Hydrochlorothiazide

Description

Hydrochlorothiazide USP 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 appears as a white or practically white crystalline powder. Hydrochlorothiazide is slightly soluble in water and freely soluble in sodium hydroxide solution, n-butylamine, and dimethylformamide. It exhibits sparing solubility 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 includes inactive ingredients such as FD&C yellow #6, microcrystalline cellulose, lactose anhydrous, sodium starch glycolate, stearic acid, and magnesium stearate.

Uses and Indications

Hydrochlorothiazide tablets USP are 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, these tablets are beneficial in treating edema resulting from renal dysfunction, such as nephrotic syndrome, acute glomerulonephritis, and chronic renal failure.

In the management of hypertension, hydrochlorothiazide tablets USP may be utilized either as a sole therapeutic agent or to enhance the effectiveness of other antihypertensive medications in patients with more severe forms of hypertension.

Limitations of Use: The routine use of diuretics, including hydrochlorothiazide, during normal pregnancy is not recommended, 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. Hydrochlorothiazide may be 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 elevating the lower extremities and using support stockings are preferred. The physiological hypervolemia that occurs during normal pregnancy is generally not harmful and does not require diuretic intervention. In rare cases where edema causes significant discomfort and is unresponsive to rest, a short course of diuretic therapy may be appropriate.

Dosage and Administration

Therapy should be individualized according to patient response. Healthcare professionals are advised to utilize the smallest dosage necessary to achieve the required therapeutic response. It is essential to monitor the patient's condition closely and adjust the dosage as needed to ensure optimal efficacy while minimizing potential side effects. Regular assessment of the patient's response will guide any necessary modifications to the treatment regimen.

Contraindications

Use of this product is contraindicated in patients with anuria due to the potential for exacerbating renal impairment. Additionally, it is contraindicated in individuals with hypersensitivity to this product or to other sulfonamide-derived drugs, as this may lead to severe allergic reactions.

Warnings and Precautions

Use of thiazide diuretics requires careful consideration in patients with specific health conditions.

Renal Considerations Thiazides should be administered with caution in individuals with severe renal disease. In such patients, the use of thiazides may precipitate azotemia, and the cumulative effects of the drug can become pronounced in those with impaired renal function. Regular monitoring of renal function is advised to mitigate potential risks.

Hepatic Function Patients with impaired hepatic function or progressive liver disease should also be closely monitored when using thiazides. Minor alterations in fluid and electrolyte balance in these individuals may lead to serious complications, including hepatic coma.

Drug Interactions Thiazides may enhance the effects of other antihypertensive medications. Healthcare professionals should be vigilant in monitoring blood pressure and adjusting dosages of concomitant antihypertensive therapies as necessary.

Allergic Reactions Sensitivity reactions can occur in patients regardless of their allergy history, including those with bronchial asthma. It is essential to observe patients for any signs of allergic response during treatment.

Systemic Lupus Erythematosus There have been reports of exacerbation or activation of systemic lupus erythematosus in patients receiving thiazides. Clinicians should be aware of this potential risk and monitor patients accordingly.

Lithium Interaction The concomitant use of lithium with diuretics, including thiazides, is generally not recommended due to the risk of lithium toxicity. Regular monitoring of lithium levels is advised for patients requiring both therapies.

Ocular Effects Hydrochlorothiazide, a sulfonamide, has been associated with acute myopia and secondary angle-closure glaucoma. This idiosyncratic reaction may present with a sudden decrease in visual acuity or ocular pain, typically occurring within hours to weeks after initiation of the drug. If these symptoms arise, it is critical to discontinue hydrochlorothiazide immediately. If intraocular pressure remains uncontrolled, prompt medical or surgical intervention may be necessary. Patients with a history of sulfonamide or penicillin allergy may be at increased risk for developing acute angle-closure glaucoma, warranting careful assessment prior to treatment initiation.

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 can manifest as anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), and respiratory distress, which may include 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 like muscle spasms, as well as nervous system effects such as dizziness, vertigo, and headache, have been noted.

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

In clinical trials and postmarketing experiences, it is important to note that sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma. The possibility of exacerbation or activation of systemic lupus erythematosus has also been reported. Furthermore, acute myopia and secondary angle-closure glaucoma have been identified as potential idiosyncratic reactions to hydrochlorothiazide, with symptoms typically occurring within hours to weeks of initiation. Prompt discontinuation of the medication is essential in such cases, and further medical or surgical intervention may be required if intraocular pressure remains uncontrolled.

