Rosustat

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ROSUSTAT (ROSUSTAT)

Composition:

Active substance: rosuvastatin;

One film-coated tablet contains 5 mg or 10 mg or 20 mg or 40 mg of rosuvastatin (as rosuvastatin calcium);

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

Film coating:

5 mg: Opadry Yellow 03K520018: hypromellose, titanium dioxide (E 171), triacetin, iron oxide (E 172);

10 mg, 20 mg, 40 mg: Opadry Pink 03K540028: hypromellose, titanium dioxide (E 171), triacetin, iron oxide (E 172).

Dosage form. Film-coated tablets.

Main physicochemical properties:

5 mg: yellow, round, biconvex, film-coated tablets, engraved with «CL» on one side and «86» on the other;

10 mg: pink, round, biconvex, film-coated tablets, engraved with «CL87» on one side and smooth on the other;

20 mg: pink, round, biconvex, film-coated tablets, engraved with «CL88» on one side and smooth on the other;

40 mg: pink, oval, biconvex, film-coated tablets, engraved with «CL89» on one side and smooth on the other.

Pharmacotherapeutic group. Lipid-lowering agents. HMG-CoA reductase inhibitors.

ATC code C10A A07.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the enzyme responsible for the rate-limiting step in converting 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a cholesterol precursor. The primary site of action of rosuvastatin is the liver, the target organ for reducing cholesterol levels.

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

Pharmacodynamic effects

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

Dose-response in patients with primary hypercholesterolemia type IIa and IIb
(adjusted mean percent change from baseline)

Table 1

The therapeutic effect is achieved within 1 week after initiation of treatment, and 90 % of the maximum treatment effect is reached within 2 weeks. Maximum effect is generally achieved within 4 weeks and persists throughout treatment.

Clinical efficacy and safety

Rosuvastatin is effective in the treatment of adults with hypercholesterolemia—with or without hypertriglyceridemia—regardless of race, sex, or age, as well as in patients from special populations, such as those with diabetes mellitus or familial hypercholesterolemia.

Rosuvastatin has been shown to effectively reduce cholesterol levels in the majority of patients with type IIa and IIb hypercholesterolemia (mean baseline LDL-C approximately 4.8 mmol/L) to target values established by the European Atherosclerosis Society (EAS; 1998) guidelines; approximately 80 % of patients receiving 10 mg of the drug achieved EAS-recommended target LDL-C levels (<3 mmol/L).

Data are available showing that in patients with heterozygous familial hypercholesterolemia treated with rosuvastatin at doses of 20 to 80 mg using an intensive dose-titration regimen, favorable effects on lipid parameters and achievement of target levels were observed at all doses. After titration to a daily dose of 40 mg (12 weeks of treatment), LDL-C decreased by 53 %. Target EAS LDL-C levels (<3 mmol/L) were achieved in 33 % of patients.

In an open-label dose-titration study, the response to rosuvastatin at doses of 20–40 mg was evaluated in 42 patients (including 8 children) with homozygous familial hypercholesterolemia. In the overall population, LDL-C levels decreased by a mean of 22 %.

It is known that in a limited number of patients, an additive effect of the drug on lowering triglyceride levels was observed when used in combination with fenofibrate, and on increasing HDL-C levels when used in combination with niacin (see section "Special instructions").

In patients aged 45–70 years with low risk of ischemic heart disease (defined as a 10-year Framingham risk score <10 %), mean baseline LDL-C of 4.0 mmol/L (154.5 mg/dL), but with subclinical atherosclerosis (defined by increased carotid intima-media thickness—CIMT), who were randomized to two groups and received either 40 mg rosuvastatin or placebo once daily for 2 years, rosuvastatin significantly slowed the progression of maximum CIMT at 12 carotid artery sites by -0.0145 mm/year [95 % CI: -0.0196, -0.0093; p<0.0001] compared to placebo. Change from baseline was -0.0014 mm/year (-0.12 %/year (statistically non-significant)) in the rosuvastatin group versus progression of +0.0131 mm/year (1.12 %/year (p<0.0001)) in the placebo group. A direct correlation between reduction in CIMT and reduction in cardiovascular event risk has not been demonstrated. The study included patients with low risk of ischemic heart disease, who do not represent the target population for use of 40 mg rosuvastatin. The 40 mg dose should only be prescribed to patients with severe hypercholesterolemia and high cardiovascular risk (see section "Dosage and administration").

Available data indicate that rosuvastatin is effective as a primary prevention measure in reducing the incidence of major atherosclerotic cardiovascular diseases. LDL-C concentrations decreased by approximately 45 % after initiation of rosuvastatin therapy.

In a post-hoc analysis of a high-risk subgroup with a baseline Framingham risk score >20 %, a significant reduction in the incidence of the composite endpoint—comprising fatal cardiovascular events, stroke, and myocardial infarction (p=0.028)—was observed in the rosuvastatin group compared to placebo. The absolute risk reduction was 8.8 events per 1000 patient-years. The overall mortality rate remained unchanged in this high-risk group (p=0.193). In a post-hoc analysis of a high-risk subgroup with a baseline SCORE risk ≥5 % (extrapolated to include data from participants aged over 65 years), a significant reduction in the incidence of the composite endpoint—comprising fatal cardiovascular events, stroke, and myocardial infarction (p=0.0003)—was observed in the rosuvastatin group compared to placebo. The absolute risk reduction expressed as event rate was 5.1 events per 1000 patient-years. The overall mortality rate in this high-risk subgroup remained unchanged (p=0.076).

Cases of discontinuation of rosuvastatin due to adverse events have been reported. The most common adverse events leading to treatment discontinuation were: myalgia (0.3 % in the rosuvastatin group, 0.2 % in placebo), abdominal pain (0.03 % in the rosuvastatin group, 0.02 % in placebo), and rash (0.02 % in the rosuvastatin group, 0.03 % in placebo). The most common adverse events observed in the rosuvastatin group with a frequency greater than or equal to that in the placebo group were urinary tract infections (8.7 % in rosuvastatin, 8.6 % in placebo), nasopharyngitis (7.6 % in rosuvastatin, 7.2 % in placebo), back pain (7.6 % in rosuvastatin, 6.9 % in placebo), and myalgia (7.6 % in rosuvastatin, 6.6 % in placebo).

Children

Available data from open-label dose-titration studies of rosuvastatin in patients aged 10–17 years (girls at Tanner stages II–IV of development, with menarche having occurred at least 1 year prior) with heterozygous familial hypercholesterolemia, receiving rosuvastatin at doses of 5, 10, or 20 mg/day, showed that LDL-C levels decreased by approximately 38.3 %, 44.6 %, and 50.0 %, respectively, in the 5, 10, and 20 mg rosuvastatin groups, compared to 0.7 % in the placebo group.

After the study treatment period, no effect on growth, weight, BMI, or sexual maturation was observed (see section "Special instructions"). Clinical trial experience in children and adolescents is limited, and the long-term effects of rosuvastatin (>1 year) on sexual maturation are unknown. This study (n=176) is not suitable for comparison of rare adverse events.

Pharmacokinetics

Absorption

Maximum plasma concentrations of rosuvastatin are reached approximately 5 hours after oral administration. Absolute bioavailability is approximately 20 %.

Distribution

Rosuvastatin is extensively metabolized in the liver, which is the primary site of cholesterol synthesis and LDL-C clearance. The volume of distribution of rosuvastatin is approximately 134 L. Approximately 90 % of rosuvastatin is bound to plasma proteins, primarily albumin.

Metabolism

Rosuvastatin undergoes limited metabolism (approximately 10 %). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin undergoes only minimal CYP450-mediated metabolism, and this metabolism is not clinically significant. CYP2C9 was the main isoenzyme involved in metabolism, with CYP2C19, 3A4, and 2D6 playing lesser roles. 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 form is considered clinically inactive. Rosuvastatin retains more than 90 % of its HMG-CoA reductase inhibitory activity in systemic circulation.

Elimination

Approximately 90 % of the rosuvastatin dose is excreted unchanged in feces (comprising both absorbed and unabsorbed active substance), and the remainder is excreted in urine.

Approximately 5 % is excreted unchanged in urine. The plasma half-life is approximately 19 hours. The half-life does not increase with higher doses. The geometric mean plasma clearance is approximately 50 L/h (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 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 were similar to those 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-fold. Population pharmacokinetic analysis did not reveal clinically significant differences between Caucasian and African patients.

Renal impairment

In a study involving patients with varying degrees of renal impairment, mild or moderate kidney disease did not affect plasma concentrations of rosuvastatin or the N-desmethyl metabolite. In patients with severe renal impairment (creatinine clearance <30 mL/min), plasma concentrations increased 3-fold and N-desmethyl metabolite concentrations increased 9-fold compared to healthy volunteers. Steady-state plasma concentrations of rosuvastatin in patients undergoing hemodialysis sessions were approximately 50 % higher than in healthy volunteers.

Hepatic impairment

In a study involving patients with varying degrees of hepatic impairment, there was no evidence of increased rosuvastatin exposure in patients with Child-Pugh scores of 7 or less. However, increased systemic exposure (at least 2-fold) was observed in 2 patients with Child-Pugh scores of 8 and 9.

Genetic polymorphism

The distribution of HMG-CoA reductase inhibitors, including rosuvastatin, involves the 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 polymorphisms 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 should be prescribed a lower daily dose of the drug.

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 administration 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 not appropriate.

Prevention of cardiovascular events

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

Contraindications.

Rosustat is contraindicated:

• in patients with hypersensitivity to rosuvastatin or to any of the excipients of the medicinal product;
• in patients with active liver disease, including of unknown etiology (persistent elevation of serum transaminases and elevation of any serum transaminase level by more than 3 times the upper limit of normal);
• in patients with severe renal impairment (creatinine clearance < 30 mL/min);
• in patients with myopathy;
• in patients concurrently receiving the combination of sofosbuvir/velpatasvir/voxilaprevir;
• in patients concurrently taking cyclosporine;
• 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 with predisposition to myopathy/rhabdomyolysis.

Factors contributing to this risk 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;
• conditions that may lead to increased plasma concentration of the drug;
• belonging to the Mongoloid race;
• concomitant use of fibrates.

Interaction with other medicinal products and other forms of interaction.

Effects of concomitant medicinal products on rosuvastatin

Inhibitors of transporter proteins

Rosuvastatin is a substrate for certain transporter proteins, including the hepatic uptake transporter OATP1B1 and the efflux transporter BCRP. Concomitant administration of Rosustat with medicinal products that inhibit these transporter proteins may increase plasma concentrations of rosuvastatin and increase the risk of myopathy.

Cyclosporine

During concomitant use of the medicinal product and cyclosporine, AUC values of rosuvastatin were on average approximately 7 times higher than those observed in healthy volunteers (see Table 2). Rosustat is contraindicated in patients who are concurrently receiving cyclosporine. Concomitant use of rosuvastatin and cyclosporine does not affect cyclosporine plasma concentrations.

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 resulted in increases in AUC and Cmax of rosuvastatin 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 the medicinal product, taking into account the expected increase in rosuvastatin exposure.

Gemfibrozil and other lipid-lowering agents

Concomitant use of the medicinal product and gemfibrozil resulted in a 2-fold increase in AUC and Cmax of rosuvastatin.

Based on data from specific studies, a pharmacokinetic interaction of clinical significance with fenofibrate is not expected; however, a pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates, and lipid-lowering doses (> or equal to 1 g/day) of niacin (nicotinic acid) increase the risk of myopathy when used concomitantly with HMG-CoA inhibitors, likely because they may cause myopathy when used individually. The 40 mg dose of Rosustat is contraindicated with concomitant use of fibrates. Treatment with Rosustat in such cases should also be initiated at a dose of 5 mg.

Ezetimibe

Concomitant administration of Rosustat 10 mg and ezetimibe 10 mg to patients with hypercholesterolemia resulted in a 1.2-fold increase in rosuvastatin AUC (Table 2). However, a pharmacodynamic interaction between Rosustat and ezetimibe that could lead to adverse effects cannot be ruled out.

Antacid medicinal products

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

Erythromycin

Concomitant administration of Rosustat and erythromycin reduced rosuvastatin AUC(0-t) 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, interactions with medicinal products 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).

Interactions requiring dose adjustment of rosuvastatin (see also Table 2)

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

If a medicinal product increases rosuvastatin AUC by less than 2-fold, the initial dose does not need to be reduced, but caution should be exercised when increasing the Rosustat dose above 20 mg.

Effect of concomitant medicinal products on rosuvastatin exposure

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

Table 2

Medicinal products/combinations that had no clinically significant effect on the AUC ratio of rosuvastatin 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; silymarin 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, initiating treatment with Rosustat or increasing its dose in patients concurrently taking vitamin K antagonists (e.g., warfarin or other coumarin anticoagulants) may lead to an increase in the international normalized ratio (INR). Discontinuation of Rosustat or reduction of its dose may result in a decrease in INR. In such cases, appropriate monitoring of INR is recommended.

Oral contraceptives/hormone replacement therapy (HRT)

Concomitant administration of Rosustat and oral contraceptives resulted in a 26% and 34% increase in AUC of ethinylestradiol and norgestrel, respectively. This increase in plasma levels should be taken into account when selecting the dose of oral contraceptives. There are no pharmacokinetic data available in patients receiving Rosustat and HRT simultaneously; therefore, a similar effect cannot be excluded. However, the combination has been widely used in women in clinical trials and was well tolerated.

Other medicinal products

Digoxin

Based on data from specific studies, a clinically significant interaction with digoxin is not expected.

Fusidic acid

Interaction studies between rosuvastatin and fusidic acid have not been conducted. The risk of myopathy, including rhabdomyolysis, may be increased when systemic fusidic acid is co-administered with statins. The mechanism of this interaction (pharmacodynamic or pharmacokinetic, or both) has not yet been established. Cases of rhabdomyolysis (including some fatal cases) have been reported in patients receiving this combination. In patients for whom systemic fusidic acid treatment is considered necessary, rosuvastatin therapy should be discontinued for the entire duration of fusidic acid treatment.

Tickagrelor

Ticagrelor may cause renal impairment and may affect renal excretion of rosuvastatin, increasing the risk of its accumulation. In some cases, concomitant use of ticagrelor and rosuvastatin has led to decreased renal function, increased creatine phosphokinase (CPK) levels, and rhabdomyolysis. Monitoring of renal function and CPK levels is recommended when ticagrelor and rosuvastatin are used concomitantly.

Children

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

Special precautions for use.

Renal effects

Cases of proteinuria (detected by "dipstick test"), predominantly of tubular origin, were observed in patients treated with Rosustat at high doses, particularly 40 mg, and were mostly transient or intermittent. Proteinuria did not indicate acute or progressive renal disease. Renal adverse events were reported more frequently during the post-marketing period with the 40 mg dose. In patients receiving the 40 mg dose, renal function should be monitored regularly.

Effects on skeletal muscle

Adverse events related to skeletal muscle, such as myalgia, myopathy, and rarely rhabdomyolysis, have been observed in patients taking rosuvastatin at any dose, particularly above 20 mg. Very rarely, cases of rhabdomyolysis have been reported with the use of ezetimibe in combination with HMG-CoA reductase inhibitors. A pharmacodynamic interaction cannot be excluded; therefore, such combination therapy should be used with caution.

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

Measurement of creatine kinase levels

Creatine kinase (CK) levels should not be measured following strenuous physical exercise or in the presence of other potential causes of elevated CK, as this may complicate interpretation of results. If baseline CK levels are markedly elevated (>5 times the upper limit of normal), repeat testing should be performed within 5–7 days to confirm the results. If the repeat test confirms a CK level >5 times the upper limit of normal, treatment with the medicinal product should not be initiated.

Before starting treatment

Rosustat, like other HMG-CoA reductase inhibitors, should be prescribed with caution in patients with factors predisposing to myopathy/rhabdomyolysis. These factors include:

• renal impairment;
• hypothyroidism;
• personal or family history of hereditary muscular disorders;
• history of myotoxicity associated with other HMG-CoA reductase inhibitors or fibrates;
• alcohol abuse;
• age >70 years;
• conditions that may lead to increased plasma concentrations of the drug;
• concomitant use of fibrates.

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

During treatment

Patients should be advised to promptly report unexplained muscle pain, weakness, or cramps, especially if accompanied by malaise or fever. In such patients, CK levels should be measured. Treatment should be discontinued if CK levels are markedly elevated (>5 × ULN) or if muscle symptoms are severe and interfere with daily activities (even if CK ≤ 5 × ULN). If symptoms resolve and CK levels return to normal, Rosustat or an alternative HMG-CoA reductase inhibitor may be cautiously reintroduced at the lowest dose and under close supervision. Routine monitoring of CK levels in patients without the aforementioned symptoms is not necessary.

