s to the muscle relaxant may result. lithium: lithium generally should not be given with diuretics. diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. nonsteroidal anti-inflammatory drugs (nsaids): in some patients, the administration of an nsaid can reduce the diuretic, natriuretic, and antihypertensive 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 spironolactone and hydrochlorothiazide tablets and nsaids are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained. acetylsalicylic acid: acetylsalicylic acid may reduce the efficacy of spironolactone. therefore, when spironolactone and hydrochlorothiazide and acetylsalicylic acid are used concomitantly, spironolactone and hydrochlorothiazide tablets may need to be titrated to higher maintenance dose and the patient should be observed closely to determine if the desired effect 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 ). cholestyramine: hyperkalemic metabolic acidosis has been reported in patients given spironolactone concurrently with cholestyramine. abiraterone: spironolactone binds to the androgen receptor and may increase prostate‑specific antigen (psa) levels in abiraterone-treated prostate cancer patients. concomitant use of spironolactone is not recommended.

terone 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. essential hypertension: • 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; • spironolactone and hydrochlorothiazide tablets are indicated for the treatment of hypertension, to lower blood pressure. lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. these benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes, including the classes to which this drug principally belongs. there are no controlled trials demonstrating risk reduction with spironolactone and hydrochlorothiazide tablets. control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. many patients will require more than one drug to achieve blood pressure goals. for specific advice on goals and management, see published guidelines, such as those of the national high blood pressure education program's joint national committee on prevention, detection, evaluation, and treatment of high blood pressure (jnc). numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. the largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmhg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). these considerations may guide selection of therapy. 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 that is not relieved by rest. in these cases, a short course of diuretics may provide relief and may be appropriate.

tered 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 tablets are given concomitantly with these drugs (see precautions: drug interactions ). spironolactone and hydrochlorothiazide tablets 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 angle-closure glaucoma with or without acute myopia and choroidal effusions hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute angle-closure glaucoma and elevated intraocular pressure with or without a noticeable acute myopic shift and/or choroidal effusions. symptoms may include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. untreated, the angle-closure glaucoma may result in permanent visual field 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.

levations of serum calcium. monitor calcium levels in patients with hypercalcemia receiving spironolactone and hydrochlorothiazide tablets. 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 spironolactone and hydrochlorothiazide tablets are discontinued. in rare instances, some breast enlargement may persist when spironolactone and hydrochlorothiazide tablets are 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.

though 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.

usculoskeletal: muscle spasm. nervous system/psychiatric: vertigo, paresthesias, dizziness, headache, restlessness. renal: renal failure, renal dysfunction, interstitial nephritis (see warnings ). skin: erythema multiforme, pruritus. special senses: transient blurred vision, xanthopsia. spironolactone digestive: gastric bleeding, ulceration, gastritis, diarrhea and cramping, nausea, vomiting. reproductive: gynecomastia (see precautions ), inability to achieve or maintain erection, irregular menses or amenorrhea, postmenopausal bleeding, breast pain. carcinoma of the breast has been reported in patients taking spironolactone but a cause and effect relationship has not been established. hematologic: leukopenia (including agranulocytosis), thrombocytopenia. hypersensitivity: fever, urticaria, maculopapular or erythematous cutaneous eruptions, anaphylactic reactions, vasculitis. metabolism: hyperkalemia, electrolyte disturbances (see warnings and precautions ) . 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. post marketing experience non-melanoma skin cancer hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer. in a study conducted in the sentinel system, increased risk was predominantly for squamous cell carcinoma (scc) and in white patients taking large cumulative doses. the increased risk for scc in the overall population was approximately 1 additional case per 16,000 patients per year, and for white patients taking a cumulative dose of ≥50,000 mg the risk increase was approximately 1 additional scc case for every 6,700 patients per year.

s to the muscle relaxant may result. lithium: lithium generally should not be given with diuretics. diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. nonsteroidal anti-inflammatory drugs (nsaids): in some patients, the administration of an nsaid can reduce the diuretic, natriuretic, and antihypertensive 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 spironolactone and hydrochlorothiazide tablets and nsaids are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained. acetylsalicylic acid: acetylsalicylic acid may reduce the efficacy of spironolactone. therefore, when spironolactone and hydrochlorothiazide and acetylsalicylic acid are used concomitantly, spironolactone and hydrochlorothiazide tablets may need to be titrated to higher maintenance dose and the patient should be observed closely to determine if the desired effect 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 ). cholestyramine: hyperkalemic metabolic acidosis has been reported in patients given spironolactone concurrently with cholestyramine. abiraterone: spironolactone binds to the androgen receptor and may increase prostate‑specific antigen (psa) levels in abiraterone-treated prostate cancer patients. concomitant use of spironolactone is not recommended.

tial 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.

nsion, even when aldosterone secretion is within normal limits. both spironolactone and hydrochlorothiazide reduce exchangeable sodium, plasma volume, body weight, and blood pressure. the diuretic and antihypertensive effects of the individual components are potentiated when spironolactone and hydrochlorothiazide are given concurrently. pharmacokinetics spironolactone is rapidly and 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 tablet aldactone is a trademark of pfizer, inc. and/or its affiliates. ) daily for 15 days. on the 15th day, spironolactone was given immediately after a low fat breakfast and blood was drawn thereafter. accumulation factor: auc (0–24 hr, day 15)/auc (0–24 hr, day 1) mean peak serum concentration mean (sd) post-steady state half-life 7-α-(thiomethyl) spirolactone (tms) 1.25 391 ng/ml at 3.2 hr 13.8 hr (6.4) (terminal) 6-β-hydroxy-7-α-(thiomethyl) spirolactone (htms) 1.50 125 ng/ml at 5.1 hr 15.0 hr (4.0) (terminal) canrenone (c) 1.41 181 ng/ml at 4.3 hr 16.5 hr (6.3) (terminal) spironolactone 1.30 80 ng/ml at 2.6 hr approximately 1.4 hr (0.5) (β half-life) the pharmacological activity of spironolactone metabolites in man is not known. however, in the adrenalectomized rat the antimineralocorticoid activities of the metabolites c, tms, and htms, relative to spironolactone, were 1.10, 1.28, and 0.32, respectively. relative to spironolactone, their binding affinities to the aldosterone receptors in rat kidney slices were 0.19, 0.86, and 0.06, respectively. in humans, the potencies of tms and 7-α-thiospirolactone in reversing the effects of the synthetic mineralocorticoid, fludrocortisone, on urinary electrolyte composition were 0.33 and 0.26, respectively, relative to spironolactone. however, since the serum concentrations of these steroids were not determined, their incomplete absorption and/or first-pass metabolism could not be ruled out as a reason for their reduced in vivo activities. spironolactone and its metabolites are more than 90% bound to plasma proteins. the metabolites are excreted primarily in the urine and secondarily in bile. the effect of food on spironolactone absorption (two 100 mg aldactone tablets) was assessed in a single dose study of 9 healthy, drug-free volunteers. food increased the bioavailability of unmetabolized spironolactone by almost 100%. the clinical importance of this finding is not known. hydrochlorothiazide is rapidly absorbed following oral administration. onset of action of hydrochlorothiazide is observed within one hour and persists for 6 to 12 hours. hydrochlorothiazide plasma concentrations attain peak levels at one to two hours and decline with a half-life of four to five hours. hydrochlorothiazide undergoes only slight metabolic alteration and is excreted in urine. it is distributed throughout the extracellular space, with essentially no tissue accumulation except in the kidney.

(terminal) spironolactone 1.30 80 ng/ml at 2.6 hr approximately 1.4 hr (0.5) (β half-life) the pharmacological activity of spironolactone metabolites in man is not known. however, in the adrenalectomized rat the antimineralocorticoid activities of the metabolites c, tms, and htms, relative to spironolactone, were 1.10, 1.28, and 0.32, respectively. relative to spironolactone, their binding affinities to the aldosterone receptors in rat kidney slices were 0.19, 0.86, and 0.06, respectively. in humans, the potencies of tms and 7-α-thiospirolactone in reversing the effects of the synthetic mineralocorticoid, fludrocortisone, on urinary electrolyte composition were 0.33 and 0.26, respectively, relative to spironolactone. however, since the serum concentrations of these steroids were not determined, their incomplete absorption and/or first-pass metabolism could not be ruled out as a reason for their reduced in vivo activities. spironolactone and its metabolites are more than 90% bound to plasma proteins. the metabolites are excreted primarily in the urine and secondarily in bile. the effect of food on spironolactone absorption (two 100 mg aldactone tablets) was assessed in a single dose study of 9 healthy, drug-free volunteers. food increased the bioavailability of unmetabolized spironolactone by almost 100%. the clinical importance of this finding is not known. hydrochlorothiazide is rapidly absorbed following oral administration. onset of action of hydrochlorothiazide is observed within one hour and persists for 6 to 12 hours. hydrochlorothiazide plasma concentrations attain peak levels at one to two hours and decline with a half-life of four to five hours. hydrochlorothiazide undergoes only slight metabolic alteration and is excreted in urine. it is distributed throughout the extracellular space, with essentially no tissue accumulation except in the kidney.

dometrial 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 50 mg spironolactone/kg/day, there were no effects on mating and fertility, but there was a small increase in incidence of stillborn pups at 50 mg/kg/day. when injected into female rats (100 mg/kg/day for 7 days, i.p.), spironolactone was found to increase the length of the estrous cycle by prolonging diestrus during treatment and inducing constant diestrus during a two week posttreatment observation period. these effects were associated with retarded ovarian follicle development and a reduction in circulating estrogen levels, which would be expected to impair mating, fertility, and fecundity. spironolactone (100 mg/kg/day), administered i.p. to female mice during a two week cohabitation period with untreated males, decreased the number of mated mice that conceived (effect shown to be caused by an inhibition of ovulation) and decreased the number of implanted embryos in those that became pregnant (effect shown to be caused by an inhibition of implantation), and at 200 mg/kg, also increased the latency period to mating. hydrochlorothiazide two year feeding studies in mice and rats conducted under the auspices of the national toxicology program (ntp) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in male and female rats (at doses of up to approximately 100 mg/kg/day). the ntp, however, found equivocal evidence for hepatocarcinogenicity in male mice. hydrochlorothiazide was not genotoxic in in vitro assays using strains ta 98, ta 100, ta 1535, ta 1537, and ta 1538 of salmonella typhimurium (ames assay) and in the chinese hamster ovary (cho) test for chromosomal aberrations, or in in vivo assays using mouse germinal cell chromosomes, chinese hamster bone marrow chromosomes, and the drosophila sex-linked recessive lethal trait gene. positive test results were obtained only in the in vitro cho sister chromatid exchange (clastogenicity) and in the mouse lymphoma cell (mutagenicity) assays, using concentrations of hydrochlorothiazide from 43 to 1300 μg/ml, and in the aspergillus nidulans 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.