Instructions for AM-Aliter tablets blister 8 mg/5 mg No. 30
Composition
active ingredients: perindopril, amlodipine;
1 tablet contains: perindopril tert-butylamine 4 mg, equivalent to 3.338 mg perindopril and amlodipine besylate 6.935 mg, equivalent to 5 mg amlodipine,
or perindopril tert-butylamine 4 mg, equivalent to 3.338 mg perindopril and amlodipine besylate 13.870 mg, equivalent to 10 mg amlodipine,
or perindopril tert-butylamine 8 mg, equivalent to 6.676 mg perindopril and amlodipine besylate 6.935 mg, equivalent to 5 mg amlodipine,
or perindopril tert-butylamine 8 mg, equivalent to 6.676 mg perindopril and amlodipine besylate 13.870 mg, equivalent to 10 mg amlodipine;
Excipients: lactose monohydrate; microcrystalline cellulose; crospovidone; sodium bicarbonate; colloidal anhydrous silicon dioxide; magnesium stearate.
Dosage form
Pills.
Main physicochemical properties: round biconvex tablets from white to almost white in color.
Pharmacotherapeutic group
Drugs affecting the renin-angiotensin system. ACE inhibitors, combinations. ACE inhibitors and calcium channel blockers. Perindopril and amlodipine. ATX code C09B B04.
Pharmacological properties
Pharmacodynamics.
Perindopril
Mechanism of action
Perindopril is an inhibitor of the enzyme that converts angiotensin I to angiotensin II (angiotensin-converting enzyme ACE). The converting enzyme, or kinase, is an exopeptidase that enables the conversion of angiotensin I to the vasoconstrictor angiotensin II and also causes the breakdown of the vasodilator bradykinin to an inactive heptapeptide. Inhibition of ACE leads to a decrease in the concentration of angiotensin II in the blood plasma, which increases the activity of plasma renin (by inhibiting the negative feedback on renin release) and reduces the secretion of aldosterone. Since ACE inactivates bradykinin, inhibition of ACE also leads to an increase in the activity of the circulating and local kallikrein-kinin system (and thus also leads to the activation of the prostaglandin system). This mechanism of action is responsible for the blood pressure lowering effect of ACE inhibitors and is partly responsible for some of their side effects (e.g., cough).
Perindopril acts through its active metabolite, perindoprilat. Other metabolites do not demonstrate activity in inhibiting ACE under experimental conditions.
Clinical efficacy and safety
Arterial hypertension.
Perindopril effectively lowers blood pressure in all degrees of arterial hypertension: mild, moderate and severe; a decrease in systolic and diastolic blood pressure is observed both in the supine and standing positions.
Perindopril reduces peripheral vascular resistance, which leads to a decrease in blood pressure. As a result, peripheral blood flow increases without affecting heart rate.
Typically, renal blood flow also increases, while glomerular filtration rate (GFR) is usually unchanged.
The maximum antihypertensive effect develops 4–6 hours after a single dose and persists for at least 24 hours: the T/P ratio (effectiveness before the next dose/maximum effectiveness) of perindopril is 87–100%.
Blood pressure decreases rapidly. In patients who respond to treatment, blood pressure normalization occurs within a month and is maintained without the occurrence of tachyphylaxis.
There is no withdrawal effect when perindopril is discontinued.
Perindopril reduces left ventricular hypertrophy.
Clinical studies have shown that perindopril has vasodilating properties. It improves the elasticity of large arteries and reduces the ratio of wall thickness to lumen for small arteries.
Prevention of cardiovascular complications in patients with documented stable coronary artery disease (CAD)
EUROPA is an international multicenter, randomized, double-blind, placebo-controlled clinical trial lasting 4 years. The study enrolled patients with established coronary artery disease and without clinically proven heart failure. Overall, 90% of patients had a history of myocardial infarction and/or revascularization surgery. Most patients in the study received perindopril in addition to standard therapy: antiplatelet agents, lipid-lowering drugs, and β-blockers.
The main efficacy endpoint was a composite of cardiovascular mortality, non-fatal myocardial infarction and/or cardiac arrest with subsequent successful resuscitation. Perindopril tert-butylamine 8 mg once daily resulted in a significant absolute reduction in the primary endpoint.
