Rosuvastatin

APPROVED

by the Order of the Ministry of Health of Ukraine

11.11.2020 No. 2595

Marketing Authorization

No. UA/18441/01/01

No. UA/18441/01/02

PACKAGE LEAFLET

for medical use of a medicinal product

ROSUVASTATIN-DARNITSA

Qualitative and quantitative composition:

active substance: rosuvastatin;

1 tablet contains rosuvastatin 10 mg in the form of rosuvastatin calcium 10.40 mg or rosuvastatin 20 mg in the form of rosuvastatin calcium 20.80 mg;

List of excipients: lactose monohydrate, microcrystalline cellulose, calcium hydrogen phosphate, crospovidone, povidone, magnesium stearate, opadray II 85F pink.

Pharmaceutical form.Film-coated tablets.

Main physical and chemical properties: pink film-coated round tablets with a biconvex surface.

Pharmacotherapeutic group. Lipid modifying agents, plain.

HMG-CoA reductase inhibitors. Rosuvastatin. ATC code С10А А07.

Pharmacological properties.

Pharmacodynamic properties.

Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, an enzyme that determines the rate of reaction and converts 3-hydroxy-3-methylglutaryl coenzyme A into mevalonate, a precursor of cholesterol. The main site of action of rosuvastatin is the liver: a target organ for lowering 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 lipoprotein (VLDL), thus reducing the total number of VLDL and LDL particles.

The medicinal product reduces the elevated levels of LDL cholesterol (LDL-C), total cholesterol and triglycerides (TG) and increases the level of high-density lipoprotein cholesterol (HDL-C). It also reduces the level of alipoprotein B (apoB), non-HDL-C, HDL-C, TG-LDL and increases the level of alipoprotein A-1 (apoA-I), the corresponding data are shown in Table 1.

The medicinal product also reduces the ratio of LDL-C/HDL-C, total cholesterol/HDL-C, non-HDL-C/HDL-C and the apoV/apoA-I ratio.

Dose response in patients with primary hypercholesterolemia type IIa and IIb

(Corrected the average change from baseline)

Table 1

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

The therapeutic effect is achieved within 1 week after the start of the medicinal product administration, 90% of the maximum effect - after 2 weeks. The maximum effect is usually achieved after 4 weeks and continues further.

Pharmacokinetic properties.

Absorption

The maximum concentration of rosuvastatin in blood plasma (C_max) is reached approximately 5 hours after oral administration. The absolute bioavailability is approximately 20%.

Distribution

Rosuvastatin is largely taken up by the liver, which is the main site of cholesterol synthesis and LDL cholesterol clearance. The volume of distribution of rosuvastatin is approximately 134 L. About 90% of rosuvastatin is bound to plasma proteins, mainly albumin.

Metabolism

Rosuvastatin is slightly metabolized (approximately 10 %). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a weak substrate for cytochrome P450-based metabolism. The main isoenzyme involved is CYP2C9, with 2C19, 3A4 and 2D6 playing a slightly smaller role. The major metabolites identified are the N-desmethyl and lactone metabolites. The N-desmethyl metabolite is approximately 50% less active than rosuvastatin, the lactone metabolite is considered clinically inactive. Rosuvastatin accounts for more than 90% of the activity of the circulating inhibitor of HMG-CoA reductase.

Excretion

Approximately 90% of the dose of rosuvastatin is excreted unchanged in the faeces (combined with the absorbed and unabsorbed active substance), and the remainder is excreted in the urine. Approximately 5 % is excreted by the kidneys unchanged. The plasma half-life is approximately 19 hours and does not increase with increasing dose. The geometric mean clearance of the medicinal product from blood plasma is approximately 50 l/h (coefficient of variation - 21.7 %). As with the use of other HMG-CoA reductase inhibitors, hepatic uptake of rosuvastatin is mediated by the OATP-C membrane transporter, which plays an important role in hepatic elimination of rosuvastatin.

Linearity.

The systemic exposure of rosuvastatin increases in proportion to the dose. With repeated daily use, the pharmacokinetic parameters do not change.

Special groups of patients

Age and gender

There is no clinically significant effect of age or gender on the pharmacokinetics of rosuvastatin in adults. The pharmacokinetics of rosuvastatin in children and adolescents with heterozygous familial hypercholesterolemia were similar to the pharmacokinetics in adult volunteers (see section “Children”).

Race

Pharmacokinetic studies have found that patients in the Mongoloid race (Japanese, Chinese, Filipinos, Vietnamese, and Koreans) have a median area under the concentration-time curve (AUC) and C_max approximately twice as high as in Caucasians; in Hindus, the median values of AUC and C_max are increased approximately 1.3 times. Population pharmacokinetic analysis did not reveal a clinically significant difference between patients of Caucasian and Negroid races.

Impaired renal function

In a study involving patients with varying degrees of impaired renal function, there were no changes in plasma concentrations of rosuvastatin or N-desmethyl metabolite in people 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 N-desmethyl metabolite levels were 9 times higher than in healthy volunteers. The equilibrium plasma concentrations of rosuvastatin in hemodialysis patients were approximately 50 % higher than in healthy volunteers.

Patients with hepatic failure

In patients with varying degrees of liver failure with a score of 7 and below on the Child-Pugh scale, no increase in the half-life of rosuvastatin was detected. However, in patients with scores of 8 and 9 points on the Child-Pugh scale, an elongation of the half-life was observed by about 2 times compared with the same indicator in patients with low indicators on the Child-Pugh scale. There is no experience with the use of rosuvastatin in patients with a score above 9 on the Child-Pugh scale.

Genetic polymorphism

The distribution of HMG-CoA reductase inhibitors, including rosuvastatin, is mediated by OATP1B1 and BCRP transport proteins. Patients with SLCO1B1 (OATP1B1) and / or ABCG2 (BCRP) genetic polymorphism are at risk of increased rosuvastatin exposure (AUC). In some cases of SLCO1B1 p.521CC and ABCG2 p.421AA polymorphisms, rosuvastatin exposure is increased compared to SLCO1B1 p.521TT or ABCG2 p.421CC genotypes. Special genotyping is not provided in clinical practice, but patients with such polymorphism are recommended to use a lower daily dose of the medicinal product.

Children

Pharmacokinetic parameters in children aged 10 to 17 years with heterozygous familial hypercholesterolemia have not been fully determined. A small study of the pharmacokinetics of rosuvastatin (in tablet form) in 18 pediatric patients showed that the AUC of the medicinal product in children was similar to the AUC in adult patients. The results also indicate that significant dose-proportional deviations are not expected.

Clinical particulars.

Therapeutic indications.

Treatment of hypercholesterolaemia

Adults and children over 10 years of age with primary hypercholesterolemia (type IIa, including heterozygous familial hypercholesterolemia) or mixed dyslipidemia (type IIb) as an adjunct to the diet when adhering to a diet and using other non-pharmacological agents (for example, exercise, weight loss) is insufficient.

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 Events

Prevention of significant cardiovascular disorder in patients at high risk for a first cardiovascular event, in addition to correcting other risk factors.

Contraindications.

- Hypersensitivity to rosuvastatin or to any other component of the medicinal product;

- liver disease in the active phase, among which a steady increase in serum transaminases of unknown etiology and any increase in serum transaminases that is 3 times higher than the upper limit of normal;

- severe renal impairment (creatinine clearance <30 ml/min);

- myopathy;

- concomitant use with cyclosporine;

- during pregnancy or lactation. The medicinal product is contraindicated in women of reproductive age who are not using proper contraception.

A dose of 40 mg is contraindicated in patients with a tendency to myopathy/rhabdomyolysis. Risk factors may include:

- moderate renal dysfunction (creatinine clearance <60 ml/min);

- hypothyroidism;

- an individual or family history of hereditary muscle diseases;

- a history of myotoxicity caused by the use of other inhibitors of HMG-CoA reductase or fibrates;

- alcohol abuse;

- situations that may lead to an increase plasma concentration of rosuvastatin;

- belonging of patients to the Mongoloid race;

- Concomitant use of fibrates (see sections "Interaction with other medicinal products and other forms of interaction", "Special warnings and precautions for use.").

Interaction with other medicinal products and other forms of interaction.

The effect of other medicinal products on rosuvastatin

Transport protein inhibitors

Rosuvastatin is a substrate for several transport proteins, including the hepatic OATP1B1 uptake transporter and the BCRP efflux transporter. Concomitant use of the medicinal product with medicinal product that inhibit these transport proteins can lead to an increase plasma concentration of rosuvastatin and an increase in the risk of myopathy (see sections "Interaction with other medicinal products and other forms of interaction", "Special warnings and precautions for use", "Posology and method of administration", see Table 2).

Cyclosporine

During the period of concomitant use, the AUC value of rosuvastatin was, on average, about 7 times higher than those observed in healthy volunteers (see Table 2). The medicinal product is contraindicated in patients taking concomitant cyclosporine (see section "Contraindications"). Concomitant use did not affect the concentration of cyclosporine in blood plasma.

Protease inhibitors

Although the exact mechanism of interaction is unknown, concomitant use of protease inhibitors can significantly increase the AUC of rosuvastatin (see Table 2). For example, in a pharmacokinetic study, co-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 an increase in the AUC and Cmax of rosuvastatin by about 3 and 7 times, respectively. Concomitant use of the medicinal product and some combinations of protease inhibitors is possible after careful consideration of dose adjustment of the medicinal product, taking into account the expected increase in the AUC of rosuvastatin (see sections "Interaction with other medicinal products and other forms of interaction", "Special warnings and precautions for use", "Posology and method of administration", see Table 2).

Gemfibrozil and other lipid-lowering medicinal products

Co-administration of rosuvastatin and gemfibrozil led to a 2 times increase in the AUC and C_max of rosuvastatin (see section "Special warnings and precautions for use").

According to special studies, no pharmacokinetically significant interaction with fenofibrate is expected, but a pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, and other fibrates (≥ 1 g/day) increase the risk of myopathy when co-administered with HMG-CoA reductase inhibitors. The dose of 40 mg is contraindicated in concomitant use of fibrates (see sections "Contraindications" and "Special warnings and precautions for use"). Such patients should also start therapy with a dose of 5 mg.

Ezetimibe

Co-administration of the medicinal product at a dose of 10 mg and ezetimibe 10 mg in patients with hypercholesterolemia led to an increase in the AUC of rosuvastatin by 1.2 times (see Table 2). A pharmacodynamic interactions between rosuvastatin and ezetimibe, which can lead to adverse effects, cannot be ruled out (see section "Special warnings and precautions for use”).

Antacids

Concomitant use of rosuvastatin with a suspension of an antacid medicinal product containing aluminum or magnesium hydroxide reduces the concentration of rosuvastatin in blood plasma by 50 %. This effect is less pronounced with the use of antacids 2 hours after the use of rosuvastatin. The clinical significance of this interaction has not been studied.

Erythromycin

Concomitant use of the medicinal product and erythromycin reduced the AUC of rosuvastatin by 20 % and C_max by 30 %. This interaction can be caused by increased intestinal peristalsis due to the action of erythromycin.

Cytochrome P450 enzymes

The results of in vitro and in vivo studies indicate that the medicinal product does not inhibit or stimulate cytochrome P450 isoenzymes. In addition, rosuvastatin is a weak substrate of these isoenzymes. Therefore, drug interactions as a result of P450-mediated metabolism are not expected. There were no clinically relevant interactions between rosuvastatin and fluconazole ((an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4).

Interactions requiring rosuvastatin dose adjustment

If it is necessary to use rosuvastatin with other medicinal products that can increase the AUC of rosuvastatin, the dose of the medicinal product should be adjusted. If the AUC of rosuvastatin is expected to increase by about 2 or more times, administration should be started with a dose of 5 mg once a day. The maximum daily dose of rosuvastatin should be adjusted so that the expected AUC of rosuvastatin does not exceed the AUC, which is observed when taking a dose of 40 mg/day without the use of drugs that interact with the medicinal product; for example, when used with gemfibrozil, the dose of rosuvastatin will be 20 mg ((increase in exposure by 1.9 times), when used with the combination of ritonavir/atazanavir - 10 mg (increase by 3.1 times).

Effect of other medicinal products of rosuvastatin exposure

(AUC; in descending order)

Table 2

Dosage regimen of the medicinal product that interacts with rosuvastatin	Rosuvastatin dosing regimen	Changes in AUC of rosuvastatin*
Cyclosporine from 75 mg twice a day to 200 mg twice a day, 6 months	10 mg once per day, 10 days	↑ 7.1 times
Regorafenib 160 mg once daily, 14 days	5 mg, single dose	↑ 3.8 times
Atazanavir 300 mg/ritonavir 100 mg once daily, 8 days	10 mg, single dose	↑ 3.1 times
Velpatasvir 100 mg once daily	10 mg, single dose	↑ 2.7 times
Ombitasvir 25 mg/paritaprevir 150 mg/ ritonavir 100 mg once daily/dasabuvir 400 mg twice daily, 14 days	5 mg, single dose	↑ 2.6 times
Grazoprevir 200 mg/elbasvir 50 mg once daily, 11 days	10 mg, single dose	↑ 2.3 times
Glecaprevir 400 mg/pibrentasvir 120 mg once daily, 7 days	5 mg once per day, 7 days	↑ 2.2 times
Lopinavir 400 mg/ritonavir 100 mg twice daily, 17 days	20 mg once per day, 7 days	↑ 2.1 times
Clopidogrel 300 mg, then 75 mg after 24 hours	20 mg, single dose	↑ 2 times
Gemfibrozil 600 mg twice per day, 7 days	80 mg, single dose	↑ 1.9 times
Eltrombopag 75 mg once daily, 5 days	10 mg, single dose	↑ 1.6 times
Darunavir 600 mg/ritonavir 100 mg twice daily, 7 days	10 mg once per day, 7 days	↑ 1.5 times
Tipranavir 500 mg/ritonavir 200 mg twice daily, 11 days	10 mg, single dose	↑ 1.4 times
Dronedarone 400 mg twice daily	Unknown	↑ 1.4 times
Itraconazole 200 mg once daily, 5 days	10 mg, single dose	↑ 1.4 times**
Ezetimibe 10 mg once per day, 14 days	10 mg once per day, 14 days	↑ 1.2 times**
Fosamprenavir 700 mg/ritonavir 100 mg twice daily, 8 days	10 mg, single dose	↔
Alleglitazar 0.3 mg, 7 days	40 mg, 7 days	↔
Silymarin 140 mg three times a day, 5 days	10 mg, single dose	↔
Fenofibrate 67 mg three times a day, 7 days	10 mg, 7 days	↔
Rifampicin 450 mg once per day, 7 days	20 mg, single dose	↔
Ketoconazole 200 mg twice daily, 7 days	80 mg, single dose	↔
Fluconazole 200 mg once daily, 11 days	80 mg, single dose	↔
Erythromycin 500 mg 4 times per day, 7 days	80 mg, single dose	↓ 20 %
Baikalin 50 mg three times a day, 14 days	20 mg, single dose	↓ 47 %

* Data presented as a change in x times represent the ratio between the use of rosuvastatin in combination and separately. The data presented as% change represent the% difference in terms of indicators when using rosuvastatin alone.

The increase is marked with ↑, no changes ↔, the decrease - ↓

** According to interaction studies at different doses of rosuvastatin, Table 2 shows the most significant ratio.

Effect of rosuvastatin on concomitant medicinal products

Vitamin K antagonists

As with other HMG-CoA reductase inhibitors, at the beginning of the use of the medicinal product or when its dose is increased in patients who are simultaneously taking vitamin K antagonists (for example, warfarin or other coumarin anticoagulants), an increase in the International Normalized Ratio (INR) is possible. Discontinuation of the medicinal product or reduction of its dose may lead to a decrease in the INR. In such cases, proper monitoring by the INR is recommended.

Oral contraceptives/hormone replacement therapy (HRT)

Concomitant use of the medicinal product and oral contraceptives increased the AUC of ethinyl estradiol and norgestrel by 26% and 34%, respectively. Such an increase in plasma blood levels should be taken into account when selecting the dose of oral contraceptives. There are no data on the pharmacokinetics of the medicinal products in patients receiving concomitant rosuvastatin and HRT, so a similar effect cannot be ruled out. However, the combination was widely used in women in clinical trials and was well tolerated.

Other medicinal products

Digoxin

According to interaction studies, no clinically significant interaction is expected.

Fusidic acid

The study of the interaction of rosuvastatin with fusidic acid was not carried out. The risk of myopathy, including with rhabdomyolysis, may be increased due to concomitant use of systemic fusidic acid with statins. The mechanism of this interaction (pharmacodynamic or pharmacokinetic, or both) has not yet been clarified. Cases of rhabdomyolysis (including fatal) have been reported in patients receiving this combination. If systemic use of fusidic acid is necessary, it is advisable to discontinue treatment with rosuvastatin during the entire period of treatment with fusidic acid.

Children

Interaction studies were conducted only in adults. The degree of interaction in children is unknown.

Special warnings and precautions for use.

Effects on the kidneys

Proteinuria, detected as a result of analysis by test strips and mainly of tubular origin, was observed in patients treated with high doses of rosuvastatin, including 40 mg, and in most cases was temporary or intermittent. Proteinuria was not a precursor to acute or progressive renal disease (see section “Undesirable effects”).

Renal adverse events were observed more often with a dose of 40 mg. Patients taking the 40 mg dose should have their kidney function checked regularly.

Effects on skeletal muscles

Disorders from the muscular-skeletal system, for example: myalgia, myopathy, rarely - rhabdomyolysis, were observed in patients taking rosuvastatin in any dose, especially more than 20 mg. Very rarely, cases of rhabdomyolysis have been reported with the use of ezetimibe in combination with HMG-CoA reductase inhibitors. As there is a possibility of pharmacodynamic interactions, this combination should be used with caution.

As with the use of other HMG-CoA reductase inhibitors, reports of cases of rhabdomyolysis associated with rosuvastatin occurred more often with a dose of 40 mg.

Determination of the level of creatine phosphokinase (CPK)

The CPK levels should not be measured after physical exercise or in the presence of possible alternative reasons for an increase in CPK, which can complicate the interpretation of the results. If the initial CPK level is significantly increased (> 5 times the upper limit of normal), an additional confirmatory analysis should be performed within 5-7 days. If the result of the re-analysis confirms the initial level> 5 times the upper limit of normal, treatment should not be started.

Before treatment

Rosuvastatin, like other HMG-CoA reductase inhibitors, should be used with caution in patients with factors causing the development of myopathy/rhabdomyolysis.

Such factors include:

– renal impairment;

- hypothyroidism;

- an individual or family history of hereditary muscle diseases;

- a history of myotoxicity caused by the use of other inhibitors of HMG-CoA reductase or fibrates;

- alcohol abuse;

- age> 70 years;

- situations that can lead to increased plasma levels of rosuvastatin (see sections "Pharmacokinetic properties", "Interaction with other medicinal products and other forms of interaction" and "Posology and method of administration");

- concomitant use with fibrates.

In these patients, treatment-related risk must be weighed against the expected benefit; clinical monitoring is also recommended. If the initial CPK levels are significantly increased (> 5 times the upper limit of the norm), treatment should not be started.

During the treatment period

Patients should be advised to notify their physician immediately of muscle pain, weakness, or seizures of unknown etiology, especially if they are accompanied by malaise or fever. In these patients, the CPK level should be measured. The use of the medicinal product should be discontinued if the CPK level is significantly increased (> 5 times the upper limit of normal) or if muscle symptoms are severe and cause daily discomfort (even if the CPK level is≤ 5 above the upper limit of normal). In case of disappearance of symptoms and normalization of CPK levels, therapy with rosuvastatin or an alternative inhibitor of HMG-CoA reductase in the smallest dose and under close supervision can be restored. Regular monitoring of the CPK level in patients without these symptoms is not required. Immune-mediated necrotizing myopathy (IMNM) has been reported very rarely during or after statin therapy, including rosuvastatin. The clinical manifestations of IMNM are the weakness of the proximal muscles and an increase in the level of CPK in the blood serum, which persists even after the discontinuation of statins.

In clinical studies, there was no evidence of an increased effects on skeletal muscle in a small number of patients taking rosuvastatin and concomitant medicinal products. However, an increase in the frequency of myositis and myopathy was observed in patients taking other inhibitors of HMG-CoA reductase with fibroic acid derivatives, including gemfibrozil, cyclosporine, nicotinic acid, azole antifungal medicinal products, protease inhibitors, and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when co-administered with some HMG-CoA reductase inhibitors. Therefore, it is not recommended to use rosuvastatin in combination with gemfibrozil. The beneficial effect of further changes in lipid levels while using rosuvastatin with fibrates or niacin should be compared with the potential risks when using such a combination. Concomitant use of fibrates and rosuvastatin at a dose of 40 mg is contraindicated.

Rosuvastatin should not be used concomitantly with systemic fusidic acid medicinal products or within 7 days after stopping treatment with fusidic acid. In patients in whom the use of systemic fusidic acid is considered essential, statin treatment should be discontinued for the entire duration of fusidic acid treatment. Cases of rhabdomyolysis (including fatal) have been reported in patients receiving this combination. Patients should be advised to seek immediate medical attention if they experience any symptoms of muscle weakness, pain, or tenderness. Statin therapy can be restored seven days after the last dose of fusidic acid. In exceptional cases, when prolonged systemic treatment with fusidic acid is necessary, for example, for the treatment of severe infections, the need for the simultaneous use of rosuvastatin and fusidic acid should be considered only on a case-by-case basis and under close medical supervision.

The medicinal product should not be used in patients with acute, severe conditions indicating myopathy or the possibility of developing renal failure due to rhabdomyolysis (such as sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolytic disorders or uncontrolled seizures).

Effects on the liver

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

It is recommended to check the biochemical parameters of liver function before treatment and after 3 months of treatment. The use of the medicinal product should be discontinued or the dose should be reduced if the serum transaminase level is more than three times the upper limit of normal. The frequency of reports of severe hepatic events (mainly an increase in the level of liver transaminases) is greater with a dose of 40 mg.

In patients with secondary hypercholesterolemia due to hypothyroidism or nephrotic syndrome, the underlying disease should be treated first before starting rosuvastatin therapy.

Rarely, fatal or non-fatal cases of liver failure have been reported in patients taking statins, including rosuvastatin. If, during treatment with rosuvastatin, serious liver damage with clinical symptoms and / or hyperbilirubinemia or jaundice develops, the use of rosuvastatin should be discontinued immediately. Unless other causes are identified, treatment with rosuvastatin should not be resumed.

Race

It is known that in the course of pharmacokinetic studies, an increase in AUC was observed in patients of the Mongoloid race, approximately twice as compared with representatives of the Caucasian race. For such patients, a dose adjustment of rosuvastatin is necessary (see sections "Pharmacokinetic properties", "Contraindications" and "Posology and method of administration").

Protease inhibitors

Increased systemic exposure to rosuvastatin has been observed in individuals receiving rosuvastatin in combination with various protease inhibitors in combination with ritonavir. Consideration should be given to both the benefits of lowering lipid levels with rosuvastatin in patients with HIV who receive protease inhibitors, and the possibility of increasing the concentration of rosuvastatin in blood plasma at the beginning of therapy and when increasing the dose of the drug in patients receiving protease inhibitors. Co-administration of rosuvastatin with protease inhibitors is not recommended unless the dose has been adjusted (see sections “Interaction with other medicinal products and other forms of interaction” and “Posology and method of administration”).

Interstitial lung disease

With the use of some statins, especially with long-term treatment, exceptional cases of interstitial lung disease have been reported (see “Undesirable effects”). Presenting features can include shortness of breath, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If interstitial lung disease is suspected, statins should be discontinued.

Diabetes mellitus

There is some evidence that statins increase blood glucose levels and in some patients who are at high risk of developing diabetes in the future may cause hyperglycaemia to a level that requires appropriate diabetes treatment. This threat, however, outweighs the reduced risk of vascular disorders with statins use, so it should not be a reason to discontinue statin therapy. Clinical and biochemical monitoring should be performed in patients at risk (fasting glucose 5.6–6.9 mmol/l, body mass index (BMI)> 30 kg/m², elevated triglycerides, hypertension).

In the JUPITER study, the overall incidence of diabetes mellitus was 2.8% in the rosuvastatin group and 2.3% in the placebo group, mainly in patients with fasting glucose levels ranging from 5.6 to 6.9 mmol/L.

Children

Evaluation of linear growth (height), body weight, body mass index (BMI) and secondary characteristics of puberty according to Tanner in children aged 10 to 17 years who received rosuvastatin is limited to a period of 1 year. During this period, no effect on height, body weight, BMI or puberty was found. The experience of clinical trials in children and patients is limited, and the long-term effects of the use of rosuvastatin (> 1 year) on puberty are unknown.

In children and adolescents taking rosuvastatin, an increase in the CPK> 10 times higher than the upper limit of normal and muscle symptoms after exercise or increased physical activity were more common than in adults (see section “Undesirable effects”).

Important information about excipients.

Rosuvastatin-Darnitsa contains lactose monohydrate, so if a patient has an intolerance to certain sugars, it is necessary to consult a doctor before taking this medicinal product. It should not be used in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

Fertility, pregnancy and lactation.

The medicinal product is contraindicated during pregnancy or lactation.

Women of reproductive age need to use proper contraception.

Because cholesterol and other products of cholesterol biosynthesis play a significant role in fetal development, the potential risk of inhibiting HMG-CoA reductase outweighs the benefit of using the medicinal product during pregnancy. Data from animal studies on reproductive toxicity are limited. If a patient becomes pregnant while taking this medicine, treatment should be stopped immediately.

Because other medicinal products in this class pass into human breast milk, and given that HMG-CoA reductase inhibitors may cause serious adverse reactions in infants, women requiring rosuvastatin treatment should be advised to refrain from breast-feeding.

Rosuvastatin passes into the milk of rats. There is no data on the penetration of the medicinal product into human breast milk (see section "Contraindications").

Effects on ability to drive and use machines.

The study of the effect of rosuvastatin on the ability to drive and work with mechanisms was not carried out. However, given the pharmacodynamic properties of the medicinal product, it is unlikely that rosuvastatin will affect this ability. The possibility of dizziness during treatment with rosuvastatin should be considered when driving or operating machinery.

Posology and method of administration.

Before starting treatment, the patient should be prescribed a standard cholesterol-lowering diet, which must be followed during treatment. The dose should be selected individually depending on the goal of the therapy and the patient's response to treatment, taking into account current recommendations.

The medicinal product can be taken in a single dose at any time and regardless of food intake.

