Ozalex

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

Composition:

Active substance: rosuvastatin;

One film-coated tablet contains 10 mg, or 20 mg, or 40 mg of rosuvastatin calcium, calculated as rosuvastatin;

Excipients: lactose monohydrate, microcrystalline cellulose, hydroxypropylcellulose low-substituted, colloidal anhydrous silicon dioxide, magnesium stearate, Opadry 03F84827 pink* coating;

*Opadry 03F84827 pink: hypromellose, titanium dioxide (E 171), iron oxide red (E 172), polyethylene glycol, talc.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: pink film-coated, round, biconvex, smooth tablets on both sides.

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

ATC code C10A A07.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

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

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

Pharmacodynamic effects

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

Rosuvastatin also reduces the ratios of LDL-C/HDL-C, total cholesterol/HDL-C, non-HDL-C/HDL-C, and apoB/apoA-I.

Therapeutic effect is achieved within 1 week after initiation of treatment, with 90% of the maximum effect reached within 2 weeks. Maximum effect is typically 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-C clearance. The volume of distribution of rosuvastatin is approximately 134 L. Approximately 90% of rosuvastatin is bound to plasma proteins, predominantly 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 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 administered dose of rosuvastatin 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 elimination half-life from plasma is approximately 19 hours and does not increase with dose escalation. The geometric mean value of plasma drug 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 to 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. The pharmacokinetics of rosuvastatin in children and adolescents with heterozygous familial hypercholesterolemia were similar to those in adult volunteers (see section "Children").

Race

Pharmacokinetic studies have shown that median values of the area under the plasma concentration-time curve (AUC) and Cmax in Mongoloid race patients (Japanese, Chinese, Filipinos, Vietnamese, and Koreans) are approximately twice those in Caucasians; in Indians, median AUC and Cmax values are increased by approximately 1.3-fold. Population pharmacokinetic analysis did not reveal clinically significant differences between Caucasian and African patients.

Renal impairment

In a study of 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 three times higher and levels of the N-desmethyl metabolite were nine 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 of patients with varying degrees of hepatic impairment, no evidence of increased rosuvastatin exposure was observed in patients with Child-Pugh scores of 7 or less. However, in two patients with scores of 8 and 9, systemic exposure was at least twice as high as in patients with lower scores. Experience with rosuvastatin in patients with Child-Pugh scores greater than 9 is lacking.

Genetic polymorphism

The distribution of HMG-CoA reductase inhibitors, including rosuvastatin, involves transport proteins OATP1B1 and BCRP. Patients with genetic polymorphisms in SLCO1B1 (OATP1B1) and/or ABCG2 (BCRP) are at risk of increased rosuvastatin exposure. For certain polymorphic forms, such as 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 are recommended to use a lower daily dose of Ozalex®.

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 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.

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 medicinal therapies (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.

The medicinal product Ozalex**®** 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 increase in 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;
• during pregnancy and 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;
• situations that may lead to increased plasma concentration of the medicinal product;
• belonging to the 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 administration of rosuvastatin with medicinal products that inhibit these transport proteins may increase plasma concentrations of rosuvastatin and increase the risk of myopathy (see sections "Interaction with other medicinal products and other types of interactions", "Special precautions for use", and "Dosage and administration", table).

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). Rosuvastatin is contraindicated in patients 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 exposure (see table). For example, in a pharmacokinetic study, concomitant administration of 10 mg rosuvastatin and a combination 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 rosuvastatin and certain combinations of protease inhibitors may be possible after careful consideration of dose adjustment of Ozalex® due to the expected increase in rosuvastatin exposure (see sections "Interaction with other medicinal products and other types of interactions", "Special precautions for use", and "Dosage and administration", table).

Gemfibrozil and other lipid-lowering agents

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

Based on data from specific studies, no pharmacokinetically significant interaction with fenofibrate is expected; however, a pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates, and lipid-lowering doses of niacin (> or = 1 g/day) increase the risk of myopathy when used concomitantly with HMG-CoA inhibitors, likely because they may cause myopathy when used alone. The 40 mg dose is contraindicated when fibrates are used concomitantly (see sections "Contraindications" and "Special precautions for use"). Such patients should also initiate therapy 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). A pharmacodynamic interaction between rosuvastatin and ezetimibe, potentially leading to adverse effects, cannot be excluded (see section "Special precautions for use").

Antacid medicinal products

Concomitant administration of rosuvastatin with suspensions of antacids containing aluminum or magnesium hydroxide reduced rosuvastatin plasma concentration by approximately 50%. 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 reduced rosuvastatin AUC by 20% and Cmax by 30%. This interaction may be due to enhanced intestinal motility 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, elevated 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. Furthermore, rosuvastatin is a weak substrate of these isoenzymes. Therefore, drug interactions due to 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 (see also table)

When co-administration of rosuvastatin with other medicinal products capable of increasing its exposure is necessary, the rosuvastatin dose should be adjusted. If an approximately 2-fold or greater increase in AUC of the drug 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 its expected exposure does not exceed that observed with a 40 mg/day dose in the absence of interacting medicinal products; for example, when used with gemfibrozil, the rosuvastatin dose should be 20 mg (1.9-fold increase in exposure), and when used with ritonavir/atazanavir combination, 10 mg (3.1-fold increase in exposure).

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

Table

Effect of concomitant medicinal products on rosuvastatin exposure

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

Increased AUC of rosuvastatin by 2-fold or more
Dosing regimen of the interacting drug	Dosing regimen of rosuvastatin	Changes in rosuvastatin AUC*
Sofosbuvir/velpatasvir/voxilaprevir (400 mg–100 mg–100 mg) + voxilaprevir (100 mg) once daily for 15 days	10 mg, single dose	↑ 7.4-fold
Cyclosporine from 75 mg twice daily to 200 mg twice daily, 6 months	10 mg once daily, 10 days	↑ 7.1-fold
Darolutamide 600 mg twice daily, 5 days	5 mg, single dose	↑ 5.2-fold
Regorafenib 160 mg once daily, 14 days	5 mg, single dose	↑ 3.8-fold
Atazanavir 300 mg/ritonavir 100 mg once daily, 8 days	10 mg, single dose	↑ 3.1-fold
Velpatasvir 100 mg once daily	10 mg, single dose	↑ 2.7-fold
Obitasvir 25 mg/paritaprevir 150 mg/ritonavir 100 mg once daily/dasabuvir 400 mg twice daily, 14 days	5 mg, single dose	↑ 2.6-fold
Glecaprevir 200 mg/elbasvir 50 mg once daily, 11 days	10 mg, single dose	↑ 2.3-fold
Glecaprevir 400 mg/pibrentasvir 120 mg once daily, 7 days	5 mg once daily, 7 days	↑ 2.2-fold
Lopinavir 400 mg/ritonavir 100 mg twice daily, 17 days	20 mg once daily, 7 days	↑ 2.1-fold
Clopidogrel 300 mg, then 75 mg after 24 hours	20 mg, single dose	↑ 2-fold
Gemfibrozil 600 mg twice daily, 7 days	80 mg, single dose	↑ 1.9-fold
Increased AUC of rosuvastatin less than 2-fold
Dosing regimen of the interacting drug	Dosing regimen of rosuvastatin	Changes in rosuvastatin AUC*
Elotrombopag 75 mg once daily, 5 days	10 mg, single dose	↑ 1.6-fold
Darunavir 600 mg/ritonavir 100 mg twice daily, 7 days	10 mg once daily, 7 days	↑ 1.5-fold
Tipranavir 500 mg/ritonavir 200 mg twice daily, 11 days	10 mg, single dose	↑ 1.4-fold
Dronedarone 400 mg twice daily	Unknown	↑ 1.4-fold
Itraconazole 200 mg once daily, 5 days	10 mg, single dose	↑ 1.4-fold **
Ezetimibe 10 mg once daily, 14 days	10 mg once daily, 14 days	↑ 1.2-fold **
Decreased AUC of rosuvastatin
Dosing regimen of the interacting drug	Dosing regimen of rosuvastatin	Changes in rosuvastatin AUC*
Erythromycin 500 mg four times daily, 7 days	80 mg, single dose	↓ 20%
Scutellaria baicalensis 50 mg three times daily, 14 days	20 mg, single dose	↓ 47%

* 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 when rosuvastatin is used alone.

