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Aldactazide®
(spironolactone with hydrochlorothiazide)


DESCRIPTIONCLINICAL PHARMACOLOGYINDICATIONS AND USAGECONTRAINDICATIONSWARNINGSPRECAUTIONSADVERSE REACTIONSDOSAGE AND ADMINISTRATIONHOW SUPPLIED


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WARNING

Spironolactone, an ingredient of Aldactazide, has been shown to be a tumorigen in chronic toxicity studies in rats (see Warnings). Aldactazide should be used only in those conditions described under Indications and Usage. Unnecessary use of this drug should be avoided.

Fixed-dose combination drugs are not indicated for initial therapy of edema or hypertension. Edema or hypertension requires therapy titrated to the individual patient. If the fixed combination represents the dosage so determined, its use may be more convenient in patient management. The treatment of hypertension and edema is not static but must be reevaluated as conditions in each patient warrant.


DESCRIPTION

Aldactazide oral tablets contain:

spironolactone 25 mg
hydrochlorothiazide 25 mg

or

spironolactone 50 mg
hydrochlorothiazide 50 mg

Spironolactone (Aldactone®), an aldosterone antagonist, is 17-hydroxy-7alpha-mercapto-3-oxo-17alpha-pregn-4-ene-21-carboxylic acid gamma-lactone acetate and has the following structural formula:

Spironolactone is practically insoluble in water, soluble in alcohol, and freely soluble in benzene and in chloroform.

Hydrochlorothiazide, a diuretic and antihypertensive, is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide and has the following structural formula:

Hydrochlorothiazide is slightly soluble in water and freely soluble in sodium hydroxide solution.

Inactive ingredients include calcium sulfate, corn starch, flavor, hydroxypropyl cellulose, hydroxypropyl methylcellulose, iron oxide, magnesium stearate, polyethylene glycol, povidone, and titanium dioxide.


CLINICAL PHARMACOLOGY

Mechanism of action: Aldactazide is a combination of two diuretic agents with different but complementary mechanisms and sites of action, thereby providing additive diuretic and antihypertensive effects. Additionally, the spironolactone component helps to minimize the potassium loss characteristically induced by the thiazide component.

The diuretic effect of spironolactone is mediated through its action as a specific pharmacologic antagonist of aldosterone, primarily by competitive binding of receptors at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule. Hydrochlorothiazide promotes the excretion of sodium and water primarily by inhibiting their reabsorption in the cortical diluting segment of the distal renal tubule.

Aldactazide is effective in significantly lowering the systolic and diastolic blood pressure in many patients with essential hypertension, even when aldosterone secretion is within normal limits.

Both spironolactone and hydrochlorothiazide reduce exchangeable sodium, plasma volume, body weight, and blood pressure. The diuretic and antihypertensive effects of the individual components are potentiated when spironolactone and hydrochlorothiazide are given concurrently.

Pharmacokinetics: Spironolactone is rapidly and extensively metabolized. Sulfur-containing products are the predominant metabolites and are thought to be primarily responsible, together with spironolactone, for the therapeutic effects of the drug. The following pharmacokinetic data were obtained from 12 healthy volunteers following the administration of 100 mg of spironolactone (Aldactone film-coated tablets) daily for 15 days. On the 15th day, spironolactone was given immediately after a low-fat breakfast and blood was drawn thereafter.

Accumulation Factor:
AUC (0-24 hr,
day 15/AUC
(0-24 hr, day 1)
Mean Peak Serum Concentration Mean (SD) Post-Steady State Half-Life
7-alpha-(thiomethyl) spirolactone (TMS) 1.25 391 ng/mL at 3.2 hr 13.8 hr (6.4) (terminal)
6-beta-hydroxy-7-alpha-(thiomethyl) spirolactone (HTMS) 1.50 125 ng/mL at 5.1 hr 15.0 hr (4.0) (terminal)
Canrenone (C) 1.41 181 ng/mL at 4.3 hr 16.5 hr (6.3) (terminal)
Spironolactone 1.30 80 ng/mL at 2.6 hr Approximately 1.4 hr (0.5) (beta half-life)

The pharmacological activity of spironolactone metabolites in man is not known. However, in the adrenalectomized rat the antimineralocorticoid activities of the metabolites C, TMS, and HTMS, relative to spironolactone, were 1.10, 1.28, and 0.32, respectively. Relative to spironolactone, their binding affinities to the aldosterone receptors in rat kidney slices were 0.19, 0.86, and 0.06, respectively.

In humans the potencies of TMS and 7-alpha-thiospirolactone in reversing the effects of the synthetic mineralocorticoid, fludrocortisone, on urinary electrolyte composition were 0.33 and 0.26, respectively, relative to spironolactone. However, since the serum concentrations of these steroids were not determined, their incomplete absorption and/or first-pass metabolism could not be ruled out as a reason for their reduced in vivo activities.

Both spironolactone and canrenone are more than 90% bound to plasma proteins. The metabolites are excreted primarily in the urine and secondarily in bile.

The effect of food on spironolactone absorption (two 100-mg Aldactone tablets) was assessed in a single dose study of 9 healthy, drug-free volunteers. Food increased the bioavailability of unmetabolized spironolactone by almost 100%. The clinical importance of this finding is not known.

Hydrochlorothiazide is rapidly absorbed following oral administration. Onset of action of hydrochlorothiazide is observed within one hour and persists for 6 to 12 hours. Hydrochlorothiazide plasma concentrations attain peak levels at one to two hours and decline with a half-life of four to five hours. Hydrochlorothiazide undergoes only slight metabolic alteration and is excreted in urine. It is distributed throughout the extracellular space, with essentially no tissue accumulation except in the kidney.


INDICATIONS AND USAGE

Spironolactone, an ingredient of Aldactazide, has been shown to be a tumorigen in chronic toxicity studies in rats (see Warnings section). Aldactazide should be used only in those conditions described below. Unnecessary use of this drug should be avoided.

Aldactazide is indicated for:

Edematous conditions for patients with:

Essential hypertension

Usage in Pregnancy. The routine use of diuretics in an otherwise healthy woman is inappropriate and exposes mother and fetus to unnecessary hazard. Diuretics do not prevent development of toxemia of pregnancy, and there is no satisfactory evidence that they are useful in the treatment of developing toxemia.

Edema during pregnancy may arise from pathologic causes or from the physiologic and mechanical consequences of pregnancy. Aldactazide is indicated in pregnancy when edema is due to pathologic causes just as it is in the absence of pregnancy (however, see Warnings section). Dependent edema in pregnancy, resulting from restriction of venous return by the expanded uterus, is properly treated through elevation of the lower extremities and use of support hose; use of diuretics to lower intravascular volume in this case is unsupported and unnecessary. There is hypervolemia during normal pregnancy which is not harmful to either the fetus or the mother (in the absence of cardiovascular disease), but which is associated with edema, including generalized edema, in the majority of pregnant women. If this edema produces discomfort, increased recumbency will often provide relief. In rare instances, this edema may cause extreme discomfort which is not relieved by rest. In these cases, a short course of diuretics may provide relief and may be appropriate.


CONTRAINDICATIONS

Aldactazide is contraindicated in patients with anuria, acute renal insufficiency, significant impairment of renal excretory function, or hyperkalemia, and in patients who are allergic to thiazide diuretics or to other sulfonamide-derived drugs. Aldactazide may also be contraindicated in acute or severe hepatic failure.


WARNINGS

Potassium supplementation, either in the form of medication or as a diet rich in potassium, should not ordinarily be given in association with Aldactazide therapy. Excessive potassium intake may cause hyperkalemia in patients receiving Aldactazide (see Precautions section). Aldactazide should not be administered concurrently with other potassium-sparing diuretics. Spironolactone, when used with ACE inhibitors, even in the presence of a diuretic, has been associated with severe hyperkalemia. Extreme caution should be exercised when Aldactazide is given concomitantly with ACE inhibitors (see Precautions).

Sulfonamide derivatives, including thiazides, have been reported to exacerbate or activate systemic lupus erythematosus.

Spironolactone has been shown to be a tumorigen in chronic toxicity studies performed in rats, with its proliferative effects manifested on endocrine organs and the liver. In one study using 25, 75, and 250 times the usual daily human dose (2 mg/kg) there was a statistically significant dose-related increase in benign adenomas of the thyroid and testes. In female rats there was a statistically significant increase in malignant mammary tumors at the mid-dose only. In male rats there was a dose-related increase in proliferative changes in the liver. At the highest dosage level (500 mg/kg), the range of effects included hepatocytomegaly, hyperplastic nodules, and hepatocellular carcinoma; the last was not statistically significant at a value of p = 0.05. A dose-related (above 20 mg/kg/day) incidence of myelocytic leukemia was observed in rats fed daily doses of potassium canrenoate for a period of one year. In long-term (two-year) oral carcinogenicity studies of potassium canrenoate in the rat, myelocytic leukemia and hepatic, thyroid, testicular, and mammary tumors were observed. Potassium canrenoate did not produce a mutagenic effect in tests using bacteria or yeast. It did produce a positive mutagenic effect in several in vitro tests in mammalian cells following metabolic activation. In an in vivo mammalian system potassium canrenoate was not mutagenic. Canrenone and canrenoic acid are the major metabolites of potassium canrenoate. Spironolactone is also metabolized to canrenone. An increased incidence of leukemia was not observed in chronic rat toxicity studies conducted with spironolactone at doses up to 500 mg/kg/day.


PRECAUTIONS

Patients receiving Aldactazide therapy should be carefully evaluated for possible disturbances of fluid and electrolyte balance. Hyperkalemia may occur in patients with impaired renal function or excessive potassium intake and can cause cardiac irregularities, which may be fatal. Consequently, no potassium supplement should ordinarily be given with Aldactazide. Hyperkalemia can be treated promptly by the rapid intravenous administration of glucose (20% to 50%) and regular insulin, using 0.25 to 0.5 units of insulin per gram of glucose. This is a temporary measure to be repeated as required. Aldactazide use should be discontinued and potassium intake (including dietary potassium) restricted.

Hypokalemia may develop as a result of profound diuresis, particularly when Aldactazide is used concomitantly with loop diuretics, glucocorticoids, or ACTH. Hypokalemia may exaggerate the effects of digitalis therapy. Potassium depletion may induce signs of digitalis intoxication at previously tolerated dosage levels.

Concomitant administration of potassium-sparing diuretics and ACE inhibitors or indomethacin has been associated with severe hyperkalemia.

Warning signs of possible fluid and electrolyte imbalance include dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal symptoms.

Aldactazide therapy may cause a transient elevation of BUN. This appears to represent a concentration phenomenon rather than renal toxicity, since the BUN level returns to normal after use of Aldactazide is discontinued. Progressive elevation of BUN is suggestive of the presence of preexisting renal impairment.

Reversible hyperchloremic metabolic acidosis, usually in association with hyperkalemia, has been reported to occur in some patients with decompensated hepatic cirrhosis, even in the presence of normal renal function.

Dilutional hyponatremia, manifested by dryness of the mouth, thirst, lethargy, and drowsiness, and confirmed by a low serum sodium level, may be induced, especially when Aldactazide is administered in combination with other diuretics. A true low-salt syndrome may rarely develop with Aldactazide therapy and may be manifested by increasing mental confusion similar to that observed with hepatic coma. This syndrome is differentiated from dilutional hyponatremia in that it does not occur with obvious fluid retention. Its treatment requires that diuretic therapy be discontinued and sodium administered.

Gynecomastia may develop in association with the use of spironolactone; physicians should be alert to its possible onset. The development of gynecomastia appears to be related to both dosage level and duration of therapy and is normally reversible when Aldactazide is discontinued. In rare instances some breast enlargement may persist when Aldactazide is discontinued.

Thiazides have been demonstrated to alter the metabolism of uric acid and carbohydrates, with possible development of hyperuricemia, gout, and decreased glucose tolerance. Thiazides may temporarily exaggerate abnormalities of glucose metabolism in diabetic patients or cause abnormalities to appear in patients with latent diabetes.

The antihypertensive effects of hydrochlorothiazide may be enhanced in patients who have undergone sympathectomy.

Pathologic changes in the parathyroid gland with hypercalcemia and hypophosphatemia have been observed in patients on prolonged thiazide therapy. Thiazides may also decrease serum PBI levels without evidence of alteration of thyroid function.

A determination of serum electrolytes to detect possible electrolyte imbalance should be performed at periodic intervals.

Both spironolactone and hydrochlorothiazide reduce the vascular responsiveness to norepinephrine. Therefore, caution should be exercised in the management of patients subjected to regional or general anesthesia while they are being treated with Aldactazide. Thiazides may also increase the responsiveness to tubocurarine.

Spironolactone has been shown to increase the half-life of digoxin. This may result in increased serum digoxin levels and subsequent digitalis toxicity. It may be necessary to reduce the maintenance and digitalization doses when spironolactone is administered, and the patient should be carefully monitored to avoid over- or underdigitalization.

Hydrochlorothiazide may raise the concentration of blood uric acid. Dosage adjustment of antigout medications may be necessary. Hydrochlorothiazide may also raise blood glucose concentrations. Dosage adjustments of insulin or hypoglycemic medications may be necessary. Concurrent use of diuretics with lithium is not recommended as it may produce lithium toxicity.

Several reports of possible interference with digoxin radioimmunoassays by spironolactone, or its metabolites, have appeared in the literature. Neither the extent nor the potential clinical significance of its interference (which may be assay-specific) has been fully established.

