Clivas® plus

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT KLYVAS® PLUS (CLIVAS PLUS)

Composition:

Active substances:

10 mg/10 mg: 1 tablet contains 10.4 mg of rosuvastatin calcium, equivalent to 10.0 mg rosuvastatin and 10.0 mg ezetimibe;

20 mg/10 mg: 1 tablet contains 20.8 mg of rosuvastatin calcium, equivalent to 20.0 mg rosuvastatin and 10.0 mg ezetimibe;

40 mg/10 mg: 1 tablet contains 41.6 mg of rosuvastatin calcium, equivalent to 40.0 mg rosuvastatin and 10.0 mg ezetimibe;

Excipients:

for 10 mg/10 mg tablets: lactose monohydrate; sodium croscarmellose; povidone K-29/32; sodium lauryl sulfate; microcrystalline cellulose 102; hypromellose 2910; colloidal anhydrous silicon dioxide; magnesium stearate; tablet coating Opadry Beige 02F270003 (hypromellose 2910 (E 464); iron oxide yellow (E 172); titanium dioxide (E 171); macrogol 4000 (E 1521); talc (E 553b));

for 20 mg/10 mg tablets: lactose monohydrate; sodium croscarmellose; povidone K-29/32; sodium lauryl sulfate; microcrystalline cellulose 102; hypromellose 2910; colloidal anhydrous silicon dioxide; magnesium stearate; tablet coating Vivacoat PC-2P-308 (hypromellose 6 (E 464); titanium dioxide (E 171); talc (E 553b); macrogol 4000 (E 1521); iron oxide yellow (E 172));

for 40 mg/10 mg tablets: lactose monohydrate; sodium croscarmellose; povidone K-29/32; sodium lauryl sulfate; microcrystalline cellulose 102; hypromellose 2910; colloidal anhydrous silicon dioxide; magnesium stearate; tablet coating Opadry White OY-L-28900 (lactose monohydrate; hypromellose 2910 (E 464); titanium dioxide (E 171); macrogol 4000 (E 1521)).

Pharmaceutical form: Film-coated tablets.

Main physico-chemical properties.

10 mg/10 mg: beige, round, biconvex film-coated tablets, approximately 10 mm in diameter, with "EL 4" embossed on one side;

20 mg/10 mg: yellow, round, biconvex film-coated tablets, approximately 10 mm in diameter, with "EL 3" embossed on one side;

40 mg/10 mg: white, round, biconvex film-coated tablets, approximately 10 mm in diameter, with "EL 2" embossed on one side.

Pharmacotherapeutic group. Lipid-modifying agents. Combinations of different lipid-modifying agents. Rosuvastatin and ezetimibe.

ATC code C10BA06.

Pharmacological properties.

Pharmacodynamics.

The medicinal product contains ezetimibe and rosuvastatin – two hypolipidemic compounds with complementary mechanisms of action. It reduces elevated levels of total cholesterol (total TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and non-high-density lipoprotein cholesterol (non-HDL-C), and also increases high-density lipoprotein cholesterol (HDL-C) levels through dual inhibition of cholesterol absorption and synthesis.

Rosuvastatin

Mechanism of action

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

Rosuvastatin increases the number of hepatic low-density lipoprotein (LDL) receptors on the cell surface, enhancing the uptake and catabolism of LDL, and inhibits hepatic production of very-low-density lipoproteins (VLDL), thereby reducing the total number of VLDL and LDL particles.

Ezetimibe

Mechanism of action

Ezetimibe is a representative of a new class of lipid-lowering agents that selectively inhibit the intestinal absorption of cholesterol and associated plant sterols. Ezetimibe is administered orally and has a mechanism of action distinct from other classes of cholesterol-lowering drugs (e.g., statins, bile acid sequestrants (resins), fibrate acid derivatives, and plant stanols). The molecular target of ezetimibe is the Niemann-Pick C1-like 1 (NPC1L1) sterol transporter, which mediates intestinal absorption of cholesterol and phytosterols.

The site of action of ezetimibe is the brush border of the small intestine, where it inhibits cholesterol absorption, thereby reducing cholesterol delivery from the intestine to the liver. In turn, statins reduce cholesterol synthesis in the liver, and together these mechanisms provide additive cholesterol-lowering effects. In a 2-week clinical study involving 18 patients with hypercholesterolemia, ezetimibe reduced cholesterol absorption by 54% compared to placebo.

Pharmacodynamic effects

Rosuvastatin reduces elevated levels of LDL-C, total cholesterol, and triglycerides, and increases HDL-C levels. It also reduces levels of Apo B, non-HDL-C, VLDL-C, VLDL-TG, and increases levels of Apo A-I (see Table 1). Rosuvastatin also reduces the LDL-C/HDL-C, total cholesterol/HDL-C, non-HDL-C/HDL-C ratios, and Apo B/Apo A-I ratio.

Table 1

Dose-dependent effect in patients with primary hypercholesterolemia (types IIa and IIb) (adjusted mean percent change from baseline)

Dose	N	LDL-C	Total Cholesterol	HDL-C	Triglycerides	Non-HDL-C	Apo B	Apo A-I
Placebo	13	-7	-5	3	-3	-7	-3	0
5 mg	17	-45	-33	13	-35	-44	-38	4
10 mg	17	-52	-36	14	-10	-48	-42	4
20 mg	17	-55	-40	8	-23	-51	-46	5
40 mg	18	-63	-46	10	-28	-60	-54	0

The therapeutic effect appears within 1 week after initiation of the medicinal product, and after 2 weeks of treatment, the effect reaches 90% of the maximum possible. Maximum effect is usually achieved after 4 weeks and is maintained thereafter.

Ezetimibe

To determine the selectivity of ezetimibe in inhibiting cholesterol absorption, a number of preclinical studies were conducted. Ezetimibe inhibited the absorption of [14C]-cholesterol without affecting the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinylestradiol, or fat-soluble vitamins A and D.

Epidemiological studies have established a direct correlation between cardiovascular disease and mortality rates and the levels of total cholesterol and LDL-C, and an inverse correlation with HDL-C levels. The use of ezetimibe in combination with a statin effectively reduces the risk of cardiovascular disease in patients with a history of ischemic heart disease and hypercholesterolemia.

Concomitant use of rosuvastatin and ezetimibe

Clinical efficacy

A 6-week randomized, double-blind, parallel-group clinical trial was conducted to evaluate the safety and efficacy of ezetimibe (10 mg) added to ongoing rosuvastatin therapy, compared to gradually increasing doses of rosuvastatin from 5 to 10 mg or from 10 to 20 mg (n = 440). Pooled data demonstrated that adding ezetimibe to ongoing rosuvastatin therapy at doses of 5 mg or 10 mg reduced LDL-C levels by 21%. In contrast, doubling the rosuvastatin dose to 10 mg or 20 mg reduced LDL-C levels by 5.7% (difference between groups 15.2%, p < 0.001).

The combination regimen of ezetimibe plus rosuvastatin at a dose of 5 mg reduced LDL-C levels more than rosuvastatin 10 mg alone (difference 12.3%, p < 0.001), and the combination of ezetimibe plus rosuvastatin 10 mg reduced LDL-C levels more than rosuvastatin 20 mg alone (difference 17.5%, p < 0.001).

A 6-week randomized study was designed to investigate the efficacy and safety of rosuvastatin 40 mg alone and in combination with ezetimibe 10 mg in patients at high risk of ischemic heart disease (n = 469). In the rosuvastatin/ezetimibe group, a significantly higher proportion of patients achieved the ATP III target LDL-C level (< 100 mg/dL, 94.0% vs. 79.1%, p < 0.001) compared to the rosuvastatin monotherapy group. Rosuvastatin 40 mg provided effective improvement in atherogenic lipid profile in this high-risk population.

In a randomized, open-label, 12-week study, the reduction in LDL-C levels was evaluated in each treatment group (rosuvastatin 10 mg/ezetimibe 10 mg, rosuvastatin 20 mg/ezetimibe 10 mg, simvastatin 40 mg/ezetimibe 10 mg, simvastatin 80 mg/ezetimibe 10 mg). In the low-dose rosuvastatin combination groups, the reduction from baseline was 59.7%, significantly exceeding the result in the low-dose simvastatin combination groups (55.2%, p < 0.05). Treatment with high-dose rosuvastatin combinations reduced LDL-C levels by 63.5% compared to 57.4% with high-dose simvastatin combinations (p < 0.001).

Pediatric patients

The European Medicines Agency has waived the obligation to submit results of studies on the use of cholesterol-lowering medicinal products in all pediatric subgroups (see section "Dosage and administration" for information on use in children).

Pharmacokinetic properties

Combination therapy with rosuvastatin and ezetimibe

Concomitant administration of 10 mg rosuvastatin and 10 mg ezetimibe in patients with hypercholesterolemia resulted in a 1.2-fold increase in rosuvastatin AUC. A pharmacodynamic interaction between rosuvastatin and ezetimibe cannot be excluded, which may lead to the occurrence of adverse reactions.

Rosuvastatin

Absorption . After oral administration, the maximum plasma concentration of rosuvastatin is reached approximately within 5 hours. Absolute bioavailability is approximately 20%.

Distribution . Rosuvastatin is extensively taken up by 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, predominantly to albumin.

Biotransformation . Only about 10% of rosuvastatin is metabolized. In vitro metabolism studies using human hepatocytes demonstrated that rosuvastatin is minimally metabolized by cytochrome P450 enzymes. The main isoenzyme involved is CYP2C9, with minor contributions from CYP2C19, 3A4, and 2D6. The main identified metabolites are N-desmethyl and lactone metabolites. The N-desmethyl metabolite is approximately 50% less active than rosuvastatin, and the lactone metabolite is considered clinically inactive. Rosuvastatin accounts for more than 90% of circulating HMG-CoA reductase inhibitor activity.

Elimination . Approximately 90% of the rosuvastatin dose is excreted unchanged in feces (comprising both absorbed and unabsorbed active substance), with the remainder excreted in urine. Approximately 5% is excreted unchanged in urine. The plasma elimination half-life is approximately 19 hours and does not increase with dose escalation. The mean geometric value of plasma clearance is approximately 50 L/h (coefficient of variation 21.7%).

As with other HMG-CoA reductase inhibitors, hepatic uptake of rosuvastatin occurs via the membrane transporter OATP-C, which plays an important role in hepatic elimination of rosuvastatin.

Linearity . Systemic exposure to rosuvastatin increases proportionally with dose. No changes in pharmacokinetic parameters of rosuvastatin were observed after repeated administration at daily doses.

Special populations

Age and gender . Age and gender of the patient did not have a clinically significant impact on the pharmacokinetics of rosuvastatin in adults. Exposure in children and adolescents with heterozygous familial hypercholesterolemia is similar to or lower than exposure in adult patients with dyslipidemia (see below under "Pediatric patients").

Race . Pharmacokinetic study results indicate that in patients of Mongoloid race (Japanese, Chinese, Filipinos, Vietnamese, and Koreans) compared to Caucasian individuals, there is approximately a 2-fold increase in median AUC and Cmax values of rosuvastatin; in Indians, there is approximately a 1.3-fold increase in median AUC and Cmax values.

Population pharmacokinetic analysis did not reveal clinically significant differences in pharmacokinetics between Caucasian and Negroid racial groups.

Renal impairment . In a study involving patients with varying degrees of renal impairment, no changes in plasma concentrations of rosuvastatin or the N-desmethyl metabolite were observed in individuals with mild or moderate impairment. In patients with severe renal impairment (creatinine clearance < 30 mL/min), plasma concentrations of rosuvastatin increased 3-fold and N-desmethyl concentrations increased 9-fold compared to healthy volunteers.

Steady-state plasma concentrations of rosuvastatin in patients undergoing hemodialysis were approximately 50% higher than in healthy volunteers.

Hepatic impairment . In a study involving patients with varying degrees of hepatic impairment, no evidence of enhanced effect of rosuvastatin was observed in patients with Child-Pugh scores of 7 or lower. However, in two patients with Child-Pugh scores of 8 and 9, systemic exposure was at least doubled compared to patients with lower Child-Pugh scores.

There is no experience with the use of the medicinal product in patients with Child-Pugh scores above 9.

Genetic polymorphism . The distribution of HMG-CoA reductase inhibitors, including rosuvastatin, involves transporter proteins OATP1B1 and BCRP. Patients with genetic polymorphisms in SLCO1B1 (OATP1B1) and/or ABCG2 (BCRP) are at risk of enhanced effects of rosuvastatin. The SLCO1B1 c.521CC and ABCG2 c.421AA polymorphisms are associated with higher exposure (AUC) to rosuvastatin compared to genotypes SLCO1B1 c.521TT or ABCG2 c.421CC. Specific genotyping is not required in clinical practice, but patients identified with these polymorphisms should be prescribed a lower daily dose of rosuvastatin/ezetimibe.

Pediatric patients . In two pharmacokinetic studies of rosuvastatin (in tablet form) involving children aged 10–17 or 6–17 years with heterozygous familial hypercholesterolemia (total of 214 patients), drug exposure was similar to or lower than in adult patients. Rosuvastatin exposure was predictable with respect to dose and duration of administration over more than 2 years of observation.

Ezetimibe

Absorption . After oral administration, ezetimibe is rapidly absorbed and actively conjugated to form the pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). The mean maximum plasma concentration (Cmax) of ezetimibe-glucuronide is reached within 1–2 hours, and of ezetimibe within 4–12 hours. Absolute bioavailability of ezetimibe cannot be determined because the compound is practically insoluble in aqueous media suitable for injection.

Concomitant food intake (with low or high fat content) does not affect the oral bioavailability of ezetimibe. Ezetimibe can be taken independently of food intake.

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

Biotransformation . Ezetimibe metabolism occurs in the small intestine and liver via glucuronide conjugation (phase II reaction), followed by biliary excretion. Minimal oxidative metabolism (phase I reaction) was observed in all species studied. Ezetimibe and ezetimibe-glucuronide are the main substances detected in plasma, accounting for approximately 10–20% and 80–90% of total drug content in plasma, respectively. Ezetimibe and ezetimibe-glucuronide are slowly eliminated from plasma via enterohepatic recirculation. The elimination half-life of ezetimibe and ezetimibe-glucuronide is approximately 22 hours.

Elimination . After oral administration of 20 mg 14C-ezetimibe to volunteers, ezetimibe accounted for approximately 93% of total radioactivity in plasma. Approximately 78% and 11% of the administered radioactive dose were excreted in feces and urine, respectively, within 10 days. Measurable levels of radioactivity in plasma were not observed after 48 hours.

Special populations

Age and gender . In elderly patients (aged 65 years and older), plasma concentrations of total ezetimibe are approximately twice those in younger patients (18–45 years). However, LDL-C reduction and safety profile in elderly and younger patients receiving ezetimibe are comparable. Therefore, dose adjustment is not required in elderly patients. Plasma concentrations of total ezetimibe in women are slightly higher (approximately 20%) than in men. LDL-C reduction and safety profile in men and women receiving ezetimibe are comparable. Therefore, patient gender is not a reason for dose adjustment.

Renal impairment . After a single 10 mg dose of ezetimibe in patients with severe renal disease (n = 8; mean 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 result is not considered clinically significant. Dose adjustment is not required in patients with renal impairment.

In this study, one patient (who had undergone kidney transplantation and was receiving multiple medications, including cyclosporine) had 12-fold higher exposure to total ezetimibe.

Hepatic impairment . After a single 10 mg dose of ezetimibe in patients with mild hepatic impairment (5 or 6 points on the Child-Pugh scale), the mean AUC of total ezetimibe increased approximately 1.7-fold compared to healthy volunteers. In a 14-day study during which ezetimibe was administered at 10 mg daily, in patients with moderate hepatic impairment (7–9 points on the Child-Pugh scale), the mean AUC of total ezetimibe increased approximately 4-fold on both day 1 and day 14 compared to healthy volunteers. Dose adjustment is not required in patients with mild hepatic impairment. Due to the unknown impact of increased ezetimibe exposure, the medicinal product is not recommended for patients with moderate or severe hepatic impairment (> 9 points on the Child-Pugh scale).

Pediatric patients . Pharmacokinetic parameters of ezetimibe in children aged ≥ 6 years and adults are similar. Pharmacokinetic data in children under 6 years of age are lacking. Clinical use experience in children and adolescents includes patients with homozygous familial hypercholesterolemia, heterozygous familial hypercholesterolemia, and sitosterolemia.

Clinical characteristics.

Indications.

Primary hypercholesterolemia

The medicinal product Clivas® Plus is indicated as an adjunct to diet for the treatment of primary hypercholesterolemia (type IIa, including heterozygous familial hypercholesterolemia) in adult patients in whom adequate disease control is achieved with concomitant administration of rosuvastatin and ezetimibe as individual medicinal products at the same doses contained in the fixed-dose combination.

Prevention of cardiovascular diseases

Clivas® Plus is indicated as a replacement therapy in adult patients whose condition is adequately controlled with concomitant administration of rosuvastatin and ezetimibe as separate medicinal products at the same doses as those contained in the combined medicinal product, for the reduction of the risk of cardiovascular diseases in patients with ischemic heart disease (IHD) and a history of acute coronary syndrome (ACS).

Contraindications.

Hypersensitivity to the active substance (rosuvastatin, ezetimibe) or to any of the excipients of the medicinal product.

Active liver disease, including persistent elevations in serum transaminase levels of unknown etiology and serum levels of any transaminase exceeding three times the upper limit of normal (ULN) (see section "Special precautions for use").

Pregnancy, breastfeeding. The medicinal product is contraindicated in women of childbearing potential who are not using appropriate contraceptive measures (see section "Use during pregnancy or breastfeeding").

Severe renal impairment (creatinine clearance < 30 mL/min).

Myopathy (see section "Special precautions for use").

Concomitant use with the combination sofosbuvir/velpatasvir/voxilaprevir (see section "Interaction with other medicinal products and other types of interactions").

Concomitant therapy with cyclosporine (see section "Interaction with other medicinal products and other types of interactions").

The 40 mg/10 mg dose is contraindicated in patients with risk factors for developing myopathy/rhabdomyolysis. These risk factors include:

• moderate to severe renal impairment (creatinine clearance < 60 mL/min);
• hypothyroidism;
• personal or family history of hereditary muscle disorders;
• history of muscle toxicity during treatment with other HMG-CoA reductase inhibitors or fibrates;
• alcohol abuse;
• conditions associated with increased plasma levels of the medicinal product;
• Mongoloid race;
• concomitant use of fibrates (see sections "Interaction with other medicinal products and other types of interactions", "Special precautions for use", and "Pharmacodynamics").

Interaction with other medicinal products and other types of interactions.

Interactions related to rosuvastatin

Effect of concomitant medicinal products on rosuvastatin

Inhibitors of transport proteins

Rosuvastatin is a substrate for certain transporter proteins, including the hepatic uptake transporter OATP1B1 and the efflux transporter BCRP. Concomitant administration of rosuvastatin with medicinal products that inhibit these transporter proteins may increase plasma concentrations of rosuvastatin and increase the risk of myopathy (see sections "Dosage and administration", "Special precautions for use", "Interaction with other medicinal products and other types of interactions", Table 2).

Tickagrelor

Ticagrelor may affect renal excretion of rosuvastatin, increasing the risk of its accumulation. Although the exact mechanism is unknown, in some cases, concomitant use of ticagrelor and rosuvastatin has led to impaired renal function, elevated creatine phosphokinase (CPK) levels, and rhabdomyolysis.

Cyclosporine

When rosuvastatin and cyclosporine are administered concomitantly, rosuvastatin AUC values were approximately 7-fold higher than those observed in healthy volunteers (see Table 2). Rosuvastatin is contraindicated in patients receiving cyclosporine (see section "Contraindications").

Concomitant administration of rosuvastatin and cyclosporine did not affect cyclosporine plasma concentrations.

Protease inhibitors

Although the exact mechanism of interaction is unknown, concomitant use of protease inhibitors may substantially increase rosuvastatin exposure (see Table 2). For example, in a pharmacokinetic study, concomitant administration of 10 mg rosuvastatin and a combination medicinal product containing two protease inhibitors (300 mg atazanavir/100 mg ritonavir) in healthy volunteers was associated with approximately 3- and 7-fold increases in rosuvastatin AUC and Cmax, respectively. Concomitant use of rosuvastatin with certain protease inhibitor combinations may be possible after careful dose adjustment of rosuvastatin based on the expected increase in exposure (see sections "Dosage and administration", "Special precautions for use", "Interaction with other medicinal products and other types of interactions", Table 2).

Gemfibrozil and other lipid-lowering agents

Concomitant administration of rosuvastatin and gemfibrozil results in a doubling of rosuvastatin Cmax and AUC values (see section "Special precautions for use").

Based on data from specific studies, no clinically significant pharmacokinetic interaction with fenofibrate is expected; however, 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 used concomitantly with HMG-CoA reductase inhibitors, likely because they may cause myopathy when administered alone. The 40 mg dose is contraindicated when coadministered with fibrates (see sections "Contraindications" and "Special precautions for use"). Such patients should also initiate rosuvastatin therapy at a 5 mg dose.

Ezetimibe

Concomitant administration of 10 mg rosuvastatin and 10 mg ezetimibe in patients with hypercholesterolemia resulted in a 1.2-fold increase in rosuvastatin AUC (see Table 2). A pharmacodynamic interaction between rosuvastatin and ezetimibe cannot be excluded, which may lead to adverse reactions (see section "Special precautions for use").

Antacids

Concomitant administration of rosuvastatin with an antacid suspension containing aluminum and magnesium hydroxide resulted in approximately a 50% reduction in rosuvastatin plasma concentration. This effect was less pronounced when the antacid was administered 2 hours after rosuvastatin. The clinical significance of this interaction has not been studied.

Erythromycin

Concomitant administration of rosuvastatin and erythromycin resulted in a 20% reduction in rosuvastatin AUC and a 30% reduction in Cmax. This interaction may be due to enhanced intestinal motility caused by erythromycin.

Cytochrome P450 enzymes

Results from in vitro and in vivo studies indicate that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. Furthermore, rosuvastatin is a weak substrate of these isoenzymes. Therefore, interactions related to metabolism via cytochrome P450 enzymes 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).

Interactions requiring dose adjustment of rosuvastatin (see also Table 2)

When rosuvastatin must be used concomitantly with other medicinal products that may increase rosuvastatin exposure, the rosuvastatin dose should be adjusted. If an increase in drug exposure (AUC) of approximately 2-fold or more is expected, rosuvastatin therapy should be initiated at a dose of 5 mg once daily. The maximum daily dose of rosuvastatin should be adjusted so that the expected rosuvastatin exposure does not exceed that observed with a 40 mg daily dose in the absence of interacting medicinal products; for example, when coadministered with gemfibrozil, the rosuvastatin dose should be limited to 20 mg (exposure increased 1.9-fold); when coadministered with ritonavir/atazanavir, the dose should be limited to 10 mg (exposure increased 3.1-fold).

If a medicinal product increases rosuvastatin AUC by less than 2-fold, no initial dose reduction is required, but caution should be exercised when increasing the rosuvastatin dose above 20 mg.

Table 2

Effect of concomitant medicinal products on rosuvastatin exposure (AUC; in descending order of magnitude) based on published clinical study data

Increased rosuvastatin AUC by 2-fold or more
Dosing regimen of the interacting drug	Rosuvastatin dosing regimen	Changes in rosuvastatin AUC*
Sofosbuvir/velpatasvir/voxilaprevir (400 mg/100 mg/100 mg) + voxilaprevir (100 mg) once daily for 15 days	10 mg, single dose	↑ 7.4-fold
Cyclosporine from 75 mg twice daily to 200 mg twice daily, 6 months	10 mg once daily, 10 days	↑ 7.1-fold
Darolutamide 600 mg twice daily, 5 days	5 mg, single dose	↑ 5.2-fold
Regorafenib 160 mg once daily, 14 days	5 mg, single dose	↑ 3.8-fold
Atazanavir 300 mg/ritonavir 100 mg once daily, 8 days	10 mg, single dose	↑ 3.1-fold
Velpatasvir 100 mg once daily	10 mg, single dose	↑ 2.7-fold
Obitasvir 25 mg/paritaprevir 150 mg/ ritonavir 100 mg once daily / dasabuvir 400 mg twice daily, 14 days	5 mg, single dose	↑ 2.6-fold
Teriflunomide	Data not available	↑ 2.5-fold
Glecaprevir 200 mg/elbasvir 50 mg once daily, 11 days	10 mg, single dose	↑ 2.3-fold
Glecaprevir 400 mg/pibrentasvir 120 mg once daily, 7 days	5 mg once daily, 7 days	↑ 2.2-fold
Lopinavir 400 mg/ritonavir 100 mg twice daily, 17 days	20 mg once daily, 7 days	↑ 2.1-fold
Capmatinib 400 mg twice daily	10 mg, single dose	↑ 2.1-fold
Clopidogrel 300 mg, then 75 mg after 24 hours	20 mg, single dose	↑ 2-fold
Fostamatinib 100 mg twice daily	20 mg, single dose	↑ 2.0-fold
Febuxostat 120 mg once daily	10 mg, single dose	↑ 1.9-fold
Bezafibrate 600 mg twice daily, 7 days	80 mg, single dose	↑ 1.9-fold
Increased rosuvastatin AUC less than 2-fold
Dosing regimen of the interacting drug	Rosuvastatin dosing regimen	Changes in rosuvastatin AUC*
Elotrombopag 75 mg once daily, 5 days	10 mg, single dose	↑ 1.6-fold
Darunavir 600 mg/ritonavir 100 mg twice daily, 7 days	10 mg once daily, 7 days	↑ 1.5-fold
Tipranavir 500 mg/ritonavir 200 mg twice daily, 11 days	10 mg, single dose	↑ 1.4-fold
Dronedarone 400 mg twice daily	Data not available	↑ 1.4-fold
Itraconazole 200 mg once daily, 5 days	10 mg, single dose	↑ 1.4-fold **
Ezetimibe 10 mg once daily, 14 days	10 mg once daily, 14 days	↑ 1.2-fold **
Decreased rosuvastatin AUC
Dosing regimen of the interacting drug	Rosuvastatin dosing regimen	Changes in rosuvastatin AUC*
Erythromycin 500 mg four times daily, 7 days	80 mg, single dose	↓ 20%
Scutellaria baicalensis 50 mg three times daily, 14 days	20 mg, single dose	↓ 47%

* Data presented as change by a factor are ratios between co-administration and administration of rosuvastatin alone. Data presented as % change represent % difference relative to values observed with rosuvastatin alone.

Increase is indicated by ↑, decrease by ↓.

** Several drug interaction studies were conducted at different doses of rosuvastatin; the most significant ratio is presented in Table 2.

Drug products/combinations that did not have a clinically significant effect on rosuvastatin AUC when co-administered: aleglitazar 0.3 mg for 7 days; fenofibrate 67 mg three times daily for 7 days; fluconazole 200 mg once daily for 11 days; fosamprenavir 700 mg/ritonavir 100 mg twice daily for 8 days; ketoconazole 200 mg twice daily for 7 days; rifampicin 450 mg once daily for 7 days; silymarin 140 mg three times daily for 5 days.

Effect of rosuvastatin on concomitant medicinal products

Vitamin K antagonists. As with other HMG-CoA reductase inhibitors, initiation or dose increase of rosuvastatin while on vitamin K antagonists (e.g., warfarin or other coumarin anticoagulants) may lead to an increase in the international normalized ratio (INR). Discontinuation or dose reduction of rosuvastatin may lead to a decrease in INR. In such situations, appropriate monitoring of INR is advisable.

Oral contraceptives/hormone replacement therapy (HRT). Concomitant administration of rosuvastatin and oral contraceptives resulted in a 26% and 34% increase in AUC of ethinylestradiol and norgestimate, respectively. These increases in plasma levels should be considered when selecting the dose of oral contraceptives. There are no data on the pharmacokinetics of medicinal products in patients receiving rosuvastatin and HRT simultaneously; therefore, an effect of rosuvastatin on the pharmacokinetics of HRT cannot be excluded. However, this combination has been widely used in women in clinical trials and was well tolerated.

Other medicinal products

Digoxin

Based on dedicated interaction studies, no clinically significant interaction with digoxin is expected.

Fusidic acid

Interaction studies between rosuvastatin and fusidic acid have not been conducted. The risk of developing myopathy, including rhabdomyolysis, may increase when systemic fusidic acid is co-administered with statins. The mechanism of this interaction (pharmacodynamic, pharmacokinetic, or both) is currently unknown. Cases of rhabdomyolysis (including fatal outcomes) have been reported in patients receiving this combination.

If systemic fusidic acid therapy is necessary, rosuvastatin treatment should be discontinued for the duration of fusidic acid treatment (see also section "Special precautions for use").

Interactions related to ezetimibe

Preclinical studies have shown that ezetimibe does not induce cytochrome P450 enzymes responsible for drug metabolism. No clinically significant pharmacokinetic interactions were observed between ezetimibe and medicinal products known to be metabolized by cytochrome P450 enzymes 1A2, 2D6, 2C8, 2C9, and 3A4 or by N-acetyltransferase.

In clinical interaction studies, ezetimibe did not affect the pharmacokinetics of dapsone, dextromethorphan, digoxin, oral contraceptives (ethinylestradiol and levonorgestrel), glipizide, tolbutamide, or midazolam when co-administered. Cimetidine did not affect the bioavailability of ezetimibe when administered concomitantly.

Antacids

Concomitant administration of antacids reduced the rate of ezetimibe absorption but did not affect its bioavailability. This reduction in absorption rate is not considered clinically significant.

Cholestyramine

Concomitant administration of cholestyramine reduced the mean AUC of total ezetimibe (ezetimibe + ezetimibe glucuronide) by approximately 55%. This interaction may result in a gradual reduction in the LDL-cholesterol (LDL-C) lowering effect when ezetimibe is added to cholestyramine (see section "Dosage and administration").

Fibrates

Physicians should be aware of the potential risk of gallstone disease and gallbladder disease in patients receiving fenofibrate and ezetimibe (see sections "Special precautions for use" and "Adverse reactions"). If gallstone disease is suspected in a patient receiving ezetimibe and fenofibrate, gallbladder imaging should be performed and such therapy discontinued (see section "Adverse reactions"). Concomitant administration of fenofibrate or gemfibrozil moderately increased total ezetimibe concentration (approximately 1.5- and 1.7-fold, respectively).

The concomitant use of ezetimibe with other fibrates has not been studied.

Fibrates may enhance cholesterol excretion into bile, leading to gallstone formation. In animal studies, ezetimibe occasionally increased biliary cholesterol levels in the gallbladder, although not in all species. A lithogenic risk associated with the therapeutic use of ezetimibe cannot be excluded.

Statins

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

Cyclosporine

In a study involving eight kidney transplant patients with creatinine clearance >50 mL/min receiving stable doses of cyclosporine, a single 10 mg dose of ezetimibe resulted in a 3.4-fold increase (range: 2.3 to 7.9-fold) in mean AUC of total ezetimibe compared to control healthy subjects receiving ezetimibe alone in another study (n = 17). In another case involving a kidney transplant patient with severe renal impairment receiving cyclosporine and multiple other medicinal products, exposure to total ezetimibe was 12 times higher than in control subjects receiving ezetimibe alone. In a two-period crossover study involving 12 healthy volunteers, daily administration of 20 mg ezetimibe for 8 days and a single 100 mg dose of cyclosporine on day 7 resulted in a mean 15% increase in cyclosporine AUC (ranging from a 10% decrease to a 51% increase) compared to administration of cyclosporine 100 mg alone. A controlled study evaluating the effect of ezetimibe on cyclosporine exposure when co-administered in kidney transplant patients has not been conducted. Caution should be exercised when initiating ezetimibe with cyclosporine. Cyclosporine concentrations should be monitored in patients receiving both ezetimibe and cyclosporine (see section "Special precautions for use").

Anticoagulants

Concomitant administration of ezetimibe (10 mg once daily) did not affect the bioavailability of warfarin or prothrombin time in a study involving twelve healthy adult males. However, post-marketing experience has reported increased INR in patients taking ezetimibe concomitantly with warfarin or fluindione. When co-administering the rosuvastatin/ezetimibe combination with warfarin, other coumarin anticoagulants, or fluindione, INR should be appropriately monitored (see section "Special precautions for use").

Paediatric population

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

Special precautions for use.

Renal effects

Proteinuria detected by urine dipstick testing, predominantly of tubular origin, has been observed in patients treated with higher doses of rosuvastatin, particularly 40 mg, and was mostly transient or intermittent in most cases. Proteinuria was not a predictor of acute or progressive kidney disease (see section "Adverse reactions"). The frequency of reports of serious renal events in post-marketing studies is higher with the 40 mg dose. Renal function should be regularly monitored in patients taking the medicinal product at a dose of 40 mg.

Skeletal muscle effects

Skeletal muscle disorders, such as myalgia, myopathy, and rarely rhabdomyolysis, have been observed in patients treated with rosuvastatin and ezetimibe, particularly at doses > 20 mg. Cases of rhabdomyolysis have very rarely been reported with ezetimibe in combination with HMG-CoA reductase inhibitors. A pharmacodynamic interaction cannot be excluded (see section "Interaction with other medicinal products and other forms of interaction"), and therefore such combination should be used with caution.

As with other HMG-CoA reductase inhibitors, the frequency of post-marketing reports of rhabdomyolysis associated with rosuvastatin use was higher with the 40 mg dose.

In case of suspected myopathy presenting with muscle symptoms or creatine kinase levels more than 10 times the upper limit of normal (ULN), treatment with the medicinal product and any other concomitantly administered medicinal product should be immediately discontinued. All patients initiating treatment with a medicinal product containing ezetimibe in combination with HMG-CoA reductase inhibitors should be informed about the risk of myopathy and the need to promptly report any muscle pain, weakness, or malaise of unknown origin.

In the international IMPROVE-IT study, 18,144 patients with established cardiovascular disease (CVD) and a history of acute coronary syndrome were randomized to receive ezetimibe/simvastatin 10/40 mg daily (n = 9,067) or simvastatin 40 mg daily (n = 9,077). During a median follow-up of 6 years, the incidence of myopathy was 0.2% with ezetimibe/simvastatin combination and 0.1% with simvastatin alone. Myopathy was defined as muscle weakness or pain of unknown etiology with serum creatine kinase levels ≥ 10 times the ULN, or with levels ≥ 5 and < 10 times the ULN on two consecutive measurements. The incidence of rhabdomyolysis was 0.1% with ezetimibe/simvastatin and 0.2% with simvastatin alone. Acute rhabdomyolysis was defined as muscle weakness or pain of unknown etiology with serum creatine kinase levels ≥ 10 times the ULN, confirmed renal impairment, ≥ 5 times the ULN and < 10 times the ULN with confirmed renal impairment on two consecutive occasions, or creatine kinase levels ≥ 10,000 IU/L without signs of renal impairment (see section "Adverse reactions").

In clinical trials involving over 9,000 patients with chronic kidney disease randomized to receive ezetimibe 10 mg in combination with statin 20 mg daily (n = 4,650) or placebo (n = 4,620) (mean observation period 4.9 years), the incidence of myopathy was 0.2% with ezetimibe in combination with simvastatin and 0.1% with placebo (see section "Adverse reactions").

Creatine kinase levels

Creatine kinase (CK) levels should not be measured after significant physical exertion or in the presence of a plausible alternative cause of elevated CK levels that could interfere with interpretation of results.

If baseline CK levels are markedly elevated (> 5 times ULN), a confirmatory test should be performed within 5–7 days to confirm the results. If the repeat test confirms baseline CK levels more than 5 times ULN, initiation of the medicinal product is not recommended.

Prior to treatment initiation

The combination of rosuvastatin/ezetimibe and other HMG-CoA reductase inhibitors should be prescribed with caution in patients with risk factors for myopathy/rhabdomyolysis. These risk factors include:

• renal impairment;
• hypothyroidism;
• personal or family history of hereditary muscular disorders;
• history of muscle toxicity due to other HMG-CoA reductase inhibitors or fibrates;
• alcohol abuse;
• age > 70 years;
• conditions that may lead to increased plasma levels of the medicinal product (see sections "Posology and method of administration", "Interaction with other medicinal products and other forms of interaction", and "Pharmacokinetics");
• concomitant use of fibrates.

In such patients, the risks associated with treatment should be weighed against the expected benefits, and clinical monitoring is recommended. Treatment should not be initiated if baseline CK levels are markedly elevated (> 5 times ULN).

During treatment

Patients should be advised to immediately report unexplained muscle pain, muscle weakness, or cramps, especially if accompanied by malaise or fever. CK levels should be measured in such patients. Treatment should be discontinued if CK levels are markedly elevated (> 5 × ULN) or if muscle symptoms are severe and cause discomfort in daily life (even if CK levels ≤ 5 × ULN). If symptoms resolve and CK levels return to normal, re-initiation of rosuvastatin or an alternative HMG-CoA reductase inhibitor at the lowest dose with close monitoring may be considered. Routine monitoring of CK levels in patients without the aforementioned symptoms is not required. Very rare cases of immune-mediated necrotizing myopathy (IMNM) have been reported during or after statin therapy, including rosuvastatin. Clinically, IMNM is characterized by proximal muscle weakness and elevated serum creatine kinase levels that persist despite discontinuation of statin therapy.

There have been reports that statins may induce or exacerbate pre-existing myasthenia gravis or ocular myasthenia (see section "Adverse reactions"). If symptoms of these conditions worsen, treatment with Clivas® Plus should be discontinued. Recurrences have been reported upon first or repeated use of the same or another statin.

Clinical trials have not provided evidence of increased skeletal muscle effects in a small number of patients receiving rosuvastatin and concomitant therapy. However, increased incidence of myositis and myopathy has been observed in patients receiving other HMG-CoA reductase inhibitors concomitantly with fibric acid derivatives, particularly gemfibrozil, as well as with cyclosporine, nicotinic acid, azole antifungals, protease inhibitors, and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when used concomitantly with certain HMG-CoA reductase inhibitors. Therefore, concomitant use of the medicinal product with gemfibrozil is not recommended. The benefit of further lipid-lowering with rosuvastatin in combination with fibrates or niacin should be carefully weighed against the potential risks associated with such combinations. The 40 mg dose is contraindicated when used concomitantly with fibrates (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Rosuvastatin should not be used concomitantly with systemic fusidic acid or within 7 days after discontinuation of fusidic acid treatment. In patients for whom systemic fusidic acid treatment is considered necessary, statin therapy should be discontinued for the entire duration of fusidic acid treatment. Cases of rhabdomyolysis (including several fatal cases) have been reported in patients receiving a combination of fusidic acid and statins (see section "Interaction with other medicinal products and other forms of interaction"). Patients should be advised to seek immediate medical attention if they experience any symptoms of muscle weakness, pain, or tenderness. Statin therapy may be resumed seven days after the last dose of fusidic acid. In exceptional cases where prolonged systemic fusidic acid is required, e.g., for the treatment of severe infections, the need for concomitant administration of rosuvastatin and fusidic acid should be considered on a case-by-case basis and administered under close medical supervision.

The medicinal product should not be prescribed to patients with acute, serious conditions indicating myopathy or with risk factors for renal failure secondary to rhabdomyolysis (e.g., sepsis, arterial hypotension, major surgery, trauma, severe metabolic, endocrine, or electrolyte disturbances, or uncontrolled seizures).

Severe cutaneous adverse reactions

Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported with rosuvastatin use, which may be life-threatening or fatal (see section "Adverse reactions"). Patients should be informed about the signs and symptoms of severe skin reactions and closely monitored during treatment. If signs or symptoms suggestive of such reactions occur, the medicinal product should be immediately discontinued and alternative treatment considered.

If a serious reaction such as SJS or DRESS develops in a patient during treatment with the medicinal product, re-treatment with this medicinal product in that patient should never be resumed.

Hepatic effects

Since the effects of increased ezetimibe exposure in patients with moderate to severe hepatic impairment are unknown, the medicinal product is not recommended for use in this patient population.

As with other HMG-CoA reductase inhibitors, rosuvastatin should be used with caution in patients who abuse alcohol and/or have a history of liver disease.

Liver function tests are recommended 3 months after initiation of rosuvastatin therapy. If serum transaminase levels exceed the upper limit of normal by more than 3 times, treatment with the rosuvastatin/ezetimibe combination should be discontinued or the dose reduced. During post-marketing use, the frequency of serious hepatic adverse events (predominantly cases of elevated hepatic transaminases) was higher with the 40 mg dose.

In patients with secondary hypercholesterolemia due to hypothyroidism or nephrotic syndrome, treatment of the underlying condition should be initiated prior to starting rosuvastatin/ezetimibe combination therapy.

Liver enzymes

During controlled clinical trials in patients receiving statin and ezetimibe combination therapy, gradual increases in transaminase levels (≥ 3 times ULN) were observed. Liver function tests should be performed at the beginning of therapy and according to statin use recommendations when using ezetimibe in combination with a statin.

In the international study "Improved Reduction of Cardiovascular Events with Vytorin" (IMPROVE-IT), 18,144 patients with established CVD and a history of acute coronary syndrome were randomized to receive ezetimibe/simvastatin 10/40 mg daily (n = 9,067) or simvastatin 40 mg daily (n = 9,077). During a median follow-up of 6 years, the incidence of elevated transaminase levels (≥ 3 × ULN) was 2.5% with ezetimibe/simvastatin and 2.3% with simvastatin alone.

Interstitial lung disease

Interstitial lung disease has been reported with some statins, particularly with long-term therapy (see section "Adverse reactions"). Possible signs may include dyspnea, non-productive cough, and worsening of general well-being (fatigue, weight loss, and fever). If interstitial lung disease is suspected, statin therapy should be discontinued.

Diabetes mellitus

Some data suggest that statins as a class increase blood glucose levels and may lead to hyperglycemia requiring treatment as diabetes in some patients at high risk of developing diabetes. However, the cardiovascular risk reduction with statin use outweighs the risk of developing hyperglycemia; therefore, this should not be a reason to discontinue statin therapy. In patients at risk of developing diabetes (fasting glucose 5.6–6.9 mmol/L, body mass index (BMI) > 30 kg/m², elevated triglycerides, arterial hypertension), clinical and biochemical parameters should be monitored according to national guidelines.

In the JUPITER study, the overall incidence of diabetes 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.

Anticoagulants

When rosuvastatin/ezetimibe combination is added to warfarin, other coumarin anticoagulants, or fluindione, international normalized ratio (INR) should be appropriately monitored (see section "Interaction with other medicinal products and other forms of interaction").

Cyclosporine

See sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction".

Fibrates

The safety and efficacy of ezetimibe with fibrates have not been established (see information above and sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

If gallstone disease is suspected in a patient receiving rosuvastatin/ezetimibe and fenofibrate, gallbladder examination should be performed and such therapy discontinued (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Protease inhibitors

Increased systemic exposure to rosuvastatin has been observed in individuals receiving rosuvastatin concomitantly with various protease inhibitors in combination with ritonavir. Both the benefit of lipid-lowering with the medicinal product in HIV patients receiving protease inhibitors and the potential for increased plasma concentrations of rosuvastatin at the initiation of therapy and with gradual dose escalation of rosuvastatin in patients receiving protease inhibitors should be considered. Concomitant use of the medicinal product with certain protease inhibitors is not recommended until dose adjustment of rosuvastatin is performed (see sections "Posology and method of administration" and "Interaction with other medicinal products and other forms of interaction").

Race

In pharmacokinetic studies of rosuvastatin, increased rosuvastatin exposure has been observed in patients of Mongoloid race compared to Caucasian race (see sections "Posology and method of administration", "Contraindications", and "Pharmacokinetics").

Children

Assessment of linear growth (height), body weight, BMI (body mass index), and secondary sexual characteristics by Tanner stage in children aged 6 to 17 years receiving rosuvastatin is limited to a 2-year period. After 2 years of investigational treatment, no effect on growth, body weight, BMI, or sexual maturation was observed (see section "Pharmacodynamics").

In a clinical study in children and adolescents receiving rosuvastatin for 52 weeks, CK levels > 10 times ULN and muscle symptoms after physical exertion or increased physical activity were observed more frequently compared to adults (see section "Adverse reactions").

The efficacy and safety of ezetimibe in patients aged 6 to 10 years with heterozygous familial or non-familial hypercholesterolemia were evaluated in a 12-week placebo-controlled clinical study. The effects of ezetimibe during treatment periods > 12 weeks in this age group were not studied.

The use of ezetimibe in patients under 6 years of age has not been studied.

The efficacy and safety of ezetimibe administered in combination with simvastatin in patients aged 10 to 17 years with heterozygous familial hypercholesterolemia were evaluated in a controlled clinical study involving boys (Tanner stage II or higher) and girls (at least one year after menarche).

The safety and efficacy of ezetimibe in combination with simvastatin in children under 10 years of age have not been studied.

The long-term efficacy of ezetimibe therapy in patients under 17 years of age for reducing morbidity and mortality in adulthood has not been studied.

If you have an intolerance to certain sugars, consult your doctor before taking this medicinal product.

The medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e., essentially sodium-free.

Use during pregnancy or breastfeeding.

Clivas® Plus is contraindicated during pregnancy and breastfeeding (see section "Contraindications"). Women of childbearing potential must use appropriate contraceptive measures.

Pregnancy

Rosuvastatin. Since cholesterol and other products of cholesterol biosynthesis are essential for fetal development, the potential risk of HMG-CoA reductase inhibition outweighs the benefit of using the medicinal product during pregnancy. Animal studies provide limited evidence of reproductive toxicity. If pregnancy occurs during treatment with the medicinal product, treatment should be immediately discontinued.

Ezetimibe. There are no clinical data on the use of ezetimibe during pregnancy.

Animal studies with ezetimibe monotherapy provided no evidence of direct or indirect harmful effects on pregnancy, embryofetal development, parturition, or postnatal development.

Lactation

Rosuvastatin. It is known that rosuvastatin is excreted in rat milk. There are no data on the excretion of rosuvastatin in human breast milk (see section "Contraindications").

Ezetimibe. Animal studies in rats have shown that ezetimibe is excreted in milk. It is unknown whether ezetimibe is excreted in human breast milk.

Fertility

There are no clinical trial data on the effect of ezetimibe or rosuvastatin on fertility in humans. Ezetimibe did not affect fertility in male or female rats. Rosuvastatin at high doses demonstrated testicular toxicity in monkeys and dogs.

Ability to influence the ability to drive and use machines.

The rosuvastatin/ezetimibe combination has no effect or a negligible effect on the ability to drive or use machines. Studies on the effect of rosuvastatin and/or ezetimibe on reaction speed during driving or operating machinery have not been conducted. When driving or operating machinery, it should be considered that dizziness may occur during treatment.

Method of Administration and Dosage

Dosage

The patient should adhere to an appropriate hypolipidemic diet and continue to follow it during treatment with the medicinal product Clivas® Plus.

The medicinal product Clivas® Plus is not suitable for initial therapy. Treatment should be initiated with monocomponent medicinal products only, and their doses adjusted as necessary; after determining the required doses, transition to the use of a combined medicinal product with corresponding fixed-dose combinations may be considered.

Patients should take the medicinal product at a dosage corresponding to their previous treatment regimen. The recommended dose is one tablet daily.

Concomitant use of bile acid sequestrants

The medicinal product Clivas® Plus should be taken ≥ 2 hours before or ≥ 4 hours after administration of a bile acid sequestrant.

Elderly patients

For patients aged > 70 years, the initial dose of rosuvastatin is 5 mg (see section "Special Warnings and Precautions for Use"). The combined medicinal product is not suitable for initial therapy. Treatment should be initiated with monocomponent agents only, and their doses adjusted as necessary; after determining the required doses, transition to the use of a combined medicinal product with corresponding fixed-dose combinations may be considered.

Renal impairment

Dose adjustment is not required in patients with mild renal impairment.

For patients with moderate renal impairment (creatinine clearance < 60 mL/min), the recommended initial dose of rosuvastatin is 5 mg.

The 40 mg/10 mg dose of the medicinal product is contraindicated in patients with moderate renal impairment.

The medicinal product Clivas® Plus is contraindicated in patients with severe renal impairment at any dose (see sections "Contraindications" and "Pharmacokinetics").

Hepatic impairment

In patients with hepatic function impairment scoring 7 or less on the Child–Pugh scale, no increase in systemic exposure to rosuvastatin was observed. However, in individuals scoring 8 or 9 on the Child–Pugh scale, systemic exposure increased (see section "Pharmacokinetics"). In such patients, assessment of renal function is advisable (see section "Special Warnings and Precautions for Use"). There is no experience with use of the medicinal product in patients scoring more than 9 points on the Child–Pugh scale. The medicinal product Clivas® Plus is contraindicated in patients with active liver disease (see section "Contraindications").

Race

Increased systemic exposure to rosuvastatin has been observed in patients of Mongoloid race (see sections "Contraindications", "Special Warnings and Precautions for Use", and "Pharmacokinetics"). The recommended initial dose of rosuvastatin in patients of Mongoloid race is 5 mg. The 40 mg/10 mg dose of Clivas® Plus is contraindicated in these patients (see sections "Contraindications" and "Pharmacokinetics").

Genetic polymorphisms

Certain types of genetic polymorphisms may lead to increased exposure to rosuvastatin. A lower daily dose is recommended for patients with any of these specific polymorphism types.

Dosing in patients with risk factors for myopathy

For patients with risk factors for developing myopathy, the recommended initial dose of rosuvastatin is 5 mg (see section "Special Warnings and Precautions for Use"). The 40 mg/10 mg dose of Clivas® Plus is contraindicated in some of these patients (see section "Contraindications").

Concomitant therapy

Rosuvastatin is a substrate of various transporter proteins (e.g., OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) increases when Clivas® Plus is used concomitantly with certain medicinal products capable of increasing plasma concentrations of rosuvastatin via interaction with these transporter proteins (e.g., cyclosporine and certain protease inhibitors, including ritonavir in combination with atazanavir, lopinavir and/or tipranavir; see sections "Interaction with Other Medicinal Products and Other Forms of Interaction" and "Special Warnings and Precautions for Use").

Where possible, alternative treatments should be considered and, in certain cases, temporary discontinuation of Clivas® Plus may be warranted. When concomitant use of such medicinal products cannot be avoided, careful consideration should be given to the benefits and risks of combination therapy and to adjusting the dose of rosuvastatin (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Method of Administration

For oral use.

The medicinal product Clivas® Plus should be taken once daily at the same time each day, independent of food intake. The tablet should be swallowed whole with water.

Children

The safety and efficacy of rosuvastatin/ezetimibe in children (under 18 years of age) have not been established; therefore, it is not recommended for use in patients under 18 years of age.

Overdose

In case of overdose, symptomatic and supportive therapy should be initiated.

Ezetimibe

In clinical studies, administration of ezetimibe at a dose of 50 mg/day for 14 days to 15 healthy volunteers or at 40 mg/day for 56 days to 18 patients with primary hypercholesterolemia was generally well tolerated. In animal studies, no toxic effects were observed after single oral doses of 5,000 mg/kg ezetimibe in rats and mice and 3,000 mg/kg in dogs.

There have been several reported cases of ezetimibe overdose, most of which did not result in adverse events. Reported adverse events were not serious.

Rosuvastatin

Liver function tests and creatine kinase (CK) levels should be monitored. Hemodialysis is unlikely to be effective.

Adverse Reactions.

Summary of safety profile

Adverse reactions observed during administration of rosuvastatin were generally mild and of a transient nature. In controlled clinical trials, less than 4% of patients receiving rosuvastatin discontinued the study due to adverse reactions.

It is known that in clinical studies lasting up to 112 weeks, 2,396 patients received ezetimibe alone at a dose of 10 mg per day, 11,308 patients received it in combination with a statin, and 185 patients received it in combination with fenofibrate. Adverse reactions were generally of mild severity and transient in nature. The overall frequency of adverse effects was similar in the ezetimibe and placebo groups. Similarly, the frequency of treatment discontinuation due to adverse reactions was comparable in both groups.

Ezetimibe is administered alone or concomitantly with a statin.

The adverse reactions listed below were observed more frequently in patients receiving ezetimibe (N = 2396) than in those receiving placebo (N = 1159), or in patients receiving ezetimibe concomitantly with a statin (N = 11308) than in those receiving statin alone (N = 9361). Post-marketing adverse reactions were reported when ezetimibe was used alone or in combination with a statin.

Adverse reactions are categorized by frequency as follows: common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), and not known (cannot be estimated from available data).

Blood and lymphatic system disorders: rare – thrombocytopenia2; not known – thrombocytopenia3.

Immune system disorders: rare – hypersensitivity reactions, including angioedema2; not known – hypersensitivity (including rash, urticaria, anaphylaxis, and angioedema)3.

Endocrine disorders: common – diabetes mellitus1,2.

Metabolism and nutrition disorders: uncommon – decreased appetite3.

Psychiatric disorders: not known – depression2,3.

Eye disorders: frequency not known – ocular form of myasthenia gravis.

Nervous system disorders: common – headache2,4, dizziness2; uncommon – paraesthesia3; very rare – polyneuropathy2, memory loss2; not known – peripheral neuropathy2, sleep disorders (including insomnia and nightmares)2, dizziness3, myasthenia gravis2.

Vascular disorders: uncommon – hot flushes3, hypertension3.

Respiratory, thoracic and mediastinal disorders: uncommon – cough3; not known – cough2, dyspnoea2,3.

Gastrointestinal disorders: common – constipation2, nausea2, abdominal pain2,3, diarrhoea3, flatulence3; uncommon – dyspepsia3, gastroesophageal reflux disease3, nausea3, dry mouth3, gastritis; rare – pancreatitis2; not known – diarrhoea2, pancreatitis3, constipation3.

Hepatobiliary disorders: rare – increased levels of liver transaminases2; very rare – jaundice2, hepatitis2; not known – hepatitis3, cholelithiasis3, cholecystitis3.

Skin and subcutaneous tissue disorders: uncommon – pruritus2,3, rash2,3, urticaria2,3; not known – Stevens-Johnson syndrome2, DRESS syndrome (clinically presenting with eosinophilia and systemic symptoms), erythema multiforme2,3.

Musculoskeletal and connective tissue disorders: common – myalgia2,3; uncommon – arthralgia3, muscle spasms3, neck pain3, back pain3, muscle weakness3, limb pain3;
rare – myopathy (including myositis)2, rhabdomyolysis2, lupus-like syndrome2, muscle rupture2; very rare – arthralgia2; not known – immune-mediated necrotizing myopathy2, tendon disorders, sometimes complicated by rupture2, myopathy/rhabdomyolysis3 (see section "Special warnings and precautions for use").

Renal and urinary disorders: very rare – haematuria2.

Reproductive system and breast disorders: very rare – gynaecomastia2.

General disorders and administration site conditions: common – asthenia2, fatigue3; uncommon – chest pain3, pain3, asthenia3, peripheral oedema3; not known – oedema2.

Investigations: common – increased levels of ALT and/or AST3; uncommon – increased blood CK levels3, increased gamma-glutamyl transferase levels3, liver function test abnormalities3.

1 Frequency depends on the presence or absence of risk factors (such as fasting glucose ≥ 5.6 mmol/L, BMI > 30 kg/m², elevated triglyceride levels, history of hypertension) – for rosuvastatin.

2 Adverse reaction profile of rosuvastatin based on data from clinical trials and long-term post-marketing use.

3 Adverse reactions observed during administration of ezetimibe (with or without a statin).

As with other HMG-CoA reductase inhibitors, the frequency of adverse reactions generally depends on the dose.

Renal effects. Proteinuria (detected by dipstick testing), predominantly of tubular origin, has been observed in patients receiving rosuvastatin. Changes in urinary protein content from negative or trace to ++ or higher were observed at some time during treatment in < 1% of patients receiving 10 mg and 20 mg doses, and in approximately 3% of patients receiving the 40 mg dose. A slight increase in the frequency of proteinuria from negative or trace to + was observed with the 20 mg dose. In most cases, proteinuria diminished or spontaneously resolved with continued treatment.

To date, based on clinical trials and post-marketing surveillance, no causal relationship has been established between proteinuria and acute or progressive kidney disease.

Cases of haematuria have been reported with rosuvastatin use; clinical trial data indicate a low frequency of occurrence.

Muscle effects. Skeletal muscle involvement, such as myalgia, myopathy (including myositis), and rarely rhabdomyolysis with or without acute renal failure, have been observed in patients receiving any dose of rosuvastatin, particularly doses > 20 mg.

In patients receiving rosuvastatin, dose-dependent increases in CK levels have been observed; in most cases, this was mild, asymptomatic, and transient. If CK levels are elevated (> 5 × ULN), treatment should be discontinued (see section "Special warnings and precautions for use").

Hepatic effects. As with other HMG-CoA reductase inhibitors, a small number of patients receiving rosuvastatin experienced dose-dependent increases in transaminase levels; in most cases, this was mild, asymptomatic, and transient.

Adverse events reported with some statins include:

• Sexual dysfunction.
• Rare cases of interstitial lung disease, particularly with long-term therapy (see section "Special warnings and precautions for use").

Rhabdomyolysis, severe renal and hepatic dysfunction (mainly cases of elevated liver transaminases) occurred more frequently with rosuvastatin 40 mg.

Concomitant use of ezetimibe and fenofibrate

Gastrointestinal disorders: abdominal pain (common).

It is known that in a multicentre, double-blind, placebo-controlled clinical study involving patients with mixed hyperlipidemia, 625 patients received treatment for 12 weeks and 576 patients for 1 year. In this study, 172 patients receiving ezetimibe and fenofibrate completed 12 weeks of therapy, and 230 patients receiving ezetimibe and fenofibrate (including 109 who received only ezetimibe during the first 12 weeks) completed 1 year of therapy. The study was not designed to compare treatment groups regarding rare adverse events. However, the incidence (95% CI) of clinically significant elevations in serum transaminases (> 3 × ULN) was 4.5% (1.9; 8.8) and 2.7% (1.2; 5.4) with fenofibrate monotherapy and ezetimibe with fenofibrate, respectively, adjusted for treatment effect. For cholecystectomy rates, the values were 0.6% (0.0; 3.1) and 1.7% (0.6; 4.0) with fenofibrate monotherapy and ezetimibe with fenofibrate, respectively.

Patients with a history of CHD and ACS

In the IMPROVE-IT study, which included 18,144 patients receiving either ezetimibe/simvastatin 10 mg/40 mg (n = 9067; 6% of whom had their dose increased to 10 mg/80 mg) or simvastatin 40 mg (n = 9077; 27% of whom had their dose increased to 80 mg), safety profiles were similar over a mean follow-up period of 6 years. Discontinuation rates due to adverse events were 10.6% for patients receiving ezetimibe/simvastatin and 10.1% for those receiving simvastatin. The incidence of myopathy was 0.2% with ezetimibe/simvastatin and 0.1% with simvastatin, where myopathy was defined as muscle weakness or pain of unknown etiology with serum creatine kinase levels ≥ 10 × ULN, or with CK levels ≥ 5 and < 10 × ULN on two consecutive measurements. The incidence of rhabdomyolysis was 0.1% with ezetimibe/simvastatin and 0.2% with simvastatin, where rhabdomyolysis was defined as muscle weakness or pain of unknown etiology with serum creatine kinase ≥ 10 × ULN with signs of renal impairment, ≥ 5 and < 10 × ULN with signs of renal impairment on two consecutive measurements, or with CK ≥ 10,000 U/L without signs of renal impairment. The incidence of consecutive transaminase elevations (≥ 3 × ULN) was 2.5% with ezetimibe/simvastatin and 2.3% with simvastatin (see section "Special warnings and precautions for use"). Adverse events related to the gallbladder occurred in 3.1% of patients receiving ezetimibe/simvastatin and 3.5% of those receiving simvastatin. Hospitalization rates for cholecystectomy were 1.5% in both treatment groups. Cancer (defined as any malignancy) was diagnosed in 10.2% of patients in both treatment groups during the study.

Patients with chronic kidney disease

In the SHARP study involving over 9,000 patients receiving 10 mg/20 mg ezetimibe/simvastatin daily (n = 4650) or placebo (n = 4620), safety profiles were comparable over a mean observation period of 4.9 years. Only serious adverse events and treatment discontinuations due to any adverse events were recorded. Discontinuation rates due to adverse events were similar (10.4% in patients receiving ezetimibe/simvastatin, 9.8% in placebo group). The incidence of myopathy/rhabdomyolysis was 0.2% in patients receiving ezetimibe/simvastatin and 0.1% in the placebo group. Consecutive transaminase elevations (≥ 3 × ULN) occurred in 0.7% of patients receiving ezetimibe/simvastatin compared to 0.6% in the placebo group. There were no statistically significant increases in predefined adverse events, including cancer (9.4% with ezetimibe plus simvastatin vs. 9.5% with placebo), hepatitis, cholecystectomy, or complications of cholelithiasis or pancreatitis.

Laboratory test results

In controlled clinical monotherapy trials, the frequency of clinically significant elevations in serum transaminases (ALT and/or AST ≥ 3 × ULN on consecutive measurements) was similar in the ezetimibe (0.5%) and placebo (0.3%) groups. In combination therapy trials, the frequency of clinically significant transaminase elevations was 1.3% in patients receiving ezetimibe with a statin and 0.4% in those receiving statin alone. Such elevations were usually asymptomatic and not associated with cholestasis, and values returned to baseline after treatment discontinuation or continuation (see section "Special warnings and precautions for use").

In clinical trials, CK levels > 10 × ULN were reported in 4 of 1674 (0.2%) patients receiving ezetimibe alone, compared to 1 of 786 (0.1%) receiving placebo, and in 1 of 917 (0.1%) patients receiving ezetimibe with a statin, compared to 4 of 929 (0.4%) receiving statin alone. No increase in the frequency of myopathy or rhabdomyolysis was observed with ezetimibe compared to the respective control groups (placebo or statin alone) (see section "Special warnings and precautions for use").

Paediatric population

The safety and efficacy of the medicinal product in children (under 18 years of age) have not yet been established.

Rosuvastatin

Elevations in creatine kinase > 10 times ULN and muscle symptoms following physical exertion or increased physical activity were observed more frequently in a 52-week clinical study involving children and adolescents compared to adults (see section "Special warnings and precautions for use"). However, the safety profile of rosuvastatin in children and adolescents was similar to that in adults.

Ezetimibe

Children aged 6 to 17 years

In a study involving children aged 6 to 10 years with heterozygous familial or non-familial hypercholesterolemia (n = 138), elevations in ALT and/or AST (≥ 3 × ULN on consecutive measurements) occurred in 1.1% (1 participant) of the ezetimibe group compared to 0% in the placebo group. No cases of CK elevation (≥ 10 × ULN) were recorded. No cases of myopathy were observed.

In a separate study involving adolescents aged 10 to 17 years with heterozygous familial hypercholesterolemia (n = 248), elevations in ALT and/or AST (≥ 3 × ULN on consecutive measurements) occurred in 3% (4 patients) of the ezetimibe/simvastatin group compared to 2% (2 patients) in the simvastatin monotherapy group; CK elevations (≥ 10 × ULN) occurred in 2% (2 patients) and 0%, respectively. No cases of myopathy were recorded.

This study did not compare rare adverse drug reactions.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua/.

Shelf life.

3 years.

Storage conditions.

Store in the original packaging, out of the reach of children. No special storage conditions are required for this medicinal product.

Packaging.

10 tablets per blister; 3 blisters per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

ELPEN PHARMACEUTICAL CO., INC

ELPEN PHARMACEUTICAL CO., INC

Manufacturer's address and location of operations. Marathonomachon Ave. 95, Pikermi Attikis, 19009, Greece

Zapion, Block 1048, Keratea, 190 01, Greece

Marketing Authorization Holder.

LLC "ASINO UKRAINE".

Address of Marketing Authorization Holder.

8 Vatslava Havela Boulevard, Kyiv, 03124, Ukraine

For suspected adverse effects and questions regarding the safety of the medicinal product, please contact the Pharmacovigilance Department of LLC "ASINO UKRAINE" at: 8 Vatslava Havela Boulevard, Kyiv, 03124, tel/fax: +38 044 281 2333.