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

	5 mg	10 mg	15 mg	20 mg	40 mg
Active substance:
rosuvastatin calcium (in terms of rosuvastatin)	5 mg	10 mg	15 mg	20 mg	40 mg
Excipients:
lactose monohydrate	93.08 mg	57.3 mg	85.95 mg	114.6 mg	229.2 mg
microcrystalline cellulose	31.02 mg	19.09 mg	28.64 mg	38.18 mg	76.36 mg
calcium hydrophosphate	11.32 mg	6.96 mg	10.44 mg	13.92 mg	27.84 mg
crospovidone	7.5 mg	5 mg	7.5 mg	10 mg	20 mg
magnesium stearate	1.88 mg	1.25 mg	1.87 mg	2.5 mg	5 mg
Film Sheath:
opedraj AMV white:	6 mg	4 mg	6 mg	8 mg	16 mg
polyvinyl alcohol	2.7312 mg	1.8208 mg	2.7312 mg	3.6416 mg	7.2832 mg
titanium dioxide	1.9200 mg	1.2800 mg	1.9200 mg	2.5600 mg	5,1200 mg
talc	1.2000 mg	0.8000 mg	1.2000 mg	1.6000 mg	3.2000 mg
soy lecithin	0.1200 mg	0,0800 mg	0.1200 mg	0.1600 mg	0.3200 mg
xanthan gum	0.0288 mg	0.0192 mg	0.0288 mg	0.0384 mg	0.0768 mg

Description:

For dosages of 5 mg, 10 mg, 15 mg, 20 mg: round tablets, coated with a white film shell, convex with engraving "R9UN 5", "R9UN 10", "R9UN 15", "R9UN 20 ", respectively, on the one hand, with a deepening and risk on the other side.

For a dosage of 40 mg: oval tablets covered with a white film shell, convex with engraving "R9UN 40" on the one hand, with a recess and risk on the other side.

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 - a hypolipidemic agent. It is a selective competitive inhibitor of HMG-CoA reductase, an enzyme that converts 3-hydroxy-3-methylglutarylcoenzyme A into mevalonate, the precursor of cholesterol. The main target of rosuvastatin is the liver, where the synthesis of cholesterol and catabolism of low-density lipoprotein (LDL). 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 increased concentration of cholesterol-LDL (LDL-C),total cholesterol, triglycerides (TG), increases the concentration of high-density lipoprotein cholesterol (HDL-C), and also reduces the concentration of apolipoprotein B (ApoB), CS-non-HDL, cholesterol-VLDL, TG-VLDL and increases the concentration of apolipoprotein AI (ApoA- I), reduces the ratio of LDL-C-HDL cholesterol, total cholesterol / cholesterol-HDL cholesterol and non-HDL / C-HDL cholesterol and the ApoB / ApoA-1 ratio.

Therapeutic effect appears within one 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 the 4th week of therapy and is maintained with regular admission.

The additive effect is noted in combination with fenofibrate for the concentration of TG and with nicotinic acid in lipid lowering doses (more than 1 g) for the concentration of cholesterol-lowering cholesterol (see also the "Specific guidance" section).

Pharmacokinetics:

Absorption and distribution

The maximum concentration (C_m_Oh) rosuvastatin in the blood plasma is reached approximately 5 hours after ingestion. The food reduces the suction speed. Penetrates through the placental barrier. Absolute bioavailability is approximately 20%. Rosuvastatin is absorbed mainly 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

Rosuvastatin undergoes a limited metabolism in the liver (about 10%). Rosuvastatin is a non-core substrate for metabolism by isoenzymes of the cytochrome P450 system. The main isoenzyme involved in the metabolism of rosuvastatin is CYP2C9. Isozymes CYP2C19, CYP3A4 and CYP2D6 are less involved in metabolism. The main revealed metabolites of rosuvastatin are N-dis-methyl and lactone metabolites. Nis 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 through the intestine (including absorbed and not absorbed rosuvastatin).The rest is excreted by the kidneys. Plasma half-life is approximately 19 hours. Half-life (T_1/2) does not change with increasing dose of the drug. The average geometric plasma clearance is approximately 50 l / h (coefficient of variation 21.7%). As in the case of other HMG-CoA reductase inhibitors, the membrane cholesterol transporter is involved in the hepatic capture of rosuvastatin, which plays an important role in the hepatic elimination of rosuvastatin. The systemic exposure of rosuvastatin increases in proportion to the dose. Pharmacokinetic parameters do not change with daily intake.

