Source: Web Search Revision Year: 2023
Pharmacotherapeutic group: ACE inhibitor and calcium channel blocker
ATC code: C09BB07
Ramiprilat, the active metabolite of the prodrug ramipril, inhibits the enzyme dipeptidylcarboxypeptidase I (synonyms: angiotensin-converting enzyme; kininase II). In plasma and tissue this enzyme catalyses the conversion of angiotensin I to the active vasoconstrictor substance angiotensin II, as well as the breakdown of the active vasodilator bradykinin. Reduced angiotensin II formation and inhibition of bradykinin breakdown lead to vasodilatation.
Since angiotensin II also stimulates the release of aldosterone, ramiprilat causes a reduction in aldosterone secretion. The average response to ACE inhibitor monotherapy was lower in black (Afro-Caribbean) hypertensive patients (usually a low-renin hypertensive population) than in non-black patients.
Administration of ramipril causes a marked reduction in peripheral arterial resistance. Generally, there are no major changes in renal plasma flow and glomerular filtration rate. Administration of ramipril to patients with hypertension leads to a reduction in supine and standing blood pressure without a compensatory rise in heart rate. In most patients the onset of the antihypertensive effect of a single dose becomes apparent 1 to 2 hours after oral administration. The peak effect of a single dose is usually reached 3 to 6 hours after oral administration. The antihypertensive effect of a single dose usually lasts for 24 hours.
The maximum antihypertensive effect of continued treatment with ramipril is generally apparent after 3 to 4 weeks. It has been shown that the antihypertensive effect is sustained under long term therapy lasting 2 years. Abrupt discontinuation of ramipril does not produce a rapid and excessive rebound increase in blood pressure.
In addition to conventional therapy with diuretics and optional cardiac glycosides, ramipril has been shown to be effective in patients with functional classes II-IV of the New-York Heart Association. The drug had beneficial effects on cardiac haemodynamics (decreased left and right ventricular filling pressures, reduced total peripheral vascular resistance, increased cardiac output and improved cardiac index). It also reduced neuroendocrine activation.
A preventive placebo-controlled study (the HOPE-study), was carried out in which ramipril was added to standard therapy in more than 9,200 patients. Patients with increased risk of cardiovascular disease following either atherothrombotic cardiovascular disease (history of coronary heart disease, stroke or peripheral vascular disease) or diabetes mellitus with at least one additional risk factor (documented microalbuminuria, hypertension, elevated total cholesterol level, low high-density lipoprotein cholesterol level or cigarette smoking) were included in the study.
The study showed that ramipril statistically significantly decreases the incidence of myocardial infarction, death from cardiovascular causes and stroke, alone and combined (primary combined events).
Table 1. The HOPE Study: Main Results:
| Ramipril % | Placebo % | relative risk (95% confidence interval) | p-value | |
|---|---|---|---|---|
| All patients | n=4,645 | N=4,652 | ||
| Primary combined events | 14.0 | 17.8 | 0.78 (0.70-0.86) | <0.001 |
| Myocardial infarction | 9.9 | 12.3 | 0.80 (0.70-0.90) | <0.001 |
| Death from cardiovascular causes | 6.1 | 8.1 | 0.74 (0.64-0.87) | <0.001 |
| Stroke | 3.4 | 4.9 | 0.68 (0.56-0.84) | <0.001 |
| Secondary endpoints | ||||
| Death from any cause | 10.4 | 12.2 | 0.84 (0.75-0.95) | 0.005 |
| Need for Revascularisation | 16.0 | 18.3 | 0.85 (0.77-0.94) | 0.002 |
| Hospitalisation for unstable angina | 12.1 | 12.3 | 0.98 (0.87-1.10) | NS |
| Hospitalisation for heart failure | 3.2 | 3.5 | 0.88 (0.70-1.10) | 0.25 |
| Complications related to diabetes | 6.4 | 7.6 | 0.84 (0.72-0.98) | 0.03 |
The MICRO-HOPE study, a predefined substudy from HOPE, investigated the effect of the addition of ramipril 10 mg to the current medical regimen versus placebo in 3,577 patients at least ≥55 years old (with no upper limit of age), with a majority of type 2 diabetes (and at least another CV risk factor), normotensive or hypertensive.
The primary analysis showed that 117 (6.5%) participants on ramipril and 149 (8.4%) on placebo developed overt nephropathy, which corresponds to a RRR 24%; 95% CI [3-40], p=0.027.
The REIN study, a multicenter randomized, double-blind parallel group, placebo-controlled study aimed at assessing the effect of treatment with ramipril on the rate of decline of glomerular function rate (GFR) in 352 normotensive or hypertensive patients (18-70 years old) suffering from mild (i.e. mean urinary protein excretion >1 and <3 g/24 h) or severe proteinuria (≥3 g/24 h) due to chronic non-diabetic nephropathy. Both subpopulations were prospectively stratified.
The main analysis of patients with the most severe proteinuria (stratum prematurely disrupted due to a clear benefit in ramipril group) showed that the mean rate of GFR decline per month was lower with ramipril than with placebo; -0.54 (0.66) vs. -0.88 (1.03) ml/min/month, p=0.038. The intergroup difference was thus 0.34 [0.03-0.65] per month, and around 4 ml/min/year; 23.1% of the patients in the ramipril group reached the combined secondary endpoint of doubling of baseline serum creatinine concentration and/or end-stage renal disease (ESRD) (need for dialysis or renal transplantation) vs. 45.5% in the placebo group (p=0.02).
Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker.
ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.
These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.
ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.
The AIRE study included more than 2,000 patients with transient/persistent clinical signs of heart failure after documented myocardial infarction. The ramipril treatment was started 3 to 10 days after the acute myocardial infarction. The study showed that after an average follow-up time of 15 months the mortality in ramipril-treated patients was 16.9% and in the placebo treated patients was 22.6%. This means an absolute mortality reduction of 5.7% and a relative risk reduction of 27% (95% CI [11-40%]).
In a randomized, double-blind, placebo-controlled clinical study involving 244 paediatric patients with hypertension (73% primary hypertension), aged 6-16 years, patients received either low dose, medium dose or high dose of ramipril to achieve plasma concentrations of ramiprilat corresponding to the adult dose range of 1.25 mg, 5 mg and 20 mg on the basis of body weight. At the end of 4 weeks, ramipril was ineffective in the endpoint of lowering systolic blood pressure but lowered diastolic blood pressure at the highest dose. Both medium and high doses of ramipril showed significant reduction of both systolic and diastolic blood pressure in children with confirmed hypertension.
This effect was not seen in a 4 week dose-escalation, randomized, double-blind withdrawal study in 218 paediatric patients aged 6-16 years (75% primary hypertension), where both diastolic and systolic blood pressures demonstrated a modest rebound but not a statistically significant return to the baseline, in all three dose levels tested [low dose (0.625mg – 2.5mg), medium dose (2.5mg – 10mg) or high dose (5mg – 20mg)] ramipril based on weight. Ramipril did not have a linear dose response in the paediatric population studied.
Amlodipine is a calcium ion influx inhibitor of the dihydropyridine group (slow channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle.
The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscle. The precise mechanism by which amlodipine relieves angina has not been fully determined but amlodipine reduces total ischaemic burden by the following two actions:
1) Amlodipine dilates peripheral arterioles and thus, reduces the total peripheral resistance (afterload) against which the heart works. Since the heart rate remains stable, this unloading of the heart reduces myocardial energy consumption and oxygen requirements.
2) The mechanism of action of amlodipine also probably involves dilatation of the main coronary arteries and coronary arterioles, both in normal and ischaemic regions. This dilatation increases myocardial oxygen delivery in patients with coronary artery spasm (Prinzmetal’s or variant angina).
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. Due to the slow onset of action, acute hypotension is not a feature of amlodipine administration.
In patients with angina, once daily administration of amlodipine increases total exercise time, time to angina onset, and time to 1 mm ST segment depression, and decreases both angina attack frequency and glyceryl trinitrate tablet consumption.
Amlodipine has not been associated with any adverse metabolic effects or changes in plasma lipids and is suitable for use in patients with asthma, diabetes, and gout.
The effectiveness of amlodipine in preventing clinical events in patients with coronary artery disease (CAD) has been evaluated in an independent, multi-centre, randomized, double-blind, placebo-controlled study of 1997 patients; Comparison of Amlodipine vs. Enalapril to Limit Occurrences of Thrombosis (CAMELOT).
Of these patients, 663 were treated with amlodipine 5-10 mg, 673 patients were treated with enalapril 10-20 mg, and 655 patients were treated with placebo, in addition to standard care of statins, beta-blockers, diuretics and aspirin, for 2 years. The key efficacy results are presented in Table 1. The results indicate that amlodipine treatment was associated with fewer hospitalizations for angina and revascularization procedures in patients with CAD.
Table 1. Incidence of significant clinical outcomes for CAMELOT:
| Cardiovascular event rates, No. (%) | Amlodipine vs. Placebo | ||||
|---|---|---|---|---|---|
| Outcomes | Amlodipine | Placebo | Enalapril | Hazard Ratio (95% CI) | P Value |
| Primary Endpoint | |||||
| Adverse cardiovascular events | 110 (16.6) | 151 (23.1) | 136 (20.2) | 0.69 (0.54-0.88) | .003 |
| Individual Components | |||||
| Coronary revascularization | 78 (11.8) | 103 (15.7) | 95 (14.1) | 0.73 (0.54-0.98) | .03 |
| Hospitalization for angina | 51 (7.7) | 84 (12.8) | 86 (12.8) | 0.58 (0.41-0.82) | .002 |
| Nonfatal MI | 14 (2.1) | 19 (2.9) | 11 (1.6) | 0.73 (0.37-1.46) | .37 |
| Stroke or TIA | 6 (0.9) | 12 (1.8) | 8 (1.2) | 0.50 (0.19-1.32) | .15 |
| Cardiovascular death | 5 (0.8) | 2 (0.3) | 5 (0.7) | 2.46 (0.48-12.7) | .27 |
| Hospitalization for CHF | 3 (0.5) | 5 (0.8) | 4 (0.6) | 0.59 (0.14-2.47) | .46 |
| Resuscitated cardiac arrest | 0 | 4 (0.6) | 1 (0.1) | NA | .04 |
| New-onset peripheral vascular disease | 5 (0.8) | 2 (0.3) | 8 (1.2) | 2.6 (0.50-13.4) | .24 |
Abbreviations: CHF, congestive heart failure; CI, confidence interval; MI, myocardial infarction; TIA, transient ischemic attack.
Haemodynamic studies and exercise based controlled clinical trials in NYHA Class II-IV heart failure patients have shown that amlodipine did not lead to clinical deterioration as measured by exercise tolerance, left ventricular ejection fraction and clinical symptomatology.
A placebo controlled study (PRAISE) designed to evaluate patients in NYHA Class III-IV heart failure receiving digoxin, diuretics and ACE inhibitors has shown that amlodipine did not lead to an increase in risk of mortality or combined mortality and morbidity with heart failure.
In follow up, long term, placebo controlled study (PRAISE-2) of amlodipine in patients with NYHA III and IV heart failure without clinical symptoms or objective findings suggestive or underlying ischaemic disease, on stable doses of ACE inhibitors, digitalis, and diuretics, amlodipine had no effect on total cardiovascular mortality. In this same population amlodipine was associated with increased reports of pulmonary oedema.
A randomized double-blind morbidity-mortality study called the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was performed to compare newer drug therapies: amlodipine 2.5-10 mg/d (calcium channel blocker) or lisinopril 10-40 mg/d (ACE-inhibitor) as first-line therapies to that of the thiazide-diuretic, chlorthalidone 12.5-25 mg/d in mild to moderate hypertension. A total of 33,357 hypertensive patients aged 55 or older were randomized and followed for a mean of 4.9 years. The patients had at least one additional CHD risk factor, including: previous myocardial infarction or stroke (>6 months prior to enrolment) or documentation of other atherosclerotic CVD (overall 51.5%), type 2 diabetes (36.1%), HDL-C <35 mg/dL (11.6%), left ventricular hypertrophy diagnosed by electrocardiogram or echocardiography (20.9%), current cigarette smoking (21.9%).
The primary endpoint was a composite of fatal CHD or non-fatal myocardial infarction. There was no significant difference in the primary endpoint between amlodipine-based therapy and chlorthalidone-based therapy: RR 0.98 95% CI(0.90-1.07) p=0.65. Among secondary endpoints, the incidence of heart failure (component of a composite combined cardiovascular endpoint) was significantly higher in the amlodipine group as compared to the chlorthalidone group (10.2%% vs 7.7%, RR 1.38, 95% CI [1.25-1.52] p<0.001). However, there was no significant difference in all-cause mortality between amlodipine-based therapy and chlorthalidone-based therapy. RR 0.96 95% CI [0.89-1.02] p=0.20.
In a study involving 268 children aged 6-17 years with predominantly secondary hypertension, comparison of a 2.5 mg dose, and 5.0 mg dose of amlodipine with placebo, showed that both doses reduced Systolic Blood Pressure significantly more than placebo. The difference between the two doses was not statistically significant.
The long-term effects of amlodipine on growth, puberty and general development have not been studied. The long-term efficacy of amlodipine on therapy in childhood to reduce cardiovascular morbidity and mortality in adulthood have also not been established.
The European Medicines Agency has waived the obligation to submit the results of studies with Ramipril/Amlodipine Glenmark in all subsets of the paediatric population in the granted indication (see section 4.2 for information on paediatric use).
Following oral administration ramipril is rapidly absorbed from the gastrointestinal tract: peak plasma concentrations of ramipril are reached within one hour. Based on urinary recovery, the extent of absorption is at least 56 % and is not significantly influenced by the presence of food in the gastrointestinal tract. The bioavailability of the active metabolite ramiprilat after oral administration of 2.5 mg and 5 mg ramipril is 45%.
Peak plasma concentrations of ramiprilat, the sole active metabolite of ramipril are reached 2-4 hours after ramipril intake. Steady state plasma concentrations of ramiprilat after once daily dosing with the usual doses of ramipril are reached by about the fourth day of treatment.
The serum protein binding of ramipril is about 73% and that of ramiprilat about 56%.
Ramipril is almost completely metabolised to ramiprilat, and to the diketopiperazine ester, the diketopiperazine acid, and the glucuronides of ramipril and ramiprilat.
Excretion of the metabolites is primarily renal.
Plasma concentrations of ramiprilat decline in a polyphasic manner. Because of its potent, saturable binding to ACE and slow dissociation from the enzyme, ramiprilat shows a prolonged terminal elimination phase at very low plasma concentrations.
After multiple once-daily doses of ramipril, the effective half-life of ramiprilat concentrations was 13-17 hours for the 5-10 mg doses and longer for the lower 1.25-2.5 mg doses. This difference is related to the saturable capacity of the enzyme to bind ramiprilat.
Renal excretion of ramiprilat is reduced in patients with impaired renal function, and renal ramiprilat clearance is proportionally related to creatinine clearance. This results in elevated plasma concentrations of ramiprilat, which decrease more slowly than in subjects with normal renal function.
In patients with impaired liver function, the metabolism of ramipril to ramiprilat was delayed, due to diminished activity of hepatic esterases, and plasma ramipril levels in these patients were increased. Peak concentrations of ramiprilat in these patients, however, are not different from those seen in subjects with normal hepatic function.
A single oral dose of ramipril produced an undetectable level of ramipril and its metabolite in breast milk. However the effect of multiple doses is not known.
The pharmacokinetic profile of ramipril was studied in 30 paediatric hypertensive patients, aged 2-16 years, weighing ≥ 10 kg. After doses of 0.05 to 0.2 mg/kg, ramipril was rapidly and extensively metabolized to ramiprilat. Peak plasma concentrations of ramiprilat occurred within 2-3 hours.
Ramiprilat clearance highly correlated with the log of body weight (p<0.01) as well as dose (p<0.001). Clearance and volume of distribution increased with increasing children age for each dose group. The dose of 0.05 mg/kg in children achieved exposure levels comparable to those in adults treated with ramipril 5 mg. The dose of 0.2 mg/kg in children resulted in exposure levels higher than the maximum recommended dose of 10 mg per day in adults.
After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels between 6-12 hours post dose. Absolute bioavailability has been estimated to be between 64 and 80%. The volume of distribution is approximately 21 l/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.
The bioavailability of amlodipine is not affected by food intake.
The terminal plasma elimination half-life is about 35-50 hours and is consistent with once daily dosing. Amlodipine is extensively metabolised by the liver to inactive metabolites with 10% of the parent compound and 60% of metabolites excreted in the urine.
Very limited clinical data are available regarding amlodipine administration in patients with hepatic impairment. Patients with hepatic insufficiency have decreased clearance of amlodipine resulting in a longer half-life and an increase in AUC of approximately 40-60%.
The time to reach peak plasma concentrations of amlodipine is similar in elderly and younger subjects. Amlodipine clearance tends to be decreased with resulting increases in AUC and elimination half-life in elderly patients. Increases in AUC and elimination half-life in patients with congestive heart failure were as expected for the patient age group studied.
A population PK study has been conducted in 74 hypertensive children aged from 1 to 17 years (with 34 patients aged 6 to 12 years and 28 patients aged 13 to 17 years) receiving amlodipine between 1.25 and 20 mg given either once or twice daily. In children 6 to 12 years and in adolescents 13-17 years of age the typical oral clearance (CL/F) was 22.5 and 27.4 L/hr respectively in males and 16.4 and 21.3 L/hr respectively in females. Large variability in exposure between individuals was observed. Data reported in children below 6 years is limited.
Oral administration of ramipril has been found to be devoid of acute toxicity in rodents and dogs. Studies involving chronic oral administration have been conducted in rats, dogs and monkeys. Indications of plasma electrolyte shifts and changes in blood picture have been found in the 3 species.
As an expression of the pharmacodynamic activity of ramipril, pronounced enlargement of the juxtaglomerular apparatus has been noted in the dog and monkey from daily doses of 250 mg/kg/d. Rats, dogs and monkeys tolerated daily doses of 2, 2.5 and 8 mg/kg/d respectively without harmful effects. Reproduction toxicology studies in the rat, rabbit and monkey did not disclose any teratogenic properties. Fertility was not impaired either in male or in female rats.
The administration of ramipril to female rats during the foetal period and lactation produced irreversible renal damage (dilatation of the renal pelvis) in the offspring at daily doses of 50 mg/kg body weight or higher.
Extensive mutagenicity testing using several test systems has yielded no indication that ramipril possesses mutagenic or genotoxic properties.
Irreversible kidney damage has been observed in very young rats given a single dose of ramipril.
Reproductive studies in rats and mice have shown delayed date of delivery, prolonged duration of labour and decreased pup survival at dosages approximately 50 times greater than the maximum recommended dosage for humans based on mg/kg.
There was no effect on the fertility of rats treated with amlodipine (males for 64 days and females 14 days prior to mating) at doses up to 10 mg/kg/day (8 times* the maximum recommended human dose of 10 mg on a mg/m² basis).
In another rat study in which male rats were treated with amlodipine besilate for 30 days at a dose comparable with the human dose based on mg/kg, decreased plasma follicle-stimulating hormone and testosterone were found as well as decreases in sperm density and in the number of mature spermatids and Sertoli cells.
Rats and mice treated with amlodipine in the diet for two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg/kg/day showed no evidence of carcinogenicity. The highest dose (for mice, similar to, and for rats twice* the maximum recommended clinical dose of 10 mg on a mg/m² basis) was close to the maximum tolerated dose for mice but not for rats.
Mutagenicity studies revealed no drug related effects at either the gene or chromosome levels.
* Based on patient weight of 50 kg.
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