Active ingredients: Simvastatin
ALPHEUS 20 mg film-coated tablets
ALPHEUS 40 mg film-coated tablets
Indications Why is Alpheus used? What is it for?
ALPHEUS contains the active substance simvastatin which belongs to a group of medicines called statins. ALPHEUS is a medicine used to reduce the levels of total cholesterol, "bad" cholesterol (LDL cholesterol) and fatty substances called triglycerides in the blood. In addition, ALPHEUS increases the levels of "good" cholesterol (HDL cholesterol).
Cholesterol is one of several fatty substances found in the bloodstream. Total cholesterol is mainly composed of LDL cholesterol and HDL cholesterol.
LDL cholesterol is often called "bad" cholesterol because it can build up in the artery walls and form plaques. Over time, this plaque buildup can lead to narrowing of the arteries. This narrowing can slow or block blood flow to vital organs such as the heart and brain. This blockage of blood flow can cause a heart attack or stroke.
HDL cholesterol is often called "good" cholesterol because it helps prevent bad cholesterol from building up in the arteries and protects against heart disease.
Triglycerides are another form of fat in the blood that can increase the risk of heart disease. You must be on a cholesterol-lowering diet while taking this medicine.
ALPHEUS is used as an adjunct to the diet to reduce cholesterol if you have:
- raised blood cholesterol levels (primary hypercholesterolaemia) or high blood fat levels (mixed hyperlipidaemia).
- a hereditary disease (homozygous familial hypercholesterolaemia) which increases your blood cholesterol levels. It is possible that you are also being treated with other treatments.
- manifest cardiovascular disease or diabetes mellitus ALPHEUS can prolong survival by reducing the risk of heart disease-related problems, regardless of blood cholesterol levels.
Most people do not have immediate symptoms due to 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 discuss goals with your doctor.
Contraindications When Alpheus should not be used
- if you are allergic to simvastatin or any of the other ingredients of this medicine
- 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, (used to treat fungal infections)
- erythromycin, clarithromycin or telithromycin (used to treat - infections)
- HIV protease inhibitors (HIV protease inhibitors are used for HIV infections)
- nefazodone (used to treat depression)
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 Alpheus
Tell your doctor or pharmacist before taking Alpheus:
- if you have any medical conditions including allergies.
- if you consume large amounts of alcohol.
- if you have ever had liver disease. In this case ALPHEUS may not be suitable for you.
- if you are due to have surgery. You may need to stop taking ALPHEUS for a short time.
- if you are taking or have taken within the last 7 days a medicine called fusidic acid (a medicine used for bacterial infections) by mouth or by injection. The combination of fusidic acid and Alpheus can cause severe muscle problems (rhabdomyolysis).
Your doctor will need to have a blood test done before you take ALPHEUS and if you have symptoms of liver problems while taking ALPHEUS. This analysis is done to know if the liver is functioning properly.
Your doctor may also order blood tests to check your liver function after starting ALPHEUS 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 of undetermined causes for no reason. This is because, rarely, muscle problems can be serious and can include injury to muscle tissue resulting in kidney damage.
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.
Interactions Which drugs or foods can modify the effect of Alpheus
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. It is particularly important that your doctor is informed if you are taking a medicine (s) with any of the following active substances. Taking ALPHEUS with any of these medicines can increase the risk of muscle problems.
- cyclosporine (often used in organ transplant patients)
- danazol (a man-made hormone used to treat endometriosis, a condition in which the lining of the uterus grows outside the uterus)
- medicines used to treat fungal infections (such as itraconazole, ketoconazole ()
- fibrates with active ingredients such as gemfibrozil and bezafibrate (used to lower cholesterol)
- erythromycin, clarithromycin, telithromycin (used to treat bacterial infections).
- HIV protease inhibitors such as indinavir, nelfinavir, ritonavir and saquinavir (used to treat AIDS)
- nefazodone (used to treat depression)
- amiodarone (used to treat an irregular heartbeat)
- verapamil or diltiazem (used to treat high blood pressure, chest pain associated with heart disease or other heart conditions)
If you need to take oral fusidic acid to treat bacterial infections, you will need to stop temporarily while using this medicine. Your doctor will tell you when to restart Alpheus. Taking Alpheus with fusidic acid it can rarely lead to muscle weakness, tenderness or pain (rhabdomyolysis).
Also, tell your doctor if you are taking medicine (s) with any of the following active substances:
- medicines with an active ingredient to prevent blood clots, such as warfarin, phenprocoumon or acenocoumarol (anticoagulants)
- fenofibrate (also used to lower cholesterol)
- niacin (also used to lower cholesterol) in high doses (≥1 g per day).
You should also tell your doctor that he is prescribing a new medicine that you are taking ALPHEUS.
ALPHEUS with food and drink
Grapefruit juice contains one or more substances that change the way the body uses certain medicines, including ALPHEUS. Consumption of grapefruit juice should be avoided.
Warnings It is important to know that:
Pregnancy and breastfeeding
Do not use ALPHEUS if you are pregnant, if you intend to become pregnant or if you suspect that you are pregnant. If you become pregnant while taking ALPHEUS, stop taking it immediately and contact your doctor.
Do not use ALPHEUS if you are breast-feeding as it is not known whether the medicine passes into breast milk. Ask your doctor or pharmacist for advice before taking any medicine.
Children
The safety and efficacy of ALPHEUS have been studied in boys between the ages of 10 and 17 and in girls who have started menstruating (menstruation) for at least one year (see section 3: How to take ALPHEUS). ALPHEUS does not has been studied in children under the age of 10. Ask your doctor for more information.
Driving and using machines
ALPHEUS 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 ALPHEUS
ALPHEUS contains lactose
ALPHEUS 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 Alpheus: Posology
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist. Your doctor will determine which tablet strength is suitable for you, based on your condition, current treatment and your risk profile. During treatment with ALPHEUS, you must follow a diet to lower your cholesterol levels.
Dosage
The recommended dose is one ALPHEUS 20 mg or 40 mg tablet by mouth once a day.
Adults
The starting dose is usually 20 mg 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. The maximum recommended dose is 40 mg per day.
Method and duration of treatment
Take ALPHEUS in the evening. You can take it regardless of meals. Continue to take ALPHEUS unless your doctor tells you to stop the treatment.
If your doctor has prescribed ALPHEUS with another cholesterol-lowering medicine containing a bile acid sequestering agent, you should take ALPHEUS at least 2 hours before or 4 hours after taking the bile acid sequestering medicine.
If you forget to take ALPHEUS
Do not take a double dose to make up for a forgotten dose; just take your usual dose of ALPHEUS the next day at the usual time.
If you stop taking ALPHEUS
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Overdose What to do if you have taken too much Alpheus
In case of accidental overdose of ALPHEUS, notify your doctor immediately or go to the nearest hospital.
Side Effects What are the side effects of Alpheus
Like all medicines, this medicine can cause side effects, although not everybody gets them.
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
- hypersensitivity reactions (allergies) which include:
- swelling of the face, tongue and throat which may cause difficulty in breathing
- severe muscle pain usually in the shoulders or hips rash with weakness in the legs and neck muscles • joint pain or inflammation (polymyalgia rheumatica)
- inflammation of blood vessels (vasculitis)
- unusual bruising, rash and swelling (dermatomyositis),
- hives, skin sensitivity to the sun, fever, flushing
- shortness of breath (dyspnoea) and feeling unwell
- lupus-like symptom complex (including rash, joint disorders, and effects on blood cells)
The following side effects have been reported:
Rare (may affect up to 1 in 1,000 patients):
- 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, inflammation of the pancreas often associated with severe abdominal pain)
- liver problems, hepatitis, yellowing of the skin and eyes (jaundice)
- rash, itching, hair loss
- weakness
- confusion.
Undesirable effects with frequency not known (frequency cannot be estimated from the available information):
- Constant muscle weakness
Additional possible side effects reported with some statins:
- sleep disturbances, including insomnia and nightmares
- memory loss
- sexual difficulties
- depression
- breathing problems including persistent cough and / or shortness of breath and fever.
- 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.
Increases in some blood test values (serum transaminases) related to liver function and muscle enzyme (creatine kinase) have been observed.
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
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 after EXP. The expiry date refers to the last day of that month.
Store below 25 ° C.
Do not throw away any medicines via wastewater or household waste.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Other Information
What ALPHEUS contains:
ALPHEUS 20 mg film-coated tablets
Each tablet contains:
the active ingredient is simvastatin 20 mg
The other ingredients are: Lactose monohydrate, butylhydroxyanisole, ascorbic acid, citric acid monohydrate, microcrystalline cellulose, pregelatinised starch, magnesium stearate, hypromellose, hydroxypropylcellulose, titanium dioxide, talc, yellow iron oxide, red iron oxide.
ALPHEUS 40 mg film-coated tablets
Each tablet contains:
the active ingredient is simvastatin 40 mg
The other ingredients are: Lactose monohydrate, butylhydroxyanisole, ascorbic acid, citric acid monohydrate, microcrystalline cellulose, pregelatinised starch, magnesium stearate, hypromellose, hydroxypropylcellulose, titanium dioxide, talc, red iron oxide.
