Prexum 5 mg and 10 mg FC tablet.

Prexum 5 mg and 10 mg are indicated for the treatment of mild to moderate hypertension. Prexum 5 mg is indicated in congestive heart failure not adequately controlled by conventional therapy with diuretics and digitalis and in whom vasodilatation is indicated.

Posology

Mild to moderate hypertension

The recommended dosage is 5 mg orally taken in the morning before breakfast, which can be increased to a single daily dose of 10 mg if necessary, after one month of treatment. In elderly patients, treatment should be initiated at a dose of 2,5 mg, which may progressively be increased to 5 mg after one month, then to 10 mg if necessary, depending on renal function.

Congestive heart failure

The treatment should be initiated under close medical supervision. Initial dose of 2,5 mg orally as a single daily dose in the morning, which may, in most instances be increased to 5 mg (once blood pressure acceptability has been demonstrated).

Concomitant diuretic therapy in hypertension

Caution is recommended in patients who are currently being treated with diuretics. As the effects of ACE-inhibitors may be potentiated in a situation where hypovolaemia may occur, the diuretic therapy should be discontinued 2 to 3 days prior to initiation of therapy with Prexum. In the case of combination with a diuretic, it is not advisable to prescribe a potassium salt or a potassium sparing agent before determining the blood potassium, and attention should be paid to possible overdose of the diuretic.

Special populations

Renal insufficiency

In patients with renal insufficiency, the dosage of perindopril must be adjusted in relation to the severity of the insufficiency.

Table 1 Dosage adjustment in renal impairment

Creatinine clearance Recommended dosage

• > 60 ml/min: 5 mg per day
• Between 30 and 60 ml/min: 2,5 mg per day
• Between 15 and 30 ml/min: 2,5 mg every other day
• Haemodialysed patients < 15 ml/min: 2,5 mg on day of dialysis

Perindopril is dialysable (70 ml/min). For patients on haemodialysis, the dose should be taken after the dialysis.

Patients with hepatic impairment

No dosage adjustment is necessary in patients with hepatic impairment.

Paediatric population

The safety and efficacy of perindopril in children and adolescents aged below 18 years have not been established.

Method of administration

For oral use. Prexum is recommended to be taken once daily in the morning before a meal.

• Hypersensitivity to any of the ingredients of Prexum.
• A history of angioedema related to previous therapy with ACE-inhibitors or angiotensin receptor blockers (ARBs): these patients must never again be given these medicines. (see section 4.4).
• Hereditary/idiopathic angioedema (see section 4.4).
• Hypertrophic obstructive cardiomyopathy (HOCM) (see section 4.4).
• Severe renal function impairment (creatinine clearance below 30 ml/min).
• In bilateral renal artery stenosis.
• Renal artery stenosis in patient with a single kidney.
• Aortic stenosis (see section 4.4).
• Concomitant therapy with potassium-sparing diuretics (such as spironolactone, triamterene, amiloride), (see section 4.5).
• Porphyria.
• In combinations with lithium: concomitant use with Prexum may lead to toxic blood concentration of lithium (see section 4.5).
• Pregnancy and lactation (see section 4.6).
• The concomitant use of Prexum with aliskiren-containing products is contraindicated. (see sections 4.4 and 4.5).
• Concomitant use with sacubitril/valsartan (see sections 4.4 and 4.5). Prexum must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections 4.4 and 4.5).
• Extracorporeal treatments leading to contact of blood with negatively charged surfaces (see section 4.5).
• Concomitant use of fluoroquinolones with ACE-inhibitors/Renin angiotensin receptor blockers is contraindicated in patients with moderate to severe renal failure (Creatinine Clearance u2264 30 ml/min) and in elderly patients.

Should a woman become pregnant while receiving Prexum, the treatment must be stopped promptly and switched to a different medicine. (see sections 4.3 and 4.6).

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, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of Prexum, angiotensin II receptor blockers or aliskiren is therefore contraindicated (see sections 4.3 and 4.5). If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure. Prexum and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy (see sections 4.3 and 4.5).

Hypotension

ACE-inhibitors may cause a fall in blood pressure. Symptomatic hypotension is rarely seen in uncomplicated hypertensive patients and is more likely to occur in patients who have been volume-depleted e.g. by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting, or who have severe renin-dependent hypertension (see sections 4.5 and 4.8). In patients with symptomatic heart failure, with or without associated renal insufficiency, symptomatic hypotension has been observed. This is most likely to occur in those patients with more severe degrees of heart failure, as reflected by the use of high doses of loop diuretics, hyponatraemia or functional renal impairment. In patients with an increased risk of symptomatic hypotension, initiation of therapy and dose adjustment should be closely monitored (see sections 4.2 and 4.8).

Similar considerations apply to patients with ischaemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident. If hypotension occurs, the patient should be placed in the supine position and, if necessary, should receive an intravenous infusion of normal saline. A transient hypotensive response is not a contra-indication to further doses, which can be given usually without difficulty once the blood pressure has increased after volume expansion. In some patients with congestive heart failure, who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with Prexum. If hypotension becomes symptomatic, a reduction of the dose or discontinuation of perindopril may be necessary.

Aortic and mitral valve stenosis / hypertrophic cardiomyopathy

Prexum should be given with caution to patients with mitral valve stenosis and obstruction in the outflow of the left ventricle, such as aortic stenosis or hypertrophic cardiomyopathy.

Renal impairment

In cases of renal impairment (creatinine clearance < 60 ml/min) the initial Prexum dosage should be adjusted according to the patientu2019s creatinine clearance (see section 4.2) and then as a function of the patientu2019s response to treatment (see section 4.8). Routine monitoring of potassium and creatinine are part of normal medical practice for these patients. In patients with symptomatic heart failure, hypotension following the initiation of therapy with ACE-inhibitors may lead to some further impairment in renal function. Acute renal failure has been reported in this situation. In patients with bilateral renal artery stenosis, or stenosis of the artery to a solitary kidney, and who have been treated with ACE-inhibitors, increases in blood urea and serum creatinine may occur. This is usually reversible upon discontinuation of therapy. It is especially likely in patients with renal insufficiency. If renovascular hypertension is also present, there is an increased risk of severe hypotension and renal insufficiency. In these patients, treatment should be started under close medical supervision with low doses and careful dose titration. Since treatment with diuretics may be a contributory factor to the above, they should be discontinued and renal function should be monitored during the first weeks of Prexum therapy. Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine, especially when Prexum was given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or Prexum may be required.

Haemodialysis patients

Anaphylactic reactions have been reported in patients dialysed with high flux membranes and treated concomitantly with an ACE-inhibitor. In these patients, consideration should be given to using a different type of dialysis membrane or different class of antihypertensive agent.

Kidney transplantation

There is no experience regarding the administration of Prexum in patients with a recent kidney transplant.

Renovascular hypertension

There is an increased risk of hypotension and renal insufficiency when patient with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with ACE-inhibitors (see section 4.3). Treatment with diuretics may be a contributory factor. Loss of renal function may occur with only minor changes in serum creatinine even in patients with unilateral renal artery stenosis.

Hypersensitivity/Angioedema

Angioedema of the face, lips, mucous membranes, tongue, glottis and/or larynx, and extremities has been reported, in patients treated with ACE-inhibitors, including Prexum (see section 4.8). This may occur at any time during therapy. In such cases, Prexum should immediately be discontinued and appropriate monitoring should be initiated and continued until the symptoms have disappeared completely. In those instances where swelling was confined to the face and lips, the condition generally resolved without treatment, although antihistamines have been useful in relieving symptoms. Angioedema associated with laryngeal oedema may be fatal. Where there is involvement of the tongue, glottis or larynx, and is likely to cause airway obstruction, emergency therapy should immediately be administered. This may include the administration of adrenaline and/or the maintenance of the patientu2019s airway. The patient should be under close medical supervision until the symptoms have disappeared.

ACE-inhibitors cause a higher rate of angioedema in black patients than in other ethnic groups. Patients with a history of angioedema unrelated to ACE-inhibitor therapy may be at increased risk of angioedema while receiving an ACE-inhibitor (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 or vomiting); in some cases, there was no prior facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan, or ultrasound or at surgery and symptoms resolved after stopping the ACE-inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE-inhibitors presenting with abdominal pain.

The combination of perindopril with sacubitril/valsartan is contraindicated due to the increased risk of angioedema (see sections 4.3 and 4.5). Sacubitril/valsartan must not be initiated until 36 hours after taking the last dose of perindopril therapy. If treatment with sacubitril/valsartan is stopped, perindopril therapy must not be initiated until 36 hours after the last dose of sacubitril/valsartan (see section 4.3 and 4.5).

Concomitant use of ACE inhibitors with other NEP inhibitors (e.g. racecadotril), mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and gliptins (e.g. linagliptin, saxagliptin, sitagliptin, vildagliptin) may lead to an increased risk of angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) (see section 4.5). Caution should be used when starting racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and gliptins (e.g. linagliptin, saxagliptin, sitagliptin, vildagliptin) in a patient already taking an ACE-inhibitor.

Fluoroquinolones and ACE-inhibitors/Renin angiotensin receptor blockers

Concomitant use of fluoroquinolones and ACE-inhibitors/Renin angiotensin receptor blockers may precipitate acute kidney injury in patients, especially those with moderate to severe renal impairment and elderly patients (see section 4.3).

Anaphylactic reactions during low-density lipoproteins (LDL) apheresis

Patients receiving ACE-inhibitors during low-density lipoprotein (LDL) apheresis with dextran sulphate have rarely experienced life-threatening anaphylactic reactions. These reactions were avoided by temporarily withholding ACE-inhibitors therapy prior to each apheresis.

Anaphylactoid reactions during desensitisation

Patients receiving ACE-inhibitors during desensitisation treatment (e.g. hymenoptera venom) have experienced anaphylactic reactions. These reactions were avoided when the ACE-inhibitors were temporarily withheld, but they reappeared upon re-challenge.

Hepatic failure

ACE-inhibitors have been associated with a syndrome that starts with cholestatic jaundice and suddenly progresses to hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE-inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the Prexum and receive appropriate medical follow-up (see section 4.8).

Neutropenia/agranulocytosis/thrombocytopenia/anaemia

Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in patients receiving ACE-inhibitors. In patients with normal renal function and no other complicating factors, neutropenia rarely occurs. Prexum should be used with extreme caution in patients with collagen vascular disease, immunosuppressant therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially if there is pre-existing impaired renal function. Some of these patients developed serious infections, which in a few instances did not respond to intensive antibiotic therapy. If Prexum is used in such patients, periodic monitoring of the white blood cell count is advised and patients should be instructed to report any sign of infection (e.g. sore throat, fever).

Race

ACE-inhibitors cause a higher rate of angioedema in black patients than in other ethnic groups. Prexum may be less effective in lowering blood pressure in black people than in other ethnic groups, possibly because of a higher prevalence of low-renin levels in the black hypertensive population.

Cough

Cough has been reported with the use of ACE-inhibitors. Characteristically, the cough is non-productive, persistent and resolves after discontinuation of therapy. ACE-inhibitors induced cough should be considered as part of the differential diagnosis of cough.

Surgery/anaesthesia

In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, Prexum may block angiotensin II formation secondary to compensatory renin release. The treatment should be discontinued one day prior to the surgery. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.

Hyperkalaemia

Elevations in serum potassium have been observed in some patients treated with Prexum. ACE-inhibitors can cause hyperkalaemia because they inhibit the release of aldosterone. The effect is usually not significant in patients with normal renal function. Patients at risk for the development of hyperkalaemia include those with renal insufficiency, age (> 70 years), uncontrolled diabetes mellitus, or those using concomitant potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene, or amiloride), potassium supplements or potassium-containing salt substitutes; or those patients taking other medicines associated with increases in serum potassium (e.g. heparin, co-trimoxazole also known as trimethoprim/sulfamethoxazole). The use of potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes particularly in patients with impaired renal function may lead to a significant increase in serum potassium. Hyperkalaemia can cause serious, sometimes fatal dysrhythmias. Potassium-sparing diuretics and angiotensin-receptor blockers should be used with caution in patients receiving ACE inhibitors, and serum potassium and renal function should be monitored. If concomitant use of the above-mentioned agents is deemed necessary, regular monitoring of serum potassium is recommended (see section 4.5).

Diabetic patients

In diabetic patients treated with oral antidiabetic agents or insulin, glycaemic control should be closely monitored during the first month of treatment with ACE-inhibitors (see section 4.5).

Lithium

The combination of lithium and Prexum is contraindicated (see sections 4.3 and 4.5).

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

The combination of Prexum and potassium sparing diuretics, potassium supplements or potassium-containing salt substitutes is generally not recommended (see section 4.5).

Primary aldosteronism

Patients with primary hyperaldosteronism generally will not respond to anti-hypertensive drugs acting through inhibition of the renin-angiotensin system. Therefore, the use of this product is not recommended.

Dual blockade of the RAAS with ARBs, ACE-inhibitors, or aliskiren

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 frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (see sections 4.3 and 4.4).

Medicines increasing the risk of angioedema

Concomitant use of ACE-inhibitors with sacubitril/valsartan is contraindicated as this increases the risk of angioedema (see section 4.3 and 4.4). Sacubitril/valsartan must not be started until 36 hours after taking the last dose of perindopril therapy. Perindopril therapy must not be started until 36 hours after the last dose of sacubitril/valsartan (see sections 4.3 and 4.4).

Concomitant use of ACE-inhibitors with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and gliptins (e.g. linagliptin, saxagliptin, sitagliptin, vildagliptin) may lead to an increased risk for angioedema (see section 4.4).

Medicines inducing hyperkalaemia

Although serum potassium usually remains within normal limits, hyperkalaemia may occur in some patients treated with Prexum. Some medicines or therapeutic classes may increase the occurrence of hyperkalaemia: aliskiren, potassium salts, potassium-sparing diuretics (e.g. spironolactone, triamterene or amiloride), ACE-inhibitors, angiotensin-II receptors antagonists, NSAIDs, heparins, immunosuppressant agents such as ciclosporin or tacrolimus and trimethoprim and cotrimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim is known to act as a potassium-sparing diuretic like amiloride. The combination of these medicines increases the risk of hyperkalaemia. Therefore, the combination of Prexum with the above-mentioned medicines is not recommended. If concomitant use is indicated, they should be used with caution and with frequent monitoring of serum potassium.

Concomitant use contraindicated (See section 4.3)

Aliskiren: In diabetic or impaired renal patients, risk of hyperkalaemia, worsening of renal function and cardiovascular morbidity and mortality increase.

Extracorporeal treatments

Extracorporeal treatments leading to contact of blood with negatively charged surfaces such as dialysis or haemofiltration with certain high-flux membranes (e.g. polyacrylonitrile membranes) and low-density lipoprotein apheresis with dextran sulphate due to increased risk of severe anaphylactoid reactions (see section 4.3). If such treatment is required, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.

Fluoroquinolones and ACE-inhibitors/Renin angiotensin receptor blockers

Concomitant use of fluoroquinolones and ACE-inhibitors/Renin angiotensin receptor blockers may precipitate acute kidney injury (see section 4.3).

Concomitant use not recommended (see section 4.4)

Aliskiren: In patients other than diabetic or impaired renal patients, risk of hyperkalaemia, worsening of renal function and cardiovascular morbidity and mortality increase (See section 4.4).

Concomitant therapy with ACE-inhibitor and angiotensin-receptor blocker: Patients with established atherosclerotic disease, heart failure, or with diabetes with end organ damage, concomitant therapy with an ACE-inhibitor and an angiotensin-receptor blocker is associated with a higher frequency of hypotension, syncope, hyperkalaemia, and worsening renal function (including acute renal failure) as compared to use of a single renin-angiotensin-aldosterone system agent. Dual blockade (e.g., by combining an ACE-inhibitor with an angiotensin II receptor antagonist) should be limited to individually defined cases with close monitoring of renal function, potassium levels, and blood pressure (see section 4.4).

Estramustine

Risk of increased adverse effects such as angioneurotic oedema (angioedema).

Potassium sparing diuretics, (e.g. triamterene, amiloride, ...), potassium (salts) containing salt substitutes

Hyperkalaemia may occur in some patients treated with Prexum. Potassium sparing diuretics (e.g. triamterene or amiloride), potassium supplements or potassium-containing salt substitutes, may lead to significant increases in serum potassium. The combination of Prexum with the above-mentioned medicines is not recommended (see section 4.4). If concomitant use is indicated because of confirmed hypokalaemia, they should be used with caution and serum potassium should frequently be monitored.

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE-inhibitors. Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and enhance the already increased risk of lithium toxicity with ACE-inhibitors. Combination of Prexum with lithium is not recommended, but if the combination proves necessary, careful monitoring of serum lithium levels should be performed (see section 4.3 and 4.4).

Concomitant use which requires special care

Antidiabetic agents

Epidemiological studies have suggested that concomitant administration of ACE-inhibitors and antidiabetic medicines (insulins, oral hypoglycaemic agents) may cause an increased blood-glucose lowering effect with the risk of hypoglycaemia. This phenomenon appeared to be more likely during the first weeks of combined treatment and in patients with renal impairment.

Baclofen

Increased antihypertensive effect. Monitor blood pressure and adapt antihypertensive dosage if necessary.

Non-potassium-sparing diuretics

Patients on diuretics, and especially those who are volume and/or salt depleted, may experience excessive reduction in blood pressure after initiation of therapy with an ACE inhibitor. The possibility of hypotensive effects can be reduced by discontinuation of the diuretic, by increasing volume or salt intake prior to initiating therapy with low and progressive doses of perindopril.

In arterial hypertension

When prior diuretic therapy can have caused salt/volume depletion, either the diuretic must be discontinued before initiating the ACE-inhibitor, in which case a non-potassium-sparing diuretic can be thereafter reintroduced or the ACE-inhibitor must be initiated with a low dosage and progressively increased.

In diuretic-treated congestive heart failure

Prexum should be initiated at a very low dosage, possibly after reducing the dosage of the associated non-potassium-sparing diuretic.

In all cases, renal function (creatinine levels) must be monitored during the first few weeks of ACE-inhibitor therapy.

Potassium-sparing diuretics (eplerenone, spironolactone)

With eplerenone or spironolactone at doses between 12,5 mg to 50 mg by day and with low doses of ACE-inhibitors: In the treatment of class II-IV heart failure (NYHA) with an ejection fraction < 40 %, and previously treated with ACE-inhibitors and loop diuretics, risk of hyperkalaemia, potentially lethal, especially in case of non-observance of the prescription recommendations on this combination. Before initiating the combination, check the absence of hyperkalaemia and renal impairment. A close monitoring of the potassium and creatinine is recommended in the first month of the treatment once a week at the beginning and, monthly thereafter.

