Lipopram - instructions for use, dose, side effects, contraindications

auxiliary substances (core): Calcium phosphate - 5.000 mg 10.000 mg 20.000 mg microcrystalline cellulose - 32.988 mg 65.976 mg 131.952 mg Lactose monohydrate - 34,000 mg 68.000 mg 136.000 mg Crospovidone (Type B) - 0,750 mg, 1,500 mg, 3,000 mg magnesium stearate -1,500 mg, 3,000 mg, 6,000 mg;

auxiliary substances (shell) Instacoat universal yellow / pink / orange: 2.00 / 4.00 / 8.00 mg (Hypromellose: 1,300 / 2,600 / 5,200 mg, macrogol: 0.260 / 0.520 / 1.040 mg talc 0.040 / 0.080 / 0.160 mg of titanium dioxide: 0.320 / 0.790 / 1.370 mg dye quinoline yellow: 0.084 / - / - mg dye iron oxide red: - / 0.010 / - mg, dye sunset sunset yellow: - / - / 0.230 mg).

Description:

Dosage of 5 mg:

Round biconvex tablets, covered with a film coating of yellow color, engraved "ML" on one side.

Dosage of 10 mg:

Round biconvex tablets, film-coated light pink color, with chasing "MICRO" on one side.

Dosage of 20 mg:

Round biconvex tablets, covered with a film shell of orange color, with engraving "MICRO" on one side.

The cross-section of the nucleus of the tablets is white or almost white in color.

Pharmacotherapeutic group:Hypolipidaemic agent - HMG-CoA reductase inhibitor

ATX: & nbsp

C.10.A.A Inhibitors of HMG-CoA reductase

C.10.A.A.07 Rosuvastatin

Pharmacodynamics:

Mechanism of action

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

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

Pharmacodynamics

Rosuvastatin reduces the elevated concentration of LDL cholesterol (LDL-C), total cholesterol, triglycerides (TG), increases the concentration of high-density lipoprotein cholesterol (HDL-C), and also reduces the concentration of apolipoprotein B (ApoV), CS-non-HDL, cholesterol-VLDL , TG-VLDL and increases the level of apolipoprotein A-I (ApoA-I), reduces the ratio of LDL-C-HDL cholesterol, total cholesterol / cholesterol-HDL cholesterol, and non-HDL / CS-HDL cholesterol and the ApoB / ApoA-1 ratio. Therapeutic effect appears within one week after the beginning of rosuvastatin therapy, after 2 weeks of treatment it reaches 90% of the maximum possible effect. The maximum therapeutic effect is usually achieved by the 4th week and is maintained with regular admission.

Clinical efficacy

Rosuvastatin is effective in adult patients with hypercholesterolemia with or without hypertriglyceridemia; regardless of race, sex or age, incl. in patients with diabetes mellitus and familial hypercholesterolemia.

In 80% of patients with hypercholesterolemia IIa and IIb type (according to Fredrickson classification (the average initial concentration of LDL-C is about 4.8 mmol / L), when taking the drug at a dose of 10 mg, the concentration of LDL-C is less than 3 mmol / l.

In patients with heterozygous familial hypercholesterolemia receiving rosuvastatin in a dose of 20-80 mg, there is a positive dynamics of lipid profile. After titration to a daily dose of 40 mg (12 weeks of therapy), the concentration of LDL-C is reduced by 53%.

In patients with homozygous familial hypercholesterolemia receiving rosuvastatin in a dose of 20 mg and 40 mg, the average decrease in the concentration of LDL-C is 22%.

The additive effect is noted in combination with fenofibrate for the concentration of triglycerides and with nicotinic acid in lipid-lowering doses (more than 1 g / day) for the concentration of HDL-C.

Pharmacokinetics:

Absorption and distribution

The maximum concentration of rosuvastatin in the blood plasma is reached approximately 5 hours after ingestion. Absolute bioavailability is approximately 20%. Rosuvastatin is metabolized primarily by the liver, which is the main site for the synthesis of cholesterol and the metabolism of LDL-C. The volume distribution of rosuvastatin is approximately 134 liters. Approximately 90% of rosuvastatin binds to blood plasma proteins, mainly albumin.

Metabolism

It is subject to limited metabolism (about 10%). Rosuvastatin is a non-core substrate for metabolism by isoenzymes of the cytochrome P450 system. The main isoenzyme involved in the metabolism of rosuvastatin is isoenzyme CYP2C9. Isozymes CYP2C19, CYP3A4 and CYP2D6 are less involved in metabolism.

The main revealed metabolites of rosuvastatin are N-desmethyl and lactone metabolites. Nis less than 50% less active than rosuvastatin, lactone metabolites are pharmacologically inactive. More than 90% of the pharmacological activity of inhibiting circulating HMG-CoA reductase is provided by rosuvastatin, the rest - by its metabolites.

Excretion

About 90% of the dose of rosuvastatin is excreted unchanged through the intestine (including absorbed and not absorbed rosuvastatin). The rest is excreted by the kidneys. Plasma half-life (T₁/₂) is approximately 19 hours. T₁/₂ does not change with increasing dose of the drug. The average geometric plasma clearance is approximately 50 l / h (coefficient of variation 21.7%). As in the case of other inhibitors of HMG-CoA reductase, the process of "hepatic" seizure rosuvastatin is involved in the membrane cholesterol transporter, which plays an important role in the hepatic elimination of rosuvastatin.

Linearity

The systemic exposure of rosuvastatin increases in proportion to the dose. Pharmacokinetic parameters do not change with daily intake.

Special populations of patients

Age and gender

Sex and age do not have a clinically significant effect on the pharmacokinetics of rosuvastatin.

Ethnic groups

Pharmacokinetic studies showed approximately a twofold increase in the median AUC (area under the concentration-time curve) and Cm(maximum concentration in blood plasma) of rosuvastatin in Asian patients (Japanese, Chinese, Filipinos, Vietnamese and Koreans) compared to Europeans; Indian patients showed an increase in the median AUC and Cmah 1,3 times. Pharmacokinetic analysis did not reveal clinically significant differences in pharmacokinetics among Europeans and representatives of the Negroid race.

Renal insufficiency

In patients with mild to moderate renal failure, the plasma concentration of rosuvastatin or N-desmethyl-rosuvastatin does not change significantly.In patients with severe renal failure (creatinine clearance (CC) less than 30 ml / min), the concentration of rosuvastatin in the blood plasma is 3 times higher, and the concentration N-desmethylrozuvastatin is 9 times higher than in healthy volunteers. The concentration of rosuvastatin in blood plasma in patients on hemodialysis was approximately 50% higher than in healthy volunteers.

Liver failure

Patients with varying degrees of hepatic insufficiency did not show an increase in T₁/₂ rosuvastatin. Patients with a score of 7 or lower on the Child-Pugh scale did not show an increase T_1/2 rosuvastatin. In two patients with scores of 8 and 9 on the Child-Pugh scale, an increase in T₁/₂ at least in 2 times. The experience with rosuvastatin in patients with a score above 9 on the Child-Pugh scale is not available.

Genetic polymorphism

Inhibitors of HMG-CoA reductase, including rosuvastatin, bind to transport proteins OATP1B1 (a polypeptide transporting organic anions involved in the capture of statins by hepatocytes) BCRP (efflux conveyor). Have carriers of genotypes SLC01B1 (OATP1B1) C.521SS and ABCG2 (BCRP) C.421AA there was an increase in exposure (AUC) to rosuvastatin in 1,6 and 2,4 times, respectively, in comparison with the carriers of genes SLC01B1 p.52ITT and ABCG2 C.421SS.

Indications:

- Primary hypercholesterolemia according to Fredrickson classification (type IIa, including familial heterozygous hypercholesterolemia) or mixed hypercholesterolemia (type IIb) As an adjunct to diet when diet and other non-pharmacological treatments (eg exercise, weight loss) are not sufficient.

- Family homozygous hypercholesterolemia as a supplement to a diet and other lipid-lowering therapy (eg, LDL-apheresis), or in cases when such therapy is not effective enough.

- Hypertriglyceridemia (type IV according to Fredrickson's classification) as a supplement to the diet.

- To slow the progression of atherosclerosis as a supplement to the diet in patients who are shown therapy to reduce the concentration of total cholesterol and LDL-C.

- Primary prevention of major cardiovascular events (stroke, heart attack, arterial revascularization) in adult patients without clinical evidence of coronary heart disease (CHD), but with an increased risk of its development (age over 50 years for men and over 60 for women, the increased concentration C-reactive protein (≥ 2 mg / L) if available,at least one of additional risk factors, such as hypertension, low concentration of HDL-C, smoking, family history of early onset of coronary artery disease).

Contraindications:

For use in a daily dose of 5 mg, 10 mg and 20 mg:

- increased sensitivity to rosuvastatin or any of the components of the drug;

- liver diseases in the active phase, including a persistent increase in serum transaminase activity and any increase in serum transaminase activity (more than 3 times the upper limit of the norm);

- severe renal dysfunction (CC less than 30 ml / min);

- myopathy;

- simultaneous administration of cyclosporine;

- in women: pregnancy, the period of breastfeeding, the lack of adequate methods of contraception;

- patients who are predisposed to the development of myotoxic complications;

- lactose intolerance, deficiency of lactase or glucose-galactose malabsorption (the preparation contains lactose).

For use in a daily dose of 40 mg:

- increased sensitivity to rosuvastatin or any of the components of the drug;

- simultaneous administration of cyclosporine;

- liver disease in the active phase,including a persistent increase in serum transaminase activity and any increase in serum transaminase activity (more than 3 times the upper limit of normal);

- patients with hepatic insufficiency;

- patients with risk factors for myopathy / rhabdomyolysis, namely:

* renal failure of moderate severity (SC less than 60 ml / min);

* hypothyroidism;

* personal or family anamnesis of muscular diseases;

* myotoxicity on the background of taking other inhibitors of HMG-CoA reductase or fibrates in the anamnesis;

- in women: pregnancy, the period of breastfeeding, lack of adequate methods of contraception;

- excessive use of alcohol;

- conditions that may lead to an increase in the plasma concentration of rosuvastatin;

- simultaneous reception of fibrates;

- patients of the Asian race;

- lactose intolerance, lactase deficiency or glucose-galactose malabsorption (the preparation contains lactose).

Carefully:

For use in a daily dose of 5 mg, 10 mg and 20 mg:

Presence of myopathy / rhabdomyolysis risk - renal failure, hypothyroidism, personal or family history of hereditary muscle diseases and a previous history of muscle toxicity with other inhibitors HMG-CoA reductase or fibrate; excessive use of alcohol; age over 65; conditions in which there was an increase in the plasma concentration of rosuvastatin; race (Asian race); simultaneous appointment with fibrates (see section "Pharmacokinetics"); liver disease in history; sepsis; arterial hypotension; extensive surgical interventions, trauma, severe metabolic, endocrine or water-electrolyte disorders or uncontrolled convulsive seizures.

For use in a daily dose of 40 mg:

Renal insufficiency of mild severity (QC more than 60 ml / min); age over 65; liver disease in history; sepsis; arterial hypotension; extensive surgical interventions, trauma, severe metabolic, endocrine or water-electrolyte disorders or uncontrolled convulsive seizures.

Application in pediatric practice

The effectiveness and safety of the drug in children under 18 years of age is not established. Experience in the use of the drug in pediatric practice is limited to a small number of children (8 years and older) with family homozygous hypercholesterolemia.Currently, it is not recommended to use Lipomime® in children under 18 years of age.

Patients with hepatic insufficiency.

Data or experience of the drug in patients with a score above 9 on the Child-Pugh scale is not available.

Pregnancy and lactation:

Lipopram® is contraindicated in pregnancy and during breastfeeding. Women of reproductive age who take Lipomime® should use adequate methods of contraception.

Since cholesterol and other cholesterol biosynthesis products are important for fetal development, the potential risk of HMG-CoA reductase inhibition is greater than the benefit of using the drug in pregnant women.

In the case of diagnosing pregnancy during therapy, taking the drug should be stopped immediately.

Data on the allocation of rosuvastatin to breast milk are not available, therefore, during the period of breastfeeding, the drug should be discontinued.

Dosing and Administration:

Inside, do not chew, swallow whole, squeezed water. The drug can be administered at any time of the day, regardless of the time of meal.

Before starting therapy with Lipomime®, the patient should begin to follow the standard hypocholesterolemic diet and continue to observe it during treatment.The dose of the drug should be selected individually depending on the purpose of therapy and the therapeutic response to treatment, taking into account the current recommendations for the target concentration of lipids.

The recommended initial dose for patients starting to take the drug, or for patients transferred from other HMG-CoA reductase inhibitors, should be 5 or 10 mg of Lipomime® once a day. When choosing the initial dose should be guided by individual cholesterol concentration and take into account the possible risk of cardiovascular complications, as well as assess the potential risk of side effects. If necessary, the dose may be increased to greater after 4 weeks.

In connection with the possible development of side effects when taking a dose of 40 mg compared with lower doses of the drug, increasing the dose to 40 mg (see the "Side effect" section) after additional doses above the recommended initial dose for 4 weeks of therapy, can be performed only in patients with severe hypercholesterolemia and a high risk of cardiovascular complications (especially in patients with familial hypercholesterolemia) who did not achieve the desired result of therapy with a dose of 20 mg,and which will be under the supervision of a specialist. It is recommended especially careful monitoring of patients receiving the drug in a dose of 40 mg. Do not administer a dose of 40 mg to patients who have not previously consulted a doctor.

After 2-4 weeks of therapy and / or with an increase in the dose of Lipoprem® it is necessary to monitor the lipid metabolism (if necessary, dose adjustment is required).

Elderly patients

No dose adjustment is required.

Patients with renal insufficiency

In patients with mild or moderate renal insufficiency, dose adjustment is not required. Contraindicated use of all dosages of the drug Lipoprem® in patients with severe renal failure (CC less than 30 ml / min.). Contraindicated the use of the drug in a dose of 40 mg in patients with moderate impaired renal function (QC less than 30 ml / min).

Patients with moderate impairment of renal function are recommended an initial dose of 5 mg.

Patients with hepatic insufficiency

Lipopram® is contraindicated in patients with active liver disease (see "Contraindications").

Special populations.

Ethnic groups

When studying the pharmacokinetic parameters of rosuvastatin in patients belonging to different ethnic groups, there was an increase in the systemic concentration of rosuvastatin among Japanese and Chinese. This fact should be taken into account when prescribing Lipopram® to these groups of patients. When prescribing doses of 10 and 20 mg, the recommended initial dose for patients of the Asian race is 5 mg. Contraindicated appointment of the drug in a dose of 40 mg to patients of the Mongoloid race (see the section "Contraindications").

Patients who are predisposed to myopathy

Contraindicated the appointment of the drug in a dose of 40 mg to patients with factors, which may indicate a predisposition to the development of myopathy (see section "Contraindications").

When appointing doses of 10 and 20 mg, the recommended initial dose for this group of patients is 5 mg (see the section "Contraindications").

Genetic polymorphism

In carriers of genotypes SLC01B1 (OATP1B1) C.521SS and ABCG2 (BCRP) C.421AA there was an increase in exposure (AUC) to rosuvastatin in 1,6 and 2,4 times, respectively, in comparison with the carriers of genes SLC01B1 p.52PT and ABCG2 C.421SS. For patients carriers of genotypes C.521SS or C.421AA, the recommended maximum dose of Lipomime® is 20 mg once a day (see Fig.sections "Pharmacokinetics", "Special instructions" and "Interaction with other medicinal products").

Concomitant therapy

Rosuvastatin binds to various transport proteins (in particular, to OATP1B1 and BCRP). With the simultaneous use of Lipopram® with medicines (such as ciclosporin, some HIV protease inhibitors, including a combination of ritonavir with atazanavir, lopinavir and / or tipranavir), which increase the concentration of rosuvastatin in blood plasma due to interaction with transport proteins, may increase the risk of myopathy (including rhabdomyolysis). You should read the instructions for using these drugs before they are administered concomitantly with Lipomime®. In such cases, the possibility of prescribing alternative therapy or temporary discontinuation should be assessed Lipomime®. If the use of the above drugs is necessary, the relationship between the benefit and the risk of concomitant therapy with Lipomime® should be assessed and the possibility of reducing its dose should be considered (see "Interactions with Other Drugs").

Side effects:

Side effects observed with the use of rosuvastatin, usually expressed slightly and pass independently. As with other inhibitors of HMG-CoA reductase, the incidence of side effects is dose-dependent.

The incidence of adverse events is as follows, according to the classification of the World Health Organization:

often (≥ 1/100, <1/10); infrequently (≥ 1/1000, <1/100); rarely (≥ 1/10 000, <1/1 000); very rarely (<1/10 000), including individual messages; frequency, unspecified (can not be calculated from available data).

The immune system

Rarely: hypersensitivity reactions, including angioedema.

From the endocrine system

Often: type 2 diabetes mellitus.

From the central nervous system

Often: headache, dizziness.

From the side of the digestive tract

Often: constipation, nausea, abdominal pain.

Rarely: pancreatitis.

From the skin

Infrequent: itchy skin, rash, hives.

From the side of the musculoskeletal system

Often: myalgia.

Rarely: myopathy (including myositis), rhabdomyolysis.

Other

Often: asthenic syndrome.

From the side of the urinary system

Patients may be diagnosed with proteinuria. Changes in the amount of protein in the urine (from absence or trace amounts to ++ or more) are observed in less than 1% of patients receiving 10-20 mg of the drug and about 3% of patients receiving 40 mg of the drug. A slight change in the amount of protein in the urine was noted when taking a dose of 20 mg. In most cases, proteinuria decreases or disappears during therapy and does not indicate the onset or progression of an existing kidney disease.

From the side of the musculoskeletal system

When rosuvastatin was used in all dosages and, in particular when taking doses of the drug in excess of 20 mg, the following effects on the musculoskeletal system were reported: myalgia, myopathy (including myositis), in rare cases rhabdomyolysis with or without acute renal failure.

A dose-related increase in activity of creatine phosphokinase (CK) is observed in a small number of patients taking rosuvastatin. In most cases, it was insignificant, asymptomatic and temporary. In the case of increased activity of CK (more than 5 times higher than the upper limit of the norm (VGN)) therapy should be suspended (see section "Special instructions").

From the side of the liver

With the use of rosuvastatin, a dose-dependent increase in the activity of "hepatic" transaminases in a small number of patients is observed. In most cases, it is insignificant, asymptomatic and temporary.

Laboratory indicators:

Increase in the concentration of glucose, bilirubin, activity of gamma-glutamyltranspeptidase, alkaline phosphatase, thyroid dysfunction.

Postmarketing application

The following side effects have been reported in the post-marketing application of the drug:

On the part of the hematopoiesis system

Unspecified frequency: thrombocytopenia.

From the side of the digestive tract

Very rarely: jaundice, hepatitis.

Rarely: increased activity of "liver" transaminases.

Unspecified frequency: diarrhea.

From the side of the musculoskeletal system

Very rarely: arthralgia.

Unspecified frequency: immuno-mediated necrotizing myopathy.

From the central nervous system

Very rare: loss or loss of memory.

Unspecified frequency: peripheral neuropathy.

From the respiratory system

Unspecified frequency: cough, shortness of breath.

From the side of the urinary system

Very rarely: hematuria.

From the skin and subcutaneous fat

Unspecified frequency: Stevens-Johnson syndrome.

From the side of the reproductive system

Very rarely: gynecomastia.

Other

Unspecified frequency: peripheral edema.

With the use of some statins, the following side effects have been reported: depression, sleep disturbances, including insomnia and nightmarish dreams, sexual dysfunction, hyperglycemia, increased concentrations of glycosylated hemoglobin. Single cases of interstitial lung disease have been reported, especially with prolonged use of drugs.

Overdose:

Symptoms: with simultaneous administration of several daily doses, the pharmacokinetic parameters of rosuvastatin do not change.

Treatment: there is no specific treatment for an overdose of rosuvastatin. In case of an overdose, it is recommended to carry out symptomatic treatment and measures aimed at maintaining the functions of vital organs and systems. It is necessary to monitor the liver function and the activity of CK. It is unlikely that hemodialysis will be effective.

Interaction:

Inhibitors of transport proteins: rosuvastatin communicates with some transport proteins, in particular, with OATP1B1 and BCRP. The concomitant use of drugs that are inhibitors of transport proteins may be accompanied by an increase in the concentration of rosuvastatin in blood plasma and an increased risk of myopathy (see Table 1 and the sections on "Dosage and administration" and "Special instructions").

Cyclosporine: with simultaneous application of rosuvastatin and cyclosporine AUC rosuvastatin was an average of 7 times higher than that seen in healthy volunteers (see Table 1). Does not affect the plasma concentration of cyclosporine. Lipopram® is contraindicated in patients taking ciclosporin (see section "Contraindications").

Gemfibrozil and other lipid-lowering agents: joint application rosuvastatin and gemfibrozil leads to an increase in 2 times the maximum concentration of rosuvastatin in blood plasma and AUC rosuvastatin. Based on the data on the specific interaction, no pharmacokinetically significant interaction with fenofibrate is expected, possibly pharmacodynamic interaction.

Gemfibrozil, fenofibrate, other fibrates and lipid-lowering doses of nicotinic acid (more than 1 g / day) increasedthe risk of myopathy with simultaneous use with HMG-CoA reductase inhibitors, possibly due to the fact that they can cause myopathy and when used in monotherapy (see section "Special instructions"). With simultaneous administration of the drug with gemfibrozil, fibrates, nicotinic acid in lipid-lowering doses (more than 1 g / day), patients are advised to take an initial dose of 5 mg.

Admission to a dose of 40 mg is contraindicated with simultaneous use with fibrates (see the sections "Contraindications", "Method of administration and dose", "Special instructions").

Ezetimibe: simultaneous application of rosuvastatin 10 mg and ezetimibe at a dose of 10 mg was not accompanied by a change AUC rosuvastatin in patients with hypercholesterolemia (see Table 1). It can not be ruled out that the risk of side effects increases due to the pharmacodynamic interaction between rosuvastatin and ezetimibe.

Inhibitors of the human immunodeficiency virus (HIV) protease: although the exact mechanism of interaction is unknown, joint intake of HIV protease inhibitors can lead to a significant increase in the exposure of rosuvastatin (see Table 1).A pharmacokinetic study on simultaneous use of 20 mg rosuvastatin with a combined preparation containing two HIV protease inhibitors (400 mg lopinavir / 100 mg ritonavir) in healthy volunteers resulted in approximately a two- and five-fold increase AUC ₍about-24) and Cmrosuvastatin, respectively. Therefore, concomitant administration of rosuvastatin and HIV protease inhibitors is not recommended (see the section on "Dosage and administration" and "Specific guidance", Table 1).

Antacids: simultaneous application of rosuvastatin and antacid suspensions, containing aluminum and magnesium hydroxide, leads to a decrease in the plasma concentration of rosuvastatin by approximately 50%. This effect is less pronounced if antacids are administered 2 hours after rosuvastatin administration. The clinical significance of this interaction has not been studied.

Erythromycin: simultaneous application of rosuvastatin and erythromycin leads to a decrease AUC rosuvastatin by 20% and Cmrosuvastatin rose by 30%. Such interaction can arise as a result of increased intestinal motility caused by the administration of erythromycin.

Isozymes of cytochrome P450: research results in vivo and in vitro showed that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. Besides, rosuvastatin is a weak substrate for these isoenzymes. There was no clinically significant interaction between rosuvastatin and fluconazole (inhibitor of isoenzymes CYP2C9 and CYP3A4) and ketoconazole (inhibitor of isoenzymes CYP2A6 CYP3A4). Thus, the interaction of rosuvastatin with other drugs at the metabolic level with participation of cytochrome P450 isoenzymes is not expected.

Fusidic acid: studies on the interaction of rosuvastatin and fusidic acid have not been conducted. As with other statins, post-marketing reports were received on cases of rhabdomyolysis with simultaneous administration of rosuvastatin and fusidic acid. It is necessary to observe patients. If necessary, a temporary discontinuation of rosuvastatin is possible.

Interaction with drugs, which requires correction of the dose of rosuvastatin (see Table 1).

The dose of Lipomime® should be adjusted when it is necessary to use it simultaneously with drugs that increase the exposure to rosuvastatin.You should read the instructions for using these drugs before they are administered concomitantly with Lipomime®. If an increase in exposure is expected to be 2 times or more, the initial dose of Lipoprem® should be 5 mg once a day. Also, the maximum daily dose of Lipopram® should be adjusted so that the expected exposure to rosuvastatin does not exceed that for a dose of 40 mg taken without simultaneous administration of medications that interact with rosuvastatin. For example, the maximum daily dose of Lipomime® with simultaneous use with gemfibrozil is 20 mg (1.9 times increase in exposure), with ritonavir / atazanavir 10 mg (increase in exposure 3.1 times).

Table 1

The effect of concomitant therapy on exposure to rosuvastatin (AUC, data are listed in descending order)

Complementary therapy regimen	Mode of taking rosuvastatin	Change AUC rosuvastatin
Cyclosporine 75-200 mg 2 times / day, 6 months.	10 mg once a day, 10 days	An increase of 7.1 times
Atazanavir 300 mg / ritonavir 100 mg 1 time / day, 8 days	10 mg once	Increase 3.1-fold
Simeprevir 152 mg 1 time / day, 7 days	10 mg once	An increase of 2.8 times
Lopinavir 400 mg / ritonavir 100 mg 2 times / day, 17 days	20 mg 1 time / day, 7 days	An increase of 2.1 times
Clopidogrel 300 mg (loading dose), then 75 mg after 24 hours	20 mg once	2 times increase
Gemfibrozil 600 mg 2 times / day, 7 days	80 mg once	Increase 1.9 times
Eltrombopag 75 mg 1 time / day, 10 days	10 mg once	Increase 1.6 times
Darunavir 600 mg / ritonavir 100 mg 2 times / day, 7 days	10 mg 1 time / day, 7 days	Increase by 1.5 times
Tipranavir 500 mg / ritonavir 200 mg 2 times / day, 11 days	10 mg once	Increase by 1.4 times
Dronedarone 400 mg 2 times / day	no data	Increase by 1.4 times
Itraconazole 200 mg 1 time / day, 5 days	10 mg or 80 mg once	Increase by 1.4 times
Ezetimibe 10 mg 1 time / day, 14 days	10 mg once a day, 14 days	Increase by 1.2 times
Fosamprenavir 700 mg / ritonavir 100 mg 2 times / day. 8 days	10 mg once	Without changes
Aleglitazar 0.3 mg 7 days	40 mg, 7 days	Without changes
Silymarin 140 mg 3 times / day, 5 days	10 mg once	Without changes
Fenofibrate 67 mg 3 times / day, 7 days	10 mg, 7 days	Without changes
Rifampicin 450 mg 1 time / day, 7 days	20 mg once	Without changes
Ketoconazole 200 mg 2 times / day, 7 days	80 mg once	Without changes
Fluconazole 200 mg 1 time / day, 11 days	80 mg once	Without changes
Erythromycin 500 mg 4 times / day, 7 days	80 mg once	Decrease by 28%
Baikalin 50 mg 3 times / day, 14 days	20 mg once	Decrease by 47%

Effect of rosuvastatin on other drugs

Antagonists of vitamin K: the initiation of rosuvastatin therapy or an increase in the dose of the drug in patients receiving both vitamin K antagonists (for example, warfarin), can lead to an increase in the International Normalized Relationship (INR). The cancellation of rosuvastatin or a decrease in the dose of a and the drug may result in a decrease in INR. In such cases, monitoring of INR is recommended.

Oral contraceptives / hormone replacement therapy: simultaneous

the use of rosuvastatin and oral contraceptives increases AUC ethinylestradiol and AUC norgestrel by 26% and 34%, respectively. Such an increase in plasma concentration should be taken into account when choosing a dose of oral contraceptives. Pharmacokinetic data on the simultaneous use of the drug Lipomime® and hormone replacement therapy are not available, therefore, it is impossible to exclude a similar effect when using this combination.However, this combination was widely used during clinical trials and was well tolerated by patients.

Other medicines: no clinically significant interaction between rosuvastatin and digoxin is expected.

Special instructions:

Renal Effects from the Urinary System

In patients receiving high doses of the drug rosuvastatin (mainly 40 mg), tubular proteinuria was observed, which in most cases was transient. Such proteinuria did not indicate an acute kidney disease or progression of kidney disease. In patients taking the drug at a dose of 40 mg, it is recommended to monitor the performance of kidneys during treatment.

From the side of the musculoskeletal system

When using the drug rosuvastatin in all dosages and, in particular when taking doses of the drug in excess of 20 mg, the following effects on the musculoskeletal system have been reported: myalgia, myopathy, in rare cases rhabdomyolysis.

Determination of the activity of creatine phosphokinase

The determination of CK should not be performed after intensive physical exertion or in the presence of other possible causes of increased activity of CK, which may lead to incorrect interpretation of the results.If the initial activity of CK is significantly increased (5 times higher than the upper limit of the norm), after 5-7 days, a second measurement should be made. Do not start therapy if a second test confirms the baseline CK activity (more than 5 times higher than the VLN).

Before the start of therapy

When prescribing the drug, as well as when prescribing other HMG-CoA reductase inhibitors, caution should be exercised for patients with existing risk factors for myopathy / rhabdomyolysis (see the section "With caution"), it is necessary to consider the relationship between the risk and possible benefits of therapy and conduct clinical monitoring .

During therapy

The patient should be informed of the need to report immediately to the doctor about cases of sudden onset of muscle pain, muscle weakness, or spasms, especially in combination with malaise and fever. In such patients, the activity of CK should be determined. Therapy should be discontinued if the activity of the CK is significantly increased (more than 5 times compared with ULN) or if the symptoms from the muscles are pronounced and cause daily discomfort (even if the activity of CK is 5 times less than that of VGN).If symptoms disappear and CPK activity returns to normal, consideration should be given to re-administering Lipomime® or other HMG-CoA reductase inhibitors in smaller doses with careful monitoring of the patient.

Routine monitoring of the activity of CKK in the absence of symptoms is inappropriate. Very rare cases of immuno-mediated necrotizing myopathy with clinical manifestations in the form of persistent weakness of proximal muscles and increased activity of CKK in the serum during treatment or with stopping of taking statins are noted. rosuvastatin. It may be necessary to conduct additional studies of the muscular system and nervous system, serological studies, as well as therapy with immunosuppressive drugs.

There were no signs of an increase in the effect on skeletal musculature when taking the drug rosuvastatin and concomitant therapy. However, an increase in the incidence of myositis and myopathy in patients taking other HMG-CoA reductase inhibitors in combination with fibrin acid derivatives, including gemfibrozil, ciclosporin, nicotinic acid in lipid-lowering doses (more than 1 g / day), azole antifungal agents, HIV protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when combined with certain HMG-CoA reductase inhibitors. Thus, simultaneous administration of the drug is not recommended rosuvastatin and gemfibrozil. The risk-to-benefit ratio should be carefully weighed in conjunction with the use of Lipopram® and fibrates or lipid-lowering doses of nicotinic acid (more than 1 g / day). Contraindicated taking Lipomime® in a dose of 40 mg together with fibrates.

In 2-4 weeks after the start of treatment and / or with an increase in the dose of Lipoprem®, control of lipid metabolism parameters is necessary (if necessary, dose adjustment is required).

From the side of the liver

It is recommended to carry out the determination of liver function indices before the start of therapy and 3 months after the start of therapy. Admission of Lipopram® should stop or reduce the dose of the drug if the activity of "hepatic" transaminases in the blood serum is 3 times higher than VGN.

In patients with hypercholesterolemia due to hypothyroidism or nephrotic syndrome, treatment of major diseases should be performed before starting treatment with Lipomime®.

Special populations.

Ethnic groups

During pharmacokinetic studies among Chinese and Japanese patients, an increase in the systemic concentration of rosuvastatin was noted in comparison with the indices obtained among patients - Europeans.

HIV protease inhibitors

It is not recommended joint use of the drug with HIV protease inhibitors.

Lactose

The drug should not be used in patients with lactase deficiency, lactose intolerance and glucose-galactose malabsorption.

Interstitial lung disease

When certain statins were used, especially for a long time, single cases of interstitial lung disease were reported. Manifestations of the disease may be shortness of breath, unproductive cough and deterioration, general well-being (weakness, weight loss and fever). If suspicion of interstitial lung disease should be stopped by statin therapy.

Diabetes mellitus type 2

In patients with a glucose concentration of 5.6 to 6.9 mmol / L, rosuvastatin therapy was associated with an increased risk of developing type 2 diabetes.

Effect on the ability to drive transp. cf. and fur:There have been no studies to study the effect of Lipopram® on the ability to drive a vehicle and use mechanisms. Care should be taken when driving vehicles or work associated with increased concentration of attention and psychomotor reaction (dizziness may occur during therapy).

Form release / dosage:Film-coated tablets, 5 mg, 10 mg and 20 mg.

Packaging:

10 tablets per blister of A1 / A1. For 3 blisters together with instructions for use in a cardboard box.

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003874

Date of registration:03.10.2016

Expiration Date:03.10.2021

The owner of the registration certificate:Micro Labs LimitedMicro Labs Limited India

Manufacturer: & nbsp

MICRO LABS, Limited India

Representation: & nbspMICRO LABS LIMITED MICRO LABS LIMITED India

Information update date: & nbsp10.04.2018

Illustrated instructions

Instructions

Lipoprem® (Lipoprime)