Hydrochlorothiazide

Uses and Indications

Hydrochlorothiazide tablets are indicated as adjunctive therapy in the management of edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid or estrogen therapy. Additionally, this medication is beneficial in treating edema resulting from various forms of renal dysfunction, including nephrotic syndrome, acute glomerulonephritis, and chronic renal failure.

In the management of hypertension, hydrochlorothiazide may be utilized either as a sole therapeutic agent or to enhance the effectiveness of other antihypertensive medications in patients with more severe forms of hypertension.

There are no teratogenic or nonteratogenic effects reported in the available data.

Dosage and Administration

The usual adult dosage for the management of edema is 25 to 100 mg daily, which may be administered as a single dose or divided into multiple doses. Many patients with edema may benefit from intermittent therapy, which involves administration on alternate days or on three to five days each week.

For the control of hypertension in adults, the recommended initial dose is 25 mg daily, administered as a single dose. This dose may be increased to 50 mg daily, which can be given as a single dose or divided into two doses.

In pediatric patients, the usual dosage for diuresis and control of hypertension is 0.5 to 1 mg per pound (1 to 2 mg/kg) per day, administered in either a single dose or two divided doses. The maximum dosage should not exceed 37.5 mg per day for infants up to 2 years of age or 100 mg per day for children aged 2 to 12 years. For infants less than 6 months of age, doses may be increased to 1.5 mg per pound (3 mg/kg) per day, administered in two divided doses, if necessary.

Contraindications

Use of this product is contraindicated in patients with anuria due to the potential for exacerbating renal impairment. Additionally, individuals with hypersensitivity to this product or to other sulfonamide-derived drugs should not use it, as this may lead to severe allergic reactions.

Warnings and Precautions

Use of thiazide diuretics requires careful consideration in patients with severe renal disease, as these agents may precipitate azotemia and lead to cumulative effects in individuals with impaired renal function. Caution is also advised in patients with impaired hepatic function or progressive liver disease, as even minor alterations in fluid and electrolyte balance can trigger hepatic coma.

Sensitivity reactions may occur in patients regardless of their allergy or bronchial asthma history. Additionally, there have been reports of exacerbation or activation of systemic lupus erythematosus associated with thiazide use. It is important to note that lithium should generally not be co-administered with diuretics due to potential interactions.

Hydrochlorothiazide, a sulfonamide, has been linked to acute myopia and secondary angle-closure glaucoma, which can manifest as a sudden decrease in visual acuity or ocular pain within hours to weeks of initiation. If these symptoms occur, discontinuation of hydrochlorothiazide is imperative, and prompt medical or surgical intervention may be necessary if intraocular pressure remains uncontrolled. Patients with a history of sulfonamide or penicillin allergy may be at increased risk for developing this condition.

All patients receiving diuretic therapy should be monitored for signs of fluid or electrolyte imbalance, including hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte levels should be assessed, particularly in cases of excessive vomiting or when parenteral fluids are administered. Warning signs of fluid and electrolyte imbalance include dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle cramps, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

Hypokalemia may occur, especially with brisk diuresis, in patients with severe cirrhosis or after prolonged therapy. Inadequate oral electrolyte intake can exacerbate hypokalemia, which may lead to cardiac arrhythmias and increase the heart's sensitivity to digitalis toxicity. Management of hypokalemia may involve the use of potassium-sparing diuretics or potassium supplements. While chloride deficits are typically mild, they may require replacement in cases of metabolic alkalosis, particularly in patients with liver or renal disease.

Dilutional hyponatremia can occur in edematous patients during hot weather; in such cases, water restriction is recommended rather than salt administration, except in rare life-threatening situations. In cases of actual salt depletion, appropriate replacement therapy is indicated.

Thiazide therapy may lead to hyperuricemia or precipitate acute gout in susceptible individuals. Diabetic patients may require adjustments to their insulin or oral hypoglycemic agents, as thiazides can induce hyperglycemia and potentially unmask latent diabetes mellitus. The antihypertensive effects of thiazides may be enhanced in patients who have undergone sympathectomy.

If progressive renal impairment is observed, it may be necessary to withhold or discontinue diuretic therapy. Thiazides are known to increase urinary magnesium excretion, which can result in hypomagnesemia. They may also decrease urinary calcium excretion, leading to intermittent elevations in serum calcium levels. Marked hypercalcemia may indicate underlying hyperparathyroidism, and thiazides should be discontinued prior to parathyroid function testing.

Finally, thiazide diuretics have been associated with increases in cholesterol and triglyceride levels. Regular monitoring of serum electrolytes is recommended to detect potential imbalances during treatment.

Side Effects

Adverse reactions associated with the use of the medication include a range of serious and common effects, categorized by system involvement.

Serious adverse reactions may include hematologic conditions such as aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia. Renal complications can manifest as renal failure, renal dysfunction, and interstitial nephritis. Hypersensitivity reactions may occur, including anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), and respiratory distress, which encompasses pneumonitis and pulmonary edema. Additionally, there is a risk of acute myopia and secondary angle-closure glaucoma, which can lead to permanent vision loss if not treated promptly. Symptoms of this reaction may include acute onset of decreased visual acuity or ocular pain, typically occurring within hours to weeks of initiating treatment.

Common adverse reactions reported include weakness, hypotension (including orthostatic hypotension), and various digestive issues such as pancreatitis, jaundice (intrahepatic cholestatic jaundice), diarrhea, vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea, and anorexia. Neurological effects may present as vertigo, paresthesias, dizziness, headache, and restlessness. Musculoskeletal symptoms can include muscle spasms, while metabolic disturbances may involve electrolyte imbalances, hyperglycemia, glycosuria, and hyperuricemia. Skin reactions such as erythema multiforme (including Stevens-Johnson syndrome), exfoliative dermatitis (including toxic epidermal necrolysis), and alopecia have also been observed.

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

Patients with severe renal disease should use this medication with caution, as thiazides may precipitate azotemia and cumulative effects can develop in those with impaired renal function. Caution is also advised in patients with impaired hepatic function or progressive liver disease, as minor alterations in fluid and electrolyte balance may precipitate hepatic coma. Sensitivity reactions can occur in patients with or without a history of allergy or bronchial asthma, and there have been reports of exacerbation or activation of systemic lupus erythematosus.

Drug Interactions

The following drug interactions have been identified, categorized by their pharmacodynamic and pharmacokinetic effects, along with recommendations for dosage adjustments or monitoring where applicable.

Pharmacodynamic Interactions

• Alcohol, Barbiturates, or Narcotics: The concomitant use of these substances may potentiate orthostatic hypotension. Patients should be monitored for signs of hypotension and advised to use caution when standing up.

• Antidiabetic Drugs (Oral Agents and Insulin): The use of this medication may necessitate dosage adjustments of the antidiabetic agents. Regular monitoring of blood glucose levels is recommended to ensure appropriate management.

• Other Antihypertensive Drugs: There is a potential for an additive effect or potentiation when used with other antihypertensive medications. Blood pressure should be closely monitored to avoid excessive hypotension.

• Corticosteroids, ACTH: The combination may lead to intensified electrolyte depletion, particularly hypokalemia. Electrolyte levels should be monitored regularly.

• Pressor Amines (e.g., Norepinephrine): There may be a decreased response to pressor amines; however, this interaction does not preclude their use. Clinical response should be assessed.

• Skeletal Muscle Relaxants, Nondepolarizing (e.g., Tubocurarine): Increased responsiveness to nondepolarizing muscle relaxants may occur. Monitoring of neuromuscular function is advised.

• Lithium: The use of diuretics is generally contraindicated with lithium due to the potential reduction in renal clearance of lithium, which increases the risk of toxicity. Serum lithium levels should be monitored closely.

• Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): These agents may diminish the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics. Patients should be observed closely for changes in blood pressure and fluid retention.

Pharmacokinetic Interactions

• Cholestyramine and Colestipol Resins: The absorption of hydrochlorothiazide is significantly impaired when used with these resins, with cholestyramine potentially reducing absorption by up to 85% and colestipol by 43%. It is advisable to separate the administration of these agents to minimize interaction.

Drug & Laboratory Test Interactions

• Thiazides should be discontinued prior to conducting tests for parathyroid function to avoid interference with test results.

Packaging & NDC

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

Pediatric Use

There are no well-controlled clinical trials in pediatric patients. Dosing information for this age group is derived from empirical use and published literature regarding the treatment of hypertension in pediatric patients.

The usual pediatric dosage ranges from 0.5 to 1 mg per pound (1 to 2 mg/kg) per day, administered in single or two divided doses. The maximum daily dosage should not exceed 37.5 mg for infants up to 2 years of age and 100 mg for children aged 2 to 12 years.

For infants less than 6 months of age, doses may need to be increased to as much as 1.5 mg per pound (3 mg/kg) per day, given in two divided doses. Caution is advised when prescribing to this population due to the lack of extensive clinical trial data.

Geriatric Use

Elderly patients may exhibit increased sensitivity to side effects, necessitating cautious use of this medication. It is essential to monitor these patients for signs of fluid or electrolyte imbalance, particularly conditions such as hyponatremia, hypochloremic alkalosis, and hypokalemia. Given the heightened susceptibility of geriatric patients to electrolyte imbalances, serum and urine electrolyte determinations should be conducted regularly.

In cases where progressive renal impairment is observed, healthcare providers should consider withholding or discontinuing diuretic therapy to mitigate potential risks. Additionally, dosage adjustments may be required for elderly patients, particularly those with diminished kidney function, to ensure safety and efficacy in this population.

Pregnancy

Hydrochlorothiazide has been studied in pregnant mice and rats during their major organogenesis periods, with doses up to 3000 mg/kg and 1000 mg/kg, respectively, showing no evidence of fetal harm. However, there are no adequate and well-controlled studies in pregnant women. Due to the limitations of animal reproduction studies in predicting human outcomes, hydrochlorothiazide should be used during pregnancy only if clearly needed.

It is important to note that thiazides cross the placental barrier and can be detected in cord blood. This raises concerns regarding potential risks to the fetus, including fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have been observed in adults. Healthcare professionals should weigh the benefits against the risks when considering the use of hydrochlorothiazide in pregnant patients.

Lactation

Thiazides are excreted in breast milk. Due to the potential for serious adverse reactions in nursing infants, healthcare professionals should consider the risks and benefits when advising lactating mothers. A decision should be made whether to discontinue nursing or to discontinue hydrochlorothiazide, taking into account the importance of the drug to the mother.

Renal Impairment

Patients with renal impairment should use this medication with caution, particularly in cases of severe renal disease. In individuals with renal disease, thiazides may precipitate azotemia, necessitating careful monitoring of renal function. Additionally, the cumulative effects of the drug may develop in patients with impaired renal function, warranting dose adjustments and vigilant oversight to mitigate potential adverse effects.

Hepatic Impairment

Patients with hepatic impairment should use thiazides with caution. In individuals with impaired hepatic function or progressive liver disease, minor alterations in fluid and electrolyte balance may precipitate hepatic coma. Therefore, careful monitoring of liver function and electrolyte levels is recommended in this population to mitigate potential risks. Adjustments to dosage may be necessary based on the severity of hepatic impairment and the patient's clinical status.

Overdosage

In cases of overdosage, the most frequently observed signs and symptoms are primarily attributed to electrolyte depletion, including hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis. It is important to note that if digitalis has been concurrently administered, hypokalemia may exacerbate the risk of cardiac arrhythmias.

Management of overdosage should involve the implementation of symptomatic and supportive measures. Induction of emesis or performance of gastric lavage is recommended to mitigate the effects of the overdose. Additionally, it is crucial to correct dehydration and any electrolyte imbalances, as well as to address hepatic coma and hypotension using established medical procedures. In cases of respiratory impairment, the administration of oxygen or the provision of artificial respiration may be necessary.

The extent to which hydrochlorothiazide can be removed from the body through hemodialysis has not been definitively established. Furthermore, it is noteworthy that the oral LD50 of hydrochlorothiazide exceeds 10 g/kg in both mouse and rat models, indicating a significant threshold for toxicity.

Nonclinical Toxicology

Hydrochlorothiazide has been evaluated for its potential teratogenic effects, with no relevant information provided. In studies assessing non-teratogenic effects, hydrochlorothiazide demonstrated no adverse impact on the fertility of both male and female mice and rats. These studies involved dietary exposure to doses of up to 100 mg/kg for mice and 4 mg/kg for rats prior to conception and throughout gestation.

Two-year feeding studies conducted under the National Toxicology Program (NTP) revealed no evidence of carcinogenic potential 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, the NTP did find equivocal evidence for hepatocarcinogenicity in male mice.

In terms of mutagenicity, hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay using various strains of Salmonella typhimurium or in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. Additionally, it did not exhibit genotoxicity in vivo in assays involving mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive results were observed only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and Mouse Lymphoma Cell (mutagenicity) assays, where concentrations of hydrochlorothiazide ranged from 43 to 1300 mcg/mL. Furthermore, positive results were noted in the Aspergillus nidulans non-disjunction assay at an unspecified concentration.

No relevant information was provided regarding animal pharmacology and toxicology.

Postmarketing Experience

Hydrochlorothiazide has been associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC). Data derived from a study conducted within the Sentinel System indicate that this increased risk is predominantly observed in white patients who are administered large cumulative doses of the medication. Specifically, the overall population exhibits an approximate increase of 1 additional case of SCC per 16,000 patients per year. In contrast, white patients receiving a cumulative dose of ≥50,000 mg demonstrate a more pronounced risk, with an estimated increase of 1 additional SCC case for every 6,700 patients per year.

Patient Counseling

Healthcare providers should instruct patients taking hydrochlorothiazide to take precautions to protect their skin from sun exposure. This includes wearing protective clothing and using sunscreen to minimize the risk of sunburn and skin damage. Additionally, healthcare providers should emphasize the importance of undergoing regular skin cancer screenings, as patients on this medication may have an increased risk.

It is also essential for healthcare providers to discuss the need for periodic determination of serum electrolytes. Patients should be informed that monitoring these levels is crucial to detect any potential electrolyte imbalances that may arise during treatment. Providers should recommend appropriate intervals for these assessments to ensure patient safety and effective management of their condition.

Storage and Handling

The product is supplied in a well-closed container that meets the specifications outlined in the United States Pharmacopeia (USP), featuring a child-resistant closure as required. It is essential to store the product at a controlled room temperature of 20-25°C (68-77°F), in accordance with USP guidelines.

Healthcare professionals are advised to ensure that this medication, along with all other medications, is kept out of the reach of children to prevent accidental ingestion or misuse.

Additional Clinical Information

Clinicians should conduct periodic determinations of serum electrolytes in patients to detect any potential electrolyte imbalances. This monitoring should occur at appropriate intervals to ensure patient safety and effective management of treatment.

FDA Insert (PDF)

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

View full prescribing information (PDF)