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

Tablets 5 mg. 1 tablet contains: active substance rosuvastatin (rosuvastatin calcium) 5.00 (5.21) mg; Excipients: cellulose microcrystalline 47.82 mg, crospovidone 30.00 mg, lactose 54.97 mg, povidone-KZO 8.50 mg, sodium stearyl fumarate 3.50 mg; sheath Opadry II 8523426 orange (polyvinyl alcohol - partially hydrolyzed 1,800 mg, titanium dioxide (E171) 1.025 mg, macrogol-3350 0.909 mg, talc 0.666 mg, ferric oxide yellow oxide (E172) 0.075 mg, ferric oxide black oxide (E172) 0.003 mg, dye solar sunset yellow (E110) 0.022 mg).

Tablets 10 mg, 20 mg, 40 mg. 1 tablet contains: active substance rosuvastatin (rosuvastatin calcium) 10.00 (10.42) / 20.00 (20.83) / 40.00 (41.67) mg; Excipients: cellulose microcrystalline 45,22 / 90,45 / 80,03 mg, crospovidone 30,00 / 60,00 / 60,00 mg, lactose 52,36 / 104,72 / 94,30 mg, povidone-KZO 8.50 / 17.00 / 17.00 mg, sodium stearyl fumarate 3.50 / 7.00 (7.00 mg; sheath Opadry II 85Р24155 pink (polyvinyl alcohol - partially hydrolyzed 1,800 / 3,600 / 3,600 mg,titanium dioxide (E171) 1,105 / 2,210 / 2,210 mg, macrogol-3350 0,909 / 1,818 / 1,818 mg, talc 0,666 / 1,332 / 1,332 mg, iron dye oxide yellow (E172) 0.009 / 0.018 / 0.018 mg, iron dye red oxide (E172 0.005 / 0.010 / 0.010 mg, azorubin dye aluminum lacquer (E 122) 0.005 / 0.009 / 0.009 mg, indigocarmine aluminum lacquer (E132) 0.001 / 0.003 / 0.003 mg).

Description:Tablets 5 mg. Round biconvex tablets, coated with a film coating from light yellow or light orange (a grayish tinge is possible) to orange, engraved with "N" on one side and "5" on the other. On a cross-section, the core is white to almost white in color.

Tablets 10 mg. Round biconvex tablets, film-coated from

light pink to pink, engraved "N" on one side and "10" on

other. On the cross-section - the core is from white to almost white.

Tablets of 20 mg. Round biconvex tablets, film-coated from

light pink to pink, engraved "N" on one side and "20" on

other. On the cross-section - the core is from white to almost white.

Tablets of 40 mg. Oval tablets, film-coated from light pink

up to pink color, with engraving "N" on one side and "40" on the other.On the transverse section - the core is from white to almost white.

Pharmacotherapeutic group:lipid-lowering agent - HMG-CoA reductase inhibitor

ATX: & nbsp

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

C.10.A.A.07 Rosuvastatin

Pharmacodynamics:

Rosuvastatin is a selective, competitive inhibitor of HMG-CoA reductase, an enzyme that converts 3-hydroxy-3-methylglugarylcoenzyme A into mevalonate, the precursor of cholesterol (Xc). The main target of the action of rosuvastatin is the liver, where the synthesis of Xc and catabolism of low-density lipoproteins (LDL) is carried out. Rosuvastatin increases the number of "hepatic" LDL receptors on the cell surface, increasing the uptake and catabolism of LDL, which in turn leads to inhibition of the synthesis of very low density lipoproteins (VLDL), thereby reducing the total number of LDL and VLDL.

Rosuvastatin reduces the elevated concentration of low-density cholesterol-lipoproteins (LDL-C), total cholesterol, triglycerides (TG), increases the concentration of high-density cholesterol-lipoproteins (Xc-HDL), and reduces the concentrations of apolipoprotein B (ApoV), Xc-nsLVP, Xc-VLDL,TG-VLDL and increases the concentration of apolipoprotein A-1 (ApoA-1), reduces the ratio of X-LDL / X-HDL, total XC / XC-HDL and Xc-non-HDL / XPS-HDL and ApoB / ApoA-1.

The therapeutic effect appears within 1 week after the beginning of rosuvastatin therapy, after 2 weeks of treatment it reaches 90% of the maximum possible effect. The maximum therapeutic effect is usually achieved by week 4 and is maintained with regular admission.

Pharmacokinetics:

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

Distribution. Rosuvastatin accumulates mainly in the liver, the main organ of the synthesis of Xc and the clearance of X-LDL. Volume of distribution (V_d) - about 134 liters. Binding to plasma proteins (predominantly with albumin) is approximately 90%.

Metabolism. Biotransformed to a small extent (about 10%), being a non-core substrate for metabolism by enzymes of the cytochrome P450 system. The main isoenzyme involved in the metabolism of rosuvastatin is CUR2C9. Isofermeyty СУР2С19, СУР3А4 and СУР2D6 are less involved in metabolism. The main revealed metabolites of rosuvastatin are N-dysmethyl and lactone metabolites. N-dysmethyl metabolite is about 50% less active than rosuvastatin, lactone metabolites are pharmacologically inactive. 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 with feces. The remainder is excreted in the urine. The half-life (T_1/2) - about 19 hours. T_1/2 does not change with increasing dose of the drug. The average value of plasma clearance is approximately 50 l / h (coefficient of variation - 21.7%). As in the case of other HMG-CoA-redukase inhibitors, the membrane anionic carrier Xc is involved in the "hepatic" capture of rosuvastatin, which plays an important role in the hepatic elimination of rosuvastatin.

Pharmacokinetics in special clinical cases.

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

Comparative studies of the pharmacokinetics of rosuvastatin in Japanese and Chinese patients living in Asia,showed approximately a twofold increase in the mean values of the area under the concentration-time curve (AUC), compared to those of Europeans living in Europe and Asia. The influence of genetic factors and environmental factors on the differences in pharmacokinetic parameters was not revealed. Pharmacokinetic analysis among different ethnic groups of patients did not reveal clinically significant differences among Europeans, Hispanics, blacks or blacks.

In patients with mild and moderately expressed renal failure, the plasma concentration of rosuvastatin or N-dimethyl metabolite does not change significantly.

In patients with severe renal failure (creatinine clearance <30 ml / min), the concentration of rosuvastatin in blood plasma is 3 times higher, and the concentration of N-dimethyl metabolite 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.

In patients with different stages of hepatic insufficiency,but an increase in T 1/2 of rosuvastatin (patientsyou with a score of 7 and below on the scale Child-I drink). In 2 patients with scores of 8 and 9

the Child-Pugh scale T1 / 2, at least 2 times. Experience withrosuvastatin in patients with baldnessscrap above 9 on the Child-Pew scaletents.

Genetic polymorphism

Inhibitors of HMG-CoA reductase, including number, rosuvastatin, communicate with trancethe binding proteins of OATP1B1 (polypeptide transport of organic anions, participationin capturing statins by hepatocytes) and VSRR (Efflux conveyor). Wearingof the genotypes SLCO1B1 (OATP1B1)

p.521SS and АВСG2 (ВССР) С.421ААthe increase of AG1C to rosuvastatin in 1,6 and 2.4 times, respectively, but compared with carriers of genotypes SLCO1B1 C.521TT and АВСG2 с.421СС.

Indications:

- Primary hypercholesterolemia according to Fredrickson classification (type IIa, 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 an adjunct to the diet.

- To slow the progression of atherosclerosis as a supplement to the diet in patients who

Therapy is shown to reduce the concentration of total cholesterol and cholesterol-LH1G1.

- Primary prevention of major cardiovascular complications (stroke, myocardial infarction, 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 (more than 2 mg / L) in the presence of at least one of additional risk factors, such as hypertension, low concentration of HDL-C, smoking, family history of early onset of CHD).

Contraindications:

For tablets 5, 10 and 20 mg. Hypersensitivity to rosuvastatin or any of the components of the drug; liver disease in the active phase, including persistent, increased activity of "liver" transaminases or any increase in the activity of "liver" transaminases (more than 3 times compared with the upper limit of the norm (VGN)), severe renal dysfunction (CC less than 30 ml / min);myopathy; simultaneous administration of cyclosporine; pregnancy; the period of breastfeeding; lack of reliable methods of contraception; lactose intolerance; deficiency of lactase or glucose-galactose malabsorption (the preparation contains lactose); age under 18 years (insufficient data on efficiency and safety); severe violations of the liver (more than 9 points on the scale Child-Pugh) (no experience of use).

For tablets 40 mg. Hypersensitivity to rosuvastatin or any of the components of the drug; simultaneous administration of cyclosporine, pregnancy; the period of breastfeeding; lack of reliable methods of contraception; lactose intolerance, lactase deficiency or glucose-galactose malabsorption (the preparation contains lactose); age under 18 years (insufficient data on efficacy and safety), liver disease in the active phase, including persistent increase in the activity of "hepatic" transaminases and any increase in the activity of "hepatic" transaminases (more than 3 times in comparison with VGN).

Patients with risk factors for myopathy / rhabdomyolysis: renal failure (CC less than 60 mL / min); hypothyroidism; personal or family analysis of muscle diseases;myotoxicity on the background of taking other inhibitors of HMG-Co-A-reductase or fibrates in anamnesis; excessive use of alcohol; conditions that may lead to an increase in the plasma concentration of rosuvastatin; simultaneous reception of fibrates; application in patients of the Asian race; severe violations of the liver (more than 9 points on the scale Child-Pugh) (no experience of use).

Carefully:

For tablets 5, 10 and 20 mg. Presence of risk factors for myopathy and / or rhabdomyolysis - renal failure, hypothyroidism, personal or family analysis of hereditary muscle diseases and a previous history of muscle toxicity with other HMG-CoA reductase inhibitors or fibrates; excessive alcohol consumption, age over 65 years, conditions in which increased plasma concentrations of rosuvastatin; race (Asian race), simultaneous use with fibrates, liver disease in history, sepsis, arterial hypotension, extensive surgery, trauma, severe metabolic, endocrine or electrolyte disorders, or uncontrolled convulsive seizures.

For tablets 40 mg.Renal failure (QC greater than 60 mL / min), age 65 years or older, history of liver disease, sepsis, hypotension, extensive surgery, trauma, severe metabolic, endocrine or electrolyte disorders, or uncontrolled convulsive seizures.

Pregnancy and lactation:

The drug Tevastor® is contraindicated in pregnancy and during breastfeeding. When diagnosing pregnancy during therapy, taking the drug should be stopped immediately.

Women of reproductive age should apply reliable methods of contraception. Because cholesterol and its biosynthetic products are important for fetal development, the potential risk of HMG-CoA reductase inhibition is greater than the benefit of the drug.

Data on the allocation of rosuvastatin in breast milk are not available, so if you need to use Tevastor® during lactation, breastfeeding should be discontinued.

Dosing and Administration:Inside at any time of the day, regardless of food intake. The tablet should be swallowed whole, washed down with water, not chewing or grinding.If you need to take the drug at a dose of 5 mg, you should divide the tablet 10 mg in half. Before starting therapy with Tevastor®, the patient should begin to follow the standard lipid-lowering diet and continue to observe it during treatment. The dose of the drug should be selected individually, depending on the indications and therapeutic response, taking into account the current recommendations on target levels of lipids. The recommended initial dose of the drug Tevastor® for patients starting to take the drug, or for patients transferred from other HMG-CoA reductase inhibitors, is 5 or 10 mg 1 time / day. When choosing the initial dose should be guided by the content of cholesterol in the patient and take into account the risk of cardiovascular complications, as well as the potential risk of side effects. If necessary, after 4 weeks, the dose may be increased. Patients with severe hypercholesterolemia and a high risk of cardiovascular complications (especially patients with familial hypercholesterolemia) who did not achieve the desired result with a dose of 20 mg during a 4-week therapy,with an increase in the dose of the drug to 40 mg should be under the supervision of the doctor in connection with the possible increase in the risk of side effects.

It is recommended especially careful monitoring of patients receiving the drug in a dose of 40 mg. After 2-4 weeks of therapy and / or increasing the dose of Tevastor®, control of lipid metabolism parameters is necessary.

In elderly patients (over 65 years of age) is recommended to start treatment with a dose of 5 mg.

Patients with renal insufficiency. In patients with renal insufficiency mild or moderate severity, dose adjustment is not required. Contraindicated use of the drug Tevastor in any dose in severe renal failure (QC less than 30 ml / min). Contraindicated the use of the drug Tevastor in a dosage of 40 mg in patients with moderate renal dysfunction (CC less than 60 ml / min). Patients with moderate impairment of renal function are recommended an initial dose of 5 mg.

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 using Tevastor ® in these groups of patients. For Asian patients, the recommended initial dose is 5 mg. Contraindicated use of the drug Tevastor in a dose of 40 mg in patients of the Asian race.

Genetic polymorphism

In carriers of genotypes SLC01В1 (ОАТР1В1) с.521СС and АВСG2 (RVRC) C.421AA, an increase in exposure (AUC) to rosuvastatin in comparison with carriers of genotypes SLC01В1 С.521ТТ and АВСG2 p.421S. For patients carrying genotypes p.521SS or C.421AA, The maximum daily dose of Tevastor® is 20 mg once a day (see the sections "Pharmacokinetics", "Special instructions" and "Interaction with other medicinal products").

Predisposition to myopathy

Contraindicated the use of the drug Tevastor in a dose of 40 mg to patients with factors that may indicate a predisposition to the development of myopathy (See section "Special instructions"). When applying doses of 10 and 20 mg, an initial dose for patients in this group of 5 mg is recommended.

Concomitant therapy

Rosuvastatin binds to various transport proteins (in particular, to OATP1B1 and VSRR).With the simultaneous use of the drug cyclosporine Tevastor® and HIV protease inhibitors (including a combination of ritonavir with atazanavir, lopinavir) increases the risk of myopathy (including rhabdomyolysis), therefore it is necessary to consider alternative therapy or temporary cancellation Tevastor® preparation. If simultaneous use of these drugs is unavoidable, the ratio of the risk of concomitant therapy with Tevastor® should be assessed and the possibility of reducing its dose should be considered.

Side effects:Side effects observed with the use of the drug Tevastor ®, usually expressed slightly and pass independently. As with other inhibitors of HMG-CoA reductase, the incidence of side effects is mainly dose-dependent. Determination of the incidence of adverse reactions: often (> 1/100, <1/10); infrequently (> 1/1000, <1/100); rarely (> 1/10 000, <1/1000); very rarely (<1/10 000), unknown frequency (can not be calculated from available data).

From the immune system: rarely - reactions of hypersensitivity, including angioedema.

From the endocrine system: often - type 2 diabetes.

From the central nervous system (CNS): often - headache, dizziness.

From the digestive system: often - constipation, nausea, abdominal pain; rarely - pancreatitis.

From the skin: infrequently - itchy skin, rash, hives.

From the musculoskeletal system: often - myalgia; rarely - myopathy (including myositis), rhabdomyolysis.

Other: often - asthenic syndrome.

Description of unwanted effects

From the side of the urinary system: patients receiving Tevastor ®, can be detected 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 the drug at a dose of 10-20 mg and about 3% of patients receiving the drug at a dose of 40 mg. 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 onset or progression of an existing kidney disease.

From the musculoskeletal system: when using Tevastor ® in all doses, especially at doses exceeding 20 mg - myalgia, myopathy (including myositis); in rare cases - rhabdomyolysis with or without acute renal failure.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.

From the side of the liver: dose-dependent increase in the activity of "hepatic" transaminases in a small number of patients. In most cases, it is insignificant, asymptomatic and temporary.

Laboratory indicators: increase in glucose concentration, bilirubin, activity of gamma-glutamyltransferase, alkaline phosphatase, and thyroid dysfunction.

Postmarketing application

From the side of the blood and lymphatic system: unknown frequency - thrombocytopenia.

From the digestive system: very rarely - jaundice, hepatitis; rarely - increased activity of "liver" transaminases; an unknown frequency is diarrhea.

From the musculoskeletal system: very rarely - arthralgia; unknown frequency - immuno-mediated necrotizing myopathy.

From the side of the central nervous system: very rarely - polyneuropathy, memory loss.

From the respiratory system: unknown frequency - cough, shortness of breath.

From the side of the urinary system: very rarely - hematuria.

From the skin and subcutaneous fat: unknown frequency - Stevens-Johnson syndrome.

On the part of the reproductive system: unknown frequency - gynecomastia.

Other: unknown frequency - peripheral edema.

Some statins reported the following side effects: depression, sleep disturbances, including insomnia and nightmarish dreams, sexual dysfunction. Single cases of interstitial lung disease have been reported, especially with prolonged use of drugs.

Overdose:With the simultaneous administration of several daily doses, the pharmacokinetic parameters of rosuvastatin do not change. There is no specific antidote. If necessary, symptomatic therapy is carried out, control of liver function and activity of CKF is necessary. Hemodialysis is not 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 BCRR.The concomitant use of drugs that are inhibitors of these transport proteins may be accompanied by an increase in the concentration of rosuvastatin in plasma and an increased risk of developing myoiata (see Table 3 and the sections on "Dosage and administration" and "Special instructions").

Cyclosporine: while using rosuvastatin and cyclosporin, LZ rosuvastatin was an average of 7 times higher than that seen in healthy volunteers (see Table 3). Does not affect the plasma concentration of cyclosporine. Rosuvastatin contraindicated in patients receiving ciclosporin (see section "Contraindications").

Inhibitors of the human immunodeficiency virus (HIV) protease: despite the fact that the exact mechanism of interaction is unknown, 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 in approximately a twofold and fivefold increase in AUC (0-24) and Cmax rosuvastatin, 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 AUC rosuvastatin (see section "Specific guidance") Based on the data but specific interaction, no pharmacokinetically significant interaction with fenofibrate is expected, possibly pharmacodynamic interaction. Gemfibrozil, fenofibrate, other fibrates and lio-reducing doses of nicotinic acid increased the risk of myocardial infarction 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"). With simultaneous administration of the drug with gemfibrozil, fibrates, nicotinic acid in lipid-lowering doses (more than 1 g / day), patients are recommended an initial dose of 5 mg,taking in a dose of 40 mg is contraindicated in a joint appointment with fibrates (see the sections "Contraindications", "Method of administration and dose", "Special instructions").

Ezetimibe: simultaneous application of rosuvastatin 10 mg and ezetimibe at a dose of 10 mg was accompanied by an increase in AUWith rosuvastatin in patients with hypercholesterolemia (see Table 3). It can not be ruled out that the risk of side effects increases due to the pharmacodynamic interaction between rosuvastatin 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 inhibitor nor inducer of cytochrome P450 isofermings. Besides, rosuvastatin is a weak substrate for these isofermings. 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 flucon ash (inhibitor of isoenzymes СУР2С9 and СУРЗА4) and ketoconazole (inhibitor of isoenzymes СUR2А6 and СУРЗА4).

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

The dose of rosuvastatin should be adjusted when it is necessary to use it together with drugs that increase the exposure to rosuvastatin. If the exposure is expected to be 2 times or more, the initial dose of rosuvastatin should be 5 mg once a day. Also, the maximum daily dose of rosuvastatin should be adjusted so that the expected exposure to rosuvastatin does not exceed that for a dose of 40 mg taken without the simultaneous administration of medications interacting with rosuvastatin.For example, the maximum daily dose of rosuvastatin 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. The effect of concomitant therapy on exposure to rosuvastatin (AUC, data are listed in descending order).

Complementary therapy regimen	Mode of taking rosuvastatin	Change AUWith rosuvastatin
Cyclosporine 75-200 mg 2 times in	10 mg once a day, 10 days	An increase of 7.1 times
day, 6
months.
Atazanavir	10 mg one	Increase
300	multiple	in 3,1 times
mg / rt
p 100 mg 1
once a day,
8 days
Lopinavir	20 mg 1 time per	Increase
400	day, 7 days	in 2,1 times
mg / rt
p 100 mg 2
times a day
ki, 17 days
Gemfibro-	80 mg one	Increase
zil 600 mg 2	multiple	in 1.9 times
times a day
ki, 7 days
Eltrombo-	10 mg one	Increase
pag 75 mg 1	multiple	in 1,6 times
once a day,
10 days
Darunavir	10 mg 1 time per	Increase
600	day, 7	in 1,5 times
mg / rt	days
p 100 mg 2
times a day
ki, 7 days
Tipranavir	10 mg one	Increase
500	Multiply	in 1,4 times
mg / rtp 200 mg twice a day, 11 days
Dronedarone 400 mg twice daily	No data	Increase by 1.4 times
Itraconazole 200 mg once a day, 5 days	10 mg or 80 mg per year	Increase by 1.4 times
Ezetimibe 10 mg once a day, 14 days	10 mg once a day, 14 days	Increase by 1.2 times
Fosamprenavir 700 mg / ritonavir 100 mg twice daily, 8 days	10 mg once	No change
Aleglitazar 0.3 mg, 7 days	40 mg, 7 days	No change
Silymarin 140 mg 3 times a day, 5 days	10 mg once	No change
Fenofibrate 67 mg 3 times a day, 7 days	10 mg, 7 days	No change
Rifampin 450 mg 1 time per day, 7 days	20 mg once	No change
Ketoconazole 200 mg 2 times a day, 7 days	80 mg once	No change
Fluconazole 200 mg once a day, 11 days	80 mg once	No change
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), can lead to an increase in the International Normalized Relationship (INR). The cancellation of rosuvastatin or a decrease in its dose may result in 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 ethinylestradiol 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 on simultaneous use of rosuvastatin 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:

Effects of the kidneys

Proteinuria, mostly of kidney origin, found as a result of testing, is observed in patients taking rosuvastatin in a dose of 40 mg and above, and in most cases is transient in nature. Such proteinuria is not a symptom of acute or progressive renal disease.The total number of cases of serious kidney complications is noted with the use of rosuvastatin in a dose of 40 mg. When using the drug Tevastor in a dose of 40 mg is recommended to monitor the indicators of kidney function.

Effects of musculoskeletal system

The effect on skeletal muscle (myalgia, myopathy and very rarely rhabdomyolysis) is observed in patients taking Tevastor®, in particular, in a dosage exceeding 20 mg. Very rare cases of rhabdomyolysis with the use of ezetimibe with inhibitors of HMG-CoA reductase have been reported. The likelihood of rhabdomyolysis, with both rosuvastatin and other HMG-CoA reductase inhibitors, is higher with a dosage of 40 mg.

Determination of CKK activity

Determination of the activity of CKK should not be performed after intensive physical exertion or in the presence of other possible causes of increased activity of CKK because of probable distortion of the results obtained. In the event that the initial activity of CK is significantly increased (5 times higher than ULN), after 5-7 days, a second measurement should be carried out. Do not start therapy if a second test confirms the initial activity of CK (5 times higher than ULN).

Before treatment

Before using Tevastor®, as well as before using other HMG-CoA reductase inhibitors, caution should be exercised in patients with existing risk factors for myopathy / rhabdomyolysis, it is necessary to evaluate the relationship between the expected risk and possible benefit of therapy and to conduct clinical observation.

