ALTACE (Page 6 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of a tumorigenic effect was found when ramipril was given by gavage to rats for up to 24 months at doses of up to 500 mg/kg/day or to mice for up to 18 months at doses of up to 1000 mg/kg/day. (For either species, these doses are about 200 times the maximum recommended human dose when compared on the basis of body surface area.) No mutagenic activity was detected in the Ames test in bacteria, the micronucleus test in mice, unscheduled DNA synthesis in a human cell line, or a forward gene-mutation assay in a Chinese hamster ovary cell line. Several metabolites and degradation products of ramipril were also negative in the Ames test. A study in rats with dosages as great as 500 mg/kg/day did not produce adverse effects on fertility.

No teratogenic effects of ramipril were seen in studies of pregnant rats, rabbits, and cynomolgus monkeys. On a body surface area basis, the doses used were up to approximately 400 times (in rats and monkeys) and 2 times (in rabbits) the recommended human dose.

14 CLINICAL STUDIES

14.1 Hypertension

ALTACE has been compared with other ACE inhibitors, beta-blockers, and thiazide diuretics as monotherapy for hypertension. It was approximately as effective as other ACE inhibitors and as atenolol.

Administration of ALTACE to patients with mild to moderate hypertension results in a reduction of both supine and standing blood pressure to about the same extent with no compensatory tachycardia. Symptomatic postural hypotension is infrequent, although it can occur in patients who are salt- and/or volume-depleted [see Warnings and Precautions (5.5)]. Use of ALTACE in combination with thiazide diuretics gives a blood pressure lowering effect greater than that seen with either agent alone.

In single-dose studies, doses of 5 mg–20 mg of ALTACE lowered blood pressure within 1–2 hours, with peak reductions achieved 3–6 hours after dosing. The antihypertensive effect of a single dose persisted for 24 hours. In longer term (4–12 weeks) controlled studies, once-daily doses of 2.5 mg–10 mg were similar in their effect, lowering supine or standing systolic and diastolic blood pressures 24 hours after dosing by about 6/4 mmHg more than placebo. In comparisons of peak vs. trough effect, the trough effect represented about 50–60% of the peak response. In a titration study comparing divided (bid) vs. qd treatment, the divided regimen was superior, indicating that for some patients, the antihypertensive effect with once-daily dosing is not adequately maintained.

In most trials, the antihypertensive effect of ALTACE increased during the first several weeks of repeated measurements. The antihypertensive effect of ALTACE has been shown to continue during long-term therapy for at least 2 years. Abrupt withdrawal of ALTACE has not resulted in a rapid increase in blood pressure. ALTACE has been compared with other ACE inhibitors, beta-blockers, and thiazide diuretics. ALTACE was approximately as effective as other ACE inhibitors and as atenolol. In both Caucasians and Blacks, hydrochlorothiazide (25 or 50 mg) was significantly more effective than ramipril.

ALTACE was less effective in blacks than in Caucasians. The effectiveness of ALTACE was not influenced by age, sex, or weight.

In a baseline controlled study of 10 patients with mild essential hypertension, blood pressure reduction was accompanied by a 15% increase in renal blood flow. In healthy volunteers, glomerular filtration rate was unchanged.

14.2 Reduction in Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes

The HOPE study was a large, multicenter, randomized, double-blind, placebo-controlled, 2 × 2 factorial design study conducted in 9541 patients (4645 on ALTACE) who were 55 years or older and considered at high risk of developing a major cardiovascular event because of a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes that was accompanied by at least one other cardiovascular risk factor (hypertension, elevated total cholesterol levels, low HDL levels, cigarette smoking, or documented microalbuminuria). Patients were either normotensive or under treatment with other antihypertensive agents. Patients were excluded if they had clinical heart failure or were known to have a low ejection fraction (<0.40). This study was designed to examine the long-term (mean of 5 years) effects of ALTACE (10 mg orally once daily) on the combined endpoint of myocardial infarction, stroke, or death from cardiovascular causes.

The HOPE study results showed that ALTACE (10 mg/day) significantly reduced the rate of myocardial infarction, stroke, or death from cardiovascular causes (826/4652 vs. 651/4645, relative risk 0.78), as well as the rates of the 3 components of the combined endpoint. The relative risk of the composite outcomes in the ALTACE group as compared to the placebo group was 0.78% (95% confidence interval, 0.70–0.86). The effect was evident after about 1 year of treatment.

Table 3. Summary of Combined Components and Endpoints—HOPE Study
OutcomePlacebo(N=4652)n (%)ALTACE (N=4645)n (%)Relative Risk (95% CI) P-Value
Combined Endpoint
Myocardial infarction, stroke, or death from cardiovascular cause826 (17.8%)651 (14.0%)0.78 (0.70–0.86)P=0.0001
Component Endpoint
Death from cardiovascular causes377 (8.1%)282 (6.1%)0.74 (0.64–0.87)P=0.0002
Myocardial infarction570 (12.3%)459 (9.9%)0.80 (0.70–0.90)P=0.0003
Stroke226 (4.9%)156 (3.4%)0.68 (0.56–0.84)P=0.0002
Overall Mortality
Death from any cause569 (12.2%)482 (10.4%)0.84 (0.75–0.95)P=0.005

Figure 1. Kaplan-Meier Estimates of the Composite Outcome of Myocardial Infarction, Stroke, or Death from Cardiovascular Causes in the Ramipril Group and the Placebo Group

Figure 1
(click image for full-size original)

ALTACE was effective in different demographic subgroups (i.e., gender, age), subgroups defined by underlying disease (e.g., cardiovascular disease, hypertension), and subgroups defined by concomitant medication. There were insufficient data to determine whether or not ALTACE was equally effective in ethnic subgroups.

This study was designed with a prespecified substudy in diabetics with at least one other cardiovascular risk factor. Effects of ALTACE on the combined endpoint and its components were similar in diabetics (N=3577) to those in the overall study population.

Table 4. Summary of Combined Endpoints and Components in Diabetics—HOPE Study
OutcomePlacebo(N=1769)n (%)ALTACE (N=1808)n (%)Relative Risk Reduction(95% CI) P-Value
Combined Endpoint
Myocardial infarction, stroke, or death from cardiovascular cause351 (19.8%)277 (15.3%)0.25 (0.12–0.36)P=0.0004
Component Endpoint
Death from cardiovascular causes172 (9.7%)112 (6.2%)0.37 (0.21–0.51)P=0.0001
Myocardial infarction229 (12.9%)185 (10.2%)0.22 (0.06–0.36)P=0.01
Stroke108 (6.1%)76 (4.2%)0.33 (0.10–0.50)P=0.007

Figure 2. The Beneficial Effect of Treatment with ALTACE on the Composite Outcome of Myocardial Infarction, Stroke, or Death from Cardiovascular Causes Overall and in Various Subgroups

Figure 2
(click image for full-size original)

Cerebrovascular disease was defined as stroke or transient ischemic attacks. The size of each symbol is proportional to the number of patients in each group. The dashed line indicates overall relative risk.

The benefits of ALTACE were observed among patients who were taking aspirin or other anti-platelet agents, beta-blockers, and lipid-lowering agents as well as diuretics and calcium channel blockers.

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