Arcalion 200

ACERTIL PLUS 5mg/1.25mg
雅施達 加利 5mg/1.25mg
Perindopril arginine / indapamide film-coated tablets 1. NAME OF THE MEDICINAL PRODUCT
4.3 Contraindications
Linked to perindopril: ACERTIL PLUS 5mg/1.25mg film-coated tablets - Hypersensitivity to perindopril or any other ACE inhibitor - History of angioedema (Quincke's oedema) associated 2. QUALITATIVE AND QUANTITATIVE COMPOSITION
with previous ACE inhibitor therapy - Hereditary/idiopathic angioedema One film-coated tablet contains 3.395 mg perindopril - Second and third trimesters of pregnancy (see section 4.6) corresponding to 5 mg perindopril arginine and 1.25 mg Linked to indapamide: indapamide. - Hypersensitivity to indapamide or to any other Excipient : 71.33 mg lactose monohydrate For a ful list of excipients, see section 6.1. - Severe renal impairment (creatinine clearance below 30 3. PHARMACEUTICAL FORM
- Hepatic encephalopathy - Severe hepatic impairment Film-coated tablet. White, rod-shaped film-coated tablet. - As a general rule, this medicine is inadvisable in combination with non antiarrhythmic agents causing 4. CLINICAL PARTICULARS
torsades de pointes (see section 4.5) - Lactation (see section 4.6). 4.1 Therapeutic indications
Linked to ACERTIL PLUS 5mg/1.25mg; Treatment of essential hypertension, ACERTIL PLUS - Hypersensitivity to any of the excipients 5mg/1.25mg film-coated tablet is indicated in patients Due to the lack of sufficient therapeutic experience, ACERTIL whose blood pressure is not adequately controlled on PLUS 5mg/1.25mg should not be used in : perindopril alone. - Dialysis patients - Patients with untreated decompensated heart failure. 4.2 Posology and method of administration
4.4 Special warnings and precautions for use
One ACERTIL PLUS 5mg/1.25mg film-coated tablet per Special warnings
day as a single dose, preferably to be taken in the Common to perindopril and indapamide:
morning, and before a meal.
Lithium: The combination of lithium and the combination of When possible individual dose titration with the perindopril and indapamide is usual y not recommended (see
components is recommended. ACERTIL PLUS section 4.5).
5mg/1.25mg film-coated tablet should be used when Linked to perindopril:
blood pressure is not adequately controlled on ACERTIL Risk of neutropenia/agranulocytosis in immunosuppressed
PLUS 2.5mg/0.625mg film-coated tablet (where patients: The risk of neutropenia appears to be dose and type
available). When clinically appropriate, direct change related and is dependent on patient's clinical status. It is
from monotherapy to ACERTIL PLUS 5mg/1.25mg rarely seen in uncomplicated patients but may occur in
film-coated tablet may be considered.
patients with some degree of renal impairment especially Elderly (see section 4.4) when it is associated with collagen vascular disease e.g. Treatment should be initiated after considering blood systemic lupus erythematosus, scleroderma and therapy with pressure response and renal function. immunosuppressive agents. It is reversible after Patients with renal impairment (see section 4.4) discontinuation of the ACE inhibitor. Strict compliance with In severe renal impairment (creatinine clearance below the predetermined dose seems to be the best way to prevent 30 ml/min), treatment is contraindicated. the onset of these events. However, if an angiotensin In patients with moderate renal impairment (creatinine converting enzyme inhibitor is to be administered to this type clearance 30-60 ml/min), it is recommended to start of patient, the risk/benefit ratio should be evaluated carefully. treatment with the adequate dosage of the free Angioedema (Quincke's oedema): Angioedema of the face, combination. extremities, lips, tongue, glottis and/or larynx has been In patients with creatinine clearance greater than or reported rarely in patients receiving treatment with equal to 60 ml/min, no dose modification is required. angiotensin converting enzyme inhibitors, including Usual medical fol ow-up wil include frequent monitoring perindopril. In such cases, treatment with perindopril should of creatinine and potassium. be stopped immediately and the patient should be monitored Patients with hepatic impairment (see sections 4.3, 4.4 until the oedema has disappeared. and 5.2) When the oedema only affects the face and the lips, the In severe hepatic impairment, treatment is effect generally recedes without treatment, even though contraindicated. anti-histamines may be used to relieve symptoms. In patients with moderate hepatic impairment, no dose Angioedema combined with laryngeal oedema may be fatal. modification is required. Involvement of tongue, glottis or larynx may lead to an Children and adolescents obstruction of the airways. A subcutaneous injection of ACERTIL PLUS 5mg/1.25mg should not be used in adrenaline at 1:1000 children and adolescents as the efficacy and tolerability of perindopril in children and adolescents, alone or in combination, have not been established. (0.3 ml to 0.5 ml) should be administered quickly and treatment can be started again either at a reduced dose or other appropriate measures taken. The prescription of an with only one of the constituents. angiotensin converting enzyme inhibitor should not Potassium levels: The combination of perindopril and subsequently be considered in these patients (see indapamide does not prevent the onset of hypokalaemia section 4.3). particularly in diabetic patients or in patients with renal Patients with a previous history of Quincke's oedema failure. As with any antihypertensive agent containing a which was not linked to taking an angiotensin converting diuretic, regular monitoring of plasma potassium levels enzyme inhibitor have an increased risk of Quincke's should be carried out. oedema with an angiotensin converting enzyme inhibitor. Excipients: ACERTIL PLUS 5mg/1.25mg should not be Anaphylactoid reactions during desensitization: administered to patients with rare hereditary problems of There have been isolated reports of patients galactose intolerance, the Lapp lactase deficiency or
experiencing sustained, life-threatening anaphylactoid glucose-galactose malabsorption.
reactions while receiving ACE inhibitors during Linked to perindopril:
desensitization treatment with hymenoptera (bees, Cough: A dry cough has been reported with the use of
wasps) venom. ACE inhibitors should be used with angiotensin converting enzyme inhibitors. It is
caution in allergic patients treated with desensitisation, characterized by its persistence and by its disappearance
and avoided in those undergoing venom immunotherapy. when treatment is withdrawn. An iatrogenic aetiology
However these reactions could be prevented by should be considered in the event of this symptom. If the
temporary withdrawal of ACE inhibitor for at least 24 prescription of an angiotensin converting enzyme inhibitor
hours before treatment in patients who require both ACE is stil preferred, continuation of treatment may be
inhibitors and desensitization.
Anaphylactoid reactions druing membrane exposure: Children and adolescents: The efficacy and tolerability of There have been reports of patients experiencing perindopril in children and adolescents, alone or in sustained, life-threatening anaphylactoid reactions while combination, have not been established. receiving ACE inhibitors during dialysis with high-flux Risk of arterial hypotension and/or renal insufficiency (in membranes or low-density lipoprotein apheresis with cases of cardiac insufficiency, water and electrolyte dextran sulphate adsorption. ACE inhibitors should be depletion, etc…): avoided in patients undergoing dialysis with high-flux Marked stimulation of the renin-angiotensin-aldosterone membranes or LDL apheresis with dextran sulphate system has been observed particularly during marked adsorption. However these reactions could be prevented water and electrolyte depletions (strict sodium-free diet or by temporary withdrawal of ACE-inhibitor for at least 24 prolonged diuretic treatment), in patients whose blood hours before treatment in patients who require both pressure was initially low, in cases of renal artery stenosis, ACE-inhibitors and LDL apheresis. congestive heart failure or cirrhosis with oedema and Potassium-sparing diuretics, potassium salts: The combination of perindopril and potassium-sparing The blocking of this system with an angiotensin converting diuretics, potassium salts is usual y not recommended enzyme inhibitor may therefore cause, particularly at the (see section 4.5). time of the first administration and during the first two Linked to indapamide:
weeks of treatment, a sudden drop in blood pressure When liver function is impaired, thiazide diuretics and and/or an increase in plasma levels of creatinine, showing thiazide-related hepatic a functional renal insufficiency. Occasionally this can be encephalopathy. Administration of the diuretic should be acute in onset, although rare, and with a variable time to stopped immediately if this occurs. Sultopride: In such cases the treatment should then be initiated at a The combination of indapamide and sultopride is usual y lower dose and increased progressively. not recommended (see section 4.5). Elderly: Renal function and potassium levels should be Precautions for use
tested before the start of treatment. The initial dose is Common to perindopril and indapamide: subsequently adjusted according to blood pressure Renal impairment: response, especially in cases of water and electrolyte In cases of severe renal impairment (creatinine clearance depletion, in order to avoid sudden onset of hypotension. < 30 ml/min), treatment is contraindicated. Patients with known atherosclerosis: The risk of In certain hypertensive patients without pre-existing hypotension exists in all patients but particular care should apparent renal lesions and for whom renal blood tests be taken in patients with ischaemic heart disease or show functional renal insufficiency, treatment should be cerebral circulatory insufficiency, with treatment being stopped and possibly restarted either at a low dose or started at a low dose. with one constituent only. Renovascular hypertension: The treatment for renovascular In these patients usual medical fol ow-up wil include hypertension is revascularization. Nonetheless, angiotensin frequent monitoring of potassium and creatinine, after converting enzyme inhibitors can be beneficial in patients two weeks of treatment and then every two months presenting with renovascular hypertension who are during therapeutic stability period. Renal failure has been awaiting corrective surgery or when such a surgery is not reported mainly in patients with severe heart failure or possible. underlying renal failure including renal artery stenosis. If ACERTIL PLUS 5mg/ 1.25mg is prescribed to patients The drug is usual y not recommended in case of bilateral with known or suspected renal artery stenosis, treatment renal artery stenosis or a single functioning kidney. should be started in a hospital setting at a low dose and Hypotension and water and electrolyte depletion: renal function and potassium levels should be monitored, There is a risk of sudden hypotension in the presence of since some patients have developed a functional renal pre-existing sodium depletion (in particular in individuals insufficiency which was reversed when treatment was with renal artery stenosis). Therefore systematic testing stopped. should be carried out for clinical signs of water and Other populations at risk: In patients with severe cardiac electrolyte depletion, which may occur with an insufficiency (grade IV) or in patients with insulin dependent intercurrent episode of diarrhoea or vomiting. Regular diabetes mellitus (spontaneous tendency to increased monitoring of plasma electrolytes should be carried out in levels of potassium), treatment should be started under such patients. Marked hypotension may require the medical supervision with a reduced initial dose. Treatment implementation of an intravenous infusion of isotonic with beta-blockers in hypertensive patients with saline. Transient hypotension is not a contraindication to continuation of treatment. After reestablishment of a satisfactory blood volume and blood pressure, coronary insufficiency should not be stopped : the ACE If low potassium levels are detected, correction is required. inhibitor should be added to the beta-blocker. Calcium levels: Thiazide diuretics and thiazide-related Anaemia: Anaemia has been observed in patients who diuretics may reduce urinary excretion of calcium and have had a kidney transplant or have been undergoing cause a mild and transient increase in plasma calcium dialysis. The reduction in haemoglobin levels is more levels. Markedly raised levels of calcium may be related to apparent as initial values were high. This effect does not undiagnosed hyperparathyroidism. In such cases the seem to be dose-dependent but may be linked to the treatment should be stopped before investigating the mechanism of action of angiotensin converting enzyme parathyroid function. inhibitors. Blood glucose: Monitoring of blood glucose is important in This reduction in haemoglobin is slight, occurs within 1 to diabetic patients, particularly when potassium levels are 6 months, and then remains stable. It is reversible when low. treatment is stopped. Treatment can be continued with Uric acid: Tendency to gout attacks may be increased in regular haematological testing. hyperuricaemic patients. Surgery: Angiotensin converting enzyme inhibitors can Renal function and diuretics: Thiazide diuretics and cause hypotension in cases of anaesthesia, especially thiazide-related diuretics are only fully effective when renal when the anaesthetic administered is an agent with function is normal or only slightly impaired (creatinine levels hypotensive potential. lower than approximately 25 mg/l, i.e. 220 umol/l for an It is therefore recommended that treatment with adult). long-acting angiotensin converting enzyme inhibitors In the elderly the value of plasma creatinine levels should such as perindopril should be discontinued where be adjusted to take account of the age, weight and sex of possible one day before surgery. the patient, according to the Cockroft formula: Aortic stenosis / hypertrophic cardiomyopathy: ACE Clcr = (140 – age) x body weight inhibitors should be used with caution in patient with an 0.814 x plasma creatinine level obstruction in the outflow tract of the left ventricle. with: age expressed in years, body weight in kg, plasma Hepatic failure: Rarely, ACE inhibitors have been creatinine level in micromol/l associated with a syndrome that starts with cholestatic This formula is suitable for an elderly male and should be jaundice and progresses to fulminant hepatic necrosis adapted for women by multiplying the result by 0.85. and (sometimes) death. The mechanism of this Hypovolaemia, resulting from the loss of water and sodium syndrome is not understood. Patients receiving ACE caused by the diuretic at the start of treatment, causes a inhibitors who develop jaundice or marked elevations of reduction in glomerular filtration. It may result in an hepatic enzymes should discontinue the ACE inhibitor increase in blood urea and creatinine levels. This transitory and receive appropriate medical fol ow-up (see section functional renal insufficiency is of no adverse consequence 4.8). in patients with normal renal function but may however Hyperkalaemia: Elevations in serum potassium have worsen a pre-existing renal impairment. been observed in some patients treated with ACE Athletes: Athletes should note that this product contains an inhibitors, including perindopril. Patients at risk for the active substance which may cause a positive reaction in development of hyperkalaemia include those with renal doping tests. insufficiency, uncontrolled diabetes mellitus, or those using potassium-sparing diuretics, 4.5 Interaction with other medicinal products and other
potassium supplements or potassium-containing salt forms of interaction
substitutes; or those patients taking other drugs Common to perindopril and indapamide:
associated with increases in serum potassium (e.g. Concomitant use not recommended:
heparin). If concomitant use of the above-mentioned Lithium: reversible increases in serum lithium
agents is deemed appropriate, regular monitoring of concentrations and toxicity have been reported during
serum potassium is recommended. The drug is usually concomitant administration of lithium with ACE inhibitors.
not recommended in case of raised plasma levels of Concomitant use of thiazide diuretics may further increase
potassium.
lithium levels and enhance the risk of lithium toxicity with Linked to indapamide:
ACE inhibitors. Use of perindopril combined with Water and electrolyte balance: indapamide with lithium is not recommended, but if the Sodium levels: These should be tested before treatment combination proves necessary, careful monitoring of serum is started, then at regular intervals. All diuretic treatment lithium levels should be performed (see section 4.4). can cause a reduction in sodium levels, which may have Concomitant use which requires special care: serious consequences. Reduction in sodium levels can - Baclofen: Potentiation of antihypertensive effect. be initially asymptomatic and regular testing is therefore Monitoring of blood pressure and renal function, and essential. Testing should be more frequent in elderly and dose adaptation of the antihypertensive if necessary. cirrhotic patients (see sections 4.8 and 4.9). - Non-steroidal anti-inflammatory medicinal products Potassium (included acetylsalicylic acid at high doses) : the hypokalaemia is a major risk with thiazide diuretics and administration of non-steroidal anti-inflammatory thiazide-related diuretics. The risk of onset of lowered medicinal product may reduce the diuretic, natriuretic potassium levels (< 3.4 mmol/l) should be prevented in and antihypertensive effects in some patients. In elderly some high risk populations such as elderly and/or patients and patients who may be dehydrated there is a malnourished subjects, whether or not they are taking risk of acute renal failure, therefore monitoring of renal multiple medications, cirrhotic patients with oedema and function at the initiation of treatment is recommended. ascites,coronary patients and patients with heart failure. Patients should be well hydrated. In such cases hypokalaemia increases the cardiac Concomitant use which requires some care: toxicity of cardiac glycosides and the risk of rhythm - Imipramine-like antidepressants (tricyclics), neuroleptics: disorders. Increased antihypertensive effect and increased risk of Subjects presenting with a long QT interval are also at orthosatatic hypotension (additive effect). risk, whether the origin is congenital or iatrogenic. - Corticosteroids, Hypokalaemia, as with bradycardia, acts as a factor antihypertensive effect (salt and water retention due to which favours the onset of severe rhythm disorders, in corticosteroids). particular torsades de pointes, which may be fatal. In all - other antihypertensive agents : use of other cases more frequent testing of potassium levels is necessary. The first measurement of plasma potassium levels should be carried out during the first week fol owing the start of treatment. antihypertensive medicinal products with perindopril/ caused by possible functional renal insufficiency linked indapamide could result in additional blood pressure to diuretics and in particular to loop diuretics. Do not use lowering ef ect. metformin when plasma creatinine levels exceed 15 mg/l Linked to perindopril:
(135 micromol/l) in men and 12 mg/l (110 micromol/l) in Concomitant use not recommended: - Potassium-sparing (spironolactone, - lodinated contrast media: In cases of dehydration triamterence, alone or in combination), potassium caused by diuretics, there is an increased risk of acute (salts): ACE inhibitors attenuate diuretic induced renal insufficiency, particularly when high doses of potassium loss. Potassium sparing diuretics e.g. iodinated contrast media are used. Rehydration should spironolactone, triamterene, or amiloride, potassium be carried out before the iodinated compound is supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium - Calcium (salts): Risk of increased levels of calcium due (potentially lethal). If concomitant use is indicated to reduced elimination of calcium in the urine. because of documented hypokalemia they should be - Ciclosporin: Risk of increased creatinine levels with no used with caution and with frequent monitoring of change in circulating levels of ciclosporin, even when serum potassium and by ECG. there is no salt and water depletion. Concomitant use which requires special care: hypoglycaemic 4.6 Pregnancy and lactation
sulphonamides): Reported with captopril and enalapril. Pregnancy: ACERTIL PLUS 5mg/1.25mg should not be The use of angiotensin converting enzyme inhibitors used during the first trimester of pregnancy. When a may increase the hypoglycaemic effect in diabetics pregnancy is planned or confirmed the switch to an receiving treatment with insulin or with hypoglycaemic alternative treatment should be initiated as soon as sulphonamides. The onset of hypoglycaemic episodes possible. Controlled studies with ACE inhibitors have not is very rare (improvement in glucose tolerance with a been done in humans, but in a limited number of cases with resulting reduction in insulin requirements). first trimester exposure there do not appear to have been Concomitant use with requires some care: any malformations consistent with human fetotoxicity as - Allopurinol, cytostatic or immunosuppressive agents, described below. systemic corticosteroids or procainamide: ACERTIL PLUS 5mg/ 1.25mg is contraindicated during the Concomitant administration with ACE inhibitors may second and third trimesters of pregnancy (see section 4.3). lead to an increased risk for leucopenia. Prolonged ACE inhibitors exposure during the second and - Anaesthetic drugs: ACE inhibitors may enhance the third trimesters is known to induce human fetotoxicity hypotensive effects of certain anaesthetic drugs. (decreased renal function, oligohydramnios, retardation of - Diuretics (thiazide or loop diuretics): Prior treatment skull ossification) and neonatal toxicity (renal failure, with high dose diuretics may result in volume depletion hypotension, hyperkalemia) (see section 5.3). and in a risk of hypotension when initiating therapy Prolonged exposure to thiazide during the third trimester of with perindorpril. pregnancy can reduce maternal plasma volume as well as Linked to indapamide:
uteroplacental blood flow, which may cause a feto-placental Concomitant use not recommended: ischemia and growth retardation. Moreover, rare cases of - Sultopride: Increased risk of ventricular arrhythmia, hypoglycemia and thrombocytopenia in neonates have especially torsades de pointes (hypokaliema favours been reported fol owing exposure near term. the occurrence of this adverse event)(see section 4.4). Should exposure to ACERTIL PLUS 5mg/1.25mg have Concomitatn use which requires special care: occurred from the second trimester of pregnancy, an - Torsades de pointes inducing drugs : Due to the risk of ultrasound check of renal function and the skull is hypokalemia, indapamide should be administered with recommended. caution when associated with medicinal products that Lactation: ACERTIL PLUS 5mg/1.25mg is contraindicated induced torsades de pointes such as class IA during lactation. antiarrhythmic agents (quinidine, hydroquinidine, The excretion of perindopril into breast milk is unknown. disopyramide); class III antiarrhythmic agents Indapamide is excreted in human milk. Indapamide is (amiodarone, dofetilide, ibutilide, bretylium, sotalol); closely related to thiazide diuretics which have been some neuroleptics (chlorpromazine, cyamemazine associated, during breast-feeding, with decrease or even levomepromazine, trifluoperazine), suppression of milk lactation. Hypersensitivity to tiapride), sulfonamide-derived drugs, hypokalaemia and nuclear butyrophenones (droperidol, haloperidol), other icterus might occur. neuroleptics (pimozide); other substances such as As, with both drugs, serious adverse reactions might occur bepridil, cisapride, diphemanil, IV erythromycin, in nursing infants, a decision should be made whether to halofantrine, mizolastine, moxifloxacin, pentamidine, discontinue nursing or to discontinue therapy taking sparfloxacin, IV vincamine, methoadone, astemizole, account the importance of this therapy for the mother. terfenadine. Prevention of low potassium levels and correction if necessary : monitoring of the QT interval. 4.7 Effects on ability to drive and use machines
- Potassium-lowering drugs : amphotericin B (IV route), Linked to perindopril, indapamide and ACERTIL PLUS
glucocorticoids and mineralocorticoids (systemic 5mg/1.25mg:
route), tetracosactide, stimulant laxatives: Increased Neither the two active substances nor ACERTIL PLUS
risk of low potassium levels (additive effect). 5mg/1.25mg affect alertness but individual reactions
Monitoring of potassium levels, and correction if related to low blood pressure may occur in some patients,
necessary; particular consideration required in cases particularly at the start of treatment or in combination with
of treatment with cardiac glycosides. Non stimulant another antihypertensive medication.
laxatives should be used.
As a result the ability to drive or operate machinery may be - Cardiac glycosides: Low potassium levels favour the impaired. toxic effects of cardiac glycosides. Potassium levels 4.8 Undesirable effects
and ECG should be monitored and treatment The
reconsidered if necessary. renin-angiotensin- aldosterone axis and tends to reduce the Concomitant use which requires some care: potassium loss caused by indapamide. Four percent of the - Metformin: Lactic acidosis due to metformin patients on treatment with ACERTIL PLUS 5mg/1.25mg experience hypokalaemia (potassium then restoring fluid and electrolyte balance in a specialized level < 3.4 mmol/l). centre until they return to normal. Blood and the lymphatic system disorders:
If marked hypotension occurs, this can be treated by Very rare (<1/10,000): placing the patient in a supine position with the head - Thrombocytopenia, leucopenia, agranulocytosis, lowered. If necessary an intravenous infusion of isotonic aplastic anaemia, haemolytic anaemia. saline may be given, or any other method of volaemic - Anaemia (see section 4.4) has been reported with expansion may be used. angiotensin converting enzyme inhibitors in specific Perindoprilat, the active form of perindopril, can be dialysed circumstances (patients who have had kidney (see section 5.2). transplants, patients undergoing haemodialysis). Nervous system disorders:
5. PHARMACOLOGICAL PROPERTIES
Uncommon (>1/1,000, <1/100): - Paresthesia, headache, asthenia, feelings of 5.1 Pharmacodynamic properties
dizziness, mood disturbances and/or sleep Pharmacotherapeutic group: perindopril and diuretics, ATD disturbances. Vascular disorders:
ACERTIL PLUS 5mg/1.25mg is a combination of Uncommon (>1/1,000, <1/100): perindopril arginine salt, an angiotensin converting enzyme - Hypotension whether orthostatic or not (see section inhibitor, and indapamide, a chlorosulphamoyl diuretic. Its pharmacological properties are derived from those of each Respiratory, thoracic and mediastinal disorders:
of the components taken separately, in addition to those Common (>1/100,<1/10): due to the additive synergic action of the two products - A dry cough has been reported with the use of when combined. angiotensin converting enzyme inhibitors. It is Pharmacological mechanism of action
characterized by its persistence and by its Linked to ACERTIL PLUS 5mg/1.25mg:
disappearance when treatment is withdrawn. An ACERTIL PLUS 5mg/1.25mg produces an additive synergy
iatrogenic aetiology should be considered in the of the antihypertensive effects of the two components.
presence of this symptom.
