Captopril and Hydrochlorothiazide

Captopril and Hydrochlorothiazide
Black Box Warning
Adult Indications and Dosage
Pediatric Indications and Dosage
Contraindications
Warnings
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration and Monitoring
IV Compatibility
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient information
Precautions with Alcohol
Brand Names
Look-Alike Drug Names
Drug Shortage Status
Price

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

Synonyms / Brand Names: Captopril and Hydrochlorothiazide

Disclaimer

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Black Box Warning

WARNING: USE IN PREGNANCY When used in pregnancy during the second and third trimesters, ACE Inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, Captopril and Hydrochlorothiazide should be discontinued as soon as possible. See full prescribing information for complete boxed 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)

Hypertension

• 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 20—40 mg PO qd or Captopril 10—20 mg PO bid (MAX 80 mg/day)

For Hypertensive Patients with Renal Impairment

• Dosing Information

• Initial dose (for creatinine clearance <30 mL/min/1.73 m² or Cr >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)

Guideline-Supported Use

Heart Failure, Stage B

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

• Class of Recommendation: Class I

• Level of Evidence: Level A

• Recommendation

• Captopril

Myocardial Infarction

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

• Class of Recommendation: Class I

• Level of Evidence: Level A

• Recommendation

• 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

Diabetic Nephropathy

• Dosing Information

• Captopril 10 mg PO qd

Kidney Disease, Non-Diabetic

• Dosing Information

• Captopril 10 mg PO qd

Left Ventricular Hypertrophy

• Dosing Information

• Captopril 20 mg PO qd for 2 weeks, followed by Captopril 40 mg qd or combination of Captopril 40 mg PO qd and Amlodipine 5 mg PO qd

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Hypertension

• Dosing Information

• Initial dose: Captopril 0.2 mg/kg PO qd (for pediatric patients above the age of 6 years)

• Captopril is not advised for children below the age of 6 years (see Pediatric Use) and in pediatric patients with glomerular filtration rate <30 mL.

• For pediatric patients who cannot swallow tablets, or for whom the calculated dosage (mg/kg) does not correspond to the available tablet strengths for Captopril, follow the suspension preparation instructions to administer Captopril HCl as a suspension (see Administration and Monitoring).

Hypertensive Patients with Renal Impairment

• Dosing Information

• Initial dose (for creatinine clearance <30 mL/min/1.73 m² or Cr >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 (Pediatric)

There is limited information about Off-Label Use and Dosage of xxxxxx tablet in pediatric patients.

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

Anaphylactoid and Possibly Related Reactions

• Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including Captopril) may be subject to a variety of adverse reactions, some of them serious.

• Head and Neck Angioedema

• Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with angiotensin-converting enzyme inhibitors. In U.S. clinical trials, symptoms consistent with angioedema were seen in none of the subjects who received placebo and in about 0.5% of the subjects who received Captopril. Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, treatment with Captopril should be discontinued and appropriate therapy instituted immediately. Where there is involvement of the tongue, glottis, or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine injection 1:1000 (0.3 mL to 0.5 mL) should be promptly administered (see Adverse Reactions).

• Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to nonblacks.

• Intestinal Angioedema

• Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

• Anaphylactoid Reactions During Desensitization

• Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.

• Anaphylactoid Reactions During Membrane Exposure

• Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption (a procedure dependent upon devices not approved in the United States).

Hypotension

• Captopril can cause symptomatic hypotension. Like other ACE inhibitors, Captopril has been only rarely associated with hypotension in uncomplicated hypertensive patients. Symptomatic hypotension is most likely to occur in patients who have been volume-and/or salt-depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Volume-and/or salt-depletion should be corrected before initiating therapy with Captopril.

• In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or azotemia and, rarely, with acute renal failure and death. In such patients, Captopril therapy should be started under close medical supervision; they should be followed closely for the first 2 weeks of treatment and whenever the dose of Captopril or diuretic is increased.

• If hypotension occurs, the patient should be placed in a supine position, and, if necessary, treated with intravenous infusion of physiological saline. Captopril treatment usually can be continued following restoration of blood pressure and volume.

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.

Hepatic Failure

• Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.

Hydrochlorothiazide

• Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function.

• Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

• Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma.

• The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.

• In general, lithium should not be given with diuretics

Adverse Reactions

Clinical Trials Experience

Captopril

• Captopril has been evaluated for safety in over 6000 patients with hypertension; over 700 of these patients were treated for at least one year. The overall incidence of reported adverse events was comparable in Captopril and placebo patients.

• The reported side effects were generally mild and transient, and there was no relation between side effects and age, duration of therapy, or total dosage within the range of 2 to 80 mg. Discontinuation of therapy because of a side effect was required in approximately 5% of U.S. patients treated with Captopril and in 3% of patients treated with placebo.

• The most common reasons for discontinuation were headache (0.6%) and cough (0.5%)

• The side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled trials in more than 1% of patients treated with Captopril are shown below.

