CRESTOR

Active material: Rosuvastatin
When ATH: C10AA07
CCF: Lipid-lowering drugs
ICD-10 codes (testimony): E78.0, E78.2
When CSF: 16.01.01
Manufacturer: ASTRAZENECA UK Ltd. (Great Britain)

PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING

Pills, coated Pink colour, round, lenticular, Engraved “ZD4522 10” on one side and a notch on the other side.

Excipients: lactose monohydrate, microcrystalline cellulose, calcium phosphate, krospovydon, magnesium stearate.

The composition of the shell: lactose monohydrate, gipromelloza (E464), glycerol triacetate, Titanium dioxide (E171), iron oxide red (E172), Purified water.

7 PC. – blisters (1) – packs cardboard.
14 PC. – blisters (2) – packs cardboard.

Pills, coated Pink colour, round, lenticular, Engraved “ZD4522 20” on one side.

Excipients: lactose monohydrate, microcrystalline cellulose, calcium phosphate, krospovydon, magnesium stearate.

The composition of the shell: lactose monohydrate, gipromelloza (E464), glycerol triacetate, Titanium dioxide (E171), iron oxide red (E172), Purified water.

7 PC. – blisters (1) – packs cardboard.
14 PC. – blisters (2) – packs cardboard.

Pills, coated Pink colour, Oval, lenticular, Engraved “ZD4522” on one side and “40” – another.

Excipients: lactose monohydrate, microcrystalline cellulose, calcium phosphate, krospovydon, magnesium stearate.

The composition of the shell: lactose monohydrate, gipromelloza (E464), glycerol triacetate, Titanium dioxide (E171), iron oxide red (E172), Purified water.

7 PC. – blisters (1) – packs cardboard.
7 PC. – blisters (4) – packs cardboard.

Pharmacological action

Lipid-lowering drugs, is a selective, competitive inhibitor of HMG-CoA reductase, enzyme, converting 3-hydroxy-3-A to mevalonate metilglutarilkoenzim, a precursor of cholesterol (Xc). The main target of rosuvastatin is the liver deystviya, where the synthesis and catabolism of LDL Xc.

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

Crestor reduces elevated LDL content Xc-, total cholesterol, TG, increases the content of Xc-HDL, and also reduces the amount of apolipoprotein B (Ups), Hs-neLPVP, Hs-LPONP, VLDL-TG and increases the level of apolipoprotein A-1 (ApoA-1), reduces the ratio of LDL-C / HDL-C, total cholesterol / HDL-C and LDL-neLPVP / HDL-C ratio and apoB / apoA-1.

The therapeutic effect occurs within 1 weeks after initiation of therapy Krestorom, through 2 weeks of treatment up 90% of maximum possible effect. Maximum therapeutic effect is usually achieved by 4 week and is supported with regular admission.

Krestoreffektiven adult patients with hypercholesterolemia with or without hypertriglyceridaemia, regardless of race, gender or age (incl. in patients with diabetes and with familial hypercholesterolemia). In 80% patients with hypercholesterolemia type IIa and IIb (mean baseline LDL-C about 4.8 mmol / l) while taking the drug at a dose of 10 mg of LDL-C level reaches values < 3 mmol / l.

In patients with heterozygous familial hypercholesterolemia, receiving a dose Crestor 20-80 mg, positive dynamics of the lipid profile (a study involving 435 patients). After titration to a daily dose of 40 mg (12 weeks of therapy) marked reduction of LDL-C to 53%. In 33% of patients achieved LDL-C levels < 3 mmol / l.

In patients with homozygous familial hypercholesterolemia, receiving a dose Crestor 20 mg 40 mg, the average reduction in LDL-C is 22%.

An additive effect was seen in combination with fenofibrate on the content of TG and nicotinic acid on the content of HDL-C.

Studies on the effect of rosuvastatin on reducing the number of complications, induced lipid disorders, such as coronary artery disease, not yet completed.

Pharmacokinetics

Absorption

C_max rosuvastatin plasma levels achieved approximately 5 hours after oral administration. The absolute bioavailability – about 20%.

Systemic exposure of rosuvastatin increases in proportion to dose. Pharmacokinetic parameters did not change with daily intake.

Distribution

Rosuvastatin accumulate predominantly in the liver. V_d – about 134 l. Plasma protein binding (mostly to albumin) approximately 90%.

Metabolism

Biotransformiroetsa to a small extent (about 10%), It is a non-core substrate for the cytochrome P450 isoenzyme system. The basic isoenzyme, involved in the metabolism of rosuvastatin, is CYP2C9. Isoenzyme CYP2C19, CYP3A4 and CYP2D6 are involved in metabolism less.

The main metabolites identified are the N-rosuvastatin dismetil and lactone metabolites. N-dismetil approximately 50% less active, than rosuvastatin, laktonovыe metabolitы pharmacologically neaktivnы. More 90% pharmacological activity inhibiting circulating HMG-CoA reductase inhibitor rosuvastatin provided, rest – its metabolites.

Deduction

About 90% rosuvastatin dose is excreted unchanged in the feces. The remaining part is excreted in urine. Plasma T_1/2 – about 19 no. T_1/2 It does not change with increasing dose. The average value of the plasma clearance is approximately 50 l / (coefficient of variation 21.7%).

As in the case of other HMG-CoA redukazy, in the process of hepatic capture rosuvastatin membrane transporter involved XC, plays an important role in hepatic elimination of rosuvastatin.

Pharmacokinetics in special clinical situations

Gender and age did not have a clinically meaningful effect on the pharmacokinetics of rosuvastatin.

Comparative studies on the pharmacokinetics of rosuvastatin in Japanese and Chinese patients, living in Asia, showed approximately twofold increase in the mean AUC, compared with the Europeans, residing in Europe and Asia. There was no influence of genetic factors and environmental factors on the resulting differences in the pharmacokinetic parameters. Pharmacokinetic analysis among the various ethnic groups of patients showed no clinically relevant differences among Europeans, latinoamerikantsev, Blacks or African Americans.

In patients with mild to moderate renal impairment the value of the plasma concentration of rosuvastatin or N-dismetila does not change.

In patients with severe renal insufficiency (CC<30 ml / min) rosuvastatin concentrations in blood plasma 3 times higher, and the concentration of N-dismetila in 9 times higher, than in healthy volunteers. The concentration in the blood plasma of rosuvastatin in patients on dialysis was approximately 50% higher, than in healthy volunteers.

In patients with different stages of liver failure revealed no increase in T_1/2 rosuvastatin (Patients with a score of 7 or below on a scale of Childe-Pugh). In 2 patients with scores 8 and 9 on a scale of Childe-Pugh was an increase in T_1/2, at least, in 2 times. Experience in the use of rosuvastatin in patients with a score higher 9 on a scale of Childe-Pugh missing.

Testimony

- Primary Hypercholesterolemia (type IIa, including heterozygous familial hypercholesterolemia) hypercholesterolemia or mixed (TYPE IIb) as an adjunct to diet, when diet and other non-pharmacological treatments (eg, physical exercise, weight loss) are insufficient;

- Homozygous familial hypercholesterolemia as an adjunct to diet and other holesterinsnizhayuschey therapy or in cases, when such therapy is not appropriate to the patient.

Dosage regimen

The drug is prescribed in any time of day regardless of the meal. Tablets should be swallowed whole, drinking water, without chewing or crushing. If necessary, the drug dose 5 mg tablet should be divided 10 mg.

Prior to initiating therapy Krestorom patient must begin to comply with the standard lipid-lowering diet and continue to observe her during treatment. The dose should be selected individually depending on indications and therapeutic response, Taking into account the current recommendations on target lipid levels.

The recommended starting dose of CRESTOR for patients, Beginners take the drug, or for patients, translated from receiving other HMG-CoA reductase, is 5 or 10 mg 1 time / day. When selecting the starting dose should be guided by the patient's cholesterol and take into account the risk of cardiovascular complications, as well as the need to evaluate the potential risk of adverse effects. If necessary, after 4 weeks the dose may be increased.

After receiving within 4 Weeks dose, exceeding the recommended initial, its subsequent increase to 40 mg can be performed only in patients with severe hypercholesterolemia and at high risk of cardiovascular complications (especially in familial hypercholesterolemia) in case of failure of the drug at a dose 20 mg under medical supervision and in specialized clinics.

Recommended especially careful monitoring of patients, received the drug at a dose of 40 mg. Not recommended the appointment of a dose 40 mg patients, previously contact the specialists. After 2-4 weeks of treatment and / or increasing the dose of CRESTOR is necessary to monitor lipid metabolism, if necessary, dose adjustment is required.

Patients with renal insufficiency, or mild to moderate severity dose adjustment is required. Patients with moderate renal impairment recommended initial dose 5 mg.

For patients of Asian race recommended starting dose is 5 mg.

Patient, predraspolozhennыh k myopathies, The recommended starting dose is 5 mg.

Side effect

Assessment of the incidence of adverse reactions: often (>1%, <10%), sometimes (>0.1%, <1%), rarely (>0.01%, <0.1%), rarely (<0.01%).

Allergic reactions: occasionally - urticaria; rarely – angioedema.

From the central and peripheral nervous system: often – headache, dizziness; very rarely - polyneuropathy.

From the digestive system: often – constipation, nausea, stomach ache; rarely - small, asymptomatic, transient increase in liver transaminases; rarely – jaundice, hepatitis.

Dermatological reactions: sometimes – itch, rash.

On the part of the musculoskeletal system: Private - myalgia; rarely – myopathy, raʙdomioliz, arthralgia. Dose-related increase in CK levels observed in a small number of patients, taking rosuvastatin. In most cases it was not significant, asymptomatic and temporary. If CPK increase over 5 times the ULN therapy should be suspended.

From the urinary system: proteinuria (<1% patients, receiving a dose 10-20 mg and about 3% patients, receiving a dose 40 mg). In most cases, proteinuria is reduced or disappears during therapy and means of acute or progression of existing kidney disease.

Other: often – asthenic syndrome.

Side effects, observed while taking CRESTOR, usually expressed slightly and tested independently.

As with other HMG-CoA reductase, the incidence of adverse events is dose-dependent.

Contraindications

Pill 10 mg 20 mg

- Liver disease in active phase, including a persistent increase in serum transaminases and any increase in transaminase activity in serum (more than 3 fold compared with CAH);

- Expressed by the human kidney (CC < 30 ml / min);

- Myopathy;

- Concomitant use of cyclosporine;

- Pregnancy;

- Lactation (breast-feeding);

- The lack of adequate methods of contraception;

- Predisposition to complications miotoksicheskih;

- Hypersensitivity to rosuvastatin or to any of the components of the drug.

Pill 40 mg

- Liver disease in active phase, including a persistent increase in serum transaminases and any increase in transaminase activity in serum (more than 3 fold compared with CAH);

- Concomitant use of cyclosporine;

- The presence of risk factors for myopathy / rhabdomyolysis: renal failure, moderate (CC < 60 ml / min); gipotireoz; personal or family history of muscle diseases; miotoksichnost in patients receiving other HMG-CoA reductase inhibitors or fibrates history; excessive drinking; states, which can lead to increased plasma concentrations of rosuvastatin; concomitant use of fibrates; patients of Asian race;

- Pregnancy;

- Lactation (breast-feeding);

- The lack of adequate methods of contraception;

- Hypersensitivity to rosuvastatin or to any of the components of the drug.

FROM caution use in patients with a history of liver disease, sepsis, hypotension, extensive surgery, injuries, severe metabolic, endocrine, or electrolyte disturbances, uncontrolled epilepsy; at the risk of myopathy / rhabdomyolysis: renal failure, gipotireoz, personal or family history of hereditary muscular diseases and previous history of muscular toxicity with other HMG-CoA reductase inhibitor or fibrate, older than 65 years, states, under which was an increase in the plasma concentration of rosuvastatin, Asian race, co-administration with fibrates.

Pregnancy and lactation

Crestor is contraindicated in pregnancy and lactation. If pregnancy occurs during therapy the drug should be discontinued immediately.

Women of reproductive age We must use adequate contraception. Since cholesterol and products of its biosynthesis are important for fetal development, the potential risk of inhibition of HMG-CoA reductase inhibitors outweigh the benefits of the drug.

Clinical data on the allocation of rosuvastatin in breast milk are absent, so if you need to use CRESTOR lactation breastfeeding should be discontinued.

IN experimental studies found, that rosuvastatin is excreted in breast milk in rats.

Cautions

When applied in a dose of CRESTOR 40 mg is recommended to monitor renal function.

In patients with existing risk factors for rhabdomyolysis is necessary to consider the ratio of expected benefits and potential risks and to carry out a clinical observation.

It should inform the patient about the need for immediate medical posts of the cases of sudden appearance of muscle pain, muscle weakness or cramps, especially in combination with malaise and fever. These patients should determine the level of CPK. Therapy should be discontinued, If CK levels increased significantly (more than 5 times compared with FHG) or if muscular symptoms are pronounced and cause daily discomfort (even if the level of CK 5 times less than the ULN). If the symptoms disappear, and CK levels returned to normal, should consider the reappointment of CRESTOR and other HMG-CoA reductase in smaller doses with careful monitoring of the patient.

Determination of CK should not be carried out after intense exercise or in the presence of other possible reasons for the increase of CPK, which can lead to misinterpretation of the results. If baseline CK significantly increased (in 5 times the ULN), through 5-7 days should be a re-measurement. Do not start treatment, If the second test confirms the initial level of CPK (in 5 times the ULN).

