Klivas

General characteristics. Structure:

Active agent: розувастатин 10 mg.

Active agent: розувастатин 20 mg.

Pharmacological properties:

Pharmacodynamics. Rozuvastatin is the selection competitive inhibitor of GMG-KOA-reduktazy, the enzyme turning GMG-KOA in мевалонат, the predecessor of XC. The main scene of action of a rozuvastatin is the liver where synthesis of XC and a catabolism of 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 LPONP, reducing thereby total quantity of LPNP and LPONP.
Rozuvastatin reduces the increased maintenance of the XC LPNP, the general XC and TG, increases the maintenance of the XC LPVP. It reduces amount of apolipoprotein B (Apov), HS-NELPVP, the XC LPONP, TG LPONP also increases the level of A-_ apolipoprotein (Apoa-І), reduces a ratio of the XC LPNP/HS LPVP, the general XC/XC LPVP and HS-NELPVP/HS LPVP and a ratio of Apov/Apoa-_.
The therapeutic effect appears during 1 week after the beginning of therapy rozuvastatiny, in 2 weeks of treatment the effect reaches 90% greatest possible. The maximum effect is, as a rule, reached in 4 weeks and after that proceeds constantly.
Clinical performance. Rozuvastatin is effective for adult patients with a hypercholesterolemia with or without gipertriglitseridemiya irrespective of race, a floor or age, including for persons with a diabetes mellitus and a family hypercholesterolemia.
At 80% of patients with a hypercholesterolemia ІІ and and ІІ in type (the average LPNP initial level XC makes about 4,8 mmol/l) against the background of administration of drug in a dose of 10 mg the LPNP level XC reaches values <3 mmol/l.
The additive effect is noted in a combination with fenofibraty concerning the maintenance of TG and with niacin concerning the maintenance of the XC LPVP.

Pharmacokinetics. Absorption and distribution. Cmax of a rozuvastatin in a blood plasma is reached approximately in 5 h after intake. Bioavailability makes ≅20%. Rozuvastatin collects in a liver. The volume of its distribution makes ≅134 l. About 90% of a rozuvastatin contact proteins of a blood plasma, generally albumine.
Metabolism. Rozuvastatin is exposed to limited metabolism (≅10%). The main revealed metabolites of a rozuvastatin are N-desmetil and lactonic metabolites. N-desmetil for ≅50% is less active, than розувастатин, lactonic metabolites pharmacological are inactive.
Removal. About 90% of a dose of a rozuvastatin are removed in not changed view with a stake. Other part is removed with urine. T½ makes ≅19 h T½ of a blood plasma does not change at increase in a dose. The average clearance makes ≅50 l/h, in the course of hepatic capture of a rozuvastatin the carrier of XC which is carrying out an important role in hepatic elimination of a rozuvastatin takes part.
Linearity. System exposure of a rozuvastatin increases in proportion to a dose. At reception of several daily doses pharmacokinetic parameters do not change.
Special populations of patients
Age and floor. There is no clinically significant influence of age and a gender on pharmacokinetics of a rozuvastatin of adults.
Ethnic groups. Influence of genetic factors and factors of the environment on pharmacokinetic parameters is not revealed. The pharmacokinetic analysis of different ethnic groups did not establish clinically significant distinctions in pharmacokinetics among representatives of Caucasian and negroid races.
Patients with a renal failure. Patients with easy or moderate renal failures have a level of concentration of a rozuvastatin and N-desmetila in a blood plasma significantly does not change. At persons with a heavy renal failure (clearance of creatinine <30 ml/min.) concentration of a rozuvastatin in a blood plasma is 3 times higher, and concentration of N-desmetila is 9 times higher, than at healthy volunteers. Concentration of a rozuvastatin in a blood plasma of the patients who are on a hemodialysis was 50% higher, than at healthy volunteers.
Patients with a liver failure. At patients with various stages of a liver failure with point ≤7 on a scale of Chayld-Pyyu increase in T½ of a rozuvastatin is not revealed. At 2 patients with points 8 and 9 on a scale of Chayld-Pyyu increase in T½ is noted at least twice. There is no experience of use of a rozuvastatin for patients with point> 9 on a scale of Chayld-Pyyu.

Indications to use:

Adults
Treatment of a hypercholesterolemia. Primary hypercholesterolemia (the IIA type, including a heterozygous family hypercholesterolemia) or the mixed dislipidemiya (IIb type), as addition to a diet when efficiency of a diet or other non-drug means (such as physical exercises, a body degrowth) are insufficient.
Homozygous family hypercholesterolemia, as addition to a diet and other lipidosnizhayushchy means (for example to LPNP aferez) or in cases when such types of treatment are inappropriate.
Prevention of cardiovascular disturbances. Klivas is shown for decrease in risk of emergence of serious cardiovascular violations at adult patients with the increased risk of development of atherosclerotic cardiovascular diseases what existence of such risk factors as age, AG, the LPNP low level XC, the increased level of S-reactive protein, smoking or existence in the family anamnesis of a prematurity of an ischemic heart disease testifies to.
Treatment of atherosclerosis. For the purpose of delay or a delay of progressing of a disease at patients to whom lipidosnizhayushchy therapy is shown.

Children and teenagers (at the age of 10–17 years: boys — ІІ a stage on Tener's scale above, girls — not less than in a year after the first periods).
Treatment of primary hypercholesterolemia (type ІІ and) or the mixed dislipidemiya (type ІІ b) as a result of a heterozygous family hypercholesterolemia, as addition to a diet when efficiency of a diet or other non-drug methods (physical exercises, a body degrowth) are insufficient.

Route of administration and doses:

Prior to treatment the patient should appoint a standard holesterinosnizhayushchy diet which needs to adhere also during treatment. The dose is required to be selected individually, depending on the purposes of therapy and efficiency of treatment, in view of the current recommendations.
Klivas it is possible to accept at any time, irrespective of meal. The tablet should not be chewed, but it is possible to divide. To wash down with water.
Treatment of a hypercholesterolemia. The recommended initial dose makes 5 or 10 mg orally 1 time a day as for the patients who were earlier not applying statines and for persons who applied other inhibitors of GMG-KOA-reduktazy before. At the choice of an initial dose it is necessary to consider the individual level of contents of XC at patients and possible cardiovascular risk, and also potential risk of development of side reactions (see further). If necessary in 4 weeks the dose can be raised. Because at use of a dose of 40 mg side reactions arise more often than at lower doses, patients should titrate a dose to the maximum level of 40 mg only with a heavy hypercholesterolemia and high cardiovascular risk (in particular to persons with a family hypercholesterolemia) at which it was not succeeded to achieve desirable result at a dose of 20 mg and which have to be under regular observation. At the beginning of use of a dose of 40 mg observation of the specialist is recommended.
Prevention of cardiovascular disturbances. During the research of decrease in risk of complications from cardiovascular system the daily dose of drug made 20 mg. Patients with a hypercholesterolemia need to carry out standard determination of level of lipids and to adhere to recommendations concerning dosing at treatment of a hypercholesterolemia.
Use for patients of advanced age. The recommended initial dose for patients aged is more senior than 70 years makes 5 mg. Other dose adjustment depending on age is not required.
Use for children. The usual dose of drug for children and teenagers with a heterozygous family hypercholesterolemia makes 5–20 mg of 1 times a day orally. For achievement of therapeutic effect the dose needs to be titrated properly. Safety and efficiency of the doses exceeding 20 mg in this population were not studied.
Dosing for patients with a renal failure. For patients with an easy and moderate renal failure there is no need for dose adjustment. The recommended initial dose for patients with a renal failure of moderate weight (the clearance of creatinine <60 ml/min.) makes 5 mg. The dose of 40 mg is contraindicated to patients with a renal failure of moderate weight. Klivas's use is contraindicated to persons with a heavy renal failure in any doses.
Dosing for patients with an abnormal liver function. Increase in system exposure of a rozuvastatin at patients with a liver failure of 7 points on a scale of Chayld-Pyyu is noted. However increase in system exposure was noted at patients whose fortune was estimated in 8 and 9 points on a scale of Chayld-Pyyu. At such patients it is necessary to carry out assessment of function of kidneys. Klivas is contraindicated to persons with liver diseases in an active stage. At patients with a heavy abnormal liver function increase in exposure of a rozuvastatin is noted therefore to them to apply Klivas in a dose> 10 mg follow with care.
Race. At patients of Mongoloid race increase in system exposure of a rozuvastatin was noted. The recommended initial dose for such patients makes 5 mg. Use of a dose of 40 mg is contraindicated. The maximum daily dose makes 20 mg.
Dosing for patients with tendency to development of a myopathy. The recommended initial dose for patients with predisposition to development of a myopathy makes 5 mg. The dose of 40 mg is contraindicated to some of such patients. The maximum daily dose makes 20 mg.

