Active ingredients: Fenofibrate
FULCRUM 200 mg hard capsules
Indications Why is Fulcro used? What is it for?
PHARMACOTHERAPEUTIC CATEGORY
Lipid-lowering substances - Hypocholesterolemic and hypotiglyceridemic agents.
THERAPEUTIC INDICATIONS
Fulcrum 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.
Fulcrum is used, along with a low-fat diet and other non-medical treatments, such as exercise and weight loss, to reduce blood fat levels.
Fulcrum can be used as an adjunct to other medicines [statins] in some circumstances where blood fat levels are not controlled with a statin alone.
Contraindications When Fulcrum should not be used
- hypersensitivity to the active substance or to any of the excipients;
- Hepatic failure (including biliary cirrhosis) and persistent liver function abnormalities of an unclear nature;
- severe kidney disease;
- known photoallergy or phototoxic reactions during treatment with fibrates or ketoprofen;
- known disease of the gallbladder;
- acute or chronic pancreatitis (inflammation of the pancreas causing abdominal pain) with the exception of acute pancreatitis due to severe hypertriglyceridaemia;
- pregnancy and breastfeeding.
The product should not be used in pediatric age, as sufficient experience is not yet available.
Precautions for use What you need to know before taking Fulcrum
Secondary causes of hyperlipidemia
Secondary causes of hyperlipidaemia, such as uncontrolled type 2 diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinaemia, obstructive liver disease, drug treatment, alcoholism, should be adequately treated before considering fenofibrate therapy.
Before resorting to the use of the product, it is advisable to test the effectiveness of a lipid-lowering dietary treatment.
Renal function: Treatment should be stopped if creatinine levels are increased by 50% above the upper limit of normal (ULN). It is recommended that creatinine be monitored for the first 3 months after starting treatment, and periodically thereafter.
Hepatic function: As with other lipid-lowering drugs, increases in transaminase levels have been reported in some patients. During treatment, periodic checks of liver function tests, blood levels, lipids and blood counts should be carried out.
Attention should be paid to patients who develop elevated transaminase levels and treatment should be discontinued if AST and ALT levels rise more than three times the upper limit of normal values.
In the event that the response to the drug is unsatisfactory or in the presence of persistent liver function test abnormalities, it is recommended to discontinue treatment.
Use with caution with a history of liver disease.
Pancreatitis: As with other fibrates, cases of pancreatitis have been reported in patients taking fenofibrate (see 4.3 and 4.8). This may represent a lack of efficacy in patients with severe hypertriglyceridaemia, a direct drug effect, or a phenomenon secondary to the formation of stones or sandy deposits in the biliary tract with obstruction of the bile duct.
Muscular system: Cases of muscle toxicity, including very rare cases of rhabdomyolysis with or without renal insufficiency, have been reported following administration of fibrates or other lipid-lowering agents. The incidence of these effects is increased in cases of hypoalbuminaemia and previous renal insufficiency. Muscle toxicity should be suspected in patients presenting with diffuse myalgia, myositis, muscle cramps and weakness and / or a marked increase in creatine phosphokinase (levels greater than 5 times normal values) In such cases, fenofibrate treatment should be discontinued.
The risk of muscle toxicity may be increased if the drug is given with another fibrate or statin, particularly in cases of pre-existing muscle disease. Consequently, co-description of fenofibrate with an HMG-CoA reductase inhibitor (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 potential muscle toxicity. To be used with caution in subjects with peptic ulcer as the latter could reactivate.
In hyperlipidemic patients taking estrogen or estrogen-containing contraceptives, it must be ascertained whether the hyperlipidaemia is of a primary or secondary nature (possible increase in lipid values caused by estrogen taken by mouth).
Interactions Which drugs or foods can modify the effect of Fulcrum
Tell your doctor or pharmacist if you have recently taken any other medicines, even those without a prescription.
Oral anticoagulants: fenofibrate increases the effect of oral anticoagulants and may increase the risk of bleeding. It is recommended to reduce the dose of anticoagulants by about one third at the start of treatment and then gradually adjust it if necessary, based on the INR (International Normalized Ratio).
Ciclosporin: some severe cases of reversible renal impairment have been reported during concomitant administration of fenofibrate and cyclosporine. Renal function in these patients should therefore be closely monitored and treatment with fenofibrate discontinued in the event of severe laboratory abnormalities. .