In clinical trials, no enhanced effect on skeletal muscle was observed in a small number of patients receiving rosuvastatin with concomitant medications. However, increased incidence of myositis and myopathy has been observed with other HMG-CoA reductase inhibitors when used concomitantly with fibric acid derivatives, including gemfibrozil, cyclosporine, nicotinic acid, azole antifungals, protease inhibitors, and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when used concomitantly with certain HMG-CoA reductase inhibitors; therefore, rosuvastatin is not recommended to be used in combination with gemfibrozil. The potential benefit of further lipid-lowering effects with concomitant use of Rosustat and fibrates or niacin should be weighed against the potential risks of such combination therapy. Concomitant use of Rosustat at a dose of 40 mg with fibrates is contraindicated.

Rosustat should not be used concomitantly with systemic fusidic acid or within 7 days after discontinuation of fusidic acid treatment. In patients for whom systemic fusidic acid is considered necessary, statin therapy should be discontinued for the entire duration of fusidic acid treatment. Cases of rhabdomyolysis (including several fatal cases) have been reported in patients receiving fusidic acid and statins concurrently. 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 exceptional cases where prolonged systemic fusidic acid treatment is required (e.g., for severe infections), the need for concomitant use of rosuvastatin and fusidic acid should be considered on a case-by-case basis and under close medical supervision.

Rosustat should not be administered to patients with acute, serious conditions predisposing to myopathy or increasing the risk of renal failure due to rhabdomyolysis (such as sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine, or electrolyte disturbances; or uncontrolled seizures).

Myasthenia gravis, ocular myasthenia. Rare cases have been reported in which statins induce de novo or exacerbate pre-existing myasthenia gravis or ocular myasthenia (see section "Adverse reactions"). If symptoms worsen, Rosustat should be discontinued. Recurrences have been reported upon re-exposure to the same or another statin.

Immune-mediated necrotizing myopathy (IMNM)

Very rare cases of immune-mediated necrotizing myopathy (IMNM) have been reported during or after statin therapy, including with rosuvastatin. Clinical features of IMNM include proximal muscle weakness and elevated serum creatine kinase levels that persist after discontinuation of statins; positive antibodies to HMG-CoA reductase; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive therapy.

Additional neuromuscular and serological investigations and immunosuppressive treatment should be considered. The risk of IMNM should be carefully weighed before initiating another statin. If therapy is initiated with another statin, patients should be monitored for signs and symptoms of IMNM.

Severe cutaneous adverse reactions

Severe cutaneous adverse reactions, including Stevens-Johnson syndrome and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), which may be life-threatening or fatal, have been reported with rosuvastatin. When prescribing the medicinal product, patients should be informed about the signs and symptoms of severe skin reactions and closely monitored. If signs or symptoms suggestive of such reactions occur, the drug should be discontinued immediately and alternative therapy considered. If a patient develops a serious reaction such as Stevens-Johnson syndrome or drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), treatment with the drug must be discontinued immediately and must never be resumed.

Hepatic effects

As with other HMG-CoA reductase inhibitors, Rosustat should be used with caution in patients who abuse alcohol and/or have a history of liver disease. Liver function should be assessed before starting treatment and again after 3 months of therapy. Increases in serum transaminases (AST or ALT) have been reported with HMG-CoA reductase inhibitors, including rosuvastatin. In most cases, these elevations were transient and resolved or decreased with continued therapy or after a short treatment interruption. Two cases of jaundice, for which a causal relationship with rosuvastatin therapy could not be established, resolved after discontinuation of therapy. No cases of hepatic failure or irreversible liver disease were reported in clinical trials.

If serum transaminase levels exceed three times the upper limit of normal, Rosustat should be discontinued. Serious hepatic disorders (predominantly elevated hepatic transaminases) have been reported more frequently during the post-marketing period with the 40 mg dose.

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

Rare post-marketing reports of fatal and non-fatal hepatic failure have been reported in patients taking statins, including rosuvastatin. If severe hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with rosuvastatin, therapy should be discontinued immediately. If no alternative etiology is identified, rosuvastatin should not be restarted.

Contraindications to the use of rosuvastatin include acute liver disease, which may include persistent elevations in transaminases of unknown etiology.

