Source: Health Products and Food Branch (CA) Revision Year: 2006
RAMACE (ramipril) is an angiotensin converting enzyme (ACE) inhibitor, which is used in the treatment of essential hypertension, following acute myocardial infarction in stabilized patients with clinically confirmed heart failure, and for the management of patients at increased risk of cardiovascular events.
Following oral administration, RAMACE is rapidly hydrolyzed to ramiprilat, 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 decrease may result in a small increase in serum potassium (see PRECAUTIONS). Decreased levels of angiotensin II and the accompanying lack of negative feedback on renal renin secretion result in increases in plasma renin activity.
ACE is identical to kininase II. Thus, ramipril may also block the degradation of the vasodepressor peptide bradykinin, which may contribute to its therapeutic effect.
Following oral administration, ramipril is rapidly absorbed with peak plasma concentrations occurring within 1 hour. The extent of absorption of ramipril is 50-60% and is not significantly altered by the presence of food in the gastrointestinal tract, although the rate of absorption is reduced. Following absorption, ramipril is rapidly hydrolyzed in the liver to its active metabolite, ramiprilat. Peak plasma concentrations of ramiprilat are reached 2-4 hours after drug intake. The serum protein binding of ramipril is about 73% and that of ramiprilat is 56%.
Ramipril is almost completely metabolized to the active metabolite ramiprilat, and to the diketopiperazine ester, the diketopiperazine acid, and the glucuronides of ramipril and ramiprilat, all of which are inactive. After oral administration of RAMACE, about 60% of the parent drug and its metabolites is excreted in the urine, and about 40% is found in the feces. Drug recovered in the feces may represent both biliary excretion of metabolites and/or unabsorbed drug. Less than 2% of the administered dose is recovered in urine as unchanged ramipril.
Following a single administration of up to 5 mg of Ramipril, plasma concentrations of ramipril and ramiprilat increase in a manner that is greater than proportional to dose; after a single administration of 5 mg to 20 mg of ramipril the plasma concentrations for both are dose-proportional. The non-linear pharmacokinetics observed at the lower doses of ramipril can be explained by the saturable binding of ramiprilat to ACE. At steady-state, the 24-hour AUC for ramiprilat is dose-proportional over the recommended dose range. The absolute bioavailabilities of ramipril and ramiprilat were 28% and 44% respectively when 5mg of oral ramipril was compared to 5mg given intravenously.
Plasma concentrations of ramiprilat decline in a triphasic manner. The initial rapid decline, which represents distribution of the drug, has a half life of 2-4 hours. Because of its potent binding to ACE and slow dissociation from the enzyme, ramiprilat shows two elimination phases. The apparent elimination phase has a half-life of 9-18 hours, and the terminal elimination phase has a prolonged half-life of >50 hours. After multiple daily doses of ramipril 5-10mg, the half-life of ramiprilat concentrations was 13-17 hours, but was considerably prolonged at 2.5mg (27-36 hours).
After once daily dosing, steady state plasma concentrations of ramiprilat are reached by the fourth dose. Steady-state concentrations of ramiprilat are higher than those seen after the first dose of RAMACE especially at low doses (2.5mg).
The urinary excretion of ramipril, ramiprilat, and their metabolites is reduced in patients with impaired renal function. In patients with creatinine clearance < 40 ml/min/1.73m², increases in Cmax and AUC of ramipril and ramiprilat compared to normal subjects were observed following multiple dosing with 5mg ramipril (see DOSAGE AND ADMINISTRATION).
In patients with impaired liver function, plasma ramipril levels increased about 3-fold, although peak concentrations of ramiprilat in these patients were not different from those seen in patients with normal hepatic function.
A single dose pharmacokinetic study conducted in a limited number of elderly patients indicated that peak ramiprilat levels and the AUC for ramiprilat are higher in older patients (see PRECAUTIONS).
Administration of RAMACE to patients with mild to moderate essential hypertension results in a reduction of both supine and standing blood pressure usually with little or no orthostatic change or change in heart rate. Symptomatic postural hypotension is infrequent, although this may occur in patients who are salt-and/or volume-depleted (see WARNINGS).
In single dose studies, doses of 5-20 mg of RAMACE lowered blood pressure within 1-2 hours, with peak reductions achieved 3-6 hours after dosing. At recommended doses given once daily, antihypertensive effects have persisted over 24 hours. The effectiveness of RAMACE appears to be similar in the elderly (over 65 years of age) and younger adult patients given the same daily doses.
In studies comparing the same daily dose of RAMACE given as a single morning dose or as a twice daily dose, blood pressure reductions at the time of morning trough blood levels were greater with the divided regimen.
While the mechanism through which RAMACE lowers blood pressure appears to result primarily from suppression of the renin-angiotensin-aldosterone system, RAMACE has an antihypertensive effect even in patients with low-renin hypertension.
The antihypertensive effect of angiotension converting enzyme inhibitors is generally lower in black patients than in non-blacks.
The antihypertensive effect of RAMACE and thiazide diuretics used concurrently is greater than that seen with either agent used alone.
Abrupt withdrawal of RAMACE has not resulted in rapid increase in blood pressure.
The effects of ramipril were assessed in patients who were at high risk for cardiovascular events, but did not have left ventricular dysfunction or heart failure. Heart Outcome Prevention Evaluation (HOPE) study included 9297 patients older than 55 years of age with a history of coronary artery disease, stroke, peripheral vascular disease or diabetes mellitus plus at least one additional cardiovascular risk factor (hypertension, elevated total cholesterol levels, low high-density lipoprotein cholesterol levels, cigarette smoking, or documented microalbuminuria). Patients were excluded if they had heart failure, low ejection fraction (<0.40), were taking an angiotensin converting enzyme inhibitor or vitamin E, had uncontrolled hypertension or overt nephropathy, or had had a myocardial infarction or stroke within four weeks before the study began. The patients were randomly assigned to receive ramipril 10 mg once daily or matching placebo for a mean of five years.
Due to the positive outcome the study was terminated prematurely by an independent monitoring board. The primary end point, the composite of death from cardiovascular causes, myocardial infarction and stroke was reached by a total of 651 ramipril treated patients (14%), as compared to 826 placebo treated patients (17.8%) (relative risk, 0.78; P<0.001). When analyzed separately, the rates of individual component of the composite primary outcome in patients treated with ramipril and placebo were as follows: death from cardiovascular causes 6.1% vs. 8.1% (RR 0.74, p<0.001), myocardial infarction 9.9% vs. 12.3% (RR 0.80, p<0.001) and stroke 3.4% vs. 4.9% of patients (RR 0.68, p<0.001), respectively.
Permanent discontinuation of treatment occurred in 28.9% of the ramipril treated patients versus 27.3% of placebo treated patients. The reasons for stopping the treatment, where the incidence was greater in the ramipril than in the placebo group, were cough (ramipril 7.3%, placebo 1.8%), hypotension/dizziness (ramipril 1.9%, placebo 1.5%) and edema (ramipril 0.4%, placebo 0.2%).
Below are summarized species-specific LD50 values for both oral and intravenous
administrations of ramipril.
Table 1. Acute Toxicity:
| Routes | Species | Sex | LD50 |
|---|---|---|---|
| Oral | Mouse | Male | 10,933 mg/kg |
| Female | 10,048 mg/kg | ||
| Rat | Male | >10,000 mg/kg | |
| Female | >10,000 mg/kg | ||
| Dog | Male | >1,000 mg/kg | |
| Intravenous | Mouse | Male | 1,194 mg/kg |
| Female | 1,158 mg/kg | ||
| Rat | Male | 688 mg/kg | |
| Female | 609 mg/kg |
The symptoms observed in mice were decreased spontaneous activity, crouching, hypothermia, dyspnea, and clonic convulsions; deaths occurred within 30 minutes after intravenous and 24 hours after oral administration. In survivors, the symptoms disappeared by 1 to 5 days after administration; necropsies revealed no abnormality in any of the surviving animals. In rats, reduced spontaneous activity was noted (oral administration), while after intravenous administration similar signs occurred as in mice; the sign of lethal toxicity was clonic convulsions (intravenous administration).
Table 2. Chronic Toxicity:
| Species | Duration | No. of animals per group | Route | Dose (mg/kg/day) | Effects |
|---|---|---|---|---|---|
| Mouse | 28 days 90 days | 2M, 2F 3M, 3F | Oral | 1000 | Reduced erythrocytes, hemoglobin, hematocrit, increased reticulocytes. Hyperplasia of juxtaglomerular apparatus. |
| Rat | 30 days | 10-15M, 10-15F | Oral | 2.5, 80, 2500 | At all doses: decrease in body weight, reduced liver weight, increased kidney weight. At 80 & 2500 mg/kg/d: Reduced heart weight. At 2500 mg/kg/d: Reduced erythrocytes, hematocrit and bilirubin, increased BUN. |
| Rat | 3 months | 10-15M, 10-15F | Oral | 2.5, 80, 500 | At all doses: Reduced chloride and GOT, increased phosphorus and BUN. At 80 mg/kg/d: Reduced heart, liver, prostate weight, increased kidney weight. Atrophic segments of renal tubules. Increased serum creatinine. At 500 mg/kg/d: Reduced body and heart weight, increased kidney and adrenal weight. Reduced erythrocytes, hemoglobin, hematocrit, increased bilirubin. Increased number of atrophic renal tubular segments. Moderate gastric mucosa necroses. |
| Rat | 3 months | 10M, 10F | Oral | 500, â…“ Ringer solution for drinking | Increased number of tubular atrophies. |
| Rat | 6 months | 10-20M, 10-20F | Oral | 0.1, 0.25, 3.2, 40, 500 | At all doses: Serum bilirubin increased, reduced heart weight. At 40 and 500 mg/kg/d: Increased kidney weight. Reduced erythrocytes, hemoglobin, hematocrit, increased BUN. Distal tubular atrophies, fibromuscular pad formations in gastric mucosa/muscularis not proliferative in nature. |
| Rat | 6 months | 20M, 20F | Oral | 3.2, 40, 500, 1/3 Ringer solution for drinking | All doses: Fibromuscular or solitary pad formation in gastric fundus mucosa/muscularis. |
| Rat | 18 months | 20-25M, 20-25F | Oral | 0.25, 3.2, 40, 500 | At 3.2 to 500 mg/kg/d: Fibromuscular pads in gastric fundus mucosa, focal atrophies in renal cortex, partly with cysts. At 40 and 500 mg/kg/d: Anemia, increased BUN and serum creatinine, urinary epithelial cells. Reduced heart weight and increased kidney and adrenal weight. |
| Dog | 30 days | 2M, 2F | Oral | 3.2, 32 | No pathological findings. |
| Dog | 3 months | 3-4M, 3-4F | Oral | 3.2, 32, 320 | At 320 mg/kg/d: Anemia, increased BUN and serum creatinine, impaired erythropoiesis. Juxtaglomerular hyperplasia. |
| Dog | 6 months | 6M, 6F | Oral | 3.2, 32, 320 | At 32 mg/kg/d: Anemia, juxtaglomerular hyperplasia. At 320 mg/kg/d: Reduced body weight. Increased BUN and serum creatinine. Distal tubular atrophies with round cell infiltrations. Anemia, juxtaglomerular hyperplasia. |
| Dog | 12 months | 6M, 6F | Oral | 2.5, 25, 250 | At all doses: Reduced body weight. At 25 and 250 mg/kg/d: Anemia and leukopenia, impaired erythropoiesis, increased hemosiderin deposition in liver and spleen, juxtaglomerular hyperplasia. At 250 mg/kg/d: Increased BUN and serum creatinine. |
| Monkey | 6 months | 4-5M, 4-5F | Oral | 0.5, 16, 500 | At 16 and 500 mg/kg/d: Increased BUN, juxtaglomerular hyperplasia. Reduced body weight. At 500 mg/kg/d: Diarrhea, anemia, increased serum creatinine, some urinary casts, leukocytes and epithelial cells. |
| Monkey | 6 months | 5M 5F | Oral | 2,8 | No pathological findings. |
Table 3. Reproduction and Teratology:
| Species | No. of animals per group | Dose (mg/kg/day) | Duration of dosing | Results |
|---|---|---|---|---|
| Rat (Wistar) | 32M, 32F | 5, 50, 500 | M 60 days before mating F14 days before mating to end of lactation | At 50 and 500 mg/kg/d: Parents renal pelvis enlargement, off-spring light brown discoloration of kidney tissue and dilatation of renal pelvis. At 500 mg/kg/d: Parents yellow-white coloring and induration of renal marrow. Fertility normal. |
| Rat (Wistar) | 20F | 10, 100, 1000 | Days 7-17 of gestation | At 1000 mg/kg/d: Reduced food consumption of mothers, reduced body weight gains of young. One young circular non-ossified area in supraoccipital bone, 1 young distortion of right scapula. No teratogenic effects. |
| Rat (Wistar) | 20-30F | 0.32, 1.25, 5, 10, 100, 1000 | Day 17 of gestation to day 21 of lactation | At 100 and 1000 mg/kg/d: Decreased gestation body weight of young, enlarged to day 21 renal pelvis up to hydronephrosis with light brown coloring of renal cortex and marrow. |
| Rat (Sprague-Dawley) | 20F | 100 | Day 17 of gestation to day 21 of lactation | Young: Enlarged renal pelvis and light brown coloration of kidney tissue. |
| Rabbit (Himalayan) | 15F | 0.4, 1, 2.5 | Day 6 to day 18 of gestation | At 0.4 mg/kg/d: One abortion, one fetus with diaphragm hernia. At 1 mg/kg/d: One abortion, one premature delivery, two animals died, no animals gained weight. One dead fetus with possible hydrocephalus. At 2.5 mg/kg/d: Two animals died, no animals gained weight, one fetus with diaphragm hernia, one with first cervical aplasia and aplasia of one thorax vertebra and one rib pair. |
| Monkey (Cynomolgus) | 4-13F | 5, 50, 500 | Days 20-25 of gestation | At all doses: No sign of terato-genesis. At 5 mg/kg/d: Two abortions, seven diarrhea, two vomiting, ten weight loss. At 50 mg/kg/d: One animal died, three abortions, seven diarrhea, two vomiting, ten weight loss. At 500 mg/kg/d: Three animals died, one abortion, four weight loss, four vomiting, four diarrhea. |
Ramipril was not mutagenic in the Ames microbial mutagen test, the HGPRT test in V79 cells, the micronucleus test in mice and the UDS test in human A549 cells.
There was no evidence of a carcinogenic effect when ramipril was administered for 104 weeks to NMRI mice at doses up to 1000 mg/kg/day and to Wistar rats at doses up to 500 mg/kg/day.
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