Hydrochlorothiazide

Description

Hydrochlorothiazide, USP is a diuretic and antihypertensive agent, chemically identified as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. It is the 3,4-dihydro derivative of chlorothiazide, with a molecular formula of C₇H₈ClN₃O₄S₂ and a molecular weight of 297.74. Hydrochlorothiazide appears as a white or practically white crystalline powder. It exhibits slight solubility in water, is freely soluble in sodium hydroxide solution, n-butylamine, and dimethylformamide, and is sparingly soluble in methanol. The compound is insoluble in ether, chloroform, and dilute mineral acids.

Each tablet intended for oral administration contains either 25 mg or 50 mg of hydrochlorothiazide, USP. The formulation also includes inactive ingredients such as corn starch, dibasic calcium phosphate dihydrate, FD&C Yellow No. 6 Aluminum Lake, lactose monohydrate, and magnesium stearate.

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. Additionally, these tablets are effective in treating edema resulting from various forms of renal dysfunction, including nephrotic syndrome, acute glomerulonephritis, and chronic renal failure. Hydrochlorothiazide is also indicated for the management of hypertension, either as a monotherapy or to enhance the efficacy of other antihypertensive agents in patients with more severe forms of hypertension.

Limitations of Use: The routine use of diuretics, including hydrochlorothiazide, during normal pregnancy is not recommended due to potential risks to both the mother and fetus. Diuretics do not prevent the development of toxemia of pregnancy, and there is insufficient evidence to support their use in treating this condition. However, thiazides may be indicated in pregnancy when edema is due to pathological causes, similar to their use in non-pregnant patients.

In cases of dependent edema during pregnancy, which may arise from venous return restriction by the gravid uterus, non-pharmacological interventions such as elevation of the lower extremities and the use of support stockings are recommended. It is important to note that hypervolemia during normal pregnancy is generally not harmful to the mother or fetus in the absence of cardiovascular disease. If edema leads to significant discomfort that is not alleviated by rest, a short course of diuretic therapy may be considered appropriate in rare instances.

Dosage and Administration

Therapy should be individualized according to patient response, utilizing the smallest dosage necessary to achieve the desired effect.

Adults:

For the management of edema, the usual adult dosage ranges from 25 mg 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 3 to 5 days each week.

In the control of hypertension, the usual initial dose for adults 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. Typically, patients do not require doses exceeding 50 mg of hydrochlorothiazide daily when used in conjunction with other antihypertensive medications.

Infants and Children:

For diuresis and the control of hypertension, the usual pediatric dosage is 0.5 mg to 1 mg per pound (1 to 2 mg/kg) per day, administered in single 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. In 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.

Renal and Hepatic Considerations Thiazides should be administered with caution in individuals with severe renal disease, as they may precipitate azotemia and lead to cumulative effects due to impaired renal function. In patients with impaired hepatic function or progressive liver disease, thiazides may cause minor alterations in fluid and electrolyte balance, potentially precipitating hepatic coma.

Drug Interactions and Sensitivity Reactions Thiazides may enhance the effects of other antihypertensive medications. Sensitivity reactions can occur in patients regardless of prior allergy or bronchial asthma history. Additionally, there is a reported risk of exacerbation or activation of systemic lupus erythematosus. It is advised that lithium not be co-administered with diuretics.

Monitoring for Electrolyte Imbalance All patients undergoing 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 imbalance include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle cramps, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

Hypokalemia and Other Electrolyte Concerns Hypokalemia may develop, especially during 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. Potassium-sparing diuretics or potassium-rich foods may be utilized to prevent or treat hypokalemia. While chloride deficits are generally mild, they may require replacement in cases of metabolic alkalosis, particularly in patients with liver or renal disease.

Hyponatremia and Hyperuricemia Dilutional hyponatremia may occur in edematous patients during hot weather, with water restriction being the preferred management strategy. In cases of actual salt depletion, appropriate salt replacement is indicated. Hyperuricemia and acute gout may also be precipitated in certain patients receiving thiazides.

Diabetes Management Diabetic patients may require dosage adjustments of insulin or oral hypoglycemic agents, as thiazide diuretics can induce hyperglycemia and potentially unmask latent diabetes mellitus.

Renal Function Monitoring If progressive renal impairment is observed, it may be necessary to withhold or discontinue diuretic therapy. Thiazides can increase urinary magnesium excretion, leading to hypomagnesemia, and may decrease urinary calcium excretion, resulting in intermittent elevations of serum calcium. Marked hypercalcemia may indicate hidden hyperparathyroidism, necessitating discontinuation of thiazides prior to parathyroid function tests.

Lipid Levels Thiazide therapy may be associated with increases in cholesterol and triglyceride levels.

Laboratory Testing Periodic serum electrolyte determinations are recommended to monitor for potential electrolyte imbalances.

Emergency Medical Attention Hydrochlorothiazide, a sulfonamide, can cause idiosyncratic reactions such as acute transient myopia and acute angle-closure glaucoma. Symptoms may include a sudden decrease in visual acuity or ocular pain, typically occurring within hours to weeks of initiating therapy. Untreated acute angle-closure glaucoma can result in permanent vision loss. Immediate discontinuation of hydrochlorothiazide is essential, and prompt medical or surgical intervention may be required if intraocular pressure remains uncontrolled.

Discontinuation of Therapy Patients should discontinue hydrochlorothiazide immediately and consult their healthcare provider if symptoms of acute angle-closure glaucoma arise.

Side Effects

Patients receiving thiazide diuretics, including hydrochlorothiazide, should be monitored for a range of adverse reactions, which can vary in seriousness and frequency.

Serious adverse reactions include the potential for acute myopia and secondary angle-closure glaucoma, which may occur as an idiosyncratic reaction to hydrochlorothiazide. Symptoms such as acute onset of decreased visual acuity or ocular pain can manifest within hours to weeks of initiating therapy. If left untreated, acute angle-closure glaucoma may lead to permanent vision loss. Additionally, caution is advised in patients with severe renal disease, as thiazides may precipitate azotemia and lead to cumulative effects in those with impaired renal function. The use of thiazides is also cautioned in patients with impaired hepatic function or progressive liver disease, as minor alterations in fluid and electrolyte balance could precipitate hepatic coma.

Sensitivity reactions may 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.

Common adverse reactions include fluid and electrolyte imbalances, such as hyponatremia, hypochloremic alkalosis, and hypokalemia. Patients should be observed for warning signs or symptoms of these imbalances, which may include 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. Hypokalemia, particularly with brisk diuresis or in the presence of severe cirrhosis, may lead to cardiac arrhythmias and can sensitize the heart to the toxic effects of digitalis, increasing ventricular irritability.

Other notable reactions include hyperuricemia, which may precipitate acute gout in certain patients, and hyperglycemia, which can unmask latent diabetes mellitus during thiazide therapy. Thiazides may also increase urinary excretion of magnesium, potentially resulting in hypomagnesemia, and decrease urinary calcium excretion, leading to intermittent elevations of serum calcium. Marked hypercalcemia may indicate hidden hyperparathyroidism. Furthermore, increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy.

Patients should be advised to protect their skin from sun exposure and undergo regular skin cancer screenings, as there is an association between thiazide use and non-melanoma skin cancer. In cases of overdose, the most common signs and symptoms are those related to electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration due to excessive diuresis. If digitalis has been administered concurrently, hypokalemia may exacerbate cardiac arrhythmias. It is also important to note that thiazides cross the placental barrier and may appear in cord blood, posing risks of fetal or neonatal jaundice, thrombocytopenia, and other adverse reactions observed in adults.

Drug Interactions

Concomitant use of thiazide diuretics with certain medications may lead to significant drug interactions, categorized primarily into pharmacodynamic and pharmacokinetic interactions.

Pharmacodynamic Interactions:

• Alcohol, Barbiturates, or Narcotics: The combination may potentiate orthostatic hypotension, necessitating careful 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: The use of additional antihypertensive agents may result in an additive effect, which could lead to hypotension. Monitoring of blood pressure is advised.

• Corticosteroids, ACTH: Concurrent use may lead to intensified electrolyte depletion, particularly hypokalemia. Regular monitoring of electrolyte levels is recommended.

• Pressor Amines (e.g., Norepinephrine): There may be a decreased response to pressor amines; however, this interaction does not preclude 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 potential for reduced renal clearance of lithium, increasing the risk of toxicity. Consultation of the package insert for lithium preparations is advised prior to co-administration.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): In some patients, NSAIDs may diminish the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics. 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 when administered with anionic exchange resins. Cholestyramine can reduce absorption by up to 85%, while colestipol can reduce it by approximately 43%. It is advisable to separate the administration of these agents to minimize interaction.

Laboratory Test Interactions:

Thiazide diuretics 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 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 extensive 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 may be required, particularly for those with renal impairment.

It is essential to monitor elderly patients for signs of fluid or electrolyte imbalance, as they may be more susceptible to these effects. Periodic determination of serum electrolytes is particularly important for geriatric patients receiving diuretic therapy.

Additionally, the antihypertensive effects of the medication may be enhanced in elderly patients, which underscores the need for careful monitoring of blood pressure and renal function. If progressive renal impairment becomes evident, consideration should be given to withholding or discontinuing diuretic therapy in this population.

Pregnancy

Hydrochlorothiazide is classified as Pregnancy Category B. Animal studies involving the oral administration of hydrochlorothiazide to pregnant mice and rats during critical periods of organogenesis, at doses up to 3000 mg/kg and 1000 mg/kg respectively, have not demonstrated any evidence of fetal harm. However, there are no adequate and well-controlled studies in pregnant women, and because animal reproduction studies are not always predictive of 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. There is a potential risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have been observed in adults. Healthcare professionals should weigh the potential 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 any dehydration and 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 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 margin of safety in these species.

Nonclinical Toxicology

Pregnancy Category B indicates that studies involving the oral administration of hydrochlorothiazide to pregnant mice and rats during their major organogenesis periods, at doses up to 3000 mg/kg and 1000 mg/kg respectively, revealed no evidence of fetal harm. However, there are no adequate and well-controlled studies in pregnant women, and since animal reproduction studies may not always predict human responses, the use of this drug during pregnancy should be considered only when clearly needed.

Thiazides are known to cross the placental barrier and can be detected in cord blood. This raises concerns regarding the potential risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have been observed in adults.

Two-year feeding studies conducted by the National Toxicology Program (NTP) in mice and rats did not demonstrate any carcinogenic potential of 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, 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 various strains of Salmonella typhimurium, 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 at concentrations ranging from 43 to 1300 mcg/mL, as well as in the Aspergillus nidulans non-disjunction assay at an unspecified concentration.

Studies indicated that hydrochlorothiazide did not adversely affect the fertility of either male or female mice and rats when these animals were exposed to doses of up to 100 mg/kg and 4 mg/kg respectively, 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 most pronounced in white patients who are administered large cumulative doses of the medication.

In the overall population, the estimated increase in risk for SCC is approximately one additional case per 16,000 patients per year. For white patients receiving a cumulative dose of 50,000 mg or more, the risk escalates to approximately one additional case of SCC for every 6,700 patients per year. These findings are based on voluntary reports and data collected through surveillance programs.

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 skin damage. Additionally, patients should be advised to undergo regular skin cancer screenings as part of their healthcare routine.

It is also important for healthcare providers to inform patients about the necessity of periodic determination of serum electrolytes. This monitoring is essential to detect any potential electrolyte imbalances that may arise during treatment. Providers should emphasize the importance of attending these follow-up appointments to ensure the patient's safety and well-being while on hydrochlorothiazide.

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° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines.

Healthcare professionals are reminded to keep this product, along with 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 occur at appropriate intervals to ensure timely identification and management of any imbalances that may arise.

FDA Insert (PDF)

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

View full prescribing information (PDF)