Rozukard

General characteristics. Structure:

Each tablet of film coated 10 mg contains:
active agent:
розувастатин - 10,000 mg (in the form of a rozuvastatin of calcium — 10,400 mg);
excipients:
kernel: lactoses monohydrate - 60,000 mg, cellulose microcrystallic - 45,400 mg, croscarmellose sodium - 1,200 mg, silicon dioxide colloid - 0,600 mg, magnesium stearate - 2,400 mg;
film cover: a gipromelloza 2910/5 - 2,500 mg, a macrogoal of 6000 - 0,400 mg, titanium dioxide - 0,325 mg, talc - 0,475 mg, dye ferrous oxide red - 0,013 mg.
Each tablet of film coated 20 mg contains:
active agent:
розувастатин - 20,000 mg (in the form of a rozuvastatin of calcium - 20,800 mg);
excipients:
kernel: lactoses monohydrate - 120,000 mg, cellulose microcrystallic - 90,800 mg, croscarmellose sodium - 2,400 mg, silicon dioxide colloid - 1,200 mg, magnesium stearate - 4,800 mg;
film cover: a gipromelloza 2910/5 - 5,000 mg, a macrogoal of 6000 - 0,800 mg, titanium dioxide - 0,650 mg, talc - 0,950 mg, dye ferrous oxide red - 0,065 mg.
Each tablet of film coated 40 mg contains:
active agent:
розувастатин - 40,000 mg (in the form of a rozuvastatin of calcium - 41,600 mg);
excipients:
kernel: lactoses monohydrate - 240,000 mg, cellulose microcrystallic — 181,600 mg, croscarmellose sodium - 4,800 mg, silicon dioxide colloid - 2,400 mg, magnesium stearate - 9,600 mg;
film cover: a gipromelloza 2910/5 - 10,000 mg, a macrogoal of 6000 - 1,600 mg, titanium dioxide - 1,300 mg, talc - 1,900 mg, dye ferrous oxide red - 0,200 mg.

Description
Tablets of 10 mg: oblong, biconvex tablets with risky, film coated light pink color.
Tablets of 20 mg: oblong, biconvex tablets, film coated pink color.
Tablets of 40 mg: oblong, biconvex tablets, film coated dark pink color.

Pharmacological properties:

Pharmacodynamics. Hypolipidemic means from group of statines. The selection competitive inhibitor Z-gidroksi-Z-metilglutaril coenzyme A (GMG-KOA) - reductases - the enzyme turning GMG-KOA in мевалонат, the predecessor of cholesterol (XC).
Increases number of receptors of lipoproteins of the low density (LPNP) by the surfaces of hepatocytes that leads to strengthening of capture and a catabolism of LPNP, inhibition of synthesis of lipoproteins of very low density (LPONP), reducing the general concentration of LPNP and LPONP. Reduces concentration of HS-LPNP, cholesterol not lipoproteins of the high density (HS-NELPVP), HS-LPONP, the general XC, (TG), TG-LPONP triglycerides, apolipoprotein B (Apov), reduces ratios of HS-LPNP/HS-LPVP, the general HS/HS-LPVP, HS-NELPVP/HS-LPVP, Apov / A-1 apolipoprotein (Apoa-I), increases concentration of HS-LPVP and Apoa-I.
Hypolipidemic action in direct ratio to the size of the appointed dose. The therapeutic effect appears during 1 week after the beginning of therapy, in 2 weeks reaches 90% from maximum, to 4 weeks reaches a maximum and after that remains to constants. It is effective at adult patients with a hypercholesterolemia with or without gipertriglitseridemiya (regardless of race, a floor or age), including, at patients with a diabetes mellitus and a family hypercholesterolemia. At 80% of patients with a hypercholesterolemia of IIA and IIb of type (classification by Fredrikson) with average initial concentration of HS-LPNP about 4,8 mmol/l against the background of administration of drug in a dose of 10 mg concentration of HS-LPNP reaches values less than 3 mmol/l. At the patients with a homozygous family hypercholesterolemia accepting drug in a dose of 20 mg and 40 mg, average decrease in concentration of HS-LPNP makes 22%.
The additive effect is noted in a combination with fenofibraty (concerning decrease in concentration of TG and with niacin in lipidsnizhayushchy doses (not less than 1 g/days) (concerning decrease in concentration of HS-LPVP).

Pharmacokinetics. Absorption
 The maximum concentration (Cmax) of a rozuvastatin in a blood plasma is reached approximately in 5 h after administration of drug. Absolute bioavailability - about 20%. System exposure of a rozuvastatin increases in proportion to a dose. Pharmacokinetic parameters do not change at daily reception.
Distribution
 Gets through a placental barrier. Rozuvastatin is absorbed preferential by a liver which is the main place of synthesis of XC and metabolism of HS-LPNP. Distribution volume - 134 l. Linkng with proteins of plasma (it is preferential with albumine) makes about 90%.
Metabolism
 It Biotransformirutsya in a liver in small degree (about 10%), being non-core substrate for isoenzymes of system of P450 cytochrome. As well as in case of other inhibitors of GMG-KOA-reduktazy, the specific membrane carrier - the polypeptide transporting (OATP) 1B1 organic anion which is carrying out an important role in its hepatic elimination is involved in process of hepatic capture of drug. The main isoenzyme participating in metabolism of a rozuvastatin is CYP2C9. Isoenzymes of CYP2C19, CYP3A4 and CYP2D6 are involved in metabolism to a lesser extent.
The main metabolites of a rozuvastatin are N-dismetil and lactonic metabolites. N-dismetil for about 50% is less active, than розувастатин, lactonic metabolites pharmacological are inactive. More than 90% of pharmacological activity on inhibition of the circulating GMG-KOA-reduktazy are provided rozuvastatiny, the rest - its metabolites.
Removal
 About 90% of a dose of a rozuvastatin are removed in not changed look through intestines, the rest - kidneys. The elimination half-life (T1/2) — about 19 h, does not change at increase in a dose of drug. Average value of plasma clearance makes about 50 l/h (coefficient of variation of 21,7%).
At patients with the slight and moderately expressed renal failure plasma concentration of a rozuvastatin or N-dismetila significantly does not change. At patients with the expressed renal failure (the clearance of creatinine (CC) less than 30 ml/min.) concentration of a rozuvastatin in a blood plasma is 3 times higher, and N-dismetila - by 9 times, than at healthy volunteers. Concentration of a rozuvastatin in a blood plasma at the patients who are on a hemodialysis is about 50% higher, than at healthy volunteers.
At patients with point 7 and below on a scale of Chayld-Pyyu increase in T1/2 of a rozuvastatin is not revealed; at patients with points 8 and 9 on a scale of Chayld-Pyyu lengthening of T1/2 is noted twice. Experience of use of drug for patients with more expressed abnormal liver functions is absent.
Gender and age do not exert clinically significant impact on pharmacokinetics of a rozuvastatin.
Ethnic groups
 Pharmacokinetic parameters of a rozuvastatin depend on race: the area under a curve "concentration time" (AUC) at representatives of Mongoloid race (Japanese, Chinese, Filipinos, Vietnamese and Koreans) is twice higher, than at representatives of Caucasian race. At Indians average AUC and S value a move is increased by 1,3 times.

Indications to use:

• Primary hypercholesterolemia (the IIA type across Fredrikson), including a heterozygous hereditary hypercholesterolemia or the mixed (combined) hypercholesterolemia (the II type across Fredrikson), as addition to a diet and other non-drug actions (an exercise stress and decrease in body weight) at inefficiency of a dietotherapy and non-drug actions;

• A homozygous form of a hereditary hypercholesterolemia and at the insufficient efficiency of a dietotherapy and other types of treatment directed to decrease in level of lipids (for example, аферез LPNP) or if such types of treatment do not suit the patient.

• Gipertriglitseridemiya (type IV across Fredrikson) as addition to a diet.

• For delay of progressing of atherosclerosis as addition to a diet at patients to whom therapy for decrease in concentration of the general XC and XC - LPNP is shown.

