Spironolactone/Hydrochlorothiazide

Uses and Indications

Spironolactone and hydrochlorothiazide tablets are indicated for the management of various edematous conditions, including:

Edematous Conditions

• Congestive Heart Failure:

  • For the management of edema and sodium retention when the patient is only partially responsive to, or intolerant of, other therapeutic measures.

  • For the treatment of diuretic-induced hypokalemia in patients with congestive heart failure when other measures are considered inappropriate.

  • For the treatment of patients with congestive heart failure taking digitalis when other therapies are considered inadequate or inappropriate.

• Cirrhosis of the Liver Accompanied by Edema and/or Ascites:

  • Indicated for maintenance therapy together with bed rest and the restriction of fluid and sodium, particularly when aldosterone levels may be exceptionally high.

• 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 diuretic-induced hypokalemia when other measures are considered inappropriate.

  • Indicated for the treatment of hypertension to lower blood pressure, thereby reducing the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.

Teratogenic Effects

The routine use of diuretics in an otherwise healthy woman is inappropriate and exposes both mother and fetus to unnecessary hazards. Diuretics do not prevent the development of toxemia of pregnancy, and there is no satisfactory evidence that they are useful in treating developing toxemia. Spironolactone and hydrochlorothiazide tablets are indicated in pregnancy when edema is due to pathologic causes.

Nonteratogenic Effects

During normal pregnancy, hypervolemia is not harmful to either the fetus or the mother (in the absence of cardiovascular disease) but 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 such cases, a short course of diuretics may provide relief and may be appropriate.

Dosage and Administration

The optimal dosage of spironolactone and hydrochlorothiazide should be established through individual titration of the components. The usual maintenance dose for spironolactone and hydrochlorothiazide tablets 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.

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. In certain cases, it may be beneficial to administer separate tablets of either spironolactone or hydrochlorothiazide in addition to the combination tablets to ensure optimal individual therapy.

Contraindications

Spironolactone and hydrochlorothiazide tablets are contraindicated in patients with anuria, acute renal insufficiency, or significant impairment of renal excretory function. The use of this medication is also contraindicated in individuals with hypercalcemia, hyperkalemia, or Addison’s disease. Additionally, patients with a known allergy to thiazide diuretics or other sulfonamide-derived drugs should not use this medication. It is contraindicated in cases of acute or severe hepatic failure.

Warnings and Precautions

Potassium supplementation, either in the form of medication or as a diet rich in potassium, should not ordinarily be given in association with spironolactone and hydrochlorothiazide therapy. Excessive potassium intake may cause hyperkalemia in patients receiving this combination therapy.

Serious Warnings

Concomitant administration of spironolactone and hydrochlorothiazide with the following drugs or potassium sources may lead to severe hyperkalemia:

• Other potassium-sparing diuretics

• ACE inhibitors

• Angiotensin II receptor antagonists

• Aldosterone blockers

• Non-steroidal anti-inflammatory drugs (NSAIDs), e.g., indomethacin

• Heparin and low molecular weight heparin

• Other drugs or conditions known to cause hyperkalemia

• Potassium supplements

• Diet rich in potassium

• Salt substitutes containing potassium

Spironolactone and hydrochlorothiazide should not be administered concurrently with other potassium-sparing diuretics. The use of spironolactone with ACE inhibitors or indomethacin, even in the presence of a diuretic, has been associated with severe hyperkalemia. Extreme caution should be exercised when these medications are given concomitantly.

Spironolactone and hydrochlorothiazide should be used with caution in patients with impaired hepatic function, as minor alterations of fluid and electrolyte balance may precipitate hepatic coma. Lithium generally should not be given with diuretics. Thiazides should be used with caution in severe renal disease, as they may precipitate azotemia and cumulative effects of the drug may develop in patients with impaired renal function. Sensitivity reactions to thiazides may occur in patients with or without a history of allergy or bronchial asthma. Additionally, sulfonamide derivatives, including thiazides, have been reported to exacerbate or activate systemic lupus erythematosus.

General Precautions

Spironolactone can cause hyperkalemia, with an increased risk in patients with renal insufficiency, diabetes mellitus, or those using drugs that raise serum potassium. Hydrochlorothiazide can cause hypokalemia and hyponatremia, with an increased risk in patients with cirrhosis, brisk diuresis, or those using drugs that lower serum potassium. Hypomagnesemia can result in hypokalemia that appears difficult to treat despite potassium repletion. It is essential to monitor serum electrolytes periodically.

Laboratory Tests

Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be conducted at appropriate intervals, particularly in the elderly and those with significant renal or hepatic impairments.

Get Emergency Medical Help

Symptoms may include acute onset of decreased visual acuity or ocular pain, typically occurring within hours to weeks of drug initiation. Untreated, 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 intraocular pressure remains uncontrolled.

Stop Taking and Call Your Doctor

The development of gynecomastia appears to be related to both dosage level and duration of therapy and is generally reversible upon discontinuation of spironolactone and hydrochlorothiazide. In rare instances, some breast enlargement may persist after discontinuation.

Side Effects

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

Serious Adverse Reactions

• Cardiovascular: Hypotension, including orthostatic hypotension, which may be aggravated by alcohol, barbiturates, narcotics, or antihypertensive drugs.

• Hematologic: Aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia.

• Renal: Renal failure, renal dysfunction, and interstitial nephritis.

• Liver/Biliary: Rare cases of mixed cholestatic/hepatocellular toxicity, with one reported fatality associated with spironolactone administration.

• Skin: Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS).

Common Adverse Reactions

• Body as a Whole: Weakness.

• Digestive: Diarrhea, vomiting, nausea, cramping, and gastric irritation. Specific to spironolactone, gastric bleeding, ulceration, and gastritis may occur.

• Musculoskeletal: Muscle spasm and leg cramps.

• Nervous System/Psychiatric: Dizziness, headache, lethargy, mental confusion, ataxia, paresthesias, and restlessness.

• Hypersensitivity: Anaphylactic reactions, fever, urticaria, maculopapular or erythematous cutaneous eruptions, and vasculitis.

Less Common Adverse Reactions

• Eye Disorders: Acute myopia and acute angle-closure glaucoma, which may lead to permanent visual field loss if untreated.

• Metabolic: Electrolyte imbalances, hyperkalemia, hyperglycemia, glycosuria, and hyperuricemia.

• Reproductive: Gynecomastia, inability to achieve or maintain an erection, irregular menses or amenorrhea, postmenopausal bleeding, and breast pain. Carcinoma of the breast has been reported, but a causal relationship has not been established.

• Skin: Erythema multiforme, pruritus, and alopecia.

• Special Senses: Transient blurred vision and xanthopsia.

Post-Marketing Experience

Hydrochlorothiazide has been associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC) in white patients taking large cumulative doses. The overall risk for SCC is approximately 1 additional case per 16,000 patients per year, and for white patients taking a cumulative dose of ≥ 50,000 mg, the risk increases to approximately 1 additional SCC case for every 6,700 patients per year.

Important Notes

Hydrochlorothiazide can cause an idiosyncratic reaction leading to acute angle-closure glaucoma and elevated intraocular pressure, which may occur within hours to weeks of drug initiation. Symptoms may include acute onset of decreased visual acuity or ocular pain. Prompt discontinuation of hydrochlorothiazide is essential, and medical or surgical interventions may be necessary if intraocular pressure remains uncontrolled. Risk factors for developing this condition may include a history of sulfonamide or penicillin allergy.

Acute overdosage of spironolactone may manifest as drowsiness, mental confusion, rash, nausea, vomiting, dizziness, or diarrhea, with rare instances of hyponatremia, hyperkalemia, or hepatic coma in patients with severe liver disease.

Drug Interactions

Concomitant administration of spironolactone and hydrochlorothiazide with certain drug classes may lead to significant interactions, particularly concerning potassium levels and blood pressure management.

Pharmacokinetic Interactions

• Hyperkalemia Risk: The use of spironolactone and hydrochlorothiazide alongside ACE inhibitors, Angiotensin II receptor antagonists, aldosterone blockers, potassium supplements, heparin, and low molecular weight heparin can result in severe hyperkalemia.

• Lithium Toxicity: Diuretics, including spironolactone, may reduce the renal clearance of lithium, increasing the risk of lithium toxicity; therefore, concomitant use is generally not recommended.

• Digoxin Levels: 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 is advised, with dose adjustments as necessary.

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

Pharmacodynamic Interactions

• Orthostatic Hypotension: The risk of orthostatic hypotension may be potentiated when spironolactone and hydrochlorothiazide are used with alcohol, barbiturates, or narcotics.

• Electrolyte Depletion: Corticosteroids and ACTH may cause intensified electrolyte depletion, particularly hypokalemia, when used concurrently with these medications.

• Skeletal Muscle Relaxants: There may be an increased responsiveness to nondepolarizing skeletal muscle relaxants (e.g., tubocurarine) when used in conjunction with spironolactone and hydrochlorothiazide.

Other Considerations

• Acetylsalicylic Acid: The efficacy of spironolactone may be reduced by acetylsalicylic acid, necessitating titration to a higher maintenance dose when used together.

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

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

Drug & Laboratory Test Interactions

• Thyroid Function Tests: Thiazides should be discontinued prior to conducting tests for parathyroid function, as they may decrease serum PBI levels without altering thyroid function.

• Digoxin Assays: There are reports of possible interference with digoxin radioimmunoassays by spironolactone or its metabolites, although the clinical significance of this interference may vary by assay.

Caution is advised when managing patients on spironolactone and hydrochlorothiazide, particularly regarding the monitoring of potassium levels and the potential for drug interactions.

Pediatric Use

Safety and effectiveness of Spironolactone and Hydrochlorothiazide in pediatric patients have not been established. Therefore, the use of this medication in children and adolescents is not recommended.

Geriatric Use

Periodic determination of serum electrolytes is recommended to detect possible electrolyte imbalances in elderly patients, particularly those with significant renal or hepatic impairments. Monitoring should be conducted at appropriate intervals to ensure safety and efficacy in this population.

Pregnancy

Studies involving the 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 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 up to 20 mg/kg/day. In these studies, no teratogenic or embryo-toxic effects were observed in mice, but the 20 mg/kg dose resulted in an increased rate of resorption and a lower number of live fetuses in rabbits. 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.

Spironolactone and hydrochlorothiazide can cross the placental barrier and may appear in cord blood. Therefore, the use of these medications in pregnant patients should involve careful consideration of the anticipated benefits against potential risks to the fetus, which may include fetal or neonatal jaundice, thrombocytopenia, and other adverse reactions observed in adults.

The routine use of diuretics in otherwise healthy pregnant women is not recommended, as it exposes both the mother and fetus to unnecessary risks. Diuretics do not prevent the development of pregnancy-related conditions such as toxemia, and their efficacy in treating such conditions is not supported by satisfactory evidence. While spironolactone and hydrochlorothiazide may be indicated for edema due to pathological causes, dependent edema resulting from normal pregnancy should primarily be managed through non-pharmacological means, such as elevation of the lower extremities and the use of support hose. In rare cases where edema causes significant discomfort not relieved by rest, a short course of diuretics may be appropriate.

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 providers should carefully consider whether to continue the medication in lactating mothers, weighing the necessity of the drug against potential risks to the breastfed infant. If the use of spironolactone is deemed essential, an alternative method of infant feeding should be considered.

Hydrochlorothiazide, a thiazide diuretic, is also present in breast milk in small amounts. However, high doses of thiazides can lead to significant diuresis, which may inhibit milk production. Therefore, the concurrent use of spironolactone and hydrochlorothiazide during breastfeeding is not recommended. If these medications are used, it is advised that doses be minimized to reduce potential risks to lactating mothers and their infants.

Renal Impairment

In patients with renal impairment, thiazide diuretics, such as Spironolactone and Hydrochlorothiazide, should be used with caution, particularly in cases of severe renal disease. The use of thiazides in this population may lead to the precipitation of azotemia, a condition characterized by elevated blood urea nitrogen and creatinine levels.

Additionally, patients with impaired renal function may experience cumulative effects from the medication, necessitating careful monitoring of renal parameters. It is essential for healthcare providers to assess renal function regularly and consider dose adjustments based on the severity of the impairment to mitigate potential adverse effects.

Hepatic Impairment

Spironolactone and hydrochlorothiazide should be used with caution in patients with hepatic impairment, as minor alterations in fluid and electrolyte balance may precipitate hepatic coma. It is essential to monitor these patients closely for any signs of fluid overload or electrolyte disturbances. Adjustments to dosage may be necessary based on the patient's clinical status and laboratory values. Regular assessment of liver function tests and electrolytes is recommended to ensure safe and effective use of the medication in this population.

Overdosage

Acute overdosage of spironolactone and hydrochlorothiazide may present with various symptoms, including drowsiness, mental confusion, maculopapular or erythematous rash, nausea, vomiting, dizziness, and diarrhea. In rare cases, patients may experience hyponatremia or hyperkalemia, particularly in those with renal impairment, as the potassium-sparing effects of spironolactone may predominate. Additionally, instances of hepatic coma may occur in patients with severe liver disease, although these are unlikely to result directly from acute overdosage.

The combined use of spironolactone and hydrochlorothiazide can intensify toxic effects, leading to electrolyte imbalances such as hypokalemia and/or hyponatremia. It is important to monitor blood urea nitrogen (BUN) levels, as transient increases have been reported with hydrochlorothiazide. Central nervous system (CNS) depression, which may manifest as lethargy or even coma, can also occur in overdose situations.

Management of overdose includes supportive treatment to maintain hydration, electrolyte balance, and vital functions. Inducing vomiting or performing gastric lavage may be necessary, as there is no specific antidote available. In cases of severe hyperkalemia, intravenous administration of calcium chloride solution, sodium bicarbonate solution, and/or glucose with rapid-acting insulin may be required. Persistent hyperkalemia may necessitate dialysis, particularly in patients with renal impairment. Immediate discontinuation of spironolactone and hydrochlorothiazide is advised in such cases.

Nonclinical Toxicology

Teratogenic Effects

Studies involving the oral administration of hydrochlorothiazide to pregnant mice and rats during their respective periods of major organogenesis, at doses up to 3000 mg/kg and 1000 mg/kg, respectively, demonstrated 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. While no teratogenic or embryo-toxic effects were observed in mice, the 20 mg/kg dose resulted in an increased rate of resorption and a lower number of live fetuses in rabbits. Due to its antiandrogenic activity and the necessity of testosterone for male morphogenesis, spironolactone may adversely affect male sex differentiation during embryogenesis. In rats administered 200 mg/kg/day of spironolactone between gestation days 13 and 21, feminization of male fetuses was noted. Offspring exposed to doses of 50 and 100 mg/kg/day during late pregnancy exhibited reproductive tract changes, including dose-dependent decreases in weights of the ventral prostate and seminal vesicle in males, and enlarged ovaries and uteri in females, along with other indications of endocrine dysfunction persisting into adulthood. The use of spironolactone and hydrochlorothiazide in pregnant women necessitates careful consideration of the anticipated benefits against potential fetal hazards.

Non-Teratogenic Effects

Both spironolactone and its metabolites, as well as hydrochlorothiazide, can cross the placental barrier and appear in cord blood. Consequently, the use of these medications in pregnant women requires weighing the anticipated benefits against potential fetal hazards, which may include fetal or neonatal jaundice, thrombocytopenia, and other adverse reactions observed in adults.

Nonclinical Toxicology

Orally administered spironolactone has been identified as a tumorigen in dietary administration studies conducted in Sprague Dawley rats, with proliferative effects observed in endocrine organs and the liver. In an 18-month study, doses of approximately 50, 150, and 500 mg/kg/day resulted in statistically significant increases in benign adenomas of the thyroid and testes, as well as a dose-related increase in liver proliferative changes, including hepatocytomegaly and hyperplastic nodules. In 24-month studies, doses of about 10, 30, 100, and 150 mg spironolactone/kg/day led to significant increases in hepatocellular adenomas and testicular interstitial cell tumors in males, along with significant increases in thyroid follicular cell adenomas and carcinomas in both sexes. Additionally, a statistically significant increase in benign uterine endometrial stromal polyps was observed in females.

A dose-related incidence of myelocytic leukemia was noted in rats receiving daily doses of potassium canrenoate (a compound chemically similar to spironolactone) above 30 mg/kg/day for one year. In two-year studies, oral administration of 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 tests using bacteria or yeast. In the absence of metabolic activation, neither compound was shown to be mutagenic in mammalian tests in vitro. In the presence of metabolic activation, spironolactone yielded negative results in some mammalian mutagenicity tests and inconclusive (but slightly positive) results in others. Potassium canrenoate showed positive mutagenicity in some mammalian tests in vitro, while results were inconclusive in others and negative in still others.

In a three-litter reproduction study involving female rats receiving dietary doses of 15 and 50 mg spironolactone/kg/day, no effects on mating and fertility were observed, although a small increase in stillborn pups was noted at 50 mg/kg/day. When administered intraperitoneally at 100 mg/kg/day for seven days, spironolactone prolonged the estrous cycle by extending diestrus during treatment and inducing constant diestrus during a two-week post-treatment observation period. These effects were linked to retarded ovarian follicle development and reduced circulating estrogen levels, which could impair mating, fertility, and fecundity. In female mice administered 100 mg/kg/day of spironolactone during a two-week cohabitation period with untreated males, a decrease in the number of mated mice that conceived was observed, attributed to inhibition of ovulation, along with a reduction in implanted embryos in those that became pregnant, and an increased latency period to mating at 200 mg/kg.

Animal Pharmacology and Toxicology

Two-year feeding studies conducted under the auspices of the National Toxicology Program (NTP) found no evidence of carcinogenic potential for hydrochlorothiazide in female mice (at doses up to approximately 600 mg/kg/day) or in male and female rats (at doses up to approximately 100 mg/kg/day). However, equivocal evidence for hepatocarcinogenicity was noted in male mice.

Hydrochlorothiazide was not genotoxic in in vitro assays using various strains of Salmonella typhimurium and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, nor in in vivo assays involving mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive results were obtained only in the in vitro CHO Sister Chromatid Exchange and Mouse Lymphoma Cell assays at specific concentrations, and in the Aspergillus nidulans non-disjunction assay at an unspecified concentration.

Hydrochlorothiazide did not adversely affect the fertility of mice and rats of either sex in studies where these species were exposed to doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to mating and throughout gestation.

Storage and Handling

Spironolactone and Hydrochlorothiazide is supplied in tablet form, including film-coated options.

The product should be stored at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines. It is essential to protect the tablets from light.

Dispensing must occur in a tight, light-resistant container that complies with USP standards, utilizing a child-resistant closure to ensure safety.