Rozulip

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ROZULIPÒ (ROSULIPÒ)

Composition:

Active substance: rosuvastatin;

One film-coated tablet contains 5.34 mg or 10.68 mg or 21.36 mg of rosuvastatin zinc (corresponding to 5 mg or 10 mg or 20 mg of rosuvastatin, respectively);

Excipients: lactose monohydrate, povidone, crospovidone, magnesium stearate, polyvinyl alcohol, titanium dioxide (E 171), macrogol 3350, talc.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

5 mg tablets: white or almost white, round, slightly biconvex, film-coated tablets, engraved with a stylized letter E on one side and number 591 on the other, odorless or nearly odorless;

10 mg tablets: white or almost white, round, slightly biconvex, film-coated tablets, engraved with a stylized letter E on one side and number 592 on the other, odorless or nearly odorless;

20 mg tablets: white or almost white, round, slightly biconvex, film-coated tablets, engraved with a stylized letter E and number 593 on one side, odorless or nearly odorless.

Pharmacotherapeutic group. Medicinal products that reduce serum cholesterol and triglyceride levels. 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 that catalyzes 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, where cholesterol synthesis occurs.

Rosuvastatin increases the number of hepatic low-density lipoprotein (LDL) receptors on the surface of liver cells, enhancing the uptake and catabolism of LDL, thereby increasing the clearance and catabolism of LDL and inhibiting hepatic synthesis of LDL, thus reducing the total number of very-low-density lipoprotein (VLDL) and LDL particles.

Pharmacodynamic effects

Rosuvastatin reduces elevated levels of LDL cholesterol, total cholesterol, and triglycerides, and increases high-density lipoprotein (HDL) cholesterol levels. It also reduces levels of apolipoprotein B (apoB), non-HDL-C, VLDL-C, VLDL-TG, and increases levels of apoA-I (see 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.

Table 1

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

(adjusted mean percentage change from baseline)

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

Clinical efficacy

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.

Based on pooled Phase III trial data, rosuvastatin effectively reduced cholesterol levels in the majority of patients with type IIa and IIb hypercholesterolemia (mean baseline LDL-C level approximately 4.8 mmol/L) to target values defined by the European Atherosclerosis Society (EAS; 1998) guidelines; approximately 80% of patients receiving the 10 mg dose achieved the EAS target LDL-C level (< 3 mmol/L).

In a large study of 435 patients with heterozygous familial hypercholesterolemia, rosuvastatin was administered at doses ranging from 20 mg to 80 mg using an intensive dose-titration regimen. The drug demonstrated favorable effects on lipid parameters and achievement of target levels at all doses. After titration to a daily dose of 40 mg (12 weeks of treatment), LDL-C decreased by 53%. The EAS target LDL-C level (< 3 mmol/L) was 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 with homozygous familial hypercholesterolemia. In the overall population, LDL-C levels decreased on average by 22%.

In clinical studies involving a limited number of patients, an additive effect of rosuvastatin was observed on triglyceride reduction when used in combination with fenofibrate, and on HDL-C elevation when used in combination with niacin (see section "Special precautions").

In a multicenter, double-blind, placebo-controlled clinical trial (METEOR), 984 patients aged 45–70 years with low risk of ischemic heart disease (defined as a Framingham risk score < 10% over 10 years), mean LDL-C level of 4.0 mmol/L (154.5 mg/dL), but with subclinical atherosclerosis (defined by increased carotid intima-media thickness [CIMT]) were randomized into two groups and received either 40 mg rosuvastatin or placebo once daily for 2 years. Compared to placebo, rosuvastatin significantly slowed the progression of maximum CIMT at 12 carotid artery sites by -0.0145 mm/year [95% confidence interval (CI) -0.0196, -0.0093; p < 0.0001]. The change from baseline was -0.0014 mm/year (-0.12%/year (statistically non-significant)) in the rosuvastatin group compared to progression of +0.0131 mm/year (1.12%/year (p < 0.0001)) in the placebo group. No direct correlation between reduction in CIMT and reduction in cardiovascular event risk was demonstrated. The METEOR study included patients with low risk of ischemic heart disease, who do not represent the target population for rosuvastatin 40 mg. The 40 mg dose should be prescribed only to patients with severe hypercholesterolemia and high risk of cardiovascular disorders (see section "Dosage and administration").

In the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), the impact of rosuvastatin on the incidence of major atherosclerotic cardiovascular events was evaluated in 17,802 men (≥ 50 years) and women (≥ 60 years).

Participants were randomly assigned to receive placebo (n = 8901) or rosuvastatin 20 mg once daily (n = 8901), with a mean follow-up of 2 years.

LDL-C concentration decreased by 45% (p < 0.001) in the rosuvastatin group compared to the placebo group.

In a post-hoc analysis of a high-risk subgroup with baseline Framingham risk score > 20% (1558 participants), a significant reduction in the incidence of the composite endpoint (including cardiovascular death, stroke, and myocardial infarction) was observed in the rosuvastatin group compared to placebo (p = 0.028). 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 another high-risk subgroup (9302 participants overall) with baseline SCORE ≥ 5% (extrapolated to include participants aged ≥ 65 years), a significant reduction in the composite endpoint (including cardiovascular death, stroke, and myocardial infarction) was observed in the rosuvastatin group compared to placebo (p = 0.0003). 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).

In the JUPITER study, 6.6% of participants in the rosuvastatin group and 6.2% in the placebo group discontinued the study drug due to adverse reactions. The most common adverse reactions leading to discontinuation were myalgia (0.3% in the rosuvastatin group, 0.2% in the placebo group), abdominal pain (0.03% in the rosuvastatin group, 0.02% in the placebo group), and rash (0.02% in the rosuvastatin group, 0.03% in the placebo group). The most common adverse reactions 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 the rosuvastatin group, 8.6% in the placebo group), nasopharyngitis (7.6% in the rosuvastatin group, 7.2% in the placebo group), back pain (7.6% in the rosuvastatin group, 6.9% in the placebo group), and myalgia (7.6% in the rosuvastatin group, 6.6% in the placebo group).

Children

In a double-blind, randomized, multicenter, placebo-controlled 12-week study (n = 176, 97 male and 79 female participants) followed by a 40-week open-label dose-titration period (n = 173, 96 male and 77 female participants), patients aged 10–17 years (Tanner stages II–IV, girls with at least 1 year since onset of menstruation) with heterozygous familial hypercholesterolemia received rosuvastatin 5 mg, 10 mg, or 20 mg daily or placebo for 12 weeks, after which all participants received rosuvastatin daily for 40 weeks. At baseline, approximately 30% of patients were aged 10–13 years, and approximately 17%, 18%, 40%, and 25% were at Tanner stages II, III, IV, and V, respectively.

LDL-C levels decreased by 38.3%, 44.6%, and 50.0% in the rosuvastatin 5 mg, 10 mg, and 20 mg groups, respectively, compared to 0.7% in the placebo group.

At the end of the 40-week open-label dose-titration period (maximum dose 20 mg once daily), the target LDL-C level of < 2.8 mmol/L was achieved in 70 of 173 patients (40.5%).

After 52 weeks of investigational treatment, no effect on growth, weight, body mass index (BMI), or sexual maturation was observed (see section "Special precautions"). Clinical trial experience in children and adolescents is limited; therefore, the long-term effects of rosuvastatin (> 1 year) on sexual maturation are unknown. This study (n = 176) is not suitable for comparing rare adverse reactions.

Pharmacokinetics

Absorption

The maximum plasma concentration (Cmax) of rosuvastatin is reached approximately 5 hours after oral administration. Absolute bioavailability is approximately 20%.

Distribution

Rosuvastatin is significantly taken up by the liver, 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 minimal metabolism (approximately 10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a weak substrate for cytochrome P450 enzyme metabolism. The main isoenzyme involved is CYP2C9, with minor contributions from 2C19, 3A4, and 2D6. The main identified metabolites are 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 rosuvastatin). The remainder of the active substance is excreted in urine. Approximately 5% is excreted unchanged in urine. The plasma half-life is approximately 19 hours and does not increase with dose escalation. The geometric mean 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 involves the OATP-C cholesterol membrane transporter. This transporter 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 in adults has been observed. 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 values of the area under the plasma concentration-time curve (AUC) and Cmax are approximately twice as high as in Caucasians; in Indians, median AUC and Cmax values are elevated by approximately 1.3 times. Population pharmacokinetic analysis did not reveal clinically significant differences between Caucasian and African patients.

Renal impairment

In a study of 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 three times higher and N-desmethyl concentrations nine 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 impairment, no evidence of increased rosuvastatin exposure was observed in patients scoring 7 or less on the Child-Pugh scale. However, in two patients scoring 8 and 9 on the Child-Pugh scale, systemic exposure was at least twice as high as in patients with lower scores. Experience with rosuvastatin in patients scoring above 9 on the Child-Pugh scale is lacking.

Genetic polymorphism

Transport proteins OATP1B1 and BCRP are involved in the pharmacokinetics of HMG-CoA reductase inhibitors, including rosuvastatin. Patients with genetic polymorphisms in SLCO1B1 (OATP1B1) and/or ABCG2 (BCRP) are at risk of increased rosuvastatin exposure. Specific polymorphisms SLCO1B1 c.521CC and ABCG2 c.421AA are associated with higher rosuvastatin exposure (AUC) compared to SLCO1B1 c.521TT or ABCG2 c.421CC genotypes. This specific genotyping is not routinely used in clinical practice, but patients identified with these polymorphisms should be prescribed a lower daily dose of rosuvastatin.

Children

Two pharmacokinetic studies of rosuvastatin (in tablet form), involving patients aged 10–17 or 6–17 years (total of 214 patients) with heterozygous familial hypercholesterolemia, demonstrated that the drug's exposure in children corresponds to that in adult patients. Rosuvastatin exposure was predictable based on dose over a 2-year period.

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 nonpharmacological 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 in cases where such treatment is inappropriate.

Prevention of cardiovascular events

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.

Rosulip® tablets, film-coated, are contraindicated:

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

The 40 mg dose is contraindicated in patients who have an increased risk of developing myopathy/rhabdomyolysis.

Factors contributing to such risk include:

• moderate renal impairment (creatinine clearance < 60 mL/min);
• hypothyroidism;
• personal or family history of hereditary muscle disorders;
• history of myotoxicity with other HMG-CoA reductase inhibitors or fibrates;
• alcohol abuse;
• conditions that may lead to increased plasma concentrations of rosuvastatin;
• Mongoloid race;
• concomitant use of fibrates.

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

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 transporter proteins, including the hepatic uptake transporter OATP1B1 and the efflux transporter BCRP. Concomitant administration of Rosulip® with medicinal products that inhibit these transporters may increase plasma concentrations of rosuvastatin and increase the risk of myopathy (see sections "Interaction with other medicinal products and other types of interactions", "Special precautions for use", and "Dosage and administration", as well as Table 2).

Cyclosporine

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

Concomitant use did 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 was associated with increases in rosuvastatin AUC and Cmax by approximately 3 and 7 times, respectively. Concomitant use of Rosulip® with certain combinations of protease inhibitors may be possible after careful consideration of dose adjustment of Rosulip®, based on the expected increase in rosuvastatin exposure (see sections "Interaction with other medicinal products and other types of interactions", "Special precautions for use", "Dosage and administration", and Table 2).

Gemfibrozil and other lipid-lowering agents

Concomitant administration of Rosulip® and gemfibrozil resulted in a doubling of rosuvastatin AUC and Cmax (see section "Special precautions for use").

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

Ezetimibe

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

Antacids

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

Erythromycin

Concomitant administration of Rosulip® 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. Additionally, 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

When Rosulip® must be used concomitantly with other medicinal products capable of increasing rosuvastatin exposure, the dose should be adjusted. If an approximately 2-fold or greater increase in AUC is expected, Rosulip® therapy should be initiated at a dose of 5 mg once daily. The maximum daily dose of Rosulip® should be adjusted so that the expected exposure to rosuvastatin does not exceed that observed with a 40 mg daily dose without interacting medicinal products; for example, when used with gemfibrozil, the dose of Rosulip® should be 20 mg (exposure increased 1.9-fold), when used with ritonavir/atazanavir combination – 10 mg (exposure increased 3.1-fold). When used concomitantly with cyclosporine – 5 mg (exposure increased 7.1-fold).

