Rosuvastatin-teva

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Rosuvastatin-Teva

Composition:

Active substance: rosuvastatin (as rosuvastatin calcium);

One film-coated tablet contains rosuvastatin 5 mg or 10 mg or 20 mg as rosuvastatin calcium 5.21 mg or 10.42 mg or 20.83 mg, respectively.

Excipients:

Core: microcrystalline cellulose (Type 102), lactose monohydrate, crospovidone (Type B), hydroxypropylcellulose, sodium hydrogencarbonate, magnesium stearate;

Film coating:

5 mg tablets: lactose monohydrate, hypromellose 2910/6cP, titanium dioxide (E 171), triacetin, iron oxide yellow (E 172);

10 mg and 20 mg tablets: lactose monohydrate, hypromellose 2910/6cP, titanium dioxide (E 171), triacetin, iron oxide red (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

5 mg tablets: yellow, round, biconvex, film-coated tablets, embossed with "5" on one side and smooth on the other side;

10 mg tablets: pink, round, biconvex, film-coated tablets, with a break line on one side and embossed with "10" on the other side;

20 mg tablets: pink, round, biconvex, film-coated tablets, with a break line on one side and embossed with "20" on the other side.

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 (CH). The primary site of action of rosuvastatin is the liver, the target organ for reducing cholesterol levels.

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

Pharmacodynamic effects. Rosuvastatin lowers elevated LDL-cholesterol (LDL-C), total cholesterol (TC), and triglyceride (TG) levels, and increases HDL-cholesterol (HDL-C) levels. It also reduces levels of apolipoprotein B (apoB), non-HDL-C, LDL-C, VLDL-TG, and increases apolipoprotein A-I (apoA-I) levels (Table 1). Rosuvastatin also reduces the ratios of LDL-C/HDL-C, total cholesterol/HDL-C, non-HDL-C/HDL-C, and apoB/apoA-I.

Table 1

Dose response in patients with primary hypercholesterolemia type IIa and IIb

(adjusted mean percent change from baseline)

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

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

Pharmacokinetics.

Absorption. Maximum plasma concentration 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 clearance of LDL-C. 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 rosuvast inflamm is a weak substrate for cytochrome P450 enzyme-based metabolism. The main isoenzyme involved is CYP2C9, with a lesser role played by 2C19, 3A4, and 2D6. 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 active substance), 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%). Hepatic uptake of rosuvastatin, as with other HMG-CoA reductase inhibitors, occurs via the membrane transporter OATP-C, which plays an important role in hepatic elimination of rosuvastatin.

Linearity. Systemic exposure to rosuvastatin increases proportionally with dose. With repeated daily administration, pharmacokinetic parameters do not change.

Age and sex. No clinically significant effect of age or sex on the pharmacokinetics of rosuvastatin in adults has been observed. The pharmacokinetics of rosuvastatin in children and adolescents with heterozygous familial hypercholesterolemia were similar to those in adult volunteers.

Racial origin. 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 in 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 of patients with varying degrees of hepatic impairment, no evidence of increased rosuvastatin exposure was observed in patients with a Child-Pugh score of 7 or less. However, in two patients with a Child-Pugh score of 8 and 9, systemic exposure 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 distribution of HMG-CoA reductase inhibitors, including rosuvastatin, involves transport proteins OATP1B1 and BCRP. Patients with genetic polymorphisms in SLCO1B1 (OATP1B1) and/or ABCG2 (BCRP) are at risk of increased rosuvastatin exposure. With 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 receive a lower daily dose of the drug.

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 dose- and duration-dependent and predictable over more than 2 years of observation.

Clinical characteristics.

Indications.

Treatment of hypercholesterolemia

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

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

Prevention of cardiovascular disorders

Prevention of major cardiovascular events in patients estimated to be at high risk of a first cardiovascular event (see section "Pharmacodynamics"), as an adjunct to correction of other risk factors.

Contraindications.

Rosuvastatin-Teva is contraindicated:

• in patients with hypersensitivity to rosuvastatin or any of the excipients of the medicinal product;
• in patients with active liver disease, including liver disease of unknown etiology, persistent elevations of serum transaminases, and any elevations of serum transaminases that are 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;
• 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 predisposition to myopathy/rhabdomyolysis. Risk factors for such predisposition include: moderate renal impairment (creatinine clearance < 60 mL/min), hypothyroidism, personal or family history of hereditary muscle disorders, history of myotoxicity with other HMG-CoA reductase inhibitors or fibrates, alcohol abuse, conditions that may lead to increased plasma concentration of the drug, Mongoloid race, and concomitant use of fibrates.

Interaction with other medicinal products and other forms of interaction.

Effect of concomitant medicinal products on rosuvastatin

Transport protein inhibitors. Rosuvastatin is a substrate for certain transport proteins, including the hepatic uptake transporter OATP1B1 and the efflux transporter BCRP. Concomitant use of rosuvastatin with medicinal products that inhibit these transport proteins may lead to increased plasma concentrations of rosuvastatin and an increased risk of myopathy.

During concomitant use of rosuvastatin and cyclosporine, rosuvastatin AUC values were on average approximately 7-fold higher than in healthy volunteers. Rosuvastatin is contraindicated in patients concurrently receiving cyclosporine. Concomitant use did not affect cyclosporine plasma concentrations.

Although the exact mechanism of interaction is unknown, concomitant use of protease inhibitors may significantly increase rosuvastatin exposure. 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 approximately 3- and 7-fold increases in rosuvastatin AUC and Cmax, respectively. Concomitant use of rosuvastatin and certain protease inhibitor combinations may be possible after careful consideration of rosuvastatin dose adjustment, due to the expected increase in exposure.

Gemfibrozil and other lipid-lowering agents. Concomitant use of rosuvastatin and gemfibrozil resulted in a 2-fold increase in rosuvastatin AUC and Cmax. Based on data from specific studies, a pharmacokinetically significant interaction with fenofibrate is not expected; however, a 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 individually.

The 40 mg dose is contraindicated when coadministered with fibrates. Such patients should also initiate therapy with a 5 mg dose.

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

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

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

Results of 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 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).

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

Interactions requiring dose adjustment of rosuvastatin

When coadministration of rosuvastatin with other medicinal products capable of increasing rosuvastatin exposure is necessary, the rosuvastatin dose should be adjusted. If a doubling or greater increase in drug exposure (AUC) is expected, rosuvastatin therapy should be initiated at a dose of 5 mg once daily. The maximum daily dose of rosuvastatin should be adjusted so that the expected exposure does not exceed that observed with a 40 mg/day dose in the absence of interacting agents; 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 a medicinal product increases rosuvastatin AUC by less than 2-fold, no initial dose reduction is required, but caution should be exercised when increasing the rosuvastatin dose above 20 mg.

Table 2

Effect of concomitant medicinal products on rosuvastatin exposure

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

Increased rosuvastatin AUC by 2-fold or more
Dosing regimen of the interacting drug	Rosuvastatin dosing regimen	Changes in rosuvastatin AUC*
Sofosbuvir/velpatasvir/voxelaprevir (400 mg-100 mg-100 mg) + voxelaprevir (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
Orthohepatvir 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 rosuvastatin AUC less than 2-fold
Dosing regimen of the interacting drug	Rosuvastatin dosing regimen	Changes in rosuvastatin AUC*
Eltrombopag 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 rosuvastatin AUC
Dosing regimen of the interacting drug	Rosuvastatin dosing regimen	Changes in rosuvastatin AUC*
Erythromycin 500 mg four times daily, 7 days	80 mg, single dose	↓ 20%
Baicalin 50 mg three times daily, 14 days	20 mg, single dose	↓ 47%

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

Increases are indicated by the symbol ↑, decreases by ↓.

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

Medicinal products/combinations that showed no clinically relevant 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; silymarin 140 mg for 5 days three times daily.

Effect of rosuvastatin on concomitant medicinal products

As with other HMG-CoA reductase inhibitors, initiation of rosuvastatin therapy or dose escalation in patients concurrently taking vitamin K antagonists (e.g., warfarin or other coumarin anticoagulants) may lead to an increased international normalized ratio (INR). Discontinuation or dose reduction of rosuvastatin may result in a decreased INR.
Appropriate monitoring of INR is recommended in such cases.

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 drug levels should be considered when selecting the dose of oral contraceptives. There are no data on the pharmacokinetics of medicinal products in patients receiving rosuvastatin and HRT simultaneously; therefore, a similar effect cannot be excluded. However, the combination has been widely used in women in clinical trials and was well tolerated.

Other medicinal products

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

Interaction studies between rosuvastatin and fusidic acid have not been conducted. The risk of developing myopathy, including rhabdomyolysis, may increase when fusidic acid is systemically co-administered with statins. The mechanism of this interaction (pharmacodynamic, pharmacokinetic, or both) is not yet known. Cases of rhabdomyolysis (including fatal cases) have been reported in patients receiving this combination. If systemic treatment with fusidic acid is necessary, rosuvastatin therapy should be discontinued for the duration of fusidic acid treatment.

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

Special Warnings and Precautions for Use.

Renal effects. Proteinuria (detected by dipstick testing), predominantly of tubular origin and mostly transient or intermittent, has been observed in patients receiving high doses of rosuvastatin, particularly 40 mg. Proteinuria was not a marker for the development of acute or progressive renal disease. The frequency of reports of serious renal adverse events in post-marketing studies is higher with the 40 mg dose. Renal function should be regularly monitored in patients receiving rosuvastatin 40 mg.

Musculoskeletal disorders (e.g., myalgia, myopathy, and rarely rhabdomyolysis) have been observed in patients taking rosuvastatin at any dose, particularly at doses exceeding 20 mg. Very rare cases of rhabdomyolysis have been reported with the use of ezetimibe in combination with HMG-CoA reductase inhibitors. A pharmacodynamic interaction cannot be ruled out; 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 (CK) levels should not be measured following significant physical exertion or in the presence of other potential causes of elevated CK levels, as this may complicate interpretation of results.

If baseline CK levels are markedly elevated (> 5 × ULN), repeat testing should be performed within 5–7 days to confirm the results. If repeat testing confirms a baseline CK level > 5 × ULN, treatment with rosuvastatin should not be initiated.

Before initiating therapy. As with other HMG-CoA reductase inhibitors, rosuvastatin 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, age > 70 years, alcohol abuse, conditions that may increase plasma levels of the drug, and concomitant use of fibrates. In such patients, the risks associated with treatment should be weighed against the expected benefits; 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 any unexplained muscle pain, weakness, or cramps, especially if accompanied by malaise or fever. In such patients, CK levels should be measured. The drug should be discontinued if CK levels are markedly elevated (> 5 × ULN) or if muscle symptoms are severe and cause daily discomfort (even if CK levels ≤ 5 × ULN). If symptoms resolve and CK levels return to normal, therapy with rosuvastatin 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 CK levels that persist even after discontinuation of statin therapy.

Clinical studies have not shown increased musculoskeletal effects in a small number of patients taking rosuvastatin with concomitant medications. However, increased incidence of myositis and myopathy has been observed in patients taking other HMG-CoA reductase inhibitors concomitantly with fibric acid derivatives, including gemfibrozil, cyclosporine, 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, the 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.

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 duration of fusidic acid treatment. Cases of rhabdomyolysis (including fatal cases) have been reported in patients receiving fusidic acid and statins concomitantly. Patients should seek immediate medical advice 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 individual cases where prolonged systemic fusidic acid therapy is required (e.g., for treatment of severe infections), the need for concomitant use of rosuvastatin and fusidic acid should be considered only on an individual basis and under close medical supervision.

Rosuvastatin should not be administered to patients with acute, serious conditions that may indicate myopathy or risk of renal failure due to rhabdomyolysis (such as sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine, or electrolyte disturbances, or uncontrolled seizures).

Myasthenia gravis, ocular myasthenia. There have been several reports of statins causing de novo myasthenia gravis or exacerbating pre-existing myasthenia gravis or ocular myasthenia. If symptoms worsen, the drug should be discontinued. Recurrences have been reported upon re-exposure to the same or another statin.

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. It is recommended to assess liver function tests before initiating therapy 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 adverse 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 that exposure in Mongoloid race patients is approximately twice that in Caucasians.

