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 the following inactive ingredients: FD&C yellow #6, microcrystalline cellulose, lactose, sodium starch glycolate, stearic acid, and magnesium stearate.

Uses and Indications

Hydrochlorothiazide USP is indicated as adjunctive therapy in the management of edema associated with various conditions, including congestive heart failure, hepatic cirrhosis, and corticosteroid or estrogen therapy. Additionally, it is beneficial in treating edema resulting from renal dysfunction, such as nephrotic syndrome, acute glomerulonephritis, and chronic renal failure.

This drug is also indicated for the management of hypertension. It may be used as a sole therapeutic agent or to enhance the effectiveness of other antihypertensive medications in patients with more severe forms of hypertension.

Use in Pregnancy:The routine use of diuretics 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 efficacy in treating this condition. Hydrochlorothiazide is indicated during pregnancy only when 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. The use of diuretics to reduce intravascular volume in this context is considered illogical and unnecessary, as hypervolemia during normal pregnancy is not harmful in the absence of cardiovascular disease. If edema causes 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 based on body weight. The recommended dosage 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. For infants up to 2 years of age, the maximum daily dosage should not exceed 37.5 mg. In children aged 2 to 12 years, the maximum daily dosage is 100 mg. 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 inability to excrete the drug, which may lead to accumulation and toxicity. Additionally, hypersensitivity to this product or to other sulfonamide-derived drugs is a contraindication, as it may result in 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 their 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 should be monitored for signs of fluid or electrolyte imbalance, including hyponatremia, hypochloremic alkalosis, and hypokalemia. Regular serum and urine electrolyte determinations are particularly crucial for patients experiencing excessive vomiting or receiving parenteral fluids. Warning signs of fluid and electrolyte imbalance may 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 particular concern, especially with brisk diuresis, severe cirrhosis, or 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 beneficial. 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 can increase urinary magnesium excretion, leading to hypomagnesemia, and may decrease urinary calcium excretion, resulting in intermittent elevations of serum calcium. Marked hypercalcemia could indicate hidden hyperparathyroidism, and thiazides should be discontinued prior to parathyroid function testing.

Patients 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 any potential imbalances during treatment.

Side Effects

Patients may experience a range of adverse reactions while undergoing treatment. The following sections categorize these reactions based on their seriousness and frequency.

Serious adverse reactions include hematologic events such as aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia. 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. Renal complications such as renal failure, renal dysfunction, and interstitial nephritis have also been reported. Skin reactions can be severe, with cases of erythema multiforme, including Stevens-Johnson syndrome, and exfoliative dermatitis, including toxic epidermal necrolysis.

Common adverse reactions reported in clinical trials and postmarketing experiences 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. Neurological symptoms such as vertigo, paresthesias, dizziness, headache, and restlessness have also been observed. Musculoskeletal reactions may include muscle spasms, while metabolic disturbances such as electrolyte imbalance, hyperglycemia, glycosuria, and hyperuricemia have been noted.

Patients may also experience transient blurred vision and xanthopsia as part of the special senses adverse reactions. Urogenital effects, including impotence, have been reported as well.

It is important to note that whenever adverse reactions are moderate or severe, the dosage of thiazide should be reduced or therapy withdrawn to mitigate risks.

Drug Interactions

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

Pharmacodynamic Interactions:

• Alcohol, Barbiturates, or Narcotics: The combination may potentiate orthostatic hypotension. Patients should be monitored for signs of hypotension and advised to use caution when standing up.

• Antidiabetic Drugs (Oral Agents and Insulin): Dosage adjustments of the antidiabetic medication may be necessary to maintain glycemic control. Close monitoring of blood glucose levels is recommended.

• Other Antihypertensive Drugs: The use of additional antihypertensive agents may result in an additive effect or potentiation of blood pressure-lowering effects. Blood pressure should be monitored regularly.

• Corticosteroids and ACTH: There is a risk of intensified electrolyte depletion, particularly hypokalemia. Electrolyte levels should be monitored, and potassium supplementation may be required.

• 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 muscle relaxants may occur. Monitoring of neuromuscular function is advised.

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: Thiazide diuretics should generally not be used concurrently with lithium due to the risk of reduced renal clearance and potential lithium toxicity. Consultation of the lithium package insert is recommended prior to co-administration.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The use of NSAIDs may diminish the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics in some patients. Close observation is warranted to ensure the desired diuretic effect is achieved.

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.

Geriatric Use

Elderly patients may exhibit increased sensitivity to side effects, necessitating cautious use of this medication in this population. It is essential to monitor these patients for signs of fluid or electrolyte imbalance, particularly as they may have reduced kidney function.

Dosage adjustments may be required for elderly patients, especially those with renal impairment, to ensure safety and efficacy. The antihypertensive effects of the medication may be enhanced in this demographic, which underscores the importance of careful monitoring of blood pressure and renal function.

Additionally, there is an increased risk of hypotension, particularly orthostatic hypotension, in elderly patients. This risk may be further exacerbated by the concurrent use of alcohol, barbiturates, narcotics, or other antihypertensive agents.

Periodic determination of serum electrolytes is particularly important in elderly patients to detect possible electrolyte imbalances, ensuring appropriate management and minimizing potential complications.

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 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 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

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 threshold for toxicity. However, the efficacy of hemodialysis in removing hydrochlorothiazide from the system has not been established. Therefore, healthcare professionals should exercise caution and monitor patients closely during the management of overdosage.

Nonclinical Toxicology

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, did not demonstrate any evidence of teratogenic effects on the fetus. 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 always 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 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.

In terms of mutagenicity, hydrochlorothiazide was not found to be 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 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 mcg/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

Adverse reactions reported in the postmarketing experience include a range of events. Weakness and hypotension, including orthostatic hypotension, have been noted, with potential aggravation by alcohol, barbiturates, narcotics, or antihypertensive drugs. Gastrointestinal disturbances such as pancreatitis, jaundice (intrahepatic cholestatic jaundice), diarrhea, vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea, and anorexia have also been documented.

Hematological events including aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia have been reported. Additionally, anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), and respiratory distress, which may include pneumonitis and pulmonary edema, have been observed. Other reactions include photosensitivity, fever, urticaria, rash, and purpura.

Electrolyte imbalances, hyperglycemia, glycosuria, and hyperuricemia have been identified, along with muscle spasms. Neurological symptoms such as vertigo, paresthesias, dizziness, headache, and restlessness have also been reported. Renal complications, including renal failure, renal dysfunction, and interstitial nephritis, have been noted.

Dermatological reactions such as erythema multiforme (including Stevens-Johnson syndrome), exfoliative dermatitis (including toxic epidermal necrolysis), and alopecia have been documented. Transient blurred vision and xanthopsia have been reported, as well as 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 inform patients about warning signs or symptoms of these imbalances, which 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.

It is important to note that hypokalemia may develop, particularly with brisk diuresis, in patients with severe cirrhosis or after prolonged therapy. Patients should be made aware that hypokalemia can lead to cardiac arrhythmias and may sensitize or exaggerate the heart's response to the toxic effects of digitalis. To prevent or treat hypokalemia, healthcare providers should discuss the use of potassium-sparing diuretics or potassium supplements, including foods rich in potassium.

In cases of metabolic alkalosis, chloride replacement may be necessary. Patients with edematous conditions in hot weather may experience dilutional hyponatremia; in such cases, water restriction is the recommended therapy, except in rare instances where hyponatremia is life-threatening. For actual salt depletion, appropriate replacement therapy should be initiated.

Patients receiving thiazides should be informed that hyperuricemia may occur, and acute gout may be precipitated in certain individuals. Diabetic patients may require dosage adjustments of insulin or oral hypoglycemic agents, as thiazide diuretics can lead to hyperglycemia and potentially unmask 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 result in hypomagnesemia, and they may decrease urinary calcium excretion, potentially causing 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 conducting tests for parathyroid function.

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

Nursing mothers should consider the potential for serious adverse reactions in nursing infants when taking thiazides. A decision should be made regarding whether to discontinue nursing or to discontinue hydrochlorothiazide, weighing the importance of the medication to the mother.

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

View full prescribing information (PDF)