CAPTOPRIL

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-Administer on an empty stomach 1 hour before meals to ensure maximum absorption.
-For patients with difficulty swallowing, the tablets may be crushed and mixed with water immediately prior to administration.
Oral Liquid Formulations
Extemporaneous oral suspension
-Shake well before administration.
-Measure dosage with a calibrated oral syringe prior to administration.

Extemporaneous Compounding-Oral
Extemporaneous preparation of 1 mg/mL captopril oral suspension:
-Place two (2) 50 mg captopril tablets in a graduated cylinder.
-Slowly add distilled water to the cylinder and shake to disintegrate and dissolve the tablets.
-Add one (1) 500 mg ascorbic acid tablet or 500 mg of sodium ascorbate injection to the cylinder.
-Add enough distilled water to bring the total volume to 100 mL.
-Place suspension in a glass bottle.
-Storage: The resulting suspension is stable for 56 days at 4 degrees C (39 degrees F).

Neutropenia (less than 1,000/mm3) with myeloid hypoplasia has resulted from use of captopril. About half of the neutropenic patients developed systemic or oral cavity infections or other features of the syndrome of agranulocytosis. Patients with impaired renal function, patients with collagen vascular disease, or patients receiving large daily doses are at greater risk. Neutropenia has usually been detected within 3 months of initiation of captopril; neutrophils generally return to normal within 2 weeks after discontinuation. About 13% of the cases of neutropenia have ended fatally; however, these were usually in patients with serious illness like collagen vascular disease, renal failure, cardiac failure or immunosuppressant therapy, or a combination of these complicating factors. Evaluate the white blood cell and differential counts prior to initiation of captopril in patients with impaired renal function, and then every 2 weeks for about 3 months, then periodically. Use captopril only after an assessment of benefit and risk, and then with caution 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. Instruct patients to report signs of infection (e.g., sore throat, pyrexia) during captopril therapy. Promptly check white cell counts in patients with suspected infection. If neutropenia is confirmed, discontinue captopril and follow patient clinically. Anemia, aplastic anemia, hemolytic anemia, pancytopenia, and thrombocytopenia have also been reported with captopril use.

Renal insufficiency, renal failure (unspecified), nephrotic syndrome, polyuria, oliguria, and increased urinary frequency have been reported in 0.1% to 0.2% of adult patients receiving captopril. Transient elevations of BUN or serum creatinine, especially in volume or salt depleted patients or those with renovascular hypertension, may occur. In addition, 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. Proteinuria has been reported in 1% of adult patients receiving captopril. Total urinary proteins greater than 1 g/day have occurred at an incidence of 0.7%. The majority of these patients had evidence of prior renal disease, were receiving doses of captopril greater than 150 mg/day, or both. Proteinuria has led to nephrotic syndrome in about 20% of patients. Proteinuria usually subsided within 6 months even with continuation of captopril treatment. Alterations in BUN and creatinine were rarely reported in patients with proteinuria.

Dysgeusia (taste alteration), consisting of diminution or loss of taste perception, was reported in approximately 2% to 4% of adult patients taking captopril. Taste impairment is usually reversible within 2 to 3 months, even if therapy is continued. Dysgeusia may also lead to weight loss. Other gastrointestinal reactions reported in 0.5% to 2% of adult patients receiving captopril, but not at a greater frequency than patients receiving placebo or other therapies in controlled trials, include gastric irritation, abdominal pain, pancreatitis, nausea, vomiting, diarrhea, anorexia, constipation, aphthous ulcers, peptic ulcer, and xerostomia. Glossitis and dyspepsia have been reported with postmarketing use of captopril.

Hypotension rarely occurs in patients receiving captopril for the treatment of hypertension, but hypotensive symptoms have required discontinuation of the drug in approximately 4% of adult patients with congestive heart failure. Excessive, prolonged, and unpredictable decreases in blood pressure have been reported in neonates and infants receiving captopril; these hypotensive episodes were associated with complications such as oliguria and seizures. Excessive hypotension is more likely in patients who are salt/volume depleted (such as those treated vigorously with diuretics), patients with heart failure, or those patients undergoing renal dialysis. Sinus tachycardia, chest pain (unspecified), and palpitations have been reported in 1% of adult patients. Angina pectoris, myocardial infarction, Raynaud's syndrome, and congestive heart failure have each occurred in 0.2% to 0.3% of patients. Other cardiovascular-related adverse events include cardiac arrest, cerebrovascular accident/insufficiency, arrhythmia exacerbation, orthostatic hypotension, and syncope.

Cough has been reported in 0.5% to 2% of adult patients treated with captopril during clinical trials. ACE inhibitor use is often associated with a dry, hacking, nonproductive cough that typically develops 1 to 2 weeks after, but may occur within hours to months after, treatment initiation. The only uniformly effective intervention is cessation of the offending agent, which should occur only after other causes (e.g., pulmonary congestion) are ruled out; cessation typically results in resolution within 1 to 4 weeks. Although the mechanism of ACE inhibitor-induced cough is unclear, it likely involves bradykinin and substance P, which are degraded by ACE and therefore accumulate in the respiratory tract with enzyme inhibition, and prostaglandins, the production of which may be stimulated by bradykinin. Dyspnea has been reported in 0.5% to 2% of adult patients receiving captopril but did not appear at increased frequency compared to placebo or other treatments used in controlled trials. Bronchospasm, eosinophilic pneumonia, and rhinitis have also been reported in patients receiving captopril.

A symptom complex has been reported during captopril therapy which may include a positive ANA, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis, eosinophilia, or interstitial nephritis. Pruritus, without rash, occurred in about 2% of adult patients in clinical trials. Approximately 4% to 7% of adult patients receiving captopril experienced a maculopapular rash, often with pruritus, and occasionally with fever, eosinophilia, and arthralgia. This reaction typically occurs within the first 4 weeks of therapy. The rash is generally mild and disappears within a few days following dosage reduction, treatment with an antihistamine, and/or discontinuing therapy. The rash may resolve even if captopril is continued. Between 7% to 10% 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 0.2% to 0.5% of adult patients. Bullous pemphigus, erythema multiforme (including Stevens-Johnson syndrome), and exfoliative dermatitis have also been reported with captopril use.

Anaphylactoid reactions and angioedema are uncommon but serious and potentially fatal adverse reactions associated with ACE inhibitor use. Angioedema may manifest as swelling of the face, lips, tongue, glottis, larynx (laryngeal edema), extremities, or, in rare cases, edema of the gastrointestinal tract. Angioedema of the upper respiratory tract can result in airway obstruction and acute respiratory distress, especially in those with a history of airway surgery. Intestinal angioedema presents as abdominal pain with or without nausea and vomiting. In some cases, patients with intestinal involvement had no prior history of facial angioedema and C-1 esterase levels were normal; intestinal angioedema was diagnosed by procedures such as abdominal CT scan or ultrasound or during surgery. Angioedema usually occurs within hours to days of treatment initiation, but may occur at any time during treatment. Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to non-Black patients. Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor. If a hypersensitivity reaction occurs, promptly discontinue captopril and provide appropriate and aggressive treatment and monitoring until complete and sustained resolution has occurred. Consider intestinal angioedema in the differential diagnosis of patients receiving ACE inhibitors who present with pain in the abdomen.

Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including captopril. Patients at increased 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.

Hepatotoxicity (hepatitis, hepatic failure) has been reported in patients receiving ACE inhibitors. Although not completely understood, hepatotoxicity has included cholestasis with jaundice, fulminant hepatic necrosis, and death. Elevated alkaline phosphatase and an increase in serum bilirubin have also been reported in patients taking captopril. Discontinue captopril and institute appropriate treatment in patients who develop jaundice or markedly elevated hepatic enzymes during therapy.

Hyponatremia, particularly in patients receiving concomitant diuretic therapy or a low-sodium diet, may occur during captopril therapy. Symptomatic hyponatremia has been reported with postmarketing use of captopril.

Dizziness, headache, malaise, fatigue, insomnia, and paresthesias were reported in 0.5% to 2% of adult patients receiving captopril, but not at a greater frequency than patients receiving placebo or other therapies in controlled trials. Ataxia, confusion, depression, nervousness, and drowsiness have been reported with postmarketing use of captopril.

Alopecia was reported in 0.5% to 2% of adult patients receiving captopril, but not at a greater frequency than patients receiving placebo or other therapies in controlled trials. Asthenia, gynecomastia, myasthenia, and blurred vision have been reported with postmarketing use of captopril.

Captopril is contraindicated in patients with a history of angiotensin-converting enzyme inhibitors (ACE inhibitors) hypersensitivity or ACE-inhibitor induced angioedema. Angiotensin-converting enzyme inhibitors (ACE inhibitors) hypersensitivity usually manifests as a result of alterations in kinin generation in sensitive individuals; there is no evidence of a specific immune-mediated reaction. However, such reactions can be potentially life-threatening, even if they are not true 'allergic' reactions. Avoid use in patients with hereditary angioedema, or idiopathic angioedema. If angioedema occurs, discontinue ACE inhibitor therapy and institute appropriate treatment. The incidence of ACE inhibitor-induced angioedema is higher in Black patients than non-Black patients. In addition, ACE inhibitors are less effective in lowering blood pressure in Black patients.

Anaphylactoid reactions have been reported in patients taking ACE inhibitors, such as captopril, who were receiving dialysis with high-flux membranes; the mechanism is unknown. When anaphylactoid symptoms such as nausea, abdominal cramps, burning, angioedema, shortness of breath or low blood pressure are recognized, stop the dialysis and initiate aggressive treatment for the hypersensitivity reaction. Anaphylactoid reactions have also occurred in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption (a procedure dependent upon devices not approved in the United States). Although a causal relationship to ACE inhibitor therapy has not been firmly established, treatment with captopril may increase the risk for anaphylactoid reactions during membrane exposure. ACE inhibitors may also precipitate low blood pressure in dialysis patients who are volume-depleted. Treatment with captopril may increase the risk of anaphylactoid reactions in patients undergoing hymenoptera venom (insect sting) allergy desensitization.

Use captopril with caution in patients who exhibit hypotension. Captopril can cause severe hypotension when administered to patients with hypovolemia or hyponatremia or to patients receiving diuretics or dialysis. This effect is due at least in part to its anti-aldosterone action. Use captopril cautiously in patients with congestive heart failure (initial doses should be lower than in the treatment of hypertension) because of a greater risk of developing hypotension. Hypotension may aggravate ischemia in patients with coronary artery disease or cerebrovascular disease precipitating a myocardial infarction or cerebrovascular accident. Use captopril with caution in patients with aortic stenosis or hypertrophic cardiomyopathy. As with all vasodilators, give ACE inhibitors with caution to patients with obstruction in the outflow tract of the left ventricle.

Correct electrolyte imbalances in patients with pre-existing hyperkalemia before captopril is initiated. ACE inhibitors can elevate serum potassium concentrations and could worsen the pre-existing condition. Hyperkalemia may be associated with serious cardiac arrhythmias. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes. Monitor patients with these risk factors closely for hyperkalemia.

According to the manufacturer, dosage adjustment of captopril is recommended in patients with renal impairment or renal failure. Treatment with ACE inhibitors has demonstrated favorable effects on the progression of renal disease in diabetic and nondiabetic patients; however, minor increases in BUN and serum creatinine may occur. These effects, more commonly reported in patients with renal artery stenosis or those receiving concomitant diuretic therapy, are usually reversible and are not considered a reason to withhold therapy unless accompanied by hyperkalemia. If captopril is initiated in patients with renal artery stenosis, monitor renal function during the first few weeks of therapy. Captopril therapy can cause neutropenia or agranulocytosis. Patients with renal disease, immunosuppression or receiving immunosuppressives, and patients with collagen-vascular disease (e.g., systemic lupus erythematosus (SLE) or scleroderma) or autoimmune disease are at a greater risk for developing these complications. Establish complete blood counts prior to and during captopril therapy when administered to these patient populations. Obtain leukocyte count with differential every 2 weeks during the first 3 months of therapy, then periodically in patients with impaired renal function receiving captopril. Use captopril with caution in patients with pre-existing bone marrow suppression.

