Cartil® rose

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT HARTIL® ROZ (HARTIL® ROZ)

Composition:

Active substances: rosuvastatin, ramipril;

Each capsule contains:

• 1 tablet containing 10.42 mg of rosuvastatin calcium (equivalent to 10 mg of rosuvastatin) and 1 tablet containing 5 mg of ramipril,

or

• 1 tablet containing 10.42 mg of rosuvastatin calcium (equivalent to 10 mg of rosuvastatin) and 1 tablet containing 10 mg of ramipril,

or

• 1 tablet containing 20.84 mg of rosuvastatin calcium (equivalent to 20 mg of rosuvastatin) and 1 tablet containing 5 mg of ramipril,

or

• 1 tablet containing 20.84 mg of rosuvastatin calcium (equivalent to 20 mg of rosuvastatin) and 1 tablet containing 10 mg of ramipril.

Excipients:

For rosuvastatin calcium tablet:

microcrystalline silicified cellulose, magnesium stearate (E 572), colloidal anhydrous silicon dioxide (E 551);

For ramipril tablet:

microcrystalline cellulose PH 102 FMC, crospovidone type B, hypromellose 2910, 3 cP, sodium stearyl fumarate, colloidal hydrophobic silicon dioxide R972, iron oxide yellow (E 172) Cl 77492, purified water;

Capsule composition 10 mg/5 mg:

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

Capsule composition 10 mg/10 mg:

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

Capsule composition 20 mg/5 mg:

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

Capsule composition 20 mg/10 mg:

titanium dioxide (E 171), iron oxide red (E 172), gelatin.

Dosage form. Hard capsules.

Main physicochemical properties:

Hard capsules 10 mg/5 mg

Hard gelatin capsules of Coni Snap type, self-closing, size 2. Capsule body and cap are unmarked. Capsule body is almost white, cap is brick-red. Each capsule contains two tablets: one round, biconvex tablet of rosuvastatin 10 mg, white or almost white, odorless or nearly odorless, with stylized marking on one side and no marking on the other side; and one round, biconvex tablet of ramipril 5 mg, pale yellow, with possible spots of white and yellowish-brown color on the surface, odorless or nearly odorless, unmarked on both sides.

Hard capsules 10 mg/10 mg

Hard gelatin capsules of Coni Snap type, self-closing, size 0. Capsule body and cap are unmarked. Capsule body is pink, cap is brick-red. Each capsule contains two tablets: one round, biconvex tablet of rosuvastatin 10 mg, white or almost white, odorless or nearly odorless, with stylized marking on one side and no marking on the other side; and one round, biconvex tablet of ramipril 10 mg, pale yellow, with possible spots of white and yellowish-brown color on the surface, odorless or nearly odorless, unmarked on both sides.

Hard capsules 20 mg/5 mg

Hard gelatin capsules of Coni Snap type, self-closing, size 0. Capsule body and cap are unmarked. Capsule body is almost white, cap is rust-brown. Each capsule contains two tablets: one round, biconvex tablet of rosuvastatin 20 mg, white or almost white, odorless or nearly odorless, with stylized marking on one side and no marking on the other side; and one round, biconvex tablet of ramipril 5 mg, pale yellow, with possible spots of white and yellowish-brown color on the surface, odorless or nearly odorless, unmarked on both sides.

Hard capsules 20 mg/10 mg

Hard gelatin capsules of Coni Snap type, self-closing, size 0. Capsule body and cap are unmarked. Capsule body is pink, cap is rust-brown. Each capsule contains two tablets: one round, biconvex tablet of rosuvastatin 20 mg, white or almost white, odorless or nearly odorless, with stylized marking on one side and no marking on the other side; and one round, biconvex tablet of ramipril 10 mg, pale yellow, with possible spots of white and yellowish-brown color on the surface, odorless or nearly odorless, unmarked on both sides.

Pharmacotherapeutic group. Lipid-lowering agents, combinations. Lipid-lowering agents in combination with other medicinal products. Rosuvastatin and ramipril. ATC code: C10BX17.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Rosuvastatin

Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the enzyme that limits the rate of 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 low-density lipoprotein (LDL) receptors on the surface of liver cells, enhancing the uptake and catabolism of LDL, and inhibits hepatic synthesis of very-low-density lipoproteins (VLDL), thereby reducing the overall levels of VLDL and LDL.

Ramipril

Ramiprilat, the active metabolite of the prodrug ramipril, is an inhibitor of the enzyme dipeptidyl carboxypeptidase I (synonyms: angiotensin-converting enzyme; kininase II). In blood plasma and tissues, this enzyme catalyzes the conversion of angiotensin I to angiotensin II (an active vasoconstrictor substance) and the breakdown of the active vasodilator bradykinin. Reduced formation of angiotensin II and inhibition of bradykinin degradation lead to vasodilation.

Since angiotensin II also stimulates the release of aldosterone, ramiprilat causes a reduction in aldosterone secretion. The response to monotherapy with ACE inhibitors has generally been less pronounced in patients of non-Caucasian race (of Afro-Caribbean origin) with arterial hypertension (a population typically characterized by low renin levels in hypertension) compared to patients of other racial groups.

Pharmacodynamic effects

Rosuvastatin

Rosuvastatin reduces elevated levels of low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides, and increases high-density lipoprotein cholesterol (HDL-C) levels.

It also reduces levels of apolipoprotein B (ApoB), non-HDL-C, VLDL-C, very-low-density lipoprotein triglycerides (VLDL-TG), and increases apolipoprotein A-I (ApoA-I) levels (see 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	Apo B	Apo A-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 treatment, with 90% of the maximum effect reached within 2 weeks. The maximum effect is usually achieved within 4 weeks and persists thereafter.

Ramipril

Antihypertensive properties. Administration of ramipril leads to a significant reduction in peripheral arterial resistance. Generally, no significant changes in renal plasma flow or glomerular filtration rate occur. Administration of ramipril to patients with arterial hypertension results in reduction of arterial blood pressure in both supine and upright positions, without compensatory increase in heart rate.

In most patients, the antihypertensive effect begins within 1–2 hours after oral administration of a single dose. The maximum effect after a single oral dose is usually achieved within 3–6 hours. The antihypertensive effect after a single dose typically lasts for 24 hours.

With long-term treatment using ramipril, the maximum antihypertensive effect is achieved within 3–4 weeks. It has been demonstrated that during prolonged therapy, the antihypertensive effect persists for up to 2 years.

Abrupt discontinuation of ramipril does not cause rapid or excessive increase in arterial blood pressure (rebound phenomenon).

Heart failure. It has been demonstrated that ramipril, when used as an adjunct to conventional therapy with diuretics and, if necessary, cardiac glycosides, is effective in patients with NYHA functional class II–IV heart failure. Ramipril exerts beneficial effects on cardiac hemodynamics (reduction in filling pressures of the left and right ventricles, reduction in total peripheral vascular resistance, increase in cardiac output, and improvement in cardiac index). It also reduces neuroendocrine activation.

Clinical efficacy and safety

Rosuvastatin

Rosuvastatin is effective in the treatment of adults with hypercholesterolemia—with or without hypertriglyceridemia—regardless of race, gender, or age, as well as in patients from special populations such as those with diabetes mellitus or 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 level approximately 4.8 mmol/L) to target values established by the European Atherosclerosis Society (EAS; 1998) guidelines. Approximately 80% of patients receiving 10 mg of rosuvastatin achieved EAS target LDL-C levels (< 3 mmol/L).

In a large study involving 435 patients with heterozygous familial hypercholesterolemia, rosuvastatin was administered at doses ranging from 20 to 80 mg using an up-titration regimen. Favorable lipid responses and achievement of target levels were observed at all dose levels. After titration to a daily dose of 40 mg (after 12 weeks of treatment), LDL-C levels decreased by 53%. Target EAS LDL-C levels (< 3 mmol/L) were achieved in 33% of patients.

In an open-label dose up-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, an additive effect of rosuvastatin on triglyceride reduction when used in combination with fenofibrate, and on HDL-C increase when used in combination with niacin, has been observed (see section "Special 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 Framingham Risk Score < 10% over 10 years), mean LDL-C level of 4.0 mmol/L (154.5 mg/dL), but with subclinical atherosclerosis (defined by increased carotid intima-media thickness [CIMT]) were randomized to receive either 40 mg of rosuvastatin or placebo once daily for 2 years. Compared with 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 not significant]) in the rosuvastatin group versus progression of +0.0131 mm/year (1.12%/year [p < 0.0001]) in the placebo group. A direct correlation between reduction in CIMT and reduction in cardiovascular event risk 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 use.

In the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), the effect of rosuvastatin on the incidence of major atherosclerotic cardiovascular events was evaluated in 17,802 men (≥50 years) and women (≥60 years).

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

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

In a retrospective analysis of a high-risk subgroup with baseline Framingham Risk Score > 20% (1558 participants), a significant reduction in the incidence of the composite endpoint (including cardiovascular death, stroke, and myocardial infarction) was observed in the rosuvastatin group compared to placebo (p = 0.028). The absolute risk reduction was 8.8 events per 1000 patient-years. The overall mortality rate remained unchanged in this high-risk group (p = 0.193).

In a retrospective analysis of another high-risk subgroup (9302 participants overall) with baseline SCORE ≥ 5% (extrapolated to include participants over 65 years of age), a significant reduction in the incidence of the composite endpoint (including cardiovascular death, stroke, and myocardial infarction) was observed in the rosuvastatin group compared to placebo (p = 0.0003). The absolute risk reduction expressed as event rate was 5.1 events per 1000 patient-years. The overall mortality rate in this high-risk subgroup remained unchanged (p = 0.076).

In the JUPITER trial, 6.6% of participants in the rosuvastatin group and 6.2% in the placebo group discontinued the study drug 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 in the placebo group were urinary tract infections (8.7% in rosuvastatin group, 8.6% in placebo), nasopharyngitis (7.6% in rosuvastatin group, 7.2% in placebo), back pain (7.6% in rosuvastatin group, 6.9% in placebo), and myalgia (7.6% in rosuvastatin group, 6.6% in placebo).

Ramipril

Prevention of cardiovascular diseases / nephroprotection

A preventive, placebo-controlled trial (the HOPE study) was conducted involving over 9,200 patients who received ramipril in addition to standard therapy. The study included patients at high risk of cardiovascular disease due to a history of atherothrombotic cardiovascular disease (prior myocardial infarction, stroke, or peripheral vascular disease) or patients with diabetes mellitus who had at least one additional risk factor (documented microalbuminuria, hypertension, elevated total cholesterol, low HDL cholesterol, or smoking).

This study demonstrated that ramipril significantly reduces the incidence of myocardial infarction, cardiovascular death, and stroke, both individually and as a combined endpoint (primary composite endpoint).

Table 2

HOPE study: main results

Parameter	Ramipril, %	Placebo, %	Relative risk (95 % confidence interval)	p value
All patients	n = 4,645	N = 4,652
Primary composite endpoint	14.0	17.8	0.78 (0.70–0.86)	< 0.001
Myocardial infarction	9.9	12.3	0.80 (0.70–0.90)	< 0.001
Cardiovascular death	6.1	8.1	0.74 (0.64–0.87)	< 0.001
Stroke	3.4	4.9	0.68 (0.56–0.84)	< 0.001
Secondary endpoints
Death from any cause	10.4	12.2	0.84 (0.75–0.95)	0.005
Need for revascularization	16.0	18.3	0.85 (0.77–0.94)	0.002
Hospitalization due to unstable angina	12.1	12.3	0.98 (0.87–1.10)	not significant
Hospitalization due to heart failure	3.2	3.5	0.88 (0.70–1.10)	0.25
Complications related to diabetes	6.4	7.6	0.84 (0.72–0.98)	0.03

During the MICRO-HOPE study, which was prospectively planned as part of the HOPE study, the effect of adding ramipril at a dose of 10 mg to existing treatment was evaluated compared to placebo in 3577 patients aged 55 years and older (no upper age limit) with normal or elevated blood pressure, most of whom had type 2 diabetes (and had at least one cardiovascular risk factor).

The primary analysis results demonstrated that overt nephropathy developed in 117 (6.5%) participants receiving ramipril and in 149 (8.4%) receiving placebo, representing a 24% relative risk reduction; 95% CI [3–40], p = 0.027.

The REIN study, a multicenter, randomized, double-blind, placebo-controlled parallel-group trial, was conducted to evaluate the impact of ramipril treatment on the rate of decline in glomerular filtration rate (GFR) in 352 patients aged 18–70 years with normal or elevated blood pressure, who had mild (mean urinary protein excretion >1 and <3 g/day) or severe (≥3 g/day) proteinuria due to chronic non-diabetic nephropathy. Both subgroups were prospectively stratified.

The main analysis results in patients with the most severe proteinuria (a subgroup that prematurely discontinued participation in the study because benefit from ramipril treatment was proven) demonstrated that the mean rate of GFR decline per month was lower with ramipril than with placebo: −0.54 (0.66) vs. −0.88 (1.03) mL/min/month, p = 0.038. Thus, the between-group difference was 0.34 [0.03–0.65] per month, approximately 4 mL/min/year; 23.1% of patients in the ramipril group reached the combined secondary endpoint—doubling of plasma creatinine concentration and/or end-stage renal disease (requirement for hemodialysis or kidney transplantation)—compared to 45.5% in the placebo group (p = 0.02).

Dual blockade of the renin-angiotensin-aldosterone system (RAAS). Two large-scale randomized controlled trials [ONTARGET (telmisartan monotherapy and in combination with ramipril on overall outcome) and VA NEPHRON-D (diabetic nephropathy in veterans)] evaluated the use of a combination of an ACE inhibitor with an angiotensin II receptor antagonist.

The ONTARGET study included patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with concomitant target organ damage. The VA NEPHRON-D study included patients with type 2 diabetes and diabetic nephropathy.

These studies did not show significant advantages of combination therapy regarding renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalemia, acute renal failure, and/or arterial hypotension was observed compared to monotherapy. Given the similar pharmacodynamic characteristics of these drugs, these results are also applicable to other ACE inhibitors and angiotensin II receptor antagonists.

Therefore, ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly in patients with diabetic nephropathy.

The ALTITUDE study (aliskiren effect in type 2 diabetes using cardiovascular and renal endpoints) evaluated the benefits of adding aliskiren to standard therapy with an ACE inhibitor or angiotensin II receptor antagonist in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. This study was prematurely terminated due to an increased risk of adverse clinical outcomes. In the aliskiren group compared to the placebo group, a higher incidence of cardiovascular death and stroke was observed, along with an increased frequency of serious adverse events of particular interest (hyperkalemia, arterial hypotension, and renal dysfunction).

Secondary prevention after acute myocardial infarction. The AIRE study included over 2000 patients with transient/permanent symptoms of heart failure following myocardial infarction. Ramipril treatment was initiated 3–10 days after the onset of acute myocardial infarction. This study demonstrated that after a mean follow-up period of 15 months, mortality in the ramipril group was 16.9% compared to 22.6% in the placebo group. This represents an absolute mortality reduction of 5.7% and a relative risk reduction of 27% (95% CI [11–40%]).

Paediatric population

Rosuvastatin

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 menarche at least 1 year prior) 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 beginning 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, 10, and 20 mg groups, respectively, compared to 0.7% in the placebo group.

At the end of the 40-week open-label titration period to achieve target levels (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, weight, BMI, or sexual maturation was observed. This study (n = 176) is not suitable for comparing rare adverse reactions.

Rosuvastatin was also evaluated in a 2-year open-label dose-titration study involving 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 rosuvastatin once daily. Patients aged 6 to 9 years (n = 64) had their dose titrated up to a maximum of 10 mg once daily, and patients aged 10 to 17 years (n = 134) up to a maximum of 20 mg once daily.

After 24 months of rosuvastatin treatment, the mean reduction from baseline LDL-C, estimated by 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, estimated by 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.

Treatment with rosuvastatin at doses of 5 mg, 10 mg, 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, TG/HDL-C, non-HDL-C/HDL-C, ApoB, 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.

In a randomized, double-blind, placebo-controlled, multicenter crossover study, rosuvastatin 20 mg once daily was evaluated versus placebo in 14 children and adolescents (aged 6 to 17 years) with homozygous familial hypercholesterolemia. The study included an active 4-week dietary lead-in phase during which patients were treated with 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 treatment period, and a 12-week maintenance phase during which all patients received 20 mg rosuvastatin. Patients on ezetimibe 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 rosuvastatin 20 mg treatment 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 TG, LDL-C/HDL-C, total cholesterol/HDL-C, non-HDL-C/HDL-C, and ApoB/ApoA-I levels were also observed after 6 weeks of rosuvastatin 20 mg treatment compared to placebo. The reduction in LDL-C after 6 weeks of rosuvastatin 20 mg treatment followed by 6 weeks of placebo treatment was maintained over 12 weeks of continuous therapy. One patient experienced further reductions in LDL-C (8.0%), total cholesterol (6.7%), and non-HDL-C (7.4%) after 6 weeks of dose titration to 40 mg.

During continued open-label treatment with rosuvastatin 20 mg in 9 of these patients up to 90 weeks, LDL-C reduction was maintained between -12.1% and -21.3%.

In an open dose-escalation 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 rosuvastatin 20 mg treatment corresponded 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 rosuvastatin studies in children of various ages for the treatment of homozygous familial hypercholesterolemia, primary combined (mixed) dyslipidemia, and prevention of cardiovascular disorders (see section "Children").

Ramipril

In a randomized, double-blind, placebo-controlled clinical study involving 244 pediatric patients aged 6–16 years with hypertension (73% of whom had primary hypertension), participants received low, medium, or high doses of ramipril to achieve plasma concentrations of ramiprilat corresponding to adult dose ranges of 1.25 mg, 5 mg, and 20 mg based on body weight. At the end of the 4-week period, ramipril was ineffective regarding the primary endpoint—reduction in systolic blood pressure—but it reduced diastolic pressure at the highest dose tested. Medium and high doses of ramipril were shown to significantly reduce both systolic and diastolic blood pressure in children with confirmed hypertension.

This effect was not observed in a 4-week randomized, double-blind, dose-escalation study assessing the effect of drug withdrawal involving 218 pediatric patients aged 6–16 years (75% of whom had primary hypertension). In this study, after drug withdrawal, a moderate rebound increase in both diastolic and systolic pressure was observed, but it was not statistically significant for return to baseline levels in all dose groups of the ramipril dose range [low (0.625–2.5 mg), medium (2.5–10 mg), or high (5–20 mg)] based on body weight. In the studied pediatric population, ramipril did not demonstrate a linear dose-response relationship.

Pharmacokinetics

Rosuvastatin

Absorption

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

Metabolism

Rosuvastatin 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 roles played by 2C19, 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 the circulating HMG-CoA reductase inhibitor activity.

Elimination

Approximately 90% of the rosuvastatin dose is excreted unchanged in feces (comprising 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 rosuvastatin 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. Pharmacokinetic parameters do not change with repeated daily administration.

Special patient populations

Age and sex

No clinically significant effect of age or sex on rosuvastatin pharmacokinetics in adults was observed.

Race

Pharmacokinetic studies revealed that median AUC and Cmax values in patients of Mongoloid race (Japanese, Chinese, Filipinos, Vietnamese, and Koreans) were approximately twice as high as in Europeans; in Indians, median AUC and Cmax values were elevated by approximately 1.3 times. Population pharmacokinetic analysis did not reveal clinically significant differences between Caucasian and African patients.

Renal impairment

In a study involving patients with varying degrees of renal impairment, no changes in plasma concentrations of rosuvastatin or N-desmethyl metabolite were observed in cases of mild or moderate renal insufficiency. In patients with severe renal impairment (creatinine clearance <30 mL/min), plasma concentrations of rosuvastatin were three times higher, and N-desmethyl metabolite levels nine 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 involving patients with varying degrees of hepatic dysfunction, no signs of increased rosuvastatin exposure were observed in patients scoring 7 or less on the Child-Pugh scale.

However, in two patients scoring 8 and 9 on the Child-Pugh scale, systemic exposure was at least twice as high as in patients with lower scores. Experience with rosuvastatin in patients scoring more than 9 on the Child-Pugh scale is lacking.

Genetic polymorphism

The distribution of HMG-CoA reductase inhibitors, including rosuvastatin, involves the transport 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 if a patient is known to have such a polymorphism, a lower daily dose of rosuvastatin is recommended.

Ramipril

Absorption. After oral administration, ramipril is rapidly absorbed from the gastrointestinal tract. Maximum plasma concentration is reached within 1 hour. Based on the amount of substance detected in urine, the absorption rate is at least 56% and is not significantly affected by the presence of food in the gastrointestinal tract. The bioavailability of the active metabolite ramiprilat after oral administration of ramipril at doses of 2.5 mg and 5 mg is 45%.

The maximum plasma concentration of ramiprilat, the sole active metabolite of ramipril, is reached 2–4 hours after ramipril administration. After administration of usual doses of ramipril once daily, steady-state plasma concentrations of ramiprilat are reached approximately on day 4 of treatment.

Distribution. Binding of ramipril to plasma proteins is approximately 73%, and for ramiprilat, approximately 56%.

Metabolism. Ramipril is almost completely metabolized to ramiprilat, diketopiperazine ester, diketopiperazine acid, and glucuronides of ramipril and ramiprilat.

Elimination. Metabolite elimination occurs primarily via renal excretion. The decline in ramiprilat plasma concentration is multiphasic. Due to strong saturable binding to ACE and slow dissociation from the enzyme complex, ramiprilat has a prolonged terminal elimination phase at very low plasma concentrations.

After repeated doses of ramipril once daily, the effective elimination half-life is 13–17 hours for doses of 5–10 mg and longer for lower doses (1.25–2.5 mg). This difference is due to the enzyme's binding capacity for ramiprilat being saturable.

Patients with renal impairment (see section "Dosage and administration"). In patients with renal impairment, renal excretion of ramiprilat is reduced, and the renal clearance of ramiprilat is proportional to creatinine clearance. This leads to higher plasma concentrations of ramiprilat, which decline more slowly than in individuals with normal renal function.

Patients with hepatic impairment (see section "Dosage and administration"). In patients with hepatic impairment, the metabolism of ramipril to ramiprilat is slowed due to reduced activity of hepatic esterases, and plasma levels of ramipril are elevated in these patients. However, maximum concentrations of ramiprilat in these patients do not differ from those in individuals with normal liver function.

Breastfeeding. After a single oral dose of ramipril, its level in breast milk was below the limit of detection. However, the effect of multiple dosing is unknown.

Preclinical safety data

Rosuvastatin

Preclinical data revealed no special hazard for humans based on conventional safety pharmacology, genotoxicity, and carcinogenicity potential studies. Specific hERG effect tests were not evaluated.

Adverse reactions not observed in clinical studies but observed in animals at exposures similar to clinical exposure levels were as follows:

• In repeat-dose toxicity studies, histopathological liver changes, likely related to the pharmacological action of rosuvastatin, were observed in mice and rats;
• A lesser effect on the gallbladder was observed in dogs but not in monkeys;
• Gonadotoxicity was observed in monkeys and dogs at higher doses;
• Reproductive toxicity was evident in rats: low body weight and poor offspring survival were observed at maternally toxic doses when systemic exposure was several times higher than with therapeutic doses.

Ramipril

Oral administration of ramipril does not cause acute toxic effects in rodents and dogs. Long-term oral administration studies were conducted in rats, dogs, and monkeys. Electrolyte balance and blood picture changes were observed in all three animal species. In dogs and monkeys receiving the drug at 250 mg/kg body weight per day, marked increases in the juxtaglomerular apparatus were observed, reflecting the pharmacodynamic activity of ramipril. Daily doses of 2, 2.5, and 8 mg/kg body weight in rats, dogs, and monkeys, respectively, did not lead to adverse effects. Irreversible kidney damage was observed in very young rats receiving a single dose of ramipril.

Reproductive toxicity studies conducted in rats, rabbits, and monkeys did not reveal any teratogenic properties of ramipril. No adverse effect on fertility was observed in either male or female rats.

Administration of ramipril to female rats during pregnancy and lactation resulted in irreversible kidney damage (dilation of the renal pelvis) in offspring at doses ≥50 mg/kg body weight per day.

Numerous mutagenicity tests using various test systems did not reveal mutagenic or genotoxic properties of ramipril.

Clinical characteristics

Indications

HARTIL® ROZ is indicated for the treatment of arterial hypertension in adult patients whose condition is adequately controlled by concomitant administration of ramipril and rosuvastatin at the same doses as in the fixed combination, and who have, in addition to arterial hypertension, one of the following conditions:

• primary hypercholesterolemia (type IIa, including heterozygous familial hypercholesterolemia),
• mixed dyslipidemia (type IIb),
• homozygous familial hypercholesterolemia,

and also for the prevention of major cardiovascular events in patients at high risk of a first cardiovascular event, as an adjunct to correction of other risk factors.

Contraindications

Rosuvastatin

• Hypersensitivity to rosuvastatin.
• Active liver disease, including persistent elevations of serum transaminases of unknown etiology, and any increases in serum transaminases exceeding 3 times the upper limit of normal (ULN).
• Severe renal impairment (creatinine clearance < 30 mL/min).
• Myopathy.
• Patients receiving concomitant combination of sofosbuvir/velpatasvir/voxilaprevir (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use with cyclosporine.

Ramipril

• Hypersensitivity to ramipril or to other angiotensin-converting enzyme (ACE) inhibitors.
• History of angioedema (hereditary, idiopathic, or previously occurring during treatment with ACE inhibitors or angiotensin II receptor antagonists).
• Concomitant use with sacubitril/valsartan (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").
• Extracorporeal treatments leading to blood contact with negatively charged surfaces (see section "Interaction with other medicinal products and other forms of interaction").
• Significant bilateral renal artery stenosis or renal artery stenosis in the presence of a single functioning kidney.
• Arterial hypotension or hemodynamically unstable conditions.
• Concomitant use of aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal dysfunction (glomerular filtration rate (GFR) < 60 mL/min/1.73 m²) (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacodynamics").

Contraindications related to the use of HARTIL® ROZ

All contraindications described above for the individual active substances also apply to the medicinal product HARTIL® ROZ.

Hypersensitivity to any excipient (see section "Composition").

The medicinal product is contraindicated during pregnancy or breastfeeding, as well as in women of childbearing potential who are not using appropriate contraceptive measures (see sections "Special precautions for use" and "Use during pregnancy and breastfeeding").

Interaction with other medicinal products and other forms of interaction

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 use of rosuvastatin with medicinal products that inhibit these transporters may increase plasma concentrations of rosuvastatin and increase the risk of myopathy (see sections "Dosage and administration", "Special precautions for use", Table 3).

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 3). HARTIL® ROZ is contraindicated in patients receiving 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 3). For example, in a pharmacokinetic study, concomitant administration of 10 mg rosuvastatin and a combined medicinal product containing two protease inhibitors (300 mg atazanavir / 100 mg ritonavir) in healthy volunteers resulted in increases in rosuvastatin AUC and Cmax by approximately 3 and 7 times, 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 "Dosage and administration", "Special precautions for use", Table 3).

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

Based on data from specific studies, a pharmacokinetically significant interaction with fenofibrate is not 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 3). A pharmacodynamic interaction between rosuvastatin and ezetimibe cannot be excluded, which may lead to adverse effects (see section "Special precautions for use").

Antacid medicinal products. Concomitant use of rosuvastatin with suspensions of antacids containing aluminium 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.

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

Ticagrelor. Ticagrelor may affect renal excretion of rosuvastatin, increasing the risk of rosuvastatin 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.

Interactions requiring rosuvastatin dose adjustment (see Table 3). If concomitant use of rosuvastatin with other medicinal products capable of increasing rosuvastatin exposure is necessary, the rosuvastatin dose should be adjusted. If an approximately 2-fold or greater increase in drug exposure (AUC) 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 exposure does not exceed that observed with a 40 mg daily dose without interacting medicinal products. For example, when used with gemfibrozil, the rosuvastatin dose would be 20 mg (exposure increased 1.9-fold); when used with ritonavir/atazanavir combination, 10 mg (exposure increased 3.1-fold).

If a medicinal product increases rosuvastatin AUC by less than 2-fold, the initial dose need not be reduced, but caution should be exercised when increasing the rosuvastatin dose above 20 mg.

Table 3

Effect of concomitant medicinal products on rosuvastatin exposure

(AUC; in order of decreasing magnitude) based on published data from clinical studies

Increased rosuvastatin AUC by 2-fold or more
Concomitant drug dosing regimen	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 75 mg 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	Data not available	↑ 2.7-fold
Paritaprevir 25 mg / ombitasvir 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 loading dose, followed by 75 mg after 24 hours	20 mg, single dose	↑ 2-fold
Fostamatinib 100 mg twice daily	20 mg, single dose	↑ 2-fold
Increased rosuvastatin AUC less than 2-fold
Concomitant drug dosing regimen	Rosuvastatin dosing regimen	Changes in rosuvastatin AUC*
Gemfibrozil 600 mg twice daily, 7 days	80 mg, single dose	↑ 1.9-fold
Febuxostat 120 mg once daily	10 mg, single dose	↑ 1.9-fold
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	Unknown	↑ 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
Concomitant drug dosing regimen	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 change in x times represent the ratio of parameters when rosuvastatin is used in combination versus alone. Data presented as % change represent the % difference relative to parameters when rosuvastatin is used alone.