Usage in Pregnancy. Spironolactone or its metabolites may, and hydrochlorothiazide does, cross the placental barrier. Therefore, the use of Aldactazide in pregnant women requires that the anticipated benefit be weighed against possible hazards to the fetus. These hazards include fetal or neonatal jaundice, thrombocytopenia, and possible other adverse reactions which have been reported in the adult.

Nursing Mothers. Canrenone, a metabolite of spironolactone, and hydrochlorothiazide appear in breast milk. If use of these drugs is deemed essential, an alternative method of infant feeding should be instituted.


ADVERSE REACTIONS

Gynecomastia is observed not infrequently. A few cases of agranulocytosis have been reported in patients taking spironolactone. Other adverse reactions that have been reported in association with the use of spironolactone are: gastrointestinal symptoms including cramping and diarrhea, drowsiness, lethargy, headache, maculopapular or erythematous cutaneous eruptions, urticaria, mental confusion, drug fever, ataxia, inability to achieve or maintain erection, irregular menses or amenorrhea, postmenopausal bleeding, hirsutism, deepening of the voice, gastric bleeding, ulceration, gastritis, vomiting, and anaphylactic reactions. Carcinoma of the breast has been reported in patients taking spironolactone, but a cause and effect relationship has not been established. A very few cases of mixed cholestatic/hepatocellular toxicity, with one reported fatality, have been reported with spironolactone administration.

Adverse reactions reported in association with the use of thiazides include: gastrointestinal symptoms (anorexia, nausea, vomiting, diarrhea, abdominal cramps), purpura, thrombocytopenia, leukopenia, agranulocytosis, dermatologic symptoms (cutaneous eruptions, pruritus, erythema multiforme), paresthesia, acute pancreatitis, jaundice, dizziness, vertigo, headache, xanthopsia, photosensitivity, necrotizing angiitis, aplastic anemia, orthostatic hypotension, muscle spasm, weakness, restlessness, hypokalemia, and anaphylactic reactions.

Adverse reactions are usually reversible upon discontinuation of Aldactazide.


DOSAGE AND ADMINISTRATION

Optimal dosage should be established by individual titration of the components (see Box Warning).

Edema in adults (congestive heart failure, hepatic cirrhosis, or nephrotic syndrome). The usual maintenance dose of Aldactazide is 100 mg each of spironolactone and hydrochlorothiazide daily, administered in a single dose or in divided doses, but may range from 25 mg to 200 mg of each component daily depending on the response to the initial titration. In some instances it may be desirable to administer separate tablets of either Aldactone (spironolactone) or hydrochlorothiazide in addition to Aldactazide in order to provide optimal individual therapy.

The onset of diuresis with Aldactazide occurs promptly and, due to prolonged effect of the spironolactone component, persists for two to three days after Aldactazide is discontinued.

Edema in children. The usual daily maintenance dose of Aldactazide should be that which provides 0.75 to 1.5 mg of spironolactone per pound of body weight (1.65 to 3.3 mg/kg).

Essential hypertension. Although the dosage will vary depending on the results of titration of the individual ingredients, many patients will be found to have an optimal response to 50 mg to 100 mg each of spironolactone and hydrochlorothiazide daily, given in a single dose or in divided doses.

Concurrent potassium supplementation is not recommended when Aldactazide is used in the long-term management of hypertension or in the treatment of most edematous conditions, since the spironolactone content of Aldactazide is usually sufficient to minimize loss induced by the hydrochlorothiazide component.


HOW SUPPLIED

Aldactazide tablets containing 25 mg of spironolactone (Aldactone) and 25 mg of hydrochlorothiazide are round, tan, film coated, with SEARLE and 1011 debossed on one side and ALDACTAZIDE and 25 on the other side, supplied as:

NDC Number Size
0025-1011-31 bottle of 100
0025-1011-51 bottle of 500
0025-1011-55 bottle of 2500
0025-1011-34 carton of 100 unit dose

Aldactazide tablets containing 50 mg of spironolactone (Aldactone) and 50 mg of hydrochlorothiazide are oblong, tan, scored, film coated, with SEARLE and 1021 debossed on the scored side and ALDACTAZIDE and 50 on the other side, supplied as:

NDC Number Size
0025-1021-31 bottle of 100
0025-1021-34 carton of 100 unit dose

Store below 77°F (25°C).

Caution: Federal law prohibits dispensing without prescription.

11/18/96

G.D. Searle & Co.
Chicago IL 60680 USA

©1996, G.D. Searle & Co.


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