CAPTOPRIL AND HYDROCHLOROTHIAZIDE TABLETS USP,
25 mg/15 mg, 25 mg/25 mg, 50 mg/15 mg, AND 50 mg/25 mg

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 WARNINGS, Captopril, Fetal/Neonatal Morbidity and Mortality.

Captopril and hydrochlorothiazide are two oral antihypertensive agents. Captopril, the first of a new class of antihypertensive agents, is a specific competitive inhibitor of angiotensin I-converting enzyme (ACE), the enzyme responsible for the conversion of angiotensin I to angiotensin II. Hydrochlorothiazide is a benzothiadiazide (thiazide) diuretic-antihypertensive. Captopril and hydrochlorothiazide tablets are available in four combinations of captopril with hydrochlorothiazide: 25 mg with 15 mg, 25 mg with 25 mg, 50 mg with 15 mg, and 50 mg with 25 mg. In addition, each tablet contains the following inactive ingredients: lactose anhydrous, magnesium stearate, microcrystalline cellulose, pregelatinized starch, and stearic acid. Captopril and hydrochlorothiazide tablets 25 mg/25 mg and 50 mg/25 mg also contain brown 70 iron oxide.

Captopril is designated chemically as 1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline; hydrochlorothiazide is 6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Their structural formulas are as follows:

Captopril

C₉H₁₅NO₃S M.W. 217.29

Hydrochlorothiazide

C₇H₈ClN₃O₄S₂ M.W. 297.73

Captopril is a white to off-white crystalline powder that may have a slight sulfurous odor; it is soluble in water (approx. 160 mg/mL), methanol, and ethanol and sparingly soluble in chloroform and ethyl acetate.

Hydrochlorothiazide is a white crystalline powder slightly soluble in water but freely soluble in sodium hydroxide solution.

Thiazides affect the renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosage all thiazides are approximately equal in their diuretic potency.

Thiazides increase excretion of sodium and chloride in approximately equivalent amounts. Natriuresis causes a secondary loss of potassium and bicarbonate.

The mechanism of the antihypertensive effect of thiazides is unknown. Thiazides do not affect normal blood pressure.

The mean plasma half-life of hydrochlorothiazide in fasted individuals has been reported to be approximately 2.5 hours.

Onset of diuresis occurs in two hours and the peak effect at about four hours. Its action persists for approximately six to twelve hours. Hydrochlorothiazide is eliminated rapidly by the kidney.

Captopril and hydrochlorothiazide tablets are indicated for the treatment of hypertension. The blood pressure lowering effects of captopril and thiazides are approximately additive.

This fixed combination drug may be used as initial therapy or substituted for previously titrated doses of the individual components.

When captopril and hydrochlorothiazide are given together it may not be necessary to administer captopril in divided doses to attain blood pressure control at trough (before the next dose). Also, with such a combination, a daily dose of 15 mg of hydrochlorothiazide may be adequate.

Treatment may, therefore, be initiated with captopril and hydrochlorothiazide tablets 25 mg/15 mg once daily. Subsequent titration should be with additional doses of the components (captopril, hydrochlorothiazide) as single agents or as captopril and hydrochlorothiazide tablets 50 mg/15 mg, 25 mg/25 mg, or 50 mg/25 mg (see DOSAGE AND ADMINISTRATION).

In using captopril and hydrochlorothiazide, consideration should be given to the risk of neutropenia/agranulocytosis (see WARNINGS).

Captopril and hydrochlorothiazide may be used for patients with normal renal function, in whom the risk is relatively low. In patients with impaired renal function, particularly those with collagen vascular disease, captopril and hydrochlorothiazide should be reserved for hypertensives who have either developed unacceptable side effects on other drugs, or have failed to respond satisfactorily to other drug combinations.

ACE inhibitors (for which adequate data are available) cause a higher rate of angioedema in black than in non-black patients (see WARNINGS, Captopril, Head and neck angioedema and Intestinal angioedema).

This product is contraindicated in patients who are hypersensitive to captopril or any other angiotensin-converting enzyme inhibitor (e.g., a patient who has experienced angioedema during therapy with any other ACE inhibitor).

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

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.

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 (see PRECAUTIONS, Drug Interactions, Hydrochlorothiazide).

