RxMed: Pharmaceutical Information – COVERSYL



Perindopril Erbumine

Angiotensin Converting Enzyme Inhibitor

Action And Clinical Pharmacology: Perindopril is a nonsulphydryl angiotensin-converting enzyme (ACE) inhibitor, which is used in the treatment of hypertension.

Following oral administration, perindopril is rapidly hydrolyzed to perindoprilat, its principal active metabolite.

Angiotensin-converting enzyme catalyzes 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 Precautions, Hyperkalemia and Potassium-Sparing Diuretics). 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 administration may interfere with the degradation of the vasodepressor peptide bradykinin. It is not known whether this effect contributes to the therapeutic activity of perindopril.

The mechanism through which perindopril lowers blood pressure appears to result primarily from suppression of the renin-angiotensin-aldosterone system. Although perindopril had an antihypertensive activity in all races studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to ACE inhibitor therapy than non-black patients.

Pharmacokinetics and Metabolism: After oral administration, perindopril is rapidly absorbed with peak plasma concentrations occurring at about 1 hour, with 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 absorption with perindopril. However, the extent of biotransformation of perindopril to perindoprilat is reduced by approximately 35%. Due to the saturable nature of ACE inhibition, pharmacodynamic effect, as measured by area under the plasma ACE inhibition curve, is reduced by approximately 15%.

Perindoprilat is not extensively bound to protein, this being only 10 to 20%, but binding is concentration dependent. The volume of distribution is approximately 0.2 L/kg for unbound perindoprilat.

Perindoprilat exhibits an apparent mean half-life of 3 to 10 hours for the majority of its elimination from plasma, as well as a prolonged terminal elimination half-life of 30 to 120 hours resulting from slow dissociation of perindoprilat from ACE binding sites. With ongoing administration of perindopril, steady-state plasma levels of perindoprilat are obtained in 3 to 6 days.

Perindopril is extensively metabolized 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 5 others that do not possess appreciable therapeutic activity. These are comprised of perindopril and perindoprilat glucuronides, a perindopril lactam, and two perindoprilat lactams.

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

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), Cmax and AUC were found to be approximately 2-fold higher than in healthy younger subjects. The higher concentrations of perindoprilat observed in these patients were reflected in greater ACE inhibition (see Precautions, Geriatrics, and Dosage, Geriatrics).

In patients with renal insufficiency, perindoprilat AUC increases with decreasing renal function. At creatinine clearances of 30 to 80 mL/min, AUC is about double that of 100 mL/min. When creatinine clearance drops below 30 mL/min, AUC increases more markedly.

Patients with heart failure have reduced perindoprilat clearance, which may result in a dose interval AUC that is increased up to 40%.

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.

Perindopril, and its active metabolite perindoprilat, are dialyzable. 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).

Pharmacodynamics: In most patients with mild to moderate essential hypertension, administration of 4 to 8 mg daily of perindopril results in a reduction of both supine and standing blood pressure with little or no effect on heart rate. Antihypertensive activity commences within 1 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 to 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 mmHg. Abrupt withdrawal of perindopril 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 perindopril is given together with thiazide-type diuretics, the antihypertensive effects are additive.

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

Indications And Clinical Uses: In the treatment of mild to moderate essential hypertension. It may be used alone or in association with other drugs, particularly thiazide diuretics.

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

Perindopril should normally be used in those patients in whom treatment with a diuretic or a beta-blocker was found ineffective or has been associated with unacceptable adverse effects.

Perindopril can also be tried as an initial agent in those patients in whom use of diuretics and/or beta-blockers is contraindicated or in patients with medical conditions in which these drugs frequently cause serious adverse effects.

The safety and efficacy of perindopril in congestive heart failure and renovascular hypertension have not been established and therefore, its use in these conditions is not recommended.

The safety and efficacy of concurrent use of perindopril with antihypertensive agents other than thiazide diuretics have not been established.

Pregnancy: When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury or even death of the developing fetus. When pregnancy is detected perindopril should be discontinued as soon as possible (see Warnings, Pregnancy, and Information for the Patient).

Contra-Indications: In patients who are hypersensitive to this product and in patients with a history of angioedema related to previous treatment with an angiotensin-converting enzyme inhibitor. tag_WarningWarnings

Manufacturers’ Warnings In Clinical States: Angioedema: Angioedema has been reported in patients treated with ACE inhibitors, including perindopril. Angioedema associated with laryngeal involvement may be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, perindopril 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, likely to cause airway obstruction, appropriate therapy (including but not limited to 0.3 to 0.5 mL of s.c. epinephrine solution 1:1 000) should be administered promptly (see Adverse Effects).