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

Pharmacokinetic studies showed approximately a twofold increase in the median AUC (area under the concentration-time curve) and C_m_Oh rosuvastatin in patients of Asian nationality (Japanese, Chinese, Filipinos, Vietnamese and Koreans) compared with Europeans, in Indian patients The increase in the median AUC and C_m_Oh in 1,3 times. The influence of genetic factors and environmental factors on the differences in pharmacokinetic parameters was not revealed.Pharmacokinetic analysis did not reveal clinically significant differences in pharmacokinetics among Europeans and representatives Negroid race.

Patients with impaired renal function

In patients with mild to moderate renal failure, the plasma concentration of rosuvastatin or Ndimethyl does not change significantly. In patients with severe renal failure (creatinine clearance <30 ml / min), the concentration of rosuvastatin in the blood plasma is 3 times higher, and the concentration Nis 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.

Patients with hepatic impairment

In patients with different stages of liver failure with a score of 7 or less scale Childe-Pugh no increase T_1/2rosuvastatin. In two patients with grades 8 and 9 on the Child-Pugh scale, lengthening T_1/2 at least 2 times. The experience with rosuvastatin in patients with a score above 9 on the Child-Pugh scale is not available.

Indications:Primary hypercholesterolemia according to Fredriksen (type IIa,including familial heterozygous hypercholesterolemia) or mixed hypercholesterolemia (type IIb) as a supplement to the standard lipid-lowering diet, when diet and other non-pharmacological therapies (eg exercise, weight loss) are inadequate.

Contraindications:

For tablets with a dosage of 5 mg, 10 mg, 15 mg, 20 mg and 40 mg:

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

- age under 18 years (effectiveness and safety not established);

- liver disease 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 (creatinine clearance less than 30 ml / min);

- myopathy;

- simultaneous administration of cyclosporine;

- in women: pregnancy, the period of breastfeeding, the lack of adequate methods of contraception;

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

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

For tablets with a dosage of 40 mg in addition to the above contraindications:

- Patients who are predisposed to developing myopathy / rhabdomyolysis, namely: renal failure of moderate severity (creatinine clearance less than 60 ml / min), hypothyroidism, personal or family anamnesis of muscle diseases, myotoxicity when receiving other inhibitors of HMG-CoA reductase or fibrates in the anamnesis, excessive use of alcohol, a condition that can lead to an increase in the plasma concentration of rosuvastatin, simultaneous reception of fibrates, patients of the Asian race.

Carefully:

For tablets with dosages of 5 mg, 10 mg, 15 mg, 20 mg:

Presence of myopathy / rhabdomyolysis risk - renal failure, hypothyroidism, personal or family anamnesis of hereditary muscle diseases and previous. a history of muscle toxicity with other HMG-CoA reductase inhibitors or fibrates, excessive alcohol use, age over 65 years, conditions in which rose plasma concentrations of rosuvastatin have been noted, race (Asian race), concomitant use with fibrates.section "Pharmacokinetic properties"); a history of liver disease, sepsis, arterial hypotension, extensive surgery, trauma, severe metabolic, proteinuria, endocrine or electrolyte disorders, or uncontrolled convulsive seizures.

For tablets with a dosage of 40 mg:

Renal failure of mild severity (CC 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.

Patients with hepatic insufficiency

Data or experience of the drug in patients with a score above 9 on the Child-Pugh scale are not available.

Pregnancy and lactation:

Rosuvastatin is contraindicated in pregnancy and during breastfeeding. 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.

Rosuvastatin is excreted in the milk of rats.

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

Dosing and Administration:

Inside, do not chew and do not grind the tablet, swallow whole, squeezed water.

Can be used at any time of the day, regardless of food intake.

Before starting rosuvastatin therapy, 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 purpose of therapy and the response to treatment, taking into account the current recommendations on target levels 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 rosuvastatin 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 developing 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 of therapy (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 be performed only 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 be under the supervision of a physician (in lipidological, diabetological or cardiological clinics) (see section "Special instructions").

It is recommended especially careful monitoring of patients receiving the drug in a dose of 40 mg. It is not recommended to use a dose of 40 mg by patients who have not previously consulted a doctor.

After 2-4 weeks of therapy and / or with an increase in the dose of rosuvastatin, monitoring of lipid metabolism parameters is necessary (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. Contraindicated use of all dosages of rosuvastatin in patients with severe renal failure (creatinine clearance less than 30 ml / min). Contraindicated use of the drug at a dosage of 40 mg to patients with moderate impaired renal function (creatinine clearance less than 60 ml / min) (see section "Special instructions" and "Pharmacodynamics"). Patients with moderate impairment of renal function are recommended an initial dose of 5 mg.

Patients with hepatic insufficiency

The experience of using the drug in patients with a score above 9 on the Child-Pugh scale is not available (see the section "Pharmacodynamics" and "Special instructions"). Rosuvastatin is contraindicated in patients with liver disease in the active phase (see the section "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 in the appointment of rosuvastatin to these patient groups. Contraindicated use of the drug in a dose of 40 mg by patients of the Asian race. The recommended initial dose for patients of the Asian race is 5 mg.

