FDA clears Merck's Prinivil to save lives when initiated in patients 24 hours after heart attack.

WEST POINT, Pa.--(BUSINESS WIRE)--Nov. 28, 1995--The U.S. Food and Drug Administration Tuesday cleared lisinopril, marketed as Prinivil(R) by Merck & Co. Inc., as the first drug in its class that can save lives when used in hemodynamically stable patients within 24 hours of heart attack.

Prinivil is one in a class of drugs called angiotensin-converting enzyme (ACE) inhibitors.

"Early treatment with Prinivil after acute heart attack has been shown to improve survival," said Alan G. Wasserman, M.D., director of the Division of Cardiology and professor of medicine and associate chairman of the Department of Medicine at George Washington University School of Medicine, Washington, D.C.

"The FDA's clearance of the drug for this new use adds to the mounting evidence that Prinivil can benefit a wide range of patients with cardiovascular conditions, including high blood pressure, congestive heart failure, and now, heart attack -- the nation's leading killer."

The drug may be used in appropriate patients after heart attack in combination with standard therapy such as thrombolytics (clot breakers), aspirin or intravenous beta-blockers.

The new indication is based on findings from GISSI-3, a randomized clinical trial involving 19,394 patients with acute heart attack at 200 medical centers throughout Italy. In the study, patients who received lisinopril alone or with nitrates within 24 hours of onset of heart attack symptoms in addition to standard therapy had an 11 percent lower risk of death after six weeks, compared to patients receiving no lisinopril.

Among the group of patients receiving lisinopril, the six-week mortality rate was 6.4 percent, compared with 7.2 percent in the patients receiving no lisinopril.

"This reduction in mortality found with the addition of Prinivil to standard therapy is very important because it is above and beyond the reduction achieved with standard therapies known to have demonstrated life-saving benefits," said Louis M. Sherwood, M.D., senior vice president, Merck Scientific and Medical Affairs.

Patients in the GISSI-3 study who received lisinopril and transdermal nitrate together experienced an even more dramatic reduction in death -- 17 percent -- compared with the group receiving standard therapy alone. In contrast, patients who received transdermal nitrate with standard therapy experienced a 2.8 percent reduction.

GISSI-3, entitled "Effects of lisinopril and transdermal glyceryl trinitrate singly and together on six-week mortality and vertricular function after acute myocardial infarction" and published in The Lancet on May 7, 1994, is the first trial to evaluate the short-term effects of administering lisinopril within the first 24 hours after a heart attack.

GISSI-3 differs from previous trials with other ACE inhibitors in that it studied the effect of the drug in a wide variety of hemodynamically stable patients who suffered heart attacks, ranging from patients with no previously known heart damage to those with various degrees of heart damage.

In contrast, other studies looked at the effect of a drug in particular sets of high-risk patients, such as those who already had heart failure or reduced ejection fraction. The findings of GISSI-3 therefore potentially suggest benefits for a broader set of patients than other studies have suggested.

Heart attack is the single largest killer of American males and females. Of the 1.5 million Americans who have heart attacks each year, about a third of them die as a result.

In addition to the new use, Prinivil is indicated for the treatment of all degrees of high blood pressure and can be used either alone or in combination with other therapies for high blood pressure. It is also indicated as adjunctive therapy to diuretics and digitalis in the management of heart failure in patients who are not responding adequately to those drugs.

Prinivil is an ACE inhibitor, a class of drugs prescribed to more than 6 million patients in the United States, primarily for the treatment of high blood pressure or congestive heart failure.

Prinivil is contraindicated in patients who are hypersensitive to any component of the medication and in patients with a history of angioedema related to previous treatment with an ACE inhibitor. ACE inhibitors should not be used by pregnant women in their second or third trimesters.

Like all ACE inhibitors, Prinivil should be discontinued as soon as pregnancy is detected because of concerns about its effects on the unborn child. As with other ACE inhibitors, Prinivil has also caused headache, dizziness and cough, and in rare cases, angioedema, a potentially dangerous swelling of the mouth and throat.

In controlled clinical trials, ACE inhibitors have been shown to have an effect on blood pressure that is less in Black patients than in non Black patients. In addition, Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema than non Blacks.

In GISSI-3, patients treated with lisinopril alone or in combination with nitrate had a higher incidence of persistent low blood pressure (9.0 percent versus 3.7 percent) and renal dysfunction (2.4 percent versus 1.1 percent) in the hospital and after six weeks. However, the increased incidence of low blood pressure in patients treated with lisinopril did not affect mortality.

For patients receiving Prinivil following heart attack, the first dosing is 5 mg given orally followed by 5 mg after 24 hours, 10 mg after 48 hours and then 10 mg once daily thereafter. Dosing should continue for six weeks.

Prinivil (lisinopril) was discovered and developed by Merck.

Merck & Co. Inc. is a leading research-driven pharmaceutical products and services company. Merck discovers, develops, manufactures and markets a broad range of innovative products to improve human and animal health. -0- Prinivil is the Merck registered trademark for lisinopril. Full prescribing information for Prinivil (lisinopril) is attached. -0- TABLETS PRINIVIL(R) (LISINOPRIL)

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, PRINIVIL should be discontinued as soon as possible. See WARNINGS, Fetal/Neonatal Morbidity and Mortality.

DESCRIPTION

PRINIVIL(a)(Lisinopril), a synthetic peptide derivative, is an oral long-acting angiotensin converting enzyme inhibitor. Lisinopril is chemically described as (S)-1-(N2-(1-carboxy-3-phenylp ropyl)-L-lysyl)-L-proline dihydrate. Its empirical formula is C21H31N3O5 2H2O and its structural formula is:

(structure here)

Lisinopril is a white to off-white, crystalline powder, with a molecular weight of 441.52. It is soluble in water and sparingly soluble in methanol and practically insoluble in ethanol.

PRINIVIL is supplied as 2.5 mg, 5 mg, 10 mg, 20 mg and 40 mg tablets for oral administration. In addition to the active ingredient lisinopril, each tablet contains the following inactive ingredients: calcium phosphate, mannitol, magnesium stearate, and starch. The 10 mg, 20 mg and 40 mg tablets also contain iron oxide.

CLINICAL PHARMACOLOGY Mechanism of Action

Lisinopril inhibits angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. The beneficial effects of lisinopril in hypertension and heart failure appear to result primarily from suppression of the renin-angiotensin-aldosterone system. Inhibition of ACE results in decreased plasma angiotensin II which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. In hypertensive patients with normal renal function treated with PRINIVIL alone for up to 24 weeks, the mean increase in serum potassium was approximately 0.1 mEq/L; however, approximately 15 percent of patients had increases greater than 0.5 mEq/L and approximately six percent had a decrease greater than 0.5 mEq/L. In the same study, patients treated with PRINIVIL and hydrochlorothiazide for up to 24 weeks had a mean decrease in serum potassium of 0.1 mEq/L; approximately 4 percent of patients had increases greater than 0.5 mEq/L and approximately 12 percent had a decrease greater than 0.5 mEq/L. (See PRECAUTIONS.) Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity.

ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of PRINIVIL remains to be elucidated.

While the mechanism through which PRINIVIL lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, PRINIVIL is antihypertensive even in patients with low-renin hypertension. Although PRINIVIL was antihypertensive in all races studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to monotherapy than non-black patients. Concomitant administration of PRINIVIL and hydrochlorothiazide further reduced blood pressure in black and non-black patients and any racial difference in blood pressure response was no longer evident.

Pharmacokinetics and Metabolism

Following oral administration of PRINIVIL, peak serum concentrations of lisinopril occur within about 7 hours, although there was a trend to a small delay in time taken to reach peak serum concentrations in acute myocardial infarction patients. Declining serum concentrations exhibit a prolonged terminal phase which does not contribute to drug accumulation. This terminal phase probably represents saturable binding to ACE and is not proportional to dose. Lisinopril does not appear to be bound to other serum proteins. Lisinopril does not undergo metabolism and is excreted unchanged entirely in the urine. Based on urinary recovery, the mean extent of absorption of lisinopril is approximately 25 percent, with large inter-subject variability (6-60 percent) at all doses tested (5-80 mg). Lisinopril absorption is not influenced by the presence of food in the gastrointestinal tract. The absolute bioavailability of lisinopril is reduced to about 16% in patients with stable NYHA Class II-IV congestive heart failure, and the volume of distribution appears to be slightly smaller than that in normal subjects.

The oral bioavailability of lisinopril in patients with acute myocardial infarction is similar to that in healthy volunteers.

Upon multiple dosing, lisinopril exhibits an effective half-life of accumulation of 12 hours.

Impaired renal function decreases elimination of lisinopril, which is excreted principally through the kidneys, but this decrease becomes clinically important only when the glomerular filtration rate is below 30 mL/min. Above this glomerular filtration rate, the elimination half-life is little changed. With greater impairment, however, peak and trough lisinopril levels increase, time to peak concentration increases and time to attain steady state is prolonged. Older patients, on average, have (approximately doubled) higher blood levels and area under the plasma concentration time curve (AUC) than younger patients. (See DOSAGE AND ADMINISTRATION.) Lisinopril can be removed by hemodialysis.

Studies in rats indicate that lisinopril crosses the blood-brain barrier poorly. Multiple doses of lisinopril in rats do not result in accumulation in any tissues. Milk of lactating rats contains radioactivity following administration of 14C lisinopril. By whole body autoradiography, radioactivity was found in the placenta following administration of labeled drug to pregnant rats, but none was found in the fetuses.

Pharmacodynamics and Clinical Effects

Hypertension: Administration of PRINIVIL to patients with hypertension results in a reduction of supine and standing blood pressure to about the same extent with no compensatory tachycardia. Symptomatic postural hypotension is usually not observed although it can occur and should be anticipated in volume and/or salt-depleted patients. (See WARNINGS.) When given together with thiazide-type diuretics, the blood pressure lowering effects of the two drugs are approximately additive.

In most patients studied, onset of antihypertensive activity was seen at one hour after oral administration of an individual dose of PRINIVIL, with peak reduction of blood pressure achieved by six hours. Although an antihypertensive effect was observed 24 hours after dosing with recommended single daily doses, the effect was more consistent and the mean effect was considerably larger in some studies with doses of 20 mg or more than with lower doses. However, at all doses studied, the mean antihypertensive effect was substantially smaller 24 hours after dosing than it was six hours after dosing.

In some patients achievement of optimal blood pressure reduction may require two to four weeks of therapy.

The antihypertensive effects of PRINIVIL are maintained during long-term therapy. Abrupt withdrawal of PRINIVIL has not been associated with a rapid increase in blood pressure or a significant increase in blood pressure compared to pretreatment levels.

Two dose-response studies utilizing a once daily regimen were conducted in 438 mild to moderate hypertensive patients not on a diuretic. Blood pressure was measured 24 hours after dosing. An antihypertensive effect of PRINIVIL was seen with 5 mg in some patients. However, in both studies blood pressure reduction occurred sooner and was greater in patients treated with 10, 20, or 80 mg of PRINIVIL. In controlled clinical studies, PRINIVIL 20-80 mg has been compared in patients with mild to moderate hypertension to hydrochlorothiazide 12.5-50 mg and with atenolol 50-500 mg; and in patients with moderate to severe hypertension to metoprolol 100-200 mg. It was superior to hydrochlorothiazide in effects on systolic and diastolic blood pressure in a population that was > caucasian. PRINIVIL was approximately equivalent to atenolol and metoprolol in effects on diastolic blood pressure and had somewhat greater effects on systolic blood pressure.

PRINIVIL had similar effectiveness and adverse effects in younger and older (>65 years) patients. It was less effective in blacks than in caucasians.

In hemodynamic studies in patients with essential hypertension, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance with little or no change in cardiac output and in heart rate. In a study in nine hypertensive patients, following administration of PRINIVIL, there was an increase in mean renal blood flow that was not significant. Data from several small studies are inconsistent with respect to the effect of PRINIVIL on glomerular filtration rate in hypertensive patients with normal renal function, but suggest that changes, if any, are not large.

In patients with renovascular hypertension PRINIVIL has been shown to be well tolerated and effective in controlling blood pressure (see PRECAUTIONS).

Heart Failure: During baseline-controlled clinical trials, in patients receiving digitalis and diuretics, single doses of PRINIVIL resulted in decreases in pulmonary capillary wedge pressure, systemic vascular resistance and blood pressure accompanied by an increase in cardiac output and no change in heart rate.

In two placebo controlled, 12-week clinical studies, PRINIVIL as adjunctive therapy to digitalis and diuretics improved the following signs and symptoms due to congestive heart failure: edema, rales, paroxysmal nocturnal dyspnea and jugular venous distention. In one of the studies beneficial response was also noted for: orthopnea, presence of third heart sound and the number of patients classified as NYHA Class III and IV. Exercise tolerance was also improved in this study. The effect of lisinopril on mortality in patients with heart failure has not been evaluated.

Acute Myocardial Infarction: The Gruppo Italiano per lo Studio della Sopravvienza nell'Infarto Miocardico (GISSI - 3) study was a multicenter, controlled, randomized, unblinded clinical trial conducted in 19,394 patients with acute myocardial infarction admitted to a coronary care unit. It was designed to examine the effects of short-term (6 week) treatment with lisinopril, nitrates, their combination, or no therapy on short-term (6 week) mortality and on long-term death and markedly impaired cardiac function. Patients presenting within 24 hours of the onset of symptoms who were hemodynamically stable were randomized, in a 2 x 2 factorial design, to six weeks of either

1) PRINIVIL alone (n = 4841),

2) nitrates alone (n = 4869),

3) PRINIVIL plus nitrates (n = 4841), or

4) open control (n = 4843).

All patients received routine therapies, including thrombolytics (72%), aspirin (84%), and a beta-blocker (31%), as appropriate, normally utilized in acute myocardial infarction (MI) patients.

The protocol excluded patients with hypotension (systolic blood pressure less than or equal to 100 mmHg), severe heart failure, cardiogenic shock and renal dysfunction (serum creatinine greater than 2 mg/dL and/or proteinuria greater than 500 mg/24 h). Doses of PRINIVIL were adjusted as necessary according to protocol. (See DOSAGE AND ADMINISTRATION.)

Study treatment was withdrawn at six weeks except where clinical conditions indicated continuation of treatment.

The primary outcomes of the trial were the overall mortality at six weeks and a combined endpoint at six months after the myocardial infarction, consisting of the number of patients who died, had late (day 4) clinical congestive heart failure, or had extensive left ventricular damage defined as ejection fraction less than or equal to 35%, or an akinetic-dyskinetic (A-D) score greater than or equal to 45%. Patients receiving PRINIVIL (n = 9646) alone or with nitrates, had an 11 percent lower risk of death (2p (two-tailed) = 0.04) compared to patients receiving no PRINIVIL (n = 9672) (6.4 percent versus 7.2 percent, respectively) at six weeks. Although patients randomized to receive PRINIVIL for up to six weeks also fared numerically better on the combined end-point at 6 months, the open nature of the assessment of heart failure, substantial loss to follow-up echocardiography, and substantial excess use of lisinopril between 6 weeks and 6 months in the group randomized to 6 weeks of lisinopril, preclude any conclusion about this endpoint.

Patients with acute myocardial infarction, treated with PRINIVIL had a higher (9.0 percent versus 3.7 percent, respectively) incidence of persistent hypotension (systolic blood pressure less than 90 mmHg for more than 1 hour) and renal dysfunction (2.4 percent versus 1.1 percent) in-hospital and at six weeks (increasing creatinine concentration to over 3 mg/dL or a doubling or more of the baseline serum creatinine concentration). See ADVERSE REACTIONS, ACUTE MYOCARDIAL INFARCTION.

INDICATIONS AND USAGE Hypertension

PRINIVIL is indicated for the treatment of hypertension. It may be used alone as initial therapy or concomitantly with other classes of antihypertensive agents.

Heart Failure

PRINIVIL is indicated as adjunctive therapy in the management of heart failure in patients who are not responding adequately to diuretics and digitalis.

Acute Myocardial Infarction

PRINIVIL is indicated for the treatment of hemodynamically stable patients within 24 hours of acute myocardial infarction, to improve survival. Patients should receive, as appropriate, the standard recommended treatments such as thrombolytics, aspirin and beta-blockers.

In using PRINIVIL, consideration should be given to the fact that another angiotensin converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen vascular disease, and that available data are insufficient to show that PRINIVIL does not have a similar risk. (See WARNINGS.)

In considering use of PRINIVIL, it should be noted that in controlled clinical trials ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks. In addition, is should be noted that black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to non-blacks.

CONTRAINDICATIONS

PRINIVIL is contraindicated in patients who are hypersensitive to this product and in patients with a history of angioedema related to previous treatment with an angiotensin converting enzyme inhibitor.

WARNINGS Anaphylactoid and Possibly Related Reactions

Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including PRINIVIL) may be subject to a variety of adverse reactions, some of them serious.

Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including PRINIVIL. This may occur at any time during treatment. In such cases PRINIVIL should be promptly discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. In instances where swelling has been confined to the face and lips the condition has generally resolved without treatment, although antihistamines have been useful in relieving symptoms. Angioedema associated with laryngeal edema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and/or measures necessary to ensure a patent airway, should be promptly provided. (See ADVERSE REACTIONS.)

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see also INDICATIONS AND USAGE and CONTRAINDICATIONS).

Anaphylactoid reactions during desensitization: Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.

Anaphylactoid reactions during membrane exposure: Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption (a procedure dependent upon devices not approved in the United States).

Hypotension

Excessive hypotension is rare in patients with uncomplicated hypertension treated with PRINIVIL alone.

Patients with heart failure given PRINIVIL commonly have some reduction in blood pressure with peak blood pressure reduction occurring 6 to 8 hours post dose, but discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed; caution should be observed when initiating therapy. (See DOSAGE AND ADMINISTRATION.)

Patients at risk of excessive hypotension, sometimes associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death, include those with the following conditions or characteristics: heart failure with systolic blood pressure below 100 mmHg, hyponatremia, high dose diuretic therapy, recent intensive diuresis or increase in diuretic dose, renal dialysis, or severe volume and/or salt depletion of any etiology. It may be advisable to eliminate the diuretic (except in patients with heart failure), reduce the diuretic dose or increase salt intake cautiously before initiating therapy with PRINIVIL in patients at risk for excessive hypotension who are able to tolerate such adjustments. (See PRECAUTIONS, Drug Interactions, and ADVERSE REACTIONS.)

Patients with acute myocardial infarction in the GISSI - 3 study had a higher (9.0 percent versus 3.7 percent) incidence of persistent hypotension (systolic blood pressure less than 90 mmHg for more than 1 hour) when treated with PRINIVIL. Treatment with PRINIVIL must not be initiated in acute myocardial infarction patients at risk of further serious hemodynamic deterioration after treatment with a vasodilator (e.g., systolic blood pressure of 100 mmHg or lower) or cardiogenic shock.

In patients at risk of excessive hypotension, therapy should be started under very close medical supervision and such patients should be followed closely for the first two weeks of treatment and whenever the dose of PRINIVIL and/or diuretic is increased. Similar considerations may apply to patients with ischemic heart or cerebrovascular disease, or in patients with acute myocardial infarction, in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.

