Roxera plus film-coated tablets 10 mg + 10 mg blister No. 30

Instructions for Roxera plus film-coated tablets 10 mg + 10 mg blister No. 30

Composition

active ingredients: rosuvastatin, ezetimibe;

1 film-coated tablet contains: 5 mg of rosuvastatin (as rosuvastatin calcium) and 10 mg of ezetimibe or 10 mg of rosuvastatin (as rosuvastatin calcium) and 10 mg of ezetimibe, or 15 mg of rosuvastatin (as rosuvastatin calcium) and 10 mg of ezetimibe, or 20 mg of rosuvastatin (as rosuvastatin calcium) and 10 mg of ezetimibe, or 40 mg of rosuvastatin (as rosuvastatin calcium) and 10 mg of ezetimibe;

Excipients: microcrystalline cellulose; lactose; mannitol (E 421); crospovidone, type A; croscarmellose sodium; magnesium stearate; povidone K 30; sodium lauryl sulfate; colloidal anhydrous silicon dioxide;

film coating: lactose monohydrate, hypromellose, titanium dioxide (E 171), triacetin, yellow iron oxide (E 172) (contained in 10 mg/10 mg and 15 mg/10 mg tablets), red iron oxide (E 172) (contained in 15 mg/10 mg, 20 mg/10 mg and 40 mg/10 mg tablets), black iron oxide (E 172) (contained in 40 mg/10 mg tablets).

Dosage form

Film-coated tablets.

Main physicochemical properties:

5 mg/10 mg tablets: white or almost white, round, slightly biconvex, film-coated tablets with beveled edges and engraved R1 on one side;

10 mg/10 mg tablets: pale brownish-yellow to pale brownish-yellow, round, slightly biconvex, film-coated tablets with beveled edges and engraved R2 on one side;

15 mg/10 mg tablets: pale pink-orange, round, slightly biconvex, film-coated tablets with beveled edges and engraved with R3 on one side;

20 mg/10 mg tablets: pale pink, round, slightly biconvex, film-coated tablets with beveled edges and engraved with R4 on one side;

40 mg/10 mg tablets: pale greyish-purple to pale greyish-purple, round, slightly biconvex, film-coated tablets with bevelled edges and engraved with R5 on one side.

Pharmacotherapeutic group

HMG-CoA reductase inhibitors in combination with other lipid-lowering agents. Rosuvastatin and ezetimibe. ATC code C10B A06.

Pharmacological properties

Pharmacodynamics

Rosuvastatin

Rosuvastatin is a selective competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of cholesterol. The primary site of action of rosuvastatin is the liver, the target organ for lowering cholesterol concentrations.

Rosuvastatin increases the number of hepatic low-density lipoprotein (LDL) receptors on the cell surface, increasing the uptake and catabolism of LDL, and leads to inhibition of hepatic synthesis of very low-density lipoprotein (VLDL), thereby reducing the total number of LDL and VLDL particles.

Rosuvastatin reduces elevated LDL-cholesterol (LDL-C), total cholesterol, and triglycerides, and slightly increases high-density lipoprotein cholesterol (HDL-C). It also reduces apolipoprotein B, non-HDL-cholesterol, VLDL-cholesterol, VLDL-triglycerides, and slightly increases apolipoprotein A-I. Rosuvastatin also reduces the LDL-C/HDL-C ratio, total cholesterol/HDL-C, non-LDL-C/HDL-C ratio, and the apolipoprotein B/apolipoprotein A-I ratio.

The therapeutic effect is manifested within 1 week after the start of therapy with rosuvastatin, after 2 weeks of treatment the effect reaches 90% of the maximum possible. The maximum effect, as a rule, is achieved 4 weeks after the start of treatment.

Clinical efficacy and safety

Rosuvastatin has been shown to be effective in adults with hypercholesterolemia with or without hypertriglyceridemia regardless of race, gender, or age, as well as in special patient populations such as patients with diabetes or patients with a family history of hypercholesterolemia.

In pooled phase III studies, rosuvastatin was effective in lowering cholesterol levels in most patients with type IIa and IIb hypercholesterolemia (mean baseline LDL-C approximately 4.8 mmol/L) to the target values established by the recognized European Atherosclerosis Society (EAS; 1998); approximately 80% of patients taking the 10 mg dose achieved the EAS target LDL-C (<3 mmol/L).

Ezetimibe

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 hepatic cholesterol synthesis, and together these mechanisms provide additional cholesterol reduction. After 2 weeks of clinical use in 18 hypercholesterolemic patients, ezetimibe reduced cholesterol absorption by 54% compared with placebo. A series of preclinical studies were conducted to determine the selectivity of ezetimibe in 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 with the level of total cholesterol and LDL-C and inversely with the level of HDL-C.

Concomitant use of ezetimibe with statins has shown efficacy in reducing the risk of cardiovascular disease in patients with cardiovascular disease and a history of acute coronary syndromes.

Clinical efficacy and safety

According to clinical studies, the use of ezetimibe, as monotherapy or in combination with statins, significantly reduces total cholesterol, LDL-C, apolipoprotein B (apo-B), triglycerides and increases HDL-C in patients with hypercholesterolemia.

Pharmacokinetics

Rosuvastatin

Absorption

The maximum concentration (Cmax) of rosuvastatin in plasma is reached approximately 5 hours after oral administration. Absolute bioavailability is approximately 20%.

Distribution

Rosuvastatin is extensively metabolized in the liver, which is the primary site of cholesterol synthesis and LDL-C clearance. The volume of distribution of rosuvastatin is approximately 134 L. Approximately 90% of rosuvastatin is bound to plasma proteins, primarily albumin.

Metabolism

Rosuvastatin metabolism is limited (approximately 10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a very poor substrate for cytochrome P450-mediated metabolism. CYP2C9 was the major isoenzyme involved in metabolism, while isoenzymes 2C19, 3A4 and 2D6 were involved to a lesser extent. The main metabolites identified are the N-desmethyl and lactone. The N-desmethyl metabolite is approximately 50% less active than rosuvastatin, and the lactone form is considered clinically 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 (consisting of absorbed and unabsorbed active substance), and the remainder is excreted in the urine. Approximately 5% is excreted unchanged in the urine. The plasma half-life is approximately 19 hours. The half-life does not increase at high doses. The geometric mean plasma clearance is approximately 50 l/h (coefficient of variation 21.7%). As with other HMG-CoA reductase inhibitors, rosuvastatin is taken up by the liver with the participation of the membrane transporter OATP-C. This transporter plays an important role in the elimination of rosuvastatin from the liver.

Linearity/nonlinearity

Systemic exposure to rosuvastatin increases in proportion to the dose. Pharmacokinetic parameters do not change when taking 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 those in adult volunteers.

Race

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 a study involving patients with varying degrees of renal impairment, mild to moderate renal disease had no effect on the plasma concentrations of rosuvastatin or its N-desmethyl metabolite. In patients with severe renal impairment (creatinine clearance < 30 ml/min), the plasma concentrations of rosuvastatin increased 3-fold and the N-desmethyl metabolite increased 9-fold compared with those in healthy volunteers. Steady-state plasma concentrations of rosuvastatin in patients undergoing hemodialysis were approximately 50% higher than in healthy volunteers.

In a study involving patients with varying degrees of hepatic impairment in patients with hepatic insufficiency with Child-Pugh scores of 7 and less, no increase in rosuvastatin exposure was observed. However, increased systemic exposure of at least twofold was observed in two patients with scores of 8 and 9, compared with patients with lower Child-Pugh scores. There is no experience in patients with Child-Pugh scores of 9 and more.

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 10-17 or 6-17 years (total of 214 patients) with heterozygous familial hypercholesterolemia showed that the drug exposure in children is consistent with that in adults. The exposure of rosuvastatin was predicted based on dose and over a 2-year time period.

Ezetimibe

Absorption

After oral administration, ezetimibe is rapidly absorbed and actively conjugated to form a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide).

The mean Cmax in plasma 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 aqueous solution for injection.

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 food intake.

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

Children

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

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) 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, ezetimibe is not recommended for use in this patient population (see section 4.4).

Patients with renal insufficiency

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

Indication

Prevention of cardiovascular complications

Roxera® Plus is indicated to reduce the risk of cardiovascular complications as replacement therapy in patients with ischemic heart disease (IHD) and a history of acute coronary syndrome (ACS) in whom sufficient disease control is achieved by the simultaneous use of rosuvastatin and ezetimibe as monocomponent drugs in the same doses as in the combination drug.

Primary hypercholesterolemia/homozygous familial hypercholesterolemia

Roxera® Plus is indicated as an adjunct to diet or other non-pharmacological measures (e.g., exercise, weight loss) for the treatment of adult patients with primary (heterozygous familial and non-familial) hypercholesterolemia or homozygous familial hypercholesterolemia, in whom adequate disease control is achieved with the simultaneous use of rosuvastatin and ezetimibe as monocomponent drugs in the same doses as in the combination drug.

Contraindication

The drug Roxera® Plus is contraindicated in:

hypersensitivity to the active substances or to any other components of the medicinal product;

active liver disease, including persistent elevations of serum transaminases of unknown etiology and any elevations in serum transaminases greater than three times the upper limit of normal (ULN);

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

myopathies;

concomitant treatment with cyclosporine;

concomitant use of the combination sofosbuvir/velpatasvir/voxilaprevir (see section “Interaction with other medicinal products and other types of interactions”);

pregnancy and during breastfeeding; women of reproductive age who do not use appropriate contraception.

Roxera Plus, film-coated tablets 40 mg/10 mg, is contraindicated in patients with myopathy or pre-existing risk factors for myopathy/rhabdomyolysis; such factors include: moderate renal impairment (creatinine clearance < 60 ml/min); hypothyroidism; personal or family history of hereditary muscle diseases; history of myotoxicity caused by other HMG-CoA reductase inhibitors or fibrates; alcohol abuse; conditions that may lead to increased plasma concentrations of rosuvastatin; 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 Roxera Plus with cyclosporine is contraindicated (see 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 1). Simultaneous use does not affect the concentration of cyclosporine in the blood plasma.

Concomitant use is not recommended.

Protease inhibitors

Concomitant use of protease inhibitors may significantly increase systemic exposure to rosuvastatin, although the exact mechanism of this interaction is unknown (see Table 1). In particular, in a pharmacokinetic study, co-administration of rosuvastatin 10 mg and a combination product containing two protease inhibitors (atazanavir 300 mg/ritonavir 100 mg) in healthy volunteers was associated with an approximately three-fold and seven-fold increase in steady-state AUC and Cmax of rosuvastatin, respectively. Concomitant use of rosuvastatin and some combination products of protease inhibitors is possible only after careful adjustment of the dose of rosuvastatin, taking into account the expected increase in rosuvastatin exposure (see sections “Special instructions for use”, “Method of administration and dosage”, as well as Table 1 in the section “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 and 4.4, and Table 1 in the Interactions with other medicinal products and other forms of interaction section).

Fibrates

Based on data from specific studies, no significant pharmacokinetic interaction with fenofibrate is expected, but a pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates and lipid-lowering doses (≥ 1 g/day) of niacin (nicotinic acid) increase the risk of myopathy when administered concomitantly with HMG-CoA reductase inhibitors, possibly because they can cause myopathy when administered alone. The 40 mg/10 mg dose is contraindicated with concomitant use of fibrates (see sections 4.3 and 4.4). Such patients should be started on a 5 mg dose of rosuvastatin.

Patients taking ezetimibe and fenofibrate are at risk of developing cholelithiasis and gallstone disease (see sections "Special warnings and precautions for use" and "Adverse reactions").

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 modestly increases total ezetimibe concentrations (approximately 1.5- to 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 cholelithiasis. In nonclinical animal studies, ezetimibe increased cholesterol levels in gallbladder bile, but not in all species. A risk of stone formation associated with the use of ezetimibe cannot be excluded.

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).

Other interactions

Antacids

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.

Concomitant use of rosuvastatin and antacid suspensions containing aluminum hydroxide and magnesium hydroxide resulted in a decrease in rosuvastatin plasma concentrations by approximately 50%. This effect was less pronounced when antacids were administered 2 hours after rosuvastatin. The clinical significance of this interaction has not been studied.

Anticoagulants

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 increases in international normalized ratio (INR) in patients to whom ezetimibe was added to warfarin or fluindione. When ezetimibe is added to warfarin, another coumarin anticoagulant, or fluindione, appropriate monitoring of INR should be considered (see section 4.4).

As with other HMG-CoA reductase inhibitors, when starting rosuvastatin or increasing its dose in patients who are simultaneously taking vitamin K antagonists (e.g. warfarin or another coumarin anticoagulant), an increase in MHC may occur.

Discontinuation of rosuvastatin or dose reduction may lead to a decrease in MNC. In such cases, appropriate monitoring of MNC is desirable.

Erythromycin

It is known that the simultaneous use of rosuvastatin and erythromycin reduced the AUC of rosuvastatin by 20% and Cmax by 30%. This interaction may be due to increased intestinal peristalsis due to the action of erythromycin.

Cytochrome P450 enzymes

In vitro and in vivo studies show that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. In addition, rosuvastatin is a poor substrate for these isoenzymes. Therefore, drug interactions through cytochrome P450-mediated metabolism are not expected. No clinically significant interactions were observed between rosuvastatin and fluconazole (an inhibitor of CYP2C9 and CYP3A4 isoenzymes) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4 isoenzymes).

In nonclinical studies, ezetimibe did not induce cytochrome P450 enzymes that metabolize the drug. No clinically significant pharmacokinetic interactions were observed between ezetimibe and drugs metabolized by cytochrome P450: 1A2, 2D6, 2C8, 2C9, 3A4 - or N-acetyltransferase.

Cholestyramine

When co-administered with cholestyramine, the mean AUC of total ezetimibe (ezetimibe and ezetimibe-glucuronide) was decreased by approximately 55%. The gradual reduction in LDL-C may be slowed when ezetimibe is added to cholestyramine (see Dosage and Administration).

Digoxin

Based on data from specific studies, no clinically significant interaction with digoxin is expected.

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 considered 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.

Ticagrelor

Ticagrelor may cause renal failure and 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.

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 increases the AUC of rosuvastatin by less than 2 times, the initial dose does not need to be reduced, but caution should be exercised when increasing the dose of Roxera Plus above 20 mg.

Table 1

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

*Data presented as x-fold change represent the ratio between rosuvastatin in combination and alone. Data presented as % change represent the percentage difference relative to rosuvastatin alone.

**Several interaction studies have been conducted with different doses of rosuvastatin, the most significant relationship is shown in the table.

Drugs/combinations that did not have a clinically significant effect on the AUC ratio of rosuvastatin when used simultaneously: aleglitazar 0.3 mg for 7 days; fenofibrate 67 mg for 7 days 3 times a day; fluconazole 200 mg for 11 days 1 time a day; fosamprenavir 700 mg / ritonavir 100 mg for 8 days 2 times a day; ketoconazole 200 mg for 7 days 2 times a day; rifampin 450 mg for 7 days 1 time a day; silymarin 140 mg for 5 days 3 times a day.

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.

Children

Interaction studies have only been conducted in adults. The extent of interaction in children is unknown.

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

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 of more than 10 times the upper limit of normal, ezetimibe, any statins, or other concomitant medications should be discontinued immediately. Patients initiating therapy with Roxera® Plus should be informed of the risk of myopathy and should immediately report any muscle pain, tenderness, or weakness (see section 4.8).

In a few cases, statins have been reported to cause de novo or exacerbate pre-existing myasthenia gravis or ocular myasthenia (see section "Adverse reactions"). If symptoms worsen, Roxera® Plus should be discontinued. Relapses have been reported when the same or a different statin was (re)administered.

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 times 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, treatment should not be initiated.

Before starting treatment

Roxera® 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;

the presence of a 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 the blood plasma (see sections "Pharmacokinetics", "Interaction with other medicinal products and other types of interactions" and "Method of administration and dosage");

concomitant use of fibrates.

In such patients, the risk associated with treatment should be weighed against the expected benefit; clinical monitoring is also recommended. If baseline levels are