Hydrochlorothiazide

Description

Hydrochlorothiazide is a diuretic and antihypertensive agent, specifically the 3,4-dihydro derivative of chlorothiazide. Its chemical name is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide1,1-dioxide, with its structural formula illustrated in an accompanying image. The compound appears as a white or practically white crystalline powder, exhibiting slight solubility in water and free solubility in sodium hydroxide solution.

Each tablet intended for oral administration contains either 25 mg or 50 mg of hydrochlorothiazide. The formulation also includes several inactive ingredients: anhydrous lactose, pregelatinized starch from corn, magnesium stearate, microcrystalline cellulose, and FD&C Yellow #6.

Uses and Indications

Hydrochlorothiazide tablets are indicated as adjunctive therapy in the management of edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. This medication has also demonstrated efficacy in treating edema resulting from various forms of renal dysfunction, including nephrotic syndrome, acute glomerulonephritis, and chronic renal failure.

In addition, hydrochlorothiazide is indicated for the management of hypertension. It may be utilized as a sole therapeutic agent or in combination with other antihypertensive medications to enhance their effectiveness in patients with more severe forms of hypertension.

There are no teratogenic or nonteratogenic effects associated with hydrochlorothiazide.

Dosage and Administration

The usual adult dosage for 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 three to five days each week.

For the control of hypertension in adults, the initial recommended dose is 25 mg daily, given as a single dose. This dose may be increased to 50 mg daily, which can be administered as a single dose or divided into two doses. It is important to note that doses exceeding 50 mg are often associated with significant reductions in serum potassium levels.

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 specific health conditions and necessitates regular monitoring to ensure patient safety.

Warnings

Thiazides should be administered with caution in individuals with severe renal disease, as they may precipitate azotemia and lead to cumulative effects in those with impaired renal function. In patients with hepatic impairment or progressive liver disease, thiazides may cause minor alterations in fluid and electrolyte balance, potentially precipitating hepatic coma. Sensitivity reactions can occur in patients regardless of prior allergy or bronchial asthma history. There have been reports of exacerbation or activation of systemic lupus erythematosus associated with thiazide use.

Lithium should generally not be co-administered with diuretics due to the risk of increased lithium levels. Hydrochlorothiazide, a sulfonamide, may cause an idiosyncratic reaction leading to acute transient myopia and secondary angle-closure glaucoma. Symptoms such as a sudden decrease in visual acuity or ocular pain may manifest within hours to weeks of initiating therapy. If acute angle-closure glaucoma occurs, it is critical to discontinue hydrochlorothiazide immediately, 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 this condition.

General Precautions

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 develop, particularly with brisk diuresis, severe cirrhosis, or prolonged therapy. Inadequate oral electrolyte intake can exacerbate hypokalemia, which may lead to cardiac arrhythmias and increased sensitivity to digitalis toxicity. Potassium-sparing diuretics or potassium-rich foods may be used to prevent or treat hypokalemia. While chloride deficits are typically mild, they may require treatment in cases of liver or renal disease.

Dilutional hyponatremia can occur in edematous patients during hot weather; water restriction is the preferred management strategy, except in rare cases of life-threatening hyponatremia. In cases of actual salt depletion, appropriate salt replacement is indicated. Hyperuricemia or acute gout may be precipitated in some patients receiving thiazides.

Diabetic patients may require adjustments in insulin or oral hypoglycemic agents, as thiazide diuretics can induce hyperglycemia and 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 can increase urinary magnesium excretion, potentially leading to hypomagnesemia, and may decrease urinary calcium excretion, resulting in intermittent elevations of serum calcium. Marked hypercalcemia may indicate hidden hyperparathyroidism, and thiazides should be discontinued prior to parathyroid function testing. Additionally, thiazide therapy may be associated with increases in cholesterol and triglyceride levels.

Laboratory Tests

Periodic monitoring of serum electrolytes is essential to detect potential electrolyte imbalances at appropriate intervals during thiazide therapy.

Side Effects

Adverse reactions associated with the use of hydrochlorothiazide have been observed in clinical trials and postmarketing experiences.

Serious adverse reactions include hypersensitivity reactions such as anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), and respiratory distress, which may manifest as pneumonitis and pulmonary edema. Additionally, renal complications such as renal failure, renal dysfunction, and interstitial nephritis have been reported. Hematologic reactions include aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia. Patients may also experience severe skin reactions, including erythema multiforme (including Stevens-Johnson syndrome) and exfoliative dermatitis (including toxic epidermal necrolysis).

