Rosulip Plus capsules 20mg+10mg, 30pcs

Composition

One 20 mg/10 mg capsule contains: active ingredients: rosuvastatin 20 mg (equivalent to 21.36 mg of rosuvastatin zinc), ezetimibe 10 mg, excipients: microcrystalline silicon cellulose (microcrystalline cellulose, colloidal anhydrous silicon dioxide), colloidal anhydrous silicon dioxide, magnesium stearate, povidone, sodium croscarmellose, mannitol, sodium lauryl sulfate, hydroxypropylcellulose with a low degree of substitution.

Pharmacological action

Rosuvastatin The maximum plasma concentration of rosuvastatin is reached approximately 5 hours after oral use. Absolute bioavailability is about 20%. Rosuvastatin is absorbed mainly by the liver, where the main synthesis of cholesterol and the elimination of LDL-C occurs. The volume of distribution of rosuvastatin is approximately 134 liters. Approximately 90% of rosuvastatin binds to plasma proteins, mainly albumin. Rosuvastatin is only slightly metabolized (about 10%). Rosuvastatin is a non-core substrate for cytochrome P450 isoenzymes. The main enzyme involved in rosuvastatin metabolism 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, and lactone derivatives are pharmacologically inactive. Rosuvastatin suppresses the activity of more than 90% of the circulating HMG-CoA reductase. Approximately 90% of the rosuvastatin dose is excreted unchanged in faeces (including absorbed and non-absorbed rosuvastatin). The remainder of the dose is excreted in the urine. About 5% of the drug dose is excreted unchanged in the urine. The half-life of the drug from the blood plasma is approximately 19 hours. The half-life does not change with increasing dose of the drug. The average geometric plasma clearance is approximately 50 liters / hour (coefficient of variation 21.7%). Similarly to other HMG-CoA reductase inhibitors, rosuvastatin’s hepatic uptake involves a membrane protein called organic anion transporter type C (OATP-C), 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: There was no clinically significant effect of age and gender on the pharmacokinetic properties of rosuvastatin. The pharmacokinetics of rosuvastatin in children and adolescents with familial heterozygous hypercholesterolemia were similar to those of adults. Race: The results of pharmacokinetic studies indicate that in comparison with people of the Caucasian race, in people of the Asian race (Japanese, Chinese, Filipino, Vietnamese and Korean), the average area under the curve “concentration-time” (AUC) and the maximum concentration of the drug in blood plasma (Cmax) are approximately 2 times higher. For Indians, these indicators are approximately 1.3 times higher than for people of the Caucasian race. Analysis of population pharmacokinetics revealed no clinically significant differences in the pharmacokinetic parameters of rosuvastatin between Caucasian and black people. Patients with impaired renal function. Mild or moderate renal impairment did not affect the plasma concentrations of rosuvastatin or the N-desmethyl metabolite. In patients with severe renal impairment (creatinine clearance In patients receiving hemodialysis, the plasma concentration of rosuvastatin at steady state was 50% higher than in healthy patients. Patients with hepatic insufficiency: In patients with varying degrees of hepatic insufficiency, there were no data on increased exposure to rosuvastatin in individuals with a value of less than 7 points on the Child-Pugh scale. However,2 participants with Child-Pugh scores of 8 and 9 had at least a twofold increase in systemic exposure to rosuvastatin compared to participants with lower Child-Pugh scores. There is no experience of using rosuvastatin in individuals with a Child-Pugh score of more than 9. Genetic polymorphism. The transport proteins OATP1B1 and BCRP are involved in the elimination of HMG-CoA reductase inhibitors, including rosuvastatin. Patients with the genetic polymorphism SLCO1B1 (OATP1B1) and / or ABCG2 (BCRP) are at risk of increased exposure to rosuvastatin. Individual polymorphisms of SLCO1B1 c. 521CC and ABCG2 c. 421AA are characterized by a 1.7-fold and 2.4-fold increase in rosuvastatin exposure (AUC), respectively, compared to the genotypes SLCO1B1 c. 521TT and ABCG2 c. 421CC. Children’s patients. The pharmacokinetic parameters of rosuvastatin in children aged 10-17 years with heterozygous hereditary hypercholesterolemia are not fully characterized. A small study of the pharmacokinetics of rosuvastatin in 18 children showed that the effects of rosuvastatin in paediatric patients appear to be similar to those in adults. In addition, the results of the study show that no significant deviations from the dose dependence are expected. Ezetimibe After oral use, ezetimibe is rapidly absorbed and largely conjugated to form the pharmacologically active phenolic glucuronide, ezetimibe glucuronide. Mean values of the maximum concentration of ezetimibe in plasma (Cmax) are observed 1-2 hours and 4-12 hours after use, respectively, for ezetimibe glucuronide and ezetimibe. The absolute bioavailability of ezetimibe cannot be determined, as it is practically insoluble in aqueous media suitable for injection. Concomitant intake of high-fat and low-fat foods does not affect the bioavailability of ezetimibe after oral use. Ezetimibe can be taken regardless of food intake. The binding of ezetimibe and its glucuronide to plasma proteins is 99.7% and 88-92%, respectively. Ezetimibe is primarily metabolized in the small intestine and liver, via glucuronidation (a phase II reaction) and subsequent biliary excretion. All the studied species showed minimal oxidative metabolism of ezetimibe (phase I reaction). Ezetimibe and ezetimibe-glucuronide, the main derivatives of the drug, account for 10-20% and 80-90% of the total drug content in blood plasma, respectively. Ezetimibe and ezetimibe-glucuronide are slowly eliminated from the blood plasma during enterohepatic recirculation. The half-lives of ezetimibe and ezetimibe glucuronide are approximately 22 hours. Age and gender of patients: In patients over 65 years of age, the concentration of total ezetimibe in blood plasma is approximately 2 times higher than in patients aged 18-45 years. The level of LDL-C reduction and safety profiles in older and younger patients taking ezetimibe are approximately the same. Therefore, no dose adjustment is required for elderly patients. The total concentration of ezetimibe is approximately 20% higher in women than in men. LDL-C reduction rates 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 insufficiency: After a single oral dose of ezetimibe 10 mg in patients with severe renal insufficiency ( creatinine clearance < 30 ml/min), the mean AUC value increased 1.5-fold compared to healthy participants. This result is not considered clinically significant. No dose adjustment is required for patients with impaired renal function. In this study, in one patient (a kidney transplant recipient who received various medications, including cyclosporine) overall exposure to all forms of ezetimibe was increased 12-fold. Patients with hepatic insufficiency: After a single dose of 10 mg ezetimibe, the mean AUC for all forms of ezetimibe was approximately 1.7 times higher than in patients with mild hepatic insufficiency (Child-Pugh score 5-6) compared to healthy participants. In a 14-day study with ezetimibe administered daily at a dose of 10 mg/day in patients with moderate hepatic insufficiency (Child-Pugh score 7-9), the mean AUC for all forms of ezetimibe was approximately 4 times higher compared to healthy participants (on days 1 and 14 of the study). No dose adjustment is required in patients with mild hepatic insufficiency. 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 such patients is not recommended. Children’s patients. The absorption and metabolism of ezetimibe are similar in children, adolescents (10-18 years) and adults. Based on the data for the total ezetimibe content, it can be concluded that there are no differences in pharmacokinetics between adults and adolescents. Pharmacokinetic data for children under 10 years of age are not available. 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 Co-use of 10 mg of rosuvastatin and 10 mg of ezetimibe resulted in a 1.2-fold increase in rosuvastatin AUC (in patients with hypercholesterolemia). A pharmacodynamic interaction between rosuvastatin and ezetimibe with respect to adverse effects cannot be excluded.

Indications

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

• if there is insufficient disease control with rosuvastatin monotherapy;
• as a substitute for therapy in patients with sufficient disease control when both substances are taken together in the same doses as the fixed combination.

Contraindications

• Avicenna sensitivity to rosuvastatin, ezetimibe or auxiliary substances;
• active liver disease, including persistent elevations of serum transaminases of unknown origin or any increase in the activity of serum transaminases more than 3 times the ULN;
• severe impairment of renal function (QC 30 ml/min);
• myopathy;
• the simultaneous use of cyclosporine;
• pregnancy;
• lactation (breastfeeding);
• women of childbearing age not using contraception;
• Rosulip® Plus 40 mg/10 mg is contraindicated in patients with predisposing factors to the development of myopathy or rhabdomyolysis, including:

Side effects

Adverse reactions reported with rosuvastatin are usually transient and mild in severity. In controlled clinical trials, the frequency of withdrawal of rosuvastatin due to adverse events was less than 4%.

In clinical trials lasting up to 112 weeks,2,396 patients received ezetimibe 10 mg/day as monotherapy,11,308 in combination with a statin, and 185 in combination with fenofibrate. Adverse reactions were usually transient and mild. The overall incidence of side effects was similar in the ezetimibe and placebo groups. The frequency of discontinuation due to adverse events was comparable in the ezetimibe and placebo groups.

An estimated 1,200 patients received a combination of rosuvastatin and ezetimibe in clinical trials. According to published data, adverse events associated with the use of this combination of drugs in patients with hypercholesterolemia include increased liver transaminases, gastrointestinal disorders and muscle pain. Both rosuvastatin and ezetimibe are known to cause these adverse events. However, a pharmacodynamic interaction between rosuvastatin and ezetimibe with respect to adverse effects cannot be excluded.

Determining the frequency of adverse events:

• very common (≥1/10), common (≥1/100, but <1/10), infrequent (≥1/1000, but <1/100), rare (≥1/10 000, but <1/1000), very rare (

1 When taking rosuvastatin frequency depends on the presence or absence of risk factors (fasting glucose ≥5.6 mmol/l, BMI >30 kg/m 2, increased levels of triglycerides, hypertension in anamnesis).

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

3 Ezetimibe monotherapy. Adverse reactions reported in patients treated with ezetimibe (n=2396) and with a higher frequency than with placebo (n=1159).

4 Ezetimibe when co-administered with a statin. Adverse reactions reported in patients taking ezetimibe and statin (n=11,308), and with a higher frequency than with statin alone (n=9,361).

5 Additional adverse reactions reported with post-marketing use of ezetimibe. Since these adverse events are identified on the basis of spontaneous reports, 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 express method), which was mainly tubular in nature.A change in proteinuria from” –/ – “initially to” ++ ” or more was observed in 1% of patients at some point in time when taking doses of 10 mg and 20 mg and in approximately 3% of patients when taking a dose of 40 mg. When taken at a dose of 20 mg, there was a slight increase in proteinuria of the ” + “degree with an initial level of proteinuria of”–/ -“. In most cases, proteinuria passed on its own or decreased with continued therapy. When analyzing data from clinical trials and post-marketing use of the drug, no causal relationship between proteinuria and acute or progressive kidney disease has been revealed to date. Hematuria has been reported in patients treated with rosuvastatin;
• according to clinical studies, the incidence of this phenomenon is low.

Musculoskeletal disorders:

• in patients treated with rosuvastatin at all doses, especially at doses >20 mg, effects on skeletal muscles were noted, for example, myalgia, myopathy (including myositis) and, in rare cases, rhabdomyolysis, with or without acute renal failure. A dose-dependent increase in CPK was also observed in patients taking rosuvastatin. Most of these cases were of minor severity-asymptomatic and transient. If CPK increases (>5 ULN), treatment should be discontinued.

Liver and biliary tract disorders:

• As with other HMG-CoA reductase inhibitors, a small number of patients treated with rosuvastatin showed a dose-dependent increase in transaminases. Most of these cases were of minor severity-asymptomatic and transient.

The frequency of reports of rhabdomyolysis, serious liver disorders (mainly increased hepatic transaminases) and kidneys is higher when taking 40 mg of rosuvastatin.

When using some statins, the following adverse events may occur::

• sexual dysfunction;
• in exceptional cases – interstitial lung diseases.

From the side of laboratory parameters:

• In controlled monotherapy trials, the incidence of clinically significant increases in serum transaminases (ALT and/or AST > 3 ULN) was similar in the ezetimibe (0.5%) and placebo (0.3%) groups. In drug combination studies, the rate of increase 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 values returned to baseline after discontinuation of treatment or during ongoing treatment.

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

Children’s patients

Safety and efficacy of Rosulip® Plus numbers for people under 18 years of age are not established.

Rosuvastatin:

• In a 52-week clinical trial of rosuvastatin, episodes of increased CPK >10 ULN and muscle tissue symptoms after exercise or increased activity were more common in children and adolescents than in adults. 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 elevated ALT and / or AST (≥3 ULN) were observed 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 CPK ≥ 10 ULN, these values were 2% (2 people) and 0%, respectively. No cases of myopathy were reported. This study was not suitable for comparing rare adverse drug reactions.

Interaction

Combinations are contraindicated

When rosuvastatin and cyclosporine were co-administered, the AUC values of rosuvastatin were, on average,7 times higher than in healthy volunteers. This combination does not affect the concentration of cyclosporine in plasma. Simultaneous use of Rosulip® Plus, cyclosporine is contraindicated.

In a study conducted in 8 kidney transplant patients with creatinine clearance>50 ml / min at a constant dose of cyclosporine, a single dose of ezetimibe at a dose of 10 mg resulted in an increase in the average ezetimibe AUC by 3.4 times (2.3 to 7.9 times) compared to the AUC in a healthy population from another study (control) receiving ezetimibe alone (n=17). In another study, a kidney transplant patient with severe renal failure was treated with cyclosporine and a number of other medications. This patient experienced a 12-fold increase in total ezetimibe exposure compared to control participants taking ezetimibe alone. In a two-step cross-sectional study of 12 healthy participants, a daily dose of 20 mg ezetimibe for 8 days + a single dose of 100 mg cyclosporine on day 7 resulted in an increase in cyclosporine AUC, on average, by 15% (range of values:

• from a decrease of 10% to an increase of 51%) compared to a single dose of cyclosporine alone at a dose of 100 mg. No controlled studies have been conducted on the effect of co-use of ezetimibe and cyclosporine on the effects of the latter in patients after kidney transplantation.

Concomitant use of rosuvastatin at a dose of 40 mg and fibrate is contraindicated.

Not recommended combinations

Although the exact mechanism of interaction is unknown, concomitant use of protease inhibitors can significantly increase the systemic exposure of rosuvastatin. For example, in a pharmacokinetic study, co-use of 10 mg of rosuvastatin and a combination drug of two protease inhibitors (atazanavir 300 mg + ritonavir 100 mg) in healthy volunteers was associated with an increase in rosuvastatin AUC approximately 3-fold, and_cmax approximately 7-fold. Concomitant use of rosuvastatin and certain combinations of protease inhibitors is possible only after careful evaluation of rosuvastatin doses adjusted based on the expected increase in rosuvastatin exposure. This combination of doses is not intended as a first-line therapy. Combined treatment should be initiated only after selecting an adequate dose of rosuvastatin or both components.

Rosuvastatin is a substrate for some carrier proteins, including the liver cell uptake transporter OATP1B1 and the BCRP excretory transporter. Simultaneous use of the drug Rozulip® The use of drugs that inhibit these transporter proteins may lead to increased plasma concentrations of rosuvastatin and an increased risk of myopathy.

Co-use of rosuvastatin and gemfibrozil resulted in a 2-fold increase in_cmax and AUC of rosuvastatin. Based on data obtained in specific interaction studies, no pharmacokinetically significant interaction with fenofibrate is expected, although a pharmacodynamic interaction is possible.

Gemfibrozil, fenofibrate, other fibrates and niacin (nicotinic acid) in hypolipidemic doses (1 g / day and above) they increase the risk of developing myopathy when used together with HMG-CoA reductase inhibitors. This is probably due to the fact that these drugs can also cause myopathy with monotherapy.

Doctors should be aware that patients taking ezetimibe and fenofibrate are at risk of developing gallstones and gallbladder diseases. If cholestasis is suspected in a patient receiving ezetimibe and fenofibrate, an examination of the gallbladder is indicated, as well as discontinuation of this therapy. Simultaneous use of fenofibrate and gemfibrozil increased the total concentrations of ezetimibe (approximately 1.5 and 1.7 times, respectively). Co-use of ezetimibe with other fibrates has not been studied. Fibrates can increase the excretion of cholesterol in the bile, which leads to cholelithiasis. In animal studies, ezetimibe sometimes (not in all animal species) led to an increase in cholesterol concentrations in the gallbladder bile. It cannot be excluded that the therapeutic use of ezetimibe is associated with the risk of developing cholelithiasis.

Interaction studies between rosuvastatin and fusidic acid have not been conducted. In the post-marketing period, when rosuvastatin and fusidic acid were taken together, muscle tissue disorders were reported, including the development of rhabdomyolysis (similar to the use of fusidic acid with other statins).

Therefore, the simultaneous use of rosuvastatin and fusidic acid is not recommended, and if the use of such a combination cannot be avoided, careful monitoring of the patient’s condition is necessary. If possible, rosuvastatin therapy should be suspended.

Other types of interaction

Concomitant use of rosuvastatin and an antacid suspension containing magnesium and aluminum hydroxides resulted in a decrease in plasma concentrations of rosuvastatin by approximately 50%. This effect was reduced by taking an antacid 2 hours after taking rosuvastatin. The clinical significance of this interaction has not been investigated.

Concomitant use of an antacid reduced the rate of absorption of ezetimibe, but did not affect the bioavailability of ezetimibe. This decrease in the rate of absorption is not considered clinically significant.

Co-use of rosuvastatin and erythromycin resultedin a 20% decrease in rosuvastatin 0-t AUCand a 30% decrease in rosuvastatin cmax. This interaction may be explained by the fact that erythromycin stimulates intestinal motility.

The results of in vitro and in vivo studies show that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. In addition, rosuvastatin is practically no substrate for these isoenzymes. Therefore, no drug interaction is expected to occur as a result of CYP3A4-mediated metabolism. There was no clinically significant interaction between rosuvastatin and fluconazole (a CYP2C9 and CYP3A4 inhibitor) or ketoconazole (a CYP2A6 and CYP3A4 inhibitor).

In preclinical studies, ezetimibe has not been shown to induce the drug-metabolizing cytochrome P450 isoenzymes. There was no clinically significant pharmacokinetic interaction between ezetimibe and drugs metabolized by CYP1A2, CYP2D6, CYP2C8, CYP2C9, CYP3A4 or N-acetyltransferase isoenzymes.

Vitamin K antagonists As with other HMG-CoA reductase inhibitors, starting or increasing the dose of rosuvastatin in patients receiving vitamin K antagonists at the same time (heparin or other coumarin anticoagulants) may lead to an increase in INR. Discontinuation or reduction of the rosuvastatin dose may result in a decrease in INR. In such situations, appropriate monitoring of INR is desirable.

Ezetimibe intake (10 mg 1 time / day) It did not affect the bioavailability of warfarin or prothrombin time, as was shown in a study conducted in 12 healthy adult men. However, there have been reports of increased INR in patients when ezetimibe is added to warfarin or fluindione. If Rosulip® If warfarin, another coumarin anticoagulant, or fluindione is added to the intake, INR should be monitored accordingly.

Oral contraceptives and hormone replacement therapy (HRT). Concomitant use of rosuvastatin and oral contraceptives resulted in a 26% and 34% increase in the AUC of ethinyl estradiol and norgestrel, respectively. This increase in the concentration of drugs in plasma should be taken into account when selecting doses of oral contraceptives. There are no pharmacokinetic data for concomitant use of rosuvastatin and HRT, so a similar interaction cannot be excluded. However, this combination is well studied in clinical studies in women, and is characterized by good tolerability.

In clinical drug interaction studies, ezetimibe did not affect the pharmacokinetics of oral contraceptives including ethinyl estradiol and levonorgestrel.

When co-administered with colestyramine, the average AUC of ezetimibe and its glucuronide decreased by approximately 55%. This interaction may prevent a consistent reduction in LDL-C when ezetimibe is added to colestyramine therapy.

No clinically significant pharmacokinetic interactions were observed when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin or rosuvastatin.

Other medicinal products

Based on data obtained in drug interaction studies, no clinically significant interaction between rosuvastatin and digoxin is expected.

In clinical drug interaction studies, ezetimibe did not affect the pharmacokinetics of dapsone, dextromethorphan, digoxin, glipizide, tolbutamide, or midazolam. Cimetidine when taken together with ezetimibe did not affect the bioavailability of the latter.

Interactions requiring dose adjustment of rosuvastatin

When co-use of rosuvastatin and other drugs that increase the systemic effect of rosuvastatin is required, dose adjustment of the latter is necessary. If the expected increase in exposure (AUC) is 2 times or higher, rosuvastatin is started at a dose of 5 mg/day. The maximum daily dose should be adjusted so that the expected systemic effect of rosuvastatin does not exceed that of rosuvastatin at a dose of 40 mg/day – without interacting drugs, at a dose of 20 mg/day – when taking rosuvastatin together with gemfibrozil (an increase of 1.9 times) and at a dose of 10 mg/day – when taken together with a combination of atazanavir and ritonavir (an increase of 3.1 times).

Table 2. Effect of concomitant use of other medications on total rosuvastatin exposure (AUC; descending interaction value), from published clinical trials

* The data given as a change of x times is the ratio of AUC when taking a combination of drugs and rosuvastatin alone. The data given as% is the percentage difference relative to the intake of rosuvastatin alone.

↑ – increase, ↔ – no changes, ↓ – decrease.

**Several interaction studies were also conducted with other dosages of rosuvastatin, the table shows the most significant change in AUC.

How to take it, course of use and dosage

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

Combination treatment should be initiated only after determining the required dose of rosuvastatin or both components of the drug.

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

Dose adjustment can be made after 4 weeks of therapy.

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

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

Rosulip® Plus should be taken ≥2 hours before or ≥4 hours after taking bile acid sequestrant.

Safety and efficacy of Rosulip® The data for patients under 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 over 70 years of age, the recommended starting dose of rosuvastatin is 5 mg. The drug Rozulip® Plus is not intended as a first-line therapy. Combination therapy should be initiated only after selecting the appropriate dose of rosuvastatin or both components.

No dose adjustment is required in patients with mild renal impairment. In patients with moderate renal impairment (CC An initial dose of rosuvastatin of 5 mg is recommended. A fixed dose combination is not intended as a first-line therapy. Combined treatment should be initiated only after selecting the appropriate dose of rosuvastatin or both components. Rosulip® Plus 40 mg / 10 mg is contraindicated in patients with moderate renal impairment. The use of any dose of rosuvastatin in patients with severe renal impairment is contraindicated.

In patients with mild hepatic impairment (Child-Pugh score 5-6) no dose adjustment is required. Rosulip®Treatment Plus 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 diseases.

Racial background:

• Increased systemic exposure to rosuvastatin has been reported in Mongoloid patients. 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. Combined treatment should be initiated 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 in some types of genetic polymorphism, the systemic effect of rosuvastatin increases. In patients with the established presence of certain types of polymorphism, the use of Rosulip®is recommended. Plus a lower daily dose.

The recommended starting dose of rosuvastatin in patients with predisposing factors to the development of myopathy is 5 mg. A fixed dose combination is not intended as a first-line therapy. Combined treatment should be initiated 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.

Simultaneous therapy with other drugs:

• rosuvastatin is a substrate of various transporter proteins (for example, OATP1B1 and BCRP). With simultaneous use of the drug Rozulip® Plus, some drugs (for example, cyclosporine and some protease inhibitors, including combinations of ritonavir with atazanavir, lopinavir and / or tipranavir), which can increase the concentration of rosuvastatin in plasma as a result of interaction with these transporter proteins, increase the risk of myopathy, including rhabdomyolysis. Alternative therapy and, if necessary, temporary discontinuation of Rosulip Plus should be considered. If it is impossible to avoid simultaneous use of these medications and the drug Rozulip® In addition, the benefits and risks of such combination therapy should be carefully evaluated and whether a dose adjustment of rosuvastatin is necessary.

Overdose

Symptoms:

• There are no data on an overdose of rosuvastatin. There is no specific therapy for rosuvastatin overdose.

In clinical trials, ezetimibe 50 mg/day in 15 healthy participants for up to 14 days or 40 mg/day in 18 patients with primary hypercholesterolemia for up to 56 days was generally well tolerated. No toxicity was observed 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, usually without adverse events. The observed adverse events were not serious.

Treatment:

• in case of overdose, symptomatic and supportive therapy should be performed. Liver function and CKD levels should be monitored. The effectiveness of hemodialysis is unlikely.

Special instructions

Effects on skeletal muscle

In the post-marketing period, cases of myopathy and rhabdomyolysis have been reported with ezetimibe. Cases of rhabdomyolysis have been reported in very rare cases, both with ezetimibe monotherapy and when ezetimibe is added to other medications associated with an increased risk of rhabdomyolysis.

If myopathy is suspected (based on muscle symptoms or elevated CPK levels), ezetimibe, all statins, and any medications associated with an increased risk of rhabdomyolysis should be discontinued immediately. At the beginning of treatment, all patients should be advised to report all episodes of gratuitous muscle pain, muscle soreness, or weakness in a timely manner.

Effects on the liver

In controlled studies, when ezetimibe and statin were co-administered, there was a consistent increase in transaminases (≥3 times the ULN).

It is recommended to determine liver function 3 months after the start of rosuvastatin therapy. Rosuvastatin should be discontinued or its dose reduced if the serum transaminase level is 3 times higher than the ULN. The frequency of serious liver events (mainly increased transaminases) observed in the post-marketing period is higher when taking rosuvastatin at a dose of 40 mg.

In patients with secondary hypercholesterolemia caused by hypothyroidism or nephrotic syndrome, before starting therapy with Rosulip® Plus, treatment of the original disease is necessary.

The efficacy and safety of ezetimibe in patients with moderate or severe hepatic impairment have not been established, so the use of Rosulip®is recommended. Plus, it is not recommended for this category of patients.

Effect on the kidneys

In patients treated with rosuvastatin at a dose of 40 mg, proteinuria was observed (determined by the express method), which was mainly tubular in nature. In most cases, proteinuria was transient or non-permanent. Proteinuria has not been shown to be a symptom of acute or progressive kidney disease. The frequency of serious renal events reported in post-marketing use is higher when taking rosuvastatin at a dose of 40 mg. Consideration should be given to monitoring renal function (every 3 months or more) when monitoring patients receiving rosuvastatin 40 mg.

Determination of CKD activity

CKD should not be determined after intense physical activity or if there are other probable reasons for increased CKD, which may make it difficult to interpret the results.

If there is a significant increase in CPK (>5 ULN), a second CPK measurement should be performed after 5-7 days. If repeated measurement confirms that the CPK level is >5 ULN, treatment should not be initiated.

Before starting treatment

Rosulip® Plus, like other HMG-CoA reductase inhibitors, should be used with caution in patients with factors predisposing to the development of myopathy or rhabdomyolysis:

• renal failure;
• hypothyroidism;
• hereditary muscle diseases in the personal or family history;
• toxic effects on the muscles when using another HMG-CoA inhibitor or fibrate;
• alcohol abuse;
• age >70 years; >
• situations in which it is possible to increase the levels of active substances in plasma;
• simultaneous use of fibrates.

In such patients, it is necessary to assess the risk and possible benefits of treatment, and it is recommended to conduct clinical monitoring. Do not start treatment with a significant initial increase in CPK activity (>5 ULN).

During treatment

Patients should immediately report cases of unexplained muscle pain, weakness, or muscle spasms, especially if such cases are accompanied by general weakness or fever. In these patients, the level of CPK should be determined. Treatment should be discontinued if there is a significant increase in CPK activity (>5 ULN) or if there are severe symptoms that cause daily discomfort (even if the CPK level is < 5 ULN). Standard monitoring of CPK in patients with no symptoms is not required.

There are very rare reports of the development of immune-mediated necrotizing myopathy during or after treatment with statins, including rosuvastatin. Clinically, this disease is characterized by weakness of the proximal muscles and an increase in serum creatinine clearance, which persists despite the withdrawal of statins.

In clinical studies, there was no evidence of an increased effect on skeletal muscle in a small number of patients taking rosuvastatin and other lipid-lowering agents at the same time. Patients taking concomitant HMG-CoA reductase inhibitors and fibroic acid derivatives (including gemfibrozil), cyclosporine, nicotinic acid, azole antifungal agents, protease inhibitors, or macrolide antibiotics showed an increased incidence of myositis and myopathy.Gemfibrozil increases the risk of myopathy when co-administered with certain HMG-CoA reductase inhibitors, so the combination of Rosulip® Plus, gemfibrozil is not recommended. Benefits of further lipid reduction with the combined use of Rosulip® Plus and fibrates or niacin should be carefully weighed against the possible risks associated with this combination of medications. Rosuvastatin at a dose of 40 mg is contraindicated when taking fibrates at the same time.

A combination of rosuvastatin and fusidic acid is not recommended:

• cases of rhabdomyolysis, including fatal cases, have been reported with this combination.

Rosulip® Plus should not be used in patients with serious acute conditions that are likely to have myopathy or who are predisposed to developing renal failure due to rhabdomyolysis (for example, sepsis, hypotension, extensive surgery, trauma, severe metabolic disorders, endocrine or electrolyte balance, uncontrolled seizures).

Patients ‘ race

Studies on the pharmacokinetics of rosuvastatin have shown an increased effect of the drug on patients of the Mongolian race compared to patients of the Caucasian race.

Protease inhibitors

Increased systemic exposure to rosuvastatin has been reported in patients receiving concomitant use of rosuvastatin and various protease inhibitors in combination with ritonavir. It should be considered as a benefit of reducing lipids when using the drug Rozulip® Both in HIV-infected patients receiving protease inhibitors, and the possibility of increasing plasma concentrations of rosuvastatin at the beginning of use and during titration of the rosuvastatin dose. Concomitant use of the drug with certain protease inhibitors is recommended only with a dose adjustment of Rozulip Plus.

Interstitial lung diseases

Interstitial lung disease has been reported in exceptional cases with certain statins, especially with long-term therapy. Symptoms of these diseases include an unproductive cough and poor overall health (fatigue, weight loss, and fever). If the patient is suspected of developing interstitial lung disease, statin therapy should be discontinued.

Diabetes mellitus

Some data suggest that statin drugs increase blood glucose levels and, in some patients at high risk of developing diabetes, may lead to hyperglycemia, the level of which corresponds to the formal definition of diabetes mellitus and requires the initiation of hypoglycemic therapy. This risk, however, is overlaid by the reduced vascular risk associated with statin use, and therefore should not be a reason to discontinue statin therapy. In patients at risk (fasting glucose levels of 5.6-6.9 mmol/l, BMI >30 kg/m2, elevated triglycerides, arterial hypertension), clinical and biochemical monitoring of diabetes mellitus should be carried out in accordance with national guidelines.

In the JUPITER study, the overall incidence of diabetes mellitus was reported to be 2.8% in the rosuvastatin group and 2.3% in the placebo group (mainly in patients with fasting glucose levels of 5.6-6.9 mmol / L).

Fibrates

The safety and efficacy of co-use of ezetimibe and fibrates have not been established. If a patient receiving Rosulip®has Plus fenofibrate, there is a suspicion of the development of cholestasis, it is necessary to conduct an examination of the gallbladder and stop this therapy.

Anticoagulants

If Rosulip® If warfarin, other coumarin anticoagulants or fluindione are added to therapy, appropriate monitoring of INR is required.

Liver diseases and alcohol consumption

Rosulip® Plus should be used with caution in patients with excessive alcohol consumption and / or a history of liver disease.

Use in pediatrics

Safety and efficacy of Rosulip® Advantages in patients under 18 years of age are not established, so the use of the drug in this age group is not recommended.

Influence on the ability to drive motor vehicles and manage mechanisms

Rosulip® Plus does not affect or has negligible effect on the ability to drive vehicles and work with mechanisms. Studies of the effect of rosuvastatin and / or ezetimibe on this ability have not been conducted. However, when driving vehicles or operating machinery, the risk of dizziness that may develop during treatment should be considered.

Data from preclinical studies

In studies with co-use of ezetimibe and statins, the observed toxic effects were consistent with those usually associated with statin use. Some toxic effects were more pronounced compared to statin use alone, which is associated with pharmacokinetic and pharmacodynamic interactions when using both drugs. There was no such interaction in clinical trials. Myopathies developed in rats only when exposed to doses several times higher than the therapeutic dose in humans (approximately 20 times higher AUC for statins and 500-2000 times higher AUC for active metabolites).

Ezetimibe (plus statins) did not show potential genotoxicity in a number of in vivo and in vitro tests. Ezetimibe has not been shown to be carcinogenic in long-term studies.

Concomitant use of ezetimibe and statins did not have a teratogenic effect in rabbits. In the offspring of pregnant rabbits, a small number of skeletal deformities were noted (fusion of the thoracic and caudal vertebrae, a decrease in the number of caudal vertebrae).

Rosuvastatin: based on preclinical data from standard pharmacological studies of safety, possible genotoxicity and carcinogenicity, no particular danger to humans is shown. Specific studies of the effect on the hERG protein were not performed. Adverse reactions not reported in clinical studies, but observed in animals whose drug concentrations were similar to those in clinical use, were as follows: in repeated toxicity studies, histopathological changes in the liver, probably caused by the pharmacological action of rosuvastatin (in mice and rats), as well as (to a lesser extent) changes in the gallbladder (in dogs, but not in monkeys). In addition, in monkeys and dogs, when used in higher doses, toxic effects on the testes were noted. Obvious reproductive toxicity was observed in rats:

• when administered at doses toxic to the mother, a decrease in litter size, litter weight, and survival of rat pups was observed. The systemic effect was several times higher than the therapeutic concentrations.

Ezetimibe:

• studies of the toxicity of ezetimibe in animals with prolonged use did not reveal any target organs for the toxic effect of ezetimibe. In dogs treated with ezetimibe for 4 weeks (≥0.03 mg / kg / day), the concentration of cholesterol in the cystic bile increased 2.5-3.5 times. However, in a study in dogs that received ezetimibe at doses up to 300 mg/kg/day for 1 year, there was no increase in the incidence of cholestasis or other changes in the liver and biliary tract. The significance of these data for humans is unknown. It cannot be excluded that the therapeutic use of ezetimibe is associated with the risk of developing cholelithiasis.

Ezetimibe did not affect the fertility of male or female rats, did not show teratogenicity in rats or rabbits, and did not affect pre – or postnatal development. Ezetimibe penetrated the placental barrier in pregnant rats and rabbits with repeated doses of 1000 mg / kg / day. Concomitant use of ezetimibe and lovastatin resulted in embryo death.

Storage conditions

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

Shelf

life is 3 years.

Any unused medicinal product or waste should be disposed of in accordance with local regulations.

Active ingredient

Rosuvastatin, Ezetimibe

Conditions of release from pharmacies

By prescription

Dosage form

Capsules