Rosulip Plus capsules 20 mg + 10 mg 30 pcs. (rosuvastatin, ezetymyb)

Pharmacological action of

Rosuvastatin

The maximum concentration of rosuvastatin in blood plasma is reached approximately 5 hours after oral administration. Absolute bioavailability is about 20%. Rosuvastatin is absorbed mainly by the liver, where the main synthesis of cholesterol and excretion of LDL-C occurs. The volume of distribution of rosuvastatin is approximately 134 liters. About 90% of rosuvastatin binds to plasma proteins, primarily albumin. Rosuvastatin is slightly metabolized (about 10%). Rosuvastatin is a non-core substrate for isoenzymes of the cytochrome P450 system. The main enzyme involved in the metabolism of rosuvastatin is CYP2C9. The enzymes CYP2C19, CYP3A4 and CYP2D6 are less involved in metabolism. The main derivatives of rosuvastatin are the N-desmethyl metabolite and lactone metabolites. N-desmethyl is approximately 50% less active than rosuvastatin, lactone derivatives are pharmacologically inactive. Rosuvastatin suppresses the activity of more than 90% of circulating HMG-CoA reductase. About 90% of the dose of rosuvastatin is excreted unchanged with feces (including absorbed and not absorbed rosuvastatin). The rest of the dose is excreted in the urine. About 5% of the dose is excreted in the urine in an unchanged state. The half-life of the drug from blood plasma is approximately 19 hours. The half-life does not change with an increase in the dose of the drug. The geometric mean plasma clearance is approximately 50 liters / hour (coefficient of variation 21.7%). Similar to other HMG-CoA reductase inhibitors, in the process of hepatic uptake of rosuvastatin, a membrane protein carrier of organic anions of type C (OATP-C) is involved, which plays an important role in the hepatic elimination of rosuvastatin. The systemic bioavailability of rosuvastatin increases in proportion to the dose. When using the drug several times a day, the pharmacokinetic parameters do not change.

Special patient groups

Age and gender: No clinically significant effect of age and gender on the pharmacokinetic properties of rosuvastatin has been observed. The pharmacokinetics of rosuvastatin when used in children and adolescents with familial heterozygous hypercholesterolemia was similar to the pharmacokinetics of adult patients.

Race: Pharmacokinetic studies indicate that, compared with people of the Caucasian race, in persons of the Asian race (Japanese, Chinese, Filipinos, Vietnamese and Koreans), the average area under the concentration-time curve (area under the curve, AUC) and the maximum concentration of the drug in blood plasma (Cmax) are approximately 2 times higher. In Indians, these indicators are approximately 1.3 times higher than in those of the Caucasian race. An analysis of population pharmacokinetics did not reveal clinically significant differences in the pharmacokinetic parameters of rosuvastatin between Caucasian and Negroid individuals.

Patients with impaired renal function. Mild or moderate renal impairment did not affect the plasma concentration of rosuvastatin or N-desmethyl metabolite. In patients with severe impaired renal function (creatinine clearance <30 ml / min), the concentration of rosuvastatin and N-desmethyl metabolite was, respectively, 3 and 9 times higher. than in healthy patients. In patients receiving hemodialysis sessions, the plasma concentration of rosuvastatin in equilibrium was 50% higher than in healthy patients.

Patients with liver failure: Patients with liver failure of varying severity did not have data on increased exposure to rosuvastatin in individuals with a value of less than 7 on the Child-Pugh scale. However, in 2 participants with values ​​of 8 and 9 on the Child-Pugh scale, an increase in the systemic effect of rosuvastatin was observed, at least 2-fold, compared with participants with lower values ​​on the Child-Pugh scale. There is no experience with the use of rosuvastatin in individuals with a value of more than 9 points on the Child-Pugh scale.

Genetic polymorphism. The transport proteins OATP1B1 and BCRP are involved in the excretion of inhibitors of HMG-CoA reductase, including rosuvastatin. Patients with genetic polymorphism SLCO1B1 (OATP1B1) and / or ABCG2 (BCRP) are at risk for increased exposure to rosuvastatin. Individual polymorphism SLCO1B1 c.521CC and ABCG2 c.421AA are characterized by an increase in exposure (AUC) of rosuvastatin 1.7 times and 2.4 times, respectively, compared with the genotypes SLCO1B1 c.521TT and ABCG2 c.421CC.

Pediatric patients. The pharmacokinetics of rosuvastatin in children of 10-17 years old with heterozygous hereditary hypercholesterolemia are not fully characterized. A small study of the pharmacokinetics of rosuvastatin in 18 children showed that the effect of rosuvastatin in pediatric patients appears to be similar to that in adults. In addition, the results of the study show that significant deviations from dose dependence are not expected.

Ezetimibe

After oral administration, ezetimibe is rapidly absorbed and substantially conjugated to form a pharmacologically active phenolic glucuronide - ezetimibe glucuronide. Average values ​​of the maximum concentration of ezetimibe in plasma (Cmax) are observed 1–2 hours and 4–12 hours after ingestion, respectively, for ezetimibe glucuronide and ezetimibe. The absolute bioavailability of ezetimibe cannot be determined, since it is practically insoluble in aqueous media suitable for injection. Concurrent ingestion of food (high and low fat) does not affect the bioavailability of ezetimibe after oral administration. Ezetimibe can be taken without regard to meals. The binding of ezetimibe and its glucuronide to plasma proteins is 99.7% and 88–92%, respectively. Ezetimibe metabolism occurs predominantly in the small intestine and in the liver through glucuronidation (phase II reaction) and subsequent excretion with bile. In all studied species, a minimally expressed oxidative metabolism of ezetimibe was noted (phase I reaction). Ezetimibe and ezetimibe-glucuronide, the main derivatives of the drug, account for 10-20% and 80-90% of the total content of the drug in blood plasma, respectively. Ezetimibe and ezetimibe-glucuronide are slowly eliminated from the blood plasma during intestinal-hepatic recirculation. The half-life of ezetimibe and ezetimibe-glucuronide is about 22 hours.

Special patient groups

Age and gender of patients: In patients older than 65 years, the concentration of total ezetimibe in the blood plasma is approximately 2 times higher than in patients aged 18-45 years. The decrease in LDL-C and safety profiles in elderly and younger patients taking ezetimibe are approximately the same. Therefore, dose adjustment for elderly patients is not required.

The total concentration of ezetimibe is approximately 20% higher in women than in men. The level of lowering LDL-C and safety profiles are approximately the same in men and women taking ezetimibe. Therefore, gender is not a reason for dose adjustment.

Patients with renal failure: After a single oral administration of ezetimibe 10 mg in patients with severe renal insufficiency (CC> 30 ml / min), the average AUC increased by 1.5 times compared with healthy participants. This result is not considered clinically significant. For patients with impaired renal function, dose adjustment is not required. In this study, in one patient (undergoing kidney transplantation, receiving various drugs, including cyclosporine), the total effect of all forms of ezetimibe was increased 12 times.

Patients with liver failure: After a single dose of 10 mg of ezetimibe, the average AUC for all forms of ezetimibe was approximately 1.7 times higher than in patients with mild liver failure (5-6 points on the Child-Pugh scale) compared with healthy participants. In a 14-day study with daily intake of ezetimibe at a dose of 10 mg / day in patients with moderate hepatic insufficiency (7–9 points on the Child-Pugh scale), the average AUC for all forms of ezetimibe was approximately 4 times higher than in healthy subjects (on the 1st and 14th day of the study). In patients with mild liver failure, dose adjustment is not required. Due to the unknown effects of increased exposure to ezetimibe in patients with moderate or significant hepatic insufficiency (> 9 points on the Child-Pugh scale), the use of ezetimibe in these patients is not recommended.

Pediatric patients. The absorption and metabolism of ezetimibe are similar in children, adolescents (10–18 years old), and in adults. Based on data for the total content of ezetimibe, it can be concluded that there are no differences in pharmacokinetics between adults and adolescents. There are no pharmacokinetic data for children under 10 years of age. Clinical experience with the drug in children and adolescents includes patients with homo- or heterozygous familial hypercholesterolemia or sitosterolemia.

Combination therapy with rosuvastatin and ezetimibe

Combined use of 10 mg of rosuvastatin and 10 mg of ezetimibe resulted in a 1.2-fold increase in AUC of rosuvastatin (in patients with hypercholesterolemia). The pharmacodynamic interaction between rosuvastatin and ezetimibe cannot be ruled out with regard to adverse effects.

