Rosuvastatin krka: detailed information

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ROSUVASTATIN KRKA

Composition:

Active substance: rosuvastatin;

One film-coated tablet contains 15 mg or 30 mg of rosuvastatin (as rosuvastatin calcium);

Excipients: microcrystalline cellulose, lactose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate;

Film coating: acrylic copolymer, polyethylene glycol 6000, titanium dioxide (E 171), lactose monohydrate.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

15 mg: white, round, biconvex film-coated tablets with bevelled edges and engraved "15" on one side;

30 mg: white, biconvex, film-coated, capsule-shaped tablets with notches on both sides.

Pharmacotherapeutic group. Hypolipidemic 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 enzyme that limits the rate of conversion of 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a cholesterol precursor. The primary site of action of rosuvastatin is the liver – the target organ for cholesterol-lowering effects.

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

Pharmacodynamic effects

Rosuvastatin reduces elevated levels of low-density lipoprotein cholesterol (LDL-C), total cholesterol, and triglycerides, and increases high-density lipoprotein cholesterol (HDL-C). It also reduces ApoB, non-HDL-C, very-low-density lipoprotein cholesterol (VLDL-C), very-low-density lipoprotein triglyceride content (TG-VLDL), and increases ApoA-I (see Table 1). Rosuvastatin also reduces the ratios of LDL-C/HDL-C, total cholesterol/HDL-C, non-HDL-C/HDL-C, and ApoB/ApoA-I.

Table 1

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

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

The therapeutic effect is obtained within 1 week after the start of treatment, and 90% of the maximum response is achieved within 2 weeks. The maximum response is usually reached within 4 weeks and is maintained thereafter.

Clinical efficacy and safety

Rosuvastatin is effective in adults with hypercholesterolemia, with or without hypertriglyceridemia, regardless of race, gender, or age, and in special patient populations such as diabetics or patients with familial hypercholesterolemia.

Phase III data demonstrate that rosuvastatin is effective in treating the majority of patients with type IIa and IIb hypercholesterolemia (mean baseline LDL-C level approximately 4.8 mmol/L) to achieve the recommended target levels of the European Atherosclerosis Society (EAS; 1998); approximately 80% of patients receiving 10 mg achieved EAS LDL-C targets (<3 mmol/L).

In a large study, 435 patients with heterozygous familial hypercholesterolemia received rosuvastatin from 20 mg to 80 mg in forced titration. All doses showed a favorable effect on lipid parameters and achievement of target levels. After titration to a daily dose of 40 mg (12 weeks of treatment), LDL-C decreased by 53%. 33% of patients achieved EAS LDL-C recommendations (<3 mmol/L).

During forced titration in an open-label study of 42 patients (including 8 pediatric patients) with homozygous familial hypercholesterolemia, response to 20–40 mg of rosuvastatin was evaluated. In the overall population, the mean reduction in LDL-C was 22%.

In clinical studies with a limited number of patients, rosuvastatin has shown additive efficacy in reducing triglycerides when used in combination with fenofibrate and increasing HDL-C when used in combination with niacin (see section "Special precautions for use").

In a multicenter, double-blind, placebo-controlled clinical trial (METEOR), 984 patients aged 45 to 70 years with low risk of ischemic heart disease (defined as a Framingham risk <10% over 10 years), with a mean LDL-C level of 4 mmol/L (154.5 mg/dL), but with subclinical atherosclerosis (detected by intima-media thickness) were randomized to receive 40 mg rosuvastatin once daily or placebo for 2 years. Rosuvastatin significantly slowed the progression rate of maximum CIMT for 12 carotid artery segments compared to placebo at -0.0145 mm/year (95% confidence interval: -0.0196 to -0.0093; p <0.0001). The change from baseline was -0.0014 mm/year (0.12%/year (non-significant)) for rosuvastatin compared to progression of +0.0131 mm/year (1.12%/year (p <0.0001)) for placebo. A direct correlation between reduction in CIMT and reduction in cardiovascular event risk has not yet been demonstrated. The population studied in METEOR has a low risk of ischemic heart disease and does not represent 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").

Rationale for statin use in primary prevention: the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), the impact of rosuvastatin on the occurrence of major atherosclerotic cardiovascular diseases was evaluated in 17,802 men (≥50 years) and women (≥60 years).

Study participants were randomly assigned to placebo (n=8,901) or rosuvastatin 20 mg once daily (n=8,901) and followed for a mean of 2 years.

