FULCROSUPRA - PACKAGE LEAFLET - LEAFLETS

Home / leaflets / 2021

Fulcrosupra - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Unwanted Effects Shelf Life

Active ingredients: Fenofibrate

Fulcrosupra 145 mg film-coated tablets

Fulcrosupra package inserts are available for pack sizes:

Fulcrosupra 145 mg film-coated tablets
Fulcrosupra 160 mg film-coated tablets

Why is Fulcrosupra used? What is it for?

Fulcrosupra belongs to a group of medicines commonly known as fibrates. These medicines are used to lower the level of fats (lipids) in the blood. For example, the fats known as triglycerides.

Fulcrosupra is used, along with a low-fat diet and other non-medical treatments, such as exercise and weight loss, to reduce blood fat levels.

Fulcrosupra can be used as an adjunct to other medicines (statins) in certain circumstances where blood fat levels are not controlled with a statin alone.

Contraindications When Fulcrosupra should not be used

Do not take Fulcrosupra if:

you are allergic to fenofibrate or any of the other ingredients of this medicine (listed in section: Further information)
you are allergic to peanuts or peanut oil or soy lecithin or related products
have had an allergic reaction or skin damage due to sunlight or UV light while taking other medicines (these medicines include other fibrates or an anti-inflammatory drug called 'Ketoprofen')
have severe liver, kidney or gallbladder problems
have pancreatitis (inflamed pancreas which causes abdominal pain) which is not caused by high levels of fat in the blood

Do not take Fulcrosupra if any of the above information applies to you. If you are not sure, talk to your doctor or pharmacist before taking Fulcrosupra

Precautions for use What you need to know before taking Fulcrosupra

Talk to your doctor, pharmacist or nurse before taking Fulcrosupra if:

have any kidney or liver problems
you may have an inflamed liver (hepatitis) - signs include yellowing of the skin and whites of the eyes (jaundice), increased liver enzymes (shown in blood tests) stomach pain and itching
have underactive thyroid gland (hypothyroidism)

If any of the above information applies to you (or you are not sure), talk to your doctor or pharmacist before taking Fulcrosupra.

Effects on the muscles:

Stop taking Fulcrosupra and consult your doctor immediately if you experience unexplained cramps or muscle pain, tenderness or weakness while taking this medicine.

This is because this medicine can cause muscle problems which can be serious.
These problems are rare but include inflammation and muscle deterioration. This can cause kidney damage or even death.

The risk of muscle breakdown is much higher in some patients. Tell your doctor if:

is over 70 years old
have kidney problems
have thyroid problems
you or a close family member have hereditary muscle problems
drinks large amounts of alcohol
are taking cholesterol-lowering drugs called statins such as simvastatin, atorvastatin, pravastatin, rosuvastatin or fluvastatin
have ever had muscle problems while being treated with statins or with fibrates (such as fenofibrate, bezafibrate or gemfibrozil)

If any of the above information applies to you (or you are not sure), tell your doctor before taking Fulcrosupra.

Interactions Which drugs or foods can modify the effect of Fulcrosupra

Tell your doctor if you are taking or have recently taken or might take any other medicines.

In particular, tell your doctor or pharmacist if you are taking any of the following medicines:

anticoagulants to thin the blood (such as warfarin)
other drugs used to control fat levels in the blood (such as statins or fibrates). Taking a statin at the same time as Fulcrosupra may increase the risk of muscle problems
a particular class of medicines to treat diabetes (such as rosiglitazone or pioglitazone)
cyclosporine (an immunosuppressant)

If any of the above information applies to you (or you are not sure), talk to your doctor or pharmacist before taking Fulcrosupra.

Fulcrosupra with food, drink and alcohol

The tablet should be taken with or without food, at any time of the day

Warnings It is important to know that:

Pregnancy, breastfeeding and fertility

Tell your doctor if you are pregnant, suspect or plan to become pregnant. As there is insufficient clinical experience with the use of Fulcrosupra during pregnancy, you should only use Fulcrosupra if your doctor deems it absolutely necessary.
It is not known whether the active substance of Fulcrosupra is excreted in human milk. Therefore you should not take Fulcrosupra if you are breastfeeding or planning to breastfeed your baby.

Ask your doctor or pharmacist for advice before taking this medicine

Driving and using machines

This medicine has no effect on your ability to drive or use tools or machines.

Fulcrosupra contains lactose and sucrose (types of sugar). If you have been told by your doctor that you cannot tolerate or digest some sugars (you have an intolerance to some sugars), please inform your doctor before taking this medicine.

Fulcrosupra contains soy lecithin. If you are allergic to peanuts or soya, do not take this medicine

Dose, Method and Time of Administration How to use Fulcrosupra: Posology

Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.

How to take this medicine

Swallow the tablet with a glass of water.
Do not crush or chew the tablet

How much medicine to take

The recommended dose is one tablet a day.

If you are taking a capsule of fenofibrate of 200 mg or a tablet of Fulcrosupra 160 mg, you can switch to a tablet of Fulcrosupra 145 mg.

People with kidney problems

If you have kidney problems, your doctor may tell you to take a lower dose. Ask your doctor or pharmacist for advice.

Use in children and adolescents

The use of Fulcrosupra is not recommended below 18 years of age

Overdose What to do if you have taken too much Fulcrosupra

If you take more Fulcrosupra than you should

If you have taken more Fulcrosupra than you should or if someone has taken your medicine, please tell your doctor or contact the nearest hospital.

If you forget to take Fulcrosupra

If you forget to take a dose, just take your next dose at the usual time.
Then take your tablet at the normal time
Do not take a double dose to make up for a forgotten dose.

If you are worried, contact your doctor.

If you stop taking Fulcrosupra

Do not stop taking Fulcrosupra unless your doctor tells you to or unless the tablets make you feel sick. This is because the abnormal levels of fat in the blood need to be treated for a long time. Remember that in addition to taking Fulcrosupra it is also important that you:

follow a low-fat diet
take regular exercise.

If your doctor stops the treatment, do not take the leftover tablets unless your doctor tells you to.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist or nurse.

Side Effects What are the side effects of Fulcrosupra

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Stop taking Fulcrosupra and see a doctor right away if you notice any of the following serious side effects - you may need urgent medical treatment:

allergic reaction - the signs may include swelling of the face, lips, tongue or throat which can cause difficulty in breathing
muscle cramps or pain, tenderness or weakness - these may be signs of muscle inflammation or breakdown, which can cause kidney damage or even death
stomach pain - this may be a sign that your pancreas is inflamed (pancreatitis)
chest pain and feeling short of breath - these may be signs of a blood clot in the lung (pulmonary embolism)
pain, redness or swelling in the legs - these may be signs of a blood clot in the leg (deep vein thrombosis)
yellowing of the skin and whites of the eyes (jaundice), or an increase in liver enzymes - these may be signs of 'inflammation of the liver (hepatitis).

Stop taking Fulcrosupra and see a doctor immediately, if you notice any of the above side effects.

Other side effects include:

Common (affecting less than 1 in 10 people):

diarrhea
stomach pain
flatulence
feeling sick (nausea)
being sick (vomiting)
increased levels of liver enzymes in the blood - shown in tests

Uncommon (affecting less than 1 in 100 people):

headache
gallstones
reduced sexual desire
rash, itching or red spots on the skin
increased creatinine (produced by the kidneys) - shown in analyzes
pancreatitis (inflammation of the pancreas causing abdominal pain)
thromboembolism: pulmonary embolism (blood clot in the lung which causes chest pain and breathlessness), deep vein thrombosis (blood clot in the leg which causes pain, redness or swelling in the legs)
muscle pain, muscle inflammation, muscle cramps and weakness

Rare (affecting less than 1 in 1000 people):

hair loss
feeling dizzy (vertigo)
feeling exhausted (fatigue)
increased urea (substance produced by the kidneys) - shown in the analyzes
increased sensitivity of your skin to sunlight, sunlamps and sun beds
decreased levels of hemoglobin (which carries oxygen in the blood) and white blood cells - shown in tests
hepatitis (inflammation of the liver), symptoms of which may be mild jaundice (yellowing of the skin and whites of the eyes), stomach pain and itching
hypersensitivity (allergic reaction)

Side effects whose probability of occurrence are not known

severe form of rash with redness, peeling and swelling of the skin that looks like severe burns
long-term lung disease
muscle deterioration
complications of gallstones
if you experience any kind of unusual breathing disorder, please tell your doctor immediately

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet.

Expiry and Retention

Keep this medicine out of the sight and reach of children.

Keep this medicine in the original package in order to protect it from light and moisture.

Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The expiry date refers to the last day of that month.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

What Fulcrosupra contains

The active ingredient is fenofibrate. Each Fulcrosupra 145 mg tablet contains 145 milligrams (mg) of fenofibrate.
The other ingredients are: sucrose, lactose monohydrate, silicated microcrystalline cellulose, crospovidone, hypromellose, sodium lauryl sulfate, sodium docusate, magnesium stearate.

Opadry® tablet coating also contains: polyvinyl alcohol, titanium dioxide (E171), talc, soy lecithin, xanthan gum.

Description of what Fulcrosupra looks like and contents of the pack

Fulcrosupra 145 mg are white, elongated, film-coated tablets with "145" on one side and "Fournier logo" on the other.

The film-coated tablets are packed in blisters of 10, 20, 28, 30, 50, 84, 90, 98, 100, 280, 300

Not all pack sizes may be marketed.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Fulcrosupra can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction04.6 Pregnancy and lactation04.7 Effects on ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical safety data06.0 INFORMATION PHARMACEUTICALS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER08 .0 MARKETING AUTHORIZATION NUMBER 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIOPharmaceuticals, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON ESTEMPORANEA PREPARATION AND CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

FULCROSUPRA 145 MG

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

One film-coated tablet contains 145 mg of fenofibrate (nanoparticles).

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Film-coated tablet.

White, oblong, film-coated tablets debossed with "145" on one side and "Fournier logo" on the other.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Therapeutic indications

Fulcrosupra 145 mg is indicated as an adjunct to diet and other non-drug treatments (e.g. exercise, weight reduction) for:

- Treatment of severe hypertriglyceridaemia with or without low HDL cholesterol levels.

- Mixed hyperlipidaemia, when a statin is contraindicated or not tolerated.

- Mixed hyperlipidaemia in patients at high cardiovascular risk, in addition to a statin, when triglyceride and HDL cholesterol levels are not adequately controlled.

04.2 Posology and method of administration

Together with the diet, this medicine constitutes a long-term treatment, the effectiveness of which must be monitored periodically.

Response to therapy should be monitored by determining serum lipid levels (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.

Dosage:

Adults: the recommended dose is one tablet containing 145 mg of fenofibrate once a day.

Patients on therapy with a 200 mg capsule or a 160 mg tablet can be switched to a 145 mg fenofibrate tablet without further dose adjustments.

Elderly patients: in elderly patients, the dose prescribed for adult patients is recommended.

Patients with renal impairment: Dosage reduction is required in patients with renal impairment.

The use of pharmaceutical forms containing a lower dose of the active ingredient (100 mg or 67 mg of fenofibrate) is recommended in these patients.

Pediatric population: the use of the 145 mg strength is contraindicated in children.

Liver disease: Patients with liver disease have not been studied.

Method of administration

The tablets should be swallowed whole with a glass of water.

Fulcrosupra 145 mg film-coated tablets can be taken at any time of the day, either with or without meals (see section 5.2).

04.3 Contraindications

• Hepatic failure (including biliary cirrhosis and persistent liver function abnormalities of an unclear nature, eg persistent elevation of transaminases);

• kidney failure;

• children (under the age of 18);

• hypersensitivity to the active substance or to any of the excipients;

• known photoallergy or phototoxic reaction during treatment with fibrates or ketoprofen;

• gallbladder disease;

• acute or chronic pancreatitis with the exception of acute pancreatitis due to severe hypertriglyceridaemia.

FULCROSUPRA 145 mg film-coated tablets should not be taken by patients allergic to peanut or peanut oil or soy lecithin or related products due to the risk of hypersensitivity reactions.

04.4 Special warnings and appropriate precautions for use

Secondary causes of hypercholesterolemia, such as uncontrolled type 2 diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemia, obstructive liver disease, drug treatment, alcoholism, should be adequately treated before starting fenofibrate therapy. For hyperlipidemic patients taking estrogen or contraceptives containing estrogen, it must be ascertained whether the hyperlipidaemia is of a primary or secondary nature (possible increase in lipid values caused by estrogens taken by mouth).

Hepatic function: As with other lipid-lowering agents, increases in transaminase levels have been reported in some patients.

In the majority of cases these elevations were transient, mild and asymptomatic. It is recommended to monitor transaminase levels every 3 months during the first 12 months of treatment and periodically thereafter.

Care should be taken in patients who develop elevated transaminase levels and treatment should be discontinued if ASAT (SGOT) and ALAT (SGPT) levels rise more than three times the upper limit of the normal range. In the presence of symptoms indicative of hepatitis (eg jaundice, pruritus), laboratory tests should be performed and discontinuation of fenofibrate treatment may be considered.

Pancreas: Pancreatitis has been reported in patients taking fenofibrate (see sections 4.3 and 4.8). This may represent a lack of efficacy in patients with severe hypertriglyceridaemia, a direct drug effect, or a secondary phenomenon mediated by the presence of gallstones or the formation of dense masses with obstruction of the common bile duct.

Muscle: Muscle toxicity, including very rare cases of rhabdomyolysis, has been reported following administration of fibrates and other lipid-lowering agents.

Patients with a personal history of hypoalbuminemia and renal insufficiency show a higher incidence of myotoxicity.

Muscle toxicity should be suspected in patients presenting with diffuse myalgia, myositis, muscle cramps and weakness and / or marked increases in CPK (levels above 5 times the upper limit of the normal range). In these cases, fenofibrate treatment should be interrupted.

Patients with predisposing factors for myopathy and / or rhabdomyolysis may be at increased risk of developing rhabdomyolysis including: age over 70 years, personal or family history of inherited muscle disorders; renal impairment; hypoalbuminemia; hypothyroidism; high alcohol consumption. The potential benefits and risks of fenofibrate therapy should be carefully weighed for these patients.

The risk of muscle toxicity may be increased if the drug is given with another fibrate or an HMG-CoA reductase (statin) inhibitor, particularly in cases of pre-existing muscle disease. Consequently, the concomitant prescription of fenofibrate with a statin should be reserved for patients with severe combined dyslipidaemia and high cardiovascular risk, without a history of muscle disease.

This combination therapy should be used with caution and patients should be closely monitored for signs of muscle toxicity.

Kidney function: Treatment should be stopped if creatinine levels are increased above 50% and the upper limit of normal (ULN). It is recommended that creatinine be monitored for the first three months after initiation of treatment and periodically thereafter (for dose recommendations, see section 4.2).

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

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

FULCROSUPRA 145 mg film-coated tablets should not be taken by patients allergic to soya lecithin or related substances due to the risk of developing hypersensitivity reactions (see section 4.3).

04.5 Interactions with other medicinal products and other forms of interaction

Oral anticoagulants: fenofibrate increases the effect of oral anticoagulants and may increase the risk of bleeding. It is recommended that the dose of anticoagulants be reduced by approximately one third at the start of treatment and then gradually adjusted if necessary, based on monitoring of the INR (International Normalized Ratio). Therefore, this combination is not recommended.

Ciclosporin: some severe cases of reversible renal function impairment have been reported during concomitant administration of fenofibrate and cyclosporine. The renal function of these patients should therefore be closely monitored and treatment with fenofibrate should be discontinued in case of severe laboratory abnormalities. .

HMG-CoA reductase inhibitors and other fibrates: the risk of serious muscle toxicity is increased if a fibrate is used in combination with HMG-CoA reductase inhibitors or with other fibrates.

This combination therapy should be used with caution and patients should be closely monitored for signs of muscle toxicity (see section 4.4).

Cytochrome P450 enzymes: Education in vitro with human liver microsomes, indicate that fenofibrate and fenofibric acid are not inhibitors of the cytochrome (CYP) P 450 isoforms CYP3A4, CYP2D6, CYP2E1 or CYP1A2. at therapeutic concentrations.

Patients concomitantly taking fenofibrate and drugs metabolised by CYP2C19, CYP2A6 and especially CYP2C9 and who have a narrow therapeutic index should be closely monitored and, if necessary, dose adjustments of these drugs are recommended.

04.6 Pregnancy and lactation

There are no adequate data on the use of fenofibrate in pregnant women.

Animal studies did not show any teratogenic effects. Embryotoxic effects were seen at doses that resulted in maternal toxicity (see section 5.3). The potential risk to humans is unknown. Therefore FULCROSUPRA 145 mg film-coated tablets should only be used in pregnancy after a careful "benefit / risk assessment".

There are no data on the excretion of fenofibrate and / or its metabolites in human milk. Therefore FULCROSUPRA 145 mg film-coated tablets should not be used by breastfeeding mothers.

04.7 Effects on ability to drive and use machines

FULCROSUPRA 145 mg film-coated tablets, does not affect the ability to drive and use machines.

04.8 Undesirable effects

The most commonly reported adverse reactions during fenofibrate treatment are digestive, gastric or intestinal disturbances.

