DESCRIPTION

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 lisinopril 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 lisinopril 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 lisinopril remains to be elucidated.
While the mechanism through which lisinopril lowers blood pressure is believed to be primarily suppression of the reninangiotensin-
aldosterone system, lisinopril is antihypertensive even in patients with low-renin hypertension. Although
lisinopril 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 lisinopril and hydrochlorothiazide further reduced blood pressure in Black and non-Black
patients and any racial differences in blood pressure response were no longer evident.

INDICATIONS AND USAGE

Hypertension
Lisinopril tablets are indicated for the treatment of hypertension. They may be used alone as initial therapy or
concomitantly with other classes of antihypertensive agents.
Heart Failure
Lisinopril tablets are indicated as adjunctive therapy in the management of heart failure in patients who are not
responding adequately to diuretics and digitalis.
Acute Myocardial Infarction
Lisinopril tablets are 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 lisinopril tablets, 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 lisinopril tablets does not have a similar risk. (See WARNINGS.)
In considering the use of lisinopril tablets, 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

Lisinopril 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 lisinopril) 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 lisinopril. 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.
Lisinopril 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 estrase 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).

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®1) 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.
1 AN69 is a registered trademark of Hospal Ltd.

Hypotension: Excessive hypotension is rare in patients with uncomplicated hypertension treated with lisinopril alone.
Patients with heart failure given lisinopril 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 lisinopril 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% versus 3.7%) incidence of persistent
hypotension (systolic blood pressure less than 90 mmHg for more than 1 hour) when treated with lisinopril. Treatment with
lisinopril 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 lisinopril 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 lisinopril
which usually can be given without difficulty once the blood pressure has stabilized. If symptomatic hypotension develops,
a dose reduction or discontinuation of lisinopril 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
lisinopril are insufficient to show that lisinopril 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/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.
In a published retrospective epidemiological study, infants whose mothers had taken an ACE inhibitor during their first
trimester of pregnancy appeared to have an increased risk of major congenital malformations compared with infants
whose mothers had not undergone first trimester exposure to ACE inhibitor drugs. The number of cases of birth defects is
small and the findings of this study have not yet been repeated.
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
lisinopril 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, lisinopril should be discontinued unless it is considered lifesaving for the mother.
Contraction stress testing (CST), a nonstress 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:
Aortic Stenosis/ Hypertrophic Cardiomyopathy: As with all vasodialators, 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 lisinopril, 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 lisinopril 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 lisinopril 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 lisinopril may be required.
Patients with acute myocardial infarction in the GISSI-3 trial treated with lisinopril 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 lisinopril
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 lisinopril (serum creatinine concentration
exceeding 3 mg/dL or a doubling from the pre-treatment value) then the physician should consider withdrawal of lisinopril.
eva luation 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 potassiumsparing
diuretics, potassium supplements and/or potassium-containing salt substitutes. Hyperkalemia can cause serious,
sometimes fatal, arrhythmias. Lisinopril should be used cautiously, if at all, with these agents and with frequent
monitoring of serum potassium. (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, 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,
lisinopril 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 angiotensinconverting
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 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 use salt substitutes containing potassium without consulting their physician.
Hypoglycemia: Diabetic patients treated with oral antidiabetic agents or insulin starting an ACE inhibitor should be told to
closely monitor for hypoglycemia, especially during the first month of combined use. (See PRECAUTIONS, Drug
Interactions.)
Leukopenia/Neutropenia: Patients should be told to report promptly any indication of infection (e.g., sore throat, fever)
which may be a sign of leukopenia/neutropenia.
Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to ACE inhibitors during pregnancy.
These patients should be asked to report pregnancies to their physicians as soon as possible.
NOTE: As with many other drugs, certain advice to patients being treated with lisinopril is warranted. This information is intended
to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.

Drug Interactions
Hypotension- Patients on Diuretic Therapy: Patients on diuretics and especially those in whom diuretic therapy was
recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with
lisinopril. The possibility of hypotensive effects with lisinopril can be minimized by either discontinuing the diuretic or
increasing the salt intake prior to initiation of treatment with lisinopril. If it is necessary to continue the diuretic, initiate
therapy with lisinopril at a dose of 5 mg daily, and provide close medical supervision after the initial dose until blood
pressure has stabilized. (See WARNINGS and DOSAGE AND ADMINISTRATION.) When a diuretic is added to the therapy
of a patient receiving lisinopril, an additional antihypertensive effect is usually observed. Studies with ACE inhibitors in
combination with diuretics indicate that the dose of the ACE inhibitor can be reduced when it is given with a diuretic.
(See DOSAGE AND ADMINISTRATION.)
Antidiabetics: Epidemiological studies have suggested that concomitant administration of ACE inhibitors and
antidiabetic medicines (insulins, oral hypoglycemic agents) may cause an increased blood-glucose-lowering effect with
risk of hypoglycemia. This phenomenon appeared to be more likely to occur during the first weeks of combined treatment
and in patients with renal impairment. In diabetic patients treated with oral antidiabetic agents or insulin, glycemic
control should be closely monitored for hypoglycemia, especially during the first month of treatment with an ACE inhibitor.
Non-steroidal Anti-inflammatory Agents: In some patients with compromised renal function who are being treated
with non-steroidal anti-inflammatory drugs, the co-administration of lisinopril may result in further deterioration of renal
function. These effects are usually reversible. In a study in 36 patients with mild to moderate hypertension where the
antihypertensive effects of lisinopril alone were compared to lisinopril given concomitantly with indomethacin, the use
of indomethacin was associated with a reduced effect, although the difference between the two regimens was not
significant.
Other Agents: Lisinopril has been used concomitantly with nitrates and/or digoxin without evidence of clinically
significant adverse interactions. This included post myocardial infarction patients who were receiving intravenous or
transdermal nitroglycerin. No clinically important pharmacokinetic interactions occurred when lisinopril was
used concomitantly with propranolol or hydrochlorothiazide. The presence of food in the stomach does not alter the
bioavailability of lisinopril.
Agents Increasing Serum Potassium: Lisinopril attenuates potassium loss caused by thiazide-type diuretics. Use of
lisinopril with potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene or amiloride), potassium
supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Therefore, if
concomitant use of these agents is indicated because of demonstrated hypokalemia, they should be used with caution and
with frequent monitoring of serum potassium. Potassium sparing agents should generally not be used in patients with heart
failure who are receiving lisinopril.

Lithium: Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs