Drug Class Description
ACE inhibitors.

Generic Name
Perindopril - cardiac failure

Drug Description
Coversyl Arginine 2.5 mg TabletsCoversyl Arginine 5 mg TabletsCoversyl Arginine 10 mg Tablets

Presentation
Film-coated tablet. 2.5 mg: White, round, convex, film-coated tablet. 5 mg: Light-green, rod-shaped film-coated tablet 10 mg: Green, round, biconvex, film-coated tablet

Indications
Hypertension: Treatment of hypertension. Heart failure: Treatment of symptomatic heart failure. Stable coronary artery disease: Reduction of risk of cardiac events in patients with a history of myocardial infarction and/or revascularisation.

Adult Dosage
It is recommended that COVERSYL ARGININE is taken once daily in the morning before a meal.The dose should be individualised according to the patient profile and blood pressure response.Hypertension:COVERSYL ARGININE may be used in monotherapy or in combination with other classes of antihypertensive therapy.The recommended starting dose is 5 mg given once daily in the morning.Patients with a strongly activated renin-angiotensin-aldosterone system (in particular, renovascular hypertension, salt and/or volume depletion, cardiac decompensation or severe hypertension) may experience an excessive drop in blood pressure following the initial dose. A starting dose of 2.5 mg is recommended in such patients and the initiation of treatment should take place under medical supervision.The dose may be increased to 10 mg once daily after one month of treatment.Symptomatic hypotension may occur following initiation of therapy with COVERSYL ARGININE; this is more likely in patients who are being treated concurrently with diuretics. Caution is therefore recommended since these patients may be volume and/or salt depleted.If possible, the diuretic should be discontinued 2 to 3 days before beginning therapy with COVERSYL ARGININE.In hypertensive patients in whom the diuretic cannot be discontinued, therapy with COVERSYL ARGININE should be initiated with a 2.5 mg dose. Renal function and serum potassium should be monitored. The subsequent dosage of COVERSYL ARGININE should be adjusted according to blood pressure response. If required, diuretic therapy may be resumed.In elderly patients treatment should be initiated at a dose of 2.5 mg which may be progressively increased to 5 mg after one month then to 10 mg if necessary depending on renal function (see table below).Symptomatic heart failure:It is recommended that COVERSYL ARGININE, generally associated with a non-potassium-sparing diuretic and/or digoxin and/or a beta-blocker, be introduced under close medical supervision with a recommended starting dose of 2.5 mg taken in the morning. This dose may be increased after 2 weeks to 5 mg once daily if tolerated. The dose adjustment should be based on the clinical response of the individual patient.In severe heart failure and in other patients considered to be at high risk (patients with impaired renal function and a tendency to have electrolyte disturbances, patients receiving simultaneous treatment with diuretics and/or treatment with vasodilating agents), treatment should be initiated under careful supervision.Patients at high risk of symptomatic hypotension e.g. patients with salt depletion with or without hyponatraemia, patients with hypovolaemia or patients who have been receiving vigorous diuretic therapy should have these conditions corrected, if possible, prior to therapy with COVERSYL ARGININE. Blood pressure, renal function and serum potassium should be monitored closely, both before and during treatment with COVERSYL ARGININE.Stable coronary artery disease:COVERSYL ARGININE should be introduced at a dose of 5 mg once daily for two weeks, then increased to 10 mg once daily, depending on renal function and provided that the 5 mg dose is well tolerated.Elderly patients should receive 2.5 mg once daily for one week, then 5 mg once daily the next week, before increasing the dose up to 10 mg once daily depending on renal function (see Table 1 “Dosage adjustment in renal impairment”). The dose should be increased only if the previous lower dose is well tolerated.Dosage adjustment in renal impairment:Dosage in patients with renal impairment should be based on creatinine clearance as outlined in table 1 below:Table 1: dosage adjustment in renal impairmentCreatinine clearance (ml/min)Recommended doseClCR 605 mg per day30 < ClCR < 602.5 mg per day15 < ClCR < 302.5 mg every other dayHaemodialysed patients *ClCR < 152.5 mg on the day of dialysis* Dialysis clearance of perindoprilat is 70 ml/min.For patients on haemodialysis, the dose should be taken after dialysis.Dosage adjustment in hepatic impairment:No dosage adjustment is necessary in patients with hepatic impairmentPaediatric use:Efficacy and safety of use in children and adolescents have not been established. Therefore, use in children and adolescentsis not recommended.

Child Dosage
Not recommended.

Elderly Dosage
2 mg daily initiated under close supervision.

Contra Indications
Hypersensitivity to perindopril, to any of the excipients or to any other ACE inhibitor; History of angioedema associated with previous ACE inhibitor therapy; Hereditary or idiopathic angioedema; Second and third trimesters of pregnancy

Special Precautions
Stable coronary artery disease:If an episode of unstable angina pectoris (major or not) occurs during the first month of perindopril treatment, a careful appraisal of the benefit/risk should be performed before treatment continuation.Hypotension:ACE inhibitors may cause a fall in blood pressure. Symptomatic hypotension is seen rarely in uncomplicated hypertensive patients and is more likely to occur in patients who have been volume-depleted e.g. by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting, or who have severe renin-dependent hypertension. In patients with symptomatic heart failure, with or without associated renal insufficiency, symptomatic hypotension has been observed. This is most likely to occur in those patients with more severe degrees of heart failure, as reflected by the use of high doses of loop diuretics, hyponatraemia or functional renal impairment. In patients at increased risk of symptomatic hypotension, initiation of therapy and dose adjustment should be closely monitored. Similar considerations apply to patients with ischaemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.If hypotension occurs, the patient should be placed in the supine position and, if necessary, should receive an intravenous infusion of sodium chloride 9 mg/ml (0.9%) solution. A transient hypotensive response is not a contraindication to further doses, which can be given usually without difficulty once the blood pressure has increased after volume expansion.In some patients with congestive heart failure who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with COVERSYL ARGININE. This effect is anticipated and is usually not a reason to discontinue treatment. If hypotension becomes symptomatic, a reduction of dose or discontinuation of COVERSYL ARGININE may be necessary.Aortic and mitral valve stenosis / hypertrophic cardiomyopathy :As with other ACE inhibitors, COVERSYL ARGININE should be given with caution to patients with mitral valve stenosis and obstruction in the outflow of the left ventricle such as aortic stenosis or hypertrophic cardiomyopathy.Impairment of renal function:In cases of renal impairment (creatinine clearance < 60 ml/min) the initial perindopril dosage should be adjusted according to the patient's creatinine clearance and then as a function of the patient's response to treatment. Routine monitoring of potassium and creatinine are part of normal medical practice for these patients.In patients with symptomatic heart failure, hypotension following the initiation of therapy with ACE inhibitors may lead to some further impairment in renal function. Acute renal failure, usually reversible, has been reported in this situation.In some patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, who have been treated with ACE inhibitors, increases in blood urea and serum creatinine, usually reversible upon discontinuation of therapy, have been seen. This is especially likely in patients with renal insufficiency. If renovascular hypertension is also present there is an increased risk of severe hypotension and renal insufficiency. In these patients, treatment should be started under close medical supervision with low doses and careful dose titration. Since treatment with diuretics may be a contributory factor to the above, they should be discontinued and renal function should be monitored during the first weeks of COVERSYL ARGININE therapy.Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when COVERSYL ARGININE has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or COVERSYL ARGININE may be required.Haemodialysis patients:Anaphylactoid reactions have been reported in patients dialysed with high flux membranes, and treated concomitantly with an ACE inhibitor. In these patients consideration should be given to using a different type of dialysis membrane or different class of antihypertensive agent.Kidney transplantation:There is no experience regarding the administration of COVERSYL ARGININE in patients with a recent kidney transplantation.Hypersensitivity/Angioedema:Angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and/or larynx has been reported rarely in patients treated with ACE inhibitors, including COVERSYL ARGININE. This may occur at any time during therapy. In such cases, COVERSYL ARGININE should promptly be discontinued and appropriate monitoring should be initiated and continued until complete resolution of symptoms has occurred. In those instances where swelling was confined to the face and lips the condition generally resolved without treatment, although antihistamines have been useful in relieving symptoms.Angioedema associated with laryngeal oedema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, emergency therapy should be administered promptly. This may include the administration of adrenaline and/or the maintenance of a patent airway. The patient should be under close medical supervision until complete and sustained resolution of symptoms has occurred.Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor.Anaphylactoid reactions during low-density lipoproteins (LDL) apheresis:Rarely, patients receiving ACE inhibitors during low-density lipoprotein (LDL) apheresis with dextran sulphate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis.Anaphylactic reactions during desensitisation:Patients receiving ACE inhibitors during desensitisation treatment (e.g. hymenoptera venom) have experienced anaphylactoid reactions. In the same patients, these reactions have beenavoided when the ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.Hepatic failure:Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.Neutropenia/Agranulocytosis/Thrombocytopenia/Anaemia:Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and no other complicating factors, neutropenia occurs rarely. Perindopril should be used with extreme caution in patients with collagen vascular disease, immunosuppressant therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially if there is pre-existing impaired renal function. Some of these patients developed serious infections, which in a few instances did not respond to intensive antibiotic therapy. If perindopril is used in such patients, periodic monitoring of white blood cell counts is advised and patients should be instructed to report any sign of infection.Race:ACE inhibitors cause a higher rate of angioedema in black patients than in non-black patients.As with other ACE inhibitors, perindopril may be less effective in lowering blood pressure in black people than in non-blacks, possibly because of a higher preva lence of low-renin states in the black hypertensive population.Cough:Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is non-productive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.Surgery/Anaesthesia:In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, COVERSYL ARGININE may block angiotensin II formation secondary to compensatory renin release. The treatment should be discontinued one day prior to the surgery. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.Hyperkalaemia:Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including perindopril. 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.Diabetic patients:In diabetic patients treated with oral antidiabetic agents or insulin, glycaemic control should be closely monitored during the first month of treatment with an ACE inhibitor.Lithium:The combination of lithium and perindopril is generally not recommended.Potassium sparing diuretics, potassium supplements or potassium-containing salt substitutesThe combination of perindopril and potassium sparing diuretics, potassium supplements or potassium-containing salt substitutes is generally not recommended.Due to the presence of lactose, patients with rare hereditary problems of galactose intolerance, glucose-galactose malabsorption, or the Lapp lactase deficiency should not take this medicinal product.

Interactions
Diuretics:Patients on diuretics, and especially those who are volume and/or salt depleted, may experience excessive reduction in blood pressure after initiation of therapy with an ACE inhibitor. The possibility of hypotensive effects can be reduced by discontinuation of the diuretic, by increasing volume or salt intake prior to initiating therapy with low and progressive doses of perindopril.Potassium sparing diuretics, potassium supplements or potassium-containing salt substitutes:Although serum potassium usually remains within normal limits, hyperkalaemia may occur in some patients treated with perindopril. Potassium sparing diuretics (e.g. spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Therefore the combination of perindopril with the above-mentioned drugs is not recommended. If concomitant use is indicated because of demonstrated hypokalaemia they should be used with caution and with frequent monitoring of serum potassium.Lithium:Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and enhance the already increased risk of lithium toxicity with ACE inhibitors. Use of perindopril with lithium is not recommended, but if the combination proves necessary, careful monitoring of serum lithium levels should be performed.Non-steroidal anti-inflammatory drugs (NSAIDs) including aspirin 3 g/day:The administration of a non-steroidal anti-inflammatory drug may reduce the antihypertensive effect of ACE inhibitors. Additionally, NSAIDs and ACE inhibitors exert an additive effect on the increase in serum potassium and may result in a deterioration of renal function. These effects are usually reversible. Rarely, acute renal failure may occur, especially in patients with compromised renal function such as those who are elderly or dehydrated.Antihypertensive agents and vasodilators:Concomitant use of these agents may increase the hypotensive effects of perindopril. Concomitant use with nitroglycerin and other nitrates, or other vasodilators, may further reduce blood pressure.Antidiabetic agents:Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic medicines (insulins, oral hypoglycaemic agents) may cause an increased blood-glucose lowering effect with risk of hypoglycaemia. This phenomenon appeared to be more likely to occur during the first weeks of combined treatment and in patients with renal impairment.Tricyclic antidepressants/Antipsychotics/Anaesthetics:Concomitant use of certain anaesthetic medicinal products, tricyclic antidepressants and antipsychotics with ACE inhibitors may result in further reduction of blood pressure.Sympathomimetics:Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.Acetylsalicylic acid, thrombolytics, beta-blockers, nitrates:Perindopril may be used concomitantly with acetylsalicylic acid (when used as a thrombolytic), thrombolytics, beta-blockers and/or nitrates.

Adverse Reactions
The following undesirable effects have been observed during treatment with perindopril and ranked under the following frequency:Very common (>1/10); common (>1/100, <1/10); uncommon (>1/1000, <1/100); rare (>1/10000, <1/1000); very rare (<1/10000), including isolated reports.Blood and the lymphatic system disorders:Decreases in haemoglobin and haematocrit, thrombocytopenia, leucopenia/neutropenia, and cases of agranulocytosis or pancytopenia, have been reported very rarely. In patients with a congenital deficiency of G-6PDH, very rare cases of haemolytic anaemia have been reported.Psychiatric disorders:Uncommon: mood or sleep disturbances.Nervous system disorders:Common: headache, dizziness, vertigo, paresthaesia.Very rare: confusion.Eye disorders:Common: vision disturbance.Ear and labyrinth disorders:Common: tinnitus.Vascular disorders:Common: hypotension and effects related to hypotension.Very rare: stroke possibly secondary to excessive hypotension in high-risk patients.Cardiac disorders: Very rare: arrhythmia, angina pectoris and myocardial infarction possibly secondary to excessive hypotension in high-risk patients.Respiratory, thoracic and mediastinal disorders:Common: cough, dyspnoea.Uncommon: bronchospasm.Very rare: eosinophilic pneumonia, rhinitis.Gastro-intestinal disorders:Common: nausea, vomiting, abdominal pain, dysgeusia, dyspepsia, diarrhoea, constipation.Uncommon: dry mouth.Very rare: pancreatitis.Hepato-biliary disorders:Very rare: hepatitis either cytolytic or cholestatic.Skin and subcutaneous tissue disorders:Common: rash, pruritus.Uncommon: angioedema of face, extremities, lips, mucous membranes, tongue, glottis and/or larynx, urticaria.Very rare: erythema multiforme.Musculoskeletal and connective tissue disorders:Common: muscle cramps.Renal and urinary disorders:Uncommon: renal insufficiency.Very rare: acute renal failure.Reproductive system and breast disorders:Uncommon: impotence.General disorders and administration site conditions:Common: asthenia.Uncommon: sweating.Investigations:Increases in blood urea and plasma creatinine, hyperkalaemia reversible on discontinuation may occur, especially in the presence of renal insufficiency, severe heart failure and renovascular hypertension. Elevation of liver enzymes and serum bilirubin have been reported rarely.Clinical trials:During the randomised period of the EUROPA study, only serious adverse events were collected. Few patients experienced serious adverse events: 16 (0.3%) of the 6122 perindopril patients and 12 (0.2%) of the 6107 placebo patients. In perindopril-treated patients, hypotension was observed in 6 patients, angioedema in 3 patients and sudden cardiac arrest in 1 patient. More patients withdrew for cough, hypotension or other intolerance on perindopril than on placebo, 6.0% (n=366) versus 2.1% (n=129) respectively.

Manufacturer
Servier Laboratories Limited

Drug Availability
(POM)

Updated
30 June 2009