Indications

Treatment of primary hypercholesterolemia in adults (in addition to a lipid-lowering diet):

with insufficient disease control with monotherapy with rosuvastatin

as a substitute for therapy in patients with sufficient disease control when both substances are taken in combination with the same dose as the fixed combination .

Composition

One capsule 20 mg / 10 mg contains:

active substances: rosuvastatin 20 mg (equivalent to 21.36 mg of rosuvastatin zinc), ezetimibe 10 mg,

excipients: microcrystalline silicon cellulose (microcrystalline cellulose, colloidal silicon dioxide anhydrous), colloidal silicon dioxide anhydrous, magnesium stearalos sodium lanolite, povolitonolone, povoliton , low substitution hydroxypropyl cellulose.

Dosing and Administration

The patient should receive an appropriate lipid-lowering diet and should continue to follow this diet during treatment with Rosulip® Plus.

Combined treatment should only begin after determining the required dose of rosuvastatin or both components of the drug.

Therapy should be individualized based on target lipid levels, the recommended goal of therapy, and response to treatment. When prescribing a dose, the risk of adverse reactions should also be considered.

Dose adjustment can be performed after 4 weeks of therapy.

The recommended daily dose is 1 capsule by mouth, regardless of the meal. Rosulip® Plus is not intended as a first-line lipid-lowering therapy. Rosulip® Plus should be taken at the same time of the day, regardless of the meal. The capsule should be swallowed whole and washed down with water.

Rosulip® Plus Capsules 10 mg / 10 mg and 20 mg / 10 mg are not intended for the treatment of patients who require a dose of 40 mg rosuvastatin.

Rosulip® Plus should be taken for 2 hours before or after 4 hours after taking the sequestrant of bile acids.

Safety and effectiveness of Rosulip® Plus in patients younger than 18 years of age have not been established. Based on the available data, it is impossible to give any recommendations on the dosage regimen in this category of patients.

In patients older than 70 years, the recommended starting dose of rosuvastatin is 5 mg. Rosulip® Plus is not intended as a first-line therapy. Combination therapy should be started only after selecting the appropriate dose of rosuvastatin or both components.

In patients with mild renal impairment, dose adjustment is not required. In patients with moderate impaired renal function (CC <60 ml / min), an initial dose of 5 mg rosuvastatin is recommended. A fixed dose combination is not intended as a first-line therapy. Combination treatment should begin only after selecting the appropriate dose of rosuvastatin or both components. Rosulip® Plus 40 mg / 10 mg is contraindicated in patients with moderate impaired renal function. The use of any dose of rosuvastatin in patients with severe impaired renal function is contraindicated.

In patients with mild hepatic impairment (5-6 Child-Pugh scores), dose adjustment is not required. Rosulip® Plus treatment is not recommended in patients with moderate (7-9 points on the Child-Pugh scale) or severe (> 9 points on the Child-Pugh scale) impaired liver function. Rosulip® Plus is contraindicated in patients with acute liver disease.

Race:

in patients of the Mongoloid race noted an increased systemic effect of rosuvastatin. In patients of East Asian origin, the recommended starting dose of rosuvastatin is 5 mg. A fixed dose combination is not suitable as a first-line therapy. Combination treatment should begin only after selecting the appropriate dose of rosuvastatin or both components. Rosulip® Plus 40 mg / 10 mg is contraindicated in this category of patients.

It is known that with some types of genetic polymorphism, the systemic effect of rosuvastatin increases. In patients with an established presence of certain types of polymorphism, the use of Rosulip® Plus at a lower daily dose is recommended.

The recommended starting dose of rosuvastatin in patients with predisposing factors for the development of myopathy is 5 mg. A fixed dose combination is not intended as a first-line therapy. Combination treatment should begin only after selecting the appropriate dose of rosuvastatin or both components. In some cases, Rosulip® Plus 40 mg / 10 mg is contraindicated in this category of patients.

Concomitant therapy with other drugs:

rosuvastatin is a substrate of various transporter proteins (for example, OATP1B1 and BCRP). While taking Rosulip® Plus and certain medications (for example, cyclosporine and some protease inhibitors, including combinations of ritonavir with atazanavir, lopinavir and / or tipranavir), which can increase plasma concentrations of rosuvastatin as a result of interaction with these proteins -transporters, there is an increase in the risk of myopathy, including rhabdomyolysis. The possibility of alternative therapy and, if required, temporary discontinuation of Rosulip® Plus should be considered. If it is impossible to avoid the simultaneous use of these drugs and Rosulip® Plus, the benefits and risks of such combination therapy should be carefully evaluated and whether dose adjustment of rosuvastatin is necessary.

Side effects

Adverse reactions observed with rosuvastatin are usually transient and have a slight severity. In controlled clinical trials, the discontinuation rate of rosuvastatin due to adverse events was less than 4%.

In clinical studies lasting up to 112 weeks, 2396 patients took ezetimibe 10 mg / day as monotherapy, 11 308 in combination with statin and 185 in combination with fenofibrate. Adverse reactions were usually transient and of minor severity. The overall incidence of side effects was similar in the ezetimibe and placebo groups. The frequency of withdrawal due to adverse events was comparable in the ezetimibe and placebo groups.

According to reports, 1,200 patients took a combination of rosuvastatin and ezetimibe in clinical trials. According to published data, the adverse effects associated with the use of this combination of drugs in patients with hypercholesterolemia include an increase in liver transaminases, gastrointestinal disturbances, and muscle pain. It is known that rosuvastatin, and ezetimibe are capable of causing these adverse events. However, the pharmacodynamic interaction between rosuvastatin and ezetimibe cannot be ruled out with regard to adverse effects.

Determination of the frequency of adverse events:

very often ( 1/10), often ( 1/100, but <1/10), infrequently ( 1/1000, but <1/100), rarely ( 1/10 000, but <1/1000), very rarely (<1/10 000), unknown (cannot be estimated based on available data).

Often

Infrequently Rarely Very rarely Unknown

From the hematopoietic system

thrombocytopenia2 thrombocytopenia5

From the immune system

hypersensitivity reactions, including Quincke's disease2 hypersensitivity (including painful skin, ) 5

From the endocrine system

diabetes mellitus1, 2

Metabolism

decreased appetite 3

Nervous system

headache2.4, dizziness2 paresthesia4 polyneuropathy2,

memory loss2 peripheral neuropathy2

sleep disturbances

(including sleeplessness and somnolence disorders

depression 2.5

From the cardiovascular system

hot flashes 3 arterial hypertension 3

From the respiratory system

cough cough2, shortness of breath 2.5

From the digestive system

constipation 2

nausea 2 b ol in the stomach2, 3

diarrhea3

flatulence3 dyspepsia3 gastroesophageal reflux disease3 nausea3

dry mouth4 gastritis4 pancreatitis2 diarrhea2

pancreatitis5 constipation5

increase in liver or biliary ducts3 indicators of liver function3 increased hepatic transaminases2 jaundice2, hepatitis2 hepatitis5, cholelithiasis5, cholecystitis5

From the skin and subcutaneous tissue

itching 2.4, skin rash 2.4, urticaria 2.4 Stevens-Joe syndrome sona2,

multiforme eritema5

From the musculoskeletal system

mialgiya2, 4 arthralgia 3 muscle cramps 3

neck pain 3 back pain 4 muscle weakness 4

limb pain 4 myopathy and myositis 2 rhabdomyolysis 2 arthralgia2 immuno-mediated necrotizing myopathy 2

side of the reproductive system and mammary gland

gynecomastia2

General reactions

asthenia2

fatigue3 chest pain3 pain3 asthenia4 peripheral edema4 edema2

asthenia5 srdlk p 1 When taking rosuvastatin, the frequency depends on the presence or absence of risk factors (fasting glucose 5.6 mmol / l, BMI> 30 kg / m2, increased triglycerides, a history of hypertension).

2Profile of adverse reactions of rosuvastatin, based on data from clinical studies and widespread post-registration use.

3 Ezetimibe monotherapy. Adverse reactions observed in patients taking ezetimibe (n = 2396), and with a greater frequency than with placebo (n = 1159).

4Ezetimibe when taken with statin. Adverse reactions observed in patients taking ezetimibe and statin (n = 11 308), and with a greater frequency than when taking statin alone (n = 9361).

5 Additional adverse reactions observed with post-registration use of ezetimibe. Since these adverse events were identified on the basis of spontaneous messages, the frequency of these events is not known and cannot be calculated.

As with other HMG-CoA reductase inhibitors, the frequency of adverse drug reactions tends to be dose dependent.

From the urinary system:

in patients treated with rosuvastatin, proteinuria was observed (determined by the rapid method), which was predominantly tubular in nature. A change in proteinuria with - / traces initially up to ++ and more was observed in 1% of patients at any given time when taken in doses of 10 mg and 20 mg and in about 3% of patients when taken in a dose of 40 mg. When taken at a dose of 20 mg, there was a slight increase in degree + proteinuria with an initial level of proteinuria - / traces. In most cases, proteinuria on its own passed or decreased with continued therapy. When analyzing data from clinical trials and the post-registration use of the drug, no causal relationship between proteinuria and acute or progressive kidney disease has been identified to date. In patients treated with rosuvastatin,

hematuria was noted according to clinical studies, the frequency of this phenomenon is low.

From the musculoskeletal system:

in patients receiving rosuvastatin in all doses, especially at doses> 20 mg, an effect on skeletal muscles, for example, myalgia, myopathy (including myositis), and, in rare cases, rhabdomyolysis, with the development of acute renal failure or without it. In patients taking rosuvastatin, a dose-dependent increase in CPK was also noted. Most of these cases were mild - asymptomatic and transient. In case of increase in KFK (> 5 VGN) treatment should be interrupted.

From the liver and biliary tract:

, as with other HMG-CoA reductase inhibitors, a small number of patients taking rosuvastatin showed a dose-dependent increase in transaminases. Most of these cases were mild - asymptomatic and transient.

The frequency of reports of rhabdomyolysis, serious liver disorders (mainly an increase in hepatic transaminases) and kidneys is higher with 40 mg of rosuvastatin.

When using some statins, the following adverse events are possible:

sexual dysfunction

in exceptional cases - interstitial lung disease.

On the part of laboratory indicators:

in controlled clinical trials of monotherapy, the incidence of a clinically significant increase in serum transaminases (ALT and / or AST 3 VGN) was similar in the ezetimibe (0.5%) and placebo (0.3%) groups. In studies of combination drugs, the increase rate was 1.3% in patients taking ezetimibe + statin, and 0.4% in patients taking statin only. These episodes of elevation were usually asymptomatic, not associated with cholestasis, and transaminase values ​​returned to baseline after discontinuation of treatment or against ongoing treatment.

In clinical trials, an increase in CK> 10 VGN was observed in 4 of 1674 (0.2%) patients taking only ezetimibe, in 1 of 786 (0.1%) patients taking placebo, in 1 of 917 patients (0.1%) taking ezetimibe + statin, and in 4 of 929 patients (0.4%), taking only statin. Compared to the corresponding control group (placebo or statin monotherapy), ezetimibe was not associated with an increase in the incidence of myopathy or rhabdomyolysis.

Pediatric Patients

Safety and efficacy of RosulipВ® Plus in individuals under 18 years of age not established.

Rosuvastatin:

in a 52-week clinical study of rosuvastatin, episodes of increased CPK> 10 VGN and symptoms of muscle tissue after exercise or increased activity were more often observed in children and adolescents compared with the frequency in adult patients. Otherwise, the safety profile of rosuvastatin in children and adolescents was similar to that in adults.

ezetimibe:

in a study involving adolescents (10-17 years old) with heterozygous familial hypercholesterolemia (n = 248), episodes of increased ALT and / or AST ( 3 VGN) were noted in 3% of patients (4 people) taking ezetimibe and simvastatin, compared with 2% (2 people) in the simvastatin monotherapy group. As for the increase in KFK 10 VGN, these values ​​were, respectively, 2% (2 people) and 0%. No cases of myopathy were noted. This study was not suitable for comparing rare adverse drug reactions.

Storage conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30 ° C.

Expiration

3 years.

Unused drug or waste should be disposed of in accordance with local regulations.

prescription

prescription

Dosage form

capsules



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