Amlodipine
Mechanism of action
The mechanism of antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscle. The exact mechanism by which amlodipine reduces angina is not fully understood, but it reduces overall exercise ischemia through the following actions:
- amlodipine dilates peripheral arterioles and thus reduces total peripheral resistance (afterload). Since the heart rate does not change, the reduction in workload on the heart reduces myocardial energy consumption and oxygen demand;
- amlodipine also partially dilates the main coronary arteries and coronary arterioles in both intact and ischemic areas of the myocardium. This dilation increases the supply of oxygen to the myocardium in patients with vasospastic angina (Prinzmetal's angina or variant angina).
In patients with hypertension, once-daily administration of amlodipine provides clinically significant reductions in supine and standing blood pressure over 24 hours. Due to its slow onset of action, amlodipine does not cause acute hypotension.
In patients with angina, taking amlodipine once daily increases the total time of physical exertion, the time to the onset of an angina attack, and increases the time to the onset of 1 mm ST segment depression, reduces the frequency of angina attacks, and reduces the need for nitroglycerin.
Amlodipine is not associated with any negative metabolic effects or changes in plasma lipid levels, so it can be used in patients with asthma, diabetes, and gout.
Coronary heart disease (CHD)
The efficacy of amlodipine in preventing clinical events in patients with coronary heart disease (CHD) was evaluated in an independent multicenter, randomized, double-blind, placebo-controlled trial, “Comparison of Amlodipine with Enalapril in Reducing Thrombosis (CAMELOT)”. For 2 years, patients received: amlodipine 5–10 mg, enalapril 10–20 mg, and placebo in addition to standard therapy with statins, β-blockers, diuretics, and aspirin. The results of the study indicate that treatment with amlodipine was associated with fewer hospitalizations for angina and fewer revascularization procedures in patients with CHD.
Heart failure
Haemodynamic studies and exercise-controlled clinical trials in patients with NYHA class II–IV heart failure have shown that amlodipine did not lead to clinical deterioration in terms of exercise tolerance, left ventricular ejection fraction and clinical symptoms.
The aim of the placebo-controlled PRAISE study was to evaluate the effect of amlodipine in patients with NYHA class III–IV heart failure who were receiving digoxin, diuretics, and ACE inhibitors. The study showed that amlodipine did not increase the risk of mortality or increase the risk of morbidity/mortality related to heart failure.
PRAISE-2 is a long-term placebo-controlled study. The aim of the study was to evaluate the effect of amlodipine in patients with NYHA class III–IV heart failure without clinical symptoms or objective evidence of or underlying ischemic disease. The patients who participated in the study were taking ACE inhibitors, digitalis, and diuretics for a long time. The study showed that amlodipine had no effect on all-cause cardiovascular mortality. In the study, amlodipine was associated with an increased incidence of pulmonary edema.
ALLHAT – a study of different types of treatments to prevent heart attacks
The ALLHAT (Antihypertensive and Lipid-lowering Treatment for Heart Attack Prevention) randomized, double-blind, morbidity/mortality trial was conducted to compare current therapeutic agents: amlodipine 2.5–10 mg/day (calcium channel blocker) or lisinopril 10–40 mg/day (ACE inhibitor) as first-line therapy and the thiazide diuretic chlorthalidone 12.5–25 mg/day in patients with mild to moderate hypertension.
The study included patients with hypertension aged 55 years and older who were followed for a mean of 4.9 years. Patients had at least one additional cardiovascular risk factor, including previous myocardial infarction or stroke or evidence of other atherosclerotic cardiovascular disease, type 2 diabetes, high-density lipoprotein (HDL) dyslipidemia, left ventricular hypertrophy as determined by electrocardiogram or echocardiography, and smoking.
The primary endpoint of the study was a composite of fatal CHD or nonfatal myocardial infarction. Among the secondary endpoints: the incidence of heart failure (a component of the composite cardiovascular endpoint) was significantly higher in the amlodipine group compared with the chlorthalidone group. There was no significant difference in all-cause mortality between amlodipine-based and chlorthalidone-based therapy.
The ASCOT-BLPA (Anglo-Scandinavian Cardiac outcomes Trial – Blood Pressure Lowering Arm) study of morbidity and mortality was conducted in patients with hypertension and at least 3 of the following cardiovascular risk factors: left ventricular hypertrophy (detected by ECG or echocardiography), other abnormalities detected on the electrocardiogram, type 2 diabetes mellitus, peripheral arterial disease, previous stroke or transient ischemic attack, male gender, age 55 years or older, microalbuminuria or proteinuria, smoking, plasma total cholesterol to HDL cholesterol ratio of 6 or more, and family history of early onset of CHD.
