Vytorin - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf life and Storage Composition and pharmaceutical form

Active ingredients: Ezetimibe, Simvastatin

VYTORIN 10 mg / 10 mg, 10 mg / 20 mg, 10 mg / 40 mg, 10 mg / 80 mg tablets

Indications Why is Vytorin used? What is it for?

VYTORIN contains the active substances ezetimibe and simvastatin. VYTORIN is a medicine that is used to lower the levels of total cholesterol, "bad" cholesterol (LDL cholesterol), and fatty substances called triglycerides in the blood. In addition, VYTORIN increases the levels of "good" cholesterol (HDL cholesterol).

VYTORIN works in two ways to lower cholesterol. The active substance ezetimibe reduces the cholesterol absorbed in the digestive tract. The active substance simvastatin which belongs to the class of "statins" inhibits the production of cholesterol synthesized by the body. Cholesterol is one of several fatty substances found in the bloodstream.

Total cholesterol is mainly composed of LDL cholesterol and HDL cholesterol. LDL cholesterol is often called "bad" cholesterol because it can build up in the artery walls and form plaques. Over time, this plaque buildup can lead to narrowing of the arteries. This narrowing can slow or block blood flow to vital organs such as the heart and brain. This blockage of blood flow can cause a heart attack or stroke.

HDL cholesterol is often called "good" cholesterol because it helps prevent bad cholesterol from building up in the arteries and protects against heart disease.

Triglycerides are another form of fat in the blood that can increase the risk of heart disease.

VYTORIN is used for patients who cannot control their cholesterol levels with diet alone. While taking this medicine, you should still follow a cholesterol-lowering diet.

VYTORIN is used as an add-on to diet to lower cholesterol if you have:

  • elevated blood cholesterol levels (primary hypercholesterolaemia) [familial and non-familial heterozygous] or elevated blood fat levels (mixed hyperlipidaemia):
  • who are not well controlled by a statin alone;
  • for which you have taken treatment with a statin and ezetimibe as separate tablets;
  • a hereditary disease (homozygous familial hypercholesterolaemia) which increases your blood cholesterol levels. It is possible that you are being treated with other treatments as well.

VYTORIN does not help you lose weight.

Contraindications When Vytorin should not be used

Do not take VYTORIN if:

  • you are allergic (hypersensitive) to ezetimibe, simvastatin, or any of the other ingredients of this medicine (listed in section 6. Contents of the pack and other information);
  • you currently have liver problems;
  • you are pregnant or breastfeeding;
  • are taking medicine (s) with one or more of the following active substances:? itraconazole, ketoconazole, posaconazole or voriconazole (used to treat fungal infections); ? erythromycin, clarithromycin or telithromycin (used to treat infections); ? HIV protease inhibitors such as indinavir, nelfinavir, ritonavir and saquinavir (HIV protease inhibitors are used to treat HIV infections); ? boceprevir or telaprevir (used to treat hepatitis C virus infections);? nefazodone (used to treat depression); or cobicistat; or gemfibrozil (used to lower cholesterol);? cyclosporine (often used in transplant patients d "organ); ? danazol (a human-made hormone used to treat endometriosis, a condition in which the lining of the womb grows outside the womb).
  • you are taking or, in the past 7 days, have taken or have been given a medicine called fusidic acid (used to treat bacterial infection).

Do not take more than 10 mg / 40 mg of VYTORIN if you are taking lomitapide (used to treat a serious and rare genetic cholesterol condition)

Ask your doctor for advice if you are not sure whether the medicine you are using is one of those listed above.

Precautions for use What you need to know before taking Vytorin

Tell your doctor

  • all your medical conditions, including allergies;
  • if you consume large amounts of alcohol or if you have ever had liver disease. In this case, VYTORIN may not be suitable for you;
  • if you are due to have surgery. You may need to stop taking VYTORIN for a short time;
  • if you are Asian, as a different dose may be appropriate for you.

Your doctor must have a blood test done before you take VYTORIN and if you have symptoms of liver problems while taking VYTORIN. This analysis is done to know if the liver is functioning properly.

  • Your doctor may also order blood tests to check liver function after starting VYTORIN therapy.

While you are being treated with this medicine, your doctor will carefully check that you do not have diabetes or that you are not at risk of developing diabetes. You are at risk of developing diabetes if you have high blood sugar and fat levels, if you are overweight and have high blood pressure.

Tell your doctor if you have severe lung disease.

Administration of VYTORIN with fibrates (some types of cholesterol-lowering medicines) should be avoided as the use of VYTORIN with fibrates has not been studied.

Contact your doctor immediately if you have muscle aches, muscle tenderness and muscle weakness of undetermined causes, as muscle problems can, rarely, be severe and lead to muscle tissue injury causing kidney damage and very rarely deaths have occurred. The risk of muscle injury is greater at higher doses of VYTORIN particularly the 10 mg / 80 mg dose.

The risk of muscle injury is also greater in some patients. Tell your doctor if any of the following apply to you:

  • have kidney problems
  • have thyroid problems
  • is 65 or older
  • is female
  • have ever had muscle problems while being treated with cholesterol-lowering medicines called "statins" (such as simvastatin, atorvastatin, and rosuvastatin) or fibrates (such as gemfibrozil and bezafibrate)
  • you or your immediate family have a hereditary muscle disease.

Also, tell your doctor or pharmacist if you have constant muscle weakness. Additional tests and medicines may be needed to diagnose and treat this condition.

Children and adolescents

The use of VYTORIN is not recommended in children under 10 years of age

Interactions Which drugs or foods can change the effect of Vytorin

Other medicines and VYTORIN

Tell your doctor if you are taking, have recently taken or might take any other medicines with any of the following active substances. Taking VYTORIN with any of these medicines may increase the risk of muscle problems (some have already been mentioned above in the "Do not take VYTORIN" section if):

  • cyclosporine (often used in patients receiving an organ transplant);
  • danazol (a man-made hormone used to treat endometriosis, a condition in which the lining of the uterus grows outside the uterus);
  • medicines with an active substance such as itraconazole, ketoconazole, fluconazole, posaconazole or voriconazole (used to treat fungal infections);
  • fibrates with active ingredients such as gemfibrozil and bezafibrate (used to lower cholesterol);
  • erythromycin, clarithromycin, telithromycin, or fusidic acid (medicines for bacterial infections). Do not take fusidic acid while you are using this medicine. See also paragraph 4 of this leaflet.
  • HIV protease inhibitors such as indinavir, nelfinavir, ritonavir and saquinavir (used to treat AIDS);
  • boceprevir or telaprevir (used to treat hepatitis C virus infections);
  • nefazodone (used to treat depression);
  • medicines with the active ingredient cobicistat;
  • amiodarone (used to treat an irregular heartbeat);
  • verapamil, diltiazem, or amlodipine (used to treat high blood pressure, chest pain associated with heart disease or other heart disease);
  • lomitapide (used to treat a serious and rare genetic cholesterol condition;
  • high doses (1 g or more per day) of niacin or nicotinic acid (also used to lower cholesterol);
  • colchicine (used to treat gout).

In addition to the medicines listed above, please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including those obtained without a prescription. In particular, tell your doctor if you are taking any of the following:

  • medicines with an active substance to prevent blood clots, such as warfarin, fluindione, phenprocoumon or acenocoumarol (anticoagulants);
  • cholestyramine (also used to lower cholesterol) as it affects the way VYTORIN works;
  • fenofibrate (also used to lower cholesterol);
  • rifampicin (used to treat tuberculosis).

You should also tell any doctor who is prescribing a new medicine that you are taking VYTORIN.

VYTORIN with food and drink

Grapefruit juice contains one or more substances that alter the metabolism of some medicines, including VYTORIN. Consumption of grapefruit juice should be avoided as it can increase the risk of muscle problems.

Warnings It is important to know that:

Pregnancy and breastfeeding

Do not use VYTORIN if you are pregnant, if you intend to become pregnant or if you suspect a pregnancy. If you become pregnant while taking VYTORIN, stop taking it immediately and contact your doctor. VYTORIN should not be used during breastfeeding as it is not known whether the medicine passes into human milk.

Ask your doctor or pharmacist for advice before taking any medicine.

Use in children

The use of VYTORIN is not recommended in children under 10 years of age.

Driving and using machines

VYTORIN is not expected to interfere with your ability to drive or use machines. However, it should be borne in mind that some people have experienced dizziness after taking VYTORIN.

VYTORIN contains lactose

VYTORIN tablets contain a sugar, lactose. If you have been told by your doctor that you have "intolerance to some sugars, contact your doctor before taking this medicine.

Dosage and method of use How to use Vytorin: Dosage

Your doctor will determine which tablet strength is suitable for you, based on your current treatment and your risk profile.

The tablets are not broken and should not be divided.

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

  • Before you start taking VYTORIN, you must have already been on a diet to lower your cholesterol levels.
  • During treatment with VYTORIN you should continue to follow this diet to lower cholesterol.

Adults: the dose is 1 tablet of VYTORIN orally once a day.

Use in adolescents (10 to 17 years of age): The dose is 1 tablet of VYTORIN orally once a day (a maximum dose of 10 mg / 40 mg once a day should not be exceeded).

The VYTORIN 10 mg / 80 mg dose is only recommended in adult patients with very high cholesterol levels and at high risk for heart disease who have not reached their ideal cholesterol level with the lowest doses.

Take VYTORIN in the evening. You can take it with or without food.

If your doctor has prescribed VYTORIN with another cholesterol-lowering medicine containing the active substance cholestyramine or any other bile acid sequestering agent you should take VYTORIN at least 2 hours before or 4 hours after taking the bile acid sequestering agent.

Overdose What to do if you have taken too much Vytorin

If you take more VYTORIN than you should:

  • contact your doctor or pharmacist.

If you forget to take VYTORIN:

  • do not take a double dose to make up for a forgotten tablet, just take the normal dose of VYTORIN the next day at the usual time.

If you stop taking VYTORIN:

  • talk to your doctor or pharmacist as your cholesterol may rise again.

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

Side Effects What are the side effects of Vytorin

Like all medicines, VYTORIN can cause side effects, although not everybody gets them (see section 2 What you need to know before you take VYTORIN).

