Crestor pills 10mg, 28pcs

Composition

1 tablet contains:

Active ingredient:  rosuvastatin (in the form of calcium salt) 10 mg;

Auxiliary substances:

lactose monohydrate;

MCC;

calcium phosphate;

crospovidone;

magnesium stearate.

Pharmacological action

Rosuvastatin is a selective competitive inhibitor of HMG-CoA reductase, an enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a cholesterol precursor. The main target of rosuvastatin action is the liver, where cholesterol synthesis and LDL catabolism are 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 VLDL synthesis, thereby reducing the total number of LDL receptors in the liver. LDL and VLDL.

Crestor® reduces elevated concentrations of cholesterol-LDL, total cholesterol, triglycerides (TG), increases the concentration of HDL-C and decreases concentrations of apolipoprotein b (Apob), HS-delpup, cholesterol-VLDL, TG-VLDL and increases the concentration of apolipoprotein A-I (Apoa-I) (see tables 1 and 2) reduces the ratio of cholesterol-LDL/HDL-C, total cholesterol/HDL-C and HS-nalit/ HDL-C and the ratio of Apob/Apoa-I.

The therapeutic effect develops within 1 week after starting therapy with Crestor®, 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 use of the drug.

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

In 80% of patients with Fredrickson type IIA and IIb hypercholesterolemia (mean baseline LDL-C concentration of about 4.8 mmol/l) against the background of taking the drug at a dose of 10 mg, the concentration of LDL-C reaches values of less than 3 mmol/l.

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

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

In patients with hypertriglyceridemia with an initial TG concentration of 273 to 817 mg / dl, treated with Crestor® at a dose of 5 to 40 mg 1 time per day for 6 weeks, the concentration of TG in blood plasma significantly decreased (see table 2).

An additive effect is observed in combination with fenofibrate in relation to the concentration of TG and with nicotinic acid in lipid-lowering doses in relation to the concentration of HDL-C (see “Special instructions”).

The METEOR study, which included 984 patients aged 45-70 years with a low risk of coronary artery disease (10-year Framingham scale risk of less than 10%), an average LDL-C concentration of 4 mmol / L (154.5 mg / dl), and subclinical atherosclerosis (which was assessed by the thickness of the carotid intima-media complex — MCI), examined the effect of rosuvastatin on the thickness of the intima-media complex.

Patients received either rosuvastatin 40 mg / day or placebo for 2 years. Rosuvastatin therapy significantly slowed the rate of progression of maximal IMT for 12 carotid artery segments compared to placebo with a difference of -0.0145 mm/year (95% confidence interval -0.0196 to -0.0093; pMETEOR was performed in patients at low risk of coronary heart disease, for whom a dose of Crestor® 40 mg is not recommended. The 40 mg dose should be used in patients with severe hypercholesterolemia and a high risk of cardiovascular disease.

Results of the JUPITER study (Rationale for using statins for primary prevention: an interventional study evaluating rosuvastatin) in 17,802 patients, rosuvastatin significantly reduced the risk of cardiovascular complications (252 in the placebo group compared to 142 in the rosuvastatin group) (p

Pharmacokinetics

Absorption and distribution

of rosuvastatin Cmax in blood plasma is achieved approximately 5 hours after oral use. Absolute bioavailability is approximately 20%.

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

Metabolism

It undergoes a limited metabolism (about 10%). Rosuvastatin is a non-core substrate for metabolism by cytochrome P450 enzymes. The main isoenzyme involved in the metabolism of rosuvastatin is CYP2C9. The isoenzymes CYP2C19, CYP3A4, and CYP2D6 are less involved in metabolism.

The main identified metabolites of rosuvastatin are N-desmethyl and lactone metabolites. N-desmethyl is approximately 50% less active than rosuvastatin, and the lactone metabolites are pharmacologically inactive. More than 90% of the pharmacological activity in inhibiting circulating HMG-CoA reductase is provided by rosuvastatin, the rest by its metabolites.

Deduction

Approximately 90% of the rosuvastatin dose is excreted unchanged through the intestine (including absorbed and unabsorbed rosuvastatin). The remaining part is excreted by the kidneys. Plasma T1 / 2 is approximately 19 h. T1 / 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 with other HMG-CoA reductase inhibitors, the hepatic uptake of rosuvastatin involves a membrane cholesterol transporter that plays an important role in hepatic elimination of rosuvastatin.

