Hydrochlorothiazide

Description

Hydrochlorothiazide (hydrochlorothiazide, USP 12.5 mg) is the 3,4-dihydro derivative of chlorothiazide, with a chemical name of 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C7H8ClN3O4S2, and it has a molecular weight of 297.74. The structural formula is provided in the accompanying documentation.

This compound appears as a white, or practically white, crystalline powder that is slightly soluble in water and freely soluble in sodium hydroxide solution. Hydrochlorothiazide capsules, USP, are formulated for oral use, containing 12.5 mg of the active ingredient per capsule.

Inactive ingredients include colloidal silicon dioxide, corn starch, lactose monohydrate, and magnesium stearate. The hard gelatin shell of the capsules is composed of gelatin, titanium dioxide, sodium lauryl sulfate, FD&C Blue #1, and FD&C Red #3. The capsules are printed with black ink, which contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, black iron oxide, and potassium hydroxide.

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 particularly suitable for patients in whom the risk of developing hyperkalemia must be avoided, including those receiving ACE inhibitors.

The routine use of diuretics, including hydrochlorothiazide, in otherwise healthy pregnant women is not recommended, as it poses unnecessary risks to both the mother and fetus. Diuretics do not prevent the onset of toxemia of pregnancy, and there is insufficient evidence to support their efficacy in treating established toxemia.

In specific circumstances, diuretics may be indicated during pregnancy when edema is attributable to pathological causes. However, for dependent edema resulting from venous return restriction due to an expanded uterus, non-pharmacological interventions such as elevating the lower extremities and using support hose are preferred. The physiological hypervolemia associated with normal pregnancy is generally not harmful to the mother or fetus, provided there are no underlying cardiovascular conditions. While this hypervolemia may lead to edema, it is typically manageable through increased recumbency.

In rare cases where edema causes significant discomfort that is unrelieved by rest, a short course of diuretics may be considered appropriate for symptom relief.

Dosage and Administration

The adult initial dose of hydrochlorothiazide capsules, USP, is one capsule administered once daily. This dosage is applicable whether the medication is prescribed as monotherapy or in conjunction with other antihypertensive agents.

It is important to note that total daily doses exceeding 50 mg are not recommended. Healthcare professionals should monitor patients for efficacy and tolerability, adjusting the dosage as necessary while adhering to the maximum recommended limits.

Contraindications

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

Warnings and Precautions

Hydrochlorothiazide, a sulfonamide, carries the risk of idiosyncratic reactions, which may lead to acute transient myopia and acute angle-closure glaucoma. Healthcare professionals should be vigilant for symptoms such as an acute onset of decreased visual acuity or ocular pain, which can occur within hours to weeks following the initiation of therapy. If left untreated, acute angle-closure glaucoma can result in permanent vision loss. The primary course of action is to discontinue hydrochlorothiazide as swiftly as possible. In cases where intraocular pressure remains uncontrolled, prompt medical or surgical interventions may be necessary. Patients with a history of sulfonamide or penicillin allergy may be at an increased risk for developing acute angle-closure glaucoma.

Additionally, it is important to note that latent diabetes mellitus may become apparent in patients receiving thiazides. Diabetic patients may require adjustments to their insulin dosage to maintain glycemic control while on this medication.

Caution is advised when prescribing hydrochlorothiazide to patients with impaired renal function, as cumulative effects of thiazides can lead to the development of azotemia in these individuals. Regular monitoring of renