Accupril™
Quinapril HCl
Angiotensin Converting Enzyme Inhibitor
Pfizer
http://www.pfizer.com/pfizer/main.jsp
Accupril Monograph PDF download here.
CPS:PIS_m001800
Date of Preparation: January 5, 2001
Date of Revision: July 13, 2004
Pharmacology
ACCUPRIL (quinapril hydrochloride) is a
nonpeptide, nonsulphydryl inhibitor of angiotensin converting enzyme (ACE),
which is used in the treatment of hypertension.
Angiotensin converting
enzyme (ACE) is a peptidyl dipeptidase that catalyzes the conversion of
angiotensin I to the vasoconstrictor angiotensin II. After absorption,
quinapril is rapidly de-esterified to quinaprilat (quinapril diacid), its
principal active metabolite. Its primary mode of action is to inhibit
circulating and tissue ACE, thereby decreasing vasopressor activity and
aldosterone secretion. Although the decrease in aldosterone is small, it results
in a small increase in serum K+ (see Precautions). Removal of
angiotensin II negative feedback on renin secretion leads to increased plasma
renin activity. Although Accupril had antihypertensive activity in all races
studied, black hypertensive patients (usually a low-renin hypertensive
population) had a smaller average response to ACE inhibitor monotherapy than
non-black patients.
ACE is identical to
kininase II. Thus, quinapril may interfere with the degradation of bradykinin,
a potent peptide vasodilator. However, it is not known whether this system
contributes to the therapeutic effects of ACCUPRIL.
The antihypertensive
effect of quinapril outlasts its inhibitory effect on circulating ACE in animal
studies. Tissue ACE inhibition more closely correlates with the duration of
antihypertensive effects and this may be related to enzyme binding
characteristics as shown for quinapril on purified tissue ACE from human kidney
and heart.
Pharmacokinetics
Following oral administration of ACCUPRIL, peak
plasma concentrations of quinapril occur within one hour. Based on the recovery
of quinapril and its metabolites in urine, the extent of absorption is at least
60%. Following absorption, quinapril is de-esterified to its major active
metabolite, quinaprilat (quinapril diacid) a potent ACE inhibitor, and to minor
inactive metabolites. Quinapril has an apparent half-life in plasma of
approximately one hour. Peak plasma quinaprilat concentrations occur
approximately 2 hours after an oral dose of ACCUPRIL. Quinaprilat is eliminated
primarily by renal excretion and has an effective accumulation half-life of
approximately 3 hours. Quinaprilat has an elimination half-life in plasma of
approximately 2 hours with a prolonged terminal phase of 25 hours. Approximately
97% of either quinapril or quinaprilat circulating in plasma is bound to
proteins.
Pharmacokinetic studies
in patients with end-stage renal disease on chronic hemodialysis or continuous
ambulatory peritoneal dialysis indicate that dialysis has little effect on the
elimination of quinapril and quinaprilat.
The disposition of
quinapril and quinaprilat in patients with renal insufficiency is similar to
that in patients with normal renal function until creatinine clearance is 60
mL/min or less. With creatinine clearance less than 60 mL/min, peak and trough
quinaprilat concentrations increase, apparent half-life increases, and time to
steady state may be delayed. The elimination of quinaprilat may be reduced in
elderly patients (>65 years) and in those with heart failure; this reduction
is attributable to decrease in renal function (see Dosage). Quinaprilat
concentrations are reduced in patients with alcoholic cirrhosis due to impaired
de-esterification of quinapril.
The rate and extent of
quinapril absorption are diminished moderately (approximately 25-30%) when
ACCUPRIL tablets are administered during a high-fat meal. However, no effect on
quinapril absorption occurs when taken during a regular meal.
Studies in rats
indicate that quinapril and its metabolites do not cross the blood-brain
barrier.
Pharmacodynamics
Administration of 10 to 40 mg of ACCUPRIL to
patients with essential hypertension results in a reduction of both sitting and
standing blood pressure with minimal effect on heart rate. Antihypertensive
activity commences within one hour with peak effects usually achieved by 2 to 4
hours after dosing. Achievement of maximum blood pressure lowering effects may
require 2 weeks of therapy in some patients. At the recommended doses, antihypertensive
effects are maintained throughout the 24-hour dosing interval in most patients.
