Spironolactone/Hydrochlorothiazide

Description

Each tablet of spironolactone and hydrochlorothiazide contains 25 mg of spironolactone, USP, and 25 mg of hydrochlorothiazide, USP. 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, molecular formula, and molecular weight. Spironolactone 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, molecular formula, and molecular weight. Hydrochlorothiazide is slightly soluble in water and freely soluble in sodium hydroxide solution.

The tablets are formulated for oral administration and include the following inactive ingredients: colloidal silicon dioxide, corn starch, D&C Yellow No. 10 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake, lactose monohydrate, magnesium stearate, L-menthol, microcrystalline cellulose, peppermint oil, sodium lauryl sulfate, and sodium starch glycolate (potato).

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 treatment of diuretic-induced hypokalemia in these patients when other measures are considered inappropriate. Additionally, it is indicated for patients with congestive heart failure who are taking digitalis and for whom other therapies are deemed 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, particularly when aldosterone levels are exceptionally high.

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 pregnant women 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 use in treating developing toxemia. However, spironolactone and hydrochlorothiazide tablets may be indicated during pregnancy when edema is due to pathologic causes. In cases of dependent edema resulting from the mechanical effects of pregnancy, non-pharmacological measures such as elevation of the lower extremities and the use of support hose are recommended, as the use of diuretics is unsupported and unnecessary.

It is important to note that hypervolemia during normal pregnancy is not harmful to the mother or fetus in the absence of cardiovascular disease, although it may be associated with generalized edema. If this edema causes discomfort, increased recumbency is often sufficient for relief. In rare instances where extreme discomfort occurs and is not alleviated 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 in divided doses. However, the dosage may vary between 25 mg to 200 mg of each component daily, depending on 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 achieve an optimal therapeutic response with a daily dosage of 50 mg to 100 mg of each component, also given in a single or divided doses.

Contraindications

Spironolactone and hydrochlorothiazide tablets are contraindicated in patients with anuria, acute renal insufficiency, or significant impairment of renal excretory function due to the risk of exacerbating renal conditions. Use is also contraindicated in patients with hypercalcemia or hyperkalemia, as these conditions may be worsened by the pharmacological effects of the medication. Additionally, patients with Addison’s disease should not use this medication due to potential complications related to adrenal insufficiency. An allergy to thiazide diuretics or other sulfonamide-derived drugs is a contraindication due to the risk of severe allergic reactions. Finally, the use of these tablets is contraindicated in patients with acute or severe hepatic failure, as it may lead to further hepatic complications.

Warnings and Precautions

Potassium supplementation, whether through medication or a potassium-rich diet, is contraindicated during treatment with spironolactone and hydrochlorothiazide. The combination of these agents may lead to hyperkalemia, particularly in patients receiving excessive potassium intake.

Concomitant use of spironolactone and hydrochlorothiazide with certain medications or potassium sources can 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, a potassium-rich diet, and salt substitutes containing potassium should be avoided.

Spironolactone and hydrochlorothiazide 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 linked to severe hyperkalemia. Therefore, extreme caution is warranted when administering these medications together.

In patients with impaired hepatic function, the use of spironolactone and hydrochlorothiazide requires careful consideration, as even minor changes in fluid and electrolyte balance may precipitate hepatic coma. Furthermore, lithium should generally be avoided in patients receiving diuretics.

Thiazides, including hydrochlorothiazide, should be used cautiously in patients with severe renal disease, as they may induce azotemia. The cumulative effects of thiazides can be pronounced in individuals with impaired renal function. Sensitivity reactions to thiazides may occur in patients regardless of prior allergy or bronchial asthma history. Additionally, sulfonamide derivatives, which include thiazides, have been reported to exacerbate or activate systemic lupus erythematosus.

Spironolactone has the potential to cause hyperkalemia, with an increased risk in patients with renal insufficiency, diabetes mellitus, or those taking medications that elevate serum potassium. 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, particularly in elderly patients and those with significant renal or hepatic impairments.

Regular laboratory tests to assess serum electrolytes should be conducted at appropriate intervals to identify any potential electrolyte imbalances.

Side Effects

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

Serious adverse reactions associated with hydrochlorothiazide include hypotension, which may manifest as orthostatic hypotension, particularly when combined with alcohol, barbiturates, narcotics, or other antihypertensive medications. Renal complications such as renal failure and interstitial nephritis have also been reported. Hematologic reactions include serious conditions such as aplastic anemia, agranulocytosis, and thrombocytopenia. Hypersensitivity reactions can be severe, including anaphylactic reactions and necrotizing angitis, which may present with respiratory distress, pneumonitis, or pulmonary edema. Additionally, acute angle-closure glaucoma, potentially leading to permanent visual field loss, has been noted, particularly in patients with a history of sulfonamide or penicillin allergy.

Common adverse reactions to hydrochlorothiazide include weakness, dizziness, headache, and gastrointestinal disturbances such as diarrhea, vomiting, and nausea. Patients may also experience metabolic issues, including electrolyte imbalances, hyperglycemia, and hyperuricemia. Dermatological reactions such as rash, purpura, and photosensitivity have been observed, along with musculoskeletal symptoms like muscle spasms.

Spironolactone is associated with serious gastrointestinal reactions, including gastric bleeding and ulceration. It may also lead to reproductive system effects such as gynecomastia and menstrual irregularities. Hematologic issues, including leukopenia and thrombocytopenia, have been reported. Serious skin reactions, including Stevens-Johnson Syndrome and toxic epidermal necrolysis, have been documented. Renal dysfunction, including renal failure, is another significant concern.

Common adverse reactions to spironolactone include gastrointestinal symptoms such as diarrhea and cramping, as well as neurological effects like lethargy, dizziness, and confusion. Patients may also experience leg cramps and various hypersensitivity reactions, including urticaria and maculopapular eruptions.

Postmarketing experience has indicated that hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma, especially in white patients taking high cumulative doses. The risk is estimated to be approximately one additional case per 16,000 patients per year in the overall population, with a significantly higher risk in those receiving cumulative doses of ≥ 50,000 mg.

Patients should be monitored for these adverse reactions, and any severe or persistent symptoms should prompt immediate medical evaluation and intervention.

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 pressor amines (e.g., norepinephrine), necessitating caution in patients undergoing regional or general anesthesia.

• There is a potential for increased responsiveness to nondepolarizing skeletal muscle relaxants (e.g., tubocurarine) when used with spironolactone.

Pharmacokinetic Interactions

• Antidiabetic drugs, including oral agents and insulin, may require dosage adjustments when used in conjunction with spironolactone.

• The renal clearance of lithium is reduced by diuretics, increasing the risk of lithium toxicity; therefore, lithium should generally not be administered with diuretics.

• 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.

• 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.

• Concurrent use of spironolactone and cholestyramine has been associated with hyperkalemic metabolic acidosis.

• 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.

Drug & Laboratory Test Interactions

• Thiazides should be discontinued prior to conducting tests for parathyroid function, as they may decrease serum 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 may vary depending on the specific assay used.

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 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. 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 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, while in the rabbit, it approximates the maximum recommended human dose. No teratogenic or other embryo-toxic effects were observed in mice; however, the 20 mg/kg dose caused an increased rate of resorption and a lower number of live fetuses in rabbits. Due to its antiandrogenic activity and the requirement of testosterone for male morphogenesis, spironolactone may adversely affect sex differentiation of the male during embryogenesis. In rats administered spironolactone at 200 mg/kg/day between gestation days 13 and 21, feminization of male fetuses was observed. Offspring exposed during late pregnancy to doses of 50 and 100 mg/kg/day exhibited changes in the reproductive tract, including dose-dependent decreases in weights of the ventral prostate and seminal vesicle in males, as well as enlarged ovaries and uteri in females, indicating potential endocrine dysfunction that persisted into adulthood.

Spironolactone or its metabolites may cross the placental barrier and appear in cord blood, and hydrochlorothiazide does cross the placental barrier. Therefore, the use of spironolactone and hydrochlorothiazide in pregnant women requires careful consideration of the anticipated benefits against the possible hazards to the fetus. Potential hazards include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have been observed in adults.

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 during breastfeeding is not recommended. If these medications are necessary, it is advised that doses be minimized to the lowest effective levels to mitigate potential risks to breastfed infants.

Renal Impairment

Patients with renal impairment should be monitored closely when using thiazides, particularly in cases of severe renal disease. Caution is advised, as thiazides may precipitate azotemia in this population. Additionally, the cumulative effects of the drug can develop in patients with reduced kidney function, necessitating careful assessment and potential dosing adjustments.

Hepatic Impairment

Patients with hepatic impairment should use spironolactone and hydrochlorothiazide 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 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.

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 associated with spironolactone and hydrochlorothiazide due to the hypokalemic effect of hydrochlorothiazide. Severe liver disease may predispose patients to hepatic coma, but such occurrences are unlikely to result solely from acute overdosage.

Given that spironolactone and hydrochlorothiazide are combined in a single formulation, the toxic effects may be exacerbated, and signs of thiazide overdosage may also be present. These can include electrolyte imbalances such as hypokalemia and/or hyponatremia. The potassium-sparing properties of spironolactone may lead to hyperkalemia, particularly in patients with compromised renal function. Additionally, blood urea nitrogen (BUN) levels may rise transiently with hydrochlorothiazide administration. Central nervous system (CNS) effects may manifest as lethargy or, in severe cases, coma.

In the event of suspected overdosage, it is crucial to monitor the patient closely for these symptoms and manage electrolyte imbalances as necessary. Supportive care should be provided, and specific interventions may be required based on the clinical presentation and laboratory findings.

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. Due to its antiandrogenic activity, spironolactone may adversely affect 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 dose-dependent decreases in the 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 in pregnant women necessitates careful consideration of the anticipated benefits against potential fetal hazards.

Spironolactone and its metabolites, as well as hydrochlorothiazide, have been shown to cross the placental barrier and appear in cord blood. This raises concerns regarding potential hazards to the fetus, including fetal or neonatal jaundice and thrombocytopenia, as well as 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, along with dose-related proliferative changes in the liver, including hepatocytomegaly and hyperplastic nodules. In 24-month studies, significant increases in hepatocellular adenomas and testicular interstitial cell tumors in males, as well as thyroid follicular cell adenomas and carcinomas in both sexes, were observed. Additionally, a statistically significant increase in benign uterine endometrial stromal polyps was noted in females.

A dose-related incidence of myelocytic leukemia was observed in rats administered potassium canrenoate, a compound chemically similar to spironolactone, at doses above 30 mg/kg/day for 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 negative for mutagenicity in the absence of metabolic activation and reported inconclusive results in the presence of metabolic activation. Potassium canrenoate showed mixed results, being positive in some tests and negative in others.

In a three-litter reproduction study with female rats receiving dietary doses of spironolactone, no effects on mating and fertility were observed, although a slight increase in stillborn pups occurred at the highest 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 a reduction in implanted embryos.

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 only observed in specific clastogenicity and mutagenicity 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

Postmarketing experience has identified an association between hydrochlorothiazide and an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC). Data from a study conducted within the Sentinel System indicated that this increased risk is predominantly observed in white patients who are administered large cumulative doses of the medication.

In the overall population, the estimated increase in risk for SCC is approximately one additional case per 16,000 patients per year. Notably, for white patients receiving a cumulative dose of 50,000 mg or more, the risk escalates to approximately one additional case of SCC for every 6,700 patients per year.

Patient Counseling

Patients receiving spironolactone and hydrochlorothiazide should be advised to avoid potassium supplements and foods that are high in potassium, including salt substitutes. It is important for healthcare providers to emphasize the potential risks associated with elevated potassium levels and the need for dietary modifications.

Patients taking hydrochlorothiazide should be instructed to protect their skin from sun exposure and to undergo regular skin cancer screenings. Healthcare providers should discuss the importance of sun safety measures and the need for vigilance regarding skin changes.

Additionally, healthcare providers should ensure that patients understand the necessity of periodic serum electrolyte determinations to monitor for possible electrolyte imbalances. This is particularly crucial for elderly patients and those with significant renal or hepatic impairments, as they may be at a higher risk for complications. Regular follow-up appointments should be encouraged to facilitate this monitoring.

Storage and Handling

The product is supplied in a tight, light-resistant container that complies with USP standards and features a child-resistant closure. It is essential to store the product at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines. Additionally, the product must be protected from light to maintain its integrity and efficacy.

Additional Clinical Information

Periodic determination of serum electrolytes is recommended to detect potential electrolyte imbalances in patients, especially among the elderly and those with significant 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 Mylan Pharmaceuticals Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)