Captopril and Hydrochlorothiazide
Synonyms / Brand Names: Captopril and Hydrochlorothiazide

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# Black Box Warning

# Overview
Captopril and Hydrochlorothiazide is an angiotensin converting enzyme inhibitor drug that is FDA approved for the treatment of hypertension. There is a Black Box Warning for this drug as shown here. Common adverse reactions include cough, dizziness, fatigue, and headache.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Initial dose (not receiving a diuretic): Captopril
- Initial dose (concurrent Captopril use): Captopril (see Warnings). If blood pressure is not controlled with Captopril alone, diuretic should be resumed and Captopril 5 mg PO qd should be used.
- Maintenance dose: Captopril 2040 mg PO qd or Captopril 1020 mg PO bid (MAX 80 mg/day)
- Dosing Information
- Initial dose (for creatinine clearance 3 mg/dL): Captopril 5 mg PO qd
- Dosage may be titrated upward until blood pressure is controlled or to a maximum total daily dose of 40 mg (see Warnings).

## Off-Label Use and Dosage (Adult)

# Pediatric Indications and Dosage

# Contraindications

### Captopril
- Hypersensitivity to Captopril or to any other ACE inhibitor
- History of angioedema with or without previous ACE inhibitor treatment

### Hydrochlorothiazide
- Hydrochlorothiazide is contraindicated in anuria. It is also contraindicated in patients who have previously demonstrated hypersensitivity to hydrochlorothiazide or other sulfonamide-derived drugs.

# Warnings

## Captopril
Reported incidences are based on clinical trials involving approximately 7000 patients.
Renal: About one of 100 patients developed proteinuria (see WARNINGS).
Each of the following has been reported in approximately 1 to 2 of 1000 patients and are of uncertain relationship to drug use: renal insufficiency, renal failure, nephrotic syndrome, polyuria, oliguria, and urinary frequency.
Hematologic: Neutropenia/agranulocytosis has occurred (see WARNINGS). Cases of anemia, thrombocytopenia, and pancytopenia have been reported.
Dermatologic: Rash, often with pruritus, and sometimes with fever, arthralgia, and eosinophilia, occurred in about 4 to 7 (depending on renal status and dose) of 100 patients, usually during the first four weeks of therapy. It is usually maculopapular, and rarely urticarial. The rash is usually mild and disappears within a few days of dosage reduction, short-term treatment with an antihistaminic agent, and/or discontinuing therapy; remission may occur even if captopril is continued. Pruritus, without rash, occurs in about 2 of 100 patients. Between 7 and 10 percent of patients with skin rash have shown eosinophilia and/or positive ANA titers. A reversible associated pemphigoid-like lesion, and photosensitivity, have also been reported.
Flushing or pallor has been reported in 2 to 5 of 1000 patients.
Cardiovascular: Hypotension may occur; see WARNINGS and PRECAUTIONS (Drug Interactions) for discussion of hypotension with captopril therapy.
Tachycardia, chest pain, and palpitations have each been observed in approximately 1 of 100 patients.
Angina pectoris, myocardial infarction, Raynaud's syndrome, and congestive heart failure have each occurred in 2 to 3 of 1000 patients.
Dysgeusia: Approximately 2 to 4 (depending on renal status and dose) of 100 patients developed a diminution or loss of taste perception. Taste impairment is reversible and usually self-limited (2 to 3 months) even with continued drug administration. Weight loss may be associated with the loss of taste.
Angioedema: Angioedema involving the extremities, face, lips, mucous membranes, tongue, glottis or larynx has been reported in approximately one in 1000 patients. Angioedema involving the upper airways has caused fatal airway obstruction. (See WARNINGS: Captopril: Head and Neck Angioedema and Intestinal Angioedema andPRECAUTIONS: Information for Patients).
Cough: Cough has been reported in 0.5 to 2% of patients treated with captopril in clinical trials (see PRECAUTIONS: General: Captopril: 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: Captopril: Anaphylactoid and Possibly Related Reactions and PRECAUTIONS: Hemodialysis).
General: asthenia, gynecomastia.
Cardiovascular: cardiac arrest, cerebrovascular accident/insufficiency, rhythm disturbances, orthostatic hypotension, syncope.
Dermatologic: bullous pemphigus, erythema multiforme (including Stevens-Johnson syndrome), exfoliative dermatitis.
Gastrointestinal: pancreatitis, glossitis, dyspepsia.
Hematologic: anemia, including aplastic and hemolytic.
Hepatobiliary: jaundice, hepatitis, including rare cases of necrosis, cholestasis.
Metabolic: symptomatic hyponatremia.
Musculoskeletal: myalgia, myasthenia.
Nervous/Psychiatric: ataxia, confusion, depression, nervousness, somnolence.
Respiratory: bronchospasm, eosinophilic pneumonitis, rhinitis.
Special Senses: blurred vision.
Urogenital: impotence.
As with other ACE inhibitors, a syndrome has been reported which may include: fever, myalgia, arthralgia, interstitial nephritis, vasculitis, rash or other dermatologic manifestations, eosinophilia and an elevated ESR.
Fetal/Neonatal Morbidity and Mortality
See WARNINGS: Captopril: Fetal/Neonatal Morbidity and Mortality.
- Gastrointestinal System:
- anorexia, gastric irritation, nausea, vomiting, cramping, diarrhea, constipation, jaundice (intrahepatic cholestatic jaundice), pancreatitis, and sialadenitis.
- Central Nervous System:
- dizziness, vertigo, paresthesias, headache, and xanthopsia.
- Hematologic:
- leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia, and hemolytic anemia.
- Cardiovascular:
- orthostatic hypotension.
- Hypersensitivity:
- purpura, photosensitivity, rash, urticaria, necrotizing angiitis (vasculitis; cutaneous vasculitis), fever, respiratory distress including pneumonitis, and anaphylactic reactions.
- Other:
- hyperglycemia,glycosuria, hyperuricemia, muscle spasm, weakness, restlessness, and transient blurred vision.
- Whenever adverse reactions are moderate or severe, thiazide dosage should be reduced or therapy withdrawn.

