Perindopril 5 / amlodipine 10 krka
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INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT
Perindopril 5/amlodipine 5 KRKA
Perindopril 5/amlodipine 10 KRKA
Perindopril 10/amlodipine 5 KRKA
Perindopril 10/amlodipine 10 KRKA
(Perindopril 5/amlodipine 5 KRKA
Perindopril 5/amlodipine 10 KRKA
Perindopril 10/amlodipine 5 KRKA
Perindopril 10/amlodipine 10 KRKA)
Composition:
Active substances: perindopril arginine and amlodipine;
One tablet contains 5 mg of perindopril arginine (equivalent to 3.395 mg of perindopril) and 5 mg of amlodipine (equivalent to 6.935 mg of amlodipine besilate), or
5 mg of perindopril arginine (equivalent to 3.395 mg of perindopril) and 10 mg of amlodipine (equivalent to 13.87 mg of amlodipine besilate), or
10 mg of perindopril arginine (equivalent to 6.79 mg of perindopril) and 5 mg of amlodipine (equivalent to 6.935 mg of amlodipine besilate), or
10 mg of perindopril arginine (equivalent to 6.79 mg of perindopril) and 10 mg of amlodipine (equivalent to 13.87 mg of amlodipine besilate);
Excipients: calcium chloride, hexahydrate; microcrystalline cellulose; microcrystalline cellulose (type 112); sodium starch glycolate (type A); sodium hydrogen carbonate; colloidal hydrated silicon dioxide; iron oxide yellow (E 172)*; magnesium stearate.
*Present in doses 5 mg/5 mg and 10 mg/10 mg.
Pharmaceutical form. Tablets.
Main physicochemical properties:
5 mg/5 mg: light brownish-yellow, round, biconvex tablets, may have single dark spots, with imprint S1 on one side of the tablet;
5 mg/10 mg: white or almost white, oval, biconvex tablets, with imprint S2 on one side of the tablet;
10 mg/5 mg: white or almost white, round, biconvex tablets, with imprint S3 on one side of the tablet;
10 mg/10 mg: light brownish-yellow, oval, biconvex tablets, may have single dark spots, with a score line on one side. One side of the score line is marked with the letter S, the other with the number 4.
Pharmacotherapeutic group. ACE inhibitors, combinations. ACE inhibitors and calcium channel blockers. Perindopril and amlodipine.
ATC code C09B B04.
Pharmacological properties.
Pharmacodynamics.
Perindopril
Mechanism of action
Perindopril is an angiotensin-converting enzyme (ACE) inhibitor. The converting enzyme, or kinase, is an exopeptidase that catalyzes the conversion of angiotensin I to angiotensin II and also promotes the breakdown of the vasodilatory agent bradykinin into an inactive heptapeptide. Inhibition of ACE activity leads to a reduction in angiotensin II concentration in blood plasma, accompanied by an increase in plasma renin activity (due to inhibition of the negative feedback regulation of renin release) and decreased aldosterone secretion. Since ACE degrades bradykinin, inhibition of this enzyme results in increased activity of the circulating and local kallikrein-kinin system and thereby activates the prostaglandin system. This mechanism contributes to the antihypertensive effect of ACE inhibitors and partially accounts for the occurrence of certain adverse effects (e.g., cough).
Perindopril is converted in the body to its active metabolite—perindoprilat. Other metabolites do not exhibit ACE-inhibiting activity in vitro.
Clinical efficacy and safety
Arterial hypertension. Perindopril effectively reduces systolic and diastolic blood pressure in all stages of arterial hypertension: mild, moderate, and severe.
Perindopril reduces peripheral vascular resistance, resulting in decreased arterial blood pressure. As a consequence, peripheral blood flow increases, while heart rate remains unchanged.
Renal blood flow generally increases, but the glomerular filtration rate remains stable.
The maximum antihypertensive effect develops within 4–6 hours after a single dose and lasts for at least 24 hours: the T/R ratio (effect just before the next dose / maximum effect) for perindopril ranges from 87% to 100%.
Blood pressure decreases rapidly. In patients who respond to treatment, normalization of blood pressure occurs within one month and is maintained over a prolonged period without the development of tachyphylaxis.
Upon discontinuation of perindopril, there is no rebound effect.
Perindopril reduces left ventricular hypertrophy.
Perindopril has vasodilatory properties, improves large artery elasticity, and reduces the wall-to-lumen ratio in small blood vessels.
Prevention of cardiovascular complications in patients with documented stable ischemic heart disease (IHD). EUROPA was a 4-year, international, multicenter, randomized, double-blind, placebo-controlled clinical trial. A total of 12,218 adult patients were randomized: 6,110 patients received 8 mg of perindopril tert-butylamine (equivalent to 10 mg of perindopril arginine) and 6,108 patients received placebo. Patients included in the study had confirmed ischemic heart disease without clinically evident heart failure. Overall, 90% of patients had a history of myocardial infarction and/or revascularization surgery. The majority of patients in the study received perindopril in addition to standard therapy with antiplatelet agents, lipid-lowering drugs, and β-blockers.
The primary efficacy endpoint was a composite outcome: cardiovascular mortality, non-fatal myocardial infarction, and/or cardiac arrest with successful resuscitation. Treatment with 8 mg of perindopril tert-butylamine (equivalent to 10 mg of perindopril arginine) once daily resulted in a statistically significant absolute reduction in the primary endpoint by 1.9% (relative risk reduction of 20%, 95% CI [9.4; 28.6] — p < 0.001).
Amlodipine
Mechanism of action
Amlodipine is a calcium ion influx inhibitor belonging to the dihydropyridine class (a slow calcium channel blocker or calcium antagonist) that blocks transmembrane calcium ion influx into vascular smooth muscle and myocardial cells.
The antihypertensive mechanism of amlodipine is due to its direct relaxant effect on vascular smooth muscle. The exact mechanism by which amlodipine reduces angina symptoms is not fully elucidated, but amlodipine reduces total ischemic burden through the following actions:
- Amlodipine dilates peripheral arterioles, thereby reducing total peripheral resistance (afterload). Since heart rate remains unchanged, the reduced cardiac workload decreases myocardial energy consumption and oxygen demand.
- Amlodipine also promotes partial dilation of major coronary arteries and coronary arterioles, both in normal and ischemic myocardial regions. This dilation increases oxygen delivery to the myocardium in patients with vasospastic angina (Prinzmetal's angina or variant angina).
In patients with arterial hypertension, once-daily administration of amlodipine provides clinically significant blood pressure reduction over 24 hours, both in the supine and standing positions. Due to its gradual onset of action, amlodipine does not cause acute hypotension.
In patients with angina, once-daily administration of amlodipine increases total exercise duration, time to onset of angina, and time to 1 mm ST-segment depression, reduces the frequency of angina attacks, and decreases the need for nitroglycerin use.
Amlodipine is not associated with any adverse metabolic effects or changes in plasma lipid levels, making it suitable for use in patients with asthma, diabetes mellitus, and gout.
Ischemic heart disease. The efficacy of amlodipine in preventing clinical events in patients with IHD was evaluated in an independent, multicenter, randomized, double-blind, placebo-controlled trial involving 1997 patients—Comparison of Amlodipine versus Enalapril to Limit Occurrences of Thrombosis (CAMELOT). Over 2 years, 663 patients received amlodipine 5–10 mg, 673 patients received enalapril 10–20 mg, and 655 patients received placebo, all in addition to standard therapy with statins, β-blockers, diuretics, and aspirin. The primary efficacy outcomes are presented in the table below. The results indicate that treatment with amlodipine was associated with fewer hospitalizations due to angina and fewer revascularization procedures in patients with IHD.
Number of major clinical events in the CAMELOT study
| Frequency of cardiovascular events, number (%) |
Amlodipine vs placebo |
||||
| Outcome |
Amlodipine |
Placebo |
Enalapril |
Relative risk (95 % CI) |
p value |
| Primary endpoint Adverse cardiovascular events |
110 (16.6) |
151 (23.1) |
136 (20.0) |
0.69 (0.54–0.88) |
0.003 |
| Individual components Coronary revascularization Hospitalizations due to angina Non-fatal myocardial infarction Stroke or transient ischemic attack Cardiovascular mortality Hospitalizations due to congestive heart failure Cardiac arrest with subsequent resuscitation Newly diagnosed peripheral vascular disease |
78 (11.8) 51 (7.7) 14 (2.1) 6 (0.9) 5 (0.8) 3 (0.5) 0 5 (0.8) |
103 (15.7) 84 (12.8) 19 (2.9) 12 (1.8) 2 (0.3) 5 (0.8) 4 (0.6) 2 (0.3) |
95 (14.1) 86 (12.8) 11 (1.6) 8 (1.2) 5 (0.7) 4 (0.6) 1 (0.1) 8 (1.2) |
0.73 (0.54–0.98) 0.58 (0.41–0.82) 0.73 (0.37–1.46) 0.50 (0.19–1.32) 2.46 (0.48–12.7) 0.59 (0.14–2.47) ̶ 2.6 (0.5–13.4) |
0.03 0.002 0.37 0.15 0.27 0.46 0.04 0.24 |
Heart failure. Hemodynamic and clinical load-controlled studies involving patients with heart failure classified as NYHA (New York Heart Association) functional class II–IV showed that amlodipine did not result in clinical worsening based on exercise tolerance, left ventricular ejection fraction, or clinical symptoms.
The objective of the placebo-controlled PRAISE study was to evaluate the effect of amlodipine in patients with heart failure classified as NYHA functional class III–IV who were receiving digoxin, diuretics, and ACE inhibitors. The study demonstrated that amlodipine did not increase morbidity/mortality or the risk of morbidity/mortality associated with heart failure.
PRAISE-2 was a long-term, placebo-controlled study. Its aim was to assess the effect of amlodipine in patients with heart failure classified as NYHA functional class III–IV, without clinical symptoms or objective evidence confirming or underlying ischemic heart disease. Patients enrolled in the study were receiving long-term treatment with ACE inhibitors, digitalis preparations, and diuretics. The study showed that amlodipine had no effect on overall cardiovascular mortality. However, within the study, amlodipine use was associated with an increased incidence of reports of pulmonary edema.
ALLHAT — a study of different treatment types for preventing heart attacks. The randomized, double-blind morbidity/mortality trial ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) was conducted in patients with mild to moderate arterial hypertension to compare modern therapeutic agents: amlodipine at a dose of 2.5–10 mg/day (a calcium channel blocker) or lisinopril at a dose of 10–40 mg/day (an ACE inhibitor) as first-line therapy versus the thiazide diuretic chlorthalidone at a dose of 12.5–25 mg/day.
The study included 33,357 hypertensive patients aged 55 years and older, followed for a mean duration of 4.9 years. Patients had at least one additional cardiovascular risk factor, including: prior myocardial infarction or stroke >6 months before enrollment, or documented other atherosclerotic cardiovascular disease (overall 51.5%), type II diabetes (36.1%), low HDL (high-density lipoprotein) cholesterol <35 mg/dL (11.6%), left ventricular hypertrophy confirmed by electrocardiogram or echocardiography (20.9%), or smoking (21.9%).
The primary endpoint of the study was a composite of fatal coronary heart disease (CHD) or nonfatal myocardial infarction. No statistically significant difference in the primary endpoint was observed between amlodipine-based therapy and chlorthalidone-based therapy: relative risk 0.98, 95% CI (0.90–1.07), p = 0.65. Regarding secondary endpoints, the incidence of heart failure (a component of the composite cardiovascular endpoint) was significantly higher in the amlodipine group compared to the chlorthalidone group (10.2% vs. 7.7%, relative risk 1.38, 95% CI [1.25–1.52], p < 0.001). However, no significant difference in all-cause mortality was observed between amlodipine-based and chlorthalidone-based therapy (relative risk 0.96, 95% CI [0.89–1.02], p = 0.20).
Properties common to perindopril and amlodipine
The morbidity and mortality trial ASCOT-BLPA (Anglo-Scandinavian Cardiac Outcomes Trial — Blood Pressure Lowering Arm) was conducted in 19,257 patients aged 40 to 79 years with hypertension and at least three of the following cardiovascular risk factors: left ventricular hypertrophy (confirmed by ECG or echocardiography), other abnormalities detected on electrocardiogram, type II diabetes, peripheral arterial disease, previous stroke or transient ischemic attack, male sex, age ≥55 years, microalbuminuria or proteinuria, smoking, total plasma cholesterol to HDL cholesterol ratio ≥6, or early onset of ischemic heart disease (IHD) in family history.
The main objective of the study was to evaluate and compare the long-term effects of two antihypertensive treatment regimens on a composite primary endpoint of nonfatal myocardial infarction (including silent myocardial infarction) and fatal complications of ischemic heart disease (IHD). Specifically, it compared the regimen of amlodipine combined with perindopril (added as needed for blood pressure control) versus atenolol combined with the diuretic bendroflumethiazide (added as needed for blood pressure control).
At the end of the study, the majority of patients (78%, 14,974 out of 19,242) were receiving at least two antihypertensive agents, while only 15% (1,401 out of 9,634) and 9% (857 out of 9,608) were receiving monotherapy with amlodipine or atenolol, respectively.
The study was prematurely terminated after a median follow-up of 5.5 years by the Data Safety Monitoring Board (DSMB) due to significantly higher mortality observed in the atenolol-based treatment group compared to the amlodipine group.
The study results showed a non-significant 10% reduction in the primary composite endpoint of nonfatal myocardial infarction (including silent infarction) and fatal complications of ischemic heart disease (IHD) in the amlodipine/perindopril group compared to the atenolol/bendroflumethiazide group. However, a significant reduction in all secondary endpoint measures (except fatal and nonfatal heart failure) was observed in the amlodipine/perindopril group.
Endpoints:
| Secondary endpoints |
Relative risk reduction |
95 % CI |
p |
| Non-fatal myocardial infarction (excluding silent) + fatal IHD |
13 % |
0.76–1.00 |
0.0458 |
| Total coronary endpoint |
13 % |
0.79–0.96 |
0.007 |
| Coronary events and interventions |
16 % |
0.78–0.90 |
< 0.0001 |
| All-cause mortality |
11 % |
0.81–0.99 |
0.0247 |
| Cardiovascular mortality |
24 % |
0.65–0.90 |
0.0010 |
| Fatal and non-fatal stroke |
23 % |
0.66–0.89 |
0.0003 |
| Fatal and non-fatal heart failure |
16 % |
0.66–1.05 |
0.1257 |
Pharmacokinetics.
The rate and extent of absorption of perindopril and amlodipine, as individual agents and as components of the fixed combination Perindopril/Amlodipine KRKA, do not differ significantly.
Perindopril
Absorption
After oral administration, perindopril is rapidly absorbed, with peak plasma concentration reached within 1 hour. The elimination half-life of perindopril in plasma is 1 hour.
Perindopril is a prodrug. 27% of the total administered perindopril reaches systemic circulation as the active metabolite—perindoprilat. In addition to the active metabolite perindoprilat, the drug forms five metabolites that are inactive. Peak plasma concentration of perindoprilat is achieved 3–4 hours after administration.
Food intake reduces the conversion of perindopril to perindoprilat, thereby decreasing its bioavailability. Therefore, the daily dose of perindopril arginine should be taken once daily in the morning before a meal.
Distribution
A linear relationship between perindopril dose and plasma concentration is observed. The volume of distribution of unbound perindoprilat is approximately 0.2 L/kg. Plasma protein binding of perindoprilat is 20%, primarily to angiotensin-converting enzyme, although this value is dose-dependent.
Elimination
Perindoprilat is excreted in urine. The terminal elimination half-life of the unbound fraction is approximately 17 hours. Steady-state plasma concentration is achieved within 4 days of starting treatment.
Elimination of perindoprilat is slowed in elderly patients, as well as in patients with cardiac or renal impairment (see section "Dosage and administration"). Therefore, routine medical monitoring should include careful monitoring of creatinine and potassium levels.
Hepatic impairment
The dialysis clearance of perindoprilat is 70 mL/min.
Perindopril kinetics are altered in patients with liver cirrhosis: hepatic clearance of perindopril is halved. However, the amount of formed perindoprilat does not decrease. Therefore, dose adjustment is not required in these patients (see sections "Special precautions" and "Dosage and administration").
Amlodipine
Absorption, distribution, plasma protein binding
After oral administration of therapeutic doses, amlodipine is well absorbed and reaches peak blood concentration 6–12 hours after administration. Absolute bioavailability ranges from 64% to 80%. The volume of distribution is approximately 21 L/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine in blood is plasma protein-bound.
Food intake does not affect the bioavailability of amlodipine.
Biotransformation/Elimination
The elimination half-life from plasma is approximately 35–50 hours, allowing for once-daily dosing.
Amlodipine is primarily metabolized in the liver to inactive metabolites. About 60% of metabolites are excreted in urine, and 10% are excreted unchanged.
Elderly patients
Time to reach peak plasma concentration of amlodipine is similar in elderly and younger patients. In elderly patients, there is a tendency toward reduced clearance of amlodipine, resulting in increased AUC and prolonged elimination half-life. Increased AUC and half-life in patients with congestive heart failure corresponded to the age-related characteristics of the studied patient population.
Hepatic impairment
There are very limited clinical data on the use of amlodipine in patients with hepatic dysfunction. In patients with hepatic impairment, clearance of amlodipine is reduced, leading to prolonged elimination half-life and an increase in AUC by approximately 40–60%.
Clinical characteristics.
Indications.
Arterial hypertension and/or ischemic heart disease (when treatment with perindopril and amlodipine is required).
Contraindications.
Contraindications associated with perindopril:
- Hypersensitivity to perindopril or to any other angiotensin-converting enzyme (ACE) inhibitors;
- History of angioedema after taking any ACE inhibitors;
- Hereditary or idiopathic angioedema;
- Pregnancy or planned pregnancy (see sections "Special precautions for use" and "Use during pregnancy or breastfeeding");
- Concomitant use of medicinal products containing aliskiren in patients with diabetes mellitus or patients with renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²) (see section "Interaction with other medicinal products and other forms of interaction");
- Concomitant use with sacubitril/valsartan combination. Perindopril therapy must 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 for use");
- Extracorporeal treatment methods leading to blood contact with negatively charged surfaces (see section "Interaction with other medicinal products and other forms of interaction");
- Severe bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney (see section "Special precautions for use").
Contraindications associated with amlodipine:
- Severe arterial hypotension;
- Hypersensitivity to the active substance or to dihydropyridine derivatives;
- Shock, including cardiogenic shock;
- Left ventricular outflow tract obstruction (e.g., severe aortic stenosis);
- Unstable angina;
- Heart failure following acute myocardial infarction with hemodynamic instability.
Contraindications associated with the medicinal product Perindopril/Amlodipine KRKA:
- All the above-mentioned contraindications associated with perindopril and amlodipine;
- Hypersensitivity to any excipient.
Interaction with other medicinal products and other forms of interaction.
Interactions related to perindopril
Clinical study 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 "Contraindications" and "Special precautions for use").
Medicinal products increasing the risk of angioedema
Concomitant use of ACE inhibitors 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. 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 of ACE inhibitors with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) increases the risk of angioedema (see section "Special precautions for use").
Medicinal products causing hyperkalemia
Serum potassium levels usually remain within normal limits, but hyperkalemia may occur in some patients treated with Perindopril/Amlodipine KRKA. Some medicinal products or therapeutic classes of medicinal products may cause hyperkalemia, namely: aliskiren, potassium salts (e.g., spironolactone, triamterene, or amiloride), potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory drugs (NSAIDs), heparins, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim, and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim acts as a potassium-sparing diuretic similar to amiloride. Concomitant use of these medicinal products increases the risk of hyperkalemia. Therefore, concomitant use of Perindopril/Amlodipine KRKA with the above-mentioned agents is not recommended. If concomitant use of these agents is necessary, they should be used with caution and serum potassium levels should be closely monitored.
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, cardiovascular morbidity, and mortality is increased.
Extracorporeal treatment methods. Extracorporeal treatment methods leading to blood contact with negatively charged surfaces, such as dialysis or hemofiltration using certain high-flux membranes (e.g., polyacrylonitrile) and low-density lipoprotein apheresis using dextran sulfate, increase the risk of severe anaphylactoid reactions (see section "Contraindications"). If such treatment is required, consideration should be given to using a different type of dialysis membrane or another class of antihypertensive agents.
Concomitant use is not recommended (see section "Special precautions for use")
Aliskiren. In all other patients, including those with diabetes mellitus or impaired renal function, the risk of hyperkalemia, worsening renal function, cardiovascular morbidity, and mortality is increased.
Published data show that in patients with established atherosclerosis, heart failure, or diabetes mellitus with target organ damage, concomitant use of ACE inhibitors and angiotensin receptor blockers is associated with increased incidence of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to monotherapy with agents affecting the renin-angiotensin-aldosterone system. Dual blockade (i.e., combination of an ACE inhibitor with angiotensin II receptor antagonists) may be used in individual cases with careful monitoring of renal function, potassium levels, and blood pressure.
Estramustine. There is a risk of increased frequency of adverse reactions, such as angioedema.
Potassium-sparing diuretics (e.g., triamterene, amiloride, etc.), potassium salts. Risk of hyperkalemia (possibly fatal), especially in patients with renal impairment (additive hyperkalemic effect). These agents are not recommended for concomitant use with perindopril (see section "Special precautions for use"). However, if concomitant use of these agents is necessary, they should be used with caution and frequent monitoring of plasma potassium levels is required. For use of spironolactone in heart failure, see section "Medicinal products requiring special attention when co-administered" below.
Lithium. Concomitant use of lithium and ACE inhibitors is not recommended due to the possibility of reversible increase in serum lithium concentration and, consequently, increased toxicity (severe neurotoxicity). However, if such combination is justified, monitoring of serum lithium concentration is recommended (see section "Special precautions for use").
Medicinal products requiring special attention when co-administered
Antidiabetic agents (insulin, oral antidiabetic agents). Epidemiological studies suggest that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral antidiabetic agents) may enhance the blood glucose-lowering effect with a risk of hypoglycemia. This phenomenon most commonly occurs during the first weeks of combination therapy and in patients with renal impairment.
Diuretics. In patients taking diuretics, especially those with disturbed water-electrolyte balance, excessive reduction in blood pressure may occur after initiation of ACE inhibitor therapy. The likelihood of developing hypotensive effect is reduced by discontinuing the diuretic, increasing circulating blood volume, or salt intake prior to starting perindopril therapy, which should be initiated at low doses with gradual dose escalation.
- In arterial hypertension, when a previously prescribed diuretic may have caused water/electrolyte deficiency, it should be discontinued before starting ACE inhibitor therapy (diuretic use may be resumed later) or the ACE inhibitor should be initiated at a low dose with gradual dose escalation.
- In congestive heart failure on diuretic therapy, ACE inhibitor therapy should be initiated at the lowest dose, possibly after reducing the diuretic dose. In any case, renal function (creatinine level) should be monitored during the first weeks of ACE inhibitor therapy.
Potassium-sparing diuretics (eplerenone, spironolactone). Particular attention is required when using eplerenone or spironolactone at doses from 12.5 mg to 50 mg daily concomitantly with low doses of ACE inhibitors. Failure to follow recommendations for prescribing such combination increases the risk of hyperkalemia (possibly fatal) during treatment of patients with NYHA class II–IV heart failure and ejection fraction < 40%, previously treated with an ACE inhibitor and a loop diuretic. Before prescribing such combination, absence of hyperkalemia and renal function impairment should be confirmed. Careful monitoring of potassium and creatinine levels is recommended weekly during the first month of treatment and monthly thereafter.
Nonsteroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid ≥ 3 g per day. Possible reduction in antihypertensive effect during concomitant use of ACE inhibitors with NSAIDs, such as: acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, nonselective NSAIDs. Concomitant use of ACE inhibitors and NSAIDs increases the risk of worsening renal function, including acute renal failure, and increased plasma potassium levels, especially in patients with a history of renal impairment. Such combination should be prescribed with caution, particularly in elderly patients. Patients should have their fluid balance restored and renal function monitored at the beginning of treatment with such combination and periodically during treatment.
Medicinal products requiring attention when co-administered
Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.
Gold. Rarely, when ACE inhibitors, including perindopril, are used concomitantly with injectable gold preparations (sodium aurothiomalate), reactions similar to those occurring with nitrates (facial flushing, hot flashes, nausea, vomiting, and hypotension) may occur.
Interactions related to amlodipine
Concomitant use is not recommended
Dantrolene (infusion). In experimental studies, ventricular fibrillation with fatal outcome and cardiovascular collapse combined with hyperkalemia were observed after intravenous administration of verapamil and dantrolene. Due to the potential for hyperkalemia, concomitant use of calcium channel blockers such as amlodipine should be avoided in patients with malignant hyperthermia or in patients suspected of having malignant hyperthermia.
Medicinal products requiring special caution when co-administered
Inducers of CYP3A4. When used concomitantly with CYP3A4 inducers, plasma concentration of amlodipine may change. Therefore, blood pressure should be monitored and dose adjustment should be performed during and after concomitant use with CYP3A4 inducers, especially when used with strong CYP3A4 inducers (e.g., rifampicin, St. John’s wort [Hypericum perforatum]).
Inhibitors of CYP3A4. Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil or diltiazem) may increase amlodipine concentration. The clinical manifestation of these pharmacokinetic changes may be greater in elderly patients. Clinical monitoring and dose adjustment are required in such cases. There is an increased risk of hypotension in patients taking clarithromycin in combination with amlodipine. Close monitoring is recommended for such patients.
Medicinal products requiring attention when co-administered
Concomitant use of amlodipine with other medicinal products with antihypertensive properties may result in additive antihypertensive effect.
Tacrolimus. When used concomitantly with amlodipine, there is a risk of increased blood levels of tacrolimus. To avoid toxic effects of tacrolimus, its blood levels should be monitored and its dose adjusted if necessary in patients receiving amlodipine.
Inhibitors of mechanistic target of rapamycin (mTOR). mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are substrates of CYP3A. Amlodipine is a weak inhibitor of CYP3A. When used concomitantly with mTOR inhibitors, amlodipine may increase the concentration of mTOR inhibitors.
