4.1. Therapeutic indications

Hypertension:

Treatment of hypertension.

Heart failure:

Treatment of symptomatic heart failure.

Stable coronary artery disease:

Reduction of risk of cardiac events in patients with a history of myocardial infarction and/or revascularisation.

4.2. Posology and method of administration

Posology

The dose should be individualised according to the patient profile (see section 4.4) and blood pressure response.

Hypertension:

Perindopril may be used in monotherapy or in combination with other classes of antihypertensive therapy (see sections 4.3, 4.4, 4.5 and 5.1).

The recommended starting dose is 4 mg given once daily in the morning.

Patients with a strongly activated renin-angiotensin-aldosterone system (in particular, renovascular hypertension, salt and/or volume depletion, cardiac decompensation or severe hypertension) may experience an excessive drop in blood pressure following the initial dose. A starting dose of 2 mg is recommended in such patients and the initiation of treatment should take place under medical supervision.

The dose may be increased to 8 mg once daily after one month of treatment.

Symptomatic hypotension may occur following initiation of therapy with perindopril; this is more likely in patients who are being treated concurrently with diuretics. Caution is therefore recommended since these patients may be volume and/or salt depleted.

If possible, the diuretic should be discontinued 2 to 3 days before beginning therapy with perindopril (see section 4.4).

In hypertensive patients in whom the diuretic cannot be discontinued, therapy with perindopril should be initiated with a 2 mg dose. Renal function and serum potassium should be monitored. The subsequent dosage of perindopril should be adjusted according to blood pressure response. If required, diuretic therapy may be resumed.

In elderly patients, treatment should be initiated at a dose of 2 mg which may be progressively increased to 4 mg after one month then to 8 mg if necessary, depending on renal function (see table below).

Symptomatic heart failure:

It is recommended that perindopril, generally associated with a non-potassium-sparing diuretic and/or digoxin and/or a beta blocker, be introduced under close medical supervision with a recommended starting dose of 2 mg taken in the morning. This dose may be increased after 2 weeks to 4 mg once daily if tolerated. The dose adjustment should be based on the clinical response of the individual patient.

In severe heart failure and in other patients considered to be at high risk (patients with impaired renal function and a tendency to have electrolyte disturbances, patients receiving simultaneous treatment with diuretics and/or treatment with vasodilating agents), treatment should be initiated under careful supervision (see section 4.4).

Patients at high risk of symptomatic hypotension e.g. patients with salt depletion with or without hyponatraemia, patients with hypovolaemia or patients who have been receiving vigorous diuretic therapy should have these conditions corrected, if possible, prior to therapy with perindopril. Blood pressure, renal function and serum potassium should be monitored closely, both before and during treatment with perindopril (see section 4.4).

Stable coronary artery disease:

Perindopril should be introduced at a dose of 4 mg once daily for two weeks, then increased to 8 mg once daily, depending on renal function and provided that the 4 mg dose is well tolerated.

Elderly patients should receive 2 mg once daily for one week, then 4 mg once daily the next week, before increasing the dose up to 8 mg once daily depending on renal function (see Table 1 “Dosage adjustment in renal impairment”). The dose should be increased only if the previous lower dose is well tolerated.

Special population:

Patients with renal impairment:

Dosage in patients with renal impairment should be based on creatinine clearance as outlined in Table 1 below:

Table 1: dosage adjustment in renal impairment

Creatinine clearance (ml/min)

Recommended dose

ClCR ≥ 60

4 mg per day

30 < ClCR < 60

2 mg per day

15 < ClCR < 30

2 mg every other day

Haemodialysed patients *

ClCR < 15

2 mg on the day of dialysis

* Dialysis clearance of perindoprilat is 70 ml/min.

For patients on haemodialysis, the dose should be taken after dialysis.

Patients with hepatic impairment:

No dosage adjustment is necessary in patients with hepatic impairment (see sections 4.4 and 5.2).

Paediatric population:

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

Currently available data are described in section 5.1 but no recommendation on a posology can be made.

Therefore, use in children and adolescents is not recommended.

Method of administration

For oral use.

Perindopril is recommended to be taken once daily in the morning before a meal.