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

In a prespecified subgroup analysis of high-risk patients with a baseline Framingham risk score >20% (1,558 patients), a significant reduction in the composite endpoint of cardiovascular death, stroke, and myocardial infarction was observed with rosuvastatin treatment compared to placebo (p=0.028). The absolute risk reduction in events per 1,000 patient-years was 8.8. Overall mortality did not change in this high-risk group (p=0.193). In a prespecified subgroup analysis of high-risk patients (total 9,302 patients) with a baseline SCORE risk ≥5% (extrapolated to include patients aged 65 years and older), a significant reduction in the composite endpoint of cardiovascular death, stroke, and myocardial infarction was observed with rosuvastatin treatment compared to placebo (p=0.0003). The absolute risk reduction in events was 5.1 per 1,000 patient-years. Overall mortality did not change in this high-risk group (p=0.076).

In the JUPITER study, 6.6% of rosuvastatin subjects and 6.2% of placebo subjects discontinued the investigational drug due to an adverse event. The most common adverse events leading to discontinuation were: myalgia (0.3% – rosuvastatin, 0.2% – placebo), abdominal pain (0.03% – rosuvastatin, 0.02% – placebo), and rash (0.02% – rosuvastatin, 0.03% – placebo). The most common adverse events with a rate exceeding or equal to placebo were urinary tract infections (8.7% – rosuvastatin, 8.6% – placebo), nasopharyngitis (7.6% – rosuvastatin, 7.2% – placebo), back pain (7.6% – rosuvastatin, 6.9% – placebo), and myalgia (7.6% – rosuvastatin, 6.6% – placebo).

Pediatric population

In a double-blind, randomized, multicenter, placebo-controlled 12-week study (n=176, 97 males and 79 females) followed by a 40-week (n=173, 96 males and 77 females) open-label, dose-titration phase study, patients aged 10–17 years (Tanner stage II–V, females at least 1 year post-menarche) with heterozygous familial hypercholesterolemia received 5 mg, 10 mg, or 20 mg rosuvastatin or placebo daily for 12 weeks, then all received rosuvastatin daily for 40 weeks. At study entry, approximately 30% of patients were aged 10–13 years and approximately 17%, 18%, 40%, and 25% were Tanner stage II, III, IV, and V, respectively.

LDL-C decreased by 38.3%, 44.6%, and 50.0% with rosuvastatin 5 mg, 10 mg, and 20 mg, respectively, compared to 0.7% with placebo. At the end of the 40-week open-label titration to target (titrated up to 20 mg once daily), 70 of 173 patients (40.5%) achieved the LDL-C goal of less than 2.8 mmol/L.

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

Rosuvastatin was also studied in a 2-year open-label, dose-titration study in 198 children with heterozygous familial hypercholesterolemia aged 6 to 17 years (88 male participants 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 rosuvastatin treatment, the least squares mean 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 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 improved lipid responses and was maintained over 2 years.

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

In a randomized, double-blind, placebo-controlled, multicenter, crossover study, rosuvastatin 20 mg once daily was compared with placebo in 14 children and adolescents (aged 6 to 17 years) with homozygous familial hypercholesterolemia. The study included a 4-week active 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 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 in total cholesterol (20.1%, p=0.003), non-HDL-C (22.9%, p=0.003), and apoB (17.1%, p=0.024) were also observed. Reductions in TG, LDL-C/HDL-C, total cholesterol/HDL-C, non-HDL-C/HDL-C, and apoB/apoA-I were also observed after 6 weeks of treatment with rosuvastatin 20 mg compared 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 over 12 weeks of continuous therapy. One patient experienced 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, the reduction in LDL-C remained between -12.1% and -21.3%.

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

The European Medicines Agency has waived the obligation to submit results of rosuvastatin studies in all subgroups of children 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 (Cmax) is reached approximately 5 hours after oral administration. Absolute bioavailability is approximately 20%.

Distribution

Rosuvastatin is extensively metabolized in 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 limited metabolism (approximately 10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin undergoes only minimal CYP450-based metabolism, and this metabolism is not clinically significant. CYP2C9 was the main isoenzyme involved in metabolism, with 2C19, 3A4, and 2D6 being less involved. The main identified metabolites are N-desmethyl and lactone metabolites. The N-desmethyl metabolite is approximately 50% less active than rosuvastatin, and the lactone form is considered clinically inactive. Rosuvastatin has more than 90% of the HMG-CoA reductase inhibitory activity circulating in the systemic circulation.

