Roxiper

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Roxiper (Roxiper®)

Composition:

Active substances: rosuvastatin (as rosuvastatin calcium), perindopril tert-butylamine, and indapamide;

One tablet contains 10 mg rosuvastatin (as rosuvastatin calcium), 4 mg perindopril tert-butylamine, and 1.25 mg indapamide, or

20 mg rosuvastatin (as rosuvastatin calcium), 4 mg perindopril tert-butylamine, and 1.25 mg indapamide, or

10 mg rosuvastatin (as rosuvastatin calcium), 8 mg perindopril tert-butylamine, and 2.5 mg indapamide, or

20 mg rosuvastatin (as rosuvastatin calcium), 8 mg perindopril tert-butylamine, and 2.5 mg indapamide;

Excipients: microcrystalline cellulose (type 112 and type 200, low moisture), crospovidone (type A), colloidal anhydrous silicon dioxide, magnesium stearate;

Film coating: polyvinyl alcohol, polyethylene glycol 3350, titanium dioxide (E 171), talc, red iron oxide (E 172), black iron oxide (E 172), yellow iron oxide (E 172)*.

* Not present in tablets of 10 mg/8 mg/2.5 mg.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

10 mg/4 mg/1.25 mg

Reddish-brown, round, slightly biconvex, film-coated tablets with bevelled edges, engraved with the mark PIR1 on one side.

20 mg/4 mg/1.25 mg

Almost pink, round, slightly biconvex, film-coated tablets with bevelled edges, engraved with the mark PIR2 on one side.

10 mg/8 mg/2.5 mg

Light pink, round, slightly biconvex, film-coated tablets with bevelled edges, engraved with the mark PIR3 on one side.

20 mg/8 mg/2.5 mg

Pale reddish-brown, round, slightly biconvex, film-coated tablets with bevelled edges, engraved with the mark PIR4 on one side.

Pharmacotherapeutic group. Lipid-lowering agents. Lipid-lowering agents in combination with other medicinal products. ATC code C10BX13.

Pharmacological properties.

Roxiper is a combination of perindopril tert-butylamine salt – an angiotensin-converting enzyme (ACE) inhibitor, indapamide – a chlorosulfonamide diuretic, and rosuvastatin – a selective and competitive HMG-CoA reductase inhibitor. The pharmacological properties are determined by the properties of each component used separately, in addition to those related to the additive synergistic effect of the combination of perindopril and indapamide.

Pharmacodynamics.

Mechanism of action

Perindopril

Perindopril is an ACE inhibitor that converts angiotensin I to angiotensin II – a vasoconstrictive substance, and also promotes the breakdown of the vasodilator agent bradykinin into an inactive heptapeptide.

Inhibition of ACE by perindopril leads to:

• reduction in aldosterone secretion;
• increased plasma renin activity, since aldosterone no longer causes negative feedback;
• reduction in total peripheral resistance, predominantly affecting the vascular bed in muscles and kidneys, without concomitant salt and water retention or reflex tachycardia during chronic treatment.

Perindopril exerts antihypertensive effects even in patients with low or normal renin concentrations.

Perindopril acts via its active metabolite, perindoprilat. Other metabolites are inactive.

Perindopril reduces the workload of the heart:

• through venodilatory action, likely due to changes in prostaglandin metabolism: reduction in preload;
• by reducing total peripheral vascular resistance: reduction in afterload.

Studies conducted in patients with heart failure have shown:

• reduction in filling pressure of the left and right ventricles;
• reduction in total peripheral vascular resistance;
• increase in cardiac output and improvement in cardiac index;
• increased regional blood flow in muscles.

In addition, performance in exercise tests significantly improves.

Indapamide

Indapamide is a sulfonamide derivative with an indole ring, pharmacologically related to thiazide diuretics. Indapamide inhibits sodium reabsorption in the cortical segment of the kidneys. This increases urinary excretion of sodium and chlorides, and to a lesser extent, excretion of potassium and magnesium, thereby increasing diuresis. This mechanism provides antihypertensive action.

Rosuvastatin

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

Rosuvastatin increases the number of hepatic receptors for low-density lipoproteins (LDL) on cell surfaces, enhancing LDL uptake and catabolism, and suppresses hepatic synthesis of very-low-density lipoproteins (VLDL), thereby reducing the total number of VLDL and LDL particles.

Pharmacodynamic effects

Related to perindopril/indapamide

The combination of perindopril/indapamide reduces systolic and diastolic blood pressure in patients with arterial hypertension of any age, both in supine and standing positions.

This antihypertensive effect lasts for 24 hours. Blood pressure reduction is achieved within less than a month without tachyphylaxis. Discontinuation of treatment is not associated with a rebound effect. Clinical studies have demonstrated that concomitant use of perindopril and indapamide results in a synergistic antihypertensive effect, which is the result of the individual components' effects.

In a multicenter, randomized, double-blind, open-label controlled study (PICXEL), the effect of the perindopril/indapamide combination on left ventricular hypertrophy was evaluated in comparison with monotherapy with enalapril using ECG.

Patients with hypertension and left ventricular hypertrophy (defined by left ventricular mass index (LVMI) > 120 g/m² in men and > 100 g/m² in women) were treated with either perindopril/indapamide 2 mg/0.625 mg or enalapril 10 mg once daily for 1 year. The dose of perindopril/indapamide 8 mg/2.5 mg or enalapril 40 mg once daily was adjusted according to blood pressure. 34% of patients were treated with perindopril/indapamide 2 mg/0.625 mg compared to 20% of patients receiving enalapril 10 mg.

At the end of treatment, LVMI decreased significantly more in the perindopril/indapamide group (-10.1 g/m²) compared to the enalapril group (-1.1 g/m²) across all randomized subgroups. The difference in LVMI between groups was -8.3 (95% confidence interval (CI) (-11.5, -5.0), p < 0.0001). The best effect on LVMI was achieved with the combination of perindopril 8 mg/indapamide 2.5 mg.

The perindopril/indapamide combination has been shown to reduce systolic and diastolic blood pressure in patients with arterial hypertension: -5.8 mm Hg (95% CI (-7.9, -3.7), p < 0.0001) for systolic blood pressure and -2.3 mm Hg (95% CI (-3.6, -0.9), p = 0.0004) for diastolic blood pressure.

Related to perindopril

Perindopril effectively reduces blood pressure in arterial hypertension of any degree: mild, moderate, and severe. Reduction in systolic and diastolic blood pressure is observed both in supine and standing positions. The maximum antihypertensive effect develops 4–6 hours after a single dose and persists for more than 24 hours. Perindopril has a high level of sustained ACE inhibition (approximately 80%) 24 hours after administration.

In patients who respond to treatment, blood pressure normalization occurs within a month and is maintained without tachyphylaxis.

Discontinuation of therapy is not associated with a rebound effect.

Perindopril has vasodilatory properties, restores elasticity of large arteries, corrects histomorphometric changes in resistance arteries, and reduces left ventricular hypertrophy. When a thiazide diuretic is added as needed, additional synergy develops.

Combining an ACE inhibitor with a thiazide diuretic reduces the risk of hypokalemia that may occur when the diuretic is used as monotherapy.

Clinical data on dual blockade of the renin-angiotensin-aldosterone system (RAAS)

Concomitant use of ACE inhibitors and angiotensin II receptor blockers was investigated in two large-scale randomized controlled trials [ONTARGET (ONgoing Telmisartan Alone and Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)].

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

The studies did not demonstrate significant beneficial effects on kidney disease and/or cardiovascular disease or mortality, whereas, compared to monotherapy, there was an increased risk of hyperkalemia, acute kidney injury, and/or arterial hypotension. Given the similarity of pharmacodynamic properties, these results are also applicable to other ACE inhibitors and angiotensin II receptor blockers.

Concomitant use of ACE inhibitors and angiotensin II receptor blockers is contraindicated in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Endpoints) investigated the benefits of adding aliskiren to standard therapy with an ACE inhibitor or angiotensin II receptor blocker in patients with type 2 diabetes and/or chronic kidney disease, cardiovascular disease. The study was terminated prematurely due to an increased risk of adverse outcomes. Cardiovascular mortality, incidence of stroke, and reports of adverse events and serious complications (hyperkalemia, arterial hypotension, or impaired kidney function) were more frequent in the aliskiren group compared to the placebo group.

Related to indapamide

The antihypertensive effect of indapamide as monotherapy lasts for 24 hours. This effect is evident at doses where diuretic properties are minimal.

The antihypertensive effect of indapamide is associated with improved arterial elasticity and reduced arteriolar resistance and total peripheral vascular resistance.

Indapamide reduces left ventricular hypertrophy.

When the recommended dose is exceeded, the therapeutic effect of thiazide and thiazide-like diuretics does not increase, while the number of adverse effects increases. If treatment is insufficiently effective, increasing the dose is not recommended.

Additionally, as shown in studies of varying duration involving patients with arterial hypertension, indapamide:

• does not affect lipid metabolism: triglycerides, LDL, and high-density lipoproteins (HDL);
• does not affect carbohydrate metabolism, even in patients with arterial hypertension and diabetes.

Related to rosuvastatin

Rosuvastatin reduces elevated levels of LDL cholesterol (LDL-C), total cholesterol (TC), and triglycerides and increases HDL cholesterol levels. It also significantly reduces apolipoprotein B, low-density lipoprotein cholesterol (LDL-C), very-low-density lipoprotein cholesterol (VLDL-C), triglycerides in VLDL, and increases apolipoprotein A-I. Rosuvastatin also reduces the ratios of LDL-C/HDL-C, TC/HDL-C, and VLDL-C/HDL-C, as well as apolipoprotein B/apolipoprotein A-I.

Therapeutic effect is achieved within 1 week after starting treatment, and 90% of the maximum effect is achieved within 2 weeks. Maximum effect is usually achieved within 4 weeks and maintained during treatment.

Rosuvastatin is effective in adults with hypercholesterolemia, with or without hypertriglyceridemia, regardless of race, sex, or age, and in specific patient groups, such as those with diabetes or familial hypercholesterolemia.

Combined phase III data showed efficacy of rosuvastatin in treating most patients with type IIa and IIb hypercholesterolemia (mean baseline LDL-C over 4.8 mmol/L) according to target values recognized by the European Atherosclerosis Society (EAS; 1998): over 80% of patients treated with a 10 mg dose achieved target LDL-C levels (< 3 mmol/L).

In a large study involving 435 patients with heterozygous familial hypercholesterolemia, rosuvastatin was administered at doses from 20 mg to 80 mg with intensive titration. All doses had beneficial effects on lipid parameters and treatment. After titration to a daily dose of 40 mg (12 weeks of treatment), LDL-C was reduced by 53%. 33% of patients achieved EAS target levels for LDL-C (< 3 mmol/L).

In an open-label study involving 42 patients with homozygous familial hypercholesterolemia, the effect of rosuvastatin at doses of 20–40 mg with intensive titration was evaluated. In the overall group, mean reduction in LDL-C was 22%.

In clinical studies with a limited number of patients, rosuvastatin had an additive effect on reducing triglycerides when used in combination with fenofibrate and on increasing HDL-C levels when used in combination with niacin (see section "Special instructions").

In a multicenter, double-blind, placebo-controlled clinical trial (METEOR), 984 patients aged 45 to 70 years with low risk of cardiovascular disease (CVD) (defined as a Framingham risk score < 10% over 10 years) and a mean LDL-C level of 4.0 mmol/L (154.5 mg/dL), but with subclinical atherosclerosis [detected by intima-media thickness (IMT)] received 40 mg of rosuvastatin once daily for 2 years. Rosuvastatin significantly reduced the progression rate of maximum IMT across 12 carotid artery segments compared to placebo by -0.0145 mm/year [95% CI -0.0196, -0.0093; p < 0.0001]. The change from baseline was -0.0014 mm/year [-0.12%/year (not significant)] for rosuvastatin, compared to progression of +0.0131 mm/year [1.12%/year (p < 0.0001)] for placebo. No direct correlation between IMT thickness and reduction in cardiovascular event risk was established. The population in the METEOR study had a low risk of CVD and did not represent the target population for rosuvastatin 40 mg. The 40 mg dose should be prescribed to patients with severe hypercholesterolemia and high cardiovascular risk (see section "Dosage and administration").

In the JUPITER study, the effect of rosuvastatin on the occurrence of major atherosclerotic cardiovascular complications was evaluated in 17,802 men (≥ 50 years) and women (≥ 60 years).

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

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

In a subsequent subgroup analysis of patients with high Framingham risk score > 20% (1558 participants), significant reduction in the composite endpoint, including cardiovascular death, stroke, or myocardial infarction, was observed with rosuvastatin treatment compared to placebo (p = 0.028). Absolute risk reduction in complication frequency was 8.8 per 1000 patient-years. In this high-risk group (p = 0.193), overall mortality did not change. In a subsequent subgroup analysis of patients (n = 9302) with high SCORE risk ≥ 5% (extrapolated to include individuals over 65 years), significant reduction in the composite endpoint, including cardiovascular death, stroke, and myocardial infarction, was observed with rosuvastatin treatment compared to placebo (p = 0.0003). Absolute reduction in complication rate was 5.1 per 1000 patient-years. Overall mortality remained unchanged in this high-risk patient group (p = 0.076).

In the JUPITER study, the proportion of individuals who discontinued the study drug due to adverse reactions was 6.6% in the rosuvastatin group and 6.2% in the placebo group. The most common adverse reactions leading to discontinuation of treatment 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 reactions reported more frequently or equally compared to the placebo group were: urinary tract infection (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).

Pharmacokinetics.

Perindopril

Absorption and bioavailability

After oral administration, perindopril is rapidly absorbed, and peak concentration is reached within 1 hour. The elimination half-life of perindopril in plasma is 1 hour.

Since food intake reduces the conversion to perindoprilat and thus bioavailability, perindopril tert-butylamine should be administered orally as a single daily dose in the morning before meals.

Distribution

The volume of distribution of free perindopril is approximately 0.2 L/kg. Protein binding of perindopril to plasma proteins is 20%, particularly to ACE, but depends on concentration.

Metabolism

Perindopril is a prodrug. 27% of the total absorbed perindopril is converted to the active metabolite perindoprilat. Additionally, five inactive metabolites are formed. Maximum plasma concentration of perindoprilat is reached within 3–4 hours.

Since the presence of food in the stomach reduces the conversion of perindopril to perindoprilat and thus reduces bioavailability, perindopril should be administered orally in the morning before meals.

Elimination

Perindoprilat is excreted in urine, and the half-life of the unbound fraction is approximately 17 hours, leading to steady-state levels within 4 days.

Linearity/non-linearity

A linear relationship between perindopril dose and its plasma concentration has been demonstrated.

Elderly patients

In elderly individuals and patients with heart or kidney failure, perindoprilat elimination is reduced.

Renal impairment

In renal impairment, the dose should be adjusted according to the degree of impairment (creatinine clearance).

Perindoprilat is removed from the circulation by dialysis, with a clearance of 70 mL/min.

Cirrhosis

In liver cirrhosis, perindopril kinetics are altered, with hepatic clearance of the parent molecule reduced by half, but the amount of perindoprilat formed remains unchanged; therefore, the drug dose does not need to be adjusted in this condition (see sections "Dosage and administration" and "Special instructions").

Indapamide

Absorption

Indapamide is rapidly and almost completely released and absorbed in the gastrointestinal tract.

Maximum serum concentration of indapamide is reached approximately 1 hour after drug intake.

Distribution

Protein binding of indapamide to plasma proteins is 79%.

Elimination

The elimination half-life from plasma ranges from 14 to 24 hours (average 18 hours). Regular drug intake does not lead to indapamide accumulation. 70% of indapamide is excreted primarily by the kidneys and 22% is excreted in feces as inactive metabolites.

Renal impairment

Pharmacokinetic parameters of the drug are unchanged in patients with impaired renal function.

Rosuvastatin

Absorption

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

Distribution

Rosuvastatin is extensively metabolized in 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 to albumin.

Metabolism

Metabolism of rosuvastatin is limited (approximately 10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin undergoes only minimal CYP450-mediated metabolism, which is not clinically significant. CYP2C9 was the main isoenzyme involved in metabolism, with minor contributions from 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 form is considered clinically inactive. Rosuvastatin has more than 90% of the inhibitory activity against HMG-CoA reductase circulating in the systemic circulation.

Elimination

Approximately 90% of the rosuvastatin dose is excreted unchanged in feces (comprising both absorbed and unabsorbed active substance), and the remainder is excreted in urine. Approximately 5% is excreted unchanged in urine. The plasma elimination half-life is approximately 20 hours. The half-life does not increase with higher dosing. The geometric mean plasma clearance is approximately 50 liters per hour (coefficient of variation 21.7%). As with other HMG-CoA reductase inhibitors, hepatic uptake of rosuvastatin involves the membrane transporter OATP-C. This transporter is important for the hepatic elimination of rosuvastatin.

Linearity/non-linearity

Systemic exposure to rosuvastatin increases proportionally with increasing dose. There is no change in pharmacokinetic parameters after multiple daily administrations.

Age and sex

Age and sex of the patient do not significantly affect the pharmacokinetics of rosuvastatin in adults. Pharmacokinetics of rosuvastatin in children and adolescents with heterozygous familial hypercholesterolemia are similar to or lower than those in adult volunteers (see section "Children" below).

Race

Pharmacokinetic studies show approximately a 2-fold increase in AUC and Cmax of rosuvastatin in patients of Asian descent (Japanese, Chinese, Filipinos, Vietnamese, and Koreans) compared to Caucasian patients; in Indians, an increase of approximately 1.3-fold in mean AUC and Cmax is observed. Pharmacokinetic analysis of patient groups did not reveal any clinically significant differences in pharmacokinetics between Caucasian and African descent populations.

Renal impairment

In a study involving patients with varying degrees of renal impairment, mild or moderate kidney disease did not affect plasma concentrations of rosuvastatin or the N-desmethyl metabolite. In patients with severe renal impairment (creatinine clearance < 30 mL/min), plasma concentration increased 3-fold, and the concentration of the N-desmethyl metabolite increased 9-fold compared to healthy volunteers. Steady-state plasma concentrations of rosuvastatin in patients undergoing hemodialysis sessions were approximately 50% higher than in healthy volunteers.

Hepatic impairment

In a study involving patients with varying degrees of hepatic impairment, no evidence of increased rosuvastatin exposure was found in patients with Child-Pugh scores of 7 or less. However, systemic exposure was at least doubled in two patients with Child-Pugh scores of 8 and 9.

Genetic polymorphisms

The disposition of HMG-CoA reductase inhibitors, including rosuvastatin, involves transport proteins OATP1B1 and BCRP. Patients with genetic polymorphisms in SLCO1B1 (OATP1B1) and/or ABCG2 (BCRP) are at risk of increased rosuvastatin exposure. Specific polymorphisms SLCO1B1 c.521CC and ABCG2 c.421AA are associated with high rosuvastatin exposure (AUC) compared to genotypes SLCO1B1 c.521TT or ABCG2 c.421CC. These specific genotypes are not established in clinical practice, but for patients with such polymorphism types, a lower daily dose of rosuvastatin is recommended.

Children

Pharmacokinetic parameters of rosuvastatin in children aged 10 to 17 years with heterozygous familial hypercholesterolemia are not fully characterized. A small pharmacokinetic study involving 18 children showed that the exposure to rosuvastatin (in tablets) in children is comparable to that in adults. Significant deviation from dose proportionality is not expected.

Clinical characteristics.

Indications.

Roxiper is indicated for replacement therapy in patients with marked hypertension and presence of one of the following factors: primary hypercholesterolemia (type IIa, including heterozygous familial hypercholesterolemia), mixed dyslipidemia (type IIb), or heterozygous familial hypercholesterolemia — in adults whose condition is adequately controlled with rosuvastatin, perindopril, and indapamide when administered concomitantly at the same doses as in the combination.

Contraindications.

Related to rosuvastatin

• Hypersensitivity to rosuvastatin.
• Active liver disease, including of unknown etiology, persistent elevation of serum transaminases, or elevation of any serum transaminase more than 3 times above the upper limit of normal.
• Myopathy.
• Concomitant use of the combination of sofosbuvir/velpatasvir/voxilaprevir (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use of cyclosporine.
• Pregnancy and breastfeeding period. Also contraindicated in women of childbearing potential who are not using appropriate contraceptive measures.

Related to perindopril

• Hypersensitivity to perindopril or any other angiotensin-converting enzyme (ACE) inhibitor.
• History of angioedema associated with previous treatment with ACE inhibitors (see section "Special precautions").
• Hereditary or idiopathic angioedema.
• Second or third trimester of pregnancy (see sections "Special precautions" and "Use during pregnancy or breastfeeding").
• Concomitant administration with medicinal products containing aliskiren in patients with diabetes mellitus or patients with renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²) (see sections "Pharmacological properties" and "Interaction with other medicinal products and other forms of interaction").
• Concomitant use with sacubitril/valsartan. Treatment with the medicinal product should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions").
• Extracorporeal treatment methods 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 stenosis of the artery of a single functioning kidney (see section "Special precautions").

Related to indapamide

• Hypersensitivity to indapamide or any other sulfonamide.
• Hepatic encephalopathy.
• Severe hepatic insufficiency.
• Hypokalemia.

Contraindications for use of Roxiper

All the above-mentioned contraindications related to each component apply to Roxiper. - Hypersensitivity to any excipient of the medicinal product.

• Severe renal impairment (creatinine clearance < 30 mL/min).
• Moderate renal impairment (creatinine clearance 30–60 mL/min) for dosage strengths 10 mg/8 mg/2.5 mg and 20 mg/8 mg/2.5 mg.
• Pregnancy or women planning to become pregnant.

Due to insufficient relevant therapeutic data, Roxiper should not be used:

• In patients on dialysis.
• In patients with untreated heart failure.

Interaction with other medicinal products and other forms of interaction.

Related to perindopril and indapamide

Concomitant use not recommended

Lithium

Reversible increases in serum lithium concentration and signs of lithium toxicity have been reported during concomitant use of lithium with ACE inhibitors. Concomitant use of indapamide and lithium is not recommended, but if combination therapy is necessary, careful monitoring of serum lithium levels is required (see section "Special precautions").

Concomitant use requiring special caution

Baclofen

Enhancement of antihypertensive effect. Monitoring of blood pressure and renal function is necessary; dose adjustment may be required if needed.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including salicylates at doses ≥ 3 g/day

NSAIDs (including acetylsalicylic acid at anti-inflammatory doses, cyclooxygenase-2 inhibitors, and nonselective NSAIDs) may reduce the antihypertensive effect of ACE inhibitors. Additionally, NSAIDs and ACE inhibitors may further increase serum potassium levels, potentially leading to worsening renal function, including acute renal failure, especially in patients with impaired renal function. The combination should be used with caution, particularly in elderly patients. Adequate hydration should be ensured, and monitoring of renal function should be considered after initiation of concomitant therapy and periodically thereafter.

Concomitant use requiring monitoring

Tricyclic antidepressants (imipramine-like), neuroleptics: enhanced hypotensive effect and increased risk of orthostatic hypotension (additive effect).

Related to perindopril

Clinical trial data indicate that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher incidence of adverse reactions such as hypotension, hyperkalemia, and reduced renal function (including acute renal failure), compared to use of a single RAAS-acting agent (see sections "Pharmacological properties", "Contraindications", and "Special precautions").

MEDICINAL PRODUCTS CAUSING HYPERKALEMIA

Although serum potassium levels usually remain within normal limits, hyperkalemia may occur in some patients receiving Roxiper. Certain drugs or therapeutic classes may increase the frequency of hyperkalemia: aliskiren, potassium salts, potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), ACE inhibitors, angiotensin II receptor antagonists, NSAIDs, heparins, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim, and cotrimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim is known to act as a potassium-sparing diuretic similar to amiloride. Combination with these agents increases the risk of hyperkalemia.

Therefore, combination of Roxiper with the above-mentioned medicinal products is not recommended. If such combination is prescribed, it should be used with caution and frequent monitoring of serum potassium levels.

Concomitant use contraindicated (see section "Contraindications")

Aliskiren

In patients with diabetes mellitus or renal impairment, the risk of hyperkalemia, worsening renal function, cardiovascular morbidity, and mortality is increased.

Extracorporeal treatment methods leading to blood contact with negatively charged surfaces, such as high-flux dialysis or hemofiltration membranes (e.g., polyacrylonitrile membranes) or for low-density lipoprotein apheresis with dextran sulfate, increase the risk of severe anaphylactoid reactions (see section "Contraindications"). If such treatment is necessary, consideration should be given to using a different type of dialysis membrane or another class of antihypertensive agents.

Agents increasing the risk of angioedema

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

Concomitant use of ACE inhibitors with racemizedotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) may increase the risk of angioedema (see section "Special precautions").

Concomitant use not recommended

Aliskiren

In any other patients, as in those with diabetes mellitus or renal impairment, the risk of hyperkalemia, worsening renal function, and cardiovascular morbidity and mortality is increased (see section "Special precautions").

Concomitant use of ACE inhibitors and angiotensin receptor blockers

Published data show that in patients with atherosclerosis, heart failure, or diabetes with target organ damage, concomitant use of ACE inhibitors and angiotensin receptor blockers is associated with increased incidence of hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to monotherapy with RAAS-acting agents. Dual blockade (i.e., combination of an ACE inhibitor with angiotensin II receptor antagonists) may be used in selected cases with careful monitoring of renal function, potassium levels, and blood pressure (see section "Special precautions").

Estramustine

Increased risk of adverse reactions such as angioedema.

Potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride and their combinations), potassium-containing salts

Hyperkalemia (potentially fatal), especially in patients with renal impairment (additive hyperkalemic effect).

Combination of perindopril with the above-mentioned agents is not recommended. However, if concomitant use is prescribed, it should be used with caution and frequent monitoring of serum potassium levels. Information on use of spironolactone in heart failure is provided in the subsection "Concomitant use requiring special caution".

Concomitant use requiring special caution

Antidiabetic agents (insulin, oral hypoglycemic agents (reported with captopril and enalapril))

Epidemiological studies have shown that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may enhance glucose-lowering effects with risk of hypoglycemia. This phenomenon is more likely during the first weeks of combination therapy and in patients with renal impairment.

Diuretics

In patients taking diuretics, especially those with disturbed water-electrolyte balance, excessive reduction in blood pressure may occur after initiation of ACE inhibitor therapy. The likelihood of hypotensive effect can be reduced by discontinuing the diuretic, increasing circulating blood volume, or salt intake before starting perindopril therapy. Treatment should be initiated with low doses and gradually increased.

In arterial hypertension, when a previously prescribed diuretic may have caused water/electrolyte deficiency, it should be discontinued before starting ACE inhibitor therapy (diuretic use may be resumed later), or the ACE inhibitor should be initiated at a low dose with gradual dose escalation.

In congestive heart failure on diuretic therapy, ACE inhibitor therapy should be initiated at the lowest dose, possibly after reducing the diuretic dose.

In any case, renal function (serum creatinine level) should be monitored during the first weeks of ACE inhibitor therapy.

Potassium-sparing diuretics (eplerenone, spironolactone)

When eplerenone or spironolactone (12.5–50 mg/day) is used concomitantly with low doses of ACE inhibitors in patients with NYHA class II–IV heart failure and ejection fraction < 40%, previously treated with ACE inhibitors and loop diuretics, there is a risk of hyperkalemia (potentially fatal), especially if recommendations for use of this combination are not followed. Before initiating such combination, absence of hyperkalemia and renal impairment should be confirmed. Careful monitoring of potassium and creatinine levels is recommended weekly during the first month of treatment and monthly thereafter.

Concomitant use requiring caution

Potassium-sparing diuretics (amiloride, spironolactone, triamterene)

Although rational combinations may be beneficial for some patients, hypokalemia or hyperkalemia (especially in patients with renal impairment or diabetes mellitus) may occur. Plasma potassium levels and ECG should be monitored, and treatment should be reviewed if necessary.

Antihypertensive agents and vasodilators

Concomitant use of antihypertensive agents may enhance the hypotensive effect of perindopril. Concomitant use with nitroglycerin and other nitrates or other vasodilators may lead to additional reduction in blood pressure.

Allopurinol, cytostatic or immunosuppressive agents, corticosteroids (systemic use), or procainamide

Concomitant use of these agents with ACE inhibitors increases the risk of leukopenia (see section "Special precautions").

Anesthetic agents

ACE inhibitors may enhance the hypotensive effects of certain anesthetic agents (see section "Special precautions").

Gold compounds

Rare anaphylactoid reactions (symptoms include facial flushing, nausea, vomiting, and hypotension) have been reported in patients receiving intravenous gold compounds (sodium aurothiomalate) and concomitant ACE inhibitor therapy, including perindopril.

Sympathomimetics may attenuate the antihypertensive effect of ACE inhibitors.

Related to indapamide

Concomitant use requiring special caution

Agents causing torsades de pointes ventricular tachycardia

Due to the risk of hypokalemia, indapamide should be used with caution when combined with medicinal products inducing torsades de pointes ventricular tachycardia, such as: class Ia antiarrhythmics (e.g., quinidine, hydroquinidine, disopyramide); class III antiarrhythmics (e.g., amiodarone, dofetilide, ibutilide, bretylium, sotalol); certain neuroleptics: phenothiazines (e.g., chlorpromazine, thioridazine, levomepromazine, trifluoperazine), benzamides (e.g., amisulpride, sulpiride, sultopride, tiapride), butyrophenones (e.g., droperidol, haloperidol), other neuroleptics (pimozide); other substances (e.g., bepridil, cisapride, diphemanil, intravenous erythromycin, halofantrine, mizolastine, moxifloxacin, intravenous vinca alkaloids, methadone, astemizole, terfenadine). Prevention of low potassium levels and correction if necessary: QT interval monitoring.

Agents reducing potassium levels, amphotericin B (intravenous), systemic glucocorticoids and mineralocorticoids (systemic), tetracosactide, stimulant laxatives

Increased risk of hypokalemia (additive effect). Plasma potassium levels should be checked and corrected if necessary; particular caution is required when using cardiac glycosides. Stimulant laxatives should not be used.

Cardiac glycosides

Hypokalemia and/or hypomagnesemia predispose to digoxin toxicity. Monitoring of plasma potassium, magnesium levels, and ECG is recommended, and treatment should be adjusted if necessary.

Allopurinol

Concomitant treatment with indapamide may increase the frequency of hypersensitivity reactions to allopurinol.

Concomitant use requiring monitoring

Metformin

In functional renal impairment associated with diuretic use, particularly loop diuretics, the risk of lactic acidosis with metformin use is increased. Metformin should not be used when plasma creatinine levels exceed 15 mg/L (135 µmol/L) in men and 12 mg/L (110 µmol/L) in women.

Iodinated contrast agents

In case of dehydration due to diuretic use, administration of iodinated contrast agents, especially at high doses, increases the risk of acute renal failure. Adequate hydration should be restored before administration of iodinated contrast agents.

Calcium salts

Risk of hypercalcemia due to reduced renal excretion of calcium.

Cyclosporine

Risk of increased plasma creatinine concentration without changes in cyclosporine blood levels, even without fluid/salt volume depletion.

Corticosteroids, tetracosactide (systemic)

Reduced antihypertensive effect (salt and water retention caused by corticosteroids).

Related to rosuvastatin

Effect on rosuvastatin of concomitantly administered medicinal products

Transport protein inhibitors

Rosuvastatin is a substrate for certain transport proteins, including OATP1B1 (involved in hepatic uptake) and the efflux transporter BCRP. Concomitant use of rosuvastatin with medicinal products that inhibit these transport proteins may increase rosuvastatin plasma concentrations and increase the risk of myopathy.

Cyclosporine

When rosuvastatin is used concomitantly with cyclosporine, rosuvastatin AUC values are on average 7 times higher than in healthy volunteers (see Table 1). Rosuvastatin is contraindicated in patients taking cyclosporine (see section "Contraindications").

Concomitant use did not affect cyclosporine plasma concentrations.

Protease inhibitors

Although the exact mechanism of interaction is unknown, concomitant use of protease inhibitors may significantly increase rosuvastatin exposure (see Table 1). 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 approximately 3-fold and 7-fold increases in rosuvastatin AUC and Cmax, respectively. Concomitant use of rosuvastatin and certain protease inhibitor combinations may be possible after careful evaluation and dose adjustment of rosuvastatin considering the expected increase in exposure (see sections "Dosage and administration", "Special precautions", and Table 1).

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 precautions").

Based on data from specific interaction studies, no significant pharmacokinetic interaction with fenofibrate is expected, but pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates, and niacin (nicotinic acid) at lipid-lowering doses (≥ 1 g/day) increase the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors, possibly because they may cause myopathy even when used alone. Doses of 30 mg and 40 mg are contraindicated when fibrates are used concomitantly (see sections "Contraindications", "Special precautions"). In such cases, therapy should also be initiated at a 5 mg dose.

Ezetimibe

Concomitant administration of 10 mg rosuvastatin and 10 mg ezetimibe in patients with hypercholesterolemia resulted in a 1.2-fold increase in rosuvastatin AUC (Table 1). However, adverse reactions due to pharmacodynamic interaction between rosuvastatin and ezetimibe cannot be excluded (see section "Special precautions").

Antacids

Concomitant administration of rosuvastatin with an antacid suspension containing aluminum and magnesium hydroxide reduces rosuvastatin plasma concentration by approximately 50%. This effect is minimized when the antacid is taken 2 hours after rosuvastatin. The clinical significance of this interaction has not been studied.

Erythromycin

Concomitant use of rosuvastatin and erythromycin reduced rosuvastatin AUC(0-t) by 20% and Cmax by 30%. This interaction may be due to increased intestinal motility caused by erythromycin.

Cytochrome P450 enzymes

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 (CYP2C9 and CYP3A4 inhibitor) or ketoconazole (CYP2A6 and CYP3A4 inhibitor).

Tickagrelor

Tickagrelor may affect renal excretion of rosuvastatin, increasing the risk of rosuvastatin accumulation. Although the exact mechanism is unknown, in some cases concomitant use of tickagrelor and rosuvastatin has led to reduced renal function, increased creatine kinase levels, and rhabdomyolysis.

Interactions requiring adjustment of rosuvastatin dose (see Table 1)

If rosuvastatin must be used concomitantly with other medicinal products that increase its exposure, the rosuvastatin dose should be adjusted. When an approximately 2-fold increase in exposure (AUC) is expected, rosuvastatin therapy should be initiated at a dose of 5 mg daily. The maximum daily dose of rosuvastatin should be adjusted so that the expected rosuvastatin concentration does not exceed that observed with a 40 mg daily dose in the absence of interaction with other medicinal products. For example, a 20 mg rosuvastatin dose when used concomitantly with gemfibrozil (1.9-fold increase in exposure) or a 10 mg rosuvastatin dose with atazanavir/ritonavir combination (3.1-fold increase in exposure).

If an increase in rosuvastatin AUC of less than 2-fold is observed, the initial dose need not be reduced, but caution should be exercised when increasing the rosuvastatin dose above 20 mg.

Table 1

Effect of concomitant medicinal products on rosuvastatin exposure

(AUC; in descending order) based on published clinical study data

Dosing regimen of the interacting drug	Dosing regimen of rosuvastatin	Changes in rosuvastatin AUC*
Increase in rosuvastatin AUC by 2-fold or more
Sofosbuvir/velpatasvir/voxelaprevir (400 mg/100 mg/100 mg) + voxelaprevir (100 mg) once daily for 15 days	10 mg, single dose	↑ 7.4-fold
Cyclosporine from 75 mg twice daily to 200 mg twice daily, 6 months	10 mg once daily, 10 days	↑ 7.1-fold
Darolutamide 600 mg twice daily, 5 days	5 mg, single dose	↑ 5.2-fold
Regorafenib 160 mg once daily, 14 days	5 mg, single dose	↑ 3.8-fold
Atazanavir 300 mg/ritonavir 100 mg once daily, 8 days	10 mg, single dose	↑ 3.1-fold
Simeprevir 150 mg once daily, 7 days	10 mg, single dose	↑ 2.8-fold
Roxadustat 200 mg every other day	10 mg, single dose	↑ 2.9-fold
Velpatasvir 100 mg once daily	10 mg, single dose	↑ 2.7-fold
Ortho-silaprevir 25 mg/paritaprevir 150 mg/ ritonavir 100 mg once daily/dasabuvir 400 mg twice daily, 14 days	5 mg, single dose	↑ 2.6-fold
Teriflunomide	unknown	↑ 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
Tafamidis 61 mg twice daily on days 1 and 2, once daily from day 3 to day 9	10 mg, single dose	↑ 2.0-fold
Fostamatinib 100 mg twice daily	20 mg, single dose	↑ 2.0-fold
Febuxostat 120 mg once daily	10 mg, single dose	↑ 1.9-fold
Gemfibrozil 600 mg twice daily, 7 days	80 mg, single dose	↑ 1.9-fold
Increase in rosuvastatin AUC less than 2-fold
Elvitegravir 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**
Aleglitazar 0.3 mg, 7 days	40 mg, 7 days	↔
Decrease 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 by x-fold represent the ratio between co-administration and administration of rosuvastatin alone. Data presented as % change represent the percentage difference relative to values when rosuvastatin is administered alone.

An increase is indicated by ↑, no change by ↔, and a decrease by ↓.

** Several interaction studies were conducted at different doses of rosuvastatin; the table presents the most significant ratio.

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

Effect of rosuvastatin on concurrently administered medicinal products

Vitamin K antagonists

At the initiation of rosuvastatin therapy or during dose titration in patients taking vitamin K antagonists (e.g., warfarin or other coumarin anticoagulants), the international normalized ratio (INR) may increase. Upon discontinuation or dose reduction of rosuvastatin, the INR may decrease. 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. The increased plasma levels should be considered when selecting the dose of oral contraceptives. There are no pharmacokinetic data available in patients receiving rosuvastatin concomitantly with HRT; therefore, a potential interaction cannot be excluded. However, this combination has been widely used in women in clinical trials and was well tolerated.

Other medicinal products

Digoxin

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

Fusidic acid

Interaction studies between rosuvastatin and fusidic acid have not been conducted. The risk of myopathy, including rhabdomyolysis, increases when fusidic acid is systemically co-administered with statins. The mechanism of this interaction (pharmacodynamic or pharmacokinetic) is currently unknown. Cases of rhabdomyolysis (including fatal outcomes) have been reported in patients receiving this combination. If systemic treatment with fusidic acid is necessary, rosuvastatin therapy should be discontinued for the entire duration of fusidic acid treatment (see section "Special precautions").

Children

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

Special precautions for use.

Lithium

Concomitant use of lithium and the combination of perindopril and indapamide is generally not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Neutropenia/Agranulocytosis/Thrombocytopenia/Anemia

Cases of neutropenia/agranulocytosis/thrombocytopenia/anemia have been reported in patients receiving ACE inhibitors. Neutropenia is rare in patients with normal renal function and no other risk factors during ACE inhibitor therapy. Perindopril should be used with particular caution in patients with collagenosis, during immunosuppressive therapy, allopurinol, procainamide, or in combination with these risk factors, especially if renal function is impaired. Some of these patients developed serious infections that were resistant to intensive antibiotic therapy in several cases. Periodic monitoring of white blood cell count is recommended when perindopril is used in such patients. Patients should also be informed that they must report any signs of infection (sore throat, fever) (see sections "Interaction with other medicinal products and other forms of interaction", "Undesirable effects").

Renovascular hypertension

When ACE inhibitors are administered to patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney, the risk of hypotension and renal failure increases (see section "Contraindications"). Concomitant diuretic therapy may be a contributing factor. Renal function impairment may manifest only as slight changes in plasma creatinine levels, even in patients with stenosis of one renal artery.

Hypersensitivity/Angioedema

Rare cases of angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and/or larynx have been reported in patients receiving ACE inhibitors, including perindopril (see section "Undesirable effects"). This may occur at any time during treatment. In such cases, perindopril must be discontinued immediately and careful monitoring and treatment initiated until complete symptom resolution. In cases of facial and lip edema, the condition may resolve spontaneously, but antihistamines may relieve symptoms.

Angioedema of the larynx may be fatal. In cases of tongue, glottis or larynx edema, airway obstruction is possible, and emergency treatment is required, which may include subcutaneous administration of epinephrine 1:1000 (0.3–0.5 mL) and/or airway management procedures.

Angioedema occurs more frequently in patients of African descent receiving ACE inhibitors compared to patients of other races.

The highest risk of angioedema with ACE inhibitor use occurs in patients with a history of angioedema unrelated to ACE inhibitor therapy (see section "Contraindications").

Rare cases of intestinal angioedema have been reported in patients receiving ACE inhibitors. These patients experienced abdominal pain (with or without nausea or vomiting); in some cases, previous facial angioedema was absent and C-1 esterase levels were normal. Diagnosis of intestinal angioedema was confirmed by abdominal computed tomography, ultrasound, or during surgery. Symptoms resolved after discontinuation of the ACE inhibitor. Intestinal angioedema should be considered in the differential diagnosis of patients with abdominal pain receiving ACE inhibitors.

Concomitant use of perindopril with sacubitril/valsartan is contraindicated due to increased risk of angioedema. Sacubitril/valsartan should not be initiated earlier than 36 hours after the last dose of perindopril. If sacubitril/valsartan therapy is discontinued, perindopril therapy should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Concomitant use of ACE inhibitors with other neutral endopeptidase (NEP) inhibitors (e.g., racecadotril), mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) also increases the risk of angioedema (e.g., airway or tongue swelling, with or without respiratory impairment) (see section "Interaction with other medicinal products and other forms of interaction"). Therefore, a careful benefit-risk assessment should be performed before initiating such therapy in patients already receiving an ACE inhibitor.

Anaphylactoid reactions during desensitization

Anaphylactoid reactions have been observed in patients receiving ACE inhibitors during desensitization procedures (e.g., to wasp or bee venom). ACE inhibitors should be used with caution in patients undergoing desensitization and avoided in patients receiving venom immunotherapy. However, these reactions can be prevented by temporarily discontinuing the ACE inhibitor at least 24 hours before treatment in patients requiring both ACE inhibitors and desensitization.

Anaphylactoid reactions during LDL apheresis

Rare, life-threatening anaphylactoid reactions have occurred in patients receiving ACE inhibitors during LDL apheresis with dextran sulfate. These reactions were resolved by temporarily discontinuing ACE inhibitors before each plasma exchange.

Patients undergoing hemodialysis

Cases of anaphylactoid reactions have been reported in patients receiving ACE inhibitors during hemodialysis with high-flux membranes (e.g., AN 69®). Such patients should be treated with a different type of dialysis membrane or an alternative class of antihypertensive agents.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism generally do not respond to antihypertensive agents acting via inhibition of the renin-angiotensin system. Therefore, this medicinal product is not recommended for such patients.

Hypokalemia

The main risk of therapy with thiazides and thiazide-like diuretics is decreased potassium concentration and hypokalemia. Hypokalemia may cause muscle disorders. Cases of rhabdomyolysis have been reported, mainly in the context of severe hypokalemia. Hypokalemia (< 3.4 mmol/L) should be prevented in patients with poor nutrition and/or multiple medications, elderly patients, patients with liver cirrhosis and ascites, and patients with ischemic heart disease and heart failure. In such patients, hypokalemia increases the cardiotoxicity of cardiac glycosides and the risk of arrhythmias.

The combination of perindopril and indapamide does not prevent the onset of hypokalemia, especially in patients with diabetes mellitus or renal insufficiency. Regular monitoring of plasma potassium levels is required during antihypertensive therapy combined with diuretics.

Hypokalemia associated with low serum magnesium concentration may be resistant to treatment unless serum magnesium levels are corrected.

Potassium-sparing agents, potassium-containing dietary supplements, or potassium-containing salt substitutes

Combination of perindopril with potassium-sparing agents, potassium-containing dietary supplements, or potassium-containing salt substitutes is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Hyperkalemia

ACE inhibitors may cause hyperkalemia as they inhibit aldosterone release. The effect is usually mild in patients with normal renal function. Risk factors for hyperkalemia include: renal insufficiency or reduced renal function, age over 70 years, diabetes mellitus, intercurrent conditions such as dehydration, acute heart failure, metabolic acidosis, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium-containing dietary supplements, potassium-containing salt substitutes, or other agents that increase serum potassium concentration (such as heparin, trimethoprim, or cotrimoxazole, also known as trimethoprim/sulfamethoxazole), particularly aldosterone antagonists or angiotensin receptor blockers, acetylsalicylic acid at doses ≥ 3 g/day, COX-2 inhibitors and non-selective NSAIDs, immunosuppressants such as cyclosporine or tacrolimus. Use of potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes, especially in patients with impaired renal function, may lead to a significant increase in serum potassium concentration. Hyperkalemia may cause serious, sometimes fatal, arrhythmias. If concomitant use of perindopril and any of the above-mentioned substances is considered necessary, they should be used with caution and serum potassium levels should be closely monitored. Patients receiving ACE inhibitors should use potassium-sparing diuretics and ACE inhibitors cautiously, and serum potassium levels and renal function should be monitored (see section "Interaction with other medicinal products and other forms of interaction").

Magnesium levels

Thiazide and thiazide-like diuretics, including indapamide, have been shown to increase urinary magnesium excretion, which may lead to hypomagnesemia (see sections "Interaction with other medicinal products and other forms of interaction" and "Undesirable effects").

Pregnancy

ACE inhibitors should not be prescribed during pregnancy. If patients receiving ACE inhibitors plan pregnancy, they should be switched to alternative antihypertensive agents with an established safety profile for use during pregnancy. If pregnancy is confirmed, ACE inhibitor therapy should be discontinued immediately and alternative therapy initiated if necessary (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Photosensitivity

Cases of photosensitivity reactions have been reported in patients receiving thiazide and thiazide-like diuretics. If such reactions occur, diuretic therapy should be discontinued. If re-administration of the diuretic is necessary, protection of exposed areas from sunlight or artificial ultraviolet sources is recommended.

Renal impairment

This medicinal product is contraindicated in severe renal impairment (creatinine clearance < 30 mL/min). Roxiper is not suitable for patients with creatinine clearance < 60 mL/min. For such patients, dose titration of individual monocomponents is recommended (see section "Dosage and administration").

For some patients with hypertension without apparent kidney damage, in whom tests show functional renal impairment, treatment should be discontinued. Therapy should be resumed starting with the lowest dose or with one of the components only.

Routine monitoring for such patients includes frequent monitoring of potassium and creatinine levels 2 weeks after initiation of therapy, then every 2 months during the period of therapeutic stability. Renal impairment has been reported, primarily in patients with severe heart failure or underlying renal impairment, including renal artery stenosis.

The drug is generally not recommended in cases of bilateral renal artery stenosis or stenosis of the artery of a single kidney.

Cases of proteinuria (detected by test strip), predominantly tubular in origin and mostly transient or intermittent, have been reported in patients receiving high doses of rosuvastatin, particularly 40 mg. However, proteinuria did not indicate acute or progressive kidney disease (see section "Undesirable effects").

Renal function and diuretics

Thiazide and thiazide-like diuretics are more effective with normal or mildly impaired renal function (plasma creatinine levels in adults < 25 mg/L or 220 µmol/L).

In elderly patients, plasma creatinine levels should be adjusted according to age, body weight, and sex using the Cockcroft formula:

Clcr = (140 – age) × body weight / 0.814 × plasma creatinine level,

where age is in years, body weight in kilograms, and plasma creatinine level in micromoles per liter. This formula is suitable for elderly men. For women, the result should be multiplied by 0.85.

Hypovolemia occurring at the beginning of treatment due to water and sodium loss from diuretic use may lead to decreased glomerular filtration. This may result in increased plasma urea and creatinine levels. In patients with normal renal function, this transient functional renal impairment resolves without consequences, but it may worsen the condition of patients with pre-existing renal impairment.

Arterial hypotension and water and electrolyte deficiency

There is a risk of sudden drop in blood pressure in patients with sodium deficiency (especially in patients with renal artery stenosis). Therefore, it is necessary to systematically check for symptoms of water and electrolyte deficiency that may occur with vomiting or diarrhea.

In such patients, plasma electrolyte levels should be regularly monitored.

In case of significant arterial hypotension, intravenous administration of isotonic saline solution may be required. Transient arterial hypotension is not a contraindication for further use of the medicinal product. After restoration of circulating blood volume and normalization of blood pressure, treatment may be resumed with a lower dose or one component of the drug.

