Rozart

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Rosart (Rosart)

Composition:

Active substance: rosuvastatin;

One film-coated tablet contains rosuvastatin 5 mg or 10 mg or 20 mg or 40 mg as 5.21 mg or 10.42 mg or 20.84 mg or 41.68 mg of rosuvastatin calcium;

Excipients: microcrystalline cellulose, crospovidone, calcium hydrogen phosphate dihydrate, lactose monohydrate, magnesium stearate;

Coating:

5 mg tablets: hypromellose, titanium dioxide (E 171), lactose monohydrate, polyethylene glycol 3350, triacetin;

10 mg tablets: hypromellose, titanium dioxide (E 171), lactose monohydrate, polyethylene glycol 3350, triacetin, carmine (E 120);

20 mg tablets: hypromellose, titanium dioxide (E 171), lactose monohydrate, polyethylene glycol 3350, triacetin, carmine (E 120);

40 mg tablets: hypromellose, titanium dioxide (E 171), lactose monohydrate, polyethylene glycol 3350, triacetin, carmine (E 120).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

5 mg tablets: white, round, 5.5 mm in diameter, biconvex film-coated tablets, with "ST 1" embossed on one side;

10 mg tablets: pink, round, 7 mm in diameter, biconvex film-coated tablets, with "ST 2" embossed on one side;

20 mg tablets: pink, round, 9 mm in diameter, biconvex film-coated tablets, with "ST 3" embossed on one side;

40 mg tablets: pink, oval, 16 mm × 8 mm in size, biconvex film-coated tablets, with "ST 4" embossed on one side.

Pharmacotherapeutic group. Hypolipidemic agents. HMG-CoA reductase inhibitors.

ATC code C10AA07.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the enzyme that catalyzes the rate-limiting step in the conversion of 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 reducing cholesterol levels.

Rosuvastatin increases the number of LDL receptor proteins on the surface of liver cells, thereby enhancing the uptake and catabolism of LDL, and inhibits hepatic production of VLDL, thus reducing the total number of LDL and VLDL particles.

Pharmacodynamic effects

Rosuvastatin reduces elevated levels of LDL-cholesterol, total cholesterol, and triglycerides, and increases HDL-cholesterol levels. It also decreases levels of apolipoprotein B (apoB), non-HDL-cholesterol, VLDL-cholesterol, triglyceride-rich VLDL, and increases apolipoprotein A-I (apoA-I) (Table 1). Rosart also reduces the ratios of LDL-C/HDL-C, total cholesterol/HDL-C, non-HDL-C/HDL-C, and apoB/apoA-I.

Table 1

Dose-response in patients with primary hypercholesterolemia type IIa and IIb

(adjusted mean percent change from baseline)

The therapeutic effect is achieved within 1 week after initiation of the medicinal product, with 90% of the maximum effect reached within 2 weeks. The maximum effect is usually achieved within 4 weeks and persists thereafter.

Pharmacokinetics

Absorption

The maximum plasma concentration of rosuvastatin is reached approximately 5 hours after oral administration. The absolute bioavailability is approximately 20%.

Distribution

Rosuvastatin is significantly taken up by the liver, which is the primary site of cholesterol synthesis and clearance of LDL-C. The volume of distribution of rosuvastatin is approximately 134 L. Approximately 90% of rosuvastatin is bound to plasma proteins, predominantly to albumin.

Metabolism

Rosuvastatin undergoes minimal metabolism (approximately 10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a weak substrate for cytochrome P450 enzyme-based metabolism. The main isoenzyme involved is CYP2C9, with a lesser role played by CYP2C19, CYP3A4, and CYP2D6. The main identified metabolites are the N-desmethyl and lactone metabolites. The N-desmethyl metabolite is approximately 50% less active than rosuvastatin, and the lactone metabolite is considered clinically inactive. Rosuvastatin accounts for more than 90% of the circulating HMG-CoA reductase inhibitor activity.

Elimination

Approximately 90% of the rosuvastatin dose is excreted unchanged in feces (including both absorbed and unabsorbed active substance), and the remainder is excreted in urine. Approximately 5% is excreted unchanged in urine. The elimination half-life from plasma is approximately 19 hours and does not increase with dose escalation. The mean geometric value of plasma drug clearance is approximately 50 L/h (coefficient of variation – 21.7%). As with other HMG-CoA reductase inhibitors, hepatic uptake of rosuvastatin occurs via the membrane transporter OATP-C, which plays an important role in the hepatic elimination of rosuvastatin.

Linearity

Systemic exposure to rosuvastatin increases proportionally with dose. Pharmacokinetic parameters do not change with repeated daily administration.

Special patient groups

Age and sex

No clinically significant effect of age or sex on the pharmacokinetics of rosuvastatin has been observed in adults. The pharmacokinetics of rosuvastatin in children and adolescents with heterozygous familial hypercholesterolemia was similar to that in adult volunteers (see section "Children").

Race

Pharmacokinetic studies have shown that in patients of Mongoloid race (Japanese, Chinese, Filipinos, Vietnamese, and Koreans), median AUC and Cmax values are approximately twice as high as in Caucasians; in Indians, median AUC and Cmax values are increased by approximately 1.3 times. Population pharmacokinetic analysis did not reveal clinically significant differences between Caucasian and Negroid race patients.

Renal impairment

In a study in patients with varying degrees of renal impairment, no changes in plasma concentrations of rosuvastatin or the N-desmethyl metabolite were observed in individuals with mild or moderate impairment. In patients with severe renal impairment (creatinine clearance < 30 mL/min), plasma concentrations of rosuvastatin were 3 times higher and levels of the N-desmethyl metabolite were 9 times higher than in healthy volunteers. Steady-state plasma concentrations of rosuvastatin in patients undergoing hemodialysis were approximately 50% higher than in healthy volunteers.

Hepatic impairment

In a study of patients with varying degrees of hepatic dysfunction, no evidence of increased rosuvastatin exposure was observed in patients with a Child-Pugh score of 7 or less. However, in two patients with scores of 8 and 9 on the Child-Pugh scale, systemic exposure was at least twice as high as in patients with lower scores. Experience with the use of rosuvastatin in patients with a Child-Pugh score greater than 9 is lacking.

Genetic polymorphism

The disposition of HMG-CoA reductase inhibitors, including rosuvastatin, involves transporter proteins OATP1B1 and BCRP. Patients with genetic polymorphisms in SLCO1B1 (OATP1B1) and/or ABCG2 (BCRP) are at risk of increased rosuvastatin exposure. With specific polymorphic forms SLCO1B1 c.521CC and ABCG2 c.421AA, rosuvastatin exposure (AUC) is increased compared to genotypes SLCO1B1 c.521TT or ABCG2 c.421CC. Routine genotyping is not required in clinical practice, but patients with such polymorphisms are recommended to use a lower daily dose of the medicinal product.

Children

Two pharmacokinetic studies of rosuvastatin (in tablet form) in children with heterozygous familial hypercholesterolemia aged 10 to 17 years or 6 to 17 years (total of 214 patients) showed that drug exposure in children was lower or similar to that in adult patients. Rosuvastatin exposure was predictable according to dose and duration of treatment over more than 2 years of observation.

Clinical characteristics.

Indications.

Treatment of hypercholesterolemia

For adults, adolescents, and children aged 6 years and older with primary hypercholesterolemia (type IIa, including heterozygous familial hypercholesterolemia) or mixed dyslipidemia (type IIb), as an adjunct to diet when dietary measures and other non-pharmacological interventions (e.g., physical exercise, weight reduction) are insufficient.

For adults, adolescents, and children aged 6 years and older with homozygous familial hypercholesterolemia, as an adjunct to diet and other lipid-lowering treatments (e.g., LDL apheresis), or when such treatment is inappropriate.

Prevention of cardiovascular disorders

Prevention of major cardiovascular events in patients estimated to be at high risk of a first cardiovascular event (see section "Pharmacodynamics"), as an adjunct to correction of other risk factors.

Contraindications.

Rosart is contraindicated in:

• Patients with hypersensitivity to rosuvastatin or any of the excipients of the medicinal product;
• Patients with active liver disease, including of unknown etiology, persistent elevations of serum transaminases, and any elevations of serum transaminases exceeding three times the upper limit of normal (ULN);
• Patients with severe renal impairment (creatinine clearance < 30 mL/min);
• Patients with myopathy;
• Patients receiving concomitant cyclosporine;
• Patients receiving the combination of sofosbuvir/velpatasvir/voxilaprevir (see section "Interaction with other medicinal products and other types of interactions");
• During pregnancy or breastfeeding, as well as in women of childbearing potential who are not using appropriate contraceptive measures.

The 40 mg dose is contraindicated in patients predisposed to myopathy/rhabdomyolysis. Risk factors include:

• Moderate renal impairment (creatinine clearance < 60 mL/min);
• Hypothyroidism;
• Personal or family history of hereditary muscle disorders;
• History of myotoxicity during treatment with other HMG-CoA reductase inhibitors or fibrates;
• Alcohol abuse;
• Situations that may lead to increased plasma concentrations of the medicinal product;
• Mongoloid race;
• Concomitant use of fibrates.

(See sections "Special precautions for use", "Interaction with other medicinal products and other types of interactions", and "Pharmacokinetics").

Interaction with other medicinal products and other types of interactions.

Effect of concomitant drugs on rosuvastatin

Inhibitors of transport proteins

Rosuvastatin is a substrate for certain transport proteins, particularly the hepatic uptake transporter OATP1B1 and the efflux transporter BCRP. Concomitant administration of rosuvastatin with medicinal products that inhibit these transport proteins may increase plasma concentrations of rosuvastatin and increase the risk of myopathy (see sections "Interaction with other medicinal products and other types of interactions", Table 2, "Special precautions for use", "Dosage and administration").

Cyclosporine

During concomitant use of rosuvastatin and cyclosporine, rosuvastatin AUC values were on average approximately 7 times higher than those observed in healthy volunteers (see Table 2). Rosuvastatin is contraindicated in patients receiving cyclosporine (see section "Contraindications").

Concomitant use did not affect plasma concentrations of cyclosporine.

Protease inhibitors

Although the exact mechanism of interaction is unknown, concomitant use of protease inhibitors may significantly increase rosuvastatin exposure (see Table 2). For example, in a pharmacokinetic study, concomitant administration of 10 mg rosuvastatin and a combined medicinal product containing two protease inhibitors (300 mg atazanavir/100 mg ritonavir) in healthy volunteers was associated with increases in rosuvastatin AUC and Cmax by approximately 3 and 7 times, respectively. Concomitant use of rosuvastatin and certain combinations of protease inhibitors may be possible after careful consideration of dose adjustment of Rosart, considering the expected increase in rosuvastatin exposure (see sections "Dosage and administration", "Special precautions for use", "Interaction with other medicinal products and other types of interactions", Table 2).

Gemfibrozil and other lipid-lowering agents

Concomitant administration of rosuvastatin and gemfibrozil resulted in a 2-fold increase in AUC and Cmax of rosuvastatin (see section "Special precautions for use").

Based on data from specific studies, no pharmacokinetically significant interaction with fenofibrate is expected; however, pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates, and lipid-lowering doses of niacin (> or equal to 1 g/day) increase the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors, likely because they may cause myopathy when used alone. The 40 mg dose is contraindicated with concomitant use of fibrates (see sections "Contraindications" and "Special precautions for use"). Such patients should also initiate therapy with a 5 mg dose.

Ezetimibe

Concomitant administration of 10 mg rosuvastatin and 10 mg ezetimibe to patients with hypercholesterolemia resulted in a 1.2-fold increase in rosuvastatin AUC (Table 2). Pharmacodynamic interaction between rosuvastatin and ezetimibe, potentially leading to adverse effects, cannot be excluded (see section "Special precautions for use").

Antacid medicinal products

Concomitant administration of rosuvastatin with suspensions of antacids containing aluminum or magnesium hydroxide reduced plasma concentrations of rosuvastatin by approximately 50%. This effect was less pronounced when antacids were administered 2 hours after rosuvastatin. The clinical significance of this interaction has not been studied.

Erythromycin

Concomitant administration of rosuvastatin and erythromycin reduced rosuvastatin AUC by 20% and Cmax by 30%. This interaction may be due to enhanced intestinal motility caused by erythromycin.

Cytochrome P450 enzymes

Results from in vitro and in vivo studies indicate that rosuvastatin does not inhibit or induce cytochrome P450 isoenzymes. In addition, rosuvastatin is a weak substrate of these isoenzymes. Therefore, drug interactions due to P450-mediated metabolism are not expected. No clinically significant interactions were observed between rosuvastatin and fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4).

Tickagrelor

Ticagrelor may affect renal excretion of rosuvastatin, increasing the risk of its accumulation. Although the exact mechanism is unknown, in some cases, concomitant use of ticagrelor and rosuvastatin has led to impaired renal function, elevated creatine kinase levels, and rhabdomyolysis.