Patients who are predisposed to myopathy

Contraindicated use of the drug in a dose of 40 mg to patients with factors predisposed to the development of myopathy (see section "Contraindications"). The recommended initial dose for this group of patients is 5 mg.

Side effects:

The incidence of side effects is dose-dependent: often (1-10%), infrequently (0.1-1%), rarely (0.01-0.1%), very rarely (<0.01%), frequency unknown or the frequency is not set (can not be calculated from available data), including individual messages.

From the nervous system: often - headache, dizziness, asthenic syndrome; very rarely - polyneuropathy, memory loss.

From the digestive system: often - constipation, nausea, abdominal pain; rarely - pancreatitis, reversible transient dose-dependent increase in the activity of "liver" transaminases; very rarely - jaundice, hepatitis; the frequency of unspecified diarrhea.

From the endocrine system: often - type 2 diabetes.

From the side of the musculoskeletal system: often - myalgia; rarely - myopathy (including myositis), rhabdomyolysis (simultaneously with impaired renal function, against the background of taking the drug at a dose of 40 mg); very rarely - arthralgia.

From the urinary system: tubular proteinuria (in less than 1% of cases - for doses of 10 mg and 20 mg, 3% of cases for a dose of 40 mg), very rarely - hematuria.

Allergic reactions: infrequently - itchy skin, rash, hives; rarely - angioedema, unspecified frequency - Stevens-Johnson syndrome.

From the laboratory indicators: the transient dose-dependent increase in activity of creatine phosphokinase (CKF) (when the activity of CK is increased by more than 5 times compared with the upper limit of the norm, therapy should be temporarily suspended), increased activity of gamma-glutamyltranspeptidase, alkaline phosphatase, bilirubin, thyroid dysfunction.

Other: depression, sleep disorder.

In post-marketing application statins (simvastatin, atorvastatin, rosuvastatin, etc.), the following adverse effects were reported: cough, dyspnea, peripheral edema,loss or loss of memory, sexual dysfunction, gynecomastia, hyperglycemia, increased concentrations of glycolic hemoglobin, single cases of interstitial lung disease (especially with prolonged use), cases of immunosupplemented necrotizing myopathy, thrombocytopenia.

Overdose:

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

Treatment: there is no specific treatment for an overdose of rosuvastatin. It is recommended to carry out symptomatic treatment and supportive measures. It is necessary to monitor the liver function and the activity of CK. Hemodialysis is ineffective.

Interaction:

Cyclosporine: Cyclosporin enhances the effect of rosuvastatin. With simultaneous application of rosuvastatin and cyclosporine AUC rosuvastatin was an average of 7 times higher than that seen in healthy volunteers (see section "Contraindications"). Simultaneous application leads to an increase in concentration rosuvastatin in the blood plasma 11 times, the concentration of cyclosporine in the blood plasma does not change.

Antagonists of vitamin K: The beginning 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 prothrombin time (International Normalized Relationships - MHO). The cancellation of rosuvastatin or a decrease in the dose of the drug may lead to a decrease MHO. In such cases, monitoring is recommended MHO.

Gemfibrozil and other lipid-lowering drugs: Gemfibrozil enhances the effect of rosuvastatin. The simultaneous use of rosuvastatin and gemfibrozil leads to an increase in 2 times C_m_Oh in blood plasma and AUC rosuvastatin (see section "Special instructions").

Based on the data on the specific interaction, no pharmacokinetically significant interaction with fenofibrates is expected, possibly pharmacodynamic interaction.

Gemfibrozil, fenofibrate, other fibrates and lipid-lowering doses of nicotinic acid (exceeding or equivalent to 1 g / day) increased the risk of myopathy with concomitant use with HMG-CoA reductase inhibitors, possibly due to the fact that they can cause myopathy and when used in monotherapy (see .section "Special instructions"). When the drug is simultaneously taken with gemfibrozil and other lipid-lowering drugs, the initial dose of 5 mg is recommended for patients.

Ezetimibe: The simultaneous use of rosuvastatin and ezetimibe was not accompanied by a change AUC and C_m_Oh both preparations.

Antacids: The simultaneous use of rosuvastatin and suspensions of antacids containing aluminum and magnesium 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.

Inhibitors of proteases: Despite the fact that the exact mechanism of interaction is unknown, simultaneous administration of protease inhibitors can lead to a significant increase in exposure to rosuvastatin. A pharmacokinetic study on the simultaneous use of 20 mg rosuvastatin with a combined preparation containing two protease inhibitors (400 mg lopinavir / 100 mg ritonavir) in healthy volunteers resulted in approximately a twofold and fourfold increase in AUC_0-24 and C_m_Oh rosuvastatin, respectively. Therefore, simultaneous administration of rosuvastatin and protease inhibitors in the treatment of patients with HIV is not recommended.

Erythromycin: The simultaneous use of rosuvastatin and erythromycin leads to a decrease AUC_(0-t)rosuvastatin by 20% and C_m_Oh rosuvastatin by 30%. Such interaction can arise as a result of increased intestinal motility caused by the administration of erythromycin.

Oral contraceptives / hormone replacement therapy: The simultaneous use of rosuvastatin and oral contraceptives increases AUC ethinylestradiol and AUC norgistril 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.

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 non-core substrate for these isoenzymes. There was no clinically significant interaction between rosuvastatin and fluconazole (inhibitor CYP2C9 and CYP3A4) and ketoconazole (inhibitor of CYP2A6 and CYP3A4). Simultaneous use of rosuvastatin and itraconazole (CYP3A4 inhibitor) increases rosuvastatin AUC by 28% (clinically insignificant). Thus, no interaction is expected associated with the metabolism of cytochrome P 450.

Other medicines: No clinically significant interaction between rosuvastatin and digoxin is expected. Simultaneous use with drugs that reduce the concentration of endogenous steroid hormones (including cimetidine, ketoconazole, spironolactone) increases the risk of reducing endogenous steroid hormones.

Special instructions:

Before the start of therapy and throughout the treatment period, a standard lipid-lowering diet should be followed. During treatment, every 2-4 weeks, the lipid profile should be monitored and, if necessary, adjusted the dose of the drug.

In patients taking the drug at a dose of 40 mg, it is recommended to monitor the indicators of kidney function.

Determination of the activity of CKD should not be performed after intensive physical exertion or in the presence of other possible causes of increase in CK, which may lead to incorrect interpretation of the results. If the initial concentration 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).

Patients with risk factors for rhabdomyolysis should consider the relationship between risk and the potential benefits of therapy and carry out clinical follow-up throughout the course of treatment.

Inform the patient of the need to report immediately to the doctor about cases of unexpected 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 compared with the upper limit of the norm) or if the symptoms from the muscles are pronounced and cause a dailyDiscomfort (even if the activity of CK is 5 times less than the upper limit of the norm). If symptoms disappear and CPK activity returns to normal, re-administration of rosuvastatin or other HMG-CoA reductase inhibitors in smaller doses should be considered with careful monitoring of the patient. Control of CKK in the absence of symptoms is not advisable. There were no signs of an increase in the effect on skeletal musculature when taking rosuvastatin 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), azole antifungal agents, protease inhibitors and macrolide antibiotics.

Gemfibrozil increases the risk of myopathy when combined with certain HMG-CoA reductase inhibitors. Thus, simultaneous use of rosuvastatin and gemfibrozil is not recommended. The risk-to-benefit ratio should be carefully weighed while using rosuvastatin and fibrates or nicotinic acid in lipid-lowering doses.

In 2-4 weeks after the start of treatment and / or with an increase in the dose of rosuvastatin, control of the lipid metabolism parameters is necessary (if necessary, dose correction is required).

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.

Taking rosuvastatin should stop or reduce the dose of the drug if the activity level of 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, the treatment of underlying diseases should be performed prior to the initiation of treatment with rosuvastatin.

During treatment with rosuvastatin should be discarded from eating green tea because of the possibility of developing seizures.

Effect on the ability to drive transp. cf. and fur:Care should be taken when driving a vehicle or work associated with increased concentration of attention and a psychomotor reaction (dizziness may occur during therapy).

Form release / dosage:

Film-coated tablets, 5 mg, 10 mg, 15 mg, 20 mg and 40 mg.

Packaging:

Dosages of 5, 10, 15 and 20 mg. For 7 or 14 tablets in a planar cell pack.

1 contour pack of 7 tablets or 2 contour packs of 14 tablets together with instructions for use in a pack of cardboard.

The dosage of 40 mg. 7 tablets in a planar cell package. For 1 or 4 contour mesh packages together with instructions for use in a pack of cardboard.

Storage conditions:In a dry, the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:2 years.

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

Terms of leave from pharmacies:On prescription

Registration number:PL-000651

Date of registration:28.09.2011

Expiration Date:28.09.2016

The owner of the registration certificate:FarmSirma Soteks, ZAO FarmSirma Soteks, ZAO Russia

Manufacturer: & nbsp

SIEGFRIED GENERICS, Ltd Malta

FarmSirma Soteks, ZAO Russia

Representation: & nbspPharm Company Sotex CJSC Pharm Company Sotex CJSC Russia

Information update date: & nbsp27.12.2016

Illustrated instructions

Instructions

Rosuvastatin (Rozuvastatine)