Akorta

General characteristics. Structure:

Active agent: розувастатин calcium – 10,4 mg or 20,8 mg (in terms of anhydrous substance that is equivalent to the maintenance of a rozuvastatin – 10,0 mg or 20,0 mg).

Excipients
Tablet kernel:
for a dosage of 10 mg - lactoses monohydrate (sugar milk) 89,50 mg, cellulose of microcrystallic 29,82 mg, calcium hydrophosphate (Е 341) 10,90 mg, кросповидон 7,50 mg, magnesium stearate of 1,88 mg;
for a dosage of 20 mg - lactoses monohydrate (sugar milk) 179,00 mg, cellulose of microcrystallic 59,64 mg, calcium hydrophosphate (Е 341) 21,80 mg, кросповидон 15,00 mg, magnesium stearate of 3,76 mg.

Cover:
for a dosage of 10 mg - OPADRAY II 30K240001 Pink (OPADRAY II 30K240001 Pink) [Lactoses monohydrate (sugar milk) 2,40 mg, a gipromelloz (gidroksipropilmetiltsellyuloz) of 1,68 mg, titanium dioxide of 1,413 mg, triacetin (glyceryl triacetate) 0,48 mg, dye ferrous oxide of red 0,027 mg] 6,00 mg;
for a dosage of 20 mg - OPADRAY II 30K240001 Pink (OPADRAY II 30K240001 Pink) [Lactoses monohydrate (sugar milk) 4,80 mg, a gipromelloz (gidroksipropilmetiltsellyuloz) of 3,36 mg, titanium dioxide of 2,826 mg, triacetin (glyceryl triacetate) 0,96 mg, dye ferrous oxide of red 0,054 mg] 12,00 mg.

Pharmacological properties:

Pharmacodynamics. Rozuvastatin represents the selection competitive inhibitor hydroxymethylglutaryl-coenzyme A (GMG-KOA) - reductases - the enzyme turning 3-gidroksi-3-metilglutaril-KOA in мевалонат which is a predecessor of cholesterol. The main target of action of a rozuvastatin is the liver where synthesis of cholesterol (XC) and a catabolism of lipoproteins of the low density (LPNP) is carried out. Rozuvastatin increases number of receptors of LPNP by the surfaces of hepatocytes, increasing capture and a catabolism of LPNP. It also slows down synthesis of the XC lipoproteins of very low density (LPONP) in liver cells, thereby reducing total quantity of LPNP and LPONP. Rozuvastatin reduces concentration holesterina-LPNP, the general cholesterol and triglycerides (TG), increases concentration of cholesterol of lipoproteins of the high density (HS-LPVP), and also reduces concentration of apolipoprotein B (Apov), cholesterol-NELPVP (concentration of the general of XC minus the maintenance of HS-LPVP), HS-LPONP, TG-LPONP and increases concentration of A-I apolipoprotein (Apoa-I). Rozuvastatin reduces a ratio of HS-LPNP/HS-LPVP, the general HS/HS-LPVP, HS-NELPVP/HS-LPVP and Apov/Apoa-I.
Hypolipidemic action in direct ratio to the size of the appointed dose.
The therapeutic effect develops within 1 week after the beginning of therapy, in 2 weeks reaches 90% of the greatest possible effect, the maximum therapeutic effect is usually reached in 4 weeks and supported at further administration of drug.
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 hereditary form a family hypercholesterolemia.
The additive effect is noted in a combination with fenofibraty (concerning decrease in concentration of TG) and niacin in lipidsnizhayushchy doses (more than 1 g/days) (concerning increase in concentration holesterina-LPVP).

