Active ingredients: Rosuvastatin
SIMESTAT 5 mg film-coated tablets
SIMESTAT 10 mg film-coated tablets
SIMESTAT 20 mg film-coated tablets
SIMESTAT 40 mg film-coated tablets
Why is Simestat used? What is it for?
Simestat belongs to a group of drugs called statins.
You have been prescribed Simestat because:
- your cholesterol level is high. This means that you are at risk of heart attack or stroke. Simestat is used in adults, adolescents and children 6 years of age and older to treat high cholesterol.
She was prescribed a statin because changing her diet and more exercise weren't enough to correct her cholesterol levels. While taking Simestat you should continue the diet to reduce cholesterol levels and continue with physical exercise.
Or
- It has other factors that increase the risk of heart attack, stroke, or related health problems.
Heart attack, stroke, and related health problems can be caused by a disease called atherosclerosis. Atherosclerosis is due to the formation of fatty deposits inside the arteries.
Why it is important to keep taking Simestat
SIMESTAT is used to correct the levels of fatty substances in the blood called lipids, the most common of which is cholesterol.
There are different types of cholesterol in the blood: the so-called "bad" cholesterol (LDL-C) and the so-called "good" cholesterol (HDL-C).
- SIMESTAT can reduce "bad" cholesterol and increase "good" cholesterol.
- It works by helping the body to block the production of "bad" cholesterol. It also improves the body's ability to eliminate "bad" cholesterol from the blood.
For many people, high cholesterol has no influence on how they feel because it does not cause any symptoms. However, if high cholesterol is left untreated, fatty deposits can build up in the blood vessel walls, leading to their narrowing.
Sometimes these narrowed blood vessels can become blocked, blocking blood flow to the heart or brain, resulting in heart attack or stroke. Lowering cholesterol levels reduces the risk of having a heart attack, stroke, or related health problems.
You must continue to take SIMESTAT, even if your cholesterol levels have returned to normal, to prevent these levels from rising again and causing fat deposits to build up. However, you must stop taking SIMESTAT on medical advice or if you are pregnant.
Contraindications When Simestat should not be used
Do not take Simestat:
- if you have ever had an allergic reaction to Simestat or any of the ingredients of this medicine;
- if you are pregnant or breastfeeding. If you become pregnant while taking Simestat, stop taking it immediately and tell your doctor. Women should avoid becoming pregnant while taking Simestat by using suitable contraceptive measures;
- if you have liver disease;
- if you have severe kidney problems;
- if you have repeated or unexplained muscle aches or pains;
- if you take a medicine called cyclosporine (used for example after organ transplantation).
If you fall into one of the above cases (or have any doubts), you must go back to the doctor and inform him. Also, do not take Simestat 40 mg (the highest dose):
- if you have moderate kidney problems (if in doubt, ask your doctor);
- if the thyroid is not functioning properly;
- if you have repeated or unexplained muscle aches or pains, a personal or family history of muscle problems, or have previously had muscle problems with other cholesterol-lowering medicines;
- if you regularly consume large amounts of alcohol;
- if you are of Asian origin (Japanese, Chinese, Filipino, Vietnamese, Korean and Indian);
- if you take other cholesterol-lowering medicines called fibrates.
If you fall under one of the above cases (or have any doubts), you should go back to the doctor and inform him.
Precautions for use What you need to know before taking Simestat
Talk to your doctor or pharmacist before taking SIMESTAT.
- if you have kidney problems;
- if you have liver problems;
- if you have had repeated or unexplained muscle aches or pains, a personal or family history of muscle problems, or have previously had muscle problems with other cholesterol-lowering drugs. Tell your doctor immediately if you have unexplained muscle aches or pains especially if accompanied by malaise or fever Also, tell your doctor or pharmacist if you have constant muscle weakness;
- if you regularly consume large amounts of alcohol;
- if the thyroid is not functioning properly;
- if you take other cholesterol-lowering medicines called fibrates. Read this leaflet carefully, even if you have taken other medicines for high cholesterol before;
- if you are taking medicines used to treat HIV infections, eg ritonavir with lopinavir and / or atazanavir, please read the section "Other medicines and SIMESTAT";
- If you take antibiotics containing fusidic acid, please read the section "Other medicines and SIMESTAT".
Children and adolescents
- if the patient is under 6 years of age: Simestat should not be given to children under 6 years of age.
- if the patient is under 18 years of age: Simestat 40 mg tablets are not suitable for use in children and adolescents under 18 years of age.
- if you are over 70 (your doctor needs to choose the right starting dose for you);
- if you have severe respiratory failure;
- if you are of Asian origin (Japanese, Chinese, Filipino, Vietnamese, Korean and Indian). Your doctor needs to choose the right starting dose for you.
If it falls into one of the above cases (or you are not sure):
- do not take Simestat 40 mg (the highest dose) and check with your doctor or pharmacist before starting Simestat at any dose.
In a small number of people, statins can have a negative effect on the liver, which can be identified by a simple test that detects increased levels of liver enzymes in the blood. liver function), before and during treatment with Simestat.
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.
Interactions Which drugs or foods can change the effect of Simestat
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
Tell your doctor if you are taking any of the following medicines: cyclosporine (used for example after organ transplantation), warfarin or clopidogrel (or any other medicine used to thin the blood), fibrates (such as gemfibrozil, fenofibrate) or any other medication used to lower cholesterol (such as ezetimibe), indigestion remedies (used to neutralize stomach acids), erythromycin (an antibiotic), fusidic acid (an antibiotic - please read the Warnings and precautions section), an oral contraceptive (the pill), hormone replacement therapy or antiviral medicines such as ritonavir with lopinavir and / or atazanavir or simeprevir (used to treat infections, including "HIV or" hepatitis C - please read the section "Warnings and precautions "). The effects of these drugs can be modified by Simestat, or the effect of Simestat can be modified by these drugs.
Warnings It is important to know that:
Pregnancy and breastfeeding
Do not take Simestat if you are pregnant or breastfeeding. If you become pregnant while taking Simestat, you must stop taking it immediately and inform your doctor.
Women should avoid becoming pregnant while taking Simestat by using appropriate contraceptive measures.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
Most people can drive cars and use machines while taking Simestat - it has no effect on their ability to drive and use machines.
However, some people feel dizzy while taking Simestat. If you feel dizzy, consult your doctor before driving or operating machinery.
SIMESTAT contains lactose
If you have been told by your doctor that you have an intolerance to some sugars (lactose or milk sugar), contact your doctor before taking Simestat. For a complete list of other ingredients, see the "Contents of the pack and other information" section.
Dose, Method and Time of Administration How to use Simestat: Posology
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
Usual dosage in adults
If you are taking Simestat for high cholesterol:
Initial dose
Treatment with Simestat should start with a dose of 5 mg or 10 mg, even if you have previously taken higher doses with other statins. The choice of the starting dose depends on:
- your cholesterol level;
- the level of risk of having a heart attack or stroke;
- the possible presence of factors that may make you more sensitive to possible undesirable effects.
Check with your doctor or pharmacist which starting dose of Simestat is best for you.
Your doctor may decide to give you the lower dose (5 mg) if you:
- is of Asian origin (Japanese, Chinese, Filipino, Vietnamese, Korean and Indian);
- is over 70 years old;
- have moderate kidney problems;
- you are at risk of muscle aches and pains (myopathy).
Increase in dose and maximum daily dose
The doctor may decide to increase the dose. All this in order to determine the most suitable dose for you. If you start with a 5 mg dose, your doctor may decide to double the dose to 10 mg, then to 20 mg and then to 40 mg if necessary. If you start with 10 mg your doctor may decide, if necessary, to double this dose to 20 mg and then to 40 mg. There should be a 4-week interval between one dose adjustment and another.
The maximum daily dose of Simestat is 40 mg. It is given only to patients with high cholesterol levels and at high risk of heart attack or stroke, whose cholesterol levels have not decreased sufficiently with the 20 mg dose.
If you are taking Simestat to reduce the risk of heart attack, stroke or related health problems:
The recommended dose is 20 mg per day. However, your doctor may decide to use a lower dose if you have any of the above risk factors.
Use in children aged 6 to 17 years
The usual starting dose is 5 mg. Your doctor may increase your dose until the Simestat strength is most appropriate for you. The maximum daily dose of Simestat is 10 mg for children aged 6 to 9 years and 20 mg for children aged 10 to 17 years. The dose should be taken once a day. Simestat 40 mg tablets should not be used in children.
Administration of the tablets
Swallow each tablet whole with a drink of water.
Simestat must be taken once a day. Simestat can be taken at any time of the day with or without food.
Try to take your tablets at about the same time each day. This can help you not to forget to take them.
Periodic cholesterol checks
It is important to go back to your doctor to check your cholesterol levels periodically to make sure your cholesterol has reached and is maintaining the correct levels. Your doctor may decide to increase the dose until the amount of Simestat is most suitable for you.
If you forget to take Simestat
Don't be alarmed, just take your next dose at the usual time. Do not take a double dose to make up for a forgotten dose.
If you stop taking Simestat
Tell your doctor if you intend to stop taking Simestat. If you stop taking Simestat your cholesterol levels may rise again. 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 Simestat
Contact your doctor or the nearest hospital for a consultation.
If you go to hospital or receive treatment for another condition, please tell the hospital doctor that you are taking Simestat.
Side Effects What are the side effects of Simestat
Like all medicines, this medicine can cause side effects, although not everybody gets them.
It is important to be aware of which of these side effects may occur. They are usually mild and disappear in a short time.
Stop taking Simestat and seek medical help immediately if any of the following allergic reactions occur:
- difficulty in breathing, with or without swelling of the face, lips, tongue and / or throat;
- swelling of the face, lips, tongue and / or throat which may cause difficulty in swallowing;
- severe itching of the skin (with raised wheals).
Also, stop taking Simestat and contact your doctor immediately if you have unusual muscle aches or pains, which last longer than you might expect. Muscle symptoms are more common in children and adolescents than in adolescents. As with other statins, a very small number of people have experienced muscle side effects and rarely these have developed into a potentially fatal muscle damage disease known as rhabdomyolysis.
Common possible side effects (these may occur in 1 in 10 and 1 in 100 patients)
- headache, stomach pain, constipation, feeling sick, muscle pain, feeling weak, dizziness
- an increase in the amount of protein in the urine - usually the values return to normal on their own without having to stop taking Simestat (only for Simestat 40 mg)
- 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 while you are being treated with this medicine.
Uncommon possible side effects (these may affect 1 in 100 and 1 in 1,000 patients)
- rash, itching and other skin reactions
- an increase in the amount of protein in the urine - these usually return to normal on their own without the need to stop treatment with Simestat (only for Simestat 5 mg, 10 mg and 20 mg).
Rare possible side effects (these may occur in 1 in 1,000 and 1 in 10,000 patients)
- severe allergic reactions - signs include swelling of the face, lips, tongue and / or throat, difficulty in swallowing and breathing, severe itchy skin (with raised wheals). If you suspect that you are having an allergic reaction, stop taking Simestat and seek medical help immediately.
- muscle damage in adults - as a precaution, stop taking Simestat and see your doctor immediately if you have unusual muscle aches or pains that go on longer than you might expect
- severe stomach pain (inflamed pancreas)
- increase in liver enzymes in the blood.
Very rare possible side effects (these may affect less than 1 in 10,000 patients)
- jaundice (yellowing of the skin and eyes), hepatitis (an "inflammation of the liver), traces of blood in the urine, damage to the nerves in the arms and legs (numbness), joint pain, memory loss and breast enlargement in men (gynecomastia ).
Side effects of unknown frequency may include:
- diarrhea (loose stools), Stevens-Johnson syndrome (manifested by blisters on the skin, mouth, eyes and genitals), cough, shortness of breath, edema (swelling), sleep disturbances, including insomnia and nightmares, sexual problems , depression, breathing problems, including persistent cough and / or shortness of breath or fever, tendon injury and constant muscle weakness.
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
- Blisters: Store below 30 ° C. Store in the original package to protect from moisture.
- Containers: Store below 30 ° C. Keep the bottle tightly closed to protect the medicine from moisture.
- 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 carton / blister / label after EXP. The expiry date refers to the last day of that month.
- 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 Simestat contains
The active substance of Simestat is rosuvastatin. Simestat film-coated tablets contain rosuvastatin calcium salt equivalent to 5 mg, 10 mg, 20 mg or 40 mg of rosuvastatin.
The other ingredients are: lactose monohydrate, microcrystalline cellulose, calcium phosphate, crospovidone, magnesium stearate, hypromellose, triacetin, titanium dioxide (E171). Simestat 10 mg, 20 mg and 40 mg film-coated tablets also contain red iron oxide (E172). Simestat 5 mg film-coated tablets also contain yellow iron oxide (E172).
What Simestat looks like and contents of the pack
Simestat is supplied in blister packs containing 7, 14, 15, 20, 28, 30, 42, 50, 56, 60, 84, 90, 98 and 100 tablets and plastic containers containing 30 and 100 tablets.
Not all pack sizes may be marketed in all states.
Simestat is supplied as tablets of four strengths:
Simestat 5 mg film-coated, yellow, round tablets marked with "ZD4522" and "5" on one side and plain on the other side.
Simestat 10 mg film-coated tablets, pink, round and marked with "ZD4522" and "10" on one side and plain on the other side.
Simestat 20 mg film-coated tablets, pink, round and marked with "ZD4522" and "20" on one side and plain on the other side.
Simestat 40 mg film-coated tablets, pink, oval and marked with "ZD4522" on one side and "40" on the other side.
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
SIMESTAT
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
5 mg:
Each film-coated tablet contains 5 mg of rosuvastatin (as rosuvastatin calcium salt). Each tablet contains 94.88 mg of lactose monohydrate.
10 mg:
Each film-coated tablet contains 10 mg of rosuvastatin (as rosuvastatin calcium salt). Each tablet contains 91.3 mg of lactose monohydrate.
20 mg:
Each film-coated tablet contains 20 mg of rosuvastatin (as rosuvastatin calcium salt). Each tablet contains 182.6 mg of lactose monohydrate.
40 mg:
Each film-coated tablet contains 40 mg of rosuvastatin (as rosuvastatin calcium salt). Each tablet contains 168.32 mg of lactose monohydrate.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
5 mg: film-coated tablets
Yellow, round tablet, debossed with "ZD4522" and "5" on one side and plain on the other side.
10 mg: film-coated tablets
Round, pink colored tablet, marked "ZD4522" and "10" on one side and plain on the other side.
20 mg: film-coated tablets
Round, pink colored tablet, marked "ZD4522" and "20" on one side and plain on the other side.
40 mg: film-coated tablets
Pink, oval-shaped tablet, marked "ZD4522" on one side and "40" on the other side.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Treatment of hypercholesterolemia
Adults, adolescents and children aged 6 years and older with primary hypercholesterolaemia (type IIa, including heterozygous familial hypercholesterolemia) or mixed dyslipidemia (type IIb) in addition to diet when the response to the latter and others non-pharmacological treatments (eg physical exercise, weight reduction) are found to be inadequate.
Homozygous familial hypercholesterolemia, in addition to diet and other lipid-lowering treatments (e.g. LDL apheresis) or when such treatments are not appropriate.
Prevention of cardiovascular events
Prevention of major cardiovascular events in patients believed to be at high risk for a first cardiovascular event (see section 5.1), as adjunct therapy to correction of other risk factors.
04.2 Posology and method of administration
Before starting treatment, the patient should be placed on a standard hypolipidic diet, which must also be maintained during treatment. The dose should be chosen taking into account the goals of therapy and the patient's response, using the therapeutic guidelines currently in use.
Simestat can be given at any time of the day, with or without food.
Treatment of hypercholesterolemia
The recommended starting dose is 5 or 10 mg once daily orally for both patients not previously treated with statins and those previously treated with other HMG-CoA reductase inhibitors. The choice of starting dose should take into account the individual cholesterol level and future cardiovascular risk, as well as the risk of potential adverse reactions (see below). If necessary, a higher dose adjustment can be made after 4 weeks (see section 5.1).
In view of the increase in adverse reaction reports with the 40 mg dose compared to the lower doses (see section 4.8), a switch to the maximum dose of 40 mg should only be considered in patients with severe high-risk cardiovascular hypercholesterolaemia (in particularly those with familial hypercholesterolemia) who with the 20 mg dose have not reached the established therapeutic objectives and on which periodic monitoring checks will be carried out (see section 4.4). Specialist supervision is recommended in case of administration of the 40 mg.
Prevention of cardiovascular events
In the cardiovascular events risk reduction study, the dose used was 20 mg per day (see section 5.1).
Pediatric population
Pediatric use should only be followed by a specialist.
Children and adolescents 6 to 17 years of age (Tanner stage
In children and adolescents with heterozygous familial hypercholesterolemia the dose initial usual is 5 mg per day.
• In children 6 to 9 years of age with heterozygous familial hypercholesterolaemia, the usual dose range is 5 to 10 mg orally once daily. The safety and efficacy of doses above 10 mg have not been studied in this population.
• In children 10 to 17 years of age with heterozygous familial hypercholesterolaemia, the usual dose range is 5 to 20 mg orally once daily. The safety and efficacy of doses above 20 mg have not been studied in this population.
Dosage adjustment should be made based on the individual response and tolerability of pediatric patients as per pediatric treatment recommendations (see section 4.4). Children and adolescents should follow a standard diet to reduce cholesterol levels before starting treatment with rosuvastatin; this diet should be continued while taking rosuvastatin.
Experience in children with homozygous familial hypercholesterolaemia is limited to a small number of children aged between 8 and 17 years.
The 40 mg tablets are not suitable for use in pediatric patients.
Children under the age of 6
The safety and efficacy of use in children less than 6 years of age have not been studied. Therefore Simestat is not recommended for use in children under 6 years of age.
Use in elderly patients
In patients over 70 years of age, the recommended starting dose is 5 mg (see section 4.4).
No other dose adjustments are necessary based on age.
Dosage in patients with renal insufficiency
No dose adjustment is necessary in patients with mild or moderate renal impairment.
In patients with moderate renal impairment (creatinine clearance
Dosage in patients with impaired hepatic function
In subjects with Child-Pugh scores ≤ 7, no "increased systemic exposure to rosuvastatin was observed, but was seen in subjects with Child-Pugh scores of 8 and 9 (see section 5.2). In these patients, an assessment of function should be considered. There is no experience in subjects with Child-Pugh scores> 9. Simestat is contraindicated in patients with active liver disease (see section 4.3).
Ethnicity
Increased systemic exposure has been observed in Asian subjects (see section 4.3, section 4.4 and section 5.2). In these patients the recommended starting dose is 5 mg.
The 40 mg dose is contraindicated in Asian patients.
Genetic polymorphisms
Specific types of genetic polymorphisms are known to lead to increased rosuvastatin exposure (see section 5.2). For those patients who have these specific types of polymorphisms, a lower daily dose of Simestat is recommended.
Dosage in patients with predisposing factors for myopathy
The recommended starting dose for patients with predisposing factors for myopathy is 5 mg (see section 4.4).
The 40 mg dose is contraindicated in some of these patients (see section 4.3).
Concomitant therapy
Rosuvastatin is a substrate for various transport proteins (eg, OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) is increased when Simestat is administered concomitantly with certain medicinal products which may increase the plasma concentration of rosuvastatin due to interactions with these protein transporters (e.g. cyclosporine and certain protease inhibitors including ritonavir combinations with atazanavir, lopinavir, and / or tipranavir; see sections 4.4 and 4.5). Whenever possible, alternative medicinal products should be considered, and, if necessary, temporary discontinuation of Simestat therapy. In situations where co-administration of these medicinal products with Simestat is unavoidable, the benefit and risk of concomitant treatment and dose adjustments of Simestat should be carefully considered (see section 4.5).
04.3 Contraindications
Simestat is contraindicated:
- in patients with hypersensitivity to rosuvastatin or to any of the excipients;
- in patients with active liver disease, including unexplained, persistent increases in serum transaminase levels and any increase in serum transaminases beyond 3 times the upper limit of normal (ULN);
- in patients with severe renal impairment (creatinine clearance
- in patients with myopathy;
- in patients treated concomitantly with cyclosporine;
- during pregnancy and breastfeeding and in women of childbearing age who do not use suitable contraceptive measures.
The 40 mg dose is contraindicated in patients with predisposing factors for myopathy / rhabdomyolysis. These factors include:
- moderate renal damage (creatinine clearance
- hypothyroidism;
- personal or family history of hereditary muscle diseases;
- previous history of muscle toxicity with other HMG-CoA reductase inhibitors or fibrates;
- alcohol abuse;
- conditions that can cause an increase in the plasma levels of the drug;
- Asian patients;
- concomitant use of fibrates;
(see sections 4.4, 4.5 and 5.2).
04.4 Special warnings and appropriate precautions for use
Effects on the kidney
In patients treated with high doses of Simestat, particularly with 40 mg, proteinuria, mostly of tubular origin, detected with the dipstick test and in most cases was transient and intermittent, has been observed. Proteinuria was not predictive of acute or progressive renal injury (see section 4.8). In the post-marketing setting, the frequency of serious renal events is higher with the 40 mg dose. In patients treated with a dose of 40 mg, evaluation of renal function should be considered during routine monitoring.
Effects on skeletal muscles
Effects on skeletal muscles, eg. myalgia, myopathy and, rarely, rhabdomyolysis. Very rare cases of rhabdomyolysis have been reported with the use of ezetimibe in combination with other HMG-CoA reductase inhibitors. A pharmacodynamic interaction cannot be excluded (see section 4.5) and caution is recommended when using this combination.
As with other HMG-CoA reductase inhibitors, in the post-marketing setting, the frequency of rhabdomyolysis associated with Simestat is higher with the 40 mg dose.
Creatine kinase assay
Creatine Kinase (CK) dosage should not be measured after strenuous physical activity or in the presence of a possible other cause of CK elevation that could confound interpretation of the result. If CK levels are significantly elevated at baseline (> 5xULN) , a confirmatory test should be performed within 5-7 days If this test confirms a baseline CK> 5xULN, treatment should not be initiated.
Before the treatment
As with other HMG-CoA reductase inhibitors, Simestat should be prescribed with caution in patients with predisposing factors for myopathy / rhabdomyolysis. Such factors include:
- kidney damage;
- hypothyroidism;
- personal or family history of hereditary muscle diseases;
- previous history of muscle toxicity with other HMG-CoA reductase inhibitors or fibrates;
- alcohol abuse;
- age> 70 years;
- cases where increased plasma levels may occur (see sections 4.2, 4.5 and 5.2);
- concomitant use of fibrates.
In these patients, the treatment-related risk should be considered in relation to the possible benefit and clinical monitoring is recommended. If CK levels are significantly elevated at baseline (> 5xULN), treatment should not be initiated.
During the treatment
Patients should be asked to report unexplained muscle pain, weakness or cramps immediately, particularly if associated with malaise or fever. In these patients, CK levels should be measured. Treatment should be discontinued in case of significant increases in CK (> 5xULN), or if muscle symptoms are severe and cause daily discomfort (even if CK levels are ≤5xULN). Resumption of therapy with Simestat or other HMG-CoA reductase inhibitors should be reconsidered if symptoms disappear and CK levels return to normal, using the lowest dose and under close medical supervision.
Routine monitoring of CK levels is not required in asymptomatic patients. There have been very rare reports of immune-mediated necrotizing myopathy (IMNM) during or after treatment with statins, including rosuvastatin. IMNM is clinically characterized by proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment.
Co-administration of Simestat and other drugs in a small number of patients treated in clinical studies did not show an increase in skeletal muscle effects. However, in patients receiving therapy with other HMG-CoA reductase inhibitors co-administered with fibric acid derivatives, including gemfibrozil, cyclosporine, nicotinic acid, azole antifungals, protease inhibitors and macrolide antibiotics, there was an increased incidence of myositis and myopathy. Gemfibrozil increases the risk of myopathy when administered concomitantly with certain HMG-CoA reductase inhibitors. Therefore, the combination of Simestat and gemfibrozil is not recommended. The benefit, in terms of further modifications of lipid levels, obtainable with the combined use of Simestat with fibrates or niacin must be carefully weighed in relation to the potential risks that such combinations entail. Concomitant use of the 40 mg dose with fibrates is contraindicated (see sections 4.5 and 4.8).
The combination with rosuvastatin and fusidic acid is not recommended. Cases of rhabdomyolysis (including some fatal) have been reported in patients treated with this combination (see section 4.5).
Simestat should not be used in patients who have an acute, serious condition that may be indicative of myopathy or predispose to the development of renal failure secondary to rhabdomyolysis (e.g. sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disturbances or uncontrolled seizures).
Effects on the liver
As with other HMG-CoA reductase inhibitors, Simestat should be used with caution in patients who consume excessive amounts of alcohol and / or have a history of liver disease. It is recommended that liver function tests be performed before starting treatment and repeated 3 months after the start of treatment. If the serum transaminase level is more than 3 times the upper limit of normal, treatment should be stopped or The dose should be reduced. In the post-marketing setting, the frequency of serious hepatic events (consisting predominantly of "hepatic transaminase elevations) is higher with the 40 mg dose.
In patients with secondary hypercholesterolaemia caused by hypothyroidism or nephrotic syndrome, the underlying disease should be treated before initiating therapy with Simestat.
Ethnicity
Pharmacokinetic studies show increased exposure in Asian subjects compared to Caucasians (see sections 4.2, 4.3 and 5.2).
Protease inhibitors
An increase in systemic exposure to rosuvastatin was observed in subjects treated with rosuvastatin concomitantly with several protease inhibitors in combination with ritonavir. Both the benefit of lipid lowering with the use of Simestat in HIV infected patients treated with protease inhibitors and the possibility of increased plasma concentrations of rosuvastatin when initiating therapy with Simestat or increasing its dosage in patients treated with protease inhibitors. Concomitant use with protease inhibitors is not recommended unless the dose of Simestat is adequate (see sections 4.2 and 4.5).
Lactose intolerance
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose / galactose malabsorption should not take this medicine.
Interstitial lung disease
Exceptional cases of interstitial lung disease have been reported with some statins, especially during long-term therapy (see Section 4.8). This can be manifested by dyspnoea, non-productive cough and worsening of general health (fatigue, weight loss and fever). If a patient is suspected of developing interstitial lung disease, statin therapy should be discontinued.
Diabetes mellitus
Some evidence suggests that statins, as a class effect, increase blood glucose and in some patients, at high risk of developing diabetes, may induce a level of hyperglycemia such that antidiabetic therapy is appropriate. This risk, however, is outweighed by the reduction in vascular risk with the use of statins and therefore should not be a reason for discontinuation of treatment. Patients at risk (fasting glucose 5.6 - 6.9 mmol / L, BMI> 30kg / m2, elevated triglyceride levels, hypertension) should be monitored both clinically and biochemically in accordance with national guidelines.
In the JUPITER study, the overall reported frequency was 2.8% in the rosuvastatin group and 2.3% in the placebo group, mainly in patients with fasting glucose 5.6 - 6.9 mmol / L.
Pediatric population
The evaluation of linear growth (height), weight, body mass index (BMI) and secondary characteristics of sexual maturation according to Tanner stages in the pediatric population aged 6 to 17 years treated with rosuvastatin is limited to a period of two years. After two years of treatment, no effects on growth, body weight, body mass index or sexual maturation were observed (see section 5.1).
In a clinical study conducted in children and adolescents treated with rosuvastatin for 52 weeks, increases in creatine kinase (CK)> 10 times the upper limit of normal and muscle symptoms following exercise or increased physical activity were observed more frequently than than reported in clinical trials on adults (see section 4.8).
04.5 Interactions with other medicinal products and other forms of interaction
Effect of co-administration of medicinal products on rosuvastatin
Protein transporter inhibitors: Rosuvastatin is a substrate for certain protein transporters including the hepatic uptake transporter OATP1B1 and the efflux transporter BCRP. Co-administration of Simestat with medicinal products that are inhibitors of these protein transporters may lead to increased plasma concentrations of rosuvastatin and an increased risk of myopathy (see sections 4.2, 4.4, and 4.5 Table 1).
Cyclosporine: During concomitant treatment with Simestat and cyclosporine the AUC values of rosuvastatin were, on average, 7 times higher than those observed in healthy volunteers (see Table 1). Simestat is contraindicated in patients concomitantly treated with cyclosporine (see section 4.3).
Concomitant administration of Simestat and cyclosporine had no effect on the plasma concentration of cyclosporine.
Protease inhibitors: Although the exact mechanism of interaction is not known, concomitant use of protease inhibitors can greatly increase rosuvastatin exposure (see Table 1). For example, in a pharmacokinetic study, co-administration of rosuvastatin 10 mg and a combination of two protease inhibitors (300 mg atazanavir / 100 mg ritonavir) in healthy volunteers was associated with an approximate three-fold increase, respectively. and seven times the steady-state AUC and Cmax of rosuvastatin. Concomitant use of Simestat and certain combinations of protease inhibitors may be considered after careful consideration of Simestat dose adjustments based on the increase. expected rosuvastatin exposure (see sections 4.2, 4.4, and 4.5 Table 1).