In instances of moderate to severe adverse reactions, it is recommended that the thiazide dosage be reduced or therapy be withdrawn. Overdosage may lead to electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration due to excessive diuresis, particularly in patients receiving digitalis, where hypokalemia may exacerbate cardiac arrhythmias.

Drug Interactions

The following drug interactions have been identified, categorized by their pharmacological effects and clinical implications.

Pharmacodynamic Interactions

• Alcohol, Barbiturates, and Narcotics: Concurrent use may potentiate orthostatic hypotension. Patients should be monitored for signs of increased hypotensive effects.

• Antidiabetic Drugs (Oral Agents and Insulin): Dosage adjustments of the antidiabetic medication may be necessary to maintain glycemic control.

• Other Antihypertensive Drugs: There is a potential for additive effects or potentiation of antihypertensive effects. Blood pressure should be monitored closely.

• Corticosteroids and ACTH: The use of these agents may lead to intensified electrolyte depletion, particularly hypokalemia. Regular monitoring of electrolyte levels is advised.

• 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 recommended.

• Lithium: The use of diuretics with lithium is generally contraindicated due to the risk of reduced renal clearance of lithium, which may lead to toxicity. Close monitoring of lithium levels is essential.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): In some patients, NSAIDs may diminish the diuretic, natriuretic, and antihypertensive effects of diuretics, including 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 hydrochlorothiazide absorption by up to 85% and 43%, respectively. It is advisable to separate the administration of these agents to minimize interaction.

Laboratory Test Interactions

• Thiazides: It is recommended that thiazide diuretics be discontinued prior to conducting tests for parathyroid function to avoid interference with test results.

Packaging & NDC

The table below lists all NDC Code configurations of Hydrochlorothiazide, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

There are 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 of the medication in children have not been established through rigorous clinical trials.

Geriatric Use

Elderly patients should be treated with caution when using thiazide diuretics, particularly in those with severe renal disease, as these medications may precipitate azotemia and lead to cumulative effects in individuals with impaired renal function. Additionally, thiazides should be administered carefully in patients with impaired hepatic function or progressive liver disease, as even minor alterations in fluid and electrolyte balance can trigger hepatic coma.

Sensitivity reactions may occur in geriatric patients, regardless of their history of allergy or bronchial asthma. Furthermore, hydrochlorothiazide has been associated with an idiosyncratic reaction that can result in acute transient myopia and acute angle-closure glaucoma, conditions that may lead to permanent vision loss if not treated promptly.

All patients receiving diuretic therapy, especially elderly patients, should be closely monitored for signs of fluid or electrolyte imbalance, as they may be more susceptible to these complications. Hypokalemia is a particular concern, especially during brisk diuresis, in the presence of severe cirrhosis, or after prolonged therapy; this risk may be heightened in elderly patients.

In diabetic elderly patients, dosage adjustments of insulin or oral hypoglycemic agents may be necessary, as they may be at an increased risk for hyperglycemia. If there are indications of progressive renal impairment, it is advisable to consider withholding or discontinuing diuretic therapy, particularly in elderly patients who may exhibit reduced kidney function.

Periodic monitoring of serum electrolytes is recommended to detect potential electrolyte imbalances, and this should be conducted at appropriate intervals, especially in the geriatric population.

Pregnancy

Hydrochlorothiazide is classified as Pregnancy Category B. Animal studies involving the oral administration of Hydrochlorothiazide Tablets to pregnant mice and rats during critical periods of organogenesis, at doses up to 3000 mg/kg and 1000 mg/kg respectively, have not demonstrated any evidence of fetal harm. However, there are no adequate and well-controlled studies in pregnant women to confirm the safety of this medication during pregnancy.

It is important to note that animal reproduction studies are not always predictive of human outcomes. Therefore, Hydrochlorothiazide should be used during pregnancy only if clearly needed. Thiazides are known to cross the placental barrier and can be detected in cord blood. There is a potential risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have been observed in adults. Healthcare professionals should weigh the benefits against the risks when considering the use of Hydrochlorothiazide in pregnant patients.

Lactation

Thiazides are excreted in breast milk. Due to the potential for serious adverse reactions in nursing infants, healthcare professionals should consider whether to discontinue nursing 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, 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 essential to monitor these patients closely for any signs of deterioration in liver function or fluid status. Adjustments to dosage may be necessary based on the severity of hepatic impairment and the patient's overall clinical condition. Regular assessment of liver function tests and electrolyte levels is recommended to ensure safe and effective use of thiazides in this population.

