Source: Pharmaceutical Benefits Scheme (AU) Revision Year: 2022 Publisher: Servier Laboratories (Aust.) Pty. Ltd., www.servier.com.au, Level 4, Building 9, 588A Swan Street, Burnley, 3121, Victoria
Perindopril (prodrug), following hydrolysis to perindoprilat, inhibits angiotensin converting enzyme (ACE) both in vitro and in vivo. It is thought that ACE inhibitors reduce blood pressure by inhibiting the enzyme which catalyses the conversion of angiotensin I to angiotensin II. Decreased plasma angiotensin II leads to increased plasma renin activity and a decrease in aldosterone. In addition to its effects on circulating ACE, PREXUM binds to and inhibits tissue converting enzyme, predominantly in the kidney and vascular wall. The contribution of this mechanism to the overall antihypertensive effect of PREXUM is unknown. Animal studies have demonstrated reversal of vascular hypertrophy and an improvement in the ratio of elastin to collagen in the vessel wall.
Studies in man have demonstrated an improvement in the visco-elastic properties of large vessels and in compliance. Studies in animals and humans suggest that specific and competitive suppression of the renin-angiotensin-aldosterone system (RAAS) is the main mechanism by which blood pressure is reduced. However, antihypertensive activity has also been observed in patients with low renin activity. PREXUM may also inhibit the degradation of the potent vasodepressor peptide, bradykinin, and this action may contribute to its antihypertensive action. PREXUM appears to reduce peripheral resistance and may influence arterial compliance.
Studies carried out in animal models of hypertension have shown that PREXUM is a specific competitive angiotensin I converting enzyme inhibitor. The administration of PREXUM to patients with essential hypertension results in a reduction in supine and standing blood pressure without any significant effect on heart rate. Abrupt withdrawal of PREXUM has not been associated with a rebound rise in blood pressure. Single dose studies have demonstrated that peak inhibition of ACE activity and peak reduction in blood pressure occurs four to six hours after administration. The durations of these effects are dose related and at the recommended dose range, both effects have been shown to be maintained over a 24-hour period.
In haemodynamic studies carried out in animal models of hypertension, blood pressure reduction after PREXUM administration was accompanied by a reduction in peripheral arterial resistance and improved arterial wall compliance. In studies carried out in patients with essential hypertension the reduction in blood pressure was accompanied by a reduction in peripheral resistance with no change, or a small increase in renal blood flow and no change in glomerular filtration rate. An increase in the compliance of large arteries was also observed. When PREXUM is administered together with a thiazide-type diuretic, the antihypertensive activity of PREXUM may be potentiated in some patients, and this effect is evident after four weeks of treatment. PREXUM, like other ACE inhibitors, may compensate for thiazide-induced hypokalaemia.
In one study of 48 patients in which low-dose perindopril equivalent to PREXUM 2.5 was compared with correspondingly low doses of enalapril (2.5 mg) or captopril (6.25 mg) in patients with congestive heart failure, significantly different blood pressure responses were noted. Blood pressure fell significantly with captopril and enalapril following the first dose. However, whilst perindopril inhibited plasma ACE comparably with enalapril, the blood pressure changes were insignificant and similar to placebo for up to ten hours of regular observation. Data regarding possibility of a late hypotensive response are not available for perindopril.
The effects of perindopril were compared to placebo in patients with stable coronary artery disease with no clinical signs of heart failure. The EUROPA (EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease) study was a multicentre, international, randomised, double blind, placebo-controlled clinical trial lasting four years. 12,218 patients aged over 18 were randomised: 6,110 patients to high dose perindopril, equivalent to PREXUM 10 and 6,108 patients to placebo.
The primary endpoint was the composite of cardiovascular mortality, non-fatal myocardial infarction, and/or cardiac arrest with successful resuscitation.
The trial population had evidence of coronary artery disease documented by previous myocardial infarction at least three months before screening, coronary revascularisation at least six months before screening, angiographic evidence of stenosis (at least 70% narrowing of one or more major coronary arteries), or positive stress test in men with a history of chest pain.
Study medication was added to conventional treatment, including medication used for the management of hyperlipidaemia, hypertension and diabetes. Patients randomised to perindopril were initiated on doses of perindopril equivalent to PREXUM 2.5 or PREXUM 5 for two weeks, and then titrated up to a dose of perindopril equivalent to PREXUM 10 during the two following weeks. A dose of perindopril equivalent to PREXUM 10 was then maintained for the whole duration of the study. If this dose was not well tolerated, it could be reduced to a dose of perindopril equivalent to PREXUM 5 once daily.
Most of the patients also received platelet inhibitors, lipid-lowering medicines and beta-blockers. At the end of the study, the proportions of patients treated with a combination of these medicines were 91%, 69% and 63% respectively.
The results of the EUROPA study, specifically the primary endpoint and its components (cardiovascular mortality, non-fatal myocardial infarction or resuscitated cardiac arrest) for the intention-to-treat (ITT) population are presented in Table 3.
Table 3 – EUROPA study results (ITT population)Note 1:
| Perindopril (N=6,110) | Placebo (N=6,108) | Absolute Risk Reduction [95% CI] | NNTNote 2 over 4.2yr trial period (per year) | Relative Risk Reduction [95% CI] | p (logrank) | |
|---|---|---|---|---|---|---|
| Cardiovascular events (Primary composite endpoint) | 488 (8.0%) | 603 (9.9%) | 1.9% [0.87; 2.90] | 54 (227) | 20% [9; 29] | 0.0003 |
| Primary endpoint component: | ||||||
| –Cardiovascular mortality | 215 (3.5%) | 249 (4.1%) | non-significant | - | 14% [-3; 28] | 0.107 |
| –Non-fatal MINote 3 | 295 (4.8%) | 378 (6.2%) | 1.4% [0.55; 2.17] | 74 (311) | 22% [10; 33] | 0.001 |
| –Cardiac arrest with successful resuscitation | 6 (0.1%) | 11 (0.2%) | non-significant | - | 46% [-47; 80] | 0.223 |
| Secondary endpoints: | ||||||
| Total mortality | 375 (6.1%) | 420 (6.9%) | non-significant | - | 11% [-2; 23] | 0.101 |
| Non-fatal and fatal MI | 320 (5.2%) | 418 (6.8%) | 1.6% [0.76; 2.44] | 63 (265) | 23.9% [12, 34] | <0.001 |
Notes:
1. The EUROPA study was designed to have adequate statistical power to detect a treatment effect on the composite primary endpoint, and not for the individual components
2. NNT = Number of patients needed to be treated to prevent one event
3. MI = Myocardial Infarction
The reduction in the primary composite endpoint was mainly due to a reduction in the number of non-fatal myocardial infarctions. There was no significant reduction in the rate of cardiovascular mortality or total mortality in patients taking perindopril compared to those taking placebo.
After a mean follow-up of 4.2 years, treatment with a dose of perindopril equivalent to PREXUM 10 once daily resulted in a significant relative risk reduction of 20% (95% CI: 9-29) in the primary combined endpoint: 488 patients (8.0%) reported events in the perindopril group compared to 603 patients (9.9%) in the placebo group (p=0.0003). Improvements in the primary composite endpoint achieved statistical significance after three years of continuous treatment on perindopril.
Following oral administration, PREXUM is rapidly absorbed with bioavailability of 24%. Elimination is rapid, occurring predominantly via the urine. Plasma half-life is approximately one hour. Bioavailability of the active metabolite perindoprilat is approximately 27%.
Peak plasma concentrations of perindoprilat occur three to four hours after oral administration of PREXUM. Protein binding of perindoprilat is 20%, principally to angiotensin converting enzyme. When PREXUM is administered chronically, steady-state perindoprilat concentration is reached within four days, and perindoprilat does not accumulate.
Apart from perindoprilat, the administration of perindopril leads to the formation of five other metabolites, all of which are inactive and exist in very low quantities. One of these is the glucuronoconjugate of perindoprilat, which is formed by a hepatic first-pass effect. This effect does not appear to have any influence on the kinetics of perindoprilat. Food intake may reduce hepatic biotransformation to perindoprilat.
Perindoprilat binds to plasma and tissue ACE, and free perindoprilat is eliminated through the urine. The terminal half-life of the unbound fraction is approximately 17 hours. The elimination of perindoprilat is reduced in elderly patients and in patients with cardiac and renal failure (see section 4.2 – Dose and method of administration).
Results from a broad set of assays for gene mutation and chromosomal damage with perindopril arginine suggest no genotoxic potential at clinical doses.
No evidence of carcinogenic activity was observed in mice and rats when perindopril erbumine was administered via drinking water at levels up to 7.5 mg/kg/day for two years. At least one ACE inhibitor has caused an increase in the incidence of oxyphilic renal tubular cells and oncocytomas in rats. The potential of the ACE inhibitor class to cause this effect in man is unknown. Moreover, the progression of oxyphilic cells to oncocytomas is rare in humans and when this occurs, it is considered as benign.
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