Linearity

Systemic exposure to rosuvastatin increases in proportion to the dose. Pharmacokinetic parameters do not change with daily use.

Special patient populations

Age and gender. Gender 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 AUC and Cmax of rosuvastatin in Asian patients (Japanese, Chinese, Filipino, Vietnamese, and Korean) compared to Europeans; in Indian patients, an increase in the median AUC and Cmax by 1.3 times was shown. Pharmacokinetic analysis revealed no clinically significant differences in pharmacokinetics between Europeans and Negroes.

Kidney failure. In patients with mild to moderate renal insufficiency, the plasma concentration of rosuvastatin or N-desmethyl does not change significantly. In patients with severe renal insufficiency (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 plasma concentration of rosuvastatin in hemodialysis patients was approximately 50% higher than in healthy volunteers.

Liver failure. In patients with various stages of hepatic insufficiency, there was no increase in T1 / 2 of rosuvastatin in patients with a score of 7 or lower on the Child-Pugh scale. Two patients with Child-Pugh scores of 8 and 9 showed at least a twofold increase in T1/2. There is no experience of using rosuvastatin in patients with a score higher than 9 on the Child-Pugh scale.

Indications

• of primary hypercholesterolemia according to Fredrickson (type IIa including heterozygous family hypercholesterolemia) or mixed hypercholesterolemia (type IIb) as an adjunct to diet when diet and other non-pharmacological treatments (e. g. exercise, weight reduction) are insufficient;
• family homozygous hypercholesterolemia as an adjunct to diet and other lepidotrigla therapy (e. g. LDL-apheresis) or if such therapy is not effective enough;
• hypertriglyceridemia (type IV according to Fredrickson) as a Supplement to the diet;
• slow the progression of atherosclerosis as an adjunct to diet in patients who have shown therapy to reduce the concentration of total cholesterol and cholesterol-LDL;
• primary prevention of major cardiovascular complications (stroke, heart attack, arterial revascularization) in adult patients without clinical signs of coronary heart disease but with an increased risk of its development (the age of 50 years for men and over 60 years for women, the increased concentration of C-reactive protein (≥2 mg/l) in the presence of at least one additional risk factors such as hypertension, low concentration of HDL-C, Smoking, family history of early coronary heart disease).

Contraindications

• Hypersensitivity;
• liver disease in the active phase, including a persistent increase in serum transaminases and any increase of transaminases in blood serum (more than 3 times compared to the ULN);
• prominent impairment of renal function (Cl creatinine less than 30 ml/min);
• myopathy;
• concomitant use of cyclosporine;
• in women: pregnancy, lactation, lack of adequate methods of contraception;
• patients predisposed to the development of myotoxic complications;
• lactose intolerance, lactase deficiency or glucose-galactose malabsorption (the drug contains lactose).

Side effects

The immune system: rarely — hypersensitivity reactions, including angioedema.

Endocrine system: often — type 2 diabetes mellitus.

From the central nervous system: often — headache, dizziness.

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

From the side of the skin: infrequently — skin pruritus, rash, urticaria.

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

Other services: often-asthenic syndrome.

From the urinary system: Proteinuria may occur in patients treated with Crestor. Changes in the amount of protein in the urine (from no or trace amounts to ++ or more) are observed in less than 1% of patients receiving 10-20 mg of the drug, and in approximately 3% of patients receiving 40 mg of the drug.

A slight change in the amount of protein in the urine was observed when taking 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 musculoskeletal system: when using the drug Crestor® in all dosages and especially when taking doses of the drug exceeding 20 mg — myalgia, myopathy (including myositis); in rare cases — rhabdomyolysis with or without acute renal failure.

A dose-dependent increase in creatine phosphokinase (CPK) activity is observed in a small number of patients taking rosuvastatin. In most cases, it was minor, asymptomatic, and temporary. In case of an increase in the level of CPK (more than 5 times compared to ULN), therapy should be suspended (see “Special instructions”).

From the liver: when using rosuvastatin, a dose-dependent increase in the activity of hepatic transaminases is observed in a small number of patients. In most cases, it is minor, asymptomatic, and temporary.

