Active ingredients: Simvastatin
SIVASTIN 10, 20, 40 mg TABLETS COATED WITH FILM
Why is Sivastin used? What is it for?
SIVASTIN is a medicine used to decrease the levels of total cholesterol, "bad" cholesterol (LDL cholesterol), and fatty substances called triglycerides in the blood. In addition, SIVASTIN increases the levels of "good" cholesterol (HDL cholesterol). SIVASTIN belongs to a group of medicines called statins.
- 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 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.
You must be on a cholesterol-lowering diet while taking this medicine. SIVASTIN is used as an adjunct to the diet to lower cholesterol if you have:
- raised blood cholesterol levels (primary hypercholesterolaemia) or high blood fat levels (mixed hyperlipidaemia).
- A hereditary disease (homozygous familial hypercholesterolemia) that increases your blood cholesterol levels. It is possible that you are also being treated with other treatments.
- Coronary heart disease (CHD) or if you are at high risk of CHD (because you have diabetes, or have had a stroke, or have "other blood vessel disease). SIVASTIN may prolong survival by reducing the risk of problems related to heart disease, regardless of blood cholesterol values.
Most people do not have immediate symptoms of high cholesterol. Your doctor can check your cholesterol with a simple blood test. Go to your doctor regularly, keep track of your cholesterol values and define goals with your doctor.
Contraindications When Sivastin should not be used
Do not take SIVASTIN
- If you are allergic (hypersensitive) to simvastatin or any of the other ingredients of this medicine (listed in section 6: Contents of the pack and other information).
- If you currently have liver problems.
- If you are pregnant or breastfeeding.
- If you 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).
- Gemfibrozil (used to lower cholesterol).
- Ciclosporin (used in organ transplant patients).
- 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)
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 Sivastin
Tell your doctor:
- of all your medical conditions, including allergies.
- If you consume large amounts of alcohol or if you have ever had liver disease. In this case SIVASTIN may not be suitable for you.
- If you need to have surgery. You may need to stop taking SIVASTIN for a short time.
- Your doctor will need to have a blood test done before you take SIVASTIN and if you have any symptoms of liver problems while taking SIVASTIN. This test is done to know if the liver is functioning properly.
- Your doctor may also order blood tests to check your liver function after starting SIVASTIN 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.
Contact your doctor immediately if you experience muscle pain, tenderness or weakness for no reason. This is because, rarely, muscle problems can be serious and can include injury to muscle tissue resulting in kidney damage; deaths have occurred very rarely.
The risk of muscle injury is greater at higher doses of SIVASTIN, particularly with the 80 mg dose. The risk of muscle injury is even greater in some patients. Talk to your doctor if any of the following apply to you:
- consume large amounts of alcohol.
- You have kidney problems.
- You have thyroid problems.
- He is 65 or older.
- It is female.
- You have ever had muscle problems while taking cholesterol-lowering medicines called "statins" or fibrates.
- You or a close family member have a hereditary muscle disease.
Interactions Which drugs or foods may change the effect of Sivastin
Other medicines and SIVASTIN
It is particularly important that your doctor is informed if you are taking a medicine (s) with any of the following active substances. Taking SIVASTIN with any of these medicines may increase the risk of muscle problems (some of these have already been listed under "Do not take SIVASTIN if").
- Ciclosporin (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 (medicines used to lower cholesterol).
- Erythromycin, clarithromycin, telithromycin, or fusidic acid (used to treat 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).
- 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 conditions).
- Colchicine (used to treat gout).
As with 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, phenprocoumon or acenocoumarol (anticoagulants).
- Fenofibrate (also used to lower cholesterol).
- Niacin (also used to lower cholesterol).
- Rifampicin (used to treat tuberculosis).
Also tell your doctor if you are taking niacin (nicotinic acid) or a product containing niacin and if you are Chinese.
You should also tell your doctor that he is prescribing a new medicine that you are taking SIVASTIN.
SIVASTIN with food and drink
Grapefruit juice contains one or more components that change the way the body uses certain medicines, including SIVASTIN. Consumption of grapefruit juice should be avoided.
Warnings It is important to know that:
Pregnancy and breastfeeding
Do not use SIVASTIN if you are pregnant, if you intend to become pregnant or if you suspect that you are pregnant. If you become pregnant while taking SIVASTIN, stop taking it immediately and contact your doctor.
Do not use SIVASTIN if you are breastfeeding as it is not known whether the medicine passes into breast milk.
Ask your doctor or pharmacist for advice before taking any medicine.
Use in children
The safety and efficacy have been studied in boys between the ages of 10 and 17 and in girls who have started menstruating (menstruating) for at least one year (see section 3: HOW TO TAKE SIVASTIN). SIVASTIN has not been studied in children under the age of 10. Ask your doctor for more information.
Driving and using machines
SIVASTIN is not expected to interfere with your ability to drive or use machines. However, it should be borne in mind that dizziness has been reported after taking SIVASTIN.
SIVASTIN contains lactose
SIVASTIN tablets contain a sugar called lactose. If you have been told by your doctor that you have "intolerance to some sugars, contact your doctor before taking this medicine.
Dose, Method and Time of Administration How to use Sivastin: Posology
Your doctor will determine which tablet strength is suitable for you, based on your condition, current treatment and your risk profile.
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
While being treated with SIVASTIN, you must follow a diet to lower your cholesterol levels.
Dosage:
The recommended dose is SIVASTIN 10 mg, 20 mg or 40 mg by mouth once a day.
Adults:
The starting dose is usually 10, 20 or, in some cases, 40 mg per day.
Your doctor may adjust your dose after at least 4 weeks to a maximum of 80 mg per day. Do not take more than 80 mg per day. Your doctor may prescribe lower doses, especially if you are taking some of the medicines listed above or have certain kidney problems.
The 80 mg dose is only recommended for adult patients with very high cholesterol levels and at high risk of heart disease who have not reached their ideal cholesterol level with the lowest doses.
Children:
For children (ages 10-17 years), the usual recommended starting dose is 10 mg per day given in the evening. The maximum recommended dose is 40 mg per day.
Method and duration of administration
Take SIVASTIN in the evening. You can take it with or without food. Continue to take SIVASTIN unless your doctor tells you to stop treatment.
If your doctor has prescribed SIVASTIN with another cholesterol-lowering medicine containing a bile acid sequestering agent, you should take SIVASTIN at least 2 hours before or 4 hours after taking the bile acid sequestering medicine.
Overdose What to do if you have taken an overdose of Sivastin
If you take more SIVASTIN than you should
- Contact your doctor or pharmacist.
If you forget to take SIVASTIN
- Do not take an extra dose; just take the usual dose of SIVASTIN the next day at the usual time.
If you stop taking SIVASTIN
- 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 Sivastin
Like all medicines, SIVASTIN can cause side effects, although not everybody gets them.
To describe the frequency with which side effects occur, the following terms are used:
- Rare (may affect up to 1 in 1,000 people)
- Very rare (may affect up to 1 in 10,000 people)
- Not known (frequency cannot be estimated from the available data)
In rare cases, the following serious side effects have been reported. If any of the following serious side effects occur, you should stop treatment and contact your doctor immediately or go to the nearest hospital emergency room.
- muscle pain, tenderness, weakness or cramps. On rare occasions, these muscle problems can be serious and can include injury to muscle tissue resulting in kidney damage; and very rarely there have been deaths
- hypersensitivity reactions (allergies) which include: o swelling of the face, tongue and throat which may cause difficulty in breathing o severe muscle pain usually in the shoulders or hips o skin rash with weakness in the legs and neck muscles or pain o joint inflammation (polymyalgia rheumatica) o inflammation of blood vessels (vasculitis) o unusual bruising, rash and swelling (dermatomyositis), hives, skin sensitivity to the sun, fever, flushing or shortness of breath (dyspnoea) and feeling sick or lupus-like symptom complex (including rash, joint disorders, and effects on blood cells)
- inflammation of the liver with the following symptoms: yellowing of the skin and eyes, itching, dark urine or pale stools, feeling tired or weak, loss of appetite, liver failure (very rare)
- inflammation of the pancreas often associated with severe abdominal pain.
The following side effects have also been rarely reported:
- low red blood cell count (anemia)
- numbness or weakness in the arms and legs
- headache, tingling sensation, dizziness
- digestive disorders (abdominal pain, constipation, flatulence, indigestion, diarrhea, nausea, vomiting)
- rash, itching, hair loss
- weakness
- difficulty falling asleep (very rare)
- poor memory (very rare), memory loss, confusion.
The following side effects have also been reported but the frequency cannot be estimated from the available information (frequency not known):
- erectile dysfunction
- depression
- inflammation of the lungs causing breathing problems including persistent cough and / or shortness of breath or fever
- tendon problems, sometimes complicated by tendon rupture.
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
Laboratory values
Increases in some blood test values related to liver function and a muscle enzyme (creatine kinase) have been observed.
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the package. The expiry date refers to the last day of the month.
Store below 30 ° C. Do not throw away 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 SIVASTIN contains
The active ingredient is simvastatin (10 mg, 20 mg, 40 mg).
The other ingredients are: butylated hydroxyanisole (E320), ascorbic acid (E300), citric acid monohydrate (E330), microcrystalline cellulose (E460), pregelatinised starch, magnesium stearate (E572) and lactose monohydrate. The tablet coating contains hypromellose (E464), hydroxypropylcellulose (E463), titanium dioxide (E171) and talc (E553b). The 10 mg and 20 mg tablets also contain yellow iron oxide (E172) and red iron oxide (E172). The 40 mg tablets also contain red iron oxide.
What SIVASTIN looks like and contents of the pack
SIVASTIN 10 mg
Blister packs of trilaminate film composed of polyvinyl chloride (PVC) / polyethylene (PE) / polyvinylidene chloride (PVDC) with aluminum foil lidding in packs of 1, 4, 10, 14, 15, 20, 28, 30, 50, 60, 98 or 100 tablets.
Polyvinyl chloride (PVC) blister packs with aluminum foil lidding in packs of 4, 10, 28 or 30 tablets.
Amber glass bottles with metal closure in packs of 30 or 50 tablets.
Polypropylene bottles in packs of 50 tablets.
High-density polyethylene (HDPE) bottles in packs of 30, 50 or 100 tablets.
Unit dose blisters containing the trilaminate film composed of polyvinyl chloride (PVC) / polyethylene (PE) / polyvinylidene chloride (PVDC) with aluminum foil lidding in packs of 49 or 500 tablets.
SIVASTIN 20 mg
Blister packs of trilaminate film composed of polyvinyl chloride (PVC) / polyethylene (PE) / polyvinylidene chloride (PVDC) with aluminum foil lidding in packs of 1, 4, 10, 14, 15, 20, 28, 30, 50, 56, 60, 84, 90, 98, 100 or 168 tablets.
Polyvinyl chloride (PVC) blister packs with aluminum foil lidding in packs of 14, 28, 30, 50 or 90 tablets.
Amber glass bottles with metal closure in packs of 30 or 50 tablets.
Polypropylene bottles in packs of 50 tablets.
High-density polyethylene (HDPE) bottles in packs of 30, 50 or 100 tablets.
Unit dose blisters containing the trilaminate film composed of polyvinyl chloride (PVC) / polyethylene (PE) / polyvinylidene chloride (PVDC) with aluminum foil lidding in packs of 28, 49, 84, 98 or 500 tablets.
SIVASTIN 40 mg
Trilaminate film blister packs consisting of polyvinyl chloride (PVC) / polyethylene (PE) / polyvinylidene chloride (PVDC) with aluminum foil lidding in packs of 1, 4, 7, 10, 14, 15, 20, 28, 30, 49, 50, 56, 60, 84, 90, 98, 100 or 168 tablets.
Polyvinyl chloride (PVC) blister packs with aluminum foil lidding in packs of 7, 14, 28, 30, 49, 50 or 90 tablets.
Amber glass bottles with metal closure in packs of 30 or 50 tablets.
Polypropylene bottles in packs of 50 tablets.
High-density polyethylene (HDPE) bottles in packs of 30, 50 or 100 tablets.
Unit dose blisters containing the trilaminate film consisting of polyvinyl chloride (PVC) / polyethylene (PE) / polyvinylidene chloride (PVDC) with aluminum foil lidding in packs of 28, 49, 98 or 100 tablets. Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
SIVASTIN TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 10 mg of simvastatin.
Each tablet contains 20 mg of simvastatin.
Each tablet contains 40 mg of simvastatin.
Excipients with known effects:
Each 10 mg tablet contains 70.7 mg of lactose monohydrate.
Each 20 mg tablet contains 141.5 mg of lactose monohydrate.
