QUIBUS - PACKAGE LEAFLET - LEAFLETS

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Quibus - Package Leaflet

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

Active ingredients: Simvastatin

QUIBUS 10 mg Film-coated tablets
QUIBUS 20 mg Film-coated tablets
QUIBUS 40 mg Film-coated tablets

Indications Why is Quibus used? What is it for?

Pharmacotherapeutic group

QUIBUS is an inhibitor of the hydroxymethylglutaryl-coenzymeA reductase (HMG-CoA reductase) enzyme, which belongs to the group of cholesterol-lowering drugs.

Therapeutic indications

Hypercholesterolemia

Treatment of primary hypercholesterolemia or mixed dyslipidaemia, as a dietary supplement, when the response to diet and other non-pharmacological treatments (e.g. exercise, weight reduction) is inadequate. Treatment of homozygous familial hypercholesterolemia as a dietary supplement and other lipid-lowering treatments (eg LDL apheresis) or if such treatments are not appropriate.

Cardiovascular prevention

Reduction of cardiovascular mortality and morbidity in patients with manifest atherosclerotic cardiovascular disease or diabetes mellitus, with normal or increased cholesterol levels, as an adjunct to the correction of other risk factors and other cardioprotective therapies.

Contraindications When Quibus should not be used

QUIBUS must not be used in case of:

Hypersensitivity (allergy) to simvastatin or to any of the other ingredients of the product.
Active liver disease or persistent elevations of serum transaminases (indicators of liver function in blood tests) with no obvious cause.
Pregnancy and breastfeeding (see "Precautions when using QUIBUS").
Concomitant administration of potent CYP3A4 inhibitors (eg itraconazole, ketoconazole, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin and nefazodone) (see "Use of other drugs").

Precautions for use What you need to know before taking Quibus

Talk to your doctor or pharmacist before taking QUIBUS if you have:

severe respiratory failure.

Tell your doctor about any current or past illness or medical problem or any allergy.

It is especially important that the doctor is informed of any liver disease he has had in the past and if large quantities of alcohol are consumed.

It is also important that your doctor is informed if you have any predisposing conditions of muscle damage such as kidney dysfunction, uncontrolled hypothyroidism, personal or family history of hereditary muscle disorders, history of manifestations of muscle toxicity with a statin or fibrate (see " Use of other drugs "and" Use in the elderly ").

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

The doctor may decide to have simple control tests performed to ensure that the liver is functioning properly before and during treatment with QUIBUS. In clinical studies, persistent elevations in serum transaminases (up to more than 3 times the ULN) have occurred in some adult patients receiving simvastatin (see "Possible Side Effects"). When the drug was discontinued or discontinued in these patients, transaminase levels usually slowly returned to pre-treatment levels.

In the event of muscle pain, tenderness or weakness without apparent explanation, you should contact your doctor immediately and discontinue treatment as severe muscle problems may occur on rare occasions. Simvastatin, like other HMG-CoA reductase inhibitors, can occasionally cause muscle problems manifesting as muscle pain, tenderness, or weakness associated with increases in blood creatine kinase (CK) levels by more than 10 times. the upper limit of the norm (see "Possible side effects"). Your doctor may decide to have simple control tests performed to check for muscle problems before and during treatment with QUIBUS.

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.

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.

If you have been told by your doctor that you have "intolerance to some sugars, contact your doctor before taking this medicinal product.

Interactions Which drugs or foods may change the effect of Quibus

The patient should tell the doctor about all medications he takes or intends to take while using QUIBUS, including those obtained without a prescription. If the doctor prescribes a new drug, the patient should inform him that he is being treated with QUIBUS.

It is especially important to tell your doctor if you take the following medications, as they may increase the risk of muscle problems (see "Possible Side Effects") and a dosage adjustment may be required (see 3. "How to take QUIBUS", Therapy concomitant):

Cyclosporine.
Danazol.
Antifungal drugs (such as itraconazole or ketoconazole).
Fibric acid derivatives (such as gemfibrozil and benzafibrate).
The antibiotics erythromycin, clarithromycin and telithromycin.
HIV protease inhibitors (such as indinavir, nelfinavir, ritonavir and saquinavir).
The antidepressant nefazodone.
Amiodarone (a drug used to treat changes in the heartbeat).
Verapamil or diltiazem (medicines used to treat high blood pressure, angina or other heart conditions).
High doses (≥1 g per day) of niacin or nicotinic acid.

It is also important to tell your doctor if you are taking anticoagulants (drugs that prevent blood clots, such as warfarin, phenprocoumon or acenocoumarol) or fenofibrate, another fibric acid derivative.

QUIBUS with food and drinks

Grapefruit juice contains one or more components that alter the metabolism of some drugs including QUIBUS. Consumption of grapefruit juice should be avoided.

Warnings It is important to know that:

Pregnancy

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

Women who are pregnant or who wish or suspect pregnancy should not use QUIBUS. If you become pregnant while taking QUIBUS, stop treatment and seek medical attention immediately.

Feeding time

Women should not breastfeed during treatment with QUIBUS.

Children

The safety and efficacy have been studied in boys between the ages of 10 and 17 and in girls who have had a menstrual cycle for at least one year (see HOW TO TAKE QUIBUS). QUIBUS has not been studied in children under the age of 10. more information, consult your doctor.

Use in the elderly

Dosage adjustments are not required in the elderly. Being over 70 years old is a predisposing factor for muscle damage.

Effects on ability to drive and use machines

No effects on ability to drive and use machines are anticipated with QUIBUS. However, it should be taken into account that dizziness has rarely been reported.

Dosage and method of use How to use Quibus: Dosage

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

You must follow a diet to lower your cholesterol levels while you are being treated with QUIBUS.

The dosage of QUIBUS is 5 mg, 10 mg, 20 mg, 40 mg or 80 mg orally once daily.

The physician may decide to adjust the dosage at intervals of not less than 4 weeks up to a maximum of 80 mg / day given as a single dose in the evening. Your doctor may decide to prescribe lower dosages, especially if you take certain medications from the list above or if you have certain kidney diseases. Continue to take QUIBUS unless your doctor tells you to stop. If QUIBUS therapy is stopped, cholesterol may rise again.

For children (10-17 years), the recommended starting dose is 10 mg per day given in the evening. The maximum recommended dose is 40 mg per day.

The 80 mg dose is only recommended in adult patients with very high cholesterol levels and at high risk of heart disease.

Concomitant therapy

QUIBUS is effective alone or in combination with bile acid sequestrants. Administration should occur either more than 2 hours before or more than 4 hours after the administration of a bile acid sequestering agent.

For patients taking cyclosporine, danazol, gemfibrozil, other fibrates (except fenofibrate) or niacin at lipid-lowering dosages (greater than or equal to 1 g / day) concomitantly with QUIBUS, the dosage of QUIBUS should not exceed 10 mg per day . In patients taking amiodarone or verapamil concomitantly with QUIBUS, the dosage of QUIBUS should not exceed 20 mg per day.

If you forget to take QUIBUS

Take QUIBUS as prescribed. If you miss a dose, do not take an extra dose.

Simply continue taking the medication according to the prescribed dosage.

Overdose What to do if you have taken too much Quibus

There is no specific treatment in case of overdose. In this case, symptomatic and supportive measures should be taken.

In case of accidental intake of an excessive dose of QUIBUS, notify your doctor immediately or go to the nearest hospital.

IF YOU HAVE ANY DOUBTS ABOUT USING QUIBUS, CONTACT YOUR DOCTOR OR PHARMACIST.

Side Effects What are the side effects of Quibus

Possible side effects

Sleep disturbances, including insomnia and nightmares
Loss of memory
Sexual difficulties
Depression
Breathing problems including persistent cough and / or shortness of breath or fever.

Like all drugs, QUIBUS can have side effects. Most of the side effects reported with QUIBUS were mild and transient in nature. The following side effects have rarely been reported: anemia, muscle pain, tenderness, weakness or cramps; digestive disorders (abdominal pain, constipation, flatulence, indigestion, diarrhea, nausea, vomiting, pancreatitis); hepatitis / jaundice (yellow skin); weakness; headache; dizziness; tingling; decreased sensation or weakness in the arms or legs; liver problems; rash; itch; hair loss; hypersensitivity (allergic reactions including swelling of the face, tongue and throat which may cause difficulty in breathing, joint pain or inflammation, inflammation of blood vessels, abnormal bruising, rash and swelling, hives, skin sensitivity to sunlight, fever, flushing, shortness of breath, and malaise); on blood tests, rare increases in serum transaminases (alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transpeptidase), increases in alkaline phosphatase, increases in serum CK levels.

Undesirable effects of unknown frequency: constant muscle weakness.

If you experience muscle pain, tenderness or weakness, contact your doctor immediately. On rare occasions, muscle problems can be serious and include the destruction of muscle tissue that causes kidney damage.

The risk of muscle tissue damage is higher for patients taking high doses of QUIBUS. This risk of muscle tissue damage is higher in patients with impaired kidney function.

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.

Other side effects may rarely occur, and as with any prescription drug, they can be serious. For more information, ask your doctor or pharmacist. They both have a more complete list of side effects.

Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please inform your doctor or pharmacist.

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.it/it/responsabili. By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

Expiry: check the expiration date indicated on the package.

The expiry date refers to the product in intact packaging, correctly stored.

Warning: do not use the medicine after the expiry date indicated on the package.

Store below 25 ° C.

KEEP THE MEDICINAL PRODUCT OUT OF THE REACH AND SIGHT OF CHILDREN

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

Other information

COMPOSITION

QUIBUS 10 mg TABLETS COATED WITH FILM

Each tablet contains: active ingredient: simvastatin 10 mg

Excipients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, hydrogenated castor oil, pregelatinized starch, talc, magnesium stearate, hypromellose, anhydrous colloidal silica, macrogol 6000, titanium dioxide butyl-hydroxyanisole.

QUIBUS 20 mg TABLETS COATED WITH FILM

Each tablet contains: active ingredient: simvastatin 20 mg

QUIBUS 40 mg TABLETS COATED WITH FILM

Each tablet contains: active ingredient: simvastatin 40 mg

Excipients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, hydrogenated castor oil, pregelatinised starch, talc, magnesium stearate, hypromellose, colloidal anhydrous silica, macrogol 6000, titanium dioxide, butyl-hydroxyanisole.

PHARMACEUTICAL FORM AND CONTENT

QUIBUS 10 mg film-coated tablets (pack of 20 tablets of 10 mg).

QUIBUS 20 mg film-coated tablets (pack of 10 and 28 tablets of 20 mg).

QUIBUS 40 mg film-coated tablets (pack of 10 and 28 tablets of 40 mg).

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

01.0 NAME OF THE MEDICINAL PRODUCT

QUIBUS TABLETS COATED WITH FILM

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

QUIBUS 10 mg film-coated tablets

Each tablet contains:

active ingredient: simvastatin 10 mg

QUIBUS 20 mg film-coated tablets

Each tablet contains:

active ingredient: simvastatin 20 mg

QUIBUS 40 mg film-coated tablets

Each tablet contains:

active ingredient: simvastatin 40 mg

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Film-coated tablets.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Hypercholesterolemia

Treatment of homozygous familial hypercholesterolemia as a dietary supplement and other lipid-lowering treatments (eg LDL apheresis) or if such treatments are not appropriate.

Cardiovascular prevention

section 5.1).

04.2 Posology and method of administration

The dosage range is 5-80 mg / day administered orally as a single dose in the evening.

Dosage adjustments, if required, should be made at intervals of not less than 4 weeks to a maximum of 80 mg / day administered as a single dose in the evening. The 80 mg dosage is only recommended in patients with severe hypercholesterolemia and at high risk of cardiovascular complications.

Hypercholesterolemia

The patient should be placed on a standard cholesterol-lowering diet and should continue this diet during treatment with QUIBUS. The starting dosage is usually 10-20 mg / day given as a single dose in the evening. Patients requiring a large LDL-C reduction (greater than 45%) can start with 20-40 mg / day given as a single dose in the evening. Dosage adjustments, if necessary, should be made as specified above.

Homozygous familial hypercholesterolaemia

Based on the results of a controlled clinical study, the recommended dosage is QUIBUS 40 mg / day in the evening or 80 mg / day in three divided doses of 20 mg, and one evening dose of 40 mg. QUIBUS should be used as an adjunct to other lipid-lowering treatments (eg LDL apheresis) in these patients or if these treatments are unavailable.

Cardiovascular prevention

The usual dosage of QUIBUS is 20 to 40 mg / day given as a single dose in the evening in patients at high risk of coronary heart disease (CHD, with or without hyperlipidaemia). Drug therapy can be initiated simultaneously with diet and exercise. Dosage adjustments, if necessary, should be made as specified above.

Concomitant therapy

QUIBUS is effective alone or in combination with bile acid sequestrants. Administration should occur either> 2 hours before or> 4 hours after administration of a bile acid sequestering agent.

For patients taking cyclosporine, danazol, gemfibrozil, other fibrates (except fenofibrate) or niacin at lipid-lowering dosages (≥ 1 g / day) concomitantly with QUIBUS, the dosage of QUIBUS should not exceed 10 mg / day. In patients taking amiodarone or verapamil concomitantly with QUIBUS, the dosage of QUIBUS should not exceed 20 mg / day (see sections 4.4 and 4.5).

Dosage in renal insufficiency

No dosage adjustments are required in patients with moderate renal impairment.

In patients with severe renal insufficiency (creatinine clearance

Use in the elderly

No dosage adjustments are required.

Use in children and adolescents (ages 10-17 years)

For children and adolescents (boys with Tanner stage II and above and girls who have been postmenarche for at least one year, 10 to 17 years of age) with heterozygous familial hypercholesterolemia, the usual recommended starting dose is 10 mg / day in single dose in the evening. Children and adolescents should be placed on a standard cholesterol-lowering diet before starting treatment with simvastatin; this diet should be continued during treatment with simvastatin.

The recommended dosage range is 10-40 mg / day; the maximum recommended dose is 40 mg / day. Doses should be individualized according to the recommended therapeutic goal according to the recommendations for pediatric treatment (see sections 4.4 and 5.1). Dosage adjustments should be implemented at intervals of 4 or more weeks.

Experience with QUIBUS in prepubertal children is limited.

04.3 Contraindications

• Hypersensitivity to simvastatin or to any of the excipients

• Active liver disease or persistent elevations of serum transaminases with no obvious cause

• Pregnancy and lactation (see section 4.6)

• Concomitant administration of potent CYP3A4 inhibitors (eg itraconazole, ketoconazole, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin and nefazodone) (see section 4.5).

04.4 Special warnings and appropriate precautions for use

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

Interstitial lung disease

Exceptional cases of interstitial lung disease have been reported with some statins, especially with long-term therapy. 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, statin therapy should be discontinued.

Myopathy / rhabdomyolysis

Simvastatin, like other HMG-CoA reductase inhibitors, can occasionally cause myopathy, manifesting as muscle pain, tenderness, or weakness associated with increases in creatine kinase (CK) levels of more than 10 times the upper limit of normal. sometimes manifests as rhabdomyolysis with or without acute renal failure secondary to myoglobinuria and fatal effects have occurred very rarely 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.

In a clinical trial database in which 41,050 patients were treated with simvastatin, with 24,747 patients (approximately 60%) treated for at least 4 years, the incidence of myopathy was approximately 0.02%, 0.08% and 0.53% at 20, 40 and 80 mg / day, respectively In these clinical studies, patients were closely monitored and some interacting medicinal products were excluded.

Measurement of creatine kinase levels

CK levels should not be measured after strenuous exercise or in the presence of any alternative cause of CK rise as this makes data interpretation difficult. If CK levels are significantly elevated at baseline (greater than 5 times the limit higher than normal) these should be re-measured after 5-7 days to confirm the results.

Before the treatment

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

Statins should be prescribed with caution 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> 70 years)

• Renal dysfunction

• Uncontrolled hypothyroidism

• Personal or family history of hereditary muscular disorders

• Have a history of muscle toxicity with a statin or fibrate

• Alcohol abuse.

In the aforementioned cases, the risk that the treatment entails must be evaluated in relation to the possible benefit, and in the case of treatment, close monitoring of the patient is recommended. If the patient has had a previous experience of muscle disorders during treatment with a fibrate or statin, treatment with a different class member 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 with no apparent cause during statin treatment, CK levels should be measured. In the event of significantly elevated CK levels (above 5 times the upper limit of normal), in the absence of strenuous exercise, therapy should be discontinued. In addition, discontinuation of treatment should be considered if muscle symptoms are severe and cause daily discomfort, even if CK values are less than 5 times the upper limit of normal. Treatment should be discontinued if myopathy is suspected for any other reason.

Only if symptoms regress and CK levels return to normal, the reintroduction of the statin or the introduction of an alternative statin at the lowest dose and under close monitoring may be considered.

Simvastatin therapy should be temporarily discontinued 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 the concomitant use of simvastatin with potent CYP3A4 inhibitors (such as itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone), and with gemospibrozil, cyclone (see section 4.2).

The risk of myopathy and rhabdomyolysis is also increased by the concomitant use of other fibrates, niacin at lipid-lowering dosages (≥ 1 g / day) or by the concomitant use of amiodarone or verapamil with the higher doses of simvastatin (see sections 4.2 and 4.5 ). There is also a slightly increased risk when diltiazem is used with simvastatin 80 mg.

Consequently, with regard to CYP3A4 inhibitors, the concomitant use of simvastatin with itraconazole, ketoconazole, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin and nefazodone is contraindicated (see sections 4.3 and 4.5). If treatment with itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin cannot be avoided, simvastatin therapy should be discontinued during treatment. In addition, caution should be exercised when combining simvastatin with some other less potent CYP3A4 inhibitors: cyclosporine, verapamil, diltiazem (see sections 4.2 and 4.5). Concomitant intake of grapefruit juice and simvastatin should be avoided.

The dosage of simvastatin should not exceed 10 mg / day in patients receiving concomitant cyclosporine, danazol, gemfibrozil, or lipid-lowering doses of niacin (≥1 g / day). Combination use of simvastatin with gemfibrozil should be avoided unless the benefits are likely to outweigh the increased risk that the combination entails. The benefits of using simvastatin 10 mg / day in combination with other fibrates (except fenofibrate), niacin, cyclosporine or danazol must be carefully weighed against the potential risks of these combinations (see sections 4.2 and 4.5).

Caution should be exercised when fenofibrate is prescribed with simvastatin, as both drugs can cause myopathy when given alone.

Concomitant use of simvastatin at doses greater than 20 mg / day with amiodarone or verapamil should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy (see sections 4.2 and 4.5).

Hepatic effects

In clinical studies, persistent elevations in serum transaminases (up to> 3 x ULN) have occurred in some adult patients receiving simvastatin. When simvastatin was discontinued or discontinued in these patients, transaminase levels usually slowly returned to pre-treatment levels.

It is recommended that liver function tests be performed prior to initiation of treatment and thereafter when clinically indicated. Patients for whom a dose of 80 mg has been established should undergo additional testing prior to dosing, 3 months after initiation of the 80 mg dose, and periodically thereafter (e.g. every 6 months). months) for the first year of treatment Particular attention must be paid to those patients who develop high levels of serum transaminases, and in these patients, the measurements must be repeated promptly and therefore performed more frequently.If transaminase levels show an increase, especially if they rise to three times the upper limit of normal and are persistent, simvastatin should be discontinued.

The product should be used with caution in patients who consume large amounts of alcohol.

As with other lipid-lowering drugs, moderate (less than 3 times the upper limit of normal) elevations in serum transaminases have been reported following treatment with simvastatin. These changes appeared soon after the initiation of simvastatin treatment, were often transient, were not accompanied by any symptoms, and discontinuation of therapy was not required.

The medicine contains lactose. Patients with rare hereditary problems of galactose intolerance, the LAPP-LACTASE deficiency or glucose-galactose malabsorption should not take this medicine.

Use in children and adolescents (ages 10-17 years)

The safety and efficacy of simvastatin in patients 10 to 17 years of age with heterozygous familial hypercholesterolaemia were evaluated in a controlled clinical study in adolescent boys at Tanner stage II and higher and in girls postmenarche for at least one year. Patients treated with simvastatin had an adverse event profile generally similar to that of patients treated with placebo. Doses above 40 mg were not studied in this population. In this limited controlled study, no obvious effects on growth or growth were observed. sexual maturation in adolescent boys or girls, or effects on menstrual cycle length in girls (see sections 4.2, 4.8 and 5.1). Adolescent girls should be advised to use appropriate contraceptive methods during simvastatin therapy (see sections 4.3 and 4.6). In patients below 18 years of age, the efficacy and safety of treatment longer than 48 weeks have not been studied and the long-term effects on physical, intellectual and sexual maturation are not known. Simvastatin has not been studied. studied in patients under the age of 10 and not even in prepubertal children and pre-menarche girls.

Reduced functionality of transport proteins

Reduced function of hepatic transport proteins OATP may increase systemic exposure to simvastatin 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 with the SLCO1B1 genotype c.521T> C.

Patients carrying the SLCO1B1 gene allele (c.521T> C), which encodes a less active OATP1B1 protein, have increased systemic exposure to simvastatin and an increased risk of myopathy. The risk of myopathy related to a high dose (80 mg) of simvastatin is approximately 1% overall, without genetic testing. Based on the results of the SEARCH study, carriers of the homozygous C allele (also called CC) treated with 80 mg have a 15% risk of developing myopathy within 1 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 with the CC genotype, should be avoided. However, the absence of this gene in genotyping does not rule out the possibility of myopathy developing.

04.5 Interactions with other medicinal products and other forms of interaction

Pharmacodynamic interactions

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

The risk of myopathy, including rhabdomyolysis, is increased during concomitant administration with fibrates and niacin (nicotinic acid) (≥ 1 g / day). Furthermore, there is a pharmacokinetic interaction with gemfibrozil leading to increased plasma levels of simvastatin (see below Pharmacokinetic interactions and sections 4.2 and 4.4). When simvastatin and fenofibrate are co-administered there is no evidence that the risk of myopathy is greater than the sum of the individual risks associated with either drug. Adequate pharmacovigilance and pharmacokinetic data are not available for the other fibrates.

Effects of other drugs on simvastatin

Interactions with CYP3A4

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, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, and nefazodone. Concomitant administration of itraconazole resulted in a more than 10-fold increase in exposure to simvastatin acid (the active metabolite beta-hydroxy acid). Telithromycin caused an 11-fold increase in exposure to simvastatin acid.

Therefore, the combination with itraconazole, ketoconazole, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin and nefazodone is contraindicated. If treatment with itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is unavoidable, simvastatin therapy should be discontinued during the course of treatment. Caution should be exercised when combining simvastatin with some other less potent CYP3A4 inhibitors: cyclosporine, verapamil, diltiazem (see sections 4.2 and 4.4).

Cyclosporine

The risk of myopathy / rhabdomyolysis is increased by concomitant administration of cyclosporine particularly with higher doses of simvastatin (see sections 4.2 and 4.4). The dosage of simvastatin should therefore not exceed 10 mg / day in patients receiving concomitant cyclosporine. Although the mechanism is not fully understood, cyclosporine has been shown to increase the AUC of HMG-CoA reductase inhibitors. The increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4.

Danazol: The risk of myopathy and rhabdomyolysis is increased by concomitant administration of danazol with higher doses of simvastatin (see sections 4.2 and 4.4).

Gemfibrozil

Gemfibrozil increases the AUC of simvastatin acid by 1.9-fold possibly due to inhibition of the glucuronidation pathway (see sections 4.2 and 4.4).

Amiodarone and verapamil

The risk of myopathy and rhabdomyolysis is increased by concomitant administration of amiodarone or verapamil with higher doses of simvastatin (see section 4.4). In an ongoing clinical study, myopathy was reported in 6% of patients treated with simvastatin 80 mg and amiodarone.

