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

Composition:

Active substance: rosuvastatin;

1 tablet contains rosuvastatin 10 mg in the form of rosuvastatin calcium 10.40 mg or rosuvastatin 20 mg in the form of rosuvastatin calcium 20.80 mg;

Excipients: lactose monohydrate, microcrystalline cellulose, calcium hydrogen phosphate, crospovidone, povidone, magnesium stearate, Opadry II 85F pink.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex film-coated tablets of pink color.

Pharmacotherapeutic group. Hypolipidemic agents.

HMG-CoA reductase inhibitors. Rosuvastatin. ATC code C10AA07.

Pharmacological Properties

Pharmacodynamics

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

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

The medicinal product reduces elevated levels of low-density lipoprotein cholesterol (LDL-C), total cholesterol, and triglycerides (TG), and increases high-density lipoprotein cholesterol (HDL-C) levels. It also reduces levels of apolipoprotein B (apoB), non-HDL-C, VLDL-C, VLDL-TG, and increases levels of apolipoprotein A-1 (apoA-I) [see Table 1].

The medicinal product 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)

Dose	N	LDL-C	Total Cholesterol	HDL-C	Triglycerides	non-HDL-C	apoB	apoA-I
Placebo	13	-7	-5	3	-3	-7	-3	0
5	17	-45	-33	13	-35	-44	-38	4
10	17	-52	-36	14	-10	-48	-42	4
20	17	-55	-40	8	-23	-51	-46	5
40	18	-63	-46	10	-28	-60	-54	0

The therapeutic effect is achieved within 1 week after initiation of treatment, with 90% of the maximum effect reached within 2 weeks. The maximum effect is usually achieved 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, sex, or age, as well as in patients from special populations such as those with diabetes or familial hypercholesterolemia.

Based on pooled data from phase III trials, 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 established 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 involving 435 patients with heterozygous familial hypercholesterolemia, rosuvastatin was administered at doses ranging from 20 mg to 80 mg according to an intensified dose-titration regimen. A favorable effect on lipid parameters and achievement of target levels were observed at all doses. After titration to a daily dose of 40 mg (12 weeks of treatment), LDL-C decreased by 53%. 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 (including 8 children) with homozygous familial hypercholesterolemia. In the overall population, LDL-C levels decreased on average by 22%.

In clinical trials involving a limited number of patients, an additive effect of rosuvastatin on triglyceride reduction was observed when used in combination with fenofibrate, and an increase in HDL-C was observed when used in combination with niacin (see section "Special Warnings and 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 to receive either 40 mg of rosuvastatin once daily or placebo for 2 years. Compared with 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 not significant]) in the rosuvastatin group compared with progression of +0.0131 mm/year (1.12%/year [p<0.0001]) in the placebo group. A direct correlation between CIMT reduction and reduced cardiovascular risk 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 the 40 mg dose of the medicinal product Preventor. The 40 mg dose should only be prescribed to patients with severe hypercholesterolemia and high cardiovascular risk (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 events was evaluated in 17,802 men (≥50 years) and women (≥60 years).

Study participants were randomly assigned to receive either 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 with the placebo group.

In a post-hoc analysis of a high-risk subgroup with a baseline Framingham risk score >20% (1558 participants), a significant reduction in the composite endpoint including cardiovascular death, stroke, and myocardial infarction was observed in the rosuvastatin group compared with 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 a baseline SCORE risk ≥5% (extrapolated to include data from 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 with 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 trial, 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 menarche) 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 with 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), 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, body weight, body mass index (BMI), or sexual maturation was observed (see section "Special Warnings and 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 targeted 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 of rosuvastatin once daily. Patients aged 6 to 9 years (n = 64) were titrated up to a maximum dose of 10 mg once daily, and patients aged 10 to 17 years (n = 134) were titrated up to a maximum dose of 20 mg once daily.

After 24 months of rosuvastatin treatment, the least-squares mean reduction in LDL-C from baseline was -43% (baseline: 236 mg/dL, month 24: 133 mg/dL). For each age group, the least-squares mean reduction in LDL-C from baseline 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 secondary lipid and lipoprotein variables: HDL-C, total cholesterol, non-HDL-C, LDL-C/HDL-C, total cholesterol/HDL-C, triglycerides/HDL-C, non-HDL-C/HDL-C, apolipoprotein B (apoB), and apoB/apoA-1. 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 Warnings and 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 diet and treatment with rosuvastatin 10 mg, a crossover phase consisting of a 6-week treatment 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 of rosuvastatin. Patients receiving ezetimibe or apheresis continued this treatment throughout the study.

A statistically significant (p = 0.005) reduction in LDL-C (22.3%; 85.4 mg/dL, or 2.2 mmol/L) was observed after 6 weeks of treatment with rosuvastatin 20 mg compared with 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, total cholesterol/HDL-C, non-HDL-C/HDL-C, and apoB/apoA-I were also observed after 6 weeks of treatment with rosuvastatin 20 mg compared with placebo. The reduction in LDL-C after 6 weeks of treatment with rosuvastatin 20 mg followed by 6 weeks of placebo treatment was maintained during 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 up 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-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 was consistent with 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, which is the primary site of cholesterol synthesis and LDL-C clearance. The volume of distribution of rosuvastatin is approximately 134 L. Approximately 90% of rosuvastatin is bound to plasma proteins, primarily to albumin.

Metabolism

Rosuvastatin undergoes minimal metabolism (approximately 10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a weak substrate for cytochrome P450 enzyme-based metabolism. The main isoenzyme involved is CYP2C9, with minor contributions from CYP2C19, CYP3A4, and CYP2D6. 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 activity of circulating HMG-CoA reductase inhibitors.

Elimination

Approximately 90% of the rosuvastatin dose is excreted unchanged in feces (including both absorbed and unabsorbed drug), and the remainder is 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 geometric mean value of plasma clearance is approximately 50 L/h (coefficient of variation: 21.7%). As with other HMG-CoA reductase inhibitors, hepatic uptake of rosuvastatin occurs via the membrane transporter OATP-C, which plays an important role in the hepatic elimination of rosuvastatin.

Linearity

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

Special Patient Populations

Age and Sex

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

Race

Pharmacokinetic studies have shown that median values of the area under the concentration-time curve (AUC) and maximum concentration (Cmax) in patients of Mongoloid race (Japanese, Chinese, Filipinos, Vietnamese, and Koreans) are approximately twice as high as in Caucasians; in Indians, 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 the N-desmethyl metabolite were observed in patients with mild or moderate renal 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 were 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 patients with varying degrees of hepatic impairment with Child-Pugh scores of 7 or lower, no increase in the elimination half-life of rosuvastatin was observed. However, in patients with Child-Pugh scores of 8 and 9, the half-life was approximately doubled compared to patients with lower scores. Experience with rosuvastatin in patients with Child-Pugh scores above 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) have an increased risk of elevated rosuvastatin exposure (AUC). In individuals with the SLCO1B1 c.521CC and/or ABCG2 c.421AA polymorphisms, rosuvastatin exposure is increased compared to those with SLCO1B1 c.521TT or ABCG2 c.421CC genotypes. Routine genotyping is not required in clinical practice, but patients with these polymorphisms should be prescribed a lower daily dose of the medicinal product.

Children

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

Clinical characteristics.

Indications.

Treatment of hypercholesterolemia

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

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

Prevention of cardiovascular events

Prevention of major cardiovascular events in patients at high risk of a first cardiovascular event, as an adjunct to correction of other risk factors.

Contraindications.

Hypersensitivity to rosuvastatin or to any of the excipients of the medicinal product.
Active liver disease, including persistent elevations of serum transaminases of unknown etiology, and any increase in serum transaminases exceeding three times the upper limit of normal.
Severe renal impairment (creatinine clearance < 30 mL/min).
Myopathy.
Concomitant use with the combination sofosbuvir/velpatasvir/voxilaprevir (see section "Interaction with other medicinal products and other forms of interaction").
Concomitant use with cyclosporine.
Pregnancy or breastfeeding. The medicinal product is contraindicated in women of childbearing potential who are not using appropriate contraceptive measures.