Protease inhibitors. Increased systemic exposure to rosuvastatin has been observed in patients receiving rosuvastatin concomitantly with various protease inhibitors in combination with ritonavir. Both the benefit of lipid-lowering with rosuvastatin in HIV-infected patients receiving protease inhibitors and the potential for increased plasma levels of rosuvastatin at the start of therapy and during dose titration should be considered. Concomitant use of the drug with protease inhibitors is not recommended unless the rosuvastatin dose is adjusted.

Interstitial lung disease. Rare cases of interstitial lung disease have been reported during treatment with some statins, particularly with long-term use. 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 increase blood glucose levels and may induce hyperglycemia requiring treatment in some patients at high risk of developing diabetes in the future. 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.

Serious skin adverse reactions. Serious skin adverse reactions, including Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS), which may be life-threatening or fatal, have been reported with rosuvastatin. Patients prescribed rosuvastatin should be informed about the signs and symptoms of serious skin reactions and monitored closely. 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 rosuvastatin, treatment with rosuvastatin should never be resumed in that patient.

Children. Assessment of linear growth (height), body weight, BMI, and secondary sexual characteristics by Tanner staging in children aged 6 to 17 years receiving rosuvastatin is limited to a 2-year period. After 2 years of treatment, no effect on growth, body weight, BMI, or sexual maturation was observed.

In a clinical study in children and adolescents receiving 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.

This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet, i.e., essentially "sodium-free."

Use during pregnancy or breastfeeding.

Rosuvastatin-Teva 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 drug during pregnancy. Animal reproductive toxicity data 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 the drug in human breast milk.

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. Given its pharmacodynamic properties, rosuvastatin is unlikely to affect this ability. However, when driving or operating machinery, the possibility of dizziness during treatment should be considered.

Dosage and Administration

Before initiating treatment, patients should be placed on a standard cholesterol-lowering diet, which should be continued throughout treatment. The dosage should be individualized according to therapeutic goals and the patient's response to treatment, following current generally accepted guidelines.

Rosuvastatin-Teva may 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 choice of initial dose should take into account individual patient 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. Since adverse reactions occur more frequently with the 40 mg dose than with lower doses, dose titration to 40 mg should be reserved only for 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. Specialist supervision is recommended when initiating treatment with the 40 mg dose.

Cardiovascular Risk Prevention

In a cardiovascular risk reduction study, the drug was administered at a dose of 20 mg once daily.

Elderly Patients. The recommended initial dose for patients aged >70 years is 5 mg. No other dose adjustment based on age is required.

For patients with mild or moderate renal impairment, no dose adjustment is required. 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.

In patients with hepatic impairment scoring 7 or less on the Child-Pugh scale, no increase in systemic exposure to rosuvastatin has been observed. However, in patients scoring 8 or 9 on the Child-Pugh scale, systemic exposure increases. Renal function assessment is advisable in such patients. Experience with the drug in patients with hepatic impairment exceeding 9 points on the Child-Pugh scale is lacking. Rosuvastatin is contraindicated in patients with active liver disease.

Race. Increased systemic exposure to the drug has been observed in patients of Mongoloid race. The recommended initial dose for patients of Mongoloid origin is 5 mg; the 40 mg dose is contraindicated in these patients.

Certain types of genetic polymorphism may lead to increased rosuvastatin exposure. Patients known to have such polymorphisms should be prescribed a lower daily dose of rosuvastatin.

Patients at Risk of Myopathy. The recommended initial dose for patients with risk factors for myopathy is 5 mg. The 40 mg dose is contraindicated in some of these patients (see section "Contraindications").

Concomitant Use. Rosuvastatin is a substrate for various transporter proteins (e.g., OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) increases when rosuvastatin is coadministered with certain drugs that may increase its plasma concentration due to interactions with these transporter proteins (e.g., cyclosporine and certain protease inhibitors, including ritonavir combinations with atazanavir, lopinavir, and/or tipranavir). Alternative therapies should be considered whenever possible, and rosuvastatin therapy should be temporarily discontinued if necessary. If concomitant use of these drugs with rosuvastatin cannot be avoided, the benefit and risk of concomitant use should be carefully weighed, and the rosuvastatin dose should be selected with caution.

Children.

The use of this 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 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.

The dose should be adjusted according to the individual child's response to treatment and tolerability, following recommendations for pediatric treatment. Before initiating rosuvastatin therapy, children and adolescents should be placed on a standard cholesterol-lowering diet, which should be maintained throughout treatment.

Homoyzgous Familial Hypercholesterolemia

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

The recommended initial dose is 5 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 the individual child's response to treatment and tolerability, following recommendations for pediatric treatment. Before initiating rosuvastatin therapy, children and adolescents should be placed on a standard cholesterol-lowering diet, which should be maintained throughout treatment.

Experience with this population at doses exceeding 20 mg is limited. The 40 mg tablets should not be used in children.

Children under 6 years of age

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

Adverse reactions

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

Below is the adverse reaction profile of rosuvastatin based on data from clinical trials and extensive post-marketing experience. Adverse reactions are classified by frequency and organ systems. Frequencies are defined as follows: common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), and not known (cannot be estimated from available data).

Blood and lymphatic system disorders.
Rare: thrombocytopenia.

Immune system disorders.
Rare: hypersensitivity reactions, including angioedema.

Endocrine disorders.
Common: diabetes mellitus^1.

Psychiatric disorders.
Not known: depression.

Nervous system disorders.
Common: headache, dizziness.
Very rare: polyneuropathy, memory loss.
Not known: peripheral neuropathy, sleep disorders (including insomnia and nightmares), myasthenia gravis.

Eye disorders.
Not known: ocular myasthenia.

Respiratory, thoracic and mediastinal disorders.
Not known: cough, dyspnea.

Gastrointestinal disorders.
Common: constipation, nausea, abdominal pain.
Rare: pancreatitis.
Not known: diarrhea.

Hepatobiliary disorders.
Rare: increased levels of liver transaminases.
Very rare: jaundice, hepatitis.

Skin and subcutaneous tissue disorders.
Uncommon: pruritus, rash, urticaria.
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 ruptures.
Very rare: arthralgia.
Not known: tendon disorders, sometimes complicated by ruptures, immune-mediated necrotizing myopathy.

Renal and urinary disorders.
Very rare: hematuria.

Reproductive system and breast disorders.
Very rare: gynecomastia.

General disorders and administration site conditions.
Common: asthenia.
Not known: edema.

^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 incidence of adverse reactions tends to be dose-dependent.

Renal effects.
Proteinuria detected by dipstick testing, predominantly of tubular origin, has been observed in patients treated with rosuvastatin. Changes in urinary protein content from negative or trace 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 negative or trace to + was observed at the 20 mg dose. In most cases, proteinuria decreased or resolved spontaneously while continuing therapy. Based on clinical trial and post-marketing data, no causal relationship has been established between proteinuria and acute or progressive kidney disease. Cases of hematuria have been reported during rosuvastatin treatment; according to available data, the frequency is low.

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

Dose-dependent increases in creatine kinase (CK) levels have been observed in patients taking rosuvastatin. In most cases, this was mild, asymptomatic, and transient. If CK levels are elevated (> 5 × ULN), treatment should be discontinued.

Hepatic effects.
As with other HMG-CoA reductase inhibitors, a dose-dependent increase in transaminase levels has been observed in a small number of patients receiving rosuvastatin. In most cases, this was mild, asymptomatic, and transient.

With some statins, sexual dysfunction and isolated cases of interstitial lung disease, particularly with long-term use, have been reported. The frequency of reports of rhabdomyolysis, serious renal and hepatic disorders (mainly increased hepatic transaminase activity) is higher with rosuvastatin 40 mg.

Pediatric population.
Elevated CK levels > 10 × ULN 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. However, the safety profile of rosuvastatin in children and adolescents was similar to that in adults.

Reporting suspected adverse reactions.
All suspected adverse reactions and lack of drug efficacy should be reported via the following link: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 25 °C. Keep out of reach of children.

Packaging. 10 tablets per blister; 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. TEVA PHARMA S.L.U.

Manufacturer's address and place of business.
Poligono Industrial Malpica s/C No. 4, 50016, Zaragoza, Spain.