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.
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.
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. 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 (0.3-0.5 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 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) and treated concomitantly
with an ACE inhibitor. In such patients, dialysis must be stopped immediately and
aggressive therapy for anaphylactoid reactions 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
lisinopril alone.
Patients with heart failure given lisinopril commonly have some reduction in blood
pressure, with peak blood pressure reduction occurring 6-8 hours postdose, 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 mm Hg, 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 DRUG INTERACTIONS and ADVERSE REACTIONS.)
Patients with acute myocardial infarction in the GISSI-3 trial had a higher (9.0% vs
3.7%) incidence of persistent hypotension (systolic blood pressure <90 mm Hg 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 at 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 2 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 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 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 intra-amniotic 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
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% vs 1.1%) incidence of renal dysfunction in-hospital and at 6 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.
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, which should be
used cautiously, if at all, with lisinopril. (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 the Patient
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 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.
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 second- and third-trimester exposure to ACE inhibitors, and they should also be told
that these consequences do not appear to have resulted from intrauterine ACE inhibitor
exposure that has been limited to the first trimester. 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.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
There was no evidence of a tumorigenic effect when lisinopril was administered for 105
weeks to male and female rats at doses of up to 90 mg/kg/day (about 56 or 9 times* the
maximum recommended daily human dose based on body weight and body surface area,
respectively). There was no evidence of carcinogenicity when lisinopril was administered
for 92 weeks to (male and female) mice at doses of up to 135 mg/kg/day (about 84
times* the maximum recommended daily human dose). This dose was 6.8 times the
maximum human dose based on body surface area in mice.
* Calculations assume a human weight of 50 kg and human body surface area of 1.62
m2.
Lisinopril was not mutagenic in the Ames microbial mutagen test with or without
metabolic activation. It was also negative in a forward mutation assay using Chinese
hamster lung cells. Lisinopril did not produce single strand DNA breaks in an in vitro
alkaline elution rat hepatocyte assay. In addition, lisinopril did not produce increases in
chromosomal aberrations in an in vitro test in Chinese hamster ovary cells or in an in
vivo study in mouse bone marrow.
There were no adverse effects on reproductive performance in male and female rats
treated with up to 300 mg/kg/day of lisinopril. This dose is 188 times and 30 times the
maximum human dose when based on mg/kg and mg/m2, respectively.
Pregnancy Category C (First Trimester) and Pregnancy Category D (Second and
Third Trimesters)
See WARNINGS, Fetal/Neonatal Morbidity and Mortality.
Nursing Mothers
Milk of lactating rats contains radioactivity following administration of 14C lisinopril. It is
not known whether this drug is excreted in human milk. Because many drugs are excreted
in human milk and because of the potential for serious adverse reactions in nursing infants
from ACE inhibitors, a decision should be made whether to discontinue nursing and/or
discontinue lisinopril, taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.