SPIRONOLACTONE AND HYDROCHLOROTHIAZIDE — spironolactone and hydrochlorothiazide tablet
Physicians Total Care, Inc.
Spironolactone has been shown to be a tumorigen in chronic toxicity studies in rats (see PRECAUTIONS). Spironolactone and hydrochlorothiazide 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.
Each tablet of spironolactone and hydrochlorothiazide contains 25 mg of spironolactone, USP and 25 mg of hydrochlorothiazide, USP. Spironolactone, 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, molecular formula, and molecular weight:
C24 H32 O4 S
M.W. = 416.59
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, molecular formula, and molecular weight:
C7 H8 ClN3 O4 S2
M.W. = 297.75
Hydrochlorothiazide is slightly soluble in water and freely soluble in sodium hydroxide solution.
Each tablet for oral administration contains 25 mg of spironolactone and 25 mg of hydrochlorothiazide and the following inactive ingredients: colloidal silicon dioxide, D&lC yellow #10 aluminum lake HT, FD&C yellow #6 aluminum lake HT, lactose, magnesium stearate, microcrystalline cellulose, menthol, peppermint oil, sodium lauryl sulfate, sodium starch glycolate and starch.
Mechanism of Action
Spironolactone and hydrochlorothiazide 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.
Spironolactone and hydrochlorothiazide 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.
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 (as tablets) daily for 15 days. On the 15th day, spironolactone was given immediately after a low-fat breakfast and blood was drawn thereafter.
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 1.1, 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-thiospironolactone 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 firstpass 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 spironolactone 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.
Spironolactone and Hydrochlorothiazide Indications and Usage
Spironolactone has been shown to be a tumorigen in chronic toxicity studies in rats (see PRECAUTIONS section). Spironolactone and hydrochlorothiazide tablets should be used only in those conditions described below. Unnecessary use of this drug should be avoided.
Spironolactone and Hydrochlorothiazide Tablets are 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. Spironolactone and hydrochlorothiazide tablets are indicated for maintenance therapy together with bed rest and the restriction of fluid and sodium.
The Nephrotic Syndrome
For nephrotic patients when treatment of the underlying disease, restriction of fluid and sodium intake, and the use of other diuretics do not provide an adequate response.
For 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.
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. Spironolactone and hydrochlorothiazide tablets are 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.
Spironolactone and hydrochlorothiazide tablets are 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. Spironolactone and hydrochlorothiazide may also be contraindicated in acute or severe hepatic failure.
Potassium supplementation, either in the form of medication or as a diet rich in potassium, should not ordinarily be given in association with spironolactone and hydrochlorothiazide therapy. Excessive potassium intake may cause hyperkalemia in patients receiving spironolactone and hydrochlorothiazide (see PRECAUTIONS: General). Spironolactone and hydrochlorothiazide 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 spironolactone and hydrochlorothiazide is given concomitantly with these drugs (see PRECAUTIONS: Drug Interaction).
Spironolactone and hydrochlorothiazide 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.
RxDrugLabels.com provides trustworthy package insert and label information about marketed prescription drugs as submitted by manufacturers to the U.S. Food and Drug Administration. Package information is not reviewed or updated separately by RxDrugLabels.com. Every individual prescription drug label and package insert entry contains a unique identifier which can be used to secure further details directly from the U.S. National Institutes of Health and/or the FDA.