Captopril tablet

Captopril tablet
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Zaghw, M.D. [2], Amr Marawan, M.D. [3]

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Black Box Warning

Fetal Toxicity See full prescribing information for complete Boxed Warning. When pregnancy is detected, discontinue captopril as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

Overview

Captopril tablet is an Angiontensin converting enzyme inhibitor that is FDA approved for the {{{indicationType}}} of hypertension, heart failure, left ventricular dysfunction after myocardial infarction, diabetic nephropathy. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypotension, rash, hyperkalemia (11% ), disorder of taste, cough (0.5% to 2%).

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Hypertension

• Dosing Information

• Initial dose: Captopril 25 mg PO bid or Captopril 25 mg PO tid; may be increased after 1 to 2 weeks to Captopril 50 mg PO bid or Captopril 50 mg PO tid, then to Captopril 100 to 150 mg PO bid/tid (in combination with a thiazide diuretic) if needed (MAX 450 mg daily)

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

In using captopril, consideration should be given to the risk of neutropenia/agranulocytosis.

Captopril 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 is effective alone and in combination with other antihypertensive agents, especially thiazide-type diuretics. The blood pressure lowering effects of captopril and thiazides are approximately additive.

Heart Failure

• Dosing Information

• Initial dose: (patients with normal or low blood pressure, vigorous diuretic therapy, volume depletion) Captopril 6.25 to 12.5 mg PO tid
• Initial dose: Captopril PO 25 mg tid
• Maintenance dose: Captopril 50 to 100 mg PO tid (MAX 450 mg PO daily)

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

• Dosing Information

• Initial dose: Captopril 6.25 mg PO for one dose starting as early as 3 days after myocardial infarction,
• Maintenance dose: Captopril 12.5 mg tid a day increased to 25 mg PO tid a day in several days; target dose 50 mg PO tid over the next several weeks as tolerated

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

• Dosing Information

• (type 1 diabetes mellitus) Captopril 25 mg PO tid
• (type 2 diabetes mellitus) Captopril 12.5 mg bid, increased to Captopril 12.5 mg tid after 3 months

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 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, 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.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

Acute ST segment elevation myocardial infarction

• Developed by: American College of Cardiology Foundation (ACCF) and American Heart Association (AHA)

• Class of Recommendation: Class I

• Level of Evidence: Level A

• Dosing Information

• An angiotensin-converting enzyme (ACE) inhibitor should be administered within the first 24 hours to all patients with STEMI with anterior location, HF, or ejection fraction (EF) less than or equal to 0.40, unless contraindicated.

Non–Guideline-Supported Use

Cystinuria

• Dosing information

• Case report 1: 150 mg/day for 26 weeks followed by 75 mg for 9 weeks

• Case report 2: 25 mg bid (titrated to achieve a concentration of urinary cystine of less than 200 mg/liter, or to a maximum of 150 mg/day)

Prophylaxis of diabetic retinopathy

• Dosing information

• Case report: 12.5 mg bid for 3 months followed by 12.5 mg tid

Erythrocytosis

• Dosing information

• 25 mg qd This beneficial effect may not be sustained.

Non-diabetic kidney disease

• Dosing information

• RCT report:

• Initial dosage: 12.5 mg bid
• Followed-up treatment: increase the dosage bi-weekly
• Final aim: either blood pressure normalization or reach the maximum of 50 mg bid

• Rearch 1

• Dosage for the first month: 6.25 mg/day
• Dosage for the second month: titrated to 12.5 mg/day
• Finally dosage: titrated to 25 mg/day

• Rsearch 2

• Initial dosage: 6.25 mg tid
• Followed-up treatment: 25 mg tid

• Case report: 25 mg/day, max: 75 mg/day

Diagnosis of primary aldosteronism

• Dosing information

• 25 mg/day

Pseudoprimary hyperaldosteronism

• Dosing information

• Case report 1: long time treatment for 6 months, maximum dose 200 mg/day
• Case reprot 2: 25 mg tid

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

FDA Package Insert for Benazepril contains no information regarding safety and efficacy in pediatric patients

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

Condition 1

Non–Guideline-Supported Use

Condition 1

• Dosing Information

• There is limited information about Off-Label Non–Guideline-Supported Use of Captopril tablet in pediatric patients.

Contraindications

• Hypersensitivity to this product or any other angiotensin-converting enzyme inhibitor
• History of angioedema during therapy with any other ACE inhibitor)

Warnings

Fetal Toxicity See full prescribing information for complete Boxed Warning. When pregnancy is detected, discontinue captopril as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

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 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 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 for hypotension, oliguria, and hyperkalemia.

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.

Adverse Reactions

Clinical Trials Experience

Reported incidences are based on clinical trials involving approximately 7000 patients.

• Renal

• About one of 100 patients developed proteinuria.

• 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. 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 antihistamine agent, and/or discontinuing therapy; remission may occur even if captopril is continued. Pruritus, without rash, occurs in about 2 of 100 patients. Between 7 and 10 percent of patients with skin rash have shown an eosinophilia and/or positive ANA titers. A reversible associated pemphigoid-like lesion, and photosensitivity, have also been reported.

• Flushing or pallor has been reported in 2 to 5 of 1000 patients.

• Cardiovascular

• Hypotension may occur; for discussion of hypotension with captopril therapy.

• Tachycardia, chest pain, and palpitations have each been observed in approximately 1 of 100 patients.

• Angina pectoris, myocardial infarction, Raynaud's syndrome, and congestive heart failure have each occurred in 2 to 3 of 1000 patients.

• Dysgeusia

• Approximately 2 to 4 (depending on renal status and dose) of 100 patients developed a diminution or loss of taste perception. Taste impairment is reversible and usually self-limited (2 to 3 months) even with continued drug administration. Weight loss may be associated with the loss of taste.

• Angioedema

• Angioedema involving the extremities, face, lips, mucous membranes, tongue, glottis or larynx has been reported in approximately one in 1000 patients. Angioedema involving the upper airways has caused fatal airway obstruction. (See WARNINGS, 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.

• 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 pemphigoid, 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.

• 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.

Postmarketing Experience

FDA Package Insert for Benazepril contains no information regarding Postmarketing Experience.

Drug Interactions

• Drug 1

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. Closely monitor blood pressure, renal function and electrolytes in patients on captopril and other agents that affect the RAS.

Do not co-administer aliskiren with captopril in patients with diabetes. Avoid use of aliskiren with captopril 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, 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 captopril 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. If resumed during captopril 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.

Drug /Laboratory Test Interaction

Captopril may cause a false-positive urine test for acetone.

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 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 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.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): D
Pregnancy Category (AUS): D

Labor and Delivery

• FDA Package Insert for Captopril contains no information regarding Labor and Delivery.

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 to the mother.

Pediatric Use

• 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 form 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 should be used in pediatric patients only if other measures for controlling blood pressure have not been effective.

Geriatic Use

• FDA Package Insert for Captopril contains no information regarding the drug in Geriatrics.

Gender

• FDA Package Insert for Captopril contains no information regarding the use of the drug and Gender.

Race

• FDA Package Insert for Captopril contains no information regarding the Race.

Renal Impairment

Dosage Adjustment in Renal Impairment

• Because captopril 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 captopril 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.

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 dose (MRHD). Anemia, leukopenia, thrombocytopenia, and bone marrow suppression occurred in dogs at doses 8 to 30 times MRHD on a body-weight basis (4 to 15 times MRHD on a surface-area basis). The reductions in hemoglobin and hematocrit values in rats and mice were only significant at 1 year and returned to normal with continued dosing by the end of the study. Marked anemia was seen at all dose levels (8 to 30 times MRHD) in dogs, whereas moderate to marked leukopenia was noted only at 15 and 30 times MRHD and thrombocytopenia at 30 times MRHD. The anemia could be reversed upon discontinuation of dosing. Bone marrow suppression occurred to a varying degree, being associated only with dogs that died or were sacrificed in a moribund condition in the 1 year study. However, in the 47-week study at a dose 30 times MRHD, bone marrow suppression was found to be reversible upon continued drug administration.

• Captopril caused hyperplasia of the juxtaglomerular apparatus of the kidneys in mice and rats at doses 7 to 200 times MRHD on a body-weight basis (0.6 to 35 times MRHD on a surface-area basis); in monkeys at 20 to 60 times MRHD on a body-weight basis (7 to 20 times MRHD on a surface-area basis); and in dogs at 30 times MRHD on a body-weight basis (15 times MRHD on a surface-area basis).

• Gastric erosions/ulcerations were increased in incidence in male rats at 20 to 200 times MRHD on a body-weight basis (3.5 and 35 times MRHD on a surface-area basis); in dogs at 30 times MRHD on a body-weight basis (15 times on MRHD on a surface-area basis); and in monkeys at 65 times MRHD on a body-weight basis (20 times MRHD on a surface-area basis). Rabbits developed gastric and intestinal ulcers when given oral doses approximately 30 times MRHD on a body-weight basis (10 times MRHD on a surface-area basis) for only 5 to 7 days.

• In the two-year rat study, irreversible and progressive variations in the caliber of retinal vessels (focal sacculations and constrictions) occurred at all dose levels (7 to 200 times MRHD) on a body-weight basis; 1 to 35 times MRHD on a surface-area basis in a dose-related fashion. The effect was first observed in the 88th week of dosing, with a progressively increased incidence thereafter, even after cessation of dosing.

Hepatic Impairment

FDA Package Insert for Captopril contains no information regarding Hepatic Impairment.

Females of Reproductive Potential and Males

• FDA Package Insert for Captopril contains no information regarding Females of Reproductive Potential and Males.

Immunocompromised Patients

• FDA Package Insert for Captopril contains no information regarding Immunocompromised Patients.

Administration and Monitoring

Administration

(Oral)

Monitoring

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.

IV Compatibility

FDA Package Insert for Benazepril contains no information regarding IV Compatibility.

Overdosage

Hypotension

Signs and Symptoms

Correction of hypotension would be of primary concern.

Management

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.

Pharmacology

Mechanism of Action

The mechanism of action of captopril 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 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 captopril may also interfere with the degradation of the vasodepressor peptide, bradykinin. Increased concentrations of bradykinin or prostaglandin E2 may also have a role in the therapeutic effect of captopril.

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.

Structure

(Description with picture)

Pharmacodynamics

After oral administration of therapeutic doses of captopril, rapid absorption occurs with peak blood levels at about one hour. The presence of food in the gastrointestinal tract reduces absorption by about 30 to 40 percent; captopril therefore should be given one hour before meals. Based on carbon-14 labeling, average minimal absorption is approximately 75 percent. In a 24-hour period, over 95 percent of the absorbed dose is eliminated in the urine; 40 to 50 percent is unchanged drug; most of the remainder is the disulfide dimer of captopril and captopril-cysteine disulfide.

Approximately 25 to 30 percent of the circulating drug is bound to plasma proteins. The apparent elimination half-life for total radioactivity in blood is probably less than 3 hours. An accurate determination of half-life of unchanged captopril is not, at present, possible, but it is probably less than 2 hours. In patients with renal impairment, however, retention of captopril occurs.

Pharmacokinetics

After oral administration of therapeutic doses of captopril, rapid absorption occurs with peak blood levels at about one hour. The presence of food in the gastrointestinal tract reduces absorption by about 30 to 40 percent; captopril therefore should be given one hour before meals. Based on carbon-14 labeling, average minimal absorption is approximately 75 percent. In a 24-hour period, over 95 percent of the absorbed dose is eliminated in the urine; 40 to 50 percent is unchanged drug; most of the remainder is the disulfide dimer of captopril and captopril-cysteine disulfide.

Approximately 25 to 30 percent of the circulating drug is bound to plasma proteins. The apparent elimination half-life for total radioactivity in blood is probably less than 3 hours. An accurate determination of half-life of unchanged captopril is not, at present, possible, but it is probably less than 2 hours. In patients with renal impairment, however, retention of captopril occurs.

Nonclinical Toxicology

FDA Package Insert for Captopril tablet contains no information regarding Nonclinical Toxicology.

Clinical Studies

Myocardial infarction

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 to 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 captopril and were randomized within 3 to 16 days post-infarction to receive either captopril or placebo in addition to conventional therapy. Captopril was 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 groups, respectively. Blood pressure increased slightly in both treatment groups during the study and was somewhat lower in the captopril group (119/74 vs. 125/77 mmHg at 1 yr).

Therapy with captopril improved long-term survival and clinical outcomes compared to placebo. The risk reduction for all cause mortality was 19% (P=0.02) and for cardiovascular death was 21% (P=0.014). Captopril treated subjects had 22% (P=0.034) fewer first hospitalizations for heart failure. Compared to placebo, 22% fewer patients receiving captopril developed symptoms of overt heart failure. There was no significant difference between groups in total hospitalizations for all cause (2056 placebo; 2036 captopril).

Captopril was well tolerated in the presence of other therapies such as aspirin, beta blockers, nitrates, vasodilators, calcium antagonists and diuretics.

Retinopathy and Proteinuria

In a multicenter, double-blind, placebo controlled trial, 409 patients, age 18 to 49 of either gender, with or without hypertension, with type I (juvenile type, onset before age 30) insulin-dependent diabetes mellitus, retinopathy, proteinuria ≥500 mg per day and serum creatinine ≤ 2.5 mg/dL, were randomized to placebo or captopril (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 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 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 group had somewhat better blood pressure control than the placebo group, but the effects of captopril on renal function were greater than would be expected from the group differences in blood pressure reduction alone. Captopril 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 to 200 mcg/min) were randomized to placebo or captopril (50 mg b.i.d.) and followed for up to 2 years. Captopril delayed the progression to overt nephropathy (proteinuria ≥ 500 mg/day) in both studies (risk reduction 67% to 76%; P<0.05). Captopril 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 does not cross the blood-brain barrier to any significant extent.

How Supplied

12.5 mg tablets in bottles of 100 (NDC 60505-0003-6) and 1000 (NDC 60505-0003-9), 25 mg tablets in bottles of 100 (NDC 60505-0004-6) and 1000 (NDC 60505-0004-9), 50 mg tablets in bottles of 100 (NDC 60505-0005-6) and 1000 (NDC 60505-0005-9), and 100 mg tablets in bottles of 100 (NDC 60505-0006-6) and 1000 (NDC 60505-0006-9).

The 12.5 mg tablet is a round, biconvex tablet, coded “APO 003” with a bisect score on one side and a plain face on the other; the 25 mg tablet is a round, biconvex tablet, coded “APO 004” on one side and a quadrisect score on the other; the 50 mg tablet is capsule shaped, biconvex tablet, coded “APO 005” with a bisect score on one side and a plain face on the other; the 100 mg tablet is capsule shaped, biconvex tablet, coded “APO 006” with a bisect score on one side and a plain face on the other.

All captopril tablets are white to off-white and may exhibit a slight sulfurous odor.

Storage

Do not store above 86°F. Keep bottles tightly closed (protect from moisture).

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

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. (SeePRECAUTIONS, 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 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 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.

Precautions with Alcohol

Alcohol-Benazepril interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Captopril tablet Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Captopril tablet Look-Alike Drug Names in the drug label.

Drug Shortage Status

Drug Shortage

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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