Elimination

Approximately 90% of the rosuvastatin dose is excreted unchanged in feces (comprising both absorbed and unabsorbed active substance), and the remainder is excreted in urine. Approximately 5% is excreted unchanged in urine. The plasma elimination half-life is approximately 20 hours. The half-life does not increase with higher doses. The geometric mean plasma clearance is approximately 50 liters/hour (coefficient of variation 21.7%). As with other HMG-CoA reductase inhibitors, hepatic uptake of rosuvastatin involves the membrane transporter OATP-C. This transporter is important for the hepatic elimination of rosuvastatin.

Linearity

Systemic exposure to rosuvastatin increases proportionally with dose. There is no change in pharmacokinetic parameters after multiple daily administrations.

Patient groups

Age and gender

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

Race

Pharmacokinetic studies show approximately a 2-fold increase in the area under the concentration-time curve (AUC) and Cmax of rosuvastatin in Asian populations (Japanese, Chinese, Filipinos, Vietnamese, and Koreans) compared to Caucasian patients; in Indians, an increase of approximately 1.3-fold in mean AUC and Cmax is observed. Pharmacokinetic analysis of patient groups did not reveal any clinically significant differences in pharmacokinetics between Caucasian and African populations.

Renal impairment

In a study involving patients with varying degrees of renal dysfunction, mild or moderate kidney disease did not affect plasma concentrations of rosuvastatin or the N-desmethyl metabolite. In patients with severe renal impairment (creatinine clearance <30 mL/min), plasma concentrations increased 3-fold, and the N-desmethyl metabolite concentration increased 9-fold compared to healthy volunteers. Steady-state plasma concentrations of rosuvastatin in patients undergoing hemodialysis sessions were approximately 50% higher than in healthy volunteers.

Hepatic impairment

In a study involving patients with varying degrees of liver dysfunction, there was no evidence of increased rosuvastatin exposure in patients with Child-Pugh scores of 7 or less. However, increased systemic exposure (at least 2-fold) was observed in 2 patients with Child-Pugh scores of 8 and 9.

Genetic polymorphism

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

Children

Two pharmacokinetic studies of rosuvastatin (in tablet form) 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 that in adult patients. Rosuvastatin exposure was predictable according to dose and duration of intake over more than 2 years of observation.

Clinical characteristics.

Indications.

Treatment of hypercholesterolemia

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

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

Prevention of cardiovascular disorders

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.

Hypersensitivity to rosuvastatin or to any of the excipients;
Active liver disease, including of unknown etiology (persistent elevation of serum transaminases and elevation of any serum transaminase level more than 3 times the upper limit of normal);
Severe renal impairment (creatinine clearance < 30 mL/min);
Concomitant use of cyclosporine;
Patients receiving concomitant sofosbuvir/velpatasvir/voxilaprevir (see section "Interaction with other medicinal products and other forms of interaction");
Contraindicated during pregnancy and breastfeeding, as well as in women of childbearing potential who are not using appropriate contraceptive measures;
Hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption;
Children (under 17 years of age) – doses of 30 mg and higher are contraindicated;
Myopathy or risk factors for myopathy/rhabdomyolysis; such factors include: moderate renal impairment (creatinine clearance < 60 mL/min); hypothyroidism; personal or family history of inherited muscle disorders; history of muscle toxicity associated with another HMG-CoA reductase inhibitor or fibrate; alcohol dependence; conditions that may lead to increased plasma levels of rosuvastatin (e.g., severe hepatic insufficiency); Mongoloid race; concomitant use of fibrates; age over 70 years.

Interaction with other medicinal products and other forms of interaction.

Effect of concomitantly administered 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 medicinal products that are inhibitors of these transporter proteins may lead to increased plasma concentrations of rosuvastatin and an increased risk of myopathy (see sections "Special precautions for use", "Dosage and administration", and Table 1).

Cyclosporine

During concomitant treatment with rosuvastatin and cyclosporine, rosuvastatin AUC values were on average 7 times higher than those observed in healthy volunteers (see table). Rosuvastatin is contraindicated in patients receiving concomitant cyclosporine (see section "Contraindications"). Concomitant administration did not affect plasma concentrations of cyclosporine.

Protease inhibitors

Although the exact mechanism of interaction is unknown, concomitant use of protease inhibitors may markedly increase the effect of rosuvastatin (see table). For example, in a pharmacokinetic study, co-administration of 10 mg rosuvastatin with a combination of two protease inhibitors (300 mg atazanavir/100 mg ritonavir) in healthy volunteers was associated with approximately 3- and 7-fold increases in AUC and Cmax of rosuvastatin, respectively. Concomitant use of rosuvastatin and certain protease inhibitor combinations may be considered after careful evaluation of rosuvastatin dose adjustment based on the expected increase in rosuvastatin exposure (see sections "Special precautions for use", "Dosage and administration", and table).

Gemfibrozil and other lipid-lowering agents

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

Based on data from specific interaction studies, no relevant pharmacokinetic interaction with fenofibrate is expected; however, pharmacodynamic interaction may occur. Gemfibrozil, fenofibrate, other fibrates, and lipid doses (≥1 g daily) of niacin (nicotinic acid) increase the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors, likely because they may cause myopathy when administered alone. Doses of 30 mg and 40 mg are contraindicated when fibrates are used concomitantly (see sections "Contraindications" and "Special precautions for use"). These patients should also start with a dose of 5 mg.

Ezetimibe

Concomitant administration of 10 mg rosuvastatin and 10 mg ezetimibe resulted in a 1.2-fold increase in rosuvastatin AUC in patients with hypercholesterolemia (see table). However, a pharmacodynamic interaction in terms of adverse effects between rosuvastatin and ezetimibe cannot be excluded (see section "Special precautions for use").

Antacids

Concomitant administration of rosuvastatin with an antacid suspension containing aluminum and magnesium hydroxide resulted in approximately a 50% reduction in plasma concentration of rosuvastatin. This effect was attenuated when the antacid was administered 2 hours after rosuvastatin KRKA. The clinical significance of this interaction has not been studied.

Erythromycin

Concomitant administration of rosuvastatin and erythromycin resulted in a 20% decrease in AUC0-t and a 30% reduction in Cmax of rosuvastatin. This interaction may be due to increased intestinal motility induced by erythromycin.

Cytochrome P450 enzymes

Results from in vitro and in vivo studies indicate that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. In addition, rosuvastatin is a poor substrate for these isoenzymes. Therefore, drug interactions due to cytochrome 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)

When concomitant administration of rosuvastatin with other medicinal products known to increase rosuvastatin exposure is necessary, the rosuvastatin dose should be adjusted. Treatment should start with a rosuvastatin dose of 5 mg once daily if an approximately 2-fold or greater increase in AUC is expected. The maximum daily dose of rosuvastatin should be adjusted so that the expected rosuvastatin exposure does not exceed that of a 40 mg daily dose of rosuvastatin taken without drug interaction; for example, a 20 mg rosuvastatin dose with gemfibrozil (1.9-fold increase) and a 10 mg rosuvastatin dose with atazanavir/ritonavir combination (3.1-fold increase).

Effect of concomitant medicinal products on rosuvastatin exposure (AUC; in order of decreasing magnitude) based on published data from clinical studies.

Dosing regimen of the interacting drug	Rosuvastatin dosing regimen	Changes in rosuvastatin AUC*
Increase in rosuvastatin AUC by 2-fold or more
Sofosbuvir/velpatasvir/voxilaprevir (400 mg/100 mg/100 mg) + voxilaprevir (100 mg) once daily for 15 days	10 mg, single dose	↑ 7.4-fold
Cyclosporine from 75 mg twice daily 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 once daily	↑ 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 once daily	↑ 2.7-fold
Obicistat 25 mg/paritaprevir 150 mg/ritonavir 100 mg once daily/dasabuvir 400 mg twice daily, 14 days	5 mg once daily	↑ 2.6-fold
Glecaprevir 200 mg/elbasvir 50 mg once daily, 11 days	10 mg once daily	↑ 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 loading dose, followed by 75 mg daily	20 mg, single dose	↑ 2-fold
Gemfibrozil 600 mg twice daily, 7 days	80 mg, single dose	↑ 1.9-fold
Increase in rosuvastatin AUC less than 2-fold
Eltrombopag 75 mg once daily, 5 days	10 mg, single dose	↑ 1.6-fold
Darunavir 600 mg/ritonavir 100 mg twice daily, 7 days	10 mg once daily, 7 days	↑ 1.5-fold
Tipranavir 500 mg/ritonavir 200 mg twice daily, 11 days	10 mg, single dose	↑ 1.4-fold
Dronedarone 400 mg twice daily	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
Erythromycin 500 mg four times daily, 7 days	80 mg, single dose	↓ 20%
Scutellaria baicalensis 50 mg three times daily, 14 days	20 mg, single dose	↓ 47%

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

Increases are indicated by ↑, decreases by ↓.

