Hydrochlorothiazide

Description

Hydrochlorothiazide, USP is the 3,4-dihydro derivative of chlorothiazide, with the chemical name 6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. The molecular formula is C7H8ClN3O4S2, and it has a molecular weight of 297.74. The structural formula is represented as follows:

Hydrochlorothiazide appears as a white, or practically white, crystalline powder that is slightly soluble in water and freely soluble in sodium hydroxide solution. It is supplied in 12.5 mg capsules for oral administration. The formulation includes inactive ingredients such as black iron oxide, colloidal silicon dioxide, gelatin, magnesium stearate, microcrystalline cellulose, pregelatinized starch, sodium lauryl sulfate, and titanium dioxide. It is important to note that FDA-approved dissolution test specifications differ from those of the USP.

Uses and Indications

Hydrochlorothiazide capsules are indicated for the management of hypertension, either as a monotherapy or in combination with other antihypertensive agents. This medication is suitable for patients in whom the risk of developing hyperkalemia must be minimized, including those receiving ACE inhibitors.

The use of diuretics, including hydrochlorothiazide, in otherwise healthy pregnant women is generally inappropriate, as it may expose both the mother and fetus to unnecessary risks. Diuretics do not prevent the onset of toxemia of pregnancy, nor is there sufficient evidence to support their efficacy in treating established toxemia.

In cases where edema during pregnancy is attributable to pathological causes, diuretics may be indicated, similar to their use in non-pregnant individuals. However, dependent edema resulting from venous return restriction due to an expanded uterus should be managed through non-pharmacological measures such as elevating the lower extremities and utilizing support hose. The routine use of diuretics to reduce intravascular volume in this context is illogical and unnecessary.

It is important to note that hypervolemia is a normal physiological condition during pregnancy and is not harmful to the mother or fetus in the absence of cardiovascular disease, despite being associated with edema in many pregnant women. If edema causes significant discomfort, increased recumbency may provide relief. In rare instances where edema leads to extreme discomfort unrelieved by rest, a short course of diuretics may be appropriate for symptom management.

Dosage and Administration

The adult initial dose of hydrochlorothiazide capsules for the control of hypertension is one capsule administered once daily. This dosage may be used alone or in combination with other antihypertensive agents. It is important to note that total daily doses exceeding 50 mg are not recommended.

Contraindications

Hydrochlorothiazide capsules are contraindicated in patients with anuria due to the lack of urine output, which may lead to adverse effects. Additionally, use is contraindicated in individuals with hypersensitivity to hydrochlorothiazide or other sulfonamide-derived drugs, as this may result in severe allergic reactions.

Warnings and Precautions

Hydrochlorothiazide, a sulfonamide, is associated with several significant warnings and precautions that healthcare professionals must consider to ensure patient safety.

Acute Myopia and Secondary Angle-Closure Glaucoma Hydrochlorothiazide can induce an idiosyncratic reaction leading to acute transient myopia and acute angle-closure glaucoma. Symptoms may present as a sudden decrease in visual acuity or ocular pain, typically occurring within hours to weeks following the initiation of therapy. It is critical to recognize that untreated acute angle-closure glaucoma can result in permanent vision loss. The primary intervention is the immediate discontinuation of hydrochlorothiazide. If intraocular pressure remains uncontrolled, prompt medical or surgical interventions should be considered. Patients with a history of sulfonamide or penicillin allergy may be at increased risk for developing acute angle-closure glaucoma.

Diabetes and Hypoglycemia Healthcare professionals should be aware that latent diabetes mellitus may become apparent in patients receiving hydrochlorothiazide. Additionally, diabetic patients on thiazide therapy may require adjustments to their insulin dosage to maintain glycemic control.

Renal Disease In patients with impaired renal function, the cumulative effects of thiazides can lead to the development of azotemia. It is essential to monitor renal function closely in these patients to prevent potential complications associated with thiazide use. Regular assessment of renal parameters is recommended to ensure safe administration of hydrochlorothiazide in this population.

Side Effects

Adverse reactions associated with hydrochlorothiazide include a range of serious and common effects, as observed in clinical trials and postmarketing experiences.

