Tevastor

General characteristics. Structure:

Tablets of 5 mg
 Contains in 1 tablet:
Active agent: розувастатин (розувастатин calcium) 5,00 (5,21) mg;
Excipients: microcrystallic 47,82 mg, кросповидон 30,00 mg, lactose of 54,97 mg, povidon-KZO 8,50 mg, sodium of the stearylfumarating 3,50 mg; a cover of Opadray of II 85F23426 orange (polyvinyl alcohol - the dioxide (E171) of 1,025 mg, a macrogoal-3350 of 0,909 mg, talc of 0,666 mg, dye which is partially hydrolyzed 1,800 mg, titanium ferrous oxide yellow (E172) of 0,075 mg, dye ferrous oxide black (E172) of 0,003 mg, dye a sunset yellow (E110) of 0,022 mg).
Tablets of 10 mg, 20 mg, 40 mg
 Contains in 1 tablet:
Active agent: розувастатин (розувастатин calcium) 10,00 (10,42)/20,00 (20,83)/40,00 (41,67) mg;
Excipients: cellulose microcrystallic 45,22/90,45 / 80,03 mg, кросповидон 30,00/60,00/60,00 mg, mg lactose 52,36/104,72/94,30, povidon-KZO 8,50/17,00/17,00 mg, sodium of the stearylfumarating 3,50/7,00/7,00 mg; a cover of Opadray of II 85F24155 pink (polyvinyl alcohol - the dioxide (E171) of 1,105/2,210/2,210 mg, a macrogoal-3350 of 0,909/1,818/1,818 mg, mg talc 0,666 / 1,332/1,332, dye which is partially hydrolyzed 1,800/3,600/3,600 mg, titanium ferrous oxide yellow (E172) of 0,009/0,018/0,018 mg, dye ferrous oxide red (E172) of 0,005/0,010/0,010 mg, dye an azoruby an aluminum varnish (Е 122) 0,005/0,009/0,009 mg, indigo carmine an aluminum varnish (E132) of 0,001/0,003/0,003 mg).

Description:
Tablets of 5 mg. Round biconvex tablets, film coated from light yellow or light orange (the grayish shade is possible) till orange color, with an engraving of "N" on one party and "5" - on another. On cross section - a kernel from white till almost white color.
Tablets of 10 mg. Round biconvex tablets, film coated from light pink till pink color, with an engraving of "N" on one party and "10" - on another. On cross section - a kernel from white till almost white color.
Tablets of 20 mg. Round biconvex tablets, film coated from light pink till pink color, with an engraving of "N" on one party and "20" - on another. On cross section - a kernel from white till almost white color.
Tablets of 40 mg. Oval tablets, film coated from light pink till pink color, with an engraving of "N" on one party and "40" - on another. On cross section - a kernel from white till almost white color.

Pharmacological properties:

Pharmacodynamics. Rozuvastatin is the selection, competitive inhibitor of GMG-KOA-reduktazy, the enzyme turning Z-gidroksi-Z-metilglutarilkoenzim And in мевалонат, the predecessor of cholesterol (Хс). The main target of action of a rozuvastatin is the liver where synthesis Hs and a catabolism of lipoproteins of the low density (LPNP) is carried out. Rozuvastatin increases number of "hepatic" receptors of LPNP by surfaces of cells, increasing capture and a catabolism of LPNP that in turn leads to inhibition of synthesis of lipoproteins of very low density (LPONP), reducing thereby total quantity of LPNP and LPONP.
Rozuvastatin reduces the increased concentration cholesterol lipoproteins of the low density (Hs-LPNP), the general cholesterol, triglycerides (TG), cholesterol lipoproteins of the high density (Hs-LPVP) increases concentration, and also reduces concentration of apolipoprotein B (Apov), Hs-NELPVP, Hs-LPONP, TG-LPONP and increases concentration of A-1 apolipoprotein (Apoa-1), reduces a ratio of Hs-LPNP/Hs-LPVP, general Hs/Hs-LPVP and Hs-NELPVP/Hs-LPVP and a ratio of Apov/Apoa-1. The therapeutic effect appears within 1 week after the beginning of therapy rozuvastaniny, in 2 weeks of treatment reaches 90% of the greatest possible effect. The maximum therapeutic effect is usually reached by 4th week and supported at regular reception.

Pharmacokinetics. Absorption. The maximum concentration (Cmax) of a rozuvastatin in a blood plasma is reached approximately in 5 h after intake. Absolute bioavailability - about 20%.
Distribution. Rozuvastatin collects preferential in a liver, the main body of synthesis of Hs and clearance of Hs-LPNP. The volume of distribution (Vd) - about 134 l. Linkng with proteins of plasma (it is preferential with albumine) makes about 90%.
Metabolism. It Biotransformirutsya in small degree (about 10%), being non-core substrate for metabolism by enzymes of system of P450 cytochrome. 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 revealed 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 view with a stake. The rest is removed with urine. The elimination half-life (Т½) - about 19 h Т½ does not change at increase in a dose of drug. Average value of plasma clearance makes about 50 l/h (coefficient of variation - 21,7%). As well as in case of other inhibitors GMG-KOA-redukazy, the membrane anion carrier of Hs which is carrying out an important role in hepatic elimination of a rozuvastatin is involved in process of "hepatic" capture of a rozuvastatin.
Pharmacokinetics in special clinical cases. Gender and age do not exert clinically significant impact on pharmacokinetics of a rozuvastatin.
Comparative researches of pharmacokinetics of a rozuvastatin at the Japanese and Chinese patients living in Asia showed approximately double increase in average values of the area under a curve "concentration time" (AUC), in comparison with indicators at the Europeans living in Europe and Asia. Influence of genetic factors and factors of the environment on the received distinctions in pharmacokinetic parameters is not revealed. The pharmacokinetic analysis among various ethnic groups of patients did not reveal clinically significant distinctions among Europeans, Latin Americans, the black or the Afro-Americans.
At patients with the slight and moderately expressed renal failure the size of plasma concentration of a rozuvastatin or N-dismetila significantly does not change.
At patients with the expressed renal failure (the clearance of creatinine (CC) <30 ml/min.) concentration of a rozuvastatin in a blood plasma is 3 times higher, and concentration of N-dismetila is 9 times higher, than at healthy volunteers. Concentration of a rozuvastatin in a blood plasma at patients on a hemodialysis was about 50% higher, than at healthy volunteers.
At patients with various stages of a liver failure increase Т½ in a rozuvastatin is not revealed (patients with point 7 and below on a scale of Chayld-Pyyu). At 2 patients with points 8 and 9 on a scale of Chayld-Pyyu increase Т½, at least, is noted twice. Experience of use of a rozuvastatin for patients with point higher than 9 on a scale of Chayld-Pyyu is absent.

Indications to use:

Primary hypercholesterolemia (the IIA type, including a family getereozigotny giperkholestreinemiya) or the mixed hypercholesterolemia (type 116) as addition to a diet when the diet and other non-drug methods of treatment (for example, physical exercises, decrease in body weight) are insufficient;
• a family homozygous hypercholesterolemia as addition to a diet and other holesterinsnizhayushchy therapy or in cases when similar therapy does not suit the patient.

Route of administration and doses:

Inside at any time irrespective of meal. The tablet should be swallowed entirely, washing down with water, not chewing and without crushing. In need of administration of drug in a dose of 5 mg it is necessary to halve a tablet of 10 mg.
Prior to therapy rozuvastatiny 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 recommendations about the target objectives of lipids. The recommended initial dose of a rozuvastatin for the patients beginning to accept drug or for the patients transferred from reception of other inhibitors of GMG-KOA-reduktazy makes 5 or 10 mg of 1 times/days. 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 can be increased.
Patients with heavy degree of a hypercholesterolemia and with high risk of cardiovascular complications (especially patients with a family hypercholesterolemia) at which the desirable result at reception of a dose of 20 mg during 4 weeks therapy was not achieved, at increase in a dose of drug up to 40 mg have to be under control of the doctor in connection with possible increase in risk of development of side effects. Especially careful observation of the patients receiving drug in a dose of 40 mg is recommended. After 2-4 weeks of therapy and/or increase in a dose of drug Tevastor is necessary control of indicators of lipidic exchange.
It is recommended to patients of advanced age (65 years are more senior) to begin treatment with a dose of 5 mg.
Easy or moderate severity dose adjustment is not required to patients with a renal failure. Drug use Tevastor in any doses is contraindicated at a heavy renal failure (KK less than 30 ml/min.). Drug use Tevastor in a dosage of 40 mg at patients with moderate renal failures is contraindicated (KK less than 60 ml/min.). The initial dose of drug of 5 mg is recommended to patients with moderate renal failures. For patients of Asian race the recommended initial dose makes 5 mg. Drug use Tevastor in a dose of 40 mg at patients of Asian race is contraindicated.
Purpose of drug Tevastor in a dose of 40 mg is contraindicated to patients with factors which can indicate predisposition to development of a myopathy (See the section "Special Instructions"). At purpose of doses 10 and 20 the initial dose for patients of this group of 5 mg is recommended.

Features of use:

The proteinuria, mostly a renal origin, found as a result of testing, is observed at the patients accepting розувастатин in a dose of 40 mg both above and in most cases has tranzitorny character. Such proteinuria is not a symptom of the acute or progressing renal pathology. Total quantity of cases of serious renal complications is noted at use of a rozuvastatin in a dose 40 mg. At drug use Tevastor in a dose of 40 mg is recommended to control indicators of function of kidneys. Influence on skeletal muscles (a mialgiya, a myopathy and it is very rare рабдомиолиз) is observed at the patients accepting drug Tevastor, in particular, in a dosage over 20 mg. Very exceptional cases of a rabdomioliz at use of an ezetimib with GMG-KOA-reduktazy inhibitors were registered. Probability of development of a rabdomioliz as at use of a rozuvastatin, and other inhibitors of GMG-KOA-reduktazy, is higher than 40 mg at a dosage.
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 because of probable distortion of the received results. If initial activity of KFK is significantly increased (5 times higher than VGN), 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 VGN).
It is necessary to warn patients about need to immediately tell the doctor at emergence of the new, earlier not noted symptoms, inexplicable muscular pain, weakness or spasms which are especially combined with fever and an indisposition. Therapy needs to be stopped if activity of KFK is 5 times higher than VGN or in the presence of the serious muscular symptoms causing constant discomfort. At disappearance of symptoms and normalization of activity of KFK, it is necessary to consider a question of repeated use of a rozuvastatin at the minimum dose and careful control. Routine monitoring of activity of KFK in the absence of symptoms is inexpedient. It is recommended to make functional diagnosis of a liver to, and within 3 months after the beginning of therapy. At patients with the secondary hypercholesterolemia caused by a hypothyroidism or a nephrotic syndrome it is necessary to carry out therapy of primary disease before purpose of drug Tevastor.

Influence on ability to control of motor transport and work with the equipment
 The researches directed to drug influence studying Tevastor on ability to control of motor transport and work with the equipment were not conducted. At drug use Tevastor it is necessary to be careful because development of dizziness is possible.

Side effects:

Side effects are classified according to the following frequency: very often - not less than 10%; often - not less than 1%, but less than 10%; infrequently - not less than 0,1%, but less than 1%; seldom - not less than 0,01%, but less than 0,1%; very seldom (including separate messages) - less than 0,01%; frequency is unknown - not enough data for phenomenon frequency assessment in population.
Allergic reactions: infrequently - urticaria, a skin itch, rash; seldom Quincke's disease, frequency it is unknown - Stephens-Johnson's syndrome. From a nervous system: often - a headache, dizziness; very seldom - polyneuropathy, memory loss.
From the alimentary system: often - a lock, nausea, abdominal pains; seldom - slight, asymptomatic, tranzitorny dozozavisimy increase of activity of "hepatic" enzymes; very seldom - jaundice, hepatitis; frequency is unknown - diarrhea. As well as at use of other inhibitors of GMG-KOA-reduktazy, the frequency of emergence of side effects has dozozavisimy character.
From a musculoskeletal system: often - a mialgiya; seldom - a myopathy; very seldom - рабдомиолиз with an acute renal failure or without it, an arthralgia. Dozozavisimy increase in activity of a kreatininfosfokinaza (KFK) is observed at a small number of the patients accepting розувастатин. In most cases increase in activity of KFK was insignificant, asymptomatic and temporary. In case of increase in activity of KFK VGN therapy rozuvastatiny is more than 5 times higher it is necessary to suspend.
From an urinary system: often - a proteinuria for a dose of 40 mg, infrequently - a proteinuria for a dose of 10-20 mg (in most cases the proteinuria decreases or disappears in the course of therapy, it is rare - a hamaturia).
Others: often - an asthenic syndrome.
Laboratory indicators: increase in concentration of glucose, bilirubin, activity gamma глютамилтранспептидазы, alkaline phosphatase, dysfunction of a thyroid gland.

