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 either 12.5 mg, 25 mg, or 50 mg of hydrochlorothiazide. 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 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. 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 caused by venous return restriction from the gravid uterus, non-pharmacological measures such as elevating the lower extremities and using support stockings are recommended. The use of diuretics to reduce intravascular volume in this context is considered illogical and unnecessary, as hypervolemia during normal pregnancy is not harmful in the absence of cardiovascular disease. In rare cases where edema causes significant discomfort not alleviated by rest, a short course of diuretic therapy may be appropriate.

Dosage and Administration

Therapy should be individualized according to patient response, utilizing the smallest dosage necessary to achieve the desired effect.

In adults, for the management of edema, the usual dosage ranges from 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 three to five days each week.

For the control of hypertension in adults, the initial recommended dose is 25 mg daily, administered as a single dose. This may be increased to 50 mg daily, which can be given as a single dose or divided into two doses. It is important to note that doses exceeding 50 mg may lead to significant reductions in serum potassium levels.

In pediatric patients, for diuresis and the control of hypertension, the typical dosage 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 used with caution in individuals with severe renal disease, as they may precipitate azotemia. In patients with impaired renal function, the cumulative effects of the drug can develop, necessitating close monitoring of renal parameters.

Hepatic Function Caution is also advised 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, highlighting the need for vigilant monitoring of liver function.

Drug Interactions Thiazides may enhance the effects of other antihypertensive medications, which could lead to hypotension. Healthcare professionals should be aware of this potential interaction when prescribing thiazides alongside other antihypertensive agents.

Allergic Reactions Sensitivity reactions can occur in patients regardless of their allergy history, including those with bronchial asthma. Therefore, it is essential to monitor for any 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.

Lithium Interaction Lithium should generally not be administered concurrently with diuretics, including thiazides, due to the risk of lithium toxicity.

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 after initiation of 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.

Electrolyte Monitoring Periodic determination of serum electrolytes is recommended to detect potential electrolyte 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. Renal complications, including renal failure, renal dysfunction, and interstitial nephritis, have also been reported. 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 such as impotence have also been observed.

In postmarketing experience, hydrochlorothiazide has been associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC) in white patients taking large cumulative doses. Data from a study conducted in the Sentinel System indicated that the overall increased risk for SCC was approximately 1 additional case per 16,000 patients per year, while for white patients receiving a cumulative dose of ≥50,000 mg, the risk increase was approximately 1 additional SCC case for every 6,700 patients per year.

Drug Interactions

Concomitant use of certain medications with hydrochlorothiazide may lead to significant drug interactions, categorized primarily into pharmacodynamic and pharmacokinetic interactions.

Pharmacodynamic Interactions

• Alcohol, Barbiturates, and Narcotics: The combination of hydrochlorothiazide with these agents 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 antidiabetic medications may be necessary when used alongside hydrochlorothiazide. Close monitoring of blood glucose levels is recommended to ensure effective glycemic control.

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

• Corticosteroids and ACTH: Co-administration 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 when used with hydrochlorothiazide; however, this interaction is not sufficient to contraindicate their use. Clinical judgment should guide the use of pressor agents.

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

• 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 essential prior to co-administration.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The concurrent use of NSAIDs may diminish the diuretic, natriuretic, and antihypertensive effects of hydrochlorothiazide. Patients should be closely observed to ensure that the desired diuretic effect is achieved.

Pharmacokinetic Interactions

• Cholestyramine and Colestipol Resins: The absorption of hydrochlorothiazide is significantly impaired in the presence of anionic exchange resins. Single doses of cholestyramine or colestipol can reduce the gastrointestinal absorption of hydrochlorothiazide by up to 85% and 43%, respectively. It is advisable to separate the administration of hydrochlorothiazide and these resins by at least 2 hours to minimize interaction.

Healthcare professionals should remain vigilant for potential interactions and adjust treatment regimens accordingly 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 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, particularly those aged 65 and older, when using thiazide diuretics, especially in the presence of severe renal disease. In such patients, thiazides may precipitate azotemia, and the cumulative effects of the drug can develop due to impaired renal function. It is essential to monitor renal function closely and consider withholding or discontinuing diuretic therapy if progressive renal impairment becomes evident.

In addition, thiazides should be used with caution in geriatric patients with impaired hepatic function or progressive liver disease, as even minor alterations in fluid and electrolyte balance may lead to hepatic coma. The risk of hypokalemia is heightened in elderly patients, particularly with brisk diuresis, severe cirrhosis, or after prolonged therapy. Therefore, periodic determination of serum electrolytes is recommended to detect potential electrolyte imbalances at appropriate intervals.

Furthermore, there have been reports of exacerbation or activation of systemic lupus erythematosus in some patients. It is also noted that the antihypertensive effects of thiazides may be enhanced in patients who have undergone sympathectomy. Generally, elderly patients do not require doses exceeding 50 mg of hydrochlorothiazide daily when used in conjunction with other antihypertensive agents. Careful monitoring and dose adjustments may be necessary to ensure safety and efficacy in this population.

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 professionals should weigh the potential 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 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 consideration of dosing adjustments and close observation during treatment.

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

Overdosage may present with a range of symptoms primarily associated with electrolyte depletion and dehydration due to excessive diuresis. The most frequently observed signs include hypokalemia, hypochloremia, and hyponatremia. In cases where digitalis has been co-administered, hypokalemia can exacerbate the risk of cardiac arrhythmias.

In the event of an overdosage, it is crucial to implement symptomatic and supportive measures. Inducing emesis or performing gastric lavage is recommended to mitigate the effects of the overdose. Additionally, it is essential to correct any dehydration and electrolyte imbalances, as well as to address hepatic coma and hypotension using established medical procedures. Should respiratory impairment occur, 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 efficacy of hemodialysis in removing hydrochlorothiazide from the system has not been established, and further evaluation may be warranted in cases of severe 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 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, as evidenced by the Ames mutagenicity assay using various strains of Salmonella typhimurium and 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 showed no genotoxic effects. 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 indicated 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, 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 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 Heritage Pharmaceuticals Inc. d/b/a Avet Pharmaceuticals Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)