Romestin® 20: detailed information

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ROMESTINâ 5, ROMESTINâ 10, ROMESTINâ 20 (ROMESTIN 5, ROMESTIN 10, ROMESTIN 20)

Composition:

Active substance: rosuvastatin;

1 tablet contains rosuvastatin calcium equivalent to rosuvastatin 5 mg, 10 mg or 20 mg;

Excipients:

5 mg: microcrystalline cellulose; calcium hydrogen phosphate anhydrous; lactose monohydrate; sodium croscarmellose; crospovidone; talc; stearic acid; colouring agent Instacoat sol (hypromellose, polyethylene glycol, talc, titanium dioxide (E 171)); brilliant blue (E 133); erythrosine (E 127);

10 mg: microcrystalline cellulose; calcium hydrogen phosphate anhydrous; lactose monohydrate; sodium croscarmellose; crospovidone; talc; stearic acid; colouring agent Instacoat sol (hypromellose, polyethylene glycol, talc, titanium dioxide (E 171)); quinoline yellow (E 104);

20 mg: microcrystalline cellulose; calcium hydrogen phosphate anhydrous; lactose monohydrate; sodium croscarmellose; crospovidone; talc; stearic acid; colouring agent Instacoat sol (hypromellose, polyethylene glycol, talc, titanium dioxide (E 171)); brilliant blue (E 133); tartrazine (E 102).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

5 mg tablets: light violet, round, biconvex film-coated tablets, with a score line on one side;

10 mg tablets: light yellow, round, biconvex film-coated tablets;

20 mg tablets: light green to green, round, biconvex film-coated tablets.

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

ATC code C10AA07.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

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

Rosuvastatin increases the number of LDL receptors on the surface of hepatocytes, enhancing the uptake and catabolism of LDL, and inhibits hepatic synthesis of VLDL, thereby reducing the total number of LDL and LDL particles.

Pharmacodynamic effects

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

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

Table 1

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. Maximum effect is usually achieved within 4 weeks and persists thereafter.

Clinical efficacy and safety

Rosuvastatin is effective in the treatment of adult patients 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 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 levels established by the European Atherosclerosis Society (EAS; 1998); approximately 80% of patients receiving 10 mg of the drug 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 ranging from 20 to 80 mg using an intensified dose-titration regimen. Favorable effects on lipid parameters and achievement of target levels were observed at all doses. After titration to a daily dose of 40 mg (12 weeks of treatment), LDL-C decreased by 53%. Target EAS LDL-C levels (<3 mmol/L) were achieved in 33% of patients.

In an open-label dose-titration study, the response to rosuvastatin at doses of 20–40 mg was evaluated in 42 patients 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 was observed on triglyceride reduction when used in combination with fenofibrate, and on HDL-C increase when used in combination with niacin (see section "Special precautions").

In a multicenter, double-blind, placebo-controlled clinical trial (METEOR), 984 patients aged 45–70 years with low risk of ischemic heart disease (defined as a Framingham risk score <10% over 10 years), 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 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% CI: -0.0196, -0.0093; p<0.0001). The change from baseline was -0.0014 mm/year (-0.12%/year (statistically non-significant)) in the rosuvastatin group compared to progression of +0.0131 mm/year (1.12%/year (p<0.0001)) in the placebo group. A direct correlation between reduction in CIMT and reduced risk of cardiovascular events has not been demonstrated. The METEOR study included patients at low risk of ischemic heart disease, who are not representative of the target population for 40 mg rosuvastatin. The 40 mg dose should only be prescribed to patients with severe hypercholesterolemia and high cardiovascular risk (see section "Dosage and administration").

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).

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

In a post-hoc analysis of a high-risk subgroup with a 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 post-hoc analysis of another high-risk subgroup (9302 participants) with a baseline SCORE ≥5% (extrapolated to include participants over 65 years of age), a significant reduction in the composite endpoint of 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. Overall mortality 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 events. The most common adverse events 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 events observed in the rosuvastatin group with a frequency greater than or equal to that in the placebo group were urinary tract infections (8.7% in rosuvastatin, 8.6% in placebo), nasopharyngitis (7.6% in rosuvastatin, 7.2% in placebo), back pain (7.6% in rosuvastatin, 6.9% in placebo), and myalgia (7.6% in rosuvastatin, 6.6% in placebo).

Children

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 (at Tanner stages II–IV, girls with at least 1 year since menarche) with heterozygous familial hypercholesterolemia received rosuvastatin at doses of 5, 10, or 20 mg/day 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% 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, body weight, BMI, or sexual maturation was observed (see section "Special precautions"). This study (n=176) is not suitable for comparing rare adverse events.

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 those aged 10 to 17 years (n=134) 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 the following 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-I. 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").

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 on diet with 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 period, 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 (22.3%; 85.4 mg/dL or 2.2 mmol/L) was observed after 6 weeks of 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, total cholesterol/HDL-C, non-HDL-C/HDL-C, and apoB/apoA-I were also observed after 6 weeks of rosuvastatin 20 mg compared to placebo. The reduction in LDL-C after 6 weeks of rosuvastatin 20 mg followed by 6 weeks of placebo 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 reductions were maintained between -12.1% and -21.3%.

In an open-label intensified 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 rosuvastatin 20 mg treatment corresponded to that observed in the previously mentioned 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 of rosuvastatin is reached approximately 5 hours after oral administration. Absolute bioavailability is approximately 20%.

Distribution

Rosuvastatin is significantly 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 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 circulating HMG-CoA reductase inhibitor activity.

Elimination

Approximately 90% of the rosuvastatin dose is excreted unchanged in feces (including both absorbed and unabsorbed drug), 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 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 involves 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 sex

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

Race

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

Renal impairment

In a study of patients with varying degrees of renal impairment, no changes in plasma concentrations of rosuvastatin or N-desmethyl metabolite were observed in individuals with mild or moderate renal insufficiency. 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 a study of patients with varying degrees of hepatic impairment, no signs of increased rosuvastatin exposure were observed in patients scoring 7 or less on the Child-Pugh scale. However, in two patients scoring 8 and 9 on the Child-Pugh scale, systemic exposure was at least twice as high as in patients with lower scores. Experience with rosuvastatin in patients scoring more than 9 on the Child-Pugh scale is lacking.

Genetic polymorphism

The distribution of HMG-CoA reductase inhibitors, including rosuvastatin, involves transport proteins OATP1B1 and BCRP. Patients with genetic polymorphisms in SLCO1B1 (OATP1B1) and/or ABCG2 (BCRP) are at risk of increased rosuvastatin exposure. With specific polymorphisms SLCO1B1 c.521CC and ABCG2 c.421AA, rosuvastatin exposure (AUC) is increased compared to genotypes SLCO1B1 c.521TT or ABCG2 c.421CC. Routine genotyping is not required in clinical practice, but patients with these polymorphisms should be prescribed a lower daily dose of rosuvastatin.

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 based on dose and duration of treatment over more than 2 years of observation.

Preclinical data.

Preclinical data revealed no special hazard for humans based on conventional studies of pharmacological safety, genotoxicity, and carcinogenic potential. Specific tests on hERG channel effects were not evaluated. Adverse reactions not observed in clinical trials but seen in animals at exposure levels similar to clinical exposure levels included: histopathological liver changes (likely due to the pharmacological action of rosuvastatin) in mice and rats; less pronounced effects on the gallbladder in dogs; no such changes were observed in monkeys. Additionally, testicular toxicity was observed in monkeys and dogs at higher doses. Reproductive toxicity was observed in rats, with reduced litter size, litter weight, and offspring survival at maternally toxic doses when systemic exposure was several times higher than therapeutic exposure.

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 in cases where such treatment is inappropriate.

Prevention of cardiovascular events

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

Contraindications.

Rosuvastatin is contraindicated:

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

The 40 mg dose is contraindicated in patients with predisposition to myopathy/rhabdomyolysis.

Factors contributing to this risk include:

moderate renal impairment (creatinine clearance <60 mL/min);
hypothyroidism;
personal or family history of hereditary muscular disorders;
history of myotoxicity during treatment with other HMG-CoA reductase inhibitors or fibrates;
alcohol abuse;
conditions that may lead to increased plasma concentration of the drug;
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 medications 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 administration of rosuvastatin 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). Rosuvastatin 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 rosuvastatin with certain combinations of protease inhibitors may be possible after careful consideration of dose adjustment of Romestin, based on 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 results in a 2-fold increase in AUC and Cmax of rosuvastatin (see section "Special precautions").