## Altered Laboratory Findings
Serum Electrolytes: Hyperkalemia: small increases in serum potassium, especially in patients with renal impairment (see PRECAUTIONS: Captopril).
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.

# Drug Interactions
- Diuretics
- Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with Captopril. The possibility of hypotensive effects with Captopril can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with Captopril. If this is not possible, the starting dose should be reduced (see Adult Indications and Dosage).
- Potassium supplements and potassium-sparing diuretics
- Concomitant use with Captopril may effect potassium levels. Monitor potassium periodically.
- Oral anticoagulants
- Interaction studies with warfarin and acenocoumarol failed to identify any clinically important effects on the serum concentrations or clinical effects of these anticoagulants.
- Lithium
- Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors (including Captopril) during therapy with lithium. Monitor lithium levels when used concomitantly with Captopril.
- 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.
- Anti-diabetics
- In rare cases, diabetic patients receiving an ACE inhibitor (including Captopril) concomitantly with insulin or oral anti-diabetics may develop hypoglycemia. Such patients should therefore be advised about the possibility of hypoglycemic reactions and should be monitored accordingly.
- Non-steroidal anti-inflammatory drugs (NSAIDs) 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.
- Miscellaneous
- Captopril has been used concomitantly with beta-adrenergic-blocking agents, calcium-channel-blocking agents, diuretics, digoxin, and hydralazine, without evidence of clinically important adverse interactions. Captopril, like other ACE inhibitors, has had less than additive effects with beta-adrenergic blockers, presumably because both drugs lower blood pressure by inhibiting parts of the renin-angiotensin system.
- The pharmacokinetics of Captopril are not affected by the following drugs: hydrochlorothiazide, furosemide, chlorthalidone, digoxin, propranolol, atenolol, nifedipine, amlodipine, naproxen, acetylsalicylic acid, or cimetidine. Likewise the administration of Captopril does not substantially affect the pharmacokinetics of these medications (cimetidine kinetics were not studied).

# Use in Specific Populations

### Pregnancy
- Fetal toxicity
- 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 mother 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 (see Pediatric Use).
- No teratogenic effects of captopril  were seen in studies of pregnant rats, mice, and rabbits. On a mg/m2 basis, the doses used in these studies were 60 times (in rats), 9 times (in mice), and more than 0.8 times (in rabbits) the maximum recommended human dose (assuming a 50-kg woman). On a mg/kg basis these multiples are 300 times (in rats), 90 times (in mice), and more than 3 times (in rabbits) the maximum recommended human dose.

### Labor and Delivery
FDA Package Insert for Captopril and Hydrochlorothiazide 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
- Neonates with a history of in utero exposure to Captopril
- 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. Captopril, which crosses the placenta, can theoretically be removed from the neonatal circulation by these means; there are occasional reports of benefit from these maneuvers with another ACE inhibitor, but experience is limited.
- The antihypertensive effects of Captopril have been evaluated in a double-blind study in pediatric patients 7 to 16 years of age (see Pharmacodynamics). The pharmacokinetics of Captopril have been evaluated in pediatric patients 6 to 16 years of age (see Pharmacokinetics) . Captopril was generally well tolerated and adverse effects were similar to those described in adults. (See Adverse Reactions). The long-term effects of Captopril on growth and development have not been studied. Infants below the age of 1 year should not be given Captopril because of the risk of effects on kidney development.
- Treatment with Captopril is not recommended in pediatric patients less than 6 years of age (see Adverse Reactions), and in children with glomerular filtration rate <30 mL/min as there are insufficient data available to support a dosing recommendation in these groups. (See Pharmacokinetics.)

### Geriatric Use
FDA Package Insert for Captopril and Hydrochlorothiazide contains no information regarding Gender.

### Gender
FDA Package Insert for Captopril and Hydrochlorothiazide contains no information regarding Gender.

### Race
FDA Package Insert for Captopril and Hydrochlorothiazide contains no information regarding Race.

### Renal Impairment
- As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin-converting enzyme inhibitors, including captopril , may be associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. In a small study of hypertensive patients with renal artery stenosis in a solitary kidney or bilateral renal artery stenosis, treatment with captopril  was associated with increases in blood urea nitrogen and serum creatinine; these increases were reversible upon discontinuation of captopril  or diuretic therapy, or both. When such patients are treated with ACE inhibitors, renal function should be monitored during the first few weeks of therapy. Some hypertensive patients with no apparent preexisting renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when captopril  has been given concomitantly with a diuretic. This is more likely to occur in patients with preexisting renal impairment. Dosage reduction of captopril  and/or discontinuation of the diuretic may be required. Evaluation of the hypertensive patient should always include assessment of renal function (see Adult Indications and Dosage).
- Because captopril and hydrochlorothiazide 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 of captopril and hydrochlorothiazide.
- After the desired therapeutic effect has been achieved, the dose intervals should be increased or the total daily dose reduced until the minimal effective dose is achieved. When concomitant diuretic therapy is required in patients with severe renal impairment, a loop diuretic (e.g., furosemide), rather than a thiazide diuretic is preferred for use with captopril; therefore, for patients with severe renal dysfunction the captopril-hydrochlorothiazide combination tablet is not usually recommended.

### Hepatic Impairment
- 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.

### 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.

### Immunocompromised Patients
FDA Package Insert for Captopril and Hydrochlorothiazide contains no information regarding Immunocompromised Patients.

### Miscellaneous
- 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 Drug Interactions).
- 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.
- 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.
- Surgery/Anesthesia
- In patients undergoing surgery or during anesthesia with agents that produce hypotension, Captopril will block the angiotensin II formation that could otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion.

# Administration and Monitoring

### Administration
- Oral dosage
- Available fixed-dose tablet formulations of captopril/hydrochlorothiazide contain 25/15, 25/25, 50/15, and 50/25 milligrams (mg).

### Monitoring
- 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.
- 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.
- 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).

# IV Compatibility
FDA Package Insert for Captopril and Hydrochlorothiazide contains no information regarding IV Compatibility.

# Overdosage

## Acute Overdose

### Signs and Symptoms
- Human overdoses of captopril  have not been reported, but the most common manifestation of human captopril  overdosage is likely to be hypotension, which can be associated with electrolyte disturbances and renal failure.

### Management
- Laboratory determinations of serum levels of captopril  and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of captopril  overdose.
- No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of captopril  and its metabolites. captopril  is only slightly dialyzable, but dialysis might be considered in overdosed patients with severely impaired renal function (see Warnings).
- Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of captopril  overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of captopril  is achieved through vasodilation and effective hypovolemia, it is reasonable to treat captopril  overdose by infusion of normal saline solution.
- If ingestion is recent, activated charcoal should be considered. Gastric decontamination (e.g., vomiting, gastric lavage) may be considered in individual cases, in the early period after ingestion.
- Patients should be closely monitored for blood pressure and clinical symptoms. Supportive management should be employed to ensure adequate hydration and to maintain systemic blood pressure.
- In the case of marked hypotension, physiological saline solution should be administered intravenously; depending on the clinical situation the use of vasopressors (e.g., catecholamines i.v.) may be considered.

## Chronic Overdose

### Signs and Symptoms
FDA Package Insert for Captopril and Hydrochlorothiazide contains no information regarding Signs and Symptoms in Chronic Overdose.

### Management
FDA Package Insert for Captopril and Hydrochlorothiazide contains no information regarding Management in Chronic Overdose.

# Pharmacology

## Mechanism of Action
- Captopril and Captoprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex.
- Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. Hypertensive patients treated with Captopril alone for up to 52 weeks had elevations of serum potassium of up to 0.2 mEq/L. Similar patients treated with Captopril and hydrochlorothiazide for up to 24 weeks had no consistent changes in their serum potassium.
- Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. In animal studies, Captopril had no inhibitory effect on the vasopressor response to angiotensin II and did not interfere with the hemodynamic effects of the autonomic neurotransmitters acetylcholine, epinephrine, and norepinephrine.
- ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of Captopril remains to be elucidated.
- While the mechanism through which Captopril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, Captopril has an antihypertensive effect even in patients with low-renin hypertension (see Adult Indications and Dosage).

## Structure
- Captopril hydrochloride is a white to off-white crystalline powder, soluble (>100 mg/mL) in water, in ethanol, and in methanol. Its chemical name is Captopril 3-amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-(3S)-benzazepine-1-acetic acid monohydrochloride.
- Its empirical formula is C24H28N2O5HCl, and its molecular weight is 460.96.
- Captoprilat, the active metabolite of Captopril, is a non-sulfhydryl angiotensin-converting enzyme inhibitor. Captopril is converted to Captoprilat by hepatic cleavage of the ester group.
- Captopril is supplied as tablets containing 5 mg, 10 mg, 20 mg, and 40 mg of Captopril hydrochloride for oral administration. The inactive ingredients are colloidal silicon dioxide, crospovidone, hydrogenated castor oil (5-mg, 10-mg, and 20-mg tablets), hypromellose, iron oxides, lactose, magnesium stearate (40-mg tablets), microcrystalline cellulose, polysorbate 80, propylene glycol (5-mg and 40-mg tablets), starch, talc, and titanium dioxide.

## Pharmacodynamics
- Single and multiple doses of 10 mg or more of Captopril cause inhibition of plasma ACE activity by at least 80%-90% for at least 24 hours after dosing. Pressor responses to exogenous angiotensin I were inhibited by 60%-90% (up to 4 hours post-dose) at the 10-mg dose.

## Pharmacokinetics
- Following oral administration of Captopril, peak plasma concentrations of Captopril are reached within 0.5-1.0 hours. The extent of absorption is at least 37% as determined by urinary recovery and is not significantly influenced by the presence of food in the GI tract.
- Cleavage of the ester group (primarily in the liver) converts Captopril to its active metabolite, Captoprilat. Peak plasma concentrations of Captoprilat are reached 1-2 hours after drug intake in the fasting state and 2-4 hours after drug intake in the nonfasting state. The serum protein binding of Captopril is about 96.7% and that of Captoprilat about 95.3%, as measured by equilibrium dialysis; on the basis of in vitro studies, the degree of protein binding should be unaffected by age, hepatic dysfunction, or concentration (over the concentration range of 0.24-23.6 mol/L).
- Captopril is almost completely metabolized to Captoprilat, which has much greater ACE inhibitory activity than Captopril, and to the glucuronide conjugates of Captopril and Captoprilat. Only trace amounts of an administered dose of Captopril can be recovered in the urine as unchanged Captopril, while about 20% of the dose is excreted as Captoprilat, 4% as Captopril glucuronide, and 8% as Captoprilat glucuronide.
- The kinetics of Captopril are approximately dose-proportional within the dosage range of 10-80 mg.
- In adults, the effective half-life of accumulation of Captoprilat following multiple dosing of Captopril hydrochloride is 10-11 hours. Thus, steady-state concentrations of Captoprilat should be reached after 2 or 3 doses of Captopril hydrochloride given once daily.
- The kinetics did not change, and there was no significant accumulation during chronic administration (28 days) of once-daily doses between 5 mg and 20 mg. Accumulation ratios based on AUC and urinary recovery of Captoprilat were 1.19 and 1.27, respectively.
- Captopril and Captoprilat are cleared predominantly by renal excretion in healthy subjects with normal renal function. Nonrenal (i.e., biliary) excretion accounts for approximately 11%-12% of Captoprilat excretion in healthy subjects. In patients with renal failure, biliary clearance may compensate to an extent for deficient renal clearance.
- In patients with renal insufficiency, the disposition of Captopril and Captoprilat in patients with mild-to-moderate renal insufficiency (creatinine clearance >30 mL/min) is similar to that in patients with normal renal function. In patients with creatinine clearance <30 mL/min, peak Captoprilat levels and the initial (alpha phase) half-life increase, and time to steady state may be delayed (see Adult Indications and Dosage).
- When dialysis was started 2 hours after ingestion of 10 mg of Captopril, approximately 6% of Captoprilat was removed in 4 hours of dialysis. The parent compound, Captopril, was not detected in the dialysate.
- In patients with hepatic insufficiency (due to cirrhosis), the pharmacokinetics of Captoprilat are essentially unaltered. The pharmacokinetics of Captopril and Captoprilat do not appear to be influenced by age.
- In pediatric patients, (N=45) hypertensive, age 6 to 16 years, given multiple daily doses of Captopril (0.1 to 0.5 mg/kg), the clearance of Captoprilat for children 6 to 12 years old was 0.35 L/hr/kg, more than twice that of healthy adults receiving a single dose of 10 mg (0.13 L/hr/kg). In adolescents, it was 0.17 L/hr/kg, 27% higher than that of healthy adults. The terminal elimination half-life of Captoprilat in pediatric patients was around 5 hours, one-third that observed in adults.

## Nonclinical Toxicology

### 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.
- 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.
- Under the auspices of the National Toxicology Program, rats and mice received hydrochlorothiazide for two years at doses up to 100 (rats) and 600 (mice) mg/kg/day. On a body weight basis, these highest doses were about 2400 times (mice) or 400 times (rats) the fosinopril sodium and hydrochlorothiazide dose of 12.5 mg, given to a 50 kg subject. On a body surface area basis, these doses are 226 times (mice) and 82 times (rats) the fosinopril sodium and hydrochlorothiazide dose. These studies uncovered no evidence of carcinogenicity in rats or female mice, but there was equivocal evidence of hepatocarcinogenicity in male mice.
- Hydrochlorothiazide was not genotoxic in in vitro assays using strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 of Salmonella typhimurium (Ames assay); in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations; or in in vivo assays using mouse germinal cell chromosomes; Chinese Hamster bone-marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Using concentrations of hydrochlorothiazide of 43 to 1300 mg/mL, positive test results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) test and in the Mouse Lymphoma Cell (mutagenicity) assays. Using an unspecified concentration of hydrochlorothiazide, positive test results were also obtained in the Aspergillus nidulans nondisjunction assay.
- No adverse effects upon fertility were seen when rats and mice received dietary hydrochlorothiazide prior to mating and throughout gestation at doses up to 4 (rats) and 100 (mice) mg/kg/day. These doses are from 3.2 (body surface area basis in rats) to 400 (weight basis in mice) times greater than the dose received by a 50 kg human receiving 12.5 mg a day.

