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-7α-mercapto-3-oxo-17α-pregn-4-ene-21-carboxylic acid γ -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, hypromellose, iron oxide, magnesium stearate, polyethylene glycol, povidone, and titanium dioxide.

Last updated on RxList: 12/16/2008

Spironolactone, an ingredient of Aldactazide, has been shown to be a tumorigen in chronic toxicity studies in rats (see PRECAUTIONS 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:

Congestive heart failure: For the management of edema and sodium retention when the patient is only partially responsive to, or is intolerant of, other therapeutic measures. The treatment of diuretic-induced hypokalemia in patients with congestive heart failure when other measures are considered inappropriate. The treatment of patients with congestive heart failure taking digitalis when other therapies are considered inadequate or inappropriate.

Cirrhosis of the liver accompanied by edema and/or ascites: Aldosterone levels may be exceptionally high in this condition. Aldactazide is indicated for maintenance therapy together with bed rest and the restriction of f.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 PRECAUTIONS: Pregnancy). 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.

Optimal dosage should be established by individual titration of the components (see Boxed 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.

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.

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
0025-1011-55	bottle of 2500

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

Store below 77°F (25°C).

Distributed by: G.D. Searle LLC., Division of Pfizer Inc, NY, NY 10017. FDA Rev date: 11/26/2002

Last updated on RxList: 12/16/2008

The following adverse reactions have been reported and, within each category (body system), are listed in order of decreasing severity.

Hydrochlorothiazide

Body as a whole: Weakness.

Cardiovascular: Hypotension including orthostatic hypotension (may be aggravated by alcohol, barbiturates, narcotics or antihypertensive drugs).

Digestive: Pancreatitis, jaundice (intrahepatic cholestatic jaundice), diarrhea, vomiting, sialoadenitis, cramping, constipation, gastric irritation, nausea, anorexia.

Hematologic:Aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia.

Hypersensitivity: Anaphylactic reactions, necrotizing angitis (vasculitis and cutaneous vasculitis), respiratory distress including pneumonitis and pulmonary edema, photosensitivity, fever, urticaria, rash, purpura.

Metabolic:Electrolyte imbalance (see PRECAUTIONS), hyperglycemia, glycosuria, hyperuricemia.

Musculoskeletal:Muscle spasm.

Nervous system/psychiatric:Vertigo, paresthesias, dizziness, headache, restlessness.

Renal: Renal failure, renal dysfunction, interstitial nephritis (see WARNINGS).

Skin: Erythema multiforme, pruritus.

Special senses: Transient blurred vision, xanthopsia.

Spironolactone

Digestive: Gastric bleeding, ulceration, gastritis, diarrhea and cramping, nausea, vomiting.

Endocrine: Gynecomastia (see PRECAUTIONS), inability to achieve or maintain erection, irregular menses or amenorrhea, postmenopausal bleeding. Carcinoma of the breast has been reported in patients taking spironolactone but a cause and effect relationship has not been established.

Hematologic: Agranulocytosis.

Hypersensitivity: Fever, urticaria, maculopapular or erythematous cutaneous eruptions, anaphylactic reactions, vasculitis.

Nervous system/psychiatric: Mental confusion, ataxia, headache, drowsiness, lethargy.

Liver/biliary: A very few cases of mixed cholestatic/hepatocellular toxicity, with one reported fatality, have been reported with spironolactone administration.

Renal: Renal dysfunction (including renal failure).

ACE inhibitors: Concomitant administration of ACE i nhibitors with potassium-sparing diuretics has been associated with severe hyperkalemia.

Alcohol, barbiturates, or narcotics: Potentiation of orthostatic hypotension may occur.

Antidiabetic drugs (eg, oral agents, insulin): Dosage adjustment of the antidiabetic drug may be required.

Corticosteroids, ACTH: Intensified electrolyte depletion, particularly hypokalemia, may occur.

Pressor amines (eg, norepinephrine): 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.

Skeletal muscle relaxants, nondepolarizing (eg, tubocurarine): Possible increased responsiveness to the muscle relaxant may result.

Lithium: Lithium generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity.

Nonsteroidal anti-inflammatory drugs (NSAIDs): In some patients, the administration of an NSAID can reduce the diuretic, natriuretic, and antihypertensive effect of loop, potassium-sparing and thiazide diuretics. Combination of NSAIDs, eg, indomethacin, with potassium-sparing diuretics has been associated with severe hyperkalemia. Therefore, when Aldactazide and NSAIDs are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.

Digoxin: 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.

Drug/Laboratory test interactions

Thiazides should be discontinued before carrying out tests for parathyroid function (see PRECAUTIONS: General). Thiazides may also decrease serum PBI levels without evidence of alteration of thyroid function.

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.

Last updated on RxList: 12/16/2008

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: General). Aldactazide should not be administered concurrently with other potassium-sparing diuretics. Spironolactone, when used with ACE inhibitors or indomethacin, even in the presence of a diuretic, has been associated with severe hyperkalemia. Extreme caution should be exercised when Aldactazide is given concomitantly with these drugs (see PRECAUTIONS: DRUG INTERACTIONS).

Aldactazide should be used with caution in patients with impaired hepatic function because minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Lithium generally should not be given with diuretics (see PRECAUTIONS: DRUG INTERACTIONS).

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 may add to or potentiate the action of other antihypertensive drugs.

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

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

General

All patients receiving diure tic therapy should be observed for evidence of fluid or electrolyte imbalance, eg, hypomagnesemia, hyponatremia, hypochloremic alkalosis, and hypokalemia or hyperkalemia.

Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause, include dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. 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.

Concomitant administration of potassium-sparing diuretics and ACE inhibitors or nonsteroidal anti-inflammatory drugs (NSAIDs), eg, indomethacin, has been associated with severe hyperkalemia.

If hyperkalemia is suspected (warning signs include paresthesia, muscle weakness, fatigue, flaccid paralysis of the extremities, bradycardia and shock) an electrocardiogram (ECG) should be obtained. However, it is important to monitor serum potassium levels because mild hyperkalemia may not be associated with ECG changes.

If hyperkalemia is present, Aldactazide should be discontinued immediately. With severe hyperkalemia, the clinical situation dictates the procedures to be employed. These include the intravenous administration of calcium chloride solution, sodium bicarbonate solution and/or the oral or parenteral administration of glucose with a rapid-acting insulin preparation. These are temporary measures to be repeated as required. Cationic exchange resins such as sodium polystyrene sulfonate may be orally or rectally administered. Persistent hyperkalemia may require dialysis.

Hypokalemia may develop as a result of profound diuresis, particularly when Aldactazide is used concomitantly with loop diuretics, glucocorticoids, or ACTH, when severe cirrhosis is present or after prolonged therapy. Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may cause cardiac arrhythmias and may exaggerate the effects of digitalis therapy. Potassium depletion may induce signs of digitalis intoxication at previously tolerated dosage levels. Although any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be required in the treatment of metabolic alkalosis.

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, and dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction rather than administration of sodium, except in rare instances when the hyponatremia is life-threatening. 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.

Hyperuricemia may occur or acute gout may be precipitated in certain patients receiving thiazides. Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia. Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.

In diabetic patients, dosage adjustments of insulin or oral hypoglycemic agents may be required. Hyperglycemia may occur with thiazide diuretics. Thus, latent diabetes mellitus may become manifest during thiazide therapy.

The antihypertensive effects of Aldactazide may be enhanced in the post-sympathetectomy patient. If progressive renal impairment becomes evident, consider withholding or discontinuing diuretic therapy.

Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function. Pathologic changes in the parathyroid gland with hypercalcemia and hypophosphatemia have been observed in patients on prolonged thiazide therapy.

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.

Laboratory tests

Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be done at appropriate intervals, particularly in the elderly and those with significant renal or hepatic impairments.

Carcinogenesis, mutagenesis, impairment of fertility

Spironolactone: Orally administered spironolactone has been shown to be a tumorigen in dietary administration studies performed in rats, with its proliferative effects manifested on endocrine organs and the liver. In an 18-month study using doses of about 50, 150 and 500 mg/kg/day, there were statistically significant increases in benign adenomas of the thyroid and testes and, in male rats, a dose-related increase in proliferative changes in the liver (including hepatocytomegaly and hyperplastic nodules). In a 24-month study in which the same strain of rat was administered doses of about 10, 30, 100 and 150 mg spironolactone/kg/day, the range of proliferative effects included significant increases in hepatocellular adenomas and testicular interstitial cell tumors in males, and significant increases in thyroid follicular cell adenomas and carcinomas in both sexes. There was also a statistically significant, but not dose-related, increase in benign uterine endometrial stromal polyps in females.

A dose-related (above 20 mg/kg/day) incidence of myelocytic leukemia was observed in rats fed daily doses of potassium canrenoate (a compound chemically similar to spironolactone and whose primary metabolite, canrenone, is also a major product of spironolactone in man) for a period of one year. In two year studies in the rat, oral administration of potassium canrenoate was associated with myelocytic leukemia and hepatic, thyroid, testicular and mammary tumors.

Neither spironolactone nor potassium canrenoate produced mutagenic effects in tests using bacteria or yeast. In the absence of metabolic activation, neither spironolactone nor potassium canrenoate has been shown to be mutagenic in mammalian tests in vitro. In the presence of metabolic activation, spironolactone has been reported to be negative in some mammalian mutagenicity tests in vitro and inconclusive (but slightly positive) for mutagenicity in other mammalian tests in vitro. In the presence of metabolic activation, potassium canrenoate has been reported to test positive for mutagenicity in some mammalian tests in vitro, inconclusive in others, and negative in still others.

In a three-litter reproduction study in which female rats received dietary doses of 15 and 50 mg spironolactone/kg/day, there were no effects on mating and fertility, but there was a small increase in incidence of stillborn pups at 50 mg/kg/day. When injected into female rats (100 mg/kg/day for 7 days, i.p.), spironolactone was found to increase the length of the estrous cycle by prolonging diestrus during treatment and inducing constant diestrus during a two week posttreatment observation period. These effects were associated with retarded ovarian follicle development and a reduction in circulating estrogen levels, which would be expected to impair mating, fertility and fecundity. Spironolactone (100 mg/kg/day), administered i.p. to female mice during a two week cohabitation period with untreated males, decreased the number of mated mice that conceived (effect shown to be caused by an inhibition of ovulation) and decreased the number of implanted embryos in those that became pregnant (effect shown to be caused by an inhibition of implantation), and at 200 mg/kg, also increased the latency period to mating.

Hydrochlorothiazide: Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in male and female rats (at doses of up to approximately 100 mg/kg/day). The NTP, however, found equivocal evidence for 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) and 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. Positive test results were obtained only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide from 43 to 1300 µg/ml, and in the Aspergillus nidulans nondisjunction assay at an unspecified concentration.

Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg, respectively, prior to mating and throughout gestation.

Pregnancy

Teratogenic effects

Pregnancy Category C.

Hydrochlorothiazide: Studies in which hydrochlorothiazide was orally administered to pregnant mice and rats during their respective periods of major organogenesis at doses up to 3000 and 1000 mg hydrochlorothiazide/kg, respectively, provided no evidence of harm to the fetus. There are, however, no adequate and well controlled studies in pregnant women.

Spironolactone: Teratology studies with spironolactone have been carried out in mice and rabbits at doses of up to 20 mg/kg/day. On a body surface area basis, this dose in the mouse is substantially below the maximum recommended human dose and, in the rabbit, approximates the maximum recommended human dose. No teratogenic or other embryo-toxic effects were observed in mice, but the 20 mg/kg dose caused an increased rate of resorption and a lower number of live fetuses in rabbits. Because of its anti-androgenic activity and the requirement of testosterone for male morphogenesis, spironolactone may have the potential for adversely affecting sex differentiation of the male during embryogenesis. When administered to rats at 200 mg/kg/day between gestation days 13 and 21 (late embryogenesis and fetal development), feminization of male fetuses was observed. Offspring exposed during late pregnancy to 50 and 100 mg/kg/day doses of spironolactone exhibited changes in the reproductive tract including dose-dependent decreases in weights of the ventral prostate and seminal vesicle in males, ovaries and uteri that were enlarged in females, and other indications of endocrine dysfunction, that persisted into adulthood. There are no adequate and well-controlled studies with Aldactazide in pregnant women. Spironolactone has known endocrine effects in animals including progestational and antiandrogenic effects. The antiandrogenic effects can result in apparent estrogenic side effects in humans, such as gynecomastia. Therefore, the use of Aldactazide in pregnant women requires that the anticipated benefit be weighed against the possible hazards to the fetus.