Interaction with other medicines:

At simultaneous use of a rozuvastatin and AUC cyclosporine of a rozuvastatin was on average 7 times higher than value which was noted at healthy volunteers, plasma concentration of cyclosporine at the same time did not change. Simultaneous use leads to increase in plasma concentration of a rozuvastatin in a blood plasma by 11 times.
The beginning of therapy rozuvastatiny or increase in a dose of drug at the patients receiving at the same time antagonists of vitamin K (for example, warfarin), can lead to increase in a prothrombin time (increase in the international normalized relation (MHO)). Cancellation of a rozuvastatin or decrease in its dose can lead to MHO reduction (in such cases MHO monitoring is recommended).
Simultaneous use of a rozuvastatin and ezetimib did not reveal changes of AUC or Stakh at one drug. However their pharmakodinamichesky interaction and emergence of adverse effects cannot be excluded.
Simultaneous use of a rozuvastatin and gemfibrozil leads to increase twice in Cmax in a blood plasma and AUC of a rozuvastatin. According to special researches of the corresponding pharmacokinetic interactions with fenofibraty other pharmakodinamichesky interactions can be noted, however. Gemofibrozil, фенофибрат, other fibrata and hypolipidemic doses of niacin, increase risk of emergence of a myopathy when are applied along with GMG-KOA-reduktazy inhibitors. It is probable because GMG-KOA inhibitors can cause a myopathy and at use in monotherapy.
Though the exact mechanism of interaction of a rozuvastatin with inhibitors of proteases is unknown, their simultaneous use can cause permanent strengthening of action of a rozuvastatin. In pharmacokinetic researches combined use of 20 mg of a rozuvastatin and combination of inhibitors of proteases (лопинавир 400 mg / ритонавир 100 mg) called about two in healthy volunteers - and fivefold increase in AUC and Cmax respectively. Therefore simultaneous use of a rozuvastatin and inhibitors of proteases at therapy of patients with the human immunodeficiency virus (HIV) is not recommended.
Simultaneous use of a rozuvastatin and suspensions of 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. Clinical value of similar interaction was not studied.
Simultaneous use of a rozuvastatin and erythromycin leads to reduction of AUC of a rozuvastatin by 20% and Cmax of a rozuvastatin by 30% probably as a result of strengthening of motility of the intestines caused by erythromycin reception. Simultaneous use of a rozuvastatin and oral contraceptives increases AUC ethinylestradiol and AUC of Norgestrelum by 26% and 34% respectively. Such increase in plasma concentration has to be considered at selection of a dose of oral contraceptives against the background of use of a rozuvastatin.
On the basis of researches of interaction of a rozuvastatin with digoxin of clinically significant interaction it is not revealed.
Results of the researches in vivo and in vitro showed what розувастатин is not either inhibitor, or the inductor of isoenzymes of system of P450 cytochrome. Besides, розувастатин is weak substrate for these isoenzymes. Clinically significant interaction between rozuvastatiny and flukonazoly (CYP2C9 and CYP3A4 inhibitor) and ketokonazoly was not noted (CYP2A6 and CYP3A4 inhibitor). Combined use of a rozuvastatin and itrakonazol (CYP3A4 inhibitor) increases AUC of a rozuvastatin by 28% (clinically not significantly). Thus, the interaction connected with system of P450 cytochrome is not expected.

