Roxampex

INSTRUCTION for medical use of the medicinal product Roxampex (Roxampex)

Composition:

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

1 tablet contains:

20 mg rosuvastatin as rosuvastatin calcium, 10 mg amlodipine as amlodipine besylate and 8 mg perindopril as perindopril tert-butylamine; or

20 mg rosuvastatin as rosuvastatin calcium, 5 mg amlodipine as amlodipine besylate and 8 mg perindopril as perindopril tert-butylamine; or

20 mg rosuvastatin as rosuvastatin calcium, 5 mg amlodipine as amlodipine besylate and 4 mg perindopril as perindopril tert-butylamine; or

10 mg rosuvastatin as rosuvastatin calcium, 10 mg amlodipine as amlodipine besylate and 8 mg perindopril as perindopril tert-butylamine; or

10 mg rosuvastatin as rosuvastatin calcium, 5 mg amlodipine as amlodipine besylate and 8 mg perindopril as perindopril tert-butylamine; or

10 mg rosuvastatin as rosuvastatin calcium, 5 mg amlodipine as amlodipine besylate and 4 mg perindopril as perindopril tert-butylamine;

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

Film coating: polyvinyl alcohol, macrogol 3350, titanium dioxide (E 171), talc, iron oxide red (E 172)1,2, iron oxide black (E 172)1,2,3, iron oxide yellow (E 172)1.

1Not present in tablets of 20 mg/10 mg/8 mg.

2Not present in tablets of 20 mg/5 mg/8 mg and 10 mg/10 mg/8 mg.

3Not present in tablets of 20 mg/5 mg/4 mg.

Medicinal form. Film-coated tablets.

Main physicochemical properties:

20 mg/10 mg/8 mg

White, round, slightly biconvex tablets with bevelled edges, film-coated, with engraved marking PAR6 on one side of the tablet.

20 mg/5 mg/8 mg

Light yellow, round, slightly biconvex tablets with bevelled edges, film-coated, with engraved marking PAR5 on one side of the tablet.

20 mg/5 mg/4 mg

Light orange-pink, round, slightly biconvex tablets with bevelled edges, film-coated, with engraved marking PAR4 on one side of the tablet.

10 mg/10 mg/8 mg

Yellowish-brown, round, slightly biconvex tablets with bevelled edges, film-coated, with engraved marking PAR3 on one side of the tablet.

10 mg/5 mg/8 mg

Pale reddish-brown, round, slightly biconvex tablets with bevelled edges, film-coated, with engraved marking PAR2 on one side of the tablet.

10 mg/5 mg/4 mg

Greyish-pink, round, slightly biconvex tablets with bevelled edges, film-coated, with engraved marking PAR1 on one side of the tablet.

Pharmacotherapeutic group. Lipid-regulating combination agents. HMG-CoA reductase inhibitors, other combinations. Rosuvastatin, amlodipine and perindopril. ATC code C10BX14.

Pharmacological properties.

Roxampex is a combination of tert-butylamine salt of perindopril — an angiotensin-converting enzyme (ACE) inhibitor, amlodipine — a calcium channel blocker, and rosuvastatin — a selective and competitive inhibitor of HMG-CoA reductase. The pharmacological properties are determined by the characteristics of each component administered separately.

Mechanism of action

Related to 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 cholesterol precursor. 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 inhibits hepatic synthesis of very-low-density lipoproteins (VLDL), thereby reducing the total number of VLDL and LDL particles.

Related to perindopril

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

Inhibition of ACE by perindopril leads to:

• reduced aldosterone secretion;
• increased plasma renin activity due to loss of negative feedback by aldosterone;
• reduced total peripheral resistance, primarily affecting vascular beds 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 cardiac workload:

• through vasodilatory effects on veins, likely due to changes in prostaglandin metabolism: reduction in preload;
• by decreasing total peripheral vascular resistance: reduction in afterload.

Studies in patients with heart failure have shown:

• reduced filling pressures in the left and right ventricles;
• reduced total peripheral vascular resistance;
• increased cardiac output and improved cardiac index;
• increased regional blood flow in muscles.

Additionally, physical exercise test parameters significantly improve.

Related to amlodipine

Amlodipine is a calcium ion influx inhibitor belonging to the dihydropyridine group (a slow calcium channel blocker or calcium ion blocker), which blocks calcium ion entry through membranes into smooth muscle cells of the myocardium and blood vessels.

The antihypertensive mechanism of amlodipine is due to its direct effect on vascular smooth muscles.

Pharmacodynamics.

Perindopril

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

In patients responding to treatment, normalization of blood pressure occurs within a month and is maintained without tachyphylaxis development.

Discontinuation of therapy does not lead to rebound hypertension.

Perindopril exhibits vasodilatory properties, restores elasticity of large arteries, corrects histomorphometric changes in arterial resistance, and reduces left ventricular hypertrophy. When a thiazide diuretic is added as needed, an additional synergistic effect occurs.

Combining an ACE inhibitor with a thiazide diuretic reduces the risk of hypokalemia, which may occur when using a diuretic 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 evaluated in two large-scale randomized (randomly assigned), controlled trials [ONTARGET (ONgoing Telmisartan Alone and Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)].

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

The studies did not demonstrate significant beneficial effects on patients with kidney and/or cardiovascular diseases or on mortality from these conditions, while an increased risk of hyperkalemia, acute kidney injury, and/or hypotension was observed compared to monotherapy. Due to the similarity in 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 on Type 2 Diabetes to Assess Cardiovascular and Renal Outcomes) was a trial assessing 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 and cardiovascular disease. The trial was prematurely terminated due to an increased risk of adverse outcomes. Cardiovascular mortality, stroke incidence, 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.

Amlodipine

The antihypertensive mechanism of the drug is due to its relaxing effect on vascular smooth muscles. The exact mechanism of amlodipine in angina is not fully established, but it is known that amlodipine reduces myocardial ischemia through two pathways:

• dilation of peripheral arterioles and reduction in total peripheral resistance (afterload), against which the heart must work. Since heart rate does not change, reduced cardiac workload leads to decreased energy expenditure and oxygen demand;
• likely dilation of major coronary arteries and coronary arterioles in both normal and ischemic myocardial zones. This increases oxygen delivery to the myocardium in patients with coronary artery spasm (Prinzmetal's angina, or variant angina). In patients with arterial hypertension, once-daily dosing provides clinically significant blood pressure reduction (both in standing and supine positions) throughout the 24-hour interval. Due to its slow onset of action, acute arterial hypotension is not typical with amlodipine administration.

In patients with angina, once-daily amlodipine increases total exercise duration, prolongs time to onset of angina and ST-segment depression by 1 mm, and reduces the frequency of angina attacks and nitroglycerin (glyceryl trinitrate) use.

Amlodipine is not associated with adverse metabolic effects or changes in plasma lipid parameters, making it suitable for patients with asthma, diabetes, and gout.

Use in patients with ischemic heart disease (IHD)

The efficacy of amlodipine in preventing clinical manifestations in patients with IHD was evaluated in an independent, multicenter, randomized, double-blind, placebo-controlled trial involving 1997 patients, "Comparison of Amlodipine versus Enalapril for Reduction of Events" (CAMELOT). Of these, 663 patients received amlodipine 5–10 mg, 673 patients received enalapril 10–20 mg, and 655 patients received placebo in addition to standard therapy with statins, beta-blockers, diuretics, and acetylsalicylic acid for 2 years. Efficacy results show that amlodipine treatment was associated with fewer hospitalizations for angina and revascularization procedures in patients with IHD.

Patients with heart failure

Hemodynamic studies and exercise-based controlled clinical trials in patients with NYHA functional class II–IV heart failure showed that amlodipine did not cause clinical worsening, as assessed by exercise tolerance, left ventricular ejection fraction, and clinical symptoms.

In a placebo-controlled trial (PRAISE) involving patients with heart failure (NYHA class III–IV) receiving digoxin, diuretics, and ACE inhibitors, amlodipine did not increase the risk of fatal outcomes or the combined risk of mortality and morbidity in patients with heart failure.

In a prospective, long-term, placebo-controlled trial (PRAISE-2) involving patients with heart failure (NYHA class III and IV) without clinical symptoms or objective evidence of ischemic heart disease, treated with ACE inhibitors, digitalis agents, and diuretics at constant doses, amlodipine did not affect overall mortality or cardiovascular mortality specifically. In this same population, amlodipine was associated with an increased incidence of pulmonary edema.

Clinical trial for myocardial infarction prevention (ALLHAT)

A randomized, double-blind, clinical trial on morbidity and mortality, "Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial" (ALLHAT), compared newer treatment methods: amlodipine 2.5–10 mg/day (calcium channel blocker) or lisinopril 10–40 mg/day (ACE inhibitor) as first-line therapy versus treatment with the thiazide diuretic chlorthalidone 12.5–25 mg/day in mild to moderate hypertension.

A total of 33,357 hypertensive patients aged 55 years and older were randomized and followed for a mean of 4.9 years. Patients had at least one additional risk factor for ischemic heart disease, including myocardial infarction or stroke (>6 months before enrollment) or confirmed other atherosclerotic cardiovascular diseases (CVD) (overall 51.5%), type 2 diabetes (36.1%), high-density lipoprotein cholesterol (HDL-C) <35 mg/dL or <0.906 mmol/L (11.6%), left ventricular hypertrophy diagnosed by electrocardiography or echocardiography (20.9%), or smoking (21.9%).

The primary endpoint was fatal ischemic heart disease or non-fatal myocardial infarction. The primary endpoint did not differ significantly between amlodipine- and chlorthalidone-based therapies: relative risk (RR) 0.98, 95% CI (0.90–1.07), p = 0.65. Among secondary endpoints, the incidence of heart failure (part of a composite cardiovascular endpoint) was significantly higher in the amlodipine group compared to the chlorthalidone group (10.2% vs. 7.7%, RR 1.38, 95% CI (1.25–1.52), p < 0.001). However, there was no significant difference between amlodipine and chlorthalidone in treatment for any cause of death: RR 0.96, 95% CI (0.89–1.02), p = 0.20.

Rosuvastatin

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

Therapeutic effects are achieved within 1 week of starting treatment, and 90% of the maximum effect is reached within 2 weeks. Maximum effect is typically achieved by 4 weeks and maintained throughout 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.

Pooled phase III data showed rosuvastatin's effectiveness in treating most patients with type IIa and IIb hypercholesterolemia (mean baseline LDL-C >4.8 mmol/L) according to target values recognized by the European Atherosclerosis Society (EAS; 1998): over 80% of patients receiving 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 of 20–80 mg with intensive titration. All doses had positive 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 LDL-C reduction reached 22%.

In clinical trials with limited patient numbers, rosuvastatin showed additive effects in reducing triglyceride levels when used in combination with fenofibrate and increasing HDL-C levels when used with niacin (see section "Special precautions").

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

In the JUPITER trial, 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 to receive placebo (n = 8,901) or rosuvastatin 20 mg daily (n = 8,901) 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 analysis of a subgroup of patients with high Framingham risk score >20% (1,558 participants), rosuvastatin treatment significantly reduced the composite endpoint including cardiovascular death, stroke, or myocardial infarction (p = 0.028). Absolute reduction in complication rate was 8.8 per 1,000 patient-years. In this high-risk group (p = 0.193), overall mortality rate did not change. In a subsequent analysis of a subgroup (n = 9,302) with high SCORE risk ≥5% (extrapolated to include individuals over 65 years), a significant reduction in the composite endpoint including cardiovascular death, stroke, and myocardial infarction (p = 0.0003) was observed with rosuvastatin versus placebo. Absolute reduction in complication rate was 5.1 per 1,000 patient-years. Overall mortality did not change in this high-risk group (p = 0.076).

In the JUPITER trial, the number 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 were: myalgia (0.3% in rosuvastatin group, 0.2% in placebo group), abdominal pain (0.03% in rosuvastatin group, 0.02% in placebo group), and rash (0.02% in rosuvastatin group, 0.03% in placebo group). The most common adverse reactions reported more frequently or equally compared to placebo were: urinary tract infection (8.7% in rosuvastatin group, 8.6% in placebo group), nasopharyngitis (7.6% in rosuvastatin group, 7.2% in placebo group), back pain (7.6% in rosuvastatin group, 6.9% in placebo group), and myalgia (7.6% in rosuvastatin group, 6.6% in placebo group).

Pharmacokinetics.

Rosuvastatin

Absorption

Maximum plasma concentration of rosuvastatin is 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. About 90% of rosuvastatin is bound to plasma proteins, primarily to albumin.

Biological transformation

Rosuvastatin undergoes limited metabolism (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 retains over 90% of its HMG-CoA reductase inhibitory activity in 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. About 5% is excreted unchanged in urine. The plasma elimination half-life is approximately 20 hours. The half-life does not increase with higher doses. 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 hepatic elimination of rosuvastatin.

Linearity/non-linearity

Systemic exposure to rosuvastatin increases proportionally with dose. There is no change in pharmacokinetic parameters after repeated daily administration.

Age and sex

Age and sex do not significantly affect rosuvastatin pharmacokinetics in adults. Rosuvastatin pharmacokinetics in children and adolescents with heterozygous familial hypercholesterolemia are similar to or lower than in adult volunteers (see section "Pediatric population" below).

Race

Pharmacokinetic studies show approximately a 2-fold increase in AUC and Cmax of rosuvastatin in Asian patients (Japanese, Chinese, Filipino, Vietnamese, and Korean) compared to Caucasian patients; in Indians, mean AUC and Cmax values are increased by approximately 1.3-fold. Pharmacokinetic analysis of patient groups did not reveal any clinically significant differences in pharmacokinetics between Caucasian and African populations.

Renal impairment

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

Hepatic impairment

In studies involving patients with varying degrees of hepatic impairment, no evidence of increased rosuvastatin exposure was observed in patients with Child-Pugh scores of 7 or less. However, systemic exposure was increased at least 2-fold 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 higher rosuvastatin exposure (AUC) compared to SLCO1B1 c.521TT or ABCG2 c.421CC genotypes. These genotypes are not routinely established in clinical practice, but lower daily doses of rosuvastatin are recommended for patients with these polymorphisms.

Perindopril

Absorption

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

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 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 elimination half-life of the unbound fraction is approximately 17 hours, achieving steady state within 4 days.

Linearity/non-linearity

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

Elderly patients

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

Renal impairment

Dose adjustment of perindopril is recommended depending on the degree of renal impairment (creatinine clearance).

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

Hepatic impairment

In liver cirrhosis, perindopril kinetics are altered, with hepatic clearance of the parent molecule halved, but the amount of formed perindoprilat unchanged; therefore, dose adjustment is not required (see sections "Dosage and administration" and "Special precautions").

Amlodipine

Absorption

After oral administration of therapeutic doses, amlodipine is well absorbed, with maximum plasma concentration reached in 6–12 hours. Absolute bioavailability is 64–80%.

Amlodipine bioavailability is not affected by food intake.

Distribution

The volume of distribution is approximately 21 L/kg. In vitro studies have shown that about 97.5% of amlodipine circulating in systemic blood is bound to plasma proteins.

Biological transformation

Amlodipine is extensively metabolized in the liver to inactive metabolites, with 10% of the parent compound and 60% of metabolites excreted in urine.

Elimination

The terminal plasma elimination half-life is 35–50 hours, consistent with once-daily dosing.

Hepatic impairment

Very limited clinical data are available on amlodipine use in patients with hepatic impairment. In patients with liver insufficiency, reduced amlodipine clearance leads to prolonged half-life and increased AUC by approximately 40–60%.

Elderly patients

Time to peak plasma concentrations of amlodipine is similar in young and elderly patients. Amlodipine clearance tends to decrease in elderly individuals, resulting in increased AUC and prolonged half-life. Increased AUC and prolonged half-life in patients with congestive heart failure were within expected ranges for this age group.

Pharmacokinetic/pharmacodynamic interaction

Concomitant administration of perindopril with rosuvastatin resulted in a slight reduction (approximately 10%) in peak concentrations of perindopril and its active metabolite perindoprilat, which does not affect the efficacy or safety of combined perindopril and rosuvastatin use.

Concomitant administration of rosuvastatin with amlodipine resulted in a slight increase (16%) in peak concentrations of rosuvastatin, which did not affect the efficacy or safety of combined rosuvastatin and amlodipine use.

Clinical characteristics.

Indications.

Roxampex is indicated for adult patients whose condition is adequately controlled by concomitant administration of monotherapy with rosuvastatin, amlodipine, and perindopril, or with rosuvastatin as a monotherapy and perindopril plus amlodipine as a fixed-dose combination in doses equivalent to those in the fixed combination, for the treatment of hypertension accompanied by one of the following conditions:

• Primary hypercholesterolemia (type IIa, including heterozygous familial hypercholesterolemia) or mixed dyslipidemia (type IIb) – as an adjunct to diet when response to diet and other non-pharmacological treatments (e.g., physical exercise, weight reduction) is inadequate;
• Homozygous familial hypercholesterolemia – as an adjunct to diet and other lipid-lowering therapies (e.g., LDL apheresis), or when such treatments are unsuitable.

Contraindications.

• Hypersensitivity to the active substances, other ACE inhibitors, dihydropyridine derivatives, or to any excipient of the medicinal product.
• Severe hepatic impairment. Active liver disease, including of unknown etiology, persistent elevation of serum transaminases, and elevation of any serum transaminase level by more than 3 times the upper limit of normal.
• Severe renal impairment (creatinine clearance < 30 mL/min).
• Myopathy.
• Concomitant use with sofosbuvir/velpatasvir/voxilaprevir (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use of cyclosporine.
• Pregnancy and breastfeeding. The drug is contraindicated in women of childbearing potential who are not using appropriate contraceptive measures.
• History of angioedema (Quincke's edema) associated with previous treatment with ACE inhibitors.
• Hereditary or idiopathic angioedema.
• Concomitant use with medicinal products containing the active substance aliskiren in patients with diabetes mellitus or renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²) (see sections "Pharmacodynamics" and "Interaction with other medicinal products and other forms of interaction").
• 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 solitary functioning kidney (see section "Special precautions").
• Concomitant use with sacubitril/valsartan. Therapy with the drug 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").
• Severe arterial hypotension.
• Shock (including cardiogenic).
• Obstruction of the left ventricular outflow tract (e.g., severe aortic stenosis).
• Hemodynamically unstable heart failure following acute myocardial infarction.

Interaction with other medicinal products and other forms of interaction.

Interactions related to rosuvastatin

Effect of concomitantly administered drugs on rosuvastatin

Transport protein inhibitors

Rosuvastatin is a substrate for certain transport proteins, including OATP1B1, which mediates hepatic uptake, and the efflux transporter BCRP. Concomitant administration of rosuvastatin with medicinal products that are inhibitors of these transport proteins may increase plasma concentrations of rosuvastatin and increase the risk of myopathy.

Cyclosporine

When rosuvastatin is co-administered 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 combination drug containing two protease inhibitors (300 mg atazanavir / 100 mg ritonavir) in healthy volunteers resulted in increases in rosuvastatin AUC and Cmax by approximately 3 and 7 times, respectively. Concomitant use of rosuvastatin and certain protease inhibitor combinations may be possible after careful 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 results from specific studies, no significant pharmacokinetic interaction with fenofibrate is expected; however, 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" and "Special precautions"). Therapy should be initiated with a 5 mg dose of rosuvastatin.

Ezetimibe

Concomitant administration of 10 mg rosuvastatin and 10 mg ezetimibe to patients with hypercholesterolemia resulted in a 1.2-fold increase in rosuvastatin AUC (Table 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 was minimized when the antacid was 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

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

Tickagrelor

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

Interactions requiring rosuvastatin dose adjustment (see Table 1)

If rosuvastatin must be used concomitantly with other medicinal products that increase its exposure, rosuvastatin doses 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 once daily. The maximum daily dose of rosuvastatin should be adjusted so that its expected concentration does not exceed that achieved with a 40 mg daily dose of rosuvastatin in the absence of interacting drugs. For example, a 20 mg dose of rosuvastatin when used concomitantly with gemfibrozil (1.9-fold increase in exposure) or a 10 mg dose of rosuvastatin with atazanavir/ritonavir combination (3.1-fold increase in exposure). If the increase in AUC is less than 2-fold, no initial dose reduction is required, 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 of magnitude) based on published data from clinical studies

Increased rosuvastatin AUC by 2 times or more than 2 times
Dosing regimen of the interacting drug	Rosuvastatin dosing regimen	Changes in rosuvastatin AUC*
Sofosbuvir/velpatasvir/voxilaprevir (400 mg/100 mg/100 mg) + voxilaprevir (100 mg) once daily for 15 days	10 mg, single dose	↑ 7.4-fold
Cyclosporine 75–200 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
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
Paritaprevir 150 mg/ritonavir 100 mg/ombitasvir 25 mg once daily and 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 loading dose, followed by 75 mg for 24 hours	20 mg, single dose	↑ 2-fold
Tafamidis 61 mg twice daily on days 1 and 2, then 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
Increased rosuvastatin AUC less than 2-fold
Dosing regimen of the interacting drug	Rosuvastatin dosing regimen	Changes in rosuvastatin AUC*
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 **
Decreased rosuvastatin AUC
Dosing regimen of the interacting drug	Rosuvastatin dosing regimen	Changes in rosuvastatin AUC*
Erythromycin 500 mg four times daily, 7 days	80 mg, single dose	↓ 20%
Baicalin 50 mg three times daily, 14 days	20 mg, single dose	↓ 47%

* Data presented as changes in x times represent the ratio between co-administration and administration of rosuvastatin alone. Data presented as % change represent the % difference relative to values observed with rosuvastatin administered alone.

Increases are indicated by ↑, no changes by ↔, and decreases by ↓.

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

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

Effect of rosuvastatin on concurrently administered medicinal products

Vitamin K antagonists

At the initiation or during dose titration of rosuvastatin in patients concurrently taking vitamin K antagonists (e.g., warfarin or other coumarin anticoagulants), the international normalized ratio (INR) may increase. After discontinuation or dose reduction of rosuvastatin, the INR may decrease. In such cases, appropriate monitoring of INR is advisable.

Oral contraceptives/hormone replacement therapy (HRT)

Concomitant administration of rosuvastatin and oral contraceptives resulted in a 26% and 34% increase in AUC of ethinylestradiol and norgestrel, respectively. The increase in plasma levels should be considered when selecting the dose of oral contraceptives. There are no data on the pharmacokinetics of drugs in patients concurrently taking rosuvastatin and HRT; therefore, interaction cannot be excluded. However, this combination has been widely used in women in clinical trials and was well tolerated.

Digoxin

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

Fusidic acid

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

Interactions related to perindopril

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

Medicinal products causing hyperkalemia

Some medicinal products or therapeutic classes of medicinal products may cause hyperkalemia: aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor blockers, NSAIDs, heparins, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim, co-trimoxazole (trimethoprim/sulfamethoxazole). Concomitant use of these medicinal products increases the risk of hyperkalemia.

Concomitant use is contraindicated (see section "Contraindications")

Aliskiren: in patients with diabetes mellitus or patients with impaired renal function, the risk of hyperkalemia, worsening renal function, and cardiovascular morbidity and mortality is increased.

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

Sacubitril/valsartan

Concomitant use of perindopril with sacubitril/valsartan is contraindicated, as concomitant administration of ACE inhibitors and sacubitril/valsartan increases the risk of angioedema. Sacubitril/valsartan should not be initiated earlier than 36 hours after the last dose of perindopril. Perindopril therapy should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Special precautions for use").

Concomitant use not recommended (see section "Special precautions for use")

Aliskiren: in any other patients, as in patients with diabetes mellitus or impaired renal function, the risk of hyperkalemia, worsening renal function, and cardiovascular morbidity and mortality is increased.

Concomitant use of ACE inhibitors and angiotensin II receptor blockers

Published data indicate that in patients with atherosclerosis, heart failure, or diabetes mellitus with target organ damage, concomitant use of ACE inhibitors and angiotensin II receptor blockers is associated with an increased incidence of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to monotherapy with agents affecting the RAAS. Dual blockade (i.e., combination of an ACE inhibitor with angiotensin II receptor blockers) may be used in individual cases with careful monitoring of renal function, potassium levels, and blood pressure.

Estramustine

The risk of adverse reactions such as angioedema (angioneurotic edema) increases.

Co-trimoxazole (trimethoprim/sulfamethoxazole)

In patients concurrently taking co-trimoxazole (trimethoprim/sulfamethoxazole), the risk of developing hyperkalemia increases (see section "Special precautions for use").

Potassium-sparing diuretics (e.g., triamterene, amiloride, alone or in combination), potassium supplements, or potassium-containing salt substitutes

Although serum potassium levels usually remain within normal limits, hyperkalemia (potentially fatal) may occur in some patients receiving perindopril, especially when associated with impaired renal function (additive hyperkalemic effects).

Potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to a significant increase in serum potassium. Concomitant administration of perindopril with other medicinal products that increase serum potassium levels, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), should be used with caution, as trimethoprim is known to act as a potassium-sparing diuretic similar to amiloride. Combination of perindopril with the above-mentioned medicinal products is not recommended (see section "Special precautions for use"). However, if concomitant use is indicated, they should be used with caution and serum potassium and creatinine levels should be closely monitored. Information on the use of spironolactone in heart failure is provided below.

Lithium

When lithium is used concomitantly with ACE inhibitors, reversible increases in serum lithium concentration and signs of toxicity have been observed. Concomitant use of perindopril with lithium is not recommended, but if combination therapy is necessary, careful monitoring of serum lithium levels is required (see section "Special precautions for use").

Concomitant use requiring special caution

Antidiabetic agents (insulin, oral antidiabetic agents)

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

Baclofen

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

Non-potassium-sparing diuretics

In patients taking diuretics, and particularly in those with impaired water-electrolyte balance, excessive reduction in blood pressure may occur after initiation of ACE inhibitor therapy. The likelihood of developing hypotensive effects can be reduced by discontinuing the diuretic, increasing circulating blood volume, or salt intake prior to 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 (in such cases, diuretic therapy may be resumed later) or the ACE inhibitor should be initiated at a low dose with gradual dose escalation.

In congestive heart failure on background 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 daily) is used concomitantly with low doses of ACE inhibitors in patients with NYHA class II–IV heart failure and ejection fraction < 40%, who have previously received 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 therapy, absence of hyperkalemia and impaired renal function should be confirmed. Careful monitoring of serum potassium and creatinine is recommended weekly during the first month of treatment and monthly thereafter.

Non-steroidal anti-inflammatory drugs (NSAIDs) (including high-dose acetylsalicylic acid ≥ 3 g/day)

NSAIDs (including acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, and non-selective 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. This combination should be used with caution, particularly in elderly patients. Patients should be adequately hydrated, and monitoring of renal function after initiation of concomitant therapy and periodic follow-up should be considered.

Medicinal products increasing the risk of angioedema

Racecadotril

ACE inhibitors (e.g., perindopril) are known to cause angioedema. This risk increases when used concomitantly with racecadotril (a medicinal product used for the treatment of acute diarrhea).

mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus)

In patients receiving mTOR inhibitors concomitantly, the risk of angioedema increases (see section "Special precautions for use").

Concomitant use requiring caution

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.

Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin)

In patients receiving a combination of a gliptin and an ACE inhibitor, the risk of developing angioedema increases due to the gliptin's inhibition of dipeptidyl peptidase-IV (DPP-IV) activity.

Tricyclic antidepressants/antipsychotics/anesthetics

Concomitant use of certain anesthetics, tricyclic antidepressants, or antipsychotics with ACE inhibitors may lead to further reduction in blood pressure (see section "Special precautions for use").

Sympathomimetics may attenuate the antihypertensive effect of ACE inhibitors.

Gold compounds

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

Cyclosporine

Hyperkalemia may occur when ACE inhibitors are used concomitantly with cyclosporine. Monitoring of serum potassium levels is recommended.

Heparin

Hyperkalemia may occur when ACE inhibitors are used concomitantly with heparin. Monitoring of serum potassium levels is recommended.

Interactions related to amlodipine

Effect of other medicinal products on amlodipine

CYP3A4 inhibitors

Concomitant administration of amlodipine and strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil, or diltiazem) may lead to a significant increase in amlodipine exposure, increasing the risk of arterial hypotension. The clinical significance of these changes may be more pronounced in elderly patients. Clinical monitoring and dose adjustment may be necessary.

CYP3A4 inducers

Plasma concentrations of amlodipine may change when co-administered with known CYP3A4 inducers. Therefore, blood pressure should be monitored and dose adjusted during and after concomitant use, especially when using potent CYP3A4 inducers (e.g., rifampicin, St. John's wort (Hypericum perforatum)).

Dantrolene (infusions)

In animal studies, ventricular fibrillation with fatal outcome and cardiovascular collapse were observed following co-administration of verapamil with intravenous dantrolene. Due to the risk of hyperkalemia, use of calcium channel blockers such as amlodipine should be avoided in patients susceptible to malignant hyperthermia and during treatment of malignant hyperthermia.

Effect of amlodipine on other medicinal products

The hypotensive effect of amlodipine potentiates the hypotensive effect of other antihypertensive agents.

Tacrolimus

There is a risk of increased blood levels of tacrolimus when used concomitantly with amlodipine, although the pharmacokinetic mechanism of this interaction is not fully established. To avoid tacrolimus toxicity, regular monitoring of blood tacrolimus levels is required when used concomitantly with amlodipine, and dose adjustment may be necessary.

mTOR inhibitors (mammalian target of rapamycin)

mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. Amlodipine may increase the effects of mTOR inhibitors when used concomitantly.

Cyclosporine

Interaction studies between cyclosporine and amlodipine have not been conducted in healthy volunteers or other patient groups, except in kidney transplant recipients, in whom variable increases in cyclosporine trough concentrations (on average 0–40%) were observed. In kidney transplant recipients receiving amlodipine, cyclosporine concentrations should be monitored and the dose reduced if necessary.

Simvastatin

Concomitant administration of multiple doses of amlodipine 10 mg and simvastatin 80 mg resulted in a 77% increase in simvastatin exposure compared to simvastatin alone. For patients receiving amlodipine, the dose of simvastatin should be limited to 20 mg daily.

Clinical interaction studies have shown that amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin, or warfarin.

Children

The extent of interaction in children is unknown.

Special precautions for use.

Stable ischemic heart disease

If an episode of unstable angina (severe or not) occurs within the first month of treatment with perindopril, the benefit/risk ratio should be carefully evaluated before continuing treatment.

Arterial hypotension

ACE inhibitors may cause a reduction in blood pressure. Symptomatic hypotension is rare in patients with uncomplicated hypertension and occurs more frequently in patients with reduced circulating blood volume, e.g., due to diuretic therapy, salt restriction, dialysis, diarrhea or vomiting, or in patients with severe renovascular hypertension (see sections "Interaction with other medicinal products and other forms of interaction" and "Undesirable effects"). Symptomatic hypotension has been observed in patients with symptomatic heart failure with or without renal impairment. The greatest likelihood of symptomatic hypotension occurs in patients with more severe degrees of heart failure, manifested by the use of high doses of loop diuretics, hyponatremia, or functional renal impairment. Patients at increased risk of symptomatic hypotension should be closely monitored at the beginning of therapy and during subsequent dose adjustments (see sections "Posology and method of administration" and "Undesirable effects"). Similar precautionary measures should be taken when treating patients with ischemic heart disease or cerebrovascular disease, where excessive reduction in blood pressure may lead to myocardial infarction or stroke.

In the event of significant arterial hypotension, the patient should be placed in a supine position and, if necessary, given an intravenous infusion of sodium chloride 9 mg/ml (0.9%) solution. Transient arterial hypotension is not a contraindication for further administration of the drug. After restoration of circulating blood volume and normalization of blood pressure, treatment may be resumed.

In some patients with congestive heart failure who have normal or low blood pressure, further reduction in systemic arterial pressure may occur during perindopril therapy.

Such a response to drug administration is expected and usually not a reason to discontinue treatment. If arterial hypotension becomes symptomatic, dose reduction or discontinuation of perindopril may be required.

Patients with heart failure

Patients with heart failure should be treated with caution. In a long-term placebo-controlled study involving patients with severe heart failure (NYHA classes III and IV), the incidence of pulmonary edema was higher in the amlodipine group than in the placebo group (see section "Pharmacodynamics"). Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as these drugs may increase the risk of future cardiovascular complications and mortality.

Stenosis of aortic or mitral valve/hypertrophic cardiomyopathy

As with other ACE inhibitors, perindopril should be used with caution in patients with mitral valve stenosis and left ventricular outflow tract obstruction, such as aortic stenosis or hypertrophic cardiomyopathy.

Renal impairment

In case of renal impairment (creatinine clearance < 60 ml/min), the initial dose of perindopril should be adjusted according to the patient's creatinine clearance (see section "Posology and method of administration"), and then according to the patient's response to treatment. Regular monitoring of potassium and creatinine levels is part of standard medical practice for such patients (see section "Undesirable effects").

In patients with symptomatic heart failure, hypotension after initiation of ACE inhibitor therapy may lead to further worsening of renal function. In such situations, acute renal impairment, usually reversible, has been reported.

In some patients with bilateral renal artery stenosis or stenosis of the artery of a solitary kidney treated with ACE inhibitors, increases in serum urea and creatinine have been observed, usually reversible after discontinuation of treatment. This is particularly likely in patients with pre-existing renal impairment. There is also an increased risk of severe hypotension and renal failure in renovascular hypertension. Such patients should start therapy under close medical supervision with low doses and careful dose titration. Since diuretic therapy may be a contributing factor to the above, its use should be discontinued and renal function monitored during the first weeks of perindopril treatment.

In some patients with arterial hypertension without underlying renal vascular disease, increases in serum urea and creatinine have been observed, usually mild and transient, particularly when perindopril is used concomitantly with diuretics. This is more likely in patients with pre-existing renal impairment. In such cases, dose reduction and/or discontinuation of the diuretic and/or perindopril may be required.

Amlodipine can be administered to such patients at usual doses. Changes in amlodipine plasma concentrations are not related to the degree of renal impairment. Amlodipine is not removed during hemodialysis.

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 without other risk factors during ACE inhibitor therapy.

Perindopril should be used with particular caution in treating patients with collagenoses, during immunosuppressive therapy, allopurinol, procainamide, or in combination with these risk factors, especially if renal impairment is present. Some of these patients developed serious infections, which in several cases were unresponsive to intensive antibiotic therapy. Periodic monitoring of white blood cell count is recommended if perindopril is used in such patients. Patients should also be informed that they must report any signs of infection (sore throat, fever).

Hypersensitivity/angioedema

Rare cases of angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and/or larynx have been reported at any time during treatment with ACE inhibitors, including perindopril (see section "Undesirable effects"). Such cases may occur at any time during treatment.

In such cases, perindopril must be discontinued immediately and careful monitoring and treatment initiated until symptoms completely resolve. In cases of facial and lip swelling, the condition may improve without treatment, but antihistamines may relieve symptoms.

Laryngeal angioedema may be fatal. In cases of tongue, glottis or larynx swelling, airway obstruction is likely, and emergency treatment is required, which may include administration of adrenaline solution and/or measures to secure the airway. Patients must remain under close medical supervision until symptoms completely resolve.

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 during treatment with ACE inhibitors. These patients experienced abdominal pain (with or without nausea or vomiting); in some cases, there was no prior history of facial angioedema and C-1 esterase levels were normal. Diagnosis of intestinal angioedema was established by abdominal computed tomography or ultrasound, or during surgical intervention. Symptoms of angioedema resolved after discontinuation of the ACE inhibitor. Intestinal angioedema should be considered in the differential diagnosis of patients with abdominal pain who are taking 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 treatment with sacubitril/valsartan 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 racecadotril, mTOR inhibitors (such as sirolimus, everolimus, temsirolimus) and vildagliptin increases the risk of angioedema (including airway or tongue swelling, with or without respiratory distress) (see section "Interaction with other medicinal products and other forms of interaction").

Caution is required when initiating racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus) or vildagliptin in patients already receiving an ACE inhibitor.

Anaphylactoid reactions during desensitization

Isolated cases of anaphylactoid reactions have been observed in patients receiving ACE inhibitors during desensitization procedures (e.g., to insect venom). ACE inhibitors should be used with caution in patients with allergies undergoing desensitization and avoided in patients undergoing immunotherapy with venom. However, these reactions can be prevented by temporarily discontinuing the ACE inhibitor for at least 24 hours before therapy in patients requiring both ACE inhibitors and desensitization.

Anaphylactoid reactions during low-density lipoprotein apheresis

Rarely, life-threatening anaphylactoid reactions occur in patients taking ACE inhibitors during LDL apheresis with dextran sulfate. Such reactions were resolved by temporarily discontinuing ACE inhibitors before each plasmapheresis.

Patients undergoing hemodialysis

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

Kidney transplantation

Experience with perindopril in patients after recent kidney transplantation is lacking.

Serum potassium

ACE inhibitors may cause hyperkalemia as they suppress aldosterone release. In patients with normal renal function, the effect is usually mild. Risk factors for hyperkalemia include renal impairment, worsening 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 salt substitutes, or other drugs causing increased serum potassium (e.g., heparin, co-trimoxazole, also known as trimethoprim/sulfamethoxazole). Use of potassium-containing dietary supplements, potassium-sparing diuretics or potassium salt substitutes, especially in patients with renal impairment, may lead to significant increases in serum potassium. Hyperkalemia may cause serious, sometimes fatal, arrhythmias. If concomitant use of perindopril and any of the above substances is considered appropriate, they should be used with caution and with frequent monitoring of serum potassium and renal function (see section "Interaction with other medicinal products and other forms of interaction").

Pregnancy and breastfeeding

Roxampex is contraindicated during pregnancy and breastfeeding as it contains the active substance rosuvastatin. ACE inhibitors should not be prescribed during pregnancy. If pregnancy is planned during ACE inhibitor therapy, they should be replaced with alternative antihypertensive agents with an established safety profile for use in pregnancy. If pregnancy is confirmed, ACE inhibitor therapy should be discontinued immediately and, if necessary, alternative therapy initiated (see sections "Contraindications" and "Use in pregnancy or breastfeeding").

Cough

Dry cough has been reported during ACE inhibitor therapy. The cough is usually non-productive, persistent, and resolves after discontinuation of treatment. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Interstitial lung disease

Isolated cases of interstitial lung disease have been reported with 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

Roxampex, containing an HMG-CoA reductase inhibitor, should be used with caution in patients with alcohol abuse and/or a history of liver disease.

Liver function should be checked before starting treatment and during the following 3 months. If serum transaminase levels exceed three times the upper limit of normal, rosuvastatin should be discontinued or the dose reduced. In the post-marketing period, the frequency of reports of serious renal impairment (mainly elevated liver transaminase levels) was higher with the 40 mg dose.

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

Rarely, ACE inhibitors have been associated with a syndrome beginning with cholestatic jaundice and progressing to spontaneous hepatic necrosis and (sometimes) fatal outcome. The mechanism of this syndrome is unknown. Patients receiving ACE inhibitors who develop jaundice or elevated liver enzymes should discontinue the inhibitor and undergo appropriate medical evaluation (see section "Undesirable effects").

In hepatic impairment, the elimination half-life of amlodipine is prolonged and AUC values increased. Dose recommendations for such patients are not established. Therefore, amlodipine therapy should be initiated at the lowest dose and used with caution both at the beginning of treatment and during dose escalation. Patients with severe hepatic impairment require slow dose escalation and careful medical supervision.

Patients with diabetes mellitus

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

Patients with diabetes mellitus receiving oral antidiabetic agents or insulin should have blood glucose levels closely monitored during the first months of ACE inhibitor therapy.

Some data suggest that statins as a class may increase blood glucose levels, and in some patients at high risk of developing diabetes mellitus, hyperglycemia may occur requiring formal diabetes management. However, the benefit of cardiovascular risk reduction with statins outweighs this risk, so it should not be a reason to discontinue statin therapy. Patients at risk of developing diabetes mellitus (fasting glucose 5.6–6.9 mmol/L, body mass index (BMI) > 30 kg/m², elevated triglycerides, hypertension) should have both chemical and biochemical parameters checked according to national guidelines.

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

Ethnic characteristics

Pharmacokinetic studies have shown increased effects of rosuvastatin in Asian patients compared to Caucasian patients (see sections "Pharmacokinetics", "Contraindications" and "Posology and method of administration").

The risk of angioedema with ACE inhibitor use is higher in black patients than in others.

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

Surgery/anesthesia

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

Therefore, it is recommended that treatment with long-acting ACE inhibitors such as perindopril be discontinued, if possible, one day before surgery. If arterial hypotension occurs due to this mechanism, it can be corrected by increasing blood volume.

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. Rhabdomyolysis has been very rarely reported with ezetimibe when 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, rhabdomyolysis associated with rosuvastatin has occurred more frequently in the post-marketing period at the 40 mg dose.

Several cases have been reported where statins caused or exacerbated pre-existing myasthenia gravis or ocular myasthenia (see section "Undesirable effects"). If symptoms worsen, treatment should be discontinued. Recurrences have been reported upon (re)initiation of the same or another statin.

Creatine kinase (CK) measurement

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

Before treatment

Rosuvastatin, like other HMG-CoA reductase inhibitors, should be used with caution in patients with factors predisposing to myopathy/rhabdomyolysis. These factors include:

• renal impairment;
• hypothyroidism;
• personal or family history of hereditary muscle disorders;
• history of myotoxicity with other HMG-CoA reductase inhibitors or fibrates;
• alcohol abuse;
• age > 70 years;
• conditions that may lead to increased plasma levels of the drug;
• concomitant use of fibrates.

In such patients, the potential risks and expected benefits of drug use should be weighed; clinical monitoring is also recommended. Treatment should not be initiated if baseline CK levels are markedly elevated (> 5 × ULN).

During treatment

Patients should be warned to report unexplained muscle pain, muscle weakness or cramps immediately, especially if accompanied by malaise or fever. CK levels should be measured in such patients. Treatment should be discontinued if CK levels are markedly elevated (> 5 × ULN) or if muscle symptoms are severe and cause discomfort in daily life (even if CK levels ≤ 5 × ULN). If symptoms resolve and CK levels return to normal, rosuvastatin or an alternative HMG-CoA reductase inhibitor may be reinitiated at the lowest doses and under close supervision. Routine CK monitoring in patients without the above symptoms is not required. Very rarely, immune-mediated necrotizing myopathy (IMNM) has 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 studies of a small number of patients receiving rosuvastatin and concomitant medications, no enhanced effect on skeletal muscle was observed. 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, niacin, 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 for use in combination with gemfibrozil. The positive 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. Concomitant use of rosuvastatin 40 mg with fibrates is contraindicated (see sections "Interaction with other medicinal products and other forms of interaction" and "Overdose").

Roxampex should not be used concomitantly with systemic fusidic acid therapy and for 7 days after discontinuation of fusidic acid. In 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) have been reported in patients receiving fusidic acid and statins in combination (see section "Interaction with other medicinal products and other forms of interaction"). Patients should seek immediate medical attention if they experience any symptoms of muscle weakness, pain or tenderness.

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

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

Rosuvastatin should not be used in patients with acute, serious conditions resembling myopathy or increasing the risk of renal failure and acute necrosis of skeletal muscles (e.g., sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, or uncontrolled seizures).

Protease inhibitors

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

Lithium

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

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

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

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

Reports indicate that concomitant use of ACE inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalemia and reduced renal function (including acute renal failure). Therefore, dual blockade of RAAS by concomitant use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is not recommended (see sections "Pharmacodynamics" 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.

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 informed of the signs and symptoms of severe skin reactions and closely monitored. If signs and symptoms suggestive of such reactions occur, the medicinal product should be discontinued immediately and alternative treatment considered.

If a patient experiences a serious reaction such as SJS or DRESS during Roxampex use, reinitiation of treatment with this medicinal product is not allowed.

Use in pregnancy or breastfeeding.

Roxampex is contraindicated during pregnancy and breastfeeding.

Pregnancy

Women of childbearing potential must use appropriate contraceptive measures.

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

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 teratogenic risk from ACE inhibitor use during the first trimester of pregnancy are inconclusive, although a small increase in risk cannot be excluded. Unless continuation of ACE inhibitor therapy is considered necessary, alternative antihypertensive therapy with an established safety profile in pregnancy should be prescribed to women planning pregnancy.

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

Effects of ACE inhibitor therapy during the second and third trimesters include fetotoxicity (reduced renal function, oligohydramnios, delayed skull ossification) 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 ossification. Newborns whose mothers used ACE inhibitors should be closely monitored for hypotension (see sections "Contraindications" and "Special precautions for use").

The safety of amlodipine use in women during pregnancy has not been established.

Reproductive toxicity was observed in animal studies at high doses.

Use during pregnancy is possible only if no safer alternative is available or if the disease itself poses a greater risk to the mother and fetus than the treatment.

Breastfeeding

Roxampex is contraindicated during breastfeeding.

Limited published data indicate the presence of rosuvastatin in human breast milk. Rosuvastatin is excreted in rat milk. Due to the mechanism of action of rosuvastatin, there is a potential risk of adverse reactions in infants.

Due to lack of available information on perindopril use, it is not recommended during breastfeeding. During breastfeeding, alternative therapy with a better-established safety profile should be preferred, especially when breastfeeding a newborn or preterm infant.

Amlodipine has been detected in human breast milk. The fraction of the maternal dose received by the infant is estimated to be in the interquartile range of 3–7%, maximum 15%. The effect of amlodipine on children is unknown. When deciding whether to continue/stop breastfeeding or continue/discontinue amlodipine therapy, the benefits of breastfeeding for the child and the benefits of amlodipine for the mother should be considered.

Fertility

No reports of effects on fertility after rosuvastatin use have been documented.

No effect of perindopril on reproductive function or fertility has been observed.

Reversible biochemical changes in sperm heads have been observed in some patients receiving calcium channel blockers. Insufficient clinical data are available on the potential effect of amlodipine on fertility. In one rat study, a negative effect on male fertility was observed.

Ability to influence reaction speed when driving or operating machinery.

Roxampex may have a negligible or moderate effect on the ability to drive or operate machinery. Dizziness may occur during treatment, which may impair the ability to drive or operate machinery.

Method of Administration and Dosage

Administer orally.

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

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

Before switching to Roxampex, patients currently receiving the same individual doses of the separate components should be monitored. The dose of Roxampex should be determined based on the doses of the individual components being used prior to switching to the fixed combination.

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

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). Roxampex is not recommended in patients with creatinine clearance ≥ 30 and < 60 mL/min. For these patients, dose titration of the individual monocomponents is recommended.

No dose adjustment is required in patients with creatinine clearance ≥ 60 mL/min.

Regular medical monitoring should include careful assessment of creatinine and potassium levels.

Hepatic Impairment

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

No dose adjustment is required in patients with moderate hepatic impairment.

In patients with hepatic impairment classified as Child-Pugh score of 7 or less, 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 "Pharmacokinetics"). Renal function should be monitored in these patients (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 compared to Caucasian patients (see sections "Pharmacokinetics", "Contraindications", and "Special Warnings and Precautions for Use").

Genetic Polymorphisms

Certain genetic polymorphisms are known to increase rosuvastatin exposure (see section "Pharmacokinetics"). Patients with any of these specific polymorphisms 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 may 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 "Interactions with Other Medicinal Products and Other Forms of Interactions" and "Special Warnings and Precautions for Use"). Alternative treatment should be considered, and temporary discontinuation of rosuvastatin therapy may be necessary. In situations where concomitant use of these medicinal products with rosuvastatin cannot be avoided, the benefits and risks of concomitant therapy should be carefully weighed, and rosuvastatin dose should be selected with caution (see section "Interactions with Other Medicinal Products and Other Forms of Interactions").

Children

Roxampex 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

Limited data are available on overdose in humans. Symptoms associated with angiotensin-converting enzyme (ACE) inhibitor overdose may include hypotension, circulatory shock, disturbances in fluid and electrolyte balance, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough.

Data on amlodipine suggest that significant overdose may lead to excessive peripheral vasodilation and reflex tachycardia. Marked and possibly prolonged systemic hypotension up to shock with fatal outcome has been reported.

Rare cases of non-cardiogenic pulmonary edema following amlodipine overdose have been reported, which may present with delayed onset (24–48 hours after ingestion) and may require mechanical ventilation. Early resuscitation measures (including fluid loading) to support perfusion and cardiac output may act as precipitating factors.

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 correction of fluid and electrolyte imbalances, are recommended in a medical setting. If pronounced hypotension develops, the patient should be placed in a supine position with the head lowered. If necessary, intravenous saline infusion or other measures to increase circulating blood volume should be administered. Liver function and creatine kinase levels should be monitored.

Perindoprilat, the active metabolite of perindopril, can be removed by dialysis (see section "Pharmacokinetics"), but hemodialysis is unlikely to be beneficial for removing rosuvastatin.

Adverse reactions.

The safety profile of perindopril corresponds to the safety profile of ACE inhibitors.

The most commonly observed adverse reactions during clinical trials and use of perindopril include dizziness, headache, paresthesia, vertigo, visual disturbances, tinnitus, arterial hypotension, cough, dyspnea, abdominal pain, constipation, diarrhea, taste disturbances (dysgeusia), dyspepsia, nausea, vomiting, pruritus, skin rashes, muscle cramps, asthenia.

Adverse reactions are classified by frequency: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), not known (isolated reports). Table 2