Laboratory parameters: increased concentration of glucose, bilirubin, GGTP activity, alkaline phosphatase, signs of thyroid dysfunction.

Post-marketing application

The following side effects have been reported with post-marketing use of Crestor.

From the digestive tract: very rarely-jaundice, hepatitis; rarely-increased activity of hepatic transaminases; unspecified frequency-diarrhea.

From the musculoskeletal system: very rarely — arthralgia; unspecified frequency-immune-mediated necrotizing myopathy.

From the central nervous system: very rarely — polyneuropathy, memory loss.

Respiratory system disorders: unspecified frequency-cough, shortness of breath.

From the urinary system: very rarely — hematuria.

From the side of the skin and subcutaneous fat: unspecified frequency-Stevens-Johnson syndrome.

From the side of the reproductive system and breast: unspecified frequency-gynecomastia.

Other services: unspecified frequency-peripheral edema.

Interaction

Effect of other medications on rosuvastatin

Transport protein inhibitors: rosuvastatin binds to some transport proteins, in particular, to OATP1 In 1 and BCRP. 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 myopathy (see Table 3 and sections “Dosage and use” and “Special Instructions”).

Cyclosporine: with the simultaneous use of rosuvastatin and cyclosporine, the AUC of rosuvastatin was on average 7 times higher than that observed in healthy volunteers (see Table 3). It does not affect the plasma concentration of cyclosporine. Crestor® is contraindicated in patients taking cyclosporine (see section “Contraindications”).

Human immunodeficiency virus (HIV)protease inhibitors: Although the exact mechanism of interaction is unknown, co-use of HIV protease inhibitors can lead to a significant increase in exposure to rosuvastatin (see Table 3). A pharmacokinetic study on the simultaneous use of 20 mg of rosuvastatip with a combination drug containing two HIV protease inhibitors (400 mg of lopinavir/100 mg of ritonavir) in healthy volunteers resulted in approximately a twofold or fivefold increase in AUC(0-24) and Cmax rosuvastatin, respectively. Therefore, simultaneous use of rosuvastatin and HIV protease inhibitors is not recommended (see sections “Dosage and use”, “Special instructions”, Table 3).

Gemfibrozil and other lipid-lowering agents: the combined use of rosuvastatin and gemfibrozil leads to a 2-fold increase in the maximum concentration of rosuvastatin in blood plasma and the AUC of rosuvastatin (see the section “Special instructions”). Based on the specific interaction data, no pharmacokinetically significant interaction with fenofibrate is expected, and a pharmacodynamic interaction is possible.

Gemfibrozil, fenofibrate, other fibrates and lipid-lowering doses of nicotinic acid increased the risk of myopathy when co-administered with HMG-CoA reductase inhibitors, possibly due to the fact that they can cause myopathy when used in monotherapy (see section “Special instructions”). When taking the drug simultaneously with gemfibrozil, fibrates, nicotinic acid in lipid-lowering doses (more than 1 g / day), patients are recommended an initial dose of 5 mg, taking a dose of 40 mg is contraindicated when co-administered with fibrates (see the sections “Contraindications”, “Method of use and doses”, “Special Instructions”). Ezetimibe: concomitant use of Crestor® at a dose of 10 mg and ezetimibe at a dose of 10 mg was accompanied by an increase in the AUC of rosuvastatin in patients with hypercholesterolemia (see Table 3). An increased risk of side effects due to the pharmacodynamic interaction between Crestor and ezetimibe cannot be excluded.

Antacids: concomitant use of rosuvastatin and antacid suspensions 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 applied 2 hours after taking rosuvastatin. The clinical significance of this interaction has not been studied.

Erythromycin: concomitant use of rosuvastatin and erythromycin resulted in a 20% decrease in rosuvastatin AUC and a 30% decrease in rosuvastatin cmax. This interaction may occur as a result of increased intestinal motility caused by taking erythromycin.

Cytochrome P450 isoenzymes: The results of in vivo and in vitro studies showed that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P 450 isoenzymes. In addition, rosuvastatin is a weak substrate for these isoenzymes. Therefore, rosuvastatin is not expected to interact with other drugs at the level of metabolism involving cytochrome P450 isoenzymes. There was no clinically significant interaction of rosuvastatin with fluconazole (an inhibitor of the CYP2C9 and CYP3A4 isoenzymes) and ketoconazole (an inhibitor of the CYP2A6 and CYP3A4 isoenzymes).

