Hydrochlorothiazide

Description

Hydrochlorothiazide 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. The compound has a structural formula that reflects its chemical composition. Hydrochlorothiazide appears as a white or almost white crystalline powder, exhibiting very slight solubility in water, while it is soluble in dilute solutions of alkali hydroxides. Each tablet intended for oral administration contains either 25 mg or 50 mg of hydrochlorothiazide. The formulation also includes inactive ingredients such as anhydrous lactose, dibasic calcium phosphate dihydrate, croscarmellose, ferric oxide orange shade, ferric oxide yellow shade, 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 and 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 context of hypertension, Hydrochlorothiazide Tablets USP may be utilized either as a monotherapy or in combination with other antihypertensive agents to enhance their effectiveness, particularly in cases of more severe 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, 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.

Hydrochlorothiazide may be indicated during pregnancy when edema is due to pathological causes, similar to its use in non-pregnant individuals. 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

The usual adult dosage for the management of 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 recommended initial dose is 25 mg daily, administered as a single dose. This dose may be increased to 50 mg daily, which can be given as either a single dose or divided into two doses.

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 a known hypersensitivity to this product or to other sulfonamide-derived drugs. Due to the potential for severe allergic reactions, individuals with such hypersensitivities should avoid this medication.

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.

Thiazides have the potential to enhance the effects of other antihypertensive medications, and sensitivity reactions may occur in patients regardless of their allergy or bronchial asthma history. Additionally, 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.

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 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, fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

Hypokalemia is a potential risk, 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 the toxic effects of digitalis. To mitigate hypokalemia, potassium-sparing diuretics or potassium-rich foods may be utilized. While chloride deficits are typically mild and may not require treatment, chloride replacement may be necessary in cases of metabolic alkalosis, particularly in patients with liver or renal disease.

Dilutional hyponatremia may 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 can increase urinary magnesium excretion, potentially leading to hypomagnesemia.

Thiazides may also decrease urinary calcium excretion, resulting in intermittent and slight elevations of serum calcium in the absence of known calcium metabolism disorders. Marked hypercalcemia may indicate hidden hyperparathyroidism, and thiazides should be discontinued prior to parathyroid function testing. Additionally, thiazide diuretic therapy may be associated with increases in cholesterol and triglyceride levels.

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

Side Effects

Adverse reactions associated with thiazide diuretics have been observed in clinical trials and postmarketing experiences. These reactions can be categorized by seriousness and frequency.

Serious adverse reactions include hematologic events 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 encompasses pneumonitis and pulmonary edema. Renal complications such as renal failure, renal dysfunction, and interstitial nephritis have also been reported, necessitating caution in patients with severe renal disease.

Common adverse reactions reported 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 manifest as erythema multiforme (including Stevens-Johnson syndrome), exfoliative dermatitis (including toxic epidermal necrolysis), and alopecia. Urogenital effects such as impotence have also been noted.

Metabolic disturbances are significant, with electrolyte imbalances being a primary concern. Patients may experience hyperglycemia, glycosuria, and hyperuricemia, with the potential for acute gout in susceptible individuals. In diabetic patients, dosage adjustments of insulin or oral hypoglycemic agents may be necessary due to the risk of hyperglycemia. Thiazides have been shown to increase urinary excretion of magnesium, potentially leading to hypomagnesemia, while they may decrease urinary calcium excretion, causing intermittent elevations of serum calcium.

All patients receiving diuretic therapy should be monitored for signs of fluid or electrolyte imbalance, including hyponatremia, hypochloremic alkalosis, and hypokalemia. Warning signs may include dryness of mouth, 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 particularly likely to develop with brisk diuresis, severe cirrhosis, or prolonged therapy.

Caution is advised when using thiazides in patients with impaired hepatic function or progressive liver disease, as minor alterations in fluid and electrolyte balance may precipitate hepatic coma. The potential for exacerbation or activation of systemic lupus erythematosus has also been reported. Furthermore, thiazides may potentiate the effects of other antihypertensive drugs, and sensitivity reactions can occur in patients with or without a history of allergy or bronchial asthma.

Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy, and lithium should generally not be administered concurrently with diuretics.

Drug Interactions

The concomitant use of certain medications with hydrochlorothiazide may lead to significant drug interactions, which can affect therapeutic outcomes and safety.

Pharmacodynamic Interactions

• Alcohol, Barbiturates, and Narcotics: The combination of hydrochlorothiazide with these agents may potentiate orthostatic hypotension. Patients should be monitored for signs of hypotension, particularly when initiating therapy or adjusting dosages.

• Antidiabetic Drugs (Oral Agents and Insulin): The use of hydrochlorothiazide may necessitate dosage adjustments of antidiabetic medications due to potential alterations in glycemic control. Close monitoring of blood glucose levels is advised.

• Other Antihypertensive Drugs: The use of hydrochlorothiazide in conjunction with other antihypertensive agents may result in an additive effect or potentiation of blood pressure-lowering effects. Blood pressure should be monitored regularly to avoid excessive hypotension.

• Corticosteroids and ACTH: Co-administration 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 when used with hydrochlorothiazide; however, this interaction is not sufficient to contraindicate 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 advisable.