Inhibitors of HMG-CoA reductase and other fibrates: see "Precautions for use".
Cytochrome P450 enzymes: In vitro studies with 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 CYP2A. mild to moderate inhibitors of CYP2C9 at therapeutic concentrations.
Patients 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.
Warnings It is important to know that:
Liver function
Moderate increases in serum transaminase levels and very rarely, cases of hepatitis may be observed during treatment with FULCRO. If symptoms suggestive of hepatitis occur (eg jaundice and pruritus) appropriate laboratory tests should be conducted and, if appropriate, treatment should be discontinued.
Muscular system
As with other lipid-lowering agents, cases of muscle toxicity (widespread myalgia, myositis, increased creatine phosphokinase, muscle cramps and weakness) and very rare cases of rhabdomyolysis have been reported. In such cases it is recommended to suspend the treatment in order to favor the regression of these symptoms.
In case of concomitant administration with another fibrate or statin, see "Precautions for use".
Pregnancy and breastfeeding
Ask your doctor or pharmacist for advice before taking any medicine.
Pregnancy: the safety of the drug administered during pregnancy and lactation has not been established. Therefore, Fulcrum 200 mg hard capsules should only be used during pregnancy after careful consideration of the risk / benefit ratio.
Lactation: It is not known whether fenofibrate and / or its metabolites are excreted in human milk. A risk to infants cannot be excluded. Therefore fenofibrate should not be used during lactation.
Effects on ability to drive and use machines
No particular effects on the ability to drive and use machines have been reported.
Important information about some of the ingredients
FULCRUM contains lactose. If you have been told by your doctor that you have an intolerance to sugars, contact your doctor before taking this medicinal product.
Dosage and method of use How to use Fulcrum: Dosage
Response to therapy should be monitored by determining serum lipid values. If after several months (eg 3 months) an adequate response is not obtained, complementary or different therapeutic measures should be considered.
Dosage:
Adults
The recommended dose is 1 capsule of 200 mg of FULCRO per day. Dietary measures should be observed during therapy with FULCRUM 200 mg hard capsules.
Special populations
Pediatric population:
the safety and efficacy of fenofibrate in children and adolescents below the age of 18 have not been established. No data are available. Therefore, the use of fenofibrate in pediatric subjects below the age of 18 is not recommended.
Senior citizens
In elderly patients with no renal impairment, the usual adult dose is recommended
Kidney damage
In patients with renal impairment, the dose of fenofibrate should be reduced, based on creatinine clearance. Fenofibrate is not recommended in patients with severe kidney disease. A dose reduction should be considered in elderly patients with impaired renal function.
Hepatic impairment
Fulcrum 200 mg hard capsules is not recommended in patients with hepatic impairment due to lack of data.
Method of administration
The capsules should be swallowed whole with a meal
Overdose What to do if you have taken too much Fulcrum
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.
In case of accidental ingestion / intake of an excessive dose of FULCRUM, notify your doctor immediately or go to the nearest hospital.
If you have any questions about the use of Fulcrum, ask your doctor or pharmacist.
Side Effects What are the side effects of Fulcrum
Like all medicines, FULCRUM can cause side effects, although not everybody gets them.
Some patients have reported the following side effects during treatment with fenofibrate:
Common side effects (reported in less than 1 in 10 patients and more than 1 in 100 patients):
- abdominal pain, nausea, vomiting, diarrhea and flatulence
- increased levels of various liver enzymes in the blood
Uncommon side effects (reported in less than 1 in 100 patients and more than 1 in 1000 patients):
- pancreatitis (inflammation of the pancreas causing abdominal pain) *
- thromboembolism: pulmonary embolism (blood clot in the lung resulting in chest pain and shortness of breath), deep vein thrombosis (blood clot in the leg or arm causing pain, redness or swelling) *
- hypersensitivity of the skin (e.g. reactions such as redness, itching, red spots on the skin)
- increased level of creatinine (substance secreted by the kidneys)
- gallstones
- increased CPK, muscle pain, muscle inflammation, muscle cramps and weakness
- headache
- sexual dysfunction
Rare side effects (reported in less than 1 in 1000 patients and more than 1 in 10,000 patients):
- hepatitis (inflammation of the liver), symptoms of which may be mild jaundice (yellowing of the skin and whites of the eye), stomach pain and itching
- hair loss
- decreased levels of hemoglobin (a pigment that carries oxygen in the blood) and decreased white blood cells
- increased sensitivity to sunlight, lamps and sun beds
- increased levels of urea (substance secreted by the kidneys)
- fatigue, dizziness
- hypersensitivity
Post marketing, some patients have also reported (with frequency not known): chronic lung tissue disease, breakdown of muscle cells, jaundice, complications of cholelithiasis (e.g. cholecystitis, cholangitis, biliary colic), severe skin reactions.
The following side effects have also been reported:
various forms of cardiac arrhythmias, signs of renal dysfunction such as: difficulty in urinating, decreased urinary excretion, presence of blood in the urine, presence of protein in the urine, constant need to eat and weight gain.
* In the FIELD study, a randomized placebo-controlled study in 9795 patients with type 2 diabetes mellitus, a statistically significant 6 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).
Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. Undesirable effects can also be reported directly via the national reporting system at "https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse". more information on the safety of this medicine. "
Expiry and Retention
EXPIRY: see the expiry date printed on the package. The expiry date refers to the product in intact packaging, correctly stored.
WARNING: do not use the medicine after the expiry date shown on the package.
The expiry date refers to the last day of the month.
Store at a temperature not exceeding 30 ° C and in the original package to protect the medicine from moisture.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.
Keep this medicine out of the sight and reach of children.
COMPOSITION
Each 200 mg capsule contains:
Active ingredient: fenofibrate 200 mg.
Excipients: lactose, magnesium stearate, pregelatinised starch, sodium lauryl sulfate, cross-linked povidone.
Containing capsule: titanium dioxide (E171), yellow iron oxide, erythrosine (E127), gelatin.
PHARMACEUTICAL FORM AND CONTENT
Hard Capsules - Box of 20 capsules
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.
01.0 NAME OF THE MEDICINAL PRODUCT
FULCRUM 200 MG HARD CAPSULES
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
One hard capsule contains:
Active principle: fenofibrate mg 200.
Excipients with known effects:
lactose monohydrate: 101 mg
For the full list of excipients, see section 6.1
03.0 PHARMACEUTICAL FORM
Hard capsules for oral use
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Fulcro is indicated in addition to diet and other non-pharmacological treatments (e.g. physical 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
Response to therapy should be monitored by determining serum lipid values. If after several months (eg 3 months) an adequate response is not obtained, complementary or different therapeutic measures should be considered.
Dosage:
Adults
The recommended dose is 1 capsule of 200 mg of FULCRO per day.
Dietary measures should be observed during therapy with FULCRUM 200 mg hard capsules.
Special populations
Pediatric population:
the safety and efficacy of fenofibrate in children and adolescents below the age of 18 have not been established. No data are available. Therefore, the use of fenofibrate in pediatric subjects below the age of 18 is not recommended.
Senior citizens
In elderly patients with no renal impairment, the usual adult dose is recommended
Kidney damage
In patients with renal impairment, the dose of fenofibrate should be reduced, based on creatinine clearance. Fenofibrate is not recommended in patients with severe kidney disease. A dose reduction should be considered in elderly patients with impaired renal function (see 4.4).
Hepatic impairment
Fulcrum 200 mg hard capsules is not recommended in patients with hepatic impairment due to lack of data.
Method of administration
The capsules should be swallowed whole with a meal
04.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
• liver failure (including biliary cirrhosis) and persistent liver function abnormalities of an unclear nature;
• severe kidney disease;
• known photoallergy or phototoxic reactions during treatment with fibrates or ketoprofen;
• known disease of the gallbladder.
• acute or chronic pancreatitis with the exception of acute pancreatitis due to severe hypertriglyceridaemia.
• pregnancy and breastfeeding
The product should not be used in children as there is not yet sufficient experience.
04.4 Special warnings and appropriate precautions for use
Secondary causes of hyperlipidemia
Secondary causes of hyperlipidaemia, such as uncontrolled type 2 diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinaemia, obstructive liver disease, drug treatment, alcoholism, should be adequately treated before considering fenofibrate therapy. Before resorting to the use of the product, it is advisable to test the effectiveness of a lipid-lowering dietary treatment.
If after several months of fenofibrate administration (3 to 6 months) serum lipid levels have not reduced satisfactorily, complementary or different therapeutic measures should be considered.
Kidney function: Treatment should be stopped if creatinine levels are increased by 50% above the upper limit of normal (ULN). It is recommended that creatinine be monitored for the first 3 months after starting treatment, and periodically thereafter.
Liver function: As with other lipid-lowering drugs, increases in transaminase levels have been reported in some patients. In the majority of cases this increase was transient, mild and asymptomatic. It is recommended to carry out frequent checks of liver function tests (in particular monitor transaminase levels every 3 months during the first 12 months of treatment), and periodically thereafter, of blood levels, lipids and blood counts.
Attention should be paid to patients who develop elevated transaminase levels and treatment should be discontinued if AST and ALT levels rise more than 3 times the upper limit of normal.
In the presence of any symptoms suggestive of hepatitis (eg jaundice, pruritus), appropriate laboratory tests should be conducted and, if necessary, treatment with fenofibrate should be discontinued.
In the event that the response to the drug is unsatisfactory or in the presence of persistent liver function test abnormalities, it is recommended to discontinue treatment.
Use with caution with a history of liver disease.
Pancreatitis: As with other fibrates, cases of pancreatitis have been reported in patients taking fenofibrate (see 4.3 and 4.8). This may represent a lack of efficacy in patients with severe hypertriglyceridaemia, a direct drug effect, or a phenomenon secondary to the formation of stones or sandy deposits in the biliary tract with obstruction of the bile duct.
Muscular systemCases of muscle toxicity, including very rare cases of rhabdomyolysis with or without renal insufficiency, have been reported following administration of fibrates or other lipid-lowering agents.
The incidence of these effects increases in case of hypoalbuminemia and previous renal insufficiency.
Muscle toxicity should be suspected in patients presenting with diffuse myalgia, myositis, muscle cramps, weakness and / or marked increase in CPK (levels 5 times the normal range). In such cases, fenofibrate treatment should be discontinued.
The risk of muscle toxicity may be increased if the drug is administered with another fibrate or with an HMG-CoA reductase inhibitor, particularly in cases of pre-existing muscle disease. Consequently, co-prescribing fenofibrate with an HMG-CoA reductase inhibitor should be reserved for patients with severe combined dyslipidaemia and high cardiovascular risk without a previous history of myopathy and closely monitoring potential muscle toxicity.
Caution should be used in the treatment of subjects with low serum albumin levels for the possible onset of myalgia, muscle cramps and rhabdomyolysis with increased creatininkinase levels.
To be used with caution in subjects with peptic ulcer as the latter could reactivate.
For hyperlipidemic patients taking estrogen or estrogen-containing contraceptives, it must be ascertained whether it is primary or secondary hyperlipidemia (possible increase in lipid values caused by estrogen taken by mouth).
Important information about some of the ingredients
FULCRO contains lactose
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
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 to reduce the dose of anticoagulants by approximately one third at the start of treatment and subsequently to gradually adjust it, if necessary, according to the INR ( International Normalized Ratio).
Cyclosporine: Some severe cases of reversible renal impairment have been reported during concomitant administration of fenofibrate and cyclosporine. Renal function in these patients should therefore be closely monitored and treatment with fenofibrate discontinued in case of severe laboratory abnormalities.
Inhibitors of HMG-CoA reductase and other fibrates: see 4.4.
Cytochrome P450 enzymes:
In vitro studies with 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 CYP2C19 and CYP2A6. CYP2C9 at therapeutic concentrations.
Patients 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
Pregnancy: Adequate data on the use of fenofibrate in pregnant women are not available. Studies performed to date in animals have not shown any teratogenic effects. 5.3). Therefore, Fulcrum 200 mg hard capsules should only be used during pregnancy after careful consideration of the risk / benefit ratio.
Lactation: It is not known whether fenofibrate and / or its metabolites are excreted in human milk. A risk to infants cannot be excluded. Therefore fenofibrate should not be used during lactation.
04.7 Effects on ability to drive and use machines
No particular effects on the ability to drive and use machines have been reported.
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:
* 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).
The following undesirable effects have also been reported: various forms of cardiac arrhythmias, signs of renal dysfunction, such as dysuria, oliguria, haematuria and proteinuria, polyphagia and weight gain.
In addition to the events reported in clinical trials, the following undesirable effects were spontaneously reported during the marketing of fenofibrate. 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 and connective tissue disorders: Rhabdomyolysis
- Hepatobiliary disorders: jaundice, complications of cholelithiasis (eg cholecystitis, cholangitis, biliary colic).
- Skin and subcutaneous tissue disorders: severe skin reactions (e.g. erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis).
"Reporting of suspected adverse reactions.
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address:" www.agenziafarmaco.gov.it/it/responsabili ".
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 resorted to and appropriate supportive measures instituted.
Fenofibrate cannot be eliminated by hemodialysis.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Therapeutic family: lipid-lowering, hypocholesterolemic and hypotiglyceride-lowering substances. Bundles.
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 PPARa).
Through the activation of PPARa, 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 PPARa 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.
FULCRUM inhibits the hepatic synthesis of fatty acids, triglycerides and cholesterol. For cholesterol, this inhibition occurs at the level of the HMG-CoA-reductase, the key enzyme in the synthesis of cholesterol. Consequently, there is a decrease in the plasma levels of lipoproteins with high atherogenetic power.
Alongside these fundamental lipid-lowering properties, a hypouricemic effect and an antiplatelet effect have been experimentally and clinically demonstrated.
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 composite primary outcome 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 lowest tertile of HDL-C (≤34 mg / dl or 0.88 mmol / L) and in the highest tertile of TGs (≥204 mg / dL or 2.3 mmol / L) at baseline, fenofibrate plus simvastatin therapy demonstrated a 31% relative reduction compared to monotherapy with simvastatin, for the composite primary outcome (hazard ratio [HR] 0.69, 95% CI 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 benefit of treatment of combination therapy in men (p = 0.037), but a potentially higher risk for primary outcome in women receiving combination therapy, compared to 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
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.
The unchanged product is not recoverable in plasma, while the major pharmacologically active plasma metabolite, fenofibric acid, is.
The mean plasma concentration is of the order of 15 g / ml for a dosage of 1 capsule of FULCRO per day, a concentration that remains stable during the periods of continued treatment.
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 glucuroconjugate.
Pharmacokinetic studies, after single administration, allow to state that there is no accumulation of product.
Fenofibric acid is not eliminated in hemodialysis treatment.
The plasma elimination half-life of fenofibric acid is of the order of 20 hours.
05.3 Preclinical safety data
Acute toxicity: the oral LD50 has been studied on several animal species and was found to be higher than 5,000 mg / kg in mice, rats and guinea pigs. In the dog, no signs of toxicity were found at the dose of 4,000 mg / kg.
The DL50 for via i.p. it is higher than 5,000 mg / kg in the rat and 500 mg / kg in the guinea pig.
Chronic toxicity: Chronic toxicity studies were conducted in rhesus monkeys and rhesus dogs.
An increase in liver enzymes and hepatomegaly were observed in the rat studies.
Liver tumors attributable to peroxisome proliferation were found in rats and mice treated with high doses. These events are specific to small rodents and have not been observed in other animal species.
This, therefore, is not relevant for therapeutic use in humans.
Mutagenesis / Teratogenesis / Reproductive toxicity:
Mutagenicity studies performed with fenofibrate were negative.
Studies in mice, rats and rabbits did not show 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 effect on fertility.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Lactose, magnesium stearate, pregelatinised starch, sodium lauryl sulfate, cross-linked povidone, titanium dioxide (E171), erythrosine (E127), yellow iron oxide, gelatin.
06.2 Incompatibility
No particular types of incompatibility have been reported.
06.3 Period of validity
3 years
06.4 Special precautions for storage
Store at a temperature not exceeding 30 ° C and in the original package to protect the medicine from moisture.
06.5 Nature of the immediate packaging and contents of the package
Case containing n. 2 opaque PVC / aluminum blisters of 10 capsules.
Each pack contains 20 capsules.
06.6 Instructions for use and handling
No special instructions for disposal.
07.0 MARKETING AUTHORIZATION HOLDER
Abbott S.r.l. - S.R. Pontina Km 52 snc - 04011 Campoverde di Aprilia (LT)
08.0 MARKETING AUTHORIZATION NUMBER
A.I.C. n. 028590014
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Renewal: November 15, 2009
10.0 DATE OF REVISION OF THE TEXT
AIFA determination of 22.11.2013
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