Risk of arterial hypotension and/or renal impairment (in heart failure, water and electrolyte imbalance)

Significant stimulation of the RAAS, especially during significant water and electrolyte imbalance (strict low-sodium diet or prolonged diuretic therapy), has been observed in patients whose initial blood pressure was low, in cases of renal artery stenosis, in heart failure with congestion, or in cirrhosis with edema and ascites.

Thus, blockade of this system by an ACE inhibitor may cause, especially at the first dose and during the first 2 weeks of treatment, unexpected drop in blood pressure and/or increase in plasma creatinine levels, indicating functional renal impairment. Occasionally, this may present as an acute episode, although rarely, with varying duration.

In such cases, perindopril therapy should be initiated with a low dose and gradually increased.

Renovascular hypertension

The treatment of renovascular hypertension is revascularization. However, ACE inhibitors may be acceptable for patients with renovascular hypertension awaiting surgical correction or if such surgery is not possible.

Perindopril/indapamide therapy in patients with renal artery stenosis or suspected stenosis should be initiated in a medical facility.

Stenosis of aortic or mitral valves/Hypertrophic cardiomyopathy

ACE inhibitors should be used with caution in the treatment of patients with left ventricular outflow tract obstruction.

Cough

A dry, non-productive, persistent cough may occur during ACE inhibitor therapy. It resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough. If ACE inhibitor use is still considered necessary, continuation of therapy may be considered.

Interstitial lung disease

Isolated cases of interstitial lung disease have been reported with the use of some statins, particularly with long-term therapy (see section "Undesirable effects"). Symptoms include dyspnea, non-productive cough, and worsening general condition (fatigue, weight loss, fever). If interstitial lung disease is suspected, statin therapy should be discontinued.

Hepatic impairment

Treatment with ACE inhibitors has occasionally been associated with a syndrome beginning as cholestatic jaundice progressing to spontaneous liver necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or increased liver enzymes should discontinue the inhibitor (see section "Undesirable effects").

Hepatic encephalopathy

With worsening liver function, thiazide and thiazide-like diuretics, especially in the presence of electrolyte imbalance, may cause hepatic encephalopathy, which may progress to hepatic coma. Diuretic therapy should be discontinued immediately upon its appearance.

Sodium levels

Plasma sodium concentration should be determined before starting therapy and at regular intervals during treatment. Any diuretic may cause hyponatremia, sometimes with very serious consequences. Since decreased plasma sodium concentration may initially be asymptomatic, regular monitoring is required. Plasma sodium concentration should be determined more frequently in elderly patients and patients with liver cirrhosis (see sections "Overdose" and "Undesirable effects").

Hyponatremia with hypovolemia may cause dehydration and orthostatic hypotension. Concomitant loss of chloride ions may lead to secondary compensatory metabolic alkalosis, which is usually mild and of minor clinical significance.

Prolongation of QT interval

Patients with prolonged QT interval have a certain risk regardless of the cause of QT prolongation (congenital or iatrogenic). Hypokalemia, as well as bradycardia, is a factor predisposing to dangerous arrhythmias, including polymorphic ventricular tachycardia of the torsades de pointes type, sometimes with fatal outcome.

In all such cases, plasma potassium levels should be monitored more frequently. The first measurement of plasma potassium concentration should be performed within the first week after starting therapy.

If low potassium levels are detected, dosage adjustment is required.

Calcium levels

Thiazide and thiazide-like diuretics may reduce calcium excretion in urine and cause a slight transient increase in plasma calcium concentration. Persistent hypercalcemia may be due to hyperparathyroidism. Therefore, diuretic therapy should be discontinued until parathyroid function is evaluated.

Uric acid

Gout attacks may occur in patients with hyperuricemia.

Elderly patients

Renal function and potassium levels should be checked before starting therapy. The initial dose should be adjusted according to blood pressure, especially in cases of water and electrolyte deficiency, to avoid hypotension.

Patients with atherosclerosis

The risk of arterial hypotension exists in all patients, but particular attention should be paid to patients with ischemic heart disease or cerebral circulation insufficiency, starting therapy with a low dose.

Diabetic patients

In patients with insulin-dependent diabetes mellitus (with a spontaneous tendency to increased potassium levels), therapy should be initiated under medical supervision with a reduced initial dose.

Diabetic patients receiving oral antidiabetic agents or insulin should have their glycemia levels carefully monitored during the first months of ACE inhibitor therapy (see section "Interaction with other medicinal products and other forms of interaction").

Some data suggest that statins may increase blood glucose levels and, in some patients at high risk of diabetes, may cause hyperglycemia, requiring standard diabetes treatment. However, this risk is outweighed by the reduction in cardiovascular disease risk with statin use, so it should not be a reason to discontinue statin therapy. In patients at risk of diabetes (fasting glucose 5.6 to 6.9 mmol/L, body mass index (BMI) > 30 kg/m², elevated triglycerides, hypertension), both chemical and biochemical parameters should be checked according to national guidelines.

In the JUPITER study, the overall frequency of diabetes was 2.8% in the rosuvastatin group and 2.3% in the placebo group, primarily in patients with fasting glucose levels from 5.6 to 6.9 mmol/L.

Blood glucose

In diabetic patients, blood glucose levels should be monitored, especially in cases of hypokalemia.

Heart failure/severe heart failure

Patients with severe heart failure (class IV) or patients with insulin-dependent diabetes mellitus (with a spontaneous tendency to increased potassium levels) should start therapy under medical supervision with a reduced initial dose. Patients with hypertension and heart failure should not discontinue beta-blocker therapy: the ACE inhibitor should be added to the beta-blocker.

Ethnic characteristics

Like other ACE inhibitors, perindopril is likely to be less effective in lowering blood pressure in black patients, possibly due to low plasma renin levels in these patients.

Pharmacokinetic studies demonstrate increased exposure to rosuvastatin in Asian patients compared to Caucasian patients (see sections "Pharmacological properties", "Dosage and administration", and "Contraindications").

Surgery/anesthesia

ACE inhibitors may cause arterial hypotension during anesthesia, especially when the anesthetic administered has hypotensive potential.

Therefore, it is recommended that therapy with long-acting ACE inhibitors, such as perindopril, be discontinued, if possible, one day before surgery.

Sportsmen

Athletes should be aware that this medicinal product contains the active substance indapamide, which may cause a positive result in doping controls.

Choroidal effusion, acute myopia, and secondary angle-closure glaucoma

Sulfonamide or its derivative drugs may cause an idiosyncratic reaction leading to choroidal effusion with visual field defect, transient myopia, and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and usually occur within hours or weeks of starting the drug. Untreated acute angle-closure glaucoma may lead to permanent vision loss. Primary treatment is discontinuation of the drug as soon as possible. If intraocular pressure remains uncontrolled, rapid medical or surgical treatment may be required. Risk factors for acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.

Effect on skeletal muscle

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

As with other HMG-CoA reductase inhibitors, post-marketing cases of rhabdomyolysis associated with rosuvastatin have occurred more frequently at the 40 mg dose. In several cases, statins have been reported to cause or exacerbate pre-existing myasthenia gravis or ocular myasthenia (see "Undesirable effects"). Roxiper therapy should be discontinued if symptoms worsen. Recurrences have been reported when the same or another statin was reintroduced.

Creatine kinase (CK) measurement

CK levels should not be measured after significant physical exertion or in the presence of possible alternative causes of elevated CK that may interfere with result interpretation. If initial CK levels are significantly elevated (> 5 × ULN [upper limit of normal]), a confirmatory test should be performed within 5–7 days. If the repeat test confirms initial CK levels > 5 × ULN, therapy should not be initiated.

Before treatment

Rosuvastatin, like other HMG-CoA reductase inhibitors, should be prescribed with caution in patients with factors predisposing to myopathy/rhabdomyolysis. Such 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 drug levels;
• concomitant use of fibrates.

In such patients, the risk and potential benefit of using the medicinal product should be weighed; clinical monitoring is also recommended. Therapy should not be initiated if initial CK levels are significantly elevated (> 5 × ULN).

During treatment

Patients should be warned to immediately report unexplained muscle pain, muscle weakness, or cramps, especially if accompanied by malaise or fever. CK levels should be determined in such patients. Therapy should be discontinued if CK levels are significantly elevated (> 5 × ULN) or if muscle symptoms are severe and cause discomfort in daily life (even if CK levels ≤ 5 × ULN). If symptoms resolve and CK levels return to normal, rosuvastatin or an alternative HMG-CoA inhibitor may be reinitiated at the lowest doses and under close supervision. Regular monitoring of CK levels is not required in patients without the above-mentioned symptoms. Very rare cases of immune-mediated necrotizing myopathy (IMNM) have been observed during and after statin use, including rosuvastatin. IMNM is characterized by proximal muscle weakness and elevated serum creatine kinase levels that do not resolve even after discontinuation of statins. In clinical trials, no increased effect on skeletal muscle was observed in a small number of patients receiving rosuvastatin and concomitant medications. However, increased frequency of myositis and myopathy has been observed in patients receiving other HMG-CoA reductase inhibitors 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 some HMG-CoA reductase inhibitors; therefore, rosuvastatin is not recommended to be used in combination with gemfibrozil. The beneficial effect of further lipid level changes with concomitant use of rosuvastatin with fibrates or niacin should be weighed against the potential risks of such combination therapy. Concomitant use of rosuvastatin at doses of 30 or 40 mg with fibrates is contraindicated (see sections "Interaction with other medicinal products and other forms of interaction" and "Overdose").

Rosuvastatin should not be used in patients with acute, serious conditions predisposing to myopathy or increasing the risk of renal failure due to rhabdomyolysis (such as sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine, or electrolyte disorders; uncontrolled seizures).

Roxiper should not be used concomitantly with systemic fusidic acid or within 7 days after discontinuation of fusidic acid therapy. For patients for whom systemic fusidic acid therapy is considered necessary, statin therapy should be discontinued for the entire duration of fusidic acid therapy. Cases of rhabdomyolysis (including fatal outcomes) 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 symptoms such as muscle weakness, pain, or fatigue.

Statin therapy may be resumed 7 days after the last dose of fusidic acid.

In exceptional cases where prolonged systemic use of fusidic acid is necessary, e.g., for the treatment of severe infections, concomitant use of rosuvastatin and fusidic acid may only be possible under close medical supervision.

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

There are reports that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of hypotension, hyperkalemia, and decreased renal function (including acute renal failure). Therefore, dual blockade of the RAAS by concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see sections "Pharmacological properties" and "Interaction with other medicinal products and other forms of interaction").

If dual blockade therapy with two RAAS blockers is considered absolutely necessary, it may only occur under specialist supervision and with careful monitoring of renal function, electrolyte levels, and blood pressure. ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Protease inhibitors

Increased systemic exposure to rosuvastatin has been observed in individuals using 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 possibility of increased rosuvastatin plasma concentrations should be evaluated at the start of therapy and when increasing the rosuvastatin dose in patients receiving protease inhibitors. Concomitant use of the medicinal product with protease inhibitors is not recommended unless the rosuvastatin dose is adjusted (see sections "Dosage and administration" and "Interaction with other medicinal products and other forms of interaction").

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. When prescribing rosuvastatin, patients should be warned about signs and symptoms of severe skin reactions and should be under close supervision. If signs and symptoms indicating a skin reaction appear, Roxiper use should be immediately discontinued and alternative treatment considered.

If a serious reaction such as SJS or DRESS occurs during Roxiper use, treatment with this drug should never be resumed in such a patient.

Use during pregnancy or breastfeeding.

Roxiper is contraindicated during pregnancy and breastfeeding. The medicinal product should not be used by pregnant women or women planning pregnancy. If pregnancy is confirmed during treatment with this medicinal product, its use must be immediately discontinued and replaced with another medicinal product permitted for use during pregnancy.

Pregnancy

Use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section "Special precautions for use"). Use of ACE inhibitors is contraindicated during the second and third trimesters of pregnancy (see sections "Contraindications" and "Special precautions for use").

Epidemiological data on the teratogenic risk of ACE inhibitors during the first trimester of pregnancy are inconclusive, but a slight increase in risk cannot be excluded. Except in cases where continuation of ACE inhibitor therapy is considered necessary, alternative antihypertensive therapy with an established safety profile for use during pregnancy should be prescribed to women planning pregnancy.

If pregnancy is confirmed, ACE inhibitor therapy should be immediately discontinued and alternative therapy initiated if necessary.

The effect of ACE inhibitor therapy during the second and third trimesters causes fetotoxicity (reduced renal function, oligohydramnios, delayed ossification of skull bones) and neonatal toxicity (renal failure, hypotension, hyperkalemia). If ACE inhibitors were used from the second trimester of pregnancy, ultrasound examination is recommended to assess renal function and skull bone status. Newborns whose mothers used ACE inhibitors should be carefully monitored for hypotension (see sections "Contraindications" and "Special precautions for use").

The amount of data (less than 300 pregnancy cases) on the use of indapamide during pregnancy is limited. Prolonged use of thiazide during the third trimester of pregnancy may reduce maternal plasma volume and uteroplacental blood flow, potentially leading to fetoplacental ischemia and growth retardation.

Animal studies do not indicate reproductive toxicity.

As a precautionary measure, it is advisable to avoid the use of indapamide during pregnancy.

Women of childbearing potential should use appropriate contraceptive methods.

Since cholesterol and other cholesterol biosynthesis products are important for fetal development, the potential risk of HMG-CoA reductase inhibition outweighs the benefit of treatment during pregnancy. Animal studies provide limited data on reproductive toxicity. If a patient becomes pregnant during treatment with the drug, therapy should be immediately discontinued.

Period of breastfeeding

Roxiper is contraindicated during breastfeeding.

Due to lack of available information on the use of perindopril, it is not recommended during breastfeeding. During breastfeeding, especially of a newborn or premature infant, alternative treatment with a better-established safety profile is preferred.

Insufficient information is available on the excretion of indapamide/metabolites in human breast milk. Increased sensitivity to sulfonamide-derived drugs and hypokalemia may occur. Risk to newborns/infants cannot be excluded. Indapamide belongs to thiazide diuretics, which suppress milk secretion during breastfeeding. Indapamide is not recommended during breastfeeding.

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

Fertility

Perindopril and indapamide

Reproductive toxicity studies showed no effect on fertility in male and female rats. There is no effect on human fertility.

Ability to affect reaction speed when driving or operating machinery.

Roxiper does not affect the ability to drive or operate machinery, but individual reactions related to low blood pressure may occur in some patients, particularly at the beginning of treatment or when used in combination with other antihypertensive drugs. Studies to determine the effect of rosuvastatin on the ability to drive or operate machinery have not been conducted. However, due to its pharmacodynamic properties, it is unlikely that rosuvastatin affects this ability. Dizziness may occur during treatment, which should be considered when driving or operating machinery.

Method of Administration and Dosage

Administer orally.

The recommended dose is 1 tablet daily, preferably in the morning before food.

Fixed-dose combination therapy is not suitable for initial treatment.

Before switching to Roxiper, patients who are concurrently receiving the same stable doses of individual components should be monitored. The dose of Roxiper should be determined based on the doses of the individual components prior to switching to the combination.

If dose adjustment is required for any active ingredient of the fixed combination for any reason (e.g., diagnosed concomitant disease, change in patient status, or drug interactions), the individual components should be reintroduced to determine appropriate dosing.

Geriatric Patients

In elderly patients, plasma creatinine should be adjusted according to age, body weight, and gender. Therapy may be initiated in elderly patients only after assessment of renal function and blood pressure.

Renal Impairment

Treatment is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min). Roxiper at doses of 10 mg/8 mg/2.5 mg and 20 mg/8 mg/2.5 mg is contraindicated in patients with moderate renal impairment (creatinine clearance 30–60 mL/min). Roxiper is not suitable for patients with creatinine clearance < 60 mL/min. For these patients, titration with individual monocomponents is recommended (see section "Special Warnings and Precautions for Use").

Regular medical monitoring includes careful assessment of creatinine and potassium levels.

Hepatic Impairment

Treatment is contraindicated in patients with severe hepatic impairment. Roxiper is contraindicated in patients with active liver disease (see section "Contraindications").

Dose adjustment is not required in patients with moderate hepatic impairment.

In patients with hepatic impairment classified as Child–Pugh score of 7 or lower, no increase in rosuvastatin exposure has been observed. However, increased systemic exposure has been observed in patients with Child–Pugh scores of 8 and 9 (see section "Pharmacological Properties"). These patients should undergo renal function monitoring (see section "Special Warnings and Precautions for Use"). There are no data available for patients with Child–Pugh scores above 9.

Ethnic Characteristics

Increased systemic exposure has been observed in Asian patients (see sections "Pharmacological Properties", "Contraindications", and "Special Warnings and Precautions for Use").

Genetic Polymorphisms

Certain genetic polymorphisms are known to cause increased rosuvastatin exposure (see section "Pharmacological Properties"). Patients with any of these specific polymorphism types should be prescribed a lower daily dose of rosuvastatin.

Concomitant Therapy

Rosuvastatin is a substrate for various transporter proteins (e.g., OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) is increased when rosuvastatin is co-administered with certain medicinal products that can increase rosuvastatin plasma concentrations via interaction with transporter proteins (e.g., 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 and Precautions for Use"). Alternative treatments should be considered whenever possible, and rosuvastatin therapy should be temporarily discontinued if necessary. In situations where concomitant use of these medicinal products with rosuvastatin cannot be avoided, the benefits and risks of combination therapy should be carefully weighed, and rosuvastatin dosage should be selected cautiously (see section "Interaction with Other Medicinal Products and Other Forms of Interactions").

Children

Roxiper should not be used in children and adolescents, as the efficacy and safety of the medicinal product in this population have not been established.

Overdose

Symptoms

The most likely adverse reaction in case of overdose is hypotension, sometimes associated with nausea, vomiting, convulsions, dizziness, drowsiness, confusion, oliguria, which may progress to anuria (due to hypovolemia). Electrolyte imbalances (low levels of sodium and potassium) may occur.

Treatment

There is no specific antidote for overdose. Symptomatic treatment and necessary supportive measures should be implemented. Gastric lavage and/or administration of activated charcoal, as well as restoration of fluid and electrolyte balance, are recommended in a medical facility. If pronounced hypotension develops, the patient should be placed in a supine position with the head lowered. If necessary, intravenous saline solution may be administered or any other method used to increase circulating blood volume. Liver function and creatine kinase levels should be monitored.

Perindoprilat—the active metabolite of perindopril—can be removed by dialysis (see section "Pharmacological Properties"), whereas hemodialysis is unlikely to be effective in removing rosuvastatin.

Adverse reactions

The safety profile of perindopril is consistent with the safety profile of ACE inhibitors.

The most commonly observed adverse reactions during treatment were:

• Perindopril: dizziness, headache, paraesthesia, taste disturbances (dysgeusia), visual disturbances, vertigo, tinnitus, hypotension, cough, dyspnoea, abdominal pain, constipation, dyspepsia, diarrhoea, nausea, vomiting, pruritus, skin rashes, muscle spasms and asthenia.
• Indapamide: hypokalaemia, hypersensitivity reactions, predominantly dermatological, in patients predisposed to allergic and asthmatic reactions, and maculopapular rashes.

Adverse reactions are classified by frequency: very common (≥ 1/10), common (≥ 1/100 – < 1/10), uncommon (≥ 1/1,000 – < 1/100), rare (≥ 1/10,000 – < 1/1,000), very rare (< 1/10,000), and not known (frequency cannot be estimated from the available data).

Body System	Adverse Reactions	Frequency
		Perindopril	Indapamide	Rosuvastatin
Infections and infestations	Rhinitis	Very rare	-	-
Blood and lymphatic system disorders	Eosinophilia	Unknown1)	-	-
	Agranulocytosis2)	Very rare	Very rare	-
	Aplastic anemia	-	Very rare	-
	Pancytopenia	Very rare	-	-
	Leukopenia	Very rare	Very rare	-
	Neutropenia2)	Very rare	-	-
	Hemolytic anemia	Very rare	Very rare	-
	Thrombocytopenia2)	Very rare	Very rare	Rare
Immune system disorders	Hypersensitivity reactions (mainly dermatological, in patients prone to allergic and asthmatic reactions and maculopapular rashes)	-	Common	Rare
Endocrine disorders	Diabetes mellitus3)	-	-	Common
	Syndrome of inappropriate antidiuretic hormone secretion (SIADH)	Rare	-	-
Metabolism and nutrition disorders	Hypoglycemia4)	Uncommon1)	-	-
	Hyperkalemia, reversible upon discontinuation of the drug2)	Uncommon1)	-	-
	Hypokalemia2)	Uncommon1)	Uncommon	-
	Hypercalcemia	-	Very rare	-
	Hypokalemia2)	-	Common	-
	Hypochloremia	-	Rare	-
	Hypomagnesemia	-	Rare	-
Psychiatric disorders	Mood and sleep disorders	Uncommon		-
	Sleep disorders	Uncommon		Unknown
	Confusion	Very rare	-	-
	Depression	Uncommon	-	Unknown
Nervous system disorders	Dizziness	Common	-	Common
	Headache	Common	Rare	Common
	Paresthesia	Common	Rare	-
	Disturbance of taste	Common	-	-
	Somnolence	Uncommon1)	-	-
	Syncope	Uncommon1)	Unknown	-
	Peripheral neuropathy	-	-	Unknown
	Mononeuritis	-	-	Very rare
	Memory loss	-	-	Very rare
	Stroke, possibly secondary to excessive hypotension in patients at high risk2)	Very rare	-	-
	Development of hepatic encephalopathy in case of liver insufficiency2)	-	Unknown	-
	Myasthenia gravis	-	-	Unknown
Eye disorders	Visual disturbance	Common	Unknown	-
	Myopia2)	-	Unknown	-
	Blurred vision	-	Unknown	-
	Acute angle-closure glaucoma	-	Unknown	-
	Choroidal effusion	-	Unknown	-
	Ocular myasthenia	-	-	Unknown
Ear and labyrinth disorders	Vertigo	Common	Rare	-
	Tinnitus	Common	-
Cardiac disorders	Palpitations	Uncommon1)	-	-
	Tachycardia	Uncommon1)	-	-
	Angina pectoris2)	Very rare	-	-
	Arrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation)	Very rare	Very rare	-
	Myocardial infarction, possibly after excessive hypotension in patients at high risk4)	Very rare	-	-
Vascular disorders	Hypotension (and effects associated with hypotension)2)	Common	Very rare	-
	Vasculitis	Uncommon1)	-	-
	Raynaud's phenomenon	Unknown	-	-
	Flushing	Rare	-	-
Respiratory, thoracic and mediastinal disorders	Cough2)	Common	-	Unknown
	Dyspnea	Common	-	Unknown
	Bronchospasm	Uncommon	-	-
	Eosinophilic pneumonia	Very rare	-	-
Gastrointestinal disorders	Abdominal pain	Common	-	Common
	Constipation	Common	Rare	Common
	Diarrhea	Very rare	-	Rare
	Dyspepsia	Common	-	-
	Nausea	Common	Rare	Common
	Vomiting	Common	Uncommon	-
	Dry mouth	Uncommon	Rare	-
	Pancreatitis	Very rare	Very rare	Rare
Hepatobiliary disorders	Hepatitis2)	Very rare	Unknown	Very rare
	Liver function disorders	-	Very rare	-
	Jaundice	-	-	Very rare
Skin and subcutaneous tissue disorders	Pruritus	Common	-	Uncommon
	Rash	Common	-	Uncommon
	Maculopapular rash	-	Common	-
	Urticaria2)	Uncommon	Very rare	Uncommon
	Angioedema2)	Uncommon	Very rare	-
	Purpura	-	Uncommon	-
	Hyperhidrosis	Uncommon1)	-	-
	Photosensitivity reaction	Uncommon1)	Unknown	-
	Pemphigoid	Uncommon	-	-
	Worsening of psoriasis	Rare1)	-	-
	Multiform erythema	Very rare	-	-
	Toxic epidermal necrolysis	-	Very rare	-
	Stevens-Johnson syndrome	-	Very rare	-
	Drug reaction with eosinophilia and systemic symptoms (DRESS)	-	-	Unknown
Musculoskeletal and connective tissue disorders	Muscle cramps	Common	Unknown	-
	Exacerbation of pre-existing systemic lupus erythematosus	-	Unknown	-
	Arthralgia	Uncommon1)	-	Very rare
	Myalgia	Uncommon1)	-	Common
	Muscle weakness	-	Unknown	-
	Myopathy (including myositis)	-	-	Rare
	Rhabdomyolysis	-	Unknown	Rare
	Tendon disorders, sometimes complicated by rupture	-	-	Unknown
	Immune-mediated necrotizing myopathy	-	-	Unknown
	Lupus-like syndrome	-	-	Rare
	Muscle rupture	-	-	Rare
Renal and urinary disorders	Renal failure	Uncommon	-	-
	Acute renal failure	Rare	Very rare	-
	Hematuria	-	-	Very rare
	Anuria/Oliguria	Rare	-	-
Reproductive system and breast disorders	Erectile dysfunction	Uncommon	Uncommon	-
	Gynecomastia	-	-	Very rare
General disorders and administration site conditions	Asthenia	Common	-	Unknown
	Chest pain	Uncommon1)	-	Common
	Malaise	Uncommon1)	-	-
	Peripheral edema	Uncommon1)	-	-
	Pyrexia	Uncommon1)	-	Unknown
	Fatigue	-	Rare	-
Investigations	Increased plasma urea levels	Uncommon1)	-	-
	Increased plasma creatinine levels	Uncommon1)	-	-
	Increased plasma bilirubin levels	Rare	-	-
	Elevated liver enzymes	Rare	Unknown	Rare
	Decreased hemoglobin and red blood cell count2)	Very rare	-	-
	Increased plasma glucose levels	-	Unknown	Common
	Increased plasma uric acid levels	-	Unknown	-
	QT interval prolongation on ECG4)	-	Unknown	-
Injury, poisoning and procedural complications	Weakness	Uncommon1)	-	-

1. The frequency of adverse reactions is based on spontaneous reports during clinical trials.
2. See section "Special precautions for use".
3. Frequency depends on the presence of risk factors (fasting blood glucose ≥ 5.6 mmol/L, BMI >30 kg/m², elevated triglyceride levels, history of hypertension).
4. See sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use".

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

Additional information regarding rosuvastatin

Description of individual adverse reactions

Proteinuria, predominantly of tubular origin (detected by urine dipstick testing), has been observed in patients treated with rosuvastatin. Changes in urinary protein content from absent or trace to "++" or higher were reported in less than 1% of patients receiving 10 mg and 20 mg doses, and in approximately 3% of patients receiving the 40 mg dose. A slight increase in the incidence of proteinuria from absent or trace to "+" was observed with the 20 mg dose. In most cases, proteinuria decreased or resolved spontaneously during continued treatment. Review of clinical trial and post-marketing data has not identified a causal relationship between proteinuria and acute or progressive kidney disease.

Hematuria has been observed in patients treated with rosuvastatin; clinical trial data indicate that its incidence is low.

Musculoskeletal effects

Skeletal muscle-related adverse events such as myalgia, myopathy (including myositis), and rarely rhabdomyolysis, with or without acute renal failure, have been observed with all rosuvastatin doses, particularly with doses > 20 mg. Rare cases of rhabdomyolysis, sometimes associated with renal failure, have been reported with rosuvastatin and other statins.

Dose-dependent increases in creatine kinase (CK) levels have been observed in patients taking rosuvastatin. In most cases, these increases were mild, asymptomatic, and transient. If CK levels are elevated (> 5 × ULN), 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 have experienced dose-dependent increases in transaminase levels; in most cases, these were mild, asymptomatic, and transient.

The following adverse reactions have been observed with some statins:

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

Paediatric population

Elevated CK levels > 10 × ULN and muscle symptoms after physical exercise or excessive physical activity were observed more frequently in children and adolescents than in adults during a 52-week clinical trial (see section "Special precautions for use"). However, the safety profile of rosuvastatin in children, adolescents, and adults is similar.

Additional information regarding indapamide

Description of individual adverse reactions

During phase II and III clinical trials comparing indapamide at doses of 1.5 mg and 2.5 mg, analysis of plasma potassium levels revealed a dose-dependent effect of indapamide:

Indapamide 1.5 mg: plasma potassium levels < 3.4 mmol/L were observed in 10% of patients and < 3.2 mmol/L in 4% of patients after 4–6 weeks of treatment. After 12 weeks of treatment, the mean decrease in plasma potassium level was 0.23 mmol/L.

Indapamide 2.5 mg: plasma potassium levels < 3.4 mmol/L were observed in 25% of patients and < 3.2 mmol/L in 10% of patients after 4–6 weeks of treatment. After 12 weeks of treatment, the mean decrease in plasma potassium level was 0.41 mmol/L.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, patients, and 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. Store in the original packaging to protect from light. The medicinal product does not require special storage temperature conditions. Keep out of reach of children.

Packaging.

10 tablets per blister; 3 or 9 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. KRKA, d.d., Novo mesto / KRKA, d.d., Novo mesto.

Manufacturer's address and location of operations.

Šmarješka cesta 6, 8501 Novo mesto, Slovenia / Smarjeska cesta 6, 8501 Novo mesto, Slovenia.