Each 40 mg tablet contains 283.0 mg of lactose monohydrate.
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 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 (see section 5.1).
04.2 Posology and method of administration
The dosing range is 5-80 mg / day administered orally as a single dose in the evening.
Dose 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 dose is only recommended in patients with severe hypercholesterolaemia and at 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 ).
Hypercholesterolemia
I | patient should be placed on a standard cholesterol-lowering diet and should continue this diet during treatment with SIVASTIN. The starting dose 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. Dose adjustments, if necessary, should be made as specified above.
Homozygous familial hypercholesterolaemia
Based on the results of a controlled clinical study, the recommended starting dose is SIVASTIN 40 mg / day in the evening. In these patients SIVASTIN should be used as an adjunct to other lipid-lowering treatments (eg LDL apheresis) or if these treatments are not available.
Cardiovascular prevention
The usual dose of SIVASTIN 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. Dose adjustments, if necessary, should be made as specified above.
Concomitant therapy
SIVASTIN 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 SIVASTIN concomitantly with fibrates, other than gemfibrozil (see section 4.3) or fenofibrate, the dose of SIVASTIN should not exceed 10 mg / day. In patients taking amiodarone, amlodipine, verapamil, or diltiazem concomitantly with SIVASTIN, the dose of SIVASTIN should not exceed 20 mg / day (see sections 4.4 and 4.5).
Doses in renal failure
No dose modifications are required in patients with moderate renal impairment.
In patients with severe renal insufficiency (creatinine clearance
Use in the elderly
No dose 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 post-menarche for at least one year, 10 to 17 years of age) with heterozygous familial hypercholesterolemia, the usual recommended starting dose is 10 mg / day given 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 dosing 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). Dose adjustments should be made at intervals of 4 or more weeks.
Experience with SIVASTIN in prepubertal children is limited.
04.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• 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 (agents that increase AUC approximately 5-fold or more) (eg itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (eg nelfinavir), boceprevir, telaprevir , erythromycin, clarithromycin, telithromycin 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
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 very rarely fatal effects 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. In a database of clinical trials in which 41,413 patients were treated with SIVASTIN, 24,747 patients (approximately 60%) 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 clinical trials, patients were closely monitored and some interacting medicinal products were excluded.
In a clinical study in which patients with a history of myocardial infarction were treated with SIVASTIN 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 simvastatin 80 mg than with other statin-based therapies with similar efficacy in lowering LDL-C. Therefore, the SIVASTIN 80 mg dose should only be used in patients with severe hypercholesterolaemia and at high risk of cardiovascular complications who have not met treatment goals with lower doses and when the benefits are expected to outweigh the potential risks. . In patients treated with simvastatin 80 mg who require an interacting agent, a lower dose of simvastatin 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).
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.
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 the dose of simvastatin 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 ≥ 65 years)
• Female sex
• Renal impairment
• Uncontrolled hypothyroidism
• Personal or family history of hereditary muscular disorders
• Have a history of muscle toxicity with a statin or fibrate
• Alcohol abuse.
In such situations, the risk should be weighed against the possible benefit, and clinical monitoring is recommended. If the patient has had a previous experience of muscle disorders while being treated 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 during statin treatment, CK levels should be measured. In case of significantly elevated CK levels (greater than 5 times the upper limit of normal), in the absence of strenuous exercise, the treatment should be stopped. 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 .
If symptoms subside and CK levels return to normal, reintroduction of the statin or introduction of an alternative statin at the lowest dose and closely monitored may be considered.
A higher incidence rate of myopathy has been observed in patients titrated to 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.
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, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (eg nelfirvir) , telaprevir, nefazodone), as well as gemfibrozil, cyclosporine and danazol. The use of these medicinal products is contraindicated (see section 4.3).
The risk of myopathy and rhabdomyolysis is also increased by the concomitant use of amiodarone, amlodipine, verapamil, or diltiazem and some doses of simvastatin (see sections 4.2 and 4.5). The risk of myopathy, including rhabdomyolysis, may be increased by use concomitant fusidic acid with statins (see section 4.5).
Consequently, for CYP3A4 inhibitors, concomitant use of simvastatin with itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (eg nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, telithromycin is contraindicated (see sections 4.3 and 4.5). If treatment with potent CYP3A4 inhibitors (agents that increase AUC approximately 5-fold or more) cannot be avoided, simvastatin therapy should be discontinued (and the use of another statin should be considered) during In addition, caution should be exercised when combining simvastatin with some other less potent CYP3A4 inhibitors: fluconazole, verapamil, diltiazem (see sections 4.2 and 4.5). Concomitant intake of grapefruit juice and simvastatin.
The use of simvastatin and gemfibrozil is contraindicated (see section 4.3). Due to the increased risk of myopathy and rhabdomyolysis, the dose of simvastatin should not exceed 10 mg / day in patients receiving simvastatin and other fibrates, except fenofibrate (see sections 4.2 and 4.5).
Caution should be exercised when prescribing fenofibrate with simvastatin, as both drugs can cause myopathy when given alone.
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 simvastatin and fusidic acid should only be evaluated on a case-by-case basis under close medical supervision.
Concomitant use of simvastatin at doses above 20 mg / day with 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 when used concomitantly with simvastatin, particularly with higher doses of simvastatin, may have an increased risk of myopathy. When SIVASTIN is co-administered with a moderate CYP3A4 inhibitor (agents that increase AUC approximately 2-5 fold), an adjustment of the simvastatin dose may be required. For some moderate CYP3A4 inhibitors eg diltiazem, a maximum dose of 20 mg of simvastatin is recommended (see section 4.2).
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.
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 closely monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and when the dose of either medicine is increased.
In an "interim analysis of an ongoing clinical outcome study, an independent safety monitoring committee identified in Chinese patients taking simvastatin 40 mg and nicotinic acid / laropiprant 2000 mg / 40 mg a" higher incidence of myopathy than to that expectation. Therefore, caution should be exercised when treating Chinese patients with simvastatin (particularly doses of 40 mg or higher) co-administered with lipid-modifying doses of niacin (nicotinic acid) (≥ 1 g / day) or products containing niacin. Because the risk of statin myopathy is dose-related, the use of simvastatin 80 mg with lipid modifying doses of niacin (nicotinic acid) (≥1 g / day) or lipid-modifying products is not recommended in Chinese patients. It is not known whether there is an increased risk of myopathy in other Asian patients treated with simvastatin co-administered with lipid modifying doses of niacin (nicotinic acid) (≥ 1 g / day) or products containing niacin.
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 (eg every 6 months). months) for the first year of treatment. Particular attention should be paid to those patients who develop elevated serum transaminase levels, and in these patients, measurements should be repeated promptly and therefore performed more frequently. If transaminase levels show an increase , especially if these rise to three times the upper limit of normal and are persistent, simvastatin 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 are 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 SIVASTIN, discontinue therapy immediately. If an alternative etiology is not found, do not restart therapy with SIVASTIN.
The product should be used with caution in patients who consume large amounts of alcohol.
As with other lipid-lowering medicinal products, moderate (less than 3 times the ULN) increases in serum transaminases have been reported following therapy with simvastatin. These changes appeared soon after initiation of simvastatin treatment, were often transient, were not accompanied by any symptoms, and no treatment interruption was required.
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. However, this risk 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.
Pulmonary interstitial pathology
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, statin therapy should be discontinued.
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 with Tanner stage II and higher and in postmenarche girls for at least one year. Patients treated with simvastatin had an adverse effect profile generally similar to that of patients treated with placebo. Doses above 40 mg were not studied in this population. In this small controlled study, there was no effect. detectable on sexual growth or maturation in adolescent boys or girls, or any effect on menstrual cycle length in girls (see sections 4.2, 4.8, and 5.1). Adolescents should be counseled on appropriate contraceptive methods during simvastatin therapy (see sections 4.3 and 4.6). In patients younger than 18 years, 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 is not known. It has been studied in patients under the age of 10, and not even in prepubertal children and pre-menarche girls.
Excipients
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
04.5 Interactions with other medicinal products and other forms of interaction
Interaction studies have only been performed in adults.
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 with fibrates. In addition, there is a "pharmacokinetic interaction with gemfibrozil leading to increased plasma levels of simvastatin (see below Pharmacokinetic interactions and sections 4.3 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 each agent. Adequate pharmacovigilance and pharmacokinetic data are not available for the other fibrates. 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).
