Hydrochlorothiazide

Description

Hydrochlorothiazide is a diuretic and antihypertensive agent, classified as 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. The structural formula of hydrochlorothiazide is provided in the accompanying documentation.

This compound appears as a white or practically white crystalline powder. It exhibits slight solubility in water, but is freely soluble in sodium hydroxide solution, n-butylamine, and dimethylformamide. Hydrochlorothiazide is sparingly soluble in methanol and is insoluble in ether, chloroform, and dilute mineral acids.

For oral administration, each tablet contains either 25 mg or 50 mg of hydrochlorothiazide. The formulation also includes inactive ingredients such as FD&C yellow #6, microcrystalline cellulose, lactose, sodium starch glycolate, stearic acid, 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 Tablets are 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, as it poses unnecessary 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 during pregnancy when edema is due to pathological causes, similar to their use in non-pregnant individuals.

In cases of dependent edema during pregnancy, which arises from venous return restriction by the gravid uterus, non-pharmacological measures such as elevating the lower extremities and using 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.

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 on 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. Typically, doses exceeding 50 mg of hydrochlorothiazide daily are not necessary when used in conjunction with other antihypertensive medications.

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 ongoing monitoring for potential adverse effects.

Warnings

Thiazides should be administered with caution in individuals with severe renal disease, as they may precipitate azotemia and lead to cumulative effects in patients with impaired renal function. In patients with compromised hepatic function or progressive liver disease, thiazides may cause minor alterations in fluid and electrolyte balance, potentially precipitating hepatic coma. Additionally, thiazides can enhance the effects of other antihypertensive medications, necessitating careful management of combined therapies.

Sensitivity reactions may occur in patients regardless of prior allergy or bronchial asthma history. There is also a reported risk of exacerbation or activation of systemic lupus erythematosus. It is advised that lithium not be co-administered with diuretics due to potential interactions.

General Precautions

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 assessments are crucial, 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 is a significant concern, especially during brisk diuresis, in patients with severe cirrhosis, or after prolonged therapy. Inadequate oral electrolyte intake can exacerbate this condition, which may lead to cardiac arrhythmias and increased sensitivity to digitalis toxicity. To mitigate hypokalemia, potassium-sparing diuretics or potassium-rich foods may be utilized. While chloride deficits are typically mild, they may require replacement therapy in cases of metabolic alkalosis, particularly in patients with liver or renal disease.

Dilutional hyponatremia may occur in edematous patients during hot weather; management should focus on water restriction rather than salt administration, except in life-threatening situations. Hyperuricemia and acute gout may also be precipitated in certain patients receiving thiazides. In diabetic patients, adjustments to insulin or oral hypoglycemic agents may be necessary, as thiazides can induce hyperglycemia and 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 prudent to withhold or discontinue diuretic therapy. Thiazides can increase urinary magnesium excretion, potentially leading to hypomagnesemia, and may decrease urinary calcium excretion, causing intermittent elevations in serum calcium levels. Marked hypercalcemia could indicate hidden hyperparathyroidism, warranting discontinuation of thiazides 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, and these assessments should be conducted at appropriate intervals throughout the course of therapy.

Emergency Medical Help Instructions

Hydrochlorothiazide, a sulfonamide, may induce an idiosyncratic reaction leading to acute transient myopia and acute angle-closure glaucoma. Symptoms, including a sudden decrease in visual acuity or ocular pain, can manifest within hours to weeks of initiating treatment. If left untreated, acute angle-closure glaucoma can result in permanent vision loss. Immediate discontinuation of hydrochlorothiazide is critical, and prompt medical or surgical intervention may be necessary if intraocular pressure remains uncontrolled.

Stop Taking and Call Your Doctor Instructions

Patients should discontinue hydrochlorothiazide immediately if symptoms of acute angle-closure glaucoma occur and seek medical attention without delay.

Side Effects

Adverse reactions associated with the use of this medication have been observed across various body systems, with some reactions categorized by seriousness and frequency.

Serious adverse reactions include hematologic events such as aplastic anemia, agranulocytosis, leucopenia, 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 and interstitial nephritis have also been reported, necessitating caution in patients with severe renal disease, as thiazides may precipitate azotemia in this population.

Common adverse reactions reported include weakness, hypotension (including orthostatic hypotension), and various digestive issues such as diarrhea, vomiting, nausea, and abdominal cramping. Patients may also experience metabolic disturbances, including electrolyte imbalances, hyperglycemia, glycosuria, and hyperuricemia. Musculoskeletal symptoms such as muscle spasms, as well as nervous system effects like dizziness, vertigo, and headaches, have been noted.