Serious adverse reactions include hematologic events such as aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia. Renal complications may manifest as renal failure, renal dysfunction, and interstitial nephritis. Hypersensitivity reactions can be severe, including anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), and respiratory distress, which may present as pneumonitis and pulmonary edema. Additionally, patients may experience acute myopia and secondary angle-closure glaucoma, which can lead to permanent vision loss if untreated. Symptoms of this condition typically arise within hours to weeks of initiating treatment and include acute onset of decreased visual acuity or ocular pain.

Common adverse reactions reported include weakness, hypotension (including orthostatic hypotension), and various digestive issues such as diarrhea, vomiting, nausea, and abdominal cramping. Patients may also experience metabolic disturbances, including electrolyte imbalances, hyperglycemia, glycosuria, and hyperuricemia. Neurological effects such as vertigo, paresthesia, dizziness, headache, and restlessness have also been noted. Musculoskeletal symptoms may include muscle spasms, while urogenital effects can manifest as impotence. Skin reactions may range from erythema multiforme, including Stevens-Johnson syndrome, to exfoliative dermatitis and alopecia. Transient blurred vision and xanthopsia have been reported as effects on special senses.

Postmarketing data indicate an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC), in patients taking hydrochlorothiazide. The risk is notably higher in white patients receiving large cumulative doses, with an estimated increase of approximately 1 additional case of SCC per 16,000 patients per year in the overall population, and 1 additional case for every 6,700 patients per year in those taking a cumulative dose of ≥50,000 mg.

Patients with a history of sulfonamide or penicillin allergy may be at increased risk for developing acute angle-closure glaucoma. Furthermore, latent diabetes mellitus may become apparent in some patients, necessitating adjustments in insulin dosage for those with diabetes. In patients with impaired renal function, thiazides may precipitate azotemia due to cumulative effects.

Drug Interactions

Concomitant use of thiazide diuretics with certain medications may lead to significant drug interactions, categorized as follows:

Pharmacodynamic Interactions:

• Alcohol, Barbiturates, or Narcotics: The combination may potentiate orthostatic hypotension, necessitating careful monitoring of blood pressure and patient symptoms.

• Antidiabetic Drugs (Oral Agents and Insulin): Dosage adjustments of antidiabetic medications may be required to maintain glycemic control when used alongside thiazide diuretics.

• Other Antihypertensive Drugs: The use of additional antihypertensive agents may result in an additive effect, which could lead to hypotension. Monitoring of blood pressure is advised.

• Corticosteroids and ACTH: Concurrent use may intensify electrolyte depletion, particularly hypokalemia. Regular monitoring of electrolyte levels is recommended.

• Skeletal Muscle Relaxants (Nondepolarizing, e.g., Tubocurarine): There may be an increased responsiveness to muscle relaxants, which should be considered during anesthesia and muscle relaxation procedures.

• Pressor Amines (e.g., Norepinephrine): There is a potential for decreased response to pressor amines; however, this interaction does not preclude their use.

Pharmacokinetic Interactions:

• Cholestyramine and Colestipol Resins: These agents can bind hydrochlorothiazide, reducing its gastrointestinal absorption by up to 85% and 43%, respectively. Administration of thiazide diuretics should be timed appropriately to avoid this interaction.

• Lithium: Thiazide diuretics can reduce renal clearance of lithium, significantly increasing the risk of lithium toxicity. Co-administration is generally not recommended, and careful monitoring of lithium levels is essential if used together.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The use of NSAIDs may diminish the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics in some patients. Close observation is warranted to ensure the desired diuretic effect is achieved.

Drug/Laboratory Test Interactions:

Thiazide diuretics 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

Safety and effectiveness in pediatric patients have not been established. Therefore, the use of this medication in children, infants, and adolescents should be approached with caution until further data is available.

Geriatric Use

Elderly patients, defined as those aged 65 years and older, may experience a greater reduction in blood pressure and an increased incidence of side effects when treated with hydrochlorothiazide. Due to these considerations, it is recommended that treatment in this population begins with the lowest available dose of hydrochlorothiazide, specifically 12.5 mg.

If further titration of the dosage is necessary, increments of 12.5 mg should be employed. Careful monitoring of blood pressure and potential adverse effects is advised to ensure the safety and efficacy of treatment in geriatric patients.

