Rosastin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ROSASTIN® (ROSASTIN)

Composition:

Active ingredient: rosuvastatin;

1 tablet contains 5.2 mg of rosuvastatin calcium, equivalent to 5 mg of rosuvastatin;

1 tablet contains 10.4 mg of rosuvastatin calcium, equivalent to 10 mg of rosuvastatin;

1 tablet contains 20.8 mg of rosuvastatin calcium, equivalent to 20 mg of rosuvastatin;

1 tablet contains 41.6 mg of rosuvastatin calcium, equivalent to 40 mg of rosuvastatin;

Excipients: sodium bicarbonate; precipitated calcium carbonate; lactose monohydrate; microcrystalline cellulose (PH 101); crosspovidone, type A; povidone (K-30); microcrystalline cellulose (PH 102); magnesium stearate;

For 5 mg tablets – film-coating mixture Opadry Yellow (03K520021): HPMC 2910/hypromellose 6 cP (E 464), titanium dioxide (E 171), triacetin, tartrazine (E 102), Ponceau 4R (E 129), indigo carmine (E 132);

For 10 mg, 20 mg, 40 mg tablets – film-coating mixture Opadry Pink (03K540034): HPMC 2910/hypromellose 6 cP (E 464), titanium dioxide (E 171), triacetin, sunset yellow FCF (E 110), Ponceau 4R (E 129), indigo carmine (E 132).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

5 mg tablets – yellow, round, biconvex film-coated tablets, engraved with "5" on one side and "R" on the other, approximately 7 mm in diameter;

10 mg tablets – pink, round, biconvex film-coated tablets, engraved with "10" on one side and "R" on the other, approximately 7 mm in diameter;

20 mg tablets – pink, round, biconvex film-coated tablets, engraved with "20" on one side and "R" on the other, approximately 9 mm in diameter;

40 mg tablets – pink, oval, biconvex film-coated tablets, engraved with "40" on one side and "R" on the other, approximately 12 mm in length and 7 mm in width.

Pharmacotherapeutic group. Hypolipidemic agents. HMG-CoA reductase inhibitors.

ATC code C10AA07.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

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

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

Rosastin® reduces elevated levels of LDL cholesterol, total cholesterol, and triglycerides, and increases high-density lipoprotein (HDL) cholesterol levels. It also reduces levels of apolipoprotein B (apoB), non-HDL cholesterol, VLDL cholesterol, VLDL triglycerides, and increases apolipoprotein A-I (apoA-I) levels. Rosastin® also reduces the ratios of LDL cholesterol/HDL cholesterol, total cholesterol/HDL cholesterol, non-HDL cholesterol/HDL cholesterol, and apoB/apoA-I.

Therapeutic effect is achieved within 1 week after initiation of treatment, with 90% of the maximum effect reached by 2 weeks. The maximum effect is usually achieved by 4 weeks and maintained thereafter.

Pharmacokinetics

Absorption

The maximum plasma concentration (Cmax) of rosuvastatin is reached approximately 5 hours after oral administration. Absolute bioavailability is approximately 20%.

Distribution

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

Metabolism

Rosuvastatin undergoes minimal metabolism (approximately 10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a weak substrate for cytochrome P450 enzyme-mediated metabolism. The main isoenzyme involved is CYP2C9, with minor contributions from CYP2C19, CYP3A4, and CYP2D6. The main identified metabolites are the 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 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 (including both absorbed and unabsorbed drug), and the remainder is excreted in urine. Approximately 5% is excreted unchanged in urine. The plasma elimination half-life is approximately 19 hours and does not increase with dose escalation. The mean geometric value of plasma clearance is approximately 50 L/h (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 the hepatic elimination of rosuvastatin.

Linearity

Systemic exposure (AUC) of rosuvastatin increases proportionally with dose. Pharmacokinetic parameters do not change with repeated daily administration.

Special Patient Populations

Age and Gender

No clinically significant effect of age or gender on the pharmacokinetics of rosuvastatin has been 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

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

Renal Impairment

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

Hepatic Impairment

In a study involving patients with varying degrees of hepatic impairment, no evidence of increased rosuvastatin AUC was observed in patients with a Child–Pugh score of 7 or less. However, in two patients with Child–Pugh scores of 8 and 9, AUC was at least twice as high as in patients with lower scores. Experience with rosuvastatin in patients with a Child–Pugh score greater than 9 is lacking.

Genetic Polymorphism

The disposition of HMG-CoA reductase inhibitors, including rosuvastatin, involves transport proteins OATP1B1 and BCRP. Patients with genetic polymorphisms in SLCO1B1 (OATP1B1) and/or ABCG2 (BCRP) are at risk of increased rosuvastatin AUC. 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 recommended in clinical practice, but patients with these polymorphisms should be prescribed a lower daily dose.

Children

Two pharmacokinetic studies of rosuvastatin (tablets) in children with heterozygous familial hypercholesterolemia aged 10 to 17 years or 6 to 17 years (total of 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 treatment over more than 2 years of observation.

Clinical characteristics

Indications

For the treatment of hypercholesterolemia

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

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

For prevention of cardiovascular disorders

For patients who are estimated to be at high risk of a first cardiovascular event (see section "Pharmacodynamics"), as an adjunct to correction of other risk factors.

Contraindications

The drug is contraindicated:

• in patients with hypersensitivity to rosuvastatin or to any of the excipients of the drug;
• in patients with active liver disease, including persistent elevations of serum transaminases of unknown etiology and any elevations of serum transaminases 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 types of interactions");
• in patients concurrently receiving cyclosporine;
• in pregnant and breastfeeding women, 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 this risk include:

• moderate renal impairment (creatinine clearance < 60 mL/min);
• hypothyroidism;
• personal or family history of hereditary muscle disorders;
• history of myotoxicity during treatment 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 "Pharmacokinetics", "Interaction with other medicinal products and other types of interactions", and "Special precautions for use").

Interaction with other medicinal products and other types of interactions

Effect of concomitant drugs on rosuvastatin

Inhibitors of transport proteins

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

Cyclosporine

During concomitant use of rosuvastatin and cyclosporine, rosuvastatin AUC values were on average approximately 7 times higher than those observed in healthy volunteers (see Table 2). The drug is contraindicated in patients who are concurrently receiving cyclosporine (see section "Contraindications").

Concomitant use did not affect cyclosporine plasma concentrations.

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 combined medicinal product containing two protease inhibitors (300 mg atazanavir/100 mg ritonavir) in healthy volunteers was associated with increases in rosuvastatin AUC and Cmax by approximately 3 and 7 times, respectively. Concomitant use of Rosastin® with certain protease inhibitor combinations may be possible after careful consideration of Rosastin® dose adjustment due to the expected increase in rosuvastatin AUC (see sections "Interaction with other medicinal products and other types of interactions", "Special precautions for use", "Method of administration and dosage", Table 2).

Gemfibrozil and other lipid-lowering agents

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

Based on data from specific pharmacokinetic studies, no clinically significant interaction with fenofibrate is expected; however, pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates, and lipid-lowering doses (≥ 1 g/day) 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 alone. The 40 mg dose is contraindicated when used concomitantly with fibrates (see sections "Contraindications" and "Special precautions for use"). Such patients should also start therapy with a 5 mg dose.

Ezetimibe

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

Antacids

Concomitant use of Rosastin® with antacid suspensions containing aluminum or magnesium hydroxide reduced rosuvastatin plasma concentrations by approximately 50%. This effect was less pronounced when antacids were administered 2 hours after Rosastin®. The clinical significance of this interaction has not been studied.

Erythromycin

Concomitant use of Rosastin® and erythromycin reduced rosuvastatin AUC by 20% and Cmax by 30%. This interaction may be due to enhanced intestinal peristalsis caused by erythromycin.

Ticagrelor

Ticagrelor may cause renal impairment and may affect renal excretion of rosuvastatin, increasing the risk of its accumulation. In some cases, concomitant use of ticagrelor and rosuvastatin has led to decreased renal function, increased creatine phosphokinase (CPK) levels, and rhabdomyolysis. Monitoring of renal function and CPK levels is recommended when ticagrelor and rosuvastatin are used concomitantly.

Cytochrome P450 enzymes

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

Interactions requiring dose adjustment of rosuvastatin

When co-administration of Rosastin® with other medicinal products capable of increasing rosuvastatin AUC is necessary, the dose of Rosastin® should be adjusted. If an increase in AUC of approximately 2-fold or more is expected, Rosastin® therapy should be initiated at a dose of 5 mg once daily. The maximum daily dose should be adjusted so that the expected rosuvastatin AUC does not exceed the AUC observed with a 40 mg/day dose without interacting drugs; for example, when used with gemfibrozil, the Rosastin® dose would be 20 mg (1.9-fold increase in AUC), and when used with ritonavir/atazanavir combination, the dose would be 10 mg (3.1-fold increase in AUC).

If the medicinal product increases rosuvastatin AUC by less than 2-fold, no initial dose reduction is required, but caution should be exercised when increasing the Rosastin® dose above 20 mg.

Table 1

Effect of concomitant medicinal products on rosuvastatin AUC (in descending order of magnitude) based on published data from clinical studies

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

Increases are indicated by ↑, decreases by ↓.

** Several interaction studies were conducted at different rosuvastatin doses; the most significant ratio is presented in Table 1.

Medicinal products/combinations that did not have a clinically significant effect on rosuvastatin AUC when co-administered: aleglitazar 0.3 mg, 7 days; fenofibrate 67 mg three times daily, 7 days; fluconazole 200 mg once daily, 11 days; fosamprenavir 700 mg/ritonavir 100 mg twice daily, 8 days; ketoconazole 200 mg twice daily, 7 days; rifampicin 450 mg once daily, 7 days; silymarin 140 mg three times daily, 5 days.

Effect of rosuvastatin on concomitant medicinal products

Vitamin K antagonists

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

Oral contraceptives / hormone replacement therapy (HRT)

Concomitant administration of Rosuvastin® and oral contraceptives resulted in a 26% and 34% increase in AUC of ethinylestradiol and norgestimate, respectively. This increase in plasma levels should be taken into account when selecting the dose of oral contraceptives. There are no data on the pharmacokinetics of drugs in patients concurrently receiving Rosuvastin® and HRT; therefore, a similar effect cannot be excluded. However, the combination has been widely used in women during clinical trials and was well tolerated.

Other medicinal products

Digoxin

Based on dedicated interaction studies, no clinically significant interaction with digoxin is expected.

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 products are co-administered with statins. The mechanism of this interaction (pharmacodynamic, pharmacokinetic, or both) has not yet been established. Cases of rhabdomyolysis (including fatal outcomes) have been reported in patients receiving this combination of medicinal products. If systemic fusidic acid therapy is necessary, rosuvastatin treatment should be discontinued for the entire duration of fusidic acid treatment. See also section "Special precautions".

Paediatric population

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

Special precautions for use

Renal effects

Proteinuria detected by dipstick testing, predominantly of tubular origin, has been observed in patients treated with higher doses of rosuvastatin, particularly 40 mg, and was mostly transient or intermittent in most cases. 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. In patients receiving the 40 mg dose, renal function should be monitored regularly during treatment.

Effects on skeletal muscle

Skeletal muscle disorders such as myalgia, myopathy, and rarely rhabdomyolysis have been observed in patients taking rosuvastatin at any dose, particularly at doses higher than 20 mg. Isolated cases of rhabdomyolysis have been reported with ezetimibe used 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 post-marketing reports of rhabdomyolysis associated with rosuvastatin use was higher at the 40 mg dose.

Creatine kinase levels

Creatine kinase (CK) levels should not be measured following strenuous physical exercise or in the presence of other potential causes of elevated CK, which may complicate interpretation of results. If baseline CK levels are markedly elevated (> 5 times ULN), a repeat test should be performed within 5–7 days to confirm the results. If repeat testing confirms that baseline CK levels exceed 5 times ULN, treatment should not be initiated.

Before starting treatment

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

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

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

During treatment

Patients should be advised to report immediately any unexplained muscle pain, weakness, or cramps, especially if accompanied by malaise or fever. CK levels should be measured in such patients. The medicinal product should be discontinued if CK levels are markedly elevated (> 5 × ULN) or if symptoms are severe and cause daily discomfort (even if CK levels ≤ 5 × ULN). If symptoms resolve and CK levels return to normal, therapy with Rosastin® 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 rosuvastatin. Clinical features of IMNM include proximal muscle weakness and elevated serum creatine kinase levels that 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, Rosastin® should be discontinued. Recurrences have been reported upon first or subsequent use of the same or another statin.

Clinical trials did not provide evidence of increased skeletal muscle effects in a small number of patients taking Rosastin® and 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, nicotinic acid, azole antifungals, protease inhibitors, and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when used concomitantly with certain HMG-CoA reductase inhibitors. Therefore, co-administration of Rosastin® with gemfibrozil is not recommended. The benefit of further lipid-lowering with Rosastin® in combination with fibrates or niacin should be carefully weighed against the potential risks associated with such combinations. The 40 mg dose is contraindicated with concomitant use of fibrates (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Rosastin® should not be used concomitantly with systemic fusidic acid or within 7 days after discontinuation of fusidic acid treatment. In patients for whom systemic fusidic acid treatment is considered necessary, statin therapy should be discontinued for the duration of fusidic acid treatment. Cases of rhabdomyolysis (including several fatal cases) have been reported in patients receiving fusidic acid and statins concomitantly (see section "Interaction with other medicinal products and other forms of interaction"). Patients should be advised to seek immediate medical attention if they experience any symptoms of muscle weakness, pain, or tenderness. Statin therapy may be restarted seven days after the last dose of fusidic acid. In exceptional cases where prolonged systemic fusidic acid treatment is required, e.g., for treatment of severe infections, the possibility of concomitant use of Rosastin® and fusidic acid should be considered on a case-by-case basis and only under close medical supervision.

Rosastin® should not be administered to patients with acute, serious conditions indicating myopathy or risk of renal failure due to rhabdomyolysis (such as sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures).

Severe skin adverse reactions

Severe skin adverse reactions, including Stevens-Johnson syndrome and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), which may be life-threatening or fatal, have been observed with rosuvastatin. When prescribing the medicinal product, 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, the drug should be discontinued immediately and alternative treatment considered. If a patient develops such a serious reaction as Stevens-Johnson syndrome or drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), treatment with Rosastin® must be discontinued immediately and never resumed.

Hepatic effects

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

Biochemical liver function tests should be performed before starting treatment and again after 3 months. Treatment with Rosastin® should be discontinued or the dose reduced if serum transaminase levels exceed three times the upper limit of normal (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 Rosastin®.

Race

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

Protease inhibitors

Increased AUC of rosuvastatin has been observed in individuals taking rosuvastatin concomitantly with various protease inhibitors in combination with ritonavir. Both the benefit of lipid-lowering with Rosastin® 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 Rosastin® in patients receiving protease inhibitors should be considered. Concomitant use of the drug with protease inhibitors is not recommended unless the dose of Rosastin® is adjusted (see sections "Interaction with other medicinal products and other forms of interaction" and "Method of administration and dosage").

