Rosulip Plus, 10 mg+10 mg capsules 30 pcs

Pharmacotherapeutic group:Hypolipidemic combined agent (HMG-CoA reductase inhibitor+cholesterol absorption inhibitor)
ATC code: C10BA06

Pharmacological properties
Mechanism of action
Rosuvastatin
Rosuvastatin is a selective, competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the enzyme that converts HMG-CoA to mevalonate, a precursor of cholesterol (CH). The main target of rosuvastatin action is the liver, where the synthesis of cholesterol and catabolism of low-density lipoproteins (LDL) take place.
Rosuvastatin increases the number of “hepatic” LDL receptors on the cell surface, increasing capture and catabolism of LDL, which in turn leads to inhibition of synthesis of very low density lipoproteins (VLDL), thus reducing the total amount of LDL and VLDL.
Ezetimibe
Ezetimibe is a representative of a new class of hypolipidemic agents that selectively inhibit the absorption of CH and some plant sterols in the intestine.
Pharmacodynamics
Rosuvastatin
Rosuvastatin reduces elevated concentrations of LDL-C, total cholesterol and triglycerides (TG), increases concentrations of high-density lipoprotein cholesterol (HDL-C) and decreases concentrations of apolipoprotein B (Apo B), low-density lipoprotein cholesterol (Non-LDL), HDL-C, TG-LDL-C, and increases apolipoprotein A-I concentration (Apo A-I) (see Tables 1 and 2). Table 1 and 2), decreases HC-LDL/ChC-LDL, total cholesterol/ChC-LDL and non-CLDL/ChC-LDL and Apo B/Apo A-I ratio.
Therapeutic effect is developed within one week after the treatment start. Within 2 weeks of therapy the efficacy reaches a level that is 90% of the maximum possible. The maximum therapeutic effect is usually reached by the 4th week of therapy and is maintained with regular use of the drug.

Table 1. Dose-dependent effect in patients with primary hypercholesterolemia (type ΙΙa and ΙΙb by Fredrickson classification) (mean adjusted percentage change from baseline).

Table 2. Dose-dependent effect in patients with hypertriglyceridemia (type ΙΙb and ΙV according to Fredrickson classification) (mean percentage change from baseline).

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Clinical effectiveness
Rosuvastatin is effective in adult patients with hypercholesterolemia with or without hypertriglyceridemia, regardless of race, sex or age, including patients with diabetes and familial hypercholesterolemia.
In 80% of patients with hypercholesterolemia of IIa and IIb types by Fredrickson classification (average baseline concentration of cholesterol-LDL is about 4.8 mmole/l) during the drug therapy in dose 10 mg cholesterol-LDL concentration reaches values less than 3 mmole/l.
In patients with homozygous familial hypercholesterolemia taking rosuvastatin at the doses of 20 mg and 40 mg the mean decrease of LDL-C concentration is 22%.
Patients with hypertriglyceridemia with initial TG concentrations of 273 to 817 mg/dL who received rosuvastatin at doses of 5 mg to 40 mg once daily for 6 weeks had significantly reduced plasma TG concentrations (see Table 2).
Additive effect is observed in combination with fenofibrate for TG concentration and with nicotinic acid at lipid-lowering doses for HDL-C concentration (see also section Cautionary Note).

Ezetimibe
Ezetimibe is effective when taken orally. Mechanism of action of ezetimibe differs from the mechanism of action of other classes of hypolipidemic agents (for example, HMG-CoA reductase inhibitors (statins), bile acid sequestrants, fibrates and plant statins). Molecular target of ezetimibe is Niemann-Pick C1-Like1 (NPC1-L1) transport protein, responsible for intestinal absorption of cholesterol and phytosterols.
ezetimibe is localized in small intestine brush border and prevents cholesterol absorption that leads to decrease of intestinal cholesterol reaching liver and due to this decrease of cholesterol reserve in liver and increase of phytosterol excretion from blood. Ezetimibe does not increase bile acid excretion (unlike bile acid sequestrants) and does not inhibit HC synthesis in the liver (unlike statins).
Statins reduce the synthesis of cholesterol in the liver. When used simultaneously, the drugs of these two groups provide additional reduction of cholesterol concentrations.
Ezetimibe used simultaneously with statins reduces the concentration of total cholesterol, LDL-C, apoB, non-HDL-C and TG, and increases plasma HDL-C concentration in patients with hypercholesterolemia to a greater extent than ezetimibe or statin used in monotherapy. Concomitant use of ezetimibe with fenofibrate reduces concentrations of total cholesterol, LDL-C, apoB, TG and non-HDL-C (calculated as the difference between total and HDL-C concentrations), and increases plasma HDL-C concentration in patients with hypercholesterolemia to a greater extent than ezetimibe or statin used in monotherapy.
Simultaneous use of ezetimibe with fenofibrate reduces end concentrations of total cholesterol, LDL-C, apo B, TG and non-HDL-C, and increases plasma HDL-C concentrations in patients with mixed hypercholesterolemia.
Clinical studies have shown that elevated concentrations of total cholesterol, LDL-C and apoB (the main protein component of LDL) contribute to the development of atherosclerosis. In addition, a decreased concentration of HDL-C is associated with the development of atherosclerosis. The results of epidemiological studies have shown that cardiovascular morbidity and mortality are directly related to the concentrations of total cholesterol and LDL-C and inversely related to HDL-C concentrations. Like LDL, lipoproteins rich in cholesterol and TG, including HDL, intermediate density lipoproteins (IDL) and remnants, may also contribute to atherosclerosis.
A series of preclinical studies were conducted to determine the selectivity of ezetimibe with regard to inhibiting cholesterol absorption.
Ezetimibe inhibited [14C]-CB absorption and had no effect on absorption of TGs, fatty acids, bile acids, progesterone, ethinylestradiol, or fat-soluble vitamins A and D.
Co-administration of rosuvastatin and ezetimibe
Adding ezetimibe to a stable dose of 5 mg or 10 mg of rosuvastatin resulted in a more pronounced decrease in LDL-C concentration compared with doubling the dose of rosuvastatin to 10 mg or 20 mg.Ezetimibe + rosuvastatin 5 mg lowered LDL-C concentration more than rosuvastatin 10 mg.
The efficacy and safety of rosuvastatin 40 mg in monotherapy and in combination with ezetimibe 10 mg in patients with high risk of coronary heart disease (CHD) were studied. Significantly more patients who received the combination rosuvastatin + ezetimibe, compared with rosuvastatin 40 mg monotherapy, achieved the target level of LDL-C concentration.Rosuvastatin 40 mg effectively improved the atherogenic lipid profile in this group of high-risk patients.
Children and adolescents
The European Medicines Agency has granted permission not to present the results of clinical trials of the combination rosuvastatin + ezetimibe in all age subgroups of children and adolescents in the treatment of elevated CHD concentrations (see

Pharmacokinetics
Absorption and distribution
Rosuvastatin
Maximum plasma concentration of rosuvastatin (Cmax) is reached approximately 5 hours after oral administration. Absolute bioavailability is approximately 20%.
Rosuvastatin is metabolized primarily by the liver, which is the main site of CH synthesis and metabolism of LDL-C. The volume of distribution (Vd) of rosuvastatin is approximately 134 liters. Approximately 90% of rosuvastatin is bound to plasma proteins, mainly to albumin.
Ezetimibe
After oral administration ezetimibe is rapidly absorbed and extensively metabolized in the small intestine and liver by conjugation into pharmacologically active phenolic glucoronide (ezetimibe-glucuronide). Cmax of ezetimibe-glucuronide is observed after 1-2 hours, of ezetimibe after 4-12 hours. Absolute bioavailability of ezetimibe cannot be determined since the substance is virtually insoluble in none of the aqueous solvents used for preparation of solutions for injection.
Food intake (low- or high-fat) did not affect the bioavailability of ezetimibe when taken orally as 10 mg tablets. Ezetimibe can be used regardless of meal times.
Ezetimibe and ezetimibe-glucuronide bind to plasma proteins by 99.7% and 88-92%, respectively.
Concomitant use of rosuvastatin at a dose of 10 mg and ezetimibe at a dose of 10 mg was accompanied by an increase in the area under the “concentration-time” curve (AUC) of rosuvastatin in patients with hypercholesterolemia (see Table 3).
Metabolism
Rosuvastatin
Subjected to limited metabolism (about 10%). Rosuvastatin is a non-core substrate for metabolism by isoenzymes of cytochrome P450 system. The main isoenzyme involved in metabolism of rosuvastatin is CYP2C9 isoenzyme. CYP2C19, CYP3A4 and CYP2D6 isoenzymes are less involved in metabolism.
The main identified metabolites of rosuvastatin are N-desmethyl and lactone metabolites. N-desmethyl is approximately 50% less active than rosuvastatin; lactone metabolites are pharmacologically inactive. More than 90% of pharmacological activity for inhibition of circulating HMG-CoA reductase is provided by rosuvastatin, the rest by its metabolites.
Ezetimibe
Metabolism of ezetimibe occurs primarily in the small intestine and liver by conjugation with glucuronide (phase II reaction) with subsequent excretion in the bile. Ezetimibe undergoes minimal oxidative metabolism (phase I reaction). Ezetimibe and ezetimibe-glucuronide (the main plasma derivatives of ezetimibe) constitute 10-20% and 80-90%, respectively, of the total plasma concentration of ezetimibe. Ezetimibe and ezetimibe-glucuronide are slowly eliminated from plasma by intestinal-hepatic recirculation. The half-life (T½) for ezetimibe and ezetimibe-glucuronide is approximately 22 hours.
Excretion
Rosuvastatin
About 90% of the dose of rosuvastatin is excreted unchanged through the intestine (including absorbed and unabsorbed rosuvastatin). The remainder is excreted by the kidneys. Plasma T1/2 is approximately 19 hours. The T1/2 does not change with increasing drug dose. Mean geometric plasma clearance is approximately 50 L/hour (coefficient of variation 21.7%). As in the case of other HMG-CoA reductase inhibitors, the membrane carrier of cholesterol is involved in “hepatic” uptake of rosuvastatin, which plays an important role in hepatic elimination of rosuvastatin.
Linearity
Systemic exposure of rosuvastatin increases in proportion to the dose. Pharmacokinetic parameters do not change with daily administration.
Ezetimibe
After oral administration of 20 mg of 14C-labeled ezetimibe, 93% of total ezetimibe (ezetimibe + ezetimibe-glucuronide) was detected in plasma of total radioactive product levels. Within 10 days, approximately 78% of the radioactive products ingested were excreted through the intestine with the bile, and 11% through the kidneys. After 48 hours no radioactive products were detected in blood plasma.
Pharmacokinetics in special groups of patients
Age and sex
Rosulip® Plus is contraindicated in children and adolescents under 18 years.
Gender and age have no clinically significant effect on the pharmacokinetics of rosuvastatin.
Pharmacokinetic parameters of ezetimibe were similar in children over 6 years old and adults. There are no pharmacokinetic data for children younger than 6 years.
In elderly patients (over 65 years) the plasma concentration of total ezetimibe is about 2 times higher than in young patients (18 to 45 years). The degree of reduction of LDL-C concentration and safety profile were comparable in elderly and younger patients receiving ezetimibe. No dose adjustment is required for elderly patients.
The plasma concentration of total ezetimibe is slightly higher in women (less than 20%) than in men. The degree of reduction of LDL-C concentration and safety profile are the same in men and women taking ezetimibe. Therefore, no dose adjustment is required for male or female patients.
Ethnic groups
Pharmacokinetic studies have shown approximately two-fold increase in median area under the curve “concentration-time” (AUC) and Cmax of rosuvastatin in Asian patients (Japanese, Chinese, Filipinos, Vietnamese and Koreans) compared to Europeans; in Indian patients a 1.3-fold increase in median AUC and Cmax was shown. Pharmacokinetic analysis revealed no clinically significant differences in pharmacokinetics among Europeans and members of the Negro race.
Renal insufficiency
In patients with mild to moderately severe renal insufficiency the plasma concentration of rosuvastatin or N-desmethyl does not change significantly. In patients with severe renal insufficiency (creatinine clearance (CK) < 30 ml/min) the plasma concentration of rosuvastatin is 3 times higher and that of N-desmethyl is 9 times higher than in healthy volunteers. Plasma concentration of rosuvastatin in patients on hemodialysis was approximately 50% higher than in healthy volunteers.
After a single dose of ezetimibe 10 mg in patients with severe renal dysfunction (n=8; IQ less than 30 ml/min/1.73 m2), the AUC value of total ezetimibe was increased approximately 1.5-fold compared to healthy volunteers (n=9). This result is not clinically significant. No dose adjustment is required for patients with impaired renal function.
In a patient after kidney transplantation who received complex therapy, including cyclosporine, the AUC of total ezetimibe increased 12-fold.
Liver failure
In patients with various stages of liver failure (with Child-Pugh score 7 and below) no increase in T1/2 of rosuvastatin was found. Two patients with Child-Pugh scores 8 and 9 showed at least 2-fold increase of T1/2. There is no experience of using rosuvastatin in patients with a Child-Pugh score above 9.
After a single dose of 10 mg ezetimibe, the mean AUC of total ezetimibe was 1.7 times greater in patients with mild hepatic impairment (Child-Pugh score 5-6) than in healthy volunteers. In a 14-day study of the use of ezetimibe at a dose of 10 mg per day involving patients with a moderate degree of liver failure (7-9 Child-Pugh scores), the mean AUC of total ezetimibe was increased 4-fold on days 1 and 14 compared with healthy volunteers.
No dose adjustment is required for patients with mild hepatic impairment. Since the consequences of increasing AUC value of total ezetimibe are unknown, ezetimibe is not recommended for patients with moderate to severe (more than 9 points by Child-Pugh scale) hepatic insufficiency (see section Caution).
Genetic polymorphisms
HMG-CoA reductase inhibitors, including rosuvastatin, bind to the transport proteins OATP1B1 (organic anion transport polypeptide involved in statin uptake by hepatocytes) and BCRP (efflux transporter). Carriers of SLCO1B1 (OATP1B1) c.521CC and ABCG2 (BCRP) c.421AA genotypes had 1.6 and 2.4-fold increased exposure (AUC) to rosuvastatin, respectively, compared with carriers of SLCO1B1 c.521T and ABCG2 c.421CC genotypes.

Indications

Active ingredient

Composition

How to take, the dosage

Interaction

Table 3.

The effect of concomitant therapy on exposure to rosuvastatin (AUC, data are given in descending order) – results of published clinical trials

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Dosing regimen of the drug with which rosuvastatin interacts

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Dosing regimen .

rosuvastatin

Change in AUC of rosuvastatin*

Cyclosporine 75-200 mg 2 times/day, 6 months

10 mg once daily, 10 days

7.1 times ↑

Regorafenib 160 mg, once daily, 14 days

5 mg, once

3.8 times ↑

Atazanavir 300 mg + ritonavir 100 mg once daily, 8 days

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10 mg, once

3.1 times ↑

Lopinavir 400 mg + ritonavir 100 mg 2 times/day, 17 days

20 mg once daily, 7 days

2.1 times ↑

Simeprevir 150 mg 1 time/day, 7 days

10 mg once

2.8 times ↑

Elbasvir 50 mg +grazoprevir 200 mg once daily

10 mg once

2.26 times ↑**

Grazoprevir 200 mg once daily

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10 mg once

1.59 times ↑**

Clopidogrel 300 mg once and 75 mg 24 hours later

20 mg, once

2 times ↑

Gemfibrozil 600 mg 2 times/day, 7 days

80 mg, once

1.9 times ↑

Eltrombopag 75 mg once daily, 10 days

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10 mg, once

1.6 times ↑

Darunavir 600 mg + ritonavir 100 mg 2 times/day, 7 days

10 mg once daily, 7 days

1.5 times ↑

Tipranavir 500 mg + ritonavir 200 mg 2 times/day, 11 days

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10 mg, once

1.4 times ↑

Dronendarone 400 mg 2 times/day

No data

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1.4 times ↑

Itraconazole 200 mg once daily, 5 days

10 mg, once

1.4 times ↑***

Fosamprenavir 700 mg + ritonavir 100 mg 2 times/day, 8 days

10 mg, once

↔

Aleglitazavir 0.3 mg, 7 days

40 mg, 7 days

↔

Silymarin 140 mg 3 times/day, 5 days

10 mg, once

Fenofibrate 67 mg 3 times/day, 7 days

10 mg, 7 days

↔

Rifampin 450 mg once daily, 7 days

20 mg, once

↔

Ketoconazole 200 mg 2 times/day, 7 days

80 mg, once

↔

Fluconazole 200 mg once daily, 11 days

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80 mg, once

↔

Erythromycin 500 mg 4 times/day, 7 days

Erythromycin 500 mg 4 times/day, 7 days/p>

80 mg, once

28% ↓

Baicalin 50 mg 3 times/day, 14 days

20 mg, once

47% ↓

*The data given as x-fold change is the ratio of AUC when taking a combination of drugs and rosuvastatin alone. Data given as % are the % difference relative to taking rosuvastatin alone.

↑ – increase, ↔ – no change, ↓ – decrease

** When co-administered with elbasvir or grazoprevir, daily dose of rosuvastatin should not exceed 10 mg.

***Few interaction studies have been performed with other doses of rosuvastatin; the table shows the most significant change in AUC.

Special Instructions

Synopsis

Contraindications

Side effects

Organ System Classes, MedDRA

Frequently

Infrequent

Rarely

very rarely

Unknown

Blood and lymphatic system disorders

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thrombocytopenia2

thrombocytopenia5

immune system disorders

sensitivity reactions, including Quincke’s edema2

Hypersensitivity (including skin rash, urticaria, anaphylaxis, and Quincke’s edema) 5

Endocrine disorders

system

diabetes mellitus

sup>1, 2

Metabolism and nutrition disorders

decreased appetite3

Mental disorders

depression2.5

Disorderson the nervous system

headache2,4,

dizziness2

paresthesia4

polyneuropathy2,

loss

memory2

peripheral neuropathy2

sleep disturbances (including insomnia and nightmares)2

dizziness5; paresthesia5

vascular disorders

vessels

tides3; increased blood pressure3

Disorders of the

respiratory system,

increased hepatic transaminase activity2

jaundice2 , hepatitis2

hepatitis5,

cholecitiasis5, cholecystitis5,

Skin and subcutaneous tissue disorders

itchy skin2.4, skin rash2.4,

urticaria2.4

Stevens-Johnson syndrome2

erythema multiforme5

Muscle and connective tissue disorders

Skeletal and connective tissue

myalgia2,4

arthralgia3; muscle spasms3;

Neck pain3

back pain4; muscle weakness4; pain in extremities4

myopathy (including myositis) 2, rhabdo-myolysis2

arthralgia2

immune-mediated necrotizing myopathy2,

dry tendon lesions, sometimes with rupture2,

myalgia5; myopathy and rhabdomyolysis5

Kidney and urinary tract disorders

hematuria2

Reproductive and mammary gland disorders

gynecomastia2

General disorders and disorders at the injection site

asthenia2

fatigue3

thoracic pain3,

pain3

asthenia4;

peripheral edema4

peripheral edema2

asthenia5

Effect on laboratory and instrumental results

studies

Increased alanine-nontransferase (ALT) activity and/or

aspartate

amino-transferase (AST)4.

increased ALT and/or AST3 activity;

creatine phosphokinase (CPK)3;

γ-glutamyl transferase (GGT)3;

deviations in biochemical measures of liver function3

Overdose

Pregnancy use

Similarities