Lipretto

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

Composition:

Active substance: rosuvastatin;

One tablet contains 10.40 mg or 20.80 mg or 41.60 mg of rosuvastatin calcium, equivalent to 10 mg or 20 mg or 40 mg of rosuvastatin;

Excipients: lactose monohydrate; microcrystalline cellulose; calcium hydrogen phosphate; sodium croscarmellose; magnesium stearate; hypromellose; titanium dioxide (E 171); talc; polyethylene glycol 6000 (macrogol 6000).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: biconvex, round, white to almost white film-coated tablets.

Pharmacotherapeutic group

Lipid-lowering agents. HMG-CoA reductase inhibitors. Rosuvastatin.

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 rate-limiting step in the conversion of 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. The primary site of action of rosuvastatin is the liver, the target organ for reducing cholesterol levels.

Rosuvastatin increases the number of LDL receptors on the surface of hepatic cells, enhancing the uptake and catabolism of LDL, and inhibits hepatic synthesis of VLDL, 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 HDL-cholesterol levels. It also reduces levels of apolipoprotein B (apoB), non-HDL-C, LDL-C, triglyceride-rich VLDL, and increases 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.

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

Clinical efficacy and safety

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

Based on pooled Phase III trial data, rosuvastatin effectively reduced cholesterol levels in most 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 the 10 mg dose achieved EAS target LDL-C levels (< 3 mmol/L).

In a large study of 435 patients with heterozygous familial hypercholesterolemia, rosuvastatin was administered at doses from 20 to 80 mg using an up-titration dosing regimen. The beneficial effect of the medicinal product on lipid parameters and achievement of target levels was observed at all doses. After up-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 up-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 on average by 22 %.

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

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), a 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 of 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: -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. A direct correlation between reduction in CIMT and reduced risk of cardiovascular events has not been demonstrated. The METEOR study included patients with low risk of ischemic heart disease, who are not representative of the target population for 40 mg rosuvastatin. 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 effect of rosuvastatin on the incidence of major atherosclerotic cardiovascular diseases was evaluated in 17,802 men (≥ 50 years) and women (≥ 60 years).

Participants were randomly assigned to receive either placebo (n = 8901) or rosuvastatin 20 mg once daily (n = 8901) and were followed for a mean of 2 years.

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

In a retrospective 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 (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 retrospective analysis of another high-risk subgroup (9302 participants overall) with baseline SCORE ≥ 5 % (extrapolated to include participants over 65 years of age), a significant reduction in the incidence of the composite endpoint, including cardiovascular death, 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).

In the JUPITER study, 6.6 % of participants in the rosuvastatin group and 6.2 % in the placebo group discontinued the investigational medicinal product due to adverse reactions. The most common adverse reactions leading to 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 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 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

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), rosuvastatin was evaluated in patients aged 10–17 years (Tanner stages II–IV, girls with at least 1 year since menarche) with heterozygous familial hypercholesterolemia. For 12 weeks, patients received rosuvastatin at doses of 5, 10, or 20 mg/day or placebo, 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 aimed at achieving target levels (maximum dose 20 mg once daily), target LDL-C levels (< 2.8 mmol/L) were achieved in 70 of 173 patients (40.5 %).

After 52 weeks of investigational treatment, no effect on growth, weight, BMI, or sexual maturation was observed (see section "Special precautions for use"). This study (n = 176) is not suitable for comparison of rare adverse reactions.

Rosuvastatin was also evaluated in a 2-year open-label study with target dose titration in 198 children with heterozygous familial hypercholesterolemia aged 6 to 17 years (88 male and 110 female participants, Tanner stage < II–V). The initial dose for all patients was 5 mg rosuvastatin once daily. Patients aged 6 to 9 years (n = 64) were titrated to a maximum dose of 10 mg once daily, and patients aged 10 to 17 years (n = 134) to a maximum dose of 20 mg once daily.

After 24 months of treatment with rosuvastatin, the mean reduction from baseline LDL-C, estimated by least squares method, was -43 % (baseline: 236 mg/dL, month 24: 133 mg/dL). For each age group, the mean reduction from baseline LDL-C, estimated by least squares method, was -43 % (baseline: 234 mg/dL, month 24: 124 mg/dL), -45 % (baseline: 234 mg/dL, month 24: 124 mg/dL), and -35 % (baseline: 241 mg/dL, month 24: 153 mg/dL) in the age groups 6 to < 10, 10 to < 14, and 14 to < 18 years, respectively.

Treatment with rosuvastatin at doses of 5 mg, 10 mg, and 20 mg also resulted in statistically significant mean changes from baseline in the following secondary lipid and lipoprotein variables: HDL-C, total cholesterol, non-HDL-C, LDL-C/HDL-C ratio, total cholesterol/HDL-C ratio, triglycerides/HDL-C ratio, non-HDL-C/HDL-C ratio, apolipoprotein B (apoB), and apoB/apoA-1 ratio. Each of these changes demonstrated improved lipid responses and was maintained over 2 years.

After 24 months of treatment, no effect on growth, body weight, BMI, or sexual maturation was observed (see section "Special precautions for use").

In a randomized, double-blind, placebo-controlled, multicenter, crossover study, rosuvastatin 20 mg once daily was compared with placebo in 14 children and adolescents (aged 6 to 17 years) with homozygous familial hypercholesterolemia. The study included a 4-week active run-in phase with dietary adherence, during which patients received rosuvastatin 10 mg, a crossover phase consisting of a 6-week treatment period with rosuvastatin 20 mg preceded or followed by a 6-week placebo treatment, and a 12-week maintenance phase during which all patients received 20 mg rosuvastatin. Patients on ezetimibe or apheresis continued these treatments throughout the study.

A statistically significant (p = 0.005) reduction in LDL-C levels (22.3 %; 85.4 mg/dL or 2.2 mmol/L) was observed after 6 weeks of treatment with rosuvastatin 20 mg compared to placebo. Statistically significant reductions were also observed in total cholesterol (20.1 %, p = 0.003), non-HDL-C (22.9 %, p = 0.003), and apoB (17.1 %, p = 0.024). Reductions in triglycerides, LDL-C/HDL-C ratio, total cholesterol/HDL-C ratio, non-HDL-C/HDL-C ratio, and apoB/apoA-I ratio were also observed after 6 weeks of rosuvastatin 20 mg treatment compared to placebo. The reduction in LDL-C after 6 weeks of rosuvastatin 20 mg treatment followed by 6 weeks of placebo treatment was maintained over 12 weeks of continuous therapy. One patient showed further reductions in LDL-C (8.0 %), total cholesterol (6.7 %), and non-HDL-C (7.4 %) after 6 weeks of treatment with dose titration to 40 mg.

During continued open-label treatment with rosuvastatin 20 mg in 9 of these patients up to 90 weeks, LDL-C reduction was maintained between -12.1 % and -21.3 %.

In an open-label dose up-titration study in 7 evaluable children and adolescents (aged 8 to 17 years) with homozygous familial hypercholesterolemia (see above), the percentage reduction in LDL-C (21.0 %), total cholesterol (19.2 %), and non-HDL-C (21.0 %) from baseline after 6 weeks of treatment with rosuvastatin 20 mg corresponded to that observed in the aforementioned study in children and adolescents with homozygous familial hypercholesterolemia.

The European Medicines Agency has waived the obligation to submit results of rosuvastatin studies in all pediatric subgroups with homozygous familial hypercholesterolemia, primary combined (mixed) dyslipidemia, and for prevention of cardiovascular disorders (see section "Dosage and administration" for information on pediatric use).

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 extensively 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-mediated metabolism. The main isoenzyme involved is CYP2C9, with minor contributions from CYP2C19, 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 active substance), with the remainder excreted in urine. Approximately 5 % is excreted unchanged in urine. The plasma elimination half-life is approximately 19 hours and does not increase with dose escalation. The mean geometric value of plasma clearance is approximately 50 L/hour (coefficient of variation 21.7 %). As with other HMG-CoA reductase inhibitors, hepatic uptake of rosuvastatin occurs via the membrane transporter OATP-C, which plays an important role in 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 gender

No clinically significant effect of age or gender on the pharmacokinetics of rosuvastatin in adults has been observed. Rosuvastatin exposure in children and adolescents with heterozygous familial hypercholesterolemia was similar to or lower than that in adult patients with dyslipidemia (see section "Children").

Race

Pharmacokinetic studies have shown that median AUC and Cmax values in patients of Mongoloid race (Japanese, Chinese, Filipino, Vietnamese, and Korean) are approximately twice as high as in Caucasians; in Indian patients, median AUC and Cmax values are approximately 1.3 times higher. 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, no changes in plasma concentrations of rosuvastatin or N-desmethyl metabolite were observed in patients with mild or moderate impairment. In patients with severe renal impairment (creatinine clearance < 30 mL/min), plasma concentrations of rosuvastatin were 3 times higher and N-desmethyl metabolite levels 9 times higher than in healthy volunteers. Steady-state plasma concentrations of rosuvastatin in patients on hemodialysis were approximately 50 % higher than in healthy volunteers.

Hepatic impairment

In a study involving patients with varying degrees of hepatic impairment, no evidence of increased rosuvastatin exposure was observed in patients with Child-Pugh scores of 7 or less. However, in two patients with Child-Pugh scores of 8 and 9, systemic exposure was at least 2 times higher than in patients with lower scores. Experience with rosuvastatin in patients with Child-Pugh scores greater than 9 is lacking.

Genetic polymorphism

The distribution of HMG-CoA reductase inhibitors, including rosuvastatin, involves transporter proteins OATP1B1 and BCRP. Patients with genetic polymorphisms in SLCO1B1 (OATP1B1) and/or ABCG2 (BCRP) are at risk of increased rosuvastatin exposure. With specific polymorphisms SLCO1B1 c.521CC and ABCG2 c.421AA, rosuvastatin exposure (AUC) is increased compared to genotypes SLCO1B1 c.521TT or ABCG2 c.421CC. Specific genotyping is not required in clinical practice, but if a patient is known to have such polymorphism, a lower daily dose of rosuvastatin is recommended.

Children

Two pharmacokinetic studies of rosuvastatin (in tablet form) in children with heterozygous familial hypercholesterolemia aged 10–17 years or 6–17 years (total 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 activity, weight reduction) are insufficient.

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

Prevention of cardiovascular 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

LIPRETTO is contraindicated in:

• Patients with hypersensitivity to rosuvastatin or any of the excipients of the medicinal product;
• Patients with active liver disease, including persistent elevations of serum transaminases of unknown etiology, and any elevations of serum transaminases exceeding three times the upper limit of normal (ULN);
• Patients with severe renal impairment (creatinine clearance < 30 mL/min);
• Patients with myopathy;
• Patients receiving concomitant combination therapy with sofosbuvir/velpatasvir/voxilaprevir (see section "Interaction with other medicinal products and other forms of interaction");
• Patients receiving concomitant cyclosporine;
• During pregnancy and 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 with other HMG-CoA reductase inhibitors or fibrates;
• Alcohol abuse;
• Situations that may lead to increased plasma concentration of the medicinal product;
• Mongoloid race;
• Concomitant use of fibrates (see sections "Special precautions", "Interaction with other medicinal products and other forms of interaction", and "Pharmacokinetics").

Interaction with other medicinal products and other forms of interaction

Effect of concomitant medicinal products on rosuvastatin

Inhibitors of transport proteins

Rosuvastatin is a substrate for certain transport proteins, including the hepatic uptake transporter OATP1B1 and the efflux transporter BCRP. Concomitant use of LIPRETTO with medicinal products that inhibit these transport proteins may lead to increased plasma concentrations of rosuvastatin and an increased risk of myopathy (see sections "Dosage and administration", "Special precautions", "Interaction with other medicinal products and other forms of interaction", Table 2).

Cyclosporine

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

Concomitant use did not affect plasma concentrations of cyclosporine.

