Included as part of the PRECAUTIONS section.
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 QBRELIS as soon as possible [see Use In specific Populations].
Angioedema And Anaphylactoid Reactions
Head and Neck Angioedema
Angioedema of the face, extremities, lips, tongue,
glottis and/or larynx, including some fatal reactions, have occurred in
patients treated with angiotensin converting enzyme inhibitors, including
lisinopril, at any time during treatment. Patients with involvement of the
tongue, glottis or larynx are likely to experience airway obstruction,
especially those with a history of airway surgery. QBRELIS should be promptly
discontinued and appropriate therapy and monitoring should be provided until
complete and sustained resolution of signs and symptoms of angioedema has
Patients with a history of angioedema unrelated to ACE
inhibitor therapy may be at increased risk of angioedema while receiving an ACE
inhibitor [see CONTRAINDICATIONS]. ACE inhibitors have been associated
with a higher rate of angioedema in Black than in non-Black patients.
Patients receiving coadministration of an ACE inhibitor
and mTOR (mammalian target of rapamycin) inhibitor (e.g., temsirolimus,
sirolimus, everolimus) therapy or a neprilysin inhibitor may be at increased
risk for angioedema [see DRUG INTERACTIONS].
Intestinal angioedema has occurred 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. In some cases, the angioedema
was diagnosed by procedures including abdominal CT scan or ultrasound, or at
surgery, and symptoms resolved after stopping the ACE inhibitor.
Anaphylactoid Reactions During Desensitization
Two patients undergoing desensitizing treatment with
hymenoptera venom while receiving ACE inhibitors sustained life-threatening
Anaphylactoid Reactions During Dialysis
Sudden and potentially life threatening anaphylactoid
reactions have occurred in some patients dialyzed with high-flux membranes 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.
Impaired Renal Function
Monitor renal function periodically in patients treated
with QBRELIS. Changes in renal function including acute renal failure can be
caused by drugs that inhibit the renin-angiotensin system. Patients whose renal
function may depend in part on the activity of the reninangiotensin system
(e.g., patients with renal artery stenosis, chronic kidney disease, severe
congestive heart failure, post-myocardial infarction or volume depletion) may
be at particular risk of developing acute renal failure on QBRELIS. Consider
withholding or discontinuing therapy in patients who develop a clinically significant
decrease in renal function on QBRELIS [see ADVERSE REACTIONS, DRUG
QBRELIS can cause symptomatic hypotension, sometimes
complicated by oliguria, progressive azotemia, acute renal failure or death.
Patients at risk of excessive hypotension include those with the following
conditions or characteristics: heart failure with systolic blood pressure below
100 mmHg, ischemic heart disease, cerebrovascular disease, hyponatremia, high
dose diuretic therapy, renal dialysis, or severe volume and/or salt depletion
of any etiology.
In these patients, QBRELIS 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 QBRELIS and/or diuretic
is increased. Avoid use of QBRELIS in patients who are hemodynamically unstable
after acute MI.
Symptomatic hypotension is also possible in patients with
severe aortic stenosis or hypertrophic cardiomyopathy.
In patients undergoing major surgery or during anesthesia
with agents that produce hypotension, QBRELIS 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
Serum potassium should be monitored periodically in
patients receiving QBRELIS. Drugs that inhibit the renin-angiotensin system can
cause hyperkalemia. Risk factors for the development of hyperkalemia include
renal insufficiency, diabetes mellitus, and the concomitant use of
potassium-sparing diuretics, potassium supplements and/or potassium-containing
salt substitutes [see DRUG INTERACTIONS].
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 treatment.
Carcinogenesis, Mutagenesis, 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 up
to 90 mg per kg per 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 up to 135 mg per kg per 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.
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 per kg per day of lisinopril.
This dose is 188 times and 30 times the maximum human dose when based on mg/kg
and mg/m², respectively.
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.
*Calculations assume a human weight of 50 kg and human
body surface area of 1.62m².
Use In Specific Populations
QBRELIS can cause fetal harm when administered to a
pregnant woman. 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. 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. When pregnancy is detected,
discontinue QBRELIS as soon as possible.
The estimated background risk of major birth defects and
miscarriage for the indicated population(s) are unknown. In the general U.S.
population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2-4% and 15-20%,
Disease-associated maternal and/or embryo/fetal risk
Hypertension in pregnancy increases the maternal risk for
pre-eclampsia, gestational diabetes, premature delivery, and delivery
complications (e.g., need for cesarean section, and post-partum hemorrhage).
Hypertension increases the fetal risk for intrauterine growth restriction and
intrauterine death. Pregnant women with hypertension should be carefully
monitored and managed accordingly.
Fetal/Neonatal Adverse Reactions
Oligohydramnios in pregnant women who use drugs affecting
the renin-angiotensin system in the second and third trimesters of pregnancy can
result in the following: reduced fetal renal function leading to anuria and
renal failure, fetal lung hypoplasia and skeletal deformations, including skull
hypoplasia, hypotension, and death. 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
Perform serial ultrasound examinations to assess the
intra-amniotic environment. 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 QBRELIS
for hypotension, oliguria, and hyperkalemia. If oliguria or hypotension occur
in neonates with a history of in utero exposure to QBRELIS, support blood
pressure and renal perfusion. Exchange transfusions or dialysis may be required
as a means of reversing hypotension and substituting for disordered renal
No data are available regarding the presence of
lisinopril in human milk or the effects of lisinopril on the breastfed infant
or on milk production. Lisinopril is present in rat milk. Because of the
potential for severe adverse reactions in the breastfed infant, advise women
not to breastfeed during treatment with QBRELIS.
Antihypertensive effects and safety of lisinopril have
been established in pediatric patients aged 6 to 16 years [see DOSAGE AND
ADMINISTRATION and Clinical Studies]. No relevant differences
between the adverse reaction profile for pediatric patients and adult patients
Safety and effectiveness of lisinopril have not been
established in pediatric patients under the age 6 or in pediatric patients with
glomerular filtration rate < 30 mL/min/1.73 m² [see DOSAGE AND
ADMINISTRATION, CLINICAL PHARMACOLOGY, and Clinical Studies].
Neonates With A History Of In Utero Exposure To QBRELIS
If oliguria or hypotension occurs, direct attention
toward support of blood pressure and renal perfusion. Exchange transfusions or
dialysis may be required as a means of reversing hypotension and/or
substituting for disordered renal function.
No dosage adjustment with QBRELIS is necessary in elderly
patients. In a clinical study of lisinopril in patients with myocardial
infarctions (GISSI-3 Trial), 4,413 (47%) were 65 and over, while 1,656 (18%)
were 75 and over. In this study, 4.8 % of patients aged 75 years and older
discontinued lisinopril treatment because of renal dysfunction vs. 1.3% of
patients younger than 75 years. No other differences in safety or effectiveness
were observed between elderly and younger patients, but greater sensitivity of
some older individuals cannot be ruled out.
ACE inhibitors, including QBRELIS, have an effect on
blood pressure that is less in Black patients than in non-Blacks.
Dose adjustment of QBRELIS is required in patients
undergoing hemodialysis or whose creatinine clearance is ≤ 30 mL/min. No
dose adjustment of QBRELIS is required in patients with creatinine clearance
> 30 mL/min [see DOSAGE AND ADMINISTRATION and CLINICAL