• Lithium: The use of hydrochlorothiazide with lithium is generally contraindicated due to the potential for reduced renal clearance of lithium, which increases the risk of lithium toxicity. Consultation of the package insert for lithium preparations is essential prior to co-administration.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The concurrent use of NSAIDs may diminish the diuretic, natriuretic, and antihypertensive effects of hydrochlorothiazide. Patients should be closely observed 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. Single doses of cholestyramine or colestipol can reduce the gastrointestinal absorption of hydrochlorothiazide by up to 85% and 43%, respectively. It is advisable to separate the administration of hydrochlorothiazide and these resins by at least 2 hours to minimize interaction.

Laboratory Test Interactions

• Parathyroid Function Tests: Thiazide diuretics, including hydrochlorothiazide, 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 primarily derived from empirical use and published literature concerning the treatment of hypertension in pediatric patients. Caution is advised when prescribing, as the safety and efficacy profiles in this population have not been established through rigorous clinical trials.

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 for geriatric patients, especially those with renal impairment.

It is essential to monitor these patients for signs of fluid or electrolyte imbalance, as they may be more susceptible to such effects. Periodic determination of serum electrolytes is particularly important for elderly patients receiving diuretic therapy. Additionally, the antihypertensive effects of the medication may be enhanced in this population, which underscores the need for careful monitoring of blood pressure and renal function.

Pregnancy

Hydrochlorothiazide has 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 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 nursing 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 prevent potential complications. No specific dosage adjustments are provided; however, clinicians should assess the risks and benefits of thiazide therapy in patients with compromised liver function.

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 artificial respiration may be necessary.

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

Nonclinical Toxicology

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

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

In studies assessing fertility, hydrochlorothiazide demonstrated no adverse effects on the reproductive capabilities of mice and rats of either sex. These studies involved dietary exposure to doses of up to 100 mg/kg for mice and 4 mg/kg for rats, administered prior to conception and throughout gestation.

Postmarketing Experience

Adverse reactions have been reported voluntarily or through surveillance programs, categorized by system organ class and listed in order of decreasing severity.

In the Body as a Whole category, weakness has been noted. Cardiovascular events include hypotension, which may present as orthostatic hypotension and could be exacerbated by alcohol, barbiturates, narcotics, or antihypertensive medications.

Digestive system reactions encompass pancreatitis, intrahepatic cholestatic jaundice, diarrhea, vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea, and anorexia. Hematologic adverse events reported include aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia.

Hypersensitivity reactions have been documented, including anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress (such as pneumonitis and pulmonary edema), photosensitivity, fever, urticaria, rash, and purpura. Metabolic disturbances include electrolyte imbalances, hyperglycemia, glycosuria, and hyperuricemia.

Musculoskeletal issues reported consist of muscle spasms. Nervous system and psychiatric reactions include vertigo, paresthesias, dizziness, headache, and restlessness. Renal adverse events include renal failure, renal dysfunction, and interstitial nephritis.

Skin reactions reported are erythema multiforme (including Stevens-Johnson syndrome), exfoliative dermatitis (including toxic epidermal necrolysis), and alopecia. Urogenital issues include impotence.

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

Warning signs of fluid and electrolyte imbalance that should be communicated to patients 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. It is important to inform patients that hypokalemia may develop, especially during brisk diuresis, in cases of severe cirrhosis, or after prolonged therapy. Hypokalemia can lead to cardiac arrhythmias and may heighten the heart's sensitivity to the toxic effects of digitalis.

Patients should be advised that hypokalemia can be prevented or treated through the use of potassium-sparing diuretics or potassium supplements, including foods rich in potassium. Additionally, chloride replacement may be necessary in the management of metabolic alkalosis. In edematous patients, particularly in hot weather, dilutional hyponatremia may occur; appropriate management involves water restriction rather than salt administration, except in rare cases of life-threatening hyponatremia. In instances of actual salt depletion, appropriate replacement therapy is recommended.

Healthcare providers should inform patients that hyperuricemia may develop, or acute gout may be triggered in certain individuals receiving thiazide diuretics. For diabetic patients, dosage adjustments of insulin or oral hypoglycemic agents may be necessary, as hyperglycemia can occur with thiazide therapy, potentially revealing latent diabetes mellitus.

If progressive renal impairment is observed, healthcare providers should consider withholding or discontinuing diuretic therapy. Thiazides are known to increase urinary excretion of magnesium, which may lead to hypomagnesemia. They may also decrease urinary calcium excretion, potentially causing intermittent and slight elevations in serum calcium levels in the absence of known calcium metabolism disorders. Marked hypercalcemia may indicate hidden hyperparathyroidism, and thiazides should be discontinued prior to conducting tests for parathyroid function.

Patients should be informed that thiazide diuretics may be associated with increases in cholesterol and triglyceride levels. Periodic monitoring of serum electrolytes is essential to detect potential 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 tight, light-resistant container to ensure its integrity and efficacy. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15° to 30°C (59° to 86°F) as defined by USP Controlled Room Temperature guidelines. Proper adherence to these storage conditions is essential for maintaining the quality of the product.

Additional Clinical Information

Clinicians should conduct periodic determinations of serum electrolytes in patients to detect any potential electrolyte imbalances. This monitoring should occur at appropriate intervals to ensure patient safety and effective management of treatment.

FDA Insert (PDF)

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

View full prescribing information (PDF)