Perindopril 8 Mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Perindopril 8 mg tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains:
8 mg perindopril tert-butylamine salt, corresponding to 6.68 mg perindopril.
Excipient: 137.33 mg lactose/tablet.
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Tablet.
White, round, slightly biconvex tablet with bevelled edges, scored on one side.
The tablet can be divided into equal halves.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Hypertension
Treatment of hypertension.
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
It is recommended to take perindopril once daily, in the morning, before a meal.
The dose should be individualised according to the patient profile (see Section 4.4) and blood pressure response.
Hypertension:
Perindopril may be administered as monotherapy or in combination with antihypertensive agents from other classes.
The recommended initial dose is 4 mg once daily, in the morning.
Patients with enhanced activation of the renin-angiotensin-aldosteron system (especially those with renovascular hypertension, salt and/or volume depletion, cardiac decompensation or severe hypertension) may experience excessive blood pressure reduction after the ingestion of the initial dose. An initial dose of 2 mg is recommended for these patients and treatment should be initiated under medical supervision.
After one month of treatment, the daily dose may be increased to 8 mg once daily.
Symptomatic hypotension may ensue after the initiation of treatment with perindopril, especially in patients treated with diuretics concurrently. Caution is therefore recommended, as these patients may be volume- and/or salt-depleted.
When feasible, the diuretic should be discontinued 2 to 3 days before initiating therapy with perindopril (see Section 4.4).
In hypertensive patients in whom the diuretic cannot be discontinued, therapy should be started by administering 2 mg perindopril. Renal function and serum potassium level should be monitored. Subsequently, the dosage of perindopril should be adjusted according to the blood pressure response. Diuretic therapy may be resumed if necessary.
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).
Stable coronary artery disease
Therapy with perindopril should be initiated at a dose of 4 mg once daily for two weeks, then increased to 8 mg once daily, depending on renal function and the tolerability of the 4-mg dose.
Elderly patients should receive 2 mg once daily for one week, then 4 mg once daily during the next week, before increasing the dose to 8 mg once daily - depending on renal function (see Table 1. Recommended dosage in renal impairment). Dose escalation may be attempted only if the previous (lower) dose was well tolerated by the patient.
Dose adjustment in renal impairment
Dosage in patients with renal impairment should be based on creatinine clearance (Clcr) (see Table 1).
able 1. Recommended dosage in renal impairment.
|
Creatinine clearance (ml/min) |
Recommended dose |
|
Clcr > 60 |
4 mg/day |
|
30 < Clcr < 60 |
2 mg/day |
|
15 < Clcr < 30 |
2 mg every other day |
|
Haemodialysed patients, Clcr < 15* |
2 mg on the day of dialysis |
* The dialysis clearance of perindoprilat is 70 ml/min. Patients on haemodialysis, should take perindopril after the dialysis session.
Dosage adjustment in hepatic impairment
No dosage adjustment is necessary in patients with hepatic impairment (see Sections 4.4 and 5.2).
Children and adolescents (less than 18 years of age)
Efficacy and safety of use in children and adolescents below 18 years of age has not been established. Therefore, use in children and adolescents is not recommended.
4.3 Contraindications
Hypersensitivity to perindopril, to other ingredients of the preparation, or to other ACE inhibitors;
History of angioedema related to previous treatment with ACE inhibitors; Hereditary or idiopathic angioedema;
Second and third trimesters of pregnancy (see sections 4.4 and 4.6).
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 benefits and risks 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 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 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 drop in blood pressure could result in myocardial infarction or a 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 contraindication to further doses, which can be given usually without difficulty, once 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 or obstruction of the outflow tract of the left ventricle (such as aortic stenosis or hypertrophic cardiomyopathy).
Kidney impairment
In cases of renal impairment (creatinine clearance <60 ml/min), the initial perindopril dosage should be adjusted according to the creatinine clearance (see Section 4.2), and then as a function of the patient’s response to treatment. Routine monitoring of serum 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 inhibitor 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 impairment. 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 withno 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.
Haemodialysed 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.
Renal 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 should promptly be discontinued, and appropriate monitoring should be initiated and continued until the 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 found useful in relieving these 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 maintainenance of patent airway. The patient should be kept under close medical supervision until complete and sustained resolution of symptoms has occurred.
Angiotensin converting enzyme inhibitors cause a higher rate of angioedema in black patients, than in non-black patients.
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.
Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis
Rarely, patients receiving ACE inhibitors during low-density lipoprotein (LDL) apheresis with dextran sulphate have rarely experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis.
Anaphylactoid reactions during desensitisation
Patients receiving ACE inhibitors during desensitisation treatment (e.g. with Hymenoptera venom) have experienced anaphylactoid reactions. In the same patients, these reactions have been avoided when the ACE inhibitors were temporarily withheld, but, they re-appeared upon inadvertent re-challenge.
Hepatic failure
Rarely, ACE inhibitor therapy has been associated with a syndrome that starts with cholestatic jaundice and progress 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 the patients should be instructed to report any sign of infection (e.g. sore throat, fever). Sporadic occurrences of haemolytic anaemia have been reported in patients with congenital G6-PD deficiency.
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 the 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
Elevation inserum potassium level have been observed in some patients treated with ACE inhibitors, including perindopril. Risk factors for the development of hyperkalemia 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 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). 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. Hyperkalemia can cause serious, sometimes fatal arrhythmias.
If concomitant use of the above-mentioned agents is deemed appropriate, they should be used with caution and with frequent 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 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).
Lactose
<Product name> tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
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).
4.5 Interactions with other medicinal products and other forms of interaction
Diuretics
Patients on diuretics, and especially those who are volume- and/or salt-depleted, may experience excessive reduction in blood pressure after the initiation of therapy with an ACE inhibitor. The possibility of hypotensive effects can be reduced by discontinuation of the diuretic, by increasing fluid and salt intake prior to initiating therapy with low and progressive doses of perindopril.
Potassium sparing diuretics, potassium supplements or potassium-containing salt substitutes Although serum potassium level usually remains within the normal limits, hyperkalaemia may occur in some patients treated with perindopril. Potassium sparing diuretics (e.g. spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Therefore, the combination of perindopril with the above-mentioned drugs is not recommended (see Section 4.4). If concomitant use is indicated because of demonstrated hypokalaemia, they should be used with caution and with frequent monitoring of serum potassium.
Lithium
Reversible increases in serum lithium concentration 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 therapy proves necessary, careful monitoring of serum lithium levels should be performed (see Section 4.4).
Non-steroidal anti-inflammatory (NSAIDs), including acetylsalicylic acid ^ 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. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.
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.
Antidiabetic agents
Epidemiological studies have suggested that the concomitant administration of ACE inhibitors and antidiabetic medicines (insulin, 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.
Acetylsalicylic acid, thrombolytics, fi-blockers, nitrates
Perindopril may be used concomitantly with acetylsalicylic acid (when used as a thrombolytic), thrombolytics, beta-blockers and/or nitrates.
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).
Lactation
Because no information is available regarding the use of perindopril tablets during breastfeeding, perindopril tabelts are 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
Perindopril tablets have 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.
As a result the ability to drive or operate machinery may be impaired.
4.8 Undesirable effects
The following undesirable effects have been observed during treatment with perindopril and
ranked according to the frequency of occurrence:
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).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Blood and 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).
Metabolism and nutrition disorders:
Not known: hypoglycaemia (see Sections 4.4 and 4.5).
Psychiatric disorders:
Uncommon: mood or sleep disturbances.
Nervous system disorders:
Common: headache, dizziness, vertigo, and paraesthesia.
Very rare: confusion.
Eye disorders:
Common: visual disturbance.
Ear and labyrinth disorders:
Common: tinnitus.
Cardiac disorders:
Very rare: arrhythmia, angina pectoris and myocardial infarction, possibly secondary to excessive hypotension in high-risk patients (see Section 4.4).
Vascular disorders:
Common: hypotension and effects related to hypotension
Very rare: stroke, possibly secondary to excessive hypotension in high-risk patients (see Section 4.4)
Not known: vasculitis
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, and constipation.
Uncommon: dry mouth.
Very rare: pancreatitis.
Hepato-biliary disorders:
Very rare: cytolytic or cholestatic hepatitis (see Section 4.4)
Skin and subcutaneous tissue disorders:
Common: rash, pruritus.
Uncommon: angioedema of face, extremities, lips, mucous membranes, tongue, glottis and/or larynx, urticaria (see section 4.4).
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 and administration site conditions:
Common: asthenia.
Uncommon: sweating.
Investigations:
Increases in blood urea and serum creatinine, and hyperkalaemia reversible on discontinuation may occur, especially in the presence of renal insufficiency, severe heart failure, and renovascular hypertension. Elevations of liver enzymes activity and serum bilirubin have been reported rarely.
Clinical studies
During the randomisation period of the EUROPA study, only serious adverse events were recorded. Serious adverse events occurred in few patients only, in 16 (0.3%) of the 6122 patients treated with perindopril and 12 (0.2%) of 6107 patients receiving placebo. In the perindopril group, hypotension was observed in 6 patients, angioedema in 3 patients, and sudden cardiac arrest in one patient. More patients discontinued treatment for cough, hypotension, or intolerance in the perindopril, than in the placebo group (6.0% vs. 2.1%, n=366 vs. n=129).
4.9 Overdose
Limited data are available for overdosage in humans. Symptoms associated with the overdosage of ACE inhibitors may include hypotension, circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough.
Recommended treatment of overdosage: administration of physiological saline by intravenous infusion. If hypotension occurs, the patient should be placed in the supine position with lower extremities propped up (anti-shock position). If available, angiontensin II infusion and/or intravenous catecholamines may be considered. Periondopril can be removed from the systemic 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.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: ACE inhibitor, plain. ATC code: C09A A04.
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 catalyzes the conversion of angiotensin I into the vasoconstrictor angiotensin II, as well as the degradation of the vasodilator bradykinin into an inactive heptapeptide. Inhibition of ACE results in a reduction of angiotensin II plasma level, which leads to increased plasma renin activity (through inhibition of the negative feedback of renin release) and the attenuated secretion of aldosterone. Since ACE inactivates bradykinin, ACE inhibition enhances the activity of systemic circulation and local kallikrein-kinin systems in the tissues (and thus activates 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).
Perindoprilat, the active metabolite is responsible for pharmacological effects of perindopril; the other metabolites do not inhibit ACE activity in vitro.
Hypertension
Perindopril is effective in all grades of hypertension (mild, moderate, and severe). It reduces systolic and diastolic blood pressure in both in the supine and in the standing position. Perindopril reduces peripheral vascular resistance and thereby systemic blood pressure. Consequently, peripheral blood flow increases with no change in heart rate.
As a rule, renal blood flow increases with usually no change in glomerular filtration rate (GFR).
The antihypertensive is maximal peaks between 4 and 6 hours after the administration of a single dose and persists for at least 24 hours; Remaining effect corresponds to approximately 87 to 100 per cent of peak effect.
Blood pressure reduction occurs rapidly. In patients responding to perindopril, normalisation of blood pressure is achieved within a month. Antihypertensive efficacy persists without the occurrence of tachyphylaxis.
Discontinuation of treatment does not lead to „rebound” elevation of blood pressure. Perindopril mitigates left ventricular hypertrophy.
In man, perindopril has been confirmed to exert vasodilatory properties. It improves the elasticity of large arteries and decreases the media/lumen ratio of small arteries.
Combination treatment achieves additive synergism of the antihypertensive effects of thiazide diuretics and perindopril. This combination reduces the risk of hypokalaemia occurring as an adverse effect of diuretic therapy.
Patients with stable coronary artery disease
The EUROPA study was a multicentre, international, randomised, double-blind, placebo-controlled clinical trial with a duration of 4 years.
Twelve thousand two hundred and eighteen (12,218) patients aged over 18 were randomised to take perindopril 8 mg (n=6110) or placebo (n=6108).
The trial population had proven coronary artery disease with no evidence of clinical heart failure. Overall, 90% of the patients had a previous myocardial infarction and/or revascularisation. The majority of patients received the study medication as an add-on to conventional therapy, which comprised inhibitors of platelet aggregation, 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 [RRR] of 20%, 95%CI [9.4; 28.6] - /><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 to placebo.
5.2 Pharmacokinetic properties
Perindopril is rapidly absorbed from the gastrointestinal tract following oral administration. Peak plasma concentration occurs within one hour; bioavailability is 65-70 per cent, on average.
Approximately 20 per cent of the total quantity of absorbed perindopril is converted into perindoprilat, the active metabolite. Further five inactive perindopril-metabolites are formed in addition. The plasma half-life of perindopril is 1 hour. Maximum plasma level of perindoprilat is achieved within 3 to 4 hours.
The ingestion of food decreases the conversion of perindopril to perindoprilat and hence bioavailability. Therefore, the daily dose of perindopril should be taken as a single dose, before the morning meal. The volume of distribution is approximately 0.2 l/kg for unbound perindoprilat. Protein binding is low (less than 30% of perindoprilat is bound to ACE), but it is concentration-dependent.
Perindoprilat is eliminated in the urine; half-life of the unbound circulating fraction is approximately 3 to 5 hours. Dissociation of perindoprilat bound to ACE results in an “effective” elimination half-life of 25 hours. During repeated dosage, steady-state pharmacokinetic conditions ensue within 4 days.
No accumulation of perindopril occurs in the organism after repeated dosage.
The elimination of perindoprilat is decreased in the elderly and in patients with heart or renal failure. Dosage adjustment in renal insufficiency is advisable, depending on the severity of impairment (as reflected by creatinine clearance).
Perindoprilat can be removed from the circulation by dialysis; its clearance is 70 ml/min.Pharmacokinetic properties of perindopril are modified in liver cirrhosis: the hepatic clearance of the parent molecule is reduced by half. However, the metabolite quantity of the formed active perindoprilat does not change and therefore, no dosage adjustment is necessary.
5.3 Preclinical safety data
In the chronic oral toxicity studies conducted on rats and monkeys, the kidney was target organ with reversible damage.
No mutagenicity has been demonstrated by in vitro or in vivo studies.
Reproductive toxicity studies (on rats, mice, rabbits and monkeys) showed no sign of embryotoxicity or teratogenicity. Nevertheless, angiotensin converting enzyme inhibitors, as a class, have been shown to induce adverse (deleterious) effects in the late stage of foetal development. In rodents and rabbits, such effects result in foetal death and congenital abnormalities (renal lesions), as well as increase peri- and postnatal mortality.
No carcinogenicity has been observed in long term studies conducted on rats and mice.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose monohydrate Cellulose, microcrystalline (E460)
Sodium hydrogen carbonate Silica, colloidal anhydrous Magnesium stearate (E572)
6.2 Incompatibilities
Not applicable
6.3. Shelf life
3 years.
6.4 Special precautions for storage
Store in the original package in order to protect from moisture. Store below 30°C
6.5 Nature and contents of container
Blisters (PVC/PE/PVDC/Al) of 7, 14, 28, 30, 50, 60, 90 or 100 tablets, in cardboard box.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
KRKA Polska Sp. z o.o., ul. Rownolegla 5, 02-235 Warsaw, Poland
8 MARKETING AUTHORISATION NUMBER(S)
PL 25847/0007
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
09/12/2010
10 DATE OF REVISION OF THE TEXT
09/12/2010