Altace

[Ramipril]

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 five years) effects of ALTACE (10 mg orally once a day) 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 infarc-tion, stroke or death from cardiovascular causes (651/ 4645 vs. 826/ 4652, relative risk 0.78), as well as the rates of the 3 components of the combined endpoint.

Altace Placebo Relative Risk Outcome (N= 4645) (N= 4652) (95% CI) no. (%) P value Combined End-point (MI, stroke, or 651 (14.0%) 826 (17.8%) 0.78 (0.70Ð 0.86), P= 0.0001 death from CV cause) Component End-point Death from 282 (6.1%) 377 (8.1%) 0.74 (0.64Ð 0.87), P= 0.0002 Cardiovascular Causes Myocardial infarction 459 (9.9%) 570 (12.3%) 0.80 (0.70Ð 0.90), P= 0.0003 Stroke 156 (3.4%) 226 (4.9%) 0.68 (0.56Ð 0.84), P= 0.0002 Overall Mortality (Death from any Cause) 482 (10.4%) 569 (12.2%) 0.84 (0.75Ð 0.95), P= 0.005

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This effect was evident after about one year of treatment. Figure 1: (Not Available)

Kaplan-Meier Estimates of the composite outcome of MI, Stroke, or Death from CV causes in the Ramipril Group and the Placebo Group. The relative risk of the composite outcomes in the Ramipril Group as compared with the Placebo Group was 0.78% (95% confidence interval, 0.70Ð 0.86).

Ramipril 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 ramipril 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 ramipril on the combined endpoint and its components were similar in diabetics (n= 3,577) to those in the overall study population.

Altace Placebo Relative Outcome (N= 1808) (N= 1769) Risk Reduction no. (%) (95% CI) Combined End-point (MI, stroke, or 277 (15.3%) 351 (19.8%) 0.25 (0.12Ð 0.36), P= 0.0004 death from CV cause) Component End-point Death from 112 (6.2%) 172 (9.7%) 0.37 (0.21Ð 0.51), P= 0.0001 Cardiovascular Causes Myocardial infarction 185 (10.2%) 229 (12.9%) 0.22 (0.06Ð 0.36), P= 0.01 Stroke 76 (4.2%) 108 (6.1%) 0.33 (0.10Ð 0.50), P= 0.007 Figure 2. The Beneficial Effect of Treatment with Ramipril on the Composite Outcome of Myocardial Infarction, Stroke, or Death from Cardiovascular Causes Overall and in Various Subgroups. Cerebrovascular disease was defined as stroke or transient ischemic attacks. The size of each symbol is proportional to the num-ber 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.

Hypertension

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.) 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 5Ð 20 mg of ALTACE lowered blood pressure within 1Ð 2 hours, with peak reductions achieved 3Ð 6 hours after dosing. The antihypertensive effect of a single dose persisted for 24 hours. In longer term (4Ð 12 weeks) controlled studies, once-daily doses of 2.5Ð 10 mg were similar in their effect, lowering supine or standing systolic and diastolic blood pressures 24 hours after dosing by about 6/ 4 mm Hg more than placebo. In comparisons of peak vs. trough effect, the trough effect represented about 50Ð 60% of the peak response. In a titration study comparing divided (bid) vs. qd treatment, the divided reg-imen was superior, indicating that for some patients the antihypertensive effect with once-daily dosing is not adequately maintained. (See DOSAGE AND ADMINISTRATION.) 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 thera-py 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. It was approx-imately as effective as other ACE inhibitors and as atenolol. In both caucasians and blacks, hydrochloroth-iazide (25 or 50 mg) was significantly more effective than ramipril. Except for thiazides, no formal interaction studies of ramipril with other antihypertensive agents have been carried out. Limited experience in controlled and uncontrolled trials combining ramipril with a calcium chan-nel blocker, a loop diuretic, or triple therapy (beta-blocker, vasodilator, and a diuretic) indicate no unusual drug-drug interactions. Other ACE inhibitors have had less than additive effects with beta adrenergic blockers, pre-sumably because both drugs lower blood pressure by inhibiting parts of the renin-angiotensin system. 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.

Heart Failure Post Myocardial Infarction

ALTACE was studied in the Acute Infarction Ramipril Efficacy (AIRE) trial. This was a multinational (main-ly European) 161-center, 2006-patient, double-blind, randomized, parallel-group study comparing ALTACE to placebo in stable patients, 2Ð 9 days after an acute myocardial infarction (MI), who had shown clinical signs of congestive heart failure (CHF) at any time after the MI. Patients in severe (NYHA class IV) heart failure, patients with unstable angina, patients with heart failure of congenital or valvular etiology, and patients with contraindications to ACE inhibitors were all excluded. The majority of patients had received thrombolytic ther-apy at the time of the index infarction, and the average time between infarction and initiation of treatment was 5 days.

Patients randomized to ramipril treatment were given an initial dose of 2.5 mg twice daily. If the initial reg-imen caused undue hypotension, the dose was reduced to 1.25 mg, but in either event doses were titrated upward (as tolerated) to a target regimen (achieved in 77% of patients randomized to ramipril) of 5 mg twice daily. Patients were then followed for an average of 15 months (range 6Ð 46). The use of ALTACE was associated with a 27% reduction (p= 0.002), in the risk of death from any cause; about 90% of the deaths that occurred were cardiovascular, mainly sudden death. The risks of progression to severe heart failure and of CHF-related hospitalization were also reduced, by 23% (p= 0.017) and 26% (p= 0.011), respectively.

The benefits of ALTACE therapy were seen in both genders, and they were not affected by the exact timing of the initiation of therapy, but older patients may have had a greater benefit than those under 65. The benefits were seen in patients on, and not on, various concomitant medications; at the time of randomization these included aspirin (about 80% of patients), diuretics (about 60%), organic nitrates (about 55%), beta-blockers (about 20%), calcium channel blockers (about 15%), and digoxin (about 12%).

Prescribing Information as of February 2003. ALTACE ® Capsules (ramipril)

USE IN PREGNANCY

When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, ALTACE ® should be discontinued as soon as possible. See WARNINGS: Fetal/ neonatal morbidity and mortality.

PRECAUTIONS

Impaired Renal Function:

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin converting enzyme inhibitors, including ALTACE, may be associated with oliguria and/ or pro-gressive azotemia and (rarely) with acute renal failure and/ or death.

In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine may occur. Experience with another angiotensin converting enzyme inhibitor suggests that these increases are usually reversible upon discontinuation of ALTACE and/ or diuretic therapy. In such patients renal function should be monitored during the first few weeks of therapy. Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea nitrogen and serum crea-tinine, usually minor and transient, especially when ALTACE has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of ALTACE and/ or dis-continuation of the diuretic may be required. Evaluation of the hypertensive patient should always include assessment of renal function. (See DOSAGE AND ADMINISTRATION.)

Hyperkalemia:

In clinical trials, hyperkalemia (serum potassium greater than 5.7 mEq/ L) occurred in approx-imately 1% of hypertensive patients receiving ALTACE (ramipril). In most cases, these were isolated values, which resolved despite continued therapy. None of these patients was discontinued from the trials because of hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/ or potassium-containing salt substitutes, which should be used cautiously, if at all, with ALTACE. (See Drug Interactions.)

Cough:

Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonpro-ductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Impaired Liver Function:

Since ramipril is primarily metabolized by hepatic esterases to its active moiety, ramiprilat, patients with impaired liver function could develop markedly elevated plasma levels of ramipril. No formal pharmacokinetic studies have been carried out in hypertensive patients with impaired liver function. However, since the renin-angiotensin system may be activated in patients with severe liver cirrhosis and/ or ascites, particular caution should be exercised in treating these patients.

Surgery/ Anesthesia:

In patients undergoing surgery or during anesthesia with agents that produce hypoten-sion, ramipril may block angiotensin II formation that would otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion.

OVERDOSAGE

Single oral doses in rats and mice of 10Ð 11 g/ kg resulted in significant lethality. In dogs, oral doses as high as 1 g/ kg induced only mild gastrointestinal distress. Limited data on human overdosage are available. The most likely clinical manifestations would be symptoms attributable to hypotension. Laboratory determinations of serum levels of ramipril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of ramipril overdose. No data are available to suggest physiological maneuvers (e. g., maneuvers to change the pH of the urine) that might accelerate elimination of ramipril and its metabolites. Similarly, it is not known which, if any, of these substances can be usefully removed from the body by hemodialysis. Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of ramipril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of ramipril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat ramipril overdose by infusion of normal saline solution.

In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor thera-py may cause excessive hypotension, which may be associated with oliguria or azotemia and, rarely, with acute renal failure and death. In such patients, ALTACE therapy should be started under close medical supervision; they should be followed closely for the first 2 weeks of treatment and whenever the dose of ramipril or diuret-ic is increased.

If hypotension occurs, the patient should be placed in a supine position and, if necessary, treated with intra-venous infusion of physiological saline. ALTACE treatment usually can be continued following restoration of blood pressure and volume.

Hepatic Failure

Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and pro-gresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not under-stood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.

Neutropenia/ Agranulocytosis

As with other ACE inhibitors, rarely, a mild Ð in isolated cases severe Ð reduction in the red blood cell count and hemoglobin content, white blood cell or platelet count may develop. In isolated cases, agranulocytosis, pancytopenia, and bone marrow depression may occur.

Hematological reactions to ACE inhibitors are more likely to occur in patients with collagen vascular disease (e. g. systemic lupus erythematosus, scleroderma) and renal impairment. Monitoring of white blood cell counts should be considered in patients with collagen-vascu-lar disease, especially if the disease is associated with impaired renal function.

Fetal/ Neonatal Morbidity and Mortality

ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, ACE inhibitors should be discontinued as soon as possible. The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death.

Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development.

Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACE inhibitor exposure.

These adverse effects do not appear to have resulted from intrauterine ACE inhibitor exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to ACE inhibitors only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should make every effort to discontinue the use of ALTACE as soon as possible.

Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and seri-al ultrasound examinations should be performed to assess the intraamniotic environment. If oligohydramnios is observed, ALTACE should be discontinued unless it is considered life-saving for the mother.

Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appro-priate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligo-hydramnios may not appear until after the fetus has sustained irreversible injury. Infants with histories of in utero exposure to ACE inhibitors should be closely observed for hypotension, olig-uria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/ or substituting for disordered renal function.

ALTACE which crosses the placenta can be removed from the neonatal circulation by these means, but limited experience has not shown that such removal is central to the treatment of these infants. No teratogenic effects of ALTACE 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.

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