Redistatin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT REDISTATIN (REDISTATIN)

Composition:

Active substance: rosuvastatin;

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

Excipients: microcrystalline cellulose; lactose monohydrate; crospovidone; meglumine; magnesium stearate; Opadry II Pink 32 K540017 (titanium dioxide (E 171), brilliant red AC (E 129), indigo carmine (E 132), yellow sunset FCF (E 110)).

Medicinal form. Film-coated tablets.

Main physico-chemical properties:

10 mg tablets: biconvex, light pink to pink, round-shaped, film-coated tablets, marked with "10" on one side and the "company logo symbol" on the other side;

20 mg tablets: biconvex, light pink to pink, round-shaped, film-coated tablets, marked with "20" on one side and the "company logo symbol" on the other side.

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

ATC code C10A A07.

Pharmacological properties.

Pharmacodynamics.

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

Rosuvastatin increases the number of hepatic low-density lipoprotein (LDL) receptors on the cell surface, enhancing the uptake and catabolism of LDL, which in turn suppresses the synthesis of very-low-density lipoproteins (VLDL), thereby reducing the overall levels of LDL and VLDL.

Rosuvastatin decreases elevated levels of low-density lipoprotein cholesterol (LDL-C), total cholesterol, and triglycerides, while increasing high-density lipoprotein cholesterol (HDL-C) levels. It also reduces apolipoprotein B (ApoB), non-high-density lipoprotein cholesterol (non-HDL-C), very-low-density lipoprotein cholesterol (VLDL-C), very-low-density lipoprotein triglycerides (VLDL-TG), and increases apolipoprotein A-I (ApoA-I) levels (Table 1). Rosuvastatin also reduces the ratios of LDL-C to high-density lipoprotein cholesterol (HDL-C), total cholesterol to HDL-C, non-low-density lipoprotein cholesterol (non-LDL-C) to HDL-C, and the ApoB/ApoA-I ratio.

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	Apo B	Apo A-I
Placebo	13	-7	-5	3	-3	-7	-3	0
5	17	-45	-33	13	-35	-44	-38	4
10	17	-52	-36	14	-10	-48	-42	4
20	17	-55	-40	8	-23	-51	-46	5
40	18	-63	-46	10	-28	-60	-54	0

The therapeutic effect is achieved within 1 week after initiation of therapy, and after 2 weeks of treatment the effect reaches 90 % of the maximum possible. Maximum effect is usually achieved after 4 weeks and remains stable thereafter.

Pharmacokinetics.

Absorption

After oral administration, maximum plasma concentration of rosuvastatin is reached approximately within 5 hours. Absolute bioavailability is about 20 %.

Distribution

Rosuvastatin accumulates in the liver, which is the primary site of cholesterol synthesis and clearance of LDL-C. The volume of distribution of rosuvastatin is approximately 134 L. Approximately 90 % of rosuvastatin is bound to plasma proteins, predominantly to albumin.

Metabolism

Rosuvastatin undergoes limited biotransformation (about 10 %). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a non-preferential substrate for cytochrome P450 isoenzymes. The main isoenzyme involved in the metabolic transformation of rosuvastatin is the CYP2C9 enzyme, while isoenzymes 2C19, 3A4, and 2D6 are less involved. The main metabolites identified for rosuvastatin are N-desmethyl and lactone metabolites. The N-desmethyl metabolite is approximately 50 % less active than rosuvastatin, and the lactone metabolite is considered clinically inactive. Rosuvastatin provides inhibition of more than 90 % of circulating HMG-CoA reductase.

Elimination

Approximately 90 % of the rosuvastatin dose is excreted unchanged in feces (as absorbed and unabsorbed active substance), the remainder is excreted in urine. Approximately 5 % is excreted unchanged in urine. The half-life from plasma is approximately 19 hours. The duration of the half-life does not change with increasing dose. The geometric mean value of plasma clearance is approximately 50 L/h (coefficient of variation 21.7 %). As with other HMG-CoA reductase inhibitors, the hepatic uptake of rosuvastatin involves the membrane transporter OATP-C. This transporter plays an important role in the hepatic elimination of rosuvastatin.

Linearity

Systemic exposure to rosuvastatin increases proportionally with dose. With repeated daily administration of the drug, no changes in pharmacokinetic parameters occur.

Special patient populations

Age and gender

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

Race

Pharmacokinetic studies have shown that in patients of Mongoloid race (Japanese, Chinese, Filipinos, Vietnamese, and Koreans), median AUC and Cmax values are approximately twice as high as in Europeans; in Indians, median AUC and Cmax values are increased approximately 1.3-fold. Population pharmacokinetic analysis did not reveal clinically significant differences between Caucasian and Black patients.

Renal impairment

Data from studies involving patients with various degrees of renal impairment indicate that mild to moderate kidney disease does not affect plasma concentrations of rosuvastatin and its metabolite, N-desmethyl. In patients with severe renal function impairment (CrCl < 30 mL/min), plasma concentration of rosuvastatin is 3 times higher, and concentration of N-desmethyl metabolite is 9 times higher than in healthy volunteers. Steady-state plasma concentration of rosuvastatin in patients undergoing hemodialysis is approximately 50 % higher than in healthy volunteers.

Hepatic impairment

Data from studies involving patients with various degrees of hepatic impairment indicate no increase in rosuvastatin exposure in patients whose disease severity is rated no higher than 7 points on the Child-Pugh scale. However, in two patients with hepatic impairment rated at 8 and 9 points on the Child-Pugh scale, rosuvastatin exposure was at least doubled compared to patients with lower disease severity. Experience with the use of the drug in patients with hepatic impairment of 9 points or higher on the Child-Pugh scale is lacking.

Genetic polymorphism

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

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.

Lipid-lowering therapy

For adults 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 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 not appropriate.

Cardiovascular risk reduction

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.

Redistatin 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 serum transaminase elevations exceeding three times the upper limit of normal (ULN);
• in patients with severe renal impairment (creatinine clearance < 30 mL/min);
• in patients with myopathy;
• in patients concurrently receiving the combination of sofosbuvir / velpatasvir / voxilaprevir (see section "Interaction with other medicinal products and other forms of interaction");
• in patients concurrently receiving 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 factors predisposing to myopathy/rhabdomyolysis. Such risk factors include:

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

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

Interaction with other medicinal products and other forms of interaction.

Effect of concomitant medications on rosuvastatin

Inhibitors of transporter proteins

Rosuvastatin is a substrate for certain transporter proteins, including the hepatic uptake transporter OATP1B1 and the efflux transporter BCRP. Concomitant administration of Redistatin 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 forms of interaction", Table 2).

Cyclosporine. When rosuvastatin and cyclosporine are administered concomitantly, the AUC (area under the curve) of rosuvastatin was on average 7 times higher than in healthy volunteers (see Table 2). The medicinal product is contraindicated in patients who are concurrently receiving cyclosporine (see section "Contraindications").

Plasma concentrations of cyclosporine were not affected.

Protease inhibitors. Although the exact mechanism of interaction is unknown, concomitant use of protease inhibitors may lead to a significant increase in rosuvastatin exposure (see Table 2). Pharmacokinetic data from a study in healthy volunteers receiving rosuvastatin 10 mg with a combination product containing two protease inhibitors (300 mg atazanavir / 100 mg ritonavir) showed increases in AUC and Cmax of rosuvastatin by approximately 3 and 7 times, respectively. Concomitant use of rosuvastatin with certain protease inhibitor combinations may be considered after careful evaluation and dose adjustment of Redistatin based on the expected increase in rosuvastatin exposure (see sections "Dosage and administration", "Special precautions", "Interaction with other medicinal products and other forms of interaction", Table 2).

Gemfibrozil and other lipid-lowering agents. Concomitant administration of rosuvastatin and gemfibrozil results in a 2-fold increase in Cmax and AUC of rosuvastatin (see section "Special precautions").

According to studies on specific drug interactions, no clinically significant pharmacokinetic interaction with fenofibrate is expected; however, pharmacodynamic interaction cannot be excluded. Gemfibrozil, fenofibrate, other fibrates, and niacin (nicotinic acid) at lipid-lowering doses (≥ 1 g/day) increase the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors, likely because these agents themselves may cause myopathy when used alone. The 40 mg dose is contraindicated when fibrates are used concomitantly (see sections "Contraindications" and "Special precautions"). Such patients should also initiate treatment with a dose of 5* mg.

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

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 less pronounced when antacids were administered 2 hours after rosuvastatin. The clinical significance of this interaction has not been studied.

Erythromycin. Concomitant administration of rosuvastatin and erythromycin resulted in a 20% decrease in rosuvastatin AUC and a 30% decrease in Cmax. This interaction may be due to enhanced intestinal motility caused by erythromycin.

Tickagrelor

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

Cytochrome P450 enzymes. Results from in vitro and in vivo studies indicate that rosuvastatin does not inhibit or induce cytochrome P450 isoenzymes. In addition, rosuvastatin is a poor substrate for these isoenzymes. Therefore, drug interactions mediated by P450 metabolism are not expected. No clinically significant interaction was observed between rosuvastatin and fluconazole (an inhibitor of CYP2C9 and CYP3A4 enzymes) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4 enzymes).

Interactions requiring dose adjustment of rosuvastatin (see also Table 2). When co-administration of Redistatin with other medicinal products that may increase rosuvastatin exposure is necessary, the dose of Redistatin should be adjusted. If an approximately 2-fold or greater increase in rosuvastatin exposure (AUC) is expected, treatment with Redistatin should be initiated at a dose of 5* mg once daily. The maximum daily dose of Redistatin should be adjusted so that the expected rosuvastatin exposure does not exceed that observed with a 40 mg dose without interacting drugs; for example, when co-administered with gemfibrozil, the Redistatin dose should be 20 mg (1.9-fold increase in exposure), and when co-administered with ritonavir/atazanavir combination, 10 mg (3.1-fold increase in exposure).

If the co-administered drug increases rosuvastatin AUC by less than 2-fold, no initial dose reduction is required; however, caution should be exercised when increasing the Redistatin dose above 20 mg.

*Administer the medicinal product at the appropriate dosage strength.

Table 2

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

Increased rosuvastatin AUC by 2 times or more
Dosing regimen of concomitant medicinal product	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-fold
Cyclosporine from 75 mg twice daily to 200 mg twice daily over 6 months	10 mg once daily for 10 days	↑ 7.1-fold
Darolutamide 600 mg twice daily, 5 days	5 mg, single dose	↑ 5.2-fold
Regorafenib 160 mg once daily for 14 days	5 mg, single dose	↑ 3.8-fold
Atazanavir 300 mg / ritonavir 100 mg once daily for 8 days	10 mg, single dose	↑ 3.1-fold
Velpatasvir 100 mg once daily	10 mg, single dose	↑ 2.7-fold
Paritaprevir 25 mg / ombitasvir 150 mg / ritonavir 100 mg once daily / dasabuvir 400 mg twice daily for 14 days	5 mg, single dose	↑ 2.6-fold
Teriflunomide	Data not available	↑ 2.5-fold
Glecaprevir 200 mg / pibrentasvir 50 mg once daily for 11 days	10 mg, single dose	↑ 2.3-fold
Glecaprevir 400 mg / pibrentasvir 120 mg once daily for 7 days	5 mg once daily for 7 days	↑ 2.2-fold
Lopinavir 400 mg / ritonavir 100 mg twice daily for 17 days	20 mg once daily for 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 for 7 days	80 mg, single dose	↑ 1.9-fold
Increased rosuvastatin AUC less than 2-fold
Dosing regimen of interacting medicinal product	Rosuvastatin dosing regimen	Changes in rosuvastatin AUC*
Elvitegravir 75 mg once daily for 5 days	10 mg, single dose	↑ 1.6-fold
Darunavir 600 mg / ritonavir 100 mg twice daily for 7 days	10 mg once daily for 7 days	↑ 1.5-fold
Tipranavir 500 mg / ritonavir 200 mg twice daily for 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 for 5 days	10 mg, single dose	** ↑ 1.4-fold
Ezetimibe 10 mg once daily for 14 days	10 mg once daily for 14 days	** ↑ 1.2-fold
Decreased rosuvastatin AUC
Dosing regimen of interacting medicinal product	Rosuvastatin dosing regimen	Changes in rosuvastatin AUC*
Erythromycin 500 mg four times daily for 7 days	80 mg, single dose	↓ by 20%
Baicalin 50 mg three times daily for 14 days	20 mg, single dose	↓ by 47%
* Data expressed as x-fold change reflect the simple ratio between values observed when rosuvastatin is co-administered with other medicinal products versus rosuvastatin monotherapy. Data expressed as change in % reflect the percentage difference compared to the value observed during rosuvastatin monotherapy. Increase is indicated by "↑", decrease by "↓". ** Several interaction studies were conducted at different rosuvastatin doses; the most significant ratio is shown in the table.

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

Effect of rosuvastatin on concomitant medicinal products

Vitamin K antagonists. As with other HMG-CoA reductase inhibitors, initiation of treatment with the medicinal product Redistatin or increasing its dose in patients concurrently receiving vitamin K antagonists (e.g., warfarin or other coumarin anticoagulants) may increase the international normalized ratio (INR). Discontinuation of rosuvastatin or reduction of its dose may lead to a decrease in INR. In such cases, appropriate monitoring of INR values is recommended.

Oral contraceptives / hormone replacement therapy (HRT). Concomitant administration of rosuvastatin and oral contraceptives led to an increase in AUC of ethinylestradiol and norgestimate by 26% and 34%, respectively. This increase in plasma concentration should be considered when selecting the dose of oral contraceptives. Pharmacokinetic data on rosuvastatin administration during hormone replacement therapy (HRT) are lacking; therefore, a similar effect cannot be excluded. However, this combination has been widely used in women in clinical trials and was well tolerated.

Other medicinal products

Digoxin. Based on specific drug interaction studies, no clinically significant interaction with digoxin is expected.

Fusidic acid. Studies investigating the drug interaction between rosuvastatin and fusidic acid have not been conducted. The risk of developing myopathy, including rhabdomyolysis, may be increased with concomitant systemic administration of fusidic acid and statins. The mechanism of this interaction (i.e., whether it is pharmacodynamic, pharmacokinetic, or both) has not yet been clarified. Cases of rhabdomyolysis (including fatal outcomes) have been reported in patients receiving this combination.

If systemic therapy with fusidic acid is necessary, rosuvastatin administration should be discontinued for the entire duration of fusidic acid treatment.

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

Special precautions for use.

Renal effects

Proteinuria, predominantly of tubular origin, detected by urine dipstick testing, has been observed with the use of rosuvastatin at high doses, particularly 40 mg, although in most cases the abnormalities were transient or intermittent. Proteinuria was not a predictor of acute or progressive kidney disease (see section "Adverse reactions"). The frequency of reports of serious renal events in post-marketing studies is higher with the 40 mg dose. Renal function should be regularly monitored in patients receiving the drug at a dose of 40 mg.

Effects on skeletal muscle

Skeletal muscle disorders such as myalgia, myopathy, and, rarely, rhabdomyolysis, have been observed in patients taking rosuvastatin at any dose, most frequently at doses > 20 mg. Very rare cases of rhabdomyolysis have been reported with the concomitant use of ezetimibe and HMG-CoA reductase inhibitors. A pharmacodynamic interaction cannot be excluded (see section "Interaction with other medicinal products and other forms of interaction"), and therefore such combination should be used with caution.