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

The following medicinal products or their combinations had no clinically significant effect on rosuvastatin AUC ratio when co-administered:

Aleglitazar 0.3 mg for 7 days; Fenofibrate 67 mg three times daily for 7 days; Fluconazole 200 mg once daily for 11 days; Fosamprenavir 700 mg/ritonavir 100 mg twice daily for 8 days; Ketoconazole 200 mg twice daily for 7 days; Rifampicin 450 mg once daily for 7 days; Silymarin 140 mg three times daily for 5 days.

Effect of rosuvastatin on co-administered medicinal products

Vitamin K antagonists

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

Oral contraception/hormone replacement therapy (HRT)

Concomitant administration of rosuvastatin and oral contraceptives resulted in a 26% and 34% increase in AUC of ethinylestradiol and norgestimate, respectively. These increased plasma levels should be considered when selecting doses of oral contraceptives. There are no pharmacokinetic data in patients taking rosuvastatin and HRT simultaneously; therefore, a similar effect cannot be excluded. However, the combination has been widely used in women in clinical trials and was well tolerated.

Other medicinal products

Digoxin

Based on specific interaction study data, no clinically significant interaction with digoxin is expected.

Fusidic acid

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

If systemic fusidic acid therapy is necessary, treatment with rosuvastatin should be discontinued for the entire duration of fusidic acid administration. See also section "Special warnings and precautions for use".

Lopinavir/ritonavir

In a pharmacological interaction study, concomitant administration of rosuvastatin and a combination product containing two protease inhibitors (lopinavir 400 mg/ritonavir 100 mg) in healthy volunteers was associated with approximately a two-fold and five-fold increase in steady-state AUC(0-24) and Cmax of rosuvastatin, respectively. Interactions between rosuvastatin and other protease inhibitors have not been studied.

Tickagrelor

Ticagrelor may cause renal impairment and affect renal elimination of rosuvastatin, increasing the risk of rosuvastatin accumulation. In some cases, concomitant use of ticagrelor and rosuvastatin has led to decreased renal function, increased CK levels, and rhabdomyolysis. When ticagrelor and rosuvastatin are used concomitantly, monitoring of renal function and CK levels is recommended.

Paediatric population

Interaction studies have been conducted only in adults. The extent of interaction in the paediatric population is unknown.

Special precautions for use.

Renal effects

Cases of proteinuria (detected by "dipstick test"), predominantly of tubular origin and mostly transient or short-lived, have been observed in patients treated with Rosuvastatin KRKA at high doses, particularly at the dose of 40 mg. Proteinuria did not indicate acute or progressive kidney disease. Renal adverse reactions have been reported more frequently during the post-marketing period with the 40 mg dose. Renal function should be monitored regularly in patients taking the drug at a dose of 30 or 40 mg.

Effects on skeletal muscle

Skeletal muscle disorders, such as myalgia, myopathy, and rarely rhabdomyolysis, have been observed in patients treated with any dose of Rosuvastatin KRKA, particularly at doses exceeding 20 mg. Very rare cases of rhabdomyolysis have been reported when ezetimibe is used in combination with HMG-CoA reductase inhibitors. A pharmacodynamic interaction cannot be excluded; therefore, such combination should be used with caution.

As with other HMG-CoA reductase inhibitors, rhabdomyolysis associated with Rosuvastatin KRKA has been reported more frequently during the post-marketing period at the 40 mg dose.

There have been reports of rare cases of immune-mediated necrotizing myopathy, clinically presenting as persistent proximal muscle weakness and elevated serum creatine kinase levels, during or after statin treatment, including rosuvastatin. In such cases, additional neuromuscular and serological investigations and immunosuppressive therapy may be required.

There have been several reports that statins may induce or exacerbate pre-existing myasthenia gravis or ocular myasthenia (see "Adverse reactions"). If symptoms worsen, rosuvastatin should be discontinued. Recurrences have been reported when the same or another statin was taken again.

Creatine phosphokinase (CPK) measurement

CPK levels should not be measured after significant physical exertion or in the presence of possible alternative causes of elevated CPK, which may interfere with result interpretation. If the initial CPK level is markedly elevated (more than 5 times the upper limit of normal (ULN)), a confirmatory test should be performed within 5–7 days. If the repeat test confirms an initial level exceeding 5 times the ULN, treatment should not be initiated.

Before treatment

Rosuvastatin KRKA, like other HMG-CoA reductase inhibitors, should be prescribed with caution in patients with factors predisposing to myopathy/rhabdomyolysis. These factors include:

renal impairment;
hypothyroidism;
personal or family history of hereditary muscle disorders;
history of myotoxicity caused by other HMG-CoA reductase inhibitors or fibrates;
alcohol abuse;
age >70 years;
conditions that may lead to increased plasma levels of the drug;
concomitant use of fibrates.

In such patients, the risk and potential benefit of drug use should be carefully weighed, and clinical monitoring is recommended. Treatment should not be initiated if the initial CPK level is significantly elevated (>5 × ULN).

During treatment

Patients should be advised to promptly report any unexplained muscle pain, weakness, or cramps, especially if accompanied by malaise or fever. CPK levels should be measured in such patients. Treatment should be discontinued if CPK levels are markedly elevated (>5 × ULN) or if muscle symptoms are severe and cause discomfort in daily life (even if CPK ≤ 5 × ULN). If symptoms resolve and CPK levels return to normal, Rosuvastatin KRKA or an alternative HMG-CoA reductase inhibitor may be cautiously reintroduced at the lowest dose and under close supervision. Routine monitoring of CPK levels is not required in patients without the aforementioned symptoms. Very rare cases of immune-mediated necrotizing myopathy (IMNM) have been reported during or after statin treatment, including rosuvastatin. Clinically, IMNM is characterized by proximal muscle weakness and elevated serum creatine kinase (CK) levels, which persist despite discontinuation of statin therapy.

In studies involving a small number of patients treated with Rosuvastatin KRKA and concomitant medications, no enhanced effects on skeletal muscle were observed. However, increased incidence of myositis and myopathy has been reported in patients treated with other HMG-CoA reductase inhibitors in combination 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, Rosuvastatin KRKA is not recommended to be used in combination with gemfibrozil. The beneficial effect on further lipid level changes with concomitant use of Rosuvastatin KRKA with fibrates or niacin should be weighed against the potential risks of such combination. Concomitant use of Rosuvastatin KRKA at a dose of 30 or 40 mg with fibrates is contraindicated.

Rosuvastatin should not be used concomitantly with systemic fusidic acid or within 7 days after discontinuation of fusidic acid treatment. In patients for whom systemic fusidic acid treatment is considered necessary, statin therapy should be discontinued throughout the duration of fusidic acid treatment. Cases of rhabdomyolysis (including some 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 circumstances, when prolonged systemic use of fusidic acid is required, e.g., for treatment of severe infections, concomitant use of a statin and fusidic acid should be considered only on a case-by-case basis and under close medical supervision.

Rosuvastatin KRKA should not be administered to patients with acute, serious conditions that may cause myopathy or increase the risk of renal failure due to rhabdomyolysis (e.g., sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine, or electrolyte disturbances; uncontrolled seizures).

Hepatic effects

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

Liver function should be assessed before starting treatment and again after 3 months of therapy. If serum transaminase levels exceed three times the ULN, Rosuvastatin KRKA should be discontinued. Serious liver function abnormalities (predominantly elevated liver transaminases) have been reported more frequently during the post-marketing period with the 40 mg dose.

In patients with secondary hypercholesterolemia due to hypothyroidism or nephrotic syndrome, treatment of the underlying condition should be initiated before starting Rosuvastatin KRKA.

Race

Pharmacokinetic studies have shown increased systemic exposure in Asian patients compared to Caucasians (see "Method of administration and dosage", "Contraindications", "Pharmacokinetics").

Protease inhibitors

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

Lactose intolerance

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

Interstitial lung disease

Isolated cases of interstitial lung disease have been reported with some statins, particularly with long-term therapy. Symptoms include dyspnea, non-productive cough, and worsening general condition (fatigue, weight loss, fever). If interstitial lung disease is suspected, statin treatment should be discontinued.

Diabetes mellitus

Some data suggest that statins as a class may increase blood glucose levels and may lead to hyperglycemia in some patients at high risk of developing diabetes, where formal diabetes management may become necessary. However, this risk is outweighed by the cardiovascular risk reduction provided by statins and should not be a reason to discontinue statin therapy. Patients at risk (fasting glucose 5.6–6.9 mmol/L, BMI >30 kg/m², elevated triglycerides, hypertension) should be monitored clinically and biochemically according to national guidelines.

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

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. Patients 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 treatment considered.

If a patient has experienced a serious reaction such as SJS or DRESS while taking rosuvastatin, reinitiating treatment with this drug is not recommended.

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 treated with rosuvastatin is limited to a 2-year period. After 2 years of treatment, no effect on growth, body weight, BMI, or sexual maturation was observed (see section "Pharmacodynamics"). In a clinical study in children and adolescents treated with rosuvastatin for 52 weeks, elevated CK levels >10 times above ULN and muscle-related symptoms after physical exertion or increased physical activity were observed more frequently compared to adults (see section "Adverse reactions").

Use during pregnancy or breastfeeding

Rosuvastatin KRKA is contraindicated during pregnancy and breastfeeding.

Women of childbearing potential should use appropriate contraceptive methods.

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

Since another drug in this class is excreted in human breast milk and considering that HMG-CoA reductase inhibitors may cause serious adverse reactions in infants, women requiring rosuvastatin treatment should be advised not to breastfeed. There are no data on the excretion of the drug in human breast milk (see section "Contraindications").

Ability to influence the speed of reactions while driving or operating machinery

No studies have been conducted to determine the effect of rosuvastatin on the ability to drive or operate machinery. Based on the pharmacodynamic properties of rosuvastatin, such an effect is unlikely. However, when driving or operating machinery, it should be considered that dizziness may occur during treatment.

Dosage and Administration.

Before initiating treatment, patients should be placed on a standard cholesterol-lowering diet, which should be continued throughout treatment. The dose should be individually adjusted according to therapeutic goals and treatment efficacy, following established guidelines.

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

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

Treatment of hypercholesterolemia

The recommended initial dose is 5 mg or 10 mg, orally once daily, both for patients who have not previously used statins and for those who have previously used other HMG-CoA reductase inhibitors. When selecting the initial dose, the patient's individual cholesterol levels, future cardiovascular risk, and potential risk of adverse reactions should be taken into account (see below). If necessary, the dose may be increased after 4 weeks to the next level. Since adverse reactions occur more frequently with the 40 mg dose than with lower doses, dose titration to 30 mg or 40 mg should be reserved only for patients with severe hypercholesterolemia and high cardiovascular risk (particularly those with familial hypercholesterolemia) in whom the desired response has not been achieved with the 20 mg dose, and who must be under regular monitoring. Specialist supervision is recommended when initiating treatment with 30 mg or 40 mg doses.

Prevention of cardiovascular events

In a clinical trial evaluating cardiovascular risk reduction, the daily dose of the drug was 20 mg. Patients with hypercholesterolemia should undergo standard lipid level assessment and follow the dosing recommendations for hypercholesterolemia treatment.

Use in elderly patients

The recommended initial dose for patients aged 70 years and older is 5 mg. No other age-related dose adjustment is required.

Dosing in patients with renal impairment

Dose adjustment is not necessary for patients with mild to moderate renal impairment. The recommended initial dose for patients with moderate renal impairment (creatinine clearance <60 mL/min) is 5 mg. The 30 mg and 40 mg doses are contraindicated in patients with moderate renal impairment. Rosuvastatin KRKA is contraindicated in patients with severe renal impairment at any dose.

Dosing in patients with hepatic impairment

No increase in systemic exposure to rosuvastatin was observed in patients with Child-Pugh class 7. However, increased systemic exposure was noted in patients classified as Child-Pugh class 8 or 9. Renal function should be assessed in these patients. Experience with the drug in patients with Child-Pugh class 9 is lacking. Rosuvastatin KRKA is contraindicated in patients with active liver disease. Increased rosuvastatin exposure has been observed in patients with severe hepatic impairment; therefore, doses exceeding 10 mg should be used with caution in such patients.

Race

Increased systemic exposure has been observed in Asian subjects (see sections "Pharmacological Properties", "Contraindications", and "Special Warnings and Precautions for Use"). The recommended initial dose for patients of Asian origin is 5 mg. The 30 mg and 40 mg doses are contraindicated in these patients.

Genetic polymorphisms

Specific types of genetic polymorphisms are known to potentially increase the effects of rosuvastatin (see section "Pharmacological Properties"). A lower daily dose of rosuvastatin is recommended for patients known to have such specific polymorphisms.

Dosing in patients predisposed to myopathy

The recommended initial dose is 5 mg for patients predisposed to myopathy (see section "Pharmacological Properties").

The 30 mg and 40 mg doses are contraindicated in some of these patients (see section "Contraindications").