• Prevention of the main cardiovascular complications (a stroke, a heart attack, arterial revascularization) at adult patients without clinical signs of the coronary heart disease (CHD), but with the increased risk of its development (the age is more senior than 50 years for men and 60 years for women, the increased concentration of S-reactive protein (≥ 2 mg/l) in the presence are more senior, than at least one of accessory factors of risk, such as arterial hypertension, low concentration of HS-LPVP, smoking, the family anamnesis of the early beginning of an ischemic heart disease).

Route of administration and doses:

 Inside, without chewing and without crushing, to swallow entirely, washing down with water, irrespective of meal at any time.
Prior to therapy by the drug ROZUKARD® the patient has to begin to keep to a standard hypolipidemic diet and to continue to observe it during treatment. The dose of drug should be selected individually depending on indications and the therapeutic answer, in view of the current standard recommendations about the target objectives of lipids. In need of administration of drug in a dose of 5 mg it is necessary to divide a tablet of 10 mg into two parts after risk.
The recommended initial dose of the drug ROZUKARD® for the patients beginning to accept drug or for the patients transferred from reception of other GMG-inhibitors of KOA-reductase makes 5 or 10 mg of 1 times a day. At the choice of an initial dose it is necessary to be guided by the content of cholesterol at the patient and to take risk of development of cardiovascular complications into account, and also it is necessary to estimate potential risk of development of side effects. In case of need in 4 weeks the dose of drug can be increased.
Due to the possible development of side effects at reception of a dose of 40 mg in comparison with lower doses of drug (see the section "Side effect") final titration to the maximum dose of 40 mg should be carried out only at patients with a severe form of a hypercholesterolemia and high risk of cardiovascular complications (especially at patients with a hereditary hypercholesterolemia) at which at reception of a dose in 20 mg the target objective of cholesterol and which will be under medical observation was not reached.
Patients with a liver failure
 With a liver failure with values on a scale of Chayld-Pyyu lower than 7 points of dose adjustment РОЗУКАРДА® it is not required from patients.
Patients with a renal failure
 With a renal failure of easy severity of dose adjustment it is not required from patients. Initial dose РОЗУКАРДА® - 5 mg a day is recommended.
At patients with a heavy renal failure (KK less than 30 ml/min.) use РОЗУКАРДА® is contraindicated.
At patients with a renal failure of moderate severity (KK of 30 - 60 ml/min.) use РОЗУКАРДА® in a dose of 40 mg a day contraindicated (see the section "Contraindications).
Special populations. Elderly patients
 At patients 65 years of dose adjustment are more senior it is not required.
Patients with predisposition to a myopathy
 Use РОЗУКАРДА® in a dose of 40 mg a day contraindicated at patients with predisposition to a myopathy (see the section "Contraindications). At purpose of doses of 10 mg and 20 mg a day the recommended initial dose РОЗУКАРДА® for this group of patients makes 5 mg a day.
Ethnic groups
 When studying pharmacokinetic parameters of a rozuvastatin increase in system concentration of drug at representatives of Mongoloid race was noted (see the section "Pharmacokinetics). It is necessary to consider this fact at appointment РОЗУКАРДА® to patients of Mongoloid race. At purpose of doses of 10 and 20 mg the recommended initial dose РОЗУКАРДА® for this group of patients makes 5 mg a day. Use РОЗУКАРДА® in a dose of 40 mg a day at representatives of Mongoloid race contraindicated (see the section "Contraindications).
At appointment РОЗУКАРДА® with gemfibrozily the dose should not exceed 10 mg a day.

Features of use:

During treatment, especially during dose adjustment РОЗУКАРДА®, each 2-4 weeks it is necessary to carry out monitoring of a lipidic profile and if necessary to change a drug dose.
It is recommended to carry out definition of indicators of function of a liver prior to therapy and in 3 months after the beginning of therapy. Administration of drug РОЗУКАРД® it is necessary to stop or reduce a drug dose if the level of activity of "hepatic" transaminases in blood serum by 3 times exceeds the upper bound of norm.
At use of the drug ROZUKARD® in a dose of 40 mg it is recommended to control pokazaktel of function of kidneys.
At patients with a hypercholesterolemia owing to a hypothyroidism or a nephrotic syndrome therapy of basic diseases has to be carried out prior to treatment by the drug ROZUKARD®.
At patients with the available risk factors of a rabdomioliz it is necessary to consider a ratio of the expected advantage and potential risk and to make clinical observation throughout all course of treatment.
It is necessary to inform the patient on need of the immediate message to the doctor about cases of unexpected emergence of muscular pains, muscular weakness or spasms, especially in combination with an indisposition and fever. At such patients it is necessary to determine the KFK level. Therapy should be stopped if activity of KFK is considerably increased (more than by 5 times in comparison with the upper bound of norm) or if muscular symptoms are sharply expressed and cause daily discomfort. If symptoms disappear, and the KFK level is returned to norm, it is necessary to consider a question of repeated purpose of the drug ROZUKARD® or other inhibitors of GMG-KOA-reduktazy in smaller doses at careful observation of the patient.
Definition of activity of KFK should not be carried out after intensive exercise stresses or in the presence of other possible reasons of increase in activity of KFK that can lead to incorrect interpretation of the received results. If the KFK initial level is significantly increased, in 5-7 days it is necessary to take repeated measurement - it is not necessary to begin therapy if the repeated test confirms initial activity of KFK (5 times higher than norm).
Routine monitoring of activity of KFK in the absence of symptoms is inexpedient. It was reported about increase in number of cases of a miositis and myopathy at the patients accepting other inhibitors of GMG-KOA-reduktazy in combination with derivatives of fibrinous acid (including gemfibrozit), cyclosporine, niacin, azolny antifungal drugs, inhibitors of proteases and makrolidny antibiotics. It is necessary to weigh carefully a ratio of the expected advantage and potential risk at combined use of the drug ROZUKARD® and fibrat or niacin (not less than 1 g/days), co-administration is not recommended gemfibrozit and.
In most cases the proteinuria decreases or disappears in the course of therapy and does not mean emergence acute or exacerbations of the existing disease of kidneys. Assessment of function of kidneys has to be carried out at routine inspection of the patients receiving a dose of 40 mg.
Women of reproductive age have to apply adequate methods of contraception. As the cholesterol and substances synthesized from cholesterol are important for fetation, the potential risk of inhibition of HMG-CoA reductase exceeds advantage of use of drug during pregnancy. In case of pregnancy in the course of therapy administration of drug has to be immediately stopped. Data concerning allocation of a rozuvastatin with milk of women are absent therefore breastfeeding needs to be stopped.
Joint purpose of a rozuvastatin and inhibitors of HIV protease is not recommended.
At prolonged use of a rozuvastatin it was reported about isolated cases of an intersticial disease of lungs. At suspicion of an intersticial disease of lungs it is necessary to stop therapy РОЗУКАРДОМ®.
When studying pharmacokinetic parameters of a rozuvastatin increase in system concentration of drug at representatives of Mongoloid race was noted (see the section "Pharmacokinetics). It is necessary to consider this fact at appointment РОЗУКАРДА® to patients of Mongoloid race.
Influence on ability of control of motor transport and work with mechanisms.
It is necessary to be careful at control of vehicles and the occupations demanding the increased concentration of attention and speed of psychomotor reactions (during therapy there can be dizziness).

Side effects:

• very often - more than 1/10,

• often - from more than 1/100 to less than 1/10,

• infrequently - from more than 1/1000 to less than 1/100,

• seldom - from more than 1/10000 to less than 1/1000,

• very seldom - from less than 1/10000, including separate messages.

• not specified frequency.
From the central nervous system: often - a headache, dizziness, an asthenic syndrome; very seldom - peripheral neuropathy, decrease in memory.
From the alimentary system: often - nausea, a lock, an abdominal pain; infrequently - vomiting; seldom - pancreatitis; very seldom - hepatitis, jaundice; not specified frequency - diarrhea.
From respiratory system: infrequently — cough, диспноэ.
From endocrine system: often - a diabetes mellitus 2 types.
From a musculoskeletal system: often - a mialgiya; very seldom - an arthralgia; seldom - a myopathy (including miozita), рабдомиолиз.
Allergic reactions: infrequently - a skin itch, a small tortoiseshell, rash; seldom - a Quincke's disease.
Skin and hypodermic cellulose: not specified frequency - Stephens-Johnson's syndrome, peripheral hypostases.
From an urinary system: often - the proteinuria (with a frequency more than 3% at the patients receiving a dose of 40 mg) decreasing in the course of therapy and which is not connected with developing of a disease of kidneys, infections of urinary tract; very seldom - a hamaturia.
Laboratory indicators: infrequently - passing dozozavisimy increase in activity of a serumal kreatinfosfokinaza (KFK), at increase more than by 5 times in comparison with the upper bound of norm therapy has to be temporarily suspended; seldom - tranzi-even increase in activity of aspartate aminotransferase and alaninaminotranspherase.
As well as at use of other inhibitors of GMG-KOA-reduktazy, the frequency of emergence has dozozavisimy character, side effects are usually expressed slightly and pass independently.
At use РОЗУКАРДА® changes of the following laboratory indicators were noted: increase in concentration of glucose, bilirubin, activity of an alkaline phosphatase, gamma глутамилтрансферазы.
At use of other statines it was reported about the following side effects: depression, sleeplessness, decrease in a potentiality.
At prolonged use of a rozuvastatin it was reported about isolated cases of an intersticial disease of lungs.

Interaction with other medicines:

Simultaneous use of a rozuvastatin and cyclosporine does not influence plasma concentration of cyclosporine, however the effect of a rozuvastatin amplifies (its removal is slowed down, AUC by 7 times, Cmax - by 11 times increases).
Erythromycin increases motility of intestines that leads to decrease in effect of a rozuvastatin (AUC decreases by 20% and Cmax for 30%).
At the patients receiving antagonists of vitamin K (for example, warfarin) monitoring of the international normalized relation (INR) as the beginning of therapy rozuvastatiny or increase in a dose of drug can lead to increase in MNO is recommended, and cancellation of a rozuvastatin or decrease in its dose can lead to its reduction. Gemfibrozil strengthens effect of a rozuvastatin (increases Cmax and AUC twice). Simultaneous use of a rozuvastatin and antacids, the containing aluminum and magnesium hydroxide, leads to decrease in plasma concentration of a rozuvastatin approximately for 50%. This effect is expressed more weakly if antacids are applied in 2 h after reception of a rozuvastatin.
Simultaneous use of a rozuvastatin and oral contraceptives increases AUC ethinylestradiol and AUC of Norgestrelum by 26% and 34% respectively that should be considered at selection of a dose of oral contraceptives. Pharmacokinetic data on simultaneous use of a rozuvastatin and gormonozamestitelny therapy are absent, therefore, it is impossible to exclude similar effect and when using this combination.
Results of researches showed what розувастатин is not either inhibitor, or the inductor of action of isoenzymes of P450 cytochrome. Rozuvastatin is non-core substrate for these isoenzymes. Clinically significant interaction with such drugs as флуконазол, кетоконазол and итраконазол, connected by metabolism with system of P450 cytochrome was not observed.
Clinically significant interaction of a rozuvastatin with digoxin or feno-fibraty is not noted, Gemfibrozil, other fibrata and hypolipidemic doses of niacin (not less than 1 g/days) increased risk of emergence of a myopathy at simultaneous use with other inhibitors of GMG-KOA-reduktazy. It is possible because they can cause a myopathy and when using as monotherapy.
Combined use of a rozuvastatin and ezetimib did not lead to changes of AUC or Cmax of both medicines.
Use of inhibitors of protease VIP (virus of an immunodeficiency of the person) with rozuvastatiny can lead to considerable strengthening of effect of a rozuvastatin. Gave a pharmacokinetic research of combined use by healthy volunteers of 20 mg of a rozuvastatin and combination of two inhibitors of HIV protease (400 mg of a lopinavir / 100 mg of a ritonavir) to about two - and to fivefold increase in AUC(0-24) and Cmax, respectively. Thus, at the patients infected with HIV, joint purpose of a rozuvastatin with inhibitors of HIV protease is not recommended.

