Crestor (Rosuvastatin) RosuvastatinRosuvastatin10 mg

Pharmacological properties Crestor 10 mg:

Crestor Rosuvastatin- a selective competitive inhibitor of HMG-CoA reductase, an enzyme that converts 3-hydroxy-3-metilglutarilkoenzim A to mevalonate, the precursor of cholesterol. The main target of rosuvastatin – the liver, where the synthesis of cholesterol and LDL catabolism.

Rosuvastatin increases the number of hepatic LDL receptors on the cell surface, increasing the capture and catabolism of LDL, which leads to inhibition of synthesis of VLDL, thereby reducing the total number of LDL and VLDL.

Rosuvastatin reduces elevated LDL cholesterol, total cholesterol and triglycerides, a slight increase HDL cholesterol levels, reduces the amount of apolipoprotein B (apoB), cholesterol neLPVP, VLDL cholesterol, VLDL triglycerides and increases the number of apolipoprotein A-I (ApoA-I), reduces the ratio LDL cholesterol / HDL cholesterol, total cholesterol / HDL cholesterol and neLPNP / HDL cholesterol ratio and apoB / ApoA-I.

The therapeutic effect appears within 1 week after initiation of therapy Crestor, after 2 weeks of treatment effect is 90% of the maximum possible. The maximum effect is usually achieved within 4 weeks and then stored permanently.

Clinical efficacy

Crestor is effective in adult patients with giperholesterinemiey, hypertriglyceridemia, and without regard to race, gender or age, including patients with diabetes and family giperholesterinemiey.

About 80% of patients with IIa and IIb giperholesterinemiey type (mean baseline LDL-C is approximately 4.8 mmol / l) in patients receiving the drug at a dose of 10 mg of LDL-C reaches values

In patients with homozygous familial hypercholesterolemia, taking Crestor in doses of 20 and 40 mg, the average reduction in LDL-C was 22%.

Observed an additive effect in combination with fenofibrate in relation to the contents of TG and nicotinic acid content in relation to HDL cholesterol.

Investigation of the influence of rosuvastatin to reduce the number of complications arising from lipid disorders such as IBS, is not yet complete.

Absorption and distribution

The maximum concentration of rosuvastatin in plasma is reached after about 5 hours after ingestion. Bioavailability is about 20%. Rosuvastatin is accumulated in the liver. The volume of distribution is approximately 134 liters. About 90% of rosuvastatin is associated with plasma proteins, primarily to albumin.

Metabolism

Rosuvastatin undergoes limited metabolism (approximately 10%). Rosuvastatin is a substrate for non-core metabolic enzymes cytochrome P450. The main isoenzyme participating in the metabolism of rosuvastatin, a CYP 2C9. Enzymes CYP 2C19, CYP 3A4 and CYP 2D6 are less involved in the metabolism. The main metabolites of rosuvastatin – N-dismetil and lactone metabolites. N-dismetil approximately 50% less active than rosuvastatin, pharmacologically inactive lactone metabolites.

Breeding

About 90% of the dose rosuvastatin appears unchanged in the feces (unabsorbed and absorbed including rosuvastatin), the rest is excreted in the urine. The half-life from plasma is approximately 19 hours and does not change with increasing dose. Geometric mean clearance is approximately 50 l / h (coefficient of variation 21.7%). As in the case of other inhibitors of HMG-CoA reductase in the liver capture of rosuvastatin participating carrier of cholesterol, plays an important role in the hepatic elimination of the drug.

Linearity

Systemic exposure increases in proportion to rosuvastatin dose. When receiving multiple daily doses for the pharmacokinetic parameters are not changed.

Features of the population of patients

Age and sex do not affect the pharmacokinetics of rosuvastatin.

Ethnic Groups

The results of comparative studies of the pharmacokinetics of rosuvastatin in patients with Asians living in Asia, showed an increase in AUC and maximum concentration levels increase approximately twofold compared with Europeans, living in Europe and Asia. Influence of genetic factors and environmental factors on the obtained differences in pharmacokinetic parameters have been identified. Pharmacokinetic analysis among different ethnic groups revealed no clinically significant differences in pharmacokinetics between patients and Caucasians Blacks.

Patients with renal insufficiency

In patients with mild or moderate impaired renal function and the concentration of rosuvastatin N-dismetila in plasma does not change significantly. In patients with severe renal insufficiency (creatinine clearance

Patients with liver failure

At different degrees of hepatic failure have been identified to increase half-life of rosuvastatin in patients with grade 7 and lower Child-Pugh. However, two patients with scores 8 and 9 to Child-Pugh noted the increase in half-life at least twice. Experience of using rosuvastatin in patients with grade 9 and higher Child-Pugh absent.

Indications Crestor 10 mg:

- treatment of atherosclerosis in order to slow disease progression in patients who have shown lipid-lowering therapy;

- Primary hypercholesterolemia (type IIa, heterozygous hypercholesterolemia including familial) hypercholesterolemia or mixed (type IIb) as an adjunct to diet when diet and other non-pharmacological treatments (eg exercise, weight loss) is not sufficient – homozygous familial hypercholesterolemia as an adjunct to diet and other holesterinsnizhayuschey therapy (eg LDL apheresis-) or in cases where such therapy is not appropriate patient;

treatment of atherosclerosis in order to slow disease progression in patients who have shown lipid-lowering therapy.

APPLICATION Crestor 10 mg:

Before treatment the patient must be assigned a standard lipid-lowering diet, to be followed during treatment with Crestor. The dose selected individually depending on the goals of therapy and response to treatment, referring to the target levels of lipids.

For patients starting treatment for drug or to the replacement of receiving other HMG-CoA reductase Crestor recommended initial dose should be 5 or 10 mg / day. To select the initial dose guided by the individual cholesterol level and take into account the risk of complications in the cardiovascular system in the future, as well as the risk of side effects. If necessary, the dose can be consistently increase no earlier than 4 weeks (see Pharmacological properties). Due to the increased risk of side effects while taking Crestor 40 mg compared with lower doses increasing the dose to 40 mg permitted after 4 weeks of treatment only in patients with severe hypercholesterolaemia and at high risk for complications of the cardiovascular system (especially in patients with familial hypercholesterolemia). Increasing the dose appropriate to the case was not achieved the desired result in the application of 20 mg and provided that the patient will be under the close supervision of a specialist. Special monitoring is recommended at the beginning of receiving 40 mg.

Crestor is used inside without chewing, drinking water, the drug can be taken at any time with or without food.

Elderly patients dosage adjustment is needed.

Patients with renal insufficiency

Patients with mild renal impairment dose adjustment is needed. In patients with renal insufficiency moderately starting dose of Crestor should be 5 mg / day.

The maximum daily dose for patients with renal insufficiency is mild at 40 mg for patients with renal failure secondary level – 20 mg.

The use of Crestor in patients with severe renal impairment is contraindicated.

The dose of 40 mg is contraindicated in patients with renal failure secondary degree (creatinine clearance

Patients with liver failure

The experience of the drug in patients with liver failure with 9 points and above on a scale of Childe Pugh absent. Crestor is contraindicated in patients with liver disease in the active phase.

Ethnic Groups

In the study of pharmacokinetic parameters of rosuvastatin in patients belonging to different ethnic groups, reported increase its systemic concentration in patients of Mongoloid race. Such patients should begin treatment with a dose of 5 mg / day, maximum daily dose should be 20 mg dose of 40 mg / day is contraindicated.

Patients who have the propensity to develop myopathy (see CONTRAINDICATIONS).

In patients who are prone to the development of myopathy, the initial dose is 5 mg, the maximum daily dose – 20 mg dose of 40 mg / day is contraindicated.

CONTRAINDICATIONS Crestor 10 mg:

- Hypersensitivity to rosuvastatin or any other component of the drug;

- Liver disease in the active phase, including a persistent increase in the level of trasaminaz, which can not be explained, and any increase in transaminases more than 3 times the upper limit of normal;

- Marked impairment of renal function (creatinine clearance

- Myopathy;

- Concurrent use of cyclosporine;

- During pregnancy and lactation;

- The drug not be administered to women not using adequate methods of contraception;

- The age of 18.

The dose of 40 mg is contraindicated in patients with increased risk of myopathy / rhabdomyolysis. These factors include:

- Renal failure, moderate (creatinine clearance

- Hypothyroidism;

- Presence of inherited muscle diseases in the individual or family history;

- Miotoksichnost caused by any other inhibitors of HMG-CoA reductase inhibitors or fibrates in history;

- Alcohol abuse;

- Conditions that can lead to increased concentration of rosuvastatin in plasma;

- Belonging to the Mongoloid race;

- Concurrent use of fibrates.

SIDE EFFECTS Crestor 10 mg:

during treatment with Crestor side effects were moderate and disappeared on their own. The frequency of discontinuation of treatment during clinical trials in connection with the development of adverse events was

By the immune system

Rare: hypersensitivity reactions, including angioedema.

The nervous system

Common: headache, dizziness.

Gastro-intestinal tract

Common: constipation, nausea, abdominal pain.

Rare: pancreatitis.

Skin and appendages

Uncommon: pruritus, rash, urticaria.

On the part of the musculoskeletal system

Common: myalgia.

Rare: myopathy and rhabdomyolysis.

General disorders

Common: asthenia.

As with other inhibitors of HMG-CoA reductase, the rate of side effects depends on the dose.

Urinary system

Patients who use Crestor may be tubular proteinuria. Changing the amount of protein in the urine (from none to trace to + + or more) was seen in

On the part of the skeletal muscles

Myalgia, myopathy and rhabdomyolysis are rarely reported in patients taking any dose, and particularly in those who received the drug over 20 mg / day.

Dose-related increase in CK levels, seen in patients receiving rosuvastatin, in most cases was small, asymptomatic and transient. With an increase in CK levels (5 and more) with rosuvastatin treatment should be suspended.

Of the liver: how and when taking other inhibitors of HMG-CoA reductase, a small number of patients noted a dose-dependent increase in transaminase levels – in most cases small, asymptomatic and temporary.

In addition to the above, after the introduction of the drug in general medical practice have noted such phenomena:

On the part of gepatobilliarnoy

Rare: increased levels of transaminases.

Very rare: jaundice, hepatitis.

On the part of the musculoskeletal system

Rare: arthralgia.

The nervous system

Very rare: polyneuropathy.

SPECIAL INSTRUCTIONS Crestor 10 mg:

Before starting treatment. Crestor, like other inhibitors of HMG-CoA reductase inhibitors should be prescribed with caution in patients with susceptibility to the development of myopathy / rhabdomyolysis. Risk factors include: kidney failure, hypothyroidism, the presence of inherited muscle diseases in the individual or family history; miotoksichnost caused by intake of other inhibitors of MMC-CoA reductase inhibitors or fibrates in history; alcohol abuse, age older than 70 years, conditions that can lead to increased concentrations of rosuvastatin in plasma, the simultaneous use of fibrates.

In such cases it is necessary to consider the risks and benefits of treatment and patients are subject to careful medical supervision. If CK levels significantly increased (5 times or more) before the start of therapy, prescribe rosuvastatin should not be.

During treatment, the patient should be informed about the need for immediate medical reports on cases of unexpected muscle pain, muscle weakness or cramps, especially if they are combined with malaise and fever. These patients need to determine the level of creatine kinase. Treatment should be discontinued if CK levels significantly increased (5 times or more) or if muscle symptoms are pronounced and cause daily discomfort (with the CPK levels did not reach 5-fold increase). If the symptoms disappear and the level of creatine kinase returned to the physiological, should consider re-appointment of Crestor or other inhibitors of HMG-CoA reductase in smaller doses. Such patients need careful monitoring. Routine monitoring CK in the absence of symptoms inappropriate. During the clinical studies revealed no signs of the growing influence of the skeletal muscles while taking Crestor and concomitant therapy. However, reported an increase in the incidence of myositis and myopathy in patients who used other inhibitors of HMG-CoA reductase inhibitors in conjunction with fibrin derived acids, including gemfibrozil, with cyclosporine, nicotinic acid, azole antifungals, protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy, while the appointment with some inhibitors of HMG-CoA reductase inhibitors. Therefore, do not assign both Crestor and gemfibrozil. Need to carefully weigh the risks and potential benefits while the appointment of Crestor and fibrates or niacin.

Concomitant use of Crestor in doses of 40 mg with fibrates is contraindicated.

Crestor should not be administered to patients with severe acute conditions such as sepsis, hypotension, major surgery, trauma, difficult metabolic, endocrine or electrolyte disorders, or uncontrolled epilepsy, which may be risk factors for myopathy / rhabdomyolysis.

The effect on the kidneys. In patients receiving Crestor in high daily doses (mostly 40 mg), tubular proteinuria observed in most cases, temporary or short-term. This proteinuria was not evidence of acute or progression of existing kidney disease. Patients receiving the drug at a dose of 40 mg is recommended to periodically monitor the performance of renal function during the entire course of treatment.

Effects on skeletal muscle. In the treatment Crestor (especially at doses> 20 mg) was observed effects of the skeletal muscles, such as myalgia, myopathy and rhabdomyolysis is rarely. In very rare cases, the simultaneous use of inhibitors of HMG-CoA reductase inhibitor and ezetimibe observed the development of rhabdomyolysis.