If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses of PRINIVIL which usually can be given without difficulty once the blood pressure has stabilized. If symptomatic hypotension develops, a dose reduction or discontinuation of PRINIVIL or concomitant diuretic may be necessary.

Neutropenia/Agranulocytosis

Another angiotensin converting enzyme inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely in uncomplicated patients but more frequently in patients with renal impairment especially if they also have a collagen vascular disease. Available data from clinical trials of PRINIVIL are insufficient to show that PRINIVIL does not cause agranulocytosis at similar rates. Marketing experience has revealed rare cases of neutropenia and bone marrow depression in which a causal relationship to lisinopril cannot be excluded. Periodic monitoring of white blood cell counts in patients with collagen vascular disease and renal disease should be considered.

Hepatic Failure

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

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 PRINIVIL 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 serial ultrasound examinations should be performed to assess the intraamniotic environment.

If oligohydramnios is observed, PRINIVIL should be discontinued unless it is considered lifesaving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios 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, oliguria, 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. Lisinopril, which crosses the placenta, has been removed from neonatal circulation by peritoneal dialysis with some clinical benefit, and theoretically may be removed by exchange transfusion, although there is no experience with the latter procedure.

No teratogenic effects of lisinopril were seen in studies of pregnant rats, mice, and rabbits. On a mg/kg basis, the doses used were up to 625 times (in mice), 188 times (in rats), and 0.6 times (in rabbits) the maximum recommended human dose.

PRECAUTIONS General

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 PRINIVIL, may be associated with oliguria and/or progressive 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 PRINIVIL and/or diuretic therapy. In such patients renal function should be monitored during the first few weeks of therapy.

Some patients with hypertension or heart failure with no apparent pre-existing renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when PRINIVIL has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or PRINIVIL may be required.

Patients with acute myocardial infarction in the GISSI - 3 study, treated with PRINIVIL, had a higher (2.4 percent versus 1.1 percent) incidence of renal dysfunction in-hospital and at six weeks (increasing creatinine concentration to over 3 mg/dL or a doubling or more of the baseline serum creatinine concentration). In acute myocardial infarction, treatment with PRINIVIL should be initiated with caution in patients with evidence of renal dysfunction, defined as serum creatinine concentration exceeding 2 mg/dL. If renal dysfunction develops during treatment with PRINIVIL (serum creatinine concentration exceeding 3 mg/dL or a doubling from the pre-treatment value) then the physician should consider withdrawal of PRINIVIL.

Evaluation of patients with hypertension, heart failure, or myocardial infarction 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 approximately 2.2 percent of hypertensive patients and 4.8 percent of patients with heart failure. In most cases these were isolated values which resolved despite continued therapy. Hyperkalemia was a cause of discontinuation of therapy in approximately 0.1 percent of hypertensive patients, 0.6 percent of patients with heart failure and 0.1 percent of patients with myocardial infarction. 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 PRINIVIL. (See Drug Interactions.)

Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive 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.

Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents that produce hypotension, PRINIVIL may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.

Information for Patients

Angioedema: Angioedema, including laryngeal edema, may occur at any time during treatment with angiotensin-converting enzyme inhibitors, including lisinopril. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing) and to take no more drug until they have consulted with the prescribing physician.

Symptomatic Hypotension: Patients should be cautioned to report lightheadedness especially during the first few days of therapy. If actual syncope occurs, the patients should be told to discontinue the drug until they have consulted with the prescribing physician.

All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; patients should be advised to consult with their physician.

Hyperkalemia: Patients should be told not to use salt substitutes containing potassium without consulting their physician.

Neutropenia: Patients should be told to report promptly any indication of infection (e.g., sore throat, fever) which may be a sign of neutropenia.

Pregnancy: Female patients of childbearing age should be told about the consequences of second- and third-trimester exposure to ACE