Features of use:

Influence on kidneys. At the patients receiving розувастатин in high doses, especially 40 mg proteinuria cases (a certain test strip), preferential canalicular origin and in most cases temporary or short were noted. The proteinuria did not testify to the acute or progressing disease of kidneys. The undesirable phenomena from kidneys were noted more often at use of a dose of 40 mg. At the patients using drug in a dose of 40 mg, function of kidneys should be controlled regularly.
Influence on skeletal muscles. Defeats of skeletal muscles, for example a mialgiya, a myopathy and it is rare — рабдомиолиз, were observed at patients at use of any doses of a rozuvastatin, and especially at doses> 20 mg. At use of an ezetimib in a combination with inhibitors of GMG-KOA-reduktazy it was very seldom reported about cases of development of a rabdomioliz. It is impossible to exclude possibilities of pharmakodinamichesky interaction, and therefore such combination should be applied with care.
As well as at use of other inhibitors of GMG-KOA-reduktazy, рабдомиолиз, connected using a rozuvastatin, developed more often at use in a dose of 40 mg.
Determination of the KFK level. The KFK level should not be measured after considerable exercise stresses or in the presence of other alternative reasons of increase in the KFK level that can prevent interpretation of results. If the KFK initial level is significantly increased (> 5 VGN), within 5–7 days it is necessary to carry out the additional confirmatory analysis. If the result of retest confirms initial level> 5 VGN, it is not necessary to begin treatment.
Before treatment. Klivas, as well as other inhibitors of HMG-CoA reductase, patients should appoint with care with factors which promote development of a myopathy / рабдомиолиза. Treat such factors: renal failure; hypothyroidism; existence in the personal or family anamnesis of hereditary muscular diseases; existence in the anamnesis of the miotoksichnost caused by other inhibitors of GMG-KOA-reduktazy or a fibratama; alcohol abuse; age> 70 years; situations which can lead to increase in level of drug in a blood plasma; simultaneous use of fibrat. At such patients it is necessary to compare risk and possible advantage at drug use; clinical monitoring is also recommended. It is not necessary to begin treatment in case of much the increased KFK initial level (> 5 VGN).
During treatment. Patients should be warned about need to report immediately about muscular pain of not clear genesis, muscular weakness or spasms, especially if they are followed by an indisposition or fervescence. At such patients it is required to determine the KFK level. It is necessary to stop treatment if the KFK level is considerably increased (> 5 VGN) or if muscular symptoms heavy and lead to discomfort in everyday life (even if the KFK level of ≤5 VGN). If symptoms pass and the KFK level is returned to norm, Klivas or alternative inhibitor of HMG-CoA reductase it is possible to try to apply again, but in the minimum doses and under careful observation. Regular control of the KFK level at patients without the above-stated symptoms is not necessary.
During clinical trials at a small amount of the patients applying розувастатин and the accompanying drugs, the strengthened influence on skeletal muscles was not noted. However the increased frequency of cases of a miositis and myopathy was observed at the patients applying other inhibitors of GMG-KOA-reduktazy with derivatives of fibroyevy acid, including gemfibrozit, cyclosporine, niacin, azolny antifungal means, inhibitors of proteases and makrolidny antibiotics. Klivas is not recommended to apply in a combination with gemfibrozily. The beneficial effect of subsequent changes of level of lipids at the combined use of Klivas with fibrata or Niacinum should be compared to potential risk at use of such combination. Simultaneous use of drug Klivas in a dose of 40 mg and fibrat contraindicated.
Klivas patients should not apply with acute, serious states which promote development of a myopathy or increase risk of development of a renal failure against the background of a rabdomioliz (such as sepsis, arterial hypotension, extensive surgical intervention, injury, heavy metabolic, endocrine or electrolytic disturbances; uncontrollable spasms).
Influence on a liver. As well as other inhibitors of GMG-KOA-reduktazy, Klivas it is necessary to apply with care at the patients who are abusing alcohol and/or having a liver disease in the anamnesis. Function of a liver is recommended to control before use of drug and in 3 months of treatment. If the level of transaminases in a blood plasma in> 3 times exceeds VGN, Klivas's use should be stopped. About serious violations of function of a liver (increase in level of hepatic transaminases is preferential) during the post-marketing period it was reported to a thicket at use of a dose of 40 mg.
At patients with the secondary hypercholesterolemia caused by a hypothyroidism or a nephrotic syndrome at first it is necessary to carry out treatment of a basic disease, and then to begin Klivas's use.
Race. During the researches of pharmacokinetics increase in system exposure at patients of Mongoloid race in comparison with Europeans is noted.
Inhibitors of proteases. Simultaneous use of drug with inhibitors of proteases is not recommended.
Intersticial disease of lungs. If it is suspected that at the patient the intersticial disease of lungs developed (диспноэ, unproductive cough and deterioration in the general state), use of statines should be stopped.
Diabetes mellitus. As well as in case of use of other inhibitors of GMG-KOA-reduktazy, at use of a rozuvastatin increase in the HbA1c level and glucose in a blood plasma is noted. It was reported about increase in frequency of development of a diabetes mellitus after use of a rozuvastatin for patients with risk factors of development of a diabetes mellitus.
Use during pregnancy and feeding by a breast. Klivas is contraindicated during pregnancy and feeding by a breast. Women of reproductive age during Klivas's reception have to apply adequate contraceptives.
As XC and other products of biosynthesis of XC are important for fetation, the potential risk of inhibition of GMG-KOA-reduktazy exceeds possible advantage of use of drug during pregnancy. If pregnancy occurred during drug use, treatment has to be immediately stopped.
Children. Do not recommend Klivas's use for children aged up to 10 years. After 52 weeks of use of a rozuvastatin of influence on growth, body weight, an index of body weight or sexual development at children at the age of 10–17 years is not revealed.
Ability to influence speed of response at control of vehicles or work with other mechanisms. Researches of influence of a rozuvastatin on ability to control of vehicles and work with other mechanisms were not conducted. However, considering pharmakodinamichesky properties, it is improbable that розувастатин will influence such ability. At control of vehicles or work with other mechanisms it is necessary to consider a possibility of dizziness during treatment by drug Klivas.

Side effects:

The side reactions noted at Klivas's use usually easy and tranzitorny. Side reactions are given below according to emergence frequency: often (> 1/100, <1/10); infrequently (> 1/1000, <1/100); seldom (> 1/10 000, <1/1000); very seldom (<1/10 000); frequency is unknown (it is impossible to establish according to the available data).
From immune system: seldom — hypersensitivity reactions, including a Quincke's disease.
From a nervous system: often — a headache, dizziness.
From a GIT: often — a lock, nausea, an abdominal pain; seldom — pancreatitis.
From skin and hypodermic cellulose: infrequently — an itch, rash, urticaria.
From a musculoskeletal system and connecting fabric: often — a mialgiya; seldom — a myopathy (including a miositis) and рабдомиолиз.
General state: often — an adynamy. As well as in case of use of other inhibitors of GMG-KOA-reduktazy, the frequency of undesirable reactions depends on a dose.
Influence on kidneys. At the patients applying Klivas cases of a proteinuria, preferential canalicular origin (a certain test strip) are noted. Changes of amount of protein in urine from absence or trace quantities to ++ or are more noted at after a while <1% of patients who accepted розувастатин in a dose 10 and 20 mg, and approximately at 3% of patients at use of a dose of 40 mg. Insignificant increase in frequency of cases of increase in protein in urine from absence or traces to + was observed at use of a dose of 20 mg. In most cases expressiveness of a proteinuria decreased or disappeared spontaneously at continuation of use of a rozuvastatin. Review of these clinical trials and post-marketing observations did not give now the chance to reveal a causal relationship between a proteinuria and the acute or progressing disease of kidneys.
The hamaturia was observed at the patients applying розувастатин and data of clinical trials confirm its low frequency.
Influence on skeletal muscles. Changes from skeletal muscles, such as mialgiya, myopathy (including a miositis) and it is rare — рабдомиолиз, with OPN or without, are noted at use of a rozuvastatin in any doses, and especially at use of doses> 20 mg. At the patients accepting розувастатин dozozavisimy increase in the KFK level which in most cases was easy, asimptomny, and temporary is noted. If the KFK level is increased (> 5 relatively VGN), treatment should be stopped.
Influence on a liver. As well as in case of use of other inhibitors of HMG-CoA reductase, at a small amount of the patients accepting розувастатин dozozavisimy increase in level of transaminases is noted; in most cases the phenomenon was easy, asimptomny and temporary.
Influence on laboratory indicators. As well as in case of use of other inhibitors of HMG-CoA reductase, at a small amount of the patients accepting розувастатин dozozavisimy increase in level of hepatic transaminases and a creatine kinase is noted. At use of a rozuvastatin increase in the HbA1c level was also noted. At a small amount of the patients applying розувастатин and other inhibitors of GMG-KOA-reduktazy, pathological changes were observed in the analysis of urine (the test strip testified to a proteinuria). The revealed protein was, as a rule, a canalicular origin. In most cases the proteinuria becomes less expressed or disappears spontaneously at continuation of therapy and does not testify to the acute or progressing disease of kidneys.
Except the above, during the post-marketing period at use of a rozuvastatin other side reactions are registered.
From a nervous system: very seldom — polyneuropathy, memory loss.
From respiratory system, bodies of a thorax and a mediastinum: frequency is unknown — cough, диспноэ.
From a GIT: frequency is unknown — diarrhea.
From gepatobiliarny system: very seldom — jaundice, hepatitis; seldom — increase in activity of hepatic transaminases.
From skin and hypodermic cellulose: frequency is unknown — Stephens's syndrome — Johnson.
From a musculoskeletal system: very seldom — an arthralgia.
From kidneys: very seldom — a hamaturia.
The general state and disturbances connected with a drug route of administration: frequency is unknown — hypostasis.
At use of some statines it was reported about such by-effects: depression; sleep disorders, including sleeplessness and dreadful dreams; disturbances of sexual function; separate cases of an intersticial disease of lungs, especially in case of long therapy.
Frequency of cases of a rabdomioliz, serious violations from kidneys and a liver (preferential increased level of transaminases) was higher than 40 mg at use of a dose.

Interaction with other medicines:

Cyclosporine. At simultaneous use of a rozuvastatin and cyclosporine AUC value of a rozuvastatin was on average 7 times higher, than at healthy volunteers. Simultaneous use did not influence concentration of cyclosporine in a blood plasma. Klivas in the range of doses of 10-40 mg do not recommend to appoint in such combination.
Antagonists of vitamin K. As well as in case of use of other inhibitors of GMG-KOA-reduktazy, an initiation of treatment by Klivas or increase in a dose at the patients receiving at the same time antagonists of vitamin K (for example warfarin or other coumarinic anticoagulants), can lead to increase in the international normalized relation (INR). After Klivas's cancellation or a dose decline of MNO can decrease. In such cases it is desirable to control MNO as appropriate.
Gemfibrozil and other hypolipidemic drugs. Simultaneous use of a rozuvastatin and gemfibrozil led to 2-fold increase in Cmax and AUC of a rozuvastatin. Proceeding from these special researches of interaction, considerable pharmacokinetic interaction with fenofibraty it is not expected, however perhaps pharmakodinamichesky interaction. Gemfibrozil, фенофибрат, other fibrata and Niacinum (niacin) in hypolipidemic doses (≥1 g/days) increase risk of development of a myopathy at the combined use with GMG-KOA-reduktazy inhibitors, it is possible because they can cause a myopathy and when using separately. Klivas's dose of 40 mg is contraindicated at simultaneous use of fibrat. Treatment by Klivas in such cases should be begun also with a dose 5 mg. For the patients who are at the same time applying gemfibrozit, Klivas's dose should not exceed 20 mg/days.
Эзетимиб. Simultaneous use of a rozuvastatin and ezetimib did not influence AUC or Cmax value of both drugs. Nevertheless, pharmakodinamichesky interaction between Klivas and ezetimiby which can result in side effects cannot be excluded.
Inhibitors of proteases. In spite of the fact that the exact mechanism of interaction is unknown, the combined use of inhibitors of proteases can lead to substantial increase of exposure of a rozuvastatin. Simultaneous use of a rozuvastatin for the HIV-positive patients applying inhibitors of proteases is not recommended.
Antiacid drugs. Simultaneous use of a rozuvastatin and the antacids containing aluminum hydroxide or magnesium leads to decrease in concentration of a rozuvastatin by ≅50%. This effect is less expressed if to accept an antacid in 2 h after reception of a rozuvastatin. Clinical value of similar interaction was not studied.
Erythromycin. Simultaneous use of Klivas and erythromycin leads to decrease in AUC0-t of a rozuvastatin by 20%, and Cmax — for 30%. Similar interaction can arise owing to strengthening of a vermicular movement of intestines as a result of effect of erythromycin.
Peroral contraceptives / гормонозаместительная therapy (GZT). Simultaneous use of a rozuvastatin and oral contraceptives led to increase in AUC ethinylestradiol and Norgestrelum by 26 and 34% respectively. Such increase in level in a blood plasma needs to be considered at selection of a dose of oral contraceptives. Patients who at the same time accept розувастатин and GZT have no data on pharmacokinetics of drugs, therefore, the possibility of interaction cannot be excluded. However the similar combination was widely applied at women during conduct of clinical trials and transferred well.
Other medicines. Proceeding from these special researches, clinically essential interaction with digoxin it is not expected.
P450 cytochrome enzymes. Results of the researches in vitro and in vivo demonstrate what розувастатин is not either inhibitor, or the inductor of isoenzymes of P450 cytochrome. Therefore the interaction between drugs connected with the metabolism mediated by P450 cytochrome is not expected.
Lopinavir/ritonavir. During the pharmacological research the combined use of a rozuvastatin and the combined drug which contained two inhibitors of proteases (лопинавир 400 mg / ритонавир 100 mg) for healthy volunteers was associated with approximately two-and fivefold increase in indicators of equilibrium AUS0-24 and Cmax for a rozuvastatin respectively. Interaction between rozuvastatiny and other inhibitors of proteases was not studied.

Contraindications:

Hypersensitivity to a rozuvastatin or any excipient; liver diseases in an active phase, including an unknown etiology, permanent increase in level of transaminases in a blood plasma and increase in level of transaminase in> 3 times in comparison with the upper bound of norm (UBN); heavy renal failures (clearance of creatinine <30 ml/min.); myopathy; simultaneous use of cyclosporine; period of pregnancy and feeding by a breast; women of reproductive age need to apply adequate contraceptives.
The dose of 40 mg is contraindicated to patients with the factors promoting development of a myopathy / рабдомиолиза. Treat such factors: renal failures of moderate weight (clearance of creatinine <60 ml/min.); hypothyroidism; existence in the personal or family anamnesis of hereditary diseases of muscles; existence in the anamnesis of the miotoksichnost caused by other inhibitors of GMG-KOA-reduktazy or fibrat; alcohol abuse; situations which can lead to increase in level of drug in a blood plasma; belonging of patients to Mongoloid race; the accompanying use of fibrat.

Overdose:

There is no specific treatment at overdose. The symptomatic treatment, is recommended a maintenance therapy. Control of function of a liver and the KFK level is necessary. It is improbable that the hemodialysis will be effective.

Storage conditions:

In original packaging at a temperature not above 25 °C.

Issue conditions:

According to the recipe

Packaging:

Tab. п / captivity. cover of 10 mg blister, No. 10, No. 30.

Tab. п / captivity. cover of 20 mg blister, No. 10, No. 30.