Rosuvastatin-Teva 5 mg tablets №30

Author Ольга Кияница

2017-05-11

Amount in a package 30
Product form Pills
Manufacturer TEVA (Israel)
Registration certificate UA/14036/01/01
The main medicament Rosuvastatin
morion code 346379

Rosuvastatin-Teva instructions for use

Composition

active ingredient: 1 tablet contains rosuvastatin 5 mg, 10 mg, 20 mg or 40 mg in the form of rosuvastatin calcium

Excipients:

core: microcrystalline cellulose, lactose, crospovidone, povidone, sodium stearyl fumarate;

coating for tablets of 5 mg of polyvinyl alcohol partially hydrolysed, titanium dioxide (E 171), macrogol 3350, talc, iron oxide yellow (E172), iron oxide black (E 172), yellow sunset FCF (E 110)
coating for tablets of 10 mg, 20 mg and 40 mg of polyvinyl alcohol partially hydrolyzed, titanium dioxide (E 171), macrogol 3350, talc, iron oxide yellow (E172), iron oxide red (E 172), carmosein (E 122), indigotine (E 132).

Dosage form

Film-coated tablets.

Pharmacological group

Lipid-lowering drugs. Inhibitors of HMG-CoA reductase. Rosuvastatin. Code ATX C10A A07.

Indications

Treatment of hypercholesterolemia

Adults and children older than 10 years with primary hypercholesterolemia (type Pa, including heterozygous familial hypercholesterolemia) or mixed dyslipidemia (type IIb) as an adjunct to the diet, when the effectiveness of diet or other non-medicated treatments (like exercise, weight loss ) is not enough.

In homozygous familial hypercholesterolemia, as an adjunct to diet and other lipid-lowering drugs (such as LDL-apheresis) or in cases where such treatments are not appropriate.

Prevention of cardiovascular disorders

Preventing a significant cardiovascular disorder in patients who are estimated to be at high risk for the first case of cardiovascular disorder (see Section "Pharmacological"), in addition to correcting other risk factors.

Contraindications

  • Hypersensitivity to rosuvastatin or any excipient;
  • active liver diseases, including a steady increase in serum transaminases of unknown etiology and any increase in transaminases in the blood serum, three times higher than the upper limit of normal (BM)
  • severe impaired renal function (creatinine clearance <30 mL / min);
  • myopathy;
  • simultaneous administration of cyclosporine;
  • the period of pregnancy and lactation, and women of reproductive age who do not use appropriate contraception.

A dose of 40 mg is contraindicated in patients with factors contributing to the development of myopathy / rhabdomyolysis. Such factors include:

  • impaired renal function of moderate severity (creatinine clearance <60 ml / min);
  • hypothyroidism
  • presence in a personal or family anamnesis of hereditary muscle diseases;
  • presence in the anamnesis of myotoxicity caused by other inhibitors of HMG-CoA reductase or fibrates;
  • alcohol abuse;
  • situations that can lead to an increase in the level of the drug in the blood plasma
  • belonging to the Mongoloid race;
  • simultaneous application of fibrates.

Dosing and Administration

Before starting treatment, the patient should be prescribed a standard hypocholesterolemic diet, which he must adhere to and during treatment. The dose should be selected individually depending on the purpose of therapy and the patient's response to treatment, guided by the recommendations of current generally accepted guidelines.

The drug Rosuvastatin-Teva can be taken at any time of the day, regardless of food intake.

Adults

Treatment of hypercholesterolemia

The recommended initial dose is 5 or 10 mg orally once a day for both patients who have not previously used statins or transferred to the drug to receive another HMG-CoA reductase inhibitor. When choosing the initial dose, you should take into account the cholesterol levels in each individual patient and the risk of cardiovascular disorders in the future, as well as the likelihood of adverse reactions. If necessary, you can increase the dose to the next level after 4 weeks (see Section "Pharmacological"). Taking into account the fact that against the backdrop of using the drug in a dose of 40 mg, unwanted reactions occur more often than at lower doses (see Section "Adverse Reactions"), finally titrating the dose to 40 mg is only for patients with severe hypercholesterolemia and a high risk of cardiovascular disorders (in particular, in patients with familial hypercholesterolemia) who failed to achieve the goal of treatment with a dose of 20 mg and who will be under regular supervision (see the "Features of application" section). At the beginning of taking the drug at a dose of 40 mg recommended by the supervision of specialists.

Prevention of cardiovascular disorders

In the study, reducing the risk of cardiovascular disorders, the drug was used at a dose of 20 mg per day (see Section "Pharmacological").

Elderly patients

The recommended initial dose for patients aged> 70 years is 5 mg. Another dose adjustment due to age is not needed.

Patients with impaired renal function

Patients with mild to moderate renal dysfunction do not need a dose adjustment. The recommended initial dose for patients with impaired renal function of moderate severity (creatinine clearance <60 ml / min) is 5 mg. The dose of 40 mg is contraindicated in patients with impaired renal function of moderate severity. Patients with severe renal dysfunction use rosuvastatin contraindicated in any doses.

Patients with impaired hepatic function

There was no increase in systemic exposure of rosuvastatin in patients with a score of 7 on the Child-Pugh scale.However, increased system exposure is noted in patients whose condition was estimated at 8 and 9 on the Child-Pugh scale. Such patients should be evaluated for renal function. The experience of using the drug for patients with a score of 9 on the Child-Pugh scale is not available. Rosuvastatin is contraindicated in patients with active liver disease.

Race

In patients of the Mongoloid race, there is an elevated system exposure of the drug. The recommended initial dose for patients of Asian descent is 5 mg.

The use of a dose of 40 mg in such patients is contraindicated.

Genetic polymorphism

Certain types of genetic polymorphism can lead to increased exposure of rosuvastatin (see Section "Pharmacokinetics"). Patients with a known presence of such types of polymorphism are advised to use a smaller dose of rosuvastatin.

Patients with a tendency to develop myopathy

The recommended initial dose for patients with a propensity to develop myopathy is 5 mg. A dose of 40 mg is contraindicated in some of these patients.

Concomitant therapy

Rosuvastatin is a substrate for various transport proteins (eg, OATI1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) increases with the simultaneous use of rosuvastatin with certain drugs capable of increasing rosuvastatin concentrations in the blood plasma through interaction with these transport proteins (eg with cyclosporine and some protease inhibitors, including combinations of ritonavir with atanasavir, lopinavir and / or tipranavir ). If possible, alternative treatment should be considered and, if necessary, temporarily discontinued with rosuvastatin treatment. In situations where simultaneous administration of these drugs together with rosuvastatin can not be avoided, we need to weigh all the benefits and risks of concomitant treatment and carefully select the dose of rosuvastatin.

Adverse Reactions

Adverse reactions observed with rosuvastatin are usually light and temporary.

On the part of the immune system: hypersensitivity reactions, including angioedema.

On the part of the endocrine system: diabetes.

From the side of the psyche: depression.

From the nervous system: peripheral neuropathy, sleep disorders, including insomnia and nightmares, headache, dizziness, polyneuropathy, memory loss.

From the respiratory system, chest and mediastinum: cough, shortness of breath.

From the digestive tract: constipation, nausea, abdominal pain, pancreatitis, diarrhea.

On the part of the digestive system: jaundice, hepatitis, increased activity of hepatic transaminases.

From the skin and subcutaneous tissue: itching, rashes, hives, Stevens-Johnson syndrome.

From the musculoskeletal system, connective tissue and bones: myalgia, myopathy (including myositis), rhabdomyolysis, immuno-mediated necrotizing myopathy, arthralgia, tendon disorders, sometimes complicated by their rupture.

From the kidneys: hematuria.

On the part of the reproductive system and mammary glands: gynecomastia.

On the part of the blood: thrombocytopenia.

Common disorders: asthenia, edema.

From the kidneys and the urinary system: hematuria.

As with other inhibitors of HMG-CoA reductase, adverse reactions with rosuvastatin are dose-dependent.

Influence on the kidneys

Proteinuria, detected by analysis on test strips and mainly of tubular origin, was observed in patients taking rosuvastatin.In most cases, proteinuria decreased or disappeared spontaneously with continued therapy. To date, there is no causal relationship between proteinuria and acute or progressive kidney disease.

Against the background of rosuvastatin, cases of hematuria were noted.

Influence on skeletal musculature

Skeletal muscle lesions, such as myalgia, myopathy (including myositis), and occasionally rhabdomyolysis with or without acute renal failure have been observed with any dose of rosuvastatin, especially at doses> 20 mg.

In patients taking rosuvastatin, a dose-dependent increase in CK levels was observed; in most cases the phenomenon was weak, asymptomatic and temporary. If the levels of CK are elevated (> 5 times higher than the upper limit of the norm), treatment should be discontinued (see Section "Application Features").

Effects on the liver

As with the use of other inhibitors of HMG-CoA reductase, a small number of patients taking rosuvastatin had a dose-related increase in transaminase levels; in most cases the phenomenon was weak, asymptomatic and temporary. When rosuvastatin was used, there was also an increase in HbA1c levels.

When using statins also reported disorders of sexual function, isolated cases of interstitial lung disease (especially in the case of prolonged therapy).

The incidence of rhabdomyolysis, severe renal and hepatic impairment (predominantly elevated transaminases) is higher with a dose of 40 mg.

With the use of rosuvastatin, an undesirable reaction was also identified, such as lethal and non-lethal hepatic insufficiency. Since this reaction was reported spontaneously from a population of an indeterminate amount, it is impossible to reliably estimate its frequency or to establish the presence of a cause-and-effect relationship with the use of the drug.

Occasionally, violations of cognitive functions were reported (eg memory impairment, forgetfulness, amnesia, memory impairment, confusion), which are associated with the use of statins. Such cognitive problems have been reported in connection with all statins. The phenomena reported in the reports are usually of a mild nature and occur after the abolition of statins, and also have a different time before the onset of symptoms (from 1 day to years) and until the symptoms disappear (median 3 weeks).

The safety profile of rosuvastatin in children and adolescents was similar to that of adults.

Overdose

There is no specific overdose treatment. Treatment is symptomatic, supportive therapy is recommended. Need control of liver function and levels of CK. It is unlikely that hemodialysis will be effective.

Use during pregnancy and lactation

Rosuvastatin is contraindicated during pregnancy and lactation.

Women of reproductive age should use appropriate contraception.

Since cholesterol and other cholesterol biosynthesis products play a significant role in the development of the fetus, the potential risk of suppressing HMG-CoA reductase exceeds the benefit of using the drug during pregnancy. Data from animal studies on toxic effects on reproductive function are limited. If the patient becomes pregnant during the period of use of this drug, treatment should be stopped immediately.

Since another drug of this class enters the breast milk and given that HMG-CoA reductase inhibitors can cause serious adverse reactions in infants, women who need treatment with rosuvastatin should be advised to refrain from breastfeeding. There are no data on the penetration of the drug into human milk (see Section "Contraindications").

Children

The use of the drug in children should be done only by a specialist.

Applied to children and adolescents aged 10 to 17 years (boys at the stage of development II and above Tanner and girls in which menstruation began less than a year ago).

The initial daily dose for children and adolescents with heterozygous familial hypercholesterolemia is 5 mg per day. The drug is usually taken orally at doses of 5 mg to 20 mg once daily. Increase the dose should be in accordance with the individual's responses to the treatment and tolerability of the drug, following the recommendations for the treatment of children (see section "Features of application"). Before starting rosuvastatin therapy, children and adolescents should be prescribed a standard hypocholesterolemic diet, which patients must adhere to during treatment. The safety and efficacy of the drug in doses greater than 20 mg in this population have not been investigated.

Tablets of 40 mg are not prescribed for children.

Children under 10 years old

The experience of treating children under the age of 10 is limited to the use of the drug in a small number of patients (aged 8 to 10 years) with homozygous familial hypercholesterolemia. Thus, rosuvastatin is not recommended for children under 10 years of age.

Application features

Influence on the kidneys

It was reported that in patients taking rosuvastatin in high doses, especially 40 mg, there were cases of proteinuria (determined by the test of the strip), mainly tubular in origin and in most cases temporary or short-lived. Proteinuria did not indicate an acute or progressive kidney disease. Undesirable effects from the kidneys were noted more often with a dose of 40 mg. In patients taking the drug at a dose of 40 mg, kidney function should be checked regularly.

Influence on skeletal musculature

Skeletal muscle lesions, such as myalgia, myopathy and rarely rhabdomyolysis, are observed in patients with all doses of rosuvastatin, especially at doses greater than 20 mg. When ezetimibe was used in combination with inhibitors of HMG-CoA reductase, rhabdomyolysis was reported. It is impossible to exclude the possibility of pharmacodynamic interaction, and therefore such a combination should be used with caution.

As with other inhibitors of HMG-CoA reductase, cases of rhabdomyolysis associated with the use of rosuvastatin are more often when a dose of 40 mg is administered. Immunopreparated necrotizing myopathy has been reported, clinically manifested by persistent proximal muscle weakness and increased serum CK levels, during treatment or after discontinuation of statin therapy, including rosuvastatin. Additional neuromuscular and serological tests may be required.May require treatment with immunosuppressive drugs

Determination of the level of CK (CK)

The level of CK should not be measured after significant physical exertion or if there are possible alternative causes of increased CK, which may interfere with the interpretation of the results. If the initial levels of CK are significantly elevated (> 5 x VGN), an additional confirmatory analysis must be made within 5-7 days. If the result of repeated analysis confirms the baseline level> 5 x VGN, treatment should not be started.

Before starting treatment

Rosuvastatin, like other inhibitors of HMG-CoA reductase, should be administered with caution to patients with factors contributing to the development of myopathy / rhabdomyolysis. Such factors include:

  • impaired renal function
  • hypothyroidism
  • presence in a personal or family anamnesis of hereditary muscle diseases;
  • presence in the anamnesis of myotoxicity caused by other inhibitors of HMG-CoA reductase or fibrates;
  • alcohol abuse;
  • age> 70 years;
  • situations that can lead to an increase in the level of the drug in the blood plasma
  • simultaneous application of fibrates.

Such patients need to compare the risk and possible benefits when using the drug, clinical monitoring is also recommended. Do not start treatment with significantly elevated baseline levels of CP (> 5 x VGN).

During the treatment period

Patients should be warned about the need to immediately report unexplained muscle pain, muscle weakness or cramps, especially if they are accompanied by malaise or fever. In such patients, the levels of CK should be determined.Treatment should be discontinued if CK levels are significantly elevated (> 5 x HMB) or if muscular symptoms are severe and cause discomfort in everyday life (even if CK levels ≤ 5 x BMH). If symptoms resolve and CK levels return to normal, rosuvastatin or an alternative HMG-CoA reductase can try to apply again, but in minimal doses and under close supervision. Very rarely reported cases of immune-mediated necrotising myopathy (IONM) during or after therapy with statins, including rosuvastatin. Clinical manifestations IONM is the weakness of the proximal muscles and increase blood serum CPK is retained even after the abolition of statins.

There was no evidence of increased skeletal muscle effects on a small number of patients who took rozuvatstatin and concomitant medications. However, increasing the frequency of myositis and myopathy observed in patients treated with other inhibitors of HMG-CoA reductase inhibitors together with fibric acid derivatives including gemfibrozil, cyclosporin, nicotinic acid, azole antifungal agents, protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy with concomitant use with some HMG-CoA. Therefore rozuvatstatin use in combination with gemfibrozil is not recommended. The use of further changes in lipid levels rozuvatstatinu when used in combination with fibrates or niacin must be carefully weighed for comparison with potential risksassociated with the use of such combinations. The dose of 40 mg is contraindicated while the use of fibrates (see. Sections "Interaction with other drugs and other forms of interaction" and "side reaction").

Rosuvastatin should not be used in patients with acute, serious condition, contributing to the development of myopathy or increase the risk of renal failure with rhabdomyolysis (such as sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine or electrolyte disorders, or uncontrolled seizures).

Effect on liver

As with other inhibitors of HMG-CoA reductase inhibitor rosuvastatin should be used with caution in patients abusing alcohol and / or with a history of liver disease.

recommended that liver function test before drug application and after 3 months of treatment. If the transaminase levels in the serum of more than three times the upper limit of normal, the use of rosuvastatin should be discontinued. No serious hepatic dysfunction (preferably increased liver transaminase) reported more frequently in the application dose of 40 mg.

Patients with secondary hypercholesterolaemia induced hypothyroidism or nephrotic syndrome, must first hold treatment of the underlying disease, and then to begin use of rosuvastatin.

Occasionally reported cases of fatal or non-fatal hepatic failure in patients treated with statins, including rosuvastatin. If during treatment with rosuvastatin developing serious liver injury with clinical symptoms and / or hyperbilirubinemia or jaundice, stop taking the drug. If other causes have been identified, it does not recover treatment with rosuvastatin.

Race

It reported an increase in the exposure of the Mongoloid race patients about half compared with the Europeans. For these patients require dose correction rosuvastatin (see. Sections "Dosage and Administration" "Contra" and "Pharmacokinetics"). For patients of Asian race starting dose of rosuvastatin should be 5 mg. Increased plasma concentrations of rosuvastatin in Asian was seen in patients (see. Section "Features of application" and "Pharmacokinetics". It should take into account the increased systemic exposure in patients Mongoloid races in which hypercholesterolemia is not adequately controlled with doses up to 20 mg.

protease inhibitors

Patients treated with rosuvastatin simultaneously with protease inhibitors ritonavir and increasing systemic exposure observed rosuvastatin. It should take into account the potential benefits of lipid lowering in the application of rosuvastatin in HIV-infected patients receiving protease inhibitors and the potential increase in rosuvastatin plasma levels at the start of therapy and dose titration of rosuvastatin.

Simultaneous application of the drug to the protease inhibitors are not recommended until the adjusted dose of rosuvastatin.

fusidic acid

Rosuvastatin should not be used together with systemic medications fuzidovoi acid or 7 days after cessation of treatment fusidic acid. Patients who used fusidic acid, treatment with statins should be stopped for the duration of treatment fuzidovoi acid. Reported cases of rhabdomyolysis (including fatal) in patients receiving statins and fusidic acid in combination (see. Section "interaction with other drugs and other forms of interaction"). The patient should be advised to seek immediate medical attention if he feels any muscle weakness, pain or sensitivity symptoms. Statin therapy may be re-initiated seven days after the last dose fuzidovoi acid. In some cases, where prolonged systemic therapy requires fusidic acid, e.g.,for the treatment of severe infections, the need for co-administration of rosuvastatin and fuzidovoi acid should only be considered individually and under close medical supervision.

Interstitial lung disease

It is known about individual cases of interstitial lung disease when applying certain statins, especially when long term therapy. Symptoms include shortness of breath disorders, non-productive cough and deterioration in general condition (fatigue, weight loss and fever). If it is suspected that a patient has developed interstitial lung disease, statin therapy should be discontinued.

Diabetes

Some evidence suggests that statins increase the level of blood glucose and in some patients, at high risk of developing diabetes in the future, may cause hyperglycemia, the level at which you want the proper treatment of diabetes. This threat, however, exceeds the reduction in the risk of vascular disorders with the use of statins and so it should not be a reason for discontinuation of therapy with statins. Patients at risk (fasting glucose 5,6-6,9 mmol / l, BMI> 30 kg / m 2, elevated levels of triglycerides, hypertension) should be set as a clinical and biochemical control on national guidelines.

As with other HMG-CoA reductase inhibitor rosuvastatin observed when applying growth HbA1c and glucose level in blood serum. In some cases, these figures may exceed the limit value for the diagnosis of diabetes, especially in patients at high risk of developing diabetes.

It was reported that rosuvastatin monotherapy does not cause a decrease in the base concentration in blood plasma cortisol levels and no effect on adrenal reserve. Care should be taken while the use of rosuvastatin and other medicines capable of reducing the level or activity of endogenous steroid hormones, such as ketoconazole, spironolactone and cimetidine.

Children

Reported no effect on height, weight, body mass index and sexual maturation by Tanner scale when using rosuvastatin children from 10 to 17 years.

Increased CPK (> 10 x ULN) and muscle symptoms after exercise or increased physical activity were observed more frequently in children in adults.

Excipients

Rosuvastatin-Teva contains lactose. Patients with rare hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not use this drug.

Tablets containing 5 mg dye sunset yellow FCF (E 110) and 10 mg tablets, 20 mg and 40 mg karmoizin contain dye, which can cause allergic reactions.

The ability to influence the reaction rate when driving vehicles or other mechanisms

Studies to determine the effect of rosuvastatin on the ability to drive vehicles and operate machinery have not been conducted. However, taking into account the pharmacodynamic properties, it is unlikely that rosuvastatin affect this ability. When road driving or operating machinery should take into account the possibility of dizziness during treatment.

Interaction with other drugs and other interactions

The effect of other drugs on the rosuvastatin

Inhibitors of transport proteins

Rosuvastatin is a substrate for certain transport proteins, including hepatic transporter capture OATR1V1 and eflyuksnogo BCRP transporter. The simultaneous use of rosuvastatin with drugs depressing these transport proteins can lead to increased concentrations of rosuvastatin in the blood plasma and increased risk of myopathy (see. Sections "Dosage and Administration" "Features of the application", "interaction with other drugs and other mechanisms "table).

Cyclosporin

During the combined use of cyclosporine rosuvastatin and rosuvastatin AUC value was an average of about 7 times higher than those observed in healthy volunteers (see. Table). Rozuvastatinprotipokazany patients who simultaneously receive cyclosporine (see. Section: "Contra ').

Simultaneous application did not affect the concentration of cyclosporine in the blood plasma.

protease inhibitors

Although the exact mechanism of the interaction is unknown, simultaneous use of protease inhibitors can significantly increase the exposure of rosuvastatin. The simultaneous use of rosuvastatin and certain combinations of protease inhibitors is possible after careful consideration correction doses of rosuvastatin, based on the expected growth rosuvastatin Exposure (cm. Sections "Dosage and Administration" "Features of the application", "interaction with other drugs and other types of interactions") .

Gemfibrozil and other lipid-lowering drugs

The simultaneous use of rosuvastatin and gemfibrozil resulted in an increase AUC and C max rosuvastatin 2 times.

Pharmacokinetic significant interaction with fenofibrate is not expected, however, possible pharmacodynamic interactions. Gemfibrozil, fenofibrate, other fibrates and lipid-lowering doses

(> Or at 1 g / day), niacin (nicotinic acid) increase the risk of myopathy while the use of inhibitors of HMG-CoA, probably due to the fact that they can cause the development of myopathy, when used separately. The dose of 40 mg is contraindicated while the use of fibrates (see. Sections "Contra" and "Application Properties"). Such patients should also begin therapy at a dose of 5 mg.

ezetimibe

The simultaneous use of rosuvastatin in a dose of 10 mg of ezetimibe and 10 mg in patients with hypercholesterolemia led to an increase in AUC of rosuvastatin 1.2 times. We can not exclude the pharmacodynamic interaction between rosuvastatin, and ezetimibe that can lead to undesirable phenomena (see. "Application Features" section).

antacids

The simultaneous use of rosuvastatin with an antacid suspension containing aluminum or magnesium hydroxide, results in a decrease in plasma rosuvastatin concentrations by approximately 50%. This effect was less pronounced in the case of antacids through 2:00 rosuvastatin. The clinical significance of this interaction has not been studied.

erythromycin

The simultaneous use of rosuvastatin and erythromycin rosuvastatin AUC decreased 20% and the C max - 30%. Such an interaction may be caused by an increase in intestinal motility due to the action of erythromycin.

fusidic acid

The risk of myopathy, including rhabdomyolysis can be increased while systemically fuzidovoi acid with statins. The mechanism of this interaction (whether pharmacodynamic or pharmacokinetic) is still unknown. It reported cases of rhabdomyolysis (including fatalities) in patients receiving this combination. When systemic treatment is necessary fusidic acid, rosuvastatin treatment should be discontinued in "Properties application" for the duration of treatment fusidic acid cm.).

Enzymes of the cytochrome P450

Rosuvastatin is not inhibited, and does not stimulate the cytochrome P450 isozymes. In addition, rosuvastatin is a weak substrate of these isoenzymes. Thus, interaction with the drug by metabolism mediated by 450, is expected. There were no clinically significant interactions between rosuvastatin and fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (CYP2A6 inhibitor and a CYP3A4).

Interactions requiring dose adjustment of rosuvastatin

If necessary, use of rosuvastatin with other medicaments capable of increasing the exposure of rosuvastatin, its dose should be adjusted. If it is expected that the drug exposure (AUC) increase approximately 2 or more times, the use of rosuvastatin should begin with a dose of 5 mg once a day. The maximum daily dose of rosuvastatin should be adjusted so that the expected exposure rosuvastatin does not exceed exposure seen with administration of a dose of 40 mg / day without the use of drugs that interact with the drug; e.g., when used with gemfibrozil dose of rosuvastatin is 20 mg (increased exposure to 1.9 times) when applying a combination of ritonavir / atazanavir - 10 mg (3.1 fold increase), while the use of cyclosporin - 5 mg (magnification 7.1 times).

