composition of the 10 mg/10 mg capsule: iron oxide yellow (E172), titanium dioxide (E171), gelatin.
Dosage form
The capsules are hard.
Main physicochemical properties:
capsules of 10 mg/ 10 mg:
Hard gelatin capsules, unmarked, self-closing, with a yellow body and a yellow cap. Each capsule contains two tablets.
Rosuvastatin 10 mg tablet: white or almost white oblong tablets with a bevel, engraved with a stylized letter E and the number 596 on one side of the tablet, odorless or almost odorless;
Ezetimibe 10 mg tablet: white or almost white, round, flat, beveled tablets, engraved with a stylized letter E on one side of the tablet and the number 612 on the other side of the tablet, odorless or almost odorless.
Pharmacotherapeutic group
HMG-CoA reductase inhibitors in combination with other hypolipidemic agents.
ATX code C10B A06.
Pharmacological properties
Pharmacodynamics
Rosuvastatin
Rosuvastatin is a selective competitive inhibitor of HMG-CoA reductase, an enzyme that regulates the rate of conversion of 3-hydroxy-3-methyl-glutaryl-coenzyme A to mevalonate, a precursor of cholesterol.
The main target of rosuvastatin is the liver, where cholesterol synthesis occurs.
Rosuvastatin increases the number of hepatic low-density lipoprotein (LDL) receptors on the cell surface, increasing the uptake and catabolism of LDL, which enhances the uptake and catabolism of LDL and, in turn, leads to inhibition of the synthesis of very low-density lipoprotein (VLDL), thereby reducing the total amount of LDL and VLDL.
Rosuvastatin reduces elevated LDL cholesterol, total cholesterol, and triglycerides, and slightly increases high-density lipoprotein (HDL) cholesterol.
It also reduces apolipoprotein B, non-HDL cholesterol, VLDL cholesterol, VLDL triglycerides and slightly increases apolipoprotein A-I. Rosuvastatin also reduces the LDL-cholesterol/HDL-cholesterol ratio, total cholesterol/HDL-cholesterol, non-LDL-cholesterol/HDL-cholesterol ratio and the apolipoprotein B/apolipoprotein A-I ratio.
The therapeutic effect is manifested within 1 week after the start of rosuvastatin therapy, after 2 weeks of treatment the effect reaches 90% of the maximum possible. The maximum effect is usually achieved 4 weeks after the start of treatment.
Ezetimibe
Ezetimibe is a member of a new class of lipid-lowering agents that selectively inhibit the intestinal absorption of cholesterol and related plant sterols. Ezetimibe is orally active and has a mechanism of action that is distinct from other classes of cholesterol-lowering drugs (e.g., statins, bile acid sequestrants (resins), acid-derived fibrates, and plant stanols). The molecular target of ezetimibe is the sterol transporter Niemann-Pick Cl-Like 1 (NPC1L1), which is responsible for the absorption of cholesterol and phytosterols in the intestine.
Ezetimibe localizes to the brush border of the small intestine and inhibits cholesterol absorption by reducing the delivery of intestinal cholesterol to the liver; statins reduce cholesterol synthesis in the liver, and together these mechanisms provide additional cholesterol reduction. After 2 weeks of clinical use in 18 patients with hypercholesterolemia, ezetimibe reduced cholesterol absorption by 54% compared with placebo.
A series of preclinical studies were conducted to determine the selectivity of ezetimibe for inhibiting cholesterol absorption. Ezetimibe inhibited the absorption of [14C]-cholesterol without affecting the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol, or the fat-soluble vitamins A and D.
Epidemiological studies have established that cardiovascular morbidity and mortality vary directly proportionally to the level of total cholesterol and LDL-C and inversely proportionally to the level of HDL-C.
The effect of ezetimibe on cardiovascular morbidity and mortality has not yet been demonstrated.
Pharmacokinetics
Ezetimibe
Absorption. After oral administration, ezetimibe is rapidly absorbed and extensively conjugated to form a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). The mean maximum plasma concentration (Cmax) of ezetimibe-glucuronide is reached after 1–2 hours, and of ezetimibe after 4–12 hours. The absolute bioavailability of ezetimibe cannot be determined because this compound is insoluble in water.
Concomitant food intake (low or high fat) does not affect the oral bioavailability of ezetimibe, particularly ezetimibe 10 mg. Ezetimibe can be taken without regard to meals.
Metabolism. Ezetimibe is metabolized in the small intestine and liver by conjugation with glucuronide (phase II reaction) followed by biliary excretion. Minimal oxidative metabolism (phase I reaction) was observed at all stages of transformation. Ezetimibe and ezetimibe-glucuronide are the major substances detected in plasma, accounting for approximately 10–20% and 80–90% of the total plasma drug content, respectively. Ezetimibe and ezetimibe-glucuronide are slowly eliminated from plasma by enterohepatic recirculation. The elimination half-life of ezetimibe and ezetimibe-glucuronide is approximately 22 hours.
Elimination: Following oral administration of 20 mg of 14C-ezetimibe to volunteers, approximately 93% of the total ezetimibe recovered in plasma was derived from the total plasma radioactivity. Approximately 78% and 11% of the administered radioactive dose were excreted in the feces and urine, respectively, within 10 days. No detectable levels of radioactivity were observed in plasma after 48 hours.
Special populations
Elderly patients
In elderly patients (over 65 years of age), plasma concentrations of total ezetimibe are approximately twice as high as in younger patients (18–45 years of age). The LDL-C reduction and safety profile are approximately the same in elderly and younger patients taking ezetimibe. Therefore, no dose adjustment is necessary for elderly patients.
Patients with hepatic insufficiency
After a single dose of 10 mg ezetimibe, the mean area under the plasma concentration-time curve (AUC) of total ezetimibe was 1.7-fold higher in patients with mild hepatic impairment (Child-Pugh score 5-6) than in healthy volunteers. In a 14-day study of ezetimibe (10 mg daily) in patients with moderate hepatic impairment (Child-Pugh score 7-9), the AUC of total ezetimibe increased approximately 4-fold on days 1 and 14 compared with healthy volunteers. No dose adjustment is necessary for patients with mild hepatic impairment. Since the effects of increased ezetimibe levels in patients with moderate or severe hepatic impairment (Child-Pugh score greater than 9) are unknown, Rosuvastatin is not recommended for use in this patient population (see Precautions).
Patients with renal insufficiency
Following a single dose of 10 mg ezetimibe in patients with severe renal impairment (n = 8; creatinine clearance ≤ 30 mL/min/1.73 m2), the mean AUC of total ezetimibe increased approximately 1.5-fold compared to healthy volunteers (n = 9). This finding is not considered clinically significant. No dose adjustment is necessary for patients with renal impairment.
In this study, one patient (who had a kidney transplant and was receiving multitherapy, including cyclosporine) had a 12-fold higher total ezetimibe level.
Sex
Plasma concentrations of total ezetimibe are slightly higher (approximately 20%) in women than in men. The LDL-C reduction and safety profile are approximately the same in men and women taking Rosulip® Plus. Therefore, no dose adjustment is necessary based on gender.
Rosuvastatin
Absorption
Cmax of rosuvastatin in blood plasma is reached approximately 5 hours after oral administration. Bioavailability is approximately 20%.
Distribution
The volume of distribution of rosuvastatin is approximately 134 L. Almost 90% of rosuvastatin binds to plasma proteins, mainly albumin.
Metabolism
Rosuvastatin undergoes limited metabolism (approximately 10%). Rosuvastatin is a weak substrate for metabolism by cytochrome P450 enzymes.
The main isoenzyme involved in the metabolism of rosuvastatin is CYP2C9.
CYP2C19, CYP3A4 and CYP2D6 enzymes are less active. The main metabolites of rosuvastatin identified are N-desmethyl and lactone metabolites. N-desmethyl is approximately 50% less active than rosuvastatin, lactone metabolites are pharmacologically inactive. More than 90% of the pharmacological activity directed at inhibiting circulating HMG-CoA reductase is provided by rosuvastatin.
Breeding
Approximately 90% of the rosuvastatin dose is excreted unchanged in the feces (including absorbed and unabsorbed rosuvastatin). The remainder of the active substance is excreted in the urine. Almost 5% is found in the urine unchanged. The half-life is approximately 9 hours. The half-life does not change with increasing dose. The geometric mean clearance is approximately 50 l/h (coefficient of variation 21.7%).
As with other HMG-CoA reductase inhibitors, the membrane cholesterol transporter OATP-C is involved in the hepatic uptake of rosuvastatin. The transporter plays an important role in the hepatic elimination of rosuvastatin.
Linearity. Systemic exposure to rosuvastatin increases in proportion to the dose. Pharmacokinetic parameters do not change after multiple daily doses.
Special patient groups
Age and gender have no clinically significant effect on the pharmacokinetics of rosuvastatin.
No genetic or environmental factors were found to influence the differences in pharmacokinetic parameters. Pharmacokinetic analysis of different ethnic groups did not reveal clinically significant differences in the pharmacokinetics of patients of Caucasian and Mongoloid races.
Patients with renal insufficiency. In patients with mild or moderate renal impairment, the plasma concentrations of rosuvastatin and N-desmethyl do not change significantly. In patients with severe renal insufficiency (creatinine clearance < 30 ml/min), the plasma concentration of rosuvastatin is 3 times higher, and the concentration of N-desmethyl is 9 times higher, than in healthy volunteers. The equilibrium plasma concentration of rosuvastatin in patients on hemodialysis was approximately 50% higher than in healthy volunteers.
Patients with hepatic impairment. Among patients with varying degrees of hepatic impairment, no increase in the half-life of rosuvastatin was observed if the Child-Pugh score did not exceed 7. However, two patients with Child-Pugh scores of 8 and 9 had at least a twofold increase in the half-life.
There is no experience with the use of rosuvastatin in patients with a score above 9 on the Child-Pugh scale.
Indication
As an adjunct to diet for patients with primary hypercholesterolemia when a combination drug is appropriate:
for patients who have not achieved an adequate result when treated with a statin alone; replacement therapy for patients with sufficient disease control with the combined use of rosuvastatin and ezetimibe in the same doses as the fixed combination Rozulip® Plus.
Contraindication
Hypersensitivity to the active substances or to any of the excipients of the drug; active liver disease, including persistent elevation of serum transaminases of unknown etiology and any elevation of serum transaminase levels three times or more of the upper limit of normal (ULN); severe renal impairment (creatinine clearance < 30 ml/min); myopathy; concomitant use of cyclosporine; children; pregnancy, breastfeeding; contraindicated in women of reproductive age not using effective contraception.
Interaction with other medicinal products and other types of interactions
Transport protein inhibitors
Rosuvastatin is a substrate for several transport proteins, including the hepatic uptake transporter OATP1B1 and the efflux transporter BCRP. Concomitant use of rosuvastatin with medicinal products that inhibit these transport proteins may lead to increased plasma concentrations of rosuvastatin and an increased risk of myopathy (see sections 4.2, 4.4, and 4.5).
Cyclosporine
During concomitant use of rosuvastatin and ciclosporin, rosuvastatin AUC values were on average approximately 7 times higher than those observed in healthy volunteers (see Table 1). Rosuvastatin is contraindicated in patients receiving concomitant ciclosporin (see section "Contraindications").
Protease inhibitors
Although the exact mechanism of interaction is unknown, concomitant use of protease inhibitors may significantly increase rosuvastatin exposure (see Table 1). For example, in a pharmacokinetic study, co-administration of 10 mg of rosuvastatin and a combination product containing two protease inhibitors (300 mg atazanavir/100 mg ritonavir) in healthy volunteers was accompanied by an increase in rosuvastatin AUC and Cmax by approximately 3 and 7 times, respectively. Co-administration of Rosuvastatin and some combinations of protease inhibitors may be possible after dose adjustment of Rosuvastatin based on the expected increase in rosuvastatin exposure (see sections 4.2, 4.4, and 4.5, Table 1).
Gemfibrozil and other lipid-lowering agents
Simultaneous use of Rozulip® Plus and gemfibrozil led to a 2-fold increase in rosuvastatin AUC and Cmax (see section "Special instructions").
Based on specific studies, no pharmacokinetically significant interaction with fenofibrate is expected, but a pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates, and lipid-lowering doses of niacin (nicotinic acid) (1 g/day or more) increase the risk of myopathy when used concomitantly with HMG-CoA inhibitors, presumably because they can cause myopathy when used alone. The 40 mg dose is contraindicated with concomitant use of fibrates (see sections 4.3 and 4.4). Concomitant administration of fenofibrate or gemfibrozil increases total ezetimibe concentrations by approximately 1.5-1.7 times, respectively. Although this increase is not considered clinically significant, concomitant administration of Rosuvastatin with gemfibrozil is contraindicated and not recommended with other fibrates.
If cholelithiasis is suspected in a patient taking ezetimibe and fenofibrate, gallbladder examination is indicated, and such therapy should be discontinued.
Concomitant administration of fenofibrate or gemfibrozil moderately increases total ezetimibe concentrations (approximately 1.5-1.7-fold, respectively).
Combination therapy with ezetimibe and other fibrates has not been studied.
Fibrates may increase cholesterol excretion into the bile, leading to gallstone disease. In animal studies, ezetimibe has occasionally increased cholesterol levels in gallbladder bile, but not in all species. There is no evidence of a risk of gallstone formation associated with the therapeutic use of ezetimibe.
Antacids
Simultaneous use of Rozulip® Plus with antacid suspensions containing aluminum or magnesium hydroxide reduced the concentration of rosuvastatin in the blood plasma by approximately 50%. This effect was less pronounced when antacids were used 2 hours after taking Rozulip® Plus. The clinical significance of this interaction has not been studied.
Concomitant administration of antacids reduces the extent of absorption of ezetimibe, but does not affect its bioavailability. This decrease in the extent of absorption is not considered clinically significant.
Erythromycin
Concomitant use of rosuvastatin and erythromycin decreased rosuvastatin AUC by 20% and Cmax by 30%. This interaction may be due to increased intestinal motility due to erythromycin.
Cytochrome P450 enzymes
In vitro and in vivo studies have shown that rosuvastatin does not inhibit or induce cytochrome P450 isoenzymes. In addition, rosuvastatin is a weak substrate for these isoenzymes. Therefore, drug interactions resulting from P450-mediated metabolism are not expected. No clinically significant interactions were observed between rosuvastatin and fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4).
In nonclinical studies, ezetimibe did not induce cytochrome P450 drug-metabolizing enzymes. No clinically significant pharmacokinetic interactions were observed between ezetimibe and drugs metabolized by cytochrome P450: 1A2, 2D6, 2C8, 2C9, 3A4, or N-acetyltransferase.
Interactions requiring dose adjustment of rosuvastatin
If it is necessary to use rosuvastatin with other drugs that can increase the exposure of rosuvastatin, the dose of the drug should be adjusted. If the exposure of the drug (AUC) is expected to increase by approximately 2 or more times, the use of Rosulip® Plus should be started at a dose of 5 mg once a day. The maximum daily dose of Rosulip® Plus should be adjusted so that the expected exposure of rosuvastatin does not exceed the exposure observed when taking a dose of 40 mg/day without the use of drugs that interact with the drug; for example, when used with gemfibrozil, the dose of Rosulip® Plus will be 20 mg (an increase in exposure of 1.9 times), when used with a combination of ritonavir/atazanavir - 10 mg (an increase of 3.1 times), when used simultaneously with cyclosporine - 5 mg (an increase of 7.1 times).
