Drug Class Description
Perindopril and diuretics

Generic Name
Perindopril arginine

Drug Description
One tablet contains 3.395 mg perindopril corresponding to 5 mg perindopril arginine and 1.25 mg indapamide.Excipient : 71.33 mg lactose monohydrate

Presentation
Film-coated tablet.White, rod-shaped film-coated tablet.

Indications
Treatment of essential hypertension, COVERSYL ARGININE PLUS 5mg/1.25mg tablet is indicated in patients whose blood pressure is not adequately controlled on perindopril alone.

Adult Dosage
Oral routeOne COVERSYL ARGININE PLUS 5mg/1.25mg 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. COVERSYL ARGININE PLUS 5mg/1.25mg tablet should be used when blood pressure is not adequately controlled on COVERSYL ARGININE PLUS 2.5mg/0.625mg tablet (where available). When clinically appropriate, direct change from monotherapy to COVERSYL ARGININE PLUS 5mg/1.25mg tablet may be considered.Patients with renal impairment In severe renal impairment (creatinine clearance below 30 ml/min), treatment is contraindicated.In patients with moderate renal impairment (creatinine clearance 30-60 ml/min), it is recommended to start treatment with the adequate dosage of the free combination.In patients with creatinine clearance greater than or equal to 60 ml/min, no dose modification is required. Usual medical follow-up will include frequent monitoring of creatinine and potassium.Patients with hepatic impairmentIn severe hepatic impairment, treatment is contraindicated.In patients with moderate hepatic impairment, no dose modification is required.

Child Dosage
COVERSYL ARGININE PLUS 5mg/1.25mg should not be used in children and adolescents as the efficacy and tolerability of perindopril in children and adolescents, alone or in combination, have not been established.

Elderly Dosage
Treatment should be initiated after considering blood pressure response and renal function.

Contra Indications
Linked to perindopril:- Hypersensitivity to perindopril or any other ACE inhibitor- History of angioedema (Quincke's oedema) associated with previous ACE inhibitor therapy- Hereditary/idiopathic angioedema- Second and third trimesters of pregnancyLinked to indapamide:- Hypersensitivity to indapamide or to any other sulphonamides- Severe renal impairment (creatinine clearance below 30 ml/min)- Hepatic encephalopathy- Severe hepatic impairment- Hypokalaemia- As a general rule, this medicine is inadvisable in combination with non antiarrhythmic agents causing torsades de pointes- LactationLinked to COVERSYL ARGININE PLUS 5mg/1.25mg:- Hypersensitivity to any of the excipientsDue to the lack of sufficient therapeutic experience, COVERSYL ARGININE PLUS 5mg/1.25mg should not be used in:- Dialysis patients- Patients with untreated decompensated heart failure.

Special Precautions
Special warningsCommon to perindopril and indapamide:Lithium:The combination of lithium and the combination of perindopril and indapamide is usually not recommended.Linked to perindopril:Risk of neutropenia/agranulocytosis in immuno-suppressed patients: The risk of neutropenia appears to be dose- and type-related and is dependent on patient's clinical status. It is rarely seen in uncomplicated patients but may occur in patients with some degree of renal impairment especially when it is associated with collagen vascular disease e.g. systemic lupus erythematosus, scleroderma and therapy with immunosuppressive agents. It is reversible after discontinuation of the ACE inhibitor.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 eva luated carefully.Angioedema (Quincke's oedema):Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported rarely in patients receiving treatment with angiotensin converting enzyme inhibitors, including perindopril. In such cases, treatment with perindopril should be stopped immediately and the patient should be monitored until the oedema has disappeared.When the oedema only affects the face and the lips, the effect generally recedes without treatment, even though anti-histamines may be used to relieve symptoms.Angioedema combined with laryngeal oedema may be fatal. Involvement of tongue, glottis or larynx may lead to an obstruction of the airways. A subcutaneous injection of adrenaline at 1:1000 (0.3 ml to 0.5 ml) should be administered quickly and other appropriate measures taken.The prescription of an angiotensin converting enzyme inhibitor should not subsequently be considered in these patients.Patients with a previous history of Quincke's oedema which was not linked to taking an angiotensin converting enzyme inhibitor have an increased risk of Quincke's oedema with an angiotensin converting enzyme inhibitor.Anaphylactoid reactions during desensitisation:There have been isolated reports of patients experiencing sustained, life-threatening anaphylactoid reactions while receiving ACE inhibitors during desensitisation treatment with hymenoptera (bees, wasps) venom. ACE inhibitors should be used with caution in allergic patients treated with desensitisation, and avoided in those undergoing venom immunotherapy. However these reactions could be prevented by temporary withdrawal of ACE inhibitor for at least 24 hours before treatment in patients who require both ACE inhibitors and desensitisatioAnaphylactoid reactions during membrane exposure:There have been reports of patients experiencing sustained, life-threatening anaphylactoid reactions while receiving ACE inhibitors during dialysis with high-flux membranes or low-density lipoprotein apheresis with dextran sulphate adsorption. ACE inhibitors should be avoided in such patients. However these reactions could be prevented by temporary withdrawal of ACE inhibitor for at least 24 hours before treatment in patients who require both ACE inhibitors and LDL apheresis.Potassium-sparing diuretics, potassium salts:The combination of perindopril and potassium-sparing diuretics, potassium salts is usually not recommended.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.Sultopride:The combination of indapamide and sultopride is usually not recommended.Precautions for useCommon to perindopril and indapamide:Renal impairment:In cases of severe renal impairment (creatinine clearance < 30 ml/min), treatment is contraindicated.In certain hypertensive patients without pre-existing apparent renal lesions and for whom renal blood tests show functional renal insufficiency, treatment should be stopped and possibly restarted either at a low dose or with one constituent only. In these patients usual medical follow-up will include frequent monitoring of potassium and creatinine, after two weeks of treatment and then every two months during therapeutic stability period. Renal failure has been reported mainly in patients with severe heart failure or underlying renal failure including renal artery stenosis.The drug is usually not recommended in case of bilateral renal artery stenosis or a single functioning kidney.Hypotension and water and electrolyte depletion:There is a risk of sudden hypotension in the presence of pre-existing sodium depletion (in particular in individuals with renal artery stenosis). Therefore systematic testing should be carried out for clinical signs of water and electrolyte 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 intravenous infusion of isotonic saline.Transient hypotension is not a contraindication to 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 particularly in diabetic patients or in patients with renal failure. As with any antihypertensive agent in combination with a diuretic, regular monitoring of plasma potassium levels should be carried out.Excipients:COVERSYL ARGININE PLUS 5mg/1.25mg should not be administered to patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.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 in the event of this symptom. If the prescription of an angiotensin converting enzyme inhibitor is still preferred, continuation of treatment may be considered.Children and adolescents:The efficacy and tolerability of perindopril in children and adolescents, alone or in combination, have not been established.Risk of arterial hypotension and/or renal insufficiency (in cases of cardiac insufficiency, water and electrolyte depletion, etc...):Marked stimulation of the renin-angiotensin-aldosterone system has been observed particularly during marked water and electrolyte depletions (strict sodium restricted diet or prolonged diuretic treatment), in patients whose blood pressure was initially low, in cases of renal artery stenosis, congestive heart failure or cirrhosis with oedema and ascites.The blocking of this system with an angiotensin converting enzyme inhibitor may therefore cause, particularly at the time of the first administration and during the first two weeks of treatment, a sudden drop in blood pressure and/or an increase in plasma levels of creatinine, showing a functional renal insufficiency. Occasionally this can be acute in onset, although rare, and with a variable time to onset.In such cases, the treatment should then be initiated at a lower dose and increased progressively.Elderly:Renal function and potassium levels should be tested before the start of treatment. The initial dose is subsequently adjusted according to blood pressure response, especially in cases of water and electrolyte depletion, in order to avoid sudden onset of hypotension.Patients with known atherosclerosis:The risk of hypotension exists in all patients but 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 revascularisation. 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.If COVERSYL ARGININE PLUS 5mg/1.25mg is prescribed to patients with known or suspected renal artery stenosis, treatment should be started in a hospital setting at a low dose and renal function and potassium levels should be monitored, since some patients have developed a functional renal insufficiency which was reversed when treatment was 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 beta-blockers in hypertensive patients with coronary insufficiency should not be stopped : the ACE inhibitor should be added to the beta-blocker.Anaemia:Anaemia has been observed in patients who have had a kidney transplant or have been undergoing dialysis. The reduction in haemoglobin levels is more apparent as initial values were 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 in haemoglobin is slight, occurs within 1 to 6 months, and then remains stable. It is reversible when treatment is stopped. Treatment can be continued with regular haematological testing.Surgery:Angiotensin converting enzyme inhibitors can cause hypotension in cases of anaesthesia, especially when the anaesthetic administered is an agent with hypotensive potential.It is therefore recommended that treatment with long-acting angiotensin converting enzyme inhibitors such as perindopril should be discontinued where possible one day before surgery.Aortic stenosis / hypertrophic cardiomyopathy:ACE inhibitors should be used with caution in patient with an obstruction in the outflow tract of the left ventricle.Hepatic failure:Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.Hyperkalaemia:Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including perindopril. Patients at risk for the development of hyperkalaemia include those with renal insufficiency, uncontrolled diabetes mellitus, or those using concomitant potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes; or those patients taking other drugs associated with increases in serum potassium (e.g. heparin). If concomitant use of the above mentioned agents is deemed appropriate, regular monitoring of serum potassium is recommended. The drug is usually not recommended in case of raised plasma levels of potassium.Linked to indapamide:Water and electrolyte 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. Reduction in sodium levels can be initially asymptomatic and regular testing is therefore essential. Testing should be more frequent in elderly and cirrhotic patients.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 mmol/l) should be prevented in some high risk populations such as 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. Hypokalaemia, as with bradycardia, acts as a factor which favours the onset of severe rhythm disorders, in particular torsades 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 first 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:Tendency to gout attacks may be increased in hyperuricaemic patients.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 lower than approximately 25 mg/l, i.e. 220 μmol/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 Cockroft formula:clcr = (140 - age) x body weight / 0.814 x plasma creatinine levelwith: age expressed in yearsbody weight in kgplasma creatinine level in micromol/lThis formula is suitable for an elderly male and should be adapted for women by multiplying the result by 0.85.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 adverse consequence in patients with normal renal function but may however worsen a pre-existing renal impairment.Athletes:Athletes should note that this product contains an active substance which may cause a positive reaction in doping tests.

Interactions
Common to perindopril and indapamide:Concomitant use not recommended:Lithium : reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. Concomitant use of thiazide diuretics may further increase lithium levels and enhance the risk of lithium toxicity with ACE inhibitors. Use of perindopril combined with indapamide with lithium is not recommended, but if the combination proves necessary, careful monitoring of serum lithium levels should be performed.Concomitant use which requires special care:- Baclofen: Potentiation of antihypertensive effect. Monitoring of blood pressure and renal function, and dose adaptation of the antihypertensive if necessary.- Non-steroidal anti-inflammatory medicinal products (included acetylsalicylic acid at high doses) : the administration of a non-steroidal anti-inflammatory medicinal product may reduce the diuretic, natriuretic and antihypertensive effects in some patients. In elderly patients and patients who may be dehydrated there is a risk of acute renal failure, therefore monitoring of renal function at the initiation of treatment is recommended. Patients should be well hydrated.Concomitant use which requires 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).- other antihypertensive agents : use of other antihypertensive medicinal products with perindopril/indapamide could result in additional blood pressure lowering effect.Linked to perindopril:Concomitant use not recommended:- Potassium-sparing diuretics (spironolactone, triamterene, alone or in combination), potassium (salts): ACE inhibitors attenuate diuretic induced potassium loss. Potassium-sparing diuretics e.g. spironolactone, triamterene, or amiloride, potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium (potentially lethal). If concomitant use is indicated because of documented hypokalaemia they should be used with caution and with frequent monitoring of serum potassium and by ECG.Concomitant use which requires 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).Concomitant use which requires some care:- Allopurinol, cytostatic or immunosuppressive agents, systemic corticosteroids or procainamide: Concomitant administration with ACE inhibitors may lead to an increased risk for leucopenia.- Anaesthetic drugs: ACE inhibitors may enhance the hypotensive effects of certain anaesthetic drugs.- Diuretics (thiazide or loop diuretics): Prior treatment with high dose diuretics may result in volume depletion and in a risk of hypotension when initiating therapy with perindopril.Linked to indapamide:Concomitant use not recommended:- Sultopride: Increased risk of ventricular arrhythmia, especially torsades de pointes (hypokalaema favours the occurrence of this adverse event)Concomitant use which requires special care:- Torsades de pointes inducing drugs : Due to the risk of hypokalaemia, indapamide should be administered with caution when associated with medicinal products that induced torsades de pointes such as class IA antiarrhythmic agents (quinidine, hydroquinidine, disopyramide); class III antiarrhythmic agents (amiodarone, dofetilide, ibutilide, bretylium, sotalol); some neuroleptics (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine), benzamides (amisulpride, sulpiride, tiapride), butyrophenones (droperidol, haloperidol), other neuroleptics (pimozide); other substances such as bepridil, cisapride, diphemanil, IV erythromycin, halofantrine, mizolastine, moxifloxacin, pentamidine, sparfloxacin, IV vincamine, methadone, astemizole, terfenadine. Prevention of low potassium levels and correction if necessary : monitoring of the QT interval.- 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. Concomitant use which requires some care:- 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 plasma 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.- 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 circulating levels of ciclosporin, even when there is no salt and water depletion.

Adverse Reactions
The administration of perindopril inhibits the renin-angiotensin-aldosterone axis and tends to reduce the potassium loss caused by indapamide. Four percent of the patients on treatment with COVERSYL ARGININE PLUS 5mg/1.25mg experience hypokalaemia (potassium level < 3.4 mmol/l).Blood and the lymphatic system disorders:Very rare ( < 1/10,000):- Thrombocytopenia, leucopenia, agranulocytosis, aplastic anaemia, haemolytic anaemia.- Anaemia has been reported with angiotensin converting enzyme inhibitors in specific circumstances (patients who have had kidney transplants, patients undergoing haemodialysis).Nervous system disorders:Uncommon ( > 1/1,000, < 1/100):- Paresthesia, headache, asthenia, feelings of dizziness, mood disturbances and/or sleep disturbances.Vascular disordersUncommon ( > 1/1,000, < 1/100):- Hypotension whether orthostatic or not.Respiratory, thoracic and mediastinal disorders:Common ( > 1/100, < 1/10):- 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 in the presence of this symptom.Gastrointestinal disorders:Common ( > 1/100, < 1/10):- constipation, dry mouth, nausea, epigastric pain, anorexia, abdominal pains, taste disturbanceVery rare ( < 1/10,000):- pancreatitisIn case of hepatic insufficiency, there is a possibility of onset of hepatic encephalopathySkin and subcutaneous tissue disorders:Uncommon ( > 1/1,000, < 1/100):- Hypersensitivity reactions, mainly dermatological, in subjects with a predisposition to allergic and asthmatic reactions- Maculopapular eruptions, purpura, possible aggravation of pre-existing acute disseminated lupus erythematosus- Skin rashVery rare ( < 1/10,000):- Angioedema (Quincke's oedema)Musculoskeletal, connective tissue and bone disorders:Uncommon ( > 1/1,000, < 1/100):- Cramps.Investigations:- Potassium depletion with particularly serious reduction in levels of potassium in some at risk populations.- Reduced sodium levels with hypovolaemia causing dehydration and orthostatic hypotension.- Increase in uric acid levels and in blood glucose levels during treatment.- 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.Rare ( > 1/10,000, < 1/1,000):- raised plasma calcium levels.

Manufacturer
Servier Laboratories

Drug Availability
(POM)

Updated
11 August 2009