Lipanthyl Penta/Lipanthyl Supra

Fenofibrate.

Lipanthyl Penta: One film-coated tablet contains 145.0mg fenofibrate (nanoparticles).
Excipients with known effect: each tablet contains: 132.00mg of Lactose monohydrate, 145.00mg of Sucrose, 0.50mg of Soybean lecithin.
Lipanthyl Supra: Each tablet contains 160.0mg fenofibrate.
Excipients with known effect: each tablet contains: 138.4mg Lactose monohydrate, 0.56mg of Soybean lecithin.
Excipients/Inactive Ingredients: Coating: Polyvinyl alcohol, Titanium dioxide (E171), Talc, Soybean lecithin, Xanthan gum.
Core: Lipanthyl Penta: Sucrose, Lactose monohydrate, Silicified microcrystalline cellulose, Crospovidone, Hypromellose, Sodium lauril sulfate, Docusate sodium, Magnesium stearate.
Lipanthyl Supra: Sodium laurilsulfate, lactose monohydrate, povidone, microcrystalline cellulose, silica colloidal anhydrous, crospovidone, sodium stearyl fumarate.

Pharmacotherapeutic Group: Serum Lipid Reducing Agents/Cholesterol and Triglycerides Reducers/Fibrates. ATC code: C10 AB 05.
Pharmacology: Pharmacodynamics: Dyslipidaemia: Fenofibrate is a fibric acid derivative 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. Activation of PPARα also induces an increase in the synthesis of apoproteins AI and AII.
The previously 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.
In addition, through modulation of the synthesis and the catabolism of VLDL fractions fenofibrate increases the LDL clearance and reduces small dense LDL, the levels of which are elevated in the atherogenic lipoprotein phenotype, a common disorder in patients at risk for coronary heart disease.
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, or a decrease of the levels of non-HDL cholesterol all of which are markers of atherogenic risk.
Extravascular deposits of cholesterol (tendinous and tuberous xanthoma) may be markedly reduced or even entirely eliminated during fenofibrate therapy.
Patients with raised levels of fibrinogen treated with fenofibrate have shown significant reductions in this parameter, as have those with raised levels of Lp(a). Other inflammatory markers such as C Reactive Protein are reduced with fenofibrate treatment.
The uricosuric effect of fenofibrate leading to reduction in uric acid levels of approximately 25% should be of additional benefit in those dyslipidaemic patients with hyperuricaemia.
Fenofibrate has been shown to possess an anti-aggregatory effect on platelets in animals and in a clinical study, which showed a reduction in platelet aggregation induced by ADP, arachidonic acid and epinephrine.
Lipanthyl Penta: Diabetic Retinopathy: Several mechanisms have been proposed to explain the effects of fenofibrate in proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME) in vitro and in rodent models. Fenofibrate was shown to reduce the retinal expression of VEGF, the major angiogenic factor in PDR and to reduce vascular permeability and apoptosis of retinal pigmented epithelium, which contributes to development of DME.
The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a multinational randomized trial of 9795 patients with type 2 diabetes mellitus. Eligible patients were randomly assigned to receive fenofibrate 200 mg/day (n=4895) or matching placebo (n=4900). In a sub study of 1012 patients (ophthalmology sub study), standardized retinal photography was done and photographs graded with Early Treatment Diabetic Retinopathy Study (ETDRS) criteria to determine the cumulative incidence of diabetic retinopathy and its component lesions. Analyses were by intention to treat. In the ophthalmology sub study, the primary endpoint of 2-step progression of retinopathy grade did not differ significantly between the two groups overall (46 [9.6%] patients on fenofibrate vs 57 [12.3%] on placebo; p=0.19) or in the subset of patients without pre-existing retinopathy (43 [11.4%] vs 43 [11.7%]; p=0.87). By contrast, in patients with pre-existing retinopathy, significantly fewer patients on fenofibrate had a 2-step progression than did those on placebo (three [3.1%] patients vs 14 [14.6%]; p=0.004).
At each clinic visit, information concerning laser treatment for diabetic retinopathy-a prespecified tertiary endpoint of the main study-was gathered. The requirement for first laser treatment for all retinopathy was significantly lower in the fenofibrate group than in the placebo group (164 [3.4%] patients on fenofibrate vs. 238 [4.9%] on placebo; hazard ratio [HR] 0.69, 95% CI 0.56-0.84; p=0.0002; absolute risk reduction 1.5% [0.7-2.3]). The need for such treatment was not affected by plasma lipid concentrations.
In a subgroup of 2856 participants of the ACCORD study, ACCORD Eye evaluated the effects of three interventions strategies, on the progression of diabetic retinopathy; intensive or standard treatment for glycaemia (target HbA1c <6.0% or 7.0 to 7.9%, respectively), dyslipidaemia (160 mg daily of fenofibrate plus simvastatin or placebo plus simvastatin) or systolic blood-pressure control (target, <120 or <140 mmHg). Progression of diabetic retinopathy was defined at 4 years by 3 or more steps on the ETDRS scale (as assessed from seven-field stereoscopic fundus photographs) or the development of diabetic retinopathy necessitating laser photocoagulation or vitrectomy.
The rate of progression of diabetic retinopathy was 6.5% with fenofibrate for intensive dyslipidaemia therapy, versus 10.2% with placebo (adjusted odds ratio, 0.60; 95% CI, 0.42 to 0.87; P=0.006). It was concluded that intensive combination treatment of dyslipidaemia reduced the rate of progression of diabetic retinopathy.
An integrated analysis was performed from Patient individual Data from the FIELD study and the published information from ACCORD Eye publications. The combined primary endpoint of ACCORD Eye was applied to FIELD i.e. 3-step ETDRS severity scale, photocoagulation or vitrectomy for proliferative diabetic retinopathy. The two studies were homogeneous (fixed effect model applicable) and showed an overall 60% reduction in the progression of diabetic retinopathy, OR: 0.40; 95% CI (0.26-0.61) for subjects with existing DR at baseline. (See figure.)

Click on icon to see table/diagram/image

FIELD and ACCORD studies excluded patients with severe non-proliferative and proliferative diabetic retinopathy at baseline.
Pharmacokinetics: LIPANTHYL PENTA 145, film-coated tablet contains 145 mg of fenofibrate nanoparticles.
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.
Absorption: Lipanthyl Penta: Maximum plasma concentrations (Cmax) occur within 2 to 4 hours after oral administration. Plasma concentrations are stable during continuous treatment in any given individual.
Contrarily to previous fenofibrate formulations, the maximum plasma concentration and overall exposure of the nanoparticle formulation is independent from food intake. Therefore, LIPANTHYL PENTA 145, film-coated tablet may be taken without regard to meals.
A food-effect study involving administration of the new 145 mg 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.
Lipanthyl Supra: 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.
Distribution: Fenofibric acid is strongly bound to plasma albumin (more than 99%).
Metabolism and excretion: After oral administration, fenofibrate is rapidly hydrolysed by esterases to the active metabolite fenofibric acid. No unchanged fenofibrate can be detected in the plasma. Fenofibrate is not a substrate for CYP3A4. 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. Fenofibric acid is not eliminated by haemodialysis.
The plasma elimination half-life of fenofibric acid is approximately 20 hours.
Toxicology: Preclinical safety data: Acute toxicity studies have yielded no relevant information about specific toxicity of fenofibrate.
In a three-month oral nonclinical study in the rat species with fenofibric acid, the active metabolite of fenofibrate, toxicity for the skeletal muscles (particularly those rich in type I - slow oxidative-myofibres) and cardiac degeneration, anemia and decreased body weight were seen at exposure levels ≥50-fold the human exposure for the skeletal toxicity and >15 fold for the cardiomyotoxicity.
Reversible ulcers and erosions in the gastro-intestinal tract occurred in dogs treated during 3 months at exposures approximately 7-fold the clinical AUC.
Studies on mutagenicity have been negative.
In rats and mice, liver tumours 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 man.
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 effects on fertility were detected in non-clinical reproductive toxicity studies conducted with fenofibrate. However reversible hypospermia and testicular vacuolation and immaturity of the ovaries were observed in a repeat-dose toxicity study with fenofibric acid in young dogs.

Hypercholesterolaemia and hypertriglyceridaemia alone or combined (type IIa, IIb, III, IV 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 hyperlipoproteinaemia is indicated if the hyperlipoproteinaemia persists despite effective treatment of the underlying disease (e.g. dyslipidaemia in diabetes mellitus).
Appropriate dietary measures initiated before therapy should be continued.
Lipanthyl Penta: LIPANTHYL PENTA 145 is indicated for the reduction in the progression of diabetic retinopathy in patients with type 2 diabetes and existing diabetic retinopathy. Lipanthyl does not replace the appropriate control of blood pressure, blood glucose and blood lipids in reducing the progression of diabetic retinopathy.

Posology: Adults: Lipanthyl Penta: The recommended dose is one tablet containing 145 mg fenofibrate taken once daily. Patients currently taking one 200mg capsule or one 160mg tablet can be changed to one 145 mg fenofibrate tablet without further dose adjustment.
For hyperlipidaemia indications, response to therapy should be monitored by determination of serum lipid values. If an adequate response has not been achieved after several months (e.g. 3 months), complementary or different therapeutic measures should be considered.
If a patient needs fenofibrate for both hyperlipidemia and diabetic retinopathy indications, only one tablet of fenofibrate 145 mg per day should be taken.
Lipanthyl Supra: 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.
Posology: Adults: The recommended dose of LIPANTHYL SUPRA 160 mg tablets is one tablet taken once daily. Patients currently taking one 160 mg tablet can be changed to one 145 mg fenofibrate tablet without further dose adjustment.
Special Populations: Geriatric population: In elderly patients, without renal impairment, the usual adult dose is recommended.
Renal impairment: Dosage reduction is required in patients with renal impairment.
In moderate chronic kidney disease (creatinine clearance 30 to 59 mL/min), and if a low dose is available, start with one capsule of 100 mg standard or 67 mg micronized once daily.
If no low dose is available, then fenofibrate is not recommended.
In patients with severe (Lipanthyl Penta)/chronic (Lipanthyl Supra) kidney disease (creatinine clearance <30 ml/min), fenofibrate is contraindicated.
Hepatic impairment: LIPANTHYL PENTA 145/LIPANTHYL SUPRA 160 is not recommended for use in patients with hepatic impairment due to the lack of data.
Paediatric population: The safety and efficacy of fenofibrate in children and adolescents younger than 18 years has not been established. No data are available. Therefore the use of fenofibrate is not recommended in paediatric subjects under 18 years.
Method of administration: Lipanthyl Penta: LIPANTHYL PENTA 145, film-coated tablet may be given at any time of the day, with or without food (see Pharmacology: Pharmacokinetics under Actions). Tablet should be swallowed whole with a glass of water.
Lipanthyl Supra: Tablets should be swallowed whole during a meal.

Only anecdotal cases of fenofibrate overdosage have been received. In the majority of cases, no overdose symptoms were reported.
No specific antidote is known. If an overdose is suspected, treat symptomatically and institute appropriate supportive measures as required. Fenofibrate cannot be eliminated by haemodialysis.

Hepatic insufficiency (including biliary cirrhosis and unexplained persistent liver function abnormality), Known gallbladder disease, Severe chronic kidney disease, Chronic or acute pancreatitis with the exception of acute pancreatitis due to severe hypertriglyceridemia, Known photoallergy or phototoxic reaction during treatment with fibrates or ketoprofen, Hypersensitivity to the active substance(s) or to any of the excipients listed in Description.
LIPANTHYL PENTA 145/LIPANTHYL SUPRA 160 should not be taken in patients allergic to peanut or arachis oil or soybean/soya lecithin or related products due to the risk of hypersensitivity reactions.

Secondary causes of hyperlipidemia: Secondary cause of hypercholesterolemia/hyperlipidemia, such as uncontrolled type 2 diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemia, obstructive liver disease, pharmacological treatment, alcoholism, should be adequately treated before fenofibrate therapy is initiated.
For hyperlipidaemic patients taking estrogens or contraceptives containing oestrogens it should be ascertained whether the hyperlipidaemia is of primary or secondary nature (possible elevation of lipid values caused by oral oestrogen).
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 should be considered.
Pancreatitis: Pancreatitis has been reported in patients receiving fenofibrate (see Contraindications and Adverse Reactions). This occurrence may represent a failure of efficacy in patients with severe hypertriglyceridemia, a direct drug effect, or a secondary phenomenon mediated through biliary tract stone or sludge formation with obstruction of the common bile duct.
Muscle: Muscle toxicity, including very rare (Lipanthyl Penta) or rare (Lipanthyl Supra) cases of rhabdomyolysis, with or without renal failure (Lipanthyl Supra), 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 (Lipanthyl Penta: levels exceeding 5 times the upper normal range) (Lipanthyl Supra: 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 (statins), especially in cases of pre-existing muscular disease. Consequently, the co-prescription of fenofibrate with a statin (Lipanthyl Penta)/an HMG-CoA reductase inhibitor (Lipanthyl Supra) or another fibrate should be reserved to patients with severe combined dyslipidaemia and high cardiovascular risk without any history of muscular disease and with a close monitoring of potential muscle toxicity (Lipanthyl Supra).
Lipanthyl Penta: This combination therapy should be used with caution and patients should be monitored closely for signs of muscle toxicity.
Renal Function: Treatment should be interrupted in case of an increase in creatinine levels >50% and ULN (upper limit of normal). It is recommended that creatinine is measured during the first three 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, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Lipanthyl Penta: This medicinal product contains sucrose, therefore patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
LIPANTHYL PENTA 145, film-coated tablet should not be taken in patients allergic to soybean lecithin or related products due to the risk of hypersensitivity reactions.
Effects on the ability to drive and use machines: LIPANTHYL PENTA 145/LIPANTHYL SUPRA 160 has no or negligible influence on the ability to drive and use machines.

Fertility: Reversible effects on fertility have been observed in animals (see Pharmacology: Toxicology: Preclinical safety data under Actions). There are no clinical data on fertility from the use of LIPANTHYL PENTA 145/LIPANTHYL SUPRA 160.
Pregnancy: There are no adequate data from the use of fenofibrate in pregnant women. Animal studies have not demonstrated any teratogenic effects. Embryotoxic effects have been shown at doses in the range of maternal toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions). The potential risk for humans is unknown. Therefore, fenofibrate should only be used during pregnancy after a careful benefit/risk assessment.
Lactation: It is unknown whether fenofibrate and/or its metabolites are excreted in human milk. A risk to the suckling child cannot be excluded. Therefore, fenofibrate should not be used during breast-feeding.

The most commonly reported ADRs during LIPANTHYL PENTA 145/LIPANTHYL SUPRA 160 therapy are digestive, gastric or intestinal disorders.
The following undesirable effects have been observed during placebo-controlled clinical trials (n=2344) with the indicated frequencies as follows: (See table.)

Click on icon to see table/diagram/image

In addition to those events reported during clinical trials, the following side effects have been reported spontaneously during postmarketing use of LIPANTHYL PENTA 145/LIPANTHYL SUPRA 160. A precise frequency cannot be estimated from the available data and is therefore classified as "not known".
Respiratory, thoracic and mediastinal disorders: Interstitial lung disease.
Musculoskeletal, connective tissue and bone 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).
Nervous system disorders: Fatigue.

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 (Lipanthyl Penta).
Cyclosporin: 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: Lipanthyl Penta: The risk of serious muscle toxicity is increased if a fibrate is used concomitantly with HMG-CoA reductase inhibitors or other fibrates.
Combination therapy with HMG-CoA reductase inhibitors should be used with caution and patients monitored closely for signs of muscle toxicity (see Precautions).
Lipanthyl Supra: The risk of severe muscle toxicity may be increased if the drug is administered in combination with another fibrate or an HMG-CoA reductase inhibitor. This 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.

Incompatibilities: Not applicable.
Special precautions for disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Lipanthyl Penta: Store in the original package in order to protect from light and moisture, at a temperature not exceeding 30°C.
Lipanthyl Supra: Store in the original package in order to protect from moisture.
Store at a temperature at or below 30°C.

Dyslipidaemic Agents

C10AB05 - fenofibrate ; Belongs to the class of fibrates. Used in the treatment of hyperlipidemia.

POM