Common adverse reactions reported include weakness, hypotension (including orthostatic hypotension), and various digestive issues such as diarrhea, vomiting, nausea, and abdominal cramping. Other gastrointestinal effects may include sialadenitis, constipation, gastric irritation, and anorexia. Neurological effects such as vertigo, paresthesias, dizziness, headache, and restlessness have also been noted. Musculoskeletal symptoms may present as muscle spasms, while metabolic disturbances can include electrolyte imbalance, hyperglycemia, glycosuria, and hyperuricemia.

Patients may experience transient blurred vision and xanthopsia as part of the special senses adverse reactions. Urogenital effects such as impotence have also been reported.

In postmarketing 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 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.

Warnings indicate that hydrochlorothiazide should be used with caution in patients with severe renal disease, as it may precipitate azotemia and cumulative effects in those with impaired renal function. Caution is also advised in patients with impaired hepatic function or progressive liver disease due to the potential for minor alterations in fluid and electrolyte balance to precipitate hepatic coma. Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma, and there is a reported possibility of exacerbation or activation of systemic lupus erythematosus.

Additionally, hydrochlorothiazide can cause acute myopia and secondary angle-closure glaucoma, which are idiosyncratic reactions. Symptoms may include an acute onset of decreased visual acuity or ocular pain, typically occurring within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss, and the primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical intervention may be necessary if intraocular pressure remains uncontrolled, particularly in patients with a history of sulfonamide or penicillin allergy.

Drug Interactions

The concomitant use of hydrochlorothiazide with certain drug classes may lead to significant interactions that require careful consideration.

Pharmacodynamic Interactions:

• Alcohol, Barbiturates, or Narcotics: The combination may potentiate orthostatic hypotension, necessitating monitoring of blood pressure and patient symptoms.

• Antidiabetic Drugs (oral agents and insulin): Dosage adjustments of the antidiabetic medication may be required to maintain glycemic control.

• Other Antihypertensive Drugs: There is a potential for additive effects or potentiation of antihypertensive effects, which may necessitate monitoring of blood pressure.

• Corticosteroids, ACTH: The use of these agents may lead to intensified electrolyte depletion, particularly hypokalemia, requiring electrolyte monitoring.

• Pressor Amines (e.g., Norepinephrine): There may be a decreased response to pressor amines; however, this interaction is not sufficient to contraindicate their use.

• Skeletal Muscle Relaxants, Nondepolarizing (e.g., Tubocurarine): Increased responsiveness to muscle relaxants may occur, warranting careful monitoring of neuromuscular function.

• Lithium: The use of diuretics with lithium is generally contraindicated due to the risk of reduced renal clearance of lithium, which can lead to toxicity. Consultation of the package insert for lithium preparations is advised prior to co-administration.

• Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): The administration of NSAIDs may reduce the diuretic, natriuretic, and antihypertensive effects of hydrochlorothiazide. Close observation is recommended to ensure the desired diuretic effect is achieved.

Pharmacokinetic Interactions:

• Cholestyramine and Colestipol Resins: The absorption of hydrochlorothiazide is significantly impaired in the presence of these anionic exchange resins, with reductions in gastrointestinal absorption of up to 85% and 43%, respectively. It is advisable to separate the administration of hydrochlorothiazide and these resins to minimize interaction.

Drug & Laboratory Test Interactions:

• Thiazides: It is recommended that thiazide diuretics 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 conducted in pediatric patients. Dosing information for this age group is derived from empirical use and published literature concerning the treatment of hypertension in pediatric patients. Healthcare professionals should refer to the Dosage and Administration section for specific guidance on dosing in infants and children. Caution is advised when prescribing to this population due to the lack of robust clinical trial data.

Geriatric Use

Elderly patients may exhibit reduced kidney function and increased sensitivity to side effects, necessitating caution when prescribing this medication. Dosage adjustments should be considered for geriatric patients, particularly those with impaired renal function, to ensure safety and efficacy.

It is essential to monitor elderly patients for signs of electrolyte imbalance, as these may be more pronounced in this population. Periodic determination of serum electrolytes is particularly important to detect any potential imbalances that could arise during treatment.

Additionally, there is an increased risk of hypotension in elderly patients, especially when this medication is used concurrently with other antihypertensive agents or substances that may induce orthostatic hypotension, such as alcohol, barbiturates, or narcotics. In cases where progressive renal impairment becomes evident, it may be necessary to withhold or discontinue diuretic therapy to prevent further complications.

