SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Perindopril tert-butylamine 8 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains perindopril tert-butylamine 8 mg (equivalent to 6.676 mg perindopril). Excipient:

Lactose anhydrous. Each tablet contains 170.40 mg lactose anhydrous.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet.

White, capsule shaped, biconvex tablets, engraved "APO" on one side and "PE" bisect "8" on the other

side. The tablets can be divided into equal halves.

4    CLINICAL PARTICULARS

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 infraction 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 section 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 tert-butylamine Tablets (see section 4.4).

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

In older people 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 tert-butylamine Tablets 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 tert-butylamine Tablets. Blood pressure, renal function and serum potassium should be monitored closely, both before and during treatment with Perindopril tert-butylamine Tablets (see section 4.4).

- Stable coronary artery disease:

Perindopril tert-butylamine Tablets 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.

Older people 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 one 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 Cl_CR > 60    4 mg per day

30 < Cl_CR < 60    2 mg per day

15 < Cl_CR < 30    2 mg every other day

Haemodialysed patients *

CIcr < 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:

Efficacy and safety of use in children and adolescents (less than 18 years) have not been established. Therefore, use in children and adolescents is not recommended.

Method of Administration

For oral use

It is recommended that Perindopril tert-butylamine Tablets are taken once daily in the morning before a meal.

4.3    Contraindications

-    Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or to any other ACE inhibitor;

-    History of angioedema associated with previous ACE inhibitor therapy;

-    Hereditary or idiopathic angioedema;

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

-    The concomitant use of Perindopril tert-butylamine tablets with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73m²) (see sections 4.4 and 5.1).

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 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 9 mg/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 tert-butylamine Tablets. 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 tert-butylamine Tablets 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 tert-butylamine Tablets 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.

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 tert-butylamine Tablets 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 4.3 Contraindications).

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.

Anaphylactoid reactions during low-density Lipoproteins LDL apheresis:

Rarely, patients receiving ACE inhibitors during low-density lipoprotein (LDL) apheresis with dextran sulphate 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 preexisting 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.

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 nonproductive, 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. Risk factors for the development of hyperkalaemia include those with renal insufficiency, worsening of renal function, age (>70 years), diabetes mellitus, intercurrent events, in particular dehydration, acute cardiac decompensation, metabolic acidosis and concomitant 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). 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. If concomitant use of the above- mentioned agents is deemed appropriate, regular monitoring of serum potassium is recommended.

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.

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).

The tablets contain lactose

Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine.

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 inducing hyperkalaemia

Some drugs or therapeutic classes may increase the occurrence of hyperkalaemia: aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin-II receptors antagonists, NSAIDs, heparins, immunosuppressant agents such as ciclosporin or tacrolimus, trimethoprim. The combination of these drugs increases the risk of hyperkalaemia.

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.

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. Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and enhance the already increased risk of lithium toxicity 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 older people. 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.

Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin):

Increased risk of angio-oedema, due to dipeptidyl peptidase IV (DPP-IV) decreased activity by the gliptin, in patients co-treated with an ACE inhibitor.

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.

Acetylsalicylic acid/ Thrombolytics /Beta-blockers /Nitrates:

Perindopril may be used concomitantly with acetylsalicylic acid (when used as a thrombolytic), thrombolytics, beta-blockers and/or nitrates.

4.6 Pregnancy and lactation

Pregnancy

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).

Lactation:

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.

4.7 Effects on ability to drive and use machines

When driving vehicles or operating machines it should be taken into account that occasionally

dizziness or weariness may occur.

4.8 Undesirable effects

The following undesirable effects have been observed during treatment 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), including isolated reports.

Psychiatric disorders

Uncommon: mood or sleep disturbances

Nervous system disorders

Common: headache, dizziness, vertigo, paresthaesia Very rare: confusion

Eye disorders

Common: vision disturbance

Ear and labyrinth disorders Common: tinnitus Cardio-vascular disorders

Common: hypotension and effects related to hypotension

Very rare: arrhythmia, angina pectoris, myocardial infarction and stroke, possibly secondary to

excessive hypotension in high-risk patients (see 4.4 Special warnings and special precautions for use)

Respiratory, thoracic and mediastinal disorders

Common: cough, dyspnoea Uncommon: bronchospasm Very rare: eosinophilic pneumonia, rhinitis

Gastrointestinal disorders

Common: nausea, vomiting, abdominal pain, dysgeusia, dyspepsia, diarrhoea, constipation

Uncommon: dry mouth

Very rare: pancreatitis

Hepatobiliary disorders

Very rare: hepatitis either cytolytic or cholestatic (see section 4.4 Special warnings and special

precautions for use)

Skin and subcutaneous tissue disorders

Common: rash, pruritus

Uncommon: angioedema of face, extremities, lips, mucous membranes, tongue, glottis and/or

larynx, urticaria (see 4.4 Special warnings and special precautions for use)

Very rare: erythema multiforme

Musculoskeletal, connective tissue and bone disorders

Common: muscle cramps

Renal and urinary disorders

Uncommon: renal insufficiency

Very rare: acute renal failure

Reproductive system and breast disorders

Uncommon: impotence

General disorders

Common: asthenia

Uncommon: sweating

Blood and the lymphatic system disorders

Decreases in haemoglobin and haematocrit, thrombocytopenia, leucopenia/neutropenia, and cases of

agranulocytosis or pancytopenia, have been reported very rarely. In patients with a congenital

deficiency of G-6PDH, very rare cases of haemolytic anaemia have been reported (see section 4.4

Special warnings and special precautions for use).

Investigations

Increases in blood urea and plasma creatinine, hyperkalaemia reversible on discontinuation may occur, especially in the presence of renal insufficiency, severe heart failure and renovascular hypertension.

Elevation of liver enzymes and serum bilirubin have been reported rarely.

Clinical trial

During the randomised period of the EUROPA study, only serious adverse events were controlled.

Few patients experienced serious adverse events: 16 (23%) of the 6122 perindopril patients and 10

(0.2%) of the 6017 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.

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 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. Perindopril may be

removed from the general circulation by haemodialysis (see 4.4 Special warnings and special

precautions for use, Haemodialysis Patients). Pacemaker therapy is indicated for therapy-resistant

bradycardia. Vital signs, serum electrolytes and creatinine concentrations should be monitored

continuously.

PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: ACE Inhibitor, plain, ATC code: CO9A AO4 Mechanism of action

Perindopril is an inhibitor of the enzyme that converts angiotensin I into angiotensin II (Angiotensin Converting Enzyme / ACE). The converting enzyme, or kinase, is an exopeptidase that allows conversion of angiotensin I into the vasoconstrictor angiotensin II as well as causing the degradation of the vasodilator bradykinin into an inactive heptapeptide. Inhibition of ACE results in a reduction of angiotensin II in the plasma, which leads to increased plasma renin activity (by inhibition of the negative feedback of renin release) and reduced secretion of aldosterone. Since ACE inactivates bradykinin, inhibition of ACE also results in an increased activity of circulating and local kallikrein- kinin systems (and thus also activation of the prostaglandin system). It is possible that this mechanism contributes to the blood pressure-lowering action of ACE inhibitors and is partially responsible for certain of their side effects (e.g. cough).

Perindopril acts through its active metabolite, perindoprilat. The other metabolites show no inhibition of ACE activity in vitro.

Clinical efficacy and safety

Hypertension:

Perindopril is active in all grades of hypertension: mild, moderate, severe; a reduction in systolic and diastolic blood pressures in both supine and standing positions is observed.

Perindopril reduces peripheral vascular resistance, leading to blood pressure reduction. As a consequence, peripheral blood flow increases, with no effect on heart rate.

Renal blood flow increases as a rule, while the glomerular filtration rate (GFR) is usually unchanged.

The antihypertensive activity is maximal between 4 and 6 hours after a single dose and is sustained for at least 24 hours: trough effects are about 87-100 % of peak effects.

The decrease in blood pressure occurs rapidly. In responding patients, normalisation is achieved within a month and persists without the occurrence of tachyphylaxis.

Discontinuation of treatment does not lead to a rebound effect.

Perindopril reduces left ventricular hypertrophy.

In man, perindopril has been confirmed to demonstrate vasodilatory properties. It improves large artery elasticity and decreases the media/lumen ratio of small arteries.

An adjunctive therapy with a thiazide diuretic produces an additive-type of synergy. The combination of an ACE inhibitor and a thiazide also decreases the risk of hypokalaemia induced by the diuretic treatment.

Heart _ failure:

Perindopril reduces cardiac work by a decrease in pre-load and after-load. Studies in patients with heart failure have demonstrated:

- decreased left and right ventricular filling pressures,

-    reduced total peripheral vascular resistance,

-    increased cardiac output and improved cardiac index.

In comparative studies, the first administration of 2 mg of perindopril to patients with mild to moderate heart failure was not associated with any significant reduction of blood pressure as compared to placebo.

Patients with stable coronary artery disease:

The EUROPA study, a multicenter, international, randomised, double-blind, placebo-controlled clinical trial, lasted 4 years. Twelve thousand two hundred and eighteen (12218) patients aged over 18 were randomised to perindopril 8 mg (n=6110) or placebo (n=6108).

The trial population had evidence of coronary artery disease with no evidence of clinical signs of heart failure. Overall, 90 % of the patients had a previous myocardial infarction and/or a previous coronary revasculariation. Most of the patients received the study medication on top of conventional therapy including platelet inhibitors, lipid lowering agents and beta-blockers.

The main efficacy criterion was the composite of cardiovascular mortality, non fatal myocardial infarction and/or cardiac arrest with successful resuscitation. The treatment with perindopril 8 mg once daily resulted in a significant absolute reduction in the primary endpoint of 1.9% (relative risk reduction of 20%, 95%CI [9.4; 28.6] - p<0.001).

In patients with a history of myocardial infarction and/or revascularisation, an absolute reduction of 2.2% corresponding to a RRR of 22.4% (95%CI [12.0; 31.6] - p<0.001) in the primary endpoint was observed by comparison with placebo.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) clinical trial data:

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of combination of an ACE-inhibitor with an angiotensin II receptor blocker.

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed.

Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.

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

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.

5.2 Pharmacokinetic properties

After oral administration, the absorption of perindopril is rapid and the peak concentration complete

within I hour. Bioavailability is 65 to 70 %.

About 20 % of the total quantity of perindopril absorbed is converted into perindoprilat, the active

metabolite. In addition to active perindoprilat, perindopril yields five metabolites, all inactive. The

plasma half-life of perindopril is equal to 1 hour. The peak plasma concentration of perindoprilat is

achieved within 3 to 4 hours.

As ingestion of food decreases conversion to perindoprilat, hence bioavailability, perindopril should

be administered orally in a single daily dose in the morning before a meal.

The volume of distribution is approximately 0.2 l/kg for unbound perindoprilat. Protein binding is

slight (binding of perindoprilat to angiotensin converting enzyme is less than 30 %), but is

concentration -dependent.

Perindoprilat is eliminated in the urine and the half-life of the unbound fraction is approximately 3 to 5

hours. Dissociation of perindoprilat bound to angiotensin converting enzyme leads to an "effective"

elimination half-life of 25 hours, resulting in steady state within 4 days.

After repeated administration, no accumulation of perindopril is observed.

Elimination of perindoprilat is decreased in the elderly, and also in patients with heart or renal failure.

Dosage adjustment in renal insufficiency is desirable depending on the degree of impairment

(creatinine clearance).

Dialysis clearance of perindoprilat is equal to 70 ml/min.

Perindopril kinetics are modified in patients with cirrhosis: hepatic clearance of the parent molecule is

reduced by half. However, the quantity of perindoprilat formed is not reduced and therefore no dosage

adjustment is required (see also sections 4.2 "Posology and method of administration" and 4.4 "Special

warnings and special precautions for use").

5.3 Preclinical safety data

In the chronic oral toxicity studies (rats and monkeys), the target organ is the kidney, with reversible

damage.

No mutagenicity has been observed in in vitro or in vivo studies.

Reproduction toxicology studies (rats, mice, rabbits and monkeys) showed no sign of embryotoxicity

or teratogenicity. However, angiotensin converting enzyme inhibitors, as a class, have been shown to

induce adverse effects on late foetal development, resulting in foetal death and congenital effects in

rodents and rabbits: renal lesions and an increase in peri- and postnatal mortality have been observed.

No carcinogenicity has been observed in long-term studies in rats and mice.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose anhydrous

Magnesium Stearate

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

3 years.

6.4    Special precautions    for storage

Store below 25°C. Store    in the original package.

6.5 Nature and contents of container

Blister pack: Aluminium/PVC/PVAC.

Package sizes: 4, 7, 14, 15, 28, 30, 50, 56, 60, 90, 100, 112, 120, 500 tablets.

6.6 Special precautions for disposal

None

7 MARKETING AUTHORISATION HOLDER

Apotex Europe B.V.

Darwinweg 20 2333 CR Leiden The Netherlands

8    MARKETING AUTHORISATION NUMBER(S)

PL 27583/0109

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

24/07/2006

10 DATE OF REVISION OF THE TEXT

10/12/2015