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. 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 is sparingly soluble in methanol and insoluble in ether, chloroform, and dilute mineral acids.

For oral administration, each tablet contains 12.5 mg, 25 mg, or 50 mg of hydrochlorothiazide USP. The tablets also include inactive ingredients such as FD&C yellow #6, lactose anhydrous, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, and stearic acid.

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 or 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 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 satisfactory evidence supporting their efficacy in treating this condition. Hydrochlorothiazide may be indicated during pregnancy when edema is due to pathological causes, similar to its use in non-pregnant patients. Dependent edema resulting from venous return restriction by the gravid uterus should be managed through elevation of the lower extremities and the use of support stockings. The use of diuretics to lower intravascular volume in this context is considered illogical and unnecessary, as hypervolemia during normal pregnancy is typically not harmful. 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.

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 hepatic coma, necessitating vigilant oversight of liver function parameters.

Drug Interactions Thiazides may enhance the effects of other antihypertensive medications. Healthcare professionals should be aware of this potential interaction and adjust treatment regimens accordingly to avoid excessive hypotension.

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

Systemic Lupus Erythematosus There have been reports of exacerbation or activation of systemic lupus erythematosus in patients taking thiazides. Clinicians should remain vigilant for any signs of this condition and manage 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 if these medications are used together.

Ocular Effects Hydrochlorothiazide, a sulfonamide, has been associated with acute myopia and secondary angle-closure glaucoma. This idiosyncratic reaction can lead to acute transient myopia and symptoms such as decreased visual acuity or ocular pain, typically occurring within hours to weeks of initiating therapy. If acute angle-closure glaucoma is suspected, 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 this condition, warranting careful assessment prior to treatment initiation.

Side Effects

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

Serious adverse reactions encompass hematologic conditions 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, renal dysfunction, and interstitial nephritis have also been reported.

Common adverse reactions include weakness, hypotension (including orthostatic hypotension), and various digestive issues such as pancreatitis, jaundice (intrahepatic cholestatic jaundice), diarrhea, vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea, and anorexia. Patients may also experience musculoskeletal symptoms like muscle spasms, as well as nervous system and psychiatric effects, including vertigo, paresthesias, dizziness, headache, and restlessness.

Skin reactions can range from erythema multiforme, including Stevens-Johnson syndrome, to exfoliative dermatitis, including toxic epidermal necrolysis and alopecia. Special senses may be affected, leading to transient blurred vision and xanthopsia. Urogenital effects such as impotence have also been noted.

In terms of metabolic effects, patients may experience electrolyte imbalances, hyperglycemia, glycosuria, and hyperuricemia.

Postmarketing experience has revealed an association between hydrochlorothiazide and an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC). In a study conducted within the Sentinel System, the increased risk was predominantly observed in white patients receiving large cumulative doses. The overall population exhibited an approximate risk increase of 1 additional case of SCC per 16,000 patients per year, while white patients taking a cumulative dose of ≥50,000 mg had an increased risk of approximately 1 additional SCC case for every 6,700 patients per year.

Drug Interactions

The following drug interactions have been identified for hydrochlorothiazide, categorized by interaction type and clinical significance.

Pharmacodynamic Interactions:

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

• Antidiabetic Drugs (Oral Agents and Insulin): Dosage adjustments of the antidiabetic medication may be necessary when used in conjunction with hydrochlorothiazide. Regular monitoring of blood glucose levels is recommended.

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

• Corticosteroids, ACTH: There is a risk of intensified electrolyte depletion, particularly hypokalemia, when these agents are used together. Electrolyte levels should be monitored regularly.

• Skeletal Muscle Relaxants (Nondepolarizing, e.g., Tubocurarine): Increased responsiveness to muscle relaxants may occur. Monitoring of neuromuscular function is advised.

• 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 recommended prior to co-administration.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The administration 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 in the presence of these anionic exchange resins. Single doses of cholestyramine or colestipol can reduce the absorption of hydrochlorothiazide by up to 85% and 43%, respectively. It is advisable to separate the administration of hydrochlorothiazide and these resins by several hours to minimize interaction.

• 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. Monitoring of blood pressure response is recommended.

Laboratory Test Interactions:

• Parathyroid Function Tests: Thiazides 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 of the medication in children have not been established through rigorous clinical trials.

Geriatric Use

Elderly patients may require special consideration when using thiazide diuretics due to the potential for adverse effects and the need for careful monitoring. Caution is advised in patients aged 65 and older, particularly those with severe renal disease, as thiazides may precipitate azotemia and lead to cumulative effects in individuals with impaired renal function.

In geriatric 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. Additionally, there have been reports of exacerbation or activation of systemic lupus erythematosus associated with thiazide use.

Elderly patients are at risk for acute myopia and secondary angle-closure glaucoma, which can occur as an idiosyncratic reaction to hydrochlorothiazide. Symptoms, including acute onset of decreased visual acuity or ocular pain, may manifest within hours to weeks of initiating therapy. If left untreated, acute angle-closure glaucoma can result in permanent vision loss.

All patients receiving diuretic therapy, particularly elderly patients, should be closely monitored for signs of fluid or electrolyte imbalance, such as hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are especially important in cases of excessive vomiting or when patients are receiving parenteral fluids. Hypokalemia may develop, particularly with brisk diuresis, in the presence of severe cirrhosis or after prolonged therapy.

In the event of progressive renal impairment, it may be necessary to withhold or discontinue diuretic therapy. Thiazides have been shown to increase urinary excretion of magnesium, potentially leading to hypomagnesemia, while they may also decrease urinary calcium excretion. Intermittent and slight elevations of serum calcium may occur in the absence of known disorders of calcium metabolism, with marked hypercalcemia possibly indicating hidden hyperparathyroidism.

For diabetic elderly patients, dosage adjustments of insulin or oral hypoglycemic agents may be necessary, as thiazide diuretics can induce hyperglycemia and potentially unmask latent diabetes mellitus. Furthermore, the antihypertensive effects of thiazides may be enhanced in patients who have undergone sympathectomy.

Periodic determination of serum electrolytes is recommended to detect possible electrolyte imbalances at appropriate intervals during treatment.

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. The use of hydrochlorothiazide during pregnancy may be associated with risks such as fetal or neonatal jaundice and thrombocytopenia, as well as other adverse reactions that have been observed in adults. Healthcare professionals should weigh the potential benefits against these risks when considering the use of this medication 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 the risks and benefits when advising lactating mothers. A decision should be made whether to discontinue nursing or to discontinue hydrochlorothiazide, taking into account the importance of the drug to the 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 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 to pregnant mice and rats during critical periods of organogenesis, at doses up to 3000 mg/kg and 1000 mg/kg respectively, revealed no evidence of teratogenic effects on the fetus. However, there are no adequate and well-controlled studies in pregnant women, and due to the limitations of animal reproduction studies in predicting 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 other adverse reactions that may also occur in adults.

Two-year feeding studies conducted by the National Toxicology Program (NTP) in mice and rats did not demonstrate any carcinogenic potential of 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, nor in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. Additionally, it did not exhibit genotoxic effects in vivo in assays involving mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, or the Drosophila sex-linked recessive lethal trait gene. Positive results were observed only in the in vitro CHO Sister Chromatid Exchange assay and the Mouse Lymphoma Cell mutagenicity assay 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 doses of up to 100 mg/kg and 4 mg/kg respectively, prior to conception and throughout gestation.

Postmarketing Experience

Postmarketing experience has identified an association between hydrochlorothiazide and an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC). Data from a study conducted within the Sentinel System indicate that this increased risk is predominantly observed in white patients who are administered large cumulative doses of the medication.

In the overall population, the estimated increase in risk for SCC is approximately one additional case per 16,000 patients per year. Notably, for white patients receiving a cumulative dose of 50,000 mg or more, the risk escalates to approximately one additional case of SCC for every 6,700 patients per year.

Patient Counseling

Healthcare providers should instruct patients taking hydrochlorothiazide to take precautions to protect their skin from sun exposure. This includes wearing protective clothing and using sunscreen to minimize the risk of skin damage. Additionally, patients should be advised to undergo regular skin cancer screenings as part of their healthcare routine.

It is important for healthcare providers to emphasize the necessity of periodic determination of serum electrolytes. This monitoring is essential to detect any potential electrolyte imbalances that may arise during treatment. Providers should recommend that patients have these tests conducted at appropriate intervals as determined by their healthcare team.

Patients should be encouraged to communicate openly with their healthcare provider regarding any side effects they may experience. They should be informed to call their doctor for medical advice about side effects and to report any adverse effects to the FDA at 1-800-FDA-1088 or to Leading Pharma, LLC at 1-844-740-7500. This ensures that patients are aware of the resources available for reporting and managing side effects effectively.

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° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines.

Healthcare professionals are reminded to keep this and all medications out of the reach of children to ensure safety.

Additional Clinical Information

Periodic determination of serum electrolytes is recommended for patients to detect potential electrolyte imbalances at appropriate intervals. Clinicians should counsel patients taking hydrochlorothiazide to protect their skin from sun exposure and to undergo regular skin cancer screenings.

Postmarketing data indicate that hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC). This risk appears to be more pronounced in white patients receiving large cumulative doses. Specifically, the overall population shows an increased risk of approximately one additional case of SCC per 16,000 patients per year, while white patients with a cumulative dose of ≥50,000 mg may experience an increase of about one additional SCC case for every 6,700 patients per year.

FDA Insert (PDF)

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

View full prescribing information (PDF)