Hydrochlorothiazide

Description

Hydrochlorothiazide, USP is a diuretic and antihypertensive agent, specifically the 3,4-dihydro derivative of chlorothiazide. Its chemical name is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, with a molecular formula of C7H8ClN3O4S2 and a molecular weight of 297.74 g/mol. The compound appears as a white, or practically white, crystalline powder. It exhibits slight solubility in water, is freely soluble in sodium hydroxide solution, n-butylamine, and dimethylformamide, sparingly soluble in methanol, and insoluble in ether, chloroform, and dilute mineral acids. Each tablet for oral administration contains hydrochlorothiazide in strengths of 12.5 mg, 25 mg, and 50 mg, along with inactive ingredients that include anhydrous lactose, D&C Yellow No.10 aluminum lake, FD&C Red No. 40 aluminum lake, magnesium stearate, pregelatinized starch, and sodium starch glycolate.

Uses and Indications

Hydrochlorothiazide tablets are indicated as adjunctive therapy in the management of edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. Additionally, these tablets are 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 are indicated for use either as a monotherapy or to enhance the effectiveness of other antihypertensive agents in patients with more severe forms of hypertension.

Limitations of Use: Routine use of diuretics, including hydrochlorothiazide, during normal pregnancy is inappropriate and 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. Thiazides may be indicated during pregnancy only when edema is due to pathological causes, similar to their use in non-pregnant patients.

Dependent edema during pregnancy, which arises from venous return restriction by the gravid uterus, should primarily be managed through non-pharmacological measures such as elevating the lower extremities and utilizing support stockings. The use of diuretics to reduce intravascular volume in this scenario is considered illogical and unnecessary, as hypervolemia during normal pregnancy is not harmful in the absence of cardiovascular disease. If edema causes significant discomfort, increased recumbency may provide relief; however, in rare cases where extreme discomfort persists despite 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 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 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, including hydrochlorothiazide, necessitates careful consideration of several warnings and precautions to ensure patient safety.

Renal Considerations Thiazides should be administered with caution in patients with severe renal disease. In such individuals, 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 require careful management when prescribed thiazides. Minor alterations in fluid and electrolyte balance may lead to serious complications, including hepatic coma. It is essential to monitor liver function parameters closely in these patients.

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 agents as necessary.

Allergic Reactions Sensitivity reactions can occur in patients regardless of their allergy history, including those with bronchial asthma. Clinicians should be alert to the possibility of such reactions and monitor patients accordingly.

Systemic Lupus Erythematosus There have been reports of exacerbation or activation of systemic lupus erythematosus in patients taking thiazides. Patients with a history of this condition should be monitored for any signs of worsening symptoms.

Lithium Interaction The concomitant use of lithium with diuretics, including thiazides, is generally not recommended due to the potential for increased lithium levels and toxicity. Regular monitoring of lithium levels is advised for patients receiving this combination.

Ocular Effects Hydrochlorothiazide, classified as a sulfonamide, may cause idiosyncratic reactions leading to acute transient myopia and acute angle-closure glaucoma. Symptoms such as a sudden decrease in visual acuity or ocular pain may manifest within hours to weeks of initiating therapy. If these symptoms occur, it is critical to discontinue hydrochlorothiazide immediately. If intraocular pressure remains uncontrolled, prompt medical or surgical intervention may be necessary to prevent permanent vision loss. Patients with a history of sulfonamide or penicillin allergy may be at increased risk for developing acute angle-closure glaucoma and should be monitored closely.

Side Effects

Adverse reactions have been observed in patients receiving treatment, categorized by seriousness and frequency.

Serious adverse reactions include hematologic events such as aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia. Renal complications, including renal failure, renal dysfunction, and interstitial nephritis, have also been reported and warrant attention (see WARNINGS). Hypersensitivity reactions can manifest as anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), and respiratory distress, which may include pneumonitis and pulmonary edema. Additionally, severe skin reactions such as erythema multiforme, including Stevens-Johnson syndrome, and exfoliative dermatitis, including toxic epidermal necrolysis, have been documented.

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. Patients may also experience musculoskeletal symptoms like muscle spasms and nervous system/psychiatric effects, including vertigo, paresthesias, dizziness, headache, and restlessness.

Metabolic disturbances such as electrolyte imbalance, hyperglycemia, glycosuria, and hyperuricemia have been noted. Skin reactions may include photosensitivity, fever, urticaria, rash, and purpura. Transient blurred vision and xanthopsia have been reported under special senses, while urogenital effects may include impotence.

In postmarketing experience, hydrochlorothiazide has been associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC). A study conducted in the Sentinel System indicated that the increased risk was predominantly observed in white patients taking large cumulative doses. The overall population showed an approximate increase of 1 additional case of SCC per 16,000 patients per year, while white patients with 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

Thiazide diuretics may interact with various drug classes, leading to significant clinical effects that warrant careful consideration.

Pharmacodynamic Interactions

• Alcohol, Barbiturates, and Narcotics: The concomitant use of these agents with thiazide diuretics may potentiate orthostatic hypotension. Patients should be monitored for signs of hypotension, and dosage adjustments may be necessary.

• Antidiabetic Drugs: Both oral antidiabetic agents and insulin may require dosage adjustments when administered alongside thiazide diuretics due to potential alterations in glycemic control.

• Corticosteroids and ACTH: The use of corticosteroids or ACTH in conjunction with thiazide diuretics may exacerbate electrolyte depletion, particularly hypokalemia. Regular monitoring of electrolyte levels is advised.

• Other Antihypertensive Drugs: When thiazide diuretics are used with other antihypertensive medications, an additive effect may occur. Blood pressure should be closely monitored to avoid excessive hypotension.

• Nondepolarizing Skeletal Muscle Relaxants: The responsiveness to nondepolarizing skeletal muscle relaxants, such as tubocurarine, may be increased when used with thiazide diuretics. Monitoring of neuromuscular function is recommended.

• Lithium: The use of lithium with diuretics is generally contraindicated due to the risk of reduced renal clearance and increased potential for lithium toxicity. Caution is advised, and alternative therapies should be considered.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): NSAIDs may diminish the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics. Close observation of blood pressure and fluid status is warranted.

Pharmacokinetic Interactions

• Cholestyramine and Colestipol Resins: These resins can significantly impair the absorption of hydrochlorothiazide, reducing its bioavailability by up to 85% and 43%, respectively. Administration of thiazide diuretics should be timed appropriately to minimize this interaction.

• Pressor Amines: The response to pressor amines, such as norepinephrine, may be diminished when used with thiazide diuretics; however, this does not contraindicate their use. Clinicians should be aware of this potential interaction when managing patients.

Monitoring and Testing Considerations

Thiazide diuretics should be discontinued prior to tests for parathyroid function to prevent interference with test results. Regular monitoring of electrolytes, blood pressure, and renal function is essential when thiazide diuretics are used in conjunction with the aforementioned agents to ensure patient safety and therapeutic efficacy.

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. Caution is advised when prescribing to this population due to the lack of robust clinical trial data.

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. In particular, thiazides should be used with caution in patients aged 65 and older, especially those with severe renal disease, as the drug may precipitate azotemia and lead to cumulative effects in individuals with impaired renal function.

Additionally, thiazides should be administered cautiously in geriatric patients with impaired hepatic function or progressive liver disease, as even minor alterations in fluid and electrolyte balance can precipitate hepatic coma. The possibility of exacerbation or activation of systemic lupus erythematosus has also been reported in this population.

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

Monitoring for signs or symptoms of fluid and electrolyte imbalance is crucial in geriatric patients. Warning signs 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 may develop, particularly with brisk diuresis, in the presence of severe cirrhosis, or after prolonged therapy.

If progressive renal impairment is observed, it is advisable to consider withholding or discontinuing diuretic therapy. Periodic determination of serum electrolytes is recommended to detect possible electrolyte imbalances at appropriate intervals.

Pregnancy

Hydrochlorothiazide has been studied in pregnant mice and rats during major organogenesis, with doses up to 3000 mg/kg and 1000 mg/kg, respectively, showing no evidence of teratogenic effects on the fetus. However, there are no adequate and well-controlled studies in pregnant women. Due to the limitations of animal reproduction studies in predicting human outcomes, hydrochlorothiazide should be used during pregnancy only if clearly needed.

It is important to note that thiazides, including hydrochlorothiazide, cross the placental barrier and can be detected in cord blood. This raises concerns regarding potential nonteratogenic effects, including the risk of fetal or neonatal jaundice, thrombocytopenia, and other adverse reactions that may also occur 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 reduced kidney function, thiazides may precipitate azotemia. Additionally, the cumulative effects of the drug may develop in patients with impaired renal function, necessitating careful monitoring and potential dosing adjustments.

Hepatic Impairment

Patients with hepatic impairment should use thiazides with caution. In individuals with impaired hepatic function or progressive liver disease, minor alterations in fluid and electrolyte balance may precipitate hepatic coma. Therefore, careful monitoring of liver function and electrolyte levels is recommended in this population to mitigate potential risks. Adjustments to dosage may be necessary based on the severity of hepatic impairment and the patient's overall clinical status.

Overdosage

In cases of overdosage, the most frequently observed signs and symptoms are primarily attributed to electrolyte depletion, including hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis.

Management of overdosage should involve the implementation of symptomatic and supportive measures. Inducing emesis or performing gastric lavage may be necessary to mitigate the effects of the overdose. Additionally, it is crucial to address dehydration and correct any electrolyte imbalances, hepatic coma, and hypotension through established medical procedures.

In instances where respiratory impairment occurs due to overdose, the administration of oxygen or the provision of artificial respiration may be required to ensure adequate respiratory function.

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 animal studies. However, clinical vigilance is essential in managing potential overdosage scenarios.

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. Due to the limitations of animal reproduction studies in predicting human responses, 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.

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

Hydrochlorothiazide was not found to be genotoxic in vitro, as evidenced by negative results in the Ames mutagenicity assay using various strains of Salmonella typhimurium and 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 also yielded negative results. 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 mcg/mL, as well as in the Aspergillus nidulans non-disjunction assay at an unspecified concentration.

Furthermore, studies indicated that hydrochlorothiazide did not adversely affect the fertility of mice and rats of either sex when 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 most pronounced 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. 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, using sunscreen with a high SPF, and avoiding prolonged sun exposure, especially during peak hours.

Additionally, healthcare providers should emphasize the importance of regular skin cancer screenings for patients on this medication. Patients should be made aware of the potential increased risk of skin cancer associated with hydrochlorothiazide and encouraged to report any unusual skin changes or lesions to their healthcare provider promptly.

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°C to 30°C (59°F to 86°F) in accordance with USP Controlled Room Temperature guidelines. Proper storage conditions are essential to maintain the quality of the product.

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 Chartwell RX, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)