The primary objective of the study was to evaluate and compare the long-term effects of two regimens of long-term antihypertensive therapy on the combined endpoint of non-fatal myocardial infarction (including silent myocardial infarction) and fatal complications of coronary artery disease, namely amlodipine in combination with perindopril, which was added when necessary to lower blood pressure, compared with atenolol therapy in combination with the diuretic bendroflumethiazide, which was added when necessary to lower blood pressure.
At the end of the study, most patients were receiving at least two antihypertensive drugs, but there were also those receiving monotherapy with amlodipine and atenolol.
The study showed a non-significant reduction in the primary endpoint of non-fatal myocardial infarction (including asymptomatic myocardial infarction) and fatal CHD in the amlodipine/perindopril group compared with the atenolol/bendroflumethiazide group. However, there was a significant reduction in all secondary endpoints (except fatal and non-fatal heart failure) in the amlodipine/perindopril group.
Pharmacokinetics.
The rate and extent of absorption of perindopril and amlodipine, both as monodrugs and as part of the fixed combination AM-ALITER, do not differ significantly.
Perindopril
Absorption
After oral administration, perindopril is rapidly absorbed, with peak plasma concentrations occurring within 1 hour. The plasma half-life of perindopril is 1 hour.
Perindopril is a prodrug. 27% of the total amount of perindopril taken reaches the bloodstream in the form of the active metabolite - perindoprilat. In addition to the active metabolite - perindoprilat, the drug forms 5 metabolites that are inactive. The maximum concentration of perindoprilat in the blood plasma is reached 3-4 hours after administration.
Food intake reduces the conversion of perindopril to perindoprilat, thus reducing its bioavailability, therefore the daily dose of perindopril tert-butylamine is recommended to be taken once in the morning before meals.
Distribution
There is a linear relationship between the dose of perindopril and its concentration in the blood plasma. The volume of distribution of unbound perindoprilat is approximately 0.2 l/kg.
The binding of perindoprilat to plasma proteins is 20%, mainly to angiotensin-converting enzyme, but this indicator is dose-dependent.
Breeding
Perindoprilat is excreted in the urine. The terminal half-life of the unbound fraction is approximately 17 hours. Steady-state plasma concentrations are reached within 4 days of initiation of treatment.
The elimination of perindoprilat is slowed in elderly patients and in patients with cardiac or renal insufficiency (see section 4.4). Therefore, routine medical supervision will include frequent monitoring of creatinine and potassium levels.
Liver failure
Dialysis clearance of perindoprilat is 70 ml/min.
The kinetics of perindopril are altered in patients with cirrhosis of the liver: the hepatic clearance of perindopril is halved. However, the amount of perindoprilat formed is not reduced. Therefore, no dose adjustment is required in such patients (see section "Special warnings and precautions for use").
Amlodipine
Absorption, distribution, binding to blood plasma proteins
After oral administration of therapeutic doses of amlodipine, it is well absorbed and reaches maximum blood concentrations 6–12 hours after administration. Absolute bioavailability is 64% to 80%. The volume of distribution is approximately 21 l/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.
Food intake does not affect the bioavailability of amlodipine.
Biotransformation/excretion
The plasma half-life is approximately 35–50 hours, which allows the drug to be administered once daily.
Amlodipine is primarily metabolized in the liver to inactive metabolites. 60% of the metabolites are excreted in the urine and 10% in unchanged form.
Elderly patients.
The time to reach maximum plasma concentrations of amlodipine is similar in elderly and younger patients. Elderly patients tend to have a lower clearance of amlodipine and, consequently, an increase in AUC and half-life. The increase in AUC and half-life in patients with congestive heart failure was consistent with the age of the patients studied.
There are very limited clinical data on the use of amlodipine in patients with hepatic impairment. In patients with hepatic impairment, the clearance of amlodipine is reduced, resulting in a prolonged half-life and an increase in AUC by approximately 40-60%.
Indication
Arterial hypertension and/or ischemic heart disease (if treatment with perindopril and amlodipine is necessary).
Contraindication
Related to perindopril:
- hypersensitivity to the active substances or to any other ACE inhibitors;
- history of angioedema associated with previous treatment with ACE inhibitors;
- congenital or idiopathic angioedema;
- pregnancy or planning a pregnancy (see section "Use during pregnancy or breastfeeding");
- simultaneous use with drugs containing the active substance aliskiren in patients with diabetes mellitus or renal insufficiency (glomerular filtration rate < 60 ml/min/1.73 m2) (see section "Interaction with other medicinal products and other types of interactions");
- simultaneous use with sacubitril/valsartan (see sections “Special instructions for use” and “Interaction with other medicinal products and other types of interactions”);
- extracorporeal treatment methods that lead to contact of blood with negatively charged surfaces (see section "Interaction with other medicinal products and other types of interactions");
- significant bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney (see section "Special warnings and precautions for use").
Related to amlodipine:
- severe arterial hypotension;
- hypersensitivity to the active substance or to dihydropyridine derivatives;
- shock, including cardiogenic shock;
- obstruction of the outlet from the left ventricle (for example, severe aortic stenosis);
- heart failure after acute myocardial infarction with unstable hemodynamics.
Related to the drug AM-ALITER:
All of the above contraindications associated with each of the components of the drug apply to the fixed combination AM-ALITER:
- hypersensitivity to any excipient.
Interaction with other medicinal products and other types of interactions
All warnings associated with each of the components of the drug apply to the fixed combination AM-ALITER.
For perindopril
Clinical trial data suggest that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through the concomitant use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher incidence of adverse reactions such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3 and 4.4).
Drugs that cause hyperkalemia.
Some medicinal products or therapeutic classes of medicinal products may cause hyperkalaemia, including aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, non-steroidal anti-inflammatory drugs (NSAIDs), heparins, immunosuppressants such as ciclosporin or tacrolimus, trimethoprim and fixed combination with sulfamethoxazole (Co-Trimoxazole). Concomitant use of these medicinal products increases the risk of hyperkalaemia.
Concomitant use is contraindicated (see section "Contraindications")
Aliskiren.
In patients with diabetes mellitus or patients with impaired renal function, the risk of hyperkalemia, deterioration of renal function and cardiovascular morbidity and mortality is increased.
Extracorporeal treatment methods.
Extracorporeal treatments that bring blood into contact with negatively charged surfaces, such as dialysis or haemofiltration using certain membranes with high hydraulic permeability (e.g. polyacrylonitrile) and low-density lipoprotein apheresis using dextran sulphate, due to an increased risk of severe anaphylactoid reactions (see section 4.3). If such treatments are necessary, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.
Sacubitril/Valsartan.
Concomitant use of perindopril with sacubitril/valsartan is contraindicated, as concomitant inhibition of neprilysin and ACE may increase 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 4.3 and 4.4).
Concomitant use is not recommended.
Aliskiren.
In all other patients, as well as in patients with diabetes mellitus or patients with impaired renal function, the risk of hyperkalemia, deterioration of renal function and cardiovascular morbidity and mortality is increased.
Published data indicate that in patients with established atherosclerosis, heart failure, or diabetes mellitus with target organ damage, concomitant use of ACE inhibitors and angiotensin receptor blockers was associated with an increased incidence of hypotension, syncope, hyperkalemia, and deterioration of renal function (including acute renal failure) compared with monotherapy with drugs that affect the renin-angiotensin-aldosterone system. Dual blockade (i.e., the combination of an ACE inhibitor with an angiotensin II receptor antagonist) may be used in individual cases with careful monitoring of renal function, potassium levels, and blood pressure.
Estramustine.
There is a risk of an increased incidence of adverse reactions such as angioedema.
Co-trimoxazole (trimethoprim/sulfamethoxazole).
In patients concomitantly using co-trimoxazole, there may be an increased risk of developing hyperkalemia (see section "Special warnings and precautions for use").
Potassium-sparing diuretics (e.g., triamterene, amiloride, and others), potassium salts.
Hyperkalemia (possibly fatal) may occur, especially in patients with renal insufficiency (additive hyperkalemic effect). These drugs are not recommended for concomitant use with perindopril (see section "Special warnings and precautions for use"). However, if concomitant use of these substances is necessary, they should be used with caution and with frequent monitoring of plasma potassium. For the use of spironolactone in heart failure, see section "Drugs with which concomitant administration requires special attention".
Lithium.
The simultaneous use of lithium and ACE inhibitors is not recommended due to the possibility of reversible increases in serum lithium concentrations and, consequently, increased toxicity (severe neurotoxicity). However, if the need for such a combination is justified, careful monitoring of serum lithium concentrations is necessary.
Drugs whose concomitant administration requires special attention
Diabetes medications (insulin, oral diabetes medications).
Epidemiological studies suggest that the concomitant use of ACE inhibitors and hypoglycemic agents (insulin, oral hypoglycemic agents) may lead to an increased hypoglycemic effect with a risk of hypoglycemia. This phenomenon may occur most often in the first weeks of combined treatment and in the case of renal insufficiency.
Diuretics.
In patients taking diuretics, and especially in those with impaired water and electrolyte balance, an excessive decrease in blood pressure is possible after starting treatment with an ACE inhibitor. The likelihood of developing a hypotensive effect is reduced if the diuretic is discontinued, the circulating blood volume is increased or salt intake is increased before starting perindopril therapy, which should be started at a low dose with a gradual increase. In arterial hypertension, when the previously prescribed diuretic could have caused water/electrolyte depletion, it should be discontinued before starting treatment with an ACE inhibitor (in such cases, the diuretic can be resumed over time) or the ACE inhibitor should be prescribed at a low dose with a gradual increase. In congestive heart failure on a diuretic, the ACE inhibitor should be started at the minimum dose, possibly after a reduction in the dose of the diuretic. In any case, it is necessary to monitor kidney function (creatinine level) during the first weeks of treatment with an ACE inhibitor.
Potassium-sparing diuretics (eplerenone, spironolactone).
Special care is required when eplerenone or spironolactone 12.5 mg to 50 mg/day are used concomitantly with low doses of an ACE inhibitor. If the recommendations for the use of this combination are not followed, there is a risk of hyperkalemia (possibly fatal) when treating patients with NYHA class II-IV heart failure and an ejection fraction < 40% who have previously been treated with an ACE inhibitor and a loop diuretic. Before prescribing this combination, it is necessary to ensure that there is no hyperkalemia and impaired renal function. It is recommended to carefully monitor potassium and creatinine weekly during the first month of treatment and monthly thereafter.
Racecadotril.
Treatment with ACE inhibitors (e.g. perindopril) is known to cause angioedema. This risk may be increased by concomitant use with racecadotril (a medicine used to treat acute diarrhoea).
mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus).
Patients taking concomitant mTOR inhibitors may be at increased risk of developing angioedema (see section 4.4).
Weakening of the antihypertensive effect is possible during the simultaneous use of ACE inhibitors with NSAIDs such as: acetylsalicylic acid in anti-inflammatory doses, COX-2 inhibitors, non-selective NSAIDs. The simultaneous use of ACE inhibitors and NSAIDs may lead to an increased risk of worsening of renal function, including the likelihood of developing acute renal failure, an increase in plasma potassium levels, especially in patients with a history of impaired renal function. Such a combination should be prescribed with caution, especially in elderly patients. Patients need to restore water balance and monitor renal function at the beginning of treatment with this combination and periodically during treatment.
Drugs whose concomitant administration requires attention
Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin).
Patients prescribed a combination of a gliptin and an ACE inhibitor are at increased risk of angioedema due to the fact that the gliptin reduces the activity of dipeptidyl peptidase-IV (DPP-IV).
Sympathomimetics.
May weaken the antihypertensive effect of ACE inhibitors.
Gold.
With the simultaneous use of ACE inhibitors, including perindopril, and injectable gold preparations (sodium aurothiomalate), reactions similar to those occurring with the use of nitrates (facial flushing, hot flashes, nausea, vomiting and hypotension) may rarely occur.
For amlodipine
Concomitant use is not recommended.
Dantrolene (infusion).
In experimental studies, fatal ventricular fibrillation and cardiovascular collapse have been observed in association with hyperkalemia following intravenous administration of verapamil and dantrolene. Because of the potential for hyperkalemia, it is recommended that concomitant administration of calcium antagonists such as amlodipine be avoided in patients with or suspected of malignant hyperthermia.
Drugs that require special caution when used concomitantly
CYP3A4 inducers.
When used concomitantly with known CYP3A4 inducers, amlodipine plasma concentrations may fluctuate. Therefore, blood pressure should be monitored and the dose adjusted during and after concomitant use, especially with strong CYP3A4 inducers (e.g. rifampicin, Hypericum perforatum).
CYP3A4 inhibitors.
Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, imidazole and triazole antifungals, macrolides such as erythromycin or clarithromycin, verapamil or diltiazem) may result in increased amlodipine concentrations. The clinical manifestation of the above pharmacokinetic changes may be more pronounced in elderly patients. In such cases, clinical monitoring and dose adjustment are necessary. There is an increased risk of hypotension in patients taking clarithromycin in combination with amlodipine. Close supervision is recommended in such patients.
Drugs whose concomitant administration requires attention
When amlodipine is used with other drugs with antihypertensive properties, additive antihypertensive effects are possible.
Tacrolimus.
There is a risk of increased blood levels of tacrolimus when co-administered with amlodipine. To avoid toxic effects of tacrolimus, it is necessary to monitor its blood levels and, if necessary, adjust its dose in patients who are added to amlodipine.
Mechanistic target of rapamycin (mTOR) inhibitors.
mTOR inhibitors such as sirolimus, temsirolimus and everolimus are substrates of CYP3A. Amlodipine is a weak CYP3A inhibitor. When co-administered with mTOR inhibitors, amlodipine may increase the concentration of mTOR inhibitors.
Cyclosporine.
No interaction studies of cyclosporine and amlodipine have been conducted in healthy volunteers or other subjects. The exception is renal transplant patients, in whom cyclosporine concentrations fluctuated with an average increase of 0% to 40%. In renal transplant patients receiving amlodipine and cyclosporine, cyclosporine blood levels should be monitored and the cyclosporine dose reduced if necessary.
Simvastatin.
Coadministration of amlodipine in multiples of 10 mg with simvastatin 80 mg resulted in a 77% increase in simvastatin concentrations compared to simvastatin alone. Patients should limit their simvastatin dose to 20 mg daily.
Other combinations.
Clinical interaction studies have shown that amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin, or warfarin.
Concomitant use of amlodipine and grapefruit or grapefruit juice may increase the bioavailability of amlodipine and, accordingly, may increase the hypotensive effect in some patients.
Common properties of perindopril and amlodipine
Drugs that require special caution when used concomitantly
Baclofen.
Enhances antihypertensive effect. It is necessary to monitor blood pressure and kidney function, and if necessary, adjust the dose.
Drugs whose concomitant administration requires attention
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 a further decrease in blood pressure, so they should be prescribed with caution.
- Corticosteroids, tetracosactide: weakening of the antihypertensive effect (due to water and salt retention by corticosteroids).
- α-blockers (prazosin, alfuzosin, doxazosin, tamsulosin, terazosin): enhance the antihypertensive effect and increase the risk of orthostatic hypotension.
- Amifostine: may enhance the antihypertensive effect of amlodipine.
- Tricyclic antidepressants/antipsychotics/anesthetics: enhance the antihypertensive effect and increase the risk of orthostatic hypotension.
Application features
All warnings associated with each of the components of the drug apply to the fixed combination AM-ALITER.
For perindopril
Hypersensitivity/angioedema.
Rare cases of angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and/or larynx have been reported with the use of ACE inhibitors, including perindopril (see section 4.8). This may occur at any time during treatment. In such cases, AM-ALITER should be discontinued immediately and the patient should be monitored until symptoms resolve. In cases where the swelling is limited to the face and lips, the patient's condition usually improves without treatment; antihistamines may be useful in reducing symptoms.
Angioedema associated with laryngeal oedema can be fatal. In cases where the oedema involves the tongue, glottis or larynx and is likely to cause airway obstruction, urgent emergency treatment is required, which may include the administration of adrenaline and/or maintenance of a patent airway. The patient should be kept under close medical supervision until complete and sustained resolution of symptoms.
Patients with a history of angioedema unrelated to ACE inhibitors may be at increased risk of developing angioedema when receiving ACE inhibitors (see section 4.3).
Intestinal angioedema has been reported rarely in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea and vomiting); in some cases, there was no previous history of facial angioedema and C-1 esterase levels were normal. The diagnosis of intestinal angioedema was made by computed tomography or ultrasound, or at the time of surgery. Symptoms of angioedema resolved after discontinuation of the ACE inhibitor. Intestinal angioedema should be considered in the differential diagnosis of abdominal pain in patients receiving ACE inhibitors (see section 4.8).
Sucubitril/Valsartan.
Concomitant use of perindopril with sacubitril/valsartan is contraindicated due to an increased risk of angioedema (see section 4.3). Sacubitril/valsartan should not be started until 36 hours after the last dose of perindopril. If treatment with sacubitril/valsartan is discontinued, perindopril should not be started until 36 hours after the last dose of sacubitril/valsartan (see sections 4.3 and 4.5).
Other neutral endopeptidase (NEP) inhibitors (e.g., racecadotril).
Concomitant use of other neutral endopeptidase (NEP) inhibitors (e.g. racecadotril) and ACE inhibitors may also lead to an increased risk of angioedema (see section 4.5). Therefore, before starting treatment
