Amlessa tablets 8 mg + 10 mg blister No. 30

Instructions for Amlessa tablets 8 mg + 10 mg blister No. 30

Composition

active ingredients: perindopril tert-butylamine and amlodipine;

1 tablet contains 4 mg perindopril tert-butylamine (equivalent to 3.34 mg perindopril) and 5 mg amlodipine (equivalent to 6.935 mg amlodipine besylate) or

4 mg perindopril tert-butylamine (equivalent to 3.34 mg perindopril) and 10 mg amlodipine (equivalent to 13.870 mg amlodipine besylate), or

8 mg perindopril tert-butylamine (equivalent to 6.68 mg perindopril) and 5 mg amlodipine (equivalent to 6.935 mg amlodipine besylate), or

8 mg perindopril tert-butylamine (equivalent to 6.68 mg perindopril) and 10 mg amlodipine (equivalent to 13.870 mg amlodipine besylate);

Excipients: microcrystalline cellulose; pregelatinized starch; sodium starch glycolate; calcium chloride, hexahydrate; sodium bicarbonate; colloidal anhydrous silicon dioxide; magnesium stearate.

Dosage form

Pills.

Main physicochemical properties:

4 mg/5 mg: white or almost white, round, slightly biconvex tablets with beveled edges;

4 mg/10 mg: white or almost white, capsule-shaped, biconvex, with a score on one side of the tablet;

8 mg/5 mg: white or almost white, round, biconvex tablets with beveled edges;

8 mg/10 mg: white or almost white, round, biconvex tablets with beveled edges and a score line on one side.

Pharmacotherapeutic group

Combined preparations of angiotensin-converting enzyme inhibitors. ACE inhibitors in combination with calcium antagonists. ATC code C09B B04.

Pharmacological properties

Pharmacodynamics.

The rate and extent of absorption of perindopril and amlodipine as monodrugs in the composition of Amlessa do not differ significantly.

Perindopril

Perindopril is an inhibitor of angiotensin-converting enzyme (ACE), which converts ACE. The converting enzyme, or kinase, is an exopeptidase that converts angiotensin I to angiotensin II and also causes the breakdown of the vasodilator agent bradykinin to an inactive heptapeptide. Inhibition of ACE activity leads to a decrease in the concentration of angiotensin II in the blood plasma, which is accompanied by an increase in plasma renin activity (by inhibiting the negative feedback of renin release) and a decrease in aldosterone secretion. Since ACE blocks bradykinin, inhibition of the activity of this enzyme leads to an increase in the activity of the circulating and local kallikrein-kinin system and, thereby, to the activation of the prostaglandin system. This mechanism contributes to the blood pressure-lowering effect of ACE inhibitors and is partly responsible for some of the side effects (such as cough).

Perindopril is converted in the body to the active metabolite perindoprilat. Other metabolites do not show inhibition of ACE activity in vitro.

Amlodipine

Amlodipine is a calcium ion antagonist that blocks the influx of calcium ions through the membranes into the smooth muscle cells of the myocardium and blood vessels. The mechanism of hypotensive action of amlodipine is due to a direct effect on the smooth muscle of the blood vessels. The exact mechanism of action of amlodipine in angina has not been established, but it is known that amlodipine reduces myocardial ischemia in two ways.

Amlodipine dilates peripheral arterioles and thus reduces the total peripheral resistance (afterload) against which the heart works. The reduction in workload on the heart leads to a decrease in energy consumption and myocardial oxygen demand.

The mechanism of action of amlodipine also probably involves dilation of the main coronary arteries and coronary arterioles. This dilation increases the oxygen supply to the myocardium in patients with Prinzmetal's angina. In patients with hypertension, once-daily dosing provides clinically significant reductions in blood pressure (both standing and supine) over a 24-hour period.

In patients with angina, once-daily administration of amlodipine prolongs total active time, time to angina onset, and time to 1 mm ST-segment depression. Amlodipine reduces the frequency of angina attacks and the need for nitroglycerin tablets.

Pharmacokinetics.

Perindopril

After oral administration, perindopril is rapidly absorbed, with peak plasma concentrations (Cmax) occurring within 1 hour. The plasma half-life (t1/2) of perindopril is 1 hour.

Perindopril is a prodrug. 27% of the administered dose of perindopril enters the bloodstream as the active metabolite perindoprilat. In addition to the active perindoprilat, perindopril forms 5 more inactive metabolites. Cmax of perindoprilat in blood plasma is reached after 3-4 hours.