Linked to perindopril:
Gastrointestinal disorders:
Perindopril is an inhibitor of the angiotensin converting Common (>1/100, <1/10): enzyme (ACE inhibitor) which converts angiotensin I to - Constipation, dry mouth, nausea, epigastric pain, angiotensin II, a vasoconstricting substance; in addition the anorexia, abdominal pains, taste disturbance enzyme stimulates the secretion of aldosterone by the Very rare (<1/10,000): adrenal cortex and stimulates the degradation of bradykinin, a vasodilatory substance, into inactive In case of hepatic insufficiency, there is a possibility of heptapeptides. onset of hepatic encephalopathy (see sections 4.3 and This results in: 4.4) - a reduction in aldosterone secretion, Skin and subcutaneous tissue disorders:
- an increase in plasma renin activity, since aldosterone Uncommon (>1/1,000, <1/100): no longer exercises negative feedback, - Hypersensitivity reactions, mainly dermatological, in - a reduction in total peripheral resistance with a subjects with a predisposition to allergic and asthmatic preferential action on the vascular bed in muscle and the kidney, with no accompanying salt and water retention or - Maculopapular eruptions, purpura, possible reflex tachycardia, with chronic treatment. aggravation of pre-existing acute disseminated lupus The antihypertensive action of perindopril also occurs in patients with low or normal renin concentrations. Perindopril acts through its active metabolite, perindoprilat. Very rare (<1/10,000): The other metabolites are inactive. - Angioedema (Quincke's oedema) (see section 4.4) Perindopril reduces the work of the heart: Musculoskeletal, connective tissue and bone - by a vasodilatory effect on veins, probably caused by
disorders:
changes in the metabolism of prostaglandins : reduction Uncommon (>1/1,000, <1/100): - by reduction of the total peripheral resistance: reduction - Potassium depletion with particularly serious reduction Studies carried out on patients with cardiac insufficiency in levels of potassium in some at risk populations (see have shown: section 4.4). - a reduction in left and right ventricular filling pressures, - Reduced sodium levels with hypovolaemia causing - a reduction in total peripheral vascular resistance, dehydration and orthostatic hypotension. - an increase in cardiac output and an improvement in the - Increase in uric acid levels and in blood glucose levels during treatment. - an increase in regional blood flow in muscle. - Slight increase in urea and in plasma creatinine levels, Exercise test results also showed improvement. reversible when treatment is stopped. This increase is Linked to indapamide:
more frequent in cases of renal artery stenosis, arterial Indapamide is a sulphonamide derivative with an indole
hypertension treated with diuretics, renal insufficiency.
ring, pharmacologically related to the thiazide group of - Increased levels of potassium, usual y transitory. diuretics. Indapamide inhibits the reabsorption of sodium in Rare (>1/10,000, <1/1,000): the cortical dilution segment. It increases the urinary - raised plasma calcium levels. excretion of sodium and chlorides and, to a lesser extent, the excretion of potassium and magnesium, thereby 4.9 Overdose
increasing urine output and having an antihypertensive The most likely adverse reaction in cases of overdose is action.
hypotension, sometimes associated with nausea, Characteristics of antihypertensive action
vomiting, cramps, dizziness, sleepiness, mental Linked to ACERTIL PLUS 5mg/1.25mg:
confusion, oliguria which may progress to anuria (due to In hypertensive patients regardless of age, ACERTIL PLUS
hypovolaemia). Salt and water disturbances (low sodium 5mg/1.25mg exerts a dose-dependent antihypertensive
levels, low potassium levels) may occur.
effect on diastolic and systolic The first measures to be taken consist of rapidly eliminating the product(s) ingested by gastric lavage and/or administration of activated charcoal, arterial pressure whilst supine or standing. This The volume of distribution is approximately 0.2 I/kg for antihypertensive effect lasts for 24 hours. The reduction unbound perindoprilat. Protein binding of perindoprilat to in blood pressure is obtained in less than one month plasma proteins is 20%, principal y to angiotensin without tachyphylaxis; stopping treatment has no converting enzyme, but is concentration-dependent. rebound effect. During clinical trials, the concomitant Perindoprilat is eliminated in the urine and the terminal administration of perindopril and indapamide produced half-life of the unbound fraction is approximately 17 hours, antihypertensive effects of a synergic nature in relation to resulting in steady-state within 4 days. each of the products administered alone. Elimination of perindoprilat is decreased in the elderly, and Linked to perindopril:
also in patients with heart or renal failure. Dosage Perindopril is active in all grades of hypertension : mild to adjustment in renal insufficiency is desirable depending on moderate or severe. A reduction in systolic and diastolic the degree of impairment (creatinine clearance). arterial pressure is observed in the lying and standing Dialysis clearance of perindoprilat is equal to 70ml/min. position. Perindopril kinetics are modified in patients with cirrhosis: The antihypertensive activity after a single dose is hepatic clearance of the parent molecule is reduced by maximal at between 4 and 6 hours and is maintained half. However, the quantity of perindoprilat formed is not over 24 hours. reduced and therefore no dosage adjustment is required There is a high degree of residual blocking of angiotensin (see sections 4.2 and 4.4). converting enzyme at 24 hours, approximately 80%. Linked to indapamide:
In patients who respond, normalized blood pressure is Indapamide is rapidly and completely absorbed from the reached after one month and is maintained without digestive tract. tachyphylaxis. The peak plasma level is reached in humans approximately Withdrawal of treatment has no rebound effect on one hour after oral administration of the product. hypertension. Plasma protein binding is 79%. Perindopril has vasodilatory properties and restores The elimination half-life is between 14 and 24 hours elasticity of the main arterial trunks, corrects (average 18 hours). Repeated administration does not histomorphometric changes in resistance arteries and produce accumulation. Elimination is mainly in the urine produces a reduction in left ventricular hypertrophy. (70% of the dose) and faeces (22%) in the form of inactive If necessary, the addition of a thiazide diuretic leads to an metabolites. additive synergy. The pharmacokinetics are unchanged in patients with renal The combination of an angiotensin converting enzyme insufficiency. inhibitor with a thiazide diuretic decreases the hypokalaemia risk associated with the diuretic alone. 5.3 Preclinical safety data
Linked to indapamide:
ACERTIL PLUS 5mg/1.25mg has slightly increased toxicity Indapamide, as monotherapy, has an antihypertensive than that of its components. Renal manifestations do not effect which lasts for 24 hours. This effect occurs at seems to be potentiated in the rat. However, the doses at which the diuretic properties are minimal. combination produces gastro-intestinal toxicity in the dog Its antihypertensive action is proportional to an and the toxic effects on the mother seems to be increased improvement in arterial compliance and a reduction in in the rat (compared to perindopril). total and arteriolar peripheral vascular resistance. Nonetheless, these adverse effects are shown at dose Indapamide reduces left ventricular hypertrophy. levels corresponding to a very marked safety margin by When a dose of thiazide diuretic and thiazide-related comparison to the therapeutic doses used. diuretics is exceeded, the antihypertensive effect reaches Preclinical studies performed separately with perindopril a plateau, whereas the adverse effects continue to and indapamide did not show genotoxic, carcinogenic or increase. If the treatment is ineffective, the dose should teratogenic potential. not be increased. Furthermore, it has been shown that in the short-term, 6. PHARMACEUTICAL PARTICULARS
mid-term and long-term in hypertensive patients,
6.1 List of excipients
- has no effect on lipid metabolism : triglycerides, LDL Core: cholesterol and HDL-cholesterol, Lactose monohydrate, Magnesium stearate (E470B), - has no effect on carbohydrate metabolism, even in Maltodextrin, Silica colloidal anhydrous (E551), Sodium diabetic hypertensive patients. starch glycolate (type A) Film-coating: 5.2 Pharmacokinetic properties
Glycerol (E422), Hypromellose (E464), Macrogol 6000, Linked to ACERTIL PLUS 5mg/1.25mg:
Magnesium stearate (E470B), Titanium dioxide (E171) The co-administration of perindopril and indapamide
does not change their pharmacokinetic properties by 6.2 Storage conditions
comparison to separate administration.
Keep the container tightly closed in order to protect from Linked to perindopril:
After oral administration, the absorption of perindopril is Keep out of the reach and sight of children. rapid and the peak concentration is achieved within 1 Do not use this drug after the expiry date printed on the hour. The plasma half-life of perindopril is equal to 1 box. hour. Store below 30oC. Perindopril is a prodrug. Twenty seven percent of the administered perindopril dose reaches the bloodstream This leaflet was last approved on February 2007.
as the active metabolite perindoprilat. In addition to active perindoprilat, perindopril yields five metabolites, all inactive. The peak plasma concentration of perindoprilat is achieved within 3 to 4 hours. As ingestion of food decreases conversion to Les Laboratoires Servier – France
perindoprilat, hence bioavailability, perindopril arginine
should be administered orally in a single daily dose in the Manufacturer:
morning before a meal.
Les Laboratoires Servier Industrie It has been demonstrated a linear relationship between 45520 Gidy - France the dose of perindopril and its plasma exposure.

Source: http://www.servier.hk/sites/default/files/spc-pil/acertil_plus_5mg-1.25mg.pdf