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 evaluating the teratogenic effects of Hydrochlorothiazide Tablets indicate a Pregnancy Category B classification. In animal studies, oral administration of hydrochlorothiazide to pregnant mice and rats during critical periods of organogenesis at doses up to 3000 mg/kg and 1000 mg/kg, respectively, did not demonstrate any evidence of fetal harm. However, it is important to note that there are no adequate and well-controlled studies in pregnant women, and animal reproduction studies may not always predict human responses. Therefore, 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.

Regarding mutagenicity, hydrochlorothiazide was not found to be genotoxic in vitro in the Ames mutagenicity assay using various strains of Salmonella typhimurium or in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. Additionally, in vivo assays involving mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene did not indicate genotoxicity. 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 nondisjunction 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.

No specific details regarding animal pharmacology and toxicology beyond the nonclinical toxicology findings are provided.

Postmarketing Experience

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

Hematological events including aplastic anemia, agranulocytosis, leucopenia, hemolytic anemia, and thrombocytopenia have been reported. Allergic reactions such as anaphylaxis, necrotizing angiitis (vasculitis and cutaneous vasculitis), and respiratory distress, including pneumonitis and pulmonary edema, have been observed, alongside photosensitivity, fever, urticaria, rash, and purpura.

Electrolyte imbalances, hyperglycemia, glycosuria, and hyperuricemia have been identified. Neurological symptoms such as muscle spasms, 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 of moderate or severe adverse reactions, it is recommended that thiazide dosage be reduced or therapy be withdrawn. For medical advice regarding side effects, patients are encouraged to contact their healthcare provider. Side effects may also be reported to the FDA at 1-800-FDA-1088 or to Leading Pharma, LLC at 844-740-7500.

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 encouraged to inform patients about the warning signs and symptoms associated with 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 in patients experiencing brisk diuresis, those with severe cirrhosis, or after prolonged therapy. Patients should be made aware that hypokalemia can lead to cardiac arrhythmias and may heighten the heart's sensitivity to the toxic effects of digitalis. To mitigate the risk of hypokalemia, healthcare providers should discuss the potential use of potassium-sparing diuretics or potassium supplements, including dietary sources rich in potassium.

In cases of edematous patients, particularly during hot weather, dilutional hyponatremia may occur. Patients should be advised that the appropriate management for this condition is water restriction, rather than salt administration, except in rare situations where hyponatremia poses a life-threatening risk. Conversely, in instances of actual salt depletion, appropriate replacement therapy should be the preferred treatment.

Patients receiving thiazide diuretics should be informed that hyperuricemia may occur, and acute gout may be precipitated in certain individuals. For diabetic patients, it may be necessary to adjust the dosage of insulin or oral hypoglycemic agents, as hyperglycemia can develop during thiazide therapy, potentially revealing latent diabetes mellitus.

Healthcare providers should also discuss the implications of progressive renal impairment, which may necessitate withholding or discontinuing diuretic therapy. Thiazides are known to increase urinary excretion of magnesium, potentially leading to hypomagnesemia. Additionally, thiazides may decrease urinary calcium excretion, resulting in intermittent and slight elevations of serum calcium in the absence of known calcium metabolism disorders. Marked hypercalcemia could indicate hidden hyperparathyroidism, and thiazides should be discontinued prior to conducting tests for parathyroid function.

Patients should be made aware that thiazide diuretics may be associated with increases in cholesterol and triglyceride levels. Regular monitoring of serum electrolytes is recommended to detect any possible electrolyte imbalances, and patients should be encouraged to report any side effects to their healthcare provider. They may also report side effects to the FDA or the manufacturer for further evaluation.

Storage and Handling

The product is supplied in a well-closed container that meets the specifications outlined in the United States Pharmacopeia (USP), featuring a child-resistant closure as required. It is essential to store the product at a temperature range of 20°-25°C (68°-77°F), in accordance with USP Controlled Room Temperature guidelines.

Healthcare professionals are advised to ensure that this medication, along with all other medications, is kept out of the reach of children to prevent accidental ingestion or misuse.

Additional Clinical Information

Periodic determination of serum electrolytes is recommended for patients to detect potential electrolyte imbalances at appropriate intervals. No further information is available regarding abuse, administration routes, patient counseling, or postmarketing experiences.

FDA Insert (PDF)

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

View full prescribing information (PDF)