INSTRUCTION

for medical use of the medicinal product

ROMESTIN 5,

ROMESTIN 10,

ROMESTIN 20

 

Composition:

active substance: rosuvastatin;

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

excipients:

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

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

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

 

Pharmaceutical form. Film-coated tablets.

Basic physical and chemical properties:

5 mg tablets: light purple, round, biconvex, film-coated tablets with a scoreline 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. Lipid-modifying agents. HMG-CoA reductase inhibitors.

ATC Code C10A A07.

 

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the rate-determining enzyme that converts 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 cholesterol lowering.

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

Pharmacodynamic effects

Rosuvastatin reduces elevated LDL-cholesterol, total cholesterol, and triglycerides, and increases HDL-cholesterol levels. It also reduces ApoB, nonHDL-C, VLDL-C, VLDL-TG and increases ApoA-I (Table 1). Rosuvastatin also reduces LDL-C/HDL-C, total C/HDL-C, nonHDL-C/HDL-C and ApoB/ApoA-I ratios.

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

Table 1

Dose	N	LDL-C	Total C	HDL-C	TG	nonHDL-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 of starting the drug, 90% of the maximum effect is achieved in 2 weeks. The maximum effect is usually achieved in 4 weeks and is maintained 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, and for special patient populations such as diabetics or patients with familial hypercholesterolemia.

In pooled data from phase III studies, rosuvastatin effectively reduced cholesterol levels in the majority of patients with hypercholesterolemia type IIa and IIb (mean baseline LDL-C approximately 4.8 mmol/L) to target levels set by the European Atherosclerosis Society (EAS; 1998); in approximately 80% of patients taking 10 mg, the EAS target LDL-C levels (<3 mmol/L).

In a large study, 435 patients with heterozygous familial hypercholesterolemia received rosuvastatin in doses from 20 to 80 mg in a forced titration regimen. A beneficial effect of the drug on lipid parameters and achievement of target levels was noted at all doses. After titration to a daily dose of 40 mg (12 weeks of treatment), LDL-C was reduced by 53%. Target EAS LDL-C levels (<3 mmol/L)

In an open-label forced titration study, the response to rosuvastatin 20-40 mg was studied in 42 patients with homozygous familial hypercholesterolemia. In the overall population, the mean LDL-C reduction was 22%.

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

In a multicentre, double-blind, placebo-controlled clinical trial (METEOR), 984 patients aged 45–70 years with low risk of coronary heart disease (defined as a Framingham risk score <10% over 10 years), a mean LDL-C of 4.0 mmol/L (154.5 mg/dL), but with subclinical atherosclerosis (defined by an increase in carotid intima-media thickness – CIMT) were randomized into two groups and received either 40 mg rosuvastatin or placebo once daily for 2 years. Compared with placebo, rosuvastatin significantly slowed the progression of the 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 (not statistically significant)) in the rosuvastatin group compared with a progression of +0.0131 mm/year (1.12%/year (p<0.0001)) in the placebo group. No direct correlation between the reduction in CIMT and a decreased risk of cardiovascular events was demonstrated. The METEOR study enrolled patients with low coronary heart disease risk, who are not representative of the target population for rosuvastatin 40 mg. The 40 mg dose should only be prescribed to patients with severe hypercholesterolemia and high cardiovascular risk (see section "Method of administration and dosage").

In the Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), the effect of rosuvastatin on the rate of major atherosclerotic cardiovascular disease was assessed in 17,802 men (≥50 years) and women (≥60 years).

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

LDL-cholesterol 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 of patients with a baseline Framingham risk score >20% (1,558 participants), a significant reduction in the rate of the combined endpoint comprising 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 a high-risk subgroup (9,302 participants total) with a baseline SCORE ≥5% (extrapolated to include data from participants over 65 years of age), a significant reduction in the rate of the combined endpoint comprising cardiovascular death, stroke, and myocardial infarction (p=0.0003) was observed in the rosuvastatin group compared to placebo. The absolute risk reduction, expressed by event rate, was 5.1 events per 1000 patient-years. The overall mortality rate in this high-risk subgroup remained unchanged (p=0.076).

In the JUPITER study, 6.6% of participants in the rosuvastatin group and 6.2% of participants in the placebo group discontinued the study drug due to adverse events. The most frequent adverse events leading to treatment discontinuation were: myalgia (0.3% in the rosuvastatin group, 0.2% in placebo), abdominal pain (0.03% in the rosuvastatin group, 0.02% in placebo), and rash (0.02% in the rosuvastatin group, 0.03% in placebo). The most frequent adverse events observed in the rosuvastatin group at a frequency greater than or equal to that noted in the placebo group were urinary tract infections (8.7% in the rosuvastatin group, 8.6% in placebo), nasopharyngitis (7.6% in the rosuvastatin group, 7.2% in placebo), back pain (7.6% in the rosuvastatin group, 6.9% in placebo), and myalgia (7.6% in the rosuvastatin group, 6.6% in placebo).

Children

In a double-blind, randomized, multicentre, placebo-controlled 12-week study (n=176, 97 male, 79 female) followed by a 40-week open-label dose-titration period (n=173, 96 male, 77 female) of rosuvastatin, patients aged 10-17 years (Tanner stage II-IV, girls at least 1 year post-menarche) with heterozygous familial hypercholesterolemia received rosuvastatin 5, 10, or 20 mg/day or placebo for 12 weeks, after which all 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 stage II, III, IV, and V, respectively.

LDL-C was reduced by 38.3%, 44.6%, and 50% in the rosuvastatin 5, 10, 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 to achieve the target level (maximum dose was 20 mg once daily), 70 out of 173 patients (40.5%) achieved the target LDL-C level of less than 2.8 mmol/L.

After 52 weeks of study treatment, no effect on growth, weight, BMI, or sexual maturation was observed (see section "Precautions for use"). This study (n=176) is not adequate for comparing rare adverse events.

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

After 24 months of treatment with rosuvastatin, the least squares mean percent reduction from baseline in LDL-C was -43% (baseline: 236 mg/dL, month 24: 133 mg/dL). For each age group, the least squares mean percent reduction from baseline in LDL-C 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, TG/HDL-C, non-HDL-C/HDL-C, apoB, and apoB/apoA-1. Each of these changes demonstrated an improvement in the lipid response and was sustained over 2 years.

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

Rosuvastatin at a dose of 20 mg once daily compared to placebo was studied in a randomized, double-blind, placebo-controlled, multicentre crossover study involving 14 children and adolescents (aged 6 to 17 years) with homozygous familial hypercholesterolemia. The study included a 4-week active dietary lead-in phase, during which patients were treated 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 treatment period, and a 12-week maintenance phase during which all patients received 20 mg rosuvastatin. Patients on ezetimibe or apheresis therapy 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 treatment with rosuvastatin 20 mg compared to placebo. Statistically significant reductions were 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 were also observed in TG levels, LDL-C/HDL-C, total cholesterol/HDL-C, non-HDL-C/HDL-C, and apoB/apoA-I after 6 weeks of treatment with rosuvastatin 20 mg compared to 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 experienced a further reduction 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 the open-label extension of treatment with rosuvastatin 20 mg in 9 of these patients for up to 90 weeks, the reduction in LDL-C was maintained within the range of -12.1% to -21.3%.

In an open-label, forced-titration study in 7 evaluable children and adolescents (aged 8 to 17 years) with homozygous familial hypercholesterolemia (see above), the percent reductions 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 were consistent with those observed in the aforementioned study in children and adolescents with homozygous familial hypercholesterolemia.

The European Medicines Agency has waived the obligation to submit the results of studies with rosuvastatin in all subsets of the paediatric population in homozygous familial hypercholesterolaemia, primary combined (mixed) dyslipidaemia, and for the prevention of cardiovascular events (see section "Method of administration and dosage" for information on paediatric use).

Pharmacokinetics.

Absorption

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

Distribution

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

Metabolism

Rosuvastatin undergoes limited 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 2C19, 3A4 and 2D6 playing a lesser role. The main identified metabolites are the N-desmethyl and lactone metabolites. The N-desmethyl metabolite is approximately 50% less active than rosuvastatin, 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 the faeces (consisting of absorbed and unabsorbed active substance), 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 increasing dose. The geometric mean plasma clearance is approximately 50 L/hr (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 the hepatic elimination of rosuvastatin.

Linearity

Systemic exposure of rosuvastatin increases proportionally to dose. No change in pharmacokinetic parameters occurs with multiple daily dosing.

Special patient populations

Age and sex

No clinically relevant effect of age or sex on the pharmacokinetics of rosuvastatin in adults was observed. The pharmacokinetics of rosuvastatin in children and adolescents with heterozygous familial hypercholesterolemia was similar to that in adult volunteers (see section “Children”).

Race

Pharmacokinetic studies have shown that in patients of Asian (Japanese, Chinese, Filipino, Vietnamese, and Korean) origin, median AUC and Cmax are approximately 2-fold higher than in Caucasians; in Indians, median AUC and Cmax are increased approximately 1.3-fold. Population pharmacokinetic analysis revealed no clinically relevant difference between Caucasian and Black patients.

Renal impairment

In a study of patients with varying degrees of renal impairment, no change in plasma concentrations of rosuvastatin or the N-desmethyl metabolite was observed in individuals with mild or moderate renal impairment. In patients with severe renal impairment (creatinine clearance <30 ml/min), plasma concentrations of rosuvastatin were 3-fold higher, and levels of the N-desmethyl metabolite were 9-fold higher, compared to healthy volunteers. Steady-state plasma concentrations of rosuvastatin in patients undergoing haemodialysis were approximately 50% higher compared to healthy volunteers.

Hepatic impairment

In a study in patients with varying degrees of hepatic impairment, no evidence of increased exposure to rosuvastatin was found in patients with a Child-Pugh score of 7 or less. However, in two patients with Child-Pugh scores of 8 and 9, systemic exposure was at least 2-fold higher than in patients with lower scores. There is no experience with rosuvastatin in patients with a Child-Pugh score greater than 9.

Genetic polymorphism

The disposition of HMG-CoA reductase inhibitors, including rosuvastatin, involves the transporter proteins OATP1B1 and BCRP. In patients with genetic polymorphisms of SLCO1B1 (OATP1B1) and/or ABCG2 (BCRP), there is a risk of increased rosuvastatin exposure. For specific polymorphisms of SLCO1B1 c.521CC and ABCG2 c.421AA, rosuvastatin exposure (AUC) is increased compared to SLCO1B1 c.521TT or ABCG2 c.421CC genotypes. Specific genotyping is not intended in clinical practice, but a lower daily dose of rosuvastatin is recommended for patients with such polymorphisms.

Children

Two pharmacokinetic studies of rosuvastatin (as tablets) in children with heterozygous familial hypercholesterolemia aged 10 to 17 years or 6 to 17 years (total 214 patients) showed that drug exposure in children was lower or similar to exposure in adult patients. Rosuvastatin exposure was predictable according to dose and duration of intake over more than 2 years of follow-up.

Preclinical data.

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, and carcinogenic potential. Specific tests for effect on the hERG gene have not been evaluated. Adverse reactions not observed in clinical studies but seen in animals at exposure levels similar to clinical exposure levels were: in repeat-dose toxicity studies, histopathological liver changes (likely due to the pharmacological action of rosuvastatin) were observed in mice and rats; to a lesser extent, effects on the gallbladder in dogs; no such changes were found 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 pup survival at maternally toxic doses where systemic exposure was several times higher than the therapeutic exposure level.

 

Clinical characteristics.

Indications.

Treatment of hypercholesterolemia

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 response to diet and other non-pharmacological treatments (e.g., exercise, weight reduction) is inadequate.

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 treatments are inappropriate.

Prevention of cardiovascular disorders

Prevention of major cardiovascular events in patients estimated to be at high risk for 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 to any of the excipients of the drug;
• - in patients with active liver disease, including persistent unexplained elevations of serum transaminases and any serum transaminase elevation exceeding 3 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 sofosbuvir/velpatasvir/voxilaprevir combination (see section “Interactions with other medicinal products and other forms of interaction”);
• - in patients receiving concomitant cyclosporine;
• - during pregnancy or breastfeeding, and in women of childbearing potential 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 with other HMG-CoA reductase inhibitors or fibrates;
• - alcohol abuse;
• - situations that may increase plasma drug concentrations;
• - Asian race;
• - concomitant use of fibrates

(see sections “Precautions for use”, “Interactions with other medicinal products and other forms of interaction”, and “Pharmacokinetics”).

 

Interactions with other medicinal products and other forms of interaction.

Effect of concomitant drugs on rosuvastatin

Inhibitors of transporter proteins

Rosuvastatin is a substrate for certain transporter proteins, including the hepatic uptake transporter OATP1B1 and the efflux transporter BCRP. Concomitant administration of rosuvastatin with drugs that inhibit these transporter proteins may lead to increased rosuvastatin plasma concentrations and increased risk of myopathy (see sections “Methods of administration and dosage”, “Precautions for use”, “Interactions 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-fold 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 cyclosporine concentrations.

Protease inhibitors

Although the exact interaction mechanism is unknown, concomitant use of protease inhibitors may significantly increase rosuvastatin exposure (see Table 2). For example, in a pharmacokinetic study, concomitant use of rosuvastatin 10 mg and a combination product containing two protease inhibitors (atazanavir 300 mg/ritonavir 100 mg) in healthy volunteers resulted in approximately 3-fold and 7-fold increases in rosuvastatin AUC and C_max, respectively. Concomitant use of rosuvastatin with certain protease inhibitor combinations is possible after careful consideration of Romestin dose adjustment, based on the expected increase in rosuvastatin exposure (see sections “Methods of administration and dosage”, “Precautions for use”, “Interactions 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 rosuvastatin AUC and Cmax (see section “Precautions for use”).