Concomitant therapy

Rosuvastatin is a substrate of various transporter proteins (e.g., OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) increases when Rosuvastatin KRKA is co-administered with certain medicinal products that may increase plasma concentrations of rosuvastatin due to interactions with these transporter proteins (e.g., cyclosporine and certain protease inhibitors, including ritonavir combinations with atazanavir, lopinavir and/or tipranavir; see sections "Interaction with Other Medicinal Products and Other Forms of Interaction" and "Special Warnings and Precautions for Use"). Alternative therapies should be considered whenever possible, and temporary discontinuation of rosuvastatin therapy should be considered if necessary. In situations where co-administration of these medicinal products with rosuvastatin is unavoidable, the benefit-risk ratio of concomitant therapy should be carefully evaluated and rosuvastatin dosing adjusted accordingly (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Children

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

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

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

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

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

The 40 mg tablets are not to be used in children.

Children under 6 years of age

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

Overdose.

There is no specific antidote in case of overdose. Treatment is symptomatic. Supportive measures should be taken if necessary. Creatine kinase (CK) levels should be monitored and liver function tests performed. Hemodialysis is unlikely to be beneficial.

Adverse Reactions

Adverse reactions observed during the use of Rosuvastatin Krka are usually mild and transient.

Blood

Thrombocytopenia.

Immune system

Hypersensitivity reactions, including angioedema.

Endocrine system

Diabetes mellitus1,2.

Psychiatric disorders

Depression.

Nervous system

Headache, dizziness, polyneuropathy, memory loss, peripheral neuropathy, sleep disorders (including insomnia and night terrors), myasthenia gravis.

Respiratory, thoracic and mediastinal system

Cough, dyspnea.

Gastrointestinal tract (GIT)

Constipation, nausea, abdominal pain, pancreatitis, diarrhea.

Hepatobiliary system

Jaundice, hepatitis, increased hepatic transaminase activity.

Skin and subcutaneous tissue

Pruritus, rash and urticaria, drug reaction with eosinophilia and systemic symptoms (DRESS).

Musculoskeletal, connective tissue and bone system

Myalgia, myopathy (including myositis) and rhabdomyolysis, lupus-like syndrome, muscle rupture, arthralgia, immune-mediated necrotizing myopathy, tendon disorders, sometimes complicated by tendon rupture.

Renal and urinary system

Hematuria.

Reproductive system and breast

Gynecomastia.

Eye disorders

Ocular myasthenia.

General disorders

Asthenia, edema.

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

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

Renal effects

Proteinuria, mostly of tubular origin (detected by "dipstick test"), has been observed in patients treated with Rosuvastatin Krka. Changes in urinary protein content from absent or trace to ++ or higher were reported in <1% of patients receiving rosuvastatin 10 mg and 20 mg, and in approximately 3% of patients receiving 40 mg. A slight increase in the frequency of proteinuria from absent or trace to + was observed with the 20 mg dose. In most cases, the intensity of proteinuria decreased or resolved spontaneously while continuing treatment. According to available studies, no causal relationship has been established between proteinuria and acute or progressive kidney disease.

Hematuria observed in patients treated with rosuvastatin has been reported at a low frequency.

Musculoskeletal effects

Skeletal muscle changes such as myalgia, myopathy (including myositis), and rarely rhabdomyolysis, with or without acute renal failure, have been observed during treatment with any dose of Rosuvastatin Krka, particularly at doses >20 mg. Rare cases of rhabdomyolysis, sometimes associated with renal failure, have been reported with rosuvastatin and other statins.

Patients treated with rosuvastatin have shown dose-dependent increases in creatine kinase (CK) levels; in most cases, this was mild, asymptomatic, and transient. If CK levels are elevated (>5 × ULN), treatment should be discontinued.

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 treated with rosuvastatin; in most cases, this was mild, asymptomatic, and transient.

Adverse events reported with some statins:

Depression.

Sleep disorders, including insomnia and night terrors.

Sexual dysfunction.

Isolated cases of interstitial lung disease, particularly with long-term therapy.

The incidence of rhabdomyolysis, serious renal and hepatic disorders (mainly elevated transaminases) was higher with the 40 mg dose.

Paediatric population

CK levels >10 × ULN and muscle symptoms following physical exertion or increased physical activity were observed more frequently in children and adolescents compared to adults in a 52-week clinical trial (see section "Special warnings and precautions for use"). On the other hand, the safety profile of rosuvastatin was similar in children and adolescents compared to adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging to protect from light. The medicinal product does not require special storage temperature conditions.

Keep out of the reach and sight of children.

Packaging.

10 tablets per blister; 3, 6 or 9 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Krka, d.d., Novo mesto, Slovenia.

Manufacturer's address and location of its operations.

Šmarješka cesta 6, 8501 Novo mesto, Slovenia.