While the dose response relationship is relatively flat, a dose of 40 mg was
somewhat more effective at trough than 10-20 mg, and twice daily dosing tended
to give a somewhat lower blood pressure than once daily dosing with the same
total daily dose. The antihypertensive effect of ACCUPRIL was maintained during
long-term therapy with no evidence of loss of effectiveness.
Hemodynamic assessments
in patients with essential hypertension indicate that blood pressure reduction
produced by quinapril is accompanied by a reduction in total peripheral
resistance and renal vascular resistance with little or no change in heart rate
and cardiac index. There was an increase in renal blood flow which was not
significant. Little or no change in glomerular filtration rate or filtration
fraction was observed.
Quinapril has been
shown to reduce microalbuminuria in patients with essential hypertension
independently of changes in systemic blood pressure.
When ACCUPRIL is given
together with thiazide-type diuretics, the antihypertensive effects are
approximately additive.
Administration of
ACCUPRIL to patients with congestive heart failure (CHF) reduces peripheral
vascular resistance, systolic and diastolic blood pressure, pulmonary capillary
wedge pressure, and increases cardiac output. The onset of effects was observed
within one hour and maximal effects occurred at 1.25 to 4 hours after
administration of Accupril. Peak hemodynamic effects correlated well with peak
plasma levels of quinaprilat (1 to 4 hours after administration).
Exercise tolerance was
improved with Accupril therapy.
The effect of ACCUPRIL
on survival in patients with heart failure has not been evaluated.
Therapeutic effects
appear to be the same for elderly (>65 years of age) and younger adult
patients given the same daily dosages, with no increase in adverse events in
elderly patients.
The antihypertensive
effect of angiotensin converting enzyme inhibitors is generally lower in black
patients than in non-blacks.
Indications
Hypertension
ACCUPRIL (quinapril hydrochloride) is indicated
in the treatment of essential hypertension. It is usually administered in
association with other drugs, particularly thiazide diuretics.
In using ACCUPRIL,
consideration should be given to the risk of angioedema (see Warnings).
ACCUPRIL should
normally be used in those patients in whom treatment with a diuretic or a
beta-blocker was found ineffective or has been associated with unacceptable
adverse effects. ACCUPRIL can also be tried as an initial agent in those
patients in whom use of diuretics and/or beta-blockers is contraindicated or in
patients with medical conditions in which these drugs frequently cause serious
adverse effects.
The safety and efficacy
of ACCUPRIL in renovascular hypertension has not been established; therefore,
use in this condition is not recommended.
Congestive Heart Failure
ACCUPRIL is indicated in the treatment of congestive
heart failure as adjunctive therapy when added to diuretics and/or digitalis
glycosides.
Treatment with ACCUPRIL
should be initiated under close medical supervision.
When used in
pregnancy during the second and third trimesters, ACE inhibitors can cause
injury or even death of the developing fetus. When pregnancy is detected
ACCUPRIL should be discontinued as soon as possible (see Warnings, Pregnancy,
and Precautions, Information to Be Provided to the Patient).
Contraindications
ACCUPRIL (quinapril hydrochloride) 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
Head and Neck Angioedema
Head and neck angioedema has been reported in
patients treated with ACCUPRIL (quinapril hydrochloride). Angioedema associated
with laryngeal involvement may be fatal. If laryngeal stridor or angioedema of
the face, tongue, or glottis occurs, ACCUPRIL should be discontinued immediately,
the patient treated appropriately 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, although antihistamines may be useful in relieving symptoms. Where
there is involvement of the tongue, glottis or larynx, likely to cause airway
obstruction, appropriate therapy (including but not limited to 0.3 to 0.5 mL of
subcutaneous epinephrine solution 1:1000) should be administered promptly (see
Adverse Effects).
The incidence of
angioedema during ACE inhibitor therapy has been reported to be higher in black
than in non-black patients.
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).
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.
Hypotension
Symptomatic hypotension has occurred after
administration of ACCUPRIL, usually after the first or second dose or when the
dose was increased. It is more likely to occur in patients who are volume
depleted by diuretic therapy, dietary salt restriction, dialysis, diarrhea, or
vomiting. In patients with ischemic heart or cerebrovascular disease, an
excessive fall in blood pressure could result in a myocardial infarction or
cerebrovascular accident (see Adverse Effects). Because of the potential fall
in blood pressure in these patients, therapy with ACCUPRIL should be started under
close medical supervision (see Dosage). Such patients should be followed
closely for the first weeks of treatment and whenever the dose of ACCUPRIL is
increased. In patients with severe congestive heart failure, with or without
associated renal insufficiency, excessive hypotension has been observed and may
be associated with oliguria and/or progressive azotemia, and rarely with acute
renal failure and/or death.
If hypotension occurs,
the patient should be placed in supine position and, if necessary, receive an
intravenous infusion of 0.9% sodium chloride. A transient hypotensive response
is not a contraindication to further doses which usually can be given without
difficulty once the blood pressure has increased after volume expansion.
However, lower doses of ACCUPRIL and/or reduced concomitant diuretic therapy
should be considered.
Neutropenia/Agranulocytosis
Agranulocytosis and bone marrow depression have
been caused by ACE inhibitors. Agranulocytosis did occur during ACCUPRIL
treatment in one patient with a history of neutropenia during previous
captopril therapy. Periodic monitoring of white blood cell counts should be
considered, especially in patients with collagen vascular disease and/or renal
disease.
Pregnancy
ACE inhibitors can cause fetal and neonatal
morbidity and mortality when administered to pregnant women. Several dozen
cases have been reported in the world literature. When pregnancy is detected,
ACCUPRIL should be discontinued as soon as possible.
In rare cases (probably
less than 0.1% of pregnancies) in which no alternative to ACE inhibitors
therapy will be found, the mothers should be apprised of the potential hazards
to their fetuses. Serial ultrasound examinations should be performed to assess
fetal development and well-being and the volume of amniotic fluid.
If oligohydramnios is
observed, ACCUPRIL should be discontinued unless it is considered life-saving
to the mother. A non-stress test (NST), and/or a biophysical profiling (BPP)
may be appropriate, depending upon the week of pregnancy. If concerns regarding
fetal well-being still persist, a contraction stress testing (CST) should be
considered. Patients and physicians should be aware, however, that
oligohydramnios may not appear until after the fetus has sustained irreversible
injury.
Infants with a history
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 impaired renal function, however; limited experience
with those procedures has not been associated with significant clinical
benefit. Hemodialysis and peritoneal dialysis have little effect on the
elimination of quinapril and quinaprilat.
Human Data
It is not known whether exposure limited to the
first trimester of pregnancy can adversely affect fetal outcome. 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.
Animal Data
No fetotoxic or teratogenic effects were
observed in rats at doses as high as 300 mg/kg/day (180 times the maximum daily
human dose), despite maternal toxicity at 150 mg/kg/day. Offspring body weights
were reduced in rats treated late in gestation and during lactation with doses
of 25 mg/kg/day or more. Quinapril hydrochloride was not teratogenic in
rabbits; however, maternal and embryo toxicity were seen in some rabbits at 1
mg/kg/day.
No adverse effects on
fertility or reproduction were observed in rats at dose levels up to 100
mg/kg/day (60 times the maximum daily human dose).
Precautions
Renal Impairment
As a consequence of inhibiting the
renin-angiotensin-aldosterone system, changes in renal function have been seen
in susceptible individuals. In patients whose renal function may depend on the
activity of the renin-angiotensin-aldosterone system, such as patients with bilateral
renal artery stenosis, unilateral renal artery stenosis to a solitary kidney,
or severe congestive heart failure, treatment with agents that inhibit this
system has been associated with oliguria, progressive azotemia, and rarely,
acute renal failure and/or death. In susceptible patients, concomitant diuretic
use may further increase risk.
Use of ACCUPRIL
(quinapril hydrochloride) should include appropriate assessment of renal
function.
Anaphylactoid Reactions during Membrane Exposure
Anaphylactoid reactions have been reported in
patients dialysed with high-flux membranes (e.g.: polyacrylonitrile [PAN]) and
treated concomitantly with an ACE inhibitor. Dialysis should be stopped
immediately if symptoms such as nausea, abdominal cramps, burning, angioedema,
shortness of breath and severe hypotension occur. Symptoms are not relieved by
antihistamines. In these patients consideration should be given to using a
different type of dialysis membrane or a different class of antihypertensive
agents.
Anaphylactoid Reactions during LDL Apheresis
Rarely, patients receiving ACE inhibitors during
low density lipoprotein apheresis with dextran sulfate have experienced
life-threatening anaphylactoid reactions. These reactions were avoided by
temporarily withholding the ACE inhibitor therapy prior to each apheresis.
Anaphylactoid Reactions during Desensitization
There have been isolated reports of patients
experiencing sustained life threatening anaphylactoid reactions while receiving
ACE inhibitors during desensitizing treatment with hymenoptera (bees, wasps)
venom. In the same patients, these reactions have been avoided when ACE
inhibitors were temporarily withheld for at least 24 hours, but they have
reappeared upon inadvertent rechallenge to an ACE inhibitor.
Hyperkalemia and Potassium-Sparing Diuretics
Elevated serum potassium (greater than 5.7
mEq/L) was observed in approximately 2% of patients receiving ACCUPRIL. In most
cases these were isolated values which resolved despite continued therapy.
Hyperkalemia was a cause of discontinuation of therapy in less than 0.1% of
hypertensive patients. Risk factors for the development of hyperkalemia may
include renal insufficiency, diabetes mellitus, and the concomitant use of
agents to treat hypokalemia (see Precautions, Drug Interactions and Adverse
Effects).
Hypoglycemia and Diabetes
ACE inhibitors may reduce insulin resistance and
may lead to hypoglycemia in diabetic patients on insulin or oral hypoglycemic
agents; closer monitoring of diabetic patients may be required.
Valvular Stenosis
There is concern on theoretical grounds that
patients with aortic stenosis might be at particular risk of decreased coronary
perfusion when treated with vasodilators because they do not develop as much
afterload reduction.
Surgery/Anaesthesia
In patients undergoing major surgery or during
anaesthesia with agents that produce hypotension, ACCUPRIL 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.
Patients with Impaired Liver Function
Hepatitis (hepatocellular and/or cholestatic),
elevations of liver enzymes and/or serum bilirubin have occurred during therapy
with other ACE inhibitors in patients with or without pre-existing liver
abnormalities. In most cases the changes were reversed on discontinuation of
the drug.
Elevations of liver
enzymes and/or serum bilirubin have been reported for ACCUPRIL (see Adverse
Effects). Should the patient receiving ACCUPRIL experience any unexplained
symptoms particularly during the first weeks or months of treatment, it is
recommended that a full set of liver function tests and any other necessary
investigation be carried out. Discontinuation of ACCUPRIL should be considered
when appropriate.
There are no adequate
studies in patients with cirrhosis and/or liver dysfunction. ACCUPRIL should be
used with particular caution in patients with pre-existing liver abnormalities.
In such patients baseline liver function tests should be obtained before
administration of the drug and close monitoring of response and metabolic
effects should apply.
Quinapril, when
combined with a diuretic should be used with caution in patients with impaired
hepatic function or progressive liver disease, since minor alterations of fluid
and electrolyte balance may precipitate hepatic coma. The metabolism of
quinapril to quinaprilat is normally dependant upon hepatic esterase.
Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due
to impaired deesterification of quinapril.
Cough
Cough has been reported with the use of ACE
inhibitors, including quinapril. Characteristically, the cough is dry and
persistent and usually disappears only after withdrawal or lowering of the
dose of ACCUPRIL. ACE inhibitor-induced cough should be considered as part of
the differential diagnosis of the cough.
Lactation
Quinapril is secreted to a limited extent in
milk of lactating rats (5% or less of the plasma drug concentration was found
in rat milk). It is not known whether quinapril or its metabolites are secreted
in human milk. Because many drugs are secreted in human milk, caution should be
exercised when ACCUPRIL is given to a nursing mother, and in general, nursing
should be interrupted.
Children
The safety and effectiveness of ACCUPRIL in
children have not been established, therefore use in this age group is not
recommended.
Geriatrics
Of the total number of subjects in clinical
studies of ACCUPRIL, 21% were 65 and over. (There was no distinction between
patients over 65 or over 75 years.) No overall differences in safety or
effectiveness were observed between these subjects and younger subjects, and
other reported clinical experience has not identified differences in responses
between the elderly and younger patients, but greater sensitivity of some older
individuals cannot be ruled out.
This drug is known to
be substantially excreted by the kidney, and the risk of toxic reactions to
this drug may be greater in patients with impaired renal function. Because
elderly patients are more likely to have decreased renal function, care should
be taken in dose selection, and it may be useful to monitor renal function.
Elderly patients
exhibited increased area under the plasma concentration time curve 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.
Occupational Hazards
Driving and Operating Machinery: The ability to
engage in activities such as operating machinery or operating a motor vehicle
may be impaired, especially when initiating quinapril therapy.
Drug Interactions
Concomitant Diuretic Therapy
Patients concomitantly taking ACE inhibitors and
diuretics, and especially those in whom diuretic therapy was recently
instituted, may occasionally experience an excessive reduction of blood
pressure after initiation of therapy. The possibility of hypotensive effects
after the first dose of ACCUPRIL can be minimized by either discontinuing the
diuretic or increasing the salt intake (except in patients with heart failure),
prior to initiation of treatment with ACCUPRIL. If it is not possible to
discontinue the diuretic, the starting dose of ACCUPRIL should be reduced and
the patient should be closely observed for several hours following initial dose
and until blood pressure has stabilized (see Warnings and Dosage).
Agents Increasing Serum Potassium
Since ACCUPRIL decreases aldosterone production,
elevation of serum potassium may occur. Potassium sparing diuretics such as
spironolactone, triamterene or amiloride, or potassium supplements should be
given only for documented hypokalemia and with caution and frequent monitoring
of serum potassium, since they may lead to a significant increase in serum
potassium. Salt substitutes which contain potassium should also be used with
caution.
Agents Causing Renin Release
The antihypertensive effect of ACCUPRIL is
augmented by antihypertensive agents that cause renin release (e.g.
diuretics).
Agents Affecting Sympathetic Activity
Agents affecting sympathetic activity (e.g.
ganglionic blocking agents or adrenergic neuron blocking agents) may be used
with caution. Beta-adrenergic blocking drugs add some further antihypertensive
effect to ACCUPRIL.
Tetracycline
Concomitant administration of tetracycline with
ACCUPRIL reduced the absorption of tetracycline in healthy volunteers (by
28-37%) due to the presence of magnesium carbonate as an excipient in the
formulation. This interaction should be considered with concomitant use of
ACCUPRIL and tetracycline or other drugs which interact with magnesium.
Lithium
As with other drugs which eliminate sodium, the
lithium elimination may be reduced. Therefore, the serum lithium levels should
be monitored carefully if lithium salts are to be administered.
Other Agents
In single dose pharmacokinetic studies, no
important changes in pharmacokinetic parameters were observed when ACCUPRIL was
used concomitantly with propranolol, hydrochlorothiazide, digoxin, or cimetidine.
No change in prothrombin time occurred when ACCUPRIL and warfarin were given
together.
Information to Be Provided to the Patient
Note: As with many other drugs, certain advice to
patients being treated with ACCUPRIL 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.
Angioedema
Angioedema, including laryngeal edema, may occur
especially following the first dose of ACCUPRIL. Patients should be so advised
and told to report immediately any signs or symptoms suggesting angioedema,
such as swelling of face, extremities, eyes, lips, tongue, difficulty in
swallowing or breathing. They should immediately stop taking ACCUPRIL and
consult with their physician.
Hypotension
Patients should be cautioned to report
light-headedness, especially during the first few days of ACCUPRIL therapy. If
actual syncope occurs, the patients should be told to discontinue the drug and
consult with their 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.
Agranulocytosis/Neutropenia
Patients should be told to report promptly to
their physician any indication of infection (e.g. sore throat, fever), as this
may be a sign of neutropenia.
Impaired Liver Function
Patients should be advised to return to the
physician if he/she experiences any symptoms possibly related to liver
dysfunction. This would include “viral-like symptoms” in the first weeks to
months of therapy (such as fever, malaise, muscle pain, rash or adenopathy
which are possible indicators of hypersensitivity reactions), or if abdominal
pain, nausea or vomiting, loss of appetite, jaundice, itching or any other
unexplained symptoms occur during therapy.
Hyperkalemia
Patients should be told not to use salt
substitutes containing potassium without consulting their physician.
Surgery
Patients planning to undergo surgery and/or
anesthesia should be told to inform their physician that they are taking an ACE
inhibitor.
Pregnancy
Since the use of ACCUPRIL during pregnancy can
cause injury and even death of the developing fetus, patients should be advised
to report promptly to their physician if they become pregnant.
Adverse Effects
Hypertension
ACCUPRIL (quinapril hydrochloride) monotherapy
has been evaluated for safety in 2005 hypertensive patients enrolled in
placebo-controlled clinical trials. These trials included 313 elderly patients.
There was no increase in the incidence of adverse events in elderly patients
given the same daily dosages. ACCUPRIL has been evaluated for long-term safety
in over 1100 patients treated for one year or more. Adverse events were usually
mild and transient in nature.
The most serious
adverse event was angioedema (0.1%). Renal insufficiency (1 case), agranulocytosis
(1 case) and mild azotemia (2 cases in CHF patients) have been reported.
Myocardial infarction and cerebrovascular accident occurred, possibly secondary
to excessive hypotension in high risk patients (see Warnings).
The most frequent adverse
events in controlled clinical trials were headache (8.1%), dizziness (4.1%),
cough (3.2%), fatigue (3.2%), rhinitis (3.2%), nausea and/or vomiting (2.3%),
and abdominal pain (2.0%).
Discontinuation of
therapy because of adverse events was required in 4.7% of patients treated with
ACCUPRIL in placebo controlled trials.
Congestive Heart Failure (CHF)
At least one adverse event was experienced by
605 (55%) of the 1108 patients with congestive heart failure. Five hundred
twenty five of these patients were evaluated for safety in controlled clinical
trials. The frequencies of adverse events were similar for both sexes as well
as for younger (< 65 years) and older (≥ 65 years) patients.
The most serious
non-fatal adverse events/reactions were angioedema (0.1%), chest pain of
unknown origin (0.8%), angina pectoris (0.4%), hypotension (0.1%), and impaired
renal function. Myocardial infarct, and cerebrovascular accident occurred (see
Warnings). Rare cases of eosinophilic pneumonitis have been reported. Hepatitis
or hepatic failure have rarely been observed with other ACE inhibitors.
The most frequent
adverse events in controlled clinical trials were dizziness (11.2%), cough
(7.6%), chest pain (6.5%), dyspnea (5.5%), fatigue (5.1%), and nausea/vomiting
(5.0%).
Discontinuation due to
adverse events in controlled clinical trials was required for 41 (8.0%)
patients. Hypotension (0.8%) and cough (0.8%) were the most common reasons for
withdrawal.
Adverse events
occurring in ≥ 0.5% of 2005 hypertensive patients treated with ACCUPRIL
monotherapy and in 525 patients with congestive heart failure treated with
ACCUPRIL as adjunctive therapy, in controlled clinical trials, are presented
in Table 1.
