Instructions for Prenesa tablets 4 mg blister No. 90
Composition
active ingredient: perindopril tert-butylamine;
1 tablet contains 2 mg or 4 mg or 8 mg of perindopril as tert-butylamine salt;
Excipients: calcium chloride hexahydrate, lactose monohydrate, crospovidone, microcrystalline cellulose, colloidal anhydrous silicon dioxide, magnesium stearate.
Dosage form
Pills.
Main physicochemical properties:
2 mg tablets: white to off-white, round, slightly biconvex, with beveled edges;
4 mg tablets: white to off-white, oval, slightly biconvex, with beveled edges and a score on one side.
8 mg tablets: white to off-white, round, slightly biconvex, with beveled edges and a score on one side.
Pharmacotherapeutic group
Angiotensin-converting enzyme (ACE) inhibitors, monocomponent. Perindopril. ATC code C09AA04.
Pharmacological properties
Pharmacodynamics.
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 a feedback mechanism) 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 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 tert-butylamine acts through its active metabolite, perindoprilat. Other metabolites do not demonstrate activity in inhibiting ACE under experimental conditions.
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 in the patient 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 (minimum efficacy/maximum efficacy during the day) 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 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.
Combination therapy with a thiazide diuretic shows an additive synergistic effect. The combination of an ACE inhibitor and a thiazide diuretic also reduces the risk of diuretic-induced hypokalemia.
Heart failure.
In experimental studies of congestive heart failure induced by coronary artery ligation, perindopril has been shown to reduce myocardial hypertrophy and excessive subendocardial collagen, restore the myosin to isoenzyme ratio, and reduce the incidence of reperfusion arrhythmia.
Perindopril tert-butylamine facilitates the work of the heart by reducing pre- and afterload on the heart.
Studies involving patients with heart failure have demonstrated:
- decrease in filling pressure of the right and left ventricles,
- reduction of systemic peripheral resistance,
- increase in cardiac index and improvement in cardiac output,
- increased regional muscle blood flow in the myocardium.
In comparative studies, the initial administration of 2 mg perindopril to patients with mild to moderate heart failure was not associated with any significant reduction in blood pressure compared with placebo.
Pharmacokinetics.
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.
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.
There is a linear relationship between the dose of perindopril and its concentration in blood plasma.
Distribution.
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.
Special patient groups.
The elimination of perindoprilat is slowed in elderly patients and in patients with heart or renal failure. It is recommended to select the dose for patients with renal failure, taking into account the degree of insufficiency (creatinine clearance).
Dialysis clearance of perindoprilat is 70 ml/min.
The kinetics of perindopril are altered in patients with cirrhosis: 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.
Indication
– Arterial hypertension.
– Heart failure.
– Prevention of recurrent stroke in patients with cerebrovascular disease.
– Prevention of cardiovascular complications in patients with documented stable ischemic heart disease.
Long-term treatment reduces the risk of myocardial infarction and heart failure (according to the results of the EUROPA study).
Contraindication
– Hypersensitivity to the active substance or to any other ingredient of the drug, as well as to other angiotensin-converting enzyme (ACE) inhibitors.
– History of angioedema associated with previous treatment with angiotensin-converting enzyme (ACE) inhibitors.
– Hereditary or idiopathic angioedema.
– Concomitant administration with drugs containing the active substance aliskiren to patients with diabetes mellitus or renal insufficiency (glomerular filtration rate < 60 ml/min/1.73 m2) (see sections “Special warnings and precautions for use” and “Interaction with other medicinal products and other types of interactions”).
– Contraindicated for women planning pregnancy and pregnant women.
Interaction with other medicinal products and other types of interactions
Drugs that cause hyperkalemia.
Some medicinal products or therapeutic classes of medicinal products may cause hyperkalaemia, such as: 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. Concomitant use of these medicinal products increases the risk of hyperkalaemia.
The concomitant use of perindopril with aliskiren is contraindicated (see section "Contraindications") in patients with diabetes mellitus or patients with impaired renal function due to the increased risk of hyperkalemia, worsening of renal function, cardiovascular morbidity and mortality and is not recommended (see section "Special warnings and precautions for use") in all other patient groups.
Concomitant use of ACE inhibitors and angiotensin receptor blockers: According to the literature, 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 to monotherapy with drugs that affect the renin-angiotensin-aldosterone system. Dual blockade (i.e. the combination of an ACE inhibitor with angiotensin II receptor antagonists) may be used in individual cases and under careful monitoring of renal function, potassium levels and blood pressure.
Estramustine: increased risk of adverse reactions such as angioedema.
Potassium-sparing diuretics (e.g. triamterene, amiloride), potassium salts:
Hyperkalemia (possibly 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 use of the above-mentioned substances is necessary, they should be used with caution and with frequent monitoring of plasma potassium.
Lithium.
Concomitant use requiring special attention.
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 in the first weeks of combined treatment and in patients with renal insufficiency.
Baclofen: increased antihypertensive effect. If necessary, blood pressure should be monitored and the dose of antihypertensive drugs should be adapted.
Diuretics: In patients taking diuretics, and especially in those with impaired water and electrolyte metabolism, an excessive decrease in blood pressure may occur 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 tert-butylamine. Treatment should be started with low doses and increased gradually.
In hypertension, when a previously prescribed diuretic may have caused water/electrolyte depletion, it should be discontinued before starting treatment with an ACE inhibitor (in such cases, the diuretic may be resumed over time), or an ACE inhibitor should be prescribed at a low dose with a gradual increase in dose.
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 is necessary:
- 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, it is necessary to ensure the absence of hyperkalemia and renal failure;
- it is recommended to carefully monitor potassium and creatinine levels weekly during the first month of treatment and monthly thereafter.
Non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid ≥ 3 g/day. A reduction in the antihypertensive effect may occur when ACE inhibitors are used concomitantly with NSAIDs such as: acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, non-selective NSAIDs. Concomitant use of ACE inhibitors and NSAIDs may increase the risk of worsening renal function, including the possibility of acute renal failure, and an increase in plasma potassium, especially in patients with a history of impaired renal function. This combination should be administered with caution, particularly in elderly patients. Patients should be rehydrated and renal function should be monitored closely, immediately after initiation of combination therapy and periodically thereafter.
Simultaneous use, which requires some attention.
Antihypertensives and vasodilators: Concomitant use of antihypertensives may increase the hypotensive effect of perindopril tert-butylamine. 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): Patients receiving a combination of a gliptin and an ACE inhibitor may be at increased risk of angioedema due to the gliptin's inhibition of dipeptidyl peptidase-IV (DPP-IV) activity.
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").
Sympathomimetics may weaken the antihypertensive effect of ACE inhibitors.
Gold: A nitrate-like reaction (symptoms include facial flushing, nausea, vomiting, and hypotension) has been reported rarely in patients receiving concomitant ACE inhibitors, including perindopril, and injectable gold (sodium aurothiomalate).
Application features
Before starting and during use of the drug, it is necessary to monitor blood pressure, kidney function and potassium in the blood plasma.
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, undergoing dialysis, experiencing 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 insufficiency. 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 tert-butylamine 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 tert-butylamine 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 adjusted 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. In such patients, treatment should be initiated under close medical supervision with low doses and with careful dose titration. Given 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 tert-butylamine.
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 given concomitantly with a diuretic. However, this is more likely to occur in patients with pre-existing renal impairment. A dose reduction and/or discontinuation of the diuretic and/or perindopril tert-butylamine may be necessary.
Patients on hemodialysis.
Anaphylactic-type reactions have been reported in patients receiving hemodialysis with high-flux polyacrylic membranes and concomitant ACE inhibitors. Therefore, a decision should be made to use a different type of dialysis membrane or a different class of antihypertensive drug in these patients.
Patients after kidney transplantation.
There is no experience with the administration of perindopril tert-butylamine to patients after a recent kidney transplant.
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 tert-butylamine (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 those rare 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 edema can be fatal. In cases where edema involves the tongue, glottis, or larynx, causing airway obstruction, 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 with abdominal pain taking ACE inhibitors.
Anaphylactoid reactions during low-density lipoprotein (LDL) plasmapheresis.
Rarely, life-threatening anaphylactoid reactions have occurred in patients receiving ACE inhibitors during low-density lipoprotein (LDL) plasmapheresis using dextran sulfate. Anaphylactoid reactions can be avoided by temporarily stopping ACE inhibitor therapy before each plasmapheresis.
Anaphylactoid reactions during desensitization therapy.
Anaphylactoid reactions may occur in patients receiving 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.
Liver failure.
Cases of a syndrome that begins with cholestatic jaundice and progresses to transient hepatic necrosis and sometimes fatal outcome have been reported rarely in patients receiving ACE inhibitors. The mechanism of this syndrome is unknown. Patients who develop jaundice or significant elevations of liver enzymes while receiving ACE inhibitors should discontinue the drug and receive appropriate medical evaluation and treatment (see section 4.8).
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 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 white blood cell counts is recommended and patients should be advised to report any signs of infection (sore throat, fever).
Racial factor.
ACE inhibitors cause angioedema more often in black patients than in non-black patients. Like other ACE inhibitors, perindopril is less effective in lowering blood pressure in black patients than in non-black patients. This may be because of the lower renin status of black hypertensive patients.
Cough.
Cough has been reported with ACE inhibitor therapy. The cough is typically non-productive, persistent, and resolves after discontinuation of the drug. Cough associated with ACE inhibitors should be considered in the differential diagnosis of cough.
Perindopril may block the secondary formation of angiotensin II in response to compensatory renin release in patients undergoing surgery or during anesthesia with drugs that cause hypotension. The drug should be discontinued one day before surgery. In the event of arterial hypotension, if it is considered that it is caused by this mechanism, the patient's condition can be normalized by increasing the volume of circulating blood.
Hyperkalemia
Some patients have experienced increases in serum potassium while taking ACE inhibitors, including perindopril. Risk factors for the development of hyperkalemia include renal failure, worsening of renal function, age (over 70 years), diabetes mellitus, intercurrent conditions such as dehydration, acute cardiac decompensation, metabolic acidosis, and concomitant use of potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene or amiloride), potassium supplements or potassium-containing salt substitutes; or those patients taking other drugs that may increase serum potassium (e.g. heparin). The use of potassium supplements, potassium-sparing diuretics or potassium-containing salt substitutes, especially in patients with impaired renal function, may lead to significant increases in serum potassium. Hyperkalemia may cause serious, sometimes fatal arrhythmias. If concomitant use of perindopril and any of the above-mentioned substances is considered appropriate, they should be used with caution and with frequent monitoring of serum potassium levels (see section 4.5).
Patients with diabetes
Diabetic patients taking oral hypoglycemic agents or insulin should have their blood glucose levels closely monitored during the first month of treatment with ACE inhibitors (see section 4.5).
Lithium
The concomitant use of lithium and perindopril is generally not recommended (see section "Interaction with other medicinal products and other types of interactions").
Potassium-sparing drugs, potassium-containing dietary supplements, or potassium-containing salt substitutes
The concomitant use of perindopril with potassium-sparing medicinal products or potassium-containing food supplements is not recommended (see section "Interaction with other medicinal products and other types of interactions").
Dual blockade of the renin-angiotensin-aldosterone system (RAAS).
There have been reports of hypotension, syncope, stroke, hyperkalemia and renal dysfunction (including acute renal failure), especially with concomitant use of drugs that affect the RAAS. The combination of an ACE inhibitor (ACEI) with an angiotensin II receptor blocker (ARB) or with aliskiren is not recommended given the dual blockade of the renin-angiotensin-aldosterone system.
In patients with diabetes mellitus or renal insufficiency (glomerular filtration rate < 60 ml/min/1.73 m2), concomitant administration with aliskiren is contraindicated (see sections “Contraindications” and “Interaction with other medicinal products and other types of interactions”).
Excipients
The drug contains lactose, therefore patients with rare hereditary problems of galactose intolerance, glucose-galactose malabsorption syndrome, or Lapp lactase deficiency are not recommended to take perindopril tertbutylamine.
Use during pregnancy or breastfeeding
Pregnancy: the use of ACE inhibitors is contraindicated during pregnancy.
When planning pregnancy, patients 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 appropriate, alternative therapy should be started.
It is known that taking ACE inhibitors during the second and third trimesters of pregnancy leads to fetotoxicity and neonatal toxicity.
In case the woman took an ACE inhibitor during the second trimester of pregnancy, it is recommended to conduct an ultrasound examination of the child's renal function and skull. Newborns whose mothers took ACE inhibitors during pregnancy should be closely monitored due to the possibility of arterial hypotension.
Breastfeeding: Perindopril tert-butylamine is not recommended for use during breast-feeding as it is not known whether it is excreted in human milk. Alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.
Fertility: No effect on reproductive capacity or fertility.
Ability to influence reaction speed when driving vehicles or other mechanisms
Perindopril tert-butylamine has no direct influence on the ability to drive or use machines. However, some patients may experience individual reactions associated with a decrease in blood pressure, especially at the beginning of treatment or when used simultaneously with other antihypertensive drugs. As a result, the ability to drive or use machines may be impaired.
Method of administration and doses
The drug is intended for adults for oral use.
It is recommended to take perindopril once a day in the morning before meals.
The dose should be selected individually for each patient, taking into account the indication for use, the patient's profile and blood pressure values (see section "Special instructions for use").
Arterial hypertension.
Perindopril can be prescribed as monotherapy or in combination with drugs from other classes of antihypertensive agents.
The recommended starting dose is 4 mg once daily, in the morning.
In patients with a highly active renin-angiotensin-aldosterone system (especially patients with renovascular hypertension, electrolyte imbalance, heart failure or severe hypertension, as well as elderly patients), an initial dose of 2 mg is recommended under medical supervision, if necessary in a hospital setting, due to the possibility of a sudden decrease in blood pressure (first-dose hypotension).
After 1 month of treatment, the dose can be increased to the maximum dose of 8 mg once a day.
Symptomatic hypotension may occur at the beginning of treatment with perindopril, especially in patients receiving diuretics. In such patients, treatment with perindopril should be initiated with caution, as they may be water and/or salt depleted. If possible, the diuretic should be discontinued 2-3 days before starting treatment with perindopril (see section 4.4).
For patients with arterial hypertension, if diuretics cannot be discontinued, treatment with perindopril should be initiated at a daily dose of 2 mg. In such patients, renal function and serum potassium should be monitored. Further increases in the dosage of perindopril should be based on blood pressure measurements, and diuretic treatment may be resumed if necessary.
Elderly patients should start treatment with a dose of 2 mg, which may be increased to 4 mg after 1 month of treatment, and then, if necessary, depending on renal function - up to 8 mg, taking into account renal function (see table below).
Heart failure.
In patients with heart failure, in whom perindopril tert-butylamine is usually prescribed concomitantly with a potassium-sparing diuretic and/or digoxin and/or a β-blocker, it is recommended that treatment be initiated under close medical supervision and with an initial dose of 2 mg taken in the morning. After 2 weeks, if the drug is well tolerated, the dose may be increased to 4 mg once daily. The dose should be adjusted individually, depending on the clinical condition of the patient.
Treatment of patients with severe heart failure and other high-risk patients (with impaired renal function and a tendency to electrolyte disturbances, patients receiving concomitant therapy with diuretics and/or vasodilators) should be initiated under close medical supervision (see section "Special warnings and precautions for use").
In patients at high risk of symptomatic hypotension, in particular in patients with electrolyte depletion with or without hyponatraemia, in patients with hypovolaemia or in those who have received intensive diuretic therapy, the above conditions should be corrected, if possible, before initiating perindopril therapy. Blood pressure, renal function and serum potassium should be closely monitored before initiating and during treatment with perindopril (see section 4.4).
Prevention of cardiovascular complications in patients with documented stable coronary heart disease.
The initial dose of perindopril is 4 mg once daily in the morning. After 2 weeks, if well tolerated and taking into account renal function, the dose may be increased to 8 mg once daily.
Elderly patients should initially be prescribed the drug in a dose of 2 g.