Table 1
Effect of concomitant medications on rosuvastatin exposure (AUC; in descending order of magnitude) based on published clinical trial data
Atazanavir 300 mg/ritonavir 100 mg once daily, 8 days
10 mg, single dose
↑ 3.1 times
Simeprivir 150 mg once daily, 7 days
10 mg, single dose
↑ 2.8 times
Lopinavir 400 mg/ritonavir 100 mg twice daily, 17 days
20 mg once daily, 7 days
↑ 2.1 times
Gemfibrozil 600 mg twice daily, 7 days
80 mg, single dose
↑ 1.9 times
Eltrombopac 75 mg once daily, 5 days
10 mg, single dose
↑ 1.6 times
Darunavir 600 mg/ritonavir 100 mg twice daily, 7 days
10 mg once daily, 7 days
↑ 1.5 times
Tipranavir 500 mg/ritonavir 200 mg twice daily, 11 days
10 mg, single dose
↑ 1.4 times
Dronedarone 400 mg twice daily
Unknown
↑ 1.4 times
Itraconazole 200 mg once daily, 5 days
10 mg, single dose
↑ 1.4 times **
Ezetimibe 10 mg once daily, 14 days
10 mg once daily, 14 days
↑ 1.2 times **
Fosamprenavir 700 mg/ritonavir 100 mg twice daily, 8 days
10 mg, single dose
↔
Aleglitazar 0.3 mg, 7 days
40 mg, 7 days
↔
Silymarin 140 mg three times a day, 5 days
10 mg, single dose
↔
Fenofibrate 67 mg three times a day, 7 days
10 mg, 7 days
↔
Rifampin 450 mg once daily, 7 days
20 mg, single dose
↔
Ketoconazole 200 mg twice daily, 7 days
80 mg, single dose
↔
Fluconazole 200 mg once daily, 11 days
80 mg, single dose
↔
Erythromycin 500 mg four times a day, 7 days
80 mg, single dose
↓ 20%
Baicalin 50 mg three times a day, 14 days
20 mg, single dose
↓ 47%
* - Data reported as x-fold change represents the ratio between rosuvastatin in combination and alone. Data reported as percentages represent the percentage difference relative to rosuvastatin alone.
Increase is indicated by the ↑ icon, no change is indicated by the ↔ icon, and decrease is indicated by the ↓ icon.
** - Several interaction studies were conducted with different doses of the drug Rozulip® Plus - the table shows the most significant correlation.
Vitamin K antagonists
As with other HMG-CoA reductase inhibitors, when starting or increasing the dose of Rosuvastatin in patients receiving concomitant vitamin K antagonists (e.g. warfarin or other coumarin anticoagulants), an increase in the international normalized ratio (INR) may occur. Discontinuation of Rosuvastatin or dose reduction may result in a decrease in INR. In such cases, appropriate monitoring of INR is recommended.
Concomitant administration of ezetimibe (10 mg once daily) had no significant effect on the bioavailability of warfarin and prothrombin time in a study of 12 healthy adult men. However, there have been postmarketing reports of increases in MNC in patients to whom ezetimibe was added to warfarin or fluindione. When ezetimibe is added to warfarin, another coumarin anticoagulant, or fluindione, MNC should be monitored appropriately.
Concomitant use of rosuvastatin and oral contraceptives resulted in an increase in the AUC of ethinylestradiol and norgestrel by 26% and 34%, respectively. This increase in plasma levels should be taken into account when selecting the dose of oral contraceptives. There are no data on the pharmacokinetics of the drugs in patients taking rosuvastatin and HRT simultaneously, so a similar effect cannot be excluded. However, the combination has been widely used in women in clinical trials and was well tolerated.
Clinical drug interaction studies of ezetimibe have not revealed any effect on the pharmacokinetics of oral contraceptives, including ethinyl estradiol and levonorgestrel.
Statins
No clinically significant pharmacokinetic interactions were observed when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, or rosuvastatin.
Other medicines
According to special studies, a clinically significant interaction of rosuvastatin with digoxin is not expected.
In clinical drug interaction studies, ezetimibe did not affect the pharmacokinetics of dapsone, dextromethorphan, digoxin, oral contraceptives (ethinyl estradiol and levonorgestrel), glipizide, tolbutamide, or midazolam when co-administered with ezetimibe. Cimetidine did not affect the bioavailability of ezetimibe when co-administered with ezetimibe.
Cholestyramine
When coadministered with cholestyramine, the mean area under the plasma concentration-time curve (AUC) of total ezetimibe (ezetimibe and ezetimibe-glucuronide) was decreased by approximately 55%. The gradual reduction in low-density lipoprotein cholesterol (LDL-C) may be slowed when ezetimibe is added to cholestyramine.
Lopinavir/ritonavir
In a pharmacology study, co-administration of rosuvastatin and a combination product containing two protease inhibitors (lopinavir 400 mg/ritonavir 100 mg) in healthy volunteers was associated with an approximately two-fold and five-fold increase in steady-state AUC(0-24) and Cmax of rosuvastatin, respectively. Interactions between rosuvastatin and other protease inhibitors have not been studied.
Fusidic acid:
The risk of myopathy, including rhabdomyolysis, may be increased when fusidic acid is used concomitantly with statins.
Application features
Effects on the kidneys
Proteinuria, detected by dipstick analysis, predominantly of tubular origin, has been observed in patients treated with higher doses of rosuvastatin, including 40 mg, and in most cases was transient or intermittent. Proteinuria was not a harbinger of acute or progressive renal disease (see section 4.8). The frequency of reports of serious renal events in post-marketing studies is higher with the 40 mg dose of rosuvastatin. In patients taking rosuvastatin at a dose of 40 mg, renal function should be monitored regularly during follow-up.
Effects on skeletal muscles
In postmarketing experience, cases of myopathy and rhabdomyolysis have been reported with ezetimibe. Most patients who developed rhabdomyolysis were taking statins concomitantly with ezetimibe. However, cases of rhabdomyolysis have been reported very rarely with ezetimibe alone and very rarely with ezetimibe given with other agents associated with a risk of rhabdomyolysis.
Isolated cases of rhabdomyolysis have been reported with the use of ezetimibe in combination with HMG-CoA reductase inhibitors. The possibility of a pharmacodynamic interaction cannot be excluded (see section 4.5), and therefore this combination should be used with caution.
Creatine kinase level
Creatine kinase (CK) levels should not be measured after significant exercise or if there are alternative causes of elevated CK that may complicate interpretation of results. If initial CK levels are significantly elevated (> 5 × ULN), a repeat test should be performed within 5–7 days to confirm the results. If the results of the repeat test confirm that the initial CK value is more than 5 times the ULN, the drug should not be started.
Before starting treatment
Rosulip® Plus, like other HMG-CoA reductase inhibitors, should be prescribed with caution in patients with a predisposition to myopathy/rhabdomyolysis. Risk factors for this include:
renal impairment; hypothyroidism; personal or family history of hereditary muscle diseases; history of myotoxicity with other HMG-CoA reductase inhibitors or fibrates; alcohol abuse; age > 70 years;
situations that may lead to increased levels of the drug in blood plasma (see sections “Method of administration and dosage”, “Interaction with other medicinal products and other types of interactions” and “Pharmacokinetics”);
concomitant use of fibrates.
In such patients, the risk of treatment should be weighed against the expected benefit; clinical monitoring is also recommended. If baseline CK levels are significantly elevated (> 5 × ULN), treatment should not be initiated.
During treatment
Patients should be asked to report unexplained muscle pain, weakness or cramps immediately, especially if accompanied by malaise or fever. In such patients, CK levels should be measured. The drug should be discontinued if CK levels are significantly elevated (> 5 × ULN) or if muscle symptoms are severe and cause daily discomfort (even if CK levels are ≤ 5 × ULN). If symptoms resolve and CK levels return to normal, rosuvastatin or an alternative HMG-CoA reductase inhibitor may be restarted at the lowest dose and under close supervision. There is no need to monitor CK levels regularly in asymptomatic patients. Cases of immune-mediated necrotizing myopathy (IMNM) have been reported very rarely during or after treatment with statins, including rosuvastatin. Clinical manifestations of IONM include proximal muscle weakness and elevated serum creatine kinase levels, which persist even after discontinuation of statins.
Studies have not shown evidence of increased skeletal muscle effects in a small number of patients taking Rosuvastatin and concomitant medications. However, an increased incidence of myositis and myopathy has been reported in patients taking other HMG-CoA reductase inhibitors with fibric acid derivatives, including gemfibrozil, cyclosporine, nicotinic acid, azole antifungals, protease inhibitors, and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when used concomitantly with some HMG-CoA inhibitors. Therefore, the use of Rosuvastatin in combination with gemfibrozil is not recommended. The benefits of further lipid-lowering effects of Rosuvastatin in combination with fibrates or niacin should be carefully weighed against the potential risks associated with the use of such combinations. The 40 mg dose is contraindicated with concomitant use of fibrates (see sections “Interaction with other medicinal products and other types of interactions” and “Adverse reactions”).
Rozulip® Plus should not be used in patients with acute, serious conditions that suggest myopathy or the possibility of developing renal failure due to rhabdomyolysis (such as sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders or uncontrolled seizures).
Effect on the liver
Like other HMG-CoA reductase inhibitors, rosuvastatin should be used with caution in patients who abuse alcohol and/or have a history of liver disease.
It is recommended to check biochemical indicators of liver function before starting treatment and 3 months later. The use of rosuvastatin should be discontinued or the dose reduced if the level of serum transaminases exceeds three times the upper limit of normal. The frequency of reports of serious hepatic events (mainly increased levels of hepatic transaminases) in the post-marketing period was higher with the 40 mg dose.
In studies, patients receiving a combination of a statin and ezetimibe have experienced gradual increases in transaminase levels (≥ 3 × ULN). When ezetimibe is combined with a statin, liver function tests should be performed at the start of therapy and according to statin recommendations.
Race
Pharmacokinetic studies indicate that exposure in patients of the Mongoloid race is approximately twice as high as in Caucasians. For such patients, dosage adjustment of rosuvastatin is required (see sections “Dosage and Administration”, “Contraindications” and “Pharmacokinetics”). For patients of the Asian race, the initial dose of rosuvastatin should be
5 mg. Increased plasma concentrations of rosuvastatin have been observed in Asian patients (see sections 4.4 and 5.2). Increased systemic exposure should be considered when treating patients of Mongoloid race whose hypercholesterolemia is not adequately controlled with doses of rosuvastatin up to 20 mg.
Protease inhibitors
Increased systemic exposure to rosuvastatin has been observed in subjects receiving rosuvastatin concomitantly with various protease inhibitors in combination with ritonavir. The benefit of lipid-lowering effects of rosuvastatin in HIV patients receiving protease inhibitors should be considered, as well as the possibility of increased plasma concentrations of rosuvastatin at the start of therapy and with an increase in the dose of rosuvastatin in patients receiving protease inhibitors. Co-administration of the drug with protease inhibitors is not recommended unless the dose of rosuvastatin is adjusted (see sections 4.2 and 4.5).
Interstitial lung disease
Exceptional cases of interstitial lung disease have been reported with some statins, particularly with long-term treatment (see section 4.8). Symptoms may include dyspnoea, non-productive cough and general malaise (fatigue, weight loss and fever). If interstitial lung disease is suspected, statins should be discontinued.
Diabetes mellitus
There is some evidence that statins increase blood glucose levels and may cause hyperglycemia in some patients at high risk of developing diabetes, which may require treatment. However, this risk is outweighed by the reduced risk of vascular events with statins and should not be a reason to discontinue statin therapy. Patients at risk (fasting glucose 5.6–6.0 mmol/L, body mass index (BMI) > 30 kg/m2, elevated triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines.
In the JUPITER study, the overall incidence of diabetes mellitus was 2.8% in the rosuvastatin group and 2.3% in the placebo group, predominantly in patients with fasting glucose levels between 5.6 and 6.9 mmol/L.
As with other HMG-CoA reductase inhibitors, increases in HbA1c and serum glucose levels have been observed with rosuvastatin. In some cases, these values may exceed the threshold for the diagnosis of diabetes.
Specifications
Characteristics
Active ingredient
Rosuvastatin, Ezetimibe
Adults
Can
ATC code
C CARDIOVASCULAR AGENTS; C10 HYPOLYPIDEMIC AGENTS; C10B Lipid-lowering agents, combinations; C10B A HMG-CoA reductase inhibitors in combination with other lipid-lowering agents; C10B A06 Rosuvastatin and ezetimibe
Country of manufacture
Hungary
Diabetics
With caution
Drivers
Can
For allergies
With caution
For children
It is impossible.
Form
Capsules
Method of application
Inside, solid
Nursing
It is impossible.
Pregnant
It is impossible.
Primary packaging
blister
Producer
Aegis
Quantity per package
30 pcs
Trade name
Rozulip
Vacation conditions
By prescription
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