Coversyl

Interactions with herbal products have not been established.

Lifestyle interactions have not been established.

The presence of food in the gastrointestinal tract does not affect the rate or extent of perindopril absorption. However, the extent of biotransformation of perindopril to perindoprilat is reduced, resulting in a decrease of perindoprilat bioavailability by 35%. Due to the saturable nature of ACE inhibition, the pharmacodynamic effect, as measured by the area under the plasma ACE inhibition-time curve, is reduced by approximately 15%. Therefore it is recommended that COVERSYL is taken before a meal.

Interactions with laboratory products/methods have not been established.

Like for other ACE inhibitors, perindoprilat binding to ACE is characterised by its high affinity but low capacity, leading to a dose dependence of the free fraction.

The influence of the binding to ACE in the terminal phase of the ACE inhibitors is well known. The value of Kd has an influence on the terminal half-life, thus on the estimation of the extrapolated AUC. Since the K_d and bound concentrations have a major impact only in the lower range of concentrations, the binding of perindoprilat to ACE should have a minor impact on steady state in therapeutic conditions.

For perindopril, the dose has no influence on the primary PK parameters and AUC increased proportionally with dose.

In patients with hypertension and stable coronary artery disease or in post-myocardial infarction patients with coronary artery disease, COVERSYL (perindopril erbumine) Tablets should be given at an initial dose of 4 mg once daily for 2 weeks, and then increased as tolerated, to a maintenance dose of 8 mg once daily, preferably to be taken early in the morning. In elderly patients (>70 years), COVERSYL Tablets should be given as a 2 mg dose once daily in the first week, followed by 4 mg once daily in the second week and 8 mg once daily for maintenance dose if tolerated.

Symptomatic hypotension occasionally may occur following the initial dose of COVERSYL and is more likely in patients who are currently being treated with a diuretic. The diuretic should, if possible, be discontinued for two or three days before beginning therapy with COVERSYL to reduce the likelihood of hypotension (see Warnings and Precautions). If the diuretic cannot be discontinued, an initial dose of 2 mg COVERSYL should be used with careful medical supervision for several hours and until blood pressure has stabilized. The dosage of COVERSYL should subsequently be titrated to the optimal response.

It is recommended that COVERSYL is taken once daily in the morning before a meal.

If a dose is missed, a double dose should not be taken, but just carry on with the next dose at the normal time.

In the elderly, treatment should begin with a 2 mg dose in the morning. If necessary, after one month of treatment this dose can be increased to 4 mg daily given in one or two divided doses.

COVERSYL is generally used in conjunction with a diuretic and, where appropriate, a digitalis glycoside in patients with congestive heart failure. Therapy should be initiated under close medical supervision. Blood pressure and renal function should be monitored, both before and during treatment with perindopril because severe hypotension and, more rarely, consequent renal failure have been reported (see Warnings and Precautions).

Initiation of therapy requires consideration of recent diuretic therapy and the possibility of severe salt/volume depletion. If possible, the dose of diuretic should be reduced before beginning treatment. Serum potassium should also be monitored (see Drug Interactions, Drug-Drug Interactions).

The recommended initial dose is 2 mg once daily taken in the morning under close medical supervision. The dose may, in most instances, be increased to 4 mg once daily (once blood pressure acceptability has been demonstrated). The usual effective dose in clinical trials was 4 mg/day administered as a single dose. Dose titration may be performed over a 2- to 4-week period.

Dosage of COVERSYL (perindopril erbumine) must be individualized and adjustment is required in the elderly, and in case of renal impairment.

The recommended initial dose of COVERSYL, in patients not on diuretics, is 4 mg once daily. Dosage should be adjusted according to blood pressure response, generally at intervals of at least 2 weeks. The usual maintenance dose is 4 to 8 mg daily administered in a single daily dose. No additional blood pressure lowering effects were achieved with doses greater than 8 mg daily.

In some patients treated once daily, the antihypertensive effect may diminish towards the end of the dosing interval. This can be evaluated by measuring blood pressure just prior to dosing to determine whether satisfactory control is maintained for 24 hours. If it is not, either twice daily administration with the same total daily dose, or an increase in dose should be considered. If blood pressure is not controlled with COVERSYL alone, a diuretic may be added. After the addition of a diuretic, it may be possible to reduce the dose of COVERSYL.

Initiation of therapy requires consideration of recent antihypertensive drug treatment, the extent of blood pressure elevation and salt restriction. The dosage of other antihypertensive agents being used with COVERSYL may need to be adjusted. The presence of food in the gastrointestinal tract reduces the bioavailability of perindoprilat.

In case of renal impairment, the dosage of COVERSYL must be adjusted. The following dosages are recommended:

In these patients, normal medical follow up includes periodic control of potassium and creatinine.

visual disturbance, lacrimation increased, conjunctivitis.

Small decreases in hemoglobin and hematocrit occurred in hypertensive patients treated with COVERSYL, but were rarely of clinical importance. In controlled clinical trials, no patient was discontinued from therapy due to the development of anemia.

Elevations of BUN or serum creatinine (BUN >40 mg/dl; serum creatinine >2.5 mg/dl) have been observed, respectively, in 0.2% and 0.3% of patients treated with COVERSYL monotherapy. Decreases in serum sodium and increases in serum creatinine occurred more frequently in patients on concomitant diuretics than in those treated with COVERSYL alone.

muscle cramps, pain in extremity, back pain, hypertonia.

In clinical trials, hyperkalemia (serum potassium >5.5 mEq/L) occurred in approximately 2.2% of the hypertensive patients compared to 1.4% in placebo (see Warnings and Precautions, Renal).

asthma, bronchospasm, dyspnoea, pulmonary fibrosis, throat irritation, rhinorrhoea, epistaxis, postnasal drip, hoarseness, sneezing.

hyperkinesia, amnesia, cerebrovascular accident (0.2%), cognitive disorders, memory impairment, perceptual distortion, somnolence, speech disorder, tremor, dysgeusia, migraine.

alopecia, erythema, dry skin, skin disorder, dermatitis, pemphigus, pruritus, purpura, rash, Steven-Johnson syndrome, hyperhidrosis, toxic skin eruption, urticaria, mucous membrane disorder.

neck pain, oedema, arthralgia, arthritis, bone pain, myalgia, myasthenia, sciatalgia, hypertonia/muscle cramps, back (lumbar) pain.

herpes simplex, peritoneal infection (mesenteric infarction, 1 patient), bronchitis, pharyngitis, pneumonia, rhinitis, sinusitis, skin infection, tinea infection, gastroenteritis, vaginitis.

oedema.

In the double-blind phase of the placebo-controlled trials in heart failure, the most frequent adverse events were: asthenia (6.6%), dizziness (6.0%), abdominal pain/gastralgia (4.2%), skin disorders (4.2%), nausea/vomiting (3.6%) and headache (3.0%), palpitations (2.4%) and muscle cramps (2.4%). Discontinuation of therapy due to adverse events was required in 5.4% of the 167 patients with perindopril, as compared to 4.7% of the 170 patients who received a placebo.

Perindopril has been evaluated for safety in the EUROPA trial. This was a double-blind, placebo-controlled study in 12 218 patients with stable coronary artery disease (CAD), the majority of which had hypertension and/or had survived a previous heart attack. The overall rate of discontinuation was 22.8% (1391/6110 patients) and 20.7% (1266/6108 patients) in the perindopril and in the placebo groups, respectively. The most common reasons for discontinuation that were more frequent on COVERSYL than placebo were cough, drug intolerance, hypotension and kidney failure.

During the open run-in period, 12 patients experienced serious ADRs attributed to perindopril: 7 episodes of hypotension, 3 episodes of syncope, 2 cases of non-fatal angioedema and one sudden death. During the double-blind treatment period, 28 patients experienced serious ADRs: 16 patients in the perindopril group experienced 24 events, and 12 patients in the placebo group had 17 events. Hypotension was the most frequent (6 episodes in the perindopril group and 3 in the placebo group), followed by angioedema of the face and/or tongue (3 and 0), syncope, (3 and 3), chest pain, angina (3 and 1), and brachycardia, arrythmia (2 and 0). All other serious ADRs occurred once in either of the treatment groups.

Atrial cardioversion, on the other hand, occurred significantly more frequently in the perindopril group: 0.5% (n=42) vs 0.3% (n=17) in the control group.

hypotension, orthostatic hypotension, peripheral coldness, intermittent claudication, vasodilation, flushing, peripheral vascular disorder (impaired peripheral circulation, swollen legs).

Other medically important adverse effects reported with other available ACE inhibitors include cardiac arrest, eosinophilic pneumonitis, neutropenia/agranulocytosis, pancytopenia, anemia (including hemolytic and aplastic), thrombocytopenia, acute renal failure, nephritis, hepatic failure, jaundice (hepatocellular or cholestatic), symptomatic hyponatremia, bullous pemphigus, acute pancreatitis, exfoliative dermatitis and a syndrome which may include: arthralgia/arthritis, vasculitis, serositis, myalgia, fever, rash or other dermatologic manifestations, a positive ANA, leukocytosis, eosinophilia or an elevated ESR. Many of these adverse effects have also been reported for perindopril.

haemolytic anaemia, leucopenia including neutropenia, thrombocytopenia, ecchymosis, haematoma.

abnormal dreams, agitation, confusional state, depression, mood altered, nervousness, illusion, sleep disturbance, libido disorder, anxiety, psychosexual disorder.

constipation, dry mouth, flatulence, haematemesis, G.I. haemorrhage, stomatitis, diarrhoea, vomiting, dyspepsia.

menstrual disorder, scrotal oedema, erectile dysfunction.

There were no significant differences in numbers of deaths between the groups (375 in the perindopril group and 420 deaths in the control group). However, ten patients died during the open run-in period of the study, of whom 7 from cardiovascular causes, including stroke. A total of 795 patients (out of 12 230; 6.5%) died during the study, 464 of the 795 died (58%) from a cardiovascular cause.

Four general practice post-marketing surveillance studies in 98 010 hypertensive patients were performed in France and Australia. The most frequent adverse events, which occurred in these studies, were cough (more than 5%) and gastrointestinal symptoms, fatigue, dizziness, headache (between 1 and 5%).

Post-marketing experience with all ACE inhibitors suggests that exposure in utero may be associated with hypotension and decreased renal perfusion in the fetus. ACE inhibitors have also been associated with fetal death in utero. No ACE inhibitor should be used in pregnancy.

For a complete report of Post-marketing Adverse Drug Reactions, please refer to Adverse Drug Reaction Overview for the most serious and important adverse drug reactions and the most frequent adverse drug reactions (incidence ≥1%-<10%).

Elevations of liver enzymes and/or serum bilirubin have been observed (see Warnings and Precautions, Special Populations).

anorexia, increased appetite, gout.

Increases in blood urea and plasma creatinine, hyperkalemia may occur especially in the presence of renal insufficiency, severe heart failure and renovascular hypertension. Elevation of liver enzymes (ALT: 1.6% COVERSYL vs 0.9% placebo, AST: 0.5% COVERSYL vs 0.4% placebo have been observed in U.S. placebo-controlled clinical trials), serum bilirubin, cholesterol increase, hematuria, and glucose increase.

chest pain, pyrexia, malaise, pain, peripheral oedema, thirst, feeling cold and hot, rigors.

syncope, arrhythmia, ventricular extrasystole, conduction disorder, cardiac murmur, palpitations, bradycardia, myocardial infarction.

vertigo, ear pain, tinnitus.

In total 56 of 1275 patients studied (4.4%) stopped treatment because of adverse reactions. In a specific study of 632 patients, 36 (5.7%) patients withdrew because of adverse events. A plausible or probable relationship with COVERSYL treatment were considered to exist in 19 (3%) cases.

haematuria, nephrolithiasis, nocturia, oliguria, polyuria, pollakiuria, urinary incontinence, urinary retention, fluid retention, renal insufficiency, flank pain.

cough, dyspnoea.

angina pectoris, arrhythmia, myocardial infarction, palpitations.

COVERSYL (perindopril erbumine) has been evaluated for safety in approximately 3000 hypertensive patients, of which, 1216 patients, 181 of which were elderly, participated in controlled clinical trials. COVERSYL has been evaluated for long-term safety in approximately 1000 patients treated for one year or more. In heart failure trials, 167 patients were treated with perindopril in 3-month placebo-controlled trials and long-term safety was assessed in 513 patients treated for 6 months or more, of which 352 have been followed for at least one year.

cytolytic hepatitis, cholestatic hepatitis.

Adverse events, irrespective of causal relationship to the drug, which occurred in less than 1.0% of hypertensive and heart failure patients treated with COVERSYL in clinical trials, are listed as follows:

anaphylactic reaction, angioneurotic oedema (head, neck, face, extremities, lips, tongue, glottis and/or larynx).

Although clinical experience has not identified significant differences in response between the elderly (>65 years) and younger patients, greater sensitivity of some older individuals cannot be ruled out.

In using COVERSYL, consideration should be given to the risk of angioedema (see Warnings and Precautions).

When using COVERSYL Tablets, consideration should be given to the fact that other angiotensin converting enzyme inhibitors have caused agranulocytosis, particularly in patients with renal impairment or collagen vascular disease (see Warnings and Precautions).

The safety and effectiveness of COVERSYL in children have not been established. Its use in this age group, therefore, is not recommended.

Each green, round, film-coated, biconvex tablet, engraved with on one face and on the other contains: perindopril erbumine 8 mg. Nonmedicinal ingredients: chlorophyllin (E141ii) aluminium lake, hydrophobic colloidal silica, lactose monohydrate, magnesium stearate and microcrystalline cellulose. Boxes containing 1 aluminum/PVC blister strip of 30 tablets.

Each light green, rod shaped, film-coated tablet, engraved with on one face and scored on both edges contains: perindopril erbumine 4 mg. Nonmedicinal ingredients: chlorophyllin (E141ii) aluminium lake, hydrophobic colloidal silica, lactose monohydrate, magnesium stearate and microcrystalline cellulose. Boxes containing 1 aluminum/PVC blister strip of 30 tablets.

Each white, round, film-coated, biconvex tablet contains: perindopril erbumine 2 mg. Nonmedicinal ingredients: hydrophobic colloidal silica, lactose monohydrate, magnesium stearate and microcrystalline cellulose. Boxes containing 1 aluminum/PVC blister strip of 30 tablets.

In diabetic patients treated with oral antidiabetic agents or insulin, glycemic control should be closely monitored during the first month of treatment with an ACE inhibitor.

ACE inhibitors may augment the hypotensive effects of anaesthetics and analgesics. In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, COVERSYL will block the angiotensin II formation that could otherwise occur secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.

Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes (e.g. polyacrylonitrile [PAN]) and treated concomitantly with an ACE inhibitor. Dialysis should be stopped immediately if symptoms such as nausea, abdominal cramps, burning, angioedema, shortness of breath and severe hypotension occur. Symptoms are not relieved by antihistamines. In these patients, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agents.

In clinical trials in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine were observed in 20% of patients. Experience with ACE inhibitors suggests that these increases are usually reversible upon discontinuation of the drug. In such patients, renal function should be monitored during the first few weeks of therapy. ACE inhibitors should be avoided in patients with known or suspected renal artery stenosis. When an ACE inhibitor is given to a patient with stenosis of the renal artery supplying a solitary kidney, or bilateral artery stenosis, acute renal insufficiency may occur. ACE inhibition may also cause a decrease in renal function in patients with stenosis of the artery supplying a transplanted kidney. It is believed that renal artery stenosis reduces the pressure in the afferent glomerular arteriole, and transglomerular hydrostatic pressure is then maintained by angiotensin II-induced constriction of the efferent arteriole. When an ACE inhibitor is given, the efferent arteriole relaxes, glomerular filtration falls, and renal failure may result. The thrombotic occlusion of a stenosed renal artery can be precipitated by ACE inhibitors.

Some hypertensive patients without apparent pre-existing renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient. These increases are more likely to occur in patients treated concomitantly with a diuretic and in patients with pre-existing renal impairment. Reduction of dosages of COVERSYL Tablets, the diuretic or both may be required. In some cases, discontinuation of either or both drugs may be necessary. Evaluation of hypertensive patients should always include an assessment of renal function (see Dosage and Administration). If deterioration in renal function has occurred after treatment with one ACE inhibitor, then it is likely to be precipitated by another and in these patients usage of another class of antihypertensive agent would be preferable. Patients with unilateral renal artery disease present a special problem as deterioration of function may not be apparent from measurement of blood urea and serum creatinine.

Some ACE inhibitors have been associated with the occurrence (up to 0.7%) of proteinuria (<1 gram/24 hours) and/or decline in renal function in patients with one or more of the following characteristics: old age, pre-existing renal disease, concomitant treatment with potassium-sparing diuretics or high doses of other diuretics, limited cardiac reserve, or treatment with a non-steroidal anti-inflammatory drug.

Perindoprilat, the active form of perindopril, is dialysable with a clearance of 70 mL/min.

ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. When pregnancy is detected, COVERSYL should be discontinued as soon as possible.

The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death.

Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function, associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development.

Prematurity, and patent ductus arteriosus and other structural cardiac malformations, as well as neurologic malformations, have also been reported following exposure in the first trimester of pregnancy.

Infants with a history of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for impaired renal function; however, limited experience with those procedures has not been associated with significant clinical benefit.

Perindoprilat, the active form of perindopril, can be removed from the body by hemodialysis (see Actions and Clinical Pharmacology, Pharmacokinetics and Metabolism; Special Populations and Conditions, Renal Insufficiency).

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.

Although clinical experience has not identified significant differences in response between the elderly (>65 years) and younger patients, greater sensitivity of some older individuals cannot be ruled out.

Renal insufficiency is commonly observed in elderly people. Care should therefore be taken when prescribing COVERSYL to elderly patients. The initial dose of COVERSYL in the elderly should always be 2 mg daily and patients should be monitored closely during the initial stages of treatment (see Dosage and Administration).

In a study of 91 elderly patients with a mean age of 71.9 years, a 6% increase in serum potassium occurred in the first month of treatment and subsequently remained stable. There was no change in the group in blood urea, creatinine or creatinine clearance.

Particular care should be taken in elderly patients with congestive heart failure who have renal and/or hepatic insufficiency.

In patients with severe congestive heart failure, where renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including COVERSYL Tablets, may be associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death.

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 clinical trials, hyperkalemia (serum potassium >5.5 mEq/L) occurred in approximately 2.2% of the hypertensive patients compared to 1.4% in placebo (see Adverse Reactions). In most cases, these were isolated values which resolved despite continued therapy. In controlled studies, no patient discontinued therapy due to hyperkalemia.

Risk factors for development of hyperkalemia may include renal impairment, diabetes mellitus, elderly patients and the concomitant use of potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes or other drugs associated with increases in serum potassium (e.g. heparin) which should be used cautiously, if at all, with COVERSYL Tablets (see Drug Interactions). In some patients hyponatremia may co-exist with hyperkalemia. If concomitant use of the above-mentioned agents is deemed appropriate, regular monitoring of serum potassium and urea is recommended.

As with other ACE inhibitors, COVERSYL 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. There is concern on theoretical grounds that patients with aortic stenosis might be at particular risk of decreased coronary perfusion when treated with vasodilators including ACE inhibitors because they do not develop as much afterload reduction. Vasodilators may tend to drop diastolic pressure, and hence coronary pressure, without producing the concomitant reduction in myocardial oxygen demand that normally accompanies vasodilation.

There have been isolated reports of patients experiencing sustained, life-threatening anaphylactoid reactions while receiving ACE inhibitors during desensitization treatment with hymenoptera (bees, wasps) venom. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld for at least 24 hours, but they reappeared upon inadvertent rechallenge.

Hepatitis (hepatocellular and/or cholestatic), elevations of liver enzymes and/or serum bilirubin have occurred during therapy with ACE inhibitors, in patients with or without pre-existing liver abnormalities. In most cases, the changes were reversed upon discontinuation of the drug.

Elevations of liver enzymes and/or serum bilirubin have been reported with COVERSYL (see Adverse Reactions). Should the patient receiving COVERSYL experience any unexplained symptoms, particularly during the first weeks or months of treatment, it is recommended that a full set of liver function tests and any other necessary investigation be carried out. Discontinuation of COVERSYL should be considered when appropriate.

COVERSYL should be used with particular caution in patients with pre-existing liver abnormalities. In such patients, baseline liver function tests should be obtained before administration of the drug and close monitoring of response and metabolic effects should apply.

Rarely, patients receiving ACE inhibitors during low density lipoprotein apheresis with dextran sulfate absorption have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding the ACE inhibitor therapy prior to each apheresis.

Taste disturbances were reported to be common (prevalence up to 12.5%) with high doses of another ACE inhibitor.

Taste disturbance with ACE inhibitors have been described as suppression of taste or a metallic sensation in the mouth. Any dysgeusia usually occurs in the first weeks of treatment and may disappear in most cases within 1-3 months.

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals.

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.

COVERSYL can cause symptomatic hypotension. COVERSYL Tablets have been associated with hypotension in 0.3% of uncomplicated hypertensive patients in U.S. placebo-controlled trials. Symptoms related to orthostatic hypotension were reported in another 0.8% of patients. It is more likely to occur after the first or second dose or when the dose was increased and in patients who are volume depleted by diuretic therapy, dietary salt restriction, dialysis, diarrhoea, or vomiting or with impaired renal function. Volume and/or salt depletion should be corrected before initiation of therapy with COVERSYL (see Dosage and Administration). In patients with ischemic heart or cerebrovascular disease and/or severe congestive heart failure, with or without associated renal insufficiency, ACE inhibitors may cause an excessive fall in blood pressure which could result in syncope, a myocardial infarction, neurological deficits, oliguria and/or progressive azotemia and, rarely, in acute renal failure and/or death (see Adverse Reactions). In all high-risk patients it is advisable to initiate treatment with COVERSYL 2 mg.

Because of the potential fall in blood pressure in these patients, therapy with COVERSYL should be started under very close medical supervision. Such patients should be followed closely for the first two weeks of treatment and whenever the dose of COVERSYL and/or diuretic is increased.

In controlled studies versus placebo and other ACE inhibitors, the first administration of 2 mg of COVERSYL in patients with mild-moderate heart failure was not associated with any significant reduction in blood pressure as compared to placebo (see Actions and Clinical Pharmacology, Pharmacodynamics).

In patients with severe congestive heart failure, with or without associated renal insufficiency, excessive hypotension can be associated with oliguria and/or progressive azotemia and, rarely, with acute renal failure and/or death.

If hypotension occurs, the patient should be placed in a supine position and, if necessary, receive an intravenous infusion of 0.9% sodium chloride. A transient hypotensive response is not a contraindication to further doses which usually can be given without difficulty once the blood pressure has increased after volume expansion. However, lower doses of COVERSYL and/or reduced concomitant diuretic therapy should be considered.

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 such as systemic lupus erythematosus or scleroderma, and those on multiple drug therapy with agents known to be nephrotoxic or myelosuppressive (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.

A dry, persistent cough, which usually disappears only after withdrawal or lowering of the dose of COVERSYL has been reported. Such possibility should be considered as part of the differential diagnosis of the cough.

The cough is often worse when lying down or at night, and has been reported more frequently in women (who account for 2/3 of the reported cases). Patients who cough may have increased bronchial reactivity compared with those who do not. The observed higher frequency of this side-effect in non-smokers may be due to a higher level of tolerance of smokers to cough.

The cough is most likely due to stimulation of the pulmonary cough reflex by kinins (bradykinin) and/or prostaglandins, which accumulate because of ACE inhibition. Once a patient has developed intolerable cough, an attempt may be made to switch the patient to another ACE inhibitor; the reaction may recur but this is not invariably the case. A change to another class of drugs may be required in severe cases.

The safety and effectiveness of COVERSYL in children have not been established. Its use in this age group, therefore, is not recommended.

Not applicable.

Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. Angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

Life-threatening angioedema has been reported with ACE inhibitors. The overall incidence is approximately 0.1-0.2%. The aetiology is thought to be non-immunogenic and may be related to accentuated bradykinin activity. Usually, the angioedema is non-pitting edema of the skin mucous membrane and subcutaneous tissue.

Angioedema involving the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with ACE inhibitors, including COVERSYL (perindopril) Tablets. Angioedema associated with laryngeal involvement may be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, COVERSYL should be discontinued immediately, the patient treated appropriately in accordance with accepted medical care, and carefully observed until the swelling disappears. In instances where swelling is confined to the face and lips, the condition generally resolves without treatment, although antihistamines may be useful in relieving symptoms. Where there is involvement of the tongue, glottis or larynx, angioedema may be fatal due to airway obstruction, appropriate therapy (including but not limited to 0.3 to 0.5 mL of subcutaneous epinephrine solution 1:1000 and oxygen) should be administered promptly (see Adverse Reactions).

Treatment of progressive angioedema should be aggressive. Failing a rapid response to medical therapy, mechanical methods to secure an airway should be undertaken before massive edema complicates oral or nasal intubation.

Patients who respond to medical treatment should be observed carefully for a possible rebound phenomenon.

The onset of angioedema associated with use of ACE inhibitors may be delayed for weeks or months.

Patients may have multiple episodes of angioedema with long symptom-free intervals.

Angioedema may occur with or without urticaria.

The incidence of angioedema during ACE inhibitor therapy has been reported to be higher in black than in non-black patients.

There are reports that switching a patient to another ACE inhibitor could be followed by a recurrence of angioedema. Because of the potential severity of this rare event, another ACE inhibitor should not be used in patients with a history of angioedema (see Contraindications).

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see Contraindications).

Due to the presence of lactose, patients with hereditary problems of galactose intolerance, glucose-galactose malabsorption or the Lapp lactose deficiency should not take this medicinal product.

The presence of concentrations of ACE inhibitor have been reported in human milk. Use of ACE inhibitors is not recommended during breast-feeding.

Dermatological reactions characterised by maculo-papular pruritic rashes and sometimes photosensitivity has been reported with another ACE inhibitor. Rare and sometimes severe skin reactions (lichenoid eruptions, psoriasis, pemphigus like rash, rosacea, Stevens-Johnson syndrome, etc.) have occurred.

Patients who develop a cutaneous reaction with one ACE inhibitor might not when switched to another drug of the same class, but there are reports of cross-reactivity.

The bioavailability of perindoprilat is increased in patients with impaired hepatic function. Plasma concentrations in patients with hepatic impairment were about 50% higher than those observed in healthy subjects or hypertensive patients with normal liver function.

In a pharmacokinetic study with single dose administration, mean peak plasma concentrations of perindoprilat were significantly higher in elderly healthy volunteers (32.5 ng/mL) than in younger volunteers (13.5 ng/mL) due to both higher bioavailability and reduced renal clearance in this group.

Single and multiple dose pharmacokinetics of perindopril were evaluated in a study of elderly hypertensive patients (72 to 91 years of age), C_max and AUC were found to be approximately two-fold higher than in healthy younger subjects. The higher concentrations of perindoprilat observed in these patients were reflected in greater ACE inhibition (see Warnings and Precautions, Geriatrics (>65 years of age) and Dosage and Administration, Recommended Dose and Dosage Adjustment).

Perindoprilat is not extensively bound to plasma proteins, this being only 10 to 20%, but the binding is concentration dependent due to the saturable binding of perindoprilat to the circulating angiotensin-converting enzyme. The volume of distribution is approximately 0.2 L/kg for unbound perindoprilat.

After oral administration, perindopril erbumine is rapidly absorbed with peak plasma concentrations occurring at about one hour, with a bioavailability of 65 to 70%.

Following absorption, perindopril is converted into perindoprilat, its active metabolite, with a mean bioavailability of about 20%. Peak plasma concentration of perindoprilat is attained within 4 to 7 hours and corresponding peak pharmacodynamic activity occurs at about 6 hours.

The presence of food in the gastrointestinal tract does not affect the rate or extent of perindopril absorption. However, the extent of biotransformation of perindopril to perindoprilat is reduced, resulting in a decrease of perindoprilat bioavailability by 35%. Due to the saturable nature of ACE inhibition, the pharmacodynamic effect, as measured by the area under the plasma ACE inhibition-time curve, is reduced by approximately 15%.

COVERSYL (perindopril erbumine) is a nonsulphydryl angiotensin converting enzyme (ACE) inhibitor, which is used in the treatment of hypertension and mild to moderate congestive heart failure.

Following oral administration, COVERSYL is rapidly hydrolysed to perindoprilat, its principal active metabolite.

Angiotensin-converting enzyme catalyses the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE activity leads to decreased levels of angiotensin II, thereby resulting in decreased vasoconstriction and decreased aldosterone secretion. The latter change may result in a small increase in serum potassium (see Warnings and Precautions, Hyperkalemia and Potassium-Sparing Diuretics, Potassium Supplements or Potassium-Containing Salt Substitutes). Decreased levels of angiotensin II and the accompanying lack of negative feedback on renal renin secretion results in increases in plasma renin activity.

ACE is identical to kininase II. Thus, perindopril erbumine administration may interfere with the degradation of the vasodepressor peptide bradykinin. It is not known whether this effect contributes to the therapeutic activity of COVERSYL.

The mechanism through which COVERSYL lowers blood pressure appears to result primarily from suppression of the renin-angiotensin-aldosterone system.

The blood pressure lowering effects of angiotensin converting enzyme (ACE) inhibitors generally are lower in black persons than Caucasian patients. The cardiovascular benefits of ACE inhibitors, in terms of risk reduction in coronary artery disease, have not been extensively studied in blacks.

The clearance of perindoprilat and other metabolites is primarily by the renal pathway.

The systemic clearance of perindopril (367 mL/min) can be split into 39% leading to perindoprilat formation and 61% to renal excretion or other biotransformations. The terminal plasma half-life of perindopril is very short (1.2 h), thus leading to no accumulation with a once daily oral dosing regimen. The terminal plasma half-life of unbound perindoprilat is 17 hours. The apparent terminal plasma half-life of perindoprilat (total concentrations) is much longer (30-120 hours) due to the very slow dissociation of perindoprilat from ACE binding sites. With on-going administration of perindopril, steady state plasma levels of perindoprilat are obtained in 3-6 days and perindoprilat accumulates 1.5-2.0 folds.

Summary of Perindopril and Perindoprilat Pharmacokinetic Parameters: Population Pharmacokinetics Combined Analysis (Clearance, Central Volume and Peripheral Volume)

In patients with renal insufficiency, perindoprilat AUC increases with decreasing renal function. At creatinine clearances of 30-80 mL/min, AUC is about double that of 100 mL/min. When creatinine clearance drops below 30 mL/min, AUC increases more markedly. Therefore the dosage of COVERSYL should be adjusted in patients with a creatinine clearance below 30 mL/min.

Perindopril, and its active metabolite perindoprilat, are dialysable. In a limited number of patients studied, perindopril hemodialysis clearance ranged from 41.7 to 76.7 mL/min (mean 52.0 mL/min). Perindoprilat hemodialysis clearance ranged from 37.4 to 91.0 mL/min (mean 67.2 mL/min).

The effectiveness of COVERSYL was not influenced by sex.

Perindopril is extensively metabolised following oral administration, with only 4 to 12% of the dose recovered unchanged in the urine. Six metabolites have been identified. They include perindoprilat, the active form, and five others that do not possess appreciable therapeutic activity. These are comprised of perindopril glucuronide, perindoprilat glucuronide, a perindopril lactam, and two perindoprilat lactams.

The two main circulating metabolites of perindopril are perindoprilat and perindoprilat glucuronide.

The two pathways identified and quantified for perindoprilat formation are the pre-systemic (first pass effect) and systemic hydrolysis of perindopril. Perindopril is indeed sensitive to a pre-systemic first-past effect, accounting for 62% of the perindoprilat formation. The systemic hydrolysis of perindopril into perindoprilat accounts for the remaining 38% left.

Patients with heart failure have reduced perindoprilat clearance, which may result in a dose interval AUC that is increased up to 40% which should lead to an initial reduction of perindopril dosage.

Pharmacokinetics differences due to genetic polymorphism have not been studied.

In most patients with mild to moderate essential hypertension, administration of 4 to 8 mg daily of COVERSYL results in a reduction of both supine and standing blood pressure with little or no effect on heart rate. Antihypertensive activity commences within one hour with peak effects usually achieved by 4 to 6 hours after dosing. At recommended doses given once daily, antihypertensive effects persist over 24 hours. The blood pressure reductions observed at trough plasma concentration were 75-100% of peak effects. When once and twice daily dosing were compared, the twice daily regimen was slightly superior, but by no more than about 0.5 to 1.0 mmHg. Abrupt withdrawal of COVERSYL has not been associated with a rapid increase in blood pressure. In studies carried out in patients with mild to moderate essential hypertension, the reduction in blood pressure was accompanied by a reduction in peripheral resistance with no change in glomerular filtration rate. When COVERSYL is given together with thiazide-type diuretics, the antihypertensive effects are additive.

In uncontrolled studies in patients with insulin-dependent diabetes, COVERSYL did not appear to affect glycemic control. In long term use in this population, no effect on urinary protein excretion was seen.

Administration of COVERSYL to patients with congestive heart failure reduces cardiac work by a decrease in preload and afterload. Clinical trials have demonstrated that perindopril decreases left and right ventricular filling pressures, reduces total peripheral vascular resistance, increases cardiac output with an improved cardiac index, and increases muscular regional blood flow. The exercise tolerance of these patients is improved and is associated with an improvement of clinical symptomatology. At the recommended doses, the hemodynamic effects are maintained throughout the 24-hour dosing interval in most patients.

In controlled studies versus placebo and other ACE inhibitors, the first administration of 2 mg of COVERSYL in patients with mild-moderate heart failure was not associated with any significant reduction in blood pressure as compared to placebo.

The efficacy of COVERSYL (perindopril erbumine) in reduction of cardiovascular risk in hypertension or post-myocardial infarction was based on one mortality/morbidity study (EUROPA trial).

The safety and effectiveness of COVERSYL in children have not been established. Its use in this age group, therefore, is not recommended.