CAPTOPRIL

Main information

  • Trade name:
  • CAPTOPRIL tablet
  • Composition:
  • CAPTOPRIL 25 mg
  • Prescription type:
  • PRESCRIPTION DRUG
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CAPTOPRIL tablet
    United States
  • Language:
  • English

Status

  • Source:
  • DailyMed - NLM - National Library of Medicine
  • Authorization status:
  • Abbreviated New Drug Application
  • Last update:
  • 06-11-2017

Summary of Product characteristics: dosage, interactions, side effects

CAPTOPRIL- captopril tablet

REMEDYREPACK INC.

----------

Captopril Tablets

CAPTOPRIL TABLETS, USP

Rev. 03/16

Rx Only

WARNING: FETAL TOXICITY

When pregnancy is detected, discontinue captopril tablets as soon as possible.

Drugs that act directly on the renin-angiotensin system can cause injury and death to the

developing fetus. See WARNINGS: Fetal Toxicity

DESCRIPTION

Captopril Tablets, USP are a specific competitive inhibitor of angiotensin I-converting enzyme (ACE),

the enzyme responsible for the conversion of angiotensin I to angiotensin II.

Captopril is designated chemically as 1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline and has the

following structural formula:

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.

Each tablet for oral administration contains 12.5 mg, 25 mg, 50 mg or 100 mg of captopril. In addition,

each tablet contains the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide,

microcrystalline cellulose, sodium starch glycolate (derived from potato), starch (derived from corn),

and stearic acid.

CLINICAL PHARMACOLOGY

Mechanism of Action:

The mechanism of action of 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.

Captopril tablets prevent 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 captopril tablets may also interfere with the degradation of the

vasodepressor peptide, bradykinin. Increased concentrations of bradykinin or prostaglandin E

may also

have a role in the therapeutic effect of captopril tablets.

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 captopril tablets, 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 tablets 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 captopril tablets 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 captopril tablets 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 captopril tablets. 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

captopril tablets 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 21to79 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

captopril tablets and were randomized within 3 to 16 days post-infarction to receive either captopril

tablets or placebo in addition to conventional therapy. Captopril tablets were initiated at 6.25 mg or 12.5

mg t.i.d. and after two weeks titrated to a target maintenance dose of 50 mg t.i.d. 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 captopril tablets

groups, respectively. Blood pressure increased slightly in both treatment groups during the study and

was somewhat lower in the captopril tablets group (119/74 vs. 125/77 mmHg at 1 yr).

Therapy with captopril tablets 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

(2,056 placebo; 2,036 captopril). Captopril tablets were 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 18to49 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 captopril tablets (25 mg t.i.d.) 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 captopril tablets 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). Captopril tablets 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 captopril tablets

group had somewhat better blood pressure control than the placebo group, but the effects of captopril

tablets on renal function were greater than would be expected from the group differences in blood

pressure reduction alone. Captopril tablets were 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 to 200 mcg/min) were

randomized to placebo or captopril tablets (50 mg b.i.d.) and followed for up to 2 years. Captopril

tablets delayed the progression to overt nephropathy (proteinuria ≥ 500 mg/day) in both studies (risk

reduction 67% to 76%; P < 0.05). Captopril tablets 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 captopril tablets does not cross the blood-brain barrier to any

significant extent.

INDICATIONS AND USAGE

Hypertens ion:

Captopril Tablets, USP are indicated for the treatment of hypertension.

In using Captopril Tablets, USP, consideration should be given to the risk of

neutropenia/agranulocytosis (see WARNINGS).

Captopril Tablets, USP 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.

Captopril Tablets, USP are 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:

Captopril Tablets, USP are 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: Captopril Tablets, USP are 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: Captopril Tablets, USP are indicated for the treatment of diabetic nephropathy

(proteinuria > 500 mg/day) in patients with type I insulin-dependent diabetes mellitus and retinopathy.

Captopril Tablets, USP 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 Captopril Tablets, USP, 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 angioedema in black than in non-

black patients (see WARNINGS: Head and Neck Angioedema and Intestinal Angioedema).

CONTRAINDICATIONS

Captopril tablets are 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).

Do not co-administer aliskiren with captopril tablets in patients with diabetes (see PRECAUTIONS,

Drug Interactions).

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 captopril

tablets) may be subject to a variety of adverse reactions, some of them serious.

Head and Neck 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.)

Patients receiving coadministration of ACE inhibitor and mTOR (mammalian target of rapamycin)

inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema.

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 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/Agranulocytos is

Neutropenia (< 1000/mm

) 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

) 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.

Hypotens ion

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 light-headedness, although in rare instance 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 t.i.d. 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 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 Toxicity

Pregnancy Category D

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of

pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting

oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential

neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When

pregnancy is detected, discontinue captopril tablets as soon as possible. These adverse outcomes are

usually associated with use of these drugs in the second and third trimester of pregnancy. Most

epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first

trimester have not distinguished drugs affecting the renin-angiotensin system from other

antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is

important to optimize outcomes for both mothers and fetus.

In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-

angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform

serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed,

discontinue captopril tablets, unless it is considered lifesaving for the mother. Fetal testing may be

appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that

oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe

infants with histories of in utero exposure to captopril tablets for hypotension, oliguria, and

hyperkalemia. (See PRECAUTIONS, Pediatric Use).

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 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.

Hemodialys is

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 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 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 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 exposure to captopril

tablets during pregnancy. Discuss treatment options with women planning to become pregnant. Patients

should be asked to report pregnancies to their physicians as soon as possible.

Drug Interactions:

Dual Blockade of the Renin-Angiotensin System (RAS)

Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is

associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including

acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS

inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use

of RAS inhibitors.

Closely monitor blood pressure, renal function and electrolytes in patients on captopril tablets and other

agents that block the RAS.

Do not co-administer aliskiren with captopril tablets in patients with diabetes. Avoid use of aliskiren

with captopril tablets in patients with renal impairment (GFR < 60 ml/min).

Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2

Inhibitors): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with

compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with

ACE inhibitors, including captopril, may result in deterioration of renal function, including possible

acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients

receiving captopril and NSAID therapy. The antihypertensive effect of ACE inhibitors, including

captopril, may be attenuated by NSAIDs.

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

captopril tablets 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 captopril tablets 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 captopril tablets. If resumed during captopril tablets 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.

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.

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 captopril 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 allopurinol were administered concomitantly for 6 days.

Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have

been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant

ACE inhibitor therapy including captopril tablets.

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 kg 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 88

week of dosing, with a progressively increased incidence thereafter, even after

cessation of dosing.

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 captopril tablets to the mother. (See PRECAUTIONS: Pediatric Use.)

Pediatric Use

Neonates with a History of In Utero Exposure to Captopril Tablets:

If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion.

Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or

substituting for disordered renal function. 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.

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.

Captopril tablets should be used in pediatric patients only if other measures for controlling blood

pressure have not been effective.

ADVERSE REACTIONS

Reported incidences are based on clinical trials involving approximately 7,000 patients.

Renal: About one of 100 patients developed proteinuria (see WARNINGS).

Each of the following has been reported in approximately 1 to 2 of 1,000 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 1,000 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 1,000 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 1,000 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 to 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 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.

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.

To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at

1-877-233-2001, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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

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 captopril

tablets.

The initial dose of captopril tablets is 25 mg b.i.d. or t.i.d. If satisfactory reduction of blood pressure

has not been achieved after one or two weeks, the dose may be increased to 50 mg b.i.d. or t.i.d.

Concomitant sodium restriction may be beneficial when captopril tablets are used alone.

The dose of captopril tablets in hypertension usually does not exceed 50 mg t.i.d. 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 captopril tablets are being started in a patient already receiving a diuretic, captopril tablets therapy

should be initiated under close medical supervision (see WARNINGS and PRECAUTIONS: Drug

Interactions regarding hypotension), with dosage and titration of captopril tablets as noted above.

If further blood pressure reduction is required, the dose of captopril tablets may be increased to 100

mg b.i.d. or t.i.d. and then, if necessary, to 150 mg b.i.d. or t.i.d. (while continuing the diuretic). The

usual dose range is 25 to 150 mg b.i.d. or t.i.d. A maximum daily dose of 450 mg captopril tablets

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 captopril tablets dosage promptly initiated at 25 mg b.i.d. or

t.i.d., under close medical supervision.

When necessitated by the patient’s clinical condition, the daily dose of captopril tablets 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 captopril tablets 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 captopril tablets 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 t.i.d. 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 t.i.d. After a dose of 50 mg t.i.d. 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 t.i.d. A maximum daily dose of 450 mg of captopril tablets should not be exceeded.

Captopril tablets should generally be used in conjunction with a diuretic and digitalis. Captopril tablets

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 t.i.d.

Therapy may be initiated as early as three days following a myocardial infarction. After a single dose

of 6.25 mg, captopril tablets therapy should be initiated at 12.5 mg t.i.d. Captopril tablets should then be

increased to 25 mg t.i.d. during the next several days and to a target dose of 50 mg t.i.d. over the next

several weeks as tolerated (see CLINICAL PHARMACOLOGY).

Captopril tablets may be used in patients treated with other post-myocardial infarction therapies, e.g.,

thrombolytics, aspirin, beta blockers.

Diabetic Nephropathy: The recommended dose of captopril tablets for long term use to treat diabetic

nephropathy is 25 mg t.i.d.

Other antihypertensives such as diuretics, beta blockers, centrally acting agents or vasodilators may be

used in conjunction with captopril tablets if additional therapy is required to further lower blood

pressure.

Dosage Adjustment in Renal Impairment: Because captopril tablets are 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 captopril tablets

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

Captopril Tablets, USP are available as follows:

12.5 mg - White, Round Tablets; Debossed "W-7" on one side and Scored on the other side.

Bottles of 100 tablets.

Bottles of 1000 tablets.

25 mg - White, Round Tablets; Debossed "WW 172" on one side and Quadrisect Scored on the other

side.

Bottles of 100 tablets.

Bottles of 1000 tablets.

50 mg - White, Oblong Tablets; Debossed "WW 173" on one side and Scored on the other side.

Bottles of 100 tablets.

Bottles of 1000 tablets.

100 mg - White, Oblong Tablets; Debossed "WW 174" on one side and Scored on the other side.

Bottles of 100 tablets.

All Captopril Tablets, USP are white and may exhibit a slight sulfurous odor.

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Keep bottles tightly closed (protect from moisture).

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

Manufactured by:

West-Ward Pharmaceuticals Corp.

Eatontown, NJ 07724

Revised March 2016

DRUG: Captopril

GENERIC: Captopril

DOSAGE: TABLET

ADMINSTRATION: ORAL

NDC: 61786-621-02

COLOR: white

SHAPE: ROUND

SCORE: Four equal pieces

SIZE: 8 mm

IMPRINT: WW;172

PACKAGING: 30 in 1 BLISTER PACK

ACTIVE INGREDIENT(S):

CAPTOPRIL 25mg in 1

INACTIVE INGREDIENT(S):

ANHYDROUS LACTOSE

SODIUM STARCH GLYCOLATE TYPE A POTATO

STARCH, CORN

CELLULOSE, MICROCRYSTALLINE

SILICON DIOXIDE

STEARIC ACID

CAPTOPRIL

captopril tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 178 6 -6 21(NDC:0 143-1172)

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

CAPTO PRIL (UNII: 9 G6 4RSX1XD) (CAPTOPRIL - UNII:9 G6 4RSX1XD)

CAPTOPRIL

25 mg

REMEDYREPACK INC.

Inactive Ingredients

Ingredient Name

Stre ng th

ANHYDRO US LACTO SE (UNII: 3SY5LH9 PMK)

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

SO DIUM STARCH GLYCO LATE TYPE A PO TATO (UNII: 58 56 J3G2A2)

STARCH, CO RN (UNII: O8 232NY3SJ)

STEARIC ACID (UNII: 4ELV7Z6 5AP)

Product Characteristics

Color

white

S core

4 pieces

S hap e

ROUND

S iz e

8 mm

Flavor

Imprint Code

WW;172

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date Marketing End Date

1

NDC:6 178 6 -6 21-0 2 30 in 1 BLISTER PACK; Type 0 : No t a Co mbinatio n Pro duct

0 3/14/20 16

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 7450 5

0 3/14/20 16

Labeler -

REMEDYREPACK INC. (829572556)

Revised: 9/2017