Rosuvastatin-aurobindo

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ROSUVASTATIN-AUROBINDO

Composition:

Active substance: rosuvastatin;

One film-coated tablet contains rosuvastatin calcium equivalent to rosuvastatin 10 mg or 20 mg;

Excipients: lactose monohydrate; calcium hydrogen phosphate anhydrous; microcrystalline cellulose; crospovidone; magnesium stearate; film coating: Opadry II Pink 32K84302 (lactose monohydrate; hypromellose 15 cP; titanium dioxide (E 171); triacetin; FD&C Red No. 40 (Allura Red AC aluminum lake); FD&C Yellow No. 6 (Sunset Yellow FCF aluminum lake); FD&C Blue No. 2 (Indigocarmine aluminum lake)), purified water.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

10 mg tablets – pink, round, biconvex, film-coated tablets marked with «J» on one side and «54» on the other side;

20 mg tablets – pink, round, biconvex, film-coated tablets marked with «J» on one side and «55» on the other side.

Pharmacotherapeutic group. Lipid-lowering agents. HMG-CoA reductase inhibitors.

ATC code C10AA07.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Rosuvastatin-Aurobindo is a selective and competitive inhibitor of HMG-CoA reductase, the enzyme that limits the rate of reaction and converts 3-hydroxy-3-methylglutaryl coenzyme A into mevalonate, a cholesterol precursor. The primary site of action of rosuvastatin is the liver—the target organ for reducing cholesterol levels.

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

Pharmacodynamic effects

Rosuvastatin-Aurobindo reduces elevated levels of LDL cholesterol, total cholesterol, and triglycerides, and increases HDL cholesterol levels. It also reduces levels of apolipoprotein B, non-HDL cholesterol, LDL cholesterol, triglyceride-rich LDL, and increases apolipoprotein A-I levels (Table 1). Rosuvastatin-Aurobindo also reduces the ratios of LDL-C/HDL-C, total cholesterol/HDL-C, non-HDL-C/HDL-C, and apoB/apoA-I.

Table 1

Dose-response in patients with primary hypercholesterolemia type IIa and IIb

(adjusted mean percentage change from baseline)

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

The therapeutic effect is achieved within 1 week after starting the medication, with 90% of the maximum effect reached within 2 weeks. The maximum effect is usually achieved within 4 weeks and persists thereafter.

Clinical efficacy and safety

Rosuvastatin-Aurobindo is effective in treating adults with hypercholesterolemia—with or without hypertriglyceridemia—regardless of race, gender, or age, as well as in patients from special groups such as those with diabetes mellitus or familial hypercholesterolemia.

Based on pooled Phase III trial data, rosuvastatin effectively reduced cholesterol levels in most patients with type IIa and IIb hypercholesterolemia (mean baseline LDL-C approximately 4.8 mmol/L) to target levels established by the European Atherosclerosis Society (EAS; 1998) guidelines; approximately 80% of patients receiving the 10 mg dose achieved EAS target LDL-C levels (< 3 mmol/L).

In a large study involving 435 patients with heterozygous familial hypercholesterolemia, rosuvastatin was administered at doses ranging from 20 to 80 mg using an intensified dose titration regimen. Favorable effects of the drug on lipid parameters and achievement of target levels were observed at all doses. After titration to a daily dose of 40 mg (12 weeks of treatment), LDL-C decreased by 53%. Target EAS LDL-C levels (< 3 mmol/L) were achieved in 33% of patients.

In an open-label dose titration study, the response to rosuvastatin at doses of 20–40 mg was evaluated in 42 patients (including 8 children) with homozygous familial hypercholesterolemia. In the overall population, LDL-C levels decreased by an average of 22%.

In clinical trials involving a limited number of patients, an additive effect of rosuvastatin on triglyceride reduction was observed when used in combination with fenofibrate, and an increase in HDL-C levels was observed 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 45–70 years with low risk of ischemic heart disease (defined as a Framingham risk score < 10% over 10 years), a mean LDL-C level of 4.0 mmol/L (154.5 mg/dL), but with subclinical atherosclerosis (defined by increased carotid intima-media thickness [CIMT]) were randomized into two groups and received either 40 mg of rosuvastatin or placebo once daily for 2 years. Compared to placebo, rosuvastatin significantly slowed the progression of maximum CIMT at 12 carotid artery sites by -0.0145 mm/year [95% confidence interval: -0.0196, -0.0093; p < 0.0001]. The change from baseline was -0.0014 mm/year (-0.12%/year (statistically not significant)) in the rosuvastatin group compared to progression of +0.0131 mm/year (1.12%/year (p < 0.0001)) in the placebo group. No direct correlation between CIMT reduction and reduced risk of cardiovascular events was demonstrated. The METEOR study included patients with low risk of ischemic heart disease, who are not representative of the target population for rosuvastatin 40 mg use. The 40 mg dose should only be prescribed to patients with severe hypercholesterolemia and high risk of cardiovascular disorders (see section "Dosage and administration").

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

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

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

In a retrospective analysis of a high-risk subgroup of patients with a baseline Framingham risk score > 20% (1558 participants), a significant reduction in the incidence of the composite endpoint, including cardiovascular death, stroke, and myocardial infarction (p = 0.028), was observed in the rosuvastatin group compared to placebo. The absolute risk reduction was 8.8 events per 1000 patient-years. The overall mortality rate remained unchanged in this high-risk group (p = 0.193). In a retrospective analysis of another high-risk subgroup (9302 participants) with a baseline SCORE risk ≥ 5% (extrapolated to include data from participants over 65 years of age), a significant reduction in the composite endpoint, including cardiovascular death, stroke, and myocardial infarction (p = 0.0003), was observed in the rosuvastatin group compared to placebo. The absolute risk reduction expressed as event rate was 5.1 events per 1000 patient-years. The overall mortality rate in this high-risk subgroup remained unchanged (p = 0.076).

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

Children

In a double-blind, randomized, multicenter, placebo-controlled 12-week study (n = 176, 97 male and 79 female participants) followed by a 40-week open-label dose titration period (n = 173, 96 male and 77 female participants), patients aged 10–17 years (Tanner stages II–IV, girls with at least 1 year since menarche) with heterozygous familial hypercholesterolemia received rosuvastatin at doses of 5, 10, or 20 mg/day or placebo for 12 weeks, after which all participants received rosuvastatin daily for 40 weeks. At the beginning of the study, approximately 30% of patients were aged 10–13 years, and approximately 17%, 18%, 40%, and 25% were at Tanner stages II, III, IV, and V, respectively.

LDL-C levels decreased by 38.3%, 44.6%, and 50.0% in the rosuvastatin 5 mg, 10 mg, and 20 mg groups, respectively, compared to 0.7% in the placebo group.

At the end of the 40-week open-label dose titration period aimed at achieving target levels (maximum dose 20 mg once daily), 70 out of 173 patients (40.5%) achieved the target LDL-C level of less than 2.8 mmol/L.

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

Rosuvastatin-Aurobindo was also studied in a two-year open-label trial with target dose titration in 198 children with heterozygous familial hypercholesterolemia aged 6 to 17 years (88 male and 110 female participants, Tanner stage < II–V). The initial dose for all patients was 5 mg rosuvastatin once daily. Patients aged 6 to 9 years (n = 64) were titrated to a maximum dose of 10 mg once daily, and patients aged 10 to 17 years (n = 134) to a maximum dose of 20 mg once daily. After 24 months of rosuvastatin treatment, the mean reduction from baseline LDL-C, estimated by least squares method, was -43% (baseline: 236 mg/dL, month 24: 133 mg/dL). For each age group, the mean reduction from baseline LDL-C, estimated by least squares method, was -43% (baseline: 234 mg/dL, month 24: 124 mg/dL), -45% (baseline: 234 mg/dL, month 24: 124 mg/dL), and -35% (baseline: 241 mg/dL, month 24: 153 mg/dL) in the age groups 6 to < 10, 10 to < 14, and 14 to < 18 years, respectively.

Treatment with rosuvastatin at doses of 5 mg, 10 mg, and 20 mg also resulted in statistically significant mean changes from baseline in the following secondary lipid and lipoprotein variables: HDL-C, total cholesterol, non-HDL-C, LDL-C/HDL-C, total cholesterol/HDL-C, triglycerides/HDL-C, non-HDL-C/HDL-C, 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 run-in phase during which patients received rosuvastatin 10 mg, a crossover phase consisting of a 6-week treatment with rosuvastatin 20 mg preceded or followed by a 6-week placebo treatment, and a 12-week maintenance phase during which all patients received 20 mg rosuvastatin. Patients receiving ezetimibe or apheresis continued these treatments throughout the study.

A statistically significant (p = 0.005) reduction in LDL-C levels (22.3%; 85.4 mg/dL, or 2.2 mmol/L) was observed after 6 weeks of rosuvastatin 20 mg treatment 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. Additionally, reductions in TG, LDL-C/HDL-C, total cholesterol/HDL-C, non-HDL-C/HDL-C, and apoB/apoA-I levels were observed after 6 weeks of rosuvastatin 20 mg treatment compared to placebo. The reduction in LDL-C after 6 weeks of rosuvastatin 20 mg treatment followed by 6 weeks of placebo treatment persisted over 12 weeks of continuous therapy. One patient showed further reductions in LDL-C (8.0%), total cholesterol (6.7%), and non-HDL-C (7.4%) after 6 weeks of dose titration to 40 mg.

During continued open-label treatment with rosuvastatin 20 mg in 9 of these patients up to 90 weeks, LDL-C reduction remained between -12.1% and -21.3%.

In an open-label intensified dose titration study in 7 evaluable children and adolescents (aged 8 to 17 years) with homozygous familial hypercholesterolemia (see above), the percentage reduction in LDL-C (21.0%), total cholesterol (19.2%), and non-HDL-C (21.0%) from baseline after 6 weeks of rosuvastatin 20 mg treatment corresponded to that observed in the 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 is reached approximately 5 hours after oral administration. Absolute bioavailability is approximately 20%.

Distribution

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

Metabolism

Rosuvastatin-Aurobindo undergoes minimal metabolism (approximately 10%). In vitro metabolism studies using human hepatocytes have shown that rosuvastatin is a weak substrate for cytochrome P450 enzyme-based metabolism. The main isoenzyme involved is CYP2C9, with minor contributions from 2C19, 3A4, and 2D6. The main metabolites identified are N-desmethyl and lactone metabolites.

The N-desmethyl metabolite is approximately 50% less active than rosuvastatin, and lactone metabolites are clinically inactive. Rosuvastatin accounts for more than 90% of the circulating HMG-CoA reductase inhibitor activity.

Elimination

Approximately 90% of the rosuvastatin dose is excreted unchanged in feces (both adsorbed and unabsorbed active substance), with the remainder excreted in urine. Approximately 5% is excreted unchanged in urine. The plasma half-life is approximately 19 hours and does not increase with dose escalation. The geometric mean value of plasma clearance is approximately 50 L/hour (coefficient of variation 21.7%). As with other HMG-CoA reductase inhibitors, hepatic uptake of rosuvastatin occurs via the membrane transporter OATP-C, which plays an important role in hepatic elimination of rosuvastatin.

Linearity

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

Special patient groups

Age and gender

No clinically significant effect of age or gender on rosuvastatin pharmacokinetics was observed in adults. Exposure to rosuvastatin in children and adolescents with heterozygous familial hypercholesterolemia was similar to or lower than in adult patients with dyslipidemia (see section "Children").

Race

It has been found that median AUC and Cmax values in Mongoloid race patients (Japanese, Chinese, Filipinos, Vietnamese, and Koreans) are approximately twice as high as in Europeans; in Indians, median AUC and Cmax values are elevated by approximately 1.3 times. Population pharmacokinetic analysis did not reveal clinically significant differences between Caucasian and African patients.

Renal impairment

No changes in plasma concentrations of rosuvastatin or the N-desmethyl metabolite (in patients with mild or moderate impairment) were observed in patients with varying degrees of renal impairment. In patients with severe renal impairment (creatinine clearance <30 mL/min), plasma concentrations of rosuvastatin and N-desmethyl metabolite were 3 and 9 times higher, respectively, compared to healthy volunteers. Steady-state plasma concentrations of rosuvastatin in patients undergoing hemodialysis were approximately 50% higher than in healthy volunteers.

Hepatic impairment

In patients with varying degrees of hepatic impairment, no signs of increased rosuvastatin exposure were observed in patients scoring 7 or less on the Child-Pugh scale. However, in two patients scoring 8 and 9 on the Child-Pugh scale, systemic exposure was at least twice as high as in patients with lower scores. Experience with rosuvastatin use in patients scoring more than 9 on the Child-Pugh scale is lacking.

Genetic polymorphism

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

Children

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

Preclinical safety data

Preclinical data revealed no special hazard for humans based on conventional safety pharmacology, genotoxicity, and carcinogenic potential studies. Specific hERG channel effect tests were not evaluated. Adverse reactions not observed in clinical trials but seen in animals at exposures similar to clinical exposure levels included: in repeat-dose toxicity studies, histopathological liver changes, likely related to the pharmacological action of rosuvastatin, observed in mice and rats; lesser effects on the gallbladder in dogs, but not in monkeys. Additionally, gonadotoxicity was observed in monkeys and dogs at higher doses. Reproductive toxicity was evident in rats; low offspring weight and survival were observed at maternally toxic doses when systemic exposure was several times higher than with therapeutic doses.

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 adherence to diet 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.

Rosuvastatin-Aurobindo is contraindicated:

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

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

Factors contributing to such risk include:

• moderate renal impairment (creatinine clearance < 60 mL/min);
• hypothyroidism;
• personal or family history of hereditary muscle disorders;
• history of myotoxicity with other HMG-CoA reductase inhibitors or fibrates;
• alcohol abuse;
• conditions that may lead to increased plasma concentration of the drug;
• Mongoloid race;
• concomitant use of fibrates.

(See sections "Special precautions", "Interaction with other medicinal products and other types of interactions", and "Pharmacokinetics").

Interaction with other medicinal products and other types of interactions.

