Spironolactone/Hydrochlorothiazide: Difference between revisions

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:* Skeletal muscle relaxants, [[nondepolarizing]] (e.g., [[tubocurarine]]): Possible increased responsiveness to the muscle relaxant may result.
:* Skeletal muscle relaxants, [[nondepolarizing]] (e.g., [[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.
:* 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]] effects of loop, potassium-sparing, and [[thiazide diuretics]]. Combination of NSAIDs, e.g., [[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.
:* Nonsteroidal anti-inflammatory drugs ([[NSAIDs]]): In some patients, the administration of an NSAID can reduce the [[diuretic]], [[natriuretic]], and [[antihypertensive]] effects of loop, potassium-sparing, and [[thiazide diuretics]]. Combination of NSAIDs, e.g., [[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. Monitor serum [[digoxin]] levels and adjust dose accordingly. Thiazide-induced electrolyte disturbances, i.e. [[hypokalemia]], [[hypomagnesemia]], increase the risk of [[digoxin]] toxicity, which may lead to fatal arrhythmic events (see Precautions).
:* [[Digoxin]]: [[Spironolactone]] has been shown to increase the half-life of [[digoxin]]. This may result in increased serum [[digoxin]] levels and subsequent digitalis toxicity. Monitor serum [[digoxin]] levels and adjust dose accordingly. Thiazide-induced electrolyte disturbances, i.e. [[hypokalemia]], [[hypomagnesemia]], increase the risk of [[digoxin]] toxicity, which may lead to fatal arrhythmic events (see Precautions).
:* [[Cholestyramine]]: Hyperkalemic metabolic acidosis has been reported in patients given [[spironolactone]] concurrently with [[cholestyramine]].
:* [[Cholestyramine]]: Hyperkalemic metabolic acidosis has been reported in patients given [[spironolactone]] concurrently with [[cholestyramine]].
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:* [[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.
:* [[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.
:* 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.
|useInPregnancyFDA======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.
|useInNursing=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.
|useInNursing=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.
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.
|useInPed=Safety and effectiveness in pediatric patients have not been established.
|useInPed=Safety and effectiveness in pediatric patients have not been established.
|mechAction=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.
|administration=Optimal dosage should be established by individual titration of the components (see boxed Warning).
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.
 
=====Edema in adults (congestive heart failure, hepatic cirrhosis, or nephrotic syndrome)=====
 
The usual maintenance dose of [[spironolactone]] and [[hydrochlorothiazide]] tablets 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 [[spironolactone]] or [[hydrochlorothiazide]] in addition to [[spironolactone]] and [[hydrochlorothiazide]] tablets in order to provide optimal individual therapy.
The onset of diuresis with [[spironolactone]] and [[hydrochlorothiazide]] tablets occurs promptly and, due to prolonged effect of the [[spironolactone]] component, persists for two to three days after [[spironolactone]] and [[hydrochlorothiazide]] tablets are 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 [[spironolactone]] and [[hydrochlorothiazide]] tablets are used in the long-term management of [[hypertension]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone ]][[spironolactone 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|monitoring=* It is important to monitor serum potassium levels because mild hyperkalemia may not be associated with ECG changes.
* 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.
*
|mechAction=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.
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.
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.
|structure=ALDACTAZIDE oral tablets contain:
|structure=ALDACTAZIDE oral tablets contain:
spironolactone . . . . . . . . . . . . . . . . . . . . 25 mg
spironolactone . . . . . . . . . . . . . . . . . . . . 25 mg
Line 174: Line 196:
spironolactone . . . . . . . . . . . . . . . . . . . . 50 mg
spironolactone . . . . . . . . . . . . . . . . . . . . 50 mg
hydrochlorothiazide . . . . . . . . . . . . . . . . 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.
[[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:
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:
 
|PK=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.
[[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:
|PK=[[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.
|nonClinToxic======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=====


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.
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.
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.
[[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.
Spironolactone and its metabolites are more than 90% bound to plasma proteins. The metabolites are excreted primarily in the urine and secondarily in bile.
[[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.
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.
|howSupplied=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:
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.
|nonClinToxic=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.
|howSupplied=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
NDC Number        Size
0025-1011-31        bottle of 100
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:
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
NDC Number        Size
0025-1021-31        bottle of 100
0025-1021-31        bottle of 100
|storage=Store below 77°F (25°C
|storage=Store below 77°F (25°C
|price===[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]==
}}
{{LabelImage
|fileName=Spironolactone hydrochlorothiazide_label_01.jpg
}}
}}

Revision as of 14:43, 14 April 2014

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]

Disclaimer

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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 {{{indicationType}}} 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)

Non–Guideline-Supported Use

Acne vulgaris
  • Dosing information
  • 50-200 mg PO
  • optimal dosage: 150-200 mg PO [1][2][3]
Ascites of patients in cirrhosis of liver
  • Dosing information
  • 100-400 mg/day (300-600 mg/day satisfies 50%-90% patients)
  • recommended initial dosage: 100-200 mg PO qd
  • 225 mg/day [4]
Proteinuria in Chronic renal failure
  • Dosing information
Proteinuria in diabetic nephropathy
  • Dosing information
Hirsutism
  • Dosing information
  • spironolactone plus cyproterone/ethinyl estradiol or flutamide alone were both significantly effective for the treatment of women with moderate to severe hirsutism in a prospective, randomized, clinical trial [7]
Idiopathic edema
  • Dosing information
  • spironolactone 50-200 mg every morning or hydrochlorothiazide 25 mg every morning [8][9]
Myocardial infarction
  • Dosing information
Prophylaxis of osteopenia; - Polycystic ovary syndrome
  • Dosing information

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)

Non–Guideline-Supported Use

Primary aldosteronism
  • Dosing information
  • initial dosage: 400 mg/day with gradual reduction to 200 mg/day [12]

Contraindications

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

Warnings

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, 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).

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 (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. Acute Myopia and Secondary Angle-Closure Glaucoma Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy. PRECAUTIONS General Serum Electrolyte Abnormalities Spironolactone can cause hyperkalemia. The risk of hyperkalemia may be increased in patients with renal insufficiency, diabetes mellitus or with concomitant use of drugs that raise serum potassium (see Drug Interactions). Hydrochlorothiazide can cause hypokalemia and hyponatremia. The risk of hypokalemia may be increased in patients with cirrhosis, brisk diuresis, or with concomitant use of drugs that lower serum potassium. Hypomagnesemia can result in hypokalemia which appears difficult to treat despite potassium repletion. Monitor serum electrolytes periodically. Other Metabolic Disturbances Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides. Hydrochlorothiazide may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricemia and precipitate gout in susceptible patients. Hydrochlorothiazide decreases urinary calcium excretion and may cause elevations of serum calcium. Monitor calcium levels in patients with hypercalcemia receiving ALDACTAZIDE. Gynecomastia 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 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

Musculoskeletal: Leg cramps.

  • Nervous system/psychiatric: Lethargy, mental confusion, ataxia, dizziness, headache, drowsiness.
  • 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).
  • Skin: Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms (DRESS), alopecia, pruritus.

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 (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.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

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 (see boxed Warning).

Edema in adults (congestive heart failure, hepatic cirrhosis, or nephrotic syndrome)

The usual maintenance dose of spironolactone and hydrochlorothiazide tablets 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 spironolactone or hydrochlorothiazide in addition to spironolactone and hydrochlorothiazide tablets in order to provide optimal individual therapy. The onset of diuresis with spironolactone and hydrochlorothiazide tablets occurs promptly and, due to prolonged effect of the spironolactone component, persists for two to three days after spironolactone and hydrochlorothiazide tablets are 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 spironolactone and hydrochlorothiazide tablets are used in the long-term management of hypertensionspironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone 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spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone spironolactone 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

  • It is important to monitor serum potassium levels because mild hyperkalemia may not be associated with ECG changes.
  • 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.

IV Compatibility

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

Overdosage

There is limited information regarding Spironolactone/Hydrochlorothiazide overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

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. 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.

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:

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

There is limited information regarding Spironolactone/Hydrochlorothiazide Patient Counseling Information in the drug label.

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.

  1. ↑ Vincenzi C, Trevisi P, Farina P, Stinchi C, Tosti A (1993) Facial contact dermatitis due to spironolactone in an anti-acne cream. Contact Dermatitis 29 (5):277-8. PMID: 8112074
  2. ↑ Hatwal A, Bhatt RP, Agrawal JK, Singh G, Bajpai HS (1988) Spironolactone and cimetidine in treatment of acne. Acta Derm Venereol 68 (1):84-7. PMID: 2449021
  3. ↑ Goodfellow A, Alaghband-Zadeh J, Carter G, Cream JJ, Holland S, Scully J et al. (1984) Oral spironolactone improves acne vulgaris and reduces sebum excretion. Br J Dermatol 111 (2):209-14. PMID: 6235834
  4. ↑ Fernández-Esparrach G, Guevara M, Sort P, Pardo A, Jiménez W, Ginès P et al. (1997) Diuretic requirements after therapeutic paracentesis in non-azotemic patients with cirrhosis. A randomized double-blind trial of spironolactone versus placebo. J Hepatol 26 (3):614-20. PMID: 9075669
  5. ↑ Bianchi S, Bigazzi R, Campese VM (2006) Long-term effects of spironolactone on proteinuria and kidney function in patients with chronic kidney disease. Kidney Int 70 (12):2116-23. DOI:10.1038/sj.ki.5001854 PMID: 17035949
  6. ↑ Schjoedt KJ, Rossing K, Juhl TR, Boomsma F, Tarnow L, Rossing P et al. (2006) Beneficial impact of spironolactone on nephrotic range albuminuria in diabetic nephropathy. Kidney Int 70 (3):536-42. DOI:10.1038/sj.ki.5001580 PMID: 16775595
  7. ↑ Karakurt F, Sahin I, Güler S, Demirbas B, Culha C, Serter R et al. (2008) Comparison of the clinical efficacy of flutamide and spironolactone plus ethinyloestradiol/cyproterone acetate in the treatment of hirsutism: a randomised controlled study. Adv Ther 25 (4):321-8. DOI:10.1007/s12325-008-0039-5 PMID: 18389188
  8. ↑ Gaby AR (1986) Idiopathic edema: 'overlooked' causes. Hosp Pract (Off Ed) 21 (2):21. PMID: 3081532
  9. ↑ Melby JC (1985) Idiopathic edema. A clinical conundrum. Hosp Pract (Off Ed) 20 (12):68E-68G, 68J, 68M passim. PMID: 3934201
  10. ↑ Hayashi M, Tsutamoto T, Wada A, Tsutsui T, Ishii C, Ohno K et al. (2003) Immediate administration of mineralocorticoid receptor antagonist spironolactone prevents post-infarct left ventricular remodeling associated with suppression of a marker of myocardial collagen synthesis in patients with first anterior acute myocardial infarction. Circulation 107 (20):2559-65. DOI:10.1161/01.CIR.0000068340.96506.0F PMID: 12732605
  11. ↑ Moghetti P, Castello R, Zamberlan N, Rossini M, Gatti D, Negri C et al. (1999) Spironolactone, but not flutamide, administration prevents bone loss in hyperandrogenic women treated with gonadotropin-releasing hormone agonist. J Clin Endocrinol Metab 84 (4):1250-4. DOI:10.1210/jcem.84.4.5606 PMID: 10199763
  12. ↑ Batista MC, Mendonça BB, Kater CE, Arnhold IJ, Rocha A, Nicolau W et al. (1986) Spironolactone-reversible rickets associated with 11 beta-hydroxysteroid dehydrogenase deficiency syndrome. J Pediatr 109 (6):989-93. PMID: 3023598

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