ROSUSTAR
(Rosuvastatin)




COMPOSITION

Active substance: rosuvastatin (as rosuvastatin calcium) 5 mg, 10 mg, 20 mg or 40 mg.

Excipients: lactose monohydrate, microcrystalline cellulose, calcium hydrogen phosphate anhydrous, crospovidone, magnesium stearate.

Coating composition: Opadry II pink 85F240091 (polyvinyl alcohol partially hydrolyzed, titanium dioxide, macrogol, talc, red iron oxide).

THERAPEUTIC INDICATIONS

- primary hypercholesterolemia (type II a according to Fredrikson), including heterozygous familial hypercholesterolemia or mixed (combined) hypercholesterolemia (type II b according to Fredrikson) - as an adjunct to diet and other drug-free activities (physical exercises and weight loss) in case of ineffective diet therapy and drug-free activities;

- homozygous familial hypercholesterolemia and in poor efficacy of diet therapy and other treatment options, intended to lower the level of lipids (for example, apheresis of LDL), or if such treatment options are not suitable for the patient;

- to arrest the progression of atherosclerosis as an adjunct to diet in patients in need of a total C and HDL-C lowering therapy;

- prevention of main cardiovascular complications (stroke, myocardial infarction, arterial revascularization) in adult patients with no clinical signs of ischemic heart disease (IHD) but with an increased risk of its development (men over 50 years old and women over 60 years old, increased C-reactive protein concentrations (≥ 2 mg/l) given at least one additional risk factor such as arterial hypertension, low concentration of HDL-C, smoking, family history of early IHD).

CONTRAINDICATIONS

- hypersensitivity to rosuvastatin or to any of the excipients;

- active liver disease including unexplained, persistant elevations of serum transaminases and any serum transaminase elevation exceeding a 3-fold increase of the upper limit of the normal range;

- severe renal insufficiency (creatinine clearance < 30 ml/min);

- myopathy;

- cyclosporine administration;

- pregnancy and lactation. The medicinal product is contra-indicated in women of childbearing potential not using appropriate contraceptive measures.

The dose of 40 mg is contra-indicated in patients with underlying risks for myopathy / rhabdomyolysis. Such risks are:

- moderate renal insufficiency (creatinine clearance < 60 ml/min);

- hypothyroidism;

- patient or family history of muscular disorders;

- history of toxic action on muscles in administration of other HMG-CoA reductase inhibitor or fibrate;

- alcohol addiction;

- situations when plasma concentrations can increase;

- Asian race;

- concomitant administration with fibrates.

ADVERSE EFFECTS

The used side effects frequency parameters presented below are classified in the following way:

frequently (from ≥ 1/100 to < 1/10), infrequently (from ≥ 1/1000 to < 1/100), rarely (from ≥ 1/10000 to < 1/1000), very rarely (< 1/10000), unspecified frequency - frequency parameters can not be estimated from the available data.

Central nervous system: frequently - headache, dizziness, asthenic syndrome; very rarely - peripheral neuropathy, memory impairment.

Digestive system: frequently - nausea, constipation, abdominal pain; infrequently - vomiting; rarely - pancreatitis; very rarely - hepatitis, jaundice; unspecified frequency - diarrhoea.

Respiratory system: infrequently - coughing, dyspnoea.

Endocrine system: frequently - type II diabetes mellitus.

Musculo-skeletal system: frequently - myalgia; very rarely - arthralgia; rarely - myopathy (including myositis), rhabdomyolysis.

Allergic reactions: infrequently - skin itching, urticaria, rash; rarely – angioedema.

Skin and subcutaneous tissue: unspecified frequency - Stevens-Johnson syndrome, peripheral oedema.

Urinary system: frequently – proteinuria (with frequency of more than 3% in patients that receive a dose of 40 mg), decreasing in the process of therapy and not attributed to renal diseases, urinary tract infections; very rarely - haematuria.

Laboratory findings: infrequently – transient dose-dependent increase of serum creatine phosphokinase (CPK) activity (in case of a five-fold increase as compared to the upper limit of the normal range, the therapy should be suspended); rarely – a transient increase in aspartate aminotransferase and alanine aminotransferase activity.

As with other HMG-CoA reductase inhibitors, the incidence is dose-related, side effects are mild and subside on their own.

In administration of the medicinal product, the laboratory parameters changed as follows: glucose concentrations, bilirubin, alkaline phosphatase and gamma glutamine transferase activity increased.

In administration of other statins, the following undesirable effects were observed: mental depression, insomnia, decreased sexual potency.

Isolated cases of interstitial lung disease were reported in long-term administration of rosuvastatin.

DOSAGE AND ADMINISTRATION

The medicinal product should be taken orally, without chewing and grinding, and swallowed whole, with water, at any time with or without food.

Prior to treatment initiation with Rosustar, the patient should be placed on a standard hypolipidemic diet to be continued during treatment. The dose should be individualised according to the therapeutic indications and patient response, using current generally accepted guidelines on lipid target levels.

Treatment of hypercholesterinemia: The recommended start dose is 5 or 10 mg once daily in both statin naive patients and in patients treated with HMG-CoA reductase inhibitors. The choice of the start dose should take into account the individual cholesterol level and future cardiovascular risks as well as the potential risks for adverse reactions. The dosage regimen can be adjusted after 4 weeks if necessary. The highest dose of 40 mg should be considered in patients with severe hypercholesterolemia at high cardiovascular risk (in particular those with familial hypercholesterolemia) who do not achieve their treatment goal on 20 mg and in whom routine follow-up will be performed. Taking into account the increased number of side effects, observed in administration of the medicinal product at a dose of 40 mg as compared to lower doses, a monitoring by a specialist is recommended if the dose is increased up to 40 mg.