Pharmacokinetics. Absorption: absolute bioavailability – 20%. Food reduces absorption speed. Time of achievement of the maximum concentration (TCmax) – 3-5 h, after intake. Gets through a placental barrier.
Distribution: розувастатин it is absorbed preferential by a liver which is the place of synthesis of cholesterol and metabolism of HS-LPNP. The volume of distribution is about 134 l. Communication with proteins of a blood plasma (it is preferential with albumine) – 90%.
Metabolism: in a liver 10% of the accepted dose are metabolized. Rozuvastatin is non-core substrate for metabolism by enzymes of system of P450 cytochrome. CYP2C9 is the main isoenzyme participating in metabolism of a rozuvastatin while isoenzymes of CYP2C19, CYP3A4, CYP2D6 are involved in his metabolism to a lesser extent.
More than 90% of pharmacological activity on inhibition of the circulating GMG-KOA-reduktazy are provided rozuvastatiny, the rest - its metabolites. 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 are pharmacological not active.
Removal: it is removed preferential in not changed look (90%) through intestines (including absorbed and not absorbed розувастатин); the rest – with kidneys. The elimination half-life (T1/2) makes about 19 h. The elimination half-life does not change at increase in a dose of drug. The average geometrical plasma clearance makes about 50 l/h (coefficient of variation of 21,7%). As well as in case of other GMG-KOA-inhibitors of reductase, the membrane carrier of cholesterol (a transport protein From organic anions) which is carrying out an important role in hepatic elimination of a rozuvastatin is involved in process of "hepatic" capture of a rozuvastatin.
System exposure of a rozuvastatin increases in proportion to a dose. Changes of pharmacokinetic parameters at daily administration of drug are not noted.
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 (the area under a curve "concentration time") and Cmax (the maximum concentration in a blood plasma) a rozuvastatina at patients of an Asian nationality (Japanese, Chinese, Filipinos, Vietnamese and Koreans) in comparison with Europeans; at the Indian patients increase in a median of AUC and Cmax in 1, 3 times is shown. The pharmacokinetic 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 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 N-dismetila - by 9 times, than at healthy volunteers. Concentration of a rozuvastatin in plasma at the patients who are on a hemodialysis is about 50% higher, than at healthy volunteers.
At patients with various stages of a liver failure with point 7 and below on a scale of Chayld-Pyyu increase in T1/2 of a rozuvastatin is not revealed; at 2 patients with points 8 and 9 on a scale of Chayld-Pyyu lengthening of T1/2 twice Chayld-Pyyu exceeding a similar indicator for patients with lower indicators on a scale is noted. Experience of use of drug for patients with more expressed abnormal liver functions (it is higher than 9 points on a scale of Chayld-Pyyu) is absent.

Indications to use:

Primary hypercholesterolemia across Fredriksen (the IIa type, 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.
Family homozygous hypercholesterolemia - as addition to a diet and other lipidsnizhayushchy therapy (for example, LPNP-aferez) or in cases when similar therapy is insufficiently effective.
Gipertriglitseridemiya (type IV across Fredriksen) as addition to a diet.
For delay of progressing of atherosclerosis as addition to a diet at patients to whom therapy for decrease in level of the general in XC and HS-LPNP is shown.

Route of administration and doses:

Prior to therapy by drug the patient has to begin to keep to a standard hypolipidemic diet and to continue to observe it during treatment. The dose of drug has to be selected individually depending on the purposes of therapy and the therapeutic answer, in view of the modern standard recommendations about target concentration of lipids.
Akort's drug is accepted inside, at any time, irrespective of meal, without chewing and without crushing a tablet, swallowing entirely, washing down with water.
The recommended initial dose (if it is not appointed differently) - 10 mg of 1 times a day as for the patients who were earlier not accepting GMG-KOA-reduktazy inhibitors and for the patients transferred to reception of this drug after therapy by other GMG-KOA-inhibitors of reductase.
In case of need, the dose can be increased in 4 weeks to 20 mg.
Due to the possible development of side effects at reception of a dose of 40 mg, in comparison with lower doses of drug, increase in a dose up to 40 mg, can be carried out only at patients with a heavy hypercholesterolemia and with high risk of cardiovascular complications (especially at patients with a family hypercholesterolemia) at which the desirable result of therapy at reception of a dose of 20 mg and which will be under medical observation was not achieved.
Especially careful observation of the patients receiving drug in a dose of 40 mg is recommended. Purpose of a dose of 40 mg is not recommended to the patients who were earlier not seeing a doctor. After 2-4 week therapies and/or at increase in a dose of drug control of indicators of lipidic exchange is necessary (if necessary dose adjustment is required).
At the patients accepting drug in a dose of 40 mg it is recommended to control indicators of function of kidneys.
At appointment with gemfibrozily the dose of a rozuvastatin should not exceed 10 mg/days.
Dose adjustment is not required to patients of advanced age.
When studying pharmacokinetic parameters at the patients belonging to different ethnic groups increase in system concentration of a rozuvastatin among Japanese and Chinese is noted. It is necessary to consider this fact at purpose of a rozuvastatin to these groups of patients. Purpose of drug in a dose of 40 mg is contraindicated to patients of Mongoloid race.
Patients with a renal failure
With a renal failure easy or moderate severity dose adjustment is not required from patients. Use of all dosages of drug of Akort for patients with a heavy renal failure is contraindicated (clearance of creatinine less than 30 ml/min.). Use of drug in a dosage of 40 mg is contraindicated to patients with moderate renal failures (clearance of creatinine less than 60 ml/min.).
Patients with a liver failure
Experience of use of drug for patients with point higher than 9 on a scale of Chayld-Pyyu is absent. Akort's drug is contraindicated to patients with liver diseases in an active phase (including at permanent increase in activity of "hepatic" transaminases, and also any increase in activity of "hepatic" transaminases in blood serum more than by 3 times in comparison with the upper bound of norm).

Features of use:

The proteinuria, preferential canalicular origin, was noted at patients at reception of high doses of a rozuvastatin, in particular 40 mg, but in most cases was periodic or short-term. It is shown that such proteinuria does not mean emergence acute or progressing of the existing disease of kidneys. At the patients accepting drug in a dose of 40 mg it is recommended to control indicators of function of kidneys during treatment.
 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. At increase in initial activity of KFK of norm 5 times higher than the upper bound in 5-7 days it is necessary to take repeated measurement. It is not necessary to begin therapy if the repeated test confirms an initial superactivity of KFK more than by 5 times in comparison with the upper bound of norm.
At patients with the available risk factors of a rabdomioliz it is necessary to consider a ratio of risk and possible advantage of therapy and to carry out 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 carry out monitoring of the level of activity of KFK. Therapy has to be stopped if activity of KFK is 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 (even if activity of KFK is 5 times less in comparison with the upper bound of norm). If symptoms disappear, and activity of KFK is returned to norm, it is necessary to consider a question of repeated purpose of drug or other inhibitors of GMG-KOA-reduktazy in smaller doses at careful observation of the patient. Routine monitoring of KFK in the absence of symptoms of a rabdomioliz 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 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 the combined appointment with some inhibitors of GMG-KOA-reduktazy. Thus, simultaneous use of a rozuvastatin and gemfibrozil is not recommended. The ratio of risk and possible advantage at combined use of a rozuvastatin and fibrat or niacin has to be carefully weighed.
Patients should not appoint Akort's drug with the acute, serious illness allowing to assume a myopathy or with possible development of a secondary renal failure (sepsis, arterial hypertension, surgical intervention, an injury, a metabolic syndrome, spasms, endocrine disturbances, electrolytic disturbances).
Akort's drug, as well as other inhibitors of GMG-KOA-reduktazy, the patients who are abusing alcohol or having in the anamnesis of a disease of a liver should accept with extra care.
It is recommended to carry out definition of activity of "hepatic" transaminases prior to therapy and in 3 months after the beginning of therapy. If activity of "hepatic" transaminases in blood serum by 3 times exceeds the upper bound of norm, a dose of drug it is necessary to reduce or stop reception. 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. At a combination of a hypercholesterolemia and a hypothyroidism or a nephrotic syndrome therapy of basic diseases has to be carried out prior to treatment rozuvastatiny.