Neonates and infants may be especially susceptible to prolonged, excessive, and unpredictable decreases in blood pressure after captopril administration. Oliguria and seizures have also been reported in neonates and infants receiving captopril.

Adverse neonatal effects after in utero exposure to captopril have included hypotension, anuria, renal failure, and death. If oliguria or hypotension occurs in a neonate with a history of in utero exposure to captopril, blood pressure and renal perfusion support may be required, as well as exchange transfusion or dialysis to reverse hypotension and/or support decreased renal function. Although captopril is effectively removed from the circulation of adult patients by hemodialysis, there is inadequate data to determine the effectiveness of hemodialysis in removing the drug from the circulation of neonates. Peritoneal dialysis is not effective in removing captopril and there is no information on the ability of exchange transfusion to remove the drug from the circulation.

Description: Captopril is an angiotensin-converting enzyme (ACE) inhibitor used in the treatment of hypertension, congestive heart failure, and various renal syndromes such as diabetic nephropathy and nephrotic syndrome. ACE inhibitors have been shown to improve symptoms and reduce mortality in patients with heart failure and are recommended as first-line therapy. As the shortest-acting of all ACE inhibitors, captopril is usually dosed two or three times a day. Captopril contains a sulfhydryl group, which may contribute to its pharmacologic action and account for some adverse reactions that occur at higher doses. Lower initial doses, a slower dose titration, and closer monitoring of blood pressure are necessary when captopril is used in neonates and infants due to a prolonged duration of action and increased sensitivity to the hemodynamic effects of the drug. Although not FDA-approved, captopril has been used in pediatric patients as young as neonates.

For the treatment of hypertension*:
Oral dosage:
Neonates: 0.01 to 0.1 mg/kg/dose PO 1 to 3 times daily, initially. Titrate up to 0.5 mg/kg/dose PO 1 to 4 times daily based on clinical response. A lower initial dose, slower dose titration, and close monitoring of blood pressure response is necessary in neonatal patients due to the potential for a prolonged duration of action.
Infants: 0.05 mg/kg/dose PO 1 to 4 times daily, initially. Titrate to clinical response (Max: 6 mg/kg/day). An initial dose of 0.05 to 0.3 mg/kg/dose PO 1 to 3 times daily titrated to clinical response (Max: 2 mg/kg/dose and 6 mg/kg/day) has been recommended based on a study of captopril in 73 pediatric patients (age: 11 days to 15 years). A lower initial dose, slower dose titration, and close monitoring of blood pressure response is necessary, especially in infants younger than 2 months and in patients at risk for hypotension (e.g., volume-depleted patients).
Children and Adolescents: 0.5 mg/kg/dose (Initial Max: 25 mg/dose) PO 3 times daily, initially. Titrate to clinical response (Max: 6 mg/kg/day [Max: 450 mg/day]).

For the management of congestive heart failure* (CHF):
Oral dosage:
Neonates: Initially, 0.01 to 0.03 mg/kg/dose PO every 8 hours titrated to clinical response (Max: 1.5 mg/kg/day) has been recommended based on the results of a retrospective review of neonates (n = 23) and infants (n = 20). In this review, captopril was initiated at 0.05 to 0.55 mg/kg/day PO divided every 8 hours and titrated to maximum doses of 0.2 to 2.3 mg/kg/day PO; however, the authors recommend a lower initial and maximum dose due to concern for increased adverse effects at higher doses.
Infants: Initial doses of 0.01 to 0.18 mg/kg/dose PO every 8 hours have been used in small retrospective studies. Doses were titrated to 0.2 to 2.5 mg/kg/day PO; however, some authors recommend a lower maximum dose of 1.5 mg/kg/day PO due to concern for increased adverse effects at higher doses.
Children: 0.1 to 2 mg/kg/dose PO every 6 to 12 hours titrated to clinical response (Max: 6 mg/kg/day) has been recommended. Initial doses are often lower than the initial doses used for hypertension (e.g., 0.3 mg/kg/dose). Although a specific total mg maximum dose has not been clearly defined, do not exceed initial and final doses recommended for adult patients (e.g., 6.25 to 25 mg/dose for initial doses and a usual maximum of 150 mg/day for the final dose).
Adolescents: Initially, 6.25 to 12.5 mg PO every 8 to 12 hours titrated to clinical response (Usual Max: 150 mg/day) has been recommended.

