Preterax

Preterax

perindopril + indapamide

Manufacturer:

Servier

Distributor:

Maxxcare
Full Prescribing Info
Contents
Perindopril arginine, indapamide.
Description
Each Preterax 2.5 mg tablet contains perindopril arginine 2.5 mg, indapamide 0.625 mg.
Each Preterax 5 mg tablet contains perindopril arginine 5 mg and indapamide 1.25 mg.
Each Preterax 10 mg tablet contains perindopril arginine 10 mg and indapamide 2.5 mg.
Action
Pharmacotherapeutic Group: Perindopril and diuretics. ATC Code: C09BA04.
Pharmacology: Pharmacodynamics: Preterax is a combination of perindopril arginine, an angiotensin-converting enzyme inhibitor, and indapamide, a chlorosulphamoyl diuretic. Its pharmacological properties are derived from each of the components taken separately, in addition to those due to the additive synergistic action of the 2 products when combined.
Mechanism of Action: Linked to Preterax: Preterax produces an additive synergy of the antihypertensive effects of the 2 components.
Linked to Perindopril: Perindopril is an inhibitor of the angiotensin-converting enzyme (ACE inhibitor) which converts angiotensin I to angiotensin II, a vasoconstricting substance; in addition, the enzyme stimulates the secretion of aldosterone by the adrenal cortex and stimulates the degradation of bradykinin, a vasodilatory substance, into inactive heptapeptides.
This results in a reduction in aldosterone secretion; an increase in plasma renin activity, since aldosterone no longer exercises negative feedback; a reduction in total peripheral resistances with a preferential action on the vascular bed in muscle and the kidney, with no accompanying salt and water retention or reflex tachycardia, with chronic treatment.
The antihypertensive action of perindopril also occurs in patients with low or normal renin concentrations.
Perindopril acts through its active metabolite, perindoprilate. The other metabolites are inactive.
Perindopril reduces the work of the heart by: A vasodilatory effect on veins, probably caused by changes in the metabolism of prostaglandins (reduction in pre-load); by reduction of the total peripheral resistances (reduction in afterload).
Studies carried out on patients with cardiac insufficiency have shown a reduction in left and right ventricular filling pressures; a reduction in total peripheral vascular resistance; an increase in cardiac output and an improvement in the cardiac index; an increase in regional blood flow in muscle.
Exercise test results also showed improvement.
Linked to Indapamide: Indapamide is a sulphonamide derivative with an indole ring, pharmacologically related to the thiazide group of diuretics. Indapamide inhibits the reabsorption of sodium in the cortical dilution segment. It increases the urinary excretion of sodium and chlorides and, to a lesser extent, the excretion of potassium and magnesium, thereby increasing urine output and having an antihypertensive action.
Characteristics of Antihypertensive Action: Linked to Preterax: In hypertensive patients regardless of age, Preterax exerts a dose-dependent antihypertensive effect on diastolic and systolic arterial pressure while supine or standing. This antihypertensive effect lasts for 24 hrs. The reduction in blood pressure is obtained in <1 month without tachyphylaxis; stopping treatment has no rebound effect. During clinical trials, the concomitant administration of perindopril and indapamide produced antihypertensive effects of a synergic nature in relation to each of the products administered alone.
Linked to Perindopril: Perindopril is active in all grades of hypertension: mild to moderate or severe. A reduction in systolic and diastolic arterial pressure is observed in decubitus and in orthostatism.
The antihypertensive activity after a single dose is maximal between 4 and 6 hrs and is maintained over 24 hrs.
There is high degree of residual blocking of angiotensin-converting enzyme at 24 hrs, approximately 80%.
In patients who respond, normalised blood pressure is reached after 1 month and is maintained without tachyphylaxis.
Withdrawal of treatment has no rebound effect on hypertension.
Perindopril has vasodilatory properties and restores elasticity of the main arterial trunks, corrects histomorphometric changes in resistance arteries and produces a reduction in left ventricular hypertrophy.
If necessary, the addition of a thiazide diuretic leads to an additive synergy. The combination of an angiotensin-converting enzyme inhibitor with a thiazide diuretic decreases the hypokalaemia risk induced by the diuretic alone.
Linked to Indapamide: Indapamide, as monotherapy, has an antihypertensive effect which lasts for 24 hrs. This effect occurs at doses at which the diuretic properties are only slight.
Its antihypertensive action is proportional to an improvement in arterial compliance and a reduction in total and arteriolar peripheral vascular resistance. Indapamide reduces left ventricular hypertrophy.
When a dose of thiazide diuretics and thiazide-related diuretics is exceeded, the antihypertensive effect reaches a plateau, whereas the adverse effects continue to increase. If the treatment is ineffective, the doses should not be increased.
Furthermore, it has been shown that in the short-term, mid-term and long-term in hypertensive patients, indapamide has no effect on lipid metabolism (triglycerides, LDL-cholesterol and HDL-cholesterol); has no effect on carbohydrate metabolism, even in diabetic hypertensive patients.
Pharmacokinetics: Linked to Preterax: The co-administration of perindopril and indapamide does not change their pharmacokinetic properties by comparison to separate administration.
Linked to Perindopril: Perindopril is rapidly absorbed by the oral route. The quantity absorbed is 65-70% of the dose administered.
It is hydrolysed into perindoprilate which is a specific angiotensin-converting enzyme inhibitor. The quantity of perindoprilate formed is altered by food intake. The peak plasma concentration of perindoprilate is reached after 3-4 hrs. Plasma protein binding is <30% but is concentration-dependent.
After repeated administration of perindopril as a single daily dose, steady state is reached after an average of 4 days. The effective elimination half-life of perindoprilate is approximately 24 hrs.
Plasma concentrations of perindoprilate are significantly higher in patients with creatinine clearance <60 mL/min, whether they are patients with renal insufficiency or elderly. Elimination is also slowed down in patients with cardiac insufficiency.
The clearance of perindopril by dialysis is 70 mL/min.
In cirrhotic patients, the kinetics of perindopril is altered: hepatic clearance of the parent substance is reduced by half. However, the quantity of perindoprilate formed is not reduced and dose adjustment is therefore not necessary.
Angiotensin-converting enzyme inhibitors cross the placenta.
Linked to Indapamide: Indapamide is rapidly and completely absorbed from the digestive tract. The peak plasma level is reached approximately 1 hr after oral administration of the product in humans. Plasma protein binding is 79%.
The elimination half-life is between 14 and 24 hrs (average 18 hrs). Repeated administration does not produce accumulation. Elimination is mainly in the urine (70% of the dose) and faeces (22%) in the form of inactive metabolites.
The pharmacokinetics is unchanged in patients with renal insufficiency.
Toxicology: Preclinical Safety Data: Preterax has slightly increased toxicity than that of its components. Renal manifestations do not seem to be potentiated in rats. However, the combination produces gastrointestinal toxicity in dogs and the toxic effects on the mother seem to be increased in rats (compared to perindopril).
Nonetheless, these adverse effects are shown at dose levels corresponding to a very marked safety margin by comparison to the therapeutic doses used (from 15-50 times the therapeutic dose).
Indications/Uses
Preterax 2.5 mg: Indicated in essential arterial hypertension in adults.
Preterax 5 mg: Treatment of essential hypertension in adults, Preterax 5 mg/1.25 mg film-coated tablet is indicated in patients whose blood pressure is not adequately controlled on perindopril alone.
Preterax 10 mg: Preterax 10 mg/2.5 mg is indicated as substitution therapy for treatment of essential hypertension, in patients already controlled with perindopril and indapamide given concurrently at the same dose level.
Dosage/Direction for Use
Preterax 2.5 mg: The usual dose is one Preterax 2.5 mg/0.625 mg film-coated tablet per day as a single dose, preferably to be taken in the morning and before a meal. If blood pressure is not controlled after one month of treatment, the dose can be doubled.
Preterax 5 mg: One Preterax 5 mg/1.25 mg film-coated tablet per day as a single dose, preferably to be taken in the morning, and before a meal.
When possible, individual dose titration with the components is recommended. Preterax 5 mg/1.25 mg film-coated tablet should be used when blood pressure is not adequately controlled on Preterax 2.5 mg/0.625 mg film-coated tablet. When clinically appropriate, direct change from monotherapy to Preterax 5 mg/1.25 mg film-coated tablet may be considered.
Preterax 10 mg: One Preterax 10 mg/2.5 mg tablet per day as a single dose, preferably to be taken in the morning, and before a meal.
Elderly: Treatment should be started at the normal dose of 1 tab/day.
Patients with Renal Insufficiency: (See Precautions.) In cases of severe renal insufficiency (creatinine clearance <30 mL/min), treatment is contraindicated. In patients with creatinine clearance ≥30 mL/min and <60 mL/min, it is recommended to start the treatment at the dose of 1 Preterax 2.5 mg tab/day, to be taken in the morning.
It is not necessary to change the dose when the creatinine clearance is >60 mL/min. The normal medical practice includes periodic control for creatinine and potassium.
Overdosage
The most likely adverse event in case of overdose is hypotension, with clinical possibility of nausea, vomiting, hypotension in Preterax 5 mg, cramps, dizziness, sleepiness, mental confusion, polyuria or oliguria which may progress to anuria (due to hypovolaemia). Salt and water disturbances (low sodium levels, low potassium levels) may occur.
The first measures to be taken consist of rapid elimination of the products ingested by gastric lavage and/or administration of activated charcoal, then restoration of fluid and electrolyte balance in a specialised centre until they return to normal.
If marked hypotension occurs, this can be treated by placing the patient in a supine position with the head lowered. If necessary, an IV infusion of isotonic saline may be given, or any other method of volaemic expansion may be used.
Perindoprilate, the active form of perindopril, can be dialysed (see Pharmacology: Pharmacokinetics under Actions).
Contraindications
Linked to Perindopril: Preterax should never be used in cases of hypersensitivity to perindopril or to any other angiotensin-converting enzyme inhibitors; previous history of angioneurotic oedema (Quincke's oedema) linked to treatment with an angiotensin-converting enzyme inhibitor; hyperkalemia; pregnancy; lactation.
Preterax 2.5 mg: Hereditary or idiopathic angioneurotic oedema.
Preterax 2.5 mg/5 mg is generally not recommended in combinations with potassium-sparing diuretics, potassium salts, lithium (see Interactions); bilateral renal artery stenosis or single functioning kidney; increased potassium levels.
Concomitant use of PRETERAX with aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2). Concomitant use with sacubitril/valsartan (see Warnings and Interactions), extracorporeal treatments leading to contact of blood with negatively charged surfaces (see Interactions), significant bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney (see Warnings).
Linked to Indapamide: Preterax should never be used in cases of hypersensitivity to sulphonamides; severe renal failure (creatinine clearance <30 mL/min), hepatic encephalopathy, severe impairment of liver function; hypokalaemia.
As a general rule, use of Preterax is not recommended in combination with non-antiarrhythmic drugs producing Torsade de pointes (see Interactions).
Linked to Preterax 2.5 mg: Hypersensitivity to any of the excipients.
As there is a lack of available data, Preterax 2.5 mg must not be used in dialysis patients; patients with untreated decompensated cardiac insufficiency.
Warnings
Linked to Perindopril: Risk of Neutropenia/Agranulocytosis in Immuno-depressive Patients: Preterax 2.5 mg: The risk of neutropenia seems to be related to the dose and to the type of patient and depends on the patient's clinical condition. This condition is rarely encountered in patients who do not present with complications, but may occur in patients with renal insufficiency associated with collagen vascular disease eg, systemic lupus erythematosus or scleroderma, and who are on immunosuppressant therapy. This risk disappears when treatment with the angiotensin-converting enzyme inhibitor is stopped.
Preterax 5 mg: Angiotensin-converting enzyme inhibitors have exceptionally led to agranulocytosis and/or bone marrow depression when they were administered at high doses and to patients with renal insufficiency when it is associated to systemic auto-immune diseases (collagen vascular diseases eg, disseminated lupus erythematosus or scleroderma), receiving treatment with immunosuppressants or treatment causing leucopenia.
Strict compliance with the predetermined dose seems to be the best way to prevent the onset of these events. However, if an angiotensin-converting enzyme inhibitor is to be administered to this type of patient, the risk/benefit ratio should be evaluated carefully.
Renovascular hypertension: increased risk of hypotension and renal insufficiency in patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney. Diuretics may be a contributory factor. Loss of renal function may occur (minor changes in serum creatinine) even in patients with unilateral renal artery stenosis.
Angioneurotic Oedema (Quincke's Oedema): Angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has rarely been reported in patients receiving treatment with an angiotensin-converting enzyme inhibitor, including perindopril. In such cases, treatment with perindopril should be stopped immediately and the patient should be monitored until oedema has disappeared.
When the oedema only affects the face and the lips, the effect generally recedes without treatment, even though antihistamines may be used to relieve symptoms.
Angioneurotic oedema combined with laryngeal oedema may be fatal. When the tongue, glottis or larynx are affected, leading to an obstruction of the airways, a subcutaneous injection of adrenaline at 1:1000 (0.3-0.5 mL) should be administered quickly and other appropriate treatments should be given.
The prescription of an angiotensin-converting enzyme inhibitor should not subsequently be considered in these patients (see Contraindications).
Patients with a previous history of Quincke's oedema which is not linked to taking an angiotensin-converting enzyme inhibitor have an increased risk of Quincke's oedema with an angiotensin-converting enzyme inhibitor.
Concomitant use of mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus): Patients taking concomitant mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) therapy may be at increased risk for angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment.
Anaphylactoid Reactions During Desensitisation: Preterax 2.5 mg: Rare cases of prolonged life-threatening anaphylactoid reactions have been reported in patients treated with an angiotensin-converting enzyme inhibitor while undergoing hymenoptera (bees, wasps) venom desensitisation. Treatment with an angiotensin-converting enzyme inhibitor should be initiated with caution in allergic patients undergoing desensitisation and must be avoided in patients following venom immunotherapy.
The occurrence of these reactions are avoided by temporarily discontinuing for at least 24 hrs the angiotensin-converting enzyme inhibitor treatment in patients necessitating both angiotensin-converting enzyme inhibitor treatment and desensitisation.
Combination with sacubitril/valsartan (contraindicated due to the increased risk of angioedema). Sacubitril/valsartan must not be initiated until 36 hours after taking the last dose of perindopril therapy. Sacubitril/valsartan must not be initiated until 36 hours after the last dose of PRETERAX. Concomitant use of other NEP inhibitors (e.g. racecadotril) and ACE inhibitors may also increase the risk of angioedema.
Anaphylactoid Reactions in Patients Exposed to Dialysis Membrane: Preterax 2.5 mg: Cases of prolonged life-threatening anaphylactoid reactions have been reported in patients receiving both an angiotensin-converting enzyme inhibitor and either dialysis with high-permeability membranes or low-density lipoprotein apheresis by adsorption on dextran sulphate. Treatment with angiotensin-converting enzyme inhibitors should be avoided in patients receiving dialysis with high permeability membranes or LDL apheresis by adsorption on dextran sulphate.
The occurrence of these reactions are avoided by temporarily discontinuing for at least 24 hrs the angiotensin-converting enzyme inhibitor treatment in patients necessitating both angiotensin-converting enzyme inhibitor treatment and an LDL apheresis.
Haemodialysis: Preterax 5 mg: Anaphylactoid reactions (oedema of the tongue and lips with dyspnoea and low blood pressure) have also been observed during haemodialysis with high-permeability membranes (polyacrylonitrile) in patients receiving treatment with angiotensin-converting enzyme inhibitors. This combination should therefore be avoided.
Linked to Indapamide: When liver function is impaired, thiazide diuretics and thiazide-related diuretics may cause hepatic encephalopathy. Administration of the diuretic should be stopped immediately if this occurs.
Primary aldosteronism: Use not recommended in patients with primary hyperaldosteronism (not responding to drugs acting through inhibition of the renin-angiotensin system).
Special Precautions
Renal Insufficiency: In cases of severe renal insufficiency (creatinine clearance <30 mL/min), the treatment is contraindicated.
In certain hypersensitive patients without preexisting apparent renal lesion and for whom the biology screen shows a functional renal insufficiency, the treatment should be stopped and possibly restarted either at a low dose or with one constituent only.
In these patients, the normal medical practice includes periodic control for potassium and creatinine after 2 weeks of treatments and then every 2 months during therapeutic stability period.
Preterax 2.5 mg: Renal insufficiency has been reported mainly in patients using Preterax 2.5 mg with severe cardiac insufficiency or renal insufficiency with renal artery stenosis.
Preterax 5 mg: In cases of renal insufficiency (creatinine clearance <60 mL/min), the dosage is reduced.
In such patients and in those suffering from glomerular nephropathy, normal medical practice includes periodic testing of potassium and creatinine levels (see Dosage & Administration).
Hypotension and Salt and Water Depletion: There is a risk of sudden hypotension in subjects with preexisting sodium depletion (particularly in patients presenting with renal artery stenosis). Therefore, systematic testing should be carried out for the clinical signs of salt and water depletion, which may occur with an intercurrent episode of diarrhoea or vomiting. Regular monitoring of plasma electrolytes should be carried out in such patients.
Marked hypotension may require the implementation of an IV infusion of isotonic saline.
Transient hypotension is not a contraindication for continuation of treatment. After re-establishment of a satisfactory blood volume and blood pressure, treatment can be started again either at a reduced dose or with only one of the constituents.
Potassium Levels: The combination of perindopril and indapamide does not prevent the onset of hypokalaemia in particular in diabetic patients or in patients with renal failure. As with any antihypertensive agent containing a diuretic, regular monitoring of plasma potassium levels should be carried out.
Linked to Perindopril: Cough: A dry cough has been reported with the use of angiotensin-converting enzyme inhibitors. It is characterised by its persistence and by its disappearance when treatment is withdrawn. An iatrogenic aetiology should be considered on the event of this symptom. If the prescription of an angiotensin-converting enzyme inhibitor is judged indispensable, continuation of treatment may be considered.
Risk of Arterial Hypotension and/or Renal Insufficiency (In Cases of Cardiac Insufficiency, Salt and Water Depletion, Etc): Marked stimulation of the renin-angiotensin-aldosterone system has been observed particularly during marked salt and water depletion (strict sodium-free diet or prolonged diuretic treatment), in patients whose blood pressure was initially low, in cases of renal arterial stenosis, congestive heart failure or cirrhosis with oedema and ascites.
The blocking of this system with an angiotensin-converting enzyme inhibitor may therefore cause a sudden drop in blood pressure, particularly at the time of the 1st administration and during the first 2 weeks of treatment and/or an increase in plasma levels of creatinine, showing a functional renal insufficiency which is sometimes acute, although this is rare and the time to onset varies more.
In all cases of this type, the treatment should then be initiated at a lower dose and increased progressively.
Patients with Known Atherosclerosis: As the risk of hypotension exists in all patients, particular care should be taken in patients with ischaemic heart disease or cerebral circulatory insufficiency, with treatment being started at a low dose.
Renovascular Hypertension: The treatment for renovascular hypertension is revascularization. Nonetheless, angiotensin-converting enzyme inhibitors can be beneficial in patients presenting with renovascular hypertension who are awaiting corrective surgery or when such a surgery is not possible.
Treatment should then be started in a hospital at a low dose and renal function and potassium levels should be monitored, since some patients have developed a functional renal insufficiency which is reversible when treatment is stopped.
Other Populations at Risk: In patients with severe cardiac insufficiency (grade IV) or in patients with insulin dependent diabetes mellitus (spontaneous tendency to increased levels of potassium), treatment should be started under medical supervision with a reduced initial dose. Treatment with β-blockers in hypertensive patients with coronary insufficiency should not be stopped: the ACE inhibitor should be added to the β-blocker.
Anaemia: Anaemia has been observed in patients who have had a kidney transplant or have been undergoing dialysis, with a reduction in haemoglobin levels which is all the more marked since the initial values are high. This effect does not seem to be dose-dependent but may be linked to the mechanism of action of angiotensin-converting enzyme inhibitors.
This reduction is slight, occurs within 1-6 months, and then remains stable. It is reversible when treatment is stopped. Treatment can be continued in this type of patient, carrying out regular haematological testing.
Surgery: Angiotensin-converting enzyme inhibitors can cause hypotension in cases of anaesthesia, and particularly when the anaesthetic administered is an agent with hypotensive potential. It is therefore recommended that treatment with long-acting angiotensin-converting enzyme inhibitors eg, perindopril, should be discontinued where possible 2 days before surgery.
Aortic Stenosis/Hypertrophic Cardiomyopathy: Preterax 2.5 mg: Angiotensin-converting enzyme inhibitors must be used with care in patients presenting with left ventricular obstruction.
Linked to Indapamide: Salt and Water Balance: Sodium Levels: These should be tested before treatment is started, then at regular intervals. All diuretic treatment can cause a reduction in sodium levels, which may have serious consequences. The reduction in sodium level can be initially asymptomatic, and regular testing is therefore essential. Testing should be more frequent in risk populations eg, elderly and cirrhotic patients (see Adverse Reactions and Overdosage).
Potassium Levels: Potassium depletion with hypokalaemia is a major risk with thiazide diuretics and thiazide-related diuretics. The risk of onset of lowered potassium levels (<3.4 micromol/L) should be prevented in some at risk populations eg, elderly and/or malnourished subjects, whether or not they are taking multiple medications; cirrhotic patients with oedema and ascites; coronary patients and patients with heart failure.
In such cases, hypokalaemia increases the cardiac toxicity of cardiac glycosides and the risk of rhythm disorders.
Subjects presenting with a long QT interval are also at risk, whether the origin is congenital or iatrogenic. The hypokalaemia, as with bradycardia, acts as a factor which favours the onset of severe rhythm disorders, in particular Torsade de pointes, which may be fatal.
In all cases more frequent testing of potassium levels is necessary. The first measurement of plasma potassium levels should be carried out during the 1st week following the start of treatment.
If low potassium levels are detected, correction is required.
Calcium Levels: Thiazide diuretics and thiazide-related diuretics may reduce urinary excretion of calcium and cause a mild and transient increase in plasma calcium levels. Markedly raised levels of calcium may be related to undiagnosed hyperparathyroidism. In such cases, the treatment should be stopped before investigating the parathyroid function.
Blood Glucose: Monitoring of blood glucose is important in diabetic patients, particularly when potassium levels are low.
Uric Acid: Patients with raised levels of uric acid may have an increased tendency to gout attacks.
Renal Function and Diuretics: Thiazide diuretics and thiazide-related diuretics are only fully effective when renal function is normal or only slightly impaired (creatinine levels approximately <25 mg/L ie, 220 micromol/L for an adult).
In the elderly the value of plasma creatinine levels should be adjusted to take account of the age, weight and sex of the patient, according to the Cockcroft formula:

Click on icon to see table/diagram/image

Hypovolaemia, resulting from the loss of water and sodium caused by the diuretic at the start of treatment, causes a reduction in glomerular filtration. It may result in an increase in blood urea and creatinine levels. This transitory functional renal insufficiency is of no consequence in subjects with normal renal function but may however worsen a preexisting renal insufficiency.
Athletes: Athletes should note that Preterax contains an active substance which may cause a positive reaction in doping tests.
Lactose: Preterax 2.5 mg contains lactose and is, in consequence, contraindicated in the case of congenital galactosemia, glucose and galactose malabsorption or lactase deficiency syndrome (rare metabolic diseases).
Effects on the Ability to Drive or Operate Machinery: Linked to Perindopril, Indapamide and Preterax: Neither the 2 active substances nor Preterax affects alertness 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.
Use in pregnancy & lactation: Preterax 2.5 mg: The presence of an angiotensin-converting enzyme inhibitor determines the contraindication for the use of this combination during pregnancy and lactation.
Linked to Perindopril: Pregnancy: No appropriate and well-controlled studies have been carried out in humans. Angiotensin-converting enzyme inhibitors cross the placenta and may lead to foetal and neonatal morbidity and mortality when administered to pregnant women.
Cases of neonatal hypotension, renal insufficiency, malformations of the face and the cranial vault and/or death have been reported when the foetus is exposed during the 2nd and 3rd trimesters of pregnancy. A reduction in foetal renal function with maternal oligohydramnios has also been observed.
Contractions of the limbs, craniofacial malformations, pulmonary hypoplasia and intrauterine growth retardation with oligohydramnios have been reported.
Infants who were exposed to angiotensin-converting enzyme inhibitors in utero should be carefully monitored for hypotension, oliguria and hyperkalaemia. Oliguria can be treated with support of blood pressure and renal blood flow.
Intrauterine growth retardation, prematurity, patent ductus arteriosus and foetal death have been reported, although no clear relationships with angiotensin-converting enzyme inhibitors or with maternal concomitant illness have been established.
No data are available on whether limited exposure in the 1st trimester of pregnancy affects the foetus.
If the patient becomes pregnant while taking an angiotensin-converting enzyme inhibitor, she must be informed of the potential risks to the foetus.
Lactation: Angiotensin-converting enzyme inhibitors can be excreted in breast milk and the effects on nursing infants are unknown. Breastfeeding is therefore contraindicated in women who are being treated with angiotensin-converting enzyme inhibitors.
Preterax 5 mg: As the combination includes an ACE inhibitor, Preterax 5 mg is contraindicated during pregnancy.
Pregnancy: Studies in animals have shown no teratogenic effects, but toxicity to the foetus was shown in several species.
In pregnant women receiving treatment with angiotensin-converting enzyme inhibitors, no epidemiological studies are available; isolated observations of pregnancies exposed in the 1st trimester are a priori reassuring with regard to malformation, with the exception of some cases of abnormalities of the skull reported with the use of angiotensin-converting enzyme inhibitors throughout pregnancy; administration during the 2nd and 3rd trimesters, particularly if continued until delivery, produces a risk of renal effects which may lead to: a reduction in renal function of the foetus, with possible oligohydramnios; neonatal renal insufficiency with hypotension and increased levels of potassium and even anuria (reversible or not).
As a consequence, the risk of malformation, if such a risk exists, is probably low. Termination of pregnancy does not appear to be appropriate if pregnancy occurs during treatment. However, the skull should be monitored by ultrasound.
In contrast, patients who discover they are pregnant while being treated with angiotensin-converting enzyme inhibitors must stop treatment immediately and for the duration of the pregnancy.
Lactation: In the absence of data, perindopril is contraindicated in women who are breastfeeding.
Linked to Indapamide: Pregnancy: As a general rule, the administration of diuretics should be avoided in pregnant women and should never be given as treatment for physiological oedema (and therefore do not require treatment) of pregnancy. Diuretics may lead to foeto-placental ischaemia, with a risk of impaired foetal growth.
Nonetheless, diuretics remain essential part of treatment of oedema from cardiac, hepatic and renal origin raised in pregnant women.
Lactation: Indapamide is excreted in small quantities in breast milk. Nonetheless, it should not be used in breastfeeding period due to the decrease and even suppression of the milk secretion; its undesirable effects in particular biological (potassium level); its belonging to sulphonamides with risks of allergy and nuclear icterus.
Use in children: The efficacy and tolerability of perindopril in children, alone or in combination, have not been established.
Use in the elderly: Renal function and potassium levels are tested before the start of treatment. The initial dose is subsequently adjusted according to blood pressure response, especially in cases of salt and water depletion, in order to avoid sudden onset of hypotension.
Use In Pregnancy & Lactation
Preterax 2.5 mg: The presence of an angiotensin-converting enzyme inhibitor determines the contraindication for the use of this combination during pregnancy and lactation.
Linked to Perindopril: Pregnancy: No appropriate and well-controlled studies have been carried out in humans. Angiotensin-converting enzyme inhibitors cross the placenta and may lead to foetal and neonatal morbidity and mortality when administered to pregnant women.
Cases of neonatal hypotension, renal insufficiency, malformations of the face and the cranial vault and/or death have been reported when the foetus is exposed during the 2nd and 3rd trimesters of pregnancy. A reduction in foetal renal function with maternal oligohydramnios has also been observed.
Contractions of the limbs, craniofacial malformations, pulmonary hypoplasia and intrauterine growth retardation with oligohydramnios have been reported.
Infants who were exposed to angiotensin-converting enzyme inhibitors in utero should be carefully monitored for hypotension, oliguria and hyperkalaemia. Oliguria can be treated with support of blood pressure and renal blood flow.
Intrauterine growth retardation, prematurity, patent ductus arteriosus and foetal death have been reported, although no clear relationships with angiotensin-converting enzyme inhibitors or with maternal concomitant illness have been established.
No data are available on whether limited exposure in the 1st trimester of pregnancy affects the foetus.
If the patient becomes pregnant while taking an angiotensin-converting enzyme inhibitor, she must be informed of the potential risks to the foetus.
Lactation: Angiotensin-converting enzyme inhibitors can be excreted in breast milk and the effects on nursing infants are unknown. Breastfeeding is therefore contraindicated in women who are being treated with angiotensin-converting enzyme inhibitors.
Preterax 5 mg: As the combination includes an ACE inhibitor, Preterax 5 mg is contraindicated during pregnancy.
Pregnancy: Studies in animals have shown no teratogenic effects, but toxicity to the foetus was shown in several species.
In pregnant women receiving treatment with angiotensin-converting enzyme inhibitors, no epidemiological studies are available; isolated observations of pregnancies exposed in the 1st trimester are a priori reassuring with regard to malformation, with the exception of some cases of abnormalities of the skull reported with the use of angiotensin-converting enzyme inhibitors throughout pregnancy; administration during the 2nd and 3rd trimesters, particularly if continued until delivery, produces a risk of renal effects which may lead to: a reduction in renal function of the foetus, with possible oligohydramnios; neonatal renal insufficiency with hypotension and increased levels of potassium and even anuria (reversible or not).
As a consequence, the risk of malformation, if such a risk exists, is probably low. Termination of pregnancy does not appear to be appropriate if pregnancy occurs during treatment. However, the skull should be monitored by ultrasound.
In contrast, patients who discover they are pregnant while being treated with angiotensin-converting enzyme inhibitors must stop treatment immediately and for the duration of the pregnancy.
Lactation: In the absence of data, perindopril is contraindicated in women who are breastfeeding.
Linked to Indapamide: Pregnancy: As a general rule, the administration of diuretics should be avoided in pregnant women and should never be given as treatment for physiological oedema (and therefore do not require treatment) of pregnancy. Diuretics may lead to foeto-placental ischaemia, with a risk of impaired foetal growth.
Nonetheless, diuretics remain essential part of treatment of oedema from cardiac, hepatic and renal origin raised in pregnant women.
Lactation: Indapamide is excreted in small quantities in breast milk. Nonetheless, it should not be used in breastfeeding period due to the decrease and even suppression of the milk secretion; its undesirable effects in particular biological (potassium level); its belonging to sulphonamides with risks of allergy and nuclear icterus.
Adverse Reactions
Linked to Perindopril: The administration of perindopril inhibits the renin-angiotensin-aldosterone axis and tends to reduce the potassium loss caused by indapamide.
During clinical trials, a reduction in potassium levels was observed in some cases. This was <3.4 micromol/L after 12 weeks of treatment and concerns 2% of patients taking Preterax. After 12 weeks of treatment, the mean reduction in potassium levels was 0.2 micromol/L.
Gastrointestinal Tract: Common (>1/100, <1/10): Constipation, dry mouth, nausea, epigastric pain, anorexia, abdominal pains, taste disturbance.
Very Rare (<1/10,000): Pancreatitis.
In case of hepatic insufficiency, there is a possibility of onset of hepatic encephalopathy (see Contraindications, Warnings and Precautions).
Respiratory System: Common (>1/100, <1/10): Dry cough has been reported with the use of angiotensin-converting enzyme inhibitors. It is characterised by its persistence and by its disappearance when treatment is withdrawn. An iatrogenic aetiology should be considered in the presence of this symptom.
Cardiovascular System: Uncommon (>1/1000, <1/100): Hypotension whether orthostatic or not (see Warnings and Precautions).
Skin Appendages: Uncommon (>1/1000, <1/100): Hypersensitivity reactions, mainly dermatological, in subjects with a predisposition to allergic and asthmatic reactions; maculopapular eruptions, purpura, possible aggravation of preexisting acute disseminated lupus erythematosus; skin rash.
Very Rare (<1/10,000): Angioneurotic oedema (Quincke's oedema) (see Warnings and Precautions).
Nervous System: Uncommon (>1/1000, <1/100): Headache, asthenia, feelings of dizziness, mood disturbances and/or sleep disturbances.
Muscular System: Uncommon (>1/1000, <1/100): Cramps, paresthesia.
Hemic System: Very Rare: (<1/10,000): Thrombocytopenia, leucopenia, agranulocytosis, aplastic anaemia hemolytic anaemia; anaemia (see Warnings and Precautions) has been reported with angiotensin-converting enzyme inhibitors in specific circumstances (patients who have had kidney transplant, patients undergoing haemodialysis).
Syndrome of inappropriate antidiuretic hormone secretion (SIADH) can be considered as a very rare but possible complication associated with ACE inhibitor therapy.
Laboratory Parameters:
Slight increase in urea and in plasma creatinine levels, reversible when treatment is stopped. This increase is more frequent in cases of renal artery stenosis, arterial hypertension treated with diuretics, renal insufficiency; increased levels of potassium, usually transitory. The undesirable effects are mainly dose-dependent: Potassium depletion with particularly serious reduction in levels of potassium in some at risk populations (see Precautions); reduced sodium levels with hypovolaemia causing dehydration and orthostatic hypotension. The concomitant loss of chloride ions may lead to compensatory metabolic alkalosis: the incidence and extent of this effect are low; an increase in uric acid levels and in blood glucose levels during treatment: the use of these diuretics should be carefully discussed in patients with gout or diabetes; rare (>1/10,000; <1/1000): raised plasma calcium levels.
Drug Interactions
Contra-indicated: Aliskiren (in diabetic or impaired renal patients), Extracorporeal treatments, Sacubitril/valsartan.
Not recommended: Aliskiren (in other patients), lithium, potassium-sparing diuretics, concomitant therapy with ACE inhibitor and angiotensin-receptor blocker, Estramustine, Co-trimoxazole (trimethoprim/sulfamethoxazole), potassium salts.
Special care: Baclofen, nonsteroidal anti-inflammatory medicinal products (including aspirin ≥3g/day), antidiabetic agents, torsades de pointes-inducing drugs, potassium-lowering drugs, non-potassium-sparing diuretics, potassium-sparing diuretics, digitalis preparation, Racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and allopurinol.
Some care: Imipramine-like antidepressants (tricyclics), neuroleptics, antihypertensive agents and vasodilatators, allopurinol, cytostatic or immunosuppressive agents, systemic corticosteroids or procainamide or tetracosactide, anesthetic drugs, gliptins, sympathomimetics, gold, metformin, iodinated contrast media, calcium (salts), ciclosporin, tacrolimus.
Combination Which Is Not Recommended:
Lithium: An increase in lithium levels may produce signs of overdose, as occurs with a sodium-free diet (reduction in renal excretion of lithium). If the combination of an angiotensin-converting enzyme inhibitor and a potassium-sparing diuretic is unavoidable, strict monitoring of lithium levels and adjustment of the dose are necessary.
Combinations Which Require Special Care: Antidiabetic Agents (Insulin, Hypoglycaemic Sulphonamides): Reported with captopril and enalapril. The use of angiotensin-converting enzyme inhibitors may increase the hypoglycaemic effect in diabetics receiving treatment with insulin or with hypoglycaemic sulphonamides. The onset of hypoglycaemic episodes is very rare (improvement in glucose tolerance with a resulting reduction in insulin requirements).
Baclofen: Potentiation of antihypertensive effect. Monitoring of blood pressure and renal function and dose adaptation of the antihypertensive if necessary.
NSAID (systemic route), High-Dose Salicylates: Acute renal insufficiency in dehydrated patients (reduction in glomerular filtration). The patient should be well hydrated; renal function should be monitored at the start of treatment.
Combinations Which Require Some Care: Imipramine-like Antidepressants (Tricyclics), Neuroleptics: Increased antihypertensive effect and increased risk of orthostatic hypotension (additive effect).
Corticosteroids, Tetracosactide: Reduction in antihypertensive effect (salt and water retention due to corticosteroids).
Linked to Perindopril: Combinations Which Are Not Recommended: Potassium-Sparing Diuretics [Spironolactone, Triamterene, alone or in combination, Potassium (salts)]: Increased levels of potassium (potentially lethal), particularly in cases of renal insufficiency (addition of potassium-sparing effects). Potassium-raising agents should not be combined with angiotensin-converting enzyme inhibitors, except when potassium levels are low.
Preterax 2.5 mg: Anaesthetics: Angiotensin-converting enzyme inhibitors may enhance the hypotensive effects of certain anaesthetic drugs.
Allopurinol, Cytostatic or Immunosuppressant Agents, Corticosteroids (systemic route) or Procainamide: Concomitant administration with angiotensin-converting enzyme inhibitors may lead to an increased risk for leucopenia.
Antihypertensive Agents: Increase in the hypotensive effect of the angiotensin-converting enzyme inhibitors.
Linked to Indapamide: Combinations Which Are Not Recommended: Non-antiarrhythmic drugs which prolong the QT interval or cause Torsade de pointes (astemizole, bepridil, erythromycin IV, halofantrine, pentamidine, sultopride, terfenadine, vincamine): Torsade de pointes (low potassium levels is a risk, as are bradycardia and preexisting long QT interval).
Substance which do not have the unwanted effect of causing Torsade de pointes should be used in cases of low potassium levels.
Combinations Which Require Special Care: NSAID (systemic route), High-Dose Salicylates: Possible reduction in the antihypertensive effect of indapamide. Acute renal insufficiency in dehydrated patients (reduction in glomerular filtration).
Hydrate the patient; monitor renal function at the start of treatment.
Potassium-Lowering Drugs: Amphotericin B (IV route), glucocorticoids and mineralocorticoids (systemic route), tetracosactide, stimulant laxatives: Increased risk of low potassium levels (additive effect). Monitoring of potassium levels, and correction if necessary; particular consideration required in cases of treatment with cardiac glycosides. Non-stimulant laxatives should be used.
Cardiac Glycosides: Low potassium levels favour the toxic effects of cardiac glycosides. Potassium levels and ECG should be monitored and treatment reconsidered if necessary.
Combinations Which Require Some Care: Potassium-Sparing Diuretics (Amiloride, Spironolactone, Triamterene): The rational combination, which is useful for some patients, does not exclude the onset of low potassium levels or, particularly in patients with renal insufficiency or diabetes, raised potassium levels. Potassium levels and ECG should be monitored and treatment reconsidered if necessary.
Antiarrhythmic Drugs which Produce Torsade de Pointes: Class IA Antiarrhythmic Agents (Quinidine, Hydroquinone, Disopyramide), Amiodarone, Bretylium, Sotalol: Torsade de pointes (low potassium levels is a risk factor, as bradycardia and a preexisting long QT interval).
Prevention of low potassium levels and correction if necessary: Monitoring of the QT interval. Antiarrhythmics should not be administered in cases of Torsade de pointes (treat using pacing).
Metformin: Lactic acidosis due to metformin caused by possible functional renal insufficiency linked to diuretics and in particular to loop diuretics. Do not use metformin when creatinine levels exceed 15 mg/L (135 micromol/L) in men and 12 mg/L (110 micromol/L) in women.
Iodinated Contrast Media: In cases of dehydration caused by diuretics, there is an increased risk of acute renal insufficiency, particularly when high doses of iodinated contrast media are used. Rehydration should be carried out before the iodinated compound is administered.
Imipramine-like Antidepressants (Tricyclics), Neuroleptics: Increased antihypertensive effect and increased risk of orthostatic hypotension (additive effect).
Calcium (Salts): Risk of increased levels of calcium due to reduced elimination of calcium in the urine.
Ciclosporin: Risk of increased creatinine levels with no change in circulation levels of ciclosporin, even when there is no salt and water depletion.
Corticosteroids, Tetracosactide (systemic route): Reduction in antihypertensive effect (salt and water retention due to corticosteroids).
Storage
Store below 30°C.
Shelf-Life:3 years.
ATC Classification
C09BA04 - perindopril and diuretics ; Belongs to the class of ACE inhibitors in combination with diuretics. Used in the treatment of cardiovascular disease.
Presentation/Packing
FC tab 2.5 mg/0.625 mg (white, rod-shaped, scored on each side) x 30's. 5 mg/1.25 mg (scored) x 30's. 10 mg/2.5 mg x 30's.
Register or sign in to continue
Asia's one-stop resource for medical news, clinical reference and education
Sign up for free
Already a member? Sign in