Rozulip Plus tablets 20 mg + 10 mg blister No. 30

Instructions for use Rozulip Plus tablets 20 mg + 10 mg blister No. 30

Composition

active ingredients: rosuvastatin, ezetimibe;

1 capsule contains two tablets:

1 tablet of rosuvastatin 10 mg (as rosuvastatin zinc) and 1 tablet of ezetimibe 10 mg;

or 1 tablet of rosuvastatin 20 mg (as rosuvastatin zinc) and 1 tablet of ezetimibe 10 mg;

or 1 tablet of rosuvastatin 40 mg (as rosuvastatin zinc) and 1 tablet of ezetimibe 10 mg;

excipients:

for rosuvastatin tablets:

microcrystalline silicon cellulose, colloidal anhydrous silicon dioxide, magnesium stearate;

for ezetimibe tablets:

povidone, croscarmellose sodium, microcrystalline cellulose, mannitol, sodium lauryl sulfate, low-substituted hydroxypropylcellulose, magnesium stearate;

composition of 10 mg / 10 mg capsules:

iron oxide yellow (E 172), titanium dioxide (E 171), gelatin;

composition of capsules 20 mg / 10 mg and 40 mg / 10 mg:

iron oxide yellow (E 172), iron oxide red (E 172), titanium dioxide (E 171), 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 round tablets with a mark on one side of the tablet and no mark on the other side, odorless or almost odorless;

ezetimibe 10 mg tablet: white or almost white, round, flat tablets with a bevel, 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;

capsules of 20 mg / 10 mg:

CONI–SNAP 0 hard gelatin capsules, unmarked, self-closing, with a yellow body and a caramel cap. Each capsule contains two tablets.

Rosuvastatin 20 mg tablet: white or almost white round tablets with a mark on one side of the tablet and no mark on the other side, odorless or almost odorless;

ezetimibe 10 mg tablet: white or almost white, round, flat tablets with a bevel, 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;

capsules of 40 mg / 10 mg:

CONI–SNAP 0 hard gelatin capsules, unmarked, self-closing, with a yellow body and a red cap. Each capsule contains two tablets.

Rosuvastatin 40 mg tablet: white or almost white oval tablets with a bevel, engraved with a stylized letter E and the number 598 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.

Mechanism of action.

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.

Pharmacodynamic effects.

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 (see Table 1). 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.

Table 1

Dose response in patients with primary hypercholesterolemia types IIa and IIb

(adjusted mean percentage change from baseline)

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.

Pharmacodynamic effects.

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 with the level of total cholesterol and LDL-C and inversely proportionally with the level of HDL-C.

The effect of ezetimibe on cardiovascular morbidity and mortality has not yet been demonstrated.

Pharmacokinetics

Concomitant use of rosuvastatin and ezetimibe.

Co-administration 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 in terms of adverse effects between rosuvastatin and ezetimibe cannot be excluded.

Rosuvastatin.

Absorption.

Cmax of rosuvastatin in blood plasma is reached approximately 5 hours after oral administration. Bioavailability is approximately 20%.

Distribution.

Rosuvastatin is extensively absorbed by the liver, which plays a major role in cholesterol synthesis and LDL-C clearance. The volume of distribution of rosuvastatin is approximately 134 L. Almost 90% of rosuvastatin is bound to plasma proteins, mainly albumin.

Metabolism.

Rosuvastatin undergoes limited metabolism (approximately 10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a poor substrate for metabolism by cytochrome P450 enzymes. The main isoenzyme involved is CYP2C9, with 2C19, 3A4 and 2D6 playing a somewhat smaller role. The main identified metabolites are the N-desmethyl and lactone metabolites. The N-desmethyl metabolite is approximately 50% less active than rosuvastatin, the lactone metabolite is considered clinically inactive. Rosuvastatin accounts for more than 90% of the circulating HMG-CoA reductase inhibitory activity.

Breeding.

Approximately 90% of a 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 elimination half-life is approximately 19 hours. The elimination 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.

There is no clinically significant effect of age or gender on the pharmacokinetics of rosuvastatin in adults. The pharmacokinetics of rosuvastatin in children and adolescents with heterozygous familial hypercholesterolemia were similar to or lower than those in adult volunteers.

Ethnic groups.

Pharmacokinetic studies demonstrate an increase of approximately 2 times the median area under the plasma concentration-time curve (AUC) and Cmax of rosuvastatin in representatives of the Mongoloid race (Japanese, Chinese, Filipinos, Vietnamese and Koreans), compared with patients of the Caucasian race; in Indians there is an increase of approximately 1.3 times the median AUC and Cmax. Population pharmacokinetic analysis did not reveal any clinically significant differences in pharmacokinetics between representatives of the Caucasian and Negroid races.

Patients with renal failure.

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 impairment (creatinine clearance < 30 ml/min), the plasma concentrations of rosuvastatin are 3 times higher, and the N-desmethyl is 9 times higher, than in healthy volunteers. The steady-state plasma concentrations of rosuvastatin in patients on hemodialysis were approximately 50% higher than in healthy volunteers.

Among patients with varying degrees of hepatic insufficiency, no increase in the half-life of rosuvastatin was observed if the Child-Pugh score did not exceed 7. However, in two patients with Child-Pugh scores of 8 and 9, an increase in the half-life by at least twofold was observed.

There is no experience with the use of rosuvastatin in patients with a score above 9 on the Child-Pugh scale.

Genetic polymorphism.

The transport proteins OATP1B1 and BCRP are involved in the pharmacokinetics of HMG-CoA reductase inhibitors, including rosuvastatin. Patients with genetic polymorphisms in SLCO1B1 (OATP1B1) and/or ABCG2 (BCRP) are at risk of increased exposure to rosuvastatin. The specific polymorphisms SLCO1B1 c.521CC and ABCG2 c.421AA are associated with higher exposure to rosuvastatin (AUC) compared with the genotypes SLCO1B1 c.521TT or ABCG2 c.421CC. This specific genotyping is not routinely used in clinical practice, but a lower daily dose of rosuvastatin is recommended for patients with these types of polymorphisms.

Children.

Two pharmacokinetic studies of rosuvastatin (tablet form) in patients aged 10-18 or 6-18 years (total of 214 patients) with heterozygous familial hypercholesterolemia showed that the drug exposure in children is consistent with that in adults. The effect of rosuvastatin was studied in a dose-dependent manner and over 2 years of use.

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. Ezetimibe can be taken without regard to meals.

Distribution.

Ezetimibe and ezetimibe-glucuronide are 99.7% and 88–92% bound to human plasma proteins, respectively.

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 main substances determined in blood plasma and constitute approximately 10–20% and 80–90% of the total plasma content of the drug, respectively. Ezetimibe and ezetimibe-glucuronide are slowly eliminated from blood plasma by enterohepatic recirculation. The half-life of ezetimibe and ezetimibe-glucuronide is approximately 22 hours.

Breeding.

Following oral administration of 20 mg of 14C-ezetimibe to volunteers, approximately 93% of the total ezetimibe radioactivity in plasma was recovered. 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 patient groups.

Age and gender.

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 ezetimibe. Therefore, no dose adjustment is necessary based on gender.

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 liver failure.

After a single dose of 10 mg ezetimibe, the mean area under the plasma concentration-time curve (AUC) for 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 for 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 failure.

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.

The pharmacokinetics of ezetimibe are similar in children aged 6 years and older and in adults. Pharmacokinetic data are not available in children under 6 years of age. Clinical experience with ezetimibe in children and adolescents has included patients with homozygous familial hypercholesterolemia, heterozygous familial hypercholesterolemia, or sitosterolemia.

Indication

The drug is prescribed in addition to diet for the treatment of adult patients with primary hypercholesterolemia in whom adequate control of the disease is achieved by the simultaneous use of rosuvastatin and ezetimibe as monocomponent drugs in the same doses as in the combination drug.

Contraindication

Rozulip® Plus is contraindicated:

- patients with hypersensitivity to the active substances (rosuvastatin, ezetimibe) or to any of the excipients of the medicinal product;

- patients with active liver disease, including persistent elevations of serum transaminases of unknown etiology and any elevation of serum transaminase levels to three times or more of the upper limit of normal (ULN);

- during pregnancy and breastfeeding, as well as women of reproductive age who do not use adequate contraception;

- patients with severe renal impairment (creatinine clearance < 30 ml/min);

- patients with myopathy;

- patients who are simultaneously receiving the combination of sofosbuvir/velpatasvir/voxilaprevir;

- patients who are simultaneously receiving cyclosporine;

- children.

Rosulip® Plus, capsules 40 mg / 10 mg, are contraindicated in patients who are at increased risk of developing myopathy/rhabdomyolysis.

Such risk factors include:

– moderate renal impairment (creatinine clearance < 60 ml/min);

– hypothyroidism;

– personal or family history of hereditary muscle diseases;

– history of myotoxicity with other HMG-CoA reductase inhibitors or fibrates;

– alcohol abuse;

– conditions that may lead to an increase in the concentration of the drug in the blood plasma;

– belonging to the Mongoloid race;

– concomitant use of fibrates.

Interaction with other medicinal products and other types of interactions

Concomitant use is contraindicated.

Cyclosporine

The simultaneous use of the drug Rozulip® Plus with cyclosporine is contraindicated (see the section "Contraindications"). During the period of concomitant use of rosuvastatin and cyclosporine, the AUC values of rosuvastatin were on average approximately 7 times higher than those observed in healthy volunteers (see table 2). Simultaneous use does not affect the concentration of cyclosporine in the blood plasma.

Concomitant use is not recommended.

Protease inhibitors

Although the exact mechanism of interaction is unknown, concomitant use of protease inhibitors may significantly increase rosuvastatin exposure (see Table 2). 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 combination protease inhibitor preparations is possible only after careful adjustment of the rosuvastatin dose, taking into account the expected increase in rosuvastatin exposure (see sections “Special instructions”, “Method of administration and dosage”, as well as Table 2).

The combination is not suitable for initial therapy. Treatment should be initiated or dose adjustments made, if necessary, with the monocomponents only, and once the required doses have been established, a switch to the appropriate fixed-dose combination may be possible.

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 and 4.4, and Table 2 in the Interactions with other medicinal products and other forms of interaction section).

Gemfibrozil and other lipid-lowering agents

Simultaneous use of the drug Rozulip® Plus and gemfibrozil led to a 2-fold increase in AUC and Cmax of rosuvastatin (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 reductase inhibitors, presumably because they can cause myopathy when used alone. The 40 mg/10 mg dose is contraindicated with concomitant use of fibrates (see sections 4.3 and 4.4).

If cholelithiasis is suspected in a patient taking ezetimibe and fenofibrate, gallbladder examination is indicated, and such therapy should be discontinued (see section "Adverse reactions").

Concomitant administration of fenofibrate or gemfibrozil moderately increases total ezetimibe concentrations (approximately 1.5-1.7 times, 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.

Fusidic acid

The risk of myopathy, including rhabdomyolysis, may be increased by concomitant systemic use of fusidic acid with statins. The mechanism of this interaction (pharmacodynamic or pharmacokinetic) is not yet known. There have been reports of rhabdomyolysis (including fatalities) in patients receiving this combination. If systemic treatment with fusidic acid is necessary, rosuvastatin should be discontinued for the duration of fusidic acid treatment (see section 4.4).

Ticagrelor

Ticagrelor may cause renal failure and may affect the renal excretion of rosuvastatin, increasing the risk of its accumulation. In some cases, concomitant administration of ticagrelor and rosuvastatin has resulted in decreased renal function, increased creatine phosphokinase (CPK) levels, and rhabdomyolysis. It is recommended to monitor renal function and CPK levels when ticagrelor and rosuvastatin are used concomitantly.

Other interactions

Antacids

Co-administration of Rosulip Plus with antacid suspensions containing aluminum or magnesium hydroxide decreased rosuvastatin plasma concentrations by approximately 50%. This effect was less pronounced when antacids were administered 2 hours after Rosulip 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.

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 lead to a decrease in INR. In such cases, appropriate monitoring of INR is advisable.

Co-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 post-marketing reports of increased MCH in patients to whom ezetimibe was added to warfarin or fluindione. When adding Rozulip® Plus to warfarin, another coumarin anticoagulant or fluindione, MCH should be monitored appropriately (see section 4.4).

Oral contraceptives/hormone replacement therapy (HRT)

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 at the same time, 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.

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.

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.

Interactions requiring dose adjustment of rosuvastatin

If concomitant use of rosuvastatin with other medicinal products that increase the exposure of rosuvastatin is necessary, the doses of the latter should be adjusted. If an increase in exposure (AUC) of approximately 2 times or more is expected, treatment should be initiated with 5 mg of rosuvastatin once daily. The maximum daily dose of rosuvastatin should be adjusted so that the expected exposure to rosuvastatin does not exceed the exposure observed when taking 40 mg of rosuvastatin per day without the use of medicinal products that interact with the drug. For example, when used with gemfibrozil, the maximum dose of rosuvastatin will be 20 mg (1.9-fold increase), and when used with the combination of atazanavir/ritonavir - 10 mg of rosuvastatin (3.1-fold increase).

If the drug exposure (AUC) is expected to increase less than 2-fold, the initial dose does not need to be reduced, but caution should be exercised when increasing the dose of rosuvastatin above 20 mg.

Table 2

Effect of concomitant medications on rosuvastatin exposure (AUC; in descending order of magnitude), based on published clinical trial data

* Data reported as x-fold change represent 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, decrease by the ↓ icon.

** Several interaction studies have been conducted with different doses of rosuvastatin - the table shows the most significant ratio.

The combination is not suitable for initial therapy. Treatment should be initiated or dose adjustments made if necessary with the monocomponents only, and once the required doses have been established, a switch to the appropriate fixed-dose combination may be possible.

Application features

Severe skin adverse reactions

Cases of severe cutaneous adverse reactions, including Stevens-Johnson syndrome and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be fatal, have been reported with rosuvastatin. When prescribing the drug, patients should be informed of the signs and symptoms of severe skin reactions and monitored closely. If symptoms suggestive of this reaction occur, the drug should be discontinued immediately and alternative treatment should be considered. If a patient develops a serious reaction such as Stevens-Johnson syndrome or drug reaction with eosinophilia and systemic symptoms (DRESS), treatment should be discontinued immediately and the drug should never be used again.

Effects on skeletal muscles

Skeletal muscle disorders, such as myalgia, myopathy and, rarely, rhabdomyolysis, have been observed in patients taking rosuvastatin at all doses, especially above 20 mg. Myopathy and rhabdomyolysis have been reported with ezetimibe. Most patients who have developed rhabdomyolysis were taking statins concomitantly with ezetimibe. However, rhabdomyolysis has been reported very rarely with ezetimibe alone and very rarely with ezetimibe in combination with other agents associated with the risk of rhabdomyolysis.

If myopia is suspected, manifested by muscle weakness and an increase in creatine phosphokinase (CPK) levels greater than 10 times the upper limit of normal, ezetimibe, any statins, or other concomitant medications should be discontinued immediately. Patients initiating therapy with Rozulip® Plus should be informed of the risk of myopathy and should promptly report any muscle pain, tenderness, or weakness (see section 4.8).

Creatine kinase level

Creatine kinase (CK) levels should not be measured after significant exercise or when alternative causes of CK elevation exist that may complicate interpretation of results. If initial CK levels are significantly elevated (> 5 × ULN), repeat testing should be performed within 5–7 days to confirm the results. If repeat testing confirms that the initial CK value is greater than 5 times ULN, the drug should not be initiated.

Before starting treatment

Rosulip® Plus, like other HMG-CoA reductase inhibitors, should be administered with caution to patients with a predisposition to myopathy/rhabdomyolysis. Risk factors for this include:

– kidney dysfunction;

– 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”);

– su