Gemfibrozil and other lipid-lowering products: Concomitant use of Simestat and gemfibrozil resulted in a 2-fold increase in rosuvastatin Cmax and AUC (see section 4.4).
Based on data obtained from specific interaction studies, no relevant pharmacokinetic interactions with fenofibrate are expected, however pharmacodynamic interactions may occur. Gemfibrozil, fenofibrate, other fibrates and lipid-lowering doses (equal to or greater than 1g / day) of niacin (nicotinic acid) increase the risk of myopathy when given concomitantly with HMG-CoA reductase inhibitors, possibly because they can cause myopathy even when given alone. Concomitant use of the 40 mg dose with fibrates is contraindicated (see sections 4.3 and 4.4). These patients should also initiate therapy with the 5 mg dose.
Ezetimibe: Concomitant use of Simestat 10 mg and ezetimibe 10 mg resulted in a 1.2-fold increase in the AUC of rosuvastatin in hypercholesterolemic subjects (Table 1). A pharmacodynamic interaction, in terms of undesirable effects, between Simestat and ezetimibe cannot be excluded (see section 4.4).
Antacids: Co-administration of Simestat and a suspension of antacids containing aluminum and magnesium hydroxide caused a decrease in the plasma concentration of rosuvastatin by approximately 50%. This effect was attenuated when antacids were administered two hours after Simestat. The clinical relevance of this interaction has not been studied.
Erythromycin: Concomitant use of Simestat and erythromycin caused a 20% decrease in AUC of rosuvastatin and a 30% decrease in Cmax. This interaction can be caused by the increase in intestinal motility caused by erythromycin.
Cytochrome P450 enzymes: The results of the studies conducted in vitro And in vivo demonstrate that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. Furthermore, rosuvastatin is not a good substrate for these isoenzymes. Therefore, drug interactions resulting from cytochrome P450 mediated metabolism are not expected.
No clinically relevant interactions were observed between rosuvastatin and fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4).
Interactions requiring rosuvastatin dose adjustments (see also Table 1): When Simestat needs to be co-administered with other medicinal products known to increase rosuvastatin exposure, the doses of Simestat should be adjusted. Start with a daily dose of Simestat of 5. mg if the predicted increase in exposure (AUC) is approximately 2-fold or greater. The maximum daily dose of Simestat should be adjusted so that the expected rosuvastatin exposure does not exceed what is likely to occur with a 40 mg daily dose of Simestat taken without potentially interacting medicinal products, eg a 20 mg dose of Simestat. with gemfibrozil (1.9-fold increase), and a 10 mg dose of Simestat with combination of atazanavir / ritonavir (3.1-fold increase).
Effect of rosuvastatin on co-administration with other medicinal products
Vitamin K antagonists: As with other HMG-CoA reductase inhibitors, initiation of treatment or an increase in the dose of Simestat in patients receiving concomitant therapy with vitamin K antagonists (eg warfarin or other coumarin anticoagulants) may result in an increase in INR (International Normalized Ratio) values. Withdrawal of treatment or a reduction in the dose of Simestat may lead to a decrease in INR. In these situations, appropriate monitoring of the INR should be carried out.
Oral contraceptives / hormone replacement therapy (HRT): The concomitant use of Simestat and oral contraceptives caused an increase in plasma concentrations (AUC) of ethinyl estradiol and norgestrel of 26% and 34%, respectively. be taken into account when choosing oral contraceptive doses. No pharmacokinetic data are available in patients taking Simestat and hormone replacement therapy concomitantly and therefore a similar effect cannot be excluded. However, in clinical trials this combination has been widely used in women and was well tolerated.
Other drugs:
Digoxin : Based on data obtained from specific interaction studies, clinically relevant interactions with digoxin are not expected.
Fusidic Acid: Interaction studies between rosuvastatin and fusidic acid have not been conducted. As with other statins, relevant muscle events including rhabdomyolysis have been reported in post-marketing experience with rosuvastatin and fusidic acid administered concomitantly.
Therefore, the combination of rosuvastatin and fusidic acid is not recommended. Temporary suspension of rosuvastatin treatment is recommended if appropriate. If unavoidable, patients should be carefully monitored.
Pediatric population: Interaction studies have only been performed in adults. The extent of interactions in the pediatric population is unknown.
04.6 Pregnancy and breastfeeding
Simestat is contraindicated during pregnancy and breastfeeding.
Women of childbearing potential must take suitable contraceptive measures.
Since cholesterol and other derivatives of cholesterol biosynthesis are essential for fetal development, the potential risk from inhibiting HMG-CoA reductase outweighs the benefits of treatment during pregnancy. Animal studies have provided evidence of limited reproductive toxicity (see section 5.3). If a patient taking Simestat becomes pregnant, treatment should be discontinued immediately.
Rosuvastatin is excreted in rat milk. There are no data available on the excretion of the drug in human breast milk (see section 4.3).
04.7 Effects on ability to drive and use machines
No studies on the ability to drive or use machines have been performed for Simestat. Given its pharmacodynamic properties, Simestat is unlikely to affect this ability. However, it should be considered that dizziness when driving may occur during treatment. or machinery is used.
04.8 Undesirable effects
Adverse reactions reported with Simestat are generally mild and transient. During controlled clinical trials, less than 4% of patients treated with Simestat discontinued the study due to adverse reactions.
Tabular list of adverse reactions
The following table presents the adverse reaction profile for rosuvastatin, based on data from clinical studies and extensive post-marketing experience. The adverse reactions listed below are categorized by frequency and organ and system class ( SOC).
The frequencies of adverse reactions are ranked according to the following convention: common (≥1 / 100,
Table 2. Adverse reactions based on data from clinical trials and post-marketing experience
As with other HMG-CoA reductase inhibitors, the incidence of adverse drug reactions tends to be dose-dependent.
Effects on the kidney: Proteinuria, mostly of tubular origin, has been found in patients treated with Simestat, detected with the dipstick test. The passage of proteins in the urine from absence of proteins or traces to ++ and beyond was found in less than 1% of patients sometimes during treatment with 10 and 20 mg and in about 3% of patients treated with 40 mg. A minor increase in the transition from no or trace to + was observed with the 20 mg dose. In most cases, proteinuria decreases or disappears spontaneously with continued therapy. From the analysis of data from clinical studies or from the "Post-marketing experience no causal link between proteinuria and acute or progressive kidney disease has been identified.
Haematuria has been observed in patients treated with Simestat and data from clinical studies show that the number of events is low.
Effects on skeletal muscles: in patients treated with Simestat, at all doses and in particular at doses> 20 mg, effects on skeletal muscles have been reported, eg. myalgia, myopathy (including myositis) and, rarely, rhabdomyolysis with and without acute renal failure.
A dose-related increase in CK levels has been observed in patients taking rosuvastatin; in most cases, these were mild, asymptomatic and transient increases. In case of high CK levels (> 5xULN), the treatment should be stopped (see section 4.4).
Liver Effects: As with other HMG-CoA reductase inhibitors, dose-related increases in transaminases have been observed in a small number of patients receiving rosuvastatin; in most cases it was a mild, asymptomatic and transient increase.
The following adverse events have been reported with some statins:
sexual dysfunctions
exceptional cases of interstitial lung disease, especially during long-term therapy (see section 4.4)
The frequency of rhabdomyolysis, severe renal events and severe hepatic events (consisting predominantly of "hepatic transaminase elevations) is higher with the 40 mg dose.
