Rosulip Plus, 20 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 during 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 statins 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% of the total plasma concentration of ezetimibe, respectively. 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, membrane cholesterol transporter 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.
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 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

Primary hypercholesterolemia
The drug Rosulip® Plus is indicated in addition to the diet in patients with primary hypercholesterolemia (except for heterozygous familial hypercholesterolemia).
Rosulip® Plus is administered as replacement therapy in patients whose lipid profile was adequately controlled by simultaneous use of individual drugs rosuvastatin and ezetimibe in doses equivalent to the corresponding doses in a fixed combination.

Active ingredient

Rosuvastatin, Ezetimibe

Composition

Ingredients per 1 capsule 5 mg+10 mg, 10 mg+10 mg, 20 mg+10 mg:
Tablet containing rosuvastatin:
Active ingredient: Rosuvastatin zinc (corresponding to rosuvastatin) 5.34 mg (5.00 mg), 10.68 mg (10.00 mg), 21.36 mg (20.00 mg).
Excipients: Microcrystalline silica cellulose* 68.71 mg, 63.33 mg, 126.67 mg; colloidal anhydrous silica 0.06 mg, 0.11 mg, 0.22 mg; magnesium stearate 0.89 mg, 0.88 mg, 1.75 mg.
* – Composition of microcrystalline cellulose: microcrystalline cellulose 98.0%, colloidal anhydrous silica 2.0%.
Tablet containing 10 mg of ezetimibe:
Active ingredient: Ezetimibe 10.00 mg.
Excipients: povidone K-25 5.00 mg, croscarmellose sodium 19.00 mg, microcrystalline cellulose 30.30 mg, mannitol 30.30 mg, sodium lauryl sulfate 4.40 mg, hyprolose 10.00 mg, magnesium stearate 1.00 mg.
Solid gelatin capsule (CONI-SNAP 0):** about 96.00 mg.
**- Solid gelatin capsule composition (CONI-SNAP 0) 10 mg+10 mg, 20 mg+10 mg, capsule base/capsule cap:
Dye iron oxide red (E172) -/-, -/0.16%; dye iron oxide yellow (E172) 0.18%/0.18%, 0.18%/0.30%; titanium dioxide (E171) 1.00%/1.00%, 1.00%/1.30%; gelatin to 100%/to 100%, to 100%/to 100%, respectively.
Contents of hard gelatin capsules (CONI-SNAP 0) 5 mg+10 mg, base of capsule/capsule lid:
Dye iron oxide yellow (E172) -/0.18%; titanium dioxide (E171) 2.00%/1.00%; gelatin to 100%/ up to 100%.

How to take, the dosage

Patients should be on an appropriate diet that lowers the concentration of lipids in the blood (hypocholesterolemic diet). During the treatment with the drug Rosulip® Plus patients should continue this diet.
The recommended daily dose is 1 capsule Rosulip® Plus.
The drug Rosulip® Plus is not intended for initial therapy.
Rosulip® Plus is administered to patients whose lipid profile was adequately controlled by concomitant use of individual drugs rosuvastatin and ezetimibe in doses equivalent to the corresponding doses in the fixed combination.
Treatment with the combination drug can be started only after establishing the necessary doses of monocomponents. When the dose is changed, titration with monocomponents is also necessary. After titration of the dose, you can switch to treatment with the appropriate drug with fixed doses.
The drug is for oral administration.
Rosulip® Plus should be taken once a day at the same time of the day, regardless of the time of meals.
Capsules should be swallowed whole with water.
Rosulip® Plus 5 mg/10 mg, 10 mg/10 mg and 20 mg/10 mg capsules are not suitable for the treatment of patients who require a 40 mg dose of rosuvastatin.
Rosulip® Plus should be taken 2 hours or more before or 4 hours or more after taking bile acid excretion medications.
Special patient populations
Children and adolescents under 18 years
The efficacy and safety of Rosulip® Plus in children and adolescents under 18 years of age has not yet been established. The currently available data are presented in sections “Side effects”, “Pharmacodynamics” and “Pharmacokinetics”, however, based on these data no recommendations for dosing regimen can be made.
Older patients
In elderly patients over 70 years the recommended starting dose of rosuvastatin is 5 mg. The combination drug Rosulip® Plus is not suitable for initial therapy. Doses of both monocomponents should be preselected before initiating treatment with the combination drug or changing its dose.
Patients with impaired renal function
In patients with renal failure of mild or moderate severity (CKR less than 60 ml/min) dose adjustment is not required.Rosulip® Plus combination drug is not suitable for initial course of therapy. Doses of both monocomponents should be preselected before initiating treatment with the combination drug or changing its dose.
In patients with severe renal impairment (CK less than 30 ml/min) the use of any doses of rosuvastatin is contraindicated.
Patients with impaired liver function
Rosulip® Plus is contraindicated in patients with active liver disease (see section Contraindications). There is no need to change the dose in patients with mild hepatic impairment (Child-Pugh score 5-6). Treatment with Rosulip® Plus is not recommended in patients with moderate hepatic impairment (Child-Pugh scores 7-9) and severe hepatic impairment (Child-Pugh score >9).
Ethnic groups
In patients of Asian origin increased systemic effect of rosuvastatin was noted (see sections Cautionary Instructions and Pharmacokinetics). In patients of Asian origin the recommended starting dose of rosuvastatin is 5 mg. A fixed dose combination is not suitable as first-line therapy. Combination treatment should be started or the dose of the drug should be changed only after selection of suitable doses of both monocomponents.
Genetic polymorphisms
Some types of genetic polymorphisms are known to increase the systemic effects of rosuvastatin (see section Pharmacokinetics). A lower daily dose of Rosulip® Plus is recommended in patients with the established presence of certain types of polymorphisms.
Patients with predisposition to myopathy
The recommended starting dose of rosuvastatin for this group of patients is 5 mg (see section Specific information). The combined drug may be administered or its dose changed only after appropriate selection of doses of both monocomponents.
Concomitant therapy
Rosuvastatin is a substrate of various transport proteins (in particular with OATP1B1 and BCRP). When co-administration of Rosulip®Plus with certain drugs (such as cyclosporine, some human immunodeficiency virus (HIV) protease inhibitors, including the combination of ritonavir with atazanavir, lopinavir and/or tipranavir) that increase the plasma concentration of rosuvastatin due to interaction with transport proteins, the risk of myopathy (including rhabdomyolysis) may increase (see sect. See sections Cautionary Note and Interaction with other medicinal products). In such cases, the possibility of prescribing alternative therapy or temporary discontinuation of Rosulip® Plus should be assessed. If the use of the above mentioned drugs and Rosulip®Plus is necessary, the benefit-risk ratio of concomitant therapy and rosuvastatin should be assessed and the possibility of reducing its dose should be considered (see section Interaction with other medicinal products).

Interaction

Contraindications
Cyclosporine:In concomitant use of rosuvastatin and cyclosporine the AUC values of rosuvastatin were on average 7 times higher compared to the values in healthy volunteers. This combination does not affect the plasma concentrations of cyclosporine.
Co-administration of Rosulip® Plus and cyclosporine is contraindicated.
In a study of eight kidney transplant patients with CK>50 mL/min while taking a steady dose of cyclosporine, a single administration of 10 mg of ezetimibe resulted in a 3.4-fold (2.3 to 7.9-fold) increase in the mean AUC of ezetimibe compared to the AUC in a healthy population from another study (control) that received ezetimibe alone (n=17). In another study, a patient after a kidney transplant, with severe renal failure, was receiving cyclosporine and many other medications. This patient had a 12-fold increase in systemic exposure to ezetimibe compared to control participants who were taking ezetimibe alone. In a two-stage cross-over study of twelve healthy participants, daily administration of 20 mg of ezetimibe for 8 days + a single daily administration of 100 mg of cyclosporine resulted in an average 15% increase in cyclosporine AUC (range: 10% decrease to 51% increase) compared to a single administration of 100 mg of cyclosporine alone. Controlled studies of the effect of co-administration of ezetimibe and cyclosporine on the effects of the latter in patients after kidney transplantation have not been conducted.
Not recommended combinations
Protease inhibitors: Although the exact mechanism of interaction is unknown, concomitant use of protease inhibitors may result in a significant increase in systemic exposure to rosuvastatin (see table). For example, in a pharmacokinetics study, co-administration of 10 mg rosuvastatin and a combined preparation of two protease inhibitors (atazanavir 300 mg + ritonavir 100 mg) in healthy volunteers was associated with an approximately three-fold increase in AUC of rosuvastatin and approximately seven-fold increase in Cmax. Concomitant use of rosuvastatin and certain protease inhibitor combinations is possible only after careful evaluation of rosuvastatin doses, adjusted based on the expected increase in rosuvastatin exposure. This dose combination is not suitable as first-line therapy. Combination therapy should be initiated only after a suitable dosage of rosuvastatin or both components has been selected.
Transporter protein inhibitors: Rosuvastatin is a substrate of several transporter proteins, including the liver cell capture transporter OATP1B1 and the excretion transporter BCRP. Concomitant use of Rosulip® Plus and drugs that inhibit these transporter proteins may lead to increased plasma concentrations of rosuvastatin and increased risk of myopathy.
Gemfibrozil and other hypolipidemic agents: co-administration of rosuvastatin and gemfibrozil leads to a 2-fold increase in Cmax and AUC of rosuvastatin (see section “Caution”). Based on the data on specific interaction, no pharmacokinetic interaction with fenofibrate is expected, pharmacodynamic interaction is possible.
Hemfibrozil, fenofibrate, other fibrates and lipid-lowering doses of niacin (nicotinic acid 1 g/day or higher) increased the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors, possibly due to the fact that they can cause myopathy when used in monotherapy.
Physicians should be aware that patients taking ezetimibe and fenofibrate are at risk of gallstone disease and gallbladder disease. If a patient taking ezetimibe and fenofibrate is suspected of developing cholestasis, an examination of the gallbladder is indicated as well as discontinuation of this therapy. Concomitant administration of fenofibrate and gemfibrozil increased total concentrations of ezetimibe (approximately 1.5 and 1.7 times, respectively). Co-administration of ezetimibe with other fibrates has not been studied. Fibrates can increase cholesterol excretion with bile, which leads to cholelithiasis. In animal studies, ezetimibe sometimes (not in all animal species) led to increased cholesterol concentrations in gallbladder bile. It cannot be excluded that therapeutic use of ezetimibe is associated with the risk of gallstone disease.
Fusidic acid:
Systemic use of fusidic acid together with statins may increase the risk of myopathy, including rhabdomyolysis. The mechanism of this interaction (whether it is pharmacodynamic and/or pharmacokinetic) is not yet known. Cases of rhabdomyolysis (in some cases fatal) have been reported in patients treated with such combinations. If treatment with fusidic acid is necessary, statins should be cancelled during the entire period of treatment with fusidic acid (see section Cautionary Instructions).
Other interactions
Antacids: Concomitant use of rosuvastatin and antacid suspensions containing aluminum and magnesium hydroxide leads to a decrease in plasma concentration of rosuvastatin by approximately 50%. This effect is weaker if antacids are used 2 hours after rosuvastatin administration. The clinical significance of this interaction has not been studied.
Erythromycin: Concomitant use of rosuvastatin and erythromycin leads to decrease of AUC of rosuvastatin by 20% and Cmax of rosuvastatin by 30%. This interaction may result from increased intestinal motility caused by erythromycin.
Cytochrome P450 isoenzymes: the results of in-vivo and in-vitro studies showed that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. In addition, rosuvastatin is a weak substrate for these isoenzymes. Therefore, no interaction of rosuvastatin with other drugs (drugs) at the level of metabolism involving cytochrome P450 isoenzymes is expected.
No clinically significant interaction of rosuvastatin with fluconazole (inhibitor of CYP2C9 and CYP3A4 isoenzymes) and ketoconazole (inhibitor of CYP2A6 and CYP3A4 isoenzymes) was noted.
In preclinical studies it was shown that ezetimibe does not induce cytochrome P450 enzymes that metabolize drugs. No clinically significant pharmacokinetic interactions between ezetimibe and drugs metabolized by cytochrome P450: 1A2, 2D6, 2C8, 2C9, 3A4 – or N-acetyltransferase
Vitamin K antagonists were noted: As with other HMG-CoA reductase inhibitors, starting or increasing the dose of rosuvastatin in patients simultaneously taking vitamin K antagonists (heparin or other coumarin anticoagulants) may increase the international normalized ratio (INR). Discontinuation or reduction of the dose of rosuvastatin may lead to a decrease in INR. Appropriate INR monitoring is desirable in such situations.
Administration of ezetimibe (10 mg once daily) did not affect warfarin bioavailability or prothrombin time, as was shown in a study of twelve healthy adult men. There are, however, reports of increased international normalized ratio, in patients when ezetimibe is added to warfarin or fluindione administration. If Rosulip® Plus is added to the administration of warfarin, another coumarin anticoagulant or fluindione, the INR should be monitored accordingly (see section Cautionary Note).
Oral contraceptives and hormone replacement therapy (HRT): Concomitant use of rosuvastatin and oral contraceptives increased the AUC of ethinylestradiol and norgestrel by 26% and 34%, respectively. This increase in plasma drug levels should be considered when selecting doses of oral contraceptives. No pharmacokinetic data are available for concomitant administration of rosuvastatin and ZGT, and therefore a similar interaction cannot be excluded. Nevertheless, this combination has been well studied in clinical studies in women and was well tolerated.
In clinical studies of drug interactions, ezetimibe did not affect the pharmacokinetics of oral contraceptives that included ethinylestradiol and levonorgestrel.
Cholestyramine: Concomitant use of cholestyramine reduced the average area under the pharmacokinetic curve (AUC) of the sum of ezetimibe and its glucuronide by approximately 55%. This interaction may prevent consistent reduction of low-density lipoprotein cholesterol (LDL-C) when adding ezetimibe to cholestyramine therapy (see section Dosage and administration).
Statins: No clinically significant pharmacokinetic interactions were noted when co-administering ezetimibe with atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin or rosuvastatin.
Other medicinal products: Based on data obtained in studies of drug interactions, no clinically significant interaction is expected between rosuvastatin and digoxin.
In clinical studies of drug interactions ezetimibe did not affect the pharmacokinetics of dapsone, dextromethorphan, digoxin, glipizide, tolbutamide or midazolam. Cimetidine when taken together with ezetimibe had no effect on the bioavailability of the latter.
Interactions with drugs that require dose adjustment of rosuvastatin (see Table 3)
When co-administration of rosuvastatin and other drugs that increase the systemic effect of rosuvastatin is required, the dose of the latter must be adjusted. If the expected increase in exposure (AUC) is 2-fold or higher, start rosuvastatin at a dose of 5 mg/day. The maximum daily dose of rosuvastatin should also be adjusted so that the expected systemic effect of rosuvastatin does not exceed that of the 40 mg dose taken without concomitant administration of drugs interacting with rosuvastatin. For example, the maximum daily dose of rosuvastatin when concomitantly administered with gemfibrozil is 20 mg (1.9-fold increase in exposure), with ritonavir/atazanavir is 10 mg (3.1-fold increase in exposure).

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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*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

Effects on skeletal muscles
In patients treated with all doses of rosuvastatin, and especially with doses >20 mg, effects of the drug on skeletal muscles were noted: e.g., development of myalgia, myopathy and (rarely) rhabdomyolysis. As with the use of other HMG-CoA reductase inhibitors, the incidence of rhabdomyolysis in post-registration use of rosuvastatin is higher when taking the dose of 40 mg.
In the post-registration period when using ezetimibe there were cases of myopathy and rhabdomyolysis. Rhabdomyolysis has very rarely been reported with both ezetimibe monotherapy and with the addition of ezetimibe to other drugs associated with an increased risk of rhabdomyolysis. If myopathy is suspected (based on muscle symptoms or increased CPK activity), ezetimibe, all statins, and any medications for which an association with increased rhabdomyolysis has been established should be stopped immediately. All patients should be warned of the risk of myopathy at the start of treatment and promptly report any episodes of unexplained muscle pain, muscle soreness or weakness (see side effects).
Liver effects
In controlled trials with co-administration of ezetimibe and statins, consistent increases in transaminases (≥3 BHN) were noted.
It is recommended to determine liver function before the start of treatment and 3 months after the start of therapy with rosuvastatin. Rosuvastatin should be discontinued or the dose should be reduced if serum transaminase activity is > 3xVH. The incidence of serious hepatic events (predominantly – increased transaminase activity) in post-registration use is more frequently observed at a dose of 40 mg rosuvastatin.
In patients with secondary hypercholesterolemia caused by hypothyroidism or nephrotic syndrome, treatment of the underlying disease is required before initiation of therapy with Rosulip® Plus.
Due to the unknown effects of increased exposure to ezetimibe in patients with moderate or severe hepatic impairment, the use of Rosulip® Plus is not recommended in these patients (see section Pharmacokinetics).
Action on the kidneys
Proteinuria detected by rapid testing, predominantly of a tubular nature, has been observed in patients treated with increased doses of rosuvastatin, particularly the 40 mg dose. In most cases, proteinuria was transient or intermittent. Proteinuria has not been found to signal the development of acute or progressive renal disease (see section Adverse effects). In the post-registration period, serious adverse renal reactions were more frequently observed with the 40 mg dose. When monitoring patients taking a dose of 40 mg, the need to monitor renal function should be considered (at least every 3 months).
Determination of creatine phosphokinase activity
CPK activity should not be determined after vigorous exercise or in the presence of other probable causes for elevated CPK activity, which may complicate interpretation of results.
If a significant increase in CPK activity (>5 VGN) is initially noted, a repeat measurement should be performed in 5-7 days. If the repeated measurement will confirm that CPK activity is >5 VGN, the treatment should not be started.
Fusidic acid
Rosulip® Plus capsules should not be used together with fusidic acid for systemic use or within 7 days after discontinuation of fusidic acid treatment. In patients who require treatment with fusidic acid, rosuvastatin should be withdrawn for the duration of treatment. Rhabdomyolysis (in some cases fatal) has been reported in patients co-treated with rosuvastatin and fusidic acid (see section Interaction with other medicinal products). Patients should be informed that they should immediately consult a physician if muscle weakness, pain or sensitivity develops.
Seven days after the last dose of fusidic acid, treatment with rosuvastatin may be started again.
In exceptional cases where prolonged treatment with fusidic acid is necessary, e.g. in severe infections, the decision on whether to combine fusidic acid and Rosulip® Plus must be made on an individual basis, weighing the potential risk of therapy against the possible benefit with careful monitoring of the patient.

Before treatment
Rosulip® Plus, like other drugs containing HMG CoA reductase inhibitors, should be prescribed with caution in patients with factors predisposing to the development of myopathy or rhabdomyolysis:
– Renal insufficiency;
– Hypothyroidism;
– Hereditary muscle disease in a personal or family history;
– Muscle toxicity with another HMG-CoA inhibitor or fibrate;
– Alcohol abuse;
– Age >70 years;
– Situations in which plasma levels of active substances may increase (see section “Pharmacokinetics”).
– Concurrent use of fibrates.
In such patients the risk and possible benefit of treatment should be assessed and clinical monitoring is recommended. Treatment should not be initiated if there is a significant baseline increase in CPK activity (>5 VGN).
During treatment
Patients should be asked to immediately report cases of unexplained muscle pain, weakness or muscle cramps, especially if such cases are accompanied by general weakness or fever. CPK activity should be measured in these patients. Treatment should be discontinued if there is a marked increase in CPK activity (>5 VGN) or if there are severe symptoms that cause daily discomfort (even if CPK activity is £5 VGN). Standard monitoring of CPK activity in patients without any symptoms is not required.
There are very rare reports of immune-mediated necrotizing myopathy during or after treatment with statins, including rosuvastatin. Clinically, this disease is characterized by proximal muscle weakness and elevated serum CPK activity that persists despite statin withdrawal.
No evidence of increased skeletal muscle action in a small number of patients concomitantly taking rosuvastatin and other hypolipidemic agents has been reported in clinical trials. Increased incidence of myositis and myopathy was noted in patients concomitantly taking other HMG-CoA reductase inhibitors and fibric acid derivatives (including gemfibrozil), cyclosporine, nicotinic acid, azole antifungal agents, protease inhibitors or macrolide antibiotics. Gemfibrozil increases the risk of myopathy when coadministered with some HMG-CoA reductase inhibitors. Therefore, the combination of Rosulip® Plus and gemfibrozil is not recommended. The benefits of further reductions in lipid levels when combining Rosulip® Plus and fibrates or niacin should be carefully compared with the possible risks of this combination of drugs.
Rosulip® Plus should not be used in patients with serious acute conditions in which myopathy is likely to occur or which predispose to renal failure due to rhabdomyolysis (e.g., sepsis, arterial hypotension, extensive surgery, trauma, severe metabolic, endocrine or electrolyte balance disorders, uncontrolled convulsions).
Ethnicity of patients
Studies of pharmacokinetics of rosuvastatin have shown an increased effect of the drug in patients of Asian origin compared to patients of European origin (see Sections Dosage and administration.
Protease inhibitors
An increased systemic effect of rosuvastatin was noted in patients who simultaneously took rosuvastatin and various protease inhibitors in combination with ritonavir. Both the lipid-lowering benefits of Rosulip® Plus in HIV-infected patients receiving protease inhibitors and the possibility of increased plasma concentrations of rosuvastatin at initiation and during dose titration of rosuvastatin should be considered. Co-administration of the drug with some protease inhibitors is recommended only with dose adjustment of Rosulip® Plus (see sections Dosage and administration and Pharmacokinetics).
Interstitial lung disease
In exceptional cases when taking some statins, especially during long-term therapy, the development of interstitial lung disease has been reported. Symptoms of such diseases include a non-productive cough and deterioration in general health (fatigue, weight loss, and fever). If a patient is suspected of developing interstitial lung disease, statin therapy should be discontinued.
Diabetes mellitus
Some data suggest that statin class drugs increase blood glucose concentrations and, in some patients at high risk of developing diabetes mellitus, may lead to hyperglycemia, a level that meets the formal definition of diabetes mellitus and requires initiation of antidiabetic therapy. This risk, however, is outweighed by the reduction in vascular risk with statins, and therefore should not be a reason to discontinue statin therapy. In patients at risk (fasting glucose concentration – 5,6-6,9 μmol/l, BMI >30 kg/m2, increased TG concentration, AH) clinical and biochemical monitoring of diabetes should be performed in accordance with national guidelines.
In the JUPITER study, the overall incidence of diabetes mellitus was reported as 2.8% in the rosuvastatin group and 2.3% in the placebo group (primarily in patients with a fasting glucose concentration of 5.6-6.9 mmol/L).
Fibrates
Safety and effectiveness of co-administration of ezetimibe and fibrates have not been established. If a patient taking Rosulip® Plus and fenofibrate is suspected to have cholestasis, a gallbladder examination should be performed and this therapy should be stopped (see sections Interaction with other medicinal products and Adverse effects).
Anticoagulants
If Rosulip® Plus is added to therapy with warfarin, other coumarin anticoagulants or fluindion, appropriate monitoring of the international normalized ratio ((INR) is required; see section Interaction with other drugs.
Cyclosporine:
See Contraindications and Interaction with Other Drugs.
Pediatric Patients
The safety and effectiveness of Rosulip® Plus in persons under 18 years of age has not yet been established and therefore the use of the drug in this age group is not recommended.
Liver disease and alcohol consumption
Rosulip® Plus should be used with caution in patients with excessive alcohol consumption and/or with a history of liver disease.

Effect on driving and operating machinery
No studies have been conducted to assess the effect of Rosulip® Plus on the ability to drive vehicles and operate machinery, but it should be noted that dizziness may occur during treatment.

Synopsis

20 mg+10 mg capsules: Solid gelatin capsules CONI-SNAP 0, unlabeled, self-closing, yellow base and cap light brown with pinkish tinge. Each capsule contains two tablets.

Contraindications

– Hypersensitivity to rosuvastatin, ezetimibe or any of the components/supplements in the drug;
– Liver disease in the active phase, including persistent increase in serum transaminase activity and any increase in serum transaminase activity (> 3 upper limit of normal (GGN);
– Moderate and severe degree of liver failure (7-9 points or more according to the Child-Pugh scale);
– Simultaneous use of cyclosporine;
– In women: Pregnancy, breastfeeding period, lack of reliable contraceptive methods in women with preserved reproductive function;
– Severe renal dysfunction (CK < 30 ml/min);
– Myopathy;
– Predisposition to develop myotoxic complications;
– Children and adolescents under 18 years.

With caution
Risk of myopathy/rhabdomyolysis – renal insufficiency, hypothyroidism, personal or family history of hereditary muscle disease and previous history of muscle toxicity with other HMG-CoA reductase inhibitors or fibrates; excessive alcohol consumption; age over 65 years; conditions with increased plasma concentrations of rosuvastatin; race (Asian race); concomitant administration with fibrates (see
Caution should be exercised when concomitant use with indirect anticoagulants (including warfarin and fluindione). Patients taking ezetimibe and fenofibrate concomitantly should be aware of the possible risk of gallbladder disease.
Children and adolescents
The efficacy and safety of Rosulip® Plus in children under 18 years of age has not yet been established, so the use of this drug is not recommended in patients in this age group.
Patients with hepatic impairment
No data or experience with the drug in patients with a Child-Pugh score above 9 (see sections Pharmacodynamics and Precautions).

Side effects

Safety Profile Summary
Adverse reactions observed when taking rosuvastatin are usually mild and go away on their own. According to data from controlled clinical trials less than 4% of patients receiving rosuvastatin dropped out of studies due to the development of adverse reactions.
In clinical trials lasting up to 112 weeks 2396 patients received ezetimibe at a dose of 10 mg daily as monotherapy, 11 308 patients – in combination with statins and 185 patients – in combination with fenofibrate. The adverse reactions were moderate and reversible. Overall incidence of adverse effects as well as % of patients dropped out of the study due to adverse reactions were similar in the groups receiving ezetimibe and placebo.
According to available data, in clinical trials 1200 patients received combined treatment with rosuvastatin and ezetimibe. According to the literature, in patients with hypercholesterolemia the most frequent adverse events associated with the combination rosuvastatin + ezetimibe were increased hepatic transaminases, gastrointestinal disturbances and muscle pain. These are known side effects for these active agents. However, in terms of side effects, a pharmacodynamic interaction between rosuvastatin and ezetimibe cannot be completely excluded.
Tabular list of adverse reactions
The frequency of adverse events is as follows:
Frequent (> 1/100, < 1/10); Infrequent (> 1/1000, < 1/100); Rare (> 1/10 000, < 1/1 000); Very rare (< 1/10 000), Frequency unknown (cannot be determined from available data).

1Dlarosuvastatin, frequency depends on the presence or absence of risk factors (fasting glucose concentration ≥5.6 mmol/L, body mass index (BMI)>30 kg/m2, increased TG concentration, history of arterial hypertension (AH)).
2The profile of adverse reactions for rosuvastatin based on data from clinical trials and extensive post-registration use.
3Adverse reactions during ezetimibe monotherapy. (n=2396), were more frequent than with placebo (n=1159).
4 Adverse reactions with ezetimibe combined with statins (n=11308), were more frequent than with statins alone (N=9361).
5 Additional adverse reactions with ezetimibe in the post-registration period. Since these adverse events have been identified based on spontaneous reports, the incidence of these events is unknown and cannot be calculated.
As with other HMG-CoA reductase inhibitors, the incidence of adverse drug reactions tends to be dose dependent.

Action on the kidneys: In patients treated with rosuvastatin the appearance of proteinuria determined by rapid method and predominantly of tubular nature was noted. A change in proteinuria from “-/trace” at baseline to “++” or greater was observed in <1% of patients at some time during doses of 10 and 20 mg and in approximately 3% of patients during doses of 40 mg. At the 20 mg dose, some increase in grade "+" proteinuria with a background proteinuria level of "-/trace" was noted. In most cases, proteinuria passed on its own or decreased with continued therapy. Analysis of data from clinical trials and post-registration use of the drug to date has not revealed a causal association between proteinuria and acute or progressive renal disease.
The occurrence of hematuria has been noted in patients treated with rosuvastatin. Data from clinical studies show a low frequency of this phenomenon.
Effects on skeletal muscle:In patients treated with all doses of rosuvastatin, especially doses >20 mg per day, skeletal muscle effects such as myalgias, myopathy (including myositis) and, in rare cases, rhabdomyolysis, with or without the development of acute renal failure were noted. A dose-dependent increase in CPK activity was also observed in patients taking rosuvastatin. Most of these cases were of low severity: asymptomatic and transient. In case of increased CPK activity (>5 VGH) treatment should be discontinued.
Liver effects: As with the use of other HMG-CoA reductase inhibitors, a small number of patients taking rosuvastatin had dose-dependent increase in transaminase activity. Most of these cases were of low severity: asymptomatic and transient.
With the use of some statins the following adverse events were noted:
– Disorders of sexual function
– In exceptional cases – interstitial lung disease (especially with prolonged therapy.
Frequent reports of rhabdomyolysis, serious hepatic disorders (mainly increased liver transaminase activity) and renal disorders when taking 40 mg of rosuvastatin per day.
Hyperglycemia and increased concentration of glycosylated hemoglobin were also reported.
Laboratory parameters
In controlled clinical trials of monotherapy the frequency of clinically significant increase of serum transaminases activity (ALT and/or AST ≥3 VGN) was similar in ezetimibe (0.5%) and placebo groups (0.3%). In drug combination studies, the frequency of elevations was 1.3% in patients taking ezetimibe + statin and 0.4% in patients taking statin alone. These elevation episodes were usually asymptomatic, were not associated with cholestasis, and transaminase activity values returned to baseline values after discontinuation of treatment or with continued treatment (see section “Special Precautions”).
In clinical trials, increased CPK >10 VGH activity was noted in 4 of 1674 (0.2%) patients taking ezetimibe alone, in 1 of 786 (0.1%) patients receiving placebo, in 1 of 917 patients (0.1%) taking ezetimibe + statin, and in 4 of 929 patients (0.4%) taking statin alone. Compared with the corresponding control group (placebo or statin monotherapy), ezetimibe administration was not associated with an increased incidence of myopathy or rhabdomyolysis.
Pediatric patients
Safety and efficacy of Rosulip® Plus in persons under 18 years of age have not been established (see section Pharmacodynamics).
Rosuvastatin:
In a 52-week clinical trial of rosuvastatin, episodes of increased CPK >10 HGH activity and muscle tissue symptoms after exercise were more frequently noted 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:
Children and adolescents aged 6 to 17 years
In a study involving children aged 6 to 10 years with hereditary heterozygous or nonhereditary hypercholesterolemia (n = 138), an increase in AST and/or ALT activity (≥3X VGN) was observed in 1.1% of patients (1 patient) who received ezetimibe and 0% who received placebo. No increase in CPK activity (≥10 VGN) or cases of myopathy were observed,
In a separate study involving adolescents (10-17 years) with heterozygous familial hypercholesterolemia (n = 248), episodes of increased ALT and/or AST (≥3 VGN) were noted in 3% of patients (4 individuals) receiving ezetimibe and simvastatin, compared with 2% (2 individuals) in the simvastatin monotherapy group. Regarding elevations of CPK ≥10 VGN, these values were 2% (2 persons) and 0%, respectively. No cases of myopathy were noted.
These studies were not suitable for comparing rare adverse drug reactions.
Reporting suspected adverse reactions
Reporting suspected adverse drug reactions is very important to allow continuous monitoring of the risk/benefit ratio of the drug. Healthcare professionals should provide information on any suspected adverse reactions to the contacts listed at the end of the instructions and through the national information collection system.

Overdose

There are no data on rosuvastatin overdose in the literature.
There is no specific therapy in case of rosuvastatin overdose.
In clinical trials, administration of ezetimibe at a dose of 50 mg/day to 15 healthy participants for up to 14 days or at a dose of 40 mg/day to 18 patients with primary hypercholesterolemia for up to 56 days was generally well tolerated. No toxicity was noted in animals after a single oral dose of ezetimibe (5000 mg/kg in rats and mice and 3000 mg/kg in dogs).
Several cases of ezetimibe overdose have been reported: they were generally not associated with the development of adverse events. The reported adverse events were not serious.
In cases of overdose, symptomatic and supportive therapy should be given. Liver function and CPK activity should be monitored. Hemodialysis benefit is unlikely.

Pregnancy use

Rosulip® Plus is contraindicated in pregnancy and during breastfeeding.
Women of reproductive age should use reliable methods of contraception.
Pregnancy
Since CHF and CHF biosynthesis products are important for fetal development, the potential risk of HMG-CoA reductase inhibition exceeds the benefits of the drug in pregnant women.
If pregnancy is diagnosed during therapy, the drug should be stopped immediately.
There are no clinical data on the use of ezetimibe during pregnancy.
Studies of ezetimibe in animals have shown no direct or indirect adverse effects on pregnancy, embryo/fetal development, labor and postnatal development. No teratogenic effects were observed when ezetimibe was administered to pregnant rats in combination with lovastatin, simvastatin, pravastatin or atorvastatin. When administered to pregnant rabbits, fetal skeletal development defects were observed with low frequency.
There are no clinical data on the use of ezetimibe in pregnancy, so caution should be exercised when prescribing the drug to pregnant women. In case of pregnancy the drug should be discontinued.
Breast-feeding
In studies on rats it was found that ezetimibe is excreted with milk. There are no data on excretion of rosuvastatin and ezetimibe with breast milk in women, therefore during breastfeeding the drug should be discontinued (see section Contraindications).
Fertility
There are no clinical data on the effect of ezetimibe on human fertility. Ezetimibe has no effect on fertility of male and female rats.

Similarities

Zeno