Treatment of hypercholesterolaemia

The recommended starting dose is 5 mg * or 10 mg orally once daily for both patients who have not previously taken statins and those who have been transferred to rosuvastatin from another HMG-CoA reductase inhibitor. When choosing an initial dose, should take into account the cholesterol level of each individual patient and the risk of cardiovascular disorders in the future, as well as the likelihood of adverse reactions. If necessary, the dose can be increased to the next level after 4 weeks (see section "Pharmacodynamic properties"). Considering that, against the background of the use of the medicinal product at a dose of 40 mg, adverse reactions occur more often than at lower doses (see section "Undesirable effects"), the final titration of the dose to 40 mg is only necessary for patients with severe hypercholesterolemia and a high risk of cardiovascular disorders (in particular in patients with familial hypercholesterolemia) in whom the goal of treatment was not achieved with a dose of 20 mg and who will be under regular observation (see section "Special warnings and precautions for use"). At the beginning of taking the medicinal product at a dose of 40 mg, the supervision of specialists is recommended.

Prevention of disorders of the cardiovascular system

In a study to reduce the risk of cardiovascular disorders, rosuvastatin was used at a dose of 20 mg per day.

Use in elderly patients

The recommended initial dose for patients aged> 70 years is 5 mg * (see section “Special warnings and precautions for use”). There is no need for another dose adjustment due to age.

Patients with renal impairment

No dose adjustment is required in patients with mild or moderate renal impairment.

The recommended starting dose for patients with moderate renal impairment (creatinine clearance <60 ml/min) is 5 mg *. A dose of 40 mg is contraindicated in patients with moderate renal impairment. The use of rosuvastatin in patients with severely impaired renal function is contraindicated in any dose (see sections "Contraindications" and "Pharmacokinetic properties").

Patients with hepatic impairment

In patients with impaired liver function, rated 7 or less on the Child-Pugh scale, an increase in systemic exposure of rosuvastatin was not observed. However, in individuals with Child-Pugh scores 8 and 9, the systemic exposure increased (see section “Pharmacokinetic properties”). In such patients, it is advisable to assess renal function (see section "Special warnings and precautions for use"). There is no experience of using the medicinal product in patients who scored more than 9 points on the Child-Pugh scale. Rosuvastatin is contraindicated in patients with active liver disease (see section "Contraindications").

Race

In patients of the Mongoloid race, an increased systemic exposure of the drug was observed (see sections “Pharmacokinetic properties”, “Contraindications” and “Special warnings and precautions for use”). The recommended starting dose for such patients is 5 mg*. The use of a dose of 40 mg in such patients is contraindicated.

Genetic polymorphism

Certain types of genetic polymorphism may increase in the AUC of rosuvastatin (see section “Pharmacokinetic properties”). A lower daily dose of rosuvastatin is recommended for patients with a known presence of these types of polymorphisms.

Patients with a tendency to develop of myopathy

The recommended initial dose for patients with risk factors for the development of myopathy is 5 mg * (see section “Special warnings and precautions for use”).

A dose of 40 mg is contraindicated in patients with a tendency to myopathy/rhabdomyolysis (see section "Contraindications").

Concomitant use

Rosuvastatin is a substrate for various transport proteins (e.g., OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) is increased when rosuvastatin is co-administered with certain medicinal products that can increase the plasma concentrations of rosuvastatin due to interactions with these transport proteins (e.g. cyclosporine and certain protease inhibitors, including ritonavir combinations and/or tipranavir, see sections "Special warnings and special precautions for use" and "Interaction with other medicinal products and other forms of interaction"). If possible, the use of alternative medicines should be considered and, if necessary, rosuvastatin therapy should be temporarily discontinued. If the concomitant use of these drugs with rosuvastatin cannot be avoided, the benefits and risks of concomitant use should be carefully weighed and the dose of rosuvastatin adjusted accordingly (see section “Interaction with other medicinal products and other forms of interaction”).

* Use the medicinal product in the appropriate dosage.

Children.

Prescribing the medicinal product to children should be carried out only by a specialist.

Use in children and adolescents aged 10 to 17 years (boys in stage II and above Tanner and girls in whom menstruation began at least a year ago).

The usual initial daily dose for children and adolescents with heterozygous familial hypercholesterolemia is 5 mg* per day. The medicinal product should be taken orally in doses from 5 mg* to 20 mg once a day. The dose should be increased according to the child's individual response to treatment and tolerability of the medicinal product, following the recommendations for the treatment of children (see section "Special warnings and special precautions for use"). Before starting rosuvastatin therapy, children and adolescents should be prescribed a standard cholesterol-lowering diet, which patients should follow during treatment. The safety and efficacy of using the medicinal product in doses greater than 20 mg in this population have not been studied. Dosage of 40 mg to apply to children.

Children under 10 years

Experience in the treatment of children under 10 years of age is limited. The medicinal product is not recommended for use in children under 10 years of age.

Overdose.

There is no specific treatment for overdose. Treatment is symptomatic, supportive therapy is recommended. It is necessary to monitor liver function and CPK levels. Hemodialysis is unlikely to be effective.

Undesirable effects.

Adverse events have been ranked under headings of frequency using the following convention: Very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, <1/100); rare (≥ 1/10000, <1/1000); very rare (<1/10000), frequency unknown (cannot be estimated from the available data).

Respiratory, thoracic and mediastinal disorders

Frequency unknown: cough, shortness of breath.

Gastrointestinal disorders:

common: constipation, nausea, abdominal pain;

rare: pancreatitis;

Frequency unknown: diarrhea.

Hepatobiliary disorders:

rare: increase liver transaminases;

very rare: jaundice, hepatitis.

Renal and urinary disorders:

very rare: hematuria.

Endocrine disorders:

common: diabetes mellitus (frequency depends on the presence of risk factors: fasting glucose level ≥ 5.6 mmol/l, BMI> 30 kg/m², elevated triglyceride levels, history of hypertension).

Nervous system disorders:

common: headache, dizziness;

very rare: polyneuropathy, memory loss;

Frequency unknown: peripheral neuropathy, sleep disorders (including insomnia and night terrors).

Psychiatric disorders:

Frequency unknown: depression.

Blood and lymphatic system disorders:

rare: thrombocytopenia.

Immune system disorders:

rare: hypersensitivity reactions, including angioneurotic edema.

Skin and subcutaneous tissue disorders:

uncommon: itching, rash, urticaria;

Frequency unknown: Stevens-Johnson syndrome.

Musculoskeletal and connective tissue disorders:

common: myalgia;

rare: myopathy (including myositis), rhabdomyolysis, lupus syndrome, muscle rupture;

very rare: arthralgia;

Frequency unknown: tendon disorders, sometimes complicated by ruptures, immune-mediated necrotizing myopathy.

Reproductive system and breast disorders:

very rare: gynecomastia.

General disorders and administration site conditions:

common: asthenia;

Frequency unknown: edema.

Effects on the kidneys

Proteinuria detected by test strip analysis and predominantly of tubular origin was observed in patients taking rosuvastatin. Changes in urinary protein content from zero or trace to ++ or more were observed in <1% of patients at some time points during the use of the medicinal product at doses of 10 mg and 20 mg and in about 3% at a dose of 40 mg. A small increase in the frequency of changes in content from zero or traces to the value of + was observed at a dose of 20 mg. In most cases, proteinuria decreased or disappeared spontaneously with continued therapy. According to clinical studies and post-marketing observations, no causal relationship has been established between proteinuria and acute or progressive kidney disease.

Cases of hematuria were observed against the background of use of medicinal product; according to clinical studies, its frequency was low.

Effects on skeletal muscles

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

A dose-dependent increase in CPK was observed in patients receiving rosuvastatin; in most cases, the phenomenon was mild, asymptomatic and temporary. If CPK levels are elevated (> 5 times the upper limit of normal), treatment should be discontinued (see section “Special warnings and precautions for use”).

Effects on the liver

As with other HMG-CoA reductase inhibitors, a small number of patients taking rosuvastatin had a dose-dependent increase in transaminases; in most cases, the phenomenon was mild, asymptomatic and temporary. An increase in HbA1c was also observed with rosuvastatin.

During the administration of certain statins, the following adverse events have been described:

- sexual dysfunction;

- isolated cases of interstitial lung disease, especially with prolonged use (see section "Special warnings and precautions for use").

The frequency of reports of rhabdomyolysis, severe renal and hepatic impairment (mainly increased activity of hepatic transaminases) is higher with the medicinal product at a dose of 40 mg.

Children

Elevations in CPK> 10 times the upper limit of normal and muscle symptoms after exercise or increased physical activity were more common in children and adolescents than in adults (see section "Special warnings and precautions for use"). 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 registration of a medicinal product is an important procedure. This allows for continued monitoring of the benefit/risk ratio for the respective drug. Healthcare providers should be informed of any suspected adverse reactions through the national alert system.

Shelf life. 3 years.

Special precautions for storage.

Store in the original package at a temperature below 25°C.

Keep out of the reach of children.

Nature and contents of container.

10 tablets in a blister container; 3 or 9 blister containers in a package.

Category of release.

Prescription only medicine.

Manufacturer.

PrJSC “Pharmaceutical firm “Darnitsa”.

The manufacturer's location and address of the place of business.

13, Boryspilska Street, Kyiv, 02093, Ukraine.

Date of last revision.

11.11.2020.