Aldactazide 25 (Spironolactone – Hydrochlorothiazide)

ALDACTAZIDE 25® ALDACTAZIDE 50®

Searle

Spironolactone – Hydrochlorothiazide

Aldosterone Antagonist – Diuretic

Action And Clinical Pharmacology: A combination of two diuretic agents with different but complementary mechanisms and sites of action. Spironolactone component helps to minimize the potassium loss which may be induced by the thiazide component. Spironolactone is a specific pharmacologic antagonist of the adrenal mineralocorticoid, aldosterone, acting primarily through competitive binding with receptors at the aldosterone-dependent sodium/potassium exchange site in the distal convoluted renal tubule. Hydrochlorothiazide promotes excretion of sodium and water primarily by inhibiting their reabsorption by the cortical diluting segment of the renal tubule, in contrast to spironolactone which exerts its effect more distally. Both spironolactone and hydrochlorothiazide reduce exchangeable sodium and plasma volume.

The effects of hydrochlorothiazide will be observed on the day of administration, but the spironolactone component does not attain its maximal effect until the third day.

Spironolactone is rapidly and extensively metabolized. Sulfur-containing products are the predominant metabolites and are thought to be primarily responsible for the therapeutic effects of the drug. Approximately 25 to 30% of the dose administered is converted to canrenone, which attains peak serum levels 2 to 4 hours after single oral administration of spironolactone. In the dose range of 25 to 200 mg, an approximately linear relationship exists between a single dose of spironolactone and plasma levels of canrenone.

Plasma concentrations of canrenone decline in 2 distinct phases, the first phase lasting from 3 to 12 hours, being more rapid than the second phase lasting from 12 to 96 hours. Canrenone clearance data, following multiple doses of spironolactone, indicate that accumulation of canrenone in the body with 100 mg once a day would be lower than with 25 mg 4 times a day. Both spironolactone and canrenone are more than 90% bound to plasma proteins. The metabolites of spironolactone are excreted both in the urine (32 to 53%), and through biliary excretion in the feces (14 to 36%).

Hydrochlorothiazide is rapidly absorbed following oral administration, with onset of action occurring within 1 hour, and the duration of action is 6 to 12 hours. Plasma concentration attains a peak at 1 to 2 hours and declines with a half-life of 4 to 5 hours. Hydrochlorothiazide undergoes only slight metabolic alteration and is excreted in the urine. It is distributed throughout the extracellular space, with essentially no tissue accumulation except in the kidney. Hydrochlorothiazide is eliminated rapidly by the kidney.

Indications And Clinical Uses: Fixed dose combination drugs are not indicated for initial therapy. Patients should be titrated on the individual drugs. If the fixed combination represents the dosage so determined, its use may be more convenient in patient management. If during maintenance therapy dosage adjustment is necessary, it is advisable to use the individual drugs.

Edematous conditions for patients with the following: Congestive heart failure: 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 fluid and sodium.

Nephrotic syndrome: In nephrotic patients who are not responsive to glucocorticoid therapy and who do not respond to other diuretics. However, Aldactazide has not been shown to affect the basic pathological process.

Essential hypertension: In patients with essential hypertension in whom other measures are considered inadequate or inappropriate. In hypertensive patients for the treatment of a diuretic induced hypokalemia when other measures are considered inappropriate.

Contra-Indications: Anuria, acute renal insufficiency, significant impairment of renal function, hyperkalemia, sensitivity to spironolactone and sensitivity to thiazides or other sulfonamide-derived drugs. Aldactazide may be contraindicated in patients with severe or progressive liver disease.

Manufacturers’ Warnings In Clinical States: Potassium Supplementation: Do not give potassium supplementation (including dietary potassium) in conjunction with Aldactazide therapy.

Excessive potassium intake may cause hyperkalemia in patients receiving Aldactazide. Do not administer concurrently with other potassium-sparing diuretics.

Tumorigenicity: Spironolactone, in chronic toxicity studies, has been shown to be a tumorigen in rats.

Use Aldactazide only for conditions described under Indications.

Precautions: Electrolyte Balance: Because of the diuretic action of Aldactazide, patients should be carefully evaluated for possible disturbance of fluid and electrolyte balance.

Hyperkalemia: Hyperkalemia may occur in patients treated with Aldactazide. This can cause cardiac irregularities, some of which may be fatal. Hyperkalemia may also occur in the absence of excessive potassium intake, particulary in patients with impaired renal function, elderly patients, or patients with diabetes.

Consequently, no potassium supplement should ordinarily be given with Aldactazide. Hyperkalemia can be treated promptly by rapid i.v. 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 if required. Aldactazide should be discontinued and potassium intake (including dietary potassium) restricted.

Hypokalemia: Hypokalemia may develop, especially with brisk diuresis, in severe cirrhosis or during concomitant use of loop diuretics, glucocorticoids, or ACTH. Digitalis therapy may exaggerate the metabolic effects of hypokalemia especially with reference to myocardial activity. If hypokalemia occurs, Aldactazide should be discontinued and consideration given to one of the following therapeutic regimens: use of hydrochlorothiazide alone with potassium supplementation as needed, or use of spironolactone alone.

Hyponatremia: During the administration of Aldactazide, patients suffering from sodium depletion must be attentively monitored and signs of electrolyte imbalance must be carefully checked.

Aldactazide may, if administered concomitantly with other diuretics, cause or aggravate hyponatremia, as manifested by dryness of the mouth, thirst, lethargy and drowsiness. A true low-salt syndrome may develop with drug therapy and may be manifested by increasing mental confusion similar to that observed with hepatic coma. This syndrome was 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

Metabolic Effects: Hyperchloremic metabolic acidosis: Reversible hyperchloremic metabolic acidosis, usually in association with hyperkalemia, has been reported in decompensated hepatic cirrhosis, even in the presence of normal renal function.

Hypochloremic Alkalosis: Hypochloremic alkalosis occurs infrequently and is rarely severe. Unduly restricted dietary sodium may complicate therapy. A chloride deficit may be corrected by using ammonium chloride (except in renal or hepatic disease) and is largely prevented by a near-normal sodium/chloride intake.

Drug Interactions: Diuretics and Antihypertensives: Although Aldactazide may be administered concomitantly with diuretics and antihypertensives, the effect is additive. Thus, it is advisable to reduce the dose of these drugs. In particular, the dose of ganglionic blocking agents should be reduced by at least 50% when Aldactazide is included in the regimen.

Hyperkalemia has been associated with the use of angiotensin converting enzyme (ACE) inhibitors in combination with potassium-sparing diuretics.

Norepinephrine and Tubocurarine: Since hydrochlorothiazide and spironolactone each reduce vascular responsiveness to norepinephrine, caution should be exercised in the management of patients subjected to regional or general anesthesia. Thiazides may also increase responsiveness to tubocurarine. Consideration should be given to discontinuation of Aldactazide therapy prior to elective surgery.

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 dose of digoxin when Aldactazide is administered, and the patient should be carefully monitored to avoid over- or under-digitalization.

Carbenoxolone: Carbenoxolone may cause sodium retention and thus decrease the effectiveness of spironolactone. Concurrent use of the 2 agents should be avoided.

Nonsteroidal Anti-inflammatory Drugs: It has been reported that ASA, mefenamic acid and indomethacin may interfere with the diuretic action of spironolactone. The mechanism may be due to the inhibition of intrarenal synthesis of prostaglandins. However, it has been shown that ASA does not alter the effect of spironolactone on blood pressure, serum electrolytes, urea nitrogen, or plasma renin activity in hypertensive patients.

Hyperkalemia has been associated with the use of indomethacin in combination with potassium-sparing diuretics.

Insulin: Insulin requirements in diabetics may be increased, decreased or unchanged. Hyperglycemia and glycosuria may be manifested in latent diabetics.

Gynecomastia: Gynecomastia may develop with the use of spironolactone and physicians should be advised of its possible occurrence. The development of gynecomastia appears to be related to both dosage and duration of therapy, and is normally reversible when Aldactazide is discontinued. If gynecomastia develops, discontinue the drug. In rare instances, some breast enlargement may persist.

Pregnancy: Spironolactone or its metabolites may, and thiazides do cross the placental barrier and appear in cord blood. When hydrochlorothiazide is used in women of child-bearing age, the potential benefits of the drug should be weighed against the possible hazards to the fetus. These hazards include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions which have occurred in the adult. In rats, feminization of the male fetus has been reported at high doses.

Lactation: Certain adverse reactions to thiazide therapy (e.g. hyperbilirubinemia, thrombocytopenia, altered carbohydrate metabolism) can occur in the newborn since thiazides have been demonstrated to appear in breast milk. Canrenone, a metabolite of spironolactone, also appears in breast milk. If use of these drugs is deemed essential, an alternative method of infant feeding should be instituted.

Laboratory Tests: General: Aldactazide therapy may result in a transient elevation of BUN, especially when azotemia exists at the beginning of treatment. This appears to represent a concentration phenomenon rather than renal toxicity, since the BUN returns to normal after Aldactazide is discontinued. Progressive elevation of BUN is suggestive of the presence of pre-existing renal impairment.

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 this interference (which may be assay-specific) has been fully established. Discontinue spironolactone for at least 4, and preferably 7 days prior to plasma cortisol determinations, if they are to be done by the method of Mattingly, that is, by fluorometric assay. No interference has been demonstrated with the competitive protein binding technique or radioimmunoassay technique.

Thiazides may decrease serum PBI levels without evidence of alteration of thyroid function.

Adrenal Vein Catheterization and Plasma Renin Activity: Discontinue spironolactone several days prior to adrenal vein catheterization for measurement of aldosterone concentrations and measurements of plasma renin activity.

Impaired Hepatic Function: Aldactazide should be used with caution in patients with impaired hepatic function, because minor alterations in electrolyte balance may precipitate hepatic coma. In the treatment of the edema/ascites of cirrhosis, when high doses are required, it is recommended that the drug dosage be decreased before diuresis is complete, in order to avoid dehydration. If mental confusion occurs, Aldactazide should be temporarily discontinued.

Miscellaneous: Orthostatic hypotension may occur and may be potentiated by alcohol, barbiturates or narcotics.

Pathological changes in the parathyroid gland, with resultant hypercalcemia and hypophosphatemia, have been observed in a few patients on prolonged thiazide therapy.

Exacerbation or activation of systemic lupus erythematosus has been reported for sulfonamide derivatives, including thiazides.

Caution is necessary in patients with hyperuricemia or a history of gout, because gout may be precipitated by thiazides.

Adverse Reactions: Spironolactone: The adverse reactions encountered most frequently with spironolactone are gynecomastia and gastrointestinal symptoms.

Gastrointestinal: nausea, cramping and diarrhea, vomiting, gastric bleeding, gastritis and ulceration.

CNS: drowsiness, dizziness, headache, mental confusion, ataxia, lethargy.

Dermatologic: maculopapular or erythematous cutaneous eruptions, urticaria.

Endocrinologic: gynecomastia, impotence, inability to achieve or maintain erection, abnormal semen (decreased motility and sperm count), irregular menses or amenorrhea and postmenopausal bleeding. Carcinoma of the breast has been reported in patients taking spironolactone, but a cause and effect relationship has not been established.

Miscellaneous: drug fever. A few cases of agranulocytosis have been reported in patients taking spironolactone.

Hydrochlorothiazide: Gastrointestinal: anorexia, gastric irritation, nausea, vomiting, cramps, diarrhea, constipation, jaundice (intrahepatic cholestatic), acute pancreatitis.