Contraindications:

For mg tablets 5, 10 and 20. Hypersensitivity to a rozuvastatin or any of drug components; liver diseases in an active phase, including permanent increase in activity of "hepatic" transaminases or any increase in activity of "hepatic" transaminases (more than by 3 times in comparison with the upper bound of norm (UBN)), heavy renal failures (KK less than 30 ml/min.); myopathy; concomitant use of cyclosporine; pregnancy; breastfeeding period; lack of reliable methods of contraception; lactose intolerance; deficit of lactase or glyukozo-galaktozny malabsorption (drug contains lactose); age up to 18 years (there are not enough data on efficiency and safety); heavy abnormal liver functions (more than 9 points on a scale of Chayld-Pyyu) (there is no experience of use).
For tablets of 40 mg. Hypersensitivity to a rozuvastatin or any of drug components; concomitant use of cyclosporine, pregnancy; breastfeeding period; lack of reliable methods of contraception; a lactose intolerance, deficit of lactase or glyukozo-galaktozny malabsorption (drug contains lactose); age up to 18 years (there are not enough data on efficiency and safety), liver diseases in an active phase, including permanent increase in activity of "hepatic" transaminases and any increase in activity of "hepatic" transaminases (more than by 3 times in comparison with VGN).
To patients with risk factors of a myopathy / рабдомиолиза: renal failure (KK less than 60 ml/min.); hypothyroidism; personal or family analysis of muscular diseases; a miotoksichnost against the background of reception of other GMG inhibitors - To - And - reductase or fibrat in the anamnesis; excessive alcohol intake; states which can lead to increase in plasma concentration of a rozuvastatin; concomitant use of fibrat; use for patients of Asian race; heavy abnormal liver functions (more than 9 points on a scale of Chayld-Pyyu) (there is no experience of use).

With care
For mg tablets 5, 10 and 20. Existence of risk factors of development of a myopathy and/or rabdomioliza - renal failure, a hypothyroidism, the personal or family analysis of hereditary muscular diseases and the previous anamnesis of muscular toxicity at use of other GMG inhibitors - To - And - reductase or fibrat; excessive alcohol intake, age is more senior than 65 years, states at which increase in plasma concentration of a rozuvastatin is noted; race (Asian race), simultaneous use from fibrata, liver diseases in the anamnesis, sepsis, arterial hypotension, extensive surgical interventions, injuries, heavy metabolic, endocrine or electrolytic disturbances or uncontrollable convulsive attacks.
For tablets of 40 mg. The renal failure (KK more than 60 ml/min.), age is more senior than 65 years, a liver disease in the anamnesis, sepsis, arterial hypotension, extensive surgical interventions, injuries, heavy metabolic, endocrine or electrolytic disturbances or uncontrollable convulsive attacks.

Use at pregnancy and during breastfeeding 
 Drug Tevastor is contraindicated at pregnancy and during breastfeeding. When diagnosing pregnancy in the course of therapy administration of drug has to be stopped immediately.
Women of reproductive age have to apply reliable methods of contraception. As cholesterol and products of its biosynthesis are important for fetation, the potential risk of inhibition of GMG-KOA-reduktazy exceeds advantage of drug use.
Data on allocation of a rozuvastatin in breast milk are absent therefore in need of drug use Tevastor in the period of a lactation breastfeeding should be stopped.

Overdose:

At a concomitant use of several daily doses pharmacokinetic parameters of a rozuvastatin do not change.
There is no specific antidote. If necessary carry out symptomatic therapy, control of function of a liver and activity of KFK is necessary. The hemodialysis is not effective.

Storage conditions:

Period of validity 2 years. Not to use after the period of validity specified on packaging. To store at a temperature not above 25 °C. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated, 5 mg, 10 mg, 20 mg and 40 mg.
On 10 tablets in the blister from PVC/PVA / aluminum foil.
3 or 9 blisters together with the application instruction in a cardboard pack.