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APO-PERINDOPRIL
January 30, 2007
, 2007
Table of Contents
SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 8 DRUG INTERACTIONS 10 DOSAGE AND ADMINISTRATION 11 OVERDOSAGE 12 ACTION AND CLINICAL PHARMACOLOGY. 13 STORAGE AND STABILITY 15 DOSAGE FORMS, COMPOSITION AND PACKAGING 15
PHARMACEUTICAL INFORMATION 16 CLINICAL TRIALS 17 DETAILED PHARMACOLOGY 20 TOXICOLOGY 21 REFERENCES 38
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APO-PERINDOPRIL
Perindopril Erbumine
| Route of Administration | Dosage Form / Strength | Clinically Relevant Nonmedicinal Ingredients |
| oral | tablet / 8 mg | lactose For a complete listing see Dosage Forms, Composition and Packaging section. |
Hypertension
APO-PERINDOPRIL (perindopril erbumine) is indicated in the initial treatment of mild to moderate essential hypertension. It may be used alone or in association with other drugs, particularly thiazide diuretics. In using APO-PERINDOPRIL, consideration should be given to the risk of angioedema (see WARNINGS AND PRECAUTIONS). The safety and efficacy of APO-PERINDOPRIL in renovascular hypertension have not been established and therefore, its use in this condition is not recommended. The safety and efficacy of concurrent use of APO-PERINDOPRIL with antihypertensive agents other than thiazide diuretics have not been established.
Congestive heart failure
APO-PERINDOPRIL is also indicated in the treatment of mild to moderate congestive heart failure, generally as adjunctive therapy to diuretics, and where appropriate a digitalis glycoside. Treatment should be initiated under close medical supervision.
Reduction of cardiovascular risk in hypertension or post-myocardial infarction
APO-PERINDOPRIL has been demonstrated to reduce the risk of cardiovascular death, non- fatal myocardial infarction, and cardiac arrest in mild or moderately hypertensive patients with stable coronary artery disease, or in patients with a previous (>3 months ago) myocardial infarction and stable coronary artery disease, when administered as an add-on to conventional treatment, such as platelet inhibitors, beta blockers, lipid-lowering agents, nitrates, calcium channel blockers or diuretics.
APO-PERINDOPRIL (perindopril erbumine) is contraindicated 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.
Angioedema has been reported in patients treated with ACE inhibitors, including perindopril erbumine. Angioedema associated with laryngeal involvement may be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, perindopril erbumine 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 subcutaneous epinephrine solution 1:1000) should be administered promptly (see ADVERSE REACTIONS). The incidence of angioedema during ACE inhibitor therapy has been reported to be higher in black than in non-black patients. 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).
Perindopril erbumine 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, diarrhoea, 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 REACTIONS). Because of the potential fall in blood pressure in these patients, therapy with perindopril erbumine 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 erbumine is increased. In controlled studies versus placebo and other ACE inhibitors, the first administration of 2 mg of perindopril erbumine in patients with mild-moderate heart failure was not associated with any significant reduction in blood pressure as compared to placebo (see ACTION 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 perindopril erbumine and/or reduced concomitant diuretic therapy should be considered.
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 erbumine cannot be excluded. Periodic monitoring of white blood cell counts should be considered, especially in patients with collagen vascular disease and/or renal disease.
ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. When pregnancy is detected, perindopril erbumine 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 neonatoal injury including hypotension, neonatoal 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 contactures, 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. Perindopril erbumine can be removed from the body by hemodialysis (see ACTION AND CLINICAL PHARMACOLOGY - Pharmacokinetics and Metabolism).
Perindopril erbumine was given to mice (1-20 mg/kg/day), rats (1-16 mg/kg/day), rabbits (0.5-5 mg/kg/day) and monkeys (1-16 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.
The presence of concentrations of ACE inhibitor have been reported in human milk. Use of ACE inhibitors is not recommended during breast-feeding.
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been seen in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive heart failure, treatment with agents that inhibit this system has been associated with oliguria, progressive azotemia, and rarely, acute renal failure and/or death. In susceptible patients, concomitant diuretic use may further increase risk. Use of perindopril erbumine should include appropriate assessment of renal function.
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.
Rarely, patients receiving ACE inhibitors during low density lipoprotein apheresis with dextran sulfate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding the ACE inhibitor therapy prior to each apheresis.
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.
A dry, persistent cough, which usually disappears only after withdrawal or lowering of the dose of perindopril erbumine has been reported. Such possibility should be considered as part of the differential diagnosis of the cough.
ACE inhibitors may augment the hypotensive effects of anaesthetics and analgesics. In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, perindopril erbumine 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.
In clinical trials, hyperkalemia (serum potassium > 5.5 mEq/L) occurred in approximately 2.2% of hypertensive patients compared to 1.4% in placebo. 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).
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.
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 erbumine (see ADVERSE REACTIONS). Should the patient receiving perindopril erbumine 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 erbumine should be considered when appropriate. Perindopril erbumine 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.
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 safety and effectiveness of perindopril erbumine in children have not been established. Its use in this age group, therefore, is not recommended.
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.
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. Perindopril erbumine 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. The most severe adverse reactions occurring in all hypertensive patients treated with perindopril erbumine 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 AND PRECAUTIONS). During the long-term safety assessment in heart failure patients, the severe adverse events occurring with the highest frequency were anginal pain (2.5%) and orthostatic hypotension (2.3%). The most frequent adverse events which occurred in North-American placebo-controlled trials with perindopril erbumine 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%), diarrhoea (4.6%) and edema (4.3%). Discontinuation of therapy because of adverse events was required in 6.9% of the patients. 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%), cutaneous signs (4.2%), nausea/vomiting (3.6%) and headache (3.0%). 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. Adverse events, irrespective of causal relationship to the drug, which occurred in less than 1.0% of hypertensive and heart failure patients treated with perindopril erbumine in controlled or uncontrolled trials, and in post-marketing experience are listed as follows: Hypertension, previous myocardial infarction, and stable coronary artery disease: 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 about 22% on drug and placebo. The most common reasons for discontinuation that were more frequent on perindopril erbumine than placebo were cough, drug intolerance and hypotension.
Body as a Whole:
anaphylactic reaction, angioedema, chest pain, neck pain, edema,
fever, malaise, pain, peripheral edema, thirst
Cardiovascular:
arrhythmia, bradycardia, cold extremities, intermittent
claudication, myocardial infarction, orthostatic hypotension, orthostatic symptoms, syncope, vasodilatation, swollen legs.
Dermatological:
alopecia, cutaneous signs, dermatitis, fever blisters, hot flushes,
pemphigus, pruritus, purpura, rash, Stevens-Johnson syndrome, sweating, toxic erythroderma, urticaria
Gastrointestinal:
anorexia, constipation, dry mouth, dry mucous membranes,
dyspepsia, flatulence, haematemesis, G.I. haemorrhage, increased appetite, mesenteric infarction (1 patient), stomatitis
Hematological:
hemolytic anemia, neutropenia, thrombocytopenia
Musculoskeletal:
arthralgia, arthritis, bone pain, hypertonia/muscle cramps, lumbar
pain, myalgia, myasthenia, sciatalgia
Neurological/Psychiatric:
abnormal dreams, agitation, amnesia, cerebrovascular accident,
cognitive dysfunction, confusion, depression, hyperkinesia, memory disturbance, mood disturbance, nervousness, perceptual distortion, sleep disturbance, somnolence, speech difficulties, tremor, vertigo
Respiratory:
asthma, bronchitis, bronchospasm, 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, libido disturbance
Special Senses:
abnormal vision, earache, lacrimation, abnormal taste, tinnitus
Laboratory Test Abnormalities
Serum electrolytes
: Hyperkalemia (see WARNINGS AND 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 erbumine monotherapy. Decreases in serum sodium and increases in serum creatinine occurred more frequently in patients on concomitant diuretics than in those treated with perindopril erbumine alone.
Hematology:
Small decreases in hemoglobin and hematocrit occurred in hypertensive patients treated with perindopril erbumine, 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 WARNINGS AND PRECAUTIONS).
In an open-labelled European study of about 47,000 patients with essential hypertension, seen in everyday medical practice, and treated for one year with perindopril erbumine, 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.
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 erbumine can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril erbumine. If it is not possible to discontinue the diuretic, the starting dose of perindopril erbumine 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 PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Since perindopril erbumine 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 a significant increase in serum potassium. Salt substitutes which contain potassium should also be used with caution.
The antihypertensive effect of perindopril erbumine is augmented by antihypertensive agents that cause renin release (e.g. diuretics).
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 (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 erbumine.
A pharmacokinetic study has shown no effect on plasma digoxin concentration when coadministered with perindopril erbumine.
Dosage of APO-PERINDOPRIL (perindopril erbumine) 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.
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.
Symptomatic hypotension occasionally may occur following the initial 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 two or three days before beginning therapy with perindopril to reduce the likelihood of hypotension (see WARNINGS AND PRECAUTIONS). 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.
Perindopril 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). 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.
In patients with hypertension and stable coronary artery disease or in post-myocardial infarction patients with coronary artery disease, perindopril 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), perindopril 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.
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.
In case of renal impairment, the dosage of perindopril must be adjusted. The following dosages are recommended:
| Creatinine clearance | Recommended dosage |
| Between 30 and 60 ml/min | 2 mg per day |
| Between 15 and 30 ml/min | 2 mg every other day |
| <15 ml/min | 2 mg on the day of dialysis |
In these patients, normal medical follow up includes periodic control of potassium and creatinine.
Limited data are available regarding overdosage of perindopril erbumine in humans. The most likely clinical manifestation would be symptoms attributable to severe hypotension, which should normally be treated by intravenous volume expansion with 0.9% sodium chloride. However, of the two cases reported in the perindopril erbumine clinical trials, one (dosage unknown) required ventilation assistance and the other developed hypothermia, circulatory arrest, and subsequently died, following ingestion of up to 180 mg of perindopril erbumine. Thus, intervention in perindopril erbumine overdosage may require vigorous support. Perindopril erbumine can be removed by hemodialysis, with clearances of about 52 ml/min for perindopril, and 67 ml/mm for perindoprilat, the active metabolite (see ACTIONS AND CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism).
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, perindopril erbumine 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). 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 perindopril erbumine. The mechanism through which perindopril erbumine lowers blood pressure appears to result primarily from suppression of the renin-angiotensin-aldosterone system. The antihypertensive effect of angiotensin converting enzyme inhibitors is generally lower in black patients than in non-blacks.
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After oral administration, perindopril erbumine is rapidly absorbed with peak plasma concentrations occurring at about one 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 on-going administration of perindopril, steady state plasma levels of perindoprilat are obtained in 3-6 days. 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 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 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 - Use in the Elderly, and DOSAGE AND ADMINISTRATION - The Elderly). 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. 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 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).
In most patients with mild to moderate essential hypertension, administration of 4 to 8 mg daily of perindopril erbumine 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 perindopril erbumine 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 erbumine is given together with thiazide- type diuretics, the antihypertensive effects are additive. In uncontrolled studies in patients with insulin-dependent diabetes, perindopril erbumine did not appear to affect glycemic control. In long term use in this population, no effect on urinary protein excretion was seen. Administration of perindopril erbumine 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 perindopril erbumine in patients with mild-moderate heart failure was not associated with any significant reduction in blood pressure as compared to placebo.
Store at room temperature 15 - 30degC. Protect from heat and humidity.
APO-PERINDOPRIL Tablets 8 mg:
Each mottled green, round, biconvex tablet, engraved "APO" on one side and "PE8" on the other side, contains 8 mg of perindopril erbumine. Available in unit dose blister packages of 30 and 100 tablets.
In addition to perindopril erbumine, each tablet contains the non-medicinal ingredients: anhydrous lactose, FD&C Blue # 2, magnesium stearate and yellow ferric oxide.