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

Measurement of creatine kinase levels

Creatine kinase (CK) levels should not be measured immediately after strenuous physical exercise or in the presence of other likely causes of elevated CK levels, as this may complicate interpretation of results. In case of significantly elevated CK levels prior to therapy initiation (> 5 times the upper limit of normal, ULN), a repeat test should be performed within 5–7 days to confirm the results. If repeat testing confirms that the baseline CK level exceeds 5 times the ULN, treatment should not be initiated.

Before starting therapy

Rosuvastatin, like other HMG-CoA reductase inhibitors, should be used with caution in patients predisposed to myopathy/rhabdomyolysis. Risk factors for the development of myopathy/rhabdomyolysis include:

• renal impairment;
• hypothyroidism;
• personal or family history of hereditary muscular disorders;
• history of muscle toxicity with other HMG-CoA reductase inhibitors or fibrates;
• alcohol abuse;
• age > 70 years;
• conditions that may increase drug plasma concentrations (see sections "Method of administration and dosage", "Interaction with other medicinal products and other forms of interaction", and "Pharmacokinetics");
• concomitant use of fibrates.

When prescribing the drug to such patients, the risk-benefit ratio of therapy should be carefully considered; continuous clinical monitoring is recommended. If baseline CK levels are markedly elevated (> 5 times ULN), treatment should not be initiated.

During therapy

Patients should be advised to immediately inform their physician if they experience unexplained muscle pain, muscle weakness, or cramps, especially if accompanied by malaise or fever. In such cases, CK concentration levels should be checked. Therapy should be discontinued in case of significantly elevated CK levels (> 5 × ULN) or in case of severe muscle symptoms causing discomfort (even if CK concentration ≤ 5 × ULN). After symptom resolution and return of CK levels to normal range, resumption of rosuvastatin therapy or alternative HMG-CoA reductase inhibitors at the lowest dose with appropriate patient monitoring may be considered. Routine monitoring of CK levels in the absence of symptoms is not required.

Very rare cases of immune-mediated necrotizing myopathy (IMNM) have been reported during or after statin therapy, including with rosuvastatin. Clinical features of IMNM include proximal muscle weakness and elevated serum creatine kinase levels, which persist even after discontinuation of statins.

There have been reports that statins, including rosuvastatin, may induce or exacerbate pre-existing myasthenia gravis or ocular myasthenia (see section "Adverse reactions"). If symptoms worsen, treatment with Redistatin should be discontinued. Recurrences have been reported upon first or repeated use of the same or another statin.

Clinical studies have not provided evidence of increased skeletal muscle effects in a small number of patients taking Redistatin and concomitant medications.

An increased frequency of myositis and myopathy has been observed in patients receiving other HMG-CoA reductase inhibitors together with fibric acid derivatives, including gemfibrozil, cyclosporine, niacin-containing products, azole antifungals, protease inhibitors, and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when used concomitantly with certain HMG-CoA reductase inhibitors. Therefore, concomitant use of rosuvastatin and gemfibrozil is not recommended. The necessity of concomitant use of rosuvastatin with fibrates or niacin should be carefully evaluated considering the potential risks associated with such combinations. The 40 mg dose is contraindicated when fibrates are used concomitantly (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Rosuvastatin should not be used concomitantly with systemic fusidic acid or within 7 days after discontinuation of fusidic acid therapy. In patients for whom fusidic acid treatment is absolutely necessary, statin therapy should be discontinued for the entire duration of fusidic acid treatment. Cases of rhabdomyolysis (including fatal cases) have been reported in patients receiving fusidic acid concomitantly with statins (see section "Interaction with other medicinal products and other forms of interaction"). Such patients should be warned to seek immediate medical attention if they experience symptoms such as muscle weakness, muscle pain, or muscle tenderness. Statin therapy should not be resumed earlier than 7 days after the last dose of fusidic acid. In exceptional circumstances, when prolonged systemic fusidic acid treatment is necessary (e.g., for treatment of severe infections), the possibility of concomitant use of rosuvastatin and fusidic acid may be considered, but only on an individual basis and under strict medical supervision.