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

Moderate renal impairment (creatinine clearance < 60 mL/min);
Hypothyroidism;
Personal or family history of hereditary muscular disorders;
History of myotoxicity induced by other HMG-CoA reductase inhibitors or fibrates;
Alcohol abuse;
Situations that may lead to increased plasma concentration of rosuvastatin;
Patients of Mongolian race;
Concomitant use of fibrates (see sections "Pharmacokinetics", "Interaction with other medicinal products and other forms of interaction", and "Special warnings and precautions for use").

Interaction with other medicinal products and other forms of interaction.

Effect of concomitant drugs on rosuvastatin

Inhibitors of transport proteins

Rosuvastatin is a substrate for certain transporter proteins, particularly the hepatic uptake transporter OATP1B1 and the efflux transporter BCRP. Concomitant use of rosuvastatin 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 forms of interaction", "Special warnings and precautions for use", and "Dosage and administration", Table 2).

Cyclosporine

During concomitant use, AUC values of rosuvastatin were on average approximately 7 times higher than those observed in healthy volunteers (see Table 2). The medicinal product Prevenitor is contraindicated in patients receiving cyclosporine concomitantly (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 substantially increase the AUC of rosuvastatin (see Table 2). For example, in a pharmacokinetic study, concomitant administration of 10 mg rosuvastatin and a combined medicinal product containing two protease inhibitors (300 mg atazanavir/100 mg ritonavir) in healthy volunteers resulted in approximately 3- and 7-fold increases in AUC and Cmax of rosuvastatin, respectively. Concomitant use of Prevenitor with certain combinations of protease inhibitors may be possible after careful consideration of dose adjustment, taking into account the expected increase in rosuvastatin AUC (see sections "Interaction with other medicinal products and other forms of interaction", "Special warnings and precautions for use", and "Dosage and administration", 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 warnings and precautions for use").

Based on data from specific studies, no pharmacokinetically significant interaction with fenofibrate is expected; however, pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates, and lipid-lowering doses of niacin (nicotinic acid) (≥1 g/day) 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 warnings and precautions for use"). Such patients should also initiate therapy with a 5 mg dose.

Ezetimibe

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

Antacids

Concomitant use of rosuvastatin with antacid suspensions 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 rosuvastatin accumulation. Although the exact mechanism is unknown, in some cases, concomitant use of ticagrelor and rosuvastatin has led to impaired renal function, elevated creatine phosphokinase (CPK) levels, and rhabdomyolysis. Monitoring of renal function and CPK 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. Furthermore, rosuvastatin is a weak substrate of these isoenzymes. Therefore, drug interactions resulting from 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 use of Prevenitor with other medicinal products capable of increasing rosuvastatin AUC is necessary, the dose of Prevenitor should be adjusted. If an increase in rosuvastatin AUC of approximately 2-fold or more is expected, treatment should be initiated at a dose of 5 mg once daily. The maximum daily dose of Prevenitor should be adjusted so that the expected rosuvastatin AUC does not exceed the AUC observed with a 40 mg/day dose without interacting agents; for example, when used with gemfibrozil, the dose of Prevenitor would be 20 mg (1.9-fold increase in exposure), and when used with the ritonavir/atazanavir combination, 10 mg (3.1-fold increase).

If a medicinal product increases rosuvastatin AUC by less than 2-fold, the initial dose need not be reduced; however, caution should be exercised when increasing the dose of Prevenitor above 20 mg.

Table 2

Effect of concomitant medicinal products on rosuvastatin exposure

(AUC; in descending order of magnitude)

Dosing regimen of the interacting drug	Dosing regimen of rosuvastatin	Changes in rosuvastatin AUC*
Sofosbuvir/velpatasvir/voxilaprevir (400 mg-100 mg-100 mg) + voxilaprevir (100 mg) once daily for 15 days	10 mg, single dose	↑ 7.4-fold
Cyclosporine from 75 mg twice daily up to 200 mg twice daily, 6 months	10 mg once daily, 10 days	↑ 7.1-fold
Atazanavir 300 mg/ritonavir 100 mg once daily, 8 days	10 mg, single dose	↑ 3.1-fold
Simeprevir 150 mg once daily, 7 days	10 mg, single dose	↑ 2.8-fold
Lopinavir 400 mg/ritonavir 100 mg twice daily, 17 days	20 mg once daily, 7 days	↑ 2.1-fold
Capmatinib 400 mg twice daily	10 mg, single dose	↑ 2.1-fold
Clopidogrel 300 mg single loading dose, then 75 mg for 24 hours	20 mg, single dose	↑ 2.0-fold
Fostamatinib 100 mg twice daily	20 mg, single dose	↑ 2.0-fold
Febuxostat 120 mg once daily	10 mg, single dose	↑ 1.9-fold
Gemfibrozil 600 mg twice daily, 7 days	80 mg, single dose	↑ 1.9-fold
Eltrombopag 75 mg once daily, 5 days	10 mg, single dose	↑ 1.6-fold
Darunavir 600 mg/ritonavir 100 mg twice daily, 7 days	10 mg once daily, 7 days	↑ 1.5-fold
Tipranavir 500 mg/ritonavir 200 mg twice daily, 11 days	10 mg, single dose	↑ 1.4-fold
Dronedarone 400 mg twice daily	data not available	↑ 1.4-fold
Itraconazole 200 mg once daily, 5 days	10 mg, single dose	↑ 1.4-fold **
Ezetimibe 10 mg once daily, 14 days	10 mg once daily, 14 days	↑ 1.2-fold **
Erythromycin 500 mg four times daily, 7 days	80 mg, single dose	↓ 20%
Baykaline 50 mg three times daily, 14 days	20 mg, single dose	↓ 47%
Regorafenib 160 mg once daily, 14 days	5 mg, single dose	↑ 3.8-fold
Velpatasvir 100 mg once daily	10 mg, single dose	↑ 2.7-fold
Obitasvir 25 mg/paritaprevir 150 mg/ ritonavir 100 mg once daily/dasabuvir 400 mg twice daily, 14 days	5 mg, single dose	↑ 2.6-fold
Teriflunomide	data not available	↑ 2.5-fold
Glecaprevir 200 mg/elbasvir 50 mg once daily, 11 days	10 mg, single dose	↑ 2.3-fold
Glecaprevir 400 mg/pibrentasvir 120 mg once daily, 7 days	5 mg once daily, 7 days	↑ 2.2-fold

* Data presented as fold change represent the ratio between concomitant use of rosuvastatin and rosuvastatin alone. Data presented as % change represent the % difference relative to values observed with rosuvastatin alone.

Increases are indicated by ↑, decreases by ↓.

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

Drugs/combinations that showed no clinically significant effect on rosuvastatin AUC 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 medications

Vitamin K antagonists

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

Oral contraceptives/hormone replacement therapy (HRT)

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

Digoxin

According to interaction studies, no clinically significant interaction is expected.

Fusidic acid

Drug interaction studies between rosuvastatin and fusidic acid have not been conducted. The risk of myopathy, including rhabdomyolysis, may increase when systemic fusidic acid is used concomitantly with statins. The mechanism of this interaction (pharmacodynamic, pharmacokinetic, or both) is not yet known. Cases of rhabdomyolysis (including some fatal cases) have been reported in patients receiving this combination.

In patients for whom systemic fusidic acid is considered necessary, treatment with rosuvastatin (Preventor) should be discontinued for the entire duration of fusidic acid therapy. See also section "Special precautions for use".

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 urine dipstick testing and predominantly of tubular origin has been observed in patients treated with higher doses of rosuvastatin, particularly 40 mg, and was mostly transient or intermittent. Proteinuria was not a predictor of acute or progressive renal disease (see section "Adverse reactions").

Renal adverse reactions occurred more frequently with the 40 mg dose. Patients receiving rosuvastatin at 40 mg should have regular monitoring of renal function.

Skeletal muscle effects

Adverse effects on the musculoskeletal system, such as myalgia, myopathy, and rarely rhabdomyolysis, have been observed in patients taking rosuvastatin at any dose, particularly at doses exceeding 20 mg. Isolated cases of rhabdomyolysis have been reported with ezetimibe used in combination with HMG-CoA reductase inhibitors. A pharmacodynamic interaction cannot be excluded; therefore, such combination should be used with caution.

As with other HMG-CoA reductase inhibitors, reports of rhabdomyolysis associated with rosuvastatin have occurred more frequently with the 40 mg dose.

Creatine phosphokinase (CPK) measurement

CPK levels should not be measured following significant physical exertion or in the presence of possible alternative causes of elevated CPK, which may complicate interpretation of results. If baseline CPK levels are markedly elevated (> 5 times the upper limit of normal), a repeat confirmatory test should be performed within 5–7 days. If the repeat test confirms levels > 5 times the upper limit of normal, treatment should not be initiated.

Before starting treatment

Rosuvastatin, like other HMG-CoA reductase inhibitors, should be prescribed with caution in patients with risk factors for developing myopathy/rhabdomyolysis.

These risk factors include:

renal impairment;
hypothyroidism;
personal or family history of hereditary muscular 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 rosuvastatin (see sections "Pharmacokinetics", "Interaction with other medicinal products and other forms of interaction", and "Method of administration and dosage");
concomitant use of fibrates.

In such patients, the treatment-related risk should be evaluated against the expected benefit; clinical monitoring is also recommended. Treatment should not be initiated if baseline CPK levels are markedly elevated (> 5 times the upper limit of normal).

During treatment

Patients should be advised to promptly inform their physician of any unexplained muscle pain, weakness, or tenderness, especially if accompanied by malaise or fever. In such patients, CPK levels should be measured. The medicinal product should be discontinued if CPK levels are markedly elevated (> 5 times the upper limit of normal) or if muscle symptoms are severe and cause daily discomfort (even if CPK ≤ 5 times the upper limit of normal). After symptoms resolve and CPK levels normalize, therapy with rosuvastatin or an alternative HMG-CoA reductase inhibitor may be restarted at the lowest dose under close supervision. Routine monitoring of CPK levels in patients without the aforementioned symptoms is not required. 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 CPK levels, which persist even after discontinuation of statins.

Myasthenia

In isolated cases, statins have been reported to induce de novo or exacerbate pre-existing myasthenia gravis or ocular myasthenia (see section "Adverse reactions"). In case of symptom exacerbation, treatment with the medicinal product Prevator should be discontinued. Recurrences have been reported upon re-administration of the same or another statin.

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

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

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

Severe skin adverse reactions

Severe skin adverse reactions, including Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS), which may be life-threatening or fatal, have been reported with rosuvastatin (see section "Adverse reactions"). Patients should be informed about the signs and symptoms of severe skin reactions, and careful monitoring during treatment is required. If signs or symptoms indicating such reactions occur, use of the medicinal product Prevator should be immediately discontinued and alternative treatment considered. If a patient develops a serious reaction such as Stevens-Johnson syndrome or DRESS related to Prevator, re-initiation of treatment with this drug is not permitted.

Hepatic effects

As with other HMG-CoA reductase inhibitors, the medicinal product Prevator should be used with caution in patients who abuse alcohol and/or have a history of liver disease.

It is recommended to assess hepatic biochemical parameters before starting treatment and after 3 months of treatment. The use of the drug should be discontinued or the dose reduced if serum transaminase levels exceed three times the upper limit of normal. The frequency of reports of serious hepatic adverse reactions (mainly elevated liver transaminases) is 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 Prevator.

Rare cases of fatal or non-fatal hepatic failure have been reported in patients taking statins, including rosuvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice develops during treatment with rosuvastatin, the drug should be discontinued immediately. If no other causes are identified, re-initiation of Prevator should not be attempted.

Race

Pharmacokinetic studies have shown approximately a twofold increase in AUC in Mongoloid race patients compared to Caucasian patients. Dose adjustment of rosuvastatin is required for such patients (see sections "Pharmacokinetics", "Contraindications", and "Method of administration and dosage"). Increased systemic exposure should be considered when treating Mongoloid race patients whose hypercholesterolemia is not adequately controlled with doses up to 20 mg.

Protease inhibitors

Increased systemic exposure to rosuvastatin has been observed in individuals taking rosuvastatin concomitantly with various protease inhibitors, particularly in combination with ritonavir. Both the benefit of lipid-lowering with rosuvastatin in HIV patients receiving protease inhibitors and the potential for increased plasma concentrations of rosuvastatin at the start of therapy and with dose escalation in patients receiving protease inhibitors should be carefully considered. Concomitant use of rosuvastatin with protease inhibitors is not recommended unless the dose of the medicinal product is adjusted (see sections "Interaction with other medicinal products and other forms of interaction" and "Method of administration and dosage").

Lactose intolerance

This medicinal product contains lactose monohydrate and should not be used 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

Some data suggest that statins increase blood glucose levels and may induce hyperglycemia requiring treatment in some patients at high risk of developing diabetes. However, the reduction in vascular risk with statin use outweighs this risk, which should not be a reason to discontinue statin therapy. Clinical and biochemical monitoring is recommended for patients at risk (fasting glucose 5.6–6.9 mmol/L, BMI > 30 kg/m², elevated triglycerides, arterial hypertension).

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 sexual maturation characteristics by Tanner stage in children aged 6 to 17 years taking rosuvastatin is limited to a 2-year period. During this period, no effect on growth, body weight, BMI, or sexual maturation was observed (see section "Pharmacodynamics"). Clinical experience with the use of the drug in children and adolescents is limited, and long-term effects (>1 year) of rosuvastatin on sexual maturation are unknown.

In children and adolescents taking rosuvastatin, CPK levels > 10 times the upper limit of normal and muscle symptoms following physical exertion or increased physical activity occurred more frequently than in adults (see section "Adverse reactions").

Excipients

This medicinal product contains lactose monohydrate; therefore, if intolerance to certain sugars is diagnosed, consultation with a physician is necessary before taking this medicinal product.

Use during pregnancy or breastfeeding

The medicinal product is contraindicated during pregnancy and breastfeeding.

Women of childbearing potential should use appropriate contraceptive measures.

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

Rosuvastatin is excreted into rat milk. There are no data on the excretion of rosuvastatin 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 drug, it is unlikely that Prevator will affect such ability. When driving or operating machinery, the possibility of dizziness during rosuvastatin treatment should be considered.

Dosage and Administration

Before initiating treatment, patients should be placed on a standard cholesterol-lowering diet, which should be maintained throughout the treatment period. The dose should be individually adjusted based on therapeutic goals and the patient's response to treatment, in accordance with current guidelines.

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

Hypercholesterolemia treatment

The recommended initial dose is 5 mg* or 10 mg orally once daily, both for patients who have not previously used statins and for those switching from another HMG-CoA reductase inhibitor to rosuvastatin. The initial dose should be selected based on the individual patient's cholesterol levels, future cardiovascular risk, and the potential for adverse reactions. Dose increases to the next level may be considered after 4 weeks if necessary (see section "Pharmacodynamics"). Since adverse reactions occur more frequently with rosuvastatin 40 mg compared to lower doses (see section "Adverse Reactions"), dose titration up to 40 mg should be reserved only for 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"). Close medical supervision is recommended when initiating treatment with the 40 mg dose.

Prevention of cardiovascular disorders

In clinical trials aimed at reducing the risk of cardiovascular events, rosuvastatin was administered at a dose of 20 mg once daily (see section "Pharmacodynamics").

Elderly patients

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

Patients with renal impairment

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

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

Patients with hepatic impairment

No increase in systemic exposure to rosuvastatin was observed in patients with hepatic impairment 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"). Renal function assessment is advisable in these patients (see section "Special Warnings and Precautions for Use"). Experience with rosuvastatin in patients scoring more than 9 points on the Child-Pugh scale is lacking. Rosuvastatin is contraindicated in patients with active liver disease (see section "Contraindications").

Race

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

Genetic polymorphism

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

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 patients predisposed to myopathy/rhabdomyolysis (see section "Contraindications").

Concomitant use

Rosuvastatin is a substrate for various transporter proteins (e.g., OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) increases when rosuvastatin is co-administered with certain medicinal products that may increase plasma concentrations of rosuvastatin 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"). Alternative therapies should be considered whenever possible, and temporary interruption of Prevenor therapy may be necessary. If concomitant use of these medicinal products with Prevenor cannot be avoided, the benefit-risk balance should be carefully evaluated, and the dose of Prevenor should be adjusted accordingly (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Children

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

It is used in children and adolescents aged 6 to 17 years (boys at Tanner stage II or higher and girls who have had menstruation for at least one year).

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

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

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

Homozygous familial hypercholesterolemia

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

The recommended initial dose is 5 mg to 10 mg once daily, depending on age, body weight, and prior statin use. Dose escalation up to the maximum dose of 20 mg once daily should be based on 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 cholesterol-lowering diet, which should be maintained throughout treatment.

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

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

Children under 6 years of age

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

Overdose.

There is no specific antidote for overdose. Treatment is symptomatic and supportive therapy is recommended. Liver function and creatine kinase (CK) levels should be monitored. Hemodialysis is unlikely to be effective.

Adverse reactions.

Adverse reactions observed during the use of rosuvastatin are generally mild and transient. Adverse reactions are classified by frequency and system organ classes (SOC). By frequency, adverse reactions are categorized as follows: common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from available data).

Eye disorders:

frequency not known: ocular myasthenia.

Respiratory, thoracic and mediastinal disorders:

frequency not known: cough, dyspnoea.

Gastrointestinal disorders:

common: constipation, nausea, abdominal pain;

rare: pancreatitis;

frequency not known: diarrhoea.

Hepatobiliary disorders:

rare: increased levels of liver transaminases;

very rare: jaundice, hepatitis.

Renal and urinary disorders:

very rare: haematuria.

Endocrine disorders:

common: diabetes mellitus (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).

Nervous system disorders:

common: headache, dizziness;

very rare: polyneuropathy, memory loss;

frequency not known: peripheral neuropathy, sleep disorders (including insomnia and nightmares), myasthenia gravis.

Psychiatric disorders:

frequency not known: depression.

Blood and lymphatic system disorders:

rare: thrombocytopenia.

Immune system disorders:

rare: hypersensitivity reactions, including angioedema.

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 ruptures;

immune-mediated necrotizing myopathy.

Reproductive system and breast disorders:

very rare: gynaecomastia.

General disorders and administration site conditions:

common: asthenia;

frequency not known: oedema.

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

Renal effects

Proteinuria, detected by urine dipstick testing and predominantly of tubular origin, has been observed in patients treated with rosuvastatin. 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 at the 20 mg dose. In most cases, proteinuria decreased or resolved spontaneously during continued therapy. Based on clinical studies and post-marketing surveillance, to date there is no evidence of a causal relationship between proteinuria and acute or progressive kidney disease.

Cases of haematuria have been observed during rosuvastatin treatment; according to clinical trial data, the frequency 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 rosuvastatin, 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, dose-dependent increases in transaminase levels have been observed in a small number of patients treated with rosuvastatin; in most cases, this was mild, asymptomatic, and transient. Increases in HbA1c levels have also been observed during rosuvastatin use.

Adverse reactions reported with some statins include:

sexual dysfunction;
isolated cases of interstitial lung disease, particularly with long-term use (see section "Special precautions");
higher reporting rates of rhabdomyolysis, serious renal and hepatic disorders (mainly increased hepatic transaminase activity) with the 40 mg dose.

Fatal and non-fatal hepatic failure has been reported as a possible adverse reaction. Since these reports were spontaneous from a population of unspecified size, it is not possible to reliably estimate their frequency or establish a causal relationship to the use of the medicinal product.

Cognitive impairment (e.g., memory decline, forgetfulness, amnesia, confusion) has been rarely reported in association with statin use. Reports of such cognitive issues have occurred with all statins. The events described in these reports are generally mild, reversible upon statin discontinuation, and have variable onset and resolution times (median 3 weeks).

Paediatric population

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 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 of suspected adverse reactions.

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and/or 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 in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach and sight of children.

Packaging.

10 tablets in a blister pack; 3 or 9 blister packs in a carton.

Prescription status.

Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnitsya".

Manufacturer's address and place of business.

13, Boryspilska Street, Kyiv, 02093, Ukraine.