Non-teratogenic effects: Spironolactone or its metabolites may, and hydrochlorothiazide does, cross the placental barrier and appear in cord blood. Therefore, the use of Aldactazide in pregnant women requires that the anticipated benefit be weighed against possible hazards to the fetus. The hazards include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.

Nursing mothers

Canrenone, a major (and active) metabolite of spironolactone, appears in human breast milk. Because spironolactone has been found to be tumorigenic in rats, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother. If use of the drug is deemed essential, an alternative method of infant feeding should be instituted.

Pediatric use

Safety and effectiveness in pediatric patients have not been established.

Last updated on RxList: 12/16/2008

The oral LD₅₀ of spironolactone is greater than 1,000 mg/kg in mice, rats, and rabbits. The oral LD₅₀ of hydrochlorothiazide is greater than 10 g/kg in both mice and rats.

Acute overdosage of spironolactone may be manifested by drowsiness, mental confusion, maculopapular or erythematous rash, nausea, vomiting, dizziness, or diarrhea. Rarely, instances of hyponatremia, hyperkalemia (less commonly seen with Aldactazide because the hydrochlorothiazide component tends to produce hypokalemia), or hepatic coma may occur in patients with severe liver disease, but these are unlikely due to acute overdosage.

However, because Aldactazide contains both spironolactone and hydrochlorothiazide, the toxic effects may be intensified, and signs of thiazide overdosage may be present. These include electrolyte imbalance such as hypokalemia and/or hyponatremia. The potassium-sparing action of spironolactone may predominate and hyperkalemia may occur, especially in patients with impaired renal function. BUN determinations have been reported to rise transiently with hydrochlorothiazide. There may be CNS depression with lethargy or even coma.

Treatment: Induce vomiting or evacuate the stomach by lavage. There is no specific antidote. Treatment is supportive to maintain hydration, electrolyte balance, and vital functions.

Patients who have renal impairment may develop spironolactone-induced hyperkalemia. In such cases, Aldactazide should be discontinued immediately. With severe hyperkalemia, the clinical situation dictates the procedures to be employed. These include the intravenous administration of calcium chloride solution, sodium bicarbonate solution and/or the oral or parenteral administration of glucose with a rapid-acting insulin preparation. These are temporary measures to be repeated as required. Cationic exchange resins such as sodium polystyrene sulfonate may be orally or rectally administered. Persistent hyperkalemia may require dialysis.

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.

Last updated on RxList: 12/16/2008

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 ex tensively 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 lowfat 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-α-(thiomethyl) spirolactone (TMS)	1.25	391 ng/mL at 3.2 hr	13.8 hr (6.4) (terminal)
6-β-hydroxy-7-α - (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) (β 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-α-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.

Spironolactone and its metabolites 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.

Last updated on RxList: 12/16/2008

Patients who receive Aldactazide should be advised to avoid potassium supplements and foods containing high levels of potassium including salt substitutes.

Last updated on RxList: 12/16/2008

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

SPIRONOLACTONE/HYDROCHLOROTHIAZIDE - ORAL

(SPY-row-no-lack-tone/HYE-droe-KLOR-oh-THYE-a-zide)

WARNING: This product contains two medications for high blood pressure and other conditions. Generally, this product should not be used when treating high blood pressure (hypertension) for the first time. Each of the two different drugs in this product should first be given separately so that your best dose of each drug can be determined. This combination product should only be used if your doctor determines that the doses of each drug in this product are right for you. Depending on your condition, your medications may need to be adjusted by your doctor on an ongoing basis.

USES: This product is used to treat high blood pressure (hypertension). Lowering high blood pressure helps prevent strokes, heart attacks, and kidney problems. This product is also used to treat swelling/water retention (edema), which can result from conditions such as heart failure, severe liver disease, or severe kidney disease. Reducing swelling/water retention can help to improve symptoms such as trouble breathing.

This product contains two medications, spironolactone and hydrochlorothiazide. Both are water pills (diuretics) that work by increasing the amount of urine that you make. This causes your body to get rid of extra salt and water, which is thought to help relax the blood vessels so that blood can flow more easily. Spironolactone also blocks the activity of a certain natural substance made by your body (aldosterone) that may contribute to swelling/fluid retention in certain conditions.

HOW TO USE: See also the Warning and Drug Interactions sections.

Take this medication by mouth, usually once daily or as directed by your doctor. If stomach upset occurs, you may take it with food or milk.

It is best to avoid taking this medication within 4 hours of your bedtime to avoid having to get up to urinate. Consult your doctor or pharmacist if you have questions about your dosing schedule.

The dosage is based on your age, medical condition and response to therapy. If you have severe liver or kidney problems, your dosage may need to be adjusted.

Cholestyramine and colestipol may decrease the absorption of this medication. If you are taking either of these drugs, separate them from this medication by at least 4 hours.

Use this medication regularly in order to get the most benefit from it. To help you remember, take it at the same time each day. It is important to continue taking this medication even if you feel well. Most people with high blood pressure do not feel sick. It may take up to several weeks before the full benefit of this drug takes effect.

Do not stop taking this medication without first consulting your doctor. Some conditions may become worse when the drug is abruptly stopped. Your dose may need to be gradually decreased.

Inform your doctor if your condition worsens (e.g., your routine blood pressure readings increase).

SIDE EFFECTS: Dizziness, lightheadedness, tiredness and blurred vision may occur as your body adjusts to the medication. You may also be more sensitive to sunburn (see Precautions section). Nausea, stomach upset, headache and restlessness may also occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

This medication may cause too much body water and salts to be lost (dehydration). Tell your doctor immediately if you have any of these unlikely but serious symptoms of dehydration: very dry mouth, thirst, muscle cramps, weakness, fast heartbeat, vomiting, severe dizziness, confusion, unusual decrease in the amount of urine, fainting, seizures.

This medication may lead to high levels of potassium. This can lead to serious (rarely fatal) heart rhythm problems. If you notice any of the following unlikely but serious side effects, seek immediate medical attention: severe muscle weakness, cold sweats, irregular breathing, fast/weak heartbeats, tingling of the hands/feet.

Tell your doctor immediately if any of these unlikely but serious side effects occur: worsening of gout, flushing, unusual tiredness, mental/mood changes (e.g., depression), rapid breathing, changes in the timing of the menstrual cycle, decreased sexual ability, enlargement of breasts in men, vision changes (yellow vision).

Tell your doctor immediately if any of these rare but very serious side effects occur: easy bruising/bleeding, signs of infection (e.g., fever, persistent sore throat), yellowing of the eyes/skin, persistent nausea/vomiting, severe stomach/abdominal pain, dark urine, slurred speech, black stools, persistent rectal bleeding, painful erections (Peyronie's disease).

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking this product, tell your doctor or pharmacist if you are allergic to either spironolactone or hydrochlorothiazide; or to other thiazide diuretics (e.g., polythiazide); or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: an inability to make urine (anuria), other severe kidney problems (e.g., acute renal failure), high potassium levels (hyperkalemia), severe liver disease.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: mild to moderate liver disease, severe kidney disease, asthma, certain immune system problems (lupus), diabetes, gout, parathyroid problems (hyperparathyroidism), high levels of fats in the blood (cholesterol or triglycerides), low salts in the blood (e.g., low sodium, potassium, calcium), loss of too much body water (dehydration), recent nerve surgery (e.g., sympathectomy).

Before having surgery, tell your doctor or dentist that you are taking this medication.

This drug may make you dizzy or drowsy; use caution while engaging in activities requiring alertness such as driving or using machinery. Limit alcoholic beverages.

To reduce dizziness and lightheadedness, get up slowly when rising from a sitting or lying position, and drink plenty of fluids. Too much sweating, diarrhea or vomiting may cause you to lose large amounts of water and salts, causing lightheadedness. Avoid heavy exercise. Report prolonged diarrhea or vomiting to your doctor.

Caution is advised when using this drug in the elderly because they may be more sensitive to its effects, especially dizziness and lightheadedness.

This medication may make you more sensitive to the sun. Avoid prolonged sun exposure, tanning booths, and sunlamps. Use a sunscreen and wear protective clothing when outdoors.

If you have diabetes, this product may make it harder to control your blood sugar levels. Check your blood sugar levels regularly as directed by your doctor. Tell your doctor immediately if you have symptoms of high blood sugar such as increased thirst and urination. Your anti-diabetic medication or diet may need to be adjusted.

This product should be used only when clearly needed during pregnancy. Babies born to mothers who have taken this medication during pregnancy may be at risk for liver problems and bleeding problems. Discuss the risks and benefits with your doctor.

Both hydrochlorothiazide and spironolactone pass into breast milk. Breast-feeding while using this medication is not recommended. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: See also How to Use section.

Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop, or change the dosage of any medicine before checking with them first.

This drug should not be used with the following medications because very serious interactions may occur: dofetilide, tacrolimus.

If you are currently using any of these medications, tell your doctor or pharmacist before starting spironolactone with hydrochlorothiazide.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: alcohol, barbiturates (e.g., phenobarbital), cisapride, diazoxide, digoxin, drugs for diabetes (e.g., glyburide, insulin), certain hormones (ACTH), lithium, mitotane, narcotic pain relievers (e.g., codeine), norepinephrine, skeletal muscle relaxants (e.g., tubocurarine), drugs that cause potassium loss (e.g., amphotericin B, corticotropin, corticosteroids including prednisone), drugs whose removal from the body is affected by the acid level in urine (e.g., amphetamine, methenamine).

This medication may increase your potassium levels. Using this product with other medications that increase your potassium levels may cause very serious (possibly fatal) side effects. These medications include: ACE inhibitors (e.g., captopril, enalapril), ARBs (e.g., candesartan, losartan), drospirenone, eplerenone, nonsteroidal anti-inflammatory drugs (NSAIDs such as ibuprofen, indomethacin, naproxen), other water pills that may increase your potassium level, including amiloride, potassium-containing products (e.g., salt substitutes), potassium supplements.

Limit foods high in potassium such as bananas, potatoes, cantaloupe, citrus fruits, dates, prunes, avocado, raisins, cooked spinach, lentils and low-salt milk. These foods may increase your potassium levels if eaten in large amounts. Discuss with your doctor or nutritionist.

Check the labels on all your medicines (e.g., cough-and-cold products, diet aids, aspirin, nonsteroidal anti-inflammatory drugs-NSAIDs for pain/fever reduction) because they may contain ingredients that could increase your blood pressure or cause a fast heartbeat (e.g., pseudoephedrine, phenylephrine, chlorpheniramine, diphenhydramine, clemastine, ibuprofen, naproxen). Ask your pharmacist about the safe use of those products.

This product can affect the results of certain lab tests (parathyroid function, urine and blood steroids). Make sure laboratory personnel and all your doctors know you use this drug.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly. Symptoms of overdose may include fainting, severe weakness, decrease in the amount of urine, slow/shallow breathing.

NOTES: Do not share this medication with others.

Lifestyle changes such as stress reduction programs, exercise, and dietary changes may increase the effectiveness of this medicine. Talk to your doctor or pharmacist about lifestyle changes that might benefit you.

Laboratory and/or medical tests (e.g., liver function tests, blood salt levels, complete blood counts) should be performed regularly to monitor your progress or check for side effects. Consult your doctor for more details.

Have your blood pressure and heart rate checked regularly while taking this medication. Learn how to monitor your own blood pressure and heart rate at home, and share the readings with your doctor.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature at 77 degrees F (25 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For enrollment information call MedicAlert at 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.