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Captopril
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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, CAPOTEN should be discontinued as soon as possible. See WARNINGS:
Fetal/Neonatal Morbidity and Mortality.
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DESCRIPTION
CAPOTEN® (captopril tablets, USP) is a specific
competitive inhibitor of angiotensin I-converting enzyme (ACE), the enzyme responsible
for the conversion of angiotensin I to angiotensin II.
CAPOTEN 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.
CAPOTEN is available in potencies of 12.5 mg, 25 mg, 50 mg,
and 100 mg as scored tablets for oral administration. Inactive ingredients:
microcrystalline cellulose, corn starch, lactose, and stearic acid.
CLINICAL PHARMACOLOGY
Mechanism of Action
The mechanism of action of CAPOTEN has not yet been fully elucidated.
Its beneficial effects in hypertension and heart failure appear to result primarily
from suppression of the renin-angio-tensin-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 angio-tensin II,a potent endogenous vasoconstrictor substance.
Angio-tensin II also stimulates aldosterone secretion from the adrenal cortex,
thereby contributing to sodium and fluid retention.
CAPOTEN 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 CAPOTEN
may also interfere with the degradation of the vasodepressor peptide, brady-
kinin. Increased concentrations of bradykinin or prostaglandin E2 may
also have a role in the therapeutic effect of CAPOTEN.
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 CAPOTEN,
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 disul-fide 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 pre-sent, 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 CAPOTEN 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 CAPOTEN 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 CAPOTEN. 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 tachycar-dia are infrequent
but may occur in volume-depleted patients. Abrupt withdrawal of CAPOTEN 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 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 symptoms
of heart failure in the past. Patients were given a test dose of 6.25 mg oral
CAPOTEN and were randomized within 3-16 days post-infarction to receive either
CAPOTEN or placebo in addition to conventional therapy. CAPOTEN 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 mmHg and 112/70 mmHg for
the placebo and CAPOTEN groups, respectively. Blood pressure increased slightly
in both treatment groups during the study and was somewhat lower in the CAPOTEN
group (119/74 vs. 125/77 mmHg at 1 yr).
Therapy with CAPOTEN 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 place-bo,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).
CAPOTEN 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 ³500 mg per day and serum
creatinine £ 2.5 mg/dL, were randomized to placebo
or CAPOTEN (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 CAPOTEN 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).
CAPOTEN 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
CAPO-TEN group had somewhat better blood pressure control than the placebo group,
but the effects of CAPOTEN on renal function were greater than would be expected
from the group differences in blood pressure reduction alone. CAPOTEN 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 µg/ min) were randomized to placebo
or CAPOTEN (50 mg bid) and followed for up to 2 years. CAPOTEN delayed the progression
to overt nephropathy (proteinuria ³ 500 mg/day) in
both studies (risk reduction 67% to 76%; P<0.05).CAPOTEN 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 CAPOTEN does not cross
the blood-brain barrier to any significant extent.
INDICATIONS AND USAGE
Hypertension
CAPOTEN (captopril tablets, USP) is indicated for the treatment
of hypertension.
In using CAPOTEN, consideration should be given to the risk
of neutropenia/ agranulocytosis (see WARNINGS).
CAPOTEN 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.
CAPOTEN is effective alone and in combination with other anti-hypertensive
agents, especially thiazide-type diuretics. The blood pressure lowering effects
of captopril and thiazides are approximately additive.
Heart Failure
CAPOTEN is indicated in the treatment of congestive heart failure
usually 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
CAPOTEN 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
CAPOTENis indicated for the treatment of diabetic nephropathy
(proteinuria >500 mg/day) in patients with type I insulin-dependent diabetes
mellitus and retinopathy. CAPOTEN 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 CAPOTEN, 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) cause a higher rate of angio-edema in black than in non-black
patients (see WARNINGS: Head and Neck
Angioedema and Intestinal Angioedema).
DOSAGE AND ADMINISTRATION
CAPOTEN 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 CAPOTEN.
The initial dose of CAPOTEN (captopril tablets, USP) 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 CAPOTEN is used alone.
The dose of CAPOTEN 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 CAPOTEN is being started in a patient already receiving
a diuretic, CAPOTEN therapy should be initiated under close medical supervision
(see WARNINGS and PRECAUTIONS:
Drug Interactions regarding hypotension),with
dosage and titration of CAPOTEN as noted above.
If further blood pressure reduction is required, the dose of
CAPOTEN 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 CAPOTEN 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
antihy-pertensive medication stopped and CAPOTEN 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 CAPOTEN 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 CAPOTEN 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 CAPOTEN
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 CAPOTEN should not be
exceeded.
CAPOTEN should generally be used in conjunction with a diuretic
and digitalis. CAPOTEN 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, CAPOTEN therapy should
be initiated at 12.5 mg tid. CAPOTEN 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 CLINICAL PHARMACOLOGY).
CAPOTEN may be used in patients treated with other post-myocardial
infarction therapies, e.g., thrombolytics, aspirin, beta blockers.
Diabetic Nephropathy
The recommended dose of CAPOTEN for long term use to treat
diabetic nephropathy is 25 mg tid.
Other antihypertensives such as diuretics, beta blockers, central-ly
acting agents or vasodilators may be used in conjunction with CAPOTEN if additional
therapy is required to further lower blood pressure.
Dosage Adjustment in Renal Impairment
Because CAPOTEN 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 CAPOTEN 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.)
HOW SUPPLIED
CAPOTEN® (Captopril Tablets, USP)
12.5 mg tablets in bottles of 100 (NDC49884-793-01),
25 mg tablets in bottles of 100 (NDC 49884-794-01) and 1000 (NDC 49884-794-10),
50 mg tablets in bottles of 100 (NDC 49884-795-01) and 1000 (NDC49884-795-10),and
100 mg tablets in bottles of 100 (NDC 49884-796-01).Bottles contain a
desiccant-charcoal canister.
Unimatic® unit-dose packs containing 100 tablets
are also available for each potency: 12.5 mg (NDC49884-793-74), 25
mg (NDC49884-794-74), 50 mg (NDC49884-795-74).
The 12.5 mg tablet is a biconvex oval with a partial
bisect bar; the 25 mg tablet is a biconvex rounded square with a quadri-sect
bar; the 50 and 100 mg tablets are biconvex ovals with a bisect bar.
All captopril tablets are white and may exhibit a slight sulfurous
odor.
Storage
Do not store above 30º C (86º F). Keep bottles tightly closed
(protect from moisture).
Manufactured by: Bristol-Myers Squibb Company
Princeton,NJ08543, Manufactured for: Par Pharmaceutical,Inc. Spring
Valley,NY10977 USA 5131DIM-10 1081433A3, Revised:06/03 J4-458M
SIDE EFFECTS
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 pancy-topenia 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 anti-histaminic
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 photo-sensitivity,
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 hypoten-sion 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 per-ception. 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: Head and Neck Angioedema, Intestinal
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, pares-thesias.
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 possible 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 cre-atinine 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.
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 CAPOTEN (captopril
tablets, USP) or initiating therapy with small doses (6.25 or 12.5 mg). 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 CAPOTEN 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 CAPOTEN. If resumed during CAPOTEN
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 coad-ministered 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.
Cardiac Glycosides
In a study of young healthy male subjects no evidence of a
direct pharmacokinetic captopril-digoxin interaction could be found.
Loop Diuretics: Furosemide administered concurrently
with cap-topril does not alter the pharmacokinetics of captopril in renally
impaired hypertensive patients.
Allopurinol
In a study of healthy male volunteers no significant pharmacokinetic
interaction occurred when captopril and allop-urinol were administered concomitantly
for 6 days.
Drug/Laboratory Test Interaction
Captopril may cause a false-positive urine test for acetone.
WARNINGS
Anaphylactoid and Possibly Related Reactions
Presumably because angiotensin-converting enzyme inhibitors
affect the metabolism of eicosanoids and polypeptides, including endogenous
bradykinin, patients receiving ACE inhibitors (including CAPOTEN) may be subject
to a variety of adverse reactions, some of them serious.
Head and Neck Angioedema
Angioedema involving the ex-tremities, 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, air-way
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.)
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.
Anaphylactoid reactions during desensitization
Two patients undergoing desensitizing treatment with hymenoptera
venom while receiving ACE inhibitors sustained life-threatening anaphy-lactoid
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
Anaphy-lactoid 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/mm3) 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 creati-nine
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 ³
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 thrombocytope-nia 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 sus-pected,
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/mm3) 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 pro-teinuric patients. In most cases, proteinuria subsided
or cleared within six months whether or not captopril was continued. Param-eters
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 diuret-ics),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 CAPOTEN (captopril tablets, USP) 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 report-ed, 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 capto-pril. 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 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 pro-teinuria, 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 withhigh-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:
Head and Neck Angioedema and Intestinal 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 diuret-ics,
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 CAPOTEN 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.
Carcinogenesis, Mutagenesis, 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 hemato-poiesis, 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-kg subject. On a body-surface-area basis,
these doses are 5 to 25 times maximum recommended 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 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 CAPOTEN 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.
CAPOTEN should be used in pediatric patients only if other
measures for controlling blood pressure have not been effective.
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