Based on study data, no pharmacokinetic interaction with fenofibrate is expected, however a pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates, and lipid-lowering doses (> or = 1 g/day) of niacin (nicotinic acid) increase the risk of myopathy when used concomitantly with HMG-CoA inhibitors, probably because they can cause myopathy when given alone. The 40 mg dose is contraindicated with concomitant fibrates (see sections “Contraindications” and “Precautions for use”). Therapy should also be initiated at 5 mg in such patients.

Ezetimibe

Concomitant use of rosuvastatin 10 mg and ezetimibe 10 mg in patients with hypercholesterolemia resulted in a 1.2-fold increase in rosuvastatin AUC (Table 2). A pharmacodynamic interaction between Romestin and ezetimibe, which may lead to adverse events, cannot be excluded (see section “Precautions for use”).

Antacids

Concomitant use of rosuvastatin with antacid suspensions containing aluminium or magnesium hydroxide reduces rosuvastatin plasma concentrations by approximately 50%. This effect is less pronounced if antacids are taken 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 C_max by 30%. This interaction may be caused by increased intestinal motility due to erythromycin.

Ticagrelor

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

Cytochrome P450 enzymes

Results from in vitro and in vivo studies indicate that rosuvastatin does not inhibit or induce cytochrome P450 isoenzymes. In addition, rosuvastatin is a weak substrate for these isoenzymes. Therefore, interactions with drugs 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 rosuvastatin dose adjustment (see also Table 2)

If concomitant use of rosuvastatin with other drugs capable of increasing rosuvastatin exposure is necessary, the dose of Romestin should be adjusted. If the expected increase in exposure (AUC) is approximately 2-fold or more, rosuvastatin should be started at 5 mg once daily. The maximum daily dose of Romestin should be adjusted so that the expected rosuvastatin exposure does not exceed that observed with a 40 mg/day dose without interacting drugs; for example, with gemfibrozil, the rosuvastatin dose would be 20 mg (1.9-fold exposure increase), with ritonavir/atazanavir combination – 10 mg (3.1-fold increase).

If the drug increases rosuvastatin AUC less than 2-fold, the starting dose need not be reduced, but caution should be exercised when increasing the rosuvastatin dose above 20 mg.

 

Effect of concomitant drugs on rosuvastatin exposure

(AUC; in decreasing order of magnitude) from published clinical study data

Table 2

Increase in rosuvastatin AUC by 2-fold or more
Dosage regimen of interacting drug	Dosage regimen of rosuvastatin	Change 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 75 mg twice daily to 200 mg twice daily, 6 months	10 mg once daily, 10 days	↑ 7.1-fold
Darolutamide 600 mg twice daily, 5 days	5 mg, single dose	↑ 5.2-fold
Regorafenib 160 mg once daily, 14 days	5 mg, single dose	↑ 3.8-fold
Atazanavir 300 mg/ritonavir 100 mg once daily, 8 days	10 mg, single dose	↑ 3.1-fold
Velpatasvir 100 mg once daily	10 mg, single dose	↑ 2.7-fold
Ombitasvir 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	Unknown	↑ 2.5-fold
Grazoprevir 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
Lopinavir 400 mg/ritonavir 100 mg twice daily, 17 days	20 mg once daily, 7 days	↑ 2.1-fold
Clopidogrel 300 mg, then 75 mg after 24 hours	20 mg, single dose	↑ 2-fold
Fostamatinib 100 mg twice daily	20 mg, single dose	↑ 2-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
Increase in rosuvastatin AUC less than 2-fold
Dosage regimen of interacting drug	Dosage regimen of rosuvastatin	Change in rosuvastatin AUC*
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	Unknown	↑ 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 **
Decrease in rosuvastatin AUC
Dosage regimen of interacting drug	Dosage regimen of rosuvastatin	Change in rosuvastatin AUC*
Erythromycin 500 mg 4 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 use in combination and alone. Data presented as % change represent the % difference relative to values with rosuvastatin alone. Increase is shown by ↑, decrease by ↓.

** Several interaction studies were conducted at different rosuvastatin doses; Table 2 shows the most significant ratio.

 

Drugs/combinations that had no clinically significant effect on rosuvastatin AUC ratio when used concomitantly: aleglitazar 0.3 mg 7 days; fenofibrate 67 mg 7 days 3 times daily; fluconazole 200 mg 11 days once daily; fosamprenavir 700 mg/ritonavir 100 mg 8 days twice daily; ketoconazole 200 mg 7 days twice daily; rifampicin 450 mg 7 days once daily; silymarin 140 mg 5 days 3 times daily.

Effect of rosuvastatin on concomitant drugs

Vitamin K antagonists

As with other HMG-CoA reductase inhibitors, initiation of Romestin or dose escalation in patients concomitantly using vitamin K antagonists (e.g., warfarin or other coumarin anticoagulants) may increase the International Normalized Ratio (INR). Discontinuation of Romestin or dose reduction may lead to a decrease in INR. In such cases, appropriate INR monitoring is desirable.

Oral contraceptives/hormone replacement therapy (HRT)

Concomitant use of rosuvastatin and oral contraceptives results in a 26% and 34% increase in ethinyl estradiol and norgestrel AUC, respectively. This increase in plasma levels should be considered when selecting oral contraceptive doses. There are no pharmacokinetic data in patients concomitantly using rosuvastatin and HRT; therefore, a similar effect cannot be excluded. However, the combination has been widely used by women in clinical studies and was well tolerated.

Other medicinal products

Digoxin

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

Fusidic acid

Interaction studies of rosuvastatin with fusidic acid have not been performed. The risk of myopathy, including rhabdomyolysis, may be increased with concomitant administration of systemic fusidic acid with statins. The mechanism of this interaction (pharmacodynamic, pharmacokinetic, or combined) is currently unknown. Cases of rhabdomyolysis (including fatalities) have been reported in patients receiving this combination. If treatment with systemic fusidic acid is necessary, rosuvastatin should be discontinued for the entire duration of fusidic acid treatment. Also see section “Precautions for use”.

Children

Interaction studies have been performed only in adults. The extent of interactions in children is unknown.

 

Precautions for use.

Renal effects

Proteinuria, detected by dipstick testing and mostly of tubular origin, has been observed in patients treated with higher doses of rosuvastatin, particularly 40 mg, and was in most cases transient or intermittent. Proteinuria was not predictive of acute or progressive renal disease (see section “Adverse reactions”). The reporting rate for serious renal events in post-marketing studies is higher at the 40 mg dose. Renal function should be monitored regularly in patients taking the 40 mg dose.

Skeletal muscle effects

Effects on skeletal muscle, e.g., myalgia, myopathy, and rarely rhabdomyolysis, have been observed in patients receiving rosuvastatin at any dose, especially more than 20 mg. Very rare cases of rhabdomyolysis have been reported with ezetimibe in combination with HMG-CoA reductase inhibitors. The possibility of a pharmacodynamic interaction cannot be excluded (see section “Interactions with other medicinal products and other forms of interaction”), and therefore caution should be exercised with such combinations.

As with other HMG-CoA reductase inhibitors, the reporting rate for rhabdomyolysis associated with rosuvastatin in the post-marketing period was higher at the 40 mg dose.

Creatine kinase levels

Creatine kinase (CK) should not be measured after strenuous exercise or in the presence of possible alternative causes of CK elevation that may complicate interpretation of results. If baseline CK levels are significantly elevated (>5 times ULN), a repeat test should be performed within 5-7 days to confirm results. If repeat testing confirms baseline CK >5 times ULN, treatment should not be initiated.

Before treatment initiation

Rosuvastatin, like other HMG-CoA reductase inhibitors, should be prescribed with caution to 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;
• - situations that may increase plasma drug levels (see sections “Method of administration and dosage” and “Interactions with other medicinal products and other forms of interaction”, and “Pharmacokinetics”);
• - concomitant use of fibrates.

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

During treatment

Patients should be asked to promptly report any unexplained muscle pain, weakness, or cramps, especially if accompanied by malaise or fever. CK levels should be measured in these patients. Treatment should be discontinued if CK levels are significantly elevated (>5 times ULN) or if muscle symptoms are severe and cause daily discomfort (even if CK levels ≤5 times ULN). If symptoms resolve and CK levels return to normal, therapy with Romestin or an alternative HMG-CoA reductase inhibitor may be resumed at the lowest dose and under close monitoring. Routine monitoring of CK levels in asymptomatic patients is not necessary. Very rare cases of immune-mediated necrotizing myopathy (IMNM) have been reported during or after statin therapy, including rosuvastatin. Clinical manifestations of IMNM include persistent proximal muscle weakness and elevated serum creatine kinase, even after statin discontinuation.

Myasthenia gravis, ocular myasthenia.

In rare cases, statins have been reported to induce “de novo” or exacerbate pre-existing myasthenia gravis or ocular myasthenia (see section “Adverse reactions”). If symptoms worsen, rosuvastatin should be discontinued. Recurrence has been reported on re-administration of the same or a different statin.

In clinical studies, there was no evidence of increased skeletal muscle effects in a small number of patients receiving rosuvastatin and concomitant medications. However, an increased frequency of myositis and myopathy has been observed in patients receiving other HMG-CoA reductase inhibitors 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 some HMG-CoA inhibitors. Therefore, concomitant use of Romestin with gemfibrozil is not recommended. The benefit of further lipid level changes with Romestin in combination with fibrates or niacin must be carefully weighed against the potential risks associated with such combinations. The 40 mg dose is contraindicated with concomitant fibrates (see sections “Interactions with other medicinal products and other forms of interaction” and “Adverse reactions”).

Rosuvastatin should not be used concomitantly with systemic fusidic acid preparations or for 7 days after stopping fusidic acid treatment. For patients requiring systemic fusidic acid, statin treatment should be discontinued for the entire duration of fusidic acid administration. Rhabdomyolysis (including fatalities) has been reported in patients receiving the combination of fusidic acid and statins (see section “Interactions with other medicinal products and other forms of interaction”). Patients should be advised to seek medical attention immediately if they experience any symptoms of muscle weakness, pain, or tenderness. Statin therapy may be restarted 7 days after the last dose of fusidic acid. In exceptional cases where prolonged systemic fusidic acid is necessary, e.g., for treating severe infections, the need for concomitant use of rosuvastatin and fusidic acid should be considered on a case-by-case basis and conducted under close medical supervision.

Romestin should not be used in patients with acute, serious conditions suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (such as sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures).

Severe cutaneous adverse reactions.

Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS), which can 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 closely monitored when prescribing rosuvastatin. If signs and symptoms suggestive of these reactions appear, rosuvastatin should be discontinued immediately and alternative treatment considered.

If a patient develops a serious reaction such as SJS or DRESS with rosuvastatin, rosuvastatin treatment for that patient should not be restarted at any time.

Hepatic effects

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

It is recommended to check liver biochemical parameters before treatment initiation and 3 months later. Romestin should be discontinued or the dose reduced if serum transaminase levels exceed 3 times the ULN. The reporting rate for serious hepatic events (mainly increased liver transaminases) in the post-marketing period was higher at the 40 mg dose.

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

Race

Pharmacokinetic studies show an approximately 2-fold increase in exposure in Asian patients compared to Caucasians (see sections “Method of administration and dosage”, “Contraindications”, and “Pharmacokinetics”).

Protease inhibitors

Increased systemic exposure to rosuvastatin has been observed in individuals using rosuvastatin concomitantly with various protease inhibitors in combination with ritonavir. Consideration should be given to both the benefit of lipid lowering with Romestin in HIV patients receiving protease inhibitors and the potential for increased rosuvastatin plasma concentrations at the start of therapy and during dose escalation of Romestin in patients receiving protease inhibitors. Concomitant use with protease inhibitors is not recommended unless the Romestin dose is adjusted (see sections “Method of administration and dosage” and “Interactions with other medicinal products and other forms of interaction”).

Lactose intolerance

The drug contains lactose. Patients with established intolerance to certain sugars should consult their doctor before taking this medicinal product.

Interstitial lung disease

Exceptional cases of interstitial lung disease have been reported with some statins, especially with long-term treatment (see section “Adverse reactions”). Features of this disease include dyspnoea, non-productive cough, and general deterioration (fatigue, weight loss, and fever). If interstitial lung disease is suspected, statin therapy should be discontinued.

Diabetes mellitus

Some evidence suggests that statins raise blood glucose levels and in some patients at high future risk of diabetes, may cause hyperglycaemia to a level requiring appropriate diabetes management. This risk, however, is outweighed by the reduction in vascular risk with statins and should not be a reason for statin discontinuation. Patients at risk (fasting glucose 5.6-6.0 mmol/L, BMI >30 kg/m², elevated triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines.

In the JUPITER study, the reported overall frequency of diabetes mellitus was 2.8% in the rosuvastatin group and 2.3% in the placebo group, mainly in patients with fasting glucose 5.6 to 6.9 mmol/L.

Children

Assessment of linear growth (height), body weight, BMI, and secondary characteristics of sexual maturation by Tanner staging in children aged 6 to 17 years taking rosuvastatin is limited to a 2-year period. After 2 years of study treatment, no effect on growth, body weight, BMI, or sexual maturation was detected (see section Pharmacodynamics). In a clinical study in children and adolescents receiving rosuvastatin for 52 weeks, CK elevations >10 times ULN and muscle symptoms following exercise or increased physical activity were observed more frequently compared to adults (see section “Adverse reactions”).

 

Pregnancy and lactation.

Rosuvastatin is contraindicated during pregnancy or breastfeeding.

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

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

Rosuvastatin is excreted in rat milk. There are no data on the excretion of the drug into human breast milk (see section “Contraindications”).

 

Effects on ability to drive and use machines.

Studies to determine the effect of rosuvastatin on the ability to drive and operate machinery have not been performed. However, given the pharmacodynamic properties, it is unlikely that rosuvastatin affects this ability. When driving or operating machinery, the possibility of dizziness during treatment should be considered.

 

Method of administration and dosage.

Before initiating treatment, the patient should be placed on a standard cholesterol-lowering diet, which should be continued during treatment. The dose should be individualized according to the goal of therapy and treatment efficacy, guided by current consensus guidelines.

Romestin may be taken at any time of day, with or without food.

Treatment of hypercholesterolemia

The recommended starting dose is 5 or 10 mg orally once daily for both statin-naïve patients and patients switched from other HMG-CoA reductase inhibitors. The choice of starting dose should consider each patient's cholesterol levels and future cardiovascular risk, as well as the potential for adverse reactions. If necessary, dose escalation to the next level can occur after 4 weeks (see section “Pharmacodynamics”). Because adverse reactions occur more frequently with the 40 mg dose compared to lower doses (see section “Adverse reactions”), final titration to the maximum 40 mg dose should only be considered in patients with severe hypercholesterolemia and high cardiovascular risk (particularly in patients with familial hypercholesterolemia) who have not achieved treatment goals on 20 mg and will be under regular supervision (see section “Precautions for use”). Specialist supervision is recommended when initiating the 40 mg dose.

Prevention of cardiovascular events

Data show that for cardiovascular risk reduction, the drug was used at a dose of 20 mg daily (see section “Pharmacodynamics”).

Use in elderly patients

The recommended starting dose for patients >70 years is 5 mg (see section “Precautions for use”). No other dose adjustment based on age is necessary.

Patients with renal impairment

No dose adjustment is required for patients with mild or moderate renal impairment.

The recommended starting 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 rosuvastatin in patients with severe renal impairment is contraindicated at all doses (see sections "Contraindications" and "Pharmacokinetics").

Patients with hepatic impairment

In patients with hepatic impairment scoring 7 or less on Child-Pugh, no increase in systemic exposure to rosuvastatin is observed. However, in individuals with Child-Pugh scores of 8 and 9, systemic exposure increased (see section “Pharmacokinetics”). Assessment of renal function is advisable in such patients (see section “Precautions for use”). There is no experience with the drug in patients with a Child-Pugh score greater than 9. Romestin is contraindicated in patients with active liver disease (see section “Contraindications”).

Race

Increased systemic exposure has been observed in Asian patients (see section “Contraindications”, “Precautions for use”, and “Pharmacokinetics”). The recommended starting dose for patients of Asian origin is 5 mg; the 40 mg dose is contraindicated in these patients.

Genetic polymorphism

Specific types of genetic polymorphism may lead to increased rosuvastatin exposure (see section “Pharmacokinetics”). A lower daily dose of rosuvastatin is recommended in patients with known presence of such polymorphism types.

Patients predisposed to myopathy

The recommended starting dose in patients predisposed to myopathy is 5 mg (see section “Precautions for use”).

The 40 mg dose is contraindicated in some of these patients (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 used concomitantly with certain drugs that may increase rosuvastatin plasma concentrations due to interaction with these transporter proteins (e.g., cyclosporine and certain protease inhibitors, including ritonavir combinations with atazanavir, lopinavir and/or tipranavir; see sections “Precautions for use” and “Interactions with other medicinal products and other forms of interaction”). Whenever possible, alternative drugs should be considered and, if necessary, temporary interruption of Romestin therapy. If concomitant use of these drugs with Romestin cannot be avoided, the benefit and risk of concomitant use should be carefully weighed and the Romestin dose adjusted accordingly (see section “Interactions with other medicinal products and other forms of interaction”).

 

Children.

Administration of the drug to children should be carried out only by a specialist.

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

Heterozygous familial hypercholesterolemia

The usual starting daily dose in children and adolescents with heterozygous familial hypercholesterolemia is 5 mg daily.

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

Dose escalation should be based on individual child's response and tolerability, following paediatric treatment guidelines (see section “Precautions for use”). Before initiating rosuvastatin therapy, children and adolescents should be placed on a standard cholesterol-lowering diet, which should be continued during 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 starting dose is 5 mg to 10 mg once daily depending on age, weight, and prior statin use. Escalation to the maximum dose of 20 mg once daily should be based on individual child's response and tolerability, following paediatric treatment guidelines (see section “Precautions for use”). Before initiating rosuvastatin therapy, children and adolescents should be placed on a standard cholesterol-lowering diet, which should be continued during treatment.

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

The 40 mg tablets should not be used in children.

Children under 6 years

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

 

Overdose.

There is no specific treatment for overdose. In case of overdose, the patient should be treated symptomatically and, if necessary, supportive measures instituted. Liver function and CK levels should be monitored. Haemodialysis is unlikely to be effective.

 

Adverse reactions.

Adverse events observed with rosuvastatin are usually mild and transient. Less than 4% of rosuvastatin-treated patients in controlled clinical studies discontinued treatment due to adverse reactions.

The adverse reaction profile of rosuvastatin below is based on data from clinical studies and extensive post-marketing experience with rosuvastatin-containing products. Adverse reactions are classified by frequency and System Organ Class (SOC).

Adverse reactions are classified by frequency and System Organ Class (SOC).

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

Blood and lymphatic system disorders: rare – thrombocytopenia.

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

Endocrine disorders: common – diabetes mellitus¹.

Psychiatric disorders: unknown – depression.

Nervous system disorders: common – headache, dizziness; very rare – polyneuropathy, memory loss; unknown – peripheral neuropathy, sleep disturbances (including insomnia and nightmares), myasthenia gravis.

Eye disorders: unknown – ocular myasthenia.

Respiratory, thoracic and mediastinal disorders: unknown – cough, dyspnoea.

Gastrointestinal disorders: common – constipation, nausea, abdominal pain; rare – pancreatitis; unknown – diarrhea.

Hepatobiliary disorders: rare – elevated liver transaminases; very rare – jaundice, hepatitis.

Skin and subcutaneous tissue disorders: uncommon – pruritus, rash, urticaria; unknown – 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; unknown – tendon disorders, sometimes complicated by rupture, 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; unknown – oedema.

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

 

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

Renal effects

Proteinuria, detected by dipstick testing and mostly of tubular origin, has been observed in patients treated with rosuvastatin. Shifts in urine protein from none or trace to ++ or more were seen in <1% of patients at some time points during treatment with 10 and 20 mg doses, and in approximately 3% of patients treated with the 40 mg dose.

A minor increase in the shift from none or trace to + was observed with the 20 mg dose. In most cases, proteinuria decreased or resolved spontaneously with continued therapy. Review of clinical trial and post-marketing data to date has not identified a causal link between proteinuria and acute or progressive renal disease.

Cases of haematuria have been reported in patients taking rosuvastatin; clinical trial data indicate the frequency is low.

Skeletal muscle effects

Effects on skeletal muscle, e.g., myalgia, myopathy (including myositis), and rarely rhabdomyolysis with or without acute renal failure, have been reported with all doses of rosuvastatin, especially at doses >20 mg.

A dose-dependent increase in CK levels has been observed in patients receiving rosuvastatin; in most cases, the event was mild, asymptomatic, and transient. If CK levels are elevated (>5 times ULN), treatment should be discontinued (see section “Precautions for use”).

Hepatic effects

As with other HMG-CoA reductase inhibitors, a dose-dependent increase in transaminase levels has been observed in a small number of patients taking rosuvastatin; in most cases, the event was mild, asymptomatic, and transient.

The following adverse events have been reported with some statins:

• - sexual dysfunction;
• - isolated cases of interstitial lung disease, especially with long-term use (see section “Precautions for use”).

The reporting rate for rhabdomyolysis, serious renal and hepatic events (mainly increased liver transaminases) is higher at the 40 mg dose.

Children

CK elevations >10 times ULN and muscle symptoms following exercise or increased physical activity were observed more frequently in a 52-week clinical study involving children and adolescents compared to adults (see section “Precautions for use”). However, the safety profile of rosuvastatin in children and adolescents was similar to that in adults.

 

Reporting of suspected adverse reactions

Reporting of adverse reactions after medicinal product registration is important. It allows continuous monitoring of the benefit/risk balance of this medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of 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 original packaging, out of reach of children, at a temperature not exceeding 30° C.

 

Packaging.

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

 

Terms of dispensing. On prescription.

 

Date of last update.

20.02.2025