LIPANTHYL 145 is indicated as supportive treatment in addition to diet or other non-drug therapies (e.g. exercise, weight loss) for the following diseases:

• Severe hypertriglyceridaemia with or without low HDL cholesterol levels

• Mixed hyperlipidemia when a statin is contraindicated or not tolerated

• for mixed hyperlipidaemia in patients at high cardiovascular risk as an adjunct to a statin when triglyceride and HDL-cholesterol levels are not adequately controlled

During therapy with this drug, the diet should be continued. The response to treatment should be monitored by determining serum lipid levels. If an adequate lipid-lowering effect is not achieved after several months of treatment with fenofibrate (e.g. 3 months), additional or alternative therapeutic measures should be considered.

Dosage:

Adult:

Recommended daily dose: 1 film-coated tablet (equivalent to 145 mg fenofibrate) daily.

Patients currently treated with fenofibrate 200 mg or fenofibrate 160 mg once daily can be switched to LIPANTHYL 145 (1 film-coated tablet daily) without further dose adjustment.

Elderly patients (65 years and older):

Dose adjustment is not necessary. The usual dose is recommended, except in renally impaired patients with an estimated (estimated) glomerular filtration rate (eGFR) < 60 ml/min/1.73 m² (see “Patients with renal impairment”).

Patients with impaired renal function:

Fenofibrate must not be taken in severely impaired renal function with an eGFR < 30 ml/min/1.73 m².

With an eGFR between 30 and 59 ml/min/1.73 m², the daily dose should not exceed 100 mg fenofibrate (standard) or 67 mg micronized.

If at follow-up the eGFR falls persistently below 30 mL/min/1.73 m², fenofibrate should be discontinued.

Impaired liver function:

Due to the lack of data, the use of LIPANTHYL 145 in patients with impaired liver function is not recommended.

Children and young people:

The safety and efficacy of fenofibrate in children and adolescents under 18 years of age has not been adequately established. No data is available. For this reason, the use of fenofibrate in children and adolescents under 18 years of age is not recommended.

Type of application:

It can be taken at any time of the day with or without food (see section 5.2). The film-coated tablet should be swallowed whole with a glass of water.

• Hepatic insufficiency (including biliary cirrhosis and unexplained persistent liver function abnormality) • Known gallbladder disease • Severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m2) • Chronic or acute pancreatitis other than acute pancreatitis due to severe hypertriglyceridaemia • Known photoallergic or phototoxic reactions during treatment with fibrates or ketoprofen • Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Because of the risk of hypersensitivity reactions, LIPANTHYL 145 should not be taken by patients who are allergic to peanut, peanut oil, soya lecithin (3-sn-phosphatidylcholine) or related substances.

Secondary causes of hyperlipidemia:

Before considering therapy with LIPANTHYL 145, secondary causes of hypercholesterolaemia such as poorly controlled type 2 diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemia, obstructive liver disease or alcoholism should be adequately treated. Secondary causes of hypercholesterolaemia can occur through pharmacological therapies with diuretics, beta-blockers, estrogens, progestins, combined oral contraceptives, immunosuppressants and protease inhibitors. In these cases, it should be checked whether the hyperlipidaemia is primary or secondary (possible increase in lipid levels caused by these drugs).

Liver:

As with other lipid-lowering medicinal products, transaminase elevations have been reported in some patients receiving fenofibrate therapy. In the majority of cases observed, the increase was transient, minor and asymptomatic. It is recommended that the transaminase

Levels to be checked at 3-month intervals during the first 12 months of treatment and periodically thereafter.

Patients found to have elevated levels of transaminases should be carefully monitored. If ASAT (SGOT) and ALAT (SGPT) levels increase to more than three times the upper limit of normal, treatment should be discontinued. Fenofibrate should be discontinued if symptoms occur that indicate hepatitis (e.g. jaundice, itching) and if laboratory tests are confirmed.

Pancreas:

Pancreatitis has been reported to occur with fenofibrate treatment (see sections 4.3 and 4.8). In patients with severe hypertriglyceridaemia, this may be due to insufficient drug efficacy, a direct drug effect, or a secondary effect mediated by choledochal duct obstructive cholelithiasis.

muscles:

Myotoxicity and, rarely, rhabdomyolysis, with or without renal failure, have been reported with the use of fibrates and other lipid-lowering agents. The incidence of this disease increases in case of hypoalbuminemia and previous renal insufficiency. There is an increased risk of developing rhabdomyolysis in patients with predisposing factors for myopathy and/or rhabdomyolysis, including patients over 70 years of age, a history or family history of muscular disorders, renal dysfunction, hypothyroidism, and heavy alcohol consumption. Careful consideration of the risk/benefit ratio of fenofibrate therapy is required for this group of patients.

Diffuse myalgia, myositis, muscle spasms, muscle weakness and/or a significant increase in creatine phosphokinase CPK (increase of more than 5 times the upper limit of normal) are indicative of myotoxicity. In these cases, the drug should be discontinued.

The risk of myotoxicity may increase when this drug is combined with another fibrate or an HMG-CoA reductase inhibitor. This is especially true if muscle disorders already exist. Therefore, the combination of fenofibrate with an HMG-CoA reductase inhibitor or another fibrate should be restricted to patients with severe combined hyperlipidemia and high cardiovascular risk, who have no prior history of muscle disease, and these patients should be closely monitored for possible be monitored for myotoxicity.

kidney function:

Lipanthyl 145 is contraindicated in severely impaired renal function (see Section 4.3). Lipanthyl 145 should be used with caution in patients with mild to moderate renal insufficiency. Dose adjustment is required in patients with an eGFR between 30 and 59 mL/min/1.73 m² (see section 4.2).

Reversible increases in blood creatinine have been observed in patients receiving fenofibrate monotherapy or in combination with statins. Creatinine elevation was generally stable over time, with no signs of further increases observed with long-term therapy. After stopping treatment, a return to baseline was observed.

In clinical trials, 10% of patients treated with the combination of fenofibrate and simvastatin had a creatinine increase from baseline greater than 30 μmol/L compared to 4.4% of patients treated with statin alone. 0.3% of patients receiving the combination treatment had clinically relevant increases in creatinine greater than 200 μmol/L.

Treatment should be discontinued if creatinine exceeds 50% of the upper limit of normal. It is recommended that creatinine levels be monitored during the first three months after initiation of therapy and periodically thereafter.

Excipients:

As this medicine contains lactose, patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Because this medicine contains sucrose, patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase deficiency should not take this medicine.

This medicinal product contains less than 1 mmol (23 mg) sodium per film-coated tablet, i.e. essentially 'sodium-free'.

Oral anticoagulants:

Fenofibrate may potentiate the effects of oral anticoagulants and consequently cause an increased risk of bleeding. Therefore, at the beginning of the therapy, the dose of the anticoagulant should be reduced by about a third and, if necessary, adjusted while monitoring the coagulation parameters (International Normalized Ratio).

Cyclosporine:

In individual cases, a significant, albeit reversible, impairment of renal function has been reported when fibrate-containing medicinal products and ciclosporin are used at the same time. Therefore, renal function should be carefully monitored in these patients and fenofibrate should be discontinued if there are significant changes in laboratory parameters.

HMG-CoA reductase inhibitors and other fibrates:

The risk of serious muscle damage is increased when a fibrate is combined with HMG-CoA reductase inhibitors or other fibrates. Such combination therapy should be used with caution and patients should be carefully monitored for signs of muscle damage (see section 4.4).

glitazones:

A few cases of reversible paradoxical HDL-cholesterol lowering have been observed when fenofibrate and glitazone are taken concomitantly. For this reason, HDL cholesterol should be monitored when combining one of these agents with the other. Should the HDL cholesterol be too low, it is recommended to stop one of the two therapies.