Effect of concomitant drugs on rosuvastatin

Inhibitors of transport proteins

Rosuvastatin-Aurobindo is a substrate for certain transporter proteins, including the hepatic uptake transporter OATP1B1 and the efflux transporter BCRP. Concomitant administration of Rosuvastatin-Aurobindo with medicinal products that inhibit these transporter proteins may lead to increased plasma concentrations of rosuvastatin and an increased risk of myopathy (see sections "Dosage and administration", "Special precautions", "Interaction with other medicinal products and other types of interactions", Table 2).

Cyclosporine

During concomitant treatment with rosuvastatin and cyclosporine, rosuvastatin AUC values were on average 7 times higher than in healthy volunteers (see Table 2). Rosuvastatin-Aurobindo is contraindicated in patients receiving concomitant cyclosporine (see section "Contraindications").

Concomitant use did not affect plasma concentrations of cyclosporine.

Protease inhibitors

Although the exact mechanism of interaction is unknown, concomitant use of protease inhibitors may significantly increase rosuvastatin AUC (see Table 2). For example, in a pharmacokinetic study, concomitant administration of 10 mg rosuvastatin and a combination drug containing two protease inhibitors (300 mg atazanavir/100 mg ritonavir) in healthy volunteers resulted in approximately 3-fold and 7-fold increases in rosuvastatin AUC and Cmax, respectively. Concomitant use of rosuvastatin and certain protease inhibitor combinations may be possible after careful consideration of rosuvastatin dose adjustment based on the expected increase in rosuvastatin AUC (see sections "Dosage and administration", "Special precautions", "Interaction with other medicinal products and other types of interactions", Table 2).

Gemfibrozil and other lipid-lowering agents

Concomitant administration of rosuvastatin and gemfibrozil resulted in a 2-fold increase in rosuvastatin AUC and Cmax (see section "Special precautions").

Pharmacokinetic interactions with fenofibrate are not expected based on available data, but pharmacodynamic interactions may occur. Gemfibrozil, fenofibrate, other fibrates, and lipid-lowering 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 used as monotherapy. The 40 mg dose is contraindicated when fibrates are used concomitantly (see sections "Contraindications" and "Special precautions"). These patients should also initiate treatment with a 5 mg dose.

Ezetimibe

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

Antacid medicinal products

Concomitant administration of Rosuvastatin-Aurobindo with suspensions of antacids containing aluminium hydroxide or magnesium hydroxide reduced rosuvastatin plasma concentrations by approximately 50%. This effect was attenuated when the antacid was administered 2 hours after rosuvastatin. The clinical significance of this interaction has not been studied.

Erythromycin

Concomitant administration of Rosuvastatin-Aurobindo and erythromycin reduced rosuvastatin AUC by 20% and Cmax by 30%. This interaction may be due to enhanced intestinal motility caused by erythromycin.

Tickagrelor

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

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 weak substrate for these isoenzymes. Therefore, drug interactions mediated by cytochrome P450 metabolism are not expected. No clinically significant interactions between rosuvastatin and fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4) have been observed.

Interactions requiring rosuvastatin dose adjustment (see Table 2)

When co-administration of rosuvastatin with other medicinal products that increase rosuvastatin AUC is necessary, the rosuvastatin dose should be adjusted. If an approximately 2-fold or greater increase in rosuvastatin AUC is expected, rosuvastatin therapy should be initiated at a dose of 5 mg once daily. The maximum daily dose of rosuvastatin should be adjusted so that the expected rosuvastatin AUC does not exceed the AUC observed with a 40 mg daily dose in the absence of interacting medicinal products; for example, when co-administered with gemfibrozil, the rosuvastatin dose should be 20 mg (1.9-fold increase in AUC), and when co-administered with ritonavir/atazanavir combination, the dose should be 10 mg (3.1-fold increase in AUC). If the medicinal product increases rosuvastatin AUC by less than 2-fold, no dose reduction is required initially, but caution should be exercised when increasing the dose of Rosuvastatin-Aurobindo above 20 mg.