Body system	Adverse reactions	Frequency
		rosuvastatin	perindopril	amlodipine
Blood and lymphatic system disorders	Eosinophilia	-	Uncommon1	-
	Agranulocytosis or pancytopenia	-	Very rare	-
	Decreased hemoglobin and hematocrit	-	Very rare	-
	Leukopenia/neutropenia	-	Very rare	Very rare
	Hemolytic anemia in patients with congenital G-6PDH deficiency2	-	Very rare	-
	Thrombocytopenia	Uncommon	Very rare	Very rare
Immune system disorders	Hypersensitivity reactions, including angioedema	Uncommon	-	Very rare
Endocrine disorders	Diabetes mellitus3	Common	-	-
	Syndrome of inappropriate antidiuretic hormone secretion (SIADH)	-	Uncommon	-
Metabolism and nutrition disorders	Hypokalemia4	-	Uncommon1	-
	Hyperkalemia, reversible upon discontinuation2	-	Uncommon1	-
	Hyponatremia2	-	Uncommon1	-
	Hyperglycemia	-	-	Very rare
Psychiatric disorders	Mood disorders	-	Uncommon	Uncommon
	Sleep disorders	Unknown	Uncommon	-
	Insomnia	-	-	Uncommon
	Depression	Unknown	Uncommon	Uncommon
	Confusion	-	Very rare	Uncommon
Nervous system disorders	Dizziness	Common	Common	Common
	Headache	Common	Common	Common
	Paresthesia	-	Common	-
	Vertigo	-	Common	-
	Somnolence	-	Uncommon1	Common
	Syncope	-	Uncommon1	Uncommon
	Peripheral neuropathy	Very rare	-	-
	Peripheral neuropathy	Unknown	-	Very rare
	Sleep disturbances (including insomnia and nightmares)	Unknown	-	-
	Memory loss	Very rare	-	-
	Tremor	-	-	Uncommon
	Hypoesthesia	-	-	Uncommon
	Hypertonia	-	-	Very rare
	Myasthenia gravis	-	-	Unknown
Eye disorders	Visual disturbance	-	Common	Common
	Eye myasthenia	-	-	Unknown
Ear and labyrinth disorders	Tinnitus		Common	Uncommon
Cardiac disorders	Palpitations	-	Uncommon1	Common
	Tachycardia	-	Uncommon1	-
	Angina pectoris2	-	Very rare	-
	Arrhythmia (including bradycardia, ventricular tachycardia, and atrial fibrillation)	-	Very rare	Uncommon
	Myocardial infarction, possibly following excessive hypotension in high-risk patients2	-	Very rare	Very rare
Vascular disorders	Hypotension (and hypotension-related effects)2	-	Common	Uncommon
	Vasculitis	-	Uncommon1	Very rare
	Stroke, possibly secondary to excessive hypotension in high-risk patients2	-	Very rare	-
	Flushing	-	Uncommon	Common
	Raynaud's phenomenon	-	Unknown	-
Respiratory, thoracic and mediastinal disorders	Cough	Unknown	Common	Uncommon
	Dyspnea	Unknown	Common	Common
	Bronchospasm	-	Uncommon	-
	Eosinophilic pneumonia	-	Very rare	-
	Rhinitis	-	Very rare	Uncommon
Gastrointestinal disorders	Abdominal pain	Common	Common	Common
	Constipation	Common	Common	-
	Diarrhea	Unknown	Common	-
	Dyspepsia	-	Common	Common
	Dysgeusia	-	Common	Uncommon
	Nausea	Common	Common	Common
	Vomiting	-	Common	Uncommon
	Dry mouth	-	Uncommon	Uncommon
	Pancreatitis	Uncommon	Very rare	Very rare
	Change in defecation rhythm (including diarrhea and constipation)	-	-	Common
	Gastritis	-	-	Very rare
	Gingival hyperplasia	-	-	Very rare
Hepatobiliary disorders	Increased liver transaminases	Uncommon	-	Very rare1
	Hepatitis, either cytolytic or cholestatic2	Very rare	Very rare	Very rare
	Jaundice	Very rare	-	Very rare
Skin and subcutaneous tissue disorders	Pruritus	Uncommon	Common	Uncommon
	Rash	Uncommon	Common	Uncommon
	Urticaria2	Uncommon	Uncommon	Uncommon
	Angioedema2	-	Uncommon	Very rare
	Photosensitivity reaction	-	Uncommon1	Very rare
	Pemphigoid	-	Uncommon1	-
	Worsening of psoriasis	-	Uncommon1	-
	Hyperhidrosis	-	Uncommon	Uncommon
	Multiform erythema	-	Very rare	Very rare
	Purpura	-	-	Uncommon
	Stevens-Johnson syndrome	Unknown	-	Very rare
	Alopecia	-	-	Uncommon
	Purpura	-	-	Uncommon
	Skin discoloration	-	-	Uncommon
	Exanthema	-	-	Uncommon
	Exfoliative dermatitis	-	-	Very rare
	Quincke's edema	-	-	Very rare
	Toxic epidermal necrolysis	-	-	Unknown
	Drug reaction with eosinophilia and systemic symptoms (DRESS)	Unknown	-	-
Musculoskeletal and connective tissue disorders	Muscle cramps	-	Common	Common
	Arthralgia	Very rare	Uncommon1	Uncommon
	Myalgia	Common	Uncommon1	Uncommon
	Myopathy (including myositis)	Uncommon	-	-
	Rhabdomyolysis	Uncommon	-	-
	Tendon disorders, sometimes complicated by rupture	Unknown	-	-
	Muscle rupture	Uncommon	-	-
	Lupus-like syndrome	Uncommon	-	-
	Immune-mediated necrotizing myopathy	Unknown	-	-
	Ankle swelling	-	-	Common
	Back pain	-	-	Uncommon
Renal and urinary disorders	Renal impairment	-	Uncommon	-
	Acute renal failure	-	Uncommon	-
	Hematuria	Very rare	-	-
	Speech disorder	-	-	Uncommon
	Nocturia	-	-	Uncommon
	Increased frequency of urination	-	-	Uncommon
	Anuria/oliguria	-	Uncommon	-
Reproductive system and breast disorders	Erectile dysfunction	-	Uncommon	Uncommon
	Gynecomastia	Very rare	-	Uncommon
General disorders and administration site conditions	Asthenia	Common	Common	-
	Fatigue	-	-	Common
	Chest pain	-	Uncommon1	Uncommon
	Pain	-	-	Uncommon
	Malaise	-	Uncommon1	Uncommon
	Peripheral edema	-	Uncommon1	-
	Pyrexia	-	Uncommon1	-
	Edema	Unknown	-	Very common
Investigations	Increased plasma urea levels	-	Uncommon1	-
	Increased plasma creatinine levels	-	Uncommon1	-
	Increased plasma bilirubin levels	-	Uncommon	-
	Elevated liver enzymes	-	Uncommon	-
	Increased or decreased body weight	-	-	Uncommon
Injury, poisoning and procedural complications	Weakness	-	Uncommon1	-

1Predominantly associated with cholestasis.

2See section "Special precautions".

3Frequency depends on the presence of risk factors (fasting blood glucose ≥ 5.6 mmol/L, BMI >30 kg/m², elevated triglyceride levels, history of hypertension).

4See sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions".

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

Additional information on rosuvastatin

Renal effects

Cases of proteinuria, predominantly of tubular origin (detected by "dipstick test"), have been observed in patients treated with rosuvastatin. Changes in urinary protein content from absent or trace to "++" or higher were reported after some time in < 1% of patients receiving 10 mg and 20 mg doses, and in approximately 3% of patients receiving the 40 mg dose. A slight increase in the frequency of proteinuria from absent or trace to "+" was observed with the 20 mg dose. In most cases, proteinuria decreased or resolved spontaneously while continuing treatment. A review of clinical trial and post-marketing data has not revealed a causal relationship between proteinuria and acute or progressive kidney disease.

Hematuria has been observed in patients taking rosuvastatin; clinical trial data indicate a low frequency of occurrence.

Musculoskeletal effects

Skeletal muscle-related changes 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.

A dose-dependent increase in creatine kinase (CK) levels has been observed in patients taking rosuvastatin; in most cases, this was mild, asymptomatic, and transient. If CK levels are elevated (> 5 × ULN), treatment should be discontinued (see section "Special precautions").

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, this was mild, asymptomatic, and transient.

Adverse reactions observed with some statins:

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

Reports of acute skeletal muscle necrosis, serious renal function impairment, and serious hepatic complications (predominantly elevated hepatic transaminases) occur more frequently with the 40 mg dose.

Paediatric population

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

Reporting suspected adverse reactions

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

Shelf life. 3 years.

Storage conditions. Store in the original packaging 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, 6, 9, or 10 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 its operations.

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