Hydrochlorothiazide

Description

Hydrochlorothiazide is a diuretic and antihypertensive agent, specifically the 3,4-dihydro derivative of chlorothiazide. It is chemically designated as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Hydrochlorothiazide USP appears as a white, or practically white, crystalline powder that is slightly soluble in water and freely soluble in sodium hydroxide solution. Each tablet for oral administration contains either 25 mg or 50 mg of hydrochlorothiazide USP. The formulation includes inactive ingredients such as dibasic calcium phosphate, lactose monohydrate, pregelatinized starch, FD&C yellow No. 6 lake, corn starch, colloidal silicon dioxide, and magnesium stearate.

Uses and Indications

Hydrochlorothiazide tablets, USP are indicated as adjunctive therapy in the management of edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid or estrogen therapy. Additionally, these tablets are 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 tablets, USP 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.

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, nor is there sufficient evidence to support their efficacy in treating this condition. During normal pregnancy, hypervolemia is typically not harmful to the mother or fetus in the absence of cardiovascular disease.

In cases of edema during pregnancy, thiazides may be indicated when the edema is due to pathological causes. For dependent edema resulting from venous return restriction by the gravid uterus, non-pharmacological measures such as elevation of the lower extremities and the use of support stockings are recommended. If edema leads to significant discomfort that is not alleviated by rest, a short course of diuretic therapy may be appropriate.

Dosage and Administration

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

In adults, for the management of edema, the usual 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.

For the control of hypertension in adults, the usual initial dose is 25 mg daily, administered as a single dose. This may be increased to 50 mg daily, which can be given as a single dose or divided into two doses. Typically, doses exceeding 50 mg of hydrochlorothiazide daily are not necessary when used in conjunction with other antihypertensive agents.

In 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. 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, where even minor alterations in fluid and electrolyte balance could trigger hepatic coma. Additionally, thiazides may enhance the effects of other antihypertensive medications, necessitating close monitoring of blood pressure and overall treatment response.

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. It is important to note that lithium should generally not be co-administered with diuretics due to potential interactions.

Hydrochlorothiazide, classified as a sulfonamide, carries a risk of idiosyncratic reactions, including acute transient myopia and acute 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, immediate discontinuation of hydrochlorothiazide is essential, and prompt medical or surgical intervention may be required 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 undergoing diuretic therapy should be monitored for signs of fluid or electrolyte imbalance, including hyponatremia, hypochloremic alkalosis, and hypokalemia. Regular serum and urine electrolyte assessments are particularly critical in cases of excessive vomiting or when patients are receiving parenteral fluids. 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, 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. To mitigate hypokalemia, potassium-sparing diuretics or potassium-rich foods may be beneficial. While chloride deficits are typically mild and may not require treatment, chloride replacement may be necessary in cases of metabolic alkalosis, especially in patients with liver or renal disease.

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

Diabetic patients may require dosage adjustments of insulin or oral hypoglycemic agents, as thiazide diuretics can induce hyperglycemia and potentially unmask latent diabetes mellitus. The antihypertensive effects of thiazides may be amplified 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 lead to hypomagnesemia. They may also decrease urinary calcium excretion, resulting in intermittent and slight elevations of 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 parathyroid function tests. Additionally, thiazide therapy may be associated with increases in cholesterol and triglyceride levels.

Periodic determination of serum electrolytes is recommended to detect potential electrolyte imbalances at appropriate intervals during treatment.

Side Effects

Adverse reactions observed in patients include a range of serious and common effects across various body systems.

Serious adverse reactions encompass hematologic conditions such as aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia. Additionally, hypersensitivity reactions may occur, including anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), and respiratory distress, which can manifest as pneumonitis and pulmonary edema. Renal complications such as renal failure, renal dysfunction, and interstitial nephritis have also been reported.

Common adverse reactions 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. Patients may also experience musculoskeletal symptoms like muscle spasms, as well as nervous system and psychiatric effects, including vertigo, paresthesias, dizziness, headache, and restlessness.

Skin reactions can range from erythema multiforme, including Stevens-Johnson syndrome, to exfoliative dermatitis, including toxic epidermal necrolysis and alopecia. Patients may also report transient blurred vision and xanthopsia as special senses effects. Urogenital issues, such as impotence, have been noted as well.

Metabolic disturbances, including electrolyte imbalance, hyperglycemia, glycosuria, and hyperuricemia, are also possible.

Of particular note, hydrochlorothiazide has been associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC). In a study conducted in the Sentinel System, the increased risk was predominantly observed in white patients taking large cumulative doses. The overall risk for SCC in the population was approximately 1 additional case per 16,000 patients per year, while for white patients with a cumulative dose of ≥50,000 mg, the risk increase was approximately 1 additional SCC case for every 6,700 patients per year.

In cases where adverse reactions are moderate or severe, it is recommended that thiazide dosage be reduced or therapy withdrawn.

Drug Interactions

The following drug interactions have been identified, categorized by their pharmacodynamic and pharmacokinetic effects, along with recommendations for dosage adjustments and 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 agent. Blood glucose levels should be closely monitored to prevent hypoglycemia.

• Other Antihypertensive Drugs: There is a potential for an additive effect or potentiation of antihypertensive effects when used in conjunction with other antihypertensive medications. Blood pressure should be monitored regularly.

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

• 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 recommended.

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

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): NSAIDs may diminish the diuretic, natriuretic, and antihypertensive effects of 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 administered with these resins, with single doses potentially reducing absorption by up to 85% (cholestyramine) and 43% (colestipol). It is advisable to separate the administration of hydrochlorothiazide and these resins by several hours 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 currently 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 populations. Healthcare professionals should consider this context when prescribing and monitoring treatment in children and adolescents.

Geriatric Use

Elderly patients may require special consideration when using thiazide diuretics due to the potential for adverse effects and the need for dosage adjustments. Caution is advised in patients aged 65 and older, particularly those with severe renal disease, as thiazides may precipitate azotemia and lead to cumulative effects in individuals with impaired renal function.

In geriatric patients with impaired hepatic function or progressive liver disease, thiazides should also be used with caution. Minor alterations in fluid and electrolyte balance in these patients may precipitate hepatic coma, necessitating careful monitoring.

There is a reported possibility of exacerbation or activation of systemic lupus erythematosus in elderly patients, which should be taken into account during treatment. Additionally, hydrochlorothiazide can cause an idiosyncratic reaction leading to acute transient myopia and acute angle-closure glaucoma. Symptoms such as a sudden decrease in visual acuity or ocular pain may occur within hours to weeks of initiating therapy.

All patients receiving diuretic therapy, including elderly patients, should be closely monitored for signs of fluid or electrolyte imbalance, including hyponatremia, hypochloremic alkalosis, and hypokalemia. Hypokalemia is particularly likely to develop with brisk diuresis, in the presence of severe cirrhosis, or after prolonged therapy.

In diabetic elderly patients, dosage adjustments of insulin or oral hypoglycemic agents may be necessary, as thiazide diuretics can induce hyperglycemia. If progressive renal impairment is observed, it may be prudent to withhold or discontinue diuretic therapy. Regular monitoring of serum electrolytes is recommended to detect any potential electrolyte imbalances at appropriate intervals.

Pregnancy

Hydrochlorothiazide is classified as a Pregnancy Category B medication. 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 may not always predict human outcomes, hydrochlorothiazide should be used during pregnancy only if clearly needed.

It is important to note that thiazides can cross the placental barrier and are detectable 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 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 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 due to the potential for minor alterations in fluid and electrolyte balance, which may precipitate hepatic coma. It is important to closely monitor these patients for any signs of deterioration in liver function and to assess their fluid and electrolyte status regularly. Adjustments to dosage may be necessary based on the severity of hepatic impairment and the patient's overall clinical condition.

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, the oral LD50 of hydrochlorothiazide has been determined to be greater than 10 g/kg in both mouse and rat models, indicating a significant margin of safety in these species.

Nonclinical Toxicology

Studies evaluating the teratogenic effects of hydrochlorothiazide indicate that it is classified as Pregnancy Category B. In animal studies, 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, did not demonstrate any evidence of fetal harm. However, it is important to note that 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 necessary.

Hydrochlorothiazide is known to cross the placental barrier and can be detected in cord blood. This raises concerns regarding potential risks such as fetal or neonatal jaundice, thrombocytopenia, and other adverse reactions that may also occur in adults.

In terms of carcinogenicity, two-year feeding studies conducted by the National Toxicology Program (NTP) in mice and rats 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.

Regarding mutagenicity, hydrochlorothiazide was not found to be 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 genotoxic effects in vivo in assays involving mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, or the Drosophila sex-linked recessive lethal trait gene. Positive results were observed only in the in vitro CHO Sister Chromatid Exchange assay and the Mouse Lymphoma Cell mutagenicity assays at specific concentrations, as well as in the Aspergillus nidulans non-disjunction assay at an unspecified concentration.

Hydrochlorothiazide did not adversely affect the fertility of either male or female mice and rats in studies where 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 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 risk 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

Patients taking hydrochlorothiazide should be advised to protect their skin from sun exposure and to undergo regular skin cancer screenings due to the increased risk of non-melanoma skin cancer associated with this medication. Healthcare providers should emphasize the importance of these precautions during counseling.

All patients receiving diuretic therapy must be monitored for signs of fluid or electrolyte imbalance, which may include conditions such as hyponatremia, hypochloremic alkalosis, and hypokalemia. Healthcare providers should inform patients about the warning signs and symptoms of fluid and electrolyte imbalance, which can manifest as dryness of the mouth, increased thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances like nausea and vomiting.

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, potentially resulting in increased ventricular irritability. Patients should be made aware that hypokalemia can be prevented or treated through the use of potassium-sparing diuretics or potassium-rich foods.

Healthcare providers should recommend periodic serum electrolyte determinations to detect any potential electrolyte imbalances at appropriate intervals. Additionally, if there is evidence of progressive renal impairment, it may be necessary to consider withholding or discontinuing diuretic therapy, and this should be discussed with patients as part of their ongoing care.

Storage and Handling

The product is supplied in a well-closed container as defined by the United States Pharmacopeia (USP), and it is required to utilize a child-resistant closure where applicable.

Storage conditions for the product should be maintained at a temperature range of 20° to 25°C (68° to 77°F). Temporary excursions are permissible between 15° to 30°C (59° to 86°F) in accordance with USP Controlled Room Temperature guidelines.

Additional Clinical Information

Periodic determination of serum electrolytes is recommended for patients to detect potential electrolyte imbalances. Clinicians should perform these assessments at appropriate intervals to ensure patient safety and effective management.

FDA Insert (PDF)

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

View full prescribing information (PDF)