Spironolactone/Hydrochlorothiazide

Description

Spironolactone and hydrochlorothiazide oral tablets contain 25 mg of spironolactone and 25 mg of hydrochlorothiazide. Spironolactone, an aldosterone antagonist, is chemically designated as 17-hydroxy-7α-mercapto-3-oxo-17α-pregn-4-ene-21-carboxylic acid γ-lactone acetate. It is characterized by its structural formula and is practically insoluble in water, soluble in alcohol, and freely soluble in benzene and chloroform. Hydrochlorothiazide, a diuretic and antihypertensive, is identified as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, with its own structural formula. Hydrochlorothiazide is slightly soluble in water and freely soluble in sodium hydroxide solution. The tablets also contain inactive ingredients, which include calcium sulfate, corn starch, flavor, hydroxypropyl cellulose, hypromellose, iron oxide, magnesium stearate, polyethylene glycol, povidone, and titanium dioxide.

Uses and Indications

Spironolactone and hydrochlorothiazide tablets are indicated for the management of various edematous conditions and essential hypertension in specific patient populations.

Edematous Conditions This drug is indicated for the treatment of edema and sodium retention in patients with congestive heart failure who are only partially responsive to, or intolerant of, other therapeutic measures. It is also indicated for the management of diuretic-induced hypokalemia in patients with congestive heart failure when other measures are deemed inappropriate. Additionally, it is indicated for patients with congestive heart failure who are taking digitalis and for whom other therapies are considered inadequate or inappropriate.

In patients with cirrhosis of the liver accompanied by edema and/or ascites, spironolactone and hydrochlorothiazide tablets are indicated for maintenance therapy, in conjunction with bed rest and the restriction of fluid and sodium intake. For patients with nephrotic syndrome, this drug is indicated when treatment of the underlying disease, along with fluid and sodium restriction and the use of other diuretics, does not yield an adequate response.

Essential Hypertension Spironolactone and hydrochlorothiazide tablets are indicated for the treatment of essential hypertension in patients for whom other measures are considered inadequate or inappropriate. This drug is also indicated for the treatment of diuretic-induced hypokalemia in hypertensive patients when other measures are deemed inappropriate. The lowering of blood pressure with this medication reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.

Limitations of Use The routine use of diuretics in otherwise healthy women during pregnancy is inappropriate and poses unnecessary risks to both mother and fetus. Diuretics do not prevent the development of toxemia of pregnancy, nor is there satisfactory evidence supporting their efficacy in treating developing toxemia. However, spironolactone and hydrochlorothiazide tablets may be indicated during pregnancy when edema is due to pathologic causes.

In cases of hypervolemia during normal pregnancy, which is generally not harmful, increased recumbency may alleviate discomfort. In rare instances where edema causes extreme discomfort not relieved by rest, a short course of diuretics may be appropriate.

Dosage and Administration

The optimal dosage of spironolactone and hydrochlorothiazide tablets should be determined through individual titration of the components. The usual maintenance dose is 100 mg of each component daily, which may be administered as a single dose or divided into multiple doses. However, dosing may range from 25 mg to 200 mg of each component daily, contingent upon the patient's response to the initial titration.

In certain cases, it may be beneficial to administer separate tablets of either spironolactone or hydrochlorothiazide alongside the combination tablets to achieve optimal individual therapy. Clinical experience suggests that many patients may attain an optimal therapeutic response with a daily dosage of 50 mg to 100 mg of each component, which can also be given in a single or divided doses.

Contraindications

Spironolactone and hydrochlorothiazide tablets are contraindicated in patients with the following conditions:

• Anuria

• Acute renal insufficiency

• Significant impairment of renal excretory function

• Hypercalcemia

• Hyperkalemia

• Addison's disease

• Allergy to thiazide diuretics or other sulfonamide-derived drugs

• Acute or severe hepatic failure

Use of this medication in these conditions may lead to serious adverse effects due to the pharmacological actions of the components.

Warnings and Precautions

Potassium supplementation, whether through medication or a potassium-rich diet, is contraindicated during treatment with spironolactone and hydrochlorothiazide tablets. Excessive potassium intake can lead to hyperkalemia in patients receiving this combination therapy.

Concomitant use of spironolactone and hydrochlorothiazide tablets with certain medications or potassium sources may significantly increase the risk of severe hyperkalemia. These include other potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, aldosterone blockers, non-steroidal anti-inflammatory drugs (NSAIDs) such as indomethacin, heparin and low molecular weight heparin, as well as any drugs or conditions known to elevate serum potassium levels. Additionally, potassium supplements, diets high in potassium, and salt substitutes containing potassium should be avoided.

Spironolactone and hydrochlorothiazide tablets should not be used concurrently with other potassium-sparing diuretics. The combination of spironolactone with ACE inhibitors or indomethacin, even in the presence of a diuretic, has been associated with severe hyperkalemia. Therefore, extreme caution is warranted when administering these medications together.

Patients with impaired hepatic function should use spironolactone and hydrochlorothiazide tablets with caution, as even minor changes in fluid and electrolyte balance may precipitate hepatic coma. Lithium should generally be avoided in patients receiving diuretics. Thiazides must be used cautiously in individuals with severe renal disease, as they may induce azotemia and cumulative effects in those with impaired renal function.

Sensitivity reactions to thiazides can occur in patients regardless of prior allergy or bronchial asthma history. Furthermore, sulfonamide derivatives, including thiazides, have been reported to exacerbate or activate systemic lupus erythematosus.

Spironolactone has the potential to cause hyperkalemia, particularly in patients with renal insufficiency, diabetes mellitus, or those taking other medications that increase serum potassium levels. Conversely, hydrochlorothiazide may lead to hypokalemia and hyponatremia, with heightened risk in patients with cirrhosis, brisk diuresis, or those on medications that lower serum potassium. Hypomagnesemia can also contribute to hypokalemia, which may be challenging to correct despite potassium repletion. Therefore, periodic monitoring of serum electrolytes is essential, especially in elderly patients and those with significant renal or hepatic impairments.

Healthcare professionals should be vigilant for symptoms indicative of angle-closure glaucoma, such as acute onset of decreased visual acuity or ocular pain, which may arise within hours to weeks of initiating treatment. If left untreated, angle-closure glaucoma can lead to permanent visual field loss. The primary intervention is the rapid discontinuation of hydrochlorothiazide, and prompt medical or surgical treatment may be necessary if intraocular pressure remains uncontrolled.

Patients should be advised to discontinue spironolactone and hydrochlorothiazide tablets and consult their healthcare provider if they experience gynecomastia, which appears to be dose-dependent and related to the duration of therapy. While this condition is typically reversible upon cessation of the medication, there are rare instances where some breast enlargement may persist.

Side Effects

Patients receiving hydrochlorothiazide may experience a range of adverse reactions, which can be categorized by seriousness and frequency.

Serious adverse reactions include hypotension, which may manifest as orthostatic hypotension and can be exacerbated by the concomitant use of alcohol, barbiturates, narcotics, or other antihypertensive medications. Additionally, patients may experience renal failure, renal dysfunction, and interstitial nephritis. Hematologic reactions such as aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia have also been reported. Hypersensitivity reactions can occur, including anaphylactic reactions, necrotizing angitis, respiratory distress (which may include pneumonitis and pulmonary edema), and severe skin reactions such as erythema multiforme.

Common adverse reactions associated with hydrochlorothiazide include weakness, dizziness, headache, and gastrointestinal disturbances such as diarrhea, vomiting, and nausea. Patients may also experience metabolic issues, including electrolyte imbalances, hyperglycemia, glycosuria, and hyperuricemia. Eye disorders such as acute myopia and acute angle-closure glaucoma have been noted, with the latter being a serious concern due to its potential to cause elevated intraocular pressure.

Spironolactone is associated with several adverse reactions as well. Serious reactions include renal dysfunction and hematologic issues such as leukopenia and thrombocytopenia. Gastrointestinal disturbances, including gastric bleeding, ulceration, and gastritis, are also notable. Patients may experience reproductive system effects, such as gynecomastia and menstrual irregularities, with a potential association between spironolactone and breast carcinoma, although a definitive cause-and-effect relationship has not been established.

Common adverse reactions to spironolactone include leg cramps, lethargy, mental confusion, dizziness, and headache. Skin reactions can range from pruritus to severe conditions such as Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN).

Postmarketing experience has indicated that hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma in white patients who have received large cumulative doses.

In cases of acute overdosage of spironolactone, symptoms may include drowsiness, mental confusion, rash, nausea, vomiting, dizziness, and diarrhea. Rarely, severe liver disease may lead to hyponatremia, hyperkalemia, or hepatic coma.

Patients should be monitored for these adverse reactions, and appropriate management strategies should be employed as necessary.

Drug Interactions

Concomitant administration of certain drug classes may lead to significant interactions that require careful monitoring and potential dosage adjustments.

Pharmacodynamic Interactions

• The use of ACE inhibitors, Angiotensin II receptor antagonists, aldosterone blockers, potassium supplements, heparin, low molecular weight heparin, and other agents known to cause hyperkalemia can result in severe hyperkalemia. Monitoring of serum potassium levels is advised.

• Alcohol, barbiturates, and narcotics may potentiate orthostatic hypotension. Caution is recommended when these substances are used concurrently.

• Corticosteroids and ACTH may lead to intensified electrolyte depletion, particularly hypokalemia. Monitoring of electrolyte levels is suggested.

• Spironolactone and hydrochlorothiazide may reduce vascular responsiveness to norepinephrine; caution should be exercised in patients undergoing regional or general anesthesia while on these medications.

• The combination of spironolactone with nondepolarizing skeletal muscle relaxants, such as tubocurarine, may increase responsiveness to these agents, necessitating careful monitoring during anesthesia.

• Lithium should generally not be administered with diuretics, as diuretics can reduce renal clearance of lithium, increasing the risk of lithium toxicity.

• The administration of nonsteroidal anti-inflammatory drugs (NSAIDs) can diminish the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics. The combination of NSAIDs with potassium-sparing diuretics has been associated with severe hyperkalemia.

• Acetylsalicylic acid may reduce the efficacy of spironolactone, and titration to a higher maintenance dose may be necessary when used together.

• Spironolactone has been shown to increase the half-life of digoxin, potentially leading to elevated serum digoxin levels and digitalis toxicity. Monitoring of serum digoxin levels and dose adjustments are recommended.

• Hyperkalemic metabolic acidosis has been reported in patients receiving spironolactone concurrently with cholestyramine.

• Spironolactone binds to the androgen receptor and may elevate prostate-specific antigen (PSA) levels in patients treated with abiraterone for prostate cancer; concomitant use is not recommended.

Pharmacokinetic Interactions

• Thiazide diuretics should be discontinued prior to conducting tests for parathyroid function, as they may affect test results. Additionally, thiazides may decrease serum protein-bound iodine (PBI) levels without altering thyroid function.

• There have been reports of possible interference with digoxin radioimmunoassays by spironolactone or its metabolites. The clinical significance of this interference remains to be fully established and may vary by assay.

Packaging & NDC

The table below lists all NDC Code configurations of Spironolactone and Hydrochlorothiazide, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Therefore, the use of this medication in children, infants, and adolescents should be approached with caution until further data is available.

Geriatric Use

Elderly patients may be at an increased risk for electrolyte imbalances, necessitating careful monitoring. It is recommended that periodic determination of serum electrolytes be conducted at appropriate intervals in this population, particularly for those aged 65 and older or those with significant renal or hepatic impairments. This precaution is essential to ensure the safe and effective use of the medication in geriatric patients, as they may have altered pharmacokinetics and pharmacodynamics that can affect treatment outcomes. Regular monitoring can help identify potential imbalances early, allowing for timely interventions.

Pregnancy

Studies involving the oral administration of hydrochlorothiazide to pregnant mice and rats during major organogenesis at doses up to 3000 mg/kg and 1000 mg/kg, respectively, have shown no evidence of fetal harm. However, there are no adequate and well-controlled studies in pregnant women.

Teratology studies with spironolactone have been conducted in mice and rabbits at doses up to 20 mg/kg/day. This dose is significantly below the maximum recommended human dose for mice and approximates it for rabbits. While no teratogenic or embryo-toxic effects were observed in mice, the 20 mg/kg dose in rabbits resulted in an increased rate of resorption and a reduced number of live fetuses. Due to its antiandrogenic activity, spironolactone may adversely affect male sex differentiation during embryogenesis. In rats administered 200 mg/kg/day between gestation days 13 and 21, feminization of male fetuses was noted. Additionally, offspring exposed to spironolactone during late pregnancy at doses of 50 and 100 mg/kg/day exhibited reproductive tract changes, including decreased weights of the ventral prostate and seminal vesicle in males and enlarged ovaries and uteri in females, with indications of persistent endocrine dysfunction into adulthood.

Both spironolactone and hydrochlorothiazide can cross the placental barrier and appear in cord blood. Therefore, the use of spironolactone and hydrochlorothiazide tablets in pregnant women should be approached with caution, weighing the anticipated benefits against potential risks to the fetus. Possible hazards include fetal or neonatal jaundice, thrombocytopenia, and other adverse reactions observed in adults. There are no adequate and well-controlled studies with spironolactone and hydrochlorothiazide tablets in pregnant women, necessitating careful consideration of the risks versus benefits in this population.

Lactation

Canrenone, a major and active metabolite of spironolactone, is excreted in human breast milk. Due to the tumorigenic potential of spironolactone observed in animal studies, lactating mothers should carefully consider whether to discontinue the drug, weighing its importance to their health. If the use of spironolactone is deemed essential, an alternative method of infant feeding should be considered.

Thiazides are also present in human milk in small amounts. However, when administered at high doses, thiazides can lead to intense diuresis, which may inhibit milk production. Therefore, the use of spironolactone and hydrochlorothiazide tablets during breastfeeding is not recommended. If these medications are used while breastfeeding, it is advised that doses be kept as low as possible to minimize potential risks to the breastfed infant.

Renal Impairment

Patients with renal impairment should use thiazides with caution, particularly in cases of severe renal disease. In this population, thiazides may precipitate azotemia, and the cumulative effects of the drug can develop due to reduced kidney function. Monitoring of renal function is advised to mitigate potential risks associated with thiazide use in these patients.

Hepatic Impairment

Patients with hepatic impairment should use spironolactone and hydrochlorothiazide tablets with caution. Minor alterations in fluid and electrolyte balance in this population may precipitate hepatic coma. Therefore, careful monitoring of liver function and electrolyte levels is recommended in these patients to mitigate potential risks associated with treatment. Adjustments to dosage may be necessary based on the severity of hepatic impairment and the patient's overall clinical status.

Overdosage

Acute overdosage of spironolactone and hydrochlorothiazide can lead to a range of symptoms and potential complications. The oral LD50 of spironolactone is greater than 1000 mg/kg in mice, rats, and rabbits, while the oral LD50 of hydrochlorothiazide exceeds 10 g/kg in both mice and rats, indicating a relatively high threshold for acute toxicity in these animal models.

Symptoms of Overdosage

Clinical manifestations of acute overdosage with spironolactone may include drowsiness, mental confusion, maculopapular or erythematous rash, nausea, vomiting, dizziness, and diarrhea. In rare cases, patients may experience hyponatremia or hyperkalemia, although hyperkalemia is less commonly observed with the combination of spironolactone and hydrochlorothiazide due to the hypokalemic effect of hydrochlorothiazide. Severe liver disease may lead to hepatic coma, but such occurrences are unlikely to result solely from acute overdosage.

Given that spironolactone and hydrochlorothiazide tablets contain both active ingredients, the toxic effects may be exacerbated. Signs of thiazide overdosage may present as electrolyte imbalances, including hypokalemia and/or hyponatremia. Conversely, the potassium-sparing properties of spironolactone may lead to hyperkalemia, particularly in patients with compromised renal function.

Management of Overdosage

Management of overdosage should focus on supportive care and symptomatic treatment. Monitoring of renal function and electrolyte levels is essential, as BUN determinations may rise transiently with hydrochlorothiazide. In cases of CNS depression, characterized by lethargy or even coma, appropriate interventions should be initiated to ensure patient safety and stability.

Healthcare professionals are advised to remain vigilant for the potential complications associated with overdosage and to implement necessary measures to mitigate risks, particularly in patients with underlying health conditions.

Nonclinical Toxicology

Studies evaluating the teratogenic effects of hydrochlorothiazide, administered orally to pregnant mice and rats during critical periods of organogenesis, revealed no evidence of fetal harm at doses up to 3000 mg/kg and 1000 mg/kg, respectively. However, there are no adequate and well-controlled studies in pregnant women. In teratology studies involving spironolactone, conducted in mice and rabbits at doses up to 20 mg/kg/day, no teratogenic or embryo-toxic effects were observed in mice. In rabbits, the same dose resulted in an increased rate of resorption and a reduced number of live fetuses. Given spironolactone's antiandrogenic activity, there is a potential risk for adverse effects on male sex differentiation during embryogenesis. In rats administered 200 mg/kg/day from gestation days 13 to 21, feminization of male fetuses was noted. Offspring exposed to spironolactone during late pregnancy at doses of 50 and 100 mg/kg/day exhibited reproductive tract changes, including decreased weights of the ventral prostate and seminal vesicle in males, and enlarged ovaries and uteri in females, with indications of persistent endocrine dysfunction into adulthood. The use of spironolactone and hydrochlorothiazide tablets in pregnant women necessitates careful consideration of the anticipated benefits against potential fetal hazards.

Spironolactone and its metabolites may cross the placental barrier and be present in cord blood. Consequently, the use of spironolactone and hydrochlorothiazide tablets in pregnant women requires weighing the anticipated benefits against possible fetal risks, which may include fetal or neonatal jaundice, thrombocytopenia, and other adverse reactions observed in adults.

In nonclinical toxicology assessments, spironolactone has demonstrated tumorigenic properties in dietary administration studies in Sprague Dawley rats, with proliferative effects noted in endocrine organs and the liver. An 18-month study indicated statistically significant increases in benign adenomas of the thyroid and testes, as well as dose-related proliferative changes in the liver among male rats. In 24-month studies, significant increases in hepatocellular adenomas and testicular interstitial cell tumors were observed in males, alongside significant increases in thyroid follicular cell adenomas and carcinomas in both sexes, and benign uterine endometrial stromal polyps in females.

A dose-related incidence of myelocytic leukemia was noted in rats receiving potassium canrenoate, a compound similar to spironolactone, at doses above 30 mg/kg/day over one year. In two-year studies, potassium canrenoate was associated with myelocytic leukemia and tumors in the liver, thyroid, testis, and mammary glands.

Neither spironolactone nor potassium canrenoate exhibited mutagenic effects in bacterial or yeast tests. In mammalian tests in vitro, spironolactone was generally negative for mutagenicity in the absence of metabolic activation, while results were inconclusive in the presence of metabolic activation. Potassium canrenoate showed mixed results for mutagenicity in mammalian tests, being positive in some and negative in others.

In a three-litter reproduction study with female rats receiving dietary spironolactone at doses of 15 and 50 mg/kg/day, no effects on mating and fertility were observed, although a slight increase in stillborn pups occurred at the higher dose. Administration of spironolactone at 100 mg/kg/day via injection increased the length of the estrous cycle and induced constant diestrus, which was associated with retarded ovarian follicle development and reduced circulating estrogen levels, potentially impairing mating and fertility. In female mice, spironolactone administration during a cohabitation period resulted in decreased conception rates and reduced numbers of implanted embryos, with increased latency to mating observed at higher doses.

Two-year feeding studies conducted by the National Toxicology Program (NTP) found no evidence of carcinogenic potential for hydrochlorothiazide in female mice or male and female rats at doses up to approximately 600 mg/kg/day and 100 mg/kg/day, respectively. However, equivocal evidence for hepatocarcinogenicity was noted in male mice. Hydrochlorothiazide was not genotoxic in various in vitro assays, including the Ames test and chromosomal aberration tests. Positive results were limited to specific in vitro assays at certain concentrations. Hydrochlorothiazide did not adversely affect fertility in mice and rats exposed to doses up to 100 mg/kg and 4 mg/kg, respectively, prior to mating and throughout gestation.

Postmarketing Experience

Hydrochlorothiazide has been associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC). Data from a study conducted within the Sentinel System indicate that this increased risk is more pronounced in white patients who have received large cumulative doses of the medication. Specifically, the overall population exhibits an approximate risk of 1 additional case of SCC per 16,000 patients per year. For white patients who have taken a cumulative dose of ≥50,000 mg, the risk escalates to approximately 1 additional case of SCC for every 6,700 patients per year.

Patient Counseling

Patients receiving spironolactone and hydrochlorothiazide tablets should be advised to avoid potassium supplements and foods that are high in potassium, including salt substitutes. This precaution is essential to prevent potential complications related to elevated potassium levels.

Healthcare providers should instruct patients taking hydrochlorothiazide to protect their skin from sun exposure. It is also important to recommend that patients undergo regular skin cancer screenings, as this medication may increase sensitivity to sunlight.

Additionally, healthcare providers should emphasize the importance of periodic determination of serum electrolytes. This monitoring is crucial to detect possible electrolyte imbalances, particularly in elderly patients and those with significant renal or hepatic impairments. Regular assessments will help ensure patient safety and the effective management of their treatment.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available for identification. It is essential to store the product at temperatures below 77°F (25°C) to maintain its integrity and efficacy. Proper storage conditions should be ensured to prevent any degradation of the product.

Additional Clinical Information

Periodic determination of serum electrolytes is recommended to identify potential electrolyte imbalances in patients, especially among the elderly and those with notable renal or hepatic impairments. Clinicians should conduct these assessments at appropriate intervals to ensure patient safety and effective management.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Spironolactone and Hydrochlorothiazide as submitted by Prasco Laboratories. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)