Interactions requiring dose adjustment of rosuvastatin

When rosuvastatin must be used concomitantly with other medicinal products capable of increasing rosuvastatin exposure, its dose should be adjusted. If an approximately 2-fold or greater increase in drug exposure (AUC) is expected, rosuvastatin therapy should be initiated at a dose of 5 mg once daily. The maximum daily dose of rosuvastatin should be adjusted so that the expected exposure does not exceed that observed with a 40 mg/day dose without interacting agents; for example, when used with gemfibrozil, the rosuvastatin dose should be 20 mg (exposure increased 1.9-fold), and when used with ritonavir/atazanavir combination, 10 mg (exposure increased 3.1-fold).

If a medicinal product increases rosuvastatin AUC by less than 2-fold, no initial dose reduction is required, but caution should be exercised when increasing the dose of Rosart beyond 20 mg.

Table 2

Effect of concomitant medicinal products on rosuvastatin exposure

(AUC; in descending order of magnitude) based on published data from clinical studies

* Data presented as change by a factor represent the ratio between rosuvastatin used in combination versus rosuvastatin used alone. Data presented as % change represent the percentage difference relative to values observed with rosuvastatin used alone.

Increases are indicated by the symbol ↑, decreases by ↓.

** Several interaction studies were conducted at different doses of rosuvastatin; the most significant ratio is presented in the table.

Drugs/combinations that showed no clinically significant effect on rosuvastatin AUC ratio when co-administered: aleglitazar 0.3 mg for 7 days; fenofibrate 67 mg for 7 days three times daily; fluconazole 200 mg for 11 days once daily; fosamprenavir 700 mg/ritonavir 100 mg for 8 days twice daily; ketoconazole 200 mg for 7 days twice daily; rifampicin 450 mg for 7 days once daily; silimarins 140 mg for 5 days three times daily.

Effect of rosuvastatin on concomitant medicinal products

Vitamin K antagonists

As with other HMG-CoA reductase inhibitors, initiation of rosuvastatin therapy or increasing its dose in patients concurrently taking vitamin K antagonists (e.g., warfarin or other coumarin anticoagulants) may increase the international normalized ratio (INR). Discontinuation of rosuvastatin or reduction of its dose may lead to a decrease in INR. In such cases, appropriate monitoring of INR is recommended.

Oral contraceptives/hormone replacement therapy (HRT)

Concomitant administration of rosuvastatin and oral contraceptives resulted in a 26% and 34% increase in AUC of ethinylestradiol and norgestimate, respectively. This increase in plasma drug levels should be considered when selecting the dose of oral contraceptives. There are no data on the pharmacokinetics of medicinal products in patients receiving rosuvastatin and HRT simultaneously; therefore, a similar effect cannot be excluded. However, this combination has been widely used in women during clinical trials and was well tolerated.

Other medicinal products

Digoxin

Based on specific interaction studies, no clinically significant interaction with digoxin is expected.

Fusidic acid

Interaction studies between rosuvastatin and fusidic acid have not been conducted. The risk of developing myopathy, including rhabdomyolysis, may increase when fusidic acid is used systemically in combination with statins. The mechanism of this interaction (pharmacodynamic, pharmacokinetic, or both) is not yet known. Cases of rhabdomyolysis (including fatal cases) have been reported in patients receiving this combination. If systemic treatment with fusidic acid is necessary, rosuvastatin should be discontinued for the entire duration of fusidic acid therapy (see section "Special precautions for use").

Paediatric population

Interaction studies have been conducted only in adults. The extent of interaction in children is unknown.

Special precautions for use.

Renal effects

Proteinuria (detected by dipstick testing), predominantly of tubular origin, mostly transient or intermittent, has been observed in patients treated with high doses of rosuvastatin, particularly 40 mg. Proteinuria was not a marker for the development of acute or progressive renal disease (see section "Adverse reactions"). The frequency of reports of serious renal events in post-marketing studies is higher with the 40 mg dose. Renal function should be regularly monitored in patients receiving the 40 mg dose.

Effects on skeletal muscle

Skeletal muscle disorders, such as myalgia, myopathy, and rarely rhabdomyolysis, have been observed in patients taking rosuvastatin at any dose, particularly above 20 mg. Very rare cases of rhabdomyolysis have been reported with ezetimibe used in combination with HMG-CoA reductase inhibitors. A pharmacodynamic interaction cannot be excluded (see section "Interaction with other medicinal products and other forms of interaction"), therefore such combination should be used with caution.

As with other HMG-CoA reductase inhibitors, the frequency of post-marketing reports of rhabdomyolysis associated with rosuvastatin use was higher at the 40 mg dose.