The following undesirable effects were observed in placebo-controlled clinical trials (n = 2344) at the frequencies listed below:

System Organ Classification (MedDRA) Municipalities> 1/100, Uncommon> 1/1000, Rare> 1 / 10,000, Very rare Frequency not known a Disorders of the blood and lymphatic system Reduction of hemoglobin, reduction of white blood cell count Disorders of the immune system Hypersensitivity Nervous system disorders Headache Vascular pathologies Thromboembolism (pulmonary embolism, deep vein thrombosis) * Respiratory, thoracic and mediastinal disorders Interstitial pneumopathies Gastrointestinal disorders Gastrointestinal signs and symptoms (abdominal pain, nausea, vomiting, diarrhea, flatulence) of moderate severity Pancreatitis * Hepatobiliary disorders Increased transaminases (see section 4.4) Cholelithiasis Hepatitis (see section 4.4) Skin and subcutaneous tissue disorders Skin hypersensitivity (e.g. rash, itching, hives) Alopecia, photosensitivity reactions Musculoskeletal, connective tissue and bone disorders Muscle disorders (e.g. myalgia, myositis, muscle spasms and weakness) Rhabdomyolysis Diseases of the reproductive system and breast Sexual dysfunction Diagnostic tests Increased creatinine in the blood Increased blood urea

* In the FIELD study, a randomized placebo-controlled study in 9795 patients with type 2 diabetes mellitus, a statistically significant increase in pancreatitis cases was observed in patients receiving fenofibrate compared to those receiving placebo (0.8 % versus 0.5%; p = 0.031). In the same study, a statistically significant increase in the incidence of pulmonary embolism was reported (0.7% in the placebo group versus 1.1% in the fenofibrate group; p = 0.022) and a non-statistically significant increase. deep vein thrombosis (placebo: 1.0% [48/4900 patients] versus fenofibrate 1.4% [67/4895 patients]; p = 0.074).

a In addition to the events reported in clinical trials, the following undesirable effects were spontaneously reported during the marketing of Fulcrosupra. From the available data it is not possible to estimate a precise frequency which is therefore to be considered "not known";

Respiratory, thoracic and mediastinal disorders: Interstitial lung disease

Musculoskeletal, connective tissue and bone disorders: Rhabdomyolysis

04.9 Overdose

Only anecdotal cases of overdose with fenofibrate have been reported. In most cases, no overdose symptoms were reported.

A specific antidote is not known. If overdose is suspected, symptomatic treatment should be sought and appropriate supportive measures instituted.

Fenofibrate cannot be eliminated by hemodialysis.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: lipid-lowering / cholesterol-lowering and hypotiglycerid-lowering / fibrate substances.

ATC code: C10AB05.

Fenofibrate is a derivative of fibric acid whose effects on the modification of the lipid structure reported in man are mediated by the activation of the alpha receptor activating the proliferation of peroxisomes (Peroxisome Proliferator Activated Receptor type alfa or PPARα).

Through the activation of PPARα, fenofibrate increases lipolysis and the elimination of atherogenic particles rich in triglycerides from the plasma, activating the lipoprotein lipase and reducing the production of apoprotein CIII. Activation of PPARα also induces an increase in the synthesis of apoproteins AI and AII.

The above described effect of fenofibrate on lipoproteins leads to a reduction of very low and low density fractions (VLDL and LDL) containing apoprotein B and to an increase in high density lipoprotein (HDL) fractions containing apoproteins AI and AII.

Furthermore, by modulating the synthesis and catabolism of VLDL fractions, fenofibrate increases LDL clearance and reduces small and dense LDLs, the levels of which are elevated in the phenotype for atherogenic lipoproteins, a "common alteration in patients with risk of coronary heart disease.

During clinical trials with fenofibrate, total cholesterol and triglycerides decreased by 20-25% and 40-55%, respectively, and HDL cholesterol increased by 10-30%.

In hypercholesterolemic patients, where LDL cholesterol levels are reduced by 20% -35%, the overall effect on cholesterol results in a decrease in the ratio of total cholesterol to HDL cholesterol, LDL cholesterol and HDL cholesterol, or Apo B and Apo AI , all of which are markers of atherogenic risk.

Because of its effect on LDL cholesterol and triglycerides, treatment with fenofibrate may be useful in hypercholesterolemic patients, with or without hypertriglyceridaemia, including secondary hyperlipoproteinemia as in type 2 diabetes mellitus.