Pediatric population: Creatine kinase elevations> 10 times the upper limit of normal and muscle symptoms following physical activity or increased physical activity were observed more frequently in a 52-week clinical study in children and adolescents than observed in adults (see section 4.4). In other respects, the safety profile of rosuvastatin was similar in children and adolescents compared to adults.
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
There is no specific treatment available in case of overdose. In such an event, symptomatic treatment and supportive measures should be instituted. Liver function and CK levels should be monitored. Hemodialysis is not believed to be of any use.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: HMG-CoA reductase inhibitors
ATC code: C10A A07
Mechanism of action
Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme of conversion from 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. The primary site of action of rosuvastatin is the liver. the target organ for lowering cholesterol.
Rosuvastatin increases the number of hepatic LDL receptors present on the cell surface, resulting in increased uptake and catabolism of LDL and inhibits hepatic synthesis of VLDL, thereby reducing the total number of VLDL and LDL particles.
Pharmacodynamic effects
Simestat reduces high levels of LDL cholesterol, total cholesterol and triglycerides and increases HDL cholesterol. It also reduces the levels of ApoB, non-HDL cholesterol, VLDL cholesterol, VLDL triglycerides and increases ApoA-I (see Table 3). Simestat also decreases the ratios of LDL-C / HDL-C, total cholesterol / HDL-C, non-HDL / HDL-C and ApoB / ApoA-I cholesterol.
Therapeutic response to Simestat is achieved within 1 week of initiation of therapy and 90% of maximal response is achieved within 2 weeks. Maximal response is usually achieved within 4 weeks and is maintained thereafter.
Clinical efficacy and safety
Simestat is effective in adults with hypercholesterolemia, with and without hypertriglyceridaemia, regardless of race, sex or age, and in special populations such as diabetics or patients with familial hypercholesterolemia.
In phase III studies, Simestat was shown to be effective in the treatment of most patients with type IIa and IIb hypercholesterolemia (mean baseline LDL-C concentration of approximately 4.8 mmol / l), in accordance with established from the guidelines of the European Atherosclerosis Society (EAS; 1998); approximately 80% of patients treated with Simestat 10 mg achieved the LDL-C goals indicated in these guidelines (
In a large study involving 435 patients with heterozygous familial hypercholesterolaemia, a dose of Simestat of 20 to 80 mg was administered according to a forced dose titration design.
All doses have been shown to have a beneficial effect on lipid parameters and facilitate the achievement of the goals set by the guidelines.
After dose escalation to 40 mg daily doses (12 weeks of therapy), the LDL-C level was reduced by 53%. 33% of patients achieved the goals reported in the EAS guidelines for LDL-C levels (
In an open-label forced dose titration study, the response to treatment with Simestat at doses of 20-40 mg was evaluated in 42 patients with homozygous familial hypercholesterolaemia. In the overall population, the mean reduction in LDL-C levels was 22%.
In clinical studies conducted in a limited number of patients, Simestat has been shown to have an additive effect in "lowering triglyceride levels when used in combination with fenofibrate and in increasing HDL-C levels when used together with niacin (see section 4.4). ).
In a multi-center, double-blind, placebo-controlled clinical study (METEOR) 984 patients, aged 45 to 70 years and at low risk of coronary artery disease (defined as Framingham's risk of subclinical atherosclerosis (assessed by " Carotid Intima Media Thickness (CIMT)) were randomized to 40 mg rosuvastatin once daily or to placebo for two years. Rosuvastatin significantly delayed by 0.0145 mm / year (95% CI -0 , 0196, -0.0093; carotid parteria versus placebo. For rosuvastatin the change from baseline was -0.0014 mm / year (-0.12% / year - not significant), compared to that of + 0.0131 mm / year (1.12% / year (p
The 40 mg dose should only be prescribed to patients with severe hypercholesterolaemia at high cardiovascular risk (see section 4.2).
In the study "Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin" (JUPITER), the effect of rosuvastatin on the occurrence of major atherosclerotic cardiovascular events was evaluated in 17,802 men (aged ≥ 50 years) and women (aged ≥ 60 years).
Study participants were randomized to receive placebo (n = 8901) or rosuvastatin 20 mg once daily (n = 8901) and followed for a mean of 2 years.
The concentration of LDL cholesterol was reduced by 45% (p
In a post-hoc analysis of a subgroup of high-risk patients with a Framingham risk score> 20% (1558 subjects) at baseline, a significant reduction was observed in the combined endpoint including death from cardiovascular causes, stroke and myocardial infarction (p = 0.028) in the rosuvastatin group compared to the placebo group. The absolute risk reduction in the event rate per 1000 patient-years was 8.8. Total mortality was unchanged in this high-risk patient group (p = 0.193). In a post-hoc analysis of a subgroup of high-risk patients (9,302 total subjects) with a baseline SCORE risk score ≥ 5% (extrapolated to include subjects over 65) a significant reduction in Combined endpoint including death from cardiovascular causes, stroke and myocardial infarction (p = 0.0003) in the rosuvastatin group versus the placebo group. The absolute risk reduction for the event rate was 5.1 per 1000 patient-years. Total mortality was unchanged in this high-risk patient group (p = 0.076).
In the JUPITER study, 6.6% of rosuvastatin-treated patients and 6.2% of placebo-treated patients discontinued the drug due to an adverse event. The most common adverse events leading to discontinuation of the drug treatment were as follows: myalgia (0.3% with rosuvastatin, 0.2% with placebo), abdominal pain (0.03% with rosuvastatin, 0.02% with placebo) and rash (0.02% with rosuvastatin, 0.03% with placebo). The most common adverse events with an incidence rate greater than or equal to placebo were the following: urinary tract infection (8.7% with rosuvastatin, 8.6% with placebo), nasopharyngitis (7.6% with rosuvastatin , 7.2% with placebo), back pain (7.6% with rosuvastatin, 6.9% with placebo) and myalgia (7.6% with rosuvastatin, 6.6% with placebo).
Pediatric population
In a double-blind, randomized, multicentre, placebo-controlled study of 12 weeks duration (n = 176, 97 males and 79 females) followed by an open-label dose titration phase of rosuvastatin over a period of 40 weeks (n = 173, 96 males and 77 females), patients aged 10 to 17 years (Tanner stage II-V, girls with menarche at least 1 year earlier) with heterozygous familial hypercholesterolaemia received daily rosuvastatin at the dose of 5, 10 or 20 mg or placebo over a 12-week period, and then all were treated daily with rosuvastatin for 40 weeks thereafter. At study enrollment, approximately 30% of patients were between the ages of 10 and 13 and approximately 17%, 18%, 40%, and 25% were in Tanner stages II, III, IV and V, respectively.
LDL cholesterol was reduced by 38.3%, 44.6%, and 50.0% with rosuvastatin doses of 5, 10, and 20 mg, respectively, compared with 0.7% for placebo.
By the end of the 40-week open-label phase, with dose adjustment until the goal of up to 20 mg per day was reached, 70 of 173 patients (40.5%) had achieved the desired LDL cholesterol level, less than 2.8 mmol / l.
After 52 weeks of the study, no effects on growth, body weight, body mass index or sexual maturation were observed (see section 4.4). The design of this study (n = 176) did not include a comparison of events. rare adverse.
