ZESTRIL®
`(lisinopril) Tablets
`
`WARNING: FETAL TOXICITY
`See full prescribing information for complete boxed warning.
` When pregnancy is detected, discontinue ZESTRIL as soon as possible.
` Drugs that act directly on the renin-angiotensin system can cause injury and death to the
`developing fetus. See Warnings: Fetal Toxicity.
`
`DESCRIPTION
`Lisinopril is an oral long-acting angiotensin converting enzyme inhibitor. Lisinopril, a synthetic
`peptide derivative, is chemically described as (S)-1-[N2-(1-carboxy-3-phenylpropyl)-L-lysyl]-L-
`
`proline dihydrate. Its empirical formula is C21H31N3O5.2H2O and its structural formula is:
`
`Lisinopril is a white to off-white, crystalline powder, with a molecular weight of 441.53. It is
`soluble in water and sparingly soluble in methanol and practically insoluble in ethanol.
`
`ZESTRIL is supplied as 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg and 40 mg tablets for oral
`administration.
`
`Inactive Ingredients:
`
`2.5 mg tablets - calcium phosphate, magnesium stearate, mannitol, starch.
`
`5, 10, 20 and 30 mg tablets - calcium phosphate, magnesium stearate, mannitol, red ferric oxide,
`starch.
`
`40 mg tablets - calcium phosphate, magnesium stearate, mannitol, starch, yellow ferric oxide.
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`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 ZESTRIL alone for
`up to 24 weeks, the mean increase in serum potassium was approximately 0.1 mEq/L; however,
`approximately 15% of patients had increases greater than 0.5 mEq/L and approximately 6% had
`a decrease greater than 0.5 mEq/L. In the same study, patients treated with ZESTRIL and
`hydrochlorothiazide for up to 24 weeks had a mean decrease in serum potassium of 0.1 mEq/L;
`approximately 4% of patients had increases greater than 0.5 mEq/L and approximately 12% 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 ZESTRIL
`remains to be elucidated.
`
`While the mechanism through which ZESTRIL lowers blood pressure is believed to be primarily
`suppression of the renin-angiotensin-aldosterone system, ZESTRIL is antihypertensive even in
`patients with low-renin hypertension. Although ZESTRIL 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 ZESTRIL and hydrochlorothiazide further reduced blood
`pressure in Black and non-Black patients and any racial differences in blood pressure response
`were no longer evident.
`
`Pharmacokinetics and Metabolism
`Adult Patients: Following oral administration of ZESTRIL, 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.
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`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%, with large intersubject variability
`(6%-60%) 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 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.
`
`Pediatric Patients: The pharmacokinetics of lisinopril were studied in 29 pediatric hypertensive
`patients between 6 years and 16 years with glomerular filtration rate > 30 mL/min/1.73 m2.
`After doses of 0.1 to 0.2 mg/kg, steady state peak plasma concentrations of lisinopril occurred
`within 6 hours and the extent of absorption based on urinary recovery was about 28%. These
`values are similar to those obtained previously in adults. The typical value of lisinopril oral
`clearance (systemic clearance/absolute bioavailability) in a child weighing 30 kg is 10 L/h,
`which increases in proportion to renal function.
`
`Pharmacodynamics and Clinical Effects
`Hypertension
`Adult Patients: Administration of ZESTRIL to patients with 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 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.
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`In most patients studied, onset of antihypertensive activity was seen at one hour after oral
`administration of an individual dose of ZESTRIL, with peak reduction of blood pressure
`achieved by 6 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 6 hours after dosing.
`
`In some patients achievement of optimal blood pressure reduction may require two to four weeks
`of therapy.
`
`The antihypertensive effects of ZESTRIL are maintained during long-term therapy. Abrupt
`withdrawal of ZESTRIL 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 ZESTRIL 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 ZESTRIL. In controlled clinical studies, ZESTRIL 20-80 mg has been
`compared in patients with mild to moderate hypertension to hydrochlorothiazide 12.5-50 mg and
`with atenolol 50-200 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 pressure
`in a population that was 3/4 Caucasian. ZESTRIL was approximately equivalent to atenolol and
`metoprolol in effects on diastolic blood pressure, and had somewhat greater effects on systolic
`blood pressure.
`
`ZESTRIL 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
`ZESTRIL, 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 lisinopril 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 ZESTRIL has been shown to be well tolerated and
`effective in controlling blood pressure (See PRECAUTIONS).
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`Pediatric Patients: In a clinical study involving 115 hypertensive pediatric patients 6 to 16 years
`of age, patients who weighed < 50 kg received either 0.625, 2.5 or 20 mg of lisinopril daily and
`patients who weighed
` 50 kg received either 1.25, 5, or 40 mg of lisinopril daily. At the end of
`2 weeks, lisinopril administered once daily lowered trough blood pressure in a dose-dependent
`manner with consistent antihypertensive efficacy demonstrated at doses > 1.25 mg (0.02 mg/kg).
`This effect was confirmed in a withdrawal phase, where the diastolic pressure rose by about 9
`mmHg more in patients randomized to placebo than it did in patients who were randomized to
`remain on the middle and high doses of lisinopril. The dose-dependent antihypertensive effect of
`lisinopril was consistent across several demographic subgroups: age, Tanner stage, gender, and
`race. In this study, lisinopril was generally well-tolerated.
`
`In the above pediatric studies, lisinopril was given either as tablets or in a suspension for those
`children and infants who were unable to swallow tablets or who required a lower dose than is
`available in tablet form (See DOSAGE AND ADMINISTRATION, Preparation of Suspension).
`
`Heart Failure: During baseline-controlled clinical trials, in patients receiving digitalis and
`diuretics, single doses of ZESTRIL 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 using doses of ZESTRIL up to 20 mg,
`ZESTRIL 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 once-daily dosing for the
`treatment of congestive heart failure was the only dosage regimen used during clinical trial
`development and was determined by the measurement of hemodynamic response. A large (over
`3000 patients) survival study, the ATLAS Trial, comparing 2.5 and 35 mg of lisinopril in
`patients with heart failure, showed that the higher dose of lisinopril had outcomes at least as
`favorable as the lower dose.
`
`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) ZESTRIL alone (n=4841), 2) nitrates alone (n=4869), 3)
`ZESTRIL 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.
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` 100 mmHg), severe
`The protocol excluded patients with hypotension (systolic blood pressure
`heart failure, cardiogenic shock, and renal dysfunction (serum creatinine >2 mg/dL and/or
`proteinuria > 500 mg/24 h). Doses of ZESTRIL 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 6 weeks and a combined end
`point at 6 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
` 35% or an akinetic-dyskinetic [A-D] score
` 45%. Patients receiving
`ZESTRIL (n=9646), alone or with nitrates, had an 11% lower risk of death (2p [two-tailed] =
`0.04) compared to patients receiving no ZESTRIL (n=9672) (6.4% vs. 7.2%, respectively) at six
`weeks. Although patients randomized to receive ZESTRIL 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 end point.
`
`Patients with acute myocardial infarction, treated with ZESTRIL, had a higher (9.0% versus
`3.7%) incidence of persistent hypotension (systolic blood pressure < 90 mmHg for more than 1
`hour) and renal dysfunction (2.4% versus 1.1%) 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
`ZESTRIL 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
`ZESTRIL 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
`ZESTRIL 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 ZESTRIL, 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
`ZESTRIL does not have a similar risk (See WARNINGS).
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`In considering the use of ZESTRIL, 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, ACE inhibitors have been associated with a higher rate of angioedema in Black than in
`non-Black patients (See WARNINGS, Anaphylactoid and Possibly Related Reactions).
`
`CONTRAINDICATIONS
`ZESTRIL 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 and in patients with hereditary or idiopathic angioedema.
`
`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 ZESTRIL) may be subject to a variety of adverse reactions, some of them
`serious.
`
`Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or
`larynx has been reported in patients treated with angiotensin converting enzyme inhibitors,
`including ZESTRIL. This may occur at any time during treatment. ACE inhibitors have been
`associated with a higher rate of angioedema in Black than in non-Black patients. ZESTRIL
`should be promptly discontinued and appropriate therapy and monitoring should be provided
`until complete and sustained resolution of signs and symptoms has occurred. Even in those
`instances where swelling of only the tongue is involved, without respiratory distress, patients
`may require prolonged observation since treatment with antihistamines and corticosteroids may
`not be sufficient. Very rarely, fatalities have been reported due to angioedema associated with
`laryngeal edema or tongue edema. Patients with involvement of the tongue, glottis or larynx are
`likely to experience airway obstruction, especially those with a history of airway surgery. 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).
`
`Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE
`inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in
`some cases there was no prior history of facial angioedema and C-1 esterase levels were normal.
`The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at
`surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should
`be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal
`pain.
`
`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).
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`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:
`Sudden and potentially life
`threatening anaphylactoid reactions have been reported in some patients dialyzed with high-flux
`membranes (e.g., AN69®*) and treated concomitantly with an ACE inhibitor. In such patients,
`dialysis must be stopped immediately, and aggressive therapy for anaphylactoid reactions must
`be initiated. Symptoms have not been relieved by antihistamines in these situations. In these
`patients, consideration should be given to using a different type of dialysis membrane or a
`different class of antihypertensive agent. Anaphylactoid reactions have also been reported in
`patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.
`
`Hypotension
`Excessive hypotension is rare in patients with uncomplicated hypertension treated with
`ZESTRIL alone.
`
`Patients with heart failure given ZESTRIL commonly have some reduction in blood pressure,
`with peak blood pressure reduction occurring 6 to 8 hours post dose. Evidence from the two-
`dose ATLAS trial suggested that incidence of hypotension may increase with dose of lisinopril in
`heart failure patients. 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 ZESTRIL 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 trial had a higher (9.0% versus 3.7%)
`incidence of persistent hypotension (systolic blood pressure < 90 mmHg for more than 1 hour)
`when treated with ZESTRIL. Treatment with ZESTRIL 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.
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`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 ZESTRIL 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 ZESTRIL which usually can be given without difficulty
`once the blood pressure has stabilized. If symptomatic hypotension develops, a dose reduction
`or discontinuation of ZESTRIL or concomitant diuretic may be necessary.
`
`Leukopenia/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 ZESTRIL are insufficient to show that ZESTRIL
`does not cause agranulocytosis at similar rates. Marketing experience has revealed rare cases of
`leukopenia/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 or hepatitis 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 Toxicity
`Pregnancy category D
`
`Use of drugs that act on the renin-angiotensin system during the second and third trimesters of
`pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death.
`Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal
`deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension,
`renal failure, and death. When pregnancy is detected, discontinue ZESTRIL as soon as possible.
`These adverse outcomes are usually associated with use of these drugs in the second and third
`trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure
`to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-
`angiotensin system from other antihypertensive agents. Appropriate management of maternal
`hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
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`In the unusual case that there is no appropriate alternative to therapy with drugs affecting the
`renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the
`fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If
`oligohydramnios is observed, discontinue ZESTRIL, unless it is considered lifesaving for the
`mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and
`physicians should be aware, however, that oligohydramnios may not appear until after the fetus
`has sustained irreversible injury. Closely observe infants with histories of in utero exposure to
`ZESTRIL for hypotension, oliguria, and hyperkalemia (see Precautions, Pediatric Use).
`
`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
`Aortic Stenosis/Hypertrophic Cardiomyopathy: As with all vasodilators, lisinopril should be
`given with caution to patients with obstruction in the outflow tract of the left ventricle.
`
`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 ZESTRIL, 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
`ZESTRIL 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 ZESTRIL 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 ZESTRIL may be required.
`
`Patients with acute myocardial infarction in the GISSI-3 trial treated with ZESTRIL had a higher
`(2.4% versus 1.1%) 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 ZESTRIL 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
`ZESTRIL (serum creatinine concentration exceeding 3 mg/dL or a doubling from the
`pre-treatment value) then the physician should consider withdrawal of ZESTRIL.
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`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% of hypertensive patients and 4.8% 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% of hypertensive
`patients; 0.6% of patients with heart failure and 0.1% 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. Hyperkalemia can cause serious, sometimes fatal,
`arrhythmias. ZESTRIL should be used cautiously, if at all, with these agents and with frequent
`monitoring of serum potassium (See PRECAUTIONS, Drug Interactions).
`
`Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin,
`persistent nonproductive cough has been reported with all ACE inhibitors, almost 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, ZESTRIL 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 ZESTRIL. 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 patient 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