Skin reactions can range from erythema multiforme, including Stevens-Johnson syndrome, to exfoliative dermatitis and alopecia. Patients may also report transient blurred vision and xanthopsia as part of the special senses adverse reactions. Urogenital effects, including impotence, have been documented as well.

In clinical trials and postmarketing experiences, acute myopia and secondary angle-closure glaucoma have been identified as idiosyncratic reactions to hydrochlorothiazide, characterized by a rapid onset of decreased visual acuity or ocular pain. These symptoms typically arise within hours to weeks of initiating therapy, and untreated cases may lead to permanent vision loss. Immediate discontinuation of hydrochlorothiazide is recommended, with prompt medical or surgical intervention considered if intraocular pressure remains uncontrolled.

Patients receiving diuretic therapy should be closely monitored for signs of fluid or electrolyte imbalance, including hyponatremia, hypochloremic alkalosis, and hypokalemia. Warning signs such as dryness of mouth, thirst, weakness, lethargy, confusion, and gastrointestinal disturbances should be promptly addressed. Hypokalemia may develop, particularly with brisk diuresis or prolonged therapy, and hyperuricemia may occur, potentially precipitating acute gout in susceptible individuals.

In diabetic patients, dosage adjustments of insulin or oral hypoglycemic agents may be necessary due to the potential for hyperglycemia during thiazide therapy. Furthermore, thiazides can increase urinary excretion of magnesium, leading to hypomagnesemia, and may decrease urinary calcium excretion, which could result in slight elevations of serum calcium levels. Marked hypercalcemia may indicate hidden hyperparathyroidism, warranting discontinuation of thiazides prior to parathyroid function testing. Lastly, increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy.

Drug Interactions

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

Pharmacodynamic Interactions

• Alcohol, Barbiturates, or Narcotics: The combination may potentiate orthostatic hypotension, necessitating caution in patients who are concurrently using these agents.

• 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 or potentiation of blood pressure-lowering effects.

• Corticosteroids and ACTH: There is a risk of intensified electrolyte depletion, particularly hypokalemia, when these agents are used together.

• Skeletal Muscle Relaxants (Nondepolarizing, e.g., Tubocurarine): Increased responsiveness to muscle relaxants may occur, which should be monitored during concurrent administration.

• Lithium: The use of diuretics, including hydrochlorothiazide, is generally contraindicated with lithium due to the potential for reduced renal clearance and increased risk of lithium 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 hydrochlorothiazide. Close monitoring is recommended to ensure the desired diuretic effect is achieved when these agents are used together.

Pharmacokinetic Interactions

• Cholestyramine and Colestipol Resins: The absorption of hydrochlorothiazide is significantly impaired in the presence of these anionic exchange resins. Single doses can reduce hydrochlorothiazide absorption by up to 85% with cholestyramine and 43% with colestipol.

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

Drug/Laboratory Test Interactions

• Thiazides and Parathyroid Function Tests: 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

Pediatric patients have not been studied in well-controlled clinical trials for this medication. Dosing recommendations for this age group are primarily based on empirical use and existing literature concerning the treatment of hypertension in pediatric populations. Healthcare professionals should refer to the Dosage and Administration section for specific guidance on dosing in infants and children. Caution is advised when prescribing this medication to pediatric patients 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 this population, especially in individuals with severe renal disease, as thiazides can precipitate azotemia and lead to cumulative effects due to impaired renal function.

In 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.

All patients receiving diuretic therapy, including geriatric patients, should be closely observed for signs of fluid or electrolyte imbalance, such as hyponatremia, hypochloremic alkalosis, and hypokalemia. Regular serum and urine electrolyte determinations are particularly important in elderly patients who are experiencing excessive vomiting or receiving parenteral fluids.

Hypokalemia is a potential risk, especially in the presence of brisk diuresis, severe cirrhosis, or after prolonged therapy. If progressive renal impairment is observed, it may be necessary to withhold or discontinue diuretic therapy to prevent further complications.

Additionally, the antihypertensive effects of thiazides may be enhanced in elderly patients who have undergone sympathectomy. Therefore, periodic determination of serum electrolytes to detect possible electrolyte imbalances should be conducted at appropriate intervals to ensure patient safety and effective management.

Pregnancy

Hydrochlorothiazide Tablets have been studied in pregnant mice and rats during their major organogenesis periods at doses up to 3000 mg/kg and 1000 mg/kg, respectively, with no evidence of fetal harm observed. 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, including Hydrochlorothiazide, 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 documented 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 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 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 extent to which hydrochlorothiazide can be removed from the body through hemodialysis remains to be established.

Nonclinical Toxicology

Studies involving the oral administration of Hydrochlorothiazide Tablets to pregnant mice and rats during critical periods of organogenesis, at doses of up to 3000 mg/kg and 1000 mg/kg, respectively, demonstrated no evidence of teratogenic effects on the fetus. However, there are no adequate and well-controlled studies in pregnant women, and since animal reproduction studies may not reliably predict human outcomes, the use of this drug during pregnancy should be considered only when clearly necessary.

Thiazides are 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 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 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 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. Additionally, it did not exhibit genotoxicity in vivo in assays involving mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive results were observed only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and Mouse Lymphoma Cell (mutagenicity) assays at concentrations ranging from 43 to 1300 μg/mL, 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 dietary doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to conception and throughout gestation.

Postmarketing Experience

Postmarketing experience has identified several adverse reactions associated with hydrochlorothiazide, reported voluntarily or through surveillance programs.

Acute myopia and secondary angle-closure glaucoma have been noted as idiosyncratic reactions, characterized by an acute onset of decreased visual acuity or ocular pain, typically occurring within hours to weeks of initiating treatment. Untreated cases may lead to permanent vision loss, necessitating prompt discontinuation of the medication and potential medical or surgical intervention if intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma include a history of sulfonamide or penicillin allergy.

The following adverse reactions have been reported, categorized by system and listed in order of decreasing severity:

• Body As A Whole: Weakness.

• Cardiovascular: Hypotension, including orthostatic hypotension, which may be exacerbated by alcohol, barbiturates, narcotics, or antihypertensive medications.

• Digestive: Pancreatitis, intrahepatic cholestatic jaundice, diarrhea, vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea, and anorexia.

• Hematologic: Aplastic anemia, agranulocytosis, leucopenia, hemolytic anemia, and thrombocytopenia.

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

• Metabolic: Electrolyte imbalance, hyperglycemia, glycosuria, and hyperuricemia.

• Musculoskeletal: Muscle spasm.

• Nervous System/Psychiatric: Vertigo, paresthesias, dizziness, headache, and restlessness.

• Renal: Renal failure, renal dysfunction, and interstitial nephritis.

• Skin: Erythema multiforme (including Stevens-Johnson syndrome), exfoliative dermatitis (including toxic epidermal necrolysis), and alopecia.

• Special Senses: Transient blurred vision and xanthopsia.

• Urogenital: Impotence.

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

Patient Counseling

Patients should be closely monitored for signs of fluid or electrolyte imbalance, which may include symptoms such 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. Healthcare providers should advise patients to report any of these symptoms promptly.

Hypokalemia may develop, particularly with brisk diuresis, in patients with severe cirrhosis or after prolonged therapy. It is important to inform patients that hypokalemia can lead to cardiac arrhythmias and may heighten the heart's sensitivity to the toxic effects of digitalis. Patients should be counseled on the potential for hypokalemia and the importance of potassium-sparing diuretics or potassium supplements, such as potassium-rich foods, to prevent or treat this condition.

Healthcare providers should emphasize the need for careful monitoring of warning signs or symptoms of fluid or electrolyte imbalance. In edematous patients, especially during hot weather, dilutional hyponatremia may occur, and patients should be advised that water restriction is the appropriate therapy, except in rare cases of life-threatening hyponatremia. In instances of actual salt depletion, appropriate replacement therapy should be discussed as the preferred treatment.

Patients receiving thiazides should be informed about the risk of hyperuricemia and the potential for acute gout. Additionally, diabetic patients may require dosage adjustments of insulin or oral hypoglycemic agents, as thiazide diuretics can lead to hyperglycemia and may reveal latent diabetes mellitus.

If patients exhibit signs of progressive renal impairment, healthcare providers should consider withholding or discontinuing diuretic therapy. It is also important to inform patients that thiazides can increase urinary excretion of magnesium, potentially leading to hypomagnesemia, and may decrease urinary calcium excretion, causing 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 parathyroid function tests.

Patients should be made aware that thiazide diuretic therapy may be associated with increases in cholesterol and triglyceride levels, and periodic serum electrolyte determinations should be conducted to detect possible imbalances.

Patients should be advised to report any signs of allergic reactions, such as rash, itching, or difficulty breathing. They should also be informed about the potential for acute myopia and secondary angle-closure glaucoma, including symptoms like decreased visual acuity or ocular pain, and the necessity to discontinue the medication if these symptoms arise.

Finally, nursing mothers should be counseled that thiazides are excreted in breast milk, and a decision should be made regarding whether to continue nursing or to discontinue hydrochlorothiazide, considering the importance of the medication to the mother’s health.

Storage and Handling

The product is supplied in a well-closed container as defined by the United States Pharmacopeia (USP) and is equipped with a child-resistant closure to ensure safety. It should be stored at a controlled room temperature ranging from 20 to 25°C (68 to 77°F) to maintain its integrity and efficacy.

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 Excellium Pharmaceutical Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)