Capozide Information
Capozide (Captopril) Use In Pregnancy
Capozide (Captopril) Description
Capozide (Captopril) (captopril and hydrochlorothiazide tablets, USP) for oral administration combines two antihypertensive agents: captopril and hydrochlorothiazide. 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. Capozide (Captopril) 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. Inactive ingredients: microcrystalline cellulose, colorant (FD&C Yellow No. 6), lactose, magnesium stearate, pregelatinized starch, and stearic acid.
Captopril is designated chemically as 1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline; hydrochlorothiazide is 6-Chloro-3,4-dihydro-2-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Graphic formulas:
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.
Capozide (Captopril) Clinical Pharmacology
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 6 to 12 hours. Hydrochlorothiazide is eliminated rapidly by the kidney.
Capozide (Captopril) Indications And Usage
Capozide (Captopril) is 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 Capozide (Captopril) 25 mg/15 mg once daily. Subsequent titration should be with additional doses of the components (captopril, hydrochlorothiazide) as single agents or as Capozide (Captopril) 50 mg/15 mg, 25 mg/25 mg, or 50 mg/25 mg (see ).
In using Capozide (Captopril) , consideration should be given to the risk of neutropenia/agranulocytosis (see ).
Capozide (Captopril) 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, Capozide (Captopril) 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 and ).
Capozide (Captopril) Warnings
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 and ).
Capozide (Captopril) Precautions
Patients should be advised to immediately report to their physician any signs or symptoms suggesting angioedema (eg, swelling of face, eyes, lips, tongue, larynx, and extremities; difficulty in swallowing or breathing; hoarseness) and to discontinue therapy (see and ).
Patients should be told to report promptly any indication of infection (eg, 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 and , and ).
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 Capozide (Captopril) should be taken one hour before meals (see ).
Carcinogenicity and fertility studies have not been conducted with Capozide (Captopril) , 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 assays: 1) Ames reverse-mutation in Salmonella; 2) forward mutation study in ; 3) mitotic gene conversion test in ; 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 2500 mg/kg total weight) was not genotoxic.
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). Anemia, leukopenia, thrombocytopenia, and bone marrow suppression occurred in dogs at doses 8 to 30 times MRHD. 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 at doses 7 to 200 times the MRHD in rats and mice, at 20 to 60 times MRHD in monkeys, and at 30 times the MRHD in dogs.
Gastric erosions/ulcerations were increased in incidence at 20 and 200 times MRHD in male rats and at 30 and 65 times MRHD in dogs and monkeys, respectively. Rabbits developed gastric and intestinal ulcers when given oral doses approximately 30 times MRHD for only five to seven 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) 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.
See
Safety and effectiveness in pediatric patients have not been established. There is limited experience reported in the literature with the use of captopril in the pediatric population; dosage, on a weight basis, was generally reported to be comparable to or less than that used in adults.
Infants, especially newborns, may be more susceptible to the adverse hemodynamic effects of captopril. Excessive, prolonged and unpredictable decreases in blood pressure and associated complications, including oliguria and seizures, have been reported.
Capozide (Captopril) should be used in pediatric patients only if other measures for controlling blood pressure have not been effective.
Capozide (Captopril) Adverse Reactions
Reported incidences are based on clinical trials involving approximately 7000 patients.
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.
Dermatologic:
Flushing or pallor has been reported in 2 to 5 of 1000 patients.
Tachycardia, chest pain, and palpitations have each been observed in approximately 1 of 100 patients.
Angina pectoris, myocardial infarction, Raynaud syndrome, and congestive heart failure have each occurred in 2 to 3 of 1000 patients.
Dysgeusia:
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.
General:
Cardiovascular:
Dermatologic:
Gastrointestinal:
Hematologic:
Hepatobiliary:
Metabolic:
Musculoskeletal:
Nervous/Psychiatric:
Respiratory:
Special Senses:
Urogenital:
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:
Central Nervous System:
Hematologic:
Cardiovascular:
Hypersensitivity:
Other:
Whenever adverse reactions are moderate or severe, thiazide dosage should be reduced or therapy withdrawn.
Hyponatremia:
BUN/Serum Creatinine:
Hematologic:
Liver Function Tests:
Capozide (Captopril) Overdosage
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.
Capozide (Captopril) Dosage And Administration
DOSAGE MUST BE INDIVIDUALIZED ACCORDING TO PATIENT’S RESPONSE.
Capozide (Captopril) may be substituted for the previously titrated individual components.
Alternatively, therapy may be instituted with a single tablet of Capozide (Captopril) 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 Capozide (Captopril) 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 six to eight weeks, dosage adjustments should generally be made at six-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.
Capozide (Captopril) should be taken one hour before meals.
Capozide (Captopril) How Supplied
Capozide (Captopril) (captopril and hydrochlorothiazide tablets, USP)
Tablets are white with distinct orange mottling; they are biconvex rounded squares with quadrisect bars.
Tablets are peach-colored and may show slight mottling; they are biconvex rounded squares with quadrisect bars.
Tablets are white with distinct orange mottling; they are biconvex ovals with a bisect bar.
Tablets are peach-colored and may show slight mottling; they are biconvex ovals with a bisect bar.
Capozide (Captopril)
