Crestor - instructions for use, dose, side effects, contraindications

Excipients: lactose monohydrate 89.50 mg (for a dosage of 10 mg), 179.00 (for a dosage of 20 mg), 164.72 mg (for a dosage of 40 mg); cellulose microcrystalline 29.82 mg (for a dosage of 10 mg), 59.64 mg (for a dosage of 20 mg), 54.92 mg (for a dosage of 40 mg); calcium phosphate 10.90 mg (for a dosage of 10 mg), 21.80 mg (for a dosage of 20 mg), 20.00 mg; (for a dosage of 40 mg); crospovidone 7.50 mg (for a dosage of 10 mg), 15.00 mg (for a dosage of 20 mg), 15.00 mg (for a dosage of 40 mg); magnesium stearate 1.88 mg (for a dosage of 10 mg), 3.76 mg (for a dosage of 20 mg), 3.76 mg (for a dosage of 40 mg);

tablet shell: lactose monohydrate 1.80 mg (for a dosage of 10 mg), 3.60 mg (for a dosage of 20 mg), 3.60 mg (for a dosage of 40 mg); hypromellose 1.26 mg (for a dosage of 10 mg), 2.52 mg (for a dosage of 20 mg), 2.52 mg (for a dosage of 40 mg), triacetin (glycerol triacetate) 0.36 mg (for a dosage of 10 mg) , 0.72 mg (for a dosage of 20 mg), 0.72 mg (for a dosage of 40 mg); titanium dioxide 1.06 mg (for a dosage of 10 mg),2.11 mg (for a dosage of 20 mg), 2.11 mg (for a dosage of 40 mg); ferric oxide red oxide 0.02 mg (for dosage, 10 mg), 0.05 mg (for a dosage of 20 mg), 0.05 mg (for a dosage of 40 mg).

Description:

Tablets 10 mg: round, biconvex tablets, covered with a pink film membrane pink, with engraving "ZD4522 10" on one side.

Tablets 20 mg: round biconvex tablets, covered with a pink film membrane, with engraving "ZD4522 20" on one side.

Tablets 40 mg: oval, biconvex tablets, covered with a pink film membrane, with engraving "ZD4522" on one side and 40 - on the other.

Pharmacotherapeutic group:Hypolipidaemic agent - HMG-CoA reductase inhibitor

ATX: & nbsp

C.10.A.A Inhibitors of HMG-CoA reductase

C.10.A.A.07 Rosuvastatin

Pharmacodynamics:

Crestor® reduces high cholesterol-LDL (cholesterol-LDL-C), total cholesterol, triglyceride (TG) concentrations, increases the concentration of high-density cholesterol (HDL-C), and also reduces the concentrations of apolipoprotein B (ApoV), CS-non-HDL, cholesterol VLDL, TG-VLDL and increases the concentration of apolipoprotein A-1 (ApoA-1) (see Tables 1 and 2), reduces the ratio of LDL-C-HDL cholesterol, total cholesterol / HDL cholesterol and non-HDL / HDL and the ratio АпоВ / АпоА-1.

Therapeutic effect develops within one week after the beginning of Krestor therapy, after 2 weeks of treatment it reaches 90% of the maximum possible effect. The maximum therapeutic effect is usually achieved by the 4th week of therapy and is maintained with regular intake of the drug.

Table 1. Dose-dependent effect in patients with primary hypercholesterolemia (type IIa and IIb according to Fredrickson) (mean adjusted percentage change compared to the baseline value).

Beforebehind	Number of patients	HS-LLNP	CommonIy HS	XC-HDL	TD	XC-non-HDL	APOP	ApA-I
Platsebo	13	-7	-5	3	-3	-7	-3	0
10 mg	17	-52	-36	14	-10	-48	-42	4
20 mg	17	-55	-40	8	-23	-51	-46	5
40 mg	18	-63	-46	10	-28	-60	-54	0

Table 2. Dose-dependent effect in patients with hypertriglyceridemia (type IV and IV according to Fredrickson) (mean percentage change compared to baseline value).

Beforebehind	Topatients	TG	HS-LLNP	General HS	HDL-C	HS-non-HDL	HS-VLDLP	TG-VLDLP
Platsebo	26	1	5	1	-3	2	2	6
10 mg	23	-37	-45	-40	8	-49	-48	-39
20 mg	27	-37	-31	-34	22	-43	-49	-40
40 mg	25	-43	-43	-40	17	-51	-56	-48

Clinical efficacy

Crestor® is effective in adult patients with hypercholesterolemia with or without hypertriglyceridemia, regardless of race, sex or age, including patients with diabetes mellitus and familial hypercholesterolemia.

In 80% of patients with Fredrickson IIa and IIb type cholesterolinemia (average baseline LDL-C concentration of about 4.8 mmol / L), when taking the drug at a dose of 10 mg, the concentration of LDL-C is less than 3 mmol / L.

In patients with heterozygous familial hypercholesterolemia, receiving Crestor® in a dose of 20-80 mg, there is a positive dynamics of lipid profile (a study involving 435 patients). After titration to a daily dose of 40 mg (12 weeks of therapy), the concentration of LDL-C is reduced by 53%. In 33% of patients the concentration of LDL-C is less than 3 mmol / l.

In patients with homozygous familial hypercholesterolemia, taking Crestor® at a dose of 20 mg and 40 mg, the average decrease in the concentration of LDL-C is 22%.

In patients with hypertriglyceridemia with an initial TG concentration of 273 to 817 mg / dl, those who received Crestor® at a dose of 5 mg to 40 mg once daily for 6 weeks were significantly reduced the concentration of TG in the blood plasma (see table 2).

The additive effect is noted in combination with fenofibrate for the concentration of triglycerides and with nicotinic acid in the lipid-lowering doses for the concentration of cholesterol-lowering cholesterol (see also the "Specific guidance" section). In the METEOR study.with the participation of 984 patients aged 45 to 70 years with a low risk of developing coronary heart disease (CHD) (a 10-year risk for the Framingham scale of less than 10%), an average LDL cholesterol concentration of 4.0 mmol / L (154.5 mg / dl ) and subclinical atherosclerosis (which was estimated by the thickness of the intima-media complex of carotid arteries - TKIM), the influence of rosuvastatin on the thickness of the intima-media complex was studied.

Patients received rosuvastatin in a dose of 40 mg / day or placebo for 2 years. Rosuvastatin therapy significantly slowed the rate of progression of the maximum TKIM for 12 segments of the carotid artery compared with placebo with a difference of -0.0145 mm / year [95% confidence interval from -0.0196 to -0.0093; p <0.001]. Compared to baseline values in the rosuvastatin group, a decrease in the maximum TKIM value by 0.0014 mm / year (0.12% / year (unreliable difference)) was observed compared to an increase of 0.0131 mm / year (1.12 % / year (p <0.001)) in the placebo group. To date, there has been no direct correlation between a decrease in TKIM and a reduction in the risk of cardiovascular events.

The METEOR trial was performed in patients with a low risk of coronary artery disease, for whom a dose of Krestor® 40 mg is not recommended.A dose of 40 mg should be used in patients with severe hypercholesterolemia and a high risk of cardiovascular disease (CVD).

The results of the JUPITER study (Justification of the use of statins for primary prevention: an interventional study evaluating rosuvastatin) in 17802 patients showed that rosuvastatin significantly reduced the risk of cardiovascular complications (252 in the placebo group compared to 142 in the rosuvastatin group) (p <0.001) with a relative risk reduction of 44%. The effectiveness of therapy was noted after the first 6 months of use. There was a statistically significant 48% reduction in the combined criterion, including death from cardiovascular causes, stroke and myocardial infarction (risk ratio: 0.52, 95%, confidence interval 0.40-0.68, p <0.001), a decrease of 54% fatal or nonfatal myocardial infarction (risk ratio: 0.46, 95%, confidence interval 0.30-0.70) and 48% fatal or nonfatal stroke. Overall mortality decreased by 20% in the rosuvastatin group (risk ratio: 0.80, 95%, confidence interval 0.67-0.97, p = 0.02). The safety profile of patients taking rosuvaetatin at a dose of 20 mg was generally similar to the safety profile in the placebo group.

Pharmacokinetics:

Absorption and distribution

The maximum concentration of rosuvastatin in the blood plasma is reached approximately 5 hours after ingestion. Absolute bioavailability is approximately 20%.

Rosuvastatin is metabolized primarily by the liver, which is the main site for the synthesis of cholesterol and the metabolism of LDL-C. The volume distribution of rosuvastatin is approximately 134 liters. Approximately 90% of rosuvastatin binds to blood plasma proteins, mainly albumin.

Metabolism

It is subject to limited metabolism (about 10%). Rosuvastatin is a non-core substrate for metabolism by enzymes of the cytochrome P450 system. The main isoenzyme involved in the metabolism of rosuvastatin is the isoenzyme СUR2С9. Isozymes СУР2С19, СУРЗА4 and СУР2Б6 are involved in metabolism to a lesser extent. The main revealed metabolites of rosuvastatin are N-desmethyl and lactone metabolites. N-desmethyl is about 50% less active than rosuvethatin, lactone metabolites are not pharmacologically active. More than 90% of the pharmacological activity of inhibiting circulating HMG-CoA reductase is provided by rosuvastatin, the rest - by its metabolites.

Excretion

About 90% of the dose of rosuvastatin is excreted unchanged through the intestine (including the absorbed and unabsorbed rosewoodctatin).

The rest is excreted by the kidneys. Plasma half-life (T1 /2) is approximately 19 hours. The half-life does not change with an increase in the dose of the drug. The average geometric plasma clearance is approximately 50 l / h (coefficient of variation 21.7%). As with other inhibitors of HMG-CoA reductase, a membrane cholesterol transporter involved in the hepatic elimination of rosuvastatin plays an important role in the hepatic elimination of rosuvastatin.

Linearity

The systemic exposure of rosuvastatin increases in proportion to the dose. Pharmacokinetic parameters do not change with daily intake.

Special populations of patients. Age and gender

Sex and age do not have a clinically significant effect on the pharmacokinetics of rosuvastatin.

Ethnic groups

Pharmacokinetic studies

showed an approximately twofold increase in the median A1_1C (area under the concentration-time curve) and Stach (maximum plasma concentration) of rosuvastatin in Asian patients (Japanese, Chinese, Filipinos,Vietnamese and Koreans) in comparison with Europeans; Indian patients showed an increase in the median AUC and Cmah 1,3 times. Pharmacokinetic analysis did not reveal clinically significant differences in pharmacokinetics among Europeans and representatives of the Negroid race.

Renal insufficiency

In patients with mild and moderate renal failure, the plasma concentration of rosuvastatin or N-desmethyl does not change significantly. In patients with severe renal failure (creatinine clearance less than 30 ml / min), the concentration of rosuvastatin in blood plasma is 3 times higher, and the concentration of N-desmethyl is 9 times higher than in healthy volunteers. The concentration of rosuvastatin in blood plasma in patients on hemodialysis was approximately 50% higher than in healthy volunteers.

Liver failure

Patients with different stages of hepatic insufficiency did not have an increase in the half-life of rosuvastatin in patients with a score of 7 or lower on the Child-Pugh scale. In two patients with scores of 8 and 9 on the Child-Pugh scale, the half-life was increased by at least 2-fold.The experience with rosuvastatin in patients with a score above 9 on the Child-Pugh scale is not available.

Genetic polymorphism

Inhibitors of HMG-CoA reductase, including Crestor®, bind to transport proteins OATP1B1 (the polypeptide for transport of organic anions involved in the capture of statins by hepatocytes) and BCRP (efflux conveyor). In carriers of genotypes SLCO1B1 (OATP1B1) FROM.521SS and ABCG2 (ВСRR) FROM.421AA there was an increase in exposure (AUC) to rosuvastatin 1.6 and 2.4 times, respectively, compared with carriers of genotypes SLCO1B1 c.521TT and ABCG2 c.421SS.

Indications:

- Primary hypercholesterolemia according to Fredrickson (type Pa, including familial heterozygous hypercholesterolemia) or mixed hypercholesterolemia (type IIb) as a supplement to the diet, when diet and other non-pharmacological methods of treatment (for example, physical exercises, weight loss) are insufficient.

- Family homozygous hypercholesterolemia as a supplement to a diet and other lipid-lowering therapy (eg, LDL-apheresis), or in cases when such therapy is not effective enough.

- Hypertriglyceridemia (type IV by Fredrickson) as a supplement to the diet.

- To slow the progression of atherosclerosis as a supplement to the diet in patients who are shown therapy to reduce the concentration of total cholesterol and LDL-C.

- Primary prevention of major cardiovascular complications (stroke, heart attack, arterial revascularization) in adult patients without clinical signs of IHD, but with an increased risk of its development (age over 50 for men and over 60 for women, increased concentration of C-reactive protein (> 2 mg / L) with at least one of additional risk factors, such as hypertension, low concentration of HDL-C, smoking, family history of early onset of coronary artery disease).

Contraindications:

For tablets 10 mg and 20 mg:

- hypersensitivity to rosuvastatin or any of the components of the drug;

- liver diseases in the active phase, including a persistent increase in serum transaminase activity and any increase in serum transaminase activity (more than 3 times the upper limit of the norm);

- severe renal dysfunction (QC less than 30 ml / min.);

- myopathy;

- simultaneous administration of cyclosporine;

- in women: pregnancy, lactation, lack of adequate methods of contraception;

- patients who are predisposed to the development of myotoxic complications;

- lactose intolerance, lactase deficiency or glucose-galactose malabsorption (the preparation contains lactose);

For tablets 40 mg:

- increased sensitivity to rosuvastatin or any of the components of the drug;

- simultaneous administration of cyclosporine;

- in women: pregnancy, lactation, lack of adequate methods of contraception;

- liver diseases in the active phase, including a persistent increase in the serum activity of transaminases and any increase in serum transaminase activity (more than 3 times the upper limit of the norm) in patients with risk factors for myopathy / rhabdomyolysis, namely:

- renal failure of moderate severity (CC less than 60 ml / min);

- hypothyroidism;

- personal or family anamnesis of muscular diseases;

- myotoxicity on the background of taking other inhibitors of HMG-CoA reductase or fibrates in the anamnesis;

- excessive use of alcohol;

- conditions that may lead to an increase in the plasma concentration of rosuvastatin;

- simultaneous reception of fibrates;

- patients of the Asian race;

- lactose intolerance, lactase deficiency or glucose-galactose malabsorption (the preparation contains lactose).

Carefully:

For tablets 10 mg and 20 mg:

The presence of a risk of myopathy / rhabdomyolysis - renal failure, hypothyroidism, personal or family history of hereditary muscle diseases and a previous history of muscle toxicity when using other inhibitors of HMG-CoA reductase or fibrates; excessive use of alcohol; age over 65; conditions in which there was an increase in the plasma concentration of rosuvastatin; race (Asian race); simultaneous appointment with fibrates (see section "Pharmacokinetics"); liver disease in history; sepsis; arterial hypotension; extensive surgical interventions, trauma, severe metabolic, endocrine or electrolyte disorders, or uncontrolled convulsive seizures.

For tablets 40 mg:

Renal insufficiency of low severity (QC more than 60 ml / min); age over 65; liver disease in history; sepsis; arterial hypotension; extensive surgical interventions, trauma, severe metabolic,endocrine or electrolyte disorders or uncontrolled convulsive seizures.

Application in pediatric practice

The effectiveness and safety of the drug in children under 18 years of age is not established. The experience of using the drug in pediatric practice is limited to a small number of children (8 years and older) with family homozygous hypercholesterolemia. Currently, it is not recommended to use Krestor® in children under 18 years of age.

Patients with hepatic insufficiency

Data or experience of the drug in patients with a score above 9 on the Child-Pugh scale is not available (see the sections "Pharmacodynamics" and "Special instructions").

Pregnancy and lactation:

Crestor® is contraindicated in pregnancy and lactation.

Women of reproductive age should apply adequate methods of contraception.

Since cholesterol and other cholesterol biosynthesis products are important for fetal development, the potential risk of HMG-CoA reductase inhibition is greater than the benefit of using the drug in pregnant women.

In case of pregnancy in the process of therapy, taking the drug should be stopped immediately.

Data on the allocation of rosuvastatin to breast milk are not available, therefore, during the period of breastfeeding, the drug should be discontinued (see "Contraindications").

Dosing and Administration:

Inside, do not chew and do not grind the tablet, swallow whole, squeezed water. The drug can be administered at any time of the day, regardless of food intake. Before starting therapy with Krestor®, the patient should begin to follow the standard hypocholesterolemic diet and continue to comply with all during treatment. The dose of the drug should be selected individually depending on the purpose of therapy and the therapeutic response to treatment, taking into account current recommendations but the target concentration of lipids.

The recommended initial dose for patients starting to take the drug, or for patients transferred from other HMG-CoA reductase inhibitors, should be 5 or 10 mg of Crestor ® once a day. When choosing the initial dose should be guided by the individual concentration of cholesterol and take into account the possible risk of cardiovascular complications,and it is also necessary to assess the potential risk of side effects. If necessary, the dose may be increased to greater after 4 weeks (see the section "Pharmacodynamics"). In connection with the possible development of side effects when taking a dose of 40 mg, compared with lower doses of the drug (see section "Side effect"), increasing the dose to 40 mg, after additional doses above the recommended initial dose for 4 weeks therapy, can only be performed in patients with severe hypercholesterolemia and a high risk of cardiovascular complications (especially in patients with familial hypercholesterolemia) who did not achieve the desired result of therapy when taking a dose of 20 mg, and which will be monitored by a specialist (see section "Special instructions"). It is recommended especially careful monitoring of patients receiving the drug in a dose of 40 mg.

Do not administer a dose of 40 mg to patients who have not previously consulted a doctor.

After 2-4 weeks of therapy and / or with an increase in the dose of the drug Krestor®, it is necessary to monitor the lipid metabolism (if necessary, dose adjustment is required).

Elderly patients

No dose adjustment is required.

Patients with renal insufficiency

In patients with mild or moderate renal insufficiency, dose adjustment is not required. In patients with severe renal insufficiency (KC less than 30 ml / min.), The use of Crestor® is contraindicated.

Contraindicated use of the drug in a dose of 40 mg to patients with moderate impaired renal function (QC less than 30-60 ml / min.) (See section "Special instructions" and "Pharmacodynia"). Patients with moderate impairment of renal function are recommended an initial dose of 5 mg.

Patients with hepatic insufficiency

Crestor® is contraindicated in patients with active liver disease (see case "Contraindications").

Special populations. Ethnic groups

When studying the pharmacokinetic parameters of rosuvastatin in patients belonging to different ethnic groups, there was an increase in the systemic concentration of rosuvastatin among Japanese and Chinese (see section "Special instructions"). This fact should be taken into account when prescribing Krsstor® to these patient groups. When prescribing doses of 10 and 20 mg, the recommended initial dose for patients of the Mongoloid race is5 mg. Contraindicated appointment of the drug in a dose of 40 mg to patients of the Mongoloid race (see the section "Contraindications").

Genetic polymorphism

In carriers of genotypes SLCO1B1 (OAТР1В1) с.521СС and ABCG2 (ВСRR) FROM.421AA there was an increase in exposure (AUC) to rosuvastatin in comparison with carriers of genotypes SLCO1B1 FROM.521TT and ABCG2 FROM.421SS. For patient carriers of genotypes FROM.521SS or FROM.421AA the recommended maximum dose of Crestor® is 20 mg once daily (see sections "Pharmacokinetics", "Specific guidance" and "Interaction with other

medicines and other types of drug interactions ").

Patients who are predisposed to myopathy

Contraindicated the appointment of the drug in a dose of 40 mg to patients with factors that may indicate a predisposition to the development of myopathy (see the section "Contraindications"), When appointing doses of 10 and 20 mg, the recommended initial dose for this group of patients is 5 mg (See " Contraindications ")

Concomitant therapy

Rosuvaetatin binds to various transport proteins (in particular, to OATP1B1 and VCRP). When the drug Krestor® is used together with medicines (such as ciclosporin, some HIV protease inhibitors, including a combination of ritonavir with atazanavir, lopinavir and / or tipranavir), which increase the plasma concentration of rosuvastatin by interacting with transport proteins, may increase the risk of myopathy (including rhabdomyolysis) (see "Specific guidance" and "Interaction with other drugs and other types of drug interactions "). You should read the instructions for the use of these drugs before they are administered with Crestor®. In such cases, the possibility of prescribing alternative therapy or temporary discontinuation of Krestor® should be evaluated. If the use of the above drugs is necessary, the relationship between benefit and risk of concomitant therapy with Crestor® should be evaluated and the possibility of reducing its dose should be considered (see "Interactions with Other Drugs and Other Drug Interactions").

Side effects:

The side effects observed with the administration of Krsstor® are usually only slightly expressed and pass on their own.As with other inhibitors of HMG-CoA reductase, the incidence of side effects is mainly dose-dependent.

The frequency of undesirable effects is as follows:

often (> 1/100, <1/10); infrequently (> 1/1000, <1/100); rarely (> 1/10000, <1/1000); very rarely (<1/10000), frequency, unspecified (can not be calculated from available data).

The immune system

Rarely: hypersensitivity reactions, including angioedema

Endocrine system

Often: diabetes mellitus type 2

From the central nervous system

Often: headache, dizziness

From the side of the digestive tract

Often: constipation, nausea, abdominal pain

Rarely: pancreatitis

From the skin

Infrequently: itching, rash, urticaria

From the side of the musculoskeletal system

Often: myalgia

Rarely: Myopathy (including myositis), rhabdomyolysis

Other

Often: asthenic syndrome

From the side of the urinary system

Patients receiving Crestor® can be diagnosed with proteinuria. Changes in the amount of protein in the urine (from absence or trace amounts to ++ or more) are observed in less than 1% of patients receiving 10-20 mg of the drug, and about 3% of patients,

receiving 40 mg of the drug.A slight change in the amount of protein in the urine was noted with a dose of 20 mg. In most cases, proteinuria decreases or disappears during therapy and does not indicate the occurrence of acute or progressive

existing kidney disease.

From the side of the locomotor system apparatus

When Krestor® was used in all dosages and, in particular, when taking doses of the drug in excess of 20 mg, the following effects on the musculoskeletal system were reported: myalgia, myopathy (including myositis), in rare cases - rhabdomyolysis with or without acute renal failure her. A dose-related increase in activity of creatine phosphokinase (CK) is observed in a small number of patients taking rosuvastatin. In most cases, it was insignificant, asymptomatic and temporary. In the case of increased activity of CK (more than 5 times compared with the upper limit of the norm) therapy should be suspended (see section "Special instructions").

From the side of the liver

With the use of rosuvastatin, a dose-dependent increase in the activity of "hepatic" transaminases in a small number of patients is observed.In most cases, it is insignificant, asymptomatic and temporary.

Laboratory indicators

When using the drug Krestor, the following changes in laboratory parameters were also observed: an increase in the concentration of glucose, bilirubin, activity of gamma-

glutamyltranspeptidase, alkaline phosphatase, thyroid dysfunction.

Postmarketing application

The following side effects have been reported in the post-marketing application of Crestor®:

On the part of the hematopoiesis system

Unspecified frequency: thrombocytopenia

From the side of the digestive tract

Very rarely: jaundice, hepatitis

Rarely: increased activity of "liver" transaminases

Unspecified frequency: diarrhea

From the side of the musculoskeletal system

Very rarely: arthralgia

Unspecified frequency: immunosupplemented necrotizing myopathy

From the central nervous system

Very rare: loss or loss of memory

Unspecified frequency: peripheral neuropathy

From the respiratory system

Unspecified frequency: cough, dyspnea

From the side of the urinary system

Very rare: hematuria

From the skin and subcutaneous fat

Unspecified frequency: Stevens-Johnson syndrome

From the reproductive system and breast

Unspecified frequency: gynecomastia

Other

Unspecified frequency: peripheral edema

Some statins reported the following side effects: depression, sleep disorders, including insomnia and nightmarish dreams, sexual dysfunction, hyperglycemia, increased concentrations of glycosylated hemoglobin. Single cases of interstitial lung disease have been reported, especially with prolonged use of drugs (see section "Special instructions").

Overdose:

With the simultaneous administration of several daily doses, the pharmacokinetic parameters of rosuvastatin do not change.

There is no specific treatment for an overdose of rosuvastatin. In case of an overdose, it is recommended to carry out symptomatic treatment and measures aimed at maintaining the functions of vital organs and systems. It is necessary to monitor liver function and the level of CK. It is unlikely that hemodialysis will be effective.

Interaction:

Effect of the use of other drugs on rosuvastatin

Inhibitors of transport proteins: rosuvastatin binds to some transport proteins, in particular, to OATP1B1 and HRPC. Concomitant use of drugs that are inhibitors of these transport proteins may be accompanied by an increase in the plasma rosuvastatin concentration and an increased risk of myopathy (see Table 3 and the sections on "Dosage and administration" and "Special instructions").

Cyclosporine: when rosuvastatin and cyclosporine AIS were administered simultaneously, rosuvastatin was on average 7 times higher than that seen in healthy volunteers (see Table 3). Does not affect the plasma concentration of cyclosporine. Crestor © is not suitable for patients taking ciclosporin (see section "Contraindications").

Inhibitors of the protease of the virus human immunodeficiency (HIV): despite the fact that the exact mechanism of interaction is unknown, a joint intake of HIV protease inhibitors can lead to a significant increase in exposure to rosuvastatin (see Table 3). A pharmacokinetic study on simultaneous use of 20 mg rosuvastatin with a combined preparation containing two HIV protease inhibitors (400 mg lopinavir / 100 mg ritonavir) in healthy volunteers resulted into approximately a twofold and fivefold increase in AUC(0-24) and Cmrosuvastatin, respectively. Therefore, concomitant administration of rosuvastatin and HIV protease inhibitors is not recommended (see sections "Dosage and administration", "Specific guidance", table 3).

Gemfibrozil and other lipid-lowering drugs: the combined use of rosuvastatin and gemfibrozil leads to an increase in 2 times the maximum concentration of rosuvastatin in blood plasma and AUWith rosuvastatin (see section "Special instructions"). Based on the data on the specific interaction, no pharmacokinetically significant interaction with fenofibrate is expected, possibly pharmacodynamic interaction. Gemfibrozil, fenofibrate, other fibrates and lipid-lowering doses of nicotinic acid increased the risk of myopathy with concomitant use with HMG-CoA reductase inhibitors, possibly due to the fact that they can cause myopathy when used in monotherapy (see section "Special instructions"). If the drug is simultaneously taken with gemfibrozil, fibrates, nicotinic acid in lipid-lowering doses (more than 1 g / day), the initial dose of 5 mg is recommended for patients, the dose of 40 mg is contraindicated in a joint appointment with fibrates.sections "Contraindications", "Method of administration and dose", "Special instructions").

Ezetimibe: simultaneous use of the drug Crestor® at a dose of 10 mg and ezetimibe at a dose of 10 mg was accompanied by an increase in AUC of rosuvastatin in patients with hypercholesterolemia (see Table 3). It can not be ruled out that there is an increased risk of side effects due to interactions between the preparation of Crestor® and ezetimibe.

Antacids: simultaneous application of rosuvastatin and suspensions of antacids containing magnesium and aluminum hydroxide, leads to a decrease in the plasma concentration of rosuvastatin by approximately 50%. This effect is less pronounced if antacids are administered 2 hours after rosuvastatin administration. The clinical significance of this interaction has not been studied.

Erythromycin: simultaneous application of rosuvastatin and erythromycin leads to a decrease in AUWith rosuvastatin by 20% and Cmrosuvastatin rose by 30%. Such interaction can arise as a result of increased intestinal motility caused by the administration of erythromycin.

Isozymes of cytochrome P450: research results in vivo and in vitro showed that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. Besides, rosuvastatin is a weak substrate for these isoenzymes. Therefore, interaction of rosuvastatin with other drugs at the metabolic level with the participation of cytochrome P450 isoenzymes is not expected. There was no clinically significant interaction between rosuvastatin and fluconazole (inhibitor of isoenzymes СУР2С9 and СУРЗА4) and ketoconazole (inhibitor of isoenzymes СUR2А6 and СУРЗА4).

Fusidic acid: Studies on the interaction of rosuvastatin and fusidic acid have not been conducted. As with the reception of other statins, post-marketing reports were received on cases of rhabdomyolysis in the joint administration of rosuvastatin and fusidic acid. Patients should be closely monitored. If necessary, a temporary discontinuation of rosuvastatin is possible.

Interaction with drugs, which requires correction of the dose of rosuvastatin (see Table 3)

The dose of Krestor® should be adjusted when it is necessary to use it together with medicines that increase the exposure to rosuvastatin.You should read the instructions for the use of these drugs before they are administered with Crestor®. If the exposure is expected to be 2 times or more, the initial dose of Crestor® should be 5 mg once daily. Also, the maximum daily dose of Krtster® so that the expected exposure to rosuvastatin does not exceed that for a dose of 40 mg taken without the simultaneous administration of medications that interact with rosuvastatin. For example, the maximum daily dose of Crestor® with simultaneous use with gemfibrozil is 20 mg (1.9 times increase in exposure), with ritonavir / atazanavir 10 mg (increase in exposure 3.1 times).

Table 3. Effect of concomitant therapy on exposure to rosuvastatin (AUC, data are listed in descending order) - results of published clinical trials

Mode

concomitant therapy

Mode of taking rosuvastatin

Changing AUC

rosuvastatin

Cycloporine 75-200 mg 2 times a day, 6 months.