Influence on ability to manage vehicles, mechanisms
It is necessary to be careful at control of vehicles and during the work connected with the increased concentration of attention and speed of psychomotor reaction (during therapy there can be dizziness).

Side effects:

As well as at use of other inhibitors of GMG-KOA-reduktazy, the frequency of emergence of side effects has dozozavisimy character.
Frequency of emergence of side effects: often (> 1/100, <1/10); infrequently (> 1/1000, <1/100); seldom (> 1/10 000, <1/1 000); very seldom (<1/10 000).
- From the central and peripheral nervous system: often – a headache, dizziness, an asthenic syndrome; infrequently – uneasiness, neuralgia, paresthesias, it is very rare - polyneuropathy, amnesia.
- From the alimentary system: often – a lock, nausea, abdominal pain; frequency is unknown – reversible passing dozozavisimy increase in activity of "hepatic" transaminases; seldom – pancreatitis; very seldom – dyspepsia (including diarrhea, a meteorism, vomiting), a gastroenteritis, jaundice, hepatitis.
- From respiratory system: often – pharyngitis; infrequently – rhinitis, sinusitis, bronchial asthma, bronchitis, cough, диспноэ, pneumonia.
- From cardiovascular system: infrequently – stenocardia, increase in arterial pressure, heartbeat, vazodilatation symptoms (including a dermahemia).
- From a musculoskeletal system: often – a mialgiya; infrequently – an arthralgia, arthritis, a muscle hyper tone, a dorsodynia, a pathological fracture of an extremity (without damages); seldom – a myopathy, рабдомиолиз (along with a renal failure, against the background of administration of drug in a dose of 40 mg); frequency is unknown – the immunomediated necrotic myopathy; the tendopatiya sometimes complicated by gaps.
- From an urinary system: a proteinuria (in less than 1% of cases – for doses of 10 mg and 20 mg, 3% of cases – for 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; frequency is unknown - peripheral hypostases.
- Allergic reactions: infrequently – skin rash, a skin itch, a small tortoiseshell; seldom – a Quincke's disease; frequency is unknown – Stephens's syndrome – Johnson.
- From laboratory indicators: increase in concentration in a blood plasma of glucose, bilirubin, increase in activity gamma глутаматрансферазы, an alkaline phosphatase. Dozozavisimy increase in activity of a kreatinfosfokinaza (KFK) was observed at insignificant number of the patients accepting розувастатин. In most cases it was insignificant, asymptomatic and temporary. At increase in activity of KFK more than by 5 times in comparison with the upper bound of norm therapy has to be temporarily suspended.
- Other: infrequently - anemia, thorax pain, a diabetes mellitus, ecchymomas, a grippopodobny syndrome, periodontal abscess; gynecomastia.
At use of some statines it was reported about the following side effects: a depression, sleep disorders, including sleeplessness and dreadful dreams, sexual dysfunction. It was reported about isolated cases of an intersticial disease of lungs, especially at prolonged use of drugs.

Interaction with other medicines:

Rozuvastatin does not influence plasma concentration of cyclosporine. Cyclosporine strengthens effect of a rozuvastatin (slows down its removal, increases AUC by 7 times, Cmax – 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 (INR)). Cancellation of a rozuvastatin or decrease in its dose can lead to reduction of MNO (in such cases monitoring of MNO is recommended).
Gemfibrozil strengthens effect of a rozuvastatin (increases it Cmax and AUC twice). Gemfibrozil, other fibrata and lipidsnizhayushchy doses of niacin (more than 1 g/days) increase risk of emergence of a myopathy at simultaneous use with GMG-KOA-reduktazy inhibitors, it is possible because they can cause a myopathy when using as monotherapy.
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 HIV inhibitors - 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 HIV inhibitors – proteases is not recommended at treatment of patients with HIV.
The antacids containing ions of aluminum and magnesium lead to decrease in plasma concentration of a rozuvastatin approximately for 50% (antacids should be applied in 2 h after reception of a rozuvastatin, clinical value of similar interaction is not studied).
Erythromycin increases motility of digestive tract that leads to decrease in effect of a rozuvastatin (reduces its AUC by 20% and Cmax for 30%).
Rozuvastatin strengthens effect of oral contraceptives (increases AUC ethinylestradiol and 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.
Clinically significant interaction of a rozuvastatin with digoxin is not expected.
Results of the researches in vivo and in vitro showed what розувастатин is not either inhibitor, or the inductor of enzymes of system of P450 cytochrome. Besides, розувастатин is non-core substrate for these enzymes. 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 metabolism by means of system of P450 cytochrome is not expected.
Simultaneous use with the medicines reducing concentration of endogenous steroid hormones (including Cimetidinum, ketokonazoly, Spironolactonum), increases risk of decrease in endogenous steroid hormones.
At a concomitant use of a rozuvastatin and an ezetimib change of AUC or Cmax of both drugs is not observed. However, it is impossible to exclude the pharmakodinamichesky interaction of a rozuvastatin and ezetimib capable to cause the undesirable phenomena.

Contraindications:

For drug in a daily dose of 10 and 20 mg: hypersensitivity to a rozuvastatin or any of components of drug, a liver disease in an active phase (including permanent increase in activity of "hepatic" transaminases, and also any increase in activity of "hepatic" transaminases in blood serum more than by 3 times in comparison with the upper bound of norm), heavy renal failures (KK less than 30 ml/min.), a lactose intolerance, deficit of lactase or glyukozo-galaktozny malabsorption (drug contains lactose), a myopathy, a concomitant use of cyclosporine, at the patients predisposed to development of miotoksichesky complications, pregnancy, the lactation period; use for the women who are not applying reliable methods of contraception; age up to 18 years (efficiency and safety are not established).
In a daily dose of 40 mg in addition to above drug is contraindicated to the listed contraindications at a hypothyroidism, the 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 concentration of a rozuvastatin in a blood plasma, to patients of Mongoloid race, a concomitant use of fibrat, a renal failure of moderate severity (KK less than 60 ml/min.).

Patients with a liver failure
Higher than 9 on a scale of Chayld-I Drink experience of use of drug for patients with point is absent.

With care
For drug in a daily dose of 10 and 20 mg: existence of 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, excessive alcohol intake, states at which increase in plasma concentration of a rozuvastatin is noted 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, uncontrollable epilepsy, race (Mongoloid race), a concomitant use of fibrat.
For drug in a daily dose of 40 mg: renal failure of easy severity (KK more than 60 ml/min.); the age is more senior than 65 years; liver diseases 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
Akort's drug is contraindicated to use at pregnancy and during breastfeeding. Women of reproductive age have to apply reliable and adequate methods of contraception. As cholesterol and other products of biosynthesis of cholesterol are important for fetation, the potential risk of inhibition ГМГ-КоА-of reductase exceeds advantage of use of drug for pregnant women. In case of pregnancy in the course of therapy administration of drug has to be immediately stopped. Data concerning allocation of a rozuvastatin with breast milk are absent therefore during breastfeeding administration of drug needs to be stopped.

Overdose:

Symptoms: strengthening of side effects. At a concomitant use of several daily doses pharmacokinetic parameters of a rozuvastatin do not change.

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 level of a kreatinfosfkinaza is necessary. The hemodialysis is inefficient.

Storage conditions:

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, 10 mg, 20 mg.
On 10 tablets in a blister strip packaging.
1, 2, 3 blister strip packagings together with the application instruction place in a pack from a cardboard.