If an increase in AUC of less than 2-fold is expected, the initial dose need not be reduced; however, caution should be exercised when increasing the rosuvastatin dose above 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 of x represent the ratio between rosuvastatin used in combination versus rosuvastatin used alone. Data expressed as % change represent the % difference relative to values observed with rosuvastatin used alone.

An upward arrow ↑ indicates an increase, a downward arrow ↓ indicates a decrease.

**Several interaction studies were conducted at different doses of Rosulip®; the most significant ratio is presented in Table 2.

Medicinal products/combinations that did not have a 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, initiation of treatment with Rosulip® 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 Rosulip® 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 Rosulip® and oral contraceptives resulted in a 26% and 34% increase in AUC of ethinylestradiol and norgestimate, respectively. This increase in plasma blood levels should be considered when selecting the dose of oral contraceptives. There are no data on the pharmacokinetics of drugs in patients who concurrently receive Rosulip® and HRT; 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 myopathy, including rhabdomyolysis, may increase when systemic fusidic acid products are used concomitantly with statins. The mechanism of this interaction (pharmacodynamic, pharmacokinetic, or both) is still unknown. Cases of rhabdomyolysis (including fatal outcomes) have been reported in patients receiving this combination. If systemic fusidic acid therapy is necessary, rosuvastatin treatment should be temporarily discontinued for the entire duration of fusidic acid treatment (see section "Special precautions").

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 kidney function, elevated creatine phosphokinase (CPK) levels, and rhabdomyolysis. Monitoring of kidney 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

Proteinuria detected by dipstick testing and predominantly of tubular origin has been observed in patients treated with higher doses of the medicinal product Rosulip®, particularly 40 mg, and was mostly transient or intermittent in most cases. Proteinuria was not a predictor of acute or progressive renal disease (see section "Adverse reactions"). The frequency of reports of serious renal adverse reactions in post-marketing studies is higher when the 40 mg dose is used. In patients receiving the 40 mg dose, renal function should be monitored regularly during treatment.

Skeletal muscle effects

Skeletal muscle disorders, such as myalgia, myopathy, and rarely rhabdomyolysis, have been observed in patients taking the medicinal product Rosulip® at any dose, particularly above 20 mg. Isolated cases of rhabdomyolysis have been reported when ezetimibe is 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 the use of Rosulip® was higher at the 40 mg dose.

Creatine kinase levels

Creatine kinase (CK) levels should not be measured after significant physical exertion or in the presence of possible alternative causes of elevated CK, which may complicate interpretation of results. If baseline CK levels are markedly elevated (> 5 times the upper limit of normal [ULN]), a repeat test should be performed within 5–7 days to confirm the results. If repeat testing confirms that baseline CK values exceed 5 times the ULN, treatment should not be initiated.

Before starting treatment

The medicinal product Rosulip®, 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 "Dosage and administration");
• concomitant use of fibrates.

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

During treatment

Patients should be instructed to report immediately any unexplained muscle pain, weakness, or cramps, especially if accompanied by malaise or fever. In such patients, CK levels should be measured. The drug should be discontinued if CK levels are markedly elevated (> 5 × ULN) or if muscle symptoms are severe and cause daily discomfort (even if CK ≤ 5 × ULN). If symptoms resolve and CK levels return to normal, therapy with Rosulip® or an alternative HMG-CoA reductase inhibitor may be restarted at the lowest dose and under close supervision. 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 with rosuvastatin. Clinical manifestations of IMNM include proximal muscle weakness and elevated serum CK levels, which persist even after discontinuation of statins.

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

Clinical trials have not shown increased skeletal muscle effects in a small number of patients taking Rosulip® 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, 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, the concomitant use of Rosulip® with gemfibrozil is not recommended. The benefit of further lipid-lowering with Rosulip® 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").

