Spironolactone/Hydrochlorothiazide

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Spironolactone/Hydrochlorothiazide
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2], Rabin Bista, M.B.B.S. [3]

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Black Box Warning

WARNING
See full prescribing information for complete Boxed Warning.
WARNING

Spironolactone, an ingredient of ALDACTAZIDE, has been shown to be a tumorigen in chronic toxicity studies in rats (see Precautions). 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.

Overview

Spironolactone/Hydrochlorothiazide is an Aldosterone antagonist that is FDA approved for the treatment of Edematous conditions of congestive heart failure, cirrhosis of the liver accompanied by edema and/or ascites, nephrotic syndrome, essential hypertension. There is a Black Box Warning for this drug as shown here. Common adverse reactions include gynecomastia, diarrhea, nausea and vomiting,somnolence,disorder of menstruation, impotence.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Congestive heart failure, hepatic cirrhosis, or nephrotic syndrome
  • Dosing Information (Optimal dosage should be established by individual titration of the components)
  • 25-200 mg/day depending on the response to the initial titration
  • usually maintaining dosage: 100 mg/day
Essential hypertension
  • Dosing Information
  • 50-100 mg/day (depending on the results of titration of the individual ingredients)

Off-Label Use and Dosage (Adult)

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Spironolactone/Hydrochlorothiazide FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Contraindications

Warnings

WARNING
See full prescribing information for complete Boxed Warning.
WARNING

Spironolactone, an ingredient of ALDACTAZIDE, has been shown to be a tumorigen in chronic toxicity studies in rats (see Precautions). 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.
Potassium supplementation
  • 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.

Concomitant administration of ALDACTAZIDE with the following drugs or potassium sources may lead to severe hyperkalemia:

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 .

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

Acute Myopia and Secondary Angle-Closure Glaucoma
PRECAUTIONS
  • General
  • Serum Electrolyte Abnormalities
  • Other Metabolic Disturbances
  • 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.
  • Somnolence and dizziness have been reported to occur in some patients. Caution is advised when driving or operating machinery until the response to initial treatment has been determined.

Adverse Reactions

Clinical Trials Experience

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

  • Hydrochlorothiazide
  • Spironolactone

Postmarketing Experience

There is limited information regarding Spironolactone/Hydrochlorothiazide Postmarketing Experience in the drug label.

Drug Interactions

ACE inhibitors, Angiotensin II receptor antagonists, aldosterone blockers, potassium supplements, heparin, low molecular weight heparin, and other drugs known to cause hyperkalemia:

Drug/Laboratory test interactions
  • Thiazides should be discontinued before carrying out tests for parathyroid function. 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.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): 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 embryotoxic 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 antiandrogenic 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 spironolactone and hydrochlorothiazide tablets 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 spironolactone and hydrochlorothiazide tablets 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 spironolactone and hydrochlorothiazide tablets 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.


Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Spironolactone/Hydrochlorothiazide in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Spironolactone/Hydrochlorothiazide during labor and delivery.

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.
  • Thiazides are excreted in human milk in small amounts. Thiazides when given at high doses can cause intense diuresis which can in turn inhibit milk production. The use of ALDACTAZIDE during breast feeding is not recommended. If ALDACTAZIDE is used during breast feeding, doses should be kept as low as possible.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatic Use

There is no FDA guidance on the use of Spironolactone/Hydrochlorothiazide in geriatric settings.

Gender

There is no FDA guidance on the use of Spironolactone/Hydrochlorothiazide with respect to specific gender populations.

Race

There is no FDA guidance on the use of Spironolactone/Hydrochlorothiazide with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Spironolactone/Hydrochlorothiazide in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Spironolactone/Hydrochlorothiazide in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Spironolactone/Hydrochlorothiazide in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Spironolactone/Hydrochlorothiazide in patients who are immunocompromised.

Administration and Monitoring

Administration

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

Edema in adults (congestive heart failure, hepatic cirrhosis, or nephrotic syndrome)
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 spironolactone and hydrochlorothiazide tablets are used in the long-term management of hypertension or in the treatment of most edematous conditions, since the spironolactone content of spironolactone and hydrochlorothiazide tablets is usually sufficient to minimize loss induced by the hydrochlorothiazide component.

Monitoring

  • Monitor serum electrolytes periodically.
  • Monitor calcium levels in patients with hypercalcemia receiving ALDACTAZIDE.
  • Monitor serum digoxin levels and adjust dose accordingly

IV Compatibility

There is limited information regarding the compatibility of Spironolactone/Hydrochlorothiazide and IV administrations.

Overdosage

The oral LD50 of spironolactoneis greater than 1,000 mg/kg in mice, rats, and rabbits. Acute overdosage of spironolactonemay be manifested by drowsiness, mental confusion, maculopapular or erythematous rash, nausea, vomiting, dizziness, or diarrhea. Rarely, instances of hyponatremia, hyperkalemia, or hepatic coma may occur in patients with severe liver disease, but these are unlikely due to acute overdosage. Hyperkalemia may occur, especially in patients with impaired renal function. However, because spironolactoneand hydrochlorothiazide tablets contain both spironolactoneand 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 spironolactonemay 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.

Pharmacology

There is limited information regarding Spironolactone/Hydrochlorothiazide Pharmacology in the drug label.

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.

Structure

  • 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.

Pharmacodynamics

There is limited information regarding Spironolactone/Hydrochlorothiazide Pharmacodynamics in the drug label.

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 lowfat breakfast and blood was drawn thereafter.


  • 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.

Nonclinical Toxicology

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 and 100 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 30 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 500 mg spironolactone/kg/day, there were no effects on mating and fertility, but there was a small increase in incidence of stillborn pups at 500 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 non-disjunction 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.

Clinical Studies

There is limited information regarding Spironolactone/Hydrochlorothiazide Clinical Studies in the drug label.

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 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

Storage

  • Store below 77°F (25°C

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

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

Precautions with Alcohol

Alcohol-Spironolactone/Hydrochlorothiazide interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Spironolactone/Hydrochlorothiazide Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Spironolactone/Hydrochlorothiazide Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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