During treatment

Patients must be warned immediately if they have new, previously unreported symptoms, unexplained muscle pain, weakness, or seizures, especially those associated with fever and malaise. Therapy should be discontinued if the activity of CK is 5-fold higher than ULN, or if there are serious muscle symptoms that cause permanent discomfort. With the disappearance of symptoms and normalization of the activity of CK. should consider re-application of rosuvastatin with a minimal dose and careful monitoring. Routine monitoring of the activity of CKK in the absence of symptoms is inexpedient. It is recommended to perform functional diagnostics of the liver before and within 3 months after the initiation of therapy. Very rare cases of immunosupplemented necrotizing myopathy with clinicalmanifestations in the form of persistent weakness of the proximal muscles and increased activity of CK in the blood serum during treatment or when the statin is discontinued. including rosuvastatin. It may be necessary to conduct additional studies of the muscular and nervous system, serological studies, as well as therapy with immunodepressant drugs. There were no signs of an increase in the effect on skeletal musculature when taking Tevastor® 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 hemofibrosil, ciclosporin, nicotinic acid in lipid-lowering doses (more than 1 g / day), azole antifungal agents, HIV protease inhibitors and macrolide antibiotics. Hemofibrosil increases the risk of myopathy when combined with certain HMG-CoA reductase inhibitors. Thus, simultaneous use of the drug Tevastor® and gemfibrozil is not recommended. It is necessary to carefully evaluate the ratio of the expected risk and possible benefit in the joint use of Tevastor® and fibrates or lipid-lowering doses of nicotinic acid.Contraindicated taking Tevastor ® in a dose of 40 mg together with fibrates (see the sections "Interaction from other medications, "" Contraindications. ") 2-4 weeks after starting treatment and / or increasing the dose of Tevastor® need monitoring indicators

lipid metabolism (if necessary dose adjustment is required).

Effects from the liver

A definition is recommended indicators of liver function before therapy and 3 months after the beginning. Taking Tevastor® should bereduce or reduce its dose, ifThe activity of "hepatic" transaminases inThe collar of blood is 3 times higher than the upper

border of norm. In patients with secondary hypercholesterolemiahemiothyroidism

or nephrotic syndrome, should to treat primary diseasebefore prescribing TevaStore®.

Special populations. Ethnic groups

During pharmacokinetic studies among Chinese and Japanese patients increased systemic concentration of rosuvastatin compared to with indicators received among patients - Europeans (see Sections "Mode of administration and dose" and "Pharmacokinetics"),

HIV protease inhibitors

Not recommended for joint application Tevastor® with inhibitors HIV protease (see section "Interaction with other medicinal products ").

Lactose intolerance

Tevastor® should not be used in patients with lactase deficiency, galactose intolerance, 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 Ipterstic lung disease. Manifestations of the disease can be shortness of breath, unproductive cough and deterioration in overall health (weakness, weight loss and fever). If there is a suspicion of interstitial lung disease, we should stop the therapy. Type 2 diabetes mellitus In patients with a glucose concentration of 5.6 to 6.9 mmol / L, Tevastor® therapy was associated with an increased risk of developing type 2 diabetes.

Effect on the ability to drive transp. cf. and fur:Studies on the study of the effect of Tevastor® on the ability to drive vehicles and work with machinery were not conducted.Care should be taken with the use of Tevastor ® in connection with the possible development of dizziness.

Form release / dosage:Tablets, film-coated, 5 mg, 10 mg, 20 mg and 40 mg.

Packaging:For 10 tablets in a blister of PVC / PVC A / aluminum foil. 3 or 9 blisters together with instructions for use in a cardboard pack.

Storage conditions:Store at a temperature not exceeding 25 ° C. Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-001357

Date of registration:15.12.2011/22.12.2015

Expiration Date:15.12.2016

The owner of the registration certificate:Teva Pharmaceutical Enterprises Co., Ltd.Teva Pharmaceutical Enterprises Co., Ltd. Israel

Manufacturer: & nbsp

TEVA Pharmaceutical Industries, Ltd. Israel

Representation: & nbspTeva Teva Israel

Information update date: & nbsp06.07.2016

Illustrated instructions

Instructions

Tevastor® (Tevastor®)