Rosulip® should not be used in patients with acute, serious conditions indicating myopathy or potential development of renal failure due to rhabdomyolysis (e.g., sepsis, arterial hypotension, major surgery, trauma, severe metabolic, endocrine, or electrolyte disturbances, or uncontrolled seizures).

Hepatic effects

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

It is recommended to assess liver function biochemistry before starting treatment and again after 3 months. Treatment with Rosulip® should be discontinued or the dose reduced if serum transaminase levels exceed three times the ULN. The frequency of post-marketing reports of serious hepatic events (predominantly 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 therapy with Rosulip®.

Race

Pharmacokinetic studies indicate approximately twofold higher exposure in Mongoloid racial groups compared to Caucasians (see sections "Pharmacokinetics", "Contraindications", and "Dosage and administration").

Protease inhibitors

Increased systemic exposure to rosuvastatin has been observed in patients taking rosuvastatin concomitantly with various protease inhibitors in combination with ritonavir. Both the benefit of lipid-lowering with Rosulip® in HIV patients receiving protease inhibitors and the potential for increased plasma concentrations of rosuvastatin at the initiation of therapy and when increasing the dose of Rosulip® in patients receiving protease inhibitors should be considered. Concomitant use of the drug with protease inhibitors is not recommended unless the dose of Rosulip® is adjusted (see sections "Interaction with other medicinal products and other forms of interaction" and "Dosage and administration").

Lactose intolerance

This medicinal product is contraindicated in patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

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 increase blood glucose levels and may cause hyperglycemia requiring appropriate diabetes treatment in some patients at high risk of developing diabetes in the future. However, the reduction in vascular risk with statin therapy outweighs this risk, so 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, hypertension) should be monitored both 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, predominantly in patients with fasting glucose levels between 5.6 and 6.9 mmol/L.

Severe skin reactions

Severe skin adverse reactions, including Stevens-Johnson syndrome and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been reported with rosuvastatin use, which may be fatal. When prescribing the medicinal product, patients should be informed about the signs and symptoms of severe skin reactions and closely monitored. If 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 must be stopped immediately and the drug should never be used again.

Children

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

In a clinical study in children and adolescents treated with rosuvastatin for 2 years, 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 Rosulip® is contraindicated during pregnancy and breastfeeding.

Women of childbearing potential should use appropriate contraceptive methods.

Since cholesterol and other products of cholesterol biosynthesis are essential for fetal development, the potential risk of HMG-CoA reductase inhibition outweighs any potential benefit of using the drug during pregnancy. Data from animal studies on reproductive toxicity are limited. If a patient becomes pregnant while taking this drug, treatment should be stopped immediately.

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

Ability to drive and use machines

No studies on the effect of Rosulip® on the ability to drive or operate machinery have been conducted. However, given the pharmacodynamic properties of the drug, it is unlikely that Rosulip® will affect such ability. Nevertheless, dizziness during treatment 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 should be continued throughout the treatment period. The dosage should be individually adjusted depending on the therapeutic goal and the patient's response to treatment, following recommendations of current widely accepted guidelines.

The medicinal product Rosulip® can be taken at any time of day, independent of food intake.

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

Treatment of Hypercholesterolemia

The recommended initial dose is 5 mg or 10 mg orally once daily, both for patients who have not previously used statins and for patients who have previously used other HMG-CoA reductase inhibitors. When selecting the initial dose, the individual cholesterol level of each patient, the future risk of cardiovascular events, and the likelihood of developing adverse reactions should be considered.

If necessary, the dose may be increased to the next level after 4 weeks (see section "Pharmacodynamics"). Since adverse reactions occur more frequently with the 40 mg dose than with lower doses (see section "Adverse Reactions"), the maximum dose of 40 mg should be titrated only in patients with severe hypercholesterolemia and high cardiovascular risk (particularly 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 Warnings and Precautions for Use"). Specialist supervision is recommended when initiating treatment with the 40 mg dose.

Prevention of Cardiovascular Events

In clinical trials evaluating cardiovascular risk reduction, the medicinal product was administered at a dose of 20 mg once daily (see section "Pharmacodynamics").