Patients should be advised to immediately report to their physician any signs or symptoms suggesting angioedema (e.g., swelling of face, eyes, lips, tongue, larynx and extremities; difficulty in swallowing or breathing; hoarseness) and to discontinue therapy. (See WARNINGS, Captopril, Head and neck angioedema and Intestinal angioedema.)

Patients should be told to report promptly any indication of infection (e.g., sore throat, fever), which may be a sign of neutropenia, or of progressive edema which might be related to proteinuria and nephrotic syndrome.

All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; patients should be advised to consult with the physician.

Patients should be advised not to use potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes without consulting their physician. (See PRECAUTIONS, General and Drug Interactions, Captopril and ADVERSE REACTIONS, Captopril.)

Patients should be warned against interruption or discontinuation of medication unless instructed by the physician.

Heart failure patients on captopril therapy should be cautioned against rapid increases in physical activity.

Patients should be informed that captopril and hydrochlorothiazide tablets should be taken one hour before meals (see DOSAGE AND ADMINISTRATION).

Serum electrolyte levels should be regularly monitored (see WARNINGS, Captopril and Hydrochlorothiazide and PRECAUTIONS, General, Hydrochlorothiazide).

Carcinogenicity and fertility studies have not been conducted with captopril and hydrochlorothiazide, however, in animals they have been conducted with the individual components as noted below. Mutagenicity studies indicate that captopril in a 2:1 combination with hydrochlorothiazide was not mutagenic or clastogenic, with or without metabolic activation, in the following in vitro assays: 1) Ames reverse-mutation in Salmonella; 2) forward mutation study in Saccharomyces pombe; 3) mitotic gene conversion test in Saccharomyces cerevisiae; and 4) sister-chromatid-exchange study in human lymphocytes.

In a cytogenetics study using human lymphocytes, there were no increases in chromosomal abnormalities without metabolic activation, nor with metabolic activation at 28 hours post-treatment. A statistically significant increase was found at 22 hours with metabolic activation at the three concentrations tested (captopril/hydrochlorothiazide in a 2:1 combination at 5, 25, 50 mcg/mL total weight); however, there was no dose response, and the difference is probably attributable to the unusual absence of any abnormalities in the negative-control cultures in this test.

In an oral micronucleus study in mice, the captopril/hydrochlorothiazide combination (2:1 mixture at 2,500 mg/kg total weight) was not genotoxic.

Both captopril and hydrochlorothiazide are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from both drugs, a decision should be made whether to discontinue nursing or to discontinue therapy taking into account the importance of captopril and hydrochlorothiazide to the mother. (See PRECAUTIONS, Pediatric Use.)

Safety and effectiveness in pediatric patients have not been established. There is limited experience reported in the literature with the use of captopril in the pediatric population; dosage, on a weight basis, was generally reported to be comparable to or less than that used in adults.

Infants, especially newborns, may be more susceptible to the adverse hemodynamic effects of captropril. Excessive, prolonged and unpredictable decreases in blood pressure and associated complications, including oliguria and seizures, have been reported.

Captopril and hydrochlorothiazide tablets should be used in pediatric patients only if other measures for controlling blood pressure have not been effective.

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

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

Each of the following has been reported in approximately 1 to 2 of 1,000 patients and are of uncertain relationship to drug use: renal insufficiency, renal failure, nephrotic syndrome, polyuria, oliguria, and urinary frequency.

Hematologic: Neutropenia/agranulocytosis has occurred (see WARNINGS). Cases of anemia, thrombocytopenia, and pancytopenia have been reported.

Dermatologic: Rash, often with pruritus, and sometimes with fever, arthralgia, and eosinophilia, occurred in about 4 to 7 (depending on renal status and dose) of 100 patients, usually during the first four weeks of therapy. It is usually maculopapular, and rarely urticarial. The rash is usually mild and disappears within a few days of dosage reduction, short-term treatment with an antihistaminic agent, and/or discontinuing therapy; remission may occur even if captopril is continued. Pruritus, without rash, occurs in about 2 of 100 patients. Between 7 and 10 percent of patients with skin rash have shown eosinophilia and/or positive ANA titers. A reversible associated pemphigoid-like lesion, and photosensitivity, have also been reported.

Flushing or pallor has been reported in 2 to 5 of 1,000 patients.

Cardiovascular: Hypotension may occur; see WARNINGS and PRECAUTIONS (Drug Interactions) for discussion of hypotension with captopril therapy.

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

Angina pectoris, myocardial infarction, Raynaud's syndrome, and congestive heart failure have each occurred in 2 to 3 of 1,000 patients.

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

Angioedema: Angioedema involving the extremities, face, lips, mucous membranes, tongue, glottis or larynx has been reported in approximately one in 1,000 patients. Angioedema involving the upper airways has caused fatal airway obstruction. (See WARNINGS, Captopril, Head and neck angioedema and Intestinal angioedema and PRECAUTIONS, Information for Patients.)

Cough: Cough has been reported in 0.5 to 2% of patients treated with captopril in clinical trials (see PRECAUTIONS, General, 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 uled 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.

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.

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.

Correction of hypotension would be of primary concern. Volume expansion with an intravenous infusion of normal saline is the treatment of choice for restoration of blood pressure.

While captopril may be removed from the adult circulation by hemodialysis, there is inadequate data concerning the effectiveness of hemodialysis for removing it from the circulation of neonates or children. Peritoneal dialysis is not effective for removing captopril; there is no information concerning exchange transfusion for removing captopril from the general circulation.

In addition to the expected diuresis, overdosage of thiazides may produce varying degrees of lethargy which may progress to coma within a few hours, with minimal depression of respiration and cardiovascular function and without evidence of serum electrolyte changes or dehydration. The mechanism of thiazide-induced CNS depression is unknown. Gastrointestinal irritation and hypermotility may occur. Transitory increase in BUN has been reported, and serum electrolyte changes may occur, especially in patients with impaired renal function.

In addition to gastric lavage and supportive therapy for stupor or coma, symptomatic treatment of gastrointestinal effects may be needed. The degree to which hydrochlorothiazide is removed by hemodialysis has not been clearly established. Measures as required to maintain hydration, electrolyte balance, respiration, and cardiovascular and renal function should be instituted.

DOSAGE MUST BE INDIVIDUALIZED ACCORDING TO PATIENT'S RESPONSE.

Captopril and hydrochlorothiazide tablets may be substituted for the previously titrated individual components.

Alternatively, therapy may be instituted with a single tablet of captopril and hydrochlorothiazide 25 mg/15 mg taken once daily. For patients insufficiently responsive to the initial dose, additional captopril or hydrochlorothiazide may be added as individual components or by using captopril and hydrochlorothiazide tablets 50 mg/15 mg, 25 mg/25 mg or 50 mg/25 mg, or divided doses may be used.

Because the full effect of a given dose may not be attained for 6 to 8 weeks, dosage adjustments should generally be made at 6 week intervals, unless the clinical situation demands more rapid adjustment.

In general, daily doses of captopril should not exceed 150 mg and of hydrochlorothiazide should not exceed 50 mg.

Captopril and hydrochlorothiazide tablets should be taken one hour before meals.

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. (See WARNINGS, Captopril, Anaphylactoid reactions during membrane exposure and PRECAUTIONS, Hemodialysis.)

Captopril and hydrochlorothiazide tablets USP are available as follows:

Captopril and hydrochlorothiazide tablets USP, 25 mg/15 mg are available as white, round tablets debossed "93" and "176" on the upper surface and quadrisected on the lower surface in bottles of 100 with desiccant/carbon canisters.

Captopril and hydrochlorothiazide tablets USP, 25 mg/25 mg are available as tan, round tablets debossed "93" and "177" on the upper surface and quadrisected on the lower surface in bottles of 100 with desiccant/carbon canisters.

Captopril and hydrochlorothiazide tablets USP, 50 mg/15 mg are available as white, oval tablets debossed "93" and "181" on the bisected side in bottles of 100 with desiccant/carbon canisters.

Captopril and hydrochlorothiazide tablets USP, 50 mg/25 mg are available as tan, oval tablets debossed "93" and "182" on the bisected side in bottles of 100 with desiccant/carbon canisters.

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

Dispense in a tight container as defined in the USP, with a child-resistant closure (as required).

Keep bottles tightly closed.

Protect from moisture.

Manufactured By:

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Rev. G 5/2006