There is evidence that fibrate treatment can reduce coronary heart disease events, but fibrates have not been shown to reduce all-cause mortality in primary or secondary prevention of cardiovascular disease.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid clinical trial was a randomized, placebo-controlled study in 5518 patients with type 2 diabetes mellitus treated with fenofibrate in addition to simvastatin. Fenofibrate plus simvastatin therapy demonstrated no significant difference from simvastatin monotherapy in the primary outcome consisting of non-fatal myocardial infarction, non-fatal stroke and cardiovascular death (hazard ratio [HR] 0.92, 95% CI 0 , 79-1.08, p = 0.32; absolute risk reduction: 0.74%).In the prespecified subgroup of patients with dyslipidemia, defined as patients in the lower tertile of HDL-C (≤34 mg / dL or 0.88 mmol / L) and in the higher tertile of TG (≥204 mg / dL or 2 , 3 mmol / l) at baseline, fenofibrate plus simvastatin therapy demonstrated a 31% relative reduction, compared to simvastatin monotherapy, for the compound primary outcome (hazard ratio [HR] 0.69, CI 95 % 0.49-0.97, p = 0.03; absolute risk reduction: 4.95%). Analysis of another prespecified subgroup 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 potentially a risk higher for the primary outcome in women receiving combination therapy than simvastatin monotherapy (p = 0.069). This was not observed in the aforementioned subgroup of patients with dyslipidaemia, but there was also no clear evidence of benefit. in women with dyslipidaemia treated with fenofibrate plus simvastatin, and a possible harmful effect in this subgroup could not be excluded.

Extravascular cholesterol deposits (tendon and tuberous xanthomas) can be markedly reduced or completely eliminated during fenofibrate therapy.

Patients with increased fibrinogen levels treated with fenofibrate showed significant reductions in this parameter as did those with increased Lp (a) levels.

Other markers of inflammation, such as C-reactive protein, are reduced with fenofibrate treatment.

The uricosuric effect of fenofibrate, which leads to a reduction of uric acid levels by approximately 25%, may be considered an additional benefit in dyslipidemic patients with hyperuricaemia.

Fenofibrate has been shown to have an antiplatelet effect on platelets in animals and in a clinical study which showed a reduction in platelet aggregation induced by ADP, arachidonic acid and epinephrine.

05.2 Pharmacokinetic properties

FULCROSUPRA 145 mg film-coated tablets contain 145 mg fenofibrate nanoparticles.

Absorption: the maximum plasma concentration (Cmax) occurs between 2 and 4 hours after oral administration. Plasma concentrations remain stable during continued treatment in each individual subject.

Contrary to previous fenofibrate formulations, the maximum plasma concentration and total exposure of the nanoparticle formulation is independent of food intake. Therefore FULCROSUPRA 145 mg film-coated tablets can be taken with or without meals. A study on food effects involving the administration of the new 145 mg tablet formulation of fenofibrate to healthy male and female subjects fasting and during a high-fat meal, demonstrated that exposure (AUC and Cmax) to "fenofibric acid is unaffected by food.

Distribution: fenofibric acid strongly binds to plasma albumin (more than 99%).

Metabolism and excretion: 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 a substrate of CYP 3A4. Hepatic microsomal metabolism is not involved.

The drug is mainly excreted in the urine.

Virtually all of the drug is eliminated within 6 days. Fenofibrate is mainly excreted in the form of fenofibric acid and its glucuronidated conjugate.

The apparent total plasma clearance of fenofibric acid is not affected in elderly patients.

Kinetic studies after single dose administration and continued treatment have shown that the drug does not accumulate. Fenofibric acid is not eliminated by hemodialysis.

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

05.3 Preclinical safety data

Chronic toxicity studies did not provide relevant information on the specific toxicity of fenofibrate.

Mutagenicity studies of fenofibrate were negative.

In rats and mice, liver tumors attributable to peroxisome proliferation were found at high doses.

These events are specific to small rodents and have not been observed in other animal species.

This is not relevant for therapeutic use in humans.

Studies in mice, rats and rabbits did not reveal any teratogenic effects. Embryotoxic effects were observed at doses causing maternal toxicity.

A prolongation of the gestation period and difficulties during delivery have been observed after administration of high doses.

There was no evidence of any effects on fertility.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

List of excipients

Nucleus:

Sucrose, lactose monohydrate, silicated microcrystalline cellulose, crospovidone, hypromellose, sodium laurilsulfate, sodium docusate, magnesium stearate.

Coating:

Polyvinyl alcohol, titanium dioxide (E171), talc, soy lecithin, xanthan gum.