Prevention of cardio-vascular diseases: The recommended rosuvastatin dose is 20 mg/day.

Use in pediatrics

Rosuvastatin may be administered to children only under the observation of health care professionals.

Children and adolescents at the age of 10-17 years old (boys scored 2 and above by Tanner scale, girls with menarche for not less than a year): the start dose of rosuvastatin for children and adolescents with heterozygous familial hypercholesterolemia is 5 mg once a day. The dose range is 5-20 mg once a day. The dose should be individualised according to the child’s response to treatment. Children and adolescents should be switched to a standard cholesterol lowering diet to be kept until the end of treament. Safety and efficacy of the medicinal product doses, exceeding 20 mg a day, haven’t been studied in this patient group.

It’s not recommended to use Rosustar at a dose of 40 mg in this patient group.

Children under 10 years old: Experience in this patient group is limited to a small number of patients (aged 8 - 10 years old) with homozygous familial hypercholesterolemia. Therefore, rosuvastatin is not recommended for children under 10 years old.

Use in the elderly

The recommended start dose is 5 mg for the patients above 70 years old. No dosage regimen adjustment is necessary in this patient group.

Use in patients with renal insufficiency

No dose adjustment is necessary in patients with mild and moderate renal insufficiency. The recommended start dose in patients with moderate renal insufficiency is 5 mg (creatinine clearance < 60 ml/min). The use of the medicinal product at a dose of 40 mg is contraindicated in patients with moderate renal insufficiency. The use of rosuvastatin is contraindicated in patients with severe renal insufficiency.

Use in patients with hepatic insufficiency

There was no increase in systemic exposure to rosuvastatin in subjects with Child-Pugh scores of 7 or below. However, increased systemic exposure has been observed in subjects with Child-Pugh scores of 8 and 9. In these patients an assessment of renal function should be considered. There is no experience in subjects with Child-Pugh scores above 9. Rosuvastatin is contraindicated in patients with any active liver diseases.

Race

Increased systemic effect of rosuvastatin has been seen in Asian subjects. The recommended start dose in such patients is 5 mg while the dose of 40 mg is contraindicated.

Doses in patients with an underlying risk for myopathy

The recommended start dose is 5 mg while the dose of 40 mg is contraindicated.

DRUG INTERACTIONS

Concomitant treatment with rosuvastatin and cyclosporine has no effect on cyclosporine plasma concentrations however rosuvastatin effect is enhanced (excretion is slowed down, AUC is increased by 7 times, Сmах - by 11 times).

Erythromycin increases gut motility, leading to the reduced effect of rosuvastatin (AUC is decreased by 20% and Сmах - by 30%).

Monitoring of the International Normalised Ratio (INR) is recommended in the patients, taking vitamin K antagonists (for example, warfarin) since the initiation of treatment with rosuvastatin or dosage up-titration of rosuvastatin may result in an increase of the INR while discontinuation or down-titration of rosuvastatin may result in a decrease of the INR. Gemfibrozil enhances the effect of rosuvastatin (a 2-fold increase in Сm ах and AUC). The simultaneous dosing of rosuvastatin with antacids containing aluminium and magnesium hydroxide result in a decrease in rosuvastatin plasma concentration of approximately 50%. This effect is mitigated when antacids are dosed 2 hours after rosuvastatin.

Concomitant use of rosuvastatin and oral contraceptives results in an increase in ethinyl oestradiol and norgestrel AUC by 26% and 34%, respectively. This fact should be considered when selecting oral contraceptive doses. There are no pharmacokinetic data available in subjects taking concomitant rosuvastatin and hormone replacement therapy and therefore a similar effect cannot be excluded.

The results from the studies show that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzyme action. Rosuvastatin is a non-core substrate for such isoenzymes. No clinically relevant interactions have been observed between rosuvastatin and fluconazole, ketoconazole and itraconazole, the metabolism of which is cytochrome P450 mediated.

No clinically relevant interactions of rosuvastatin with digoxin or fenofibrate are reported. Gemfibrozil, other fibrates and lipid lowering doses of nicotinic acid (not less than 1 g a day) increase the risk of myopathy when given concomitantly with other HMG-CoA reductase inhibitors, probably because they can produce myopathy when given alone.

Concomitant administration of rosuvastatin and ezetimibe doesn’t lead to the changes in AUC or Сmax of both medicinal products.

Administration of HIV protease inhibitors with rosuvastatin can lead to significant increase of the effect of rosuvastatin. A pharmacokinetic study of concomitant administration of rosuvastatin at a dose of 20 mg and a combination of two HIV protease inhibitors (400 mg lopinavir/100 mg ritonavir) by healthy volunteers shows that this combination leads to about two- and five-fold increase of AUC(0-24) and Сmах respectively. Thus concomitant administration of rosuvastatin with HIV protease inhibitors is not recommended for HIV-positive patients.

PREGNANCY AND LACTATION

The medicinal product is contraindicated in pregnancy and lactation.

Women of child bearing potential should use appropriate contraceptive measures when taking the medicinal product. Since cholesterol and other products of cholesterol biosynthesis are essential for the development of the foetus, the potential risk from inhibition of HMG-CoA reductase outweighs the advantage of treatment during pregnancy. If a patient becomes pregnant during use of rosuvastatin, treatment should be discontinued immediately.

Rosuvastatin is excreted in the milk of rats. There are no data with respect to excretion in milk in humans.

MANUFACTURED FORM AND PACKAGE

Film coated tablets.

10 tablets in a blister.

2, 3, 5, 6 or 9 blisters with the enclosed leaflet in a carton box.

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