An "analysis of the available clinical studies showed an" incidence of myopathy of approximately 1% in patients treated with simvastatin 40 mg or 80 mg and verapamil. In a pharmacokinetic study, concomitant administration with verapamil resulted in an increase 2.3 times the exposure to simvastatin acid presumably due, in part, to inhibition of CYP3A4. Therefore, simvastatin dosage should not exceed 20 mg / day in patients receiving concomitant amiodarone or verapamil, unless that the clinical benefit is not likely to outweigh the increased risk of myopathy and rhabdomyolysis.

Diltiazem

An "analysis of available clinical trials showed a" 1% incidence of myopathy in patients treated with simvastatin 80 mg and diltiazem. The risk of myopathy in patients taking 40 mg simvastatin was not increased by concomitant diltiazem (see section 4.4). In a pharmacokinetic study, concomitant administration of diltiazem caused a 2.7-fold increase in exposure to simvastatin acid, possibly due to inhibition of CYP3A4. Therefore, the dose of simvastatin should not exceed 40 mg / day in patients on concomitant therapy with diltiazem, unless the clinical benefit is likely to outweigh the increased risk of myopathy and rhabdomyolysis.

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 to simvastatin acid. Intake of 240 ml of grapefruit juice in the morning and simvastatin in the evening resulted in a 1.9-fold increase. The intake of grapefruit juice during treatment with simvastatin should therefore be avoided.

Effects of simvastatin on the pharmacokinetics of other drugs

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 had a modest potentiating effect of coumarin anticoagulants: prothrombin time reported as International Normalized Ratio (INR) increased from a baseline of 1.7 to 1.8 and a baseline of 2.6 to 3.4 in volunteers and study patients, respectively. Very rare cases of elevated INR have been reported. In patients treated with coumarin anticoagulants, the Prothrombin time should be determined before starting treatment with simvastatin and frequently enough during the early stages of therapy to ensure that no significant alteration in prothrombin time occurs. Once a stable prothrombin time has been documented, Prothrombin times can be monitored at the intervals routinely recommended for patients receiving coumarin anticoagulants. tina is modified or 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

QUIBUS is contraindicated during pregnancy (see section 4.3).

Safety 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 QUIBUS or another closely related HMG-CoA reductase inhibitor, the incidence of congenital anomalies was comparable to that observed 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 QUIBUS or other closely related HMG-CoA reductase inhibitors differs from that seen in the general population, treatment of mothers with QUIBUS may reduce fetal levels. of mevalonate, a precursor of cholesterol biosynthesis. Atherosclerosis is a chronic process and routinely discontinuing lipid-lowering drugs during pregnancy should have limited impact on the long-term risk associated with primary hypercholesterolemia. For these reasons, QUIBUS does not should be used in women who are pregnant, wish to become pregnant or suspect they are pregnant. Treatment with QUIBUS should be suspended for the duration of pregnancy or until it is determined that the woman is not pregnant (see section 4.3 ).

Feeding time

It is unknown whether simvastatin or its metabolites are excreted in human milk. As many drugs are excreted in breast milk and as serious adverse reactions may occur, women taking QUIBUS should not breastfeed (see section 4.3).

04.7 Effects on ability to drive and use machines

QUIBUS has no or negligible influence on the ability to drive and use machines. However, it should be taken into account that dizziness while driving or using machines has rarely been reported in post-marketing experience.

04.8 Undesirable effects

The frequencies of the following adverse effects, reported in clinical trials and / or post-marketing use, are ranked based on the assessment of their incidence rates in large long-term placebo-controlled clinical trials, including HPS and 4S with 20,536 and 4,444 patients respectively (see section 5.1). For HPS, only serious adverse events were recorded in addition to myalgia, increases in serum transaminases and CK. For 4S, all adverse effects listed below were recorded. If the incidence rates for simvastatin were lower or similar to those related to placebo in these studies, and there were reports of spontaneous events reasonably classifiable as causally related, these adverse events were classified as "rare".

In the "HPS (see section 5.1) of 20,536 patients treated with QUIBUS 40 mg / day (n = 10,269) or placebo (n = 10,267), the safety profiles were comparable between patients treated with QUIBUS 40 mg and patients treated with placebo. over the 5-year average duration of the study. Discontinuation rates due to side effects were comparable (4.8% in patients treated with QUIBUS 40 mg versus 5.1% in patients treated with placebo). of myopathy was less than 0.1% in patients treated with QUIBUS 40 mg. There were elevated transaminase levels (greater than 3 times the upper limit of normal confirmed by repeat testing) in 0.21% (n = 21) of patients treated with QUIBUS 40 mg compared with 0.09% (n = 9 ) of patients treated with placebo.

The frequencies of adverse events are sorted according to the following criterion: very common (> 1/10), common (≥ 1/100,

Alterations of the blood and lymphatic system:

Rare: anemia.