File:Captopril tablet adverse reactions.png

• Other adverse experiences reported in controlled clinical trials (in less than 1% of Captopril patients or with less than 1% difference in incidence between Captopril or placebo treatment), and rarer events seen in post-marketing experience, include the following (in some, a causal relationship to drug use is uncertain):

• Dermatologic

• Stevens-Johnson syndrome, pemphigus, apparent hypersensitivity reactions (manifested by dermatitis, pruritus, or rash), photosensitivity, and flushing.

• Gastrointestinal

• Nausea, pancreatitis, constipation, gastritis, vomiting, and melena.

• Hematologic

• Thrombocytopenia and hemolytic anemia.

• Neurologic and Psychiatric

• Anxiety, decreased libido, hypertonia, insomnia, nervousness, and paresthesia.

• Other

• Fatigue, asthma, bronchitis, dyspnea, sinusitis, urinary tract infection, frequent urination, infection, arthritis, impotence, alopecia, arthralgia, myalgia, asthenia, sweating.

• Another potentially important adverse experience, eosinophilic pneumonitis, has been attributed to other ACE inhibitors.

• Clinical Laboratory Test Findings

• Hemoglobin

• Decreases in hemoglobin (a low value and a decrease of 5 g/dL) were rare, occurring in only 1 of 2,014 patients receiving Captopril alone and in 1 of 1,357 patients receiving Captopril plus a diuretic. No U.S. patients discontinued treatment because of decreases in hemoglobin.

• Other (causal relationships unknown)

• Elevations of uric acid, blood glucose, serum bilirubin, and liver enzymes (see Warnings) have been reported, as have scattered incidents of hyponatremia, electrocardiographic changes, eosinophilia, and proteinuria.

• Pediatric Patients

• The adverse experience profile for pediatric patients appears to be similar to that seen in adult patients.

Hydrochlorthiazide

• 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.

Postmarketing Experience

FDA Package Insert for Captopril and Hydrochlorothiazide contains no information regarding Postmarketing Experience.

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

Pregnancy Category (FDA): D

Pregnancy Category (AUS): Captopril and Hydrochlorothiazide is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.

• 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 (see PRECAUTIONS: General: Cough).

• The following have been reported in about 0.5 to 2 percent of patients but did not appear at increased frequency compared to placebo or other treatments used in controlled trials: gastric irritation, abdominal pain, nausea, vomiting, diarrhea, anorexia, constipation, aphthous ulcers, peptic ulcer, dizziness, headache, malaise, fatigue, insomnia, dry mouth, dyspnea, alopecia, paresthesias.

• Other clinical adverse effects reported since the drug was marketed are listed below by body system. In this setting, an incidence or causal relationship cannot be accurately determined.

• Surgery/Anesthesia

• In patients undergoing surgery or during anesthesia with agents that produce hypotension, xxxxxx 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

Serum 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.

Renal Function with Usage of Non-Steroidal Anti-Inflammatory Agents

• 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.

Renal Function with 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).

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 and Hydrochlorothiazide
Systematic (IUPAC) name
6-chloro-1,1-dioxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide
Identifiers
CAS number	58-93-5
ATC code	C03AA03
PubChem	3639
DrugBank	DB00999
Chemical data
Formula	Template:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox
Mol. mass	297.74
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	Variably absorbed from GI tract. Bioavailability ~ 70%
Metabolism	does not undergo significant metabolism (>95% excreted unchanged in urine)
Half life	5.6–14.8 h
Excretion	Primarily excreted unchanged in urine
Therapeutic considerations
Pregnancy cat.	B (D if used to treat pregnancy-induced hypertension)
Legal status	Template:Unicode Prescription only
Routes	Oral (capsules, tablets, oral solution)

• 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-[[1-(ethoxy-carbonyl)-3-phenyl-(1S)-propyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-(3S)-benzazepine-1-acetic acid monohydrochloride.

• Its empirical formula is C24H28N2O5•HCl, 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 xxxxxx 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 µmol/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

Hydrochlorothiazide

• 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

Hypertension and Heart Failure

Adult

• 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.

Pediatric

• 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 xxxxxx 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 xxxxxx. 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

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

Keep container tightly closed.

• Storage

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

Drug Name: Captopril 25 MG / HCTZ 15 MG Oral Tablet Ingredient(s): Captopril mixture with Hydrochlorothiazide Imprint: M;81 Color(s): White Shape: Round Size (mm): 7.00 Score: 4 Drug Label Author: Mylan Phamaceuticals Inc.

Drug Name: Captopril 50 MG / HCTZ 15 MG Oral Tablet Ingredient(s): Captopril mixture with Hydrochlorothiazide Imprint: M;84 Color(s): White Shape: Oval Size (mm): 15.00 Score: 2 Drug Label Author: Mylan Phamaceuticals Inc.

Drug Name: Captopril 50 MG / HCTZ 15 MG Oral Tablet Ingredient(s): Captopril mixture with Hydrochlorothiazide Imprint: M;86 Color(s): Pink Shape: Oval Size (mm): 8.00 Score: 1 Drug Label Author: Mylan Phamaceuticals Inc.

Patient Information

Patient Information from FDA

• Pregnancy

• Female patients of childbearing age should be told about the consequences of exposure to xxxxxx 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, xxxxxx 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

References