The following common side effects have been reported (may affect up to 1 in 10 people):

  • muscle aches
  • increases in blood laboratory test values ​​for liver (transaminase) and / or muscle (CK) function

The following uncommon side effects have been reported (may affect up to 1 in 100 people):

  • increases in blood test values ​​relating to liver function; increases in blood uric acid values; increases in the time it takes for blood to clot; presence of protein in the urine; decreased body weight
  • dizziness headache; tingling sensation
  • abdominal pain; indigestion; flatulence; nausea; He retched; abdominal bloating; diarrhea; dry mouth; stomach ache
  • rash; itch; urticaria
  • joint pain; muscular pain; sensitivity; weakness or spasms; neck pain; pain in the arms or legs; back pain
  • unusual tiredness or weakness; feeling tired; chest pain; swelling, especially of the hands and feet
  • sleep disorder; difficulty falling asleep

In addition, the following side effects have been reported in people taking VYTORIN or medicines containing the active substances ezetimibe or simvastatin:

  • low number of red blood cells (anemia); decreased number of blood cells, which can cause bruising / bleeding (thrombocytopenia)
  • loss of sensation or weakness in the arms and legs; poor memory; memory loss; confusion
  • breathing problems including persistent cough and / or shortness of breath or fever
  • constipation
  • inflammation of the pancreas often with severe abdominal pain
  • inflammation of the liver with the following symptoms: yellowing of the skin and eyes; itch; dark-colored urine or light-colored stools; feeling tired or weak; loss of appetite; liver failure; gallbladder stones or inflammation of the gallbladder (which can cause abdominal pain, nausea and vomiting)
  • hair loss; raised red rash, sometimes with target-shaped lesions (erythema multiforme)
  • a hypersensitivity reaction which has included some of the following characteristics: hypersensitivity (allergic reactions including swelling of the face, lips, tongue and / or throat which may cause difficulty in breathing or swallowing and requires immediate treatment, pain or inflammation joints, inflammation of blood vessels, abnormal bruising, rash and swelling, hives, skin sensitivity to the sun, fever, flushing, shortness of breath and feeling sick, lupus-like symptoms (which include rash, skin problems) joints, and effects on white blood cells)
  • muscular pain; sensitivity; muscle weakness or cramps; muscle injuries; tendon problems, sometimes complicated by tendon rupture
  • decreased appetite
  • hot flashes; high blood pressure
  • ache
  • erectile dysfunction
  • depression
  • changes in some blood test values ​​relating to liver function

Additional possible side effects reported with some statins:

  • sleep disturbances, including nightmares
  • sexual difficulties
  • diabetes. It is more likely if you have high blood sugar and fat levels, are overweight and have high blood pressure. Your doctor will monitor you during treatment with this medicine.
  • muscle pain, tenderness or weakness which is constant which may not go away after stopping VYTORIN (frequency not known).

Contact your doctor immediately if you have muscle aches, muscle tenderness and muscle weakness of undetermined causes, as muscle problems can, rarely, be severe and lead to muscle tissue injury causing kidney damage and very rarely deaths have occurred.

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. You can also report side effects directly via the national reporting system at: www.agenziafarmaco.gov.it/it/responsabili. By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

  • Keep this medicine out of the sight and reach of children.
  • Do not use this medicine after the expiry date which is stated on the container after "EXP".
  • Do not store VYTORIN tablets at temperatures above 30 ° C.

Blisters: Store in the original package to protect the medicine from light and moisture.

Bottles: Keep bottles tightly closed to protect the medicine from light and moisture.

Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Composition and pharmaceutical form

What VYTORIN contains

The active substances of VYTORIN are ezetimibe and simvastatin. Each tablet contains 10 mg ezetimibe and 10 mg, 20 mg, 40 mg, or 80 mg simvastatin.

The other ingredients are: butylhydroxyanisole, citric acid monohydrate, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, propyl gallate.

What VYTORIN looks like and contents of the pack

VYTORIN is available in white to off-white capsule-shaped tablets with the code '311 "," 312 "," 313 ", or" 315 "on one side. The tablets are not broken and should not be divided.

VYTORIN is available in packs of 7, 10, 14, 28, 30, 50, 56, 84, 90, 98, multipack containing 98 (2 packs of 49), 100, or 300 tablets.

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 Vytorin 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 interaction 04.6 Pregnancy and lactation 04.7 Effects on ability to drive and use machines 04.8 Undesirable effects 04.9 Overdose 05.0 PHARMACOLOGICAL PROPERTIES 05.1 Pharmacodynamic properties 05.2 Pharmacokinetic properties 05.3 Preclinical safety data 06.0 PHARMACEUTICAL PARTICULARS 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 HOLDER 08.0 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 RADIO DRUGS, COMPLETE DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS AND QUALITY CONTROLS

01.0 NAME OF THE MEDICINAL PRODUCT

VYTORIN TABLETS

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 10 mg of ezetimibe and 10, 20, 40 or 80 mg of simvastatin.

Excipient (s):

Each 10 mg / 10 mg tablet contains 58.2 mg of lactose monohydrate.

Each 10 mg / 20 mg tablet contains 126.5 mg of lactose monohydrate.

Each 10 mg / 40 mg tablet contains 262.9 mg of lactose monohydrate.

Each 10 mg / 80 mg tablet contains 535.8 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Tablet.

White to off-white capsule-shaped tablets with the code "311", "312", "313" or "315" on one side.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Hypercholesterolemia

VYTORIN is indicated as an add-on to diet in patients with primary hypercholesterolaemia (heterozygous familial and non-familial) or with mixed hyperlipidaemia where the use of a combination product is indicated:

• patients not adequately controlled on a statin alone;

• patients already treated with a statin and ezetimibe.

VYTORIN contains ezetimibe and simvastatin. Simvastatin (20-40 mg) has been shown to reduce the frequency of cardiovascular events (see section 5.1). A beneficial effect of ezetimibe on cardiovascular morbidity and mortality has not yet been demonstrated.

Homozygous Familial Hypercholesterolaemia (Homozygous IF)

VYTORIN is indicated as an add-on to diet in patients with homozygous familial hypercholesterolaemia. Patients may also undergo additional therapeutic measures (for example, low-density lipoprotein [LDL] apheresis).


04.2 Posology and method of administration

Hypercholesterolemia

The patient should follow an adequate low-fat dietary regimen and should continue the diet during treatment with VYTORIN.

The medicine should be administered orally. The dose range of VYTORIN is 10 mg / 10 mg / day to 10 mg / 80 mg / day in the evening. Dosages may not all be available in all member states. The usual dose is 10 mg / 20 mg / day. o 10 mg / 40 mg / day administered in the evening as a single dose. The dose of 10 mg / 80 mg is only recommended in patients with severe hypercholesterolaemia and high risk of cardiovascular complications who have not achieved therapeutic goals with lower doses and when the benefits are expected to outweigh the potential risks (see sections 4.4 and 5.1).

Low-density lipoprotein cholesterol (LDL-C) level, the risk of coronary heart disease, and the patient's response to current cholesterol-lowering therapy should be considered at the start of treatment or when the dose is changed.

The dose of VYTORIN should be individualized based on the recognized efficacy of the different strengths of VYTORIN (see section 5.1, Table 1) and on the response to ongoing cholesterol-lowering therapy. Dose adjustments, if required, should be made at intervals. not less than 4 weeks VYTORIN can be given with or without meals The tablet should not be divided.

Homozygous familial hypercholesterolaemia

The recommended starting dose for patients with homozygous familial hypercholesterolaemia is VYTORIN 10 mg / 40 mg / day in the evening. The 10 mg / 80 mg dose is only recommended when the benefits are expected to outweigh the potential risks (see above; sections 4.3 and 4.4). VYTORIN can be used in these patients as an adjuvant to other lipid-lowering treatments (eg LDL apheresis) or if such treatments are not available.

Concomitant administration with other medicinal products

Administration of VYTORIN should occur either ≥2 hours before or ≥4 hours after administration of a bile acid sequestering agent.

In patients taking amiodarone, amlodipine, verapamil, or diltiazem concomitantly with VYTORIN, the dose of VYTORIN should not exceed 10 mg / 20 mg / day (see sections 4.4 and 4.5).

In patients receiving lipid-lowering doses of niacin (≥1 g / day) concomitantly with VYTORIN, the dose of VYTORIN should not exceed 10 mg / 20 mg / day (see sections 4.4 and 4.5).

Use in the elderly

No dose adjustment is required in elderly patients (see section 5.2).

Use in children and adolescents

The initiation of treatment must be carried out under the supervision of a specialist.

Adolescents ≥10 years (pubertal status: boys in Tanner stage II and higher and girls who have been post-menarche for at least one year): Clinical experience in pediatric and adolescent patients (10 to 17 years) is limited. The usual recommended starting dose is 10 mg / 10 mg once daily in the evening The recommended dosage range is 10 mg / 10 mg up to a maximum of 10 mg / 40 mg / day (see sections 4.4 and 5.2).

Children

Use in case of liver damage

No dose adjustment is required in mild (Child-Pugh score 5 to 6) hepatic impairment. Treatment with VYTORIN is not recommended in patients with moderate (Child-Pugh score 7 to 9) or severe hepatic impairment. (Child-Pugh score> 9), (see sections 4.4 and 5.2).

Use in case of kidney damage

No dose modification is required in patients with mild renal impairment (estimated glomerular filtration rate ≥60 ml / min / 1.73 m2). In patients with chronic kidney disease and estimated glomerular filtration rate 2, the recommended dose of VYTORIN is 10/20 mg once daily in the evening (see sections 4.4, 5.1, and 5.2). Higher doses should be administered with caution.


04.3 Contraindications

Hypersensitivity to ezetimibe, simvastatin, or to any of the excipients.

Pregnancy and lactation (see section 4.6).

Active liver disease or elevated, persistent and indeterminate values ​​of serum transaminases.

Concomitant administration of potent CYP3A4 inhibitors (agents that increase AUC approximately 5-fold or more) (eg, itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (eg nelfinavir ) boceprevir, telaprevir and nefazodone) (see sections 4.4 and 4.5).

Concomitant administration of gemfibrozil, cyclosporine, or danazol (see sections 4.4. And 4.5).


04.4 Special warnings and appropriate precautions for use

Myopathy / rhabdomyolysis

Cases of myopathy and rhabdomyolysis have been reported in post-marketing experience with ezetimibe. Most patients who developed rhabdomyolysis were on concomitant therapy with ezetimibe and a statin. However, rhabdomyolysis has been reported very rarely with ezetimibe and monotherapy. very rarely with the addition of ezetimibe to other agents known to be associated with an increased risk of rhabdomyolysis.

VYTORIN contains simvastatin. Simvastatin, like other HMG-CoA reductase inhibitors, occasionally causes myopathy, manifesting as muscle pain, tenderness, or weakness associated with elevations in creatine kinase (CK) levels above 10 times the upper limit of normal. Myopathy sometimes manifests as rhabdomyolysis with or without acute renal failure secondary to myoglobinuria and very rarely fatal outcomes have occurred The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma.

As with other HMG-CoA reductase inhibitors, the risk of myopathy / rhabdomyolysis is dose related to simvastatin. In a clinical trial database in which 41,413 patients were treated with simvastatin, 24,747 (approximately 60%) of whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was approximately 0.03%, 0.08% and 0.61% at 20, 40 and 80 mg / day, respectively . In these studies, patients were closely monitored and some interacting medicines were excluded.

In a clinical study in which patients with a history of myocardial infarction were treated with simvastatin 80 mg / day (mean follow-up of 6.7 years), the incidence of myopathy was approximately 1.0% compared with at an incidence of 0.02% seen in patients treated with 20 mg / day. Approximately half of these cases of myopathy occurred during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1% (see sections 4.8 and 5.1).

The risk of myopathy is higher in patients treated with VYTORIN 10/80 mg than with other statin-based therapies with similar efficacy in lowering LDL-C. Therefore, the VYTORIN 10/80 mg dose should only be used in patients with severe hypercholesterolaemia and at high risk of cardiovascular complications who have not achieved treatment goals with lower doses and when benefits are expected to exceed the potential risks. In patients treated with VYTORIN 10/80 mg who require an interacting agent, a lower dose of VYTORIN or an alternative statin regimen with a lower potential for drug-drug interactions should be used (see below. Measures to reduce the risk of myopathy caused by drug interactions and paragraphs 4.2, 4.3, and 4.5).

In a clinical study in which over 9,000 patients with chronic kidney disease were randomized to receive VYTORIN 10/20 mg daily (n = 4,650) or placebo (n = 4,620) (median follow-up of 4.9 years), l "incidence of myopathy was 0.2% for VYTORIN and 0.1% for placebo (see section 4.8).

In a clinical study in which patients at high risk of cardiovascular disease were treated with simvastatin 40 mg / day (median follow-up of 3.9 years), the incidence of myopathy was approximately 0.05% for patients. non-Chinese (n = 7,367) versus 0.24% for Chinese patients (n = 5,468). Although the only Asian population evaluated in this clinical study was Chinese, caution should be exercised when prescribing VYTORIN to Asian patients and the lowest dose must necessarily be used.

Reduced functionality of transport proteins

Reduced function of hepatic OATP transport proteins may increase systemic exposure to simvastatin acid and increase the risk of myopathy and rhabdomyolysis. Impaired function may occur both as a result of inhibition by interacting drugs (eg cyclosporine) and in patients carriers of the SLCO1B1 genotype c.521T> C.

Patients carrying the SLCO1B1 gene allele (c.521T> C) encoding a less active OATP1B1 protein have increased systemic exposure to simvastatin acid and a greater risk of myopathy. The risk of myopathy related to a high dose (80 mg) of simvastatin is approximately 1% in general, without genetic testing. Based on the results of the SEARCH study, homozygous C (also called CC) carriers treated with 80 mg they have a 15% risk of developing myopathy within one year, while the risk in heterozygous carriers of the C allele (CT) is 1.5%. The relative risk is 0.3% in patients with the most common genotype (TT) (see section 5.2). Where available, genotyping for the presence of the C allele should be considered as part of the benefit-risk assessment before prescribing simvastatin 80 mg to individual patients and high doses, in those in whom CC genotype is found, should be avoided. However, the absence of this gene in genotyping does not rule out the possibility of myopathy developing.

Measurement of creatine kinase levels

CK levels should not be measured after strenuous exercise or in the presence of any alternative cause of CK increase as this can make the data difficult to interpret. If CK levels are significantly elevated at baseline (greater than 5 times the upper limit of normal), these should be re-measured within 5-7 days for results to be confirmed.

Before the treatment

All patients starting VYTORIN therapy or increasing the dose of VYTORIN should be informed of the risk of myopathy and instructed to report any unexplained muscle pain, tenderness and weakness immediately.

Caution should be exercised in patients with predisposing factors for rhabdomyolysis. In order to establish a baseline reference value, the CK level should be measured before starting treatment in the following cases:

• elderly (age ≥ 65 years)

• female sex

• kidney damage

• uncontrolled hypothyroidism

• personal or family history of hereditary muscular disorders

• history of previous episodes of muscle toxicity with a statin or fibrate

• alcohol abuse.

In the above cases, the risk that the treatment entails must be weighed against the possible benefit, and in the case of treatment, closer monitoring of the patient is recommended. If the patient has had a previous experience of muscle disorders while being treated with a fibrate or a statin, treatment with any statin-containing product (such as VYTORIN) should only be started with caution. If CK levels are significantly elevated at baseline (greater than 5 times the upper limit of normal), treatment should not be initiated.

During the treatment

If the patient reports muscle pain, weakness or cramps during treatment with VYTORIN, CK levels should be measured. In the event of significantly elevated CK levels (greater than 5 times the upper limit of normal), in the absence of strenuous exercise, therapy should be discontinued. Discontinuation of treatment may be considered in the event of severe muscle symptoms causing daily discomfort, even if CK values ​​remain below 5 times the upper limit of normal. Treatment should be discontinued if there is suspicion of myopathy for any other reason.

There have been very rare reports of immune-mediated necrotizing myopathy (IMNM) during or after treatment with some statins. IMNM is clinically characterized by persistent proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment (see section 4.8).

If symptoms subside and CK levels return to normal, reintroduction of VYTORIN, or another product containing another statin, at the lowest dose and under close monitoring may be considered.

A higher incidence rate of myopathy has been observed in patients titrated to simvastatin 80 mg (see section 5.1). It is recommended that CK levels be measured periodically as they may be useful in identifying subclinical cases of myopathy. However, there is no certainty that such monitoring will prevent myopathy.

VYTORIN therapy should be temporarily interrupted a few days before major elective surgery and if any major medical or surgical condition develops.

Measures to reduce the risk of myopathy caused by drug interactions (see also section 4.5)

The risk of myopathy and rhabdomyolysis is significantly increased by concomitant use of VYTORIN with potent CYP3A4 inhibitors (such as itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (eg nelfrevinavir), bocepirvir) telaprevir, nefazodone), as with cyclosporine, danazol and gemfibrozil. The use of these medicinal products is contraindicated (see section 4.3).

Due to the presence of simvastatin in VYTORIN, the risk of myopathy and rhabdomyolysis is also increased by the concomitant use of other fibrates, niacin at lipid-lowering doses (≥ 1 g / day) or by the concomitant use of amiodarone, amlodipine, verapamil or diltiazem with some doses of VYTORIN (see sections 4.2 and 4.5). The risk of myopathy, including rhabdomyolysis, may be increased when VYTORIN is co-administered with fusidic acid (see section 4.5).

Consequently, with regard to CYP3A4 inhibitors, the concomitant use of VYTORIN with itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (eg nelfinavir), boceprevir, telaprevir, erythromycin, contra-clarithromycin, and telphromycin is nephromycin. (see sections 4.3 and 4.5). If therapy with potent CYP3A4 inhibitors (agents that increase AUC approximately 5-fold or more) cannot be avoided, VYTORIN treatment should be discontinued (and the use of another statin should be considered) during In addition, caution should be exercised when combining VYTORIN with some other less potent CYP3A4 inhibitors: fluconazole, verapamil, diltiazem (see sections 4.2 and 4.5). Concomitant intake of grapefruit juice and VYTORIN should be avoided.

Simvastatin should not be co-administered with fusidic acid. There have been reports of rhabdomyolysis (including some deaths) in patients receiving this combination (see section 4.5). In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued for the duration of fusidic acid treatment. Patients should be advised to seek immediate medical attention if symptoms develop. muscle weakness, pain or tenderness.

Statin therapy can be reintroduced seven days after the last dose of fusidic acid. In exceptional circumstances where prolonged systemic use of fusidic acid is required, for example to treat severe infections, the need for co -Administration of VYTORIN and fusidic acid should only be evaluated on a case-by-case basis under strict medical supervision.

Concomitant use of VYTORIN at doses greater than 10 mg / 20 mg per day and niacin at lipid-lowering doses (≥1 g / day) should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy. (see sections 4.2 and 4.5).

Rare cases of myopathy / rhabdomyolysis have been associated with concomitant administration of HMG-CoA reductase inhibitors and lipid-modifying doses of niacin (nicotinic acid) (≥ 1 g / day), both of which can cause myopathy when given. alone.

There was no There was no additional benefit on cardiovascular outcomes with the addition of doses of niacin (nicotinic acid) capable of modifying the lipid profile (≥1 g / day).

Therefore, physicians considering combination therapy with simvastatin and lipid-modifying doses of niacin (nicotinic acid) (≥ 1 g / day) or niacin-containing products should carefully weigh the potential benefits and risks and should monitor patients carefully for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and when doses of either drug are increased.

In addition, in this study, the incidence of myopathy was approximately 0.24% for Chinese patients treated with simvastatin 40 mg or ezetimibe / simvastatin 10/40 mg compared to 1.24% for Chinese patients treated with simvastatin. 40 mg or ezetimibe / simvastatin 10/40 mg co-administered with nicotinic acid / laropiprant 2,000 mg / 40 mg modified release. Although the only Asian population evaluated in this clinical study was the Chinese one, since the incidence of myopathy is higher in Chinese patients than in non-Chinese patients, the concomitant administration of VITORYN with doses of niacin (nicotinic acid) can modify the lipid profile (≥ 1 g / day) is not recommended in Asian patients.

Acipimox is structurally related to niacin. Although acipimox has not been studied, the risk of muscle related toxic effects may be similar to that of niacin.

Concomitant use of VYTORIN at doses above 10 mg / 20 mg daily and amiodarone, amlodipine, verapamil or diltiazem should be avoided (see sections 4.2 and 4.5).

Patients taking other medicinal products known to have a moderate inhibitory effect on CYP3A4 at therapeutic doses when used concomitantly with VYTORIN, particularly with higher doses of VYTORIN, may have an increased risk of myopathy.

In case of co-administration of VYTORIN with a moderate inhibitor of CYP3A4 (agents that increase the AUC approximately 2-5 fold), a dose adjustment may be necessary. For some moderate CYP3A4 inhibitors eg diltiazem, a maximum dose of 10/20 mg of VYTORIN is recommended (see section 4.2).

The safety and efficacy of VYTORIN administered with fibrates have not been studied. There is an increased risk of myopathy when concomitant use of simvastatin and fibrates (especially gemfibrozil) is used. Therefore, concomitant use of VYTORIN and gemfibrozil is contraindicated ( see section 4.3) and concomitant use with other fibrates is not recommended (see section 4.5).

Liver enzymes

In controlled combination dosing studies in which patients were treated with ezetimibe and simvastatin, consecutive elevations in transaminases (≥3 times upper limit of normal [ULN]) were observed (see section 4.8).

In a controlled clinical trial in which over 9,000 patients with chronic kidney disease were randomized to receive VYTORIN 10/20 mg daily (n = 4,650) or placebo (n = 4,620) (median follow-up period of 4.9 years ), the incidence of consecutive transaminase elevations (> 3 times ULN) was 0.7% for VYTORIN and 0.6% for placebo (see section 4.8).

It is recommended that liver function tests be performed before initiating treatment with VYTORIN and thereafter when clinically indicated. Patients titrated to the 10 mg / 80 mg dose should undergo an additional test before titration, 3 months after titration to the 10 mg / 80 mg dose, and periodically thereafter (e.g., every six months) for the first year of treatment. Particular attention should be paid to patients who develop elevations in serum transaminases and in these patients, blood tests should be repeated promptly and performed more frequently thereafter. If transaminase levels show evidence of progression, particularly if they rise to 3 times the ULN and are persistent, drug treatment should be discontinued. Note that ALT may arise from muscle, therefore an increase in ALT and CK may indicate myopathy (see above Myopathy / rhabdomyolysis).

There have been rare post-marketing reports of fatal and non-fatal hepatic failure in patients taking statins, including simvastatin. If severe liver injury with clinical symptoms and / or hyperbilirubinaemia or jaundice occurs during treatment with VYTORIN, discontinue therapy immediately. If an alternative etiology is not found, do not restart therapy with VYTORIN.

VYTORIN should be used with caution in patients who consume significant amounts of alcohol.

Hepatic insufficiency

Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic impairment, VYTORIN is not recommended (see section 5.2).

Diabetes mellitus

Some evidence suggests that statins as a class effect increase blood glucose and in some patients, at high risk of developing diabetes, may induce a level of hyperglycemia such that antidiabetic therapy is appropriate.

This risk, however, is outweighed by the reduction in vascular risk with the use of statins and therefore should not be a reason for stopping treatment with statins.

Patients at risk (fasting glucose 5.6 to 6.9 mmol / L, BMI> 30 kg / m2, elevated triglyceride levels, hypertension) should be monitored both clinically and biochemically in accordance with national guidelines. .

Pediatric patients (10 to 17 years of age)

The safety and efficacy of ezetimibe co-administered with simvastatin in patients 10 to 17 years of age with heterozygous familial hypercholesterolaemia were evaluated in a controlled clinical study in adolescent boys (Tanner stage II or higher) and in girls. in post-menarche for at least a year.

In this limited controlled study, there was generally no effect on sexual growth or maturation in adolescent boys or girls, or any effect on menstrual cycle length in girls. However, the effects of ezetimibe over a treatment period> 33 weeks on sexual growth and maturation have not been studied (see sections 4.2 and 4.8).

The safety and efficacy of ezetimibe co-administered with simvastatin doses greater than 40 mg daily have not been studied in pediatric patients 10 to 17 years of age.

Ezetimibe has not been studied in patients less than 10 years of age or in pre-menarche girls (see sections 4.2 and 4.8).

The long-term efficacy of ezetimibe therapy in patients less than 17 years of age to reduce adult morbidity and mortality has not been studied.

Bundles

The safety and efficacy of ezetimibe administered with fibrates have not been established (see above and sections 4.3 and 4.5).

Anticoagulants

If VYTORIN is added to warfarin, another coumarin anticoagulant, or fluindione, the International Normalized Ratio should be adequately monitored (see section 4.5).

Interstitial lung disease

Cases of interstitial lung disease have been reported with some statins, including simvastatin, especially with long-term therapy (see section 4.8). Symptoms may include dyspnoea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected that a patient has developed interstitial lung disease, VYTORIN therapy should be discontinued.

Excipients

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

Pharmacodynamic interactions

Interactions with lipid-lowering medicinal products that can cause myopathy when given alone

The risk of myopathy, including rhabdomyolysis, is increased during concomitant administration of simvastatin with fibrates. In addition, a "pharmacokinetic interaction of simvastatin with gemfibrozil causes increased plasma levels of simvastatin (see below, Pharmacokinetic interactions and sections 4.3 and 4.4). Rare cases of myopathy / rhabdomyolysis have been associated with concomitant administration of simvastatin and lipid modifying doses of niacin (≥ 1 g / day) (see section 4.4).

Fibrates may increase the excretion of cholesterol in the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased the cholesterol in the gallbladder bile (see section 5.3). Although the relevance of these preclinical data to humans is unknown, concomitant administration of VYTORIN with fibrates is not recommended (see section 4.4).

Pharmacokinetic interactions

Prescribing recommendations for interacting agents are summarized in the following table (further details are included in the text; see also sections 4.2, 4.3 and 4.4).

Interacting drugs associated with increased risk of myopathy / rhabdomyolysis Interacting agents Prescribing Recommendations Potent inhibitors of CYP3A4, e.g. Contraindicated with VYTORIN Itraconazole Ketoconazole Posaconazole Voriconazole Erythromycin Clarithromycin Telithromycin HIV protease inhibitors (eg nelfinavir) Boceprevir Telaprevir Nefazodone Cyclosporine Danazol Gemfibrozil Other Fibrates Not recommended with VYTORIN Fusidic acid Niacin (nicotinic acid) (≥ 1 g / day) For Asian patients, not recommended with VYTORIN Amiodarone Do not exceed 10 mg / 20 mg of VYTORIN per day Amlodipine Verapamil Diltiazem Niacin (≥1 g / day) Grapefruit juice Avoid grapefruit juice when taking VYTORIN

Effects of other medicinal products on VYTORIN

VYTORIN

Niacin: In a study of 15 healthy adults, concomitant use of VYTORIN (10 mg / 20 mg daily for 7 days) produced a small increase in the mean AUC values ​​of niacin (22%) and nicotinuric acid (19 %), given as NIASPAN prolonged-release tablets (1,000 mg for 2 days and 2,000 mg for 5 days taken after a low-fat breakfast). In the same study, concomitant use of NIASPAN resulted in a slight increase in the mean AUC values ​​of ezetimibe (9%), total ezetimibe (26%), simvastatin (20%) and simvastatin acid (35%) ( see sections 4.2 and 4.4).

No drug interaction studies have been performed with higher doses of simvastatin.

Ezetimibe

Antacids: Concomitant administration of antacids decreased the absorption rate of ezetimibe but had no effect on the bioavailability of ezetimibe. This decrease in the rate of absorption is not considered to be clinically significant.

Cholestyramine: concomitant administration of cholestyramine decreased the mean area under the curve (AUC) of total ezetimibe (ezetimibe + ezetimibe-glucuronide) by approximately 55%. The further reduction in low density lipoprotein cholesterol (LDL-C) due to the addition of VYTORIN to cholestyramine may be decreased by this interaction (see section 4.2).

Ciclosporin: In a study of eight post-renal transplant patients with creatinine clearance> 50 ml / min at stable doses of ciclosporin, administration of a single 10 mg dose of ezetimibe resulted in a 3.4-fold increase (range of 2.3 - 7.9 times) of the mean AUC for total ezetimibe compared to a healthy control population from another study treated with ezetimibe alone (n = 17). In a different study, a transplant patient with severe renal insufficiency treated with cyclosporine and several other medicinal products, showed a 12-fold higher "total exposure to" ezetimibe compared to related controls treated with ezetimibe alone. In a two-period crossover study, out of twelve healthy subjects, daily administration of ezetimibe 20 mg for 8 days with cyclosporine 100 mg single dose on day 7 resulted in a mean 15% increase in cyclosporine AUC (range between one 10% decrease and 51% increase) compared to a single dose of 100 mg cyclosporine alone. No controlled studies have been performed on the effect of concomitant administration of ezetimibe on cyclosporine exposure in renal transplant patients. Concomitant administration of VYTORIN and cyclosporine is contraindicated (see section 4.3).

Bundles: Concomitant administration of fenofibrate or gemfibrozil increased the total concentrations of ezetimibe approximately 1.5 and 1.7-fold, respectively. Although these increases are not considered to be clinically significant, concomitant administration of VYTORIN with gemfibrozil is contraindicated and with other fibrates is not recommended (see sections 4.3 and 4.4).

Simvastatin

Simvastatin is a substrate of cytochrome P450 3A4. Potent inhibitors of cytochrome P450 3A4 increase the risk of myopathy and rhabdomyolysis by increasing the concentration of HMG-CoA reductase inhibitory activity in plasma during simvastatin therapy. Such inhibitors include itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (eg nelfinavir), boceprevir, telaprevir and nefazodone. times of exposure of simvastatin acid (the active beta-hydroxy acid metabolite). Telithromycin caused an 11-fold increase in exposure of simvastatin acid.

The combination with itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (eg nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin and nefazodone is contraindicated, as well as with gemfibrozil, cyclospor 4.3). If treatment with potent CYP3A4 inhibitors (agents that increase AUC approximately 5-fold or more) is unavoidable, VYTORIN therapy should be discontinued (and the use of another statin should be considered) during the course of the Treatment Caution should be exercised when combining VYTORIN with some other less potent CYP3A4 inhibitors: fluconazole, verapamil or diltiazem (see sections 4.2 and 4.4).

Fluconazole: Rare cases of rhabdomyolysis associated with concomitant administration of simvastatin and fluconazole have been reported (see section 4.4).

Cyclosporine: the risk of myopathy / rhabdomyolysis is increased by the concomitant administration of ciclosporin with VYTORIN; therefore use with cyclosporine is contraindicated (see sections 4.3 and 4.4). Although the mechanism is not fully understood, cyclosporine has been shown to increase the AUC of HMG-CoA reductase inhibitors. of simvastatin acid is presumably due, in part, to inhibition of CYP3A4 and / or OATP1B1.

Danazol: the risk of myopathy and rhabdomyolysis is increased by the concomitant administration of danazol with VYTORIN; therefore, use with danazol is contraindicated (see sections 4.3 and 4.4).

Gemfibrozil: gemfibrozil increases the AUC of the acid metabolite of simvastatin by 1.9-fold, possibly due to inhibition of glucuronidation and / or OATP1B1 (see sections 4.3 and 4.4). Concomitant administration with gemfibrozil is contraindicated.

Fusidic acid

The risk of myopathy including rhabdomyolysis may be increased by the concomitant administration of systemic fusidic acid with statins. Co-administration of this combination may cause increased plasma concentrations of both agents. The mechanism of this interaction (whether pharmacodynamic or pharmacokinetic, or both) is still unknown. There have been reports of rhabdomyolysis (including some deaths) in patients receiving this combination. If treatment with fusidic acid is required, VYTORIN treatment should be discontinued for the duration of fusidic acid treatment (see section 4.4).

Amiodarone: the risk of myopathy and rhabdomyolysis is increased by the concomitant administration of amiodarone with simvastatin (see section 4.4). In a clinical study, myopathy was reported in 6% of patients treated with simvastatin 80 mg and amiodarone. Therefore, the dose of VYTORIN should not exceed 10 mg / 20 mg per day in patients receiving concomitant amiodarone therapy.

Calcium channel blockers

Verapamil: The risk of myopathy and rhabdomyolysis is increased by concomitant administration of verapamil with simvastatin 40 mg or 80 mg (see section 4.4).

In a pharmacokinetic study, concomitant administration of simvastatin with verapamil resulted in a 2.3-fold increase in simvastatin acid exposure presumably due, in part, to inhibition of CYP3A4. The dose of VYTORIN should therefore not exceed 10 mg / 20 mg per day in patients receiving concomitant therapy with verapamil.

• Diltiazem: The risk of myopathy and rhabdomyolysis is increased by concomitant administration of diltiazem with simvastatin 80 mg (see section 4.4). In a pharmacokinetic study, concomitant administration of diltiazem and simvastatin caused a 2.7-fold increase in simvastatin acid exposure, possibly due to inhibition of CYP3A4. The dose of VYTORIN should therefore not exceed 10 mg / 20 mg per day in patients receiving concomitant therapy with diltiazem.

Amlodipine: patients on concomitant therapy with amlodipine and simvastatin have an increased risk of myopathy. In a pharmacokinetic study, concomitant administration of amlodipine caused a 1.6-fold increase in exposure of simvastatin acid. The dose of VYTORIN should therefore not exceed 10 mg / 20 mg daily in patients receiving amlodipine concomitant.

Moderate CYP3A4 inhibitors

Patients taking other medicinal products known to have a moderate inhibitory effect on CYP3A4 when used concomitantly with VYTORIN, particularly with higher doses of VYTORIN, may have an increased risk of myopathy (see section 4.4).

Inhibitors of the transport protein OATP1B1

Simvastatin acid is a substrate of the transport protein OATP1B1. Concomitant administration of medicinal products that are inhibitors of the transport protein OATP1B1 may lead to increased plasma concentrations of simvastatin acid and an increased risk of myopathy (see sections 4.3 and 4.4).

Grapefruit juice: grapefruit juice inhibits cytochrome P450 3A4. Concomitant intake of simvastatin and large amounts (more than one liter per day) of grapefruit juice resulted in a 7-fold increase in exposure of simvastatin acid. Intake of 240 ml of grapefruit juice in the morning and simvastatin in the evening also resulted in a 1.9-fold increase. Intake of grapefruit juice during treatment with VYTORIN should therefore be avoided.

Colchicine: There have been reports of myopathy and rhabdomyolysis with the concomitant administration of colchicine and simvastatin, in patients with renal insufficiency. Close clinical monitoring of such patients taking this combination is advised.

Rifampicin: Since rifampicin is a potent inducer of CYP3A4, patients undertaking long-term rifampicin therapy (e.g. treatment of tuberculosis) may experience loss of efficacy of simvastatin. In a pharmacokinetic study in healthy volunteers, the area under the plasma concentration curve (AUC) for simvastatin acid was decreased by 93% with concomitant administration of rifampicin.

Niacin: Cases of myopathy / rhabdomyolysis have been observed with simvastatin co-administered with lipid modifying doses of niacin (≥ 1 g / day) (see section 4.4).