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

Evidence suggests that statins as a class may increase blood glucose levels and may induce hyperglycemia requiring treatment in some patients at high risk of developing diabetes mellitus in the future. However, this risk is outweighed by the reduction in vascular risk with statin use, and therefore should not be a reason to discontinue statin therapy. Patients at risk (fasting glucose 5.6–6.9 mmol/L, body mass index (BMI) > 30 kg/m², elevated triglycerides, hypertension) should be monitored clinically and biochemically according to national guidelines.

In the JUPITER clinical trial, the overall incidence of diabetes mellitus 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, and secondary sexual characteristics by Tanner staging in children aged 6 to 17 years taking rosuvastatin is limited to a 2-year period. After 2 years of investigational treatment, no effect on growth, body weight, BMI, or sexual maturation was observed (see section "Pharmacodynamics").

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

Lactose intolerance

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

Azo dyes

The medicinal product contains azo dyes tartrazine (E 102) and sunset yellow FCF (E 110), which may cause allergic reactions.

Use during pregnancy or breastfeeding

Rosastin® is contraindicated during pregnancy and breastfeeding.

Women of childbearing potential should use appropriate contraceptive measures.

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

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

Ability to affect reaction speed when driving or operating machinery

Studies on the effect of rosuvastatin on the ability to drive or operate machinery have not been conducted. However, given the pharmacodynamic properties of the drug, it is unlikely that Rosastin® 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 therapy, patients should be placed on a standard hypocholesterolemic diet, which must be maintained throughout treatment. The dosage should be individually adjusted based on therapeutic goals and the patient's response to treatment, in accordance with current established guidelines.

Rozastin® can be taken at any time of day, regardless of food intake.

Hypercholesterolemia Treatment

The recommended initial dose is 5 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 selection of initial dose should take into account individual cholesterol levels, future cardiovascular risk, and the likelihood of adverse reactions. Dose increases to the next level may be considered after 4 weeks (see section "Pharmacodynamics"). Due to the higher incidence of adverse reactions with the 40 mg dose compared to lower doses (see section "Adverse Reactions"), the 40 mg dose 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 the 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, rosuvastatin was administered at a dose of 20 mg daily (see section "Pharmacological Properties").

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. Rozastin® is contraindicated in any dosage in patients with severe renal impairment (see sections "Pharmacokinetics" and "Contraindications").

Patients with Hepatic Impairment

In patients with hepatic impairment scoring 7 or less on the Child-Pugh scale, no increase in rosuvastatin AUC was observed. However, in individuals scoring 8 or 9, AUC was increased (see section "Pharmacokinetics"). Renal function assessment is advisable in these patients (see section "Special Warnings and Precautions for Use"). Experience with the drug in patients scoring more than 9 on the Child-Pugh scale is lacking. Rozastin® is contraindicated in patients with active liver disease (see section "Contraindications").

Race

Increased AUC of the drug has been observed in patients of Mongoloid race (see sections "Pharmacokinetics", "Contraindications", and "Special Warnings and Precautions for Use"). The recommended initial dose for patients of Asian origin is 5 mg; the 40 mg dose is contraindicated in these patients.

Genetic Polymorphism

Certain types of genetic polymorphism may lead to increased rosuvastatin AUC (see section "Pharmacokinetics"). Patients known to have such polymorphism types are recommended to receive 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 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 transporter proteins (e.g., OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) increases when Rozastin® is co-administered with certain medicinal products that may increase rosuvastatin plasma concentrations due to interactions with these transporter proteins (e.g., cyclosporine and certain protease inhibitors, including ritonavir combinations with atazanavir, lopinavir, and/or tipranavir; see sections "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 Rozastin® therapy may be necessary. If concomitant use of these medicinal products with Rozastin® cannot be avoided, the benefit-risk balance should be carefully evaluated and the Rozastin® dose adjusted accordingly (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Children

