Rozulip

General characteristics. Structure:

Active ingredient: each tablet contains 5 mg, 10 mg, 20 mg or 40 mg of a rozuvastatin (in the form of, respectively, 5,34 mg, 10,68 mg, 21,36 mg and 42,72 mg розувастатин zinc).

Excipients: лудипресс 65,16/130,32/260,64/521,28 mg (lactoses monohydrate (93%), povidone (3,5%), кросповидон (3,5%)), кросповидон 3,75/7,5/15/30 mg, magnesium mg stearate 0,75/1,5/3/6; cover: опадрай II white 85F 18422 1,9/3,8/7,5/15 mg (polyvinyl alcohol (40%), titanium dioxide (25%), macrogoal 3350 (20,2%), talc (14,8%)).

Description:

Tablets of 5 mg: Round biconvex tablets, film coated white or almost white color, with an engraving E on one party of a tablet and number 591 on other party of a tablet, without or almost inodorous.

Tablets of 10 mg: Round biconvex tablets, film coated white or almost white color, with an engraving E on one party of a tablet and number 592 on other party of a tablet, without or almost inodorous.

Tablets of 20 mg: Round biconvex tablets, film coated white or almost white color, with an engraving E and number 593 on one party of a tablet, without or almost inodorous.

Tablets of 40 mg: Oval biconvex tablets, film coated white or almost white color, with an engraving E and number 594 on one party of a tablet, without or almost inodorous. Pharmakoterapevtichesky group: hypolipidemic means - GMG-KOA-reduktazy inhibitor.

Pharmacological properties:

Pharmacodynamics. Action mechanism

Rozuvastatin is a selection and competitive inhibitor of GMG-KOA-reduktazy – the enzyme catalyzing transformation of 3-hydroxy-3-methylglutaryl-coenzyme A in мевалонат which is a predecessor of cholesterol (Хс). Rozuvastatin increases the number of receptors of lipoproteins of the low density (LPNP) by surfaces of cells of a liver at the expense of what absorption and a catabolism of LPNP amplifies, and also synthesis of lipoproteins of very low density (LPONP) in a liver is suppressed. As a result total quantity of particles of LPONP decreases and Lpnp.Farmakodinamicheskiye effektysnizhat the increased concentration of cholesterol of lipoproteins of the low density (Hs-LPNP), the general cholesterol and triglycerides, and also increases concentration of cholesterol of lipoproteins of the high density (Hs-LPVP). Besides, розувастатин reduces concentration of apolipoprotein B (Apov), cholesterol неЛПВП (Hs-NELPVP), cholesterol of lipoproteins of very low density (Hs-LPONP), triglycerides of lipoproteins of very low density (TG-LPONP) and increases the content of A-I apolipoprotein (Apoa-I). Also розувастатин reduces a ratio of Hs-LPNP/Hs-LPVP, the general cholesterol / Hs-LPVP, Hs-NELPVP/Hs-LPVP and Apov/Apoa-I.

The therapeutic effect of drug is shown within one week after an initiation of treatment. In 2 weeks of therapy efficiency reaches the level which makes 90% from greatest possible. The maximum therapeutic effect is usually reached by 4th week of therapy and supported at regular reception. Safety and efficiency of a rozuvastatin in children's population are not proved. For this category of patients experience of use of drug is limited to a small amount of patients (age of 8 years and is more senior) with a homozygous hereditary hypercholesterolemia. Pharmakokinetikavsasyvaniye. The maximum concentration of a rozuvastatin in a blood plasma is reached approximately in 5 h after intake. Absolute bioavailability of drug makes about 20%. Distribution. Rozuvastatin is intensively absorbed by a liver where there is the main synthesis of cholesterol and removal of Hs-LPNP. The volume of distribution of a rozuvastatin reaches 134 l. About 90% of a rozuvastatin contact proteins of a blood plasma, are preferential with albumine.

Metabolism. Rozuvastatin is exposed to limited metabolism (about 10%) in a liver. Is non-core substrate for isoenzymes 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-desmetil 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. About 5% of a dose of drug are removed by kidneys in not changed look. The drug elimination half-life makes about 19 h of a blood plasma and does not change at increase in a dose of drug. The plasma clearance of a rozuvastatin reaches on average 50 l/h (coefficient of variation – 21,7%). As well as in case of other inhibitors of HMG-CoA reductase, the membrane carrier of cholesterol which is carrying out an important role in hepatic elimination of a rozuvastatin is involved in process of "hepatic" capture of a rozuvastatin.

System bioavailability of a rozuvastatin increases in proportion to a dose. At drug use several times in days pharmacokinetic parameters do not change.

SPECIAL GROUPS OF PATIENTS

Gender and age do not exert clinically significant impact on pharmacokinetics of a rozuvastatin. Pharmacokinetic researches showed approximately double increase in a median of AUC and Cmax of a rozuvastatin in a blood plasma at patients of an Asian nationality (Japanese, Chinese, Filipinos, Vietnamese and Koreans), in comparison with representatives of Caucasian race; at the Indian patients increase in a median of AUC and Cmax by 1,3 times is shown. The analysis did not reveal clinically significant distinctions in pharmacokinetics among Europeans and representatives of negroid race. 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 (clearance of KK creatinine       less than 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 in T1/2 of 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 in T1/2, 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 across Fredriksen, including a family heterozygous hypercholesterolemia) or the mixed hypercholesterolemia (IIb type) 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.

Homozygous hereditary hypercholesterolemia as addition to a diet and other methods of treatment directed to decrease in level of lipids in blood (for example, аферез LPNP), and also in cases when these methods are insufficiently effective.

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

For delay of progressing of atherosclerosis as addition to a diet at patients, including to which therapy for decrease in level of general Hs and Hs-LPNP is shown.

Route of administration and doses:

Inside, not to chew and not to crush a tablet, to swallow entirely, washing down with water. Drug Rozulip can be accepted at any time, irrespective of meal.

Before beginning treatment with drug Rozulip, the patient needs to appoint a standard diet with the low content of cholesterol. The patient has to keep to a diet during all course of therapy. The dose of drug should be selected individually depending on indications and the therapeutic response to treatment, in view of the current recommendations about the target objectives of lipids. The recommended initial dose of drug Rozulip 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 once 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 can be increased. After reception within 4 weeks of the dose exceeding recommended initial the subsequent its increase to 40 mg can be carried out only at patients with heavy degree of a hypercholesterolemia and with high risk of cardiovascular complications (especially at patients with a family hypercholesterolemia) at which the desirable result of therapy at reception in a dose of 20 mg and which will be under observation of the specialist was not achieved. Especially careful observation of the patients receiving drug in a dose of 40 mg is recommended.

For treatment of patients 65 years the recommended initial dose of 5 mg are more senior. Need for other changes of a dose of drug connected with age patients no.

Easy or moderate severity of dose adjustment is not required to patients with a renal failure. To patients with moderate renal failures (KK less than 60 ml/min.) recommends an initial dose of drug of 5 mg. The dose of 40 mg is contraindicated to patients with moderate renal failures. At a heavy renal failure drug Rozulip is contraindicated in any doses (see the section "Contraindications").

At purpose of doses of 10 and 20 mg the recommended initial dose for patients of Asian race makes 5 mg. Purpose of drug in a dose of 40 mg is contraindicated to patients of Asian race (see the section "Contraindications").

At purpose of doses of 10 and 20 mg the recommended initial dose for the patients predisposed to a myopathy, the recommended initial dose makes 5 mg. Purpose of drug in a dose of 40 mg is contraindicated to patients with factors which can indicate predisposition to development of a myopathy (see the section "Contraindications").

After 2-4 weeks of therapy and/or at increase in a dose of drug Rozulip is necessary control of indicators of lipidic exchange, if necessary dose adjustment is required.

Side effects:

Against the background of therapy rozuvastatiny preferential easy and passing undesirable phenomena were registered. Similar to other inhibitors of GMG-KOA-reduktazy, the frequency of the undesirable reactions connected with therapy rozuvastatiny is characterized by dependence on a dose. Classification of undesirable reactions depending on emergence frequency: often (from> 1/100 to <1/10), infrequently (from> 1/1000 to <1/100), it is rare (from> 1/10000 to <1/1000), is very rare (<1/10000), not specified frequency (it is impossible to define proceeding from available data).

From immune system: seldom - hypersensitivity reactions, including a Quincke's disease.

From a nervous system: often - a headache, dizziness; very seldom - polyneuropathy, memory loss.

From the alimentary system: often - a lock, nausea, an abdominal pain; infrequently – slight, asymptomatic, tranzitorny increase of activity of "hepatic" transaminases; seldom - pancreatitis; not specified frequency - diarrhea; very seldom - jaundice, hepatitis.

From skin and hypodermic structures: infrequently - a skin itch, rash and a small tortoiseshell; not specified frequency - Stephens-Johnson's syndrome.

From a musculoskeletal system: often - a mialgiya; seldom - a myopathy (including a miositis) and рабдомиолиз with an acute renal failure or without it. Dozozavisimy increase in concentration of a kreatinfosfokinaza (KFK) is observed at a small number of the patients accepting розувастатин. In most cases it was insignificant, asymptomatic and temporary. In case of increase in concentration of KFK therapy more than 5 times higher than VGN should be suspended. Very seldom - an arthralgia.

From an urinary system: a proteinuria (less than 1% of the patients receiving a dose of 10-20 mg and about 3% of the patients receiving a dose of 40 mg). In most cases the proteinuria decreases or disappears in the course of therapy and does not mean emergence acute or progressing of the existing disease of kidneys. Very seldom - a hamaturia.

From a respiratory organs: frequency is unknown - cough, short wind.

From laboratory indicators: increase in concentration of glucose, bilirubin, activity gamma глютамилтранспептидазы, alkaline fosfaza.

Others: often - an asthenic syndrome; dysfunctions of a thyroid gland are possible.

The following undesirable phenomena were registered against the background of therapy by some statines: sleep disorders, including sleeplessness and dreadful dreams; disturbances of sexual function; depression; very exceptional cases of an intersticial disease of lungs which generally were registered at long-term therapy by statines.

Interaction with other medicines:

Cyclosporine. 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. Combined use leads to increase in concentration of a rozuvastatin in a blood plasma by 11 times, plasma concentration of cyclosporine at the same time does not change.

Antagonists of vitamin K. 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 and the international normalized relation (INR). Cancellation of a rozuvastatin or decrease in its dose can lead to reduction of MNO. In such cases control of MNO is recommended.

Gemfibrozil and hypolipidemic means. Combined use of a rozuvastatin and gemfibrozil leads to increase twice in Cmax in a blood plasma and AUC of a rozuvastatin. Perhaps pharmakodinamichesky interaction. Gemfibrozil, other fibrata and niacin in lipidsnizhayushchy doses (more 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. At a concomitant use of drug with gemfibrozily, fibrata, niacin in lipidsnizhayushchy doses (more than 1 g/days) to patients recommend an initial dose of drug of 5 mg. Therapy rozuvastatiny in a dose of 40 mg is contraindicated at the accompanying use of fibrat.

Эзетимиб. Simultaneous use of drug Rozulip and an ezetimiba was not followed by change of AUC and Cmax of both medicines. Nevertheless, between rozuvastatiny and ezetimiby it is impossible to exclude pharmakodinamichesky interaction with development of side effects.

Inhibitors of proteases. In spite of the fact that the exact mechanism of interaction is unknown, joint reception of inhibitors of proteases can lead to significant increase in exposure of a rozuvastatin. The pharmacokinetic research on simultaneous use of 20 mg of a rozuvastatin with the combined drug containing two inhibitors of proteases (400 mg lopinavira/100 mg of a ritonavir) at healthy volunteers led to approximately double and fivefold increase in AUC(0-24) and Cmax of a rozuvastatin, respectively. Therefore the concomitant use of a rozuvastatin and inhibitors of proteases at treatment of patients with the human immunodeficiency virus (HIV) is not recommended. Antacids. 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 suspension of antacids is applied in 2 h after reception of a rozuvastatin. Clinical value of similar interaction was not studied.

Erythromycin.

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.

Peroral contraceptives / gormonozamestitelny therapy (GZT). 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 Rozulip's use. Pharmacokinetic data on simultaneous use of Rozulip and gormonozamestitelny therapy are absent, therefore, it is impossible to exclude similar effect and when using this combination. However the similar combination was widely used during conduct of clinical trials and well transferred by patients.

Other medicines. Clinically significant interaction of a rozuvastatin with digoxin is not expected.

P450 cytochrome isoenzymes. 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 (inhibitor of isoenzymes of CYP2C9 and CYP3A4) and ketokonazoly was not noted (inhibitor of isoenzymes of CYP2A6 and CYP3A4). Combined use of a rozuvastatin and itrakonazol (CYP3A4 isoenzyme inhibitor) increases AUC of a rozuvastatin by 28% (clinically not significantly). Thus, the interaction connected with system of P450 cytochrome is not expected. SPECIAL INSTRUCTIONS

At drug use Rozulip in a dose of 40 mg is recommended to control indicators of function of kidneys.

At drug use Rozulip in all doses, especially more than 20 mg, were reported about development of a mialgiya, myopathy and in rare instances of a rabdomioliz.

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 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 a superactivity of KFK (5 times higher than VGN).

At purpose of drug Rozulip (also as well as other inhibitors of GMG-KOA-reduktazy) 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.

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 define activity of KFK. Therapy should be stopped if activity of KFK is considerably increased (more than by 5 times in comparison with VGN) or if muscular symptoms are sharply expressed and cause daily discomfort (even if activity of KFK is 5 times less in comparison with VGN). If symptoms disappear, and activity of KFK is returned to norm, it is necessary to consider a question of repeated appointment of Rozulip or other inhibitors of GMG-KOA-reduktazy in smaller doses at careful observation of the patient. Routine monitoring of activity of KFK in the absence of symptoms is inexpedient.

Signs of increase in toxic impact on skeletal muscles at drug use are noted Rozulip as a part of a combination therapy. 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 fibroyevy acid (including gemfibrozit), cyclosporine, niacin in lipidsnizhayushchy doses (more than 1 g/days), azolny antifungal drugs, inhibitors of proteases and makrolidny antibiotics. Gemfibrozil increases risk of emergence of a myopathy at co-administration with some inhibitors of GMG-KOA-reduktazy. Thus, drug co-administration Rozulip is not recommended and gemfibrozit. It is necessary to weigh carefully a ratio of the expected advantage and potential risk at combined use of drug Rozulip and fibrat or niacin in lipidsnizhayushchy doses (more than 1 g/days). In 2-4 weeks after an initiation of treatment and/or at increase in a dose of drug Rozulip is necessary control of indicators of lipidic exchange (if necessary dose adjustment is required).

It is recommended to carry out definition of activity of transaminases prior to therapy and in 3 months after the beginning of therapy. Administration of drug Rozulip it is necessary to stop or reduce a drug dose if activity of transaminases in blood serum by 3 times exceeds VGN.U of patients with a hypercholesterolemia owing to a hypothyroidism or a nephrotic syndrome therapy of basic diseases should be carried out prior to treatment by drug Rozulip.

Clinical experience and data on use of drug for patients with the abnormal liver functions corresponding to more than 9 points on a scale of Chayld-Pyyu no.

Very exceptional cases of an intersticial disease of lungs were registered at the patients receiving some drugs from group of statines. As a rule, these cases were observed at long-term therapy by statines. The intersticial disease of lungs is shown by short wind, unproductive cough and deterioration in the general state (increased fatigue, decrease in body weight and fever). If the intersticial disease of lungs is suspected, therapy by statines should be stopped.

Results of pharmacokinetic researches demonstrate that at patients of Asian race bioavailability of a rozuvastatin is higher, than at Europeans.

Patients with a lactose intolerance, deficit of lactase or glyukozo-galaktozny malabsorption as drug contains lactose should not accept this drug. Use in a pediatriieffektivnost and safety of use of drug for children up to 18 years it is not established. Experience of use of drug in pediatric practice is limited by a small amount of children (of 8 years and is more senior) a family homozygous hypercholesterolemia. Now Rozulip at children is not recommended to apply. Influence on ability to driving of motor transport and to control of mechanisms.

Patients have to be careful at control of motor transport or work, the requiring increased concentration of attention and speed of psychomotor reaction as during therapy there can be dizziness.

Contraindications:

For tablets of 10 mg and 20 mg – hypersensitivity to a rozuvastatin and other components of drug;

– liver diseases in an active phase, including permanent increase in serumal activity of transaminases and any increase in activity of transaminases in blood serum (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, the lactation period, and also lack of adequate methods of contraception at women with safe reproductive function;

– predisposition to development of miotoksichesky complications;

– children's age up to 18 years (in view of lack of sufficient clinical data efficiency and safety are not established, see the section "Special Instructions");

– a lactose intolerance, deficit of lactase or glyukozo-galaktozny malabsorption (drug contains lactose).

For tablets of 40 mg – hypersensitivity to a rozuvastatin and other components of drug;

– liver diseases in an active phase, including permanent increase in serumal activity of transaminases and any increase in activity of transaminases in blood serum (more than by 3 times in comparison with VGN), experience of use of drug for patients with point higher than 9 on a scale of Chayld-Pyyu is absent;

– concomitant use of cyclosporine;

– existence of risk factors of development of a myopathy / рабдомиолиза: renal failure of moderate severity (KK less than 60 ml/min.); hypothyroidism; personal or family anamnesis of muscular diseases; a miotoksichnost against the background of reception of other inhibitors of GMG-KOA-reduktazy or fibrat in the anamnesis; excessive alcohol intake; states which can lead to increase in plasma concentration of a rozuvastatin; concomitant use of fibrat; patients of Asian race;

– pregnancy, the lactation period, and also lack of adequate methods of contraception to women with safe reproductive function;

– children's age up to 18 years (in view of lack of sufficient clinical data efficiency and safety are not established, see the section "Special Instructions");

– a lactose intolerance, deficit of lactase or glyukozo-galaktozny malabsorption (drug contains lactose). With care to use drug in the form of mg tablets 10 and 20 with risk of development of a myopathy / рабдомиолиза - a renal failure, a hypothyroidism, the personal or family anamnesis of hereditary muscular diseases and the previous anamnesis of muscular toxicity at use of other inhibitors of GMG-KOA-reduktazy or fibrat; at excessive alcohol intake; at patients in 65 years are more senior; states at which increase in plasma concentration of a rozuvastatin is noted; at patients of Asian race; along with fibrata; at liver diseases in the anamnesis; sepsis; arterial hypotension; extensive surgical interventions, injuries; at heavy metabolic, endocrine or electrolytic disturbances or uncontrollable convulsive attacks.

With care to use drug in the form of tablets of 40 mg at patients with a renal failure of easy severity (KK more than 60 ml/min.); 65 years are aged more senior; at liver diseases in the anamnesis; sepsis; arterial hypotension; extensive surgical interventions, injuries, heavy metabolic, endocrine or electrolytic disturbances or uncontrollable convulsive attacks. 

Use of drug at pregnancy and feeding by a breast

Rozulip is contraindicated at pregnancy and in the period of a lactation (breastfeeding). When diagnosing pregnancy in the course of therapy administration of drug has to be stopped immediately.

Women of reproductive age have to apply adequate methods of contraception. As Hs 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 with breast milk are absent therefore in need of use of drug in the period of a lactation breastfeeding should be stopped.

Overdose:

Treatment: there is no specific antidote. It is recommended to hold the symptomatic treatment and events directed to maintenance of functions of vitals and systems. Control of function of a liver and the KFK level in blood serum is necessary. Efficiency of a hemodialysis is improbable.

Storage conditions:

Period of validity 2 years. Not to use after the expiration specified on packaging. To store at a temperature not over 30 ºС. To store drug 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 7 tablets in the blister from the combined film of "cold" (polyamide / an aluminum foil /
PVC)//aluminum foil. 2, 4 or 8 blisters together with the application instruction in a cardboard pack.