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

Concomitant use of coumarin anticoagulants

Caution should be exercised when using anticoagulants concomitantly with rosuvastatin due to the potentiation of the anticoagulant effect of coumarin derivatives on prothrombin time/INR (International Normalized Ratio). In patients receiving coumarin anticoagulants and rosuvastatin concomitantly, INR should be measured before starting rosuvastatin and frequently during the initial phase of therapy to ensure no significant change in INR occurs.

Race

Pharmacokinetic studies indicate that systemic exposure is approximately twice as high in Mongoloid race patients compared to Caucasians.

Protease inhibitors

Increased systemic exposure to rosuvastatin has been observed in individuals taking rosuvastatin concomitantly with various protease inhibitors in combination with ritonavir. Both the benefit of lipid-lowering with Rosustat in HIV patients receiving protease inhibitors and the potential for increased plasma concentrations of rosuvastatin should be considered at the start of therapy and when increasing the dose of Rosustat in patients receiving protease inhibitors. Concomitant use of the medicinal product with certain protease inhibitors is not recommended unless the dose of Rosustat is adjusted.

Interstitial lung disease

Isolated cases of interstitial lung disease have been reported with the use of some statins, particularly with long-term therapy. Symptoms include dyspnea, non-productive cough, and worsening general condition (fatigue, weight loss, and fever). If interstitial lung disease is suspected in a patient, statin therapy should be discontinued.

Diabetes mellitus

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

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

Although clinical studies have shown that rosuvastatin alone does not reduce basal plasma cortisol concentration or impair adrenal reserve, caution should be exercised when rosuvastatin is used concomitantly with drugs that may reduce levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine.

Children

Assessment of linear growth (height), body weight, BMI (body mass index), and secondary sexual characteristics according to Tanner in children aged 6 to 17 years receiving 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. In a clinical study in children and adolescents receiving rosuvastatin for 52 weeks, CK levels >10 times the upper normal limit and muscle symptoms after physical exertion or increased physical activity were observed more frequently than in adults.

Lactose intolerance

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

Use during pregnancy or breastfeeding.

Pregnancy

Rosustat 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 crucial role in fetal development, the potential risk of inhibiting HMG-CoA reductase outweighs the benefit of using the drug during pregnancy. Data from animal studies on reproductive toxicity are limited. If a patient becomes pregnant while taking this medicinal product, treatment should be discontinued immediately.

Rosuvastatin passes into the milk of rats. There are no data on the passage of the drug into human breast milk.

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

Before initiating treatment, patients should be placed on a standard cholesterol-lowering diet, which should be continued throughout the treatment period. The dosage should be individually adjusted according to the therapeutic goal and treatment efficacy, following current established guidelines.

Rosuvast can be taken at any time of day, independent of food intake.

The tablet should not be chewed or crushed. It should be swallowed whole with water.

Hypercholesterolemia Treatment

The recommended initial dose is 5 or 10 mg orally once daily, both for patients who have not previously used statins and for those who have previously used other HMG-CoA reductase inhibitors. The initial dose selection should take into account the patient's individual cholesterol levels, future cardiovascular risk, and the potential risk of adverse reactions (see below). If necessary, the dose may be increased after 4 weeks. Since adverse reactions occur more frequently with the 40 mg dose compared to lower doses, dose titration to 40 mg should only be considered in patients with severe hypercholesterolemia and high cardiovascular risk (particularly those with familial hypercholesterolemia) who have not achieved the desired response with a 20 mg dose and who should be under close monitoring. Specialist supervision is recommended when initiating the 40 mg dose.

Prevention of Cardiovascular Disorders

In the cardiovascular risk reduction study, the daily dose of the drug was 20 mg. In patients with hypercholesterolemia, standard lipid level monitoring should be performed, and dosage recommendations for hypercholesterolemia treatment should be followed.

Use in Elderly Patients

The recommended initial dose for patients aged over 70 years is 5 mg. No other age-related dosage adjustment is required.

Dosage in Patients with Renal Impairment

No dosage adjustment is necessary for patients with mild to 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. Rosuvast is contraindicated in patients with severe renal impairment at any dose.

Dosage in Patients with Hepatic Impairment

No increase in systemic exposure to rosuvastatin was observed in patients with a Child-Pugh score of 7. However, increased systemic exposure has been reported in patients with a Child-Pugh score of 8 or 9. Renal function should be assessed in such patients. There is no experience with the use of the drug in patients with a Child-Pugh score of 9. Rosuvast is contraindicated in patients with active liver disease.