Table

Effect of concomitant medications on exposure rosuvastatin

The dosage regimen of the drug interacts The dosage regimen of rosuvastatin Changes in AUC of rosuvastatin *
Cyclosporin 75 mg twice daily and 200 mg twice daily, 6 months 10 mg once a day, 10 days ↑ 7,1 times
Atazanavir 300 mg / ritonavir 100 mg once a day, 8 days 10 mg once ↑ 3,1 times
Simeprivir 150 mg once a day, 7 days 10 mg once ↑ 2,8 times
Lopinavir 400 mg / 100 mg ritonavir twice per day, 17 days 20 mg once a day, 7 days ↑ 2,1 times
Gemfibrozil 600 mg twice a day, 7 days 80 mg, single dose ↑ 1.9-fold
Eltrombopak 75 mg once a day, 5 days 10 mg once ↑ 1,6 times
Darunavir 600 mg / 100 mg ritonavir twice per day, 7 days 10 mg once a day, 7 days ↑ 1,5 times
Tipranavir 500 mg / 200 mg ritonavir twice per day, 11 days 10 mg once ↑ 1,4 times
Dronedarone 400 mg twice a day unknown ↑ 1,4 times
Itraconazole 200 mg once a day, 5 days 10 mg once ↑ 1.4 times **
Ezetimibe 10 mg once a day, 14 days 10 mg once a day, 14 days ↑ 1,2 times **
Fosamprenavir 700 mg / 100 mg ritonavir twice per day, 8 days 10 mg once
Aleglitazar 0.3 mg, 7 days 40 mg, 7 days
Silymarin 140 mg three times a day, 5 days 10 mg, once
Fenofibrate 67 mg three times a day, 7 days 10 mg, 7 days
Rifampicin 450 mg once daily, 7 days 20 mg, once
Ketoconazole 200 mg twice daily, 7 days 80 mg, once
Fluconazole 200 mg once daily, 11 days 80 mg, once
Erythromycin 500 mg four times a day, 7 days 80 mg, once ↓ 28%
Baikalin 50 mg three times a day, 14 days 20 mg, once ↓ 47%

* Data presented as a change in x times is the ratio between the application of rosuvastatin in combination and separately. The data presented in the form of a% change is the% difference in the ratio with rosuvastatin alone.

The magnification is indicated by the ↑ symbol, no changes ↔, the decrease is ↓.

Effect of rosuvastatin on concomitant medications

Antagonists of vitamin K

As in other HMG-CoA reductase inhibitors, an increase in the international normalized ratio (MHC) may be possible at the beginning of rosuvastatin administration or with an increase in its dose in patients concomitantly taking vitamin K antagonists (eg warfarin or another anticoagulant coumarin). Cancellation of rosuvastatin or a decrease in its dose may lead to a decrease in MFW. In such cases, the desired proper monitoring of the MES.

Oral contraceptives / hormone replacement therapy (HRT)

Simultaneous use of rosuvastatin and oral contraceptives led to an increase in the AUC of ethinylestradiol and norgestrel by 26% and 34%, respectively. Such an increase in plasma blood levels should be considered when choosing a dose of oral contraceptives. Data of pharmacokinetics of drugs in patients taking rosuvastatin and HRT at the same time, no, therefore, such an effect can not be ruled out. However, the combination was widely used by women in clinical trials and was well tolerated.

Other medicines

According to special studies, no clinically significant interaction with digoxin is expected.

Lopinavir / ritonavir

The simultaneous use of rosuvastatin and a combined preparation containing two protease inhibitors (lopinavir 400 mg / ritonavir 100 mg) was associated with an approximately twofold and fivefold increase in the equilibrium AUC (0-24) and C m ax values for rosuvastatin, respectively. The interaction between rosuvastatin and other protease inhibitors has not been studied.

Children

The interaction was studied only in adults. The degree of interaction in children is unknown.

Pharmacological properties

Pharmacodynamics.

Rosuvastatin is a selective competitive inhibitor of HMG-CoA reductase, an enzyme that converts 3-hydroxy-3-methylglutarylcoenzyme A into mevalonate, the precursor of cholesterol. The main place of action of rosuvastatin is the liver, where the synthesis of cholesterol (CS) and catabolism of low density lipoprotein (LDL) occurs.

Rosuvastatin increases the number of hepatic LDL receptors on the cell surface, increasing the uptake and catabolism of LDL, which in turn leads to inhibition of the synthesis of very low density lipoproteins (VLDL), thereby reducing the total number of LDL and VLDL.

Rosuvastatin reduces elevated levels of LDL cholesterol, total cholesterol and triglycerides and increases HDL cholesterol levels. It also reduces the levels of apoB, cholesterol-non-HDL, cholesterol-VLDL, TG-VLDL and increases the level of apoA-I.

Rosuvatatinakozh reduces the ratio of LDL / HDL cholesterol, total cholesterol / cholesterol-HDL cholesterol, non-HDL cholesterol / HDL-C, and apo / apoA-I.

Therapeutic effect is manifested within 1 week after the beginning of rosuvastatin therapy, after 2 weeks of treatment the effect reaches 90% of the maximum possible. The maximum effect, as a rule, is achieved after 4 weeks and after that it continues constantly.

Pharmacokinetics.

Suction and distribution

The maximum concentration of rosuvastatin in blood plasma is reached at 5:00 after ingestion. Bioavailability is approximately 20%. Rosuvastatin accumulates in the liver. The volume of its distribution is approximately 134 liters.Almost 90% of rosuvastatin binds to plasma proteins, mainly albumin.

Metabolism

Rosuvastatin undergoes limited metabolism (about 10%). Rosuvastatin is a non-core substrate for metabolism by enzymes of the cytochrome P450 system. The main isoenzyme involved in the metabolism of rosuvastatin is CYP2C9.Enzymes CYP2C19, CYP3A4 and CYP2D6 are less involved in metabolism. The main revealed metabolites of rosuvastatin are N-dysmethyl and lactone metabolites. N-dimethyl is about 50% less active than rosuvastatin, lactone metabolites are pharmacologically inactive.

Conclusion

Approximately 90% of the dose of rosuvastatin is excreted unchanged with feces (including absorbed and unabsorbed rosuvastatin). The other part is excreted in the urine. The half-life is approximately 19 hours. The half-life does not change with increasing dose. The average geometric clearance is approximately 50 l / h (the coefficient of variation is 21.7%). As with other HMG-CoA reductase inhibitors, cholesterol transporter takes part in the hepatic engagement of rosuvastatin, which plays an important role in the hepatic elimination of rosuvastatin.

Linearity

The systemic exposure of rosuvastatin increases in proportion to the dose. When several daily doses are taken, the pharmacokinetic parameters do not change.

Special populations of patients

Age and gender

There is no clinically significant effect of age and sex on the pharmacokinetics of rosuvastatin in adults.

Ethnic groups

An increase in the AUC (area under the concentration-time curve) and Cmax was approximately twice in the Mongoloid race in Asia, compared to the corresponding figures for Europeans living in Europe and Asia. The influence of genetic factors and environmental factors on differences in pharmacokinetics has not been revealed. There were no clinically significant differences in pharmacokinetics in representatives of the Caucasoid and Negroid races.

Patients with renal insufficiency

In patients with mild to moderate impairment of renal function, the level of rosuvastatin and N-dimethyl concentrations in plasma does not change significantly.

Patients with hepatic insufficiency

The experience with rosuvastatin in patients with a score above 9 on the Child-Pugh scale is not available.

Genetic polymorphism

HMG-CoA reductase inhibitors, including rosuvastatin, bind to transport proteins OATP1B1 and BCRP. Patients with polymorphism of SLCO1B1 (OATP1B1) and / or ABCG2 (BCRP) genes have a risk of increased exposure to rosuvastatin. Individual polymorphism of SLCO1B1 with. 521SS and АВСG2 с.421АА is associated with a corresponding increase in the exposure of rosuvastatin (AUC) by approximately 1.7 and 2.4 times compared with the genotypes of SLCO1B1 c.521TT or ABCG2.

Basic physical and chemical properties

tablets 5 mg orange round biconvex tablets coated with a film sheath, embossed with "N" on one side and embossed "5" on the other side of the tablet; without cracks and chips;
tablets 10 mg light pink or pink round biconvex tablets, film-coated, embossed "N" on one side and embossed "10" on the other side of the tablet; without cracks and chips;
tablets 20 mg light pink or pink round biconvex tablets, film-coated, embossed "N" on one side and embossed "20" on the other side of the tablet; without cracks and chips;
tablets 40 mg light pink or pink oval tablets, film-coated, embossed with "N" on one side and embossed "40" on the other side of the tablet; without cracks and chips.

Shelf life

2 years.

Storage conditions

For tablets of 5 mg stored at a temperature of no higher than 25 ° C in a place inaccessible to children. Store the blister in a cardboard box to protect it from moisture and light.
For tablets of 10 mg, 20 mg, 40 mg stored at a temperature of no higher than 30 ° C in a place inaccessible to children.Store the blister in a cardboard box to protect it from moisture and light.

Packaging

For 10 tablets in a blister, 3 blisters per box.

Category of leave

On prescription.

 


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