Effects of VYTORIN on the pharmacokinetics of other medicinal products

Ezetimibe

In preclinical studies, ezetimibe has been shown not to induce cytochrome P450 enzymes involved in drug metabolism. No clinically significant pharmacokinetic interactions have been observed between ezetimibe and drugs subject to metabolism by cytochromes P450 1A2, 2D6. 2C8, 2C9 and 3A4, or N-acetyltransferase.

Anticoagulants: In a study of twelve healthy adult men, concomitant administration of ezetimibe (10 mg once daily) had no significant effect on warfarin bioavailability and prothrombin time. There have, however, been post-marketing reports of increases in the International Normalized Ratio in patients who had added ezetimibe to warfarin or fluindione. If VYTORIN is added to warfarin or another coumarin anticoagulant, or to fluindione, the INR should be adequately monitored (see section 4.4).

Simvastatin

Simvastatin has no inhibitory effect on cytochrome P450 3A4. Therefore, an action of simvastatin on plasma concentrations of substances metabolised via cytochrome P450 3A4 is not expected.

Oral anticoagulants: in two clinical studies, one in normal volunteers and the other in hypercholesterolemic patients, simvastatin 20-40 mg / day moderately potentiated the effect of coumarin anticoagulants; prothrombin time reported as International Normalized Ratio (INR) increased from a baseline of 1.7 to 1.8 and from a baseline of 2.6 to 3.4 in the volunteers and study patients, respectively. Very rare cases of elevated INR have been reported. In patients treated with coumarin anticoagulants, prothrombin time should be determined before initiating treatment with VYTORIN and frequently enough during the early stages of therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals routinely recommended for patients on coumarin anticoagulants. If the dose of VYTORIN is changed or administration is interrupted, the same procedure must be repeated. Simvastatin therapy has not been associated with bleeding or changes in prothrombin time in patients not on anticoagulant therapy.


04.6 Pregnancy and breastfeeding

Pregnancy

Atherosclerosis is a chronic process and routinely discontinuing lipid-lowering drugs during pregnancy must have negligible impact on the long-term risk associated with primary hypercholesterolemia.

VYTORIN

VYTORIN is contraindicated during pregnancy. No clinical data are available on the use of VYTORIN during pregnancy. Animal studies in combination therapy have shown reproductive toxicity (see section 5.3).

Simvastatin

The safety of simvastatin in pregnant women has not been established. No controlled clinical studies have been conducted with simvastatin in pregnant women. There have been rare reports of congenital abnormalities following intrauterine exposure to HMG-CoA reductase inhibitors. However, in a prospective analysis of approximately 200 pregnancies exposed during the first trimester to simvastatin or another closely related HMG-CoA reductase inhibitor, the incidence of congenital anomalies was comparable to that seen in the general population. This number of pregnancies was statistically sufficient to rule out an increase in congenital anomalies of 2.5 times or greater than the baseline incidence.

Although there is no evidence that the incidence of congenital abnormalities in the offspring of patients treated with simvastatin or other closely related HMG-CoA reductase inhibitors differs from that seen in the general population, treatment of mothers with simvastatin may reduce fetal levels. of mevalonate, a precursor of cholesterol biosynthesis. For this reason, VYTORIN should not be used in women who are pregnant, wishing to become pregnant or suspect they are pregnant. Treatment with VYTORIN should be suspended for the duration of pregnancy or until that it has not been determined that the woman is not pregnant (see section 4.3).

Ezetimibe

There are no data on the use of ezetimibe during pregnancy.

Feeding time

VYTORIN is contraindicated during lactation. Studies in rats have shown that ezetimibe is excreted in milk. It is not known whether the active components of VYTORIN are excreted in human milk (see section 4.3).


04.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. However, when driving or using machines it should be borne in mind that dizziness has been reported.


04.8 Undesirable effects

The safety of VYTORIN (or of concomitant administration of ezetimibe and simvastatin equivalent to VYTORIN) has been evaluated in approximately 12,000 patients in clinical studies.

The frequencies of undesirable effects are classified as follows: very common (≥ 1/10), common ≥ 1/100,

The following undesirable effects were observed in patients treated with VYTORIN (N = 2,404) and with higher incidence than placebo (N = 1,340).

Undesirable effects with VYTORIN with higher incidence than placebo System and organ classification Side effects Frequency Diagnostic tests increased ALT and / or AST; increased blood CK common increased bilirubinemia; increased uric acid; increased gamma-glutamyltransferase; increase in the international normalized ratio; proteinuria; weight decrease Uncommon Nervous system disorders dizziness; headache Uncommon Gastrointestinal disorders abdominal pain; abdominal discomfort; pain in the upper abdomen; dyspepsia; flatulence; nausea; vomiting Uncommon Skin and subcutaneous tissue disorders itch; rash Uncommon Musculoskeletal and connective tissue disorders arthralgia; muscle spasms; muscle weakness; musculoskeletal disorder; neck pain; pain in extremities Uncommon General disorders and administration site conditions asthenia; fatigue; malaise; peripheral edema Uncommon Psychiatric disorders sleep disturbance Uncommon

The following undesirable effects were observed in patients treated with VYTORIN (N = 9,595) and with a higher incidence than statins once administered (N = 8,883).

Undesirable effects with VYTORIN with higher incidence than statins System and organ classification Side effects Frequency Diagnostic tests increased ALT and / or AST common increased bilirubinemia; increased blood CK; increased gamma-glutamyltransferase Uncommon Nervous system disorders headache; paresthesia Uncommon Gastrointestinal disorders abdominal distension; diarrhea; dry mouth; dyspepsia; flatulence; gastroesophageal reflux disease; He retched Uncommon Skin and subcutaneous tissue disorders itch; rash; urticaria Uncommon Musculoskeletal and connective tissue disorders myalgia common arthralgia; back pain; muscle spasms; muscle weakness; musculoskeletal pain; pain in extremities Uncommon General disorders and administration site conditions asthenia; chest pain; fatigue; peripheral edema Uncommon Psychiatric disorders insomnia Uncommon

Pediatric patients (10 to 17 years of age)

In a study performed in adolescent patients (10 to 17 years of age) with heterozygous familial hypercholesterolaemia (n = 248), elevations in ALT and / or AST (≥ 3 X ULN, consecutive) were observed in 3% ( 4 patients) of patients in the ezetimibe / simvastatin group versus 2% (2 patients) of patients in the simvastatin monotherapy group; the percentages of CPK increases (≥10 X ULN) were 2% (2 patients) and 0%, respectively. No cases of myopathy have been reported.

This study was not suitable for comparing rare drug adverse reactions.

Patients with chronic kidney disease

In the Study of Heart and Renal Protection (SHARP) (see section 5.1), involving over 9,000 patients treated with VYTORIN 10/20 mg daily (n = 4,650) or placebo (n = 4,620), the safety profiles are were comparable during a median follow-up period of 4.9 years. In this study, only serious adverse events and discontinuations due to any adverse event were recorded. Discontinuation rates due to adverse events were comparable (10.4% in patients treated with VYTORIN, 9.8% in patients treated with placebo). The incidence of myopathy / rhabdomyolysis was 0.2% in patients treated with VYTORIN and 0.1% in patients treated with placebo. Consecutive elevations in transaminases (> 3x ULN) occurred in 0.7% of patients. treated with VYTORIN compared with 0.6% of patients treated with placebo. In this study, there were no statistically significant increases in the incidence of pre-specified adverse events, including cancer (9.4% for VYTORIN, 9.5% for placebo), hepatitis, cholecystectomy or complications of gallstones or pancreatitis.

Diagnostic investigations

In combination dosing studies, the incidence of clinically important elevations in serum transaminases (ALT and / or AST ≥ 3 X ULN, consecutive values) was 1.7% in patients treated with VYTORIN. These elevations were generally asymptomatic. not associated with cholestasis, and returned to baseline after discontinuation of therapy or during the course of treatment (see section 4.4).

Clinically relevant increases in CK (≥10 X ULN) were observed in 0.2% of patients treated with VYTORIN.

Post-marketing experience

The following additional undesirable effects have been reported in post-marketing use with VYTORIN or in clinical trials or during post-marketing use with one of the individual components.

Disorders of the blood and lymphatic system: thrombocytopenia; anemia

Nervous system disorders: peripheral neuropathy; memory impairment

Respiratory, thoracic and mediastinal disorders: cough; dyspnea; interstitial lung disease (see section 4.4)

Gastrointestinal disorders: constipation; pancreatitis; gastritis

Skin and subcutaneous tissue disorders: alopecia; erythema multiforme; hypersensitivity reactions, including rash, urticaria, anaphylaxis, angioedema

Musculoskeletal and connective tissue disorders: muscle cramps; myopathy * (including myositis); rhabdomyolysis with or without acute renal failure (see section 4.4); tendinopathy, sometimes complicated by rupture; immune-mediated necrotizing myopathy (IMNM) (frequency not known) **.

* In a clinical study, myopathy occurred commonly in patients treated with simvastatin 80 mg / day compared to patients treated with 20 mg / day (1.0% vs 0.02%, respectively) (see sections 4.4 and 4.5) .

** There have been very rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, during or after treatment with some statins. IMNM is characterized by: persistent proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents (see section 4.4 ).

Metabolism and nutrition disorders: decreased appetite

Vascular disorders: hot flashes; hypertension

General Disorders and Administration Site Conditions: Pain

Hepatobiliary disorders: hepatitis / jaundice; fatal and non-fatal liver failure; cholelithiasis; cholecystitis

Reproductive system and breast disorders: erectile dysfunction

Psychiatric disorders: depression, insomnia

Apparent hypersensitivity syndrome has been reported rarely, including some of the following: angioedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, increased erythrocyte sedimentation rate, arthritis and arthralgia, urticaria, photosensitivity, fever, hot flashes, wheezing and malaise.

Investigations: elevated alkaline phosphatase; abnormal liver function test.

Increases in HbA1c and fasting serum glucose levels have been reported with statins, including simvastatin.

There have been rare post-marketing reports of cognitive impairment (eg, memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use, including simvastatin. The reports were generally non-serious. and reversible after discontinuation of statin therapy, with varying times for symptom onset (1 day to years) and symptom resolution (median 3 weeks).

The following additional adverse events have been reported with some statins:

• Sleep disturbances, including nightmares

• Sexual dysfunction

• Diabetes mellitus: frequency will depend on the presence or absence of risk factors (fasting blood glucose ≥ 5.6 mmol / L, BMI> 30 kg / m2, elevated triglyceride levels, history of hypertension).


04.9 Overdose

VYTORIN

In the event of an overdose, symptomatic and supportive measures should be employed. Concomitant administration of ezetimibe (1,000 mg / kg) and simvastatin (1,000 mg / kg) was well tolerated in acute oral toxicity studies in mice and rats. No clinical signs of toxicity were observed in these animals. The oral LD50 estimate for both species was ezetimibe ≥ 1,000 mg / kg / simvastatin ≥ 1,000 mg / kg.

Ezetimibe

In clinical studies, administration of ezetimibe, 50 mg / day to 15 healthy subjects for up to 14 days, or 40 mg / day to 18 patients with primary hypercholesterolaemia for up to 56 days, was generally well tolerated. Few cases of overdose have been reported; most of them were not associated with side effects. The side effects reported were not serious. In animals, no toxicity was observed after single oral doses of 5,000 mg / kg of ezetimibe in rats and mice and 3,000 mg / kg in dogs.

