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, perindopril 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 perindopril 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. Perindopril may also inhibit the degradation of the potent vasodepressor peptide, bradykinin, and this action may contribute to its antihypertensive action. Perindopril appears to reduce peripheral resistance and may influence arterial compliance.
Studies carried out in animal models of hypertension have shown that perindopril is a specific competitive angiotensin I converting enzyme inhibitor. The administration of perindopril 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 perindopril 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 perindopril 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 perindopril is administered together with a thiazide-type diuretic, the antihypertensive activity of perinodpril may be potentiated in some patients, and this effect is evident after four weeks of treatment. Perindopril, like other ACE inhibitors, may compensate for thiazide-induced hypokalaemia.
In one study of 48 patients in which low-dose perindopril equivalent to perindopril arginine 2.5 mg 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.
Amlodipine is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle.
Experimental data suggest that amlodipine binds to both dihydropyridine and non-dihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterised by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.
Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure. The precise mechanism by which amlodipine relieves angina has not been fully determined but amlodipine reduces the total ischaemic burden by the following two actions:
Following administration of therapeutic doses to patients with hypertension, Amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing.
With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients.
Amlodipine has shown no harmful effect on lipid levels and is suitable for use in patients with asthma, diabetes and gout.
As with other calcium channel blockers, haemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In haemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when co-administered with beta-blockers to man. Similar findings, however, have been observed in normal or well-compensated patients with heart failure with medicines possessing significant negative inotropic effects.
In patients with hypertension and normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.
Clinical trials using COVERAM consist of three bioequivalence studies and a pharmacokinetic interaction study (see section 5.2 – Pharmacokinetic properties).
No other clinical trials have been conducted with COVERAM, including trials to assess its long-term effects on cardiovascular morbidity or mortality. However the effects of the individual components of COVERAM have been assessed in clinical trials as detailed below. The combined use of perindopril and amlodipine has been studied in patients with hypertension who have additional cardiovascular risk factors in the AngloScandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA).
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 perindopril arginine 10 mg 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 mellitus. Patients randomised to perindopril were initiated on doses of perindopril equivalent to perindopril arginine 2.5 mg or perindopril arginine 5 mg for two weeks, and then titrated up to a dose of perindopril equivalent to perindopril arginine 10 mg during the two following weeks. A dose of perindopril equivalent to perindopril arginine 10 mg 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 perindopril arginine 5 mg 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 on these combined medicines were 91%, 69% and 63% respectively.
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 perindopril arginine 10 mg 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.
Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man. In patients with chronic stable angina, intravenous administration of 10 mg of amlodipine and a further 10 mg of amlodipine after a 30-minute interval produced peripheral vasodilation and afterload reduction, but did not significantly alter A-H and H-V conduction and sinus node recovery time after pacing. Similar results were obtained in patients receiving amlodipine and beta-blockers in combination. In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse events on electrocardiographic parameters were observed. In clinical trials with angina patients alone, amlodipine treatment did not alter electrocardiographic intervals or produce higher degrees of AV block.
In patients with hypertension once daily dosing provides clinically significant reductions of blood pressure in both the supine and standing positions throughout the 24-hour interval post dose. Due to the slow onset of action, acute hypotension is not a feature of amlodipine administration. The blood pressure effect is maintained over the 24-hour dosing interval, with little difference in peak and trough effect. Tolerance has not been demonstrated in patients studied for up to one year. Effects on diastolic pressure were similar in young and older patients. The effect on systolic pressure was greater in older patients, perhaps because of greater baseline systolic pressure.
In patients with angina, once daily administration of amlodipine increases total exercise time to angina onset and total work time to 1 mm ST segment depression and decreases both angina attack frequency and nitroglycerine tablet consumption. The sustained efficacy of amlodipine in angina patients has been demonstrated over long-term dosing. In patients with angina there were no clinically significant reductions in blood pressure (4/1 mmHg) or changes in heart rate (+0.3 bpm).
Amlodipine (5-10 mg per day) has been studied in a placebo-controlled trial of 1,153 patients with NYHA Class III or IV heart failure on stable doses of ACE inhibitor, digoxin and diuretics. Follow-up was at least six months, with a mean of about 14 months. There was no effect on the primary endpoint of the study of allcause mortality and cardiac morbidity (as defined by life-threatening arrhythmia, acute myocardial infarction, or hospitalisation for worsened heart failure), or on NYHA classification or symptoms of heart failure.
Amlodipine has been compared to placebo in four eight-to-twelve-week studies of patients with NYHA class II/III heart failure, involving a total of 697 patients. In these studies, efficacy in regard to the primary and secondary endpoints was not demonstrated and there was no evidence of worsened heart failure based on measures of exercise tolerance, NYHA classification, symptoms, or LVEF (see section 4.4 – Special warnings and precautions for use).
Three studies have demonstrated bioequivalence between one tablet of the fixed combination of perindopril/amlodipine and the co-administration of one tablet of perindopril plus one tablet of amlodipine, at dose ranges equivalent to COVERAM 5/10, COVERAM 10/5 and COVERAM 10/10.
The results of these studies were similar across the different doses and demonstrated that the rate and extent of absorption of perindopril and amlodipine in COVERAM are not significantly different, respectively, from the rate and extent of absorption of perindopril and amlodipine in individual tablet formulations.
A pharmacokinetic interaction study between perindopril arginine 10 mg and amlodipine 10 mg revealed that the extent and rate of bioavailability of perindopril, perindoprilat and amlodipine are similar for perindopril arginine 10 mg or amlodipine 10 mg administered alone or within a co-administration. No pharmacokinetic interaction exists between these two formulations.
Following oral administration, perindopril 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 perindopril. When perindopril 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.
Protein binding of perindoprilat is 20%, principally to angiotensin converting enzyme. 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
After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels between six to twelve hours post-dose. This may reflect significant initial uptake by the liver, followed by a phase of redistribution. This interval is shorter (two to eight hours) in patients with hepatic impairment. Absolute bioavailability has been estimated to be between 64 and 90%.
In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.
Amlodipine is extensively metabolised by the liver to inactive metabolites with 10% of the parent compound and 60% of metabolites excreted in the urine.
The bioavailability of amlodipine is not altered by the presence of food. The volume of distribution is approximately 20 L/kg. The terminal plasma elimination half-life is about 35-50 hours and is consistent with once daily dosing. Steady state plasma levels are reached after seven to eight days of consecutive dosing. In elderly patients with hypertension (mean age 69 years) there was a decrease in clearance of amlodipine from plasma as compared to young volunteers (mean age 36 years) with a resulting increase in the area under the curve (AUC) of about 60%.
No genotoxicity studies of perindopril in combination with amlodipine have been conducted.
Results from a broad set of assays for gene mutation and chromosomal damage with perindopril suggest no genotoxic potential at clinical doses.
Perindopril showed no evidence of genotoxicity potential in assays for gene mutation (Ames reverse mutation test, mouse lymphoma thymidine kinase assay), chromosomal damage (mouse micronucleus test, Chinese hamster bone marrow cells in vivo, human lymphocytes in vitro) and other genotoxic effects (gene conversion assay in Saccharomyces cerevisiae, unscheduled DNA synthesis in rat hepatic cells).
In animal studies, amlodipine had no teratogenic effects in rats (18 mg/kg) or rabbits (10 mg/kg).
No carcinogenicity or genotoxicity studies of perindopril in combination with amlodipine have been conducted.
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.
The carcinogenic potential of amlodipine has not been fully elucidated. Amlodipine did not induce any tumours when tested in rats at oral doses up to 2.5 mg/kg. This dose gave rise to plasma levels that are similar to those achieved clinically.
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