Hydrochlorothiazide

Description

Hydrochlorothiazide is a diuretic and antihypertensive agent, classified as the 3,4-dihydro derivative of chlorothiazide. The chemical name for hydrochlorothiazide 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.

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

For oral administration, each tablet contains hydrochlorothiazide in strengths of 12.5 mg, 25 mg, or 50 mg. The tablets also include inactive ingredients such as 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 management of hypertension, hydrochlorothiazide tablets may be utilized either as a monotherapy or in conjunction with other antihypertensive agents to enhance their effectiveness, particularly in cases of more severe hypertension.

Limitations of Use: Routine use of diuretics, including hydrochlorothiazide, during normal pregnancy is not recommended, as it may expose both the mother and fetus to unnecessary risks. Diuretics do not prevent the development of toxemia of pregnancy, nor is there sufficient evidence to support 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, non-pharmacological measures such as elevating the lower extremities and using support stockings are appropriate. The use of diuretics to reduce intravascular volume in cases of dependent edema during normal pregnancy is considered illogical and unnecessary, as hypervolemia is typically not harmful to the mother or fetus in the absence of cardiovascular disease. In rare instances where edema causes significant discomfort that is not alleviated by rest, a short course of diuretic therapy may be warranted to provide relief.

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 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 used with caution in individuals with severe renal disease, as they may precipitate azotemia. Patients with impaired renal function are at risk for cumulative effects of the drug, necessitating close monitoring of renal parameters.

Hepatic Function In patients with impaired hepatic function or progressive liver disease, thiazides may lead to minor alterations in fluid and electrolyte balance, which could precipitate hepatic coma. Therefore, careful assessment of liver function is recommended prior to and during treatment.

Drug Interactions Thiazides may enhance the effects of other antihypertensive medications. Healthcare professionals should monitor patients for additive effects when these agents are used concurrently.

Allergic Reactions Sensitivity reactions can occur in patients regardless of their allergy history, including those with bronchial asthma. Vigilance for signs of allergic reactions is advised.

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

Lithium Interaction Lithium should generally not be administered in conjunction with diuretics due to the risk of lithium toxicity. Regular monitoring of lithium levels is essential in patients receiving both therapies.

Ocular Effects Hydrochlorothiazide, a sulfonamide, may cause 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 occurring within hours to weeks of initiation. If acute angle-closure glaucoma is suspected, immediate discontinuation of hydrochlorothiazide is critical, and prompt medical or surgical intervention may be necessary if intraocular pressure remains uncontrolled. Patients with a history of sulfonamide or penicillin allergy may be at increased risk for developing this condition.

Electrolyte Monitoring Periodic determination of serum electrolytes is recommended 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 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. Additionally, hypersensitivity reactions may occur, including anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), and respiratory distress, which encompasses pneumonitis and pulmonary edema. Renal complications such as renal failure, renal dysfunction, and interstitial nephritis have also been reported, necessitating careful monitoring.

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, as well as nervous system and psychiatric effects, including vertigo, paresthesias, dizziness, headache, and restlessness.

Skin reactions can manifest as erythema multiforme (including Stevens-Johnson syndrome), exfoliative dermatitis (including toxic epidermal necrolysis), and alopecia. Patients may report transient blurred vision and xanthopsia as special senses effects. Urogenital issues, such as impotence, have also been noted.

In postmarketing experience, hydrochlorothiazide has been associated with 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 taking large cumulative doses. The overall risk for SCC in the population was approximately 1 additional case per 16,000 patients per year, while for white patients with a cumulative dose of ≥50,000 mg, the risk increase was approximately 1 additional SCC case for every 6,700 patients per year.

Patients should be monitored for these adverse reactions, and appropriate measures should be taken to manage them as necessary.

Drug Interactions

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

Pharmacodynamic Interactions

• Alcohol, Barbiturates, and Narcotics: Concurrent use 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 lead to 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.

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

• Lithium: The use of diuretics with lithium is generally contraindicated due to the potential for reduced renal clearance of lithium, increasing the risk of toxicity. Refer to the package insert for specific lithium preparations before co-administration.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): 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 can reduce hydrochlorothiazide absorption 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; however, this interaction is not sufficient to contraindicate their use. Monitoring of blood pressure response is recommended.

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, particularly those aged 65 and older. Caution is advised in patients with severe renal disease, as thiazides can precipitate azotemia and lead to cumulative effects in individuals with impaired renal function. If progressive renal impairment is observed, it may be necessary to withhold or discontinue diuretic therapy.

In addition, thiazides should be used cautiously in patients with impaired hepatic function or progressive liver disease, as even minor alterations in fluid and electrolyte balance can precipitate hepatic coma. Monitoring for signs of fluid or electrolyte imbalance is essential for all patients receiving diuretic therapy. Elderly patients should be observed for symptoms such as hyponatremia, hypochloremic alkalosis, and hypokalemia. Warning signs of fluid and electrolyte imbalance include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle cramps, hypotension, oliguria, tachycardia, and gastrointestinal disturbances like nausea and vomiting.

Hypokalemia is a particular concern, especially in cases of brisk diuresis, severe cirrhosis, or prolonged therapy. This condition can lead to cardiac arrhythmias and may sensitize the heart to the toxic effects of digitalis, increasing the risk of ventricular irritability. To mitigate the risk of hypokalemia, potassium-sparing diuretics or potassium supplements, such as potassium-rich foods, may be beneficial.

In 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 and urine electrolytes is particularly important, especially in patients experiencing excessive vomiting or receiving parenteral fluids. Regular monitoring should be conducted at appropriate intervals to detect any potential electrolyte imbalances.

Pregnancy

Hydrochlorothiazide has been evaluated in animal studies where it was administered orally to pregnant mice and rats during critical periods of organogenesis at doses up to 3,000 mg/kg and 1,000 mg/kg, respectively. These studies did not demonstrate any evidence of teratogenic effects on the fetus. However, there are no adequate and well-controlled studies in pregnant women, and because animal reproduction studies are not always predictive of 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 possibly other adverse reactions that have been observed in adults. Healthcare providers should weigh the potential benefits against the risks when considering the use of hydrochlorothiazide in pregnant patients.

Lactation

There are no specific statements regarding nursing mothers or lactation in the provided text. Therefore, the effects of the medication on breastfed infants and the excretion of the drug in human milk remain undetermined. Healthcare professionals should consider the lack of data when advising lactating mothers on the use of this medication.

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 to closely monitor these patients for any signs of deterioration in liver function and to assess their 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 associated with 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 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 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 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.

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.

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 genotoxicity 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 (clastogenicity) and 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.

In terms of fertility, hydrochlorothiazide did not adversely affect the reproductive capabilities of mice and rats of either sex 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

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

Dispense in a tight, light-resistant container to ensure product integrity. The product 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.

Additional Clinical Information

Clinicians should conduct periodic determinations of serum electrolytes in patients to detect 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)