CPS:Accupril_t1Click here for Table 1
Table 1: ACCUPRIL
Adverse Events in Patients (≥ 0.5%) with
Hypertension and Congestive Heart Failure in Controlled Clinical Trials
(Irrespective of Causal Relationship)
|
|
Hypertensiona
% Patients
(N=2005)
|
Congestive Heart
Failureb
% Patients
(N=525)
|
|
Body as a Whole
|
|
Chest Pain
|
1.2
|
6.5
|
|
Fatigue
|
3.2
|
5.1
|
|
Headache
|
8.1
|
3.2
|
|
Back Pain
|
1.3
|
1.7
|
|
Asthenia
|
1.0
|
1.7
|
|
Peripheral Edema
|
0.9
|
1.5
|
|
Generalized Edema
|
0.7
|
0.2
|
|
Cardiovascular System
|
|
Hypotension
|
1.0
|
3.4
|
|
Angina Pectoris
|
0.2
|
2.3
|
|
Palpitation
|
0.4
|
1.3
|
|
Tachycardia
|
0.2
|
1.1
|
|
Myocardial Infarct
|
—
|
0.6
|
|
Arrhythmia
|
0.1
|
0.6
|
|
Digestive System
|
|
Nausea and/or vomiting
|
2.3
|
5.0
|
|
Abdominal pain
|
2.0
|
2.5
|
|
Diarrhea
|
1.9
|
3.4
|
|
Dyspepsia
|
1.9
|
1.5
|
|
Dry mouth or throat
|
0.4
|
0.8
|
|
Musculoskeletal System
|
|
Myalgia
|
1.7
|
2.9
|
|
Nervous System
|
|
Dizziness
|
4.1
|
11.2
|
|
Insomnia
|
1.3
|
1.1
|
|
Paresthesia
|
1.0
|
1.3
|
|
Nervousness
|
1.0
|
0.2
|
|
Somnolence
|
0.9
|
0.6
|
|
Syncope
|
0.3
|
0.6
|
|
Vertigo
|
0.4
|
0.8
|
|
Depression
|
0.6
|
1.0
|
|
Respiratory
|
|
Cough
|
3.2
|
7.6
|
|
Dyspnea
|
0.9
|
5.5
|
|
Hemoptysis
|
—
|
0.6
|
|
Rhinitis
|
3.2
|
2.5
|
|
Skin and Appendages
|
|
Rash
|
0.6
|
1.9
|
|
Sweating increased
|
0.8
|
1.1
|
|
Pruritus
|
0.6
|
0.4
|
|
Urogenital System
|
|
Impotence
|
0.5
|
0.2
|
|
Special Senses
|
|
Amblyopia
|
0.3
|
1.3
|
|
Unusual Taste
|
0.1
|
0.8
|
|
Abnormal Vision
|
0.1
|
0.6
|
|
Taste Loss
|
0.2
|
0.6
|
|
|
|
|
|
|
a ACCUPRIL monotherapy.
b ACCUPRIL as adjunctive therapy to
diuretic and/or digitalis.
Adverse events occurring in <0.5% of patients
with hypertension or congestive heart failure include:
Body as a whole
Allergy, face edema, chill, weight increase,
dehydration.
Cardiovascular
Vasodilatation, cerebrovascular accident, heart
failure, ventricular tachycardia, atrial flutter.
Digestive System
Constipation, tongue edema, GI hemorrhage,
anorexia, bloody stools.
Hemic and Lymphatic System
Anemia, including hemolytic anemia,
agranulocytosis.
Nervous System
Confusion, amnesia, anxiety, arthralgia.
Musculoskeletal System
Arthritis.
Respiratory System
Asthma, hoarseness.
Skin and Appendages
Dermatitis, urticaria, eczema, Stevens-Johnson
syndrome.
Urogenital system
Dysuria, polyuria, impaired renal function.
Special Senses
Tinnitus.
Laboratory Deviations
Hematuria, WBC decreased, elevated BUN,
hyperglycemia, azotemia.
Clinical adverse experiences probably, possibly,
or definitely related, or of uncertain relationship to therapy occuring in 0.5%
to ≤ 1.0% of the patients treated with quinapril (with or without
concomitant diuretic) in controlled or uncontrolled clinical trials and less
frequent events seen in clinical trials or post-marketing experience (indicated
by a *) included:
