia, obstructive liver disease, other pharmacological treatment, alcoholism) should be ruled out or treated before therapy with LIPANTHYL SUPRA 160/LIPANTHYL PENTA 145 is initiated.
Response to therapy should be monitored by determination of serum lipid values (total cholesterol), LDL-Cholesterol, triglycerides), if an adequate response has not been achieved after several months (e.g. 3 months) complementary or different therapeutic measures should be considered.
For hyperlipidemic patients taking estrogens or contraceptives containing estrogens, it should be ascertained whether the hyperlipidemia is of primary or secondary nature (possible elevation of lipid values caused by oral estrogen).
Liver Function: As with other lipid lowering agents, increases have been reported in transaminase levels in some patients. In the majority of cases these elevations were transient, minor and asymptomatic. It is recommended that transaminase levels be monitored every 3 months during the first 12 months of treatment and thereafter periodically. Attention should be paid to patients who develop increase in transaminase levels and therapy should be discontinued if ASAT (SGOT) and ALAT (SGPT) levels increase to more than 3 times the upper limit of the normal range. When symptoms indicative of hepatitis occur (e.g. jaundice, pruritus), laboratory tests are to be conducted for verification and diagnosis is confirmed by laboratory testing, discontinuation of fenofibrate therapy may should be considered discontinued.
Pancreatitis: One pancreatitis has been reported in patients receiving fenofibrate.
This occurrence may represent a failure of efficacy in patients with severe hypertriglyceridemia, a direct effect of the medicinal product, or to a secondary phenomenon mediated through biliary tract stone or sludge formation with obstruction of the common bile duct.
Muscle: Muscle toxicity, including rare cases of rhabdomyolysis, has been reported with administration of fibrates and other lipid-lowering agents. The incidence of this disorder increases in cases of hypoalbuminaemia and previous renal insufficiency. Patients with pre-disposing factors for myopathy and/or rhabdomyolysis, including age above 70 years old, personal or familial history of hereditary muscular disorders, renal impairment, hypothyroidism and high alcohol intake, may be at an increased risk of developing rhabdomyolysis. For these patients, the putative benefits and risks of fenofibrate therapy should be carefully weighed up.
Muscle toxicity should be suspected in patients presenting diffuse myalgia, myositis, muscular cramps and weakness and/or marked increases in CPK (levels exceeding 5 times the normal range). In such cases treatment with fenofibrate should be stopped.
The risk of muscle toxicity may be increased if the drug is administered with another fibrate or an HMG-CoA reductase inhibitor, especially in cases of preexisting muscular disease. Consequently, the co-prescription of fenofibrate with an HMG-CoA reductase inhibitor or another fibrate, should be reserved to patients with severe combined dyslipidaemia and high cardiovascular risk without any history of muscular disease. This combination therapy should be used with caution and patients should be monitored closely for signs of and with a close monitoring of potential muscle toxicity.
Renal Function:
Treatment should be interrupted in case of an increase in creatinine levels > 50% ULN (upper limit of normal). It is recommended that creatinine measurement may be considered during the first three months after initiation of treatment and thereafter periodically (for dose recommendations, see Dosage & Administration).
Lipanthyl Penta 145: Treatment should be discontinued in case of an increase in creatinine levels to > 50% above the upper limit of normal. It is recommended that creatinine is measured during the first 3 months after initiation of treatment and thereafter periodically (for dose recommendations, see Dosage & Administration).
Excipients: This medicinal product contains lactose. Therefore, patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take LIPANTHYL SUPRA 160/LIPANTHYL PENTA 145.
This medicinal product contains sucrose (sugar). Therefore, patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take LIPANTHYL SUPRA 160/LIPANTHYL PENTA 145.
Patients allergic to soya lecithin or related products should not take LIPANTHYL SUPRA 160/LIPANTHYL PENTA 145 due to the risk of hypersensitivity reactions (see Contraindications).
Fenofibrate was not shown to reduce coronary heart disease morbidity and mortality in 2 large, randomized controlled trials (the ACCORD lipid trial and FIELD study) in patients with type 2 diabetes mellitus.
Effects on the ability to drive and use machines: LIPANTHYL SUPRA 160/LIPANTHYL PENTA 145 has no influence on the ability to drive and use machines.
Use In Pregnancy & Lactation
Pregnancy: There are no adequate data on the use of fenofibrate during pregnancy. Animal studies have not demonstrated any teratogenic effects. Embryotoxic effects were observed at doses in the range of maternal toxicity (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). It is unknown if this is of relevance to therapeutic use in humans. Therefore, LIPANTHYL SUPRA 160/LIPANTHYL PENTA 145 should only be used during pregnancy after a careful benefit/risk assessment.
Lactation: There are no data on the excretion of fenofibrate and/or its metabolites into breast milk. A risk to the suckling child cannot be excluded. Consequently, LIPANTHYL SUPRA 160/LIPANTHYL PENTA 145 should not be used in nursing mothers.
Adverse Reactions
Lipanthyl Supra 160: The frequencies: 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.
Gastrointestinal disorders: Common: Digestive, gastric or intestinal disorders (abdominal pain, nausea, vomiting, diarrhoea, and flatulence).
Uncommon: Pancreatitis.
Hepato-biliary disorders: Common: Moderately elevated levels of serum transaminases.
Uncommon: Cholelithiasis.
Rare: episodes of hepatitis. When symptoms (e.g. jaundice, pruritus) indicative of hepatitis occur, laboratory tests are to be conducted for verification and fenofibrate discontinued, if applicable.
Skin and subcutaneous tissue disorders: Uncommon: rashes, pruritus, urticaria.
Rare: alopecia, cutaneous photosensitivity reactions with erythema, vesiculation or nodulation on parts of the skin exposed to sunlight or artificial UV light (e.g. sunlamp) individual cases (even after many months of uncomplicated use).
Musculoskeletal, connective tissue and bone disorders: Uncommon: diffuse myalgia, myositis, muscular cramps and weakness.
Not known: rhabdomyolysis.
Cardiovascular system: Uncommon: Thromboembolism (pulmonary embolism, deep vein thrombosis).
Blood and lymphatic system disorders: Rare: decrease in haemoglobin and leukocytes.
Nervous system disorders: Uncommon: sexual asthenia, headache.
Respiratory, thoracic and mediastinal disorders: Not known: intestinal pneumopathies.
Hepatobiliary disorders: Jaundice, complications of cholethiasis (e.g. cholecystitis, cholangitis, biliary colic).
Investigation: Uncommon: Increases in serum creatinine and urea.
Skin and Subcutaneous Tissue Disorders: severe cutaneous reactions (e.g. erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis)
*In the FIELD-study, a randomized placebo-controlled trial perfomed in 9795 patients with type 2 diabetes mellitus, a statistically significant increase in pancreatitis cases was observed in patients receiving fenofibrate versus patients receiving placebo (0.8% versus 0.5%; p=0.031). In the same study, a statistically significant increase was reported in the incidence of pulmonary embolism (0.7% in the placebo group versus 1.1% in the fenofibrate group; p=0.022) and a statistically non-significant increase in deep vein thrombosis (placebo: 1.0 % [48/4900 patients] versus fenofibrate 1.4% [67/4895 patients]; p= 0.074).
Lipanthyl Penta 145: The most commonly reported adverse effects during fenofibrate therapy are digestive, gastric or intestinal disorders.
The following undesirable effects have been observed during plcaebo-controlled clinical trials (n=2344) with the frequencies indicated as follows: see Table.

Click on icon to see table/diagram/image

*In the FIELD-study, a randomized placebo-controlled trial perfomed in 9795 patients with type 2 diabetes mellitus, a statistically significant increase in pancreatitis cases was observed in patients receiving fenofibrate versus patients receiving placebo (0.8% versus 0.5%; p=0.031). In the same study, a statistically significant increase was reported in the incidence of pulmonary embolism (0.7% in the placebo group versus 1.1% in the fenofibrate group; p=0.022) and a statistically non-significant increase in deep vein thrombosis (placebo: 1.0 % [48/4900 patients] versus fenofibrate 1.4% [67/4895 patients]; p= 0.074).
Respiratory tract, thoracic and mediastinal disorders: Interstitial pulmonary disease.
Musculoskeletal and connective tissue disorders: Rhabdomyolysis.
Hepatobiliary disorders: Jaundice, complications of cholelithiasis (e.g. cholecystitis, cholangitis, biliary colic).
Skin and Subcutaneous Tissue Disorders: Severe cutaneous reactions (e.g. erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis).
Drug Interactions
Oral anticoagulants: Fenofibrate enhances oral anticoagulant effect and may increase risk of bleeding. It is recommended that the dose of anticoagulants is reduced by about one third at the start of treatment and then gradually adjusted if necessary according to INR (International Normalised Ratio) monitoring. Therefore, this combination is not recommended.
Cyclosporine: Some severe cases of reversible renal function impairment have been reported during concomitant administration of fenofibrate and cyclosporin. The renal function of these patients must therefore be closely monitored and the treatment with fenofibrate stopped in the case of severe alteration of laboratory parameters.
HMG-CoA reductase inhibitors and other fibrates: The risk of severe muscle toxicity is increased if the fenofibrate a fibrate is used concomitantly with HMG-CoA reductase inhibitors or other fibrates. Such combination therapy should be used with caution and patients should be monitored closely for signs of muscle toxicity (see Precautions).
Glitazones: Some cases of reversible paradoxical reduction of HDL-cholesterol have been reported during concomitant administration of fenofibrate and glitazones. Therefore, it is recommended to monitor HDL-cholesterol if one of these components is added to the other and stopping of either therapy if HDL-cholesterol is too low.
Cytochrome P450 enzymes: 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.
Caution For Usage
Incompatibilities: Not applicable.
Instructions for Use and Handling: No special requirements.
Storage
Lipanthyl Supra 160: Store in the original package at a temperature below + 25°C.
Lipanthyl Penta 145: Store in the original package, at a temperature not exceeding 30°C.
Shelf-life: 3 years.
ATC Classification
C10AB05 - fenofibrate ; Belongs to the class of fibrates. Used in the treatment of hyperlipidemia.
Presentation/Packing
Lipanthyl Supra 160: Film-coated tab 160 mg (micronised) x 30's.
Lipanthyl Penta 145: Film-coated tab 145 mg (nanoparticles) (white, oblong, engraved "145" on one side and the "F" logo on the other side) x 30's.
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