Table 2

Effect of concomitant medicinal products on rosuvastatin AUC

(in descending order of magnitude) based on published data from clinical studies

Increased rosuvastatin AUC by 2 times or more
Dosing regimen of the interacting drug	Rosuvastatin dosing regimen	Changes in rosuvastatin AUC*
Sofosbuvir / velpatasvir / voxilaprevir (400 mg - 100 mg - 100 mg) + voxilaprevir (100 mg) once daily for 15 days	10 mg, single dose	↑ 7.4 times
Cyclosporine from 75 mg twice daily to 200 mg twice daily, 6 months	10 mg once daily, 10 days	↑ 7.1 times
Darolutamide 600 mg twice daily, 5 days	5 mg, single dose	↑ 5.2 times
Regorafenib 160 mg once daily, 14 days	5 mg, single dose	↑ 3.8 times
Atazanavir 300 mg / ritonavir 100 mg once daily, 8 days	10 mg, single dose	↑ 3.1 times
Velpatasvir 100 mg once daily	10 mg, single dose	↑ 2.7 times
Paritaprevir 150 mg / ombitasvir 25 mg / ritonavir 100 mg once daily / dasabuvir 400 mg twice daily, 14 days	5 mg, single dose	↑ 2.6 times
Teriflunomide	Data not available	↑ 2.5 times
Glecaprevir 200 mg / elbasvir 50 mg once daily, 11 days	10 mg, single dose	↑ 2.3 times
Glecaprevir 400 mg / pibrentasvir 120 mg once daily, 7 days	5 mg once daily, 7 days	↑ 2.2 times
Lopinavir 400 mg / ritonavir 100 mg twice daily, 17 days	20 mg once daily, 7 days	↑ 2.1 times
Capmatinib 400 mg twice daily	10 mg, single dose	↑ 2.1 times
Clopidogrel 300 mg, then 75 mg after 24 hours	20 mg, single dose	↑ 2 times
Fostamatinib 100 mg twice daily	20 mg, single dose	↑ 2.0 times
Febuxostat 120 mg once daily	10 mg, single dose	↑ 1.9 times
Gemfibrozil 600 mg twice daily, 7 days	80 mg, single dose	↑ 1.9 times
Increased rosuvastatin AUC less than 2 times
Dosing regimen of the interacting drug	Rosuvastatin dosing regimen	Changes in rosuvastatin AUC*
Elvitegravir 75 mg once daily, 5 days	10 mg, single dose	↑ 1.6 times
Darunavir 600 mg / ritonavir 100 mg twice daily, 7 days	10 mg once daily, 7 days	↑ 1.5 times
Tipranavir 500 mg / ritonavir 200 mg twice daily, 11 days	10 mg, single dose	↑ 1.4 times
Dronedarone 400 mg twice daily	Data not available	↑ 1.4 times
Itraconazole 200 mg once daily, 5 days	10 mg, single dose	↑ 1.4 times **
Ezetimibe 10 mg once daily, 14 days	10 mg once daily, 14 days	↑ 1.2 times **
Decreased rosuvastatin AUC
Dosing regimen of the interacting drug	Rosuvastatin dosing regimen	Changes in rosuvastatin AUC*
Erythromycin 500 mg four times daily, 7 days	80 mg, single dose	↓ 20 %
Baykaline 50 mg three times daily, 14 days	20 mg, single dose	↓ 47 %

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

Increases are indicated by ↑, decreases by ↓.

** Several interaction studies were conducted at different doses of the medicinal product; the most significant ratio is presented in Table 2.

Medicinal products/combinations that had no clinically significant effect on the AUC ratio of rosuvastatin when administered concomitantly: aleglitazar 0.3 mg for 7 days; fenofibrate 67 mg three times a day 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 a day for 5 days.

Effect of rosuvastatin on concomitant medicinal products

Vitamin K antagonists

As with other HMG-CoA reductase inhibitors, initiation of treatment with Rosuvastatin-Aurobindo or increasing its dose 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 may result in a decrease in INR. Appropriate monitoring of INR is recommended in such situations.

Oral contraceptives/hormone replacement therapy (HRT)

Concomitant administration of Rosuvastatin-Aurobindo and oral contraceptives resulted in a 26% and 34% increase in AUC of ethinylestradiol and norgestrel, respectively. These increased plasma levels should be considered when selecting doses of oral contraceptives. There are no pharmacokinetic data available 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. According to data from specific interaction studies, no clinically significant interaction with digoxin was observed.

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

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

Paediatric population

Interaction studies have only been conducted in adults. The extent of interaction in children is unknown.

Special precautions for use.

Renal effects

Proteinuria, detected by urine dipstick testing and predominantly of tubular origin, has been observed in patients treated with higher doses of Rosuvastatin-Aurobindo, particularly 40 mg, and in most cases was transient or intermittent. Proteinuria was not a predictor of acute or progressive kidney disease (see section "Adverse reactions"). The frequency of serious renal events in post-marketing studies is higher with the 40 mg dose. In patients receiving the 40 mg dose, renal function should be monitored regularly during treatment.

Skeletal muscle effects

Skeletal muscle disorders such as myalgia, myopathy, and rarely rhabdomyolysis, have been observed in patients taking Rosuvastatin-Aurobindo at any dose, particularly at doses exceeding 20 mg. Isolated cases of rhabdomyolysis have been reported with ezetimibe in combination with HMG-CoA reductase inhibitors. A pharmacodynamic interaction cannot be excluded (see section "Interaction with other medicinal products and other forms of interaction"), therefore such combination should be used with caution. As with other HMG-CoA reductase inhibitors, the frequency of rhabdomyolysis associated with rosuvastatin use is higher during the post-marketing period with the 40 mg dose.

Creatine kinase levels

Creatine kinase (CK) levels should not be measured after significant physical exertion or in the presence of possible alternative causes of elevated CK, which may complicate interpretation of results. If baseline CK levels are markedly elevated (>5 times the upper limit of normal [ULN]), a repeat test should be performed within 5–7 days to confirm the results. If the repeat test confirms that the initial CK value exceeds 5 times the ULN, treatment with the medicinal product should not be initiated.

Before starting treatment

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

• renal impairment;
• hypothyroidism;
• personal or family history of hereditary muscle disorders;
• history of myotoxicity with other HMG-CoA reductase inhibitors or fibrates;
• alcohol abuse;
• age > 70 years;
• conditions that may lead to increased plasma levels of the drug (see sections "Dosage and administration", "Interaction with other medicinal products and other forms of interaction", and "Pharmacokinetics");
• concomitant use of fibrates.

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

During treatment

Patients should be advised to report immediately any unexplained muscle pain, weakness, or tenderness, especially if accompanied by malaise or fever. In such patients, CK levels should be measured. The drug should be discontinued if CK levels are markedly elevated (>5 times ULN) or if muscle symptoms are severe and cause daily discomfort (even if CK ≤5 times ULN). If symptoms resolve and CK levels return to normal, therapy with Rosuvastatin-Aurobindo or an alternative HMG-CoA reductase inhibitor may be restarted at the lowest dose and under close supervision. Routine monitoring of CK levels in asymptomatic patients is not necessary. Very rare cases of immune-mediated necrotizing myopathy (IMNM) have been reported during or after statin therapy, including with rosuvastatin. Clinical manifestations of IMNM include proximal muscle weakness and elevated serum CK levels, which persist even after discontinuation of statins.

There is no evidence of increased skeletal muscle effects in a small number of patients who took Rosuvastatin-Aurobindo with concomitant medications.

However, increased incidence of myositis and myopathy has been observed in patients taking other HMG-CoA reductase inhibitors concomitantly with fibric acid derivatives, including gemfibrozil, cyclosporine, niacin, azole antifungals, protease inhibitors, and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when used concomitantly with certain HMG-CoA reductase inhibitors. Therefore, co-administration of Rosuvastatin-Aurobindo with gemfibrozil is not recommended. The benefit of further lipid-lowering with Rosuvastatin-Aurobindo in combination with fibrates or niacin should be carefully weighed against the potential risks associated with such combinations. The 40 mg dose is contraindicated when fibrates are used concomitantly (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Concomitant use of Rosuvastatin-Aurobindo with systemic fusidic acid or within 7 days of stopping fusidic acid treatment is not recommended. In patients for whom systemic fusidic acid treatment is considered necessary, statin therapy should be discontinued throughout the duration of fusidic acid treatment (see section "Interaction with other medicinal products and other forms of interaction"). Cases of rhabdomyolysis (including fatal cases) have been reported in patients receiving this combination.

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 cases where prolonged use of fusidic acid is required, e.g., for treatment of severe infections, the need for concomitant use of rosuvastatin and fusidic acid should be considered on a case-by-case basis and under close medical supervision. Rosuvastatin-Aurobindo should not be administered to patients with acute, serious conditions indicating myopathy or risk of developing renal failure due to rhabdomyolysis (e.g., sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine, or electrolyte disorders, or uncontrolled seizures).

In rare cases, statins have been reported to induce de novo or exacerbate pre-existing myasthenia gravis or ocular myasthenia (see section "Adverse reactions"). If symptoms worsen, treatment with Rosuvastatin-Aurobindo should be discontinued. Recurrences have been reported upon re-challenge with the same or another statin.

Severe skin adverse reactions

Severe skin adverse reactions have been reported with rosuvastatin, including Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS), which may be life-threatening or fatal (see section "Adverse reactions"). Patients should be informed about the signs and symptoms of severe skin reactions, and careful monitoring during treatment is required. If signs or symptoms 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 related to Rosuvastatin-Aurobindo, re-administration of Rosuvastatin-Aurobindo is contraindicated.

Hepatic effects

As with other HMG-CoA reductase inhibitors, Rosuvastatin-Aurobindo should be used with caution in patients who consume alcohol excessively and/or have a history of liver disease. Liver function tests should be performed before starting treatment and again after 3 months. Treatment with Rosuvastatin-Aurobindo should be discontinued or the dose reduced if serum transaminase levels exceed three times the ULN. The frequency of post-marketing reports of serious hepatic events (mainly elevated liver transaminases) was higher with the 40 mg dose. In patients with secondary hypercholesterolemia due to hypothyroidism or nephrotic syndrome, the underlying condition should be treated before initiating therapy with Rosuvastatin-Aurobindo.

Race

Pharmacokinetic studies indicate that AUC is approximately doubled in patients of Mongoloid race compared to Caucasians (see sections "Pharmacokinetics", "Contraindications", and "Dosage and administration").

Protease inhibitors

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

Lactose intolerance

Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Interstitial lung disease

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

Diabetes mellitus

Some evidence indicates that statins increase blood glucose levels and may induce hyperglycemia requiring treatment in some patients at high risk of developing diabetes. However, the benefit of reduced vascular risk with statin use outweighs this risk, and therefore should not be a reason for discontinuation of statin therapy. Patients at risk (fasting glucose 5.6–6.0 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.

Children

Assessment of linear growth (height), body weight, BMI, 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, CK elevations >10 times ULN and muscle 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-Aurobindo is contraindicated during pregnancy and breastfeeding.

Women of childbearing potential must use appropriate contraceptive measures. Since cholesterol and other products of cholesterol biosynthesis play a vital role in fetal development, the potential risk of HMG-CoA reductase inhibition outweighs any benefit of drug use during pregnancy.

Animal reproductive toxicity data are limited. If a patient becomes pregnant while taking the drug, treatment should be discontinued immediately.

Rosuvastatin is excreted in rat milk. There are no data on excretion in human breast milk (see section "Contraindications").

Ability to drive and use machines

Studies on the effect of rosuvastatin on the ability to drive and operate machinery have not been conducted. However, due to the pharmacodynamic properties of the drug, it is unlikely that Rosuvastatin-Aurobindo will affect such ability. When driving or operating machinery, the possibility of dizziness during treatment should be considered.

Method of Administration and Dosage.

Before initiating treatment, patients should be placed on a standard hypocholesterolemic diet, which should be maintained throughout therapy. The dosage should be individually adjusted according to therapeutic goals and the patient's response to treatment, following recommendations from current accepted guidelines.

Rosuvastatin-Aurobindo may be taken at any time of day, regardless of food intake.

Hypercholesterolemia Treatment

The recommended initial dose is 5 mg* or 10 mg orally once daily, both for patients who have not previously used statins and for those switching from another HMG-CoA reductase inhibitor. The choice of initial dose should consider the individual patient's cholesterol levels, future cardiovascular risk, and the likelihood of adverse reactions. Dose increases to the next level may be considered after 4 weeks, if necessary (see section "Pharmacodynamics"). Since adverse reactions occur more frequently with the 40 mg dose compared to lower doses (see section "Adverse Reactions"), the maximum dose of 40 mg should only be titrated in patients with severe hypercholesterolemia and high cardiovascular risk (particularly those with familial hypercholesterolemia) who have not achieved treatment goals with a 20 mg dose and who will be under regular monitoring (see section "Special Warnings and Precautions for Use"). Specialist supervision is recommended when initiating treatment with the 40 mg dose.

Prevention of Cardiovascular Events

In a cardiovascular risk reduction study, the drug was administered at a dose of 20 mg daily (see section "Pharmacodynamics").

Elderly Patients

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

Patients with Renal Impairment

Dose adjustment is not required in patients with mild or moderate renal impairment. The recommended initial dose for patients with moderate renal impairment (creatinine clearance <60 mL/min) is 5 mg*. The 40 mg dose is contraindicated in patients with moderate renal impairment. The use of rosuvastatin tablets is contraindicated in patients with severe renal impairment at any dose (see sections "Contraindications" and "Pharmacokinetics").

Patients with Hepatic Impairment

In patients with hepatic impairment scoring 7 or less on the Child-Pugh scale, no increase in systemic exposure to rosuvastatin was observed. However, in patients scoring 8 or 9 on the Child-Pugh scale, systemic exposure increased (see section "Pharmacokinetics"). Renal function assessment is advisable in these patients. There is no experience with the use of the drug in patients scoring more than 9 on the Child-Pugh scale. Rosuvastatin-Aurobindo is contraindicated in patients with active liver disease (see section "Contraindications").

Race

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

Genetic Polymorphism

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

Patients Predisposed to Myopathy

The recommended initial dose for patients with risk factors for myopathy is 5 mg* (see section "Special Warnings and Precautions for Use"). The 40 mg dose is contraindicated in some of these patients (see section "Contraindications").

Concomitant Use

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

*Use the medicinal product at the appropriate dosage strength.

Children.

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

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

Heterozygous Familial Hypercholesterolemia

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

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

Before initiating rosuvastatin therapy, children and adolescents should be placed on a standard hypocholesterolemic diet, which should be maintained throughout treatment. The safety and efficacy of doses above 20 mg in this population have not been studied. Dose increases should be based on the individual child's response to treatment and drug tolerability, in accordance with treatment recommendations for children (see section "Special Warnings and Precautions for Use").

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 response to treatment and drug tolerability, in accordance with treatment recommendations for children (see section "Special Warnings and Precautions for Use"). Before initiating rosuvastatin therapy, children and adolescents should be placed on a standard hypocholesterolemic diet, which should be maintained throughout treatment.

Assessment of linear growth (height), body weight, BMI (body mass index), and secondary sexual characteristics according to Tanner in children aged 6 to 17 years receiving 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, elevations in CK levels >10 times the upper normal limit and muscle symptoms following physical exertion or increased physical activity were observed more frequently compared to adults (see section "Adverse Reactions").

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

The 40 mg tablets should not 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-Aurobindo is not recommended for use in children under 6 years of age.

Overdose.

There is no specific antidote for overdose. In case of overdose, symptomatic treatment should be administered, and supportive measures taken as needed. Liver function and CK levels should be monitored. Hemodialysis is unlikely to be effective.

Adverse Reactions

Adverse events observed during rosuvastatin use are generally mild and transient. In controlled clinical studies, less than 4% of patients receiving rosuvastatin discontinued treatment due to adverse reactions.

The list of adverse reactions below is based on data from clinical trials and extensive post-marketing experience. The reactions are classified according to frequency and organized by system organ class:

Very common (> 1/100, < 1/10); uncommon (> 1/1000, < 1/100); rare (> 1/10000, < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated from available data).

Eye disorders

Frequency not known: ocular myasthenia.

Immune system disorders

Rare: hypersensitivity reactions, including angioedema.

Endocrine system disorders

Very common: diabetes mellitus¹.

Nervous system disorders

Very common: headache, dizziness.

Very rare: polyneuropathy, memory loss.

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

Psychiatric disorders

Frequency not known: depression.

Gastrointestinal disorders

Very common: constipation, nausea, abdominal pain.

Rare: pancreatitis.

Frequency not known: diarrhea.

Skin and subcutaneous tissue disorders

Uncommon: pruritus, rash, urticaria.

Frequency not known: Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS).

Musculoskeletal and connective tissue disorders

Very common: myalgia.

Rare: myopathy (including myositis), rhabdomyolysis, lupus-like syndrome, muscle rupture.

Very rare: arthralgia.

Frequency not known: tendon disorders, sometimes complicated by tendon rupture, immune-mediated necrotizing myopathy.

General disorders

Very common: asthenia.

Frequency not known: edema.

Hepatobiliary disorders

Rare: increased levels of liver transaminases.

Very rare: jaundice, hepatitis.

Respiratory, thoracic and mediastinal disorders

Frequency not known: cough, dyspnea.

Blood and lymphatic system disorders

Rare: thrombocytopenia.

Renal and urinary disorders

Very rare: hematuria.

Reproductive system and breast disorders

Very rare: gynecomastia.

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

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

Renal effects

Proteinuria detected by dipstick testing in patients treated with rosuvastatin is predominantly of tubular origin. An increase in urinary protein from negative or trace to ++ or higher was observed in < 1% of patients receiving 10 or 20 mg rosuvastatin and in approximately 3% of patients receiving 40 mg rosuvastatin. Trace to + proteinuria was observed with the 20 mg dose. In most cases, proteinuria decreases or resolves spontaneously during continued therapy. A review of clinical trial and post-marketing data to date has not identified a causal relationship between proteinuria and acute or progressive kidney disease.

Hematuria has been observed in patients treated with rosuvastatin; clinical trial data indicate a low frequency of occurrence.

Musculoskeletal effects

Skeletal muscle disorders such as myalgia, myopathy (including myositis), and rarely rhabdomyolysis, with or without acute renal failure, have been reported with all doses of rosuvastatin, particularly at doses > 20 mg.

Dose-dependent increases in CK levels have been observed in patients taking rosuvastatin; most cases were mild, asymptomatic, and transient. If CK levels are elevated (> 5 times ULN), treatment should be discontinued (see section "Special precautions").

Hepatic effects

As with other HMG-CoA reductase inhibitors, a small number of patients receiving rosuvastatin have experienced dose-dependent increases in transaminase levels. In most cases, these changes were mild, asymptomatic, and transient.

Adverse events reported with some statins:

• Sexual dysfunction;
• Isolated cases of interstitial lung disease, particularly with long-term use (see section "Special precautions");
• Higher frequency of reports of rhabdomyolysis, serious renal and hepatic adverse events (mainly increased hepatic transaminase activity) with the 40 mg dose.

Paediatric population

Elevations in CK levels > 10 times ULN and muscle-related symptoms following physical exertion or increased physical activity were observed more frequently in a 52-week study involving children and adolescents compared to adults (see section "Special precautions"). However, the safety profile of rosuvastatin in children and adolescents was similar to that in adults.

Reporting 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 are requested to report any suspected adverse reactions via the national reporting system.

Shelf life. 2 years.

Storage conditions. Store out of reach of children at a temperature not exceeding 25 °C.

Packaging. 10 film-coated tablets per blister, 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Aurobindo Pharma Limited - Unit VII.

Manufacturer's address.

Special Economic Zone, TSIIC, Plot No. S1, Sy. Nos. 411/P, 425/P, 434/P, 435/P and 458/P, Green Industrial Park, Polepally Village, Jedcherla Mandal, Mahabubnagar District, Telangana State, 509302, India.