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

Excipients: lactose monohydrate 82.525 mg, 165.05 mg, 330.1 mg, calcium phosphate 6.25 mg, 12.5 mg, 25.0 mg, microcrystalline cellulose 2.50 mg, 5.0 mg, 10.0 mg, crospovidone 1.50 mg, 3.0 mg, 6.0 mg, butyl hydroxytoluene 0.025 mg, 0.05 mg, 0.1 mg, talc 1.50 mg, 3.0 mg, 6.0 mg, magnesium stearate 0.50 mg, 1.0 mg, 2.0 mg;

Tablet shells: Opaprai II yellow (31K82825) (hypromellose (28,000%), titanium dioxide (20.300%), lactose monohydrate (40,000%), triacetin (8,000%), iron oxide yellow oxide (3.700%)) 2.0 mg / ; Opaprai II pink (31K84972) (hypromellose (28,000%), titanium dioxide (23,400%), lactose monohydrate (40,000%), triacetin (8,000%), iron oxide red oxide (0.600%)) - 4.0 mg / 8 , 0 mg.

Description:

Dosage of 5 mg:

Round biconvex tablets, covered with a film coating of yellow color. On the cross section, the core of the tablet is from white to almost white.

Dosage of 10 mg:

Round biconvex tablets, covered with a film coating of pink color. On the cross section, the core of the tablet is from white to almost white.

Dosage of 20 mg:

Round biconvex tablets, covered with a film shell of pink color, with a risk on one side. On the cross section, the core of the tablet is from white to almost white.

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 to mevalonic acid, the precursor of cholesterol. The main target of rosuvastatin, is the liver, where the synthesis of cholesterol (CS) and catabolism of low density lipoprotein (LDL).

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

Pharmacodynamics

Rosuvastatin decreases the elevated concentration of LDL-cholesterol (LDL-C), total cholesterol, triglycerides (TG) and increases high-density lipoprotein cholesterol (HDL-C), and also reduces the concentration of apolipoprotein B (apoB) neLPVP-cholesterol, HS- VLDL, T-VLDL and increases the concentration of apolipoprotein A-I (ApoA-I) (see Tables 1 and 2), reduces the ratio of LDL-C-HDL cholesterol, total cholesterol / cholesterol-HDL cholesterol and non-HDL / C-HDL cholesterol and the ApoB / ApoA ratio-I.

The therapeutic effect is within one week after initiation of treatment with rosuvastatin, after 2 weeks of treatment up to 90% of the maximum possible effect. The maximum therapeutic effect is usually achieved by the 4th week of therapy and is maintained with regular intake of the drug.

Table 1. Dose-dependent effect in patients with primary hypercholesterolemia (type IIa and IIb according to Fredrickson's classification) (mean adjusted percentage change compared to the original value).

Dose	Number of patients	HS- LDL	General information HS	HS- HDL	TG	CS-non-HDL	APOP	Apo A-I
Placebo	13	-7	-5	3	-3	-7	-3	0
5 mg	17	-45	-33	13	-35	-44	-38	4
10 mg	17	-52	-36	14	-10	-48	-42	4
20 mg	17	-55	-40	8	-23	-51	-46	5
40 mg	18	-63	-46	10	-28	-60	-54	0

Table 2. Dose-dependent effect in patients with hypertriglyceridemia (type IIb and IV, according to Fredrickson's classification) (mean percentage change in comparison the original value).

Dose	Number of patients	TG	HS- LDL	General information HS	HS- HDL	CS-non-HDL	HS- VLDLP	TG- VLDLP
Placebo	26	1	5	1	-3	2	2	6
5 mg	25	-21	-28	-24	3	-29	-25	-24
10 mg	23	-37	-45	-40	8	-49	-48	-39
20 mg	27	-37	-31	-34	22	-43	-49	-40
40 mg	25	43	-43	-40	17	-51	-56	-48

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 Pf and Pb type hypercholesterolemia according to Fredrickson classification (mean initial concentration of LDL-C in 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 the 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%.

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

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-desmethylrozuvastatin 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 the 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 unabsorbed rosuvastatin). The rest is excreted by the kidneys. The plasma half-life (T1 / 2) is approximately 19 hours. T1 / 2 does not change with increasing dose of rosuvastatin. The average geometric plasma clearance is approximately 50 l / h (coefficient of variation 21.7%). As in the case of other HMG-CoA reductase inhibitors, a membrane cholesterol transporter involved in the hepatic elimination of rosuvastatin 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 Cmah (maximum concentration in the blood plasma) of rosuvastatin in patients of the Mongoloid race (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 concentrations 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 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 different stages of hepatic insufficiency did not have an increase in T1 / 2 rosuvastatin in patients with 7 points or lower on the Child-Pugh scale. Two patients with the 8th and 9th points on the Child-Pugh scale had an increase in T1 / 2, at least 2-fold. The experience with rosuvastatin in patients with more than 9 points on the Child-Pugh scale is not available.

Genetic polymorphism

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

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 where such therapy is not effective enough.

- Hypertriglyceridemia (type IV according to Fredrickson 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.

- Primary prevention of major cardiovascular complications (stroke, myocardial infarction, arterial revascularization) in adults without clinical signs of coronary artery disease (ischemic heart disease), but with an increased risk of its development (age over 50 for men and over 60 for women, increased concentration of C-reactive protein (≥ 2 mg / l) with at least one of additional risk factors, such as hypertension, low concentration of HDL-C, smoking, family history of early onset of CHD).

Contraindications:

For the drug Rosuphast 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 persistent increase in serum activity of "liver" transaminases and any increase in the activity of transaminases in the serum (more than 3 times compared with the upper limit of the norm (VGN))

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

- children under 18 years of age

For the drug Rosuphast in a daily dose of 40 mg:

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

- simultaneous administration of cyclosporine

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

- 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 as compared with IGN)

- 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;

- excessive use of alcohol;

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

- simultaneous reception of fibrates;

- use of patients of the Asian race;

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

- children's age till 18 years.

Carefully:

For the drug Rosuphast in a daily dose of 5 mg, 10 mg and 20 mg:

The presence of a risk of myopathy / rhabdomyolysis - renal failure, hypothyroidism, personal or family history of hereditary muscle diseases and a previous history of muscle toxicity when using other inhibitors of HMG-CoA reductase or fibrates; 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 the drug Rosuphast 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.

Patients with hepatic insufficiency

Data or experience of the drug in patients with more than 9 points on the Child-Pugh scale is not available (see the sections "Pharmacodynamics" and "Special instructions").

Pregnancy and lactation:

RosUpast is contraindicated during pregnancy and during breastfeeding. Women of childbearing age should apply adequate methods of contraception. Because cholesterol and other cholesterol biosynthesis products are important for fetal development, the potential risk of inhibiting HMG-CoA reductase exceeds 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 with breast milk are not available, so during lactation breastfeeding should be discontinued (see section "Contraindications").

Dosing and Administration:

Inside, do not chew and do not grind the tablet, 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 RosUpast, 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 current recommendations for target lipid concentrations.

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 RosUfast 1 time per day.

When choosing the initial dose, one should be guided by the individual concentration of cholesterol and take into account the possible risk of cardiovascular complications,and it is also necessary to assess the potential risk of side effects. If necessary, the dose may be increased to greater after 4 weeks (see the section "Pharmacodynamics").

In connection with the possible development of side effects when taking a dose of 40 mg, compared with lower doses of the drug (see section "Side effect"), increasing the dose to 40 mg, after additional doses above the recommended initial dose for 4 weeks 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 when taking a dose of 20 mg and which will be be under the supervision of a specialist (see section "Special instructions"). 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 increasing the dose of RosUpast, the control of the lipid metabolism parameters is necessary (if necessary, dose correction 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. In patients with severe renal failure (CC less than 30 ml / min.), The use of RosUpast is contraindicated. Contraindicated use of the drug in a dose of 40 mg to patients with moderate impaired renal function (QC 30-60 ml / min.) (See section "Special instructions" and "Pharmacodynamics"). Patients with moderate impairment of renal function are recommended an initial dose of 5 mg.

Patients with hepatic insufficiency

RosUpast is contraindicated in patients with liver diseases in the active phase (see the section "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 (see section "Special instructions"). This fact should be taken into account when prescribing RosUsafast to these groups of patients. When appointing doses of 10 and 20 mg, the recommended initial dose for patients of the Mongoloid 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").

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 comparison with carriers of genotypes SLC01B1 p.52ITT and ABCG2 C.421SS. For patient carriers of genotypes SLC01B1 C.521SS and ABCG2 C.421AA the recommended maximum dose of RosUfast is 20 mg once a day (see sections "Pharmacokinetics", "Special instructions" and "Interaction with other drugs and other types of drug interactions").

Patients who are predisposed to myopathy

Contraindicated the appointment of the drug in a dose of 40 mg to patients with factors that may indicate a predisposition to the development of myopathy (see section "Contraindications"). When appointing up to 10 and 20 mg, the recommended initial dose for this group of patients is 5 mg (see section "Contraindications").

Concomitant therapy

Rosuvastatin binds to various transport proteins (in particular, to OATP1B1 and BCRP). With the simultaneous use of the drug RosUfast 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 by interacting with transport proteins, may increase the risk of myopathy (including rhabdomyolysis) (see "Special instructions" and " Interactions with Other Drugs and Other Types of Drug Interactions ").

It should be read the instructions for the use of these drugs before they are administered concomitantly with RosUpast.

In such cases, one should evaluate the possibility of prescribing alternative therapy or temporary discontinuation of RosUfast. If the use of the above drugs is necessary, the ratio of benefit and risk of concomitant therapy with RosUFast should be assessed and the possibility of dose reduction should be considered (see "Interactions with Other Drugs and Other Drug Interactions").

Side effects:

The side effects observed with the use of RosUpast, are usually only slightly expressed and pass on their own.As with other inhibitors of HMG-CoA reductase, the incidence of side effects is mainly 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 (can not be calculated on the basis of available data)

The immune system

Rarely: hypersensitivity reactions, including angioedema

Endocrine system

Often: diabetes mellitus type 2

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, skin rash, urticaria

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 receiving Rosuzfast can 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 with 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

In applying the drug Rozufast at all doses, and particularly when receiving doses greater than 20 mg have been reported for the following effects on the musculoskeletal system: myalgia, myopathy (including myositis), in rare cases - rhabdomyolysis with acute renal failure or without .

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 increasing the activity of CK (more than 5 times compared with FHG) therapy should be stopped (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

With the use of RosUpast, the following changes in laboratory parameters were also observed: an increase in the concentration of glucose, bilirubin, activity of gamma-glutamyltranspeptidase, alkaline phosphatase, thyroid dysfunction.

Postmarketing application

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, dyspnea

From the side of the urinary system

Very rare: hematuria

From the skin and subcutaneous fat:

Unspecified frequency: Stevens-Johnson syndrome

From the reproductive system and the breast:

Unspecified frequency: 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 (see section "Special instructions").

Overdose:

Symptoms: with the 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 liver function and the level of 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 these transport proteins may be accompanied by an increase in the concentration of rosuvastatin in the blood plasma and an increased risk of myopathy (see Table 3 and the sections "Dosing and Administration" and "Specific Guidance").

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 3). Taking RosUfast does not affect the plasma concentration of cyclosporine. RosUpast is contraindicated in patients taking ciclosporin (see section "Contraindications").

Inhibitors of the human immunodeficiency virus (HIV) protease: despite the fact that the exact mechanism of interaction is unknown, co-administration of HIV protease inhibitors can lead to a significant increase in the exposure of rosuvastatin (see Table 3). Pharmacokinetic studies on the simultaneous use of 20 mg rosuvastatin with a combined preparation containing two HIV protease inhibitors (400 mg lopinavir / 100 mg ritonavir) in healthyvolunteers led to approximately a two-fold and five-fold increase AUC_0-24) and Cmrosuvastatin, respectively. Therefore, simultaneous administration of rosuvastatin and protease inhibitors HIV is not recommended (see section "Dosing and Administration", "Specific guidance", table 3).

Gemfibrozil and other lipid-lowering drugs: the combined use of rosuvastatin and gemfibrozil leads to an increase in 2 times the maximum concentration of rosuvastatin in blood plasma and AUC rosuvastatin (see section "Special instructions"). Based on the data on the specific interaction, no pharmacokinetically significant interaction with fenofibrates is expected, possibly pharmacodynamic interaction.

Gemfibrozil, fenofibrate, other fibrates and lipid-lowering doses of nicotinic acid (more than 1 g / day) increased the risk of myopathy with simultaneous use with HMG-CoA reductase inhibitors, possibly due to the fact that they can cause myopathy when used in monotherapy (see " Special instructions"). With simultaneous administration of the drug with gemfibrozil, fibrates, nicotinic acid in lipid-lowering doses (more than 1 g / day), patients are recommendedthe initial dose of the drug is 5 mg, taking in a dose of 40 mg is contraindicated in a joint appointment with fibrates (see the sections "Contraindications", "Method of administration and dose", "Special instructions").

Ezetimibe: simultaneous application of the drug Rosufast in a dose of 10 mg and ezetimibe at a dose of 10 mg was not accompanied by a change AUC rosuvastatin in patients with hypercholesterolemia (increased AUC rosuvastatin 1.2 times, see table 3). It is impossible to exclude an increased risk of side effects due to the pharmacodynamic interaction between the drug Rosufast and ezetimibe.

Antacids: simultaneous application of rosuvastatin and suspensions of antacids 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 for 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 enzymes. Therefore, interaction of rosuvastatin with other drugs at the metabolic level with the participation of cytochrome P450 isoenzymes is not expected. There was no clinically significant interaction between rosuvastatin and fluconazole (inhibitor of isoenzymes CYP2C9 and CYP3A4) and ketoconazole (inhibitor of isoenzymes CYP2A6 and CYP3A4).

Fusidic acid: studies on the interaction of rosuvastatin and fusidic acid was not performed. As with other statins, post-marketing reports were received on cases of rhabdomyolysis with simultaneous application of rosuvastatin with fusidic acid. Care must be taken to monitor patients. If necessary, a temporary discontinuation of rosuvastatin is possible.

Interaction with drugs, which requires correction of the dose of rosuvastatin (see Table 3).

The dose of RosUpast should be adjusted if necessary for its joint use with drugs that increase exposure to rosuvastatin.It should be read the instructions for the use of these drugs before they are administered concomitantly with RosUpast.

If the exposure is expected to be 2 times or more, the initial dose of RosUfast should be 5 mg once a day. Also, the maximum daily dose of RosUfast should be adjusted so that the expected exposure to rosuvastatin does not exceed that for a dose of 40 mg taken without the simultaneous administration of medications that interact with rosuvastatin. For example, the maximum daily dose of Rosofast with simultaneous application with gemfibrozil is 20 mg (1.9 times increase in exposure), with ritonavir / atazanavir 10 mg (increase in exposure 3.1 times).

Table 3. Effect of concomitant therapy on exposure to rosuvastatin (AUC, data are listed in descending order) - results of published clinical trials

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

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 the drug may lead to a decrease in INR. In such cases, monitoring of INR is recommended.

Oral contraceptives / hormone replacement therapy: simultaneous 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 Rosuphast 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:

From the urinary system

In patients who received high doses of the drug Rosufast (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 Rosupast in all dosages and, especially when taking doses of the drug, exceeding 20 mg, the following effects on the musculoskeletal system were reported: myalgia, myopathy, in rare cases rhabdomyolysis.

Determination of the activity of creatine phosphokinase

Determination of CKK activity 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.In the event that the initial activity of CK is significantly increased (5 times higher than VGN), after 5-7 days, a second measurement should be made. It should not be started therapy, if the repeated test confirms the initial activity of CKK (more than 5 times higher than the VLN).

Before the start of therapy

When prescribing RosUpast, as with other HMG-CoA reductase inhibitors, caution should be exercised in patients with existing risk factors for myopathy / rhabdomyolysis (see "With caution"), the risk-to-benefit ratio should be considered and clinical observation.

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 CK is significantly increased (more than 5 times compared to IGN) or if the symptoms from the muscles are pronounced and cause daily discomfort (even if the activity of CK is 5 times less compared to VGN).If symptoms disappear and CPK activity returns to normal, consideration should be given to re-administering RosUfast or other HMG-CoA reductase inhibitors in smaller doses with close 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 blood serum during treatment and with stopping of taking statins, including rosuvastatin, were noted. It may be necessary to conduct additional studies of the muscular and nervous system, serological studies, as well as therapy with immunosuppressive agents

There were no signs of an increase in the effect on skeletal musculature when taking Rosoufast 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, protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when combined with certain HMG-CoA reductase inhibitors. Thus, the simultaneous administration of the drug RosUfast and gemfibrozil is not recommended. The risk-to-benefit ratio should be carefully weighed against the combined use of RosUpast and the fibrate or lipid-lowering doses of nicotinic acid (more than 1 g / day). Contraindicated taking Rosofast 40 mg together with fibrates (see the sections "Interaction with other drugs and other forms of drug interactions," "Contraindications").

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

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. Taking RosUFast should stop or reduce the dose of the drug if the activity of "hepatic" transaminases in the serum is 3 times higher than the upper limit of the norm.

In patients with hypercholesterolemia due to hypothyroidism or nephrotic syndrome, the treatment of underlying diseases should be performed before starting treatment with RosUpast.

Special Populations

Ethnic groups

During pharmacokinetic studies, an increase in the systemic concentration of rosuvastatin was noted among Chinese and Japanese patients compared to those obtained among patients - Europeans (see the sections "Dosage and Administration" and "Pharmacokinetics").

HIV protease inhibitors

It is not recommended to use the drug jointly with HIV protease inhibitors (see "Interaction with other drugs and other interactions").

Lactose

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

Interstitial lung disease

With the use of some statins, especially for a long time, single cases of interstitial lung disease have been reported. Manifestations of the disease may be shortness of breath, unproductive cough and deterioration in overall health (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, RosUpast 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 RosUpast preparation on the ability to drive a vehicle and use mechanisms. Care should be taken when driving a motor vehicle or work that requires a high concentration of attention and speed of psychomotor reactions (risk of dizziness).

Form release / dosage:

The tablets covered with a film membrane 5, 10, 20 mg.

Packaging:

10 tablets per blister Al / Al.

For 3 blisters together with instructions for use in a pack of cardboard.

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

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

Terms of leave from pharmacies:On prescription

Registration number:LP-004119

Date of registration:03.02.2017

Expiration Date:03.02.2022

The owner of the registration certificate:Rowecq LimitedRowecq Limited United Kingdom

Manufacturer: & nbsp

BAFNA PHARMACEUTICALS LTD India

Representation: & nbspROUTEC LIMITEDROUTEC LIMITEDUnited Kingdom

Information update date: & nbsp09.03.2017

Illustrated instructions

Instructions

Rosufast (Rozufast)