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

Ezetimibe

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

Antacid agents

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

Erythromycin

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

Tickagrelor

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

Cytochrome P450 enzymes

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

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

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

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

Effect of concomitant medicinal products on rosuvastatin exposure

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

Table 2

Increased rosuvastatin AUC by 2 times or more than 2 times
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 times
Cyclosporine from 75 mg twice daily to 200 mg twice daily, 6 months	10 mg once daily, 10 days	↑ 7.1 times
Darolutamide 600 mg twice daily, 5 days	5 mg, single dose	↑ 5.2 times
Regorafenib 160 mg once daily, 14 days	5 mg, single dose	↑ 3.8 times
Atazanavir 300 mg/ritonavir 100 mg once daily, 8 days	10 mg, single dose	↑ 3.1 times
Velpatasvir 100 mg once daily	10 mg, single dose	↑ 2.7 times
Obritasvir 25 mg/paritaprevir 150 mg/ritonavir 100 mg once daily/dasabuvir 400 mg twice daily, 14 days	5 mg, single dose	↑ 2.6 times
Teriflunomide	Unknown	↑ 2.5 times
Glecaprevir 200 mg/elbasvir 50 mg once daily, 11 days	10 mg, single dose	↑ 2.3 times
Glecaprevir 400 mg/pibrentasvir 120 mg once daily, 7 days	5 mg once daily, 7 days	↑ 2.2 times
Lopinavir 400 mg/ritonavir 100 mg twice daily, 17 days	20 mg once daily, 7 days	↑ 2.1 times
Clopidogrel 300 mg, then 75 mg after 24 hours	20 mg, single dose	↑ 2 times
Fostamatinib 100 mg twice daily	20 mg, single dose	↑ 2 times
Febuxostat 120 mg once daily	10 mg, single dose	↑ 1.9 times
Gemfibrozil 600 mg twice daily, 7 days	80 mg, single dose	↑ 1.9 times
Increased rosuvastatin AUC less than 2 times
Dosing regimen of the interacting drug	Dosing regimen of rosuvastatin	Changes in rosuvastatin AUC*
Eltrombopag 75 mg once daily, 5 days	10 mg, single dose	↑ 1.6 times
Darunavir 600 mg/ritonavir 100 mg twice daily, 7 days	10 mg once daily, 7 days	↑ 1.5 times
Tipranavir 500 mg/ritonavir 200 mg twice daily, 11 days	10 mg, single dose	↑ 1.4 times
Dronedarone 400 mg twice daily	Unknown	↑ 1.4 times
Itraconazole 200 mg once daily, 5 days	10 mg, single dose	↑ 1.4 times **
Ezetimibe 10 mg once daily, 14 days	10 mg once daily, 14 days	↑ 1.2 times **
Decreased rosuvastatin AUC
Dosing regimen of the interacting drug	Dosing regimen of rosuvastatin	Changes in rosuvastatin AUC*
Erythromycin 500 mg four times daily, 7 days	80 mg, single dose	↓ 20 %
Baicalin 50 mg three times daily, 14 days	20 mg, single dose	↓ 47 %
Data presented as fold change represent the ratio between rosuvastatin administered in combination versus alone. Data presented as percent change represent the percentage difference compared to rosuvastatin administered alone. Increases are indicated by ↑, decreases by ↓. *Multiple interaction studies were conducted at different rosuvastatin doses; the most significant ratio is presented in Table 2.

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

Effect of rosuvastatin on concomitant medicinal products

Vitamin K antagonists

As with other HMG-CoA reductase inhibitors, initiation of treatment with the medicinal product Romestin 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 Romestin or reduction of its dose may lead to a decrease in INR. In such cases, appropriate monitoring of INR is recommended.

Oral contraceptives/hormone replacement therapy (HRT)

Concomitant administration of rosuvastatin and oral contraceptives results 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 drugs in patients concurrently receiving rosuvastatin and HRT; therefore, a similar effect cannot be excluded. However, the combination has been widely used by women in clinical trials and was well tolerated.

Other medicinal products

Digoxin

Data indicate that no clinically significant interaction with digoxin is expected.

Fusidic acid

Studies on the interaction between rosuvastatin and fusidic acid have not been conducted. The risk of myopathy, including rhabdomyolysis, may increase when systemic fusidic acid is co-administered with statins. The mechanism of this interaction (pharmacodynamic or pharmacokinetic, or combined) is currently unknown. Cases of rhabdomyolysis (including fatal cases) have been reported in patients receiving this combination. If systemic fusidic acid treatment is necessary, rosuvastatin administration should be discontinued for the entire duration of fusidic acid therapy. See also section "Special warnings and 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 dipstick testing, predominantly of tubular origin, has been observed in patients treated with higher doses of rosuvastatin, particularly 40 mg, and was mostly transient or intermittent in nature. 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 of the drug.

Skeletal muscle effects

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

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

Creatine kinase levels

Creatine kinase (CK) levels should not be measured following strenuous physical exercise or in the presence of possible alternative causes of elevated CK, which may complicate interpretation of results. If initial CK levels are markedly elevated (>5 times the ULN), repeat testing should be performed within 5–7 days to confirm the results. If repeat testing confirms that the initial CK level exceeds 5 times the ULN, treatment should not be initiated.

Prior to initiating therapy

Rosuvastatin, as with 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 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 the drug (see sections "Posology and method of administration", "Interaction with other medicinal products and other forms of interaction", and "Pharmacokinetics");
concomitant use of fibrates.

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

During therapy

Patients should be instructed to promptly report any unexplained muscle pain, weakness, or cramps, especially if accompanied by malaise or fever. CK levels should be measured in such patients. The drug should be discontinued if CK levels are markedly elevated (>5 times the ULN) or if muscle symptoms are severe and cause daily discomfort (even if CK levels ≤ 5 times ULN). Therapy with Romestin or an alternative HMG-CoA reductase inhibitor may be resumed at the lowest dose and under close monitoring 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 with rosuvastatin. Clinical features of IMNM include proximal muscle weakness and elevated serum creatine kinase levels that persist even after discontinuation of statin therapy.

Myasthenia gravis, ocular myasthenia.

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

Clinical trials did not provide 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, 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 Romestin with gemfibrozil is not recommended. The benefit of further lipid-lowering with Romestin 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").

Rosuvastatin should not be administered concurrently with systemic fusidic acid or within 7 days after discontinuation of fusidic acid treatment. For patients requiring systemic fusidic acid, statin therapy should be discontinued throughout the duration of fusidic acid treatment. Cases of rhabdomyolysis (including fatal cases) have been reported in patients receiving fusidic acid and statins in combination (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 7 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, the need for concomitant use of rosuvastatin and fusidic acid should be considered on a case-by-case basis and under close medical supervision.

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

Severe skin adverse reactions.

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

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

Hepatic effects

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

It is recommended to assess liver function biochemistry before starting treatment and again after 3 months. Treatment with Romestin should be discontinued or the dose reduced if serum transaminase levels exceed three times the ULN. The frequency of post-marketing reports of serious hepatic events (predominantly elevated liver transaminases) was higher with the 40 mg dose.

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

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 Romestin 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 Romestin in patients receiving protease inhibitors should be considered. Concomitant use of the drug with protease inhibitors is not recommended unless the Romestin dose is adjusted (see sections "Posology and method of administration" and "Interaction with other medicinal products and other forms of interaction").

Lactose intolerance

The medicine contains lactose. Patients with diagnosed intolerance to certain sugars should consult their physician before taking this medicinal product.

Interstitial lung disease

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

Diabetes

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

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

Children

Assessment of linear growth (height), body weight, BMI (body mass index), and secondary sexual characteristics by Tanner staging in children aged 6 to 17 years receiving rosuvastatin is limited to a 2-year period. After 2 years of investigational treatment, no effect on growth, body weight, BMI, or sexual maturation was observed (see section "Pharmacodynamics"). In a clinical study in children and adolescents treated with rosuvastatin for 52 weeks, CK levels >10 times ULN 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.

Rosuvastatin is contraindicated during pregnancy and breastfeeding.

Women of childbearing potential should use appropriate contraceptive measures during treatment with rosuvastatin.

Since cholesterol and other products of cholesterol biosynthesis are essential for fetal development, the potential risk of HMG-CoA reductase inhibition outweighs any possible benefit of using the drug during pregnancy. Animal studies have shown limited evidence of reproductive toxicity (see section "Preclinical data"). If a patient becomes pregnant during treatment, therapy should be discontinued immediately.

Rosuvastatin crosses into the milk of rats. Data on the passage of the drug into human breast milk are not available (see section "Contraindications").

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

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

Romestin can be taken at any time of day, regardless of food intake.

Treatment of Hypercholesterolemia

The recommended initial dose is 5 or 10 mg orally once daily, both for patients who have not previously used statins and for those who have previously used other HMG-CoA reductase inhibitors. The selection of the initial dose should take into account the individual patient's 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"). Due to the higher incidence of adverse reactions with the 40 mg dose compared to lower doses (see section "Adverse Reactions"), dose titration up to the maximum dose of 40 mg should only be considered in patients with severe hypercholesterolemia and high cardiovascular risk (particularly patients with familial hypercholesterolemia) who have not achieved treatment goals with a 20 mg dose and who will be under regular monitoring (see section "Special Precautions"). Specialist supervision is recommended when initiating treatment with the 40 mg dose.

Prevention of Cardiovascular Events

Data are available showing reduction in cardiovascular event risk with the drug administered at a dose of 20 mg once daily (see section "Pharmacodynamics").

Use in Elderly Patients

The recommended initial dose for patients aged >70 years is 5 mg (see section "Special Precautions"). No other age-related dose adjustment 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. Use of rosuvastatin is contraindicated in patients with severe renal impairment at any dose (see sections "Contraindications" and "Pharmacokinetics").

Patients with Hepatic Impairment

In patients with hepatic impairment scoring 7 or less on the Child-Pugh scale, no increase in systemic exposure to rosuvastatin has been observed. However, in patients scoring 8 or 9 on the Child-Pugh scale, systemic exposure increases (see section "Pharmacokinetics"). Renal function assessment is advisable in these patients (see section "Special Precautions"). Experience with the drug in patients scoring more than 9 on the Child-Pugh scale is lacking. Romestin 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 "Contraindications", "Special Precautions", and "Pharmacokinetics"). The recommended initial dose for patients of Asian origin is 5 mg; the 40 mg dose is contraindicated in these patients.

Genetic Polymorphism

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

Patients Predisposed to Myopathy

The recommended initial dose for patients predisposed to developing myopathy is 5 mg (see section "Special Precautions").

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

Concomitant Use

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

Children

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

Use in children and adolescents aged 6 to 17 years (Tanner stage <II–V).

Heterozygous Familial Hypercholesterolemia

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

The usual dose for children aged 6 to 9 years with heterozygous familial hypercholesterolemia is 5 mg to 10 mg orally once daily. The safety and efficacy of doses exceeding 10 mg 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 orally once daily. The safety and efficacy of doses exceeding 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, following recommendations for pediatric treatment (see section "Special Precautions"). Before initiating rosuvastatin therapy, children and adolescents should be placed on a standard hypocholesterolemic 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 once daily, depending on age, body weight, and prior statin use. Dose escalation to the maximum dose of 20 mg once daily should be based on the individual child's treatment response and drug tolerability, following recommendations for pediatric treatment (see section "Special Precautions"). Before initiating rosuvastatin therapy, children and adolescents should be placed on a standard hypocholesterolemic diet, which should be maintained throughout treatment.

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

40 mg tablets should not be used in children.

Children under 6 years of age

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

Overdose.

There is no specific antidote for overdose. In case of overdose, the patient should be treated symptomatically and supportive measures should be 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. Less than 4% of patients receiving rosuvastatin in controlled clinical trials discontinued treatment due to adverse reactions.

The adverse reaction profile of rosuvastatin presented below is based on data from clinical trials and extensive post-marketing experience. Adverse reactions are classified by frequency and by 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 (≥1/10000 to <1/1000), very rare (<1/10000), 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, 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.

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.

Renal and urinary disorders: very rare – haematuria.

Reproductive system and breast disorders: very rare – gynaecomastia.

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

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

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

Renal effects

Proteinuria detected by dipstick testing, predominantly of tubular origin, has been observed in patients taking rosuvastatin. Changes in urinary protein content from negative 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 change from negative or trace to + was observed with the 20 mg dose. In most cases, proteinuria decreased or resolved spontaneously while continuing therapy. To date, based on clinical trial and post-marketing data, no causal relationship has been established between proteinuria and acute or progressive kidney disease.

Cases of haematuria have been reported 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 "Dosage and administration").

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 the use of certain statins, the following adverse events have been reported:

sexual dysfunction;
isolated cases of interstitial lung disease, particularly with long-term use (see section "Dosage and administration").

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

Paediatric population

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 "Dosage and administration"). However, the safety profile of rosuvastatin in children and adolescents was similar to that in adults.

Reporting suspected adverse reactions

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

Shelf life. 3 years.

Storage conditions.

Store in the original packaging, protected from light, in a place inaccessible to children, at a temperature not exceeding 30°C.

Packaging.

10 tablets in a blister; 3 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Artura Pharmaceuticals Pvt. Ltd. (ROMESTIN® 5, ROMESTIN® 10, ROMESTIN® 20).

Ananta Medicare Limited (ROMESTIN® 10, ROMESTIN® 20).

Manufacturer's address and place of business.

Artura Pharmaceuticals Pvt. Ltd.

1505 Portia Road, Sri City SEZ, Sedyavedu Mandal, Chittoor District – 517 588, Andhra Pradesh State, India.

Ananta Medicare Limited

Chak 17 ML, Agro Food Park Road, RIICO Industrial Area, Udiog Vihar, Sri Ganganagar-335002 (Rajasthan), India.

Marketing Authorisation Holder.

Ananta Medicare Limited

Address of the Marketing Authorisation Holder and/or its representative.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.