Hydrochlorothiazide

Description

Hydrochlorothiazide is 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. Hydrochlorothiazide is slightly soluble in water, 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. Each tablet for oral administration contains 12.5 mg, 25 mg, or 50 mg of hydrochlorothiazide, 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.

For dependent edema in pregnancy, which arises from venous return restriction by the gravid uterus, treatment should focus on non-pharmacological measures such as elevating the lower extremities and utilizing support stockings. The use of diuretics to reduce intravascular volume in cases of dependent edema during pregnancy is considered illogical and unnecessary. It is important to note that hypervolemia during normal pregnancy is typically not harmful to the mother or fetus in the absence of cardiovascular disease. While this hypervolemia may occasionally be associated with discomfort due to edema, increased recumbency often alleviates such discomfort. In rare instances where edema causes extreme discomfort unrelieved by rest, a short course of diuretic therapy may be appropriate.

Dosage and Administration

The usual adult dosage for the management of edema is 25 to 100 mg daily, which may be administered as a single dose or divided into multiple doses. Many patients with edema may benefit from intermittent therapy, which involves administration on alternate days or on three to five days each week.

For the control of hypertension in adults, the recommended initial dose is 25 mg daily, administered as a single dose. This dose may be increased to 50 mg daily, which can be given as either a single dose or divided into two doses.

In pediatric patients, the usual dosage for diuresis and control of hypertension is 0.5 to 1 mg per pound (1 to 2 mg/kg) per day, administered in either a single dose or two divided doses. The maximum dosage should not exceed 37.5 mg per day for infants up to 2 years of age or 100 mg per day for children aged 2 to 12 years. For infants less than 6 months of age, doses may be increased to 1.5 mg per pound (3 mg/kg) per day, administered in two divided doses, if necessary.

Contraindications

Use of this product is contraindicated in patients with 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 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 Caution is also warranted in patients with impaired hepatic function or progressive liver disease. Minor alterations in fluid and electrolyte balance in these patients may lead to hepatic coma. Close monitoring of liver function and electrolyte levels is recommended.

Drug Interactions Thiazides may enhance the effects of other antihypertensive medications, necessitating careful management of blood pressure and potential adjustments in therapy.

Allergic Reactions Sensitivity reactions can occur in patients regardless of their allergy history, including those with bronchial asthma. Healthcare professionals should remain vigilant for signs of allergic responses.

Systemic Lupus Erythematosus There have been reports of exacerbation or activation of systemic lupus erythematosus in patients taking thiazides. Clinicians should monitor for any signs of this condition in susceptible individuals.

Lithium Interaction The concomitant use of lithium with diuretics is generally not recommended due to the potential for increased lithium levels and toxicity.

Ocular Effects Hydrochlorothiazide, classified as a sulfonamide, may lead to idiosyncratic reactions such as acute transient myopia and acute angle-closure glaucoma. Symptoms may include a sudden decrease in visual acuity or ocular pain, typically manifesting within hours to weeks after initiation of therapy. If acute angle-closure glaucoma occurs, 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.

Electrolyte Monitoring Periodic assessment of serum electrolytes is essential to detect potential imbalances. Regular monitoring should be conducted at appropriate intervals to ensure patient safety and effective management of therapy.

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, leukopenia, hemolytic anemia, and thrombocytopenia. Renal complications may also arise, including renal failure, renal dysfunction, and interstitial nephritis. Hypersensitivity reactions can be severe, presenting as anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), and respiratory distress, which may include pneumonitis and pulmonary edema. Additionally, skin reactions such as erythema multiforme, including Stevens-Johnson syndrome, and exfoliative dermatitis, including toxic epidermal necrolysis, have 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. Metabolic disturbances such as electrolyte imbalance, hyperglycemia, glycosuria, and hyperuricemia have also been noted.

In terms of urogenital effects, impotence has been reported, while transient blurred vision and xanthopsia are noted under special senses.

Postmarketing experience has revealed an association between hydrochlorothiazide and an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC). Data from a study conducted in the Sentinel System indicated that the increased risk was predominantly observed in white patients receiving large cumulative doses. Specifically, the overall population exhibited an approximate 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

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, necessitating careful blood pressure monitoring and possible dosage adjustments.

• Pressor Amines (e.g., Norepinephrine): The response to pressor amines may be diminished when used with thiazide diuretics; however, this does not contraindicate their use. Clinicians should be aware of this interaction and monitor patient response.

• Non-Depolarizing Skeletal Muscle Relaxants (e.g., Tubocurarine): Increased responsiveness to non-depolarizing skeletal muscle relaxants may occur when used with thiazide diuretics. Monitoring of neuromuscular function is recommended.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The effectiveness of thiazide diuretics may be reduced by NSAIDs, which can diminish diuretic, natriuretic, and antihypertensive effects. Close observation of blood pressure and fluid status is warranted.

Pharmacokinetic Interactions

• Cholestyramine and Colestipol Resins: These resins can significantly impair the gastrointestinal absorption of hydrochlorothiazide, reducing its absorption by up to 85% and 43%, respectively. It is advisable to separate the administration of these agents from thiazide diuretics to minimize interaction.

• Lithium: The use of lithium with diuretics is generally contraindicated due to the potential for reduced renal clearance and an increased risk of lithium toxicity. Monitoring of lithium levels is essential if co-administration is unavoidable.

In summary, careful monitoring and potential dosage adjustments are critical when thiazide diuretics are used in conjunction with the aforementioned drug classes to mitigate the risk of adverse effects and ensure 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 primarily 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 may include an acute onset of decreased visual acuity or ocular pain, typically manifesting within hours to weeks after initiation of therapy.

Monitoring for signs or symptoms of fluid and electrolyte imbalance is crucial in geriatric patients. Warning signs may include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. Hypokalemia may develop, particularly with brisk diuresis, in cases 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, ensuring the safety and efficacy of treatment in elderly patients.

Pregnancy

Hydrochlorothiazide has been studied in pregnant mice and rats during their major organogenesis periods, with doses up to 3,000 mg/kg and 1,000 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 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 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

There are no specific statements regarding the use of this medication in lactating mothers or its effects on breastfed infants. Healthcare professionals should consider the absence of data when advising lactating mothers about the use of this medication.

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, highlighting the importance of dose adjustments and vigilant oversight in this group.

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 include electrolyte depletion, specifically hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis.

Management of overdosage should begin with the induction of emesis or the performance of gastric lavage to reduce the absorption of the drug. It is crucial to correct any dehydration and electrolyte imbalances through established medical procedures.

Should respiratory impairment arise as a consequence of the overdose, it is essential to provide supplemental oxygen or initiate artificial respiration as necessary to ensure adequate oxygenation.

The oral LD50 of hydrochlorothiazide has been determined to be greater than 10 g/kg in both mice and rats. However, the extent to which hydrochlorothiazide can be removed from the body via hemodialysis remains undetermined. Therefore, healthcare professionals should exercise caution and monitor patients closely in the event of suspected overdosage.

Nonclinical Toxicology

Studies involving the oral administration of hydrochlorothiazide to pregnant mice and rats during critical periods of organogenesis, at doses up to 3,000 mg/kg and 1,000 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 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 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.

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 assays at concentrations ranging from 43 to 1,300 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 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 for maintaining the quality of the product.

Additional Clinical Information

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

FDA Insert (PDF)

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

View full prescribing information (PDF)