Determination of creatine kinase. Determination of CK should not be done after intense exercise or if there are other possible causes of the increased creatine kinase, which can lead to misinterpretation of results. In the case when the initial level of CPK increased (5 times or more), a repeat test is necessary to carry out in 5-7 days. You should not start treatment if the second test confirms the initial high level of creatine kinase (5 times the upper limit of normal).

Children. Efficacy and safety of children has not been established. Experience in use in pediatric patients is limited to a small number of children (aged 8 years and older) with homozygous familial hypercholesterolemia. Crestor apply to the treatment of children is not recommended.

INTERACTION Crestor 10 mg:

Cyclosporine: the simultaneous use of rosuvastatin and cyclosporine AUC rosuvastatin was on average 7 times higher compared to that in healthy volunteers. Simultaneous application does not affect the concentration of cyclosporine in the blood plasma.

Vitamin K antagonists: As in the case of other inhibitors of HMG Co-A reductase inhibitors at the beginning of therapy in increasing doses in patients receiving both vitamin K antagonists (eg warfarin) may mark an increase in prothrombin time (INR – International Normalised Ratio). Removal of the drug or dose reduction leads to a decrease in INR. In such cases, monitoring of INR.

Gemfibrozil and other lipid-lowering agents: simultaneous use of rosuvastatin and gemifibrozila leads to an increase in the maximum concentration of rosuvastatin in plasma (Cmax) and AUC increased rosuvastatin twice. Pharmacokinetic interaction with fibrates is not expected, but there is a possibility of pharmacodynamic interactions. Gemfibrozil, other fibrates gemofibraty and lipid-lowering doses of nicotinic acid (or equivalent doses above 1 g / day) increased the risk of myopathy, while the use of inhibitors of HMG-CoA reductase inhibitors, probably due to the fact that the latter can cause myopathy when use as monotherapy. Thus patients are advised to begin therapy with 5 mg / day.

Ezetimibe: the simultaneous use of Crestor and ezetimibe did not lead to changes in the maximum kontsenrtratsii in serum and AUC for both drugs. Nevertheless, we should not exclude them farmakologicheskogoe interaction in terms of adverse reactions (see PRECAUTIONS).

Lopinavir / ritonavir: a farmakokineticheskoi study in healthy volunteers, concurrent use of Crestor with a combined product consisting of two protease inhibitors (400 mg lopinavira/100 ritonavora mg) was associated with an increase in AUC for Crestor is approximately 2 times the maximum concentration of about 5 times. Interactions with other protease inhibitors have not been studied. In the appointment of Crestor in patients with HIV taking lopinavir / ritonavir should be taken into account the ratio prolza / risk, especially early in treatment or when increasing the dose.

Antacids: the simultaneous use of rosuvastatin and antacids containing aluminum or magnesium hydroxide, leads to a decrease in plasma concentrations of rosuvastatin by 50%. This effect is less pronounced when taking antacids within 2 hours after taking rosuvastatin. The clinical significance of this interaction have not studied.

Erythromycin: concurrent use of erythromycin and rosuvastatin reduces the AUC by 20% rosuvastatin and rosuvastatin Cmax by 30%. Such an interaction may occur due to increased intestinal motility as a result of receiving erythromycin.

Oral contraceptives / hormone replacement therapy: the simultaneous use of rosuvastatin and oral contraceptives increases the AUC of ethinyl estradiol and norgestrel AUC of 26 and 34% respectively. Such an increase in plasma concentrations should be considered when assigning contraceptives. Pharmacokinetic data on the simultaneous use of Crestor and hormone replacement funds are not available, so this interaction can not be excluded. However, such a combination is widely used in clinical trials and patients tolerated it well.

Other drugs: a clinically significant interaction with digoxin is expected.

Cytochrome P450 enzymes: a study in vitro and in vivo studies have shown that rosuvastatin is not an inhibitor nor an inducer of cytochrome P450 enzymes. In addition, rosuvastatin is a poor substrate for these enzymes. Not defined clinically significant interaction between rosuvastatin and fluconazole (an inhibitor of 2A9 and SYR SYR 3A4) or ketoconazole (an inhibitor of 2A6 and P CY SYR 3A4). Simultaneous administration of rosuvastatin and itraconazole (inhibitor CY R3A4) increases the AUC rosuvastatin by 28% (no clinical significance). Thus, the interaction associated with the metabolism of cytochrome P450 are not expected.

Overdose Crestor 10 mg:

No specific treatment, treatment is symptomatic, supportive therapy is recommended, requires monitoring of liver function and CK levels. The effectiveness of hemodialysis is unlikely.