Fusidic acid: studies on the interaction of rosuvastatin and fusidic acid have not been conducted. As with other statins, there have been post-marketing reports of rhabdomyolysis with co-use of rosuvastatin and fusidic acid. Patients should be closely monitored. If necessary, it is possible to temporarily stop taking rosuvastatin.

Drug interactions that require dose adjustment of rosuvastatin (see table 3) The dose of Crestor® should be adjusted if it is necessary to use it together with drugs that increase exposure to rosuvastatin. You should read the instructions for use of these drugs before prescribing them together with Crestor®. If exposure is expected to increase by a factor of 2 or more, the initial dose of Crestor® should be 5 mg once a day. It is also necessary to adjust the maximum daily dose of Crestor®so that the expected exposure to rosuvastatin does not exceed that for a dose of 40 mg taken without simultaneous use of drugs that interact with rosuvastatin. For example, the maximum daily dose of Crestor® when used concomitantly with gemfibrozil is 20 mg (1.9-fold increase in exposure), with ritonavir/atazanavir-10 mg (3.1-fold increase in exposure).

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

Effect of rosuvastatin on other medications

Vitamin K antagonists: Starting rosuvastatin therapy or increasing the dose of the drug in patients receiving concomitant vitamin K antagonists (for example, warfarin) may lead to an increase in the International Normalized Ratio (MHO). Discontinuation of rosuvastatin or a reduction in the dose of the drug may lead to a decrease in MHO. In such cases, MHO monitoring is recommended.

Oral contraceptives/Hormone replacement therapy: concomitant use of rosuvastatin and oral contraceptives increases the AUC of ethinyl estradiol and AUC of norgestrel by 26% and 34%, respectively. Such an increase in plasma concentration should be taken into account when selecting the dose of oral contraceptives.

Pharmacokinetic data on the concomitant use of Crestor® and hormone replacement therapy are not available, therefore, a similar effect cannot be excluded when using this combination. However, this combination was widely used during clinical trials and was well tolerated by patients.

Other medicinal products: no clinically significant interaction of rosuvastatin with digoxin is expected.

How to take, course of use and dosage

Inside, without chewing or crushing the tablet, swallowing whole, washed down with water. The drug can be prescribed at any time of the day, regardless of food intake.

Before starting therapy with Crestor, the patient should start following a standard hypocholesterolemic diet and continue to follow it during treatment. The dose of the drug should be selected individually, depending on the goals of therapy and the therapeutic response to treatment, taking into account current recommendations for the target concentration of lipids.

The recommended starting dose for patients starting to take the drug, or for patients transferred from taking other HMG-CoA reductase inhibitors, should be 5 or 10 mg of Crestor 1 time per day. When choosing the initial dose, you should be guided by the individual cholesterol concentration and take into account the possible risk of cardiovascular complications, as well as the potential risk of side effects. If necessary, the dose can be increased to a larger one after 4 weeks.

Due to the possible development of side effects when taking a dose of 40 mg, compared with lower doses of the drug, an increase in the dose to 40 mg, after an additional dose above the recommended initial dose for 4 weeks of therapy, can only be carried out in patients with severe hypercholesterolemia and at high risk of cardiovascular complications (especially in patients with familial hypercholesterolemia), Especially careful monitoring of patients receiving the drug at a dose of 40 mg is recommended.

It is not recommended to prescribe 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 Crestor®, monitoring of lipid metabolism parameters is necessary (if necessary, dose adjustment is required).

Elderly patients. No dose adjustment is required.

Patients with renal insufficiency. No dose adjustment is required in patients with mild or moderate renal insufficiency. In patients with severe renal insufficiency (creatinine clearance less than 30 ml/min), the use of Crestor® is contraindicated. It is contraindicated to use the drug at a dose of 40 mg in patients with moderate renal impairment (creatinine clearance 30-60 ml / min). In patients with moderate renal impairment, an initial dose of 5 mg is recommended.

Patients with hepatic insufficiency. Crestor® is contraindicated in patients with active liver disease.

