Spironolactone/Hydrochlorothiazide

Description

Spironolactone, USP, is a medication with a strength of 25 mg. Its chemical name is 17-hydroxy-7α-mercapto-3-oxo-17α-pregn-4-ene-21-carboxylic acid γ-lactone acetate. Spironolactone is practically insoluble in water, soluble in alcohol, and freely soluble in benzene and chloroform. Hydrochlorothiazide, USP, is also included at a strength of 25 mg, with the chemical name 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Hydrochlorothiazide is slightly soluble in water and freely soluble in sodium hydroxide solution. The formulation contains several inactive ingredients, including anhydrous lactose, colloidal silicon dioxide, D&C yellow #10 lake, docusate sodium, FD&C yellow #6 lake, magnesium stearate, microcrystalline cellulose, peppermint flavor, povidone, sodium benzoate, and sodium starch glycolate.

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 used in 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 This drug is indicated for the treatment of essential hypertension in patients for whom other measures are considered inadequate or inappropriate. It is also indicated for the treatment of diuretic-induced hypokalemia in hypertensive patients when other measures are deemed inappropriate. The primary purpose of this medication in hypertensive patients is to lower blood pressure.

Limitations of Use The routine use of diuretics in otherwise healthy women during pregnancy is inappropriate and poses unnecessary risks to both the 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. Spironolactone and hydrochlorothiazide tablets may be indicated during pregnancy only when edema is due to pathologic causes.

Nonteratogenic Effects During normal pregnancy, hypervolemia is common and typically does not harm the mother or fetus in the absence of cardiovascular disease. While this condition may lead to generalized edema in many pregnant women, increased recumbency often alleviates 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 established 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 range from 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 in conjunction with spironolactone and hydrochlorothiazide tablets to achieve optimal individual therapy. Clinical experience indicates that many patients may achieve an optimal response with a daily dosage of 50 mg to 100 mg of each component, also given in a single dose or in 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 components. Additionally, the tablets should not be administered to individuals with Addison's disease, as this may lead to severe electrolyte imbalances. Patients with a known allergy to thiazide diuretics or other sulfonamide-derived drugs should avoid these tablets to prevent allergic reactions. Finally, the use of these tablets is contraindicated in cases of acute or severe hepatic failure, as this may lead to further hepatic complications.

Warnings and Precautions

Potassium supplementation, whether through medication or a potassium-rich diet, is contraindicated during therapy with spironolactone and hydrochlorothiazide tablets. The risk of hyperkalemia is significantly increased in patients receiving this combination.

Concomitant use of spironolactone and hydrochlorothiazide tablets with certain medications or potassium sources can lead to 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 cause hyperkalemia. Additionally, potassium supplements, diets rich in potassium, and salt substitutes containing potassium should be avoided.

Spironolactone and hydrochlorothiazide tablets must not be administered 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 these drugs are used together.

Patients with impaired hepatic function should use spironolactone and hydrochlorothiazide tablets with caution, as even minor alterations in fluid and electrolyte balance may precipitate hepatic coma. Furthermore, lithium should generally be avoided in patients taking diuretics.

Thiazides should be used cautiously in patients with severe renal disease, as they may precipitate azotemia. The cumulative effects of thiazides can develop in individuals with impaired renal function. Additionally, thiazides may enhance the effects of other antihypertensive medications.

Sensitivity reactions to thiazides can occur in patients with or without a history of allergy or bronchial asthma. It is also important to note that sulfonamide derivatives, including thiazides, have been reported to exacerbate or activate systemic lupus erythematosus.

To ensure safe use of spironolactone and hydrochlorothiazide tablets, periodic determination of serum electrolytes is recommended to monitor for possible electrolyte imbalances. This is particularly important for elderly patients and those with significant renal or hepatic impairments.

Side Effects

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

Serious adverse reactions include cardiovascular events such as hypotension, including orthostatic hypotension, which may be exacerbated by concomitant use of alcohol, barbiturates, narcotics, or other antihypertensive medications. Hematologic reactions such as aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia have also been reported. Renal complications, including renal failure and interstitial nephritis, are notable serious concerns. Hypersensitivity reactions can manifest as anaphylactic reactions, necrotizing angitis, respiratory distress (including pneumonitis and pulmonary edema), and severe skin reactions such as erythema multiforme and purpura.

Common adverse reactions observed in clinical trials and postmarketing experiences 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. Eye disorders such as acute myopia and acute angle-closure glaucoma, as well as musculoskeletal symptoms like muscle spasms, have been reported.

In the context of spironolactone, common adverse reactions include gastrointestinal disturbances such as gastric bleeding, ulceration, and cramping, as well as reproductive issues like gynecomastia and menstrual irregularities. Neurological effects such as lethargy, mental confusion, and dizziness are also noted. Serious adverse reactions may include renal dysfunction and rare cases of mixed cholestatic/hepatocellular toxicity, with one reported fatality. Hypersensitivity reactions, including Stevens-Johnson Syndrome and toxic epidermal necrolysis, have been documented.

Postmarketing data indicate that hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC) in white patients receiving large cumulative doses. The overall risk for SCC in the general population is approximately one additional case per 16,000 patients per year, while for white patients taking a cumulative dose of ≥50,000 mg, the risk increases to approximately one additional case for every 6,700 patients per year.

Healthcare providers should monitor patients for these adverse reactions and consider the risk-benefit profile when prescribing these medications.

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, and low molecular weight heparin concurrently may result in severe hyperkalemia. Monitoring of serum potassium levels is advised.

• Alcohol, barbiturates, and narcotics may enhance the risk of orthostatic hypotension. Caution is recommended when these agents are used together.

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

• Nondepolarizing skeletal muscle relaxants, such as tubocurarine, may exhibit increased responsiveness when administered with this medication. Caution is advised during anesthesia.

• The combination of spironolactone and cholestyramine has been associated with hyperkalemic metabolic acidosis. Monitoring of potassium levels is recommended.

Pharmacokinetic Interactions:

• Antidiabetic drug dosages may require adjustment when used in conjunction with this medication. Close monitoring of blood glucose levels is advised.

• Diuretics may decrease the renal clearance of lithium, thereby increasing the risk of lithium toxicity. Monitoring of lithium levels is recommended.

• Nonsteroidal anti-inflammatory drugs (NSAIDs) can diminish the diuretic, natriuretic, and antihypertensive effects of diuretics. Severe hyperkalemia may occur with potassium-sparing diuretics; monitoring of potassium levels is essential.

• Acetylsalicylic acid may reduce the efficacy of spironolactone, necessitating potential dose titration.

• Spironolactone may prolong the half-life of digoxin, leading to elevated serum levels and potential toxicity. Close monitoring of digoxin levels is advised.

• Spironolactone or its metabolites may interfere with digoxin radioimmunoassays, although the clinical significance remains uncertain.

• The use of spironolactone in patients receiving abiraterone may increase PSA levels; concomitant use is not recommended.

• Caution is warranted when spironolactone is used with mitotane, as it may reduce mitotane plasma levels.

• Thiazide diuretics should be discontinued prior to parathyroid function tests, as they may lower serum PBI levels without affecting thyroid function.

In summary, careful consideration of these interactions is essential for optimizing therapeutic outcomes and minimizing adverse effects. Regular monitoring and potential dosage adjustments are recommended where applicable.

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 healthcare providers perform periodic determinations of serum electrolytes at appropriate intervals in this population, particularly for those aged 65 and older or those with significant renal or hepatic impairments. This proactive approach is essential to ensure the safety and efficacy of treatment in geriatric patients, as they may have altered pharmacokinetics and pharmacodynamics that can affect drug metabolism and excretion. Regular monitoring can help mitigate potential complications associated with electrolyte disturbances.

Pregnancy

The routine use of diuretics in otherwise healthy pregnant patients is inappropriate and poses unnecessary risks to both the mother and fetus. Diuretics have not been shown to prevent the development of toxemia of pregnancy, nor is there satisfactory evidence supporting their efficacy in treating this condition once it develops.

Spironolactone and hydrochlorothiazide tablets may be indicated during pregnancy when edema is due to pathological causes, similar to their use in non-pregnant individuals. However, dependent edema commonly observed in pregnancy, which results from venous return restriction by the expanded uterus, should primarily be managed through non-pharmacological measures such as elevating the lower extremities and utilizing support hose. The use of diuretics to reduce intravascular volume in this context is unsupported and unnecessary.

It is important to note that hypervolemia is a normal physiological occurrence during pregnancy and is generally not harmful to either the mother or fetus, provided there are no underlying cardiovascular issues. This condition is often associated with edema, including generalized edema, affecting a majority of pregnant women. If this edema leads to discomfort, increased recumbency may offer relief. In rare cases where extreme discomfort persists despite rest, a short course of diuretics may be considered appropriate to alleviate symptoms.

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, healthcare professionals should consider whether to discontinue the drug, weighing its importance to the lactating mother. If the use of spironolactone is deemed essential, an alternative method of infant feeding should be considered.

Thiazides are also excreted in small amounts in human milk. 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, it is advised to keep doses 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 these patients may precipitate hepatic coma. Therefore, careful monitoring of liver function and electrolyte levels is recommended to mitigate potential risks associated with the use of these medications in individuals with compromised liver function.

