CAPTOPRIL
DESCRIPTION:
USE IN PREGNANCY
WHEN USED IN PREGNANCY DURING THE SECOND
AND THIRD TRIMESTERS, ACE INHIBITORS CAN
CAUSE INJURY AND EVEN DEATH TO THE
DEVELOPING FETUS. When pregnancy is
detected, ACETEN should be discontinued as
soon as possible. SEE WARNINGS:
FETAL/NEONATAL MORBIDITY AND MORTALITY.
ACETEN (captopril tablets) is a specific competitive inhibitor of angiotensin
I-converting enzyme (ACE), the enzyme responsible for the conversion of
angiotensin I to angiotensin II.
ACETEN (captopril tablets) is designated chemically as 1-((2S)-3-mercapto- 2-
methylpropionyl)-L-proline (MW 217.29).
Captopril is a white to off-white crystalline powder that may have a slight
sulfurous odor; it is soluble in water (approx. 160 mg/mL), methanol, and
ethanol and sparingly soluble in chloroform and ethyl acetate.
ACTIONS/CLINICAL PHARMACOLOGY:
MECHANISM OF ACTION
The mechanism of action of ACETEN (captopril tablets) has not yet been fully
elucidated. Its beneficial effects in hypertension and heart failure appear to
result primarily from suppression of the renin-angiotensin-aldosterone system.
However, there is no consistent correlation between renin levels and response to
the drug. Renin, an enzyme synthesized by the kidneys, is released into the
circulation where it acts on a plasma globulin substrate to produce angiotensin
I, a relatively inactive decapeptide. Angiotensin I is then converted by
angiotensin converting enzyme (ACE) to angiotensin II, a potent endogenous
vasoconstrictor substance. Angiotensin II also stimulates aldosterone secretion
from the adrenal cortex, thereby contributing to sodium and fluid retention.
ACETEN (captopril tablets) prevents the conversion of angiotensin I to
angiotensin II by inhibition of ACE, a peptidyldipeptide carboxy hydrolase. This
inhibition has been demonstrated in both healthy human subjects and in animals
by showing that the elevation of blood pressure caused by exogenously
administered angiotensin I was attenuated or abolished by captopril. In animal
studies, captopril did not alter the pressor responses to a number of other
agents, including angiotensin II and norepinephrine, indicating specificity of
action.
ACE is identical to "bradykininase", and ACETEN (captopril tablets) may also
interfere with the degradation of the vasodepressor peptide, bradykinin.
Increased concentrations of bradykinin or prostaglandin E2 may also have a role
in the therapeutic effect of ACETEN.
Inhibition of ACE results in decreased plasma angiotensin II and increased
plasma renin activity (PRA), the latter resulting from loss of negative feedback
on renin release caused by reduction in angiotensin II. The reduction of
angiotensin II leads to decreased aldosterone secretion, and, as a result, small
increases in serum potassium may occur along with sodium and fluid loss.
The antihypertensive effects persist for a longer period of time than does
demonstrable inhibition of circulating ACE. It is not known whether the ACE
present in vascular endothelium is inhibited longer than the ACE in circulating
blood.
PHARMACOKINETICS
After oral administration of therapeutic doses of ACETEN, rapid absorption
occurs with peak blood levels at about one hour. The presence of food in the
gastrointestinal tract reduces absorption by about 30 to 40 percent; captopril
therefore should be given one hour before meals. Based on carbon-14 labeling,
average minimal absorption is approximately 75 percent. In a 24-hour period,
over 95 percent of the absorbed dose is eliminated in the urine; 40 to 50
percent is unchanged drug; most of the remainder is the disulfide dimer of
captopril and captopril- cysteine disulfide.
Approximately 25 to 30 percent of the circulating drug is bound to plasma
proteins. The apparent elimination half-life for total radioactivity in blood is
probably less than 3 hours. An accurate determination of half-life of unchanged
captopril is not, at present, possible, but it is probably less than 2 hours. In
patients with renal impairment, however, retention of captopril occurs (see
DOSAGE AND ADMINISTRATION).
PHARMACODYNAMICS
Administration of ACETEN results in a reduction of peripheral arterial
resistance in hypertensive patients with either no change, or an increase, in
cardiac output. There is an increase in renal blood flow following
administration of ACETEN and glomerular filtration rate is usually unchanged.
Reductions of blood pressure are usually maximal 60 to 90 minutes after oral
administration of an individual dose of ACETEN. The duration of effect is dose
related. The reduction in blood pressure may be progressive, so to achieve
maximal therapeutic effects, several weeks of therapy may be required. The blood
pressure lowering effects of captopril and thiazide-type diuretics are additive.
In contrast, captopril and beta-blockers have a less than additive effect.
Blood pressure is lowered to about the same extent in both standing and supine
positions. Orthostatic effects and tachycardia are infrequent but may occur in
volume-depleted patients. Abrupt withdrawal of ACETEN has not been associated
with a rapid increase in blood pressure.
In patients with heart failure, significantly decreased peripheral (systemic
vascular) resistance and blood pressure (afterload), reduced pulmonary capillary
wedge pressure (preload) and pulmonary vascular resistance, increased cardiac
output, and increased exercise tolerance time (ETT) have been demonstrated.
These hemodynamic and clinical effects occur after the first dose and appear to
persist for the duration of therapy. Placebo controlled studies of 12 weeks
duration in patients who did not respond adequately to diuretics and digitalis
show no tolerance to beneficial effects on ETT; open studies, with exposure up
to 18 months in some cases, also indicate that ETT benefit is maintained.
Clinical improvement has been observed in some patients where acute hemodynamic
effects were minimal.
The Survival and Ventricular Enlargement (SAVE) study was a multicenter,
randomized, double- blind, placebo-controlled trial conducted in 2,231 patients
(age 21-79 years) who survived the acute phase of a myocardial infarction and
did not have active ischemia. Patients had left ventricular dysfunction (LVD),
defined as a resting left ventricular ejection fraction =40%, but at the time
of randomization were not sufficiently symptomatic to require ACE inhibitor
therapy for heart failure. About half of the patients had had symptoms of heart
failure in the past. Patients were given a test dose of 6.25 mg oral ACETEN
(captopril tablets) and were randomized within 3-16 days post-infarction to
receive either ACETEN or placebo in addition to conventional therapy. ACETEN
was initiated at 6.25 mg or 12.5 mg tid and after two weeks titrated to a target
maintenance dose of 50 mg tid. About 80% of patients were receiving the target
dose at the end of the study. Patients were followed for a minimum of two years
and for up to five years, with an average follow-up of 3.5 years.
Baseline blood pressure was 113/70 mm Hg and 112/70 mm Hg for the placebo and
ACETEN groups, respectively. Blood pressure increased slightly in both
treatment groups during the study and was somewhat lower in the ACETEN group
(119/74 vs. 125/77 mm Hg at 1 yr).
Therapy with ACETEN improved long-term survival and clinical outcomes compared
to placebo. The risk reduction for all cause mortality was 19% (P=0.02) and for
cardiovascular death was 21% (P=0.014). Captopril treated subjects had 22%
(P=0.034) fewer first hospitalizations for heart failure. Compared to placebo,
22% fewer patients receiving captopril developed symptoms of overt heart
failure. There was no significant difference between groups in total
hospitalizations for all cause (2056 placebo; 2036 captopril).
ACETEN was well tolerated in the presence of other therapies such as aspirin,
beta blockers, nitrates, vasodilators, calcium antagonists and diuretics.
In a multicenter, double-blind, placebo controlled trial, 409 patients, age 18-
49 of either gender, with or without hypertension, with type I (juvenile type,
onset before age 30) insulin-dependent diabetes mellitus, retinopathy,
proteinuria >/=500 mg per day and serum creatinine =2.5 mg/dL, were randomized
to placebo or ACETEN (25 mg tid) and followed for up to 4.8 years (median 3
years). To achieve blood pressure control, additional antihypertensive agents
(diuretics, beta blockers, centrally acting agents, or vasodilators) were added
as needed for patients in both groups.
The ACETEN group had a 51% reduction in risk of doubling of serum creatinine (P
<0.01) and a 51% reduction in risk for the combined endpoint of end-stage renal
disease (dialysis or transplantation) or death (P <0.01). ACETEN treatment
resulted in a 30% reduction in urine protein excretion within the first 3 months
(P <0.05), which was maintained throughout the trial. The ACETEN group had
somewhat better blood pressure control than the placebo group, but the effects
of ACETEN on renal function were greater than would be expected from the group
differences in blood pressure reduction alone. ACETEN was well-tolerated in
this patient population.
In two multicenter, double-blind, placebo controlled studies, a total of 235
normotensive patients with insulin-dependent diabetes mellitus, retinopathy and
microalbuminuria (20-200 mcgm/min) were randomized to placebo or ACETEN (50 mg
bid) and followed for up to 2 years. ACETEN delayed the progression to overt
nephropathy (proteinuria >/=500 mg/day) in both studies (risk reduction 67% to
76%; P <0.05). ACETEN also reduced the albumin excretion rate. However, the
long term clinical benefit of reducing the progression from microalbuminuria to
proteinuria has not been established.
Studies in rats and cats indicate that ACETEN (captopril tablets) does not
cross the blood- brain barrier to any significant extent.
INDICATIONS AND USAGE:
HYPERTENSION: ACETEN is indicated for the treatment of hypertension.
In using ACETEN, consideration should be given to the risk of
neutropenia/agranulocytosis (see WARNINGS).
ACETEN may be used as initial therapy for patients with normal renal function,
in whom the risk is relatively low. In patients with impaired renal function,
particularly those with collagen vascular disease, captopril should be reserved
for hypertensives who have either developed unacceptable side effects on other
drugs, or have failed to respond satisfactorily to drug combinations.
ACETEN is effective alone and in combination with other antihypertensive
agents, especially thiazide-type diuretics. The blood pressure lowering effects
of captopril and thiazides are approximately additive.
HEART FAILURE: ACETEN is indicated in the treatment of congestive heart failure
in combination with diuretics and digitalis. The beneficial effect of captopril
in heart failure does not require the presence of digitalis, however, most
controlled clinical trial experience with captopril has been in patients
receiving digitalis, as well as diuretic treatment.
LEFT VENTRICULAR DYSFUNCTION AFTER MYOCARDIAL INFARCTION: ACETEN is indicated
to improve survival following myocardial infarction in clinically stable
patients with left ventricular dysfunction manifested as an ejection fraction
=40% and to reduce the incidence of overt heart failure and subsequent
hospitalizations for congestive heart failure in these patients.
DIABETIC NEPHROPATHY: ACETEN is indicated for the treatment of diabetic
nephropathy (proteinuria >500 mg/day) in patients with type I insulin-dependent
diabetes mellitus and retinopathy. ACETEN decreases the rate of progression of
renal insufficiency and development of serious adverse clinical outcomes (death
or need for renal transplantation or dialysis).
In considering use of ACETEN, it should be noted that in controlled trials ACE
inhibitors have an effect on blood pressure that is less in black patients than
in non-blacks. In addition, ACE inhibitors (for which adequate data are
available) use a higher rate of angioedema in black than in non-black patients
(see WARNINGS: ANGIOEDEMA).
CONTRAINDICATIONS:
ACETEN is contraindicated in patients who are hypersensitive to this product or
any other angiotensin-converting enzyme inhibitor (e.g., a patient who has
experienced angioedema during therapy with any other ACE inhibitor).
WARNINGS:
USE IN PREGNANCY
WHEN USED IN PREGNANCY DURING THE SECOND
AND THIRD TRIMESTERS, ACE INHIBITORS CAN
CAUSE INJURY AND EVEN DEATH TO THE
DEVELOPING FETUS. When pregnancy is
detected, ACETEN should be discontinued as
soon as possible. SEE WARNINGS:
FETAL/NEONATAL MORBIDITY AND MORTALITY.
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 ACETEN) may be subject to a
variety of adverse reactions, some of them serious./ ANGIOEDEMA: Angioedema
involving the extremities, face, lips, mucous membranes, tongue, glottis or
larynx has been seen in patients treated with ACE inhibitors, including
captopril. If angioedema involves the tongue, glottis or larynx, airway
obstruction may occur and be fatal. Emergency therapy, including but not
necessarily limited to, subcutaneous administration of a 1:1000 solution of
epinephrine should be promptly instituted.
Swelling confined to the face, mucous membranes of the mouth, lips and
extremities has usually resolved with discontinuation of captopril; some cases
required medical therapy. (See PRECAUTIONS: Information for Patients and ADVERSE
REACTIONS.)
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.
NEUTROPENIA/AGRANULOCYTOSIS
Neutropenia (<1000/mm(cube)) with myeloid hypoplasia has resulted from use of
captopril. About half of the neutropenic patients developed systemic or oral
cavity infections or other features of the syndrome of agranulocytosis.
The risk of neutropenia is dependent on the clinical status of the patient:
In clinical trials in patients with hypertension who have normal renal function
(serum creatinine less than 1.6 mg/dL and no collagen vascular disease),
neutropenia has been seen in one patient out of over 8,600 exposed.
In patients with some degree of renal failure (serum creatinine at least 1.6
mg/dL) but no collagen vascular disease, the risk of neutropenia in clinical
trials was about 1 per 500, a frequency over 15 times that for uncomplicated
hypertension. Daily doses of captopril were relatively high in these patients,
particularly in view of their diminished renal function. In foreign marketing
experience in patients with renal failure, use of allopurinol concomitantly
with captopril has been associated with neutropenia but this association has not
appeared in U.S. reports.
In patients with collagen vascular diseases (e.g., systemic lupus
erythematosus, scleroderma) and impaired renal function, neutropenia occurred
in 3.7 percent of patients in clinical trials.
While none of the over 750 patients in formal clinical trials of heart failure
developed neutropenia, it has occurred during the subsequent clinical
experience. About half of the reported cases had serum creatinine >/= 1.6 mg/dL
and more than 75 percent were in patients also receiving procainamide. In heart
failure, it appears that the same risk factors for neutropenia are present.
The neutropenia has usually been detected within three months after captopril
was started. Bone marrow examinations in patients with neutropenia consistently
showed myeloid hypoplasia, frequently accompanied by erythroid hypoplasia and
decreased numbers of megakaryocytes (e.g., hypoplastic bone marrow and
pancytopenia); anemia and thrombocytopenia were sometimes seen.
In general, neutrophils returned to normal in about two weeks after captopril
was discontinued, and serious infections were limited to clinically complex
patients. About 13 percent of the cases of neutropenia have ended fatally, but
almost all fatalities were in patients with serious illness, having collagen
vascular disease, renal failure, heart failure or immunosuppressant therapy, or
a combination of these complicating factors.
EVALUATION OF THE HYPERTENSIVE OR HEART FAILURE PATIENT SHOULD ALWAYS INCLUDE
ASSESSMENT OF RENAL FUNCTION.
If captopril is used in patients with impaired renal function, white blood cell
and differential counts should be evaluated prior to starting treatment and at
approximately two-week intervals for about three months, then periodically.
In patients with collagen vascular disease or who are exposed to other drugs
known to affect the white cells or immune response, particularly when there is
impaired renal function, captopril should be used only after an assessment of
benefit and risk, and then with caution.
All patients treated with captopril should be told to report any signs of
infection (e.g., sore throat, fever). If infection is suspected, white cell
counts should be performed without delay.
Since discontinuation of captopril and other drugs has generally led to prompt
return of the white count to normal, upon confirmation of neutropenia
(neutrophil count < 1000/mm(cube)) the physician should withdraw captopril and
closely follow the patient's course.
PROTEINURIA
Total urinary proteins greater than 1 g per day were seen in about 0.7 percent
of patients receiving captopril. About 90 percent of affected patients had
evidence of prior renal disease or received relatively high doses of captopril
(in excess of 150 mg/day), or both. The nephrotic syndrome occurred in about
one-fifth of proteinuric patients. In most cases, proteinuria subsided or
cleared within six months whether or not captopril was continued. Parameters of
renal function, such as BUN and creatinine, were seldom altered in the patients
with proteinuria.
HYPOTENSION
Excessive hypotension was rarely seen in hypertensive patients but is a possible
consequence of captopril use in salt/volume depleted persons (such as those
treated vigorously with diuretics), patients with heart failure or those
patients undergoing renal dialysis. (See PRECAUTIONS: Drug Interactions.)
In heart failure, where the blood pressure was either normal or low, transient
decreases in mean blood pressure greater than 20 percent were recorded in about
half of the patients. This transient hypotension is more likely to occur after
any of the first several doses and is usually well tolerated, producing either
no symptoms or brief mild lightheadedness, although in rare instances it has
been associated with arrhythmia or conduction defects. Hypotension was the
reason for discontinuation of drug in 3.6 percent of patients with heart
failure.
BECAUSE OF THE POTENTIAL FALL IN BLOOD PRESSURE IN THESE PATIENTS, THERAPY
SHOULD BE STARTED UNDER VERY CLOSE MEDICAL SUPERVISION. A starting dose of 6.25
or 12.5 mg tid may minimize the hypotensive effect. Patients should be followed
closely for the first two weeks of treatment and whenever the dose of captopril
and/or diuretic is increased. In patients with heart failure, reducing the dose
of diuretic, if feasible, may minimize the fall in blood pressure.
Hypotension is not Per Se a reason to discontinue captopril. Some decrease of
systemic blood pressure is a common and desirable observation upon initiation of
ACETEN (captopril tablets) treatment in heart failure. The magnitude of the
decrease is greatest early in the course of treatment; this effect stabilizes
within a week or two, and generally returns to pretreatment levels, without a
decrease in therapeutic efficacy, within two months.
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 captopril 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, captopril 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. While
captopril may be removed from the adult circulation by hemodialysis, there is
inadequate data concerning the effectiveness of hemodialysis for removing it
from the circulation of neonates or children. Peritoneal dialysis is not
effective for removing captopril; there is no information concerning exchange
transfusion for removing captopril from the general circulation.
When captopril was given to rabbits at doses about 0.8 to 70 times (on a mg/kg
basis) the maximum recommended human dose, low incidences of craniofacial
malformations were seen. No teratogenic effects of captopril were seen in
studies of pregnant rats and hamsters. On a mg/kg basis, the doses used were up
to 150 times (in hamsters) and 625 times (in rats) the maximum recommended human
dose.
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.
PRECAUTIONS:
GENERAL
Impaired Renal Function
Hypertension--Some patients with renal disease, particularly those with severe
renal artery stenosis, have developed increases in BUN and serum creatinine
after reduction of blood pressure with captopril. Captopril dosage reduction
and/or discontinuation of diuretic may be required. For some of these patients,
it may not be possible to normalize blood pressure and maintain adequate renal
perfusion.
Heart Failure--About 20 percent of patients develop stable elevations of BUN and
serum creatinine greater than 20 percent above normal or baseline upon long-term
treatment with captopril. Less than 5 percent of patients, generally those with
severe preexisting renal disease, required discontinuation of treatment due to
progressively increasing creatinine; subsequent improvement probably depends
upon the severity of the underlying renal disease.
See ACTIONS/CLINICAL PHARMACOLOGY, DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS:
Altered Laboratory Findings.
Hyperkalemia: Elevations in serum potassium have been observed in some patients
treated with ACE inhibitors, including captopril. When treated with ACE
inhibitors, patients at risk for the development of hyperkalemia include those
with: renal insufficiency; diabetes mellitus; and those using concomitant
potassium-sparing diuretics, potassium supplements or potassium-containing salt
substitutes; or other drugs associated with increases in serum potassium. In a
trial of type I diabetic patients with proteinuria, the incidence of withdrawal
of treatment with captopril for hyperkalemia was 2% (4/207). In two trials of
normotensive type I diabetic patients with microalbuminuria, no captopril group
subjects had hyperkalemia (0/116). (See PRECAUTIONS: Information for Patients
and Drug Interactions; ADVERSE REACTIONS: Altered Laboratory Findings.)
Cough: Presumably due to the inhibition of the degradation of endogenous
bradykinin, persistent nonproductive cough has been reported with all ACE
inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-
induced cough should be considered in the differential diagnosis of cough.
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 as others.
Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia
with agents that produce hypotension, captopril 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.
HEMODIALYSIS
Recent clinical observations have shown an association of hypersensitivity-like
(anaphylactoid) reactions during hemodialysis with high-flux dialysis membranes
(e.g., AN69) in patients receiving ACE inhibitors. In these patients,
consideration should be given to using a different type of dialysis membrane or
a different class of medication. (See WARNINGS: Anaphylactoid reactions during
membrane exposure.)
INFORMATION FOR PATIENTS
Patients should be advised to immediately report to their physician any signs or
symptoms suggesting angioedema (e.g., swelling of face, eyes, lips, tongue,
larynx and extremities; difficulty in swallowing or breathing; hoarseness) and
to discontinue therapy. (See WARNINGS: Angioedema.)
Patients should be told to report promptly any indication of infection (e.g.,
sore throat, fever), which may be a sign of neutropenia, or of progressive edema
which might be related to proteinuria and nephrotic syndrome.
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 the
physician.
Patients should be advised not to use potassium- sparing diuretics, potassium
supplements or potassium-containing salt substitutes without consulting their
physician. (See PRECAUTIONS: General and Drug Interactions; ADVERSE REACTIONS.)
Patients should be warned against interruption or discontinuation of medication
unless instructed by the physician.
Heart failure patients on captopril therapy should be cautioned against rapid
increases in physical activity.
Patients should be informed that ACETEN (captopril tablets) should be taken one
hour before meals (see DOSAGE AND ADMINISTRATION).
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.
DRUG INTERACTIONS
Hypotension--Patients On Diuretic Therapy: Patients on diuretics and especially
those in whom diuretic therapy was recently instituted, as well as those on
severe dietary salt restriction or dialysis, may occasionally experience a
precipitous reduction of blood pressure usually within the first hour after
receiving the initial dose of captopril.
The possibility of hypotensive effects with captopril can be minimized by either
discontinuing the diuretic or increasing the salt intake approximately one week
prior to initiation of treatment with ACETEN (captopril tablets) or initiating
therapy with small doses (6.25 or 12.5mg). Alternatively, provide medical
supervision for at least one hour after the initial dose. If hypotension occurs,
the patient should be placed in a supine position and, if necessary, receive an
intravenous infusion of normal saline. This transient hypotensive response is
not a contraindication to further doses which can be given without difficulty
once the blood pressure has increased after volume expansion.
Agents Having Vasodilator Activity: Data on the effect of concomitant use of
other vasodilators in patients receiving ACETEN for heart failure are not
available; therefore, nitroglycerin or other nitrates (as used for management of
angina) or other drugs having vasodilator activity should, if possible, be
discontinued before starting ACETEN. If resumed during ACETEN therapy, such
agents should be administered cautiously, and perhaps at lower dosage.
Agents Causing Renin Release: Captopril's effect will be augmented by
antihypertensive agents that cause renin release. For example, diuretics (e.g.,
thiazides) may activate the renin- angiotensin-aldosterone system.
Agents Affecting Sympathetic Activity: The sympathetic nervous system may be
especially important in supporting blood pressure in patients receiving
captopril alone or with diuretics. Therefore, agents affecting sympathetic
activity (e.g., ganglionic blocking agents or adrenergic neuron blocking agents)
should be used with caution. Beta-adrenergic blocking drugs add some further
antihypertensive effect to captopril, but the overall response is less than
additive.
Agents Increasing Serum Potassium: Since captopril 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 then with caution, since
they may lead to a significant increase of serum potassium. Salt substitutes
containing potassium should also be used with caution.
Inhibitors Of Endogenous Prostaglandin Synthesis: It has been reported that
indomethacin may reduce the antihypertensive effect of captopril, especially in
cases of low renin hypertension. Other nonsteroidal anti-inflammatory agents
(e.g., aspirin) may also have this effect.
Lithium: Increased serum lithium levels and symptoms of lithium toxicity have
been reported in patients receiving concomitant lithium and ACE inhibitor
therapy. These drugs should be coadministered with caution and frequent
monitoring of serum lithium levels is recommended. If a diuretic is also used,
it may increase the risk of lithium toxicity.
DRUG/LABORATORY TEST INTERACTION
Captopril may cause a false-positive urine test for acetone.
CARCINOGENESIS, MUTAGENESIS AND IMPAIRMENT OF FERTILITY
Two-year studies with doses of 50 to 1350 mg/kg/day in mice and rats failed to
show any evidence of carcinogenic potential. The high dose in these studies is
150 times the maximum recommended human dose of 450 mg, assuming a 50-kg
subject. On a body-surface-area basis, the high doses for mice and rats are 13
and 26 times the maximum recommended human dose, respectively.
Studies in rats have revealed no impairment of fertility.
ANIMAL TOXICOLOGY
Chronic oral toxicity studies were conducted in rats (2 years), dogs (47 weeks;
1 year), mice (2 years), and monkeys (1 year). Significant drug- related
toxicity included effects on hematopoiesis, renal toxicity, erosion/ulceration
of the stomach, and variation of retinal blood vessels.
Reductions in hemoglobin and/or hematocrit values were seen in mice, rats, and
monkeys at doses 50 to 150 times the maximum recommended human dose (MRHD) of
450 mg, assuming a 50-mg subject. On a body-surface-area basis, these doses are
5 to 25 times maximum recommended human dose (MRHD). Anemia, leukopenia,
thrombocytopenia, and bone marrow suppression occurred in dogs at doses 8 to 30
times MRHD on a body-weight basis (4 to 15 times MRHD on a surface-area basis).
The reductions in hemoglobin and hematocrit values in rats and mice were only
significant at 1 year and returned to normal with continued dosing by the end of
the study. Marked anemia was seen at all dose levels (8 to 30 times MRHD) in
dogs, whereas moderate to marked leukopenia was noted only at 15 and 30 times
MRHD and thrombocytopenia at 30 times MRHD. The anemia could be reversed upon
discontinuation of dosing. Bone marrow suppression occurred to a varying degree,
being associated only with dogs that died or were sacrificed in a moribund
condition in the 1 year study. However, in the 47-week study at a dose 30 times
MRHD, bone marrow suppression was found to be reversible upon continued drug
administration.
Captopril caused hyperplasia of the juxtaglomerular apparatus of the kidneys in
mice and rats at doses 7 to 200 times MRHD on a body- weight basis (0.6 to 35
times MRHD on a surface- area basis); in monkeys at 20 to 60 times MRHD on a
body-weight basis (7 to 20 times MRHD on a surface-area basis); and in dogs at
30 times MRHD on a body-weight basis (15 times MRHD on a surface-area basis).
Gastric erosions/ulcerations were increased in incidence in male rats at 20 to
200 times MRHD on a body-weight basis (3.5 and 35 times MRHD on a surface-area
basis); in dogs at 30 times MRHD on a body-weight basis (15 times on MRHD on a
surface-area basis); and in monkeys at 65 times MRHD on a body-weight basis (20
times MRHD on a surface-area basis). Rabbits developed gastric and intestinal
ulcers when given oral doses approximately 30 times MRHD on a body-weight basis
(10 times MRHD on a surface-area basis) for only 5 to 7 days.
In the two-year rat study, irreversible and progressive variations in the
caliber of retinal vessels (focal sacculations and constrictions) occurred at
all dose levels (7 to 200 times MRHD) on a body-weight basis; 1 to 35 times MRHD
on a surface-area basis in a dose-related fashion. The effect was first observed
in the 88th week of dosing, with a progressively increased incidence thereafter,
even after cessation of dosing.
PREGNANCY CATEGORIES C (FIRST TRIMESTER) AND D (SECOND AND THIRD TRIMESTERS)
SEE WARNINGS: FETAL/NEONATAL MORBIDITY AND MORTALITY.
NURSING MOTHERS
Concentrations of captopril in human milk are approximately one percent of those
in maternal blood. Because of the potential for serious adverse reactions in
nursing infants from captopril, a decision should be made whether to discontinue
nursing or to discontinue the drug, taking into account the importance of
ACETEN to the mother. (See PRECAUTIONS: Pediatric Use.)
PEDIATRIC USE
Safety and effectiveness in pediatric patients have not been established. There
is limited experience reported in the literature with the use of captopril in
the pediatric population; dosage, on a weight basis, was generally reported to
be comparable to or less than that used in adults.
Infants, especially newborns, may be more susceptible to the adverse hemodynamic
effects of captopril. Excessive, prolonged and unpredictable decreases in blood
pressure and associated complications, including oliguria and seizures, have
been reported.
ACETEN (captopril tablets) should be used in children only if other measures
for controlling blood pressure have not been effective.
DRUG INTERACTIONS:
Hypotension--Patients On Diuretic Therapy: Patients on diuretics and especially
those in whom diuretic therapy was recently instituted, as well as those on
severe dietary salt restriction or dialysis, may occasionally experience a
precipitous reduction of blood pressure usually within the first hour after
receiving the initial dose of captopril.
The possibility of hypotensive effects with captopril can be minimized by either
discontinuing the diuretic or increasing the salt intake approximately one week
prior to initiation of treatment with ACETEN (captopril tablets) or initiating
therapy with small doses (6.25 or 12.5mg). Alternatively, provide medical
supervision for at least one hour after the initial dose. If hypotension occurs,
the patient should be placed in a supine position and, if necessary, receive an
intravenous infusion of normal saline. This transient hypotensive response is
not a contraindication to further doses which can be given without difficulty
once the blood pressure has increased after volume expansion.
Agents Having Vasodilator Activity: Data on the effect of concomitant use of
other vasodilators in patients receiving ACETEN for heart failure are not
available; therefore, nitroglycerin or other nitrates (as used for management of
angina) or other drugs having vasodilator activity should, if possible, be
discontinued before starting ACETEN. If resumed during ACETEN therapy, such
agents should be administered cautiously, and perhaps at lower dosage.
Agents Causing Renin Release: Captopril's effect will be augmented by
antihypertensive agents that cause renin release. For example, diuretics (e.g.,
thiazides) may activate the renin- angiotensin-aldosterone system.
Agents Affecting Sympathetic Activity: The sympathetic nervous system may be
especially important in supporting blood pressure in patients receiving
captopril alone or with diuretics. Therefore, agents affecting sympathetic
activity (e.g., ganglionic blocking agents or adrenergic neuron blocking agents)
should be used with caution. Beta-adrenergic blocking drugs add some further
antihypertensive effect to captopril, but the overall response is less than
additive.
Agents Increasing Serum Potassium: Since captopril 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 then with caution, since
they may lead to a significant increase of serum potassium. Salt substitutes
containing potassium should also be used with caution.
Inhibitors Of Endogenous Prostaglandin Synthesis: It has been reported that
indomethacin may reduce the antihypertensive effect of captopril, especially in
cases of low renin hypertension. Other nonsteroidal anti-inflammatory agents
(e.g., aspirin) may also have this effect.
Lithium: Increased serum lithium levels and symptoms of lithium toxicity have
been reported in patients receiving concomitant lithium and ACE inhibitor
therapy. These drugs should be coadministered with caution and frequent
monitoring of serum lithium levels is recommended. If a diuretic is also used,
it may increase the risk of lithium toxicity.
(See Also PRECAUTIONS.)
ADVERSE REACTIONS:
Reported incidences are based on clinical trials involving approximately 7000
patients.
Renal: About one of 100 patients developed proteinuria (see WARNINGS).
Each of the following has been reported in approximately 1 to 2 of 1000 patients
and are of uncertain relationship to drug use: renal insufficiency, renal
failure, nephrotic syndrome, polyuria, oliguria, and urinary frequency.
Hematologic: Neutropenia/agranulocytosis has occurred (see WARNINGS). Cases of
anemia, thrombocytopenia, and pancytopenia have been reported.
Dermatologic: Rash, often with pruritus, and sometimes with fever, arthralgia,
and eosinophilia, occurred in about 4 to 7 (depending on renal status and dose)
of 100 patients, usually during the first four weeks of therapy. It is usually
maculopapular, and rarely urticarial. The rash is usually mild and disappears
within a few days of dosage reduction, short-term treatment with an
antihistaminic agent, and/or discontinuing therapy; remission may occur even if
captopril is continued. Pruritus, without rash, occurs in about 2 of 100
patients. Between 7 and 10 percent of patients with skin rash have shown an
eosinophilia and/or positive ANA titers. A reversible associated pemphigoid-like
lesion, and photosensitivity, have also been reported.
Flushing or pallor has been reported in 2 to 5 of 1000 patients.
Cardiovascular: Hypotension may occur; see WARNINGS and PRECAUTIONS (Drug
Interactions) for discussion of hypotension with captopril therapy.
Tachycardia, chest pain, and palpitations have each been observed in
approximately 1 of 100 patients.
Angina pectoris, myocardial infarction, Raynaud's syndrome, and congestive heart
failure have each occurred in 2 to 3 of 1000 patients.
Dysgeusia: Approximately 2 to 4 (depending on renal status and dose) of 100
patients developed a diminution or loss of taste perception. Taste impairment is
reversible and usually self-limited (2 to 3 months) even with continued drug
administration. Weight loss may be associated with the loss of taste.
Angioedema: Angioedema involving the extremities, face, lips, mucous membranes,
tongue, glottis or larynx has been reported in approximately one in 1000
patients. Angioedema involving the upper airways has caused fatal airway
obstruction. (See WARNINGS: Angioedema and PRECAUTIONS: Information for
Patients.)
Cough: Cough has been reported in 0.5-2% of patients treated with captopril in
clinical trials (see PRECAUTIONS: General, Cough).
The following have been reported in about 0.5 to 2 percent of patients but did
not appear at increased frequency compared to placebo or other treatments used
in controlled trials: gastric irritation, abdominal pain, nausea, vomiting,
diarrhea, anorexia, constipation, aphthous ulcers, peptic ulcer, dizziness,
headache, malaise, fatigue, insomnia, dry mouth, dyspnea, alopecia,
paresthesias.
Other clinical adverse effects reported since the drug was marketed are listed
below by body system. In this setting, an incidence or causal relationship
cannot be accurately determined.
Body As A Whole: Anaphylactoid reactions (see WARNINGS: Anaphylactoid and
possibly related reactions and PRECAUTIONS: Hemodialysis).
General: Asthenia, gynecomastia.
Cardiovascular: Cardiac arrest, cerebrovascular accident/insufficiency, rhythm
disturbances, orthostatic hypotension, syncope.
Dermatologic: Bullous pemphigus, erythema multiforme (including Stevens-Johnson
syndrome), exfoliative dermatitis.
Gastrointestinal: Pancreatitis, glossitis, dyspepsia.
Hematologic: Anemia, including aplastic and hemolytic.
Hepatobiliary: Jaundice, hepatitis, including rare cases of necrosis,
cholestasis.
Metabolic: Symptomatic hyponatremia.
Musculoskeletal: Myalgia, myasthenia.
Nervous/Psychiatric: Ataxia, confusion, depression, nervousness, somnolence.
Respiratory: Bronchospasm, eosinophilic pneumonitis, rhinitis.
Special Senses: Blurred vision.
Urogenital: Impotence.
As with other ACE inhibitors, a syndrome has been reported which may include:
fever, myalgia, arthralgia, interstitial nephritis, vasculitis, rash or other
dermatologic manifestations, eosinophilia and an elevated ESR.
FETAL/NEONATAL MORBIDITY AND MORTALITY
SEE WARNINGS: FETAL/NEONATAL MORBIDITY AND MORTALITY.
ALTERED LABORATORY FINDINGS
Serum Electrolytes: Hyperkalemia: small increases in serum potassium, especially
in patients with renal impairment (see PRECAUTIONS).
Hyponatremia: particularly in patients receiving a low sodium diet or
concomitant diuretics.
BUN/Serum Creatinine: Transient elevations of BUN or serum creatinine especially
in volume or salt depleted patients or those with renovascular hypertension may
occur. Rapid reduction of longstanding or markedly elevated blood pressure can
result in decreases in the glomerular filtration rate and, in turn, lead to
increases in BUN or serum creatinine.
Hematologic: A positive ANA has been reported.
Liver Function Tests: Elevations of liver transaminases, alkaline phosphatase,
and serum bilirubin have occurred.
OVERDOSAGE:
Correction of hypotension would be of primary concern. Volume expansion with an
intravenous infusion of normal saline is the treatment of choice for restoration
of blood pressure.
While captopril may be removed from the adult circulation by hemodialysis, there
is inadequate data concerning the effectiveness of hemodialysis for removing it
from the circulation of neonates or children. Peritoneal dialysis is not
effective for removing captopril; there is no information concerning exchange
transfusion for removing captopril from the general circulation.
DOSAGE AND ADMINISTRATION:
ACETEN (captopril tablets) should be taken one hour before meals. Dosage must
be individualized.
HYPERTENSION--Initiation of therapy requires consideration of recent
antihypertensive drug treatment, the extent of blood pressure elevation, salt
restriction, and other clinical circumstances. If possible, discontinue the
patient's previous antihypertensive drug regimen for one week before starting
ACETEN.
The initial dose of ACETEN is 25 mg bid or tid. If satisfactory reduction of
blood pressure has not been achieved after one or two weeks, the dose may be
increased to 50 mg bid or tid. Concomitant sodium restriction may be beneficial
when ACETEN is used alone.
The dose of ACETEN in hypertension usually does not exceed 50 mg tid.
Therefore, if the blood pressure has not been satisfactorily controlled after
one to two weeks at this dose, (and the patient is not already receiving a
diuretic), a modest dose of a thiazide-type diuretic (e.g., hydrochlorothiazide,
25 mg daily), should be added. The diuretic dose may be increased at one- to
two-week intervals until its highest usual antihypertensive dose is reached.
If ACETEN is being started in a patient already receiving a diuretic, ACETEN
therapy should be initiated under close medical supervision (see WARNINGS and
PRECAUTIONS (Drug Interactions) regarding hypotension), with dosage and
titration of ACETEN as noted above.
If further blood pressure reduction is required, the dose of ACETEN may be
increased to 100 mg bid or tid and then, if necessary, to 150 mg bid or tid
(while continuing the diuretic). The usual dose range is 25 to 150 mg bid or
tid. A maximum daily dose of 450 mg ACETEN should not be exceeded.
For patients with severe hypertension (e.g., accelerated or malignant
hypertension), when temporary discontinuation of current antihypertensive
therapy is not practical or desirable, or when prompt titration to more
normotensive blood pressure levels is indicated, diuretic should be continued
but other current antihypertensive medication stopped and ACETEN dosage
promptly initiated at 25 mg bid or tid, under close medical supervision.
When necessitated by the patient's clinical condition, the daily dose of ACETEN
may be increased every 24 hours or less under continuous medical supervision
until a satisfactory blood pressure response is obtained or the maximum dose of
ACETEN is reached. In this regimen, addition of a more potent diuretic, e.g.,
furosemide, may also be indicated.
Beta-blockers may also be used in conjunction with ACETEN therapy (see
PRECAUTIONS: Drug Interactions), but the effects of the two drugs are less than
additive.
HEART FAILURE--Initiation of therapy requires consideration of recent diuretic
therapy and the possibility of severe salt/volume depletion. In patients with
either normal or low blood pressure, who have been vigorously treated with
diuretics and who may be hyponatremic and/or hypovolemic, a starting dose of
6.25 or 12.5 mg tid may minimize the magnitude or duration of the hypotensive
effect (see WARNINGS: Hypotension); for these patients, titration to the usual
daily dosage can then occur within the next several days.
For most patients the usual initial daily dosage is 25 mg tid. After a dose of
50 mg tid is reached, further increases in dosage should be delayed, where
possible, for at least two weeks to determine if a satisfactory response occurs.
Most patients studied have had a satisfactory clinical improvement at 50 or 100
mg tid. A maximum daily dose of 450 mg of ACETEN (captopril tablets) should not
be exceeded.
ACETEN should generally be used in conjunction with a diuretic and digitalis.
ACETEN therapy must be initiated under very close medical supervision.
LEFT VENTRICULAR DYSFUNCTION AFTER MYOCARDIAL INFARCTION: The recommended dose
for long-term use in patients following a myocardial infarction is a target
maintenance dose of 50 mg tid.
Therapy may be initiated as early as three days following a myocardial
infarction. After a single dose of 6.25 mg, ACETEN therapy should be initiated
at 12.5 mg tid. ACETEN should then be increased to 25 mg tid during the next
several days and to a target dose of 50 mg tid over the next several weeks as
tolerated (see ACTIONS/CLINICAL PHARMACOLOGY).
ACETEN may be used in patients treated with other post-myocardial infarction
therapies, e.g., thrombolytics, aspirin, beta blockers.
DIABETIC NEPHROPATHY: The recommended dose of ACETEN for long term use to treat
diabetic nephropathy is 25 mg tid.
Other antihypertensives such as diuretics, beta blockers, centrally acting
agents or vasodilators may be used in conjunction with ACETEN if additional
therapy is required to further lower blood pressure.
DOSAGE ADJUSTMENT IN RENAL IMPAIRMENT--Because ACETEN (captopril tablets) is
excreted primarily by the kidneys, excretion rates are reduced in patients with
impaired renal function. These patients will take longer to reach steady-state
captopril levels and will reach higher steady- state levels for a given daily
dose than patients with normal renal function. Therefore, these patients may
respond to smaller or less frequent doses.
Accordingly, for patients with significant renal impairment, initial daily
dosage of ACETEN should be reduced, and smaller increments utilized for
titration, which should be quite slow (one- to two-week intervals). After the
desired therapeutic effect has been achieved, the dose should be slowly back-
titrated to determine the minimal effective dose. When concomitant diuretic
therapy is required, a loop diuretic (e.g., furosemide), rather than a thiazide
diuretic, is preferred in patients with severe renal impairment. (See WARNINGS:
Anaphylactoid reactions during membrane exposure and PRECAUTIONS: Hemodialysis.)
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