Increases are indicated by ↑, decreases by ↓.

** Several interaction studies were conducted at different doses of rosuvastatin; the most significant ratio is presented in Table 3.

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

Effect of rosuvastatin on concomitant drugs

Vitamin K antagonists. As with other HMG-CoA reductase inhibitors, initiation of rosuvastatin or dose increase 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 dose reduction 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 norgestimate, respectively. Such increases in plasma levels should be considered when selecting the dose of oral contraceptives. There are no data on the pharmacokinetics of drugs in patients concurrently receiving rosuvastatin and HRT; 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. Based on specific 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 myopathy, including rhabdomyolysis, may be increased when fusidic acid is systemically co-administered with statins. The mechanism of this interaction (pharmacodynamic or pharmacokinetic, or both) has not yet been fully elucidated. Cases of rhabdomyolysis (including some fatal cases) have been reported in patients receiving this combination.

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

Ramipril

Clinical study data have demonstrated that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combined use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is associated with an increased incidence of adverse events such as hypotension, hyperkalemia, and worsening renal function (including acute renal failure), compared to use of a single agent affecting the RAAS (see sections "Pharmacodynamics", "Contraindications", and "Special precautions for use").

Contraindicated combinations

Sacubitril/valsartan. Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema (see sections "Contraindications" and "Special precautions for use"). Ramipril therapy should be initiated only 36 hours after the last dose of sacubitril/valsartan. Sacubitril/valsartan therapy should be initiated only 36 hours after the last dose of ramipril.

Extracorporeal therapy methods. Extracorporeal therapy methods involving blood contact with negatively charged surfaces, such as dialysis or hemofiltration using certain high-flux membranes (e.g., polyacrylonitrile membranes) and low-density lipoprotein apheresis using dextran sulfate, are contraindicated due to an increased risk of severe anaphylactoid reactions (see section "Contraindications"). If such treatment is necessary, consideration should be given to using an alternative dialysis membrane or another class of antihypertensive agents.

Combinations requiring precautions

Potassium salts, heparin, potassium-sparing diuretics, and other active substances that increase plasma potassium levels (including angiotensin II antagonists, trimethoprim and its fixed combinations with sulfamethoxazole, tacrolimus, cyclosporine). Hyperkalemia may occur; therefore, plasma potassium levels should be closely monitored.

Antihypertensive drugs (e.g., diuretics) and other substances capable of lowering blood pressure (e.g., nitrates, tricyclic antidepressants, anesthetics, alcohol, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin). An increased risk of hypotension should be anticipated.

Vasopressor sympathomimetics and other substances (e.g., isoprenaline, dobutamine, dopamine, epinephrine) that may reduce the antihypertensive effect of ramipril. Blood pressure should be closely monitored.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics, and other substances that may cause blood count changes. Increased likelihood of hematological reactions (see section "Special precautions for use").

Litium salts. ACE inhibitors may reduce lithium excretion, potentially leading to increased lithium toxicity. Lithium levels should be closely monitored.

Antidiabetic agents, including insulin. Hypoglycemic reactions may occur. Blood glucose levels should be closely monitored.

Nonsteroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid. A reduced antihypertensive effect of ramipril is expected. Moreover, concomitant use of ACE inhibitors and NSAIDs may be associated with an increased risk of worsening renal function and elevated blood potassium levels.

mTOR inhibitors (mammalian target of rapamycin) or vildagliptin. There may be an increased risk of angioedema in patients receiving concomitant therapy with mTOR inhibitors (e.g., temsirolimus, everolimus, sirolimus) or vildagliptin. Such therapy should be initiated with caution (see section "Special precautions for use").

Neprilysin inhibitors (NEP). There have been reports of a potential increased risk of angioedema with concomitant use of ACE inhibitors and neprilysin inhibitors (neutral endopeptidase), such as racecadotril (see section "Special precautions for use").

Sacubitril/valsartan. Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema.

Special precautions for use

Rosuvastatin

Severe skin 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. When prescribing rosuvastatin, patients should be informed about signs and symptoms of severe skin reactions and closely monitored. If signs or symptoms suggestive of the above-mentioned reactions occur, treatment with HARTIL® ROS should be discontinued immediately, and alternative therapy should be considered.

If a patient has experienced a serious reaction such as SJS or DRESS during treatment with HARTIL® ROS, re-treatment with this medicinal product is contraindicated.

Renal effects

Proteinuria, detected by urine dipstick testing and predominantly of tubular origin, has been observed in patients treated with higher doses of rosuvastatin, particularly 40 mg, and was mostly transient or intermittent. Proteinuria was not a predictor of acute or progressive kidney disease (see section "Adverse reactions").

Musculoskeletal effects

Skeletal muscle disorders such as myalgia, myopathy, and rarely rhabdomyolysis, have been observed in patients taking rosuvastatin at any dose, especially above 20 mg. Very rarely, cases of rhabdomyolysis have 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"), therefore such combination should be used with caution.

Myasthenia gravis, ocular myasthenia

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 subsequent use of the same or another statin.

Creatine kinase levels

Creatine kinase (CK) levels should not be measured after strenuous physical exercise or in the presence of other potential 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 results. If repeat testing confirms that baseline CK exceeds 5 times ULN, treatment should not be initiated.

Before starting treatment

HARTIL® ROS, like 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 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 rosuvastatin (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 potential benefits and risks of rosuvastatin use should be carefully weighed; clinical monitoring is also recommended. Treatment should not be initiated if baseline CK levels are markedly elevated (> 5 times ULN).

During treatment

Patients should be advised to promptly report unexplained muscle pain, 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 times ULN) or if muscle symptoms are severe and cause daily discomfort (even if CK levels ≤ 5 times ULN). After symptoms resolve and CK levels return to normal, therapy with rosuvastatin or an alternative HMG-CoA reductase inhibitor may be restarted at the lowest dose under close supervision. Routine CK monitoring in asymptomatic patients is not required. Very rarely, immune-mediated necrotizing myopathy (IMNM) has been reported during or after statin therapy, including rosuvastatin.

Clinical manifestations of IMNM include proximal muscle weakness and elevated serum creatine kinase levels, which persist even after discontinuation of statins.

Clinical studies have not shown increased musculoskeletal effects 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 together with fibrates, including gemfibrozil, cyclosporine, niacin, 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 HARTIL® ROS with gemfibrozil is not recommended. The benefit of further lipid-lowering with HARTIL® ROS in combination with fibrates or niacin should be carefully weighed against the potential risks associated with such combinations.

HARTIL® ROS should not be used concomitantly with systemic fusidic acid or within 7 days after discontinuation of fusidic acid treatment. Patients for whom systemic fusidic acid treatment is considered necessary should discontinue statin therapy 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 seek immediate medical attention if they experience any symptoms of muscle weakness, pain, or tenderness.

Statin therapy may be resumed 7 days after the last dose of fusidic acid. In exceptional cases where prolonged systemic fusidic acid treatment is required, e.g., for treatment of severe infections, the possibility of concomitant use of HARTIL® ROS and fusidic acid should be considered on a case-by-case basis and only under close medical supervision.

HARTIL® ROS should not be administered to patients with acute, serious conditions indicating myopathy or risk of renal failure due to rhabdomyolysis (such as sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine, or electrolyte disorders, or uncontrolled seizures).

Hepatic effects

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

Liver function tests should be performed before starting treatment and after 3 months. Rosuvastatin treatment should be discontinued or the dose reduced if serum transaminase levels exceed three times the upper limit of normal.

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

Race

Pharmacokinetic studies indicate increased exposure in patients of Mongoloid race 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 HARTIL® ROS in HIV patients receiving protease inhibitors and the potential for increased plasma concentrations of rosuvastatin at the start of therapy and with dose escalation should be considered. Concomitant use with certain protease inhibitors is not recommended unless the dose of HARTIL® ROS 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 therapy (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 increase blood glucose levels and may induce hyperglycemia requiring treatment in some patients at high risk of developing diabetes mellitus in the future. However, the reduction in vascular risk with statin use outweighs this risk, 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 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.

Ramipril

Special patient groups

Pregnancy

Treatment with ACE inhibitors (such as ramipril) or angiotensin II receptor antagonists should not be initiated during pregnancy. Except in cases where continued treatment with an ACE inhibitor/angiotensin II receptor antagonist is absolutely necessary, women planning pregnancy should be switched to another antihypertensive agent considered safe during pregnancy. As soon as pregnancy is diagnosed, treatment with ACE inhibitors/angiotensin II receptor antagonists should be discontinued immediately and, if necessary, alternative therapy initiated (see sections "Contraindications" and "Use during pregnancy or lactation").

Patients at high risk of arterial hypotension

• Patients with markedly increased activity of the renin-angiotensin-aldosterone system

In patients with markedly increased activity of the renin-angiotensin-aldosterone system, there is a risk of sudden and significant reduction in blood pressure and worsening of renal function due to ACE inhibition, especially when the ACE inhibitor or concomitant diuretic is initiated or the dose is first increased.

Markedly increased activity of the renin-angiotensin-aldosterone system requiring medical supervision, including continuous blood pressure monitoring, may be expected, for example, in patients:

• with severe arterial hypertension;
• with decompensated congestive heart failure;
• with hemodynamically significant obstruction to inflow or outflow from the left ventricle (e.g., aortic or mitral valve stenosis);
• with unilateral renal artery stenosis and a functioning contralateral kidney;
• who have or may develop fluid or electrolyte depletion (including those receiving diuretics);
• with liver cirrhosis and/or ascites;
• undergoing major surgery or anesthesia with agents causing arterial hypotension.

Generally, correction of dehydration, hypovolemia, or electrolyte depletion is recommended before starting treatment (however, for patients with heart failure, such corrective measures should be carefully considered regarding the risk of volume overload).

• Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

Evidence supports that concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren increases the risk of arterial hypotension, hyperkalemia, and worsening renal function (including development of acute renal failure). Therefore, dual blockade of RAAS by combined use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is not recommended (see sections "Pharmacodynamics" and "Interaction with other medicinal products and other forms of interaction").

If dual blockade therapy is considered absolutely necessary, it should be used only under specialist supervision and with frequent and careful monitoring of renal function, electrolyte levels, and blood pressure.

ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly in patients with diabetic nephropathy.

• Transient or persistent heart failure after myocardial infarction
• Patients at risk of cardiac or cerebral ischemia in case of acute arterial hypotension

Special medical supervision is required during the initial phase of treatment.

• Elderly patients

See section "Posology and method of administration".

Surgery

If possible, treatment with ACE inhibitors such as ramipril should be discontinued one day before surgery.

Renal function monitoring

Renal function should be assessed before and during treatment, and dosage adjusted accordingly, especially during the first weeks of therapy. Particular caution is required in patients with impaired renal function (see section "Posology and method of administration"). There is a risk of worsening renal function, particularly in patients with congestive heart failure or after kidney transplantation.

Angioedema

Angioedema has been reported in patients receiving ACE inhibitors, including ramipril (see section "Adverse reactions"). The risk of angioedema (e.g., airway or tongue swelling, with or without respiratory distress) is increased in patients receiving concomitant medications that may cause angioedema, such as mammalian target of rapamycin (mTOR) inhibitors (e.g., temsirolimus, everolimus, sirolimus) or vildagliptin, or neprilysin (NEP) inhibitors (such as racecadotril). Combination of ramipril with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

If angioedema develops, HARTIL® ROS should be discontinued. Immediate emergency treatment should be initiated. The patient should remain under medical supervision for at least 12–24 hours and may be discharged only after complete resolution of symptoms.

Angioedema of the intestine has been observed in patients receiving ACE inhibitors, including ramipril (see section "Adverse reactions"). These patients presented with abdominal pain (with or without nausea/vomiting).

Anaphylactic reactions during desensitization

The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens are increased with ACE inhibitors. Temporary discontinuation of HARTIL® ROS is recommended before desensitization.

Electrolyte balance monitoring. Hyperkalemia

Hyperkalemia has been observed in some patients receiving ACE inhibitors, including ramipril. Patients at risk of hyperkalemia include those with renal impairment, patients aged 70 years or older, patients with uncontrolled diabetes mellitus, patients taking potassium salts, potassium-sparing diuretics, or other active substances that increase plasma potassium levels, or patients with conditions such as dehydration, acute heart decompensation, or metabolic acidosis. If concomitant use of the above-mentioned medications is considered appropriate, regular monitoring of plasma potassium levels is recommended (see section "Interaction with other medicinal products and other forms of interaction").

Electrolyte balance monitoring. Hyponatremia

Syndrome of inappropriate antidiuretic hormone secretion with subsequent hyponatremia has been observed in some patients receiving ramipril. Regular monitoring of serum sodium levels is recommended in elderly patients and other patients at risk of hyponatremia.

Neutropenia/agranulocytosis

Cases of neutropenia/agranulocytosis, as well as thrombocytopenia and anemia, have been reported rarely. Bone marrow suppression has also been reported. To detect possible leukopenia, monitoring of white blood cell count is recommended. More frequent monitoring is advisable at the beginning of treatment and in patients with renal impairment, concomitant collagenosis (e.g., systemic lupus erythematosus or scleroderma), or use of other medicinal products that may cause blood count changes (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Ethnic differences

ACE inhibitors cause angioedema more frequently in patients of Black race than in other ethnic groups. As with other ACE inhibitors, the antihypertensive effect of ramipril may be less pronounced in patients of Black race compared to other ethnic groups. This may be due to the higher prevalence of low-renin hypertension in Black patients with arterial hypertension.

Cough

Cough has been reported with ACE inhibitors. The cough is typically non-productive, persistent, and resolves after discontinuation of therapy. The possibility of ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Sodium content

This medicinal product contains less than 1 mmol (23 mg) of sodium per capsule, i.e., is essentially "sodium-free".

Use during pregnancy or lactation

The medicinal product is contraindicated during pregnancy and breastfeeding. Women of childbearing potential should use appropriate contraceptive measures (see section "Contraindications").

Pregnancy

Rosuvastatin

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 of using the medicinal product during pregnancy. Animal studies on reproductive toxicity are limited. If pregnancy is confirmed during treatment with this medicinal product, treatment should be discontinued immediately.

Ramipril

Epidemiological data on teratogenic risk after use of ACE inhibitors in the first trimester of pregnancy are inconclusive; however, a small increased risk cannot be excluded. If continued therapy with an ACE inhibitor is considered necessary, women planning pregnancy should be switched to an alternative antihypertensive agent with an established safety profile during pregnancy. If pregnancy is diagnosed, treatment with ACE inhibitors should be discontinued immediately and alternative therapy initiated.

It is known that use of ACE inhibitors during the second and third trimesters of pregnancy causes fetal toxicity in humans (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia). If an ACE inhibitor is used during the second trimester of pregnancy, ultrasound monitoring of fetal renal function and skull development is recommended. Newborns whose mothers have taken ACE inhibitors should be carefully monitored for signs of arterial hypotension, oliguria, and hyperkalemia (see sections "Contraindications" and "Special precautions for use").

Lactation

Rosuvastatin

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

Ramipril

Due to lack of information on the use of ramipril during breastfeeding (see section "Pharmacological properties"), this medicinal product is not recommended for administration to breastfeeding women. Safer alternatives, especially for nursing newborns or premature infants, should be preferred.

Fertility

There are no data on the effect on fertility.

Ability to affect reaction speed when driving or operating machinery

Some adverse effects (e.g., symptoms of low blood pressure such as dizziness) may impair a patient's ability to concentrate and reduce reaction speed, posing a risk in situations where these abilities are particularly important (e.g., driving vehicles or operating machinery).

This is generally possible at the beginning of treatment or when switching from other medications. After taking the first dose or subsequent dose increase, driving vehicles or operating machinery should be avoided for several hours.

Method of Administration and Dosage

Dosage

The recommended dose is 1 capsule daily with the corresponding content of active substances.

HARTIL® ROZ is not suitable for initial therapy. Initiation of treatment or, if necessary, dose adjustment should only be performed with titration of the dose of each component of the drug, and after establishing appropriate doses, transition to a fixed-dose combination of corresponding concentration is possible.

The patient should adhere to a standard cholesterol-lowering diet, which should be continued during treatment.

HARTIL® ROZ is not suitable for patients requiring rosuvastatin at a dose of 40 mg.

Elderly patients

The recommended initial dose for patients aged >70 years is 5 mg of rosuvastatin (see section "Special Warnings and Precautions for Use"). Consideration should be given to reducing the initial dose of ramipril to 1.25 mg, with subsequent dose titration of ramipril being more gradual, especially in very elderly and frail patients.

HARTIL® ROZ is not suitable for initial therapy. Initiation of treatment or, if necessary, dose adjustment should only be performed with titration of the dose of each component of the drug. After establishing appropriate doses, transition to a fixed-dose combination of corresponding concentration is possible.

Patients with Renal Impairment

HARTIL® ROZ can be used in patients with mild or moderate renal impairment.

The daily dose for patients with renal impairment depends on creatinine clearance (see section "Pharmacokinetics").

Rosuvastatin:

• for patients with mild and moderate renal impairment, no dose adjustment is required.

Ramipril:

• if creatinine clearance is ≥60 mL/min, the maximum daily dose of ramipril is 10 mg;
• if creatinine clearance is 30–60 mL/min, the maximum daily dose of ramipril is 5 mg.

Fixed-dose combination is not suitable for initial therapy. Initiation of treatment or dose adjustment, if necessary, should only be performed using monocomponent agents.

Use of HARTIL® ROZ in patients with severe renal impairment is contraindicated (see section "Contraindications" and "Pharmacokinetics").

Patients with Hepatic Impairment

HARTIL® ROZ is not suitable for treating patients with hepatic impairment, as the maximum daily dose of ramipril in such cases should be 2.5 mg.

HARTIL® ROZ is contraindicated in patients with active liver disease (see section "Contraindications").

Ethnic Differences

Increased systemic exposure to rosuvastatin has been observed in patients of Mongoloid race (see sections "Special Warnings and Precautions for Use" and "Pharmacokinetics"). The recommended initial dose of rosuvastatin for patients of Mongoloid race is 5 mg. HARTIL® ROZ is not suitable for initial therapy. Initiation of treatment or dose adjustment, if necessary, should only be performed using monocomponent agents.

Genetic Polymorphism

Certain types of genetic polymorphism may lead to increased rosuvastatin exposure (see section "Pharmacokinetics"). Patients known to have such polymorphism types are recommended to receive a lower daily dose of HARTIL® ROZ.

Patients Predisposed to Myopathy

The recommended initial dose of rosuvastatin for patients with risk factors for myopathy is 5 mg (see section "Special Warnings and Precautions for Use"). Fixed-dose combination is not suitable for initial therapy. Initiation of treatment or dose adjustment, if necessary, should only be performed using monocomponent agents.

Concomitant Use

Rosuvastatin is a substrate of various transporter proteins (e.g., OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) increases when HARTIL® ROZ is co-administered with certain medicinal products that may increase plasma concentrations of rosuvastatin due to interactions with these transporter proteins (e.g., cyclosporine and certain protease inhibitors, including ritonavir combinations with atazanavir, lopinavir and/or tipranavir; see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction"). If possible, alternative medicinal products should be considered and, if necessary, temporary discontinuation of HARTIL® ROZ therapy should be implemented. If concomitant use of these medicinal products with HARTIL® ROZ cannot be avoided, the benefit and risk of concomitant use should be carefully weighed and the rosuvastatin dose should be appropriately adjusted (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Method of Administration

Oral use.

HARTIL® ROZ is recommended to be taken once daily at the same time each day, independent of food intake.

Children

Safety and efficacy of HARTIL® ROZ in children (under 18 years of age) have not been established. Available data are presented in the "Pharmacodynamics" section, but no dosage recommendations can be provided. HARTIL® ROZ is not recommended for use in children (under 18 years of age).

Overdose

Rosuvastatin

There is no specific antidote for overdose. In case of overdose, treatment is symptomatic, and supportive measures should be taken if necessary. Liver function and CK levels should be monitored. Hemodialysis is unlikely to be effective.

Ramipril

Symptoms

Symptoms caused by ACE inhibitors overdose may include excessive peripheral vasodilation (with marked hypotension, shock), bradycardia, electrolyte imbalance, and renal failure.

Treatment

The patient should be closely observed and symptomatic and supportive therapy should be administered. Proposed therapeutic measures include primary detoxification (gastric lavage, administration of adsorbents), as well as measures aimed at restoring stable hemodynamics, including administration of alpha-1 adrenergic agonists or angiotensin II (angiotensinamide). Ramiprilat, the active metabolite of ramipril, is poorly removed from systemic circulation by hemodialysis.

Adverse reactions

Rosuvastatin

Adverse reactions observed during rosuvastatin administration are generally mild and transient. In controlled clinical studies, fewer than 4% of patients receiving rosuvastatin discontinued treatment due to adverse reactions.

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

Renal effects. Proteinuria, predominantly of tubular origin, has been detected by dipstick testing in patients treated with rosuvastatin. Changes in urinary protein levels from none or trace to ++ or higher were observed in <1% of patients intermittently during treatment with 10 and 20 mg doses. A slight increase in the frequency of changes from none 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 data, to date no causal relationship has been established between proteinuria and acute or progressive kidney disease.

Hematuria has been very rarely observed in patients receiving rosuvastatin.

Musculoskeletal effects. Skeletal muscle disorders such as myalgia, myopathy (including myositis), and rarely rhabdomyolysis with or without acute renal failure have been reported with all rosuvastatin doses, particularly at doses >20 mg.

Dose-dependent increases in creatine kinase (CK) levels have been observed in patients taking rosuvastatin; in most cases, this finding 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").

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

Adverse events reported with some statins include:

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

Ramipril

The safety profile of ramipril includes data on persistent dry cough and reactions related to arterial hypotension. Serious adverse reactions include angioedema, hyperkalemia, hepatic or renal dysfunction, pancreatitis, severe skin reactions, and neutropenia/agranulocytosis.

Table 4 lists adverse reactions observed during treatment with rosuvastatin and ramipril.

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

Table 4

Body System	Adverse Reactions	Frequency
		Rosuvastatin	Ramipril
Blood and lymphatic system disorders	Eosinophilia	−	Uncommon
	Thrombocytopenia	Rare	−
	Decreased leukocyte count (including neutropenia or agranulocytosis)	−	Rare
	Decreased erythrocyte count	−	Rare
	Hemoglobin decrease	−	Rare
	Decreased platelet count	−	Rare
	Bone marrow failure	−	Not known
	Pancytopenia	−	Not known
	Hemolytic anemia	−	Not known
Immune system disorders	Hypersensitivity reactions, including angioedema 1	Rare	Uncommon
	Anaphylactic or anaphylactoid reactions	−	Not known
	Elevated antinuclear antibody levels	−	Not known
Endocrine disorders	Diabetes mellitus2	Common	−
	Syndrome of inappropriate antidiuretic hormone secretion	−	Not known
Metabolism and nutrition disorders	Increased blood potassium levels	−	Common
	Anorexia	−	Uncommon
	Decreased appetite	−	Uncommon
	Decreased blood sodium levels	−	Not known
Psychiatric disorders	Mood decreased	−	Uncommon
	Anxiety	−	Uncommon
	Nervousness	−	Uncommon
	Restlessness	−	Uncommon
	Sleep disorders, including somnolence	−	Uncommon
	Sleep disturbances (including insomnia and nightmares)	Not known	−
	Confusional state	−	Rare
	Inattention	−	Not known
	Depression	Not known	−
Nervous system disorders	Headache	Common	Common
	Dizziness	Common	Common
	Vertigo	−	Uncommon
	Paraesthesia	−	Uncommon
	Ageusia	−	Uncommon
	Dysgeusia	−	Uncommon
	Tremor	−	Rare
	Loss of balance	−	Rare
	Peripheral neuropathy	Very rare	−
	Memory loss	Very rare	−
	Cerebral ischemia, including ischemic stroke and transient ischemic attack	−	Not known
	Psychomotor performance disturbances	−	Not known
	Burning sensation	−	Not known
	Parosmia	−	Not known
	Peripheral neuropathy	Not known	−
	Myasthenia gravis	Not known	−
Eye disorders	Visual disturbances, including blurred vision	−	Uncommon
	Conjunctivitis	−	Rare
	Ocular myasthenia	Not known	−
Ear and labyrinth disorders	Hearing disturbances	−	Rare
	Tinnitus	−	Rare
Cardiac disorders	Myocardial ischemia, including angina or myocardial infarction	−	Uncommon
	Tachycardia	−	Uncommon
	Arrhythmia	−	Uncommon
	Palpitations	−	Uncommon
	Peripheral edema	−	Uncommon
Vascular disorders	Arterial hypotension	−	Common
	Orthostatic hypotension	−	Common
	Syncope	−	Common
	Flushing	−	Uncommon
	Vascular stenosis	−	Rare
	Hypoperfusion	−	Rare
	Angioedema	−	Rare
	Raynaud's phenomenon	−	Not known
Respiratory, thoracic and mediastinal disorders	Non-productive irritative cough	−	Common
	Bronchitis	−	Common
	Sinusitis	−	Common
	Dyspnea	Not known	Common
	Bronchospasm, including asthma exacerbation	−	Uncommon
	Nasal congestion	−	Uncommon
	Cough	Not known	−
Gastrointestinal disorders	Inflammatory events in the gastrointestinal tract	−	Common
	Digestive disorders	−	Common
	Diarrhea	Not known	Common
	Constipation	Common	Uncommon
	Nausea	Common	Common
	Vomiting	−	Common
	Abdominal pain	Common	−
	Abdominal discomfort	−	Common
	Dyspepsia	−	Common
	Pancreatitis3	Rare	Uncommon
	Elevated pancreatic enzymes	−	Uncommon
	Angioneurotic edema of the small intestine	−	Uncommon
	Upper abdominal pain, including gastritis-associated	−	Uncommon
	Dry mouth	−	Uncommon
	Glossitis	−	Rare
	Aphthous stomatitis	−	Not known
Hepatobiliary disorders	Elevated liver enzymes and/or conjugated bilirubin	−	Uncommon
	Elevated liver transaminases	Rare	−
	Cholestatic jaundice	−	Rare
	Liver cell injury	−	Rare
	Jaundice	Very rare	−
	Hepatitis	Very rare	−
	Acute liver failure	−	Not known
	Cholestatic or cytolytic hepatitis (in very rare cases, fatal)	−	Not known
Skin and subcutaneous tissue disorders	Rash, including maculopapular	−	Common
	Rash	Uncommon	−
	Pruritus	Uncommon	Uncommon
	Hyperhidrosis	−	Uncommon
	Exfoliative dermatitis	−	Rare
	Urticaria	Uncommon	Rare
	Onycholysis	−	Rare
	Photosensitivity reaction	−	Very rare
	Toxic epidermal necrolysis	−	Not known
	Stevens-Johnson syndrome	Not known	Not known
	Drug reaction with eosinophilia and systemic symptoms (DRESS)	Not known	−
	Multiform erythema	−	Not known
	Pemphigus	−	Not known
	Worsening of psoriasis	−	Not known
	Psoriatic dermatitis	−	Not known
	Pemphigoid or lichenoid exanthema or enanthema	−	Not known
	Alopecia	−	Not known
Musculoskeletal and connective tissue disorders	Myalgia	Common	Common
	Muscle spasms	−	Common
	Myopathy (including myositis)	Rare	−
	Rhabdomyolysis	Rare	−
	Lupus-like syndrome	Rare
	Muscle rupture	Rare
	Arthralgia	Very rare	Uncommon
	Tendon disorders, sometimes complicated by rupture	Not known	−
	Immune-mediated necrotizing myopathy (IMNM)	Not known	−
Renal and urinary disorders	Hematuria	Very rare	−
	Renal function impairment, including acute renal failure	−	Uncommon
	Increased diuresis	−	Uncommon
	Worsening of background proteinuria	−	Uncommon
	Elevated blood urea levels	−	Uncommon
	Elevated blood creatinine levels	−	Uncommon
Reproductive system and breast disorders	Transient erectile impotence	−	Uncommon
	Decreased libido	−	Uncommon
	Gynecomastia	Very rare	Not known
General disorders	Chest pain	−	Common
	Malaise	−	Common
	Pyrexia	−	Uncommon
	Asthenia	Common	Rare
	Edema	Not known	−

1 In very rare cases, airway obstruction due to angioneurotic edema may result in a fatal outcome.

2 Frequency depends on the presence or absence of risk factors (fasting blood glucose ≥ 5.6 mmol/L, BMI > 30 kg/m², elevated triglyceride levels, history of arterial hypertension).

3 Fatal outcomes have been reported in isolated cases with the use of ACE inhibitors.

Reporting of suspected adverse reactions

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

Shelf life

3 years.

Storage conditions

Store at a temperature not exceeding 25 °C.

Keep in the original packaging to protect from light and moisture.

Keep out of reach of children.

Packaging

10 capsules per blister; 3 blisters per cardboard box.

Prescription status: By prescription only.

Manufacturer

Egis Pharmaceuticals Ltd., Hungary.

Manufacturer's address and location of manufacturing site

1165 Budapest, Bekéscsaba Industrial Park, Bekényfeldi Street 118-120, Hungary.

9900 Kermend, Matyas Kiraly Street 65, Hungary.