Overdosage

Acute overdosage of spironolactone and hydrochlorothiazide can lead to a range of symptoms and complications that require prompt medical attention.

Toxicity Profile 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. Symptoms 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, hyperkalemia, or hepatic coma, particularly in those with severe liver disease.

Electrolyte Imbalance The concomitant use of spironolactone and hydrochlorothiazide can exacerbate toxic effects, leading to significant electrolyte imbalances such as hypokalemia and/or hyponatremia. The potassium-sparing properties of spironolactone may lead to hyperkalemia, especially in patients with impaired renal function. Central nervous system (CNS) depression, characterized by lethargy or even coma, may also occur in overdose situations.

Management of Overdosage In the event of an overdose, immediate treatment is essential. Inducing vomiting or performing gastric lavage is recommended, as there is no specific antidote available. Supportive care should focus on maintaining hydration, electrolyte balance, and vital functions.

For patients exhibiting signs of spironolactone-induced hyperkalemia, particularly those with renal impairment, it is crucial to discontinue both spironolactone and hydrochlorothiazide immediately. Severe hyperkalemia may necessitate intravenous administration of calcium chloride solution, sodium bicarbonate solution, and/or glucose with rapid-acting insulin. In cases of persistent hyperkalemia, dialysis may be required to restore normal potassium levels.

Healthcare professionals should remain vigilant for these potential complications and manage them accordingly to ensure patient safety and recovery.

Nonclinical Toxicology

Studies evaluating the teratogenic effects of hydrochlorothiazide have demonstrated that oral administration to pregnant mice and rats during critical periods of organogenesis, at doses up to 3,000 mg/kg and 1,000 mg/kg respectively, did not result in fetal harm. However, there are no adequate and well-controlled studies in pregnant women. In contrast, teratology studies with spironolactone in mice and rabbits at doses up to 20 mg/kg/day revealed no teratogenic effects in mice, while the highest dose in rabbits led to an increased rate of resorption and a reduced number of live fetuses. Due to its antiandrogenic properties, 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 observed. 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. 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 necessitates weighing the anticipated benefits against possible risks to the fetus, which may include fetal or neonatal jaundice, thrombocytopenia, and other adverse reactions observed in adults.

In nonclinical toxicology studies, spironolactone has been identified as a tumorigen in dietary administration studies in Sprague Dawley rats, with proliferative effects noted in endocrine organs and the liver. An 18-month study revealed statistically significant increases in benign adenomas of the thyroid and testes, along with dose-related liver changes in male rats. In 24-month studies, significant increases in hepatocellular adenomas and testicular interstitial cell tumors were observed in males, as well as thyroid follicular cell adenomas and carcinomas in both sexes. Additionally, a 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 related 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 various organs.

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.

In a reproduction study involving female rats receiving dietary spironolactone, no effects on mating and fertility were observed, although a slight increase in stillborn pups occurred at the highest dose. Administration of spironolactone via injection resulted in prolonged estrous cycles and impaired ovarian follicle development, which could affect fertility. In female mice, spironolactone administration decreased conception rates and the number of implanted embryos.

Hydrochlorothiazide has been evaluated in two-year feeding studies conducted by the National Toxicology Program (NTP), which found no evidence of carcinogenic potential in female mice or male and female rats at specified doses. However, equivocal evidence for hepatocarcinogenicity was noted in male mice. Hydrochlorothiazide was not genotoxic in various in vitro and in vivo assays, with positive results only in specific clastogenicity and mutagenicity tests at certain concentrations. Furthermore, it did not adversely affect fertility in mice and rats exposed to dietary doses 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 notably observed in white patients who are administered 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 receiving a cumulative dose of 50,000 mg or more, 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. Healthcare providers should emphasize the importance of monitoring dietary intake to prevent potential complications related to elevated potassium levels.

Additionally, patients taking hydrochlorothiazide should be instructed to protect their skin from sun exposure and to undergo regular skin cancer screenings, as there is an associated risk of non-melanoma skin cancer with this medication. It is crucial for healthcare providers to discuss sun safety measures and the importance of early detection through routine screenings.

Healthcare providers should also ensure that periodic determination of serum electrolytes is conducted to detect any possible electrolyte imbalances. This is particularly important for elderly patients and those with significant renal or hepatic impairments, as they may be at a higher risk for such imbalances. Regular monitoring should be emphasized to maintain patient safety and optimize treatment outcomes.

Storage and Handling

The product is supplied in a tight, light-resistant container to ensure its integrity and efficacy. It should be stored at a controlled temperature range of 20° to 25°C (68° to 77°F) to maintain optimal conditions. Proper handling and storage are essential to preserve the quality 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 Sun Pharmaceutical Industries, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)