Pregnancy

Hydrochlorothiazide has been evaluated in animal studies for teratogenic effects, 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 evidence of harm to 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, 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 and thrombocytopenia, as well as other adverse reactions that may occur in adults. Healthcare professionals should carefully consider the benefits and risks when prescribing hydrochlorothiazide to 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 nursing or to discontinue hydrochlorothiazide, weighing the importance of the medication to the lactating mother.

Renal Impairment

Patients with renal impairment may experience cumulative effects of thiazides due to reduced kidney function. In these individuals, the use of thiazides can precipitate azotemia. Therefore, careful monitoring and consideration of dosing adjustments are recommended for patients with impaired renal function to mitigate potential adverse effects.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters have not been defined.

Overdosage

Overdosage may present with a range of symptoms primarily associated with electrolyte depletion and dehydration. The most frequently observed signs include hypokalemia, hypochloremia, and hyponatremia, which can result from excessive diuresis. In cases where digitalis has been co-administered, hypokalemia may further 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 research may be warranted to clarify this aspect of management.

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, did not demonstrate teratogenic effects. However, there are no adequate and well-controlled studies in pregnant women, and since animal reproduction studies may not reliably predict 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 have been observed in adults.

Two-year feeding studies conducted by the National Toxicology Program (NTP) in mice and rats revealed 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 of 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 genotoxicity in vivo in assays involving mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and 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.

Hydrochlorothiazide did not adversely affect the fertility of either male or female mice and rats 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

Hydrochlorothiazide has been associated with 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 notably observed in white patients who are administered large cumulative doses of the medication. Specifically, the overall population exhibits an approximate risk of 1 additional case of SCC per 16,000 patients per year. For white patients receiving a cumulative dose of ≥50,000 mg, the risk escalates to approximately 1 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 and to undergo regular skin cancer screenings. It is important for patients to be monitored for signs of fluid or electrolyte disturbances, including conditions such as hyponatremia, hypochloremic alkalosis, hypokalemia, and hypomagnesemia.

Patients should be made aware of warning signs or symptoms indicative of fluid and electrolyte imbalance, which may include dryness of the mouth, increased thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. To mitigate the risk of hypokalemia, patients may be advised to consider potassium supplementation or to increase their intake of potassium-rich foods.

Healthcare providers should inform patients about the serious nature of dilutional hyponatremia, which can be life-threatening and may occur in edematous patients during hot weather. In such cases, appropriate management typically involves water restriction rather than salt administration, except in rare instances where hyponatremia poses an immediate threat to life.

Patients should be instructed to report any signs of acute myopia or ocular pain, as these symptoms may suggest the development of acute angle-closure glaucoma. Diabetic patients should be advised that latent diabetes mellitus may become apparent, necessitating potential adjustments to their insulin dosage.

Thiazides should be used with caution in patients with impaired hepatic function, as they can precipitate hepatic coma in those with severe liver disease. Patients should also be encouraged to consult their healthcare provider prior to initiating any new medications, including over-the-counter drugs, due to the potential for interactions with thiazides.

It is essential to inform patients about the possibility of increased sensitivity to the effects of alcohol, barbiturates, or narcotics, which may lead to orthostatic hypotension. Patients should be advised to monitor for signs of hyperuricemia or acute gout, as these conditions may be precipitated by thiazide use.

Finally, nursing mothers should be made aware that thiazides are excreted in breast milk and should consider the importance of the medication to their health when deciding whether to continue nursing or to discontinue the drug.

Storage and Handling

The product is supplied in accordance with the following specifications: it should be stored at a temperature range of 20°C to 25°C (68°F to 77°F), adhering to the guidelines set forth by USP Controlled Room Temperature. It is essential to protect the product from light, moisture, and freezing conditions. Freezing at temperatures of -20°C (-4°F) is strictly prohibited. Additionally, the container must be kept tightly closed to maintain the integrity of the product.

Additional Clinical Information

Thiazides should be discontinued prior to conducting tests for parathyroid function to ensure accurate results. Patients prescribed hydrochlorothiazide are advised to protect their skin from sun exposure and to participate in 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 is notably higher 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 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 Unichem Pharmaceuticals (USA) , Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)