Pregnancy

Hydrochlorothiazide is classified as Pregnancy Category B. Animal studies involving the oral administration of hydrochlorothiazide to pregnant mice and rats during major organogenesis at doses up to 3000 mg/kg and 1000 mg/kg, respectively, have shown no evidence of harm to the fetus. However, there are no adequate and well-controlled studies in pregnant women. Due to the limitations of animal reproduction studies in predicting human response, 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 fetal or neonatal complications, including the risk of jaundice, thrombocytopenia, and possibly other adverse reactions that have been observed in adults. Healthcare professionals should carefully weigh the benefits and 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 whether to discontinue breastfeeding or to discontinue hydrochlorothiazide, weighing the importance of the medication to the lactating 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 overall 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 artificial respiration may be necessary.

The extent to which hydrochlorothiazide can be removed from the body through hemodialysis has not been definitively established. For reference, the oral LD50 of hydrochlorothiazide is greater than 10 g/kg in both mouse and rat models, indicating a relatively high threshold for acute toxicity in these species.

Nonclinical Toxicology

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

Hydrochlorothiazide was not found to be genotoxic in vitro in the Ames mutagenicity assay using Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538, nor in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. In vivo assays involving mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene also showed no genotoxic effects. Positive results were observed only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and Mouse Lymphoma Cell (mutagenicity) assays, which utilized hydrochlorothiazide concentrations ranging from 43 to 1300 mg/ml, as well as in the Aspergillus nidulans non-disjunction assay at an unspecified concentration.

In studies assessing fertility, hydrochlorothiazide demonstrated no adverse effects on the reproductive capabilities of mice and rats of either sex. These studies involved dietary exposure to doses of up to 100 mg/kg for mice and 4 mg/kg for rats, administered prior to conception 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 indicate that this increased risk is more pronounced in white patients receiving large cumulative doses of the medication. Specifically, the overall population exhibits an approximate risk of 1 additional case of SCC per 16,000 patients per year. For white patients who have taken a cumulative dose of ≥50,000 mg, the risk escalates to approximately 1 additional case of SCC for every 6,700 patients per year.

In instances where adverse reactions are classified as moderate or severe, it is recommended that the dosage of thiazides be reduced or that therapy be discontinued.

Patient Counseling

Patients taking hydrochlorothiazide should be advised to protect their skin from sun exposure and to undergo regular skin cancer screenings, as there is an increased risk of non-melanoma skin cancer associated with this medication. Healthcare providers should emphasize the importance of monitoring for signs of fluid or electrolyte imbalance in all patients receiving diuretic therapy. This includes being vigilant for symptoms such as dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances like nausea and vomiting.

Patients should be informed that hypokalemia may develop, particularly with brisk diuresis, in cases of severe cirrhosis, or after prolonged therapy. It is crucial to communicate that hypokalemia can lead to cardiac arrhythmias and may heighten the heart's sensitivity to the toxic effects of digitalis, resulting in increased ventricular irritability. To prevent or manage hypokalemia, healthcare providers may recommend the use of potassium-sparing diuretics or potassium-rich foods.

In cases of edematous patients experiencing dilutional hyponatremia, especially in hot weather, water restriction is the preferred management strategy, rather than salt administration, unless the hyponatremia is life-threatening. For patients with actual salt depletion, appropriate salt replacement therapy should be initiated. Additionally, healthcare providers should inform patients that hyperuricemia or acute gout may occur in some individuals receiving thiazides.

For diabetic patients, it may be necessary to adjust the dosage of insulin or oral hypoglycemic agents, as thiazide diuretics can lead to hyperglycemia. The antihypertensive effects of hydrochlorothiazide may be enhanced in patients who have undergone sympathectomy. If there are signs of progressive renal impairment, healthcare providers should consider withholding or discontinuing diuretic therapy.

Thiazides can increase urinary excretion of magnesium, potentially leading to hypomagnesemia, and may decrease urinary calcium excretion, which can cause slight elevations in serum calcium levels in the absence of known calcium metabolism disorders. Marked hypercalcemia may indicate hidden hyperparathyroidism, and thiazides should be discontinued prior to conducting tests for parathyroid function. Regular monitoring of serum electrolytes is recommended to detect any possible electrolyte imbalances at appropriate intervals.

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 temperature range of 20-25°C (68-77°F), in accordance with USP Controlled Room Temperature guidelines.

Healthcare professionals are reminded to keep this and all medications out of the reach of children to ensure safety.

Additional Clinical Information

Clinicians should conduct periodic determinations of serum electrolytes in patients to monitor for potential electrolyte imbalances. This assessment should be performed at appropriate intervals to ensure patient safety and effective management.

FDA Insert (PDF)

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

View full prescribing information (PDF)