Increases are indicated by ↑, decreases by ↓.

** Several interaction studies were conducted at different rosuvastatin doses; the table presents the most significant ratio.

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

Effect of rosuvastatin on concomitant medicinal products

Vitamin K antagonists

As with other HMG-CoA reductase inhibitors, initiation of rosuvastatin 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 rosuvastatin 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 rosuvastatin and oral contraceptives resulted in a 26% and 34% increase in AUC of ethinylestradiol and norgestimate, respectively. This increase in plasma levels should be considered when selecting the dose of oral contraceptives. There are no data on the pharmacokinetics of medicinal products in patients concurrently receiving rosuvastatin and HRT; therefore, a similar effect cannot be excluded. However, the combination has been widely used in women in clinical trials and was well tolerated.

Other medicinal products

Digoxin

Based on specific interaction 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 myopathy, including rhabdomyolysis, may be increased when systemic fusidic acid is co-administered with statins. The mechanism of this interaction (pharmacodynamic or pharmacokinetic, or both) has not yet been 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 warnings and precautions for use".

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 and 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 nature. Proteinuria was not a predictor of acute or progressive renal 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 taking the medicinal product at the 40 mg dose.

Skeletal muscle effects

Skeletal muscle disorders such as myalgia, myopathy, and rarely rhabdomyolysis have been observed in patients taking rosuvastatin at any dose, particularly above 20 mg. Very rare 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), repeat testing should be performed within 5–7 days to confirm the results. If repeat testing confirms that baseline CK is more than 5 times above 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 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 medicinal product (see sections "Pharmacokinetics", "Interaction with other medicinal products and other forms of interaction", and "Posology and method of administration");
• 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 × ULN), treatment should not be initiated.

During treatment

Patients should be advised to promptly report unexplained muscle pain, weakness, or tenderness, 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 muscle symptoms are severe and cause daily discomfort (even if CK ≤ 5 × ULN). Therapy with rosuvastatin or an alternative HMG-CoA reductase inhibitor may be restarted at the lowest dose and under close supervision once symptoms have resolved and CK levels have returned to normal.

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 creatine kinase levels, which persist even after discontinuation of statins.

Clinical studies have not provided evidence of increased skeletal muscle effects in a small number of patients taking rosuvastatin 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, niacin, 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 with gemfibrozil is not recommended. The benefit of further lipid-lowering with rosuvastatin 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").

Rosuvastatin should not be used concomitantly with systemic fusidic acid or within 7 days after discontinuation of fusidic acid treatment. In patients for whom systemic fusidic acid is considered necessary, statin therapy should be discontinued for the entire duration of fusidic acid treatment. Cases of rhabdomyolysis (including several fatal cases) have been reported in patients receiving concomitant fusidic acid and statins (see section "Interaction with other medicinal products and other forms of interaction").

Patients should be advised to seek immediate medical attention if they experience any symptoms of muscle weakness, pain, or tenderness. Statin therapy may be restarted 7 days after the last dose of fusidic acid. In exceptional cases where prolonged systemic fusidic acid treatment is required, e.g., for treatment of severe infections, concomitant use of rosuvastatin and fusidic acid should only be considered on a case-by-case basis and under close medical supervision.

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

Severe skin adverse reactions

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

If a patient develops a serious reaction such as SJS or DRESS while taking Ozalex®, future re-initiation of rosuvastatin therapy should be avoided.

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. Rosuvastatin 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 rosuvastatin therapy.

Race

Pharmacokinetic studies indicate approximately twofold higher exposure in Mongoloid race patients compared to Caucasians (see sections "Pharmacokinetics", "Contraindications", and "Posology and method of 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 in HIV patients receiving protease inhibitors and the potential for increased plasma concentrations of rosuvastatin at the initiation of therapy and with dose escalation should be considered. Concomitant use of the medicinal product with certain protease inhibitors is not recommended unless the rosuvastatin dose is adjusted (see sections "Interaction with other medicinal products and other forms of interaction" and "Posology and method of administration").

Interstitial lung disease

Rare cases of interstitial lung disease have been reported during therapy with some statins, particularly with long-term treatment (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 in some patients at high risk of future diabetes may lead to hyperglycemia requiring treatment. However, this risk is outweighed by the reduction in vascular risk with statin use and should not be a reason to discontinue 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 between 5.6 and 6.9 mmol/L.

Children

Assessment of linear growth (height), body weight, BMI, and sexual maturation (Tanner stages) in children aged 6 to 17 years taking 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").

Myasthenia gravis/ocular myasthenia

Several cases of de novo occurrence or exacerbation of existing myasthenia gravis or ocular myasthenia have been reported with statin use (see section "Adverse reactions"). Ozalex® should be discontinued if symptoms worsen. Recurrences have been reported upon re-exposure to the same or another statin.

Excipients

The product contains lactose. If the patient has known intolerance to certain sugars, consultation with a physician is recommended before taking this medicinal product.

Use during pregnancy or breastfeeding

Rosuvastatin is contraindicated during pregnancy and breastfeeding.

Women of childbearing potential must 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 medicinal product during pregnancy. Animal studies on reproductive toxicity are limited. If a patient becomes pregnant while taking this medicinal product, treatment should be discontinued immediately.

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

Ability to influence the speed of reactions while 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 medicinal product, it is unlikely that rosuvastatin would affect such ability. Dizziness may occur during treatment, and this should be considered when driving or operating machinery.

Method of Administration and Dosage

Before initiating treatment, patients should be placed on a standard hypocholesterolemic diet, which should be maintained throughout the treatment period. The dosage should be individually adjusted based on the therapeutic goal and the patient's response to treatment, in accordance with current accepted guidelines.

The medicinal product Ozalex® can be taken at any time of day, independent 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 switched from another HMG-CoA reductase inhibitor.

*Since the tablet is not divisible, when prescribing a dose lower than 10 mg, rosuvastatin-containing products allowing such dosing should be used.

The initial dose selection should consider the individual patient's cholesterol levels, future cardiovascular risk, and the likelihood of adverse reactions. If necessary, the dose may be increased to the next level 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 maximum dose of 40 mg should only be titrated in patients with severe hypercholesterolemia and high cardiovascular risk (particularly in patients 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"). Specialized supervision is recommended when initiating treatment with the 40 mg dose.

Prevention of Cardiovascular Disorders

In cardiovascular risk reduction studies, the medicinal product was administered at a dose of 20 mg once 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.

*Since the tablet is not divisible, when prescribing a dose lower than 10 mg, rosuvastatin-containing products allowing such dosing should be used.

Patients with Renal Impairment

Dose adjustment is not required in patients with mild or moderate renal dysfunction.

The recommended initial dose for patients with moderate renal impairment (creatinine clearance <60 mL/min) is 5* mg.

*Since the tablet is not divisible, when prescribing a dose lower than 10 mg, rosuvastatin-containing products allowing such dos游戏副本 should be used.

The 40 mg dose is contraindicated in patients with moderate renal impairment. The use of Ozalex® is contraindicated in any dosage in patients with severe renal impairment (see sections "Pharmacokinetics" and "Contraindications").

Patients with Hepatic Impairment

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

Race

Increased systemic exposure to the medicinal product 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 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 rosuvastatin exposure (see section "Pharmacokinetics"). Patients known to have such polymorphism types are recommended to receive a lower daily dose of Ozalex®.

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").

*Since the tablet is not divisible, when prescribing a dose lower than 10 mg, rosuvastatin-containing products allowing such dosing should be used.

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 Ozalex® 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 whenever possible, and temporary interruption of Ozalex® therapy may be necessary. If concomitant use of these medicinal products with Ozalex® cannot be avoided, the benefit-risk balance should be carefully evaluated, and the dose of Ozalex® should be appropriately adjusted (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.

*Since the tablet is not divisible, when prescribing a dose lower than 10 mg, rosuvastatin-containing products allowing such dosing should be used.

• 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.

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

Homozogous 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. The dose may be increased up to the maximum of 20 mg once daily according to the individual child's response to treatment and drug tolerability, following recommendations for pediatric treatment (see section "Special Warnings and Precautions for Use"). Before initiating rosuvastatin therapy, children and adolescents should be placed on a standard hypocholesterolemic diet, which should be maintained throughout treatment.

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

Tablets of 40 mg are not 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, Ozalex® 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 necessary. Liver function and CK levels should be monitored. Hemodialysis is unlikely to be effective.

Adverse reactions.

The frequency category is defined as follows: very common (≥ 1/10); common (≥ 1/100 – < 1/10); uncommon (≥ 1/1000 – < 1/100); rare (≥ 1/10,000 – < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from the available data).

Blood and lymphatic system disorders: rare – thrombocytopenia.

Immune system disorders: rare – hypersensitivity reactions, including angioedema.

Endocrine disorders: common – diabetes*.

Psychiatric disorders: frequency not known – depression.

Nervous system disorders: common – headache, dizziness; very rare – polyneuropathy, memory loss; frequency not known – peripheral neuropathy, sleep disorders (including insomnia and night terrors), myasthenia gravis.

Eye disorders.

Not known: ocular myasthenia.

Respiratory, thoracic and mediastinal disorders: frequency not known – cough, dyspnoea.

Gastrointestinal disorders: common – constipation, nausea, abdominal pain; rare – pancreatitis; frequency not known – diarrhoea.

Hepatobiliary disorders: rare – increased levels of liver transaminases; very rare – jaundice, hepatitis.

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: common – myalgia; rare – myopathy (including myositis), rhabdomyolysis, lupus-like syndrome, muscle rupture; very rare – arthralgia; frequency not known – tendon disorders, sometimes complicated by ruptures, immune-mediated necrotizing myopathy.

Renal and urinary disorders: very rare – haematuria.

Reproductive system and breast disorders: very rare – gynaecomastia.

General disorders and administration site conditions: common – asthenia; frequency not known – oedema.

*Frequency depends on the presence of risk factors (fasting glucose level ≥ 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 traces to ++ or higher were observed in < 1 % of patients intermittently during treatment with 10 mg and 20 mg doses, and in approximately 3 % of patients receiving the 40 mg dose. A slight increase in the frequency of changes from zero or traces to + was observed at the 20 mg dose. In most cases, proteinuria decreased or resolved spontaneously while continuing therapy. Clinical studies and post-marketing surveillance data have not established a causal relationship between proteinuria and acute or progressive kidney disease.

Cases of haematuria have been reported during rosuvastatin treatment, although the frequency was low according to clinical trial data.

Musculoskeletal effects

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

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

Hepatic effects

As with other HMG-CoA reductase inhibitors, a small number of patients treated with rosuvastatin have experienced dose-dependent increases in transaminase levels; in most cases, this effect was mild, asymptomatic, and transient.

With the use of some statins, the following adverse reactions have been reported: sexual dysfunction, isolated cases of interstitial lung disease, particularly with long-term use (see section "Special precautions").

The frequency of reports of rhabdomyolysis and serious renal and hepatic adverse reactions (mainly increased hepatic transaminase activity) is higher when the drug is administered at a dose of 40 mg.

Paediatric population

Elevated 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 a 52-week clinical 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 of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C.

Keep out of the reach and sight of children.

Packaging.

10 mg tablets: 14 tablets in a blister. 2 or 6 blisters in a cardboard pack.

20 mg and 40 mg tablets: 14 tablets in a blister. 2 blisters in a cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

LLC "KUSUM PHARM" (for 10 mg, 20 mg, 40 mg dosages).

Manufacturer's address and place of business.

40020, Ukraine, Sumy region, Sumy city, Skryabina Street, 54.

or

Manufacturer.

LLC "GLEDPHARM LTD" (for 10 mg, 20 mg dosages).

Manufacturer's address and place of business.

40020, Ukraine, Sumy region, Sumy city, Davydovskoho Hryhoriia Street, 54.