CNS: dizziness, vertigo, paresthesia, headache, xanthopsia.

Dermatologic: hypersensitivity, purpura, photosensitivity, rash, urticaria, necrotizing angiitis, pruritus and erythema multiforme.

Hematologic: leukopenia, thrombocytopenic purpura, agranulocytosis, aplastic anemia.

Cardiovascular: orthostatic hypotension may occur and may be potentiated by alcohol, barbiturates or narcotics.

Miscellaneous: muscle spasm, weakness, nitrogen retention, hypokalemia, hyperglycemia, glycosuria and hyperuricemia.

Adverse reactions due to Aldactazide are usually reversible upon discontinuation of Aldactazide. In rare instances, some gynecomastia may persist.

Symptoms And Treatment Of Overdose: Symptoms: There have been no reports of fatal overdose in man (except indirectly through hyperkalemia). Nausea and vomiting occurs, and (much more rarely) drowsiness, mental confusion, diarrhea or a maculopapular or erythematous rash. These manifestations disappear promptly on discontinuation of medication. Hyperkalemia may be exacerbated. Thrombocytopenic purpura and granulocytopenia have occurred with thiazide therapy.

Treatment: No specific antidote. No persistent toxicity has occurred or is expected. Appearance of effects described above requires only discontinuation of drug. Induce vomiting and evacuate the stomach by lavage. For hyperkalemia, discontinue Aldactazide, reduce potassium intake, consider administration of potassium-excreting diuretics, i.v. glucose with regular insulin (see Precautions), ion-exchange resins, or dialysis. Treat fluid depletion and electrolyte imbalances appropriately if present.

Dosage And Administration: Optimal dosage should be established by individual titration of the components.

Treatment should be continued for 2 weeks before optimal effectiveness can be assessed.

Adults: Edema (congestive heart failure, hepatic cirrhosis, nephrotic syndrome): Daily dosage of 2 to 4 tablets Aldactazide 25 or 1 to 2 tablets Aldactazide 50 in single or divided doses should be adequate for most patients, but may range from 2 to 8 tablets Aldactazide 25 daily or 1 to 4 tablets Aldactazide 50.

Children: Edema: The usual daily maintenance dose of Aldactazide should be that which provides 1.65 to 3.3 mg of spironolactone/kg of body weight.

Essential hypertension: In essential hypertension, a daily dosage of 2 to 4 Aldactazide 25 tablets or 1 to 2 Aldactazide 50 tablets in single or divided doses, will be adequate for most patients, but may range from 2 to 8 tablets of Aldactazide 25 or 1 to 4 tablets of Aldactazide 50.

Since Aldactazide increases the action of other antihypertensive drugs, especially the ganglionic blocking agents, the dosage of such drugs should be reduced by at least 50% when Aldactazide is added to the regimen.

Availability And Storage: Aldactazide 25: Each white to off-white round, standard biconvex, compressed tablet, 9.5 mm in diameter, impressed “201/SEARLE” on one side, plain on the other, contains: spironolactone 25 mg and hydrochlorothiazide 25 mg. Nonmedicinal ingredients: calcium sulfate, cornstarch, magnesium stearate, peppermint flavoring and povidone. Bottles of 250. Store below 30°C.

Aldactazide 50: Each white to off-white round, standard biconvex, compressed tablet, 11.1 mm in diameter, impressed “244/SEARLE” on one side, plain on the other, contains: spironolactone 50 mg and hydrochlorothiazide 50 mg. Nonmedicinal ingredients: calcium sulfate, cornstarch, magnesium stearate, peppermint flavoring and povidone. Bottles of 250. Store below 30°C.

ALDACTAZIDE 25® ALDACTAZIDE 50® Searle Spironolactone – Hydrochlorothiazide Aldosterone Antagonist – Diuretic

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