Cytochrome P450 enzymes:

In vitro studies in human liver microsomes indicate that fenofibrate and fenofibric acid do not inhibit cytochrome (CYP) P450 isoforms CYP3A4, CYP2D6, CYP2E1 or CYP1A2. They are weak inhibitors of CYP2C19 and CYP2A6 and moderate inhibitors of CYP2C9 at therapeutic concentrations.

Patients who, in addition to fenofibrate, are taking other drugs with a narrow therapeutic index that are metabolised by CYP2C19, CYP2A6 and especially CYP2C9 should be carefully monitored. If necessary, the dosage of these drugs should be adjusted.

Pregnancy:

There are insufficient data on the use of fenofibrate in pregnant women. No teratogenic effects were observed in animal experiments. Embryotoxic effects were observed at doses in the maternally toxic range (see 5.3). The possible risk for humans is unknown. Therefore, LIPANTHYL 145 should only be taken during pregnancy after a careful assessment of the risk-benefit ratio.

Breastfeeding:

It is not known whether fenofibrate and/or its metabolites are excreted in human milk. A risk to the breastfed child cannot be excluded. Therefore, LIPANTHYL 145 should not be taken while breastfeeding.

fertility:

Reversible impairment of fertility has been observed in animal studies (see section 5.3).

There are no clinical data on the influence of LIPANTHYL 145 on fertility.

LIPANTHYL 145 has no or negligible influence on the ability to drive and use machines.

4.8 Adverse Reactions

The most frequently reported undesirable effects associated with fenofibrate treatment are indigestion or gastrointestinal disorders.

The following adverse reactions have been observed in placebo-controlled trials (n=2344) and post-marketing with the frequencies below:

MedDRA system organ classes	Frequently (≥1/100 to <1/10)	Occasionally (≥1/1,000 to <1/100)	Rarely (≥1/10,000 to <1/1,000)	Frequency unknown (cannot be derived from the available data)
Blood and lymphatic system disorders			decrease in hemoglobin, Decrease in leukocyte count
diseases of the immune system			hypersensitivity
Diseases of the nervous system		Headache
vascular diseases		Thromboembolism (pulmonary embolism, deep vein thrombosis)*
Respiratory, thoracic and mediastinal disorders				Interstitial lung diseases
Diseases of the gastrointestinal tract	Gastrointestinal signs and symptoms (abdominal pain, nausea, vomiting, diarrhea, flatulence)	pancreatitis*
Liver and biliary diseases	increase in transaminases (see section 4.4)	cholelithiasis (see section 4.4)	hepatitis	Jaundice, complications of cholelithiasis (eg, cholecystitis, cholangitis, biliary colic)a
Skin and subcutaneous tissue disorders		Hypersensitivity of the skin (e.g. erythema, pruritus, urticaria)	alopecia photosensitivity	Severe skin reactions (eg, erythema multiforme, Steven-Johnson syndrome, toxic epidermal necrolysis)a
Musculoskeletal, connective tissue and bone disorders		muscle diseases (e.g. myalgia, myositis, muscle spasms and weakness)		rhabdomyolysis
Diseases of the genital organs and the mammary gland		sexual dysfunction
General disorders and administration site conditions				fatigue
investigations	Increase in blood homocysteine**	Increase in blood creatinine	Increase in blood urea

* In the FIELD study, a randomized, placebo-controlled clinical trial of 9,795 patients with type 2 diabetes mellitus, there was a statistically significant increase in the incidence of pancreatitis in patients receiving fenofibrate compared to patients receiving placebo observed (0.8% vs. 0.5%; p=0.031). In the same study, there was a statistically significant increase 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 cases of deep vein thrombosis [placebo 1% ( 48/4900 patients) versus fenofibrate 1.4% (67/4895 patients); p=0.074] reported.

** The average increase in blood homocysteine levels in the treated patients in the FIELD study was 6.5 μmol/L and was reversible after stopping fenofibrate treatment. The increased risk of a venous thrombotic event may be related to the increase in homocysteine levels. The clinical significance is unclear.

Reporting suspected side effects

Post-authorisation reporting of suspected adverse reactions is important. It allows continuous monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected side effects.

To report any side effect(s): -National Pharmacovigilance Center (NPC) o SFDA Call Center: 19999 o E-mail: npc.drug@sfda.gov.sa o Website: https://ade.sfda.gov.sa

 

Only isolated cases of fenofibrate overdose have been reported to date. In the majority of cases no overdose symptoms were reported. A specific antidote is unknown. If overdose is suspected, treat symptomatically and provide appropriate supportive measures. Fenofibrate is not hemodialysable.

 

Pharmacotherapeutic group: Lipid-lowering agents/Cholesterol and triglyceride-lowering preparations/Fibrates

ATC code: C10AB05

Fenofibrate is a derivative of fibric acid whose lipid-regulating effects in humans are based on activation of PPARα (Peroxisome Proliferator Activated Receptor Type Alpha).

The activation of PPARα increases the activity of lipoprotein lipase and reduces the formation of apolipoprotein CIII. Through this mechanism, fenofibrate increases lipolysis and elimination of atherogenic, triglyceride-rich particles from plasma. Furthermore, the synthesis of the apolipoproteins AI and AII is increased by the activation of PPARα.

The effects of fenofibrate listed above lead to a reduction in very low-density and low-density lipoproteins (VLDL and LDL), which contain apolipoprotein B, and an increase in the formation of apo AI and apo AII high-density lipoproteins (HDL).

Patients at increased risk of CHD often exhibit an atherogenic lipoprotein phenotype characterized by an increased proportion of small-dense LDL particles. By regulating VLDL synthesis and catabolism, fenofibrate decreases small-dense LDL levels and increases LDL clearance.

In clinical studies with fenofibrate, total cholesterol was reduced by up to 20-25%, triglycerides by 40-55% and HDL-cholesterol increased by 10-30%.

In hypercholesterolemic patients in whom LDL reductions of 20-35% have been observed, the overall effect on cholesterol (LDL, HDL) results in a reduction in total-HDL-cholesterol, LDL-cholesterol/HDL-cholesterol, and of the Apo B/Apo AI ratio. The quotients mentioned are used as markers for the atherogenic risk.

There is evidence that treatment with fibrates reduces the incidence of coronary artery disease events. However, there is no evidence of a positive effect on all-cause mortality in the primary or secondary prevention of cardiovascular disease.

The ACCORD (Action to Control Cardiovascular Risk in Diabetes) Lipid study was a randomized, placebo-controlled study in 5,518 patients with type 2 diabetes mellitus, treated with fenofibrate in addition to simvastatin. No significant differences in the composite primary endpoint of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death were observed with fenofibrate plus simvastatin treatment versus simvastatin monotherapy (hazard ratio [HR] 0.92; 95%- CI: 0.79-1.08, p=0.32, absolute risk reduction: 0.74%). In the pre-specified subgroup of dyslipidemic patients, defined as those patients in the lowest tertile of HDL-C (≤ 34 mg/dL or 0.88 mmol/L) and in the top tertile of TG (≥ 204 mg /dl or 2.3 mmol/l), a relative risk reduction of 31% in relation to the combined primary endpoint was observed in treatment with fenofibrate plus simvastatin compared to simvastatin monotherapy (hazard ratio [HR] 0.69; 95 %CI: 0.49-0.97, p=0.03, absolute risk reduction: 4.95%). Another pre-specified subgroup analysis revealed a statistically significant treatment gender interaction (p=0.01), indicating a possible treatment benefit of combination therapy in men (p=0.037) while in women for combination therapy versus simvastatin monotherapy There was a potentially higher risk of reaching the primary endpoint (p=0.069). Such an interaction was not observed in the previously mentioned subgroup of dyslipidaemic patients, but there was no clear evidence of the benefit of treating dyslipidaemic women with fenofibrate plus simvastatin; furthermore, a possible adverse effect could not be excluded in this subgroup.

Extravascular cholesterol deposits (tendon xanthomas and tuberous xanthomas) may partially or completely regress during fenofibrate therapy.

In patients with elevated Lp(a) or fibrinogen levels at the start, treatment with fenofibrate resulted in a significant reduction in the Lp(a) or fibrinogen levels. Other markers of inflammation, such as B. C-reactive protein, are also reduced under fenofibrate.

Fenofibrate reduces uric acid levels by about 25%. This is of additional benefit to lipid-metabolic patients with hyperuricemia.

In animal experiments and in a clinical study, fenofibrate inhibited platelet aggregation induced by ADP, arachidonic acid and adrenaline.

LIPANTHYL 145 contains 145 mg fenofibrate as nanoparticles in the form of a film-coated tablet.

absorption:

Maximum plasma levels (Cmax) are reached 2-4 hours after oral administration. With repeated application, the plasma concentrations remain constant in all subjects.

In contrast to previous fenofibrate formulations, however, the maximum plasma concentrations and the total uptake of the present nanotechnology formulation are not dependent on food intake, so that intake can take place independently of a meal.

In a study in healthy male and female volunteers, the fenofibrate 145 mg film-coated tablet formulation was administered under fasting conditions and with a high-fat meal; there was no effect of food consumption on fenofibric acid AUC and Cmax.

Distribution:

Fenofibric acid is highly (>99%) bound to albumin.

Metabolism and Elimination:

After oral administration, fenofibrate is rapidly hydrolyzed by esterases to the active metabolite fenofibric acid. Unchanged fenofibrate cannot be detected in plasma. Fenofibrate is not subject to CYP3A4. No hepatic microsomal metabolism is involved.

The drug is mainly excreted renally and almost completely within 6 days. Fenofibrate is mainly eliminated in the form of fenofibric acid and its glucuronide conjugates. The plasma excretion of fenofibric acid is not altered in elderly patients.

Pharmacokinetic studies with single and repeated doses demonstrated that the drug does not accumulate. Fenofibric acid is not hemodialysable.

The plasma elimination half-life of fenofibric acid is approximately 20 hours.

In a 3-month non-clinical study in rats, oral administration of fenofibric acid, the active metabolite of fenofibrate, was associated with striated muscle toxicity (particularly type I fibres), cardiac failure, anemia and decreased body weight. No toxicity to striated muscle was observed up to a dose of 30 mg/kg (approximately 17 times the recommended human dose (MRHD)). No evidence of cardiac toxicity was observed at a dose approximately three times the MRDH. Reversible ulcers and erosions in the gastrointestinal tract occurred in dogs treated for three months. No gastrointestinal lesions were observed in this study up to a dose of approximately five times the MHRD.

Studies on the mutagenicity of fenofibrate were negative.

Liver tumors which can be attributed to peroxisome proliferation were found in rats and mice at high doses. These changes are specific to small rodents and have not been observed in other animal species. This does not result in any relevance for therapeutic use in humans.

Studies in mice, rats and rabbits did not provide any evidence of a teratogenic effect. Embryotoxic effects were observed at doses in the maternally toxic range. At high doses, the gestation period was prolonged and the birth process was impaired. Reversible hypospermia, testicular vasculature and immature ovaries were observed in a repeat dose study of fenofibric acid in young dogs. However, there was no evidence of an effect on fertility in preclinical reproductive studies with fenofibrate.

tablet core:

sucrose

Lactose Monohydrate

Microcrystalline cellulose, siliconized

crospovidone

hypromellose

Sodium Lauryl Sulfate

docusate sodium

Magnesium Stearate (Ph. Eur.)

film coating:

polyvinyl alcohol

Titanium Dioxide (E171)

talc

3-sn-phosphatidylcholine from soybeans

xanthan gum

Not applicable.

3 years

Store at a temperature below 30° C.

Thermoformed clear PVC/PE/PVDC composite blisters sealed with an aluminum complex.

Lipanthyl 145 mg is supplied in blister strips, in packs of 30 film-coated tablets.

Any unused medicine or other waste material should be disposed of in accordance with local requirements