Description of what ALPHEUS looks like and contents of the pack:
ALPHEUS 20 mg film-coated tablets
Packaged in blister packs of 10 and 28 tablets of 20 mg.
ALPHEUS 40 mg film-coated tablets
Packaged in blister packs 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.
01.0 NAME OF THE MEDICINAL PRODUCT
ALPHEUS TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 20 mg of simvastatin.
Each tablet contains 40 mg of simvastatin.
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 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. given as a single dose in the evening.The dosage of 80 mg is only recommended in patients with severe hypercholesterolaemia 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 ALPHEUS. 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 ALPHEUS dosage is 40 mg / day in the evening or 80 mg / day in three divided doses of 20 mg, 20 mg, and one evening dose of 40 mg. ALPHEUS 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 ALPHEUS 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
ALPHEUS 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 ALPHEUS, the dosage of ALPHEUS should not exceed 10 mg / day. In patients taking amiodarone or verapamil concomitantly with ALPHEUS, the dosage of ALPHEUS 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 (10-17 years of age)
For children and adolescents (boys with Tanner stage II and above and girls who have been post-menarche for at least one year, aged 10 to 17 years) with heterozygous familial hypercholesterolemia, the usual recommended starting dose is 10 mg once daily. day, in the evening. Children and adolescents should be placed on a standard cholesterol-lowering diet prior to treatment with simvastatin and should continue this diet 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 ALPHEUS in pre-pubertal 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
Myopathy / rhabdomyolysis
Simvastatin, like other HMG-CoA reductase inhibitors, can occasionally cause myopathy manifesting as muscle pain, tenderness, or weakness associated with elevations in creatine kinase (CK) levels of more than 10 times the upper limit of normal. sometimes manifesting 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.
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.
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.
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> 30 Kg / m2 , elevated triglyceride levels, hypertension) should be monitored both clinically and biochemically in accordance with national guidelines.
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
- Presence of previous episodes 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 concomitant use of other fibrates, niacin at lipid-lowering dosages (≥ 1 g / day) or by concomitant use of amiodarone or verapamil with 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 should 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).
Alpheus should not be administered concomitantly with systemic formulations containing fusidic acid or within 7 days of ending treatment with fusidic acid. In patients in whom the use of fusidic acid in systemic therapy is considered essential, treatment with statins should be withheld for the duration of fusidic acid treatment. Cases of rhabdomyolysis (including some fatal cases) have been reported in patients receiving fusidic acid and combined statins (see section 4.5). Patients should be advised to seek immediate medical attention if they experience any symptoms of muscle weakness, pain or tenderness.
Statin therapy can be reintroduced 7 days after the last dose of fusidic acid.
In exceptional circumstances, in which the intake of fusidic acid is prolonged, eg for the treatment of severe infections, the need for the concomitant administration of Alpheus and fusidic acid should only be considered on a case-by-case basis and under careful medical supervision.
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 should be paid to those patients who develop elevated serum transaminase levels, and in these patients, the 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.
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.
Reduced functionality of transport proteins
Reduced function of the 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 genotype SLC01B1 C.521T> C. Patients carrying the allele of the SLC01B1 gene (C.521T> C), which encodes a less active OATP1B1 protein, have an "increased systemic exposure to simvastatin and a greater risk of myopathy. risk of myopathy related to a high dose (SO mg) of simvastatin is about 1% in general, without genetic testing Based on the results of the SEARCH study, carriers of the homozygous C allele (also called CC) treated with SO mg have a 15% risk of developing myopathy within one year, while the risk in heterozygous carriers of the C {CT) allele 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 80 mg of simvastatin 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.
Interstitial lung disease
Exceptional cases of interstitial lung disease have been reported with some statins, 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 (10-17 years of age)
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 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. on 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 therapy with simvastatin (see sections paragraphs 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. has been studied in patients under the age of 10, and not even in pre-pubertal children and pre-menarche girls.
Warning 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.
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, telithromycin is unavoidable, therapy with simvastatin 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
Gemfìbrozil 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 the available clinical studies showed a" incidence of myopathy of 1% in patients treated with simvastatin 80 mg and diltiazem. The risk of myopathy in patients taking simvastatin 40 mg was not increased by concomitant diltiazem (see 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.
Fusidic acid
The risk of myopathy, including rhabdomyolysis may be increased by the concomitant use of systemic fusidic acid and statins. The mechanism of this interaction (whether it is pharmacodynamic, pharmacokinetic or both) is still unknown. Cases of rhabdomyolysis (including some fatal cases) have been reported in patients taking this combination.
If fusidic acid treatment is necessary, Alpheus treatment should be discontinued during fusidic acid treatment. (see also section 4.4)
04.6 Pregnancy and breastfeeding
Pregnancy
ALPHEUS 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 ALPHEUS 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 ALPHEUS or other closely related HMG-CoA reductase inhibitors differs from that seen in the general population, treatment of mothers with ALPHEUS 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, ALPHEUS does not should be used in women who are pregnant, wish to become pregnant or suspect they are pregnant. Treatment with ALPHEUS 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 ALPHEUS should not breastfeed (see section 4.3).
04.7 Effects on ability to drive and use machines
ALPHEUS 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 simvastatin 40 mg / day (n = 10,269) or placebo (n = 10,267), the safety profiles were comparable between patients treated with simvastatin 40 mg and patients treated with placebo in the Median study duration of 5 years. Discontinuation rates due to side effects were comparable (4.8% in patients treated with simvastatin 40 mg versus 5.1% in patients treated with placebo). myopathy was less than 0.1% in patients treated with simvastatin 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 simvastatin 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.
Frequency not known: immune-mediated necrotizing myopathy (see section 4.4).
General Disorders and Administration Site Changes:
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 , dyspnea and malaise.
Searches:
Rare: increases in serum transaminases (alanine aminotransferase, aspartate amino transferase, gamma-glutamyl transpeptidase) (see section 4.4 Hepatic effects), increases in alkaline phosphatase; increases in serum CK levels (see section 4.4).
Class effects: sleep disturbances, including insomnia and nightmares, memory loss, sexual dysfunction, depression.
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).
Exceptional cases of interstitial lung disease, especially with long-term therapy (see section 4.4).
Children and adolescents (10-17 years of age)
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 simvastatin 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 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.
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 simvastatin. 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 were studied on 20,536 patients (40-80 years) with or without hyperlipidemia and with coronary heart disease, other occlusive arterial diseases or diabetes mellitus. In this study, 10,269 patients were treated 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) by 27 % (p
Simvastatin reduced the need for coronary revascularization procedures (including coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) and peripheral revascularization procedures and other non-coronary revascularization procedures by 30% (stroke by 25% (LDL cholesterol) below 3.0 mmol / L at 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% (absolute risk reduction of 3.5%). Simvastatin also decreased the risk of major coronary events (CHD death plus hospital-proven silent non-fatal MI) by 34%. In addition, simvastatin significantly reduced the risk of cerebrovascular events fatal and non-fatal (stroke and attack transient ischemic) by 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 (10-17 years of age)
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 levels of 8.3% (placebo: 3.6%). The long-term benefits of ALPHEUS 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 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
Alial wearers SLC01B1 and S21T> C 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 SLCOIBI 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
1 20 mg film-coated tablet contains :
Excipients: Lactose monohydrate, butylhydroxyanisole, ascorbic acid, citric acid monohydrate, microcrystalline cellulose, pregelatinised starch, magnesium stearate, hypromellose, hydroxypropylcellulose, titanium dioxide, talc, yellow iron oxide, red iron oxide.
1 40 mg film-coated tablet contains :
Excipients: Lactose monohydrate, butylhydroxyanisole, ascorbic acid, citric acid monohydrate, microcrystalline cellulose, pregelatinised starch, magnesium stearate, hypromellose, hydroxypropylcellulose, titanium dioxide, talc, red iron oxide.
06.2 Incompatibility
Not relevant.
06.3 Period of validity
In intact packaging: 2 years.
06.4 Special precautions for storage
Store at a temperature below 25 ° C.
06.5 Nature of the immediate packaging and contents of the package
20 mg film-coated tablets
PVC / PE / PVDC / Al heat-sealed blister in lithographed cardboard box.
Carton containing 10 tablets in blister packs.
Carton containing 28 tablets in two blisters of 14 tablets.
40 mg film-coated tablets
PVC / PE / PVDC / Al heat-sealed blister in lithographed cardboard box.
Carton containing 10 tablets in blister packs.
Carton containing 28 tablets in two blisters of 14 tablets.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
S.F. GROUP S.r.l.
Via Tiburtina, 1143
00156 Rome - Italy
08.0 MARKETING AUTHORIZATION NUMBER
ALPHEUS 20 mg film-coated tablets:
10 film-coated tablets of 20 mg AIC n.037359015
ALPHEUS 20 mg film-coated tablets:
28 film-coated tablets of 20 mg AIC n.037359027
ALPHEUS 40 mg film-coated tablets:
10 film-coated tablets of 40 mg AIC n.037359039
ALPHEUS 40 mg film-coated tablets:
28 film-coated tablets of 40 mg AIC n.037359041
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
12 April 2007
10.0 DATE OF REVISION OF THE TEXT
April 2016