Cyclosporine. Studies on interaction between cyclosporine and amlodipine in healthy volunteers or other individuals have not been conducted. The exception is kidney transplant patients, in whom fluctuations in cyclosporine concentration were observed with an average increase from 0% to 40%. Kidney transplant patients taking amlodipine and cyclosporine should have cyclosporine blood levels monitored and cyclosporine dose reduced if necessary.
Simvastatin. Administration of amlodipine at doses multiple of 10 mg in combination with 80 mg simvastatin resulted in a 77% increase in simvastatin concentration compared to monotherapy. Patients should limit simvastatin dose to 20 mg per day.
Other combinations
Clinical interaction studies have demonstrated that amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin, or warfarin.
Grapefruit or grapefruit juice should not be used concomitantly with amlodipine, as in some patients bioavailability may increase, leading to enhanced hypotensive effect.
Interactions related to fixed combination Perindopril/Amlodipine KRKA
Medicinal products requiring special caution when co-administered
Baclofen enhances the antihypertensive effect. Blood pressure should be monitored and dose adjusted if necessary.
Medicinal products requiring attention when co-administered
- Antihypertensive agents (such as beta-blockers) and vasodilators:
Concomitant use of these agents may enhance the hypotensive effect of perindopril and amlodipine.
Concomitant use with nitroglycerin and other nitrates or with other vasodilators may cause further reduction in blood pressure; therefore, they should be prescribed with caution.
- Corticosteroids, tetracosactide reduce antihypertensive effect (due to water and salt retention by corticosteroids).
- Alpha-blockers (prazosin, alfuzosin, doxazosin, tamsulosin, terazosin) enhance antihypertensive effect and increase the risk of orthostatic hypotension.
- Amifostine may enhance the antihypertensive effect of amlodipine.
- Tricyclic antidepressants / antipsychotropic agents / anesthetics enhance antihypertensive effect and increase the risk of orthostatic hypotension.
Special precautions for use.
All precautions regarding the use of perindopril and amlodipine also apply to the medicinal product Perindopril/amlodipine KRKA.
Special precautions for use of perindopril
Hypersensitivity / angioedema
Rare cases of angioedema affecting the face, extremities, lips, mucous membranes, tongue, glottis and/or larynx have been reported in patients receiving angiotensin-converting enzyme (ACE) inhibitors, including perindopril (see section "Adverse reactions"). These reactions may occur at any time during treatment. In such cases, the drug must be discontinued immediately and appropriate monitoring of the patient's condition should be instituted until complete resolution of symptoms. In individual cases where swelling is limited to the face and lips, the patient's condition usually improves without treatment. Administration of antihistamines may be helpful in relieving symptoms.
Angioedema associated with laryngeal edema may be fatal. In cases where swelling involves the tongue, glottis or larynx, causing airway obstruction, emergency therapy is required, which may include administration of adrenaline and/or securing airway patency. Patients require careful medical monitoring until symptoms have completely resolved and their condition has stabilized.
Patients with a history of angioedema unrelated to ACE inhibitor therapy have an increased risk of developing angioedema during ACE inhibitor treatment (see section "Contraindications").
Rare cases of intestinal angioedema have been reported in patients receiving ACE inhibitors. These patients experienced abdominal pain (with or without nausea or vomiting); in some cases, there was no prior history of facial angioedema and serum C-1 esterase levels were normal. The diagnosis of intestinal angioedema was established by abdominal computed tomography, 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 presenting with abdominal pain who are taking ACE inhibitors (see section "Adverse reactions").
Concomitant use of perindopril with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see section "Contraindications"). Therapy with sacubitril/valsartan should be initiated only 36 hours after the last dose of perindopril. If treatment with sacubitril/valsartan is discontinued, perindopril therapy must 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 neutral endopeptidase (NEP) inhibitors (e.g. racecadotril), mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus), or gliptins (e.g. linagliptin, saxagliptin, sitagliptin, vildagliptin) increases the risk of angioedema (e.g. airway or tongue swelling, with or without respiratory compromise) (see section "Interaction with other medicinal products and other forms of interaction"). Caution should be exercised when initiating treatment with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus), or gliptins (e.g. linagliptin, saxagliptin, sitagliptin, vildagliptin) in patients already receiving ACE inhibitors.
Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis
Rare, life-threatening anaphylactoid reactions have been reported in patients receiving ACE inhibitors during LDL apheresis with dextran sulfate. These anaphylactoid reactions can be avoided by temporarily discontinuing ACE inhibitor therapy prior to each apheresis session.
Anaphylactoid reactions during desensitization therapy
Anaphylactoid reactions may occur in patients receiving ACE inhibitors during desensitization therapy with bee venom-containing products. These reactions can be avoided by temporarily discontinuing the ACE inhibitor, but reactions may recur if provocation tests are performed carelessly.
Neutropenia/agranulocytosis/thrombocytopenia/anemia
Cases of neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients receiving ACE inhibitors. Neutropenia is rare in patients with normal renal function and no other risk factors. Perindopril should be used with extreme caution in patients with collagen vascular diseases, during immunosuppressive therapy, with allopurinol or procainamide, and especially when these risk factors are combined, particularly in the presence of impaired renal function. Serious infections, occasionally unresponsive to intensive antibiotic therapy, may develop in such patients. If perindopril is administered to these patients, periodic monitoring of white blood cell counts is recommended, and patients should be advised to report any signs of infection (e.g. sore throat, fever).
Renovascular hypertension
Patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney treated with ACE inhibitors are at increased risk of hypotension and renal failure (see section "Contraindications"). Concomitant diuretic therapy may be a contributing factor. Loss of renal function may occur with only minor changes in serum creatinine, even in patients with unilateral renal artery stenosis.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
Data 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 the RAAS by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see section "Interaction with other medicinal products and other forms of interaction"). If dual blockade therapy is considered absolutely necessary, it should be performed only under specialist supervision with frequent and 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.
Primary hyperaldosteronism
Patients with primary hyperaldosteronism generally do not respond to antihypertensive drugs acting through inhibition of the renin-angiotensin system. Therefore, use of this medicinal product is not recommended.
Precautions for use
Hypotension
ACE inhibitors may cause a reduction in blood pressure. Symptomatic hypotension is less common in patients with uncomplicated hypertension and is more likely in patients with hypovolemia, such as those receiving diuretics, on a low-salt diet, on dialysis, or with diarrhea or vomiting, as well as in patients with severe renin-dependent hypertension (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions"). Patients at high risk of symptomatic hypotension during treatment should be closely monitored for blood pressure, renal function, and serum potassium levels. Similar recommendations apply to patients with ischemic heart disease or cerebrovascular disease, in whom excessive reduction in blood pressure may lead to myocardial infarction or cerebrovascular accident.
If hypotension occurs, the patient should be placed in a supine position and, if necessary, given an intravenous infusion of 0.9% (9 mg/mL) sodium chloride solution. Transient hypotension is not a contraindication to further use of the drug, which can usually be resumed without difficulty after restoration of blood volume and blood pressure.
Stenosis of aortic and mitral valves / hypertrophic cardiomyopathy
As with other ACE inhibitors, perindopril should be used with caution in patients with mitral valve stenosis or left ventricular outflow tract obstruction (aortic stenosis or hypertrophic cardiomyopathy).
Renal impairment
In patients with renal impairment (creatinine clearance < 60 mL/min), the initial dose of perindopril should be adjusted according to the patient's creatinine clearance (see section "Dosage and administration"), and subsequently based on the patient's response to treatment. Monitoring of serum potassium and creatinine levels is standard practice in such patients (see section "Adverse reactions").
In some patients with bilateral renal artery stenosis or stenosis of the artery to a single kidney receiving ACE inhibitors, increases in blood urea nitrogen and serum creatinine have been observed, which were usually reversible upon discontinuation of therapy. Such increases are particularly likely in patients with pre-existing renal impairment. If renovascular hypertension is also present, there is an increased risk of severe hypotension and renal failure. In some patients with hypertension but no apparent renal vascular disease, increases in blood urea and serum creatinine have been observed, usually minor and transient, especially when perindopril is used concomitantly with a diuretic. This phenomenon is more likely in patients with pre-existing renal impairment.
Hepatic impairment
Rare cases of a syndrome beginning with cholestatic jaundice and progressing to fulminant hepatic necrosis, sometimes fatal, have been reported in patients receiving ACE inhibitors. The mechanism of this syndrome is unknown. Patients who develop jaundice or marked elevations in liver enzymes while receiving an ACE inhibitor should discontinue the drug, undergo appropriate medical evaluation, and receive treatment (see section "Adverse reactions").
Racial factors
ACE inhibitors cause angioedema more frequently in black patients than in patients of other races. As with other ACE inhibitors, perindopril is less effective in reducing blood pressure in black patients than in patients of other races, possibly due to lower plasma renin levels in black patients with hypertension.
Cough
Cough has been reported during ACE inhibitor therapy. The cough is typically non-productive, persistent, and resolves after discontinuation of the drug. Cough due to ACE inhibitor use should be considered in the differential diagnosis of cough.
Surgery / anesthesia
Perindopril may block the secondary formation of angiotensin II in response to compensatory renin release in patients undergoing surgery or receiving anesthetic agents that cause hypotension. The drug should be discontinued one day before surgery. If hypotension occurs and is thought to be due to this mechanism, the patient's condition can be normalized by increasing circulating blood volume.
Hyperkalemia
Elevated serum potassium levels have been observed in some patients receiving ACE inhibitors, including perindopril. ACE inhibitors may cause hyperkalemia by inhibiting aldosterone release. The effect is usually minor in patients with normal renal function. Risk factors for hyperkalemia include renal impairment, worsening renal function, age > 70 years, diabetes mellitus, concomitant conditions such as dehydration, acute heart failure, metabolic acidosis, and concomitant use of potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes; use of other drugs associated with increased serum potassium (e.g. heparin, co-trimoxazole [trimethoprim/sulfamethoxazole]), and especially aldosterone antagonists or angiotensin receptor blockers. Use of potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes, particularly in patients with impaired renal function, may lead to significant increases in serum potassium. Hyperkalemia may cause serious, sometimes fatal, arrhythmias. Potassium-sparing diuretics and angiotensin receptor blockers should be used cautiously in patients receiving ACE inhibitors, and serum potassium levels and renal function should be monitored. If concomitant use of perindopril and any of the above-mentioned drugs is considered appropriate, they should be used with caution and serum potassium levels should be monitored frequently (see section "Special precautions for use").
Patients with diabetes mellitus
Patients with diabetes mellitus receiving oral antidiabetic agents or insulin should have their blood glucose levels closely monitored during the first month of ACE inhibitor therapy (see section "Interaction with other medicinal products and other forms of interaction").
Precautions for use of amlodipine
The safety and efficacy of amlodipine in hypertensive crisis have not been established.
Use in patients with heart failure
Patients with heart failure should be treated with caution.
In a long-term, placebo-controlled study in patients with severe heart failure (NYHA class III-IV), the incidence of pulmonary edema was higher in the amlodipine group than in the placebo group (see section "Pharmacological properties"). Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular complications and mortality.
Hepatic impairment
The elimination half-life of amlodipine is prolonged and AUC values are higher in patients with hepatic impairment; dosage recommendations have not been established. Therefore, amlodipine therapy should be initiated at the lower end of the dosing range, and caution should be exercised both at the start of treatment and when increasing the dose. Patients with severe hepatic impairment may require slow dose titration and careful monitoring.
Elderly patients
Dose increases should be made cautiously in elderly patients (see sections "Dosage and administration" and "Pharmacokinetics").
Renal impairment
Amlodipine can be used at usual doses in these patients. Changes in amlodipine plasma concentrations do not correlate with the degree of renal impairment. Amlodipine is not dialyzable.
Precautions for use of fixed combination Perindopril/amlodipine KRKA
Interactions
Concomitant use of the medicinal product Perindopril/amlodipine KRKA with lithium, potassium-sparing diuretics, potassium-containing dietary supplements, or dantrolene is not recommended.
Sodium
The medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. is essentially "sodium-free".
Use during pregnancy or breastfeeding.
Use of the medicinal product Perindopril/amlodipine KRKA during pregnancy is contraindicated.
Perindopril/amlodipine KRKA is not recommended during breastfeeding. Therefore, a decision should be made whether to discontinue breastfeeding or discontinue the medicinal product, taking into account the importance of the therapy for the mother.
Pregnancy
Perindopril. Use of ACE inhibitors is contraindicated during pregnancy.
Epidemiological data on the teratogenic risk of ACE inhibitors during the first trimester of pregnancy are inconclusive; however, a small increased risk cannot be excluded. Women planning pregnancy should be switched to alternative antihypertensive therapy with an established safety profile during pregnancy. If pregnancy is confirmed, ACE inhibitor therapy should be discontinued immediately and, if possible, alternative therapy initiated.
It is known that use of ACE inhibitors during the second and third trimesters of pregnancy may cause fetal toxicity (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalemia).
If ACE inhibitors are used during the second trimester of pregnancy, ultrasound evaluation of fetal renal function and skull ossification is recommended.
Infants born to mothers who have taken ACE inhibitors should be carefully monitored for hypotension, oliguria, and hyperkalemia (see sections "Contraindications" and "Special precautions for use").