Race

Increased systemic exposure to the drug has been observed in patients of Mongoloid race. The recommended initial dose for patients of Mongoloid race 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.

Dosage in Patients Predisposed to Myopathy

The recommended initial dose for patients predisposed to myopathy is 5 mg.

The 40 mg dose is contraindicated in some of these patients.

Concomitant Therapy

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 rosuvastatin plasma concentrations due to interactions with these transporter proteins (e.g., cyclosporine and certain protease inhibitors, including ritonavir combinations with atazanavir, lopinavir and/or tipranavir). Alternative medicinal products should be considered, and temporary discontinuation of rosuvastatin therapy should be considered if necessary. In situations where concomitant use of these medicinal products with rosuvastatin cannot be avoided, the benefit and risk of concomitant treatment and dose adjustment of rosuvastatin should be carefully evaluated.

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 above 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 above 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 Warnings and Precautions for Use"). Before initiating rosuvastatin therapy, children and adolescents should be placed on a standard hypocholesterolemic diet, which should be maintained throughout the treatment period.

Homozygous 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 according to the individual child's response to treatment and drug tolerability, following recommendations for pediatric treatment (see section "Special Warnings and Precautions for Use"). Before initiating rosuvastatin therapy, children and adolescents should be placed on a standard hypocholesterolemic diet, which should be maintained throughout the treatment period.

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

40 mg tablets should not be used in children.

Children under 6 years of age

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

Overdose.

There is no specific treatment for overdose. Treatment should be symptomatic. If necessary, supportive measures should be taken. Creatine kinase (CK) levels should be monitored, and liver function tests should be performed. Hemodialysis is unlikely to be effective.

Adverse Reactions

Adverse reactions observed during administration of Rosustat are generally mild and transient. In controlled clinical studies, less than 4% of patients receiving the drug discontinued treatment due to adverse reactions.

List of adverse reactions in table form

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 classes (SOC). According to 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).

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

As with other HMG-CoA reductase inhibitors, the frequency of adverse reactions depends on the dose.

Renal effects

Cases of proteinuria, predominantly of tubular origin (detected by urine dipstick testing), have been observed in patients treated with Rosustat. Changes in urinary protein content from absent or trace to ++ or higher were observed over time in <1% of patients receiving 10 mg and 20 mg doses, and in approximately 3% of patients receiving the 40 mg dose. A slight increase in the frequency of urinary protein elevation from absent or trace to + was observed with the 20 mg dose. In most cases, the degree of proteinuria decreased or resolved spontaneously while continuing treatment. Based on clinical trial data and post-marketing surveillance, there is currently no evidence of a causal relationship between proteinuria and acute or progressive kidney disease.

Hematuria observed in patients treated with Rosustat has been reported at a low frequency in clinical studies. Although the clinical significance of this finding is unknown, dose reduction should be considered in patients receiving rosuvastatin therapy who have unexplained persistent proteinuria and/or hematuria detected during routine urinalysis.

Musculoskeletal effects

Skeletal muscle-related changes such as myalgia, myopathy (including myositis), and rarely rhabdomyolysis, with or without acute renal failure, have been observed during treatment with any dose of Rosustat, particularly with doses >20 mg. Rare cases of rhabdomyolysis, sometimes associated with renal failure, have been reported with rosuvastatin as well as other statins. In patients treated with rosuvastatin, dose-dependent increases in creatine phosphokinase (CPK) levels have been observed; in most cases, this was mild, asymptomatic, and transient. If CPK levels are elevated (>5 × ULN), treatment should be discontinued.

Hepatic effects

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

With the use of some statins, the following adverse effects have been reported:

• sexual dysfunction;
• isolated cases of interstitial lung disease, particularly with long-term use (see section "Special precautions").

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

Pediatric population

Elevations in creatine kinase levels >10 times above ULN 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 precautions"). However, the safety profile of rosuvastatin in children and adolescents was similar to that in adults.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the drug. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of drug efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging.

10 tablets per blister; 3 or 9 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

MACLEOD'S PHARMACEUTICALS LIMITED.

Manufacturer's address and site of operations.

Village Thedda, P.O. Lodhymaira, Tehsil Baddi, District Solan, Himachal Pradesh, 174101, India.