Simvastatin

Few cases of overdose have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: HMG-CoA reductase inhibitors in combination with other pharmacological agents that modify the lipid profile.

ATC code: C10BA02.

VYTORIN (ezetimibe / simvastatin) is a lipid-lowering product that selectively inhibits the intestinal absorption of cholesterol and related plant sterols and inhibits the endogenous synthesis of cholesterol.

Mechanism of action:

VYTORIN

Plasma cholesterol is derived from intestinal absorption and endogenous synthesis. VYTORIN contains ezetimibe and simvastatin, two lipid-lowering compounds with complementary mechanisms of action. VYTORIN reduces elevated levels of total cholesterol (total-C), LDL-C, apolipoprotein B (Apo B), triglycerides (TG), non-high-density lipoprotein (C-non-HDL) cholesterol, and increases the cholesterol of high density lipoprotein (HDL-C) through the double inhibition of the absorption and synthesis of cholesterol.

Ezetimibe

Ezetimibe inhibits the intestinal absorption of cholesterol. Ezetimibe is orally active and has a mechanism of action that differs from that of other classes of cholesterol-lowering substances (eg statins, bile acid sequestrants [resins], fibric acid derivatives and plant stanols). The molecular target of ezetimibe is the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), responsible for the intestinal uptake of cholesterol and phytosterols.

Ezetimibe is localized at the level of the brush border of the small intestine and inhibits the absorption of cholesterol, causing a decrease in the passage of intestinal cholesterol to the liver; statins reduce the synthesis of cholesterol in the liver and these two distinct mechanisms produce a complementary reduction in cholesterol. In a 2-week clinical study of 18 hypercholesterolemic patients, ezetimibe inhibited intestinal absorption of cholesterol by 54% compared to placebo.

A series of preclinical studies were performed to determine the selectivity of ezetimibe in inhibiting the absorption of cholesterol. Ezetimibe inhibited the absorption of [14C] -cholesterol with no effect on the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol, or fat-soluble vitamins A and D.

Simvastatin

Following oral ingestion, simvastatin, which is an inactive lactone, is hydrolyzed in the liver into the corresponding active beta-hydroxyacid form which has potent inhibitory activity on HMG-CoA reductase (3-hydroxy-3methylglutaryl CoA reductase). This enzyme catalyses the conversion of HMG-CoA to mevalonate, an early and limiting step in cholesterol biosynthesis.

Simvastatin has been shown to reduce both normal and elevated LDL-C concentrations. LDL is formed from very low density lipoprotein (VLDL) and is mainly catabolized by the high affinity LDL receptor. C-VLDL) and induction of the LDL receptor, leading to a reduction in production and an increase in LDL-C catabolism. Apolipoprotein B also decreases substantially during treatment with simvastatin. Simvastatin also moderately increases HDL-C and reduces plasma TG. As a result of these alterations, the ratios between total cholesterol / HDL-C and LDL-C / C- HDL are reduced.

CLINICAL STUDIES

In controlled clinical trials, VYTORIN significantly reduced total-C, LDL-C, Apo B, TG, and non-HDL-C, and increased HDL-C in patients with hypercholesterolemia.

Primary hypercholesterolemia

In an 8-week, double-blind, placebo-controlled study, 240 patients with hypercholesterolaemia already on simvastatin monotherapy and who failed to achieve LDL-C goal according to the National Cholesterol Education Program (NCEP) (from 2, 6 to 4.1 mmol / l [100 to 160 mg / dl depending on baseline characteristics) were randomized to receive ezetimibe 10 mg or placebo in addition to their pre-existing simvastatin therapy. did not meet LDL-C target at baseline (~ 80%), significantly more patients randomized to ezetimibe given with simvastatin achieved LDL-C target at study endpoint compared to patients randomized to placebo administered concomitantly with simvastatin, 76% and 21.5%, respectively.

Corresponding reductions in LDL-C for ezetimibe or placebo administered concomitantly with simvastatin were significantly different (27% and 3%, respectively).

Furthermore, ezetimibe, administered concomitantly with simvastatin therapy, significantly decreased total-C, Apo B, TGs compared to placebo administered concomitantly with simvastatin.

In a 24-week double-blind multicenter study, 214 patients with type 2 diabetes mellitus treated with thiazolidinediones (rosiglitazone and pioglitazone) for a minimum of 3 months and simvastatin 20 mg for a minimum of 6 weeks with a mean LDL-C of 2.4 mmol / l (93 mg / dl), were randomized to receive either simvastatin 40 mg or concomitant administration of active substances equivalent to VYTORIN 10 mg / 20 mg. VYTORIN 10 mg / 20 mg was significantly more effective than doubling the simvastatin dose to 40 mg in further reducing LDL-C (-21% and 0%, respectively), total-C (-14% and -1 %, respectively), Apo B (-14% and -2%, respectively), and non-HDL C (-20% and -2%, respectively) over the reductions observed with simvastatin 20 mg. for HDL-C and TG between the two treatment groups, the results were not influenced by the type of treatment with thiazolidinediones.

The efficacy of the different strengths of VYTORIN (10 mg / 10 mg to 10 mg / 80 mg / day) was demonstrated in a 12-week, double-blind, placebo-controlled, multicenter study including all doses. available of VYTORIN and all related strengths of simvastatin.

When comparing patients treated with all strengths of VYTORIN to patients treated with all strengths of simvastatin, VYTORIN significantly reduced total-C, LDL-C and TG (see Table 1) and also Apo B (-42% and -29%, respectively), non-HDL-C (-49% and -34%, respectively) and C-reactive protein (-33% and -9%, respectively). The effects of VYTORIN on HDL-C were similar to the effects seen with simvastatin. A further analysis showed that VYTORIN significantly increased HDL-C compared with placebo.

Table 1

Response to VYTORIN in patients with primary hypercholesterolaemia

(mean changea% from baseline in the absence of treatmentb)

Treatment (Daily doses) No. Total C C-LDL C-HDL TGa Combined data (all doses of VYTORIN) c 353 -38 -53 +8 -28 Combined data (all doses of simvastatin) c 349 -26 -38 +8 -15 Ezetimibe 10 mg 92 -14 -20 +7 -13 Placebo 93 +2 +3 +2 -2 VYTORIN per dose 10/10 87 -32 -46 +9 -21 10/20 86 -37 -51 +8 -31 10/40 89 -39 -55 +9 -32 10/80 91 -43 -61 +6 -28 Simvastatin per dose 10 mg 81 -21 -31 +5 -4 20 mg 90 -24 -35 +6 -14 40 mg 91 -29 -42 +8 -19 80 mg 87 -32 -46 +11 -26

a For triglycerides, median% deviation from baseline

b Basal - not in lipid-lowering drug treatment

c Combined doses of VYTORIN (10 / 10-10 / 80) significantly reduced total-C, LDL-C, and TG, compared to simvastatin, and significantly increased HDL-C compared to placebo.

In a similarly designed study, results for all lipid parameters were generally consistent. In a combined analysis of these two studies, the lipid response to VYTORIN was similar in patients with TG levels greater than or less than 200 mg / dL.

In a multicentre, double-blind, controlled clinical trial (ENHANCE), 720 patients with heterozygous familial hypercholesterolaemia were randomized to receive ezetimibe 10 mg in combination with simvastatin 80 mg (n = 357) or simvastatin 80 mg (n = 363) for 2 years. The primary objective of the study was to investigate the effect of the combination therapy ezetimibe / simvastatin on the thickness of the tunica intima and media (IMT) of the carotid artery compared to simvastatin alone. The impact of this marker is not yet demonstrated. surrogate for cardiovascular morbidity and mortality.

The primary endpoint, the mean IMT change of all six carotid segments, was not significantly different (p = 0.29) between the two treatment groups based on B-mode ultrasound measurements. With ezetimibe 10 mg in combination with simvastatin 80 mg or simvastatin 80 mg alone, the thickness of the intima and medial tunics increased by 0.0111 mm and 0.0058 mm, respectively, over the 2-year study duration (at baseline, mean carotid IMT measurement was 0.68 mm and 0.69 mm, respectively).

Ezetimibe 10 mg in combination with simvastatin 80 mg decreased LDL-C, total-C, Apo B, and TG significantly more than simvastatin 80 mg. For the two treatment groups the percent increase in C -HDL was similar. Adverse reactions reported with ezetimibe 10 mg in combination with simvastatin 80 mg were consistent with its known safety profile.

VYTORIN contains simvastatin. In two large placebo-controlled clinical trials, Scandinavian Simvastatin Survival Study (20-40 mg n = 4,444 patients) e Heart Protection Study (40 mg; N = 20,536 patients), the effect of simvastatin therapy was evaluated in patients at high risk of coronary events due to ongoing coronary heart disease, diabetes, peripheral vascular disease, history of stroke or other cerebrovascular disease. treatment with simvastatin has been shown to reduce: the risk of overall mortality through the reduction of deaths due to CHD; the risk of non-fatal myocardial infarction and stroke; and the need for surgery with coronary and non-coronary revascularization procedures .

The Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine ​​(SEARCH) evaluated the effect of treatment with simvastatin 80 mg versus 20 mg (median follow-up of 6.7 years) on major vascular events (MVEs; defined as fatal ischemic heart disease, non-fatal myocardial infarction, coronary revascularization procedure, non-fatal or fatal stroke, or peripheral revascularization procedure) in 12,064 patients with a history of myocardial infarction. There was no significant difference in the incidence of MVEs between the 2 groups; simvastatin 20 mg (n = 1,553; 25.7%) vs.simvastatin 80 mg (n = 1,477; 24.5%); RR 0.94, 95% CI: 0.88 to 1.01. The absolute difference in LDL-C level between the two groups over the course of the study was 0.35 ± 0.01 mmol / L. The safety profiles were similar between the two treatment groups except for the incidence of myopathy which was approximately 1.0% for patients treated with simvastatin 80 mg compared to 0.02% for patients treated with 20. mg. Approximately half of these myopathy cases occurred during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1%.

VYTORIN has been shown to reduce major cardiovascular events in patients with chronic kidney disease; however, an increase in the benefit of VYTORIN on cardiovascular morbidity and mortality compared to that demonstrated for simvastatin has not been definitively established.

Clinical studies in pediatric patients (10 to 17 years of age)

In a multicentre, double-blind, controlled study, 142 boys (Tanner stage II and higher) and 106 postmenarche girls, 10 to 17 years of age (mean age 14.2 years) with heterozygous familial hypercholesterolemia (IF heterozygous) with baseline LDL-C values ​​between 4.1 and 10.4 mmol / L were randomized to ezetimibe 10 mg co-administered with simvastatin (10, 20 or 40 mg) or simvastatin (10, 20 or 40 mg) alone for 6 weeks, ezetimibe and simvastatin 40 mg co-administered or simvastatin 40 mg alone for the next 27 weeks, and then ezetimibe and simvastatin (10 mg, 20 mg, or 40 mg) co-administered open label for 20 weeks.

At week 6, ezetimibe co-administered with simvastatin (all doses) significantly decreased total-C (38% vs 26%), LDL-C (49% vs 34%), Apo B (39% vs 27%) and non-HDL-C (47% vs 33%) versus simvastatin alone (all doses). Results were similar between the two treatment groups for TG and HDL-C (-17 % vs -12% and +7% vs +6%, respectively). At week 33, the results were consistent with those of week 6 and significantly more patients on ezetimibe and simvastatin 40 mg (62%) achieved "ideal therapeutic goal according to NCEP AAP (

The safety and efficacy of ezetimibe co-administered with simvastatin doses greater than 40 mg daily have not been studied in pediatric patients 10 to 17 years of age. Efficacy has not been studied in patients below 17 years of age. long-term therapy with ezetimibe in reducing morbidity and mortality in adulthood.