Since food intake reduces the conversion of perindopril to perindoprilat, and therefore its bioavailability, it is recommended that perindopril tert-butylamine be taken orally in a single daily dose in the morning before meals.

There is a linear relationship between the dose of perindopril and its concentration in blood plasma.

The elimination of perindoprilat is reduced in elderly patients and in patients with heart or renal failure. Therefore, regular monitoring of potassium and creatinine levels is necessary.

The dialysis clearance of perindoprilat is 70 ml/min.

The kinetics of perindopril are altered in patients with cirrhosis: the hepatic clearance of the parent molecule is halved. However, the amount of perindoprilat formed is not reduced. Therefore, no dose adjustment is required in such patients.

Amlodipine

After oral administration in therapeutic doses, amlodipine is well absorbed and reaches Cmax 6-12 hours after administration. Absolute bioavailability is from 64 to 80%. The volume of distribution is approximately 21 l/kg. Food intake does not affect the bioavailability of amlodipine. In vitro studies have shown that approximately 97.5% of circulating amlodipine binds to plasma proteins.

T1/2 is approximately 35-50 hours, which allows the drug to be administered once a day. Amlodipine is metabolized in the liver to form inactive metabolites. 60% of the dose is excreted in the urine, and 10% of the drug is excreted unchanged.

Use in elderly patients. The time required to reach Cmax of amlodipine is the same in both elderly and younger patients. In elderly people, there is a tendency for amlodipine clearance to decrease, resulting in an increase in AUC (area under the concentration-time curve) and t1/2. The recommended dosage regimen for elderly patients is similar, but dose increases should be made with caution.

Use in patients with renal insufficiency (see section "Method of administration and dosage").

Use in patients with impaired liver function. T1/2 of amlodipine, like all calcium antagonists, is increased in patients with impaired liver function.

Indication

Arterial hypertension and/or ischemic heart disease (if treatment with perindopril and amlodipine is necessary).

Contraindication

Hypersensitivity to perindopril (or to any other ACE inhibitors), to amlodipine (or to other dihydropyridines) or to any of the excipients of the drug;

history of angioedema after taking any ACE inhibitors;

idiopathic or hereditary angioedema;

severe arterial hypotension;

shock, including cardiogenic shock;

obstruction of the left ventricular outflow tract (for example, severe aortic stenosis);

unstable angina;

heart failure after acute myocardial infarction (within the first 28 days);

pregnant women or women planning to become pregnant (see section "Use during pregnancy or breastfeeding");

simultaneous use with drugs containing the active substance aliskiren in patients with diabetes mellitus or patients with renal insufficiency (glomerular filtration rate < 60 ml/min/1.73 m2) (see sections “Interaction with other medicinal products and other types of interactions” and “Special precautions for use”);

Concomitant use with sacubitril/valsartan. Perindopril therapy should not be started 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 warnings and precautions for use”);

extracorporeal treatments that result in blood coming into contact 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").

Interaction with other medicinal products and other types of interactions

All warnings associated with each of the components of the drug also apply to Amlessa.

For perindopril

Concomitant use is contraindicated.

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

Clinical trial data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher incidence of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared with the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).

Sacubitril/valsartan. Concomitant use of perindopril with sacubitril/valsartan is contraindicated because 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 of ACE inhibitors and angiotensin receptor blockers

Published data have shown that in patients with established atherosclerosis, heart failure, or diabetes mellitus with target organ damage, the 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 (RAAS). Dual blockade (i.e., the combination of an ACE inhibitor with angiotensin II receptor antagonists) may be used in individual cases and with careful monitoring of renal function, potassium levels, and blood pressure.

Estramustine

The risk of adverse reactions such as angioedema increases.

Co-trimoxazole (trimethoprim/sulfamethoxazole): Patients receiving co-trimoxazole may be at increased risk of developing hyperkalemia (see section 4.4).

Potassium-sparing diuretics, potassium supplements, or salt substitutes containing potassium

Although serum potassium usually remains within normal limits, hyperkalemia (potentially fatal) may occur in some patients treated with perindopril, especially in combination with impaired renal function (additive hyperkalemic effect). Potassium-sparing diuretics (e.g. spironolactone, triamterene or amiloride), potassium supplements or salt substitutes containing potassium may lead to significant increases in serum potassium. Caution should also be exercised when perindopril is administered concomitantly with other agents that increase serum potassium, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim is known to act as a potassium-sparing diuretic like amiloride. Therefore, the combination of perindopril with the above-mentioned drugs is not recommended. If concomitant use is indicated, they should be used with caution and with frequent monitoring of serum potassium.

Cyclosporine

Hyperkalemia may occur with concomitant use of ACE inhibitors with cyclosporine. Monitoring of serum potassium is recommended.

Heparin

Hyperkalemia may occur with concomitant use of ACE inhibitors with heparin. Monitoring of serum potassium is recommended.

Potassium-sparing diuretics (e.g. triamterene, amiloride), potassium salts

Hyperkalemia (including fatal) may occur, especially in patients with renal insufficiency (additive hyperkalemic effect). The above-mentioned drugs are not recommended for concomitant use with perindopril (see section "Special warnings and precautions for use"). However, if concomitant administration of the above-mentioned substances is necessary, they should be used with caution and frequent monitoring of potassium in the blood plasma should be performed.

Lithium

When using ACE inhibitors with lithium preparations, a reversible increase in plasma lithium concentration is possible and, accordingly, an increase in the risk of its toxic effects. It is not recommended to use perindopril with lithium preparations. In case of proven need for such use, careful monitoring of lithium levels in the blood plasma is mandatory (see section "Special instructions").

Concomitant use requiring special attention

Drugs that cause hyperkalemia

Some drugs or therapeutic classes may increase the risk of hyperkalemia: aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, NSAIDs, heparins, immunosuppressants such as ciclosporin or tacrolimus, trimethoprim and fixed-dose combination with sulfamethoxazole (Co-Trimoxazole). The combination of these drugs increases the risk of hyperkalemia.

Antidiabetic agents (insulin, oral hypoglycemic agents)

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 is most likely to occur during the first weeks of combined treatment and in patients with renal insufficiency.

Baclofen

The antihypertensive effect is enhanced. If necessary, blood pressure should be monitored and the dose of antihypertensive drugs should be adapted.

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, it is necessary to monitor kidney function (creatinine level) during the first weeks of treatment with an ACE inhibitor.

Potassium-sparing diuretics (eplerenone, spironolactone)

In the case of simultaneous use of eplerenone or spironolactone in doses from 12.5 mg to 50 mg per day with low doses of an ACE inhibitor, it should be borne in mind that:

If the recommendations for prescribing this combination are not followed, there is a risk of hyperkalemia (possibly fatal) during the treatment of patients with NYHA class II-IV heart failure and an ejection fraction < 40%, who were previously treated with an ACE inhibitor and a loop diuretic;

before prescribing such a combination, one should make sure that there is no hyperkalemia and renal failure;

It is recommended to carefully monitor potassium and creatinine levels 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 receiving concomitant mTOR inhibitors may be at increased risk of developing angioedema (see section 4.4).

NSAIDs, including acetylsalicylic acid ≥ 3 g/day

The antihypertensive effect may be reduced when ACE inhibitors are used concomitantly with NSAIDs, such as acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, non-selective NSAIDs. The concomitant use of ACE inhibitors and NSAIDs may lead to an increased risk of worsening of renal function, including the possibility of developing acute renal failure, an increase in plasma potassium levels, especially in patients with a history of impaired renal function. This combination should be administered with caution, especially in elderly patients. Patients should be rehydrated and attention should be paid to monitoring renal function immediately after the initiation of combination therapy and periodically thereafter.

Concomitant use requiring attention

Antihypertensives and vasodilators

Concomitant use of antihypertensive agents may increase the hypotensive effect of perindopril. Concomitant use with nitroglycerin and other nitrates or with other vasodilators may contribute to an additional decrease in blood pressure.

Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin)

In patients prescribed a combination of a gliptin and an ACE inhibitor, there may be an increased risk of angioedema due to the fact that the gliptin reduces the activity of dipeptidyl peptidase-IV (DPP-IV).

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

Diuretics

In patients taking diuretics, and especially in those with impaired water and electrolyte metabolism, an excessive decrease in blood pressure is possible after starting treatment with an ACE inhibitor. The likelihood of developing a hypotensive effect is reduced by discontinuing the diuretic, increasing the circulating blood volume or salt intake before starting therapy with perindopril. Treatment should be started with low doses and gradually increased.

Sympathomimetics may weaken the antihypertensive effect of ACE inhibitors.

Gold: A nitrate-like reaction (symptoms: facial flushing, nausea, vomiting, and hypotension) has occurred rarely in patients receiving concomitant ACE inhibitors, including perindopril, and injectable gold (sodium aurothiomalate).

For amlodipine

Effects of other drugs on amlodipine

CYP3A4 inhibitors

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

It is not recommended to use amlodipine and grapefruit or grapefruit juice simultaneously, since in some patients the bioavailability of amlodipine may increase, which primarily leads to increased hypotensive effect.

CYP3A4 inducers

Plasma concentrations of amlodipine may be altered when used concomitantly with known CYP3A4 inducers. Therefore, blood pressure should be monitored and dose adjustments considered both during and after concomitant medication, especially with strong CYP3A4 inducers (e.g. rifampicin, St. John's wort).

Fatal ventricular fibrillation and cardiovascular collapse associated with hyperkalemia have been observed in animals following intravenous administration of verapamil and dantrolene. Due to the risk of hyperkalemia, it is recommended that calcium channel blockers such as amlodipine be avoided in patients predisposed to malignant hyperthermia and in the treatment of malignant hyperthermia.

Effect of amlodipine on other medicinal products

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

Tacrolimus

There is a risk of increased blood levels of tacrolimus when co-administered with amlodipine, but the pharmacokinetic mechanism of this interaction has not been fully established. To avoid tacrolimus toxicity, regular monitoring of tacrolimus blood levels and, if necessary, dosage adjustment are required when amlodipine is co-administered.

Cyclosporine

No interaction studies have been conducted with ciclosporin and amlodipine in healthy volunteers or other populations, except in renal transplant patients, where a variable increase in ciclosporin trough concentrations (mean 0-40%) was observed. In renal transplant patients receiving amlodipine, monitoring of ciclosporin concentrations should be considered and, if necessary, a reduction in the ciclosporin dose should be considered.

Simvastatin

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

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

Mechanistic target of rapamycin (mTOR) inhibitors

mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are substrates of CYP3A. Amlodipine is a weak inhibitor of CYP3A. When co-administered with mTOR inhibitors, amlodipine may increase the exposure of mTOR inhibitors.

Application features

All warnings associated with each of the components of the drug apply to Amlessa.

For perindopril

Special precautions

Hypersensitivity/angioedema

Rare cases of angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and/or larynx have been reported in patients receiving ACE inhibitors, including perindopril (see section 4.8). This may occur at any time during treatment. In such cases, the drug should be discontinued immediately and the patient should be monitored until symptoms resolve. In isolated 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 causing airway obstruction, urgent emergency treatment is required, which may include administration of adrenaline and/or airway management. Patients should be closely monitored until symptoms resolve and the condition stabilizes.

Patients with a history of angioedema unrelated to ACE inhibitor therapy are at increased risk of developing angioedema while receiving an ACE inhibitor (see section 4.3).

Rare cases of intestinal angioedema have been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or 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 abdominal computed tomography or ultrasound, or at the time of surgery. Symptoms of angioedema resolved after discontinuation of the ACE inhibitor. Intestinal angioedema should be excluded in the differential diagnosis of patients presenting with abdominal pain while taking ACE inhibitors (see section 4.8).

Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin may lead to an increased risk of angioedema (e.g. swelling of the airways or speech, with or without respiratory distress) (see section 4.5). Caution should be exercised when administering racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin to a patient already taking an ACE inhibitor.

Anaphylactoid reactions during low-density lipoprotein (LDL) plasmapheresis

Rarely, life-threatening anaphylactoid reactions may occur in patients receiving ACE inhibitors during plasmapheresis of LDL using dextran sulfate. The development of anaphylactoid reactions can be avoided by temporarily stopping ACE inhibitor treatment before each plasmapheresis.

Anaphylactoid reactions during desensitization therapy

Anaphylactoid reactions may occur in patients taking ACE inhibitors during desensitization treatment with bee venom-containing drugs. These reactions can be avoided by temporarily discontinuing the ACE inhibitor, but the reactions may recur if provocation tests are performed carelessly.

Neutropenia/agranulocytosis/thrombocytopenia/anemia

Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in patients taking ACE inhibitors. Neutropenia is rare in patients with normal renal function and in the absence of other risk factors. Perindopril should be administered with great caution to patients with collagen vascular diseases, immunosuppressants, allopurinol or procainamide or a combination of these aggravating factors, especially in the presence of pre-existing renal impairment. Serious infections may occasionally develop in these patients, which in rare cases may not respond to intensive antibiotic therapy. If perindopril is prescribed to such patients, periodic monitoring of the white blood cell count is recommended and patients should be advised to report any signs of infection (sore throat, fever).

Renovascular hypertension

Patients with bilateral renal artery stenosis or stenosis of the artery to a solitary functioning kidney are at increased risk of hypotension and renal failure when treated with ACE inhibitors (see section 4.3). Diuretic therapy may be beneficial. 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)

There is evidence that the concomitant use of ACE inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalemia and decreased renal function (including acute renal failure). Therefore, dual blockade of the RAAS through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is not recommended (see sections 4.5 and 5.1).

If dual blockade therapy is considered absolutely necessary, it should only be done under specialist supervision and with frequent, 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 aldosteronism

Patients with primary hyperaldosteronism generally do not respond to antihypertensive drugs that act through inhibition of the renin-angiotensin system. Therefore, the use of this drug is not recommended.

Pregnancy

ACE inhibitors should not be used during pregnancy. Patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if possible, alternative therapy should be started (see sections 4.3 and 4.8).

Precautions for use

Stable ischemic heart disease

If an episode of unstable angina (of any severity) occurs during the first month of treatment with perindopril, the risk/benefit ratio should be carefully weighed before deciding whether to continue therapy.

ACE inhibitors may cause a decrease in blood pressure. Symptomatic hypotension is less common in patients with uncomplicated hypertension and is more likely in patients who are volume-depleted, taking diuretics, on a salt-restricted diet, on dialysis, in patients with diarrhoea or vomiting, or in patients with severe renin-dependent hypertension (see sections 4.5 and 4.8). Symptomatic hypotension is more likely in patients with symptomatic heart failure, with or without concomitant renal insufficiency. Symptomatic hypotension is most likely to occur in patients with more severe heart failure, who are receiving high doses of loop diuretics, who have hyponatremia or functional renal failure. To reduce the risk of symptomatic hypotension, patients should be closely monitored during initiation of therapy and during dose titration (see sections 4.2 and 4.8). The same precautions apply to patients with ischemic heart disease or cerebrovascular disease, in whom an excessive decrease in blood pressure could result in myocardial infarction or stroke.

If hypotension occurs, the patient should be placed in the supine position and, if necessary, intravenously administered 0.9% (9 mg/ml) sodium chloride solution. Transient hypotension is not a contraindication to continued use of the drug, which can usually be used without any problems after volume restoration and blood pressure increase.

In some patients with congestive heart failure with normal or low blood pressure, perindopril may cause an additional decrease in systemic blood pressure. This effect is expected and usually does not require discontinuation of the drug. If hypotension becomes symptomatic, it may be necessary to reduce the dose or discontinue the drug.

Aortic and mitral valve stenosis/hypertrophic cardiomyopathy

As with other ACE inhibitors, perindopril should be administered with caution to patients with mitral valve stenosis or left ventricular outflow obstruction (aortic stenosis or hypertrophic cardiomyopathy).

Kidney failure

In case of renal insufficiency (creatinine clearance < 60 ml/min), the initial dose of perindopril should be adjusted according to the patient's creatinine clearance (see section 4.2) and then according to the patient's response to treatment. Monitoring of potassium and creatinine is standard practice in such patients (see section 4.8).

In patients with symptomatic heart failure, hypotension occurring at the start of ACE inhibitors may lead to deterioration of renal function, in some cases with the development of acute renal failure, which is usually reversible.

In some patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, increases in blood urea and serum creatinine have been observed during treatment with ACE inhibitors, which usually return to normal after discontinuation of treatment. This is especially true in patients with renal insufficiency. In the presence of concomitant renovascular hypertension, the risk of severe hypotension and renal insufficiency increases. Treatment of such patients should be initiated under close medical supervision, with low doses and with careful dose titration. In view of the above, diuretic treatment may contribute to the development of arterial hypotension, so they should be discontinued and renal function should be monitored during the first weeks of treatment with perindopril.

Some hypertensive patients without pre-existing renovascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, particularly when perindopril tert-butylamine has been administered concomitantly with a diuretic. However, this is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or perindopril may be necessary.

Liver failure