Disorders of the nervous system:

Rare: headache, paraesthesia, dizziness, peripheral neuropathy.

Gastrointestinal system:

Rare: constipation, abdominal pain, bloating, dyspepsia, diarrhea, nausea, vomiting, pancreatitis.

Hepatobiliary system:

Rare: hepatitis / jaundice.

Skin and appendages:

Rare: rash, itching, alopecia.

Musculoskeletal system, connective tissue and bone tissue:

Rare: myopathy, rhabdomyolysis (see section 4.4), myalgia, muscle cramps.

General disorders and changes in the administration site:

Rare: asthenia.

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

Searches:

Rare: increases in serum transaminases (alanine aminotransferase, aspartate aminotransferase,? -glutamyl transpeptidase) (see section 4.4 Hepatic effects), increases in alkaline phosphatase; increases in serum CK levels (see section 4.4).

The following adverse effects have been reported with some statins:

Class effects

- Sleep disturbances including insomnia and nightmares

- Loss of memory

- Sexual dysfunction

- Depression

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

- Exceptional cases of interstitial lung disease, especially with long-term therapy (see section 4.4)

Children and adolescents (ages 10-17 years)

In a 48-week study of children and adolescents (boys with Tanner stage II and above and girls in post-menarche for at least one year) aged 10 to 17 years with heterozygous familial hypercholesterolaemia (n = 175), the profile Safety and tolerability of the simvastatin group was generally similar to that of the placebo group. The long-term effects on physical, intellectual and sexual maturation are not known. There are currently insufficient data available after one year of treatment (see sections 4.2, 4.4 and 5.1).

04.9 Overdose

A limited number of overdose cases have been reported to date; the maximum dose taken was 3.6 g. All patients recovered without consequences. There is no specific treatment in case of overdose. In this case, symptomatic and supportive measures should be taken.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: HMG-CoA reductase inhibitors

ATC code: C10AA01

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

Simvastatin has been shown to reduce both normal and elevated LDL-C concentrations. LDL is formed from very low density protein (VLDL) and is mainly catabolized by the high affinity LDL receptor.The mechanism of the LDL-lowering effect of simvastatin may involve both the reduction of the VLDL cholesterol concentration (C-VLDL) and the 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 simvastin. Furthermore, simvastatin moderately increases HDL-C and reduces plasma TG. As a result of these alterations the ratios between total cholesterol and HDL-C and LDL-C and HDL-C are reduced.

High risk of coronary heart disease (CHD) or existing coronary heart disease

In the Heart Protection Study (HPS), the effects of simvastatin therapy on 20,536 patients (40-80 years) with or without hyperlipidemia and with coronary heart disease, other occlusive arterial diseases or diabetes mellitus were investigated. treated 10,269 patients with simvastatin, 40 mg / day and 10,267 with placebo for a mean duration of 5 years. At baseline 6,793 patients (33%) had LDL-C levels below 116 mg / dL; 5,063 patients (25%) ) had levels between 116 mg / dL and 135 mg / dL; and 8,680 patients (42%) had levels above 135 mg / dL.

Treatment with simvastatin 40 mg / day compared with placebo significantly reduced the risk of all cause mortality (1,328 [12.9%] for patients treated with simvastatin compared to 1,507 [14.7%] for patients treated with placebo; p = 0.0003), due to an 18% reduction in coronary death rate (587 [5.7%] vs 707 [6.9%]; p = 0.0005; 1.2% reduction in absolute risk). The reduction in non-vascular deaths did not reach statistical significance. Simvastatin also decreased the risk of major coronary events (a composite endpoint including non-fatal MI and CHD deaths) of 27% (p coronary bypass or percutaneous transluminal coronary angioplasty) and of peripheral revascularization procedures and other non-coronary revascularization procedures 30% (p stroke 25% (p LDL cholesterol below 3.0 mmol / L to inclusion.

In the Scandinavian Simvastatin Survival Study (4S), the effect of simvastatin therapy on overall mortality was evaluated in 4,444 patients with CHD and a baseline total cholesterol of 212-309 mg / dL (5.5-8.0 mmol / L) In this randomized, double-blind, placebo-controlled, multicenter study, patients with angina or previous myocardial infarction (MI) were treated with diet, standard treatment measures and simvastatin 20-40 mg / day (n = 2,221 ) or placebo (n = 2,223) for a median duration of 5.4 years. Simvastatin reduced the risk of death by 30% (absolute risk reduction 3.3%). The risk of CHD death was reduced by 42 % (3.5% absolute risk reduction). Simvastatin also decreased the risk of major coronary events (CHD death plus hospital-proven silent non-fatal MI) by 34%. Simvastatin also significantly reduced the risk of fatal and non-fatal cerebrovascular events (ic tus and transient ischemic attack) of 28%. There was no significant statistical difference between the groups in non-cardiovascular mortality.

Primary hypercholesterolemia and combined hyperlipidemia

In comparative efficacy and safety studies of simvastatin 10, 20, 40 and 80 mg / day in patients with hypercholesterolaemia, the mean reductions in LDL-C were 30, 38, 41 and 47%, respectively. In studies in patients with combined (mixed) hyperlipidaemia of simvastatin 40 mg and 80 mg the median reductions in triglycerides were 28 and 33% (placebo: 2%), respectively, and the mean increases in HDL-C were 2%. 13 and 16% (placebo: 3%), respectively.

Clinical studies in children and adolescents (ages 10-17 years)

In a double-blind, placebo-controlled study, 175 patients (99 boys with Tanner stage II and above and 76 girls in post-menarche for at least one year) aged 10 to 17 years (mean age of 14.1 years ) with heterozygous familial hypercholesterolaemia (heFH) were randomized to treatment with simvastatin or placebo for 24 weeks (baseline study). The study inclusion criterion required a baseline LDL-C level between 160 and 400 mg / dL and at least one parent with an LDL-C level> 189 mg / dL. The simvastatin dosage (once daily in the evening) was 10 mg for the first 8 weeks, 20 mg for the second 8 weeks and 40 mg thereafter. In a 24-week extension of the study, 144 patients were selected to continue therapy and received simvastatin 40 mg or placebo.

Simvastatin significantly reduced plasma LDL-C, TG and Apo B levels. The results obtained in the 48-week study extension were comparable to those observed in the base study.

After 24 weeks of treatment, the mean LDL-C value achieved was 124.9 mg / dL (range: 64.0-289.0 mg / dL) in the 40 mg simvastatin group compared to 207.8 mg / dL (range: 128.0-334.0 mg / dL) in the placebo group.

After 24 weeks of simvastatin treatment (with dose increases from 10, 20 to 40 mg per day at 8-week intervals), there was a reduction in mean LDL-C levels of 36.8% (placebo: increased 1.1% from baseline), Apo B by 32.4% (placebo: 0.5%) and median TG levels by 7.9% (placebo: 3.2%) and increased mean HDL-C of 8.3% (placebo 3.6%). The long-term benefits of QUIBUS on cardiovascular events are not known in children with heFH.

In children with heterozygous familial hypercholesterolaemia, the safety and efficacy of doses above 40 mg daily have not been studied. The long-term efficacy of simvastatin therapy in childhood on reducing morbidity and mortality in adulthood has not been established. .

05.2 Pharmacokinetic properties

Simvastatin is an inactive lactone readily hydrolyzed in vivo to the corresponding beta-hydroxy acid form, a potent inhibitor of HMG-CoA reductase. Hydrolysis takes place mainly in the liver; the rate of hydrolysis in human plasma is very slow.

Pharmacokinetic properties were evaluated in adults. No pharmacokinetic data are available in children and adolescents.

Absorption

In humans, simvastatin is well absorbed and undergoes an extensive primary extraction process in the liver. Hepatic extraction depends on the extent of blood flow to the liver. The liver is the primary site of action of the active form. The availability of the beta-hydroxyacid derivative into the systemic circulation following an oral dose of simvastatin was found to be less than 5% of the dose. The maximum plasma concentration of the active inhibitors is reached 1-2 hours after administration of simvastatin. concomitant food does not affect absorption.

Single and multiple dose pharmacokinetics of simvastatin showed that there is no drug accumulation after multiple dosing.

Distribution

Simvastatin and its active metabolite are more than 95% bound to proteins.

Elimination

Simvastatin is actively transported to hepatocytes via the carrier OATP1B1.

Simvastatin is a substrate of CYP 3A4 (see sections 4.3 and 4.5). The major metabolites of simvastatin present in human plasma are beta-hydroxy acid and 4 other active metabolites. After an oral dose of radioactive 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 absorbed equivalents excreted in the bile and the non-absorbed ones. After intravenous injection of the beta-hydroxyacid metabolite, its mean half-life was 1.9 hours. Only an average of 0.3% of the intravenous dose was excreted in the urine as inhibitory substances.

Special populations

Carriers of the "SLCO1B1 c.521T> C allele 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. In patients with SLCO1B1 polymorphism there is a risk of increased exposure to simvastatin, which may lead to an increased risk of rhabdomyolysis (see section 4.4).

05.3 Preclinical safety data

Based on conventional animal studies of pharmacodynamics, repeated dose toxicity, genotoxicity and carcinogenicity, there are no other risks to the patient than those expected based on the pharmacological mechanism. At maximally tolerated doses in rats and rabbits, simvastatin produced no fetal malformations, and had no effects on fertility, reproductive function or neonatal development.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, hydrogenated castor oil, pregelatinised starch, talc, magnesium stearate, hypromellose, colloidal anhydrous silica, macrogol 6000, titanium dioxide, butyl hydroxyanisole.