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

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

Heterozygous Familial Hypercholesterolemia

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

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

Dose increases should be made according to the individual child's response to treatment and drug tolerability, in accordance with pediatric treatment recommendations (see section "Special Warnings and Precautions for Use"). Prior to initiating rosuvastatin therapy, children and adolescents should be placed on a standard hypocholesterolemic diet, which must 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 to 10 mg once daily, depending on age, body weight, and prior statin use. Dose increases up to the maximum dose of 20 mg once daily should be made according to the individual child's response to treatment and drug tolerability, in accordance with pediatric treatment recommendations (see section "Special Warnings and Precautions for Use"). Prior to initiating rosuvastatin therapy, children and adolescents should be placed on a standard hypocholesterolemic diet, which must be maintained throughout treatment.

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

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

Children Under 6 Years of Age

The safety and efficacy of the medicinal product in children under 6 years of age have not been studied. Therefore, Rozastin® 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 implemented as needed. Liver function and CK levels should be monitored. Hemodialysis is unlikely to be effective.

Adverse Reactions

Adverse events observed during administration of Rosatin® are generally mild and transient. In controlled clinical studies, fewer than 4% of patients receiving Rosatin® discontinued the study due to adverse reactions.

Table 2 presents the adverse reaction profile of rosuvastatin based on data from clinical studies and extensive post-marketing experience. Adverse reactions are classified by frequency and by system organ classes.

By frequency, adverse reactions are categorized as follows: common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), and frequency not known (cannot be estimated from available data).

Table 2

Adverse reactions based on clinical studies and post-marketing experience

1 Frequency depends on the presence of risk factors (fasting glucose ≥ 5.6 mmol/L, BMI > 30 kg/m², elevated triglyceride levels, history of 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 and predominantly of tubular origin has been observed in patients treated with rosuvastatin. Changes in urinary protein content from zero or trace to ++ or higher were observed in < 1% of patients at certain time points during treatment with 10 and 20 mg doses, and in approximately 3% of patients at the 40 mg dose. A slight increase in frequency of change from zero or trace to + was observed at the 20 mg dose. In most cases, proteinuria decreased or resolved spontaneously while continuing therapy. To date, based on clinical studies and post-marketing surveillance, no causal relationship has been established between proteinuria and acute or progressive kidney disease.

Cases of hematuria have been reported during treatment with Rosatin®; according to clinical trial data, the frequency was low.

Skeletal muscle 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 Rosatin®, particularly at doses > 20 mg.

In patients taking rosuvastatin, dose-dependent increases in creatine kinase (CK) levels have been observed; in most cases, this phenomenon was mild, asymptomatic, and transient. If CK levels are elevated (> 5 times the upper limit of normal), treatment should be discontinued (see section "Dosage and Administration").

Hepatic effects

As with other HMG-CoA reductase inhibitors, a small number of patients taking rosuvastatin have shown dose-dependent increases in transaminase levels; in most cases, this was mild, asymptomatic, and transient. Increases in HbA1c levels have also been observed during treatment with rosuvastatin.

With the use of some statins, adverse events such as sexual dysfunction have been reported. Isolated cases of interstitial lung disease, particularly with long-term use, have also been observed (see section "Dosage and Administration").

The frequency of reports of rhabdomyolysis and serious renal and hepatic adverse events (mainly increased hepatic transaminase activity) is higher with the 40 mg dose.

Pediatric population

Elevations in creatine kinase levels > 10 times the upper limit of normal and muscle-related symptoms following physical exertion or increased physical activity were observed more frequently in pediatric and adolescent clinical trials with rosuvastatin compared to adults (see section "Dosage and Administration"). However, the safety profile of rosuvastatin in children and adolescents was similar to that in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 4 years.

Storage conditions. Store 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 status. Prescription only.

Manufacturer. Micro Labs Limited

Manufacturer's address and location of operations

Plot No. S.155 – S.159 and N1, Verna Industrial Estate, Phase III and Phase IV, Verna Salcette, In-403 722, India