Rosuvastatin was evaluated in a two-year, open-label, dose-titration objective clinical study conducted in 198 children with heterozygous familial hypercholesterolaemia aged 6 to 17 years (88 males and 110 females, Tanner stage After 24 months of rosuvastatin treatment, the LS mean percent reduction from baseline in LDL cholesterol was -43% (baseline: 236 mg / dL, month 24: 133 mg / dL). For each age group, LS mean percentage reductions from baseline LDL cholesterol were -43% (baseline: 234 mg / dL, month 24: 124 mg / dL), -45% (baseline: 234 mg / dL, month 24: 124 mg / dL), and -35% (baseline: 241 mg / dL, month 24: 153 mg / dL) in age groups 6 to Rosuvastatin 5 mg, 10 mg and 20 mg also resulted in statistically significant mean changes from baseline for the following secondary lipid and lipoprotein variables: HDL cholesterol, total cholesterol (TC), non-HDL cholesterol, LDL cholesterol / HDL cholesterol, cholesterol total / HDL cholesterol, triglycerides / HDL cholesterol, non-HDL cholesterol / HDL cholesterol, ApoB, ApoB / ApoA-1. Each of these changes led to an improvement in lipid profile responses and was maintained over the two years. No effect on growth, weight, BMI or sexual maturation was detected after 24 months of treatment (see section 4.4). The European Medicines Agency has waived the obligation to submit the results of studies with rosuvastatin in all subsets of the pediatric population in the treatment of homozygous familial hypercholesterolemia, primary combined (mixed) dyslipidaemia, and in the prevention of cardiovascular events ( see section 4.2 for information on pediatric use). Absorption: The maximum plasma concentration of rosuvastatin is reached approximately 5 hours after oral administration. Absolute bioavailability is approximately 20%. Distribution: Rosuvastatin is extensively extracted from the circulation in the liver, which is the primary site of cholesterol synthesis and LDL-C elimination. The volume of distribution of rosuvastatin is approximately 134 L. About 90% of rosuvastatin is bound to plasma proteins, mainly albumin. Metabolism: Rosuvastatin is metabolised to a limited extent (approximately 10%). Metabolism studies (in vitro) on human hepatocytes indicate that rosuvastatin is not a good substrate for cytochrome P450. The major isoenzyme involved is CYP2C9, while 2C19, 3A4 and 2D6 are involved to a lesser extent. The major metabolites identified are the N-desmethyl and lactone metabolites. The N-desmethyl metabolite is approximately 50% less active than rosuvastatin, while the lactone form is considered clinically inactive. Rosuvastatin is responsible for more than 90% of the inhibitory activity of circulating HMG-CoA reductase. Excretion: Rosuvastatin is eliminated unchanged in the faeces for about 90% (comprising both the absorbed and the non-absorbed active substance), while the remainder is excreted in the urine. About 5% is excreted unchanged in the urine. The half-life is approximately 19 hours and does not change with increasing dosage. The geometric mean of plasma clearance is approximately 50 liters / hour (coefficient of variation 21.7%). As with other HMG-CoA reductase inhibitors, hepatic uptake of rosuvastatin involves the membrane transporter OATP-C. This transporter is important for the hepatic elimination of rosuvastatin. Linearity: Systemic exposure of rosuvastatin increases in proportion to the dose. Pharmacokinetic parameters do not change after multiple dose administration. Special populations Age and gender: There was no clinically relevant effect of age or gender on the pharmacokinetics of rosuvastatin in adults. Exposure in children and adolescents with heterozygous familial hypercholesterolaemia appears to be similar or lower than that in adult patients with dyslipidaemia. . (see "Pediatric Population" later in the text). Race: Pharmacokinetic studies show an approximately 2-fold increase in median AUC and Cmax values in Asian subjects (Japanese, Chinese, Filipino, Vietnamese and Korean) compared to Caucasians. Asian-Indian subjects show an approximately 1.3-fold increase in median AUC and Cmax. A population pharmacokinetic analysis revealed no clinically relevant differences in pharmacokinetics between the Caucasian and Black groups. Renal impairment: In a study conducted in subjects with varying degrees of renal impairment, the presence of mild to moderate renal disease had no influence on the plasma concentrations of rosuvastatin or the N-desmethyl metabolite. In subjects with severe renal impairment (creatinine clearance Hepatic impairment: In a study involving subjects with varying degrees of hepatic impairment, there was no evidence of "increased systemic exposure to rosuvastatin in subjects with Child-Pugh scores ≤ 7; in two subjects with very severe liver disease. (Child-Pugh score of 8 and 9) there was a 2-fold increase in rosuvastatin exposure compared to subjects with lower Child-Pugh scores. There is no experience in subjects with Child-Pugh scores> 9. Genetic polymorphisms: Hepatic uptake of HMG-CoA reductase inhibitors, including rosuvastatin, involves the protein transporters OATP1B1 and BCRP. Patients with genetic polymorphisms SLCO1B1 (OATP1B1) and / or ABCG2 (BCRP) are at increased risk of rosuvastatin exposure. Individual polymorphisms of SLCO1B1 c.521CC and ABCG2 c.421AA are associated with higher rosuvastatin exposure (AUC) than the SLCO1B1 c.521TT or ABCG2 c.421CC genotypes. This specific genotyping is not established in clinical practice, but for patients who are found to have these types of polymorphisms, a lower daily dose of Simestat is recommended. Pediatric population: Two pharmacokinetic studies with rosuvastatin (administered as tablets) in pediatric patients with heterozygous familial hypercholesterolaemia aged between 10 and 17 years or between 6 and 17 years (for a total of 214 patients) showed that exposure in pediatric patients it is comparable to or less than that in adult patients. Rosuvastatin exposure was predictable with respect to dosage and time over a two-year period. Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, carcinogenic potential. Specific tests for effects on hERG have not been evaluated. Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical ones, were as follows: Histopathological changes of the liver were observed in repeated dose toxicity studies, possibly due to the pharmacological action of rosuvastatin, in mice, rats and to a lesser extent effects on gallbladder in dogs but not in monkeys In addition, testicular toxicity was observed in monkeys and dogs at higher doses. Reproductive toxicity was evident in rats, with litters of reduced size, weight and puppy survival observed at maternal toxic doses, where systemic exposures were well above the therapeutic exposure level. Core of the tablet lactose monohydrate, microcrystalline cellulose, calcium phosphate, crospovidone, magnesium stearate. Tablet coating lactose monohydrate, hypromellose, triacetin, titanium dioxide (E171), iron oxide, yellow (E172) (5 mg tablets), iron oxide, red (E172) (10 mg, 20 mg and 40 mg tablets) Not relevant 3 years. Blisters: Store below 30 ° C. Store in the original package in order to protect from moisture. High density polyethylene containers: store below 30 ° C. Keep the bottle tightly closed to protect the medicine from moisture. 5 mg, 10 mg, 20 mg and 40 mg: Pack sizes: aluminum / aluminum blisters of 7, 14, 15, 20, 28, 30, 42, 50, 56, 60, 84, 90, 98 and 100 tablets. High density polyethylene (HDPE) containers of 30 and 100 tablets. Not all pack sizes may be marketed. Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations. Simesa S.p.A. Ferraris Palace Via Ludovico il Moro 6 / C Basiglio (MI) 20080 035884461 "5 MG TABLETS COATED WITH FILM" 7 TABLETS IN BLISTER AL / AL 035884473 "5 MG TABLETS COATED WITH FILM" 14 TABLETS IN AL / AL BLISTER 035884485 "5 MG TABLETS COATED WITH FILM" 15 TABLETS IN BLISTER AL / AL 035884497 "5 MG TABLETS COATED WITH FILM" 20 TABLETS IN BLISTER AL / AL 035884509 "5 MG TABLETS COATED WITH FILM" 28 TABLETS IN AL / AL BLISTER 035884511 "5 MG TABLETS COATED WITH FILM" 30 TABLETS IN AL / AL BLISTER 035884523 "5 MG TABLETS COATED WITH FILM" 42 TABLETS IN BLISTER AL / AL 035884535 "5 MG TABLETS COATED WITH FILM" 50 TABLETS IN AL / AL BLISTER 035884547 "5 MG TABLETS COATED WITH FILM 56 TABLETS IN BLISTER AL / AL 035884550 "5 MG TABLETS COATED WITH FILM" 60 TABLETS IN AL / AL BLISTER 035884562 "5 MG TABLETS COATED WITH FILM" 84 TABLETS IN BLISTER AL / AL 035884612 "5 MG TABLETS COATED WITH FILM" 90 TABLETS IN AL / AL BLISTER 035884574 "5 MG TABLETS COATED WITH FILM" 98 TABLETS IN BLISTER AL / AL 035884586 "5 MG TABLETS COATED WITH FILM" 100 TABLETS IN BLISTER AL / AL 035884598 "5 MG FILM COATED TABLETS" 30 TABLETS IN HDPE BOTTLE 035884600 "5 MG TABLETS COATED WITH FILM" 100 TABLETS IN HDPE BOTTLE 035884016 "10 MG TABLETS COATED WITH FILM" 7 TABLETS IN BLISTER AL / AL 035884028 "10 MG TABLETS COATED WITH FILM" 14 TABLETS IN BLISTER AL / AL 035884030 "10 MG TABLETS COATED WITH FILM" 15 TABLETS IN BLISTER AL / AL 035884042 "10 MG TABLETS COATED WITH FILM" 20 TABLETS IN BLISTER AL / AL 035884055 "10 MG TABLETS COATED WITH FILM" 28 TABLETS IN BLISTER AL / AL 035884067 "10 MG TABLETS COATED WITH FILM" 30 TABLETS IN BLISTER AL / AL 035884079 "10 MG TABLETS COATED WITH FILM" 42 TABLETS IN BLISTER AL / AL 035884081 "10 MG TABLETS COATED WITH FILM" 50 TABLETS IN BLISTER AL / AL 035884093 "10 MG TABLETS COATED WITH FILM" 56 TABLETS IN BLISTER AL / AL 035884105 "10 MG TABLETS COATED WITH FILM" 60 TABLETS IN BLISTER AL / AL 035884117 "10 MG TABLETS COATED WITH FILM" 84 TABLETS IN BLISTER AL / AL 035884624 "10 MG TABLETS COATED WITH FILM" 90 TABLETS IN AL / AL BLISTER 035884129 "10 MG TABLETS COATED WITH FILM" 98 TABLETS IN BLISTER AL / AL 035884131 "10 MG TABLETS COATED WITH FILM" 100 TABLETS IN BLISTER AL / AL 035884143 "10 MG TABLETS COATED WITH FILM" 30 TABLETS IN HDPE BOTTLE 035884156 "10 MG TABLETS COATED WITH FILM" 100 TABLETS IN HDPE BOTTLE 035884168 "20 MG TABLETS COATED WITH FILM" 7 TABLETS IN BLISTER AL / AL 035884170 "20 MG TABLETS COATED WITH FILM" 14 TABLETS IN AL / AL BLISTER 035884182 "20 MG TABLETS COATED WITH FILM" 15 TABLETS IN AL / AL BLISTER 035884194 "20 MG TABLETS COATED WITH FILM" 20 TABLETS IN AL / AL BLISTER 035884206 "20 MG TABLETS COATED WITH FILM" 28 TABLETS IN BLISTER AL / AL 035884218 "20 MG TABLETS COATED WITH FILM" 30 TABLETS IN AL / AL BLISTER 035884220 "20 MG TABLETS COATED WITH FILM" 42 TABLETS IN AL / AL BLISTER 035884232 "20 MG TABLETS COATED WITH FILM" 50 TABLETS IN AL / AL BLISTER 035884244 "20 MG TABLETS COATED WITH FILM" 56 TABLETS IN AL / AL BLISTER 035884257 "20 MG TABLETS COATED WITH FILM" 60 TABLETS IN AL / AL BLISTER 035884269 "20 MG TABLETS COATED WITH FILM" 84 TABLETS IN BLISTER AL / AL 035884636 "20 MG TABLETS COATED WITH FILM" 90 TABLETS IN AL / AL BLISTER 035884271 "20 MG TABLETS COATED WITH FILM" 98 TABLETS IN BLISTER AL / AL 035884283 "20 MG TABLETS COATED WITH FILM" 100 TABLETS IN BLISTER AL / AL 035884295 "20 MG TABLETS COATED WITH FILM" 30 TABLETS IN HDPE BOTTLE 035884307 "20 MG TABLETS COATED WITH FILM" 100 TABLETS IN HDPE BOTTLE 035884319 "40 MG TABLETS COATED WITH FILM" 7 TABLETS IN BLISTER AL / AL 035884321 "40 MG TABLETS COATED WITH FILM" 14 TABLETS IN AL / AL BLISTER 035884333 "40 MG TABLETS COATED WITH FILM" 15 TABLETS IN AL / AL BLISTER 035884345 "40 MG TABLETS COATED WITH FILM" 20 TABLETS IN AL / AL BLISTER 035884358 "40 MG TABLETS COATED WITH FILM" 28 TABLETS IN AL / AL BLISTER 035884360 "40 MG TABLETS COATED WITH FILM" 30 TABLETS IN AL / AL BLISTER 035884372 "40 MG TABLETS COATED WITH FILM" 42 TABLETS IN BLISTER AL / AL 035884384 "40 MG TABLETS COATED WITH FILM" 50 TABLETS IN AL / AL BLISTER 035884396 "40 MG TABLETS COATED WITH FILM" 56 TABLETS IN AL / AL BLISTER 035884408 "40 MG TABLETS COATED WITH FILM" 60 TABLETS IN AL / AL BLISTER 035884410 "40 MG TABLETS COATED WITH FILM" 84 TABLETS IN BLISTER AL / AL 035884648 "40 MG TABLETS COATED WITH FILM" 90 TABLETS IN AL / AL BLISTER 035884422 "40 MG TABLETS COATED WITH FILM" 98 TABLETS IN BLISTER AL / AL 035884434 "40 MG TABLETS COATED WITH FILM" 100 TABLETS IN BLISTER AL / AL 035884446 "40 MG FILM COATED TABLETS" 30 TABLETS IN HDPE BOTTLE 035884459 "40 MG FILM COATED TABLETS" 100 TABLETS IN HDPE BOTTLE Date of first authorization: January 2004 Date of most recent renewal: October 2014 March 15, 201605.2 Pharmacokinetic properties
05.3 Preclinical safety data
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
06.2 Incompatibility
06.3 Period of validity
06.4 Special precautions for storage
06.5 Nature of the immediate packaging and contents of the package
06.6 Instructions for use and handling
07.0 MARKETING AUTHORIZATION HOLDER
08.0 MARKETING AUTHORIZATION NUMBER
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
10.0 DATE OF REVISION OF THE TEXT
11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY
12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL
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