Homozygous Familial Hypercholesterolaemia (Homozygous IF)

A 12-week, double-blind, randomized study was performed in patients with a clinical and / or genotypic diagnosis of homozygous IF. Data from a subgroup of patients (n = 14) treated with simvastatin 40 mg at baseline were analyzed. Increasing simvastatin dosage from 40 to 80 mg (n = 5) resulted in a 13% decrease in LDL-C from baseline compared to 40 mg simvastatin. Co-administration of ezetimibe and simvastatin equivalent to VYTORIN (10 mg / 40 mg and 10 mg / 80 mg combined, n = 9) produced a 23% reduction in LDL-C from baseline compared to simvastatin 40 mg. In patients co-administered with ezetimibe and simvastatin equivalent to VYTORIN (10 mg / 80 mg, n = 5), an LDL-C reduction of 29% from baseline was produced compared with simvastatin 40 mg.

Prevention of major vascular events in chronic kidney disease (CKD)

The Study of Heart and Renal Protection (SHARP) was a multinational, randomized, placebo-controlled, double-blind study of 9,438 patients with chronic kidney disease, one third of whom were on dialysis at baseline. A total of 4,650 patients were assigned to VYTORIN 10/20 and 4,620 to placebo, and followed for a median of 4.9 years. Patients had a mean age of 62 years and 63% were male, 72% Caucasian, 23% diabetic and, for those not on dialysis, the mean estimated glomerular filtration rate (eGFR) was 26.5 mL / min. / 1.73 m2. There was no lipid-based study inclusion criterion. The mean baseline LDL-C was 108 mg / dL. After one year, including patients no longer taking study drug, LDL-C was reduced by 26% compared to placebo by simvastatin 20 mg alone and by 38% by VYTORIN 10/20 mg.

The primary comparison specified in the SHARP protocol was a "intention-to-treat analysis of" major vascular events "(MVE; defined as non-fatal myocardial infarction or cardiac death, stroke, or any revascularization procedure) only in those patients initially randomized to VYTORIN (n = 4,193) or placebo (n = 4,191) groups. Secondary analyzes included the same composite analyzed for the entire randomized cohort (study baseline or 1 year) to VYTORIN (n = 4,650) or placebo (n = 4,620) as well as the components of this composite.

The primary endpoint analysis showed that VYTORIN significantly reduced the risk of major vascular events (749 event patients in the placebo group vs. 639 in the VYTORIN group) with a relative risk reduction of 16% (p = 0.001).

However, the design of this study did not allow for a separate contribution of the monocomponent ezetimibe on efficacy to significantly reduce the risk of major vascular events in patients with CKD.

Individual components of MVEs in all randomized patients are shown in Table 2. VYTORIN significantly reduced the risk of stroke and any revascularization, with no significant numerical differences favoring VYTORIN for non-fatal myocardial infarction and cardiac death.

Table 2

Major vascular events by treatment group in all randomized patients in SHARPa

Outcome VYTORIN 10/20 (N = 4,650) Placebo (N = 4,620) Risk Report (95% CI) P value Major vascular events 701 (15,1%) 814 (17,6%) 0,85 (0,77-0,94) 0,001 Non-fatal myocardial infarction 134 (2,9%) 159 (3,4%) 0,84 (0,66-1,05) 0,12 Cardiac death 253 (5,4%) 272 (5,9%) 0,93 (0,78-1,10) 0,38 Any type of stroke 171 (3,7%) 210 (4,5%) 0,81 (0,66-0,99) 0,038 Non-hemorrhagic stroke 131 (2,8%) 174 (3,8%) 0,75 (0,60-0,94) 0,011 Hemorrhagic stroke 45 (1,0%) 37 (0,8%) 1,21 (0,78-1,86) 0,40 Any kind of revascularization 284 (6,1%) 352 (7,6%) 0,79 (0,68-0,93) 0,004 Major atherosclerotic events (MAE) b 526 (11,3%) 619 (13,4%) 0,83 (0,74-0,94) 0,002

a Analysis by intention of treatment on all SHARP patients randomized to VYTORIN or placebo at baseline or at 1 year

b MAE; defined as the composite of non-fatal myocardial infarction, coronary death, non-stroke

hemorrhagic, or any revascularization

The absolute reduction in LDL cholesterol achieved with VYTORIN was lower among patients with a lower baseline LDL-C (

Aortic stenosis

Simvastatin and Ezetimibe for the Treatment of Aortic Stenosis (SEAS) was a multicenter, double-blind, placebo-controlled study with a mean duration of 4.4 years in 1,873 patients with asymptomatic aortic stenosis (AS), documented by rate peak aortic flow measured by Doppler between 2.5 and 4.0 m / s. Only patients were enrolled for whom statin treatment was not deemed necessary in order to reduce the risk of atherosclerotic cardiovascular disease. Patients were randomized in a 1: 1 ratio to receive placebo or ezetimibe 10 mg and simvastatin 40 mg daily in co-administration.

The primary endpoint was the composite of major cardiovascular events (MCE) consisting of cardiovascular death, surgical aortic valve replacement (AVR), congestive heart failure (CHF) resulting from progression of AS, non-fatal myocardial infarction, coronary artery bypass graft (CABG) ), percutaneous coronary intervention (PCI), hospitalization for unstable angina, and non-haemorrhagic stroke The key secondary endpoints were composite subsets of the event categories of the primary endpoint.

Compared to placebo, ezetimibe / simvastatin 10/40 mg did not significantly reduce the risk of MCE. The primary outcome occurred in 333 patients (35.3%) in the ezetimibe / simvastatin group and in 355 patients (38.2%) in the placebo group (hazard ratio in the ezetimibe / simvastatin group, 0.96; confidence interval 95%, 0.83 to 1.12; p = 0.59) Aortic valve replacement was performed in 267 patients (28.3%) in the ezetimibe / simvastatin group and in 278 patients (29.9 %) in the placebo group (hazard ratio, 1.00; 95% CI, 0.84 to 1.18; p = 0.97) Fewer patients had ischemic cardiovascular events in the ezetimibe / simvastatin group (n = 148) compared to the placebo group (n = 187) (hazard ratio, 0.78; 95% CI, 0.63 to 0.97; p = 0.02), mainly due to the smaller number of patients they had undergone coronary artery bypass grafting.

Cancer occurred more frequently in the ezetimibe / simvastatin group (105 versus 70, p = 0.01). The clinical relevance of this observation is uncertain as in the larger SHARP study the total number of patients with any type of incident cancer (438 in the ezetimibe / simvastatin group versus 439 in the placebo group) was not different and therefore the outcome of the SEAS study it could not be confirmed by SHARP.


05.2 "Pharmacokinetic properties

No significant pharmacokinetic interactions were observed during concomitant administration of ezetimibe and simvastatin.

Absorption:

VYTORIN

VYTORIN is bioequivalent to concomitant administration of ezetimibe and simvastatin.

Ezetimibe

Following oral administration, ezetimibe is rapidly and extensively absorbed conjugated to the pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). Mean peak plasma concentrations (Cmax) are observed within 1-2 hours for ezetimibe-glucuronide and 4 -12 hours for ezetimibe. The absolute bioavailability of ezetimibe cannot be determined as the compound is virtually insoluble in an aqueous medium suitable for an injection.

Concomitant food administration (high-fat or non-fat meals) had no effect on the oral bioavailability of ezetimibe given as 10 mg tablets.

Simvastatin

The availability of the active β-hydroxy acid to the systemic circulation following an oral dose of simvastatin was found to be less than 5% of the dose, consistent with extensive hepatic first pass extraction. The major metabolites of simvastatin present in human plasma are the β-hydroxy acid and four other active metabolites.

The plasma profiles of both total and active inhibitors were not changed by administration of simvastatin immediately before a standard meal compared to fasting.

Distribution:

Ezetimibe

Ezetimibe and ezetimibe-glucuronide are bound 99.7% and 88-92% to human plasma proteins, respectively.

Simvastatin

Both simvastatin and β-hydroxy acid are bound to human plasma proteins (95%).

Single and multiple dose pharmacokinetics of simvastatin showed no drug accumulation after multiple doses. In all of the above pharmacokinetic studies, the maximum concentration of inhibitors occurred 1.3 to 2.4 hours post-dose.

Biotransformation:

Ezetimibe

Ezetimibe is metabolised primarily in the small intestine and liver via glucuronide conjugation (a phase II reaction) with subsequent biliary excretion. Minimal oxidative metabolism (a phase I reaction) was observed in all species evaluated. Ezetimibe and ezetimibe glucuronide are the major drug derived compounds found in plasma, accounting for approximately 10-20% and 80-90% of the total drug present in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are slowly eliminated. from plasma with evidence of significant enterohepatic cycle. The half-life of ezetimibe and ezetimibe-glucuronide is approximately 22 hours.

Simvastatin

Simvastatin is an inactive lactone which is rapidly hydrolyzed in vivo in the corresponding β-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Hydrolysis occurs mainly in the liver; the rate of hydrolysis in human plasma is very slow.

In humans, simvastatin is well absorbed and undergoes prompt first pass extraction in the liver. Extraction in the liver is dependent on hepatic blood flow. The liver is its primary site of action, with subsequent excretion of equivalent substances in the bile. The availability of the active drug in the systemic circulation is therefore low.

After intravenous administration of the β-hydroxy acid metabolite, its mean half-life was 1.9 hours.

Elimination:

Ezetimibe

Following oral administration of 14C ezetimibe (20 mg) in humans, total ezetimibe accounted for approximately 93% of the total plasma radioactivity. Approximately 78% and 11% of the administered radioactivity was recovered in the faeces and urine, respectively, over a 10-day sample collection period. After 48 hours, there were no detectable levels of radioactivity in the plasma.

Simvastatin

Simvastatin acid is actively transported to hepatocytes via the carrier OATP1B1.

After administration of an oral dose of simvastatin in humans, 13% of the radioactivity was excreted in the urine and 60% in the faeces within 96 hours. The amount found in faeces represents the equivalent substances excreted in the bile as well as the unabsorbed drug. After intravenous administration of the β-hydroxy acid metabolite, only an average of 0.3% of the intravenous dose was excreted in the urine as inhibitors.

Special populations:

Pediatric patients

The absorption and metabolism of ezetimibe are similar in children and adolescents (10 to 18 years) and adults. There are no pharmacokinetic differences between adolescents and adults based on total ezetimibe. Pharmacokinetic data in the pediatric population sitosterolemia (see section 4.2).

Geriatric patients

Plasma concentrations of total ezetimibe are approximately twice as high in the elderly (≥ 65 years) as in the young (18-45 years). LDL-C reduction and safety profile are comparable between elderly and younger individuals treated with ezetimibe (see section 4.2).

Hepatic insufficiency

Following administration of a single 10 mg dose of ezetimibe, the mean area under the curve (AUC) for total ezetimibe increased approximately 1.7-fold in patients with mild hepatic impairment (Child Pugh score 5 or 6), compared to healthy subjects. In a 14-day multiple-dose (10 mg / day) study in patients with moderate hepatic impairment (Child Pugh score 7 to 9), mean AUC for total ezetimibe increased approximately 4 times per day 1 and at day 14 compared to healthy subjects. No dose adjustment is necessary in patients with mild hepatic impairment. Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic impairment (Child Pugh score> 9), ezetimibe is not recommended in these patients (see sections 4.2. And 4.4).