4.3. Contraindications

• Hypersensitivity to the active substance (perindopril), to any other ACE inhibitor or to any of the excipients (listed in section 6.1).

• History of angioedema associated with previous ACE inhibitor therapy (see section 4.4).

• Hereditary or idiopathic angioedema.

• Second and third trimesters of pregnancy (see sections 4.4 and 4.6).

• Concomitant use of perindopril with aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.5 and 5.1).

• Concomitant use with sacubitril/valsartan. Perindopril 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).

• Significant bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney (see section 4.4).

4.4. Special warnings and precautions for use

Stable coronary artery disease:

If an episode of unstable angina pectoris (major or not) occurs during the first month of perindopril treatment, a careful appraisal of the benefit/risk should be performed before treatment continuation.

Hypotension:

ACE inhibitors may cause a fall in blood pressure. Symptomatic hypotension is seen rarely 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 at 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 sodium chloride 9mg/ml (0.9%) solution. A transient hypotensive response is not a contraindication 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 perindopril.

This effect is anticipated and is usually not a reason to discontinue treatment. If hypotension becomes symptomatic, a reduction of dose or discontinuation of perindopril may be necessary.

Aortic and mitral valve stenosis/hypertrophic cardiomyopathy:

As with other ACE inhibitors, perindopril 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 perindopril dosage should be adjusted according to the patient's creatinine clearance (see section 4.2) and then as a function of the patient's response to treatment. Routine monitoring of potassium and creatinine are part of normal medical practice for these patients (see section 4.8).

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, usually reversible, has been reported in this situation.

In some patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, who have been treated with ACE inhibitors, increases in blood urea and serum creatinine, usually reversible upon discontinuation of therapy, have been seen. This 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 perindopril therapy.

Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when perindopril has been 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 perindopril may be required.

Haemodialysis patients:

Anaphylactoid 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 perindopril in patients with a recent kidney transplantation.

Renovascular hypertension:

There is an increased risk of hypotension and renal insufficiency when patients 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, extremities, lips, mucous membranes, tongue, glottis and/or larynx has been reported rarely in patients treated with ACE inhibitors, including perindopril (see section 4.8). This may occur at any time during therapy.

In such cases, perindopril should promptly be discontinued and appropriate monitoring should be initiated and continued until complete resolution of symptoms has occurred. 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, likely to cause airway obstruction, emergency therapy should be administered promptly. This may include the administration of adrenaline and/or the maintenance of a patent airway. The patient should be under close medical supervision until complete and sustained resolution of symptoms has occurred.

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 section 4.3). 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 sections 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) and may increase the 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, and temsirolimus) and gliptins (e.g. linagliptin, saxagliptin, sitagliptin, vildagliptin) in a patient already taking an ACE inhibitor.

Anaphylactoid reactions during low-density lipoproteins (LDL) apheresis:

Rarely, patients receiving ACE inhibitors during low-density lipoprotein (LDL) apheresis with dextran sulfate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis.

Anaphylactic reactions during desensitisation:

Patients receiving ACE inhibitors during desensitisation treatment (e.g. hymenoptera venom) have experienced anaphylactoid reactions. In the same patients, these reactions have been avoided when the ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.

Hepatic failure:

Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant 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 ACE inhibitor 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 occurs rarely.

Perindopril 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 perindopril is used in such patients, periodic monitoring of white blood cell counts 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 non-black patients.

As with other ACE inhibitors, perindopril may be less effective in lowering blood pressure in black people than in non-blacks, possibly because of a higher prevalence of low-renin states 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 inhibitor-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, perindopril 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 ACE inhibitors, including perindopril. ACE inhibitors can cause hyperkalaemia because they inhibit the release of aldosterone. The effect is usually not significant in patients with normal renal function.

Risk factors for the development of hyperkalaemia include those with renal insufficiency worsening of renal function, age (> 70 years), diabetes mellitus, inter-current events, in particular 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 associated with increases in serum potassium (e.g. heparin, co-trimoxazole also known as trimethoprim/sulfamethoxazole) and especially aldosterone antagonists or angiotensin-receptor blockers..

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 arrhythmias.

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 appropriate, they should be used with caution and with frequent monitoring of serum potassium (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 an ACE inhibitor (see section 4.5).

Lithium:

The combination of lithium and perindopril is generally not recommended (see section 4.5)

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

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

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 ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).

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.

ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

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.

Pregnancy:

ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, 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 appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Excipients:

Due to the presence of lactose, patients with rare hereditary problems of galactose intolerance, glucose-galactose malabsorption or total lactase deficiency should not take this medicinal product.

4.5. Interaction with other medicinal products and other forms of interaction

Clinical trial data has 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 (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).

Drugs increasing the risk of angioedema

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated as this increases the risk of angioedema (see sections 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 4.3and 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).

Drugs inducing hyperkalaemia

Although serum potassium usually remains within normal limits, hyperkalaemia may occur in some patients treated with perindopril. Some drugs 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, trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim is known to act as a potassium-sparing diuretic like amiloride. The combination of these drugs increases the risk of hyperkalaemia. 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.

Concomitant use contra-indicated (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 sulfate 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.

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.

Concomitant therapy with ACE inhibitor and angiotensin-receptor blocker:

It has been reported in the literature that in patients with established atherosclerotic disease, heart failure, or with diabetes with end organ damage, concomitant therapy with ACE inhibitor and 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.

Estramustine:

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

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

Hyperkalaemia (potentially lethal), especially in conjunction with renal impairment (additive hyperkalaemic effects).

The combination of perindopril with the above-mentioned drugs is not recommended (see section 4.4). If concomitant use is nonetheless indicated, they should be used with caution and with frequent monitoring of serum potassium. For use of spironolactone in heart failure, see below.

Lithium:

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. Use of perindopril with lithium is not recommended, but if the combination proves necessary, careful monitoring of serum lithium levels should be performed (see section 4.4).

Concomitant use which requires special care:

Antidiabetic agents (insulins, oral hypoglycaemic 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 risk of hypoglycaemia.

This phenomenon appeared to be more likely to occur 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, the ACE inhibitor 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 kalaemia and creatinaemia 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 aspirin ≥3 g/day:

When ACE-inhibitors are administered simultaneously with non-steroidal anti-inflammatory drugs (i.e. acetylsalicylic acid at anti-inflammatory dosage regimens, COX-2 inhibitors and non-selective NSAIDs), attenuation of the antihypertensive effect may occur. Concomitant use of ACE inhibitors and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.

Concomitant use which requires some care:

Antihypertensive agents and vasodilators:

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

Tricyclic antidepressants/Antipsychotics/Anaesthetics:

Concomitant use of certain anaesthetic medicinal products, 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 ACE inhibitors.

Gold:

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

4.6. Pregnancy and lactation

Pregnancy

The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contraindicated during the second and third trimester of pregnancy (see sections 4.3 and 4.4).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however, a small increase in risk cannot be excluded.

Unless continued ACE inhibitor therapy is considered essential, 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 appropriate, alternative therapy should be started.

Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3). 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 sections 4.3 and 4.4).

Breast-feeding

Because no information is available regarding the use of perindopril during breastfeeding, perindopril 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.

4.7. Effects on ability to drive and use machines

Perindopril 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 anti-hypertensive medication.

As a result, the ability to drive or operate machinery may be impaired.

4.8. Undesirable effects

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 undesirable effects have been observed during clinical trials and/or post-marketing use with perindopril and ranked under the following frequency:

Very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000); not known (cannot be estimated from the available data).

MedDRA

System Organ Class

Undesirable Effects

Frequency

Blood and Lymphatic System Disorders

Eosinophilia

Uncommon*

Agranulocytosis or pancytopenia

Very rare

Haemoglobin decreased and haematocrit decreased

Very rare

Leucopenia/neutropenia

Very rare

Haemolytic anaemia in patients with a congenital deficiency of G-6PDH (see section 4.4)

Very rare

Thrombocytopenia

Very rare

Endocrine disorders

Syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Rare

Metabolism and Nutrition Disorders

Hypoglycaemia (see sections 4.4 and 4.5)

Uncommon*

Hyperkalaemia, reversible on discontinuation (see section 4.4)

Uncommon*

Hyponatraemia

Uncommon*

Psychiatric Disorders

Mood disturbances

Uncommon

Sleep disorder

Uncommon

Depression

Uncommon*

Nervous System Disorders

Dizziness

Common

Headache

Common

Paraesthesia

Common

Vertigo

Common

Somnolence

Uncommon*

Syncope

Uncommon*

Confusion

Very rare

Eye Disorders

Visual disturbances

Common

Ear and Labyrinth Disorders

Tinnitus

Common

Cardiac Disorders

Palpitations

Uncommon*

Tachycardia

Uncommon*

Angina pectoris (see section 4.4)

Very rare

Arrhythmia

Very rare

Myocardial infarction, possibly secondary to excessive hypotension in high risk patients (see section 4.4)

Very rare

Vascular Disorders

Hypotension (and effects related to hypotension)

Common

Vasculitis

Uncommon*

Flushing

Rare*

Stroke possibly secondary to excessive hypotension in high-risk patients (see section 4.4)

Very rare

Raynaud's Phenomenon

Not known

Respiratory, Thoracic and Mediastinal Disorders

Cough

Common

Dyspnoea

Common

Bronchospasm

Uncommon

Eosinophilic pneumonia

Very rare

Rhinitis

Very rare

Gastro-intestinal Disorders

Abdominal pain

Common

Constipation

Common

Diarrhoea

Common

Dysgeusia

Common

Dyspepsia

Common

Nausea

Common

Vomiting

Common

Dry mouth

Uncommon

Pancreatitis

Very rare

Hepato-biliary Disorders

Hepatitis either cytolytic or cholestatic (see section 4.4)

Very rare

Skin and Subcutaneous Tissue Disorders

Pruritis

Common

Rash

Common

Urticaria (see section 4.4)

Uncommon

Angioedema of face, extremities, lips, mucous membranes, tongue, glottis and/or larynx (see section 4.4)

Uncommon

Photosensitivity reactions

Uncommon*

Pemphigoid

Uncommon*

Psoriasis aggravation

Rare*

Hyperhidrosis

Uncommon

Erythema multiforme

Very rare

Musculoskeletal and Connective Tissue Disorders

Muscle cramps

Common

Arthralgia

Uncommon*

Myalgia

Uncommon*

Renal and Urinary Disorders

Renal insufficiency

Uncommon

Acute renal failure

Rare*

Anuria/oliguria

Rare*

Reproductive System and Breast Disorders

Erectile dysfunction

Uncommon

General Disorders and Administration Site Condition

Asthenia

Common

Chest pain

Uncommon*

Malaise

Uncommon*

Oedema peripheral

Uncommon*

Pyrexia

Uncommon*

Investigations

Blood urea increased

Uncommon*

Blood creatinine increased

Uncommon*

Blood bilirubin increased

Rare

Hepatic enzyme increased

Rare

Injury, Poisoning and Procedural Complications

Fall

Uncommon*

* Frequency calculated from clinical trials for adverse events detected from spontaneous report

Clinical trials:

During the randomised period of the EUROPA study, only serious adverse events were collected. Few patients experienced serious adverse events: 16 (0.3%) of the 6122 perindopril patients and 12 (0.2%) of the 6107 placebo patients. In perindopril-treated patients, hypotension was observed in 6 patients, angioedema in 3 patients and sudden cardiac arrest in 1 patient. More patients withdrew for cough, hypotension or other intolerance on perindopril than on placebo, 6.0% (n=366) versus 2.1% (n=129) respectively.

Reporting of suspected adverse reactions:

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA yellow card in the Google play or Apple app store.

4.9. Overdose

Limited data are available for overdosage in humans. Symptoms associated with overdosage of ACE inhibitors may include hypotension, circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough.

The recommended treatment of overdosage is intravenous infusion of sodium chloride 9mg/ml (0.9%) 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. Perindopril may be removed from the general circulation by haemodialysis (see section 4.4). Pacemaker therapy is indicated for therapy-resistant bradycardia. Vital signs, serum electrolytes and creatinine concentrations should be monitored continuously.