Special populations

Ethnic groups. When studying the pharmacokinetic parameters of rosuvastatin in patients belonging to different ethnic groups, an increase in the systemic concentration of rosuvastatin in Japanese and Chinese was noted. This fact should be taken into account when prescribing Crestor® to these groups of patients. When prescribing doses of 10 and 20 mg, the recommended starting dose for patients of the Mongolian race is 5 mg. It is contraindicated to prescribe the drug at a dose of 40 mg to patients of the Mongolian race.

Patients predisposed to myopathy. It is contraindicated to prescribe the drug at a dose of 40 mg to patients with factors that may indicate a predisposition to the development of myopathy. When prescribing doses of 10 and 20 mg, the recommended initial dose for this group of patients is 5 mg.

Overdose

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

Treatment: there is no specific antidote.

If necessary, carry out symptomatic therapy, it is necessary to monitor liver function and CKD levels. It is unlikely that hemodialysis will be effective.

Special instructions

Use Crestor with caution in the presence of risk factors for rhabdomyolysis (including renal failure, hypothyroidism, personal or family history of hereditary muscle diseases and a previous history of muscle toxicity when using other HMG-CoA reductase inhibitors or fibrates), with chronic alcoholism, patients over the age of 70, with a history of liver diseases, sepsis, hypotension, with extensive surgical interventions, injuries, severe metabolic endocrine or electrolyte disorders, with uncontrolled epilepsy.

Before starting Crestor therapy, the patient should start following a standard lipid-lowering diet and continue to follow it throughout the entire treatment period. The dose of the drug is selected individually, depending on the goals of therapy and the response to treatment, taking into account generally accepted recommendations.

When using Crestor at a dose of 40 mg, it is recommended to monitor the indicators of renal function.

In patients with existing risk factors for rhabdomyolysis, it is necessary to consider the risk – benefit ratio of therapy and conduct clinical monitoring.

The patient should be informed of the need to immediately inform the doctor about cases of unexpected muscle pain, muscle weakness or spasms, especially in combination with malaise and fever. In such patients, the level of CPK should be determined. Therapy should be discontinued if the CPK level is significantly increased (more than 5 times higher than the ULN) or if muscle symptoms are severe and cause daily discomfort (even if the CPK level is 5 times lower than the ULN). If symptoms disappear and CK levels return to normal, consideration should be given to re-prescribing Crestor or other HMG-CoA reductase inhibitors in lower doses, with careful monitoring of the patient.

CPK determination should not be performed after intense physical activity or in the presence of other possible causes of increased CPK, which may lead to misinterpretation of the results obtained. If the initial CPK level is significantly elevated (5 times higher than ULN), a second measurement should be performed after 5-7 days. Do not start therapy if a repeated test confirms the initial CPK level (5 times higher than ULN).

Routine monitoring of CPK in the absence of symptoms is not advisable.

There were no signs of increased toxic effects on skeletal muscles when using Crestor as part of combination therapy. An increased incidence of myositis and myopathy has been reported in patients treated with other HMG-CoA reductase inhibitors in combination with fibrinic acid derivatives (including gemfibrozil), cyclosporine, nicotinic acid, azole antifungal drugs, protease inhibitors, and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when co-administered with certain HMG-CoA reductase inhibitors. Therefore, simultaneous use of Crestor and gemfibrozil is not recommended. The risk-benefit ratio of Crestor and fibrates or niacin should be carefully weighed.

It is recommended to determine liver function indicators before the start of therapy and 3 months after the start of therapy. Taking Crestor should be discontinued or the dose of the drug should be reduced if the level of transaminase activity in the blood serum is 3 times higher than the ULN. In patients with hypercholesterolemia due to hypothyroidism or nephrotic syndrome, treatment of the underlying diseases should be carried out before starting treatment with Crestor.

Influence on the ability to drive motor vehicles and manage mechanisms

When engaging in potentially dangerous activities, patients should be aware that dizziness may occur during therapy.

Form of production

Crestor tablets, pink film-coated, round, biconvex, with the inscription “ZD4522 10” on one side.

Storage conditions

At a temperature not exceeding 30 °C

Shelf life

3 years

Active ingredient

Rosuvastatin

Conditions of release from pharmacies

By prescription

Dosage form

Tablets