Pharmacokinetic interactions
The following table summarizes the prescribing recommendations for agents that interact with simvastatin (further details are contained in the text; see also sections 4.2, 4.3, and 4.4).
Effects of other medicinal products on simvastatin
Interactions with CYP3A4 inhibitors
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. 1O-fold of exposure to the acid metabolite of simvastatin (the active beta-hydroxy acid metabolite). Telithromycin caused an 11-fold increase in exposure to the acid metabolite.
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, simvastatin 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 simvastatin 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 concomitant administration of cyclosporine with simvastatin; 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. The increase in AUC for the acid metabolite is presumably due, in part, to inhibition of CYP3A4.
Danazol
The risk of myopathy and rhabdomyolysis is increased by concomitant administration of danazol with simvastatin; therefore, use with danazol is contraindicated (see sections 4.3 and 4.4).
Gemfibrozil
Gemfibrozil increases the AUC of the acid metabolite 1.9-fold, possibly due to inhibition of the glucuronidation pathway (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, simvastatin 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 simvastatin dose should not exceed 20 mg / 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 with verapamil resulted in a 2.3-fold increase in exposure to the acid metabolite presumably due, in part, to inhibition of CYP3A4. The dose of simvastatin should therefore not exceed 20 mg / 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 caused a 2.7-fold increase in exposure to the acid metabolite, possibly due to inhibition of CYP3A4. The dose of simvastatin should therefore not exceed 20 mg / 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 to the acid metabolite. Therefore, the dose of simvastatin should not exceed 20 mg / day in patients receiving concomitant amlodipine.
Moderate inhibitors of CYP3A4
Patients taking other medicinal products known to have a moderate inhibitory effect on CYP3A4 when used concomitantly with simvastatin, particularly with higher doses of simvastatin, may have an increased risk of myopathy (see section 4.4).
Niacin (nicotinic acid)
Rare cases of myopathy / rhabdomyolysis have been associated with concomitant administration of simvastatin and lipid modifying dosages of niacin (nicotinic acid) (≥1 g / day). In a pharmacokinetic study, coadministration of a single dose of 2 g prolonged-release nicotinic acid and simvastatin 20 mg resulted in a slight increase in the AUC of simvastatin and simvastatin acid and in the C of simvastatin acid in plasma concentrations.
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 the acid metabolite. Intake of 240 ml of grapefruit juice in the morning and simvastatin in the evening also resulted in a 1.9-fold increase. Grapefruit juice intake during treatment with simvastatin 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 from 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.
Effects of simvastatin on the pharmacokinetics of other medicinal products
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 trials, one in healthy 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 of prothrombin time occurs. Once a stable prothrombin time is documented, timing of prothrombin can be monitored at the intervals routinely recommended for patients receiving coumarin anticoagulants. If it is changed or the 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 lactation
Pregnancy
SIVASTIN 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 SIVASTIN 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 SIVASTIN or other closely related HMG-CoA reductase inhibitors differs from that seen in the general population, treatment of mothers with SIVASTIN 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, SIVASTIN does not should be used in women who are pregnant, attempting to become pregnant or suspect they are pregnant. Treatment with SIVASTIN should be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant (see sections 4.3 and 5.3).
Feeding time
It is unknown whether simvastatin or its metabolites are excreted in human milk. As many medicinal products are excreted in breast milk and as serious adverse reactions may occur, women taking SIVASTIN should not breastfeed (see section 4.3).
04.7 Effects on ability to drive and use machines
SIVASTIN has no or negligible influence on the ability to drive or 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 across 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 "HPS (see section 5.1) of 20,536 patients treated with SIVASTIN 40 mg / day (n = 10,269) or placebo (n = 10,267), the safety profiles were comparable between patients treated with SIVASTIN 40 mg and patients treated with placebo. over the 5-year average duration of the study. The frequency of treatment discontinuation due to undesirable effects was comparable (4.8% in patients treated with SIVASTIN 40 mg versus 5.1% in patients treated with placebo). of myopathy was less than 0.1% in patients treated with SIVASTIN 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 SIVASTIN 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,
Disorders of the blood and lymphatic system:
Rare: anemia.
Psychiatric disorders:
Very rare: insomnia.
Not known: depression.
Nervous system disorders:
Rare: headache, paraesthesia, dizziness, peripheral neuropathy.
Very rare: memory impairment.
Respiratory, thoracic and mediastinal disorders:
Not known: interstitial lung disease (see section 4.4).
Gastrointestinal disorders:
Rare: constipation, abdominal pain, flatulence, dyspepsia, diarrhea, nausea, vomiting, pancreatitis.
Hepatobiliary disorders:
Rare: hepatitis / jaundice.
Very rare: fatal and non-fatal liver failure.
Skin and subcutaneous tissue disorders:
Rare: rash, itching, alopecia.
Musculoskeletal and connective tissue disorders:
Rare: myopathy * (including myositis), rhabdomyolysis with or without acute renal failure (see section 4.4), myalgia, muscle cramps.
* In a clinical study, myopathy occurred commonly in patients treated with SIVASTIN 80 mg / day compared to patients treated with 20 mg / day (1.0% vs 0.02%, respectively) (see sections 4.4 and 4.5). .
Not known: immune-mediated necrotizing myopathy (see section 4.4), tendinopathy, sometimes complicated by rupture.
Reproductive system and breast disorders:
Not known: erectile dysfunction.
General disorders and administration site conditions:
Rare: asthenia.
Apparent hypersensitivity syndrome including some of the following features has been reported rarely: angioedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, increased ESR, arthritis and arthralgia, urticaria, photosensitivity, fever, flushing , dyspnea and malaise.
Diagnostic tests:
Rare: increases in serum transaminases (alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transpeptidase) (see section 4.4 Hepatic effects), increases in alkaline phosphatase; increases in serum CK levels (see section 4.4).
Increases in HbA1c and fasting serum glucose levels have been reported with statins, including SIVASTIN.
There are rare post-marketing reports of cognitive impairment (eg, memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive problems have been reported with all statins. were generally non-serious, and reversible after stopping statin therapy, with varying times for symptom onset (1 day to years) and symptom resolution (median 3 weeks).
The following additional side effects have been reported with some statins:
• Sleep disturbances, including nightmares
• Sexual dysfunction
• Diabetes mellitus: frequency depends 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).
Children and adolescents (ages 10-17 years)
In a 48-week study of children and adolescents (boys in Tanner stage II and above and girls in postmenarche for at least one year) aged 10 to 17 years with heterozygous familial hypercholesterolemia (n = 175), the profile Safety and tolerability of the SIVASTIN group was generally similar to that of the placebo group. The long-term effects on physical, intellectual, and sexual maturation are unknown. There are currently insufficient data available after one year of treatment (see sections 4.2, 4.4, and 5.1).
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address http://www.agenziafarmaco.gov.it/it/responsabili.
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: C10A A01.
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.
SIVASTIN has been shown to reduce both normal and elevated LDL-C concentrations. LDL is formed from very low density protein (VLDL) and is catabolized mainly by the high affinity LDL receptor. The mechanism of the LDL-lowering effect of SIVASTIN may involve both the reduction of the VLDL cholesterol concentration ( C-VLDL) and induction of the LDL receptor leading to a reduction in production and an increase in LDL-C catabolism. Apolipoprotein B also substantially decreases during treatment with SIVASTIN. Ino | tre SIVASTIN moderately increases HDL-C and reduces plasma TG. As a result of these alterations, the ratios between total cholesterol and HDL-C and between LDL-C and C-HDL are reduced.
High risk of coronary heart disease (CHD) or existing coronary heart disease
In the Heart Protection Study (HPS) the effects of SIVASTIN 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 studied. In this study, they were treated 10,269 patients with SIVASTIN, 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 SIVASTIN 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. SIVASTIN also decreased the risk of major coronary events (a composite endpoint including non-fatal MI and CHD deaths) by 27 % (p coronary by-pass or percutaneous transluminal coronary angioplasty) and peripheral revascularization procedures and other non-coronary revascularization procedures 30% (p stroke 25% (p coronary artery disease but with cerebrovascular or peripheral artery disease, women and men, those aged below or above 70 years at the time of entry into the study, presence or absence of hypertension and primarily those with LDL cholesterol below 3.0 mmol / L at inclusion.
In the Scandinavian Simvastatin Survival Study (4S), the effect of SIVASTIN therapy on total 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 SIVASTIN 20-40 mg / day (n = 2221 ) or placebo (n = 2,223) for a median duration of 5.4 years. SIVASTIN reduced the risk of death by 30% (absolute risk reduction 3.3%). The risk of CHD death was reduced by 42% (absolute risk reduction of 3.5%). SIVASTIN also decreased the risk of major coronary events (CHD death plus hospital-proven silent non-fatal MI) by 34%. In addition, SIVASTIN significantly reduced the risk of cerebrovascular events. fatal and non-fatal (stroke and transient ischemic attack o) 28%. There was no statistically significant difference between the groups in non-cardiovascular mortality.
The Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) evaluated the effect of treatment with SIVASTIN 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; SIVASTIN 20 mg (n = 1,553; 25.7%) vs. SIVASTIN 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 "incidence of myopathy which was approximately 1.0% for patients treated with SIVASTIN 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%.
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 postmenarche 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 study, 144 patients were selected to continue therapy and received simvastatin 40 mg or placebo.
SIVASTIN significantly reduced plasma LDL-C, TG and Apo B levels. Results from the 48-week extension study were comparable to those seen in the base study.
After 24 weeks of treatment, the mean LDL-C value of 124.9 mg / dl (range: 64.0-289.0 mg / dl) compared to 207.8 mg / dl was obtained in the SIVASTIN 40 mg group. (range: 128.0-334.0 mg / dl) obtained 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), SIVASTIN reduced mean LDL-C levels by 36.8% (placebo: 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 levels of HDL-C of 8.3% (placebo: 3,6%). The long-term benefits of SIVASTIN on cardiovascular events are not known in children with heFH.
In children with heterozygous familial hypercholesterolaemia, the safety and efficacy of doses greater than 40 mg per day have not been studied. The long-term efficacy of simvastatin therapy in reducing morbidity and mortality seen in adults has not been established in childhood.
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-hydroxy acid 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 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% protein bound.
Elimination
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. Following 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.
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
Inside of the tablet
Butylated hydroxyanisole (E320)
Ascorbic acid (E300)
Citric acid monohydrate (E330)
Microcrystalline cellulose (E460)
Pregelatinised starch
Magnesium stearate (E572)
Lactose monohydrate
Tablet coating
Hypromellose (E464)
Hydroxypropylcellulose (E463)
Titanium dioxide (E171)
Talc (E553b)
Yellow iron oxide (E172) (10 and 20 mg tablets)
Red iron oxide (E172) (10, 20 and 40 mg tablets)
06.2 Incompatibility
Not relevant.
06.3 Period of validity
2 years.
06.4 Special precautions for storage
Store below 30 ° C.
06.5 Nature of the immediate packaging and contents of the package
SIVASTIN 10 mg
Packaging in blister packs of trilaminate film composed of polyvinyl chloride (PVC) / polyethylene (PE) / polyvinylidene chloride (PVDC) with aluminum foil as cover in packs of 20 tablets.
SIVASTIN 20 mg
Blister packs of trilaminate film composed of polyvinyl chloride (PVC) / polyethylene (PE) / polyvinylidene chloride (PVDC) with aluminum foil lidding in packs of 10 and 28 tablets.
SIVASTIN 40 mg
Blister packs of trilaminate film composed of polyvinyl chloride (PVC) / polyethylene (PE) / polyvinylidene chloride (PVDC) with aluminum foil lidding in packs of 10 and 28 tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
SIGMA-TAU Industrie Farmaceutiche Riunite S.p.A.
Viale Shakespeare, 47 - 00144 Rome
08.0 MARKETING AUTHORIZATION NUMBER
SIVASTIN 10 mg film-coated tablets: 20 film-coated tablets AIC n. 027208014
SIVASTIN 20 mg film-coated tablets: 10 film-coated tablets AIC n. 027208026
SIVASTIN 20 mg film-coated tablets: 28 film-coated tablets AIC n. 027208103
SIVASTIN 40 mg film-coated tablets: 10 film-coated tablets AIC n. 027208040
SIVASTIN 40 mg film-coated tablets: 28 film-coated tablets AIC n. 027208115
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
SIVASTIN 10 mg film-coated tablets and SIVASTIN 20 mg film-coated tablets
Date of first authorization: April 1989
Date of most recent renewal: July 2008
SIVASTIN 40 mg film-coated tablets
Date of first authorization: 21 July 1998
Date of most recent renewal: July 2008
10.0 DATE OF REVISION OF THE TEXT
December 2015
