Hydrochlorothiazide

Description

Hydrochlorothiazide USP 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, with the molecular formula C₇H₈ClN₃O₄S₂ and a molecular weight of 297.74. Hydrochlorothiazide USP 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 USP. The formulation also includes inactive ingredients such as corn starch, FD&C yellow #6, dibasic calcium phosphate, lactose monohydrate, and magnesium stearate.

Uses and Indications

Hydrochlorothiazide USP is indicated as adjunctive therapy in the management of edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. It is also effective in treating edema resulting from various forms of renal dysfunction, including nephrotic syndrome, acute glomerulonephritis, and chronic renal failure. Additionally, Hydrochlorothiazide USP is 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 USP, 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 use in treating this condition.

In cases where edema during pregnancy is due to pathological causes, thiazides may be indicated, similar to their use in non-pregnant patients. However, dependent edema resulting from the mechanical effects of pregnancy should be managed through non-pharmacological measures such as elevation of the lower extremities and the use of support stockings. During normal pregnancy, hypervolemia is typically not harmful to the mother or fetus in the absence of cardiovascular disease. If edema causes significant discomfort, increased recumbency may provide relief. In rare instances where discomfort is extreme and unrelieved by rest, a short course of diuretic therapy may be appropriate.

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 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. Furthermore, lithium should generally be avoided in conjunction with diuretics due to potential interactions.

All patients undergoing diuretic therapy must be monitored for signs of fluid or electrolyte imbalance, including hyponatremia, hypochloremic alkalosis, and hypokalemia. Regular serum and urine electrolyte determinations are crucial, particularly in cases of excessive vomiting or when patients are receiving parenteral fluids. Clinicians should be vigilant for warning signs of fluid and electrolyte imbalance, which may manifest as 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 is a particular concern, especially during brisk diuresis, in patients with severe cirrhosis, or after prolonged therapy.

Interference with adequate 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 recommended. While chloride deficits are typically mild and may not require treatment, chloride replacement may be necessary in cases of metabolic alkalosis. In edematous patients, dilutional hyponatremia may occur, particularly in hot weather; water restriction is the preferred management strategy, except in rare cases of life-threatening hyponatremia. In instances of actual salt depletion, appropriate replacement therapy is indicated. Hyperuricemia and acute gout may also 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. Additionally, these agents may 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 parathyroid function testing.

Clinicians should be aware that thiazide diuretic therapy may be associated with increases in cholesterol and triglyceride levels. Regular monitoring of serum electrolytes is recommended to detect potential imbalances, with determinations performed at appropriate intervals to ensure patient safety and therapeutic efficacy.

Side Effects

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

Serious adverse reactions may include hematologic conditions such as aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia. Renal complications such as renal failure, renal dysfunction, and interstitial nephritis have also been reported, necessitating caution in patients with severe renal disease, as thiazides may precipitate azotemia in this population. Additionally, hypersensitivity reactions can occur, including anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), and respiratory distress, which may manifest as pneumonitis and pulmonary edema. The exacerbation or activation of systemic lupus erythematosus has been noted in some patients.

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 and nervous system/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. Special senses may be affected, with reports of transient blurred vision and xanthopsia. Urogenital effects such as impotence have also been documented.

Electrolyte imbalances, hyperglycemia, glycosuria, and hyperuricemia are metabolic concerns that should be monitored. It is important to note that sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma. Caution is advised when using this treatment in patients with impaired hepatic function or progressive liver disease, as minor alterations in fluid and electrolyte balance may precipitate hepatic coma.

In clinical trials and postmarketing experiences, the cumulative effects of the drug have been observed in patients with impaired renal function, highlighting the need for careful monitoring and management of these patients.

Drug Interactions

Concomitant use of thiazide diuretics with certain medications may lead to significant 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: There is a potential for additive effects or potentiation of antihypertensive effects, which may require monitoring of blood pressure and possible dosage adjustments.

• Corticosteroids and ACTH: Concurrent use may lead to intensified electrolyte depletion, particularly hypokalemia, warranting regular monitoring of electrolyte levels.

• 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, necessitating careful monitoring of neuromuscular function.

Pharmacokinetic Interactions:

• Cholestyramine and Colestipol Resins: These anionic exchange resins can significantly impair the absorption of hydrochlorothiazide, reducing its gastrointestinal absorption by up to 85% and 43%, respectively. It is advisable to separate the administration of these agents from thiazide diuretics.

• 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 recommended prior to concurrent use.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): In some patients, NSAIDs may diminish the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics. Close observation is advised to ensure the desired diuretic effect is achieved when these agents are used together.

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 robust clinical trial data.

Geriatric Use

Elderly patients may require special consideration when using thiazide diuretics, particularly those aged 65 and older. Caution is advised in patients with severe renal disease, as thiazides can precipitate azotemia and lead to cumulative effects due to impaired renal function. In such cases, careful monitoring of renal status is essential, and if progressive renal impairment is observed, it may be necessary to withhold or discontinue diuretic therapy.

Thiazides should also be used cautiously in geriatric patients with impaired hepatic function or progressive liver disease. Minor alterations in fluid and electrolyte balance in these patients can precipitate hepatic coma, necessitating vigilant observation.

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

In diabetic elderly patients, dosage adjustments of insulin or oral hypoglycemic agents may be required to maintain glycemic control. Additionally, periodic determination of serum electrolytes is recommended to detect potential electrolyte imbalances at appropriate intervals.

It is important to note that the antihypertensive effects of thiazides may be enhanced in patients who have undergone sympathectomy, which may necessitate further monitoring and possible dose adjustments.

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 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 be treated with caution, particularly those with severe renal disease. In this population, 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, highlighting the importance of dose adjustments and vigilant oversight in this group.

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 for healthcare providers to closely monitor these patients for any signs of deterioration in liver function and to assess 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

Overdosage may present with a range of symptoms primarily associated with electrolyte depletion and dehydration due to excessive diuresis. The most frequently observed signs include hypokalemia, hypochloremia, and hyponatremia. In cases where digitalis has been co-administered, hypokalemia can exacerbate the risk of cardiac arrhythmias, necessitating careful monitoring of cardiac function.

In the event of an overdosage, it is imperative to implement symptomatic and supportive measures promptly. Induction of emesis or performing gastric lavage is recommended to mitigate the effects of the overdose. Additionally, it is crucial to address dehydration and correct any electrolyte imbalances, hepatic coma, and hypotension using established medical procedures. In instances of respiratory impairment, the administration of oxygen or artificial respiration may be required to ensure adequate oxygenation.

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. However, the efficacy of hemodialysis in removing hydrochlorothiazide from the system has not been established, and further research may be necessary to clarify this aspect of management.

Nonclinical Toxicology

Studies evaluating the teratogenic effects of hydrochlorothiazide involved oral administration to pregnant mice and rats during critical periods of organogenesis, with doses reaching up to 3000 mg/kg in mice and 1000 mg/kg in rats. These studies 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. Given that animal reproduction studies may not reliably predict human outcomes, 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 to the fetus, including fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have been observed 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 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, the NTP did find equivocal evidence of hepatocarcinogenicity in male mice.

Hydrochlorothiazide was assessed for genotoxicity and was found to be non-genotoxic in vitro in the Ames mutagenicity assay using various strains of Salmonella typhimurium and 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, 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 at concentrations ranging from 43 to 1300 mcg/mL, as well as in the Aspergillus nidulans non-disjunction assay at an unspecified concentration.

Regarding fertility, hydrochlorothiazide did not adversely affect the reproductive capabilities of mice and rats of either sex in studies where these animals were exposed to dietary doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to conception and throughout gestation.

Postmarketing Experience

The following adverse reactions have been reported voluntarily or through surveillance programs, categorized by system and listed in order of decreasing severity:

Body as a Whole: Reports of weakness have been noted.

Cardiovascular: Instances of hypotension, including orthostatic hypotension, have been documented. These may be exacerbated by the concurrent use of alcohol, barbiturates, narcotics, or antihypertensive medications.

Digestive: Adverse events such as pancreatitis, jaundice (specifically intrahepatic cholestatic jaundice), diarrhea, vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea, and anorexia have been observed.

Hematologic: Cases of aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia have been reported.

Hypersensitivity: Anaphylactic reactions, necrotizing angiitis (including vasculitis and cutaneous vasculitis), respiratory distress (encompassing pneumonitis and pulmonary edema), photosensitivity, fever, urticaria, rash, and purpura have been documented.

Metabolic: Reports of electrolyte imbalances, hyperglycemia, glycosuria, and hyperuricemia have been noted.

Musculoskeletal: Muscle spasms have been reported.

Nervous System/Psychiatric: Adverse reactions including vertigo, paresthesias, dizziness, headache, and restlessness have been observed.

Renal: Instances of renal failure, renal dysfunction, and interstitial nephritis have been documented.

Skin: Reports of erythema multiforme (including Stevens-Johnson syndrome), exfoliative dermatitis (including toxic epidermal necrolysis), and alopecia have been noted.

Special Senses: Transient blurred vision and xanthopsia have been reported.

Urogenital: Cases of impotence have been documented.

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

Patient Counseling

Patients should be closely monitored for signs of fluid or electrolyte imbalance, including conditions such as hyponatremia, hypochloremic alkalosis, and hypokalemia. Healthcare providers are advised to conduct serum and urine electrolyte determinations, particularly in patients experiencing excessive vomiting or those receiving parenteral fluids.

Patients should be informed about warning signs and symptoms indicative of fluid and electrolyte imbalance. These may include dryness of the mouth, increased thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

Hypokalemia is a potential risk, especially in cases of brisk diuresis, severe cirrhosis, or prolonged therapy. It is important to communicate that hypokalemia can lead to cardiac arrhythmias and may heighten the heart's sensitivity to the toxic effects of digitalis. To prevent or manage hypokalemia, healthcare providers may recommend potassium-sparing diuretics or dietary potassium supplements.

In cases of metabolic alkalosis, chloride replacement may be necessary. Patients should be made aware that dilutional hyponatremia can occur in edematous individuals during hot weather, and that the appropriate management is water restriction rather than salt administration, except in rare, life-threatening situations. Conversely, in cases of actual salt depletion, appropriate replacement therapy is essential.

Healthcare providers should also discuss the potential for hyperuricemia or acute gout in patients receiving thiazide diuretics. For diabetic patients, dosage adjustments of insulin or oral hypoglycemic agents may be required, as thiazide diuretics can lead to hyperglycemia and potentially unmask latent diabetes mellitus.

If progressive renal impairment is observed, it may be necessary to consider withholding or discontinuing diuretic therapy. Thiazides are known to increase urinary excretion of magnesium, which can result in hypomagnesemia, while they may also decrease urinary calcium excretion, potentially causing intermittent slight elevations in serum calcium levels in the absence of known calcium metabolism disorders. Marked hypercalcemia may indicate hidden hyperparathyroidism, necessitating the discontinuation of thiazides prior to parathyroid function tests.

Patients should be informed that thiazide diuretic therapy may be associated with increases in cholesterol and triglyceride levels. Regular monitoring of serum electrolytes is recommended to detect any possible imbalances, and patients should be observed closely when hydrochlorothiazide is used in conjunction with non-steroidal anti-inflammatory agents to ensure the desired diuretic effect is achieved.

Storage and Handling

The product is supplied in a well-closed container that meets the specifications outlined in the United States Pharmacopeia (USP), including a child-resistant closure as required. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines. Proper handling and storage conditions are essential to maintain the integrity of the product.

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 Contract Pharmacy Services-PA. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)