If pregnancy is confirmed during treatment with this product, use should be discontinued immediately and replaced with another medicinal product approved for use in pregnancy.
Amlodipine. The safety of amlodipine use during pregnancy has not been established.
Reproductive toxicity was observed in animal studies with high doses. Use during pregnancy is recommended only when no safer alternative exists and when the underlying condition poses greater risk to mother and fetus.
Breastfeeding
Perindopril. Perindopril is not recommended during breastfeeding due to lack of data. An alternative treatment with a better-studied safety profile should be considered, especially when breastfeeding a newborn or preterm infant.
Amlodipine passes into human breast milk. The fraction of the maternal dose received by the infant has been estimated at an interquartile range of 3–7%, maximum 15%. Since information on the use of Perindopril/amlodipine KRKA during breastfeeding is lacking, the product is not recommended during this period. Medicinal products with better-established safety profiles during breastfeeding should be preferred, especially for newborns or preterm infants.
The effect of amlodipine on infants is unknown. The decision on whether to continue/stop breastfeeding or continue/stop amlodipine therapy should be made taking into account the benefits of breastfeeding for the child and the benefits of amlodipine therapy for the mother.
Fertility
Perindopril. No effect on reproductive capacity or fertility has been observed.
Amlodipine. Reversible biochemical changes in sperm head have been reported in some patients receiving calcium channel blockers. Clinical data on the potential effect of amlodipine on fertility are insufficient. An adverse effect on male fertility was observed in one rat study.
Ability to influence reaction speed when driving or operating machinery.
No studies on the effect of the medicinal product on the ability to drive or operate machinery have been conducted. Amlodipine may have a minor or moderate effect on the ability to drive or operate machinery. If patients experience dizziness, headache, fatigue, or nausea, their reaction ability may be impaired. Caution is recommended, especially at the beginning of treatment.
Dosage and Administration.
For oral use.
Initiate treatment with 1 tablet once daily, preferably taken in the morning before food.
The use of this fixed-dose combination is not suitable for initial therapy.
The dosage range of the medicinal product allows flexible adjustment of the component ratio according to clinical needs. The dose should be individually adjusted for each patient, taking into account the indication, disease course, and blood pressure levels.
Patients with renal impairment and elderly patients (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use")
Elimination of perindoprilat is slowed in elderly patients and in patients with renal impairment. Therefore, frequent monitoring of creatinine and potassium levels is required during treatment.
The medicinal product Perindopril/amlodipine KRKA can be prescribed to patients with CC [creatinine clearance] ≥ 60 mL/min. Perindopril/amlodipine KRKA is contraindicated in patients with CC < 60 mL/min in this dosage form. For such patients, individual dose titration of perindopril and amlodipine is recommended.
Changes in amlodipine plasma concentration do not correlate with the severity of renal impairment.
Patients with hepatic impairment (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use")
Dose recommendations for patients with mild to moderate hepatic impairment have not been established; therefore, dose selection should be cautious, starting from the lower end of the dosing range (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use"). To determine the optimal initial and maintenance dose in patients with hepatic impairment, dose titration should be performed individually using the free combination of amlodipine and perindopril. The pharmacokinetics of amlodipine in patients with severe hepatic impairment have not been studied. Amlodipine administration in patients with marked hepatic insufficiency should begin with the lowest dose and be slowly titrated.
Children
The medicinal product is not recommended for use in children (under 18 years of age) due to lack of data in this patient group.
Overdose
There is no information available on overdose of Perindopril/amlodipine KRKA in humans.
Data on intentional amlodipine overdose are limited. Symptoms: Based on available data, ingestion of very high doses may lead to excessive peripheral vasodilation and reflex tachycardia. Severe, possibly prolonged systemic hypotension and shock with fatal outcome have been reported.
Rare cases of non-cardiogenic pulmonary edema following amlodipine overdose have been reported, which may not manifest immediately (appearing 24–48 hours after intake) and may require mechanical ventilation. Early resuscitation measures (including fluid loading) to support perfusion and cardiac output may be provocative factors.
Treatment: Clinically significant hypotension caused by amlodipine overdose requires active cardiovascular support, including careful monitoring of cardiac and respiratory function, placing the patient in a supine position with elevated legs, and close monitoring of circulating blood volume and urine output.
Administration of a vasoconstrictor may be beneficial to restore vascular tone and blood pressure, provided there are no contraindications. Intravenous calcium gluconate may help counteract the effects of calcium channel blockade.
In some cases, gastric lavage may be appropriate. Studies in volunteers have shown that administration of activated charcoal 2 hours after ingestion of 10 mg amlodipine reduces the rate of amlodipine absorption. Amlodipine is highly protein-bound in systemic circulation; therefore, hemodialysis is ineffective.
Information on perindopril overdose is limited. In cases of ACE inhibitor overdose, the following may occur: hypotension, circulatory shock, electrolyte imbalance, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough.
In case of overdose, intravenous administration of 0.9% sodium chloride solution is recommended. If hypotension occurs, the patient should be placed in a supine position. Administration of angiotensin II and/or intravenous catecholamines should be considered. Perindopril can be removed from systemic circulation by hemodialysis (see section "Special Warnings and Precautions for Use"). In case of persistent bradycardia unresponsive to treatment, temporary cardiac pacing may be considered. Careful monitoring of vital signs, serum electrolyte levels, and serum creatinine is required.
Adverse reactions
The most commonly reported adverse reactions with perindopril and amlodipine used separately are: edema, somnolence, dizziness, headache (particularly at the beginning of treatment), taste disturbance (dysgeusia), paresthesia, visual disturbances (including diplopia), tinnitus, vertigo, palpitations, flushing, hypotension (and associated symptoms), dyspnea, cough, abdominal pain, nausea, vomiting, dyspepsia, altered defecation rhythm, diarrhea, constipation, pruritus, rash, exanthema, joint swelling (ankle edema), muscle cramps, increased fatigue, asthenia.
The adverse effects observed during treatment with perindopril or amlodipine used separately are listed below by MedDRA (Medical Dictionary for Regulatory Activities) system organ classes and frequency categories: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); not known (frequency cannot be estimated from the available data). Within each frequency grouping, adverse reactions are listed in order of decreasing seriousness.
In most patients, adverse events are mild and transient.
| Body systems |
Adverse reactions |
Frequency |
|
| Amlodipine |
Perindopril |
||
| Infections and infestations |
Rhinitis |
uncommon |
very rare |
| Blood and lymphatic system |
Eosinophilia |
- |
uncommon* |
| Leukopenia/neutropenia1 |
very rare |
very rare |
|
| Agranulocytosis or pancytopenia1 |
- |
very rare |
|
| Thrombocytopenia1 |
very rare |
very rare |
|
| Hemolytic anemia in patients with congenital G-6PDH enzyme deficiency1 |
- |
very rare |
|
| Immune system |
Hypersensitivity |
very rare |
uncommon |
| Endocrine system |
Syndrome of inappropriate antidiuretic hormone secretion (SIADH) |
- |
rare |
| Metabolism and nutrition |
Hypoglycemia2 |
- |
uncommon* |
| Hyperkalemia, resolving after drug discontinuation1 |
- |
uncommon* |
|
| Hyponatremia |
- |
uncommon* |
|
| Hyperglycemia |
very rare |
- |
|
| Psychiatric |
Insomnia |
uncommon |
uncommon |
| Mood changes (including anxiety) |
uncommon |
uncommon |
|
| Depression |
uncommon |
uncommon |
|
| Sleep disorders |
- |
uncommon |
|
| Nervous system |
Somnolence (mainly at the beginning of treatment) |
common |
- |
| Dizziness (mainly at the beginning of treatment) |
common |
common |
|
| Headache (mainly at the beginning of treatment) |
common |
common |
|
| Tremor |
uncommon |
- |
|
| Hypesthesia |
uncommon |
- |
|
| Paraesthesia |
uncommon |
common |
|
| Hypertonia |
very rare |
- |
|
| Peripheral neuropathy |
very rare |
- |
|
| Dysgeusia |
uncommon |
- |
|
| Syncope |
- |
common |
|
| Confusion |
rare |
very rare |
|
| Cerebrovascular disorders, possibly secondary to excessive arterial hypotension in high-risk patients1 |
- |
very rare |
|
| Extrapyramidal disorder (extrapyramidal syndrome) |
unknown |
- |
|
| Eye organs |
Visual disturbances |
common |
common |
| Diplopia |
common |
- |
|
| Ear and vestibular organs |
Tinnitus |
uncommon |
common |
| Vertigo |
- |
common |
|
| Heart |
Palpitations |
common |
uncommon* |
| Tachycardia |
- |
uncommon* |
|
| Angina pectoris1 |
very rare |
||
| Myocardial infarction, possibly due to marked arterial hypotension in high-risk patients1 |
very rare |
very rare |
|
| Arrhythmia (including bradycardia, ventricular tachycardia, and atrial fibrillation) |
uncommon |
very rare |
|
| Vascular system |
Hypotension (and related symptoms) |
uncommon |
common |
| Flushing |
common |
rare |
|
| Vasculitis |
very rare |
uncommon* |
|
| Raynaud's syndrome |
- |
unknown |
|
| Respiratory system |
Dyspnea |
common |
common |
| Cough |
uncommon |
common |
|
| Bronchospasm |
- |
uncommon |
|
| Eosinophilic pneumonia |
- |
very rare |
|
| Gastrointestinal system |
Gingival hyperplasia |
very rare |
- |
| Abdominal pain |
common |
common |
|
| Nausea |
common |
common |
|
| Vomiting |
uncommon |
common |
|
| Dyspepsia |
uncommon |
common |
|
| Change in defecation rhythm |
common |
- |
|
| Dry mouth |
uncommon |
uncommon |
|
| Diarrhea |
- |
common |
|
| Constipation |
- |
common |
|
| Pancreatitis |
very rare |
very rare |
|
| Gastritis |
very rare |
- |
|
| Liver and biliary system |
Hepatitis, cholestatic jaundice |
very rare |
- |
| Elevated liver enzyme levels (mainly corresponding to cholestasis) |
very rare |
- |
|
| Cytolytic or cholestatic hepatitis1 |
- |
very rare |
|
| Skin and subcutaneous tissue |
Quincke's edema |
very rare |
- |
| Angioneurotic edema of face, extremities, lips, mucous membranes, tongue, glottis and/or larynx1 |
very rare |
uncommon |
|
| Multiform erythema |
very rare |
very rare |
|
| Alopecia |
uncommon |
- |
|
| Purpura |
uncommon |
- |
|
| Skin color change |
uncommon |
- |
|
| Increased sweating |
uncommon |
uncommon |
|
| Pruritus Urticaria (see section 4.4) |
uncommon |
common |
|
| Rash, exanthema |
uncommon |
common |
|
| Stevens-Johnson syndrome |
very rare |
- |
|
| Pemphigoid |
- |
uncommon* |
|
| Photosensitivity reactions |
very rare |
uncommon* |
|
| Psoriasis exacerbation |
- |
rare |
|
| Exfoliative dermatitis |
very rare |
- |
|
| Urticaria1 |
uncommon |
- |
|
| Toxic epidermal necrolysis |
unknown |
- |
|
| Musculoskeletal and connective tissue |
Arthralgia |
uncommon |
uncommon* |
| Joint swelling (ankle swelling) |
common |
- |
|
| Myalgia |
uncommon |
uncommon* |
|
| Muscle cramps |
common |
common |
|
| Back pain |
uncommon |
- |
|
| Kidneys and urinary system |
Urinary disorders, nocturia, increased frequency of urination |
uncommon |
- |
| Renal failure |
- |
uncommon |
|
| Acute renal failure |
- |
rare |
|
| Anuria/oliguria |
- |
rare |
|
| Reproductive system and breast |
Erectile dysfunction |
uncommon |
uncommon |
| Gynecomastia |
uncommon |
- |
|
| General and administration site conditions |
Peripheral edema |
common |
- |
| Edema |
very common |
- |
|
| Malaise |
common |
- |
|
| Chest pain |
uncommon |
- |
|
| Asthenia |
common |
common |
|
| Pain |
uncommon |
- |
|
| Malaise |
uncommon |
uncommon* |
|
| Hyperthermia |
- |
uncommon* |
|
| Investigations |
Increased body weight, decreased body weight |
uncommon |
- |
| Increased blood urea levels |
- |
uncommon* |
|
| Increased blood creatinine levels |
- |
uncommon* |
|
| Increased blood bilirubin levels |
- |
rare |
|
| Increased liver enzyme levels |
-- |
rare |
|
| Decreased hemoglobin and hematocrit levels |
- |
unknown |
|
| Injuries, poisonings and procedural complications |
Fall |
- |
uncommon* |
* The frequency of adverse reactions identified from spontaneous reports was calculated based on clinical trial data.
1 See section "Special precautions for use".
2 See sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use".
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.
Shelf life. 2 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 in a blister; 3 or 9 blisters per cardboard box.
Prescription status. Prescription only.
Manufacturer. KRKA, d.d., Novo mesto / KRKA, d.d., Novo mesto.
Manufacturer's address and location of its business operations.
Smarjeska cesta 6, 8501 Novo mesto, Slovenia / Smarjeska cesta 6, 8501 Novo mesto, Slovenia.