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).

Hypotension: Perindopril can cause symptomatic hypotension. 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, diarrhea, or vomiting. In patients with ischemic heart or cerebrovascular disease, an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident (see Adverse Effects). Because of the potential fall in blood pressure in these patients, therapy with perindopril should be started under close medical supervision. Such patients should be followed closely for the first weeks of treatment and whenever the dose of perindopril is increased. 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 progressive death.

If hypotension occurs, the patient should be placed in a supine position and, if necessary, receive an i.v. 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 perindopril and/or reduced concomitant diuretic therapy should be considered.

Neutropenia/Agranulocytosis: Agranulocytosis and bone marrow depression have been caused by ACE inhibitors. Several cases of neutropenia have been reported in which a causal relationship to the administration of perindopril cannot be excluded. Periodic monitoring of white blood cell counts should be considered, especially in patients with collagen vascular disease and/or renal disease.

Pregnancy: ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, perindopril should be discontinued as soon as possible.

In rare cases (probably less than 1 in every 1 000 pregnancies) in which no alternative to ACE inhibitors therapy will be found, the mothers should be apprised of the potential hazards to their fetuses. Serial ultrasound examinations should be performed to assess fetal development and well-being and the volume of amniotic fluid.

If oligohydramnios is observed, perindopril should be discontinued unless it is considered lifesaving to the mother. A nonstress test (NST) and/or a biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. If concerns regarding fetal well-being still persist, a contraction stress testing (CST) should be considered. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

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. Perindopril can be removed from the body by hemodialysis (see Pharmacology, Pharmacokinetics and Metabolism).

Human data: It is not known whether exposure limited to the first trimester of pregnancy can adversely affect fetal outcome. 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; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACE inhibitor exposure.

Animal data: Perindopril was given to mice (1 to 20 mg/kg/day), rats (1 to 16 mg/kg/day), rabbits (0.5 to 5 mg/kg/day) and monkeys (1 to 16 mg/kg/day) during the gestation period. At the highest dose in rats (16 mg/kg/day), maternal toxicity was associated with fetal toxicity but neither embryotoxicity nor teratogenicity was observed. A study in monkeys at high dose (16 mg/kg/day) demonstrated no fetal toxicity although maternal toxicity was slight.

Precautions: Renal Impairment: Renal function should be assessed before initiating therapy with perindopril.

Perindopril should be used with caution in patients with renal insufficiency as they may require reduced or less frequent dosing (see Dosage). Close monitoring of renal function during therapy should be performed as deemed appropriate in those with renal insufficiency. In the majority, renal function will not alter, or may improve.

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

In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine had been observed in some patients following ACE inhibitor therapy. These increases were almost always reversible upon discontinuation of the ACE inhibitor and/or diuretic therapy. In such patients, renal function should be closely monitored.

Some hypertensive patients, with no apparent pre-existing renal disease, have developed increases in blood urea and creatinine especially when ACE inhibitor has been given concurrently with a diuretic. Dosage reduction and/or discontinuation of the diuretic and/or perindopril may be required.

Anaphylactoid Reactions during Membrane Exposure: 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.

Anaphylactoid Reactions during Desensitization: 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.

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

Surgery/Anesthesia: ACE inhibitors may augment the hypotensive effects of anesthetics and analgesics. In patients undergoing major surgery or during anesthesia with agents that produce hypotension, perindopril 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.

Hyperkalemia and Potassium-Sparing Diuretics: In clinical trials, hyperkalemia (serum potassium >5.7 mEq/L) occurred in approximately 1.4% of hypertensive patients. 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 insufficiency, diabetes mellitus, 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) (see Drug Interactions).

Valvular Stenosis: There is concern on theoretical grounds that patients with aortic stenosis might be at particular risk of decreased coronary perfusion when treated with vasodilators because they do not develop as much afterload reduction.

Patients with Impaired Liver Function: 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 perindopril (see Adverse Effects). Should the patient receiving perindopril 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 perindopril should be considered when appropriate.

Perindopril 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.

Lactation: Milk of lactating rats contains radioactivity following administration of perindopril. It is not known whether perindopril is secreted in human milk. Because many drugs are secreted in human milk, caution should be exercised when perindopril is given to a nursing mother, and in general, nursing should be interrupted.

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

Geriatrics: 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.

Drug Interactions: Concomitant Diuretic Therapy: Patients concomitantly taking ACE inhibitors and diuretics, and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy. The possibility of hypotensive effects after the first dose of perindopril can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If it is not possible to discontinue the diuretic, the starting dose of perindopril can be reduced, and the patient should be closely observed for several hours following the initial dose and until blood pressure has stabilized (see Warnings and Dosage).

Agents Increasing Serum Potassium: Since perindopril decreases aldosterone production, elevation of serum potassium may occur. Potassium-sparing diuretics such as spironolactone, triamterene or amiloride, or potassium supplements should be given only for documented hypokalemia and with caution and frequent monitoring of serum potassium, since they may lead to significant increase in serum potassium. Salt substitutes that contain potassium should also be used with caution.

Agents Causing Renin Release: The antihypertensive effect of perindopril is augmented by antihypertensive agents that cause renin release (e.g., diuretics).

Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be further increased.

Agents Affecting Sympathetic Activity: Agents affecting sympathetic activity (e.g., ganglionic blocking agents or adrenergic neuron blocking agents) may be used with caution. Beta-adrenergic blocking drugs add further antihypertensive effect to perindopril.

Digoxin: A pharmacokinetic study has shown no effect on plasma digoxin concentration when coadministered with perindopril.

Information for the Patient: Angioedema: Angioedema, including laryngeal edema, may occur especially following the first dose of perindopril. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, eyes, lips, tongue, difficulty in swallowing or breathing); they should immediately stop taking perindopril and consult with their physician (see Warnings).

Hypotension: Patients should be cautioned to report light-headedness, especially during the first few days of perindopril therapy. If actual syncope occurs, patients should be told to discontinue the drug and consult with their physician.

All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; patients should be advised to consult with their physician.

Agranulocytosis/Neutropenia: Patients should be advised to report promptly any signs or symptoms of infection (e.g., pharyngitis, fever) since this may be a sign of neutropenia (see Warnings and Adverse Effects).

Impaired Liver Function: Patients should be advised to return to the physician if he/she experiences any symptoms possibly related to liver dysfunction. This would include “viral-like symptoms” in the first weeks to months of therapy (such as fever, malaise, muscle pain, rash or adenopathy which are possible indicators of hypersensitivity reactions), or if abdominal pain, nausea or vomiting, loss of appetite, jaundice, itching or any other unexplained symptoms occur during therapy.

Hyperkalemia: Patients should be advised not to use potassium supplements or salt substitutes containing potassium without consulting their physician (see Precautions and Adverse Effects).

Pregnancy: Since the use of perindopril during pregnancy can cause injury and even death of the developing fetus, patients should be advised to report promptly to their physician if they become pregnant.

Adverse Reactions: Perindopril has been evaluated for safety in approximately 3 000 hypertensive patients, of which, 1 216 patients, 181 of which were elderly, participated in controlled clinical trials. Perindopril has been evaluated for long-term safety in approximately 1 000 patients treated for 1 year or more.

The most severe adverse reactions occurring in all patients treated with perindopril in controlled clinical trials were: angioedema (0.1%), orthostatic hypotension (0.4%) and syncope (0.6%). Myocardial infarction and cerebrovascular accident occurred possibly secondary to excessive hypotension in high risk patients (see Warnings).

The most frequent adverse events which occurred in North-American placebo-controlled trials with perindopril monotherapy in hypertension (n=630) were: headache (26.0%), cough (13.0%), asthenia (8.7%), dizziness (8.6%), upper respiratory infection (7.9%), back pain (6.8%), diarrhea (4.6%) and edema (4.3%). Discontinuation of therapy because of adverse events was required in 6.9% of the patients.

Adverse events, irrespective of causal relationship to the drug, which occurred in less than 1% of hypertensive patients treated with perindopril in controlled or uncontrolled trials, and in post-marketing experience are listed as follows:

Body as a Whole: anaphylactic reaction (0.1%), angioedema (0.1%), chest pain, neck pain, edema, facial edema (0.3%), fever, malaise, pain, peripheral edema, thirst.

Cardiovascular: arrhythmia, bradycardia, cold extremities, myocardial infarction (0.3%), orthostatic hypotension (0.4%), orthostatic symptoms, syncope, vasodilatation.

Dermatological: alopecia, cutaneous signs, dermatitis, fever blisters, pruritus, purpura (0.1%), rash, sweating, urticaria, toxic erythroderma.

Gastrointestinal: anorexia, constipation, dry mouth, dry mucous membranes, dyspepsia, flatulence, gastrointestinal hemorrhage, increased appetite, mesenteric infarction (1 patient), stomatitis.

Hematological: neutropenia, thrombocytopenia.

Musculoskeletal: arthralgia, arthritis, bone pain, hypertonia/muscle cramps, myalgia, myasthenia.

Neurological/Psychiatric: abnormal dreams, agitation, amnesia, cerebrovascular accident (0.3%), cognitive dysfunction, confusion, depression, hyperkinesia, memory disturbance, mood disturbance, nervousness, perceptual distortion, somnolence, speech difficulties, tremor, vertigo.

Respiratory: bronchitis, dyspnea, pharyngitis, pneumonia, rhinitis, sinusitis, throat disorder, pulmonary fibrosis.

Urogenital: hematuria, kidney stones, menstrual disorder, nocturia, oliguria, polyuria, scrotal edema, urinary frequency, urinary incontinence, urinary retention, renal failure.

Special Senses: abnormal vision, earache, lacrimation, abnormal taste, tinnitus.

Laboratory Test Abnormalities: Serum electrolytes: hyperkalemia (see Precautions).

Blood Urea Nitrogen/Serum Creatinine: 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 perindopril monotherapy. Decreases in serum sodium and increases in serum creatinine occurred more frequently in patients on concomitant diuretics than in those treated with perindopril alone.

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

Liver Function: Elevations of liver enzymes and/or serum bilirubin have been observed (see Precautions).

In an open-labelled European study of about 47 000 patients with essential hypertension, seen in everyday medical practice, and treated for 1 year with perindopril, with or without multiple other medications, the most frequently observed adverse events were: cough 9.7%, digestive symptoms 2.0%, fatigue 1.8%, headache 1.4% and dizziness 1.4%. In total, 5.1% of patients in this study withdrew due to adverse events, 3.2% due to cough.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Limited data are available regarding overdosage of perindopril in humans. The most likely clinical manifestation would be symptoms attributable to severe hypotension, which should normally be treated by i.v. volume expansion with 0.9% sodium chloride.

However, of the 2 cases reported in the perindopril clinical trials, 1 (dosage unknown) required ventilation assistance and the other developed hypothermia, circulatory arrest, and subsequently died, following ingestion of up to 180 mg of perindopril. Thus, intervention in perindopril overdosage may require vigorous support.

Perindopril can be removed by hemodialysis, with clearances of about 52 mL/min for perindopril, and 67 mL/min for perindoprilat, the active metabolite (see Pharmacology, Pharmacokinetics and Metabolism).

Dosage And Administration: Dosage of perindopril must be individualized.

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 perindopril may need to be adjusted. The presence of food in the gastrointestinal tract reduces bioavailability of perindoprilat.

Monotherapy: The recommended initial dose of perindopril, 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 perindopril alone, a diuretic may be added. After the addition of a diuretic, it may be possible to reduce the dose of perindopril.

Concomitant Diuretic Therapy: Symptomatic hypotension occasionally may occur following the inital dose of perindopril and is more likely in patients who are currently being treated with a diuretic. The diuretic should, if possible, be discontinued for 2 or 3 days before beginning therapy with perindopril to reduce the likelihood of hypotension (see Warnings). If the diuretic cannot be discontinued, an initial dose of 2 mg perindopril should be used with careful medical supervision for several hours and until blood pressure has stabilized. The dosage of perindopril should subsequently be titrated to the optimal response.

Geriatrics: In the elderly, treatment should begin with a 2 mg dose in the morning. If necessary, after 1 month of treatment this dose can be increased to 4 mg daily given in 1 or 2 divided doses.

Renal Impairment: In case of renal impairment, the dosage of perindopril must be adjusted. The following dosages are recommended: see Table I.

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

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

4 mg: Each white, rod-shaped biconvex, scored tablet contains: perindopril erbumine 4 mg. Nonmedicinal ingredients: hydrophobic colloidal silica, lactose, magnesium stearate and microcrystalline cellulose. Boxes containing 1 aluminum/PVC blister strip of 30 tablets.

Store at room temperature (15 to 30°C).

COVERSYL® Servier Perindopril Erbumine Angiotensin Converting Enzyme Inhibitor

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