Contraindications:

Contraindications for mg tablets 10 and 20

• Hypersensitivity to a rozuvastatin or other components of drug;

• Liver diseases in an active phase or steady increase in serumal activity of "hepatic" transaminases (more than by 3 times in comparison with the upper bound of norm) not clear genesis, a liver failure (severity from 7 to 9 points on a scale of Chayld-Pyyu);

• Increase in concentration of a kreatininfosfokinaza (KFK) in blood more than by 5 times in comparison with the upper bound of norm (UBN);

• Hereditary diseases, such as a lactose intolerance, deficit of lactase or glyukozo-galaktozny malabsorption (in connection with existence in composition of lactose);

• The expressed renal failures (KK less than 30 ml/min.);

• Myopathy;

• The patients predisposed to development of miotoksichesky complications;

• Concomitant use of cyclosporine;

• Combined use with inhibitors of HIV proteases;

• The women of reproductive age who are not using adequate methods of contraception;

• Pregnancy and period of a lactation;

• Age up to 18 years (efficiency and safety are not established).
Contraindications for tablets of 40 mg (addition to contraindications for mg tablets 10 and 20)

• Existence of the following risk factors of development of a myopathy / рабдомиолиза:
   1. The Miotoksichnost against the background of reception of other inhibitors of GMG-KOA-reduktazy or fibrat in the anamnesis;
   2. Hypothyroidism;
   3. Renal failure of moderate severity (KK of 30 - 60 ml/min.);
   4. Excessive alcohol intake;
   5. States which can lead to increase in plasma concentration of a rozuvastatin;
   6. Concomitant use of fibrat;

• Patients of Mongoloid race;

• Family anamnesis of muscular diseases.
With care:
For mg tablets 10 and 20:
at liver diseases in the anamnesis; sepsis; arterial hypotension; extensive surgical interventions; injuries; heavy metabolic, endocrine or electrolytic disturbances; uncontrollable spasms; at easy and average degree of a renal failure; hypothyroidism; anamnesis of muscular toxicity; at use of other inhibitors of GMG-KOA-reduktazy or fibrat; hereditary muscular diseases in the anamnesis; age 65 years are more senior; states at which increase in concentration of a rozuvastatin in a blood plasma is noted; Mongoloid race; at co-administration from fibrata; at excessive alcohol intake.
For tablets of 40 mg:
at a renal failure of moderate severity (KK more than 60 ml/min.); age 65 years are more senior; liver diseases in the anamnesis; sepsis; arterial hypotension; extensive surgical interventions; injuries; heavy metabolic, endocrine or electrolytic disturbances; uncontrollable spasms.

Use at pregnancy and in the period of a lactation
 Use of the drug ROZUKARD® for women of reproductive age is possible only in case of use of reliable methods of contraception and if the patient is informed on possible risk of treatment for a fruit.
As the cholesterol and substances synthesized from cholesterol are important for fetation, the potential risk of inhibition of HMG-CoA reductase exceeds advantage of use of drug during pregnancy. РОЗУКАРД® it is contraindicated at pregnancy and in the period of a lactation. In case of diagnosing of pregnancy in the course of therapy by drug reception РОЗУКАРДА® has to be immediately stopped, and the patient is warned about potential risk for a fruit.
In need of use of drug in the period of a lactation, considering a possibility of the undesirable phenomena at babies, it is necessary to resolve an issue of the breastfeeding termination.

Overdose:

At a concomitant use of several daily doses pharmacokinetic parameters of a rozuvastatin do not change.
Treatment: there is no specific treatment, symptomatic therapy for maintenance of functions of vitals and systems is carried out. Control of indicators of function of a liver and activity of KFK is necessary. The hemodialysis is inefficient.

Storage conditions:

At a temperature not above 25 °C in original packaging. To store in the place, unavailable to children! Period of validity 2 years. Drug cannot be used after the expiry date specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets film coated 10 mg, 20 mg, 40 mg.
On 10 tablets in the blister from A1/A1. On 3 or 9 blisters are placed in a cardboard pack together with the application instruction.