Use in Elderly Patients

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

Patients with Renal Impairment

No dose adjustment is required for 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 to severe renal impairment. The use of Rosulip® in patients with severe renal impairment is contraindicated at all doses (see sections "Pharmacokinetics" and "Contraindications").

Patients with Hepatic Impairment

In patients with hepatic impairment classified as 7 or less on the Child–Pugh scale, no increase in systemic exposure to rosuvastatin was observed. However, in patients with hepatic impairment classified as 8 or 9 on the Child–Pugh scale, systemic exposure increased (see section "Pharmacokinetics"). In such patients, assessment of renal function is advisable (see section "Special Warnings and Precautions for Use"). Experience with the use of this medicinal product in patients scoring more than 9 points on the Child–Pugh scale is lacking. This medicinal product 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 Warnings and Precautions for Use"). 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 of Rosulip®.

Patients Predisposed to Myopathy

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

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

Concomitant Therapy

Rosuvastatin is a substrate of various transporter proteins (e.g., OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) is increased when rosuvastatin is co-administered with certain medicinal products capable of increasing rosuvastatin plasma concentrations through interaction with these transporter proteins (e.g., cyclosporine and certain protease inhibitors, including ritonavir combinations with atazanavir, lopinavir and/or tipranavir). Prescribers are advised to review the relevant information on medicinal products considered for concomitant use with Rosulip®. Therefore, alternative treatments should be considered, and if necessary, temporary discontinuation of rosuvastatin therapy should be considered. In situations where concomitant administration of these medicinal products with rosuvastatin cannot be avoided, the benefits and risks of concomitant therapy should be carefully weighed, and the rosuvastatin dose should be carefully selected.

Children

The use of the medicinal product in children should be performed only by a specialist.

The medicinal product can be used in 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 recommended 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 recommended 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 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.

Homoygous 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 dose 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 treatment of this patient group at doses exceeding 20 mg is limited.

40 mg tablets are not to 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, Rosulip® 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 applied if necessary. Liver function and CK levels should be monitored. Hemodialysis is unlikely to be effective.

Adverse reactions

Adverse reactions observed during the use of the medicinal product Rosulip® are generally mild and transient. In controlled clinical studies, less than 4% of patients receiving rosuvastatin discontinued treatment due to adverse reactions.

List of adverse reactions in table form

Table 3 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.

According to frequency, adverse reactions are categorized as follows: common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10,000 to <1/1,000), very rare (<1/10,000), and not known (cannot be estimated from the available data).

Table 3

Adverse reactions based on data from 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 Rosulip®. Changes in urinary protein content from zero or trace to ++ or higher were observed in < 1% of patients at certain time points 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 changes from zero or trace to + was observed with the 20 mg dose. In most cases, proteinuria decreased or resolved spontaneously during continued therapy. Based on clinical studies and post-marketing surveillance data, no causal relationship between proteinuria and acute or progressive kidney disease has been established to date.

Cases of hematuria have been reported during treatment with Rosulip®; however, the frequency was low according to clinical trial data.

Musculoskeletal effects

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

In patients taking rosuvastatin, dose-dependent increases in creatine kinase (CK) levels have been observed; in most cases, this effect was mild, asymptomatic, and transient. If CK levels are elevated (> 5 times the upper limit of normal), treatment should be discontinued (see section "Special 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 effect was mild, asymptomatic, and transient. Increased HbA1c levels have also been observed during treatment with rosuvastatin.

Adverse reactions reported with some statins include:

Sexual dysfunction.

Isolated cases of interstitial lung disease, particularly with long-term use (see section "Special precautions for use").

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

Pediatric population

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 precautions for use"). However, the safety profile of rosuvastatin in children and adolescents was similar to that in adults.

Reporting of suspected adverse reactions

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

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in a place inaccessible to children.

Packaging.

7 tablets per blister; 2, 4, or 8 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Egis Pharmaceuticals PLC.

Manufacturer's address and location of manufacturing site.

For 5 mg dosage:

1165 Budapest, Bekényföldi Street 118-120, Hungary.

For 10 mg and 20 mg dosages:

9900 Kermend, Matyas kiraly Street 65, Hungary.

1165 Budapest, Bekényföldi Street 118-120, Hungary.