Kidney failure

Ezetimibe

After a single 10 mg dose of ezetimibe in patients with severe renal disease (n = 8; mean CrCl ≤30 mL / min), the mean AUC for total ezetimibe increased approximately 1.5-fold compared to healthy subjects. (n = 9), (see section 4.2).

An additional patient in this study (post kidney transplant and treated with multiple drug therapy including cyclosporine) had a 12-fold "exposure to" total ezetimibe.

Simvastatin

In a study with patients with severe renal impairment (creatinine clearance

Sex

Plasma concentrations of total ezetimibe are slightly higher (approximately 20%) in women than in men. LDL-C reduction and safety profile are comparable between men and women treated with ezetimibe.

SLCO1B1 polymorphism

Carriers of the c.521T> C allele of the SLCO1B1 gene have reduced OATP1B1 activity. The mean exposure (AUC) to the main active metabolite, simvastatin acid, is 120% in heterozygous carriers of the C allele (CT) and 221% in homozygotes (CC) compared to that of patients who have the most common genotype (TT). The C allele has a frequency of 18% in the European population. There is a risk of increased exposure to simvastatin acid in patients with SLCO1B1 polymorphism, which may lead to an increased risk of rhabdomyolysis (see section 4.4).


05.3 Preclinical safety data

VYTORIN

In concomitant administration studies with ezetimibe and simvastatin the toxic effects observed were essentially those typically associated with statins. Some of the toxic effects were more pronounced than those seen with statin treatment alone. This is attributed to pharmacokinetic and / or pharmacodynamic interactions in concomitant administration. Interactions of this kind did not occur in clinical studies. Episodes of myopathy occurred in rats only following exposure to doses several times higher than the therapeutic dose in humans (approximately 20 times the AUC level for simvastatin and 1,800 times the AUC level for the active metabolite). . There was no evidence that concomitant administration of ezetimibe had any effect on the myotoxic potential of simvastatin.

In dogs co-administered with ezetimibe and statins, at low exposures (bile duct hyperplasia, pigment accumulation, mononuclear cell infiltration and small hepatocytes). These alterations did not evolve with exposure to prolonged doses up to 14 months. An overall recovery of liver test results was observed after discontinuation of exposure. These data are in line with those described with HMG-CoA inhibitors or attributed to the very low cholesterol levels achieved in the dogs under study.

Concomitant administration of ezetimibe and simvastatin was not teratogenic in rats. A limited number of skeletal deformities (fusion of the caudal vertebrae, reduced number of the caudal vertebrae) have been observed in pregnant female rabbits.

In a series of essays in vivo And in vitro Ezetimibe, administered alone or co-administered with simvastatin, did not show genotoxic potential.

Ezetimibe

Chronic toxicity animal studies with ezetimibe did not identify target organs for toxic effects. In dogs treated for 4 weeks with ezetimibe (≥ 0.03 mg / kg / day) the cholesterol concentration in the bile increased by a factor of 2.5 to 3.5. However, no increased incidence of cholelithiasis or other hepatobiliary effects was observed in a one-year dog study treated with doses up to 300 mg / kg / day. The clinical value of these data for humans is unknown. A risk of lithogenesis associated with the therapeutic use of ezetimibe cannot be excluded.

Long-term carcinogenicity tests on ezetimibe were negative.

Ezetimibe had no effect on fertility in either sex in rats, no teratogenicity was detected in rats or rabbits, nor was pre- or postnatal development altered. Ezetimibe crossed the placental barrier in female rats. and pregnant rabbits who received multiple doses of 1,000 mg / kg / day.

Simvastatin

Based on conventional animal studies of pharmacodynamics, repeated dose toxicity, genotoxicity and carcinogenesis, there are no risks for the patient other than those expected on the basis of the pharmacological mechanism. At maximally tolerated doses in both rats and rabbits, simvastatin did not result in fetal malformations, and had no effects on fertility, reproductive function or neonatal development.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Butylhydroxyanisole

Citric acid monohydrate

Croscarmellose sodium

Hypromellose

Lactose monohydrate

Magnesium stearate

Microcrystalline cellulose

Propyl gallate


06.2 Incompatibility

Not relevant.


06.3 Period of validity

2 years.


06.4 Special precautions for storage

Do not store above 30 ° C.

Blisters: Store in the original package to protect the medicine from light and moisture.

Bottles: Keep the bottle tightly closed to protect the medicine from light and moisture.


06.5 Nature of the immediate packaging and contents of the package

VYTORIN 10 mg / 10 mg, 10 mg / 20mg, and 10 mg / 40 mg

White high density polyethylene (HDPE) bottle with child resistant polypropylene closure and desiccant silicon gel, sealed with a special tab, containing 100 tablets.

VYTORIN 10 mg / 10 mg

PVC / Aluminum polyamide blister welded to aluminum foil using vinyl resin. The tablets can be extracted by pressing on the plastic pocket. Packs of 7, 10, 14, 28, 30, 50, 56, 84, 98, multipack containing 98 (2 boxes of 49), 100 or 300 tablets.

Single-dose blister in PVC / aluminum polyamide welded to aluminum foil using vinyl resin. The tablets can be extracted by pressure on the plastic pocket. Packs of 30, 50, 100 or 300 tablets.

VYTORIN 10 mg / 20 mg, 10 mg / 40 mg

Opaque polychlorotrifluoroethylene / PVC blister sealed to aluminum foil using vinyl resin. The tablets can be extracted by pressing on the plastic pocket. Pack of 90 tablets.

VYTORIN 10 mg / 20 mg, 10 mg / 40 mg, and 10 mg / 80 mg

Opaque polychlorotrifluoroethylene / PVC blister sealed to aluminum foil using vinyl resin. The tablets can be extracted by pressure on the plastic pocket. Packs of 7, 10, 14, 28, 30, 50, 56, 84, 98, 100 or 300 tablets.

Single-dose blisters in polychlorotrifluoroethylene / PVC welded to aluminum foil using vinyl resin. The tablets can be extracted by pressure on the plastic pocket. Packs of 30, 50, 100 or 300 tablets.

Not all pack sizes may be marketed.


06.6 Instructions for use and handling

No special instructions.

07.0 MARKETING AUTHORIZATION HOLDER

Neopharmed Gentili S.r.l.

Via San Giuseppe Cottolengo, 15

20143 Milan, Italy

08.0 MARKETING AUTHORIZATION NUMBER

100 tablets in bottle of 10 mg / 10 mg AIC n. 036690016

7 tablets in blister packs of 10 mg / 10 mg AIC n. 036690028

10 tablets in blister packs of 10 mg / 10 mg AIC n. 036690030

14 tablets in blister packs of 10 mg / 10 mg AIC n. 036690042

28 tablets in blisters of 10 mg / 10 mg AIC n. 036690055

30 tablets in blister packs of 10 mg / 10 mg AIC n. 036690067

50 tablets in blisters of 10 mg / 10 mg AIC n. 036690079

56 tablets in blister packs of 10 mg / 10 mg AIC n. 036690081

98 tablets in blister packs of 10 mg / 10 mg AIC n. 036690093

2 x 49 tablets in blister packs of 10 mg / 10 mg AIC n. 036690648

100 tablets in blisters of 10 mg / 10 mg AIC n. 036690105

300 tablets in blister packs of 10 mg / 10 mg AIC n. 036690117

30 tablets in 10 mg / 10 mg single-dose blisters AIC n. 036690129

50 tablets in 10 mg / 10 mg single-dose blisters AIC n. 036690131

100 tablets in 10 mg / 10 mg single-dose blisters AIC n. 036690143

300 tablets in 10 mg / 10 mg single-dose blisters AIC n. 036690156

100 tablets in bottle of 10 mg / 20 mg AIC n. 036690168

7 tablets in blister packs of 10 mg / 20 mg AIC n. 036690170

10 tablets in blister packs of 10 mg / 20 mg AIC n. 036690182

14 tablets in blister packs of 10 mg / 20 mg AIC n. 036690194

28 tablets in blister packs of 10 mg / 20 mg AIC n. 036690206

30 tablets in blister packs of 10 mg / 20 mg AIC n. 036690218

50 tablets in blisters of 10 mg / 20 mg AIC n. 036690220

56 tablets in blister packs of 10 mg / 20 mg AIC n. 036690232

98 tablets in blister packs of 10 mg / 20 mg AIC n. 036690244

100 tablets in blisters of 10 mg / 20 mg AIC n. 036690257

300 tablets in blisters of 10 mg / 20 mg AIC n. 036690269

30 tablets in 10 mg / 20 mg single-dose blisters AIC n. 036690271

50 tablets in 10 mg / 20 mg single-dose blisters AIC n. 036690283

100 tablets in 10 mg / 20 mg single-dose blisters AIC n. 036690295

300 tablets in 10 mg / 20 mg single-dose blisters AIC n. 036690307

100 tablets in bottle of 10 mg / 40 mg AIC n. 036690319

7 tablets in blister packs of 10 mg / 40 mg AIC n. 036690321

10 tablets in blister packs of 10 mg / 40 mg AIC n. 036690333

14 tablets in blister packs of 10 mg / 40 mg AIC n. 036690345

28 tablets in blister packs of 10 mg / 40 mg AIC n. 036690358

30 tablets in blister packs of 10 mg / 40 mg AIC n. 036690360

50 tablets in blister packs of 10 mg / 40 mg AIC n. 036690372

56 tablets in blister packs of 10 mg / 40 mg AIC n. 036690384

98 tablets in blister packs of 10 mg / 40 mg AIC n. 036690396

100 tablets in blisters of 10 mg / 40 mg AIC n. 036690408

300 tablets in blister packs of 10 mg / 40 mg AIC n. 036690410

30 tablets in 10 mg / 40 mg single-dose blisters AIC n. 036690422

50 tablets in 10 mg / 40 mg single-dose blisters AIC n. 036690434

100 tablets in 10 mg / 40 mg single-dose blisters AIC n. 036690446

300 tablets in 10 mg / 40 mg single-dose blisters AIC n. 036690459

7 tablets in blister packs of 10 mg / 80 mg AIC n. 036690461

10 tablets in blister packs of 10 mg / 80 mg AIC n. 036690473

14 tablets in blister packs of 10 mg / 80 mg AIC n. 036690485

28 tablets in blisters of 10 mg / 80 mg AIC n. 036690497

30 tablets in blisters of 10 mg / 80 mg AIC n. 036690509

50 tablets in blisters of 10 mg / 80 mg AIC n. 036690511

56 tablets in blisters of 10 mg / 80 mg AIC n. 036690523

98 tablets in blister packs of 10 mg / 80 mg AIC n. 036690535

100 tablets in blister packs of 10 mg / 80 mg AIC n. 036690547

300 tablets in blisters of 10 mg / 80 mg AIC n. 036690550

30 tablets in 10 mg / 80 mg single-dose blisters AIC n. 036690562

50 tablets in 10 mg / 80 mg single-dose blisters AIC n. 036690574

100 tablets in single-dose blisters of 10 mg / 80 mg AIC n. 036690586

300 tablets in 10 mg / 80 mg single-dose blisters AIC n. 036690598

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

Date of first authorization: August 2005

Last renewal date: February 2010

10.0 DATE OF REVISION OF THE TEXT

September 2015

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL

none:  traumatology examples-diet centrifuged