# Clinical Studies
- 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.
- 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.
- In a clinical study of 107 pediatric patients, 7 to 16 years of age, with either systolic or diastolic pressure above the 95th percentile, patients were given 0.1 or 0.2 mg/kg then titrated up to 0.3 or 0.6 mg/kg with a maximum dose of 40 mg once daily. After four weeks of treatment, the 85 patients whose blood pressure was reduced on therapy were then randomized to either placebo or Captopril and were followed up for an additional two weeks. At the end of two weeks, blood pressure (both systolic and diastolic) in children withdrawn to placebo rose by 4 to 6 mmHg more than in children on Captopril. No dose-response was observed for the three doses.

# How Supplied
- Captopril and Hydrochlorothiazide Tablets, USP 25 mg/15 mg are supplied as white, round, quadrisected, biconvex tablets containing 25 mg of captopril and 15 mg of hydrochlorothiazide. The tablet is debossed with M 81 on one side and is quadrisected on the reverse side. They are available as follows:
- National Drug Code (NDC): NDC 0378-0081-01
- Bottles of 100 tablets
- Captopril and Hydrochlorothiazide Tablets, USP 25 mg/25 mg are supplied as peach, round, quadrisected, biconvex, tablets containing 25 mg of captopril and 25 mg of hydrochlorothiazide. The tablet is debossed with M 83 on one side and is quadrisected on the reverse side. They are available as follows:
- National Drug Code (NDC): NDC 0378-0083-01
- Bottles of 100 tablets
- Captopril and Hydrochlorothiazide Tablets, USP 50 mg/15 mg are supplied as white, partially bisected, biconvex, capsule shaped tablets containing 50 mg of captopril and 15 mg of hydrochlorothiazide. The tablet is debossed withM 84 on one side and is partially bisected on both sides. They are available as follows:
- National Drug Code (NDC): NDC 0378-0084-01
- Bottles of 100 tablets
- Captopril and Hydrochlorothiazide Tablets, USP 50 mg/25 mg are supplied as peach, partially bisected, biconvex, capsule shaped tablets containing 50 mg of captopril and 25 mg of hydrochlorothiazide. The tablet is debossed with M 86 on one side and is partially bisected on both sides. They are available as follows:
- National Drug Code (NDC): NDC 0378-0086-01
- Bottles of 100 tablets
- Storage
- Store at 20 to 25C (68 to 77F).  Protect from moisture.
- Manufactured by
- Mylan Pharmaceuticals Inc.
- Morgantown, WV 26505
REVISED MARCH 2006
CPHZ:R
- Novartis Pharmaceuticals Corporation, Suffern, New York 10901
- Distributed by
- Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936

# Images

## Drug Images

# Label images

# Patient Information

## Patient Information from FDA
- 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.
- Angioedema
- Angioedema, including laryngeal edema, can occur at any time with treatment with ACE inhibitors. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, eyes, lips, or tongue, or difficulty in breathing) and to take no more drug until they have consulted with the prescribing physician.
- Symptomatic Hypotension
- Patients should be cautioned that lightheadedness can occur, especially during the first days of therapy, and it should be reported to the prescribing physician. Patients should be told that if syncope occurs, Captopril should be discontinued until the prescribing physician has been consulted.
- All patients should be cautioned that inadequate fluid intake or excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope.
- Hyperkalemia
- Patients should be told not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician.
- Neutropenia
- Patients should be told to promptly report any indication of infection (e.g., sore throat, fever), which could be a sign of neutropenia.

## Patient Information from NLM
For patient information about Captopril from NLM, click here.

# Precautions with Alcohol
Alcohol-Captopril and Hydrochlorothiazide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
Capoten (USA)

# Look-Alike Drug Names
captopril - carvedilol

# Drug Shortage Status

# Price