Protease inhibitors

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

Gemfibrozil and other lipid-lowering agents

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

Based on data from specific studies, a pharmacokinetically significant interaction with fenofibrate is not expected; however, a pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates, and lipid-lowering doses (≥ 1 g/day) of niacin (nicotinic acid) increase the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors, likely because they may cause myopathy when used alone. The 40 mg dose is contraindicated with concomitant use of fibrates (see sections "Contraindications" and "Special precautions"). Such patients should also initiate therapy with a 5 mg dose of rosuvastatin.

Ezetimibe

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

Antacid medicinal products

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

Erythromycin

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

Ticagrelor

Ticagrelor may cause renal impairment and 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, elevated CK levels, and rhabdomyolysis. Monitoring of renal function and CK levels is recommended when ticagrelor and rosuvastatin are used concomitantly.

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, drug interactions due to P450-mediated metabolism are not expected. No clinically significant interactions were observed between rosuvastatin and fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4).

Interactions requiring rosuvastatin dose adjustment (see also Table 2)

If coadministration of LIPRETTO with other medicinal products capable of increasing rosuvastatin exposure is necessary, the dose of LIPRETTO should be adjusted. If rosuvastatin exposure (AUC) is expected to increase by approximately 2-fold or more, treatment with rosuvastatin should be initiated at a dose of 5 mg* once daily. The maximum daily dose of LIPRETTO should be adjusted so that the expected rosuvastatin exposure does not exceed the exposure observed with a 40 mg/day dose in the absence of interacting medicinal products. For example, when used with gemfibrozil, the dose of LIPRETTO would be 20 mg (1.9-fold increase in exposure), and when used with ritonavir/atazanavir combination, 10 mg (3.1-fold increase in exposure).

If a medicinal product increases rosuvastatin AUC by less than 2-fold, the initial dose need not be reduced, but caution should be exercised when increasing the dose of LIPRETTO 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

* Rosuvastatin-containing medicinal products are used at the corresponding dosage.

** Data presented as fold change represent the ratio between administration of rosuvastatin in combination versus rosuvastatin alone. Data presented as % change represent the % difference relative to values observed with rosuvastatin administered alone.

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

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

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

Effect of rosuvastatin on concomitant medicinal products

Vitamin K antagonists

As with other HMG-CoA reductase inhibitors, initiation of treatment with the medicinal product LIPRETTO 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 LIPRETTO 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 LIPRETTO with oral contraceptives resulted in a 26% and 34% increase in AUC of ethinylestradiol and norgestrel, respectively. This increase in plasma levels should be considered when selecting the dose of oral contraceptives. There are no data on the pharmacokinetics of medicinal products in patients concurrently receiving rosuvastatin and HRT; therefore, a similar effect cannot be excluded. However, this combination has been widely used in women in 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 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. See also section "Special precautions".

Paediatric population

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

Special precautions for use

Renal effects

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

Musculoskeletal effects

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

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

Creatine kinase levels

Creatine kinase (CK) levels should not be measured following significant physical exertion or in the presence of other potential causes of elevated CK, which 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 results. If repeat testing confirms baseline CK levels exceeding 5 times the upper limit of normal, treatment should not be initiated.

Before initiating therapy

LIPRETTO, 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 medicinal product (see sections "Posology and method of administration", "Interaction with other medicinal products and other forms of interaction", and "Pharmacokinetics");
• 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 markedly elevated (> 5 times the upper limit of normal).

During treatment

Patients should be advised to report immediately any unexplained muscle pain, weakness, or cramps, particularly if accompanied by malaise or fever. CK levels should be measured in such patients. The medicinal product should be discontinued if CK levels are markedly elevated (> 5 × upper limit of normal) or if muscle symptoms are severe and cause daily discomfort (even if CK levels ≤ 5 × upper limit of normal). Therapy with LIPRETTO or an alternative HMG-CoA reductase inhibitor may be restarted at the lowest dose and under close supervision once symptoms have resolved and CK levels have returned to normal. Routine monitoring of CK levels in asymptomatic patients is not necessary. Very rare cases of immune-mediated necrotizing myopathy (IMNM) have been reported during or after statin therapy, including rosuvastatin. Clinical features of IMNM include proximal muscle weakness and elevated serum creatine kinase levels that persist even after discontinuation of statins.

There have been reports that statins, including rosuvastatin, may induce or exacerbate pre-existing myasthenia gravis or ocular myasthenia (see section "Adverse reactions"). If symptoms worsen, treatment with LIPRETTO should be discontinued. Recurrences have been reported upon initial or repeated use of the same or another statin.

Clinical trials have not shown increased musculoskeletal effects in a small number of patients taking rosuvastatin with concomitant medications. However, increased incidence of myositis and myopathy has been observed in patients taking other HMG-CoA reductase inhibitors concomitantly with fibric acid derivatives, including gemfibrozil, cyclosporine, 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, co-administration of LIPRETTO with gemfibrozil is not recommended. The benefit of further lipid-lowering with LIPRETTO 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").

LIPRETTO must not be co-administered with systemic fusidic acid or within 7 days of stopping fusidic acid treatment. In patients requiring systemic fusidic acid, statin therapy should be discontinued for the duration of fusidic acid treatment. Cases of rhabdomyolysis (including several fatal cases) have been reported in patients receiving concomitant fusidic acid and statins (see section "Interaction with other medicinal products and other forms of interaction"). Patients should be advised to seek immediate medical attention if they experience any symptoms of muscle weakness, pain, or tenderness. Statin therapy may be restarted seven days after the last dose of fusidic acid. In exceptional cases where prolonged systemic fusidic acid treatment is necessary, e.g., for treatment of severe infections, concomitant use of LIPRETTO and fusidic acid should only be considered on a case-by-case basis and under strict medical supervision.

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

Severe cutaneous adverse reactions

Severe cutaneous adverse reactions, including Stevens-Johnson syndrome and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been reported with rosuvastatin use and may be life-threatening or fatal. Patients should be informed of the signs and symptoms of severe skin reactions and closely monitored. If signs or symptoms suggestive of such reactions occur, LIPRETTO should be discontinued immediately and alternative therapy considered. If a patient develops such a serious reaction as Stevens-Johnson syndrome or DRESS syndrome, treatment with the medicinal product must be discontinued immediately and not resumed.

Hepatic effects

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

Liver function tests should be performed before starting treatment and again after 3 months. Treatment with LIPRETTO should be discontinued or the dose reduced if serum transaminase levels exceed three times the upper limit of normal. The frequency of post-marketing reports of serious hepatic events (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 LIPRETTO.

Race

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

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 LIPRETTO in HIV patients receiving protease inhibitors and the potential for increased plasma concentrations of rosuvastatin at the initiation of therapy and with dose escalation of LIPRETTO in patients receiving protease inhibitors should be considered. Concomitant use of the medicinal product with certain protease inhibitors is not recommended unless the dose of LIPRETTO is adjusted (see sections "Posology and method of administration" and "Interaction with other medicinal products and other forms of interaction").

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 (fatigue, weight loss, fever). If interstitial lung disease is suspected, statin therapy should be discontinued.

Diabetes mellitus

Evidence suggests that statins, as a class, increase blood glucose levels and may cause hyperglycemia requiring treatment in some patients at high risk of developing diabetes. However, the reduction in vascular risk with statin use outweighs this risk, and therefore should not be a reason to discontinue statin therapy. Patients at risk (fasting glucose 5.6–6.9 mmol/L, BMI > 30 kg/m², elevated triglycerides, 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.

Children

Assessment of linear growth (height), body weight, BMI, 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 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 52 weeks, CK elevations > 10 times the upper limit of normal and muscle symptoms following physical exertion or increased physical activity were observed more frequently than in adults (see section "Adverse reactions").

Use during pregnancy or breastfeeding

LIPRETTO is contraindicated during pregnancy and breastfeeding.

Women of childbearing potential must use appropriate contraceptive measures.

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

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

Ability to affect reaction speed when driving or operating machinery

Studies on the effect of rosuvastatin on the ability to drive or operate machinery have not been conducted. However, given the pharmacodynamic properties of the medicinal product, it is unlikely to affect such ability. Dizziness may occur during treatment and should be considered when driving or operating machinery.

Dosage and Administration

Prior to initiating therapy, patients should be placed on a standard cholesterol-lowering diet, which should be continued throughout treatment. The dosage should be individually adjusted depending on the therapeutic goal and the patient's response to treatment, in accordance with recommendations of current widely accepted guidelines.

LIPRETTO may be taken at any time of day, independently of food intake.

Treatment of hypercholesterolemia

The recommended initial dose is 5 mg* or 10 mg of rosuvastatin orally once daily, both for patients who have not previously been treated with statins and for those switching from another HMG-CoA reductase inhibitor. The selection of the initial dose should take into account individual patient cholesterol levels, future cardiovascular risk, and the likelihood of developing adverse reactions. 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 used only in patients with severe hypercholesterolemia and high cardiovascular risk (particularly those with familial hypercholesterolemia) who have not achieved treatment goals 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 a study assessing cardiovascular risk reduction, the medicinal product was administered at a dose of 20 mg daily (see section "Pharmacodynamics").

Elderly patients

The recommended initial dose for patients aged >70 years is 5 mg* of rosuvastatin (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 in patients with mild or moderate renal dysfunction.

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

Patients with hepatic impairment

No increase in systemic exposure to rosuvastatin was observed in patients with hepatic dysfunction scoring 7 or less on the Child–Pugh scale. However, increased systemic exposure was observed in patients scoring 8 or 9 on the Child–Pugh scale (see section "Pharmacokinetics"). In such patients, renal function assessment is advisable (see section "Special Warnings and Precautions for Use"). Experience with the medicinal product in patients scoring more than 9 on the Child–Pugh scale is lacking. LIPRETTO 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 Mongolian race (see sections "Contraindications", "Special Warnings and Precautions for Use", and "Pharmacokinetics"). The recommended initial dose for patients of Mongolian race is 5 mg* of rosuvastatin; the 40 mg dose is contraindicated in these patients.

Genetic polymorphism

Certain types of genetic polymorphism may lead to increased rosuvastatin exposure (see section "Pharmacokinetics"). Patients known to have such polymorphism types should be prescribed a lower daily dose of LIPRETTO.

Patients predisposed to myopathy

The recommended initial dose for patients with risk factors for myopathy is 5 mg* of rosuvastatin (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) increases when LIPRETTO 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; see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction"). Where possible, alternative medicinal products should be considered, and temporary interruption of LIPRETTO therapy may be necessary. If concomitant use of these medicinal products with LIPRETTO cannot be avoided, the benefit and risk of concomitant therapy should be carefully weighed, and the LIPRETTO dose should be adjusted accordingly (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

* Medicinal products containing rosuvastatin in the appropriate dosage strength should be used.

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* of rosuvastatin.

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

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

The dose should be increased according to the individual child's response to treatment and drug tolerability, in accordance with recommendations for pediatric treatment (see section "Special Warnings and Precautions for Use"). Prior to initiating rosuvastatin therapy, children and adolescents should be placed on a standard cholesterol-lowering diet, which should be maintained throughout treatment.

Homoyzgous 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 of rosuvastatin once daily, depending on the patient's age, body weight, and prior statin use. Dose escalation to the maximum of 20 mg once daily should be based on the individual child's response to treatment and drug tolerability, in accordance with recommendations for pediatric treatment (see section "Special Warnings and Precautions for Use"). Prior to initiating rosuvastatin therapy, children and adolescents should be placed on a standard cholesterol-lowering diet, which should be maintained throughout treatment.

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

40 mg tablets should not be used in children.

* Medicinal products containing rosuvastatin in the appropriate dosage strength should be used.

Children under 6 years of age

The safety and efficacy of rosuvastatin in children under 6 years of age have not been established. Therefore, LIPRETTO is not recommended for use in children under 6 years of age.

Overdose

There is no specific antidote for overdose. In case of overdose, symptomatic treatment should be administered and supportive measures taken as necessary. Liver function and CK levels should be monitored. Hemodialysis is unlikely to be effective.

Adverse Reactions

Adverse events observed during rosuvastatin use are generally mild and transient. In controlled clinical trials, less than 4% of patients receiving rosuvastatin discontinued treatment due to adverse reactions.

Adverse reaction list

Below is the profile of adverse reactions to rosuvastatin based on clinical trial data and extensive post-marketing experience. Adverse reactions are classified by frequency and by system organ classes.

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

Blood and lymphatic system disorders: rare – thrombocytopenia.

Immune system disorders: rare – hypersensitivity reactions, including angioedema.

Endocrine disorders: common – diabetes mellitus^1.

Psychiatric disorders: frequency not known – depression.

Nervous system disorders: common – headache, dizziness; very rare – polyneuropathy, memory loss; frequency not known – peripheral neuropathy, sleep disorders (including insomnia and nightmares), myasthenia gravis.

Eye disorders: frequency not known – ocular myasthenia.

Respiratory, thoracic and mediastinal disorders: frequency not known – cough, dyspnea.

Gastrointestinal disorders: common – constipation, nausea, abdominal pain; rare – pancreatitis; frequency not known – diarrhea.

Hepatobiliary disorders: rare – increased levels of liver transaminases; very rare – jaundice, hepatitis.

Skin and subcutaneous tissue disorders: uncommon – pruritus, rash, urticaria; frequency not known – Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS).

Musculoskeletal and connective tissue disorders: common – myalgia; rare – myopathy (including myositis), rhabdomyolysis, lupus-like syndrome, muscle rupture; very rare – arthralgia; frequency not known – tendon disorders, sometimes complicated by tendon rupture, immune-mediated necrotizing myopathy.

Renal and urinary disorders: very rare – hematuria.

Reproductive system and breast disorders: very rare – gynecomastia.

General disorders and administration site conditions: common – asthenia; frequency not known – edema.

^1 Frequency depends on the presence of risk factors (fasting glucose ≥ 5.6 mmol/L, BMI > 30 kg/m², elevated triglyceride levels, history of 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 taking rosuvastatin. Changes in urinary protein content from zero or trace to ++ or higher were observed in < 1% of patients intermittently during treatment with 10 mg and 20 mg doses, and in approximately 3% of patients receiving the 40 mg dose. A slight increase in the frequency of changes from zero or trace to + was observed at the 20 mg dose. In most cases, proteinuria decreased or resolved spontaneously while continuing therapy. To date, based on clinical trials and post-marketing surveillance, no causal relationship has been established between proteinuria and acute or progressive kidney disease.

Hematuria has been reported during rosuvastatin use; however, its frequency in clinical trials was low.

Musculoskeletal effects

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

In patients taking rosuvastopen, dose-dependent increases in creatine kinase (CK) levels have been observed; in most cases, this 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").

Hepatic effects

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

With some statins, adverse events such as sexual dysfunction and rare cases of interstitial lung disease, particularly with long-term use, have been reported (see section "Special precautions").

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

Children

Elevations in creatine kinase 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"). However, the safety profile of rosuvastatin in children and adolescents was similar to that in adults.

Reporting suspected adverse reactions after medicine authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, or their legal representatives, are encouraged to report all suspected adverse reactions and lack of 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 mg and 20 mg tablets

10 tablets per blister, 3 blisters together with the instruction for medical use in a cardboard box; or 9 blisters together with the instruction for medical use in a cardboard box.

Alternatively, 30 tablets in a bottle, 1 bottle together with the instruction for medical use in a cardboard box.

40 mg tablets

10 tablets per blister, 3 blisters together with the instruction for medical use in a cardboard box.

Alternatively, 30 tablets in a bottle, 1 bottle together with the instruction for medical use in a cardboard box.

Prescription status

Prescription only.

Manufacturer

LLC NPF "MIKROKHEM" (responsible for batch release, excluding batch control/testing).

Manufacturer's location and address of place of business

5, Budyndustrії St., Kyiv, 01013, Ukraine.

Marketing authorization holder

LLC NPF "MIKROKHEM".

Address of the marketing authorization holder

5, Budyndustrії St., Kyiv, 01013, Ukraine.

You can report an adverse event associated with this medicine at +38 (050) 309-83-54 (24/7).