CONTRAINDICATIONS
Quinapril HCl is contraindicated in patients who are hypersensitive to this product and in patients
with a history of angioedema related to previous treatment with an ACE inhibitor.
WARNINGS
Anaphylactoid and Possibly Related Reactions: Presumably because angiotensin-converting
inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin,
patients receiving ACE inhibitors (including quinapril HCl) may be subject to a variety of adverse
reactions, some of them serious.
Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been
reported in patients treated with ACE inhibitors and has been seen in 0.1% of patients receiving
quinapril HCl.
In two similarly sized U.S. postmarketing trials that, combined, enrolled over 3,000 black patients
and over 19,000 non-blacks, angioedema was reported in 0.30% and 0.55% of blacks (in study 1
and 2 respectively) and 0.39% and 0.17% of non-blacks.
Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the
face, tongue, or glottis occurs, treatment with quinapril HCl should be discontinued immediately, the
patient treated in accordance with accepted medical care, and carefully observed until the swelling
disappears. In instances where swelling is confined to the face and lips, the condition generally
resolves without treatment; antihistamines may be useful in relieving symptoms. Where there is
involvement of the tongue, glottis, or larynx likely to cause airway obstruction,
emergency therapy including, but not limited to, subcutaneous epinephrine solution
1:1000 (0.3 to 0.5 ml), should be promptly administered (see ADVERSE REACTIONS.)
Patients with a History of Angioedema: 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
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.
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.
Hypotension: Excessive hypotension is rare in patients with uncomplicated hypertension treated
with quinapril HCl alone. Patients with heart failure given quinapril HCl commonly have some
reduction in blood pressure, 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 in patients with heart failure (see DOSAGE AND
ADMINISTRATION.) In controlled studies, syncope was observed in 0.4% of patients (N=3203);
this incidence was similar to that observed for captopril (1%) and enalapril (0.8%).
Patients at a risk of excessive hypotension, sometimes associated with oliguria and/or progressive
azotemia, and rarely with acute renal failure and/or death, include patients with the following
conditions or characteristics: heart failure, 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 cautiously increase salt intake (except in patients with heart failure) before
initiating therapy with quinapril HCl in patients at risk for excessive hypotension who are able to
tolerate such adjustments.
In patients at risk of excessive hypotension, therapy with quinapril HCl should be started under
close medical supervision. Such patients should be followed closely for the first two weeks of
treatment and whenever the dose of quinapril HCl and/or diuretic is increased. Similar
considerations may apply to patients with ischemic heart or cerebrovascular disease in whom an
excessive fall in blood pressure could result in a myocardial infarction or a 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 quinapril HCl, which usually can be given without difficulty
once the blood pressure has stabilized. If symptomatic hypotension develops, a dose reduction or
discontinuation of quinapril HCl or concomitant diuretic may be necessary.
Neutropenia/Agranulocytosis: Another ACE inhibitor, captopril, has been shown to cause
agranulocytosis and bone marrow depression rarely in patients with uncomplicated hypertension, but
more frequently in patients with renal impairment, especially if they also have a collagen vascular
disease, such as systemic lupus erythematosus or scleroderma. Agranulocytosis did occur during
quinapril HCl treatment in one patient with a history of neutropenia during previous captopril
therapy. Available data from clinical trials of quinapril HCl are insufficient to show that, in patients
without prior reactions to other ACE inhibitors, quinapril HCl does not cause agranulocytosis at
similar rates. As with other ACE inhibitors, periodic monitoring of white blood cell counts in patients
with collagen vascular disease and/or renal disease should be considered.
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 quinapril HCl 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, quinapril HCl should be discontinued unless it is considered
life-saving 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
a means of reversing hypotension and/or substituting for disordered renal function. Removal of
quinapril HCl, which crosses the placenta, from the neonatal circulation is not significantly
accelerated by these means.
No teratogenic effects of quinapril HCl were seen in studies of pregnant rats and rabbits. On a
mg/kg basis, the doses used were up to 180 times (in rats) and one time (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 heart failure whose renal function may depend on the activity of the
renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including quinapril HCl, may
be associated with oliguria and/or progressive azotemia and rarely acute renal failure and/or death.
In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis, increases
in blood urea nitrogen and serum creatinine have been observed in some patients following ACE
inhibitor therapy. These increases were almost always reversible upon discontinuation of the ACE
inhibitor 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 preexisting renal vascular disease
have developed increases in blood urea and serum creatinine, usually minor and transient, especially
when quinapril HCl has been given concomitantly with a diuretic. This is more likely to occur in
patients with preexisting renal impairment. Dosage reduction and/or discontinuation of any diuretic
and/or quinapril HCl may be required.
Evaluation of Patients with Hypertension or Heart Failure Should Always Include
Assessment of Renal Function: (see DOSAGE AND ADMINISTRATION.)
Hyperkalemia and Potassium-Sparing Diuretics: In clinical trials, hyperkalemia (serum
potassium ³5.8 mmol/L) occurred in approximately 2% of patients receiving quinapril HCl. In most
cases, elevated serum potassium levels were isolated values which resolved despite continued
therapy. Less than 0.1% of patients discontinued therapy due to 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,
which should be used cautiously, if at all, with quinapril HCl (see DRUG INTERACTIONS.)
Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin, persistant
non-productive cough has been reported with all ACE inhibitors, always resolving after
disconinuation 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, quinapril HCl will 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
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.
Angioedema: Angioedema, including laryngeal edema can occur with treatment with ACE
inhibitors, especially following the first dose. 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 stop taking the drug until they have consulted
with their physician (see WARNINGS.)
Symptomatic Hypotension: Patients should be cautioned that lightheadedness can occur,
especially during the first few days of quinapril HCl therapy, and that it should be reported to a
physician. If actual syncope occurs, patients should be told to not take the drug until they have
consulted with their physician (see WARNINGS.)
All patients should be cautioned that inadequate fluid intake or excessive perspiration, diarrhea, or
vomiting can lead to an excessive fall in blood pressure because of reduction in fluid volume, with
the same consequences of lightheadedness and possible syncope.
Patients planning to undergo any surgery and/or anesthesia should be told to inform their physician
that they are taking an ACE inhibitor.
Hyperkalemia: Patients should be told not to use potassium supplements or salt substitutes
containing potassium without consulting their physician (see PRECAUTIONS.)
Neutropenia: Patients should be told to report promptly any indication of infection (e.g., sore
throat, fever) which could be a sign of neutropenia.
NOTE: As with many other drugs, certain advice to patients being treated with quinapril HCl 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
Quinapril hydrochloride was not carcinogenic in mice or rats when given in doses up to 75 or 100
mg/kg/day (50 to 60 times the maximum human daily dose, respectively, on an mg/kg basis and 3.8
to 10 times the maximum human daily dose when based on an mg/m2 basis) for 104 weeks. Female
rats given the highest dose level had an increased incidence of mesenteric lymph node
hemangiomas and skin/subcutaneous lipomas. Neither quinapril nor quinaprilat were mutagenic in
the Ames bacterial assay with or without metabolic activation. Quinapril was also negative in the
following genetic toxicology studies: in vitro mammalian cell point mutation, sister chromatid
exchange in cultured mammalian cells, micronucleus test with mice, in vitro chromosome
aberration with V79 cultured lung cells, and in an in vivo cytogenetic study with rat bone marrow.
There were no adverse effects on fertility or reproduction in rats at doses up to 100 mg/kg/day (60
and 10 times the maximum daily human dose when based on mg/kg and mg/m2, respectively).
Pregnancy
Pregnancy Category C (first trimester) and D (second and third trimesters): See
WARNINGS, Fetal/Neonatal Morbidity and Mortality.
Nursing Mothers
Because quinapril HCI is secreted in human milk, caution should be exercised when this drug is
administered to a nursing woman.
Geriatric Use
Elderly patients exhibited increased area under the plasma concentration time curve (AUC) and
peak levels for quinaprilat compared to values observed in younger patients; this appeared to relate
to decreased renal function rather than to age itself. In controlled and uncontrolled studies of
quinapril HCl where 918 (21%) patients were 65 years and older, no overall differences in
effectiveness or safety were observed between older and younger patients. However, greater
sensitivity of some older individual patients cannot be ruled out.
Pediatric Use
The safety and effectiveness of quinapril HCl in children have not been established.