Rosuvastatin krka
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ROSUVASTATIN KRKA (Rosuvastatin KRKA)
Composition:
Active substance: rosuvastatin;
One film-coated tablet contains 5 mg, 10 mg, 20 mg, or 40 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), monohydrate lactose.
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
5 mg: white, round, slightly biconvex, film-coated tablets with bevelled edges and engraved «5» on one side.
10 mg: white, round, slightly biconvex, film-coated tablets with bevelled edges and engraved «10» on one side.
20 mg: white, round, film-coated tablets with bevelled edges.
40 mg: white, biconvex, film-coated tablets in a capsule shape.
Pharmacotherapeutic group. Hypolipidemic agents. HMG-CoA reductase inhibitors.
ATC code: C10AA07.
Pharmacological properties.
Pharmacodynamics.
Mechanism of action
Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the enzyme that catalyzes the conversion of 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of cholesterol. The primary site of action of rosuvastatin is the liver—the target organ for cholesterol reduction.
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) levels. It also reduces ApoB, non-HDL-C, very-low-density lipoprotein cholesterol (VLDL-C), very-low-density lipoprotein triglyceride complex (TG-VLDL), and increases ApoA-I (see Table 1). Rosuvastatin also reduces the LDL-C/HDL-C, total cholesterol/HDL-C, and non-HDL-C/HDL-C ratios, as well as the ApoB/ApoA-I ratio.
Table 1
Dose response in patients with primary hypercholesterolemia (types IIa and IIb) (adjusted mean percentage change from baseline)
| Dose |
N |
LDL-C |
total cholesterol |
HDL-C |
triglyceride complex |
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 starting 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) in achieving the recommended target levels of the European Atherosclerosis Society (EAS; 1998); approximately 80 % of patients receiving 10 mg achieved EAS LDL-C goals (<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 demonstrated favorable effects on lipid parameters and achievement of target levels. After titration to a daily dose of 40 mg (12 weeks of treatment), LDL-C was reduced 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 instructions").
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 Framingham risk <10 % over 10 years) and 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 of rosuvastatin once daily or placebo for 2 years. Rosuvastatin significantly slowed the rate of progression of maximum CIMT at 12 carotid artery sites compared to placebo by -0.0145 mm/year (95 % CI: -0.0196 to -0.0093; p <0.0001). The change from baseline was -0.0014 mm/year (0.12 %/year (not 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 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 of 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 JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) study evaluated the effect of rosuvastatin on the incidence of major atherosclerotic cardiovascular diseases in 17,802 men (≥50 years) and women (≥60 years).
Study participants were randomly assigned to receive placebo (n=8,901) or rosuvastatin 20 mg once daily (n=8,901) and were 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 study 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 of rosuvastatin or placebo daily for 12 weeks, followed by all receiving 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 5 mg, 10 mg, and 20 mg of rosuvastatin, respectively, compared to 0.7 % with placebo. At the end of the 40-week open-label titration to target (dose titrated up to 20 mg once daily), 70 out 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 instructions"). This study (n=176) was not powered to compare rare adverse events.
Rosuvastatin was also studied in a 2-year open-label study with target dose titration in 198 children with heterozygous familial hypercholesterolemia aged 6 to 17 years (88 male and 110 female participants, Tanner stage <II–V). The initial dose for all patients was 5 mg of 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 mean reduction from baseline LDL-C, determined by the least squares method, was -43 % (baseline level: 236 mg/dl, month 24: 133 mg/dl). For each age group, the mean reduction from baseline LDL-C, determined by the least squares method, was -43 % (baseline level: 234 mg/dl, month 24: 124 mg/dl), -45 % (baseline level: 234 mg/dl, month 24: 124 mg/dl), and -35 % (baseline level: 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 instructions").
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 run-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 of 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 levels 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 showed 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 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. The 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.
Excretion
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 half-life is approximately 19 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 increasing 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 was observed in adults. The pharmacokinetics of rosuvastatin in children and adolescents with heterozygous familial hypercholesterolemia were similar to those in adult volunteers (see section "Children").
Race
Pharmacokinetic studies demonstrate approximately a 2-fold increase in the area under the concentration-time curve (AUC) and Cmax of rosuvastatin in Asian populations (Japanese, Chinese, Filipino, Vietnamese, and Korean) compared to Caucasian patients; in Indians, an increase of approximately 1.3-fold in mean AUC and Cmax values is observed. Pharmacokinetic analysis of patient groups did not reveal any clinically significant differences in pharmacokinetics between Caucasian and Black populations.
Renal impairment
In a study involving patients with varying degrees of renal impairment, mild or moderate kidney disease did not affect the plasma concentration of rosuvastatin or the N-desmethyl metabolite. In patients with severe renal impairment (creatinine clearance <30 ml/min), plasma concentration increased 3-fold, and the concentration of the N-desmethyl metabolite increased 9-fold compared to healthy volunteers. Steady-state plasma concentration of rosuvastatin in patients undergoing hemodialysis sessions was approximately 50 % higher than in healthy volunteers.
Hepatic impairment
In a study involving patients with varying degrees of hepatic impairment, 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 transport proteins OATP1B1 and BCRP. Patients with genetic polymorphisms in SLCO1B1 (OATP1B1) and/or ABCG2 (BCRP) are at risk of increased rosuvastatin exposure. With specific forms of polymorphism SLCO1B1 c.521CC and ABCG2 c.421AA, rosuvastatin AUC is increased compared to genotypes SLCO1B1 c.521TT or ABCG2 c.421CC. Routine genotyping is not required in clinical practice, but patients with such polymorphisms are recommended to receive 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 treatments are 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.
Doses of 5 mg, 10 mg, 15 mg, and 20 mg are contraindicated:
- in patients with hypersensitivity to rosuvastatin or to any excipient;
- in patients with active liver disease, including liver disease of unknown etiology, persistent elevations in serum transaminases, and elevations in any serum transaminase level exceeding 3 times the upper limit of normal;
- in patients with severe renal impairment (creatinine clearance < 30 mL/min);
- in patients with myopathy;
- in patients concurrently taking cyclosporine;
- in patients concurrently taking sofosbuvir/velpatasvir/voxilaprevir (see "Interaction with other medicinal products and other forms of interaction");
- in patients with pre-existing risk factors for myotoxic complications;
- during pregnancy or breastfeeding, as well as in women of childbearing potential who are not using appropriate contraceptive measures;
- in children under 6 years of age.
Doses of 30 mg and 40 mg are contraindicated:
- in patients with hypersensitivity to rosuvastatin or to any excipient;
- in patients with active liver disease, including unexplained, persistent elevations in serum transaminases and any elevation in serum transaminase levels exceeding 3 times the upper limit of normal;
- in patients concurrently taking cyclosporine;
- during pregnancy or breastfeeding, and in women of childbearing potential who are not using appropriate contraceptive measures;
- in children;
- in patients with myopathy or pre-existing 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 myotoxicity from another HMG-CoA reductase inhibitor or fibrate; alcohol abuse; conditions that may increase plasma levels (e.g., severe hepatic insufficiency); Asian ancestry; concomitant use of fibrates; age over 70 years.
Interaction with other medicinal products and other forms of interaction.
Effects of concomitantly administered medicinal products on rosuvastatin
Transporter protein inhibitors
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-fold and 7-fold increases in AUC and Cmax of rosuvastatin, respectively. Concomitant use of rosuvastatin with 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 is expected with fenofibrate, but a pharmacodynamic interaction may occur. Gemfibrozil, fenofibrate, other fibrates, and lipid-altering 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 start with a 5 mg dose.
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 rosuvastatin plasma concentration. This effect was mitigated 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 erythromycin-induced enhancement of intestinal motility.
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. Furthermore, 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. Initiation with a rosuvastatin dose of 5 mg once daily is recommended if the expected increase in AUC is approximately 2-fold or higher. 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).
Table 2
Effect of concomitant medicinal products on rosuvastatin exposure
(AUC; in descending order of magnitude) based on published data from clinical studies
| Increased AUC of rosuvastatin by 2 times or more |
||
| Dosing regimen of the interacting drug |
Dosing regimen of rosuvastatin |
Changes in rosuvastatin AUC* |
| Sofosbuvir/velpatasvir/voxilaprevir (400 mg-100 mg-100 mg) + voxilaprevir (100 mg) once daily for 15 days |
10 mg, single dose |
↑ 7.4-fold |
| Cyclosporine from 75 mg twice daily 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 |
| Obitasvir 25 mg/paritaprevir 150 mg/ ritonavir 100 mg once daily / dasabuvir 400 mg twice daily, 14 days |
5 mg, single dose |
↑ 2.6-fold |
| Teriflunomide |
Data not available |
↑ 2.5-fold |
| Glecaprevir 200 mg/elbasvir 50 mg once daily, 11 days |
10 mg, single dose |
↑ 2.3-fold |
| Glecaprevir 400 mg/pibrentasvir 120 mg once daily, 7 days |
5 mg once daily, 7 days |
↑ 2.2-fold |
| Lopinavir 400 mg/ritonavir 100 mg twice daily, 17 days |
20 mg once daily, 7 days |
↑ 2.1-fold |
| Capmatinib 400 mg twice daily |
10 mg, single dose |
↑ 2.1-fold |
| Clopidogrel 300 mg, then 75 mg after 24 hours |
20 mg, single dose |
↑ 2-fold |
| Fostamatinib 100 mg twice daily |
20 mg, single dose |
↑ 2.0-fold |
| Febuxostat 120 mg once daily |
10 mg, single dose |
↑ 1.9-fold |
| Gemfibrozil 600 mg twice daily, 7 days |
80 mg, single dose |
↑ 1.9-fold |
| Increased AUC of rosuvastatin less than 2-fold |
||
| Dosing regimen of the interacting drug |
Dosing regimen of rosuvastatin |
Changes in rosuvastatin AUC* |
| Elotrombopag 75 mg once daily, 5 days |
10 mg, single dose |
↑ 1.6-fold |
| Darunavir 600 mg/ritonavir 100 mg twice daily, 7 days |
10 mg once daily, 7 days |
↑ 1.5-fold |
| Tipranavir 500 mg/ritonavir 200 mg twice daily, 11 days |
10 mg, single dose |
↑ 1.4-fold |
| Dronedarone 400 mg twice daily |
Data not available |
↑ 1.4-fold |
| Itraconazole 200 mg once daily, 5 days |
10 mg, single dose |
↑ 1.4-fold ** |
| Ezetimibe 10 mg once daily, 14 days |
10 mg once daily, 14 days |
↑ 1.2-fold ** |
| Decreased AUC of rosuvastatin |
||
| Dosing regimen of the interacting drug |
Dosing regimen of rosuvastatin |
Changes in rosuvastatin AUC* |
| Erythromycin 500 mg four times daily, 7 days |
80 mg, single dose |
↓ 20% |
| Baicalin 50 mg three times daily, 14 days |
20 mg, single dose |
↓ 47% |
*Data presented as a change in fold represent the ratio between co-administration and administration of rosuvastatin alone. Data presented as % change represent the % difference compared to values when rosuvastatin was administered alone.
Increase is indicated by ↑, decrease by ↓.
**Several interaction studies were conducted at different doses of rosuvastatin; the table presents the most significant ratio.
The following medicinal products or their combinations had no clinically significant effect on the AUC ratio of rosuvastatin when administered concomitantly:
Aleglitazar 0.3 mg for 7 days of dosing; 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 dose adjustment 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. Appropriate monitoring of INR is recommended in such situations.
Oral contraceptives/hormone replacement therapy (HRT)
Concomitant administration of rosuvastatin and oral contraceptives resulted in a 26% and 34% increase in AUC of ethinylestradiol and norgestimate, respectively. These increased plasma levels should be considered when selecting doses of oral contraceptives. There are no pharmacokinetic data available in patients taking rosuvastain concomitantly with HRT; 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
Interaction studies between rosuvastatin and fusidic acid have not been conducted. The risk of myopathy, including rhabdomyolysis, may be increased when systemic fusidic acid is 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 treatment with systemic fusidic acid is necessary, rosuvastatin therapy should be discontinued for the entire duration of fusidic acid administration. See also section "Special precautions".
Lopinavir/ritonavir
In a pharmacological study, concomitant administration of rosuvastatin and a combined preparation 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
Tickagrelor may cause renal impairment and affect renal elimination of rosuvastatin, increasing the risk of rosuvastatin accumulation. In some cases, concomitant use of tickagrelor and rosuvastatin has led to decreased renal function, increased CK levels, and rhabdomyolysis. When tickagrelor and rosuvastatin are used concomitantly, monitoring of renal function and CK levels is recommended.
Paediatric population
Interaction studies have been performed only in adults. The extent of interaction in the paediatric population is unknown.
Special precautions.
Renal effects
Cases of proteinuria (detected by "dipstick testing"), predominantly of tubular origin and mostly transient or short-term, have been observed in patients treated with high doses of the medicinal product Rosuvastatin KRKA, particularly at a dose of 40 mg. Proteinuria did not indicate acute or progressive kidney disease. Renal adverse events 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 doses of 30 or 40 mg.
Skeletal muscle effects
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 therapy should be used with caution.
As with other HMG-CoA reductase inhibitors, cases of rhabdomyolysis associated with Rosuvastatin KRKA have occurred 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 therapy, including rosuvastatin. In such cases, additional neuromuscular and serological investigations and treatment with immunosuppressive agents 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 therapy should be discontinued. Recurrences have been reported when the same or another statin was taken again.
Measurement of creatine phosphokinase (CPK) levels
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 to patients with risk factors predisposing to myopathy/rhabdomyolysis. These factors include:
- renal impairment;
- hypothyroidism;
- personal or family history of hereditary muscular 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 benefit-risk ratio of treatment should be carefully evaluated, 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 report immediately any unexplained muscle pain, weakness, or cramps, especially if accompanied by malaise or fever. In such patients, CPK levels should be measured. 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 reinitiated at the lowest possible 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 therapy, 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 receiving Rosuvastatin KRKA and concomitant medications, no enhanced effect on skeletal muscle was observed. However, an increased incidence of myositis and myopathy has been observed in patients receiving other HMG-CoA reductase inhibitors in combination with fibric acid derivatives, including gemfibrozil, cyclosporine, niacin, azole antifungals, protease inhibitors, and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when used concomitantly with certain HMG-CoA reductase inhibitors; therefore, Rosuvastatin KRKA is not recommended to be used in combination with gemfibrozil. The potential benefits of further lipid-lowering effects with concomitant use of Rosuvastatin KRKA with fibrates or niacin should be weighed against the potential risks of such combination therapy. Concomitant use of Rosuvastatin KRKA at doses 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 restarted 7 days after the last dose of fusidic acid.
In exceptional circumstances, when prolonged systemic use of fusidic acid is required, for example for the treatment of severe infections, the necessity of concomitant use of a statin and fusidic acid should be considered 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 predispose to 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 checked before starting treatment and again after 3 months of therapy. If serum transaminase levels exceed three times the ULN, treatment with Rosuvastatin KRKA should be discontinued. Serious liver function abnormalities (mainly 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 benefits of lipid-lowering with rosuvastatin in HIV patients receiving protease inhibitors and the potential for increased plasma concentrations of rosuvastatin upon initiation and dose titration of rosuvastatin in patients receiving protease inhibitors should be considered. Concomitant use with protease inhibitors is not recommended unless the dose of rosuvastatin 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 conditions of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
Interstitial lung disease
Isolated cases of interstitial lung disease have been reported with the use of some statins, particularly with long-term therapy. Symptoms include dyspnea, non-productive cough, and deterioration in general health (fatigue, weight loss, fever). If interstitial lung disease is suspected, statin therapy should be discontinued.
Diabetes mellitus
Some data suggest that statins as a class may increase blood glucose levels and, in some patients at high risk of developing diabetes, may lead to hyperglycemia requiring formal antidiabetic treatment. 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, primarily 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), which may be life-threatening or fatal, have been reported with rosuvastatin use. 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 therapy considered.
If a patient develops a serious reaction such as SJS or DRESS while taking rosuvastatin, reinitiation of treatment with this drug is contraindicated.
Children
Assessment of linear growth (height), body weight, BMI (body mass index), and sexual maturation characteristics according to Tanner in children aged 6 to 17 years receiving rosuvastatin is limited to a 2-year period. After 2 years of investigational treatment, no effect on growth, body weight, BMI, or sexual maturation was observed (see section "Pharmacodynamics"). In a clinical study in children and adolescents treated with rosuvastatin for 52 weeks, CK levels >10 times the ULN and muscle-related symptoms after physical exertion or increased physical activity were observed more frequently than in 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 from 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 therapy 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 affect reaction speed when driving or operating machinery.
No studies have been conducted to assess 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.
Method of Administration and Dosage.
Before initiating treatment, patients should be placed on a standard hypocholesterolemic diet, which should be continued throughout the treatment period. The dose should be individually adjusted according to therapeutic goals and treatment efficacy, following established clinical 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 must not be chewed or crushed.
Hypercholesterolemia Treatment
The recommended initial dose is 5 mg or 10 mg orally once daily, both for patients who have not previously used statins and for those switching from other HMG-CoA reductase inhibitors. The choice of initial dose should take into account the patient's individual cholesterol levels, future cardiovascular risk, and potential risk of adverse reactions (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 only be considered in patients with severe hypercholesterolemia and high cardiovascular risk (particularly those with familial hypercholesterolemia) who have not achieved the desired response 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 clinical trials evaluating cardiovascular risk reduction, the daily dose of the drug was 20 mg. Patients with hypercholesterolemia should undergo standard lipid level monitoring and follow dosage recommendations for hypercholesterolemia treatment.
Use in Elderly Patients
The recommended initial dose for patients aged 70 years and older is 5 mg. No further age-related dose adjustment is required.
Dosing in Patients with Renal Impairment
Dose adjustment is not required in 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 a Child-Pugh score of 7. However, increased systemic exposure has been reported in patients with a Child-Pugh score of 8 or 9. Renal function should be assessed in these patients. Experience with the drug in patients with a Child-Pugh score of 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 Precautions"). 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 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 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 for several 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 Precautions"). Alternative therapies should be considered whenever possible, and temporary discontinuation of rosuvastatin therapy may be considered if necessary. In situations where concomitant use of these medicinal products with rosuvastatin is unavoidable, the benefit-risk ratio of combination therapy should be carefully evaluated and rosuvastatin dosing adjusted accordingly (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").
Children
The use of this medicinal product in children should be initiated 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 have not been studied in this population.
- The usual dose for children aged 10 to 17 years with heterozygous familial hypercholesterolemia is 5 mg to 20 mg orally once daily. The safety and efficacy of doses exceeding 20 mg have not been studied in this population.
Dose increases should be based on the individual child's response to treatment and drug tolerability, following recommendations for pediatric treatment (see section "Special Precautions"). Before initiating rosuvastatin therapy, children and adolescents should be placed on a standard hypocholesterolemic diet, which should be maintained throughout treatment.
Homoyzgous Familial Hypercholesterolemia
The recommended maximum dose for children aged 6 to 17 years with homozygous familial hypercholesterolemia is 20 mg once daily.
The recommended initial dose is 5 mg to 10 mg once daily, depending on age, body weight, and prior statin use. Dose escalation to the maximum of 20 mg once daily should be based on the individual child's treatment response and drug tolerability, following recommendations for pediatric treatment (see section "Special Precautions"). Before initiating rosuvastatin therapy, children and adolescents should be placed on a standard hypocholesterolemic diet, which should be maintained throughout treatment.
Experience with 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 implemented 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, myasthenia gravis.
Respiratory, thoracic and mediastinal disorders
Cough, dyspnea.
Gastrointestinal disorders
Constipation, nausea, abdominal pain, pancreatitis, diarrhea.
Hepatobiliary disorders
Jaundice, hepatitis, increased hepatic transaminase activity.
Skin and subcutaneous tissue disorders
Pruritus, rash and urticaria, drug reaction with eosinophilia and systemic symptoms (DRESS).
Musculoskeletal and connective tissue disorders
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 disorders
Hematuria.
Reproductive system and breast disorders
Gynecomastia.
Eye disorders
Ocular myasthenia.
General disorders
Asthenia, edema.
1 Frequency depends on the presence of risk factors (fasting plasma 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 less than 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 degree of proteinuria decreased or resolved spontaneously while continuing treatment. To date, studies have not demonstrated a causal relationship 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 with all doses of Rosuvastatin KRKA, particularly with doses >20 mg. Rare cases of rhabdomyolysis, sometimes associated with renal failure, have been reported with rosuvastatin and other statins.
Dose-dependent increases in creatine kinase (CK) levels have been observed in patients treated with rosuvastatin. In most cases, this was mild, asymptomatic, and transient. Treatment should be discontinued if CK levels are elevated (>5 × ULN).
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 nightmares.
Sexual dysfunction.
Isolated cases of interstitial lung disease, particularly with long-term therapy.
The incidence of rhabdomyolysis and serious renal and hepatic adverse events (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 precautions"). Otherwise, 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 important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.
Shelf life: 3 years.
Storage conditions
Store in the original packaging to protect from light. The medicine 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 operations
Šmarješka cesta 6, 8501 Novo mesto, Slovenia.