10 mg 1 time per day, 10 days

An increase of 7.1 times

Atazanavir 300 mg / ritonavir 100 mg 1 time per day, 8 days

10 mg once

Increase 3.1-fold

Symeprevir 150 mg 1 time per day, 7 days

10 mg once

An increase of 2.8 times

Lopinavir 400 mg / ritonavir 100 mg 2 times per day, 17 days

20 mg 1 time per day, 7 days

An increase of 2.1 times

Clopidogrel 300 mg (loading dose), then 75 mg after 24 hours

20 mg once

2 times increase

Gemfibrozil 600 mg 2 times a day, 7 days

80 mg once

Increase 1.9 times

Eltrombopag 75 mg 1 time per day, 10 days

10 mg once

Increase 1.6 times

Darunavrin 600 mg / ritonavir 100 mg 1 time per day, 7 days

10 mg 1 time per day, 7 days

Increase by 1.5 times

Tipranavir 500 mg / ritonavir 200 mg 2 times per day, 11 days

10 mg once

Increase by 1.4 times

Dronedarone 400 mg 2 times a day.

No data

Increase by 1.4 times

Itraconazole 200 mg 1 time per day, 5 days

10 mg or 80 mg once

Increase by 1.4 times

Ezetimibe 10 mg 1 time per day, 14 days

10 mg once a day, 14 days

Increase by 1.2 times

Fosamprenavir 700 mg / ritonavir 100 mg 2 times per day, 8 days

10 mg once

Without changes

Aleglitazar 0.3 mg, 7 days

40 mg, 7 days

Without changes

Silymarin 140 mg 3 times a day, 5 days

10 mg once

Without changes

Fenofibrate 67 mg 3 times a day, 7 days

10 mg, 7 days

Without changes

Rifamine 450 mg once a day, 7 days

20 mg once

Without changes

Ketoconazole 200 mg 2 times per day, 7 days

80 mg once

Without changes

Fluconazole 200 mg 1 time per day, 11 days

80 mg once

Without changes

Erythromycin 500 mg 4 times per day, 7 days

80 mg once

Decrease by 28%

Baikalin 50 mg 3 times a day, 14 days

20 mg once

Decrease by 47%

Effect of rosuvastatin on other drugs

Antagonists of vitamin K: the initiation of rosuvastatin therapy or an increase in the dose of the drug in patients receiving both vitamin K antagonists (for example, warfarin), may lead to an increase in the International Normalized Relationship (INR). The cancellation of rosuvastatin or a decrease in the dose of the drug may lead to a decrease in INR. In such cases, monitoring of INR is recommended.

Oral contraceptives / hormone replacement therapy: simultaneous application of rosuvastatin and oral contraceptives increases AUWith ethinyl estradiol and AUWith norgestrel by 26% and 34%, respectively. Such an increase in plasma concentration should be taken into account when choosing a dose of oral contraceptives.

Pharmacokinetic data but the simultaneous use of the drug Krestor ® and hormone replacement therapy are absent, therefore, it is impossible to exclude a similar effect when using this combination.However, this combination was widely used during clinical trials and was well tolerated by patients.

Other medicines: no clinically significant interaction between rosuvastatin and digoxin is expected.

Special instructions:

Renal Effects

In patients who received high doses of the drug Krestor® (mostly 40 mg), tubular proteinuria was observed, which in most cases was transient. Such proteinuria did not indicate an acute kidney disease or progression of kidney disease. In patients taking the drug at a dose of 40 mg, it is recommended to monitor the performance of kidneys during treatment.

From the side of the musculoskeletal system

When using Krestor® in all dosages and, in particular, when taking doses of the drug in excess of 20 mg, the following effects on the musculoskeletal system were reported: myalgia, myopathy, in rare cases rhabdomyolysis.

Determination of the activity of creatine phosphokinase

Determination of CKK activity should not be performed after intensive physical exertion or in the presence of other possible causes of increased activity of CK, which may lead to incorrect interpretation of the results.If the initial activity of CK is significantly increased (5 times higher than the upper limit of the norm), after 5-7 days, a second measurement should be made. Do not start therapy if a second test confirms the baseline CK activity (more than 5 times higher than the upper limit of the norm).

Before the start of therapy

Caution should be exercised in patients with existing risk factors for myopathy / rhabdomyolysis (see the section "With caution") when prescribing the Krestor® preparation, as well as when prescribing other HMG-CoA reductase inhibitors, it is necessary to consider the relationship between the risk and possible benefit of therapy and conduct clinical observation.

During therapy

The patient should be informed of the need to report immediately to the doctor about cases of sudden onset of muscle pain, muscle weakness, or spasms, especially in combination with malaise and fever. In such patients, the activity of CK should be determined. Therapy should be discontinued if the activity of CK is significantly increased (more than 5 times the upper limit of the norm) or if the symptoms from the muscles are pronounced and cause daily discomfort (even if the activity of CK is increased by no more than 5 times compared to the upper limit of the norm).If symptoms disappear and CPK activity returns to normal, consideration should be given to re-administering Crestor® or other HMG-CoA reductase inhibitors in smaller doses with close monitoring of the patient. Routine monitoring of the activity of CKK in the absence of symptoms is inappropriate. Very rare cases of immuno-mediated necrotizing myopathies with clinical manifestations in the form of persistent weakness of proximal muscles and increased activity of CKK in blood serum during treatment or when stopping the use of statins, including rosuvastatin. It may be necessary to conduct additional studies of the muscular and nervous system, serological studies, as well as therapy with immunosuppressive drugs. There were no signs of an increase in the effect on skeletal muscle when taking Crestor® and concomitant therapy. However, an increase in the incidence of myositis and myopathy in patients taking other HMG-CoA reductase inhibitors in combination with fibrin acid derivatives, including gemfibrozil, ciclosporin, nicotinic acid in lipid-lowering doses (more than 1 g / day), azole antifungal agents, HIV protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when combined with some HMG-CoA reductase inhibitors. Thus, the simultaneous administration of Crestor® and gemfibrozil is not recommended. The risk-to-benefit ratio should be carefully weighed in conjunction with the use of the Krestor® drug and fibrate or lipid-lowering doses of nicotinic acid. Contraindicated taking Krestor ® in a dose of 40 mg together with fibrates (see the sections "Interaction with other drugs and other forms of drug interaction", "Contraindications"). In 2-4 weeks after the start of treatment and / or with an increase in the dose of the drug Krestor®, it is necessary to monitor the lipid metabolism (if necessary, dose adjustment is required).

Liver

It is recommended to carry out the determination of liver function indices before the start of therapy and 3 months after the start of therapy. Admission of the drug Krestor® should stop or reduce the dose of the drug if the activity of "hepatic" transaminases in the serum is 3 times higher than the upper limit of the norm.In patients with hypercholesterolemia due to hypothyroidism or nephrotic syndrome, treatment of major illnesses should be performed prior to the commencement of treatment with Crestor®.

Special populations. Ethnic groups

In the course of pharmacokinetic studies, an increase in the systemic concentration of rosuvastatin was noted among Chinese and Japanese patients compared to those obtained among European patients (see the "Dosing and Administration" and "Pharmacokinetics" sections).

HIV protease inhibitors

It is not recommended to use the drug jointly with HIV protease inhibitors (see "Interaction with other drugs and other interactions").

Lactose

The drug should not be used in patients with lactase deficiency, intolerance to galactose and glucose galactose malabsorption.

Interstitial lung disease

With the use of some statins, especially for a long time, there have been reports of single cases of interstitial lung disease. Manifestations of the disease can be shortness of breath, unproductive cough and deterioration in overall health (weakness, weight loss and fever).If suspicion of interstitial lung disease should be stopped by statin therapy.

Diabetes mellitus type 2

In patients with glucose concentration from 5.6 to 6.9 mmol / L, Crestor® therapy was associated with an increased risk of developing type 2 diabetes.

Effect on the ability to drive transp. cf. and fur:

There have been no studies to study the effect of Crestor® on the ability to drive a vehicle and use mechanisms. However, based on the pharmacodynamic properties, Crestor® should not have such an effect. Care should be taken when driving vehicles or work associated with increased concentration of attention and psychomotor reaction (dizziness may occur during therapy).

Form release / dosage:

Tablets, film-coated, 10 mg, 20 mg and 40 mg.

Packaging:

For tablets 10 mg: 7 tablets in an aluminum laminate / aluminum foil blister formed from a molding laminate consisting of a polyamide / soft aluminum foil / unplasticized PVC film sealed with hardened aluminum foil coated with a thermo lacquer; 1 blister in a cardboard box with instructions for use

or 14 tablets in an aluminum laminate / aluminum foil blister made of a molding laminate consisting of a polyamide / soft aluminum foil / unplasticized PVC film sealed with a hardened aluminum foil covered with a thermo lacquer; for 2, 7 or 9 blisters in a cardboard box with instructions for use.

For tablets of 20 mg: 14 tablets in an aluminum laminate / aluminum foil blister, formed from a molding laminate consisting of a polyamide / soft aluminum foil / unplasticized polyvinyl chloride (PVC) film sealed with hardened aluminum foil coated with a thermo lacquer; 2 or 9 blisters in a cardboard box with instructions for use.

For tablets 40 mg: 7 tablets in an aluminum laminate / aluminum foil blister formed from a molding laminate consisting of a polyamide / soft aluminum foil / unplasticized polyvinyl chloride (PVC) film sealed with hardened aluminum foil coated with a thermo lacquer; 4 blisters in a cardboard box with instructions for use.

Storage conditions:At temperatures not higher than 30 ° C, out of reach of children.

Shelf life:3 years. Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N015644 / 01

Date of registration:24.03.2009 / 27.11.2017

Expiration Date:Unlimited

The owner of the registration certificate:AstraZeneca UK LtdAstraZeneca UK Ltd United Kingdom

Manufacturer: & nbsp

IPR PHARMACEUTICALS, Inc. Puerto Rico

Representation: & nbspAstraZeneca Pharmaceuticals Ltd.AstraZeneca Pharmaceuticals Ltd.

Information update date: & nbsp05.02.2018

Illustrated instructions

Instructions

Crestor® (Crestor®)