Rosuvastatin should not be used in case of an acute condition characteristic of myopathy or in case of renal failure secondary to rhabdomyolysis (e.g., in sepsis, arterial hypotension, major surgical procedures, trauma, severe metabolic or endocrine disorders, severe electrolyte imbalance, or uncontrolled epilepsy).

Severe skin adverse reactions

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

If a patient develops a serious reaction such as SJS or DRESS while taking rosuvastatin, reinitiating treatment with this drug is contraindicated.

Hepatic effects

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

Liver function tests are recommended before starting therapy and again 3 months after initiation. Rosuvastatin therapy should be discontinued or the dose reduced if serum transaminase levels exceed three times the upper limit of normal. The frequency of serious hepatic events (predominantly elevated liver transaminases) in the post-marketing period was higher 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 therapy.

Race

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

Protease inhibitors

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

Lactose intolerance

Redistatin contains lactose. This medicinal product should not be prescribed to patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Interstitial lung disease

There have been isolated reports of interstitial lung disease associated with the use of some statins, particularly during long-term therapy (see section "Adverse reactions"). Symptoms may 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

Evidence suggests that statins increase blood glucose levels and may cause hyperglycemia sufficient to require diabetes treatment in some patients at high risk of developing diabetes. However, the reduction in vascular risk with statin use outweighs this risk, and therefore it 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, arterial hypertension) should be monitored clinically and biochemically according to national guidelines.

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

Children

Assessment of linear growth (height), body weight, BMI (body mass index), and development of secondary sexual characteristics according to Tanner staging in children aged 6 to 17 years on 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.

In a clinical study in children receiving rosuvastatin for 52 weeks, CK levels >10 times ULN and muscle symptoms after physical exertion or increased physical activity were observed more frequently compared to adults (see section "Adverse reactions").

Allergic reactions

Redistatin 10 mg and 20 mg tablets contain the colorant Yellow West FCF, which may cause allergic reactions.

Use during pregnancy or breastfeeding

The use of rosuvastatin during pregnancy or breastfeeding is contraindicated.

Women of childbearing potential should use reliable contraception.

Since cholesterol and other products of cholesterol biosynthesis are essential for fetal development, the potential risk of HMG-CoA reductase inhibition during pregnancy outweighs the benefit of therapy. Animal reproductive toxicity data are limited. If pregnancy occurs during treatment, therapy should be discontinued immediately.

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

Ability to influence reaction speed when driving or operating machinery

Studies on the effect of Redistatin on the ability to drive or operate machinery have not been conducted. However, given the pharmacodynamic properties of the drug, it is unlikely that Redistatin will affect this ability. When driving or operating machinery, the possibility of dizziness during treatment should be taken into account.

Method of Administration and Dosage

Prior to initiating treatment, patients should be placed on a standard cholesterol-lowering diet, which should be continued during therapy. The dose should be individualized based on therapeutic goals and response to treatment, in accordance with current guidelines.

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

Treatment of Hypercholesterolemia

The recommended initial dose is 5 mg* or 10 mg orally once daily for patients who have not previously received statin therapy, as well as for patients previously treated with other HMG-CoA reductase inhibitors. The choice of initial dose should consider the individual patient's cholesterol levels, future risk of cardiovascular events, and the potential for adverse reactions. Dose adjustments, if necessary, should be made at 4-week intervals (see section "Pharmacodynamics"). Due to the increased frequency of adverse reactions with the 40 mg dose compared to lower doses (see section "Adverse Reactions"), dose escalation to 40 mg is recommended only for the treatment of patients with severe hypercholesterolemia, or those at high cardiovascular risk (e.g., patients with familial hypercholesterolemia), when treatment with 20 mg daily does not achieve the desired response despite regular medical monitoring (see section "Special Precautions"). The 40 mg dose should be administered under specialist supervision.

Prevention of Cardiovascular Disorders

In clinical trials evaluating the effect of the drug on reducing cardiovascular risk, the dose used was 20 mg once daily.

Use in Elderly Patients

For patients aged >70 years, the recommended initial dose is 5 mg* (see section "Special Precautions"). No other dose adjustments based on age are 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. Rosuvastatin is contraindicated in patients with severe renal impairment at any dose (see sections "Contraindications" and "Pharmacokinetics").

Patients with Hepatic Impairment

No increase in systemic exposure to rosuvastatin was observed in patients with Child-Pugh class 7 or lower hepatic impairment. However, increased systemic exposure to rosuvastatin was observed in patients with Child-Pugh class 8 and 9 hepatic impairment (see section "Pharmacokinetics"). Renal function should be monitored regularly in such patients (see section "Special Precautions"). There is no experience with the use of rosuvastatin in patients with hepatic impairment above Child-Pugh class 9. Rosuvastatin is contraindicated in patients with active liver disease (see section "Contraindications").

Racial Considerations

Increased systemic exposure to the drug has been observed in patients of Mongoloid race (see sections "Contraindications", "Special Precautions", and "Pharmacokinetics"). The recommended initial dose for patients of 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 exposure to rosuvastatin (see section "Pharmacokinetics"). Patients known to have such polymorphisms should be prescribed a lower daily dose.

Patients Predisposed to Myopathy

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

Concomitant Use

Rosuvastatin is a substrate for several transporter proteins (e.g., OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) is increased when Redistatin is co-administered with certain medicinal products that may increase plasma concentrations of rosuvastatin via interaction with these transporter proteins (e.g., cyclosporine and certain protease inhibitors, including ritonavir combinations with atazanavir, lopinavir and/or tipranavir; see sections "Special Precautions" and "Interaction with Other Medicinal Products and Other Forms of Interaction"). Alternative therapy should be considered whenever possible, and temporary discontinuation of treatment may be necessary. In situations where concomitant use of these medicinal products with Redistatin cannot be avoided, the benefits and risks of combination therapy should be carefully evaluated, and the dose of Redistatin should be adjusted accordingly (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

*Administer the medicinal product at the appropriate dosage strength.

Pediatric Use

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

Children and Adolescents Aged 6 to 17 Years (Tanner Stage ˂II-V).

Heterozygous Familial Hypercholesterolemia

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

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

Dose escalation should be based on individual response to treatment and tolerability, in accordance with pediatric treatment recommendations (see section "Special Precautions"). Prior to initiating rosuvastatin therapy, children and adolescents should be placed on a standard hypocholesterolemic diet, which should be maintained throughout treatment.

Homoygous Familial Hypercholesterolemia

The recommended maximum dose for children aged 6 to 17 years with homozygous familial hypercholesterolemia is 20 mg once daily.

The recommended initial dose is 5* mg to 10 mg once daily, depending on age, body weight, and prior statin use. Dose escalation to the maximum dose of 20 mg once daily should be based on individual response and tolerability, in accordance with pediatric treatment recommendations (see section "Special Precautions"). Prior to 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.

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 established. Therefore, the product is not recommended for use in children under 6 years of age.

*Administer the medicinal product at the appropriate dosage strength.

Overdose

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

Adverse reactions.

Adverse reactions observed during administration of the drug are usually mild and transient. Less than 4% of patients receiving rosuvastatin in controlled clinical studies discontinued treatment due to the development of adverse reactions.

The adverse reaction profile of rosuvastatin based on data from clinical studies and extensive post-marketing experience is presented in Table 3 below. Adverse reactions are classified by frequency and by system organ classes (SOC).

Adverse reactions are listed below according to their frequency of occurrence: common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), frequency not known (cannot be estimated from available data).