Non-steroidal anti-inflammatory drugs (NSAIDs) including acetylsalicylic acid

The administration of non-steroidal anti-inflammatory drugs (NSAIDs) (i.e. acetylsalicylic acid at anti-inflammatory dosage regimens, COX-2 inhibitors and non-selective NSAIDs) may reduce the antihypertensive effect of ACE-inhibitors. Additionally, NSAIDs and ACE-inhibitors exert an additive effect on the increase in serum potassium and may result in a deterioration of renal function. These effects are usually reversible. Acute renal failure may occur, especially in patients with compromised renal function like the elderly or dehydrated patients.

Concomitant use which requires some care

Antihypertensive agents and vasodilators

Concomitant use of these agents may increase the hypotensive effects of Prexum. Concomitant use with nitroglycerin and other nitrates, or other vasodilators, may further reduce blood pressure.

Tricyclic antidepressants/antipsychotics/anaesthetics

Concomitant use of certain anaesthetic medicines, tricyclic antidepressants and antipsychotics with ACE-inhibitors may result in further reduction of blood pressure (see section 4.4).

Sympathomimetics

Sympathomimetics may reduce the antihypertensive effects of Prexum.

Gold

Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been rarely reported in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE-inhibitor therapy including perindopril.

Pregnancy

Prexum is contraindicated during pregnancy and lactation. Pregnant women should be informed of the potential hazards to the foetus and must not take Prexum during pregnancy (see section 4.3). Patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with Prexum should be stopped immediately and if appropriate, alternative therapy should be started. Foetal exposure to ACE-inhibitors during the first trimester of pregnancy has been reported to be associated with an increased risk of malformations of the cardiovascular (atrial and/or ventricular septal defect, pulmonic stenosis, patent ductus arteriosus) and central nervous system (microcephaly spins bifida) and of kidney malformations. ACE-inhibitors, such as Prexum pass through the placenta and can be presumed to cause disturbance in foetal blood pressure regularity mechanisms. Oligohydramnios as well as hypotension, oliguria and anuria in newborns have been reported after administration of ACE-inhibitors in the second and third trimester. Cases of defective skull ossification have been observed. Prematurity and low birth mass can occur. Should exposure to ACE-inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension (see also section 4.3).

Lactation

It is not known whether perindopril is excreted into human breast milk. Therefore, the use of Prexum is not recommended in women who are breastfeeding. Prexum is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

Fertility

There was no effect on reproductive performance or fertility.

Prexum has no direct influence on the ability to drive and use machines but individual reactions related to low blood pressure may occur in some patients, particularly at the start of treatment or in combination with another antihypertensive medication.

a. Summary of safety profile.

The safety profile of perindopril is consistent with the safety profile of ACE-inhibitors: The most frequent adverse events reported in clinical trials and observed with perindopril are: dizziness, headache, paraesthesia, vertigo, visual disturbances, tinnitus, hypotension, cough, dyspnoea, abdominal pain, constipation, diarrhoea, dysgeusia, dyspepsia, nausea, vomiting, pruritis, rash, muscle cramps, and asthenia.

b. Tabulated list of adverse reactions.

The following side effects have been observed during treatment with Prexum and ranked under the following frequency Very common (u2265 1/10); common (u2265 1/100, < 1/10); uncommon (u2265 1/1 000, < 1/100); rare (u2265 1/10 000, < 1/1 000); very rare (< 1/10 000); including isolated reports, not known (cannot be estimated from the available data).

Symptoms associated with overdose of ACE-inhibitors may include hypotension, circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety and cough. The recommended treatment of an overdose is an intravenous infusion of normal saline solution. If hypotension occurs, the patient should be placed in the shock position. If available, treatment with angiotensin II infusion and/or intravenous catecholamines may also be considered. Prexum may be removed from the general circulation by haemodialysis. Pacemaker therapy is indicated for therapy-resistant bradycardia. Vital signs, serum electrolytes and creatinine concentrations should be monitored continuously. Expected symptoms and signs would be linked to hypotension. Further treatment is symptomatic and supportive.