Creatine kinase (CK) levels

CK levels should not be measured after significant physical exertion or when possible alternative causes of elevated CK are present, as these may complicate interpretation of results. If baseline CK levels are markedly elevated (> 5 times the upper limit of normal [ULN]), repeat testing should be performed within 5–7 days to confirm the results. If repeat testing confirms that the initial CK value exceeds 5 times the ULN, treatment should not be initiated.

Before starting treatment

Rosart, like other HMG-CoA reductase inhibitors, should be prescribed with caution in patients predisposed to myopathy/rhabdomyolysis. Risk factors include:

• renal impairment;
• hypothyroidism;
• personal or family history of hereditary muscle disorders;
• history of myotoxicity with other HMG-CoA reductase inhibitors or fibrates;
• alcohol abuse;
• age > 70 years;
• conditions that may lead to increased plasma levels of the drug (see sections "Pharmacokinetics", "Interaction with other medicinal products and other forms of interaction", and "Posology and method of administration");
• concomitant use of fibrates.

In such patients, the risk associated with treatment should be weighed against the expected benefit; clinical monitoring is also recommended. Treatment should not be initiated if baseline CK levels are markedly elevated (> 5 times ULN).

During treatment

Patients should be advised to report immediately any unexplained muscle pain, weakness, or tenderness, especially if accompanied by malaise or fever. CK levels should be measured in such patients. The drug should be discontinued if CK levels are markedly elevated (> 5 times ULN) or if muscle symptoms are severe and cause daily discomfort (even if CK levels ≤ 5 × ULN). If symptoms resolve and CK levels return to normal, therapy with rosuvastatin or an alternative HMG-CoA reductase inhibitor may be restarted at the lowest dose and under close monitoring. Routine monitoring of CK levels in asymptomatic patients is not necessary. Very rare cases of immune-mediated necrotizing myopathy (IMNM) have been reported during or after statin therapy, including rosuvastatin. Clinical features of IMNM include proximal muscle weakness and elevated serum CK levels, which persist even after discontinuation of statins.

Clinical trials have not provided evidence of increased skeletal muscle effects in a small number of patients taking rosuvastatin with concomitant medications. However, increased incidence of myositis and myopathy has been observed in patients taking other HMG-CoA reductase inhibitors concomitantly with fibric acid derivatives, including gemfibrozil, cyclosporine, niacin, azole antifungals, protease inhibitors, and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when used concomitantly with certain HMG-CoA reductase inhibitors. Therefore, the concomitant use of rosuvastatin with gemfibrozil is not recommended. The benefit of further lipid-lowering with rosuvastatin in combination with fibrates or niacin should be carefully weighed against the potential risks associated with such combinations. The 40 mg dose is contraindicated when fibrates are used concomitantly (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Fusidic acid

Rosuvastatin should not be used concomitantly with systemic fusidic acid preparations or within 7 days after discontinuation of fusidic acid treatment. In patients for whom systemic fusidic acid treatment is considered necessary, statin therapy should be discontinued for the entire duration of fusidic acid treatment. Cases of rhabdomyolysis (including fatal cases) have been reported in patients receiving fusidic acid and statins concomitantly (see section "Interaction with other medicinal products and other forms of interaction"). Patients should be advised to seek immediate medical attention if they experience any symptoms of muscle weakness, pain, or tenderness. Statin therapy may be restarted 7 days after the last dose of fusidic acid. In individual cases where prolonged systemic fusidic acid therapy is required, e.g., for treatment of severe infections, the need for concomitant use of rosuvastatin and fusidic acid should be considered only on an individual basis and under close medical supervision.

Rosuvastatin should not be administered to patients with acute serious conditions indicating myopathy or risk of developing renal failure due to rhabdomyolysis (such as sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures).

Myasthenia gravis, ocular myasthenia

There have been several reports of statins causing de novo myasthenia gravis or exacerbating pre-existing myasthenia gravis or ocular myasthenia. If symptoms worsen, the drug should be discontinued. Recurrences have been reported upon re-challenge with the same or another statin.

Hepatic effects

As with other HMG-CoA reductase inhibitors, rosuvastatin should be used with caution in patients who consume alcohol excessively and/or have a history of liver disease.

Liver function tests should be performed before starting treatment and again after 3 months. Rosuvastatin therapy should be discontinued or the dose reduced if serum transaminase levels exceed three times the upper limit of normal. The frequency of post-marketing reports of serious hepatic events (mainly elevated liver transaminases) was higher with the 40 mg dose.

In patients with secondary hypercholesterolemia due to hypothyroidism or nephrotic syndrome, the underlying condition should be treated before initiating rosuvastatin therapy.

Race

Pharmacokinetic studies indicate approximately twofold higher exposure in patients of Mongoloid race compared to Caucasians (see sections "Pharmacokinetics", "Contraindications", and "Posology and method of administration").

Protease inhibitors

Increased systemic exposure to rosuvastatin has been observed in patients receiving rosuvastatin concomitantly with various protease inhibitors in combination with ritonavir. Both the benefit of lipid-lowering with rosuvastatin in HIV-infected patients receiving protease inhibitors and the potential for increased plasma levels of rosuvastatin at the start of therapy and during dose titration should be considered. Concomitant use of the drug with certain protease inhibitors is not recommended unless the rosuvastatin dose is adjusted (see sections "Posology and method of administration" and "Interaction with other medicinal products and other forms of interaction").

Lactose intolerance

Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Interstitial lung disease

Rare cases of interstitial lung disease have been reported during treatment with some statins, particularly with long-term use (see section "Adverse reactions"). Manifestations may include dyspnea, non-productive cough, and general deterioration in health (fatigue, weight loss, fever). If interstitial lung disease is suspected, statin therapy should be discontinued.

Diabetes mellitus

Evidence suggests that statins as a class increase blood glucose levels and may induce hyperglycemia requiring treatment in some patients at high risk of developing diabetes. However, the reduction in cardiovascular risk with statin use outweighs this risk, and therefore should not be a reason to discontinue statin therapy. Patients at risk (fasting glucose 5.6–6.0 mmol/L, body mass index [BMI] > 30 kg/m², elevated triglycerides, hypertension) should be monitored clinically and biochemically according to national guidelines.

In the JUPITER trial, the overall incidence of diabetes was 2.8% in the rosuvastatin group and 2.3% in the placebo group, primarily in patients with fasting glucose levels between 5.6 and 6.9 mmol/L.

Serious skin adverse reactions

Serious skin adverse reactions, including Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS), which may be life-threatening or fatal, have been reported with rosuvastatin use. Patients prescribed rosuvastatin should be informed about the signs and symptoms of serious skin reactions and closely monitored. If signs or symptoms suggestive of these reactions occur, rosuvastatin should be discontinued immediately and alternative therapy considered.

If a patient develops a serious reaction such as SJS or DRESS while taking rosuvastatin, treatment with rosuvastatin should never be resumed in that patient.

Children

Assessment of linear growth (height), body weight, BMI, and secondary sexual characteristics by Tanner staging in children aged 6 to 17 years treated with rosuvastatin is limited to a 2-year period. After 2 years of investigational treatment, no effect on growth, body weight, BMI, or sexual maturation was observed (see section "Pharmacodynamics").

In a clinical trial in children and adolescents treated with rosuvastatin for 52 weeks, CK elevations > 10 times ULN and muscle symptoms after physical exertion or increased physical activity were observed more frequently than in adults (see section "Adverse reactions").

Use during pregnancy or breastfeeding

The medicinal product is contraindicated during pregnancy and breastfeeding.

Women of childbearing potential should use appropriate contraceptive measures.

Since cholesterol and other products of cholesterol biosynthesis play a vital role in fetal development, the potential risk of HMG-CoA reductase inhibition outweighs any benefit of using the drug during pregnancy. Animal studies on reproductive toxicity are limited. If a patient becomes pregnant while taking this medicinal product, treatment should be discontinued immediately.

Rosuvastatin crosses into rat milk. There are no data on the excretion of the drug into human breast milk (see section "Contraindications").

Ability to affect driving and operating machinery

No studies have been conducted to determine the effect of rosuvastatin on the ability to drive or operate machinery. However, given its pharmacodynamic properties, it is unlikely that rosuvastatin will affect such ability. Nevertheless, dizziness may occur during treatment, and this should be considered when driving or operating machinery.

Method of Administration and Dosage.

Before initiating treatment, patients should be placed on a standard cholesterol-lowering diet, which they must continue throughout the treatment period. The dosage should be individually adjusted based on therapeutic goals and the patient's response to treatment, following recommendations of current accepted guidelines.

The medicinal product Rosart can be taken at any time of day, regardless of food intake.