For the treatment of proteinuria* associated with congenital nephrotic syndrome*, nephrotic syndrome*, or diabetic nephropathy*:
Oral dosage:
Neonates and Infants: Initial doses of 0.1 to 0.25 mg/kg/dose PO every 8 hours titrated to clinical response (Max: 6 mg/kg/day) have been used in combination with indomethacin (0.3 to 3 mg/kg/day PO divided every 12 hours) and unilateral nephrectomy in a small observational study (n = 7) of patients with congenital nephrotic syndrome. Treatment resulted in statistically significant increases in plasma albumin and decreases in albumin infusions over the follow-up period of 36 to 88 months.
Children and Adolescents: Initial doses of 0.3 to 1 mg/kg/dose PO 3 times daily titrated to clinical response up to a maximum dose of 6 mg/kg/day (administered in 3 divided doses) have been successful in reducing proteinuria or microalbuminuria in small studies (n = 8 to 15) of patients with diabetes or nephrotic syndrome unresponsive to conventional therapy. Although a specific total mg maximum dose has not been clearly defined, do not exceed initial and final doses recommended for adult patients (e.g., 25 mg/dose for initial doses and usual maximum of 150 mg/day for the final dose).

For the treatment of hypertensive urgency*:
Oral dosage:
Infants: 0.05 mg/kg/dose PO 1 to 4 times daily, initially. Titrate to clinical response (Max: 6 mg/kg/day).
Children and Adolescents: 0.5 mg/kg/dose (Initial Max: 25 mg/dose) PO 3 times daily, initially. Titrate to clinical response (Max: 6 mg/kg/day [Max: 450 mg/day]).

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established; however, doses up to 6 mg/kg/day PO have been used off-label. A lower maximum of 1.5 mg/kg/day PO is recommended for congestive heart failure.
-Infants
Safety and efficacy have not been established; however, doses up to 6 mg/kg/day PO have been used off-label. A lower maximum dose of 1.5 mg/kg/day is recommended for congestive heart failure.
-Children
Safety and efficacy have not been established; however, doses up to 6 mg/kg/day PO (Max: 450 mg/day PO) have been used off-label.
-Adolescents
Safety and efficacy have not been established; however, doses up to 6 mg/kg/day PO (Max: 450 mg/day PO) have been used off-label.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing
Dosage adjustment of captopril may be necessary for patients with renal impairment. The following initial dosage adjustments have been recommended for pediatric patients:
CrCl more than 50 mL/minute/1.73 m2: no dosage adjustment needed.
CrCl 10 to 50 mL/minute/1.73 m2: reduce dose by 25%.
CrCl less than 10 mL/minute/1.73 m2: reduce dose by 50%.

Intermittent hemodialysis and Peritoneal dialysis
Reduce the initial dose by 50% then titrate to the desired clinical effect.

Continuous renal replacement therapy (CRRT)
Reduce the initial dose by 25% (assuming a dialysis dose of 2,000 mL/minute/1.73 m2) then titrate to the desired clinical effect.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Captopril has a high affinity for angiotensin converting enzyme (ACE) and competes with angiotensin I, the natural substrate, to block its conversion to angiotensin II. Angiotensin II is a potent vasoconstrictor and a negative feedback mediator for renin activity. Thus, as a result of lower angiotensin II plasma levels, blood pressure decreases and plasma renin activity increases. In addition, baroreceptor reflex mechanisms are stimulated by the drop in blood pressure. Kininase II, identical to ACE, is an enzyme that degrades bradykinin, a potent vasodilator, to inactive peptides. Whether increased bradykinin levels play a part in the therapeutic effects of ACE inhibitors is presently unclear. Bradykinin-induced vasodilation is thought to be of secondary importance in the blood-pressure lowering effect of ACE inhibitors. A bradykinin mechanism may, however, contribute to ACE-inhibitor-induced angioneurotic edema and cough.

The "local" activity of ACE inhibitors may be more responsible for their clinical effects than systemic activity. ACE-inhibiting drugs may act locally (i.e., within a specific tissue) to reduce vascular tone by decreasing local angiotensin II-induced sympathetic activity and/or by decreasing local angiotensin II-induced vasoconstrictive activity. ACE inhibitors may inhibit presynaptic norepinephrine release and postsynaptic adrenergic receptor activity, decreasing vascular sensitivity to vasopressor activity. Decreases in plasma angiotensin II levels reduce aldosterone secretion, with a subsequent decrease in sodium and water retention.

Captopril dilates arterioles, thereby lowering total peripheral vascular resistance. In hypertensive patients, blood pressure is decreased with little or no change in heart rate, stroke volume, or cardiac output. However, captopril can increase cardiac output, cardiac index, stroke volume, and exercise tolerance in patients with congestive heart failure. The drug also decreases pulmonary wedge pressure, pulmonary vascular resistance, and mean arterial and right atrial pressures in these patients. As antihypertensives, ACE inhibitors reduce LVH and do not worsen insulin resistance or hyperlipidemia.

Pharmacokinetics: Captopril is administered orally. Captopril distributes into most body tissues and is approximately 25% to 30% bound to proteins. The drug is metabolized (50%) in the liver to inactive metabolites, followed by excretion of the unchanged drug and its metabolites in the urine. Captopril renal elimination occurs primarily by tubular excretion. In adult patients with normal renal function, the half-life of captopril is less than 2 hours.

Affected cytochrome P450 isoenzymes and drug transporters: P-gp
Captopril is an inhibitor of P-gp and may increase the plasma concentrations of drugs that are substrates of P-gp.


-Route-Specific Pharmacokinetics
Oral Route
After oral administration, captopril is rapidly absorbed from the GI tract. If given with food, absorption decreases by 30% to 40%. Noticeable antihypertensive effects begin within 15 minutes; with maximal reductions in blood pressure occurring within 60 to 90 minutes. The reduction in blood therapy is progressive with continued use, with maximum beneficial effects requiring several weeks of therapy. The effects of a dose of captopril generally last about 4 to 10 hours, but the duration of action can be prolonged in patients with renal dysfunction or young pediatric patients with immature renal function.


-Special Populations
Pediatrics
Infants
The half-life of captopril in infants with congestive heart failure may be prolonged compared to older pediatric patients and adults. The mean half-life, clearance, and Tmax of captopril in 10 infants with congestive heart failure after an oral dose of 1 mg/kg was 1.2 to 12.4 hours (median 2 hours), 0.7 to 2.1 L/kg/hour (median 0.9 L/kg/hour), and 1 to 2 hours (median 1.5 hours), respectively.

Children and Adolescents
The half-life, clearance, and Tmax of captopril in 8 normotensive children and adolescents (5 to 18 years of age) with renal scarring after an oral dose of 0.7 mg/kg was 0.98 to 2.3 hours (mean 1.5 hours), 0.46 to 3.58 L/kg/hour (mean 1.74 L/kg/hour), and 0.5 to 2 hours, respectively.

Renal Impairment
The pharmacokinetics of captopril may be significantly affected by renal impairment. In hypertensive children and adolescents with renal disease, the clearance of captopril decreased from 27.2 mL/kg/minute in a patient with a CrCl of 59 mL/minute/1.73 m2 to 14.1 to 18.8 mL/kg/minute in patients with a CrCl of 10 to 21 mL/minute/1.73 m2. The half-life of captopril significantly increases to over 20 to 40 hours in adult patients with CrCl less than 20 mL/minute.