Table 3

Adverse reactions based on data from clinical studies and post-marketing experience

System organ class	Common	Uncommon	Rare	Very rare	Frequency not known
Blood and lymphatic system disorders			Thrombocyto- penia
Immune system disorders			Hypersensitivity reactions, including angioedema
Endocrine disorders	Diabetes mellitus1
Psychiatric disorders					Depression
Nervous system disorders	Headache, dizziness			Polyneuropathy, memory loss	Peripheral neuropathy, sleep disorders (including insomnia and nightmares), myasthenia gravis
Eye disorders					Ocular myasthenia
Respiratory, thoracic and mediastinal disorders					Cough, dyspnoea
Gastrointestinal disorders	Constipation, nausea, abdominal pain		Pancreatitis		Diarrhoea
Hepatobiliary disorders			Elevated liver transaminase levels	Jaundice, hepatitis
Skin and subcutaneous tissue disorders		Pruritus, rash, urticaria			Stevens-Johnson syndrome, drug-induced eosinophilia with systemic symptoms (DRESS syndrome)
Musculoskeletal and connective tissue disorders	Myalgia		Myopathy (including myositis), rabdomyolysis, lupus-like syndrome, muscle rupture	Arthralgia	Disorders of tendons, sometimes complicated by rupture; immune-mediated necrotizing myopathy
Renal and urinary disorders				Hematuria
Reproductive system and breast disorders				Gynaecomastia
General disorders and administration site conditions	Generalised weakness				Swelling
1 Frequency depends on the presence of risk factors (fasting glucose ≥ 5.6 mmol/L, BMI > 30 kg/m², elevated blood triglyceride levels, history of arterial hypertension).

As with other HMG-CoA reductase inhibitors, the frequency of adverse reactions tends to depend on the dose of the drug.

Renal disorders: proteinuria detected by dipstick testing, predominantly of tubular origin, has been observed in patients treated with rosuvastatin. An increase in urinary protein from absent or trace levels to ++ or greater at various stages of therapy was observed in < 1% of patients receiving the drug at doses of 10 and 20 mg, and in approximately 3% of patients receiving the drug at a dose of 40 mg. A slight increase from absent or trace levels to + was also observed at a dose of 20 mg. In most cases, proteinuria decreased or resolved spontaneously while continuing therapy.

Based on clinical studies and post-marketing surveillance, there is currently no evidence of a causal relationship between proteinuria and acute or progressive kidney disease.

Cases of hematuria have been reported during treatment with the medicinal product; according to clinical studies, the frequency was low.

Skeletal muscle disorders: skeletal muscle involvement such as myalgia, myopathy (including myositis), and rarely rhabdomyolysis with or without acute renal failure, have been observed in patients receiving rosuvastatin at any dose, particularly at doses > 20 mg.

In patients receiving rosuvastatin, dose-dependent increases in CK levels have been observed. In most cases, this phenomenon was mild, asymptomatic, and transient. If CK levels are elevated (> 5 times the ULN), further therapy should be discontinued (see section "Special instructions").

Hepatic disorders: as with other HMG-CoA reductase inhibitors, dose-dependent increases in transaminase activity have been observed in a small number of patients treated with rosuvastatin. In most cases, this phenomenon was mild, asymptomatic, and transient.

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

sexual dysfunction;

isolated cases of interstitial lung disease, particularly with long-term therapy (see section "Special instructions").

The frequency of reports of rhabdomyolysis, serious renal and hepatic disorders (mainly increased hepatic transaminase activity) is higher when the medicinal product is used at a dose of 40 mg.

Children

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

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions during the post-marketing period is important. This allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are obliged to report any suspected adverse reactions through the national reporting system.

Shelf life: 3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging to protect from moisture. Keep out of reach of children.

Packaging.

10 tablets per blister, 3 blisters per cardboard box.

Prescription category: Prescription only.

Manufacturer.

Dr. Reddy’s Laboratories Ltd, FTO – II.

Manufacturer's address and site of operations.

Survey No. 42R, 43, 44R, 45R, 46R, 53, 54, 83, Bachupally, Bachupally Mandal, Medchal Malkajgiri District – 500090, Telangana State, India.