Routine monitoring of creatine kinase in the absence of symptoms is not appropriate.

There was no evidence of increased toxic effects on skeletal muscles when using CRESTOR combination therapy in. It has been reported to increase the incidence of myositis and myopathy patients, taking other inhibitors of HMG-CoA reductase inhibitor in combination with a fibric acid (including gemfibrozil), cyclosporine, nicotinic acid, azole antifungals, protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when combined with the appointment of some HMG-CoA reductase. Thus, Not recommended simultaneous appointment of CRESTOR and gemfibrozil. You should carefully consider the ratio of expected benefits and potential risks in the combined use of CRESTOR and fibrates or niacin.

It is recommended that the definition of liver function tests before and after treatment 3 months after initiation of therapy. Admission CRESTOR should be discontinued or the dose reduced, if the level of transaminase activity in serum 3 times the ULN.

In patients with hypercholesterolemia due to hypothyroidism or nephrotic syndrome therapy of major diseases should be performed prior to treatment Krestorom.

Use in Pediatrics

The efficacy and safety of the drug in children have not been established. The experience of the drug in pediatric patients is limited to a small number of observations – Children 8 years and older with homozygous familial hypercholesterolemia. Currently, Crestor is not recommended for use in children.

Effects on ability to drive vehicles and management mechanisms

Not conducted research on the effect of Crestor on the ability to drive vehicles and operate machinery. Based on the pharmacodynamic properties, not supposed, that Crestor has such influence.

When classes potentially hazardous activities should take into account patients, that during the treatment may occur dizziness.

Overdose

At the same time taking multiple daily doses of rosuvastatin pharmacokinetic parameters are not changed.

Treatment: No specific antidote. If necessary spend symptomatic therapy, necessary to monitor liver function and CK levels. Unlikely, that hemodialysis is effective.

Drug Interactions

With simultaneous use of rosuvastatin and cyclosporine AUC of rosuvastatin it was average 7 times higher than the, which was observed in healthy volunteers, plasma concentration of cyclosporine is not changed.

Initiation of therapy with rosuvastatin or increasing the dose of the drug in patients, receiving concomitant vitamin K antagonists (eg, warfarin), can lead to an increase in prothrombin time (an increase in INR). Cancel rosuvastatin or decrease the dose may reduce the INR (In such cases, monitoring of INR).

The combined use of gemfibrozil and rosuvastatin increases in 2 times C_max plasma rosuvastatin and AUC.

Concomitant use of rosuvastatin and antacids, containing aluminum and magnesium hydroxide, It leads to a decrease in plasma concentrations of rosuvastatin approximately 50%. This effect is less pronounced, If antacids are used by 2 hours after receiving rosuvastatin. The clinical significance of this interaction has not been studied.

The simultaneous use of rosuvastatin and erythromycin decreases the AUC rosuvastatin on 20% and C_max of rosuvastatin 30%, probably, by enhancing gut motility, caused by taking erythromycin.

Concomitant use of rosuvastatin and oral contraceptives increases the AUC of ethinyl estradiol and norgestrel AUC for 26% and 34% respectively. This increase in plasma concentrations should be considered when selecting the dose of oral contraceptives during treatment with CRESTOR (This combination was widely used during the clinical trials and was well tolerated by patients). Pharmacokinetic data on the simultaneous use of Crestor and no hormone replacement therapy, Consequently, a similar effect can not be excluded when using this combination.

No clinically significant interaction is expected rosuvastatin with digoxin or fenofibrate. Gemfiʙrozil, other fibrates and lipid lowering doses of niacin (greater than or equivalent 1 g / day) increased risk of myopathy when used simultaneously with other inhibitors of HMG-CoA reductase. Perhaps due to the fact, they can cause myopathy and when used as monotherapy.

Results of in vivo and in vitro have shown, rosuvastatin is neither an inhibitor, no inducer isozymes of cytochrome P450. Besides, rosuvastatin is a poor substrate for these enzymes. There were no clinically significant interaction between rosuvastatin and fluconazole (ингибитором CYP2C9 и CYP3A4) and ketokonazolom (ингибитором CYP2A6 и CYP3A4). The combined use of rosuvastatin and itraconazole (CYP3A4 inhibitor) AUC increases rosuvastatin on 28% (clinically insignificant). Thus, It is not expected to interact, associated with cytochrome P450.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The drug should be stored out of reach of children at or above 30 ° C. Shelf life - 3 year.