Treatment of Hypercholesterolemia

The recommended initial dose is 5 or 10 mg orally once daily, both for patients who have not previously used statins and for those switching from another HMG-CoA reductase inhibitor. The choice of initial dose should take into account individual patient cholesterol levels, future cardiovascular risk, and the likelihood of adverse reactions. If necessary, the dose may be increased to the next level after 4 weeks (see section "Pharmacodynamics"). Due to the higher incidence of adverse reactions with the 40 mg dose compared to lower doses (see section "Adverse Reactions"), dose titration to 40 mg should only be considered in patients with severe hypercholesterolemia and high cardiovascular risk (particularly in patients with familial hypercholesterolemia) in whom treatment goals have not been achieved with a 20 mg dose and who will be under regular monitoring (see section "Special Precautions"). Close specialist supervision is recommended when initiating treatment with the 40 mg dose.

Prevention of Cardiovascular Events

In clinical trials assessing cardiovascular risk reduction, the medicinal product was administered at a dose of 20 mg once daily.

Elderly Patients

The recommended initial dose for patients aged >70 years is 5 mg (see section "Special Precautions"). No other dose adjustment based on age is required.

Patients with Renal Impairment

Dose adjustment is not required in patients with mild or moderate renal impairment.

The recommended initial dose for patients with moderate renal impairment (creatinine clearance <60 mL/min) is 5 mg. The 40 mg dose is contraindicated in patients with moderate renal impairment. Rosuvastatin is contraindicated in patients with severe renal impairment at any dose (see sections "Pharmacokinetics" and "Contraindications").

Patients with Hepatic Impairment

In patients with hepatic impairment scoring 7 or less on the Child–Pugh scale, no increase in systemic exposure to rosuvastatin was observed. However, in patients scoring 8 or 9 on the Child–Pugh scale, systemic exposure increased (see section "Pharmacokinetics"). Renal function assessment is advisable in such patients (see section "Special Precautions"). Experience with the medicinal product in patients scoring more than 9 on the Child–Pugh scale is lacking. Rosuvastatin is contraindicated in patients with active liver disease (see section "Contraindications").

Race

Increased systemic exposure to the medicinal product has been observed in patients of Mongoloid race (see sections "Pharmacokinetics", "Contraindications", and "Special Precautions"). The recommended initial dose for Asian patients is 5 mg; the 40 mg dose is contraindicated in these patients.

Genetic Polymorphism

Certain types of genetic polymorphism may lead to increased exposure to rosuvastatin (see section "Pharmacokinetics"). Patients known to have such polymorphism types are recommended to receive a lower daily dose of the medicinal product Rosart.

Patients with Predisposition to Myopathy

The recommended initial dose for patients with risk factors for myopathy is 5 mg (see section "Special Precautions").

The 40 mg dose is contraindicated in some of these patients (see section "Contraindications").

Concomitant Use

Rosuvastatin is a substrate of various transporter proteins (e.g., OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) increases when rosuvastatin is co-administered with certain medicinal products that may increase its plasma concentration due to interactions with these transporter proteins (e.g., cyclosporine and certain protease inhibitors, including ritonavir combinations with atazanavir, lopinavir, and/or tipranavir; see sections "Special Precautions" and "Interaction with Other Medicinal Products and Other Forms of Interaction"). Alternative medicinal products should be considered whenever possible, and temporary discontinuation of rosuvastatin therapy may be necessary. If concomitant use of these medicinal products with rosuvastatin cannot be avoided, the benefit and risk of concomitant use should be carefully weighed, and the rosuvastatin dose should be carefully selected (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Children

Administration of the medicinal product to children should be performed only by a specialist.

Children and adolescents aged 6 to 17 years (Tanner stage ˂ II–V)

Heterozygous Familial Hypercholesterolemia

The usual initial daily dose for children and adolescents with heterozygous familial hypercholesterolemia is 5 mg once daily.

• The usual dose for children aged 6 to 9 years with heterozygous familial hypercholesterolemia is 5 mg to 10 mg orally once daily. The safety and efficacy of doses exceeding 10 mg in this population have not been studied.
• The usual dose for children aged 10 to 17 years with heterozygous familial hypercholesterolemia is 5 mg to 20 mg orally once daily. The safety and efficacy of doses exceeding 20 mg in this population have not been studied.

The dose should be increased according to the individual child's response to treatment and drug tolerability, following recommendations for pediatric treatment (see section "Special Precautions"). Before initiating rosuvastatin therapy, children and adolescents should be placed on a standard cholesterol-lowering diet, which they must continue throughout treatment.

Homozogous Familial Hypercholesterolemia

The recommended maximum dose for children aged 6 to 17 years with homozygous familial hypercholesterolemia is 20 mg once daily.

The recommended initial dose is 5 mg to 10 mg once daily, depending on age, body weight, and prior statin use. The dose may be increased up to the maximum of 20 mg once daily, based on the individual child's response to treatment and drug tolerability, following recommendations for pediatric treatment (see section "Special Precautions"). Before initiating rosuvastatin therapy, children and adolescents should be placed on a standard cholesterol-lowering diet, which they must continue throughout treatment.

Experience with doses exceeding 20 mg in this population is limited.

Tablets of 40 mg are not to be used in children.

Children under 6 years of age

Safety and efficacy of the medicinal product in children under 6 years of age have not been studied. Therefore, the medicinal product Rosart is not recommended for use in children under 6 years of age.

Overdose.

There is no specific antidote for overdose. In case of overdose, the patient should be treated symptomatically and supportive measures should be implemented as needed. Liver function and CK levels should be monitored. Hemodialysis is unlikely to be effective.

Adverse reactions

Adverse events observed during administration of rosuvastatin are generally mild and transient.

In controlled clinical studies, less than 4% of patients receiving rosuvastatin discontinued treatment due to adverse reactions.

The table below presents the adverse reaction profile of rosuvastatin based on data from clinical studies and extensive post-marketing experience. Adverse reactions are classified by frequency and by system organ class.

By frequency, adverse reactions are categorized as follows: common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), and frequency not known (cannot be estimated from available data).

Table 3

Adverse reactions based on clinical studies and post-marketing experience

1 Frequency depends on the presence of risk factors (fasting glucose ≥ 5.6 mmol/L, BMI > 30 kg/m², elevated triglyceride levels, history of arterial hypertension).

As with other HMG-CoA reductase inhibitors, the frequency of adverse reactions tends to be dose-dependent.

Renal effects

Proteinuria, detected by dipstick testing and predominantly of tubular origin, has been observed in patients treated with rosuvastatin. Changes in urinary protein content from zero or traces to ++ or higher were observed in < 1% of patients intermittently during treatment with 10 mg and 20 mg doses, and in approximately 3% of patients receiving the 40 mg dose. A slight increase in the frequency of change from zero or traces to + was observed at the 20 mg dose. In most cases, proteinuria decreased or resolved spontaneously while continuing therapy. Based on clinical studies and post-marketing surveillance data, no causal relationship has been established between proteinuria and acute or progressive kidney disease to date.

Hematuria has been reported during rosuvastatin treatment; available data indicate low frequency.

Skeletal muscle effects

Skeletal muscle disorders such as myalgia, myopathy (including myositis), and rarely rhabdomyolysis with or without acute renal failure have been reported with all doses of rosuvastatin, particularly at doses > 20 mg.

In patients taking rosuvastatin, dose-dependent increases in CK levels have been observed; in most cases, this phenomenon was mild, asymptomatic, and transient. If CK levels are elevated (> 5 times the upper limit of normal), treatment should be discontinued (see section "Special warnings and precautions for use").

Hepatic effects

As with other HMG-CoA reductase inhibitors, a small number of patients receiving rosuvastatin have experienced dose-dependent increases in transaminase levels; in most cases, this phenomenon was mild, asymptomatic, and transient.

With some statins, sexual dysfunction and isolated cases of interstitial lung disease, particularly with long-term use, have been reported (see section "Special warnings and precautions for use").

The frequency of reports of rhabdomyolysis and serious renal and hepatic disorders (predominantly increased hepatic transaminase activity) is higher when the drug is used at a dose of 40 mg.

Children

Elevations in CK levels > 10 times the upper limit of normal and muscle-related symptoms following physical exertion or increased physical activity were observed more frequently in a 52-week clinical study involving children and adolescents compared to adults (see section "Special warnings and precautions for use"). However, the safety profile of rosuvastatin in children and adolescents was similar to that in adults.

Reporting suspected adverse reactions. All suspected adverse reactions and lack of drug efficacy should be reported via the following link: https://aisf.dec.gov.ua

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C. Keep out of reach and sight of children.

Packaging.

10 tablets per blister; 3 or 9 blisters per carton.

Prescription status. Prescription only.

Manufacturer.

Actavis LTD.

Manufacturer's address and place of business.

VBL015, VBL016 Bulebel Industrial Building, ZTN 3000, Zejtun, Malta.