Ezatro

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EZATRO (Ezatro)

Composition:

Active substances: rosuvastatin and ezetimibe;

One film-coated tablet contains:

10 mg/10 mg: 10.4 mg calcium rosuvastatin equivalent to 10.0 mg rosuvastatin, and 10.0 mg ezetimibe;

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

Excipients:

10 mg/10 mg: lactose monohydrate; sodium croscarmellose; povidone; sodium lauryl sulfate; microcrystalline cellulose; hypromellose; colloidal anhydrous silicon dioxide; magnesium stearate; tablet coating Opadry Beige (hypromellose; yellow iron oxide (E 172), titanium dioxide (E 171), talc, macrogol);

20 mg/10 mg: lactose monohydrate; sodium croscarmellose; povidone; sodium lauryl sulfate; microcrystalline cellulose; hypromellose; colloidal anhydrous silicon dioxide; magnesium stearate; tablet coating Vivacoat Yellow (hypromellose; titanium dioxide (E 171); talc; macrogol; yellow iron oxide (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties.

10 mg/10 mg: biconvex, round, beige-colored film-coated tablets, with "MR 4" embossed on one side.

20 mg/10 mg: biconvex, round, yellow-colored film-coated tablets, with "MR 3" embossed on one side.

Pharmacotherapeutic group. Hypolipidemic agents, combinations. Combinations of different hypolipidemic agents. Rosuvastatin and ezetimibe. ATC code C10BA06.

Pharmacological properties.

Pharmacodynamics.

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 precursor of cholesterol. The primary site of action of rosuvastatin is the liver, the target organ for reducing cholesterol levels.

Rosuvastatin increases the number of LDL receptors on the surface of hepatic cells, enhancing the uptake and catabolism of LDL, and inhibits hepatic synthesis of LDL, thereby reducing the total number of LDL and LDL-related particles.

Pharmacodynamic effect

Rosuvastatin reduces elevated levels of LDL-cholesterol, total cholesterol, and triglycerides, and increases HDL-cholesterol levels. It also reduces levels of apolipoprotein B, non-HDL-C, LDL-C, triglyceride-rich lipoproteins (TRL-C), and increases apolipoprotein A-I (Table 1). Rosuvastatin also reduces the ratios of LDL-C/HDL-C, total cholesterol/HDL-C, non-HDL-C/HDL-C, and apoB/apoA-I.

Table 1

Dose-response in patients with primary hypercholesterolemia type IIa and IIb

(adjusted mean percentage change from baseline)

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

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

Clinical efficacy and safety

Rosuvastatin is effective in the treatment of adults with hypercholesterolemia – with or without hypertriglyceridemia – regardless of race, sex or age, as well as in the treatment of patients in special groups, such as those with diabetes mellitus or patients with familial hypercholesterolemia.

Based on pooled data from phase III studies, rosuvastatin effectively reduced cholesterol levels in most patients with type IIa and IIb hypercholesterolemia (mean baseline LDL-C approximately 4.8 mmol/l) to target levels established by the European Atherosclerosis Society (EAS; 1998) guidelines; approximately 80 % of patients receiving the medicinal product at a dose of 10 mg achieved EAS target LDL-C levels (< 3 mmol/l).

In a large study of 435 patients with heterozygous familial hypercholesterolemia, rosuvastatin was administered at doses ranging from 20 to 80 mg according to an intensified dose titration regimen. The beneficial effect of the medicinal product on lipid parameters and achievement of target levels was observed at all doses. After titration to a daily dose of 40 mg (12 weeks of treatment), LDL-C decreased by 53 %. EAS target LDL-C levels (< 3 mmol/l) were achieved in 33 % of patients.

In an open-label dose titration study, the response to rosuvastatin at doses of 20–40 mg was evaluated in 42 patients (including 8 children) with homozygous familial hypercholesterolemia. In the overall population, LDL-C levels decreased on average by 22 %.

In clinical studies involving a limited number of patients, combination therapy with rosuvastatin and fenofibrate showed an additive effect on triglyceride reduction, while combination therapy with rosuvastatin and niacin showed an additive effect on HDL-C elevation (see section "Special warnings and precautions for use").

In a multicenter, double-blind, placebo-controlled clinical trial (METEOR), 984 patients aged 45–70 years with low risk of ischemic heart disease (defined as a Framingham risk score < 10 % over 10 years), mean LDL-C of 4.0 mmol/l (154.5 mg/dl), but with subclinical atherosclerosis (defined by increased carotid intima-media thickness (CIMT)) were randomized into two groups and received either 40 mg of rosuvastatin or placebo once daily for 2 years. Compared to placebo, rosuvastatin significantly slowed the progression of maximum CIMT at 12 carotid artery sites by -0.0145 mm/year [95 % confidence interval -0.0196, -0.0093; p < 0.0001].

The change from baseline was -0.0014 mm/year (-0.12 %/year (statistically non-significant)) in the rosuvastatin group compared to progression of +0.0131 mm/year (1.12 %/year (p < 0.0001)) in the placebo group. A direct correlation between CIMT reduction and reduced risk of cardiovascular events has not been demonstrated. The METEOR study included patients with low risk of ischemic heart disease who are not representative of the target population for rosuvastatin 40 mg. The 40 mg dose should only be prescribed to patients with severe hypercholesterolemia and high risk of cardiovascular disorders (see section "Posology and method of administration").

In an interventional rosuvastatin trial designed to support the use of statins for primary prevention (JUPITER), the effect of rosuvastatin on the incidence of major atherosclerotic cardiovascular diseases was evaluated in 17,802 men (≥ 50 years) and women (≥ 60 years).

Study participants were randomly assigned to receive either placebo (n = 8901) or rosuvastatin 20 mg once daily (n = 8901) and were followed for a mean of 2 years.

LDL-C concentrations decreased by 45 % (p < 0.001) in the rosuvastatin group compared to the placebo group.

A post-hoc analysis of data from a high-risk subgroup with a baseline Framingham risk score >20 % (1558 participants) showed a significant reduction in the incidence of the composite endpoint, including cardiovascular death, stroke, and myocardial infarction (p = 0.028), in the rosuvastatin group compared to the placebo group. The absolute risk reduction for these events was 8.8 cases per 1000 patient-years. The all-cause mortality rate remained unchanged in this high-risk group (p = 0.193). A post-hoc analysis of data from a high-risk subgroup (9302 participants overall) with a baseline SCORE ≥ 5 % (extrapolated to include data from participants over 65 years of age) showed a significant reduction in the incidence of the composite endpoint, including cardiovascular death, stroke, and myocardial infarction (p = 0.0003), in the rosuvastatin group compared to the placebo group. The absolute risk reduction expressed as event rate was 5.1 cases per 1000 patient-years. The all-cause mortality rate in this high-risk subgroup remained unchanged (p = 0.076).

In the JUPITER study, 6.6 % of participants in the rosuvastatin group and 6.2 % in the placebo group discontinued the investigational medicinal product due to adverse events. The most common adverse events leading to discontinuation were myalgia (0.3 % in the rosuvastatin group, 0.2 % in the placebo group), abdominal pain (0.03 % in the rosuvastatin group, 0.02 % in the placebo group), and rash (0.02 % in the rosuvastatin group, 0.03 % in the placebo group). The most common adverse events observed in the rosuvastatin group with a frequency greater than or equal to that observed in the placebo group were urinary tract infections (8.7 % in the rosuvastatin group, 8.6 % in the placebo group), nasopharyngitis (7.6 % in the rosuvastatin group, 7.2 % in the placebo group), back pain (7.6 % in the rosuvastatin group, 6.9 % in the placebo group), and myalgia (7.6 % in the rosuvastatin group, 6.6 % in the placebo group).

Children

In a double-blind, randomized, multicenter, placebo-controlled 12-week study (n = 176, 97 male and 79 female participants) followed by a 40-week open-label dose titration period (n = 173, 96 male and 77 female participants), patients aged 10–17 years (Tanner stages II–IV, girls with at least 1 year since onset of menstruation) with heterozygous familial hypercholesterolemia received rosuvastatin at doses of 5, 10, or 20 mg/day or placebo for 12 weeks, after which all participants received rosuvastatin daily for 40 weeks. At the start of the study, approximately 30 % of patients were aged 10–13 years, and approximately 17 %, 18 %, 40 %, and 25 % were at Tanner stages II, III, IV, and V, respectively.

LDL-C levels decreased by 38.3 %, 44.6 %, and 50.0 % in the rosuvastatin 5 mg, 10 mg, and 20 mg groups, respectively, compared to 0.7 % in the placebo group.

At the end of the 40-week open-label dose titration period to achieve the target level (maximum dose 20 mg once daily), the target LDL-C level of < 2.8 mmol/l was achieved in 70 of 173 patients (40.5 %).

After 52 weeks of investigational treatment, no effect on growth, body weight, BMI, or sexual maturation was observed (see section "Special warnings and precautions for use"). This study (n = 176) is not suitable for comparison of rare adverse events.

Rosuvastatin was also evaluated in a 2-year open-label study with target dose titration in 198 children with heterozygous familial hypercholesterolemia aged 6 to 17 years (88 male and 110 female participants, Tanner stage < II–V). The initial dose for all patients was 5 mg of rosuvastatin once daily. Patients aged 6 to 9 years (n = 64) were titrated to a maximum dose of 10 mg once daily, and patients aged 10 to 17 years (n = 134) were titrated to a maximum dose of 20 mg once daily.

After 24 months of rosuvastatin treatment, the mean reduction from baseline LDL-C, determined by the least squares method, was -43 % (baseline: 236 mg/dl, month 24: 133 mg/dl). For each age group, the mean reduction from baseline LDL-C, determined by the least squares method, was -43 % (baseline: 234 mg/dl, month 24: 124 mg/dl), -45 % (baseline: 234 mg/dl, month 24: 124 mg/dl), and -35 % (baseline: 241 mg/dl, month 24: 153 mg/dl) in the age groups 6 to < 10, 10 to < 14, and 14 to < 18 years, respectively.

The use of rosuvastatin at doses of 5, 10, and 20 mg also resulted in statistically significant mean changes from baseline in the following secondary lipid and lipoprotein variables: HDL-C, total cholesterol, non-HDL-C, LDL-C/HDL-C, total cholesterol/HDL-C, triglycerides/HDL-C, non-HDL-C/HDL-C, apoB, and apoB/apoA-1. Each of these changes demonstrated improved lipid responses and was maintained over 2 years.

After 24 months of treatment, no effect on growth, body weight, BMI, or sexual maturation was observed (see section "Special warnings and precautions for use").

In a randomized, double-blind, placebo-controlled, multicenter crossover study, rosuvastatin 20 mg once daily was compared with placebo in 14 children and adolescents (aged 6 to 17 years) with homozygous familial hypercholesterolemia. The study included a 4-week active dietary run-in phase during which patients received rosuvastatin 10 mg, a crossover phase consisting of a 6-week treatment period with rosuvastatin 20 mg preceded or followed by a 6-week placebo period, and a 12-week maintenance phase during which all patients received 20 mg of rosuvastatin. Patients on ezetimibe therapy or apheresis continued this treatment throughout the study.

A statistically significant (p = 0.005) reduction in LDL-C levels (22.3 %; 85.4 mg/dl, or 2.2 mmol/l) was observed after 6 weeks of treatment with rosuvastatin 20 mg compared to placebo. Statistically significant reductions in total cholesterol (20.1 %, p = 0.003), non-HDL-C (22.9 %, p = 0.003), and apoB (17.1 %, p = 0.024) were also observed. Reductions in triglyceride levels, LDL-C/HDL-C, total cholesterol/HDL-C, non-HDL-C/HDL-C, and apoB/apoA-I were also observed after 6 weeks of treatment with rosuvastatin 20 mg compared to placebo. The reduction in LDL-C after 6 weeks of treatment with rosuvastatin 20 mg followed by 6 weeks of placebo was maintained over 12 weeks of continuous therapy. In one patient, further reductions in LDL-C (8.0 %), total cholesterol (6.7 %), and non-HDL-C (7.4 %) were observed after 6 weeks of treatment with dose titration to 40 mg.

During continued open-label treatment with rosuvastatin 20 mg in 9 of these patients up to 90 weeks, the reduction in LDL-C levels ranged from -12.1 % to -21.3 %.

In an open-label dose titration study in 7 evaluable children and adolescents (aged 8 to 17 years) with homozygous familial hypercholesterolemia (see above), the percentage reduction in LDL-C (21.0 %), total cholesterol (19.2 %), and non-HDL-C (21.0 %) from baseline after 6 weeks of treatment with rosuvastatin 20 mg was comparable to that observed in the aforementioned study in children and adolescents with homozygous familial hypercholesterolemia.

The European Medicines Agency has waived the obligation to submit results of studies in all pediatric subgroups treated with rosuvastatin for homozygous familial hypercholesterolemia, primary combined (mixed) dyslipidemia, and for prevention of cardiovascular disorders (see section "Posology and method of administration" for information on pediatric use).

Ezetimibe

Mechanism of action

Ezetimibe is a representative of a new class of lipid-lowering agents that selectively inhibit intestinal cholesterol and related plant sterol absorption. Ezetimibe is orally active 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, responsible for cholesterol and phytosterol uptake in the intestine.

Ezetimibe localizes to the brush border of the small intestine and inhibits cholesterol absorption, reducing intestinal cholesterol delivery to the liver; statins reduce cholesterol synthesis in the liver, and together these mechanisms provide additional cholesterol reduction. After two weeks of clinical use in 18 patients with hypercholesterolemia, ezetimibe reduced cholesterol absorption by 54 % compared to placebo.

Pharmacodynamic effects

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, ethinylestradiol, or fat-soluble vitamins A and D.

Epidemiological studies have established that cardiovascular disease and mortality are directly related to total cholesterol and LDL-C levels and inversely related to HDL-C levels.

The use of ezetimibe with a statin effectively reduces the risk of cardiovascular events in patients with ischemic heart disease and a history of acute coronary syndrome (ACS).

Clinical efficacy and safety

In controlled clinical studies, ezetimibe as monotherapy, as well as when co-administered with a statin, significantly reduced total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo-B), and triglycerides (TG), and increased high-density lipoprotein cholesterol (HDL-C) in patients with hypercholesterolemia.

Primary hypercholesterolemia

In a double-blind, placebo-controlled 8-week study, 769 patients with hypercholesterolemia who were already receiving statin monotherapy but whose LDL-C levels did not meet target levels according to the National Cholesterol Education Program (NCEP) guidelines (2.6 to 4.1 mmol/l [100 to 160 mg/dl], depending on baseline characteristics) were randomized to receive ezetimibe 10 mg or placebo in addition to their current statin therapy.

Among patients receiving statins whose LDL-C levels did not meet target levels at baseline (~82 %), significantly more patients randomized to receive ezetimibe achieved target LDL-C levels at the study endpoint compared to those randomized to receive placebo, 72 % vs. 19 %, respectively.

Reductions in LDL-C levels differed significantly (25 % and 4 % with ezetimibe and placebo, respectively). Additionally, ezetimibe added to ongoing statin therapy significantly reduced total-C, Apo-B, and TG levels and increased HDL-C levels compared to placebo. Ezetimibe or placebo added to statin therapy reduced mean C-reactive protein levels by 10 % and 0 %, respectively, from baseline.

In two double-blind, randomized, placebo-controlled 12-week studies involving 1719 patients with primary hypercholesterolemia, ezetimibe 10 mg significantly reduced total-C (13 %), LDL-C (19 %), Apo-B (14 %), and TG (8 %) and increased HDL-C (3 %) compared to placebo. Additionally, ezetimibe did not affect the concentration of fat-soluble vitamins A, D, and E, did not alter prothrombin time, and, like other lipid-lowering agents, did not reduce adrenal corticosteroid hormone production.

Children

In a multicenter, double-blind, controlled study, 138 patients (59 boys and 79 girls) aged 6 to 10 years (mean age 8.3 years) with heterozygous familial or non-familial hypercholesterolemia (HeFH) with baseline LDL-C levels of 3.74–9.92 mmol/l were randomized to receive ezetimibe 10 mg or placebo for 12 weeks.

At week 12, ezetimibe significantly reduced total-C (-21 % vs. 0 %), LDL-C (-28 % vs. -1 %), Apo-B (-22 % vs. -1 %), and non-HDL-C (-26 % vs. 0 %) compared to placebo. Results for the two treatment groups were similar for TG and HDL-C (-6 % vs. +8 % and +2 % vs. +1 %, respectively).

Homozygous sitosterolemia (phytosterolemia)

In a double-blind, placebo-controlled 8-week study, 37 patients with homozygous sitosterolemia were randomized to receive ezetimibe 10 mg (n = 30) or placebo (n = 7). Some patients received other treatments (e.g., statins, resins). Ezetimibe significantly reduced both primary plant sterols, sitosterol and campesterol, by 21 % and 24 %, respectively, compared to baseline. The impact of sitosterol reduction on morbidity and mortality in this population is unknown.

Combination of rosuvastatin and ezetimibe

Clinical efficacy

The objective of a 6-week, randomized, double-blind, parallel-group clinical trial was to evaluate the safety and efficacy of ezetimibe (10 mg) added to ongoing rosuvastatin therapy compared to gradually increasing rosuvastatin doses 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 by 21 %. In contrast, doubling the rosuvastatin dose to 10 mg or 20 mg resulted in a 5.7 % reduction in LDL-C (difference between groups 15.2 %, p < 0.001).

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

A 6-week randomized study was designed to evaluate 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 group receiving rosuvastatin/ezetimibe, 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 the atherogenic lipid profile in this high-risk population.

In a randomized, open-label 12-week study, the LDL-C reduction level 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)). With high-dose rosuvastatin combinations, LDL-C levels decreased 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 "Posology and method of administration" for information on pediatric use).

Pharmacokinetics.

Rosuvastatin

Absorption

Maximum plasma concentration of rosuvastatin is reached approximately 5 hours after oral administration. Absolute bioavailability is approximately 20 %.

Distribution

Rosuvastatin is significantly taken up by the liver, 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 undergoes minimal metabolism (approximately 10 %). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a weak substrate for cytochrome P450 enzyme-based metabolism. The main isoenzyme involved is CYP2C9, with minor contributions from CYP2C19, 3A4, and 2D6. The main identified metabolites are the 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 the circulating HMG-CoA reductase inhibitor activity.

Elimination

Approximately 90 % of the rosuvastatin dose is excreted unchanged in feces (including 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. The geometric mean 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 OATP-C membrane transporter, which plays an important role in the hepatic elimination of rosuvastatin.

Linearity

Systemic exposure to rosuvastatin increases proportionally with dose. Pharmacokinetic parameters do not change with repeated daily administration.

Special patient groups

Age and sex

No clinically significant effect of age or sex on rosuvastatin pharmacokinetics in adults has been observed. Rosuvastatin pharmacokinetics in children and adolescents with heterozygous familial hypercholesterolemia were similar to those in adult volunteers (see section "Children").

Race

Pharmacokinetic studies have shown that median AUC and Cmax values in Mongoloid race patients (Japanese, Chinese, Filipinos, Vietnamese, and Koreans) are approximately twice as high as in Caucasians; in Indians, median AUC and Cmax values are approximately 1.3 times higher. Population pharmacokinetic analysis did not reveal clinically significant differences between Caucasian and Negroid race patients.

Renal impairment

In a study of patients with varying degrees of renal impairment, no changes in plasma concentrations of rosuvastatin or the N-desmethyl metabolite were observed in patients with mild or moderate impairment. In patients with severe renal impairment (creatinine clearance < 30 ml/min), plasma concentrations of rosuvastatin were 3 times higher and N-desmethyl metabolite levels were 9 times higher than in healthy volunteers. Steady-state plasma concentrations of rosuvastatin in patients on hemodialysis were approximately 50 % higher than in healthy volunteers.

Hepatic impairment

In a study of patients with varying degrees of hepatic impairment, no signs of increased rosuvastatin exposure were observed in patients with a Child-Pugh score of 7 or less. However, in two patients with Child-Pugh scores of 8 and 9, systemic exposure was at least twice as high as in patients with lower scores. Experience with rosuvastatin in patients with a Child-Pugh score greater than 9 is lacking.

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 increased rosuvastatin exposure. With specific polymorphisms SLCO1B1 c.521CC and ABCG2 c.421AA, rosuvastatin exposure (AUC) is increased compared to genotypes SLCO1B1 c.521TT or ABCG2 c.421CC. Special genotyping is not required in clinical practice, but patients with such polymorphisms are recommended to use a lower daily dose of rosuvastatin.

Children

Two pharmacokinetic studies of rosuvastatin (in tablet form) in children with heterozygous familial hypercholesterolemia aged 10 to 17 years or 6 to 17 years (total 214 patients) showed that drug exposure in children was lower or similar to that in adult patients. Rosuvastatin exposure was predictable according 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). In plasma, the mean maximum concentration (Cmax) of ezetimibe-glucuronide is reached within 1–2 hours, and that of ezetimibe within 4–12 hours. Absolute bioavailability of ezetimibe cannot be determined because this compound is insoluble in aqueous media suitable for injection.

Concomitant food intake (low or high fat) 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.

Metabolism

The primary metabolism of ezetimibe 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 at all stages of transformation. Ezetimibe and ezetimibe-glucuronide are the main substances detected in plasma and account for approximately 10–20 % and 80–90 % of the total drug content in plasma, respectively. Ezetimibe and ezetimibe-glucuronide are slowly eliminated from plasma through enterohepatic recirculation. The elimination half-life of ezetimibe and ezetimibe-glucuronide is approximately 22 hours.

Elimination

After administration of 20 mg 14C-ezetimibe to volunteers, approximately 93 % of total ezetimibe was detected in plasma relative to total plasma radioactivity. Approximately 78 % and 11 % of the administered radioactive dose were excreted in feces and urine, respectively, within 10 days. Traces of radioactivity in plasma were not detected after 48 hours.

Special patient groups

Children

Ezetimibe pharmacokinetics are similar in children aged 6 years and older and adults. Pharmacokinetic data for children under 6 years of age are lacking. Clinical experience in children and adolescents includes patients with HoFH, HeFH, or sitosterolemia.

Elderly patients

In elderly patients (over 65 years), total ezetimibe plasma concentration is approximately twice as high as in younger patients (18–45 years). LDL-C reduction and safety profile are approximately similar in elderly and younger patients taking ezetimibe. Therefore, dose adjustment is not required for elderly patients.

Hepatic impairment

After a single 10 mg dose of ezetimibe, the mean area under the concentration-time curve (AUC) of total ezetimibe was 1.7 times higher in patients with mild hepatic impairment (5–6 points on the Child-Pugh scale) than in healthy volunteers. In a 14-day multiple-dose study (10 mg daily) in patients with moderate hepatic impairment (7–9 points on the Child-Pugh scale), the AUC of total ezetimibe increased approximately 4-fold on day 1 and day 14 compared to healthy volunteers. Dose adjustment is not required for patients with mild hepatic impairment. Since the effects of increased ezetimibe exposure in patients with moderate or severe hepatic impairment (more than 9 points on the Child-Pugh scale) are unknown, ezetimibe is not recommended for use in this patient population (see section "Special warnings and precautions for use").

Renal impairment

After a single 10 mg dose of ezetimibe in patients with severe renal impairment (n = 8; creatinine clearance ≤ 30 ml/min/1.73 m²), the mean AUC of total ezetimibe increased approximately 1.5-fold compared to healthy volunteers (n = 9). This result is not considered clinically significant. Dose adjustment is not required for patients with renal impairment.

One patient in this study (who had a kidney transplant and was receiving multiple therapies, including cyclosporine) had total ezetimibe levels 12 times higher.

Sex

Total ezetimibe plasma concentration is slightly higher (approximately 20 %) in women than in men. LDL-C reduction and safety profile are approximately similar in men and women taking ezetimibe. Therefore, dose adjustment based on patient sex is not required.

Clinical characteristics.

Indications.

Primary hypercholesterolemia

For adults with primary hypercholesterolemia (type IIa, including heterozygous familial hypercholesterolemia) or mixed dyslipidemia (type IIb), in whom adequate disease control is achieved with concomitant administration of rosuvastatin and ezetimibe as individual medicinal products at the same doses as those contained in the combined medicinal product.

Cardiovascular disease prevention

The medicinal product is indicated as a replacement therapy for adult patients who are adequately controlled on concomitant treatment with rosuvastatin and ezetimibe as separate medicinal products at the same doses as those in the combined medicinal product, for reduction of the risk of cardiovascular disease in patients with a history of ischemic heart disease (IHD) and acute coronary syndrome (ACS).

Contraindications.

EZATRO is contraindicated:

• in patients with hypersensitivity to the active substances (rosuvastatin, ezetimibe) or to any of the excipients of the medicinal product;
• in patients with active liver disease, including persistent elevations of serum transaminases of unknown etiology and any elevations of serum transaminases exceeding 3 times the upper limit of normal (ULN);
• in patients with severe renal impairment (creatinine clearance < 30 mL/min);
• in patients with myopathy;
• in patients receiving concomitant combination therapy with sofosbuvir/velpatasvir/voxilaprevir (see section "Interaction with other medicinal products and other forms of interaction");
• in patients receiving concomitant cyclosporine;
• during pregnancy and breastfeeding, as well as in women of childbearing potential who are not using appropriate contraceptive measures;
• in children.

Interaction with other medicinal products and other forms of interaction.

Interactions related to rosuvastatin

Effect of concomitant medicinal products on rosuvastatin

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

Cyclosporine. During concomitant use of rosuvastatin and cyclosporine, rosuvastatin AUC values were on average approximately 7 times higher than those observed in healthy volunteers (see Table 2). EZATRO is contraindicated in patients receiving concomitant cyclosporine (see section "Contraindications").

Concomitant use did not affect plasma concentrations of cyclosporine.

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

Gemfibrozil and other lipid-lowering agents. Concomitant use of rosuvastatin and gemfibrozil resulted in a 2-fold increase in rosuvastatin AUC and Cmax (see section "Special warnings and precautions for use").

Based on data from specific studies, no pharmacokinetically significant 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 used alone.

Ezetimibe. Concomitant administration of 10 mg rosuvastatin and 10 mg ezetimibe to patients with hypercholesterolemia resulted in a 1.2-fold increase in rosuvastatin AUC (Table 2).

A pharmacodynamic interaction between rosuvastatin and ezetimibe cannot be excluded, which may lead to adverse events (see section "Special warnings and precautions for use").

Antacid medicinal products. Concomitant use of rosuvastatin with antacid suspensions containing aluminium hydroxide or magnesium hydroxide reduced plasma concentrations of rosuvastatin 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.

Erythromycin. Concomitant use of rosuvastatin and erythromycin reduced rosuvastatin AUC by 20% and Cmax by 30%. This interaction may be due to enhanced intestinal motility caused by erythromycin.

Ticagrelor. 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 decreased renal function, elevated creatine phosphokinase levels, and rhabdomyolysis.

Cytochrome P450 enzymes. Results from in vitro and in vivo studies indicate that rosuvastatin does not inhibit or induce cytochrome P450 isoenzymes. In addition, rosuvastatin is a weak substrate of these isoenzymes. Therefore, drug interactions mediated by P450 metabolism are not expected. No clinically significant interactions were observed between rosuvastatin and fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4).

Interactions requiring rosuvastatin dose adjustment (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 rosuvastatin exposure (AUC) is expected to increase approximately 2-fold or more, treatment should be initiated at a dose of 5 mg once daily. The maximum daily rosuvastatin dose should be adjusted so that the expected exposure does not exceed that observed with a 40 mg/day dose in the absence of interacting medicinal products. For example, when used with gemfibrozil, the rosuvastatin dose should be 20 mg (1.9-fold increase in exposure); when used with ritonavir/atazanavir combination, the dose should be 10 mg (3.1-fold increase in exposure).

If a medicinal product increases rosuvastatin AUC by less than 2-fold, no initial dose reduction is required; however, 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 times or more
Dosing regimen of 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 up 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
Paritaprevir 150 mg/ombitasvir 25 mg/ ritonavir 100 mg once daily and 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-fold
Febuxostat 120 mg once daily	10 mg, single dose	↑ 1.9-fold
Gemfibrozil 600 mg twice daily, 7 days	80 mg, single dose	↑ 1.9-fold
Increased rosuvastatin AUC less than 2-fold
Dosing regimen of interacting drug	Rosuvastatin dosing regimen	Changes in rosuvastatin AUC*
Eltrombopag 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 interacting drug	Rosuvastatin dosing regimen	Changes in rosuvastatin AUC*
Erythromycin 500 mg four times daily, 7 days	80 mg, single dose	↓ 20%
Baicalin 50 mg three times daily, 14 days	20 mg, single dose	↓ 47%

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

Increases are indicated by ↑, decreases by ↓.

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

Medicinal products/combinations that had no clinically significant effect on rosuvastatin AUC when administered concomitantly: aleglitazar 0.3 mg, 7 days; fenofibrate 67 mg, 7 days three times daily; fluconazole 200 mg, 11 days once daily; fosamprenavir 700 mg / ritonavir 100 mg, 8 days twice daily; ketoconazole 200 mg, 7 days twice daily; rifampicin 450 mg, 7 days once daily; silymarin 140 mg, 5 days three times daily.

Effect of rosuvastatin on concomitant medicinal products

Vitamin K antagonists. As with other HMG-CoA reductase inhibitors, initiation of rosuvastatin therapy or increasing its dose in patients concurrently taking vitamin K antagonists (e.g., warfarin or other coumarin anticoagulants) may increase the international normalized ratio (INR). Discontinuation of rosuvastatin or reduction of its dose may lead to a decrease in INR. In such cases, appropriate monitoring of INR is recommended.

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 norgestrel, respectively. This increase 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, a similar effect cannot be excluded. However, this combination has been widely used in women during clinical trials and was well tolerated.

Other medicinal products

Digoxin. Special studies did not indicate any clinically significant interaction with digoxin.

Fusidic acid. Interaction studies between rosuvastatin and fusidic acid have not been conducted. The risk of myopathy, including rhabdomyolysis, may be increased when systemic fusidic acid is co-administered with statins. The mechanism of this interaction (pharmacodynamic or pharmacokinetic, or both) has not yet been established. Cases of rhabdomyolysis (including some fatal cases) have been reported in patients receiving this combination.

For patients in whom systemic fusidic acid is considered necessary, rosuvastatin treatment should be discontinued for the entire duration of fusidic acid therapy (see section "Special precautions").

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

Interactions related to ezetimibe

Preclinical studies have shown that ezetimibe does not induce cytochrome P450 enzymes involved in drug metabolism. No clinically significant pharmacokinetic interactions were observed between ezetimibe and drugs metabolized by cytochrome P450 enzymes 1A2, 2D6, 2C8, 2C9, and 3A4 or by N-acetyltransferase.

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

Antacids. Concomitant administration of antacids reduces the extent of absorption of ezetimibe but does not affect its bioavailability. This reduction in absorption extent is not considered clinically significant.

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

Fibrates. When patients are receiving fenofibrate and ezetimibe, physicians should be aware of the potential risk of gallstone formation and gallbladder disease. In patients suspected of having gallstones while receiving ezetimibe and fenofibrate, gallbladder investigations are indicated and such therapy should be discontinued (see section "Adverse reactions").

Concomitant administration of fenofibrate or gemfibrozil slightly increased the total concentration of ezetimibe (approximately 1.5- and 1.7-fold, respectively).

Concomitant administration of ezetimibe with other fibrates has not been studied.

Fibrates may increase biliary cholesterol excretion, leading to gallstone formation. In animal studies, ezetimibe sometimes increased biliary cholesterol levels, but not in all species. A lithogenic risk associated with 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 8 kidney transplant patients with creatinine clearance > 50 mL/min receiving a stable dose of cyclosporine, a single 10 mg dose of ezetimibe resulted in a 3.4-fold increase (range: 2.3 to 7.9-fold) in the mean AUC of total ezetimibe compared to control healthy subjects receiving ezetimibe alone. In another study (n = 17), a 12-fold increase in exposure to total ezetimibe was observed in a kidney transplant patient with severe renal insufficiency receiving cyclosporine and multiple other drugs, compared to control subjects receiving ezetimibe alone. In a two-period crossover study involving 12 healthy volunteers, daily administration of 20 mg ezetimibe for 8 days, with a single 100 mg dose of cyclosporine on day 7, resulted in a mean 15% increase in cyclosporine AUC (range: 10% decrease to 51% increase) compared to administration of a single 100 mg dose of cyclosporine alone. A controlled study evaluating the effect of concomitant ezetimibe on cyclosporine exposure in kidney transplant patients has not been conducted. Ezetimibe therapy should be initiated with caution in patients taking cyclosporine. Cyclosporine concentrations should be monitored in patients receiving both ezetimibe and cyclosporine (see section "Special precautions").

Anticoagulants. Concomitant administration of ezetimibe (10 mg once daily) had no significant effect on warfarin bioavailability or prothrombin time in a study involving 12 healthy adult males. However, post-marketing reports have described increased international normalized ratio (INR) in patients receiving ezetimibe added to warfarin or fluindione. When ezetimibe is administered with warfarin, another coumarin anticoagulant, or fluindione, INR should be appropriately monitored (see section "Special precautions").

Children. Interaction studies were conducted in adults only.

Special precautions for use.

Renal effects

Proteinuria detected by dipstick testing and predominantly of tubular origin has been observed in patients treated with higher doses of rosuvastatin, particularly 40 mg, and in most cases was transient or intermittent. 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. In patients receiving the medicinal product at a dose of 40 mg, renal function should be monitored regularly.

Skeletal muscle effects

Skeletal muscle disorders such as myalgia, myopathy, and rarely rhabdomyolysis have been observed in patients taking rosuvastatin at any dose, particularly above 20 mg. Cases of rhabdomyolysis have very rarely been reported with ezetimibe used 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 at the 40 mg dose.

Cases of rhabdomyolysis have been reported very rarely with ezetimibe monotherapy and when ezetimibe is added to other agents known to be associated with an increased risk of rhabdomyolysis. If myopathy is suspected, manifested by muscle symptoms or creatine kinase levels more than 10 times the upper limit of normal (ULN), ezetimibe, another statin, and any other concurrently administered drugs should be discontinued immediately. All patients initiating ezetimibe therapy should be informed about the risk of myopathy and the need to promptly report any muscle pain, fatigue, or unexplained weakness.

Creatine kinase levels

Creatine kinase (CK) levels should not be measured following significant physical exertion or in the presence of alternative causes of elevated CK, which may complicate interpretation of results. If baseline CK levels are markedly elevated (> 5 times ULN), repeat testing should be performed within 5–7 days to confirm the results. If repeat testing confirms that baseline CK levels exceed 5 times ULN, initiation of the medicinal product is not recommended.

Before initiating therapy

Rosuvastatin, like other HMG-CoA reductase inhibitors, should be prescribed with caution in patients predisposed to myopathy/rhabdomyolysis. Risk factors include:

• renal impairment;
• hypothyroidism;
• personal or family history of hereditary muscle disorders;
• history of myotoxicity with 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 treatment-related risk should be evaluated against the expected benefit; clinical monitoring is also recommended. If baseline CK levels are markedly elevated (> 5 times ULN), treatment should not be initiated.

During therapy

Patients should be advised to report immediately any muscle pain, weakness, or cramps of unknown origin, especially if accompanied by malaise or fever. In such patients, CK levels should be measured. The medicinal product should be discontinued if CK levels are markedly elevated (> 5 times ULN) or if muscle symptoms are severe and cause daily discomfort (even if CK levels are less than 5 times or equal to 5 times ULN). Therapy with rosuvastatin or an alternative HMG-CoA reductase inhibitor may be resumed at the lowest dose and under close monitoring once symptoms have resolved and CK levels have returned to normal. Routine monitoring of CK levels in asymptomatic patients is not necessary. Very rare cases of immune-mediated necrotizing myopathy (IMNM) have been reported during or after statin therapy, including rosuvastatin. Clinical features of IMNM include proximal muscle weakness and elevated serum creatine kinase levels, which persist even after discontinuation of statins.

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

In clinical trials, no evidence of increased skeletal muscle effects was observed in a small number of patients taking rosuvastatin and concomitant medications. However, increased incidence of myositis and myopathy has been observed in patients taking other HMG-CoA reductase inhibitors concomitantly with fibric acid derivatives, including gemfibrozil, cyclosporine, nicotinic acid, azole antifungals, protease inhibitors, and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when used concomitantly with certain HMG-CoA reductase inhibitors. Therefore, co-administration of rosuvastatin 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 fibrates are used concomitantly (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 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 fusidic acid and statins in combination (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 restarted seven days after the last dose of fusidic acid. In exceptional cases where prolonged systemic action of fusidic acid is required, e.g., for treatment of severe infections, concomitant use of rosuvastatin and fusidic acid should be considered only on a case-by-case basis and such use requires careful medical supervision.

Rosuvastatin should not be administered to patients with acute, serious conditions indicating myopathy or potential for renal failure due to rhabdomyolysis (such as sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures).

Severe skin adverse reactions

Severe skin 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"). When prescribing the medicinal product, patients should be informed about signs and symptoms of severe skin reactions, and careful monitoring during treatment is required. If signs or symptoms suggestive of such reactions occur, EZATRO should be discontinued immediately and alternative treatment considered.

If a serious reaction such as SJS or DRESS develops in relation to rosuvastatin use, re-treatment with EZATRO is contraindicated.

Hepatic effects

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

It is recommended to check liver function biochemistry before starting treatment and again after 3 months. Rosuvastatin should be discontinued or the dose reduced if serum transaminase levels exceed three times the upper limit of normal. The frequency of post-marketing reports of serious hepatic events (mainly elevated liver transaminases) was higher with the 40 mg dose.

In patients with secondary hypercholesterolemia due to hypothyroidism or nephrotic syndrome, the underlying condition should be treated before initiating rosuvastatin therapy.

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

Liver enzymes

In controlled combination therapy studies in patients receiving ezetimibe with statins, consistent increases in transaminase levels (≥ 3 times ULN) were observed. When ezetimibe is used in combination with a statin, liver function tests should be performed at the start of therapy and according to statin-specific recommendations.

Race

Pharmacokinetic studies indicate approximately twofold higher exposure in Mongoloid race patients compared to Caucasians (see sections "Posology and method of administration", "Contraindications", and "Pharmacokinetics").

Protease inhibitors

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

Interstitial lung disease

Rare cases of interstitial lung disease have been reported during treatment with some statins, particularly with long-term use (see section "Adverse reactions"). Manifestations may include dyspnea, non-productive cough, and general deterioration (fatigue, weight loss, fever). If interstitial lung disease is suspected, statin therapy should be discontinued.

Diabetes mellitus

Evidence suggests that statins as a class may increase blood glucose levels and may induce hyperglycemia requiring treatment in some patients at high risk of developing diabetes mellitus in the future. However, this risk is outweighed by the reduction in vascular risk with statin use, and therefore should not be a reason to discontinue statin therapy. Patients at risk (fasting glucose 5.6–6.9 mmol/L, BMI > 30 kg/m², elevated triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines.

In the JUPITER study, the overall incidence of diabetes mellitus was 2.8% in the rosuvastatin group and 2.3% in the placebo group, predominantly in patients with fasting glucose levels between 5.6 and 6.9 mmol/L.

Fibrates

The safety and efficacy of co-administration of ezetimibe with fibrates have not been established.

If cholelithiasis is suspected in a patient receiving ezetimibe and fenofibrate, gallbladder examination and discontinuation of such therapy are indicated.

Cyclosporine

Initiation of ezetimibe therapy in patients taking cyclosporine should be done with caution. Cyclosporine concentrations should be monitored in patients receiving both ezetimibe and cyclosporine.

Anticoagulants

If ezetimibe is used concomitantly with warfarin, other coumarin anticoagulants, or fluindione, INR should be appropriately monitored.

Children

Assessment of linear growth (height), body weight, body mass index (BMI), and secondary sexual characteristics according to Tanner in children aged 6 to 17 years treated with 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 treated with 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 have been evaluated in a placebo-controlled clinical study over 12 weeks. The effect of ezetimibe beyond 12 weeks of treatment in this age group has not been studied.

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

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

Excipients. This medicinal product contains lactose monohydrate. If you have been diagnosed with an intolerance to certain sugars, consult your doctor before taking this medicinal product.

Use during pregnancy or breastfeeding.

Therapy with the medicinal product EZATRO is contraindicated during pregnancy or breastfeeding (see section "Contraindications").

Pregnancy

Rosuvastatin. Women of childbearing potential must use appropriate contraceptive measures.

Since cholesterol and other products of cholesterol biosynthesis play a crucial role in fetal development, the potential risk of HMG-CoA reductase inhibition outweighs any benefit from using the medicinal product during pregnancy. Data from animal studies on reproductive toxicity are limited. If a patient becomes pregnant while taking this medicinal product, treatment should be discontinued immediately.

Ezetimibe. Clinical data on the use of ezetimibe during pregnancy are lacking. Animal studies with ezetimibe as monotherapy showed no direct or indirect harmful effects on pregnancy, fetal or embryonic development, parturition, or postnatal development.

Breastfeeding period

Rosuvastatin. Rosuvastatin is excreted into the milk of rats. Data on the excretion of rosuvastatin into human breast milk are not available (see section "Contraindications").

Ezetimibe. Animal studies in rats have shown that ezetimibe is excreted into the milk of lactating animals. It is unknown whether ezetimibe is excreted into human breast milk.

Fertility

Clinical data on the effect of ezetimibe on human fertility are lacking. Ezetimibe showed no effect in animal studies.

Ability to influence reaction speed when driving or operating machinery.

Studies on the effect of rosuvastatin and/or ezetimibe on the ability to drive or operate machinery have not been conducted. However, when driving or operating machinery, the possibility of dizziness during treatment should be considered.

Dosage and Administration

Before initiating treatment, patients should be placed on a standard cholesterol-lowering diet, which should be continued throughout the course of treatment.

The medicinal product EZATRO is not suitable for initial therapy. Initiation of treatment or dose adjustment, if necessary, should be performed only with monocomponent medicinal products; after appropriate doses have been established, transition to the corresponding fixed-dose combination may be considered.

The recommended daily dose of the medicinal product EZATRO is 1 tablet, which can be taken at any time of day, regardless of food intake.

The medicinal product EZATRO should be taken ≥ 2 hours before or ≥ 4 hours after administration of bile acid sequestrants.

Elderly patients

For patients aged > 70 years, the recommended starting dose of rosuvastatin is 5 mg (see section "Special Warnings"). This fixed combination medicinal product is not used as first-line therapy. Combination therapy should only be initiated after appropriate doses of rosuvastatin or both components have been established.

Patients with renal impairment

Dose adjustment is not required in patients with mild to moderate renal impairment. The recommended starting dose of rosuvastatin in patients with moderate renal impairment (creatinine clearance < 60 mL/min) is 5 mg.

Fixed-dose combinations are not used as first-line therapy. Combination treatment should only be initiated after appropriate dosing of rosuvastatin or both components has been established.

Rosuvastatin is contraindicated in patients with severe renal impairment at any dose.

Patients with hepatic impairment

Dose adjustment is not required in patients with mild hepatic impairment (Child-Pugh score 5–6). The medicinal product EZATRO is not recommended for patients with moderate (Child-Pugh score 7–9) or severe (Child-Pugh score > 9) hepatic impairment (see section "Special Warnings"). EZATRO is contraindicated in patients with acute liver disease.

Race

Increased systemic exposure to rosuvastatin has been observed in patients of Mongoloid race (see sections "Pharmacokinetics", "Contraindications", "Special Warnings"). The recommended starting dose of rosuvastatin for patients of Asian origin is 5 mg.

The medicinal product EZATRO is not used as first-line hypolipidemic therapy.

Combination treatment should be initiated only after appropriate dosing of rosuvastatin or both components has been established.

Genetic polymorphism

Certain types of genetic polymorphism are known to increase systemic exposure to rosuvastatin. Patients with identified polymorphism types should be administered a lower daily dose of the medicinal product EZATRO.

Dosing in patients predisposed to myopathy

The recommended starting dose of rosuvastatin for patients predisposed to myopathy is 5 mg (see section "Special Warnings"). Fixed-dose combinations are not used as first-line hypolipidemic therapy. Combination treatment should be initiated only after appropriate dosing of rosuvastatin or both components has been established.

Concomitant therapy

Rosuvastatin is a substrate for various transporter proteins (e.g., OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) is increased when EZATRO is co-administered with certain medicinal products that can increase plasma concentrations of rosuvastatin via interactions with these transporter proteins (such as cyclosporine and certain protease inhibitors, including ritonavir combinations with atazanavir, lopinavir and/or tipranavir; see sections "Interaction with Other Medicinal Products and Other Forms of Interactions" and "Special Warnings"). Alternative treatment should be considered, and temporary discontinuation of EZATRO may be necessary. In situations where concomitant administration of these medicinal products with EZATRO cannot be avoided, the benefits and risks of concomitant therapy should be carefully weighed and rosuvastatin dose should be carefully selected (see section "Interaction with Other Medicinal Products and Other Forms of Interactions").

Administration method

For oral use.

The medicinal product EZATRO should be taken once daily at the same time each day, regardless 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, the medicinal product EZATRO is not recommended for this age group.

Overdose

Rosuvastatin. There is no specific antidote for rosuvastatin overdose. In case of overdose, symptomatic and supportive treatment should be administered as needed. Liver function tests and CK levels should be monitored. Hemodialysis is unlikely to be effective.

Ezetimibe. In studies where ezetimibe 50 mg/day was administered to 15 healthy subjects for 14 days or 40 mg/day to 18 patients with primary hypercholesterolemia for up to 56 days, it was generally well tolerated. No toxicity was observed in rats, mice, and dogs after single oral doses of 5000 mg/kg, 5000 mg/kg, and 3000 mg/kg ezetimibe, respectively.

Several cases of ezetimibe overdose have been reported; in most cases, no adverse effects occurred. Observed adverse effects were not serious. In case of overdose, symptomatic and supportive measures should be taken.

Adverse reactions.

Adverse events observed during treatment with rosuvastatin are usually mild and transient. In controlled clinical studies, less than 4% of patients receiving rosuvastatin discontinued treatment due to adverse reactions.

In studies lasting up to 112 weeks, ezetimibe at a dose of 10 mg once daily was administered alone to 2396 patients or in combination with a statin to 11,308 patients or with fenofibrate to 185 patients. Adverse reactions were generally mild and transient.

The overall incidence of adverse reactions was similar in the ezetimibe and placebo groups, as was the rate of discontinuation due to adverse events.

The adverse reactions listed below were observed in clinical studies in patients treated with ezetimibe (N = 2396) and occurred more frequently than in the placebo group (N = 1159), or were observed in patients treated with ezetimibe in combination with a statin (N = 11,308) and occurred more frequently than in the statin-only group (N = 9361). Post-marketing reports of adverse reactions have been received with ezetimibe used alone or in combination with a statine.

There are clinical data from studies in which 1200 patients received the combination of rosuvastatin and ezetimibe. The most common adverse reactions associated with the combined use of rosuvastatin and ezetimibe in patients with hypercholesterolemia were increased levels of liver transaminases, gastrointestinal disturbances, and muscle pain. These are known adverse reactions to the active substances of the medicinal product. However, a pharmacodynamic interaction between rosuvastatin and ezetimibe that may lead to adverse events cannot be excluded (see section "Pharmacological properties").

The frequency of adverse effects is classified as follows: very common (≥ 1/10), 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 the available data).

Blood and lymphatic system disorders:
Rare – thrombocytopenia²; not known – thrombocytopenia⁵.

Immune system disorders:
Rare – hypersensitivity reactions, including angioedema²; not known – hypersensitivity, including rash, urticaria, anaphylaxis, and angioedema⁵.

Endocrine disorders:
Common – diabetes mellitus^1,2.

Metabolism and nutrition disorders:
Uncommon – decreased appetite³.

Psychiatric disorders:
Not known – depression^2,5.

Nervous system disorders:
Common – headache^2,4, dizziness²; uncommon – paraesthesia⁴; very rare – polyneuropathy², memory loss²; not known – peripheral neuropathy², sleep disorders (including insomnia and nightmares)², myasthenia gravis², dizziness⁵, paraesthesia⁵.

Eye disorders:
Not known – ocular myasthenia.

Vascular disorders:
Uncommon – flushing³, hypertension³.

Respiratory, thoracic and mediastinal disorders:
Uncommon – cough³; not known – cough², dyspnea², dyspnoea³.

Gastrointestinal disorders:
Common – constipation², nausea², abdominal pain^2,3, diarrhea³, flatulence³; uncommon – dyspepsia³, gastroesophageal reflux³, nausea³, dry mouth⁴, gastritis⁴; rare – pancreatitis²; not known – diarrhea², pancreatitis⁵, constipation⁵.

Hepatobiliary disorders:
Rare – increased liver transaminase levels²; very rare – jaundice², hepatitis²; not known – hepatitis⁵, cholelithiasis⁵, cholecystitis⁵.

Skin and subcutaneous tissue disorders:
Uncommon – pruritus^2,4, rash^2,4, urticaria^2,4; not known – Stevens-Johnson syndrome², drug reaction with eosinophilia and systemic symptoms (DRESS)⁵, erythema multiforme⁵.

Musculoskeletal and connective tissue disorders:
Common – myalgia^2,4; uncommon – arthralgia³, muscle spasms³, neck pain³, back pain⁴, muscle weakness⁴, limb pain⁴; 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, myalgia⁵, myopathy/rhabdomyolysis⁵ (see section "Special 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, asthenia⁴, peripheral edema⁴; not known – edema², asthenia⁵.

Investigations:
Common – increased levels of ALT and/or AST⁴; uncommon – increased levels of ALT and/or AST³, increased serum creatine kinase (CK) levels³, increased gamma-glutamyl transferase levels³, abnormal liver function tests³.

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

2 Adverse reaction profile of rosuvastatin based on clinical studies and extensive post-marketing experience.

3 Adverse reactions observed in clinical studies of ezetimibe (used as monotherapy). In patients receiving ezetimibe (n = 2396), adverse reactions occurred more frequently than with placebo (n = 1159).

4 Adverse reactions observed in clinical studies of ezetimibe (used concomitantly with a statin). In patients receiving ezetimibe with a statin (n = 11,308), adverse reactions occurred more frequently than with statin alone (n = 9361).

5 During post-marketing use of ezetimibe. Since these adverse effects were reported from spontaneous reports, their actual frequency is unknown and cannot be estimated.

As with other HMG-CoA reductase inhibitors, the frequency of adverse reactions tends to be dose-dependent.

Renal effects

Proteinuria, predominantly of tubular origin, was detected by dipstick analysis in patients treated with rosuvastatin. Changes in urinary protein content from zero or trace to ++ or higher were observed intermittently in < 1% of patients during treatment with 10 and 20 mg doses, and in approximately 3% of patients at the 40 mg dose. A slight increase in the frequency of changes from zero or trace to + was observed at the 20 mg dose. In most cases, proteinuria decreased or resolved spontaneously while continuing therapy. Based on clinical studies and post-marketing surveillance, to date, no causal relationship has been established between proteinuria and acute or progressive kidney disease.

Cases of haematuria have been reported during treatment with rosuvastatin; clinical studies indicate a low frequency.

Musculoskeletal effects

Skeletal muscle involvement, such as myalgia, myopathy (including myositis), and rarely rhabdomyolysis, with or without acute kidney injury, has been reported with all doses of rosuvastatin, particularly at doses > 20 mg.

In patients taking 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 times the upper limit of normal), treatment should be discontinued (see section "Special precautions for use").

Hepatic effects

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

With the use of some statins, the following adverse events have been reported:

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

The frequency of reports of rhabdomyolysis, serious renal and hepatic disorders (mainly increased hepatic transaminase activity) is higher when the medicinal product is used at a dose of 40 mg.

Laboratory findings

During controlled clinical monotherapy studies, clinically significant increases in serum transaminases (ALT and/or AST ≥ 3 times the upper limit of normal) were similar in the ezetimibe (0.5%) and placebo (0.3%) groups. In combination therapy studies, the frequency of such increases was 1.3% in patients receiving ezetimibe with a statin and 0.4% in patients receiving statin alone. Such increases were usually asymptomatic, not associated with cholestasis, and returned to baseline levels after discontinuation of therapy or during continued treatment.

In clinical studies, increases in CK levels ≥ 10 times the upper limit of normal were observed in 4 out of 1674 patients (0.2%) receiving ezetimibe alone, compared to 1 out of 786 patients (0.1%) receiving placebo, and in 1 out of 917 patients (0.1%) receiving ezetimibe with a statin, compared to 4 out of 929 patients (0.4%) receiving statin alone. There was no increased risk of myopathy or rhabdomyolysis with ezetimibe compared to the respective control groups (placebo or statin alone).

Children

Rosuvastatin. Increases in creatine kinase levels > 10 times the upper limit of normal and muscle-related 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 precautions for use"). However, the safety profile of rosuvastatin in children and adolescents was similar to that in adults.

Ezetimibe. In a clinical study involving children aged 6 to 10 years with heterozygous familial or non-familial hypercholesterolemia (n = 138), increases in ALT and/or AST levels (≥ 3 times the upper limit of normal, confirmed) were observed in 1.1% (1 patient) of patients receiving ezetimibe, compared to 0% in the placebo group. No increases in CK levels (≥ 10 times the upper limit of normal) were observed. No cases of myopathy were reported.

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

Shelf life.

3 years.

Storage conditions.

No special temperature storage conditions required. Store in the original packaging to protect from moisture and light.

Packaging.

10 tablets in a blister, 3 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Medicair Biosciences Laboratories S.A.

Manufacturer's address and place of business.

Atinon-Lamias National Road 61st Km, Schimatari, 32009, Greece.

Marketing Authorization Holder.

LLC NVF "MIKROKHIM".

Address of the Marketing Authorization Holder and/or its representative.

Ukraine, 01013, Kyiv, Budyndustrії St., 5.

To report an adverse event related to the use of this medicinal product, please contact the pharmacovigilance system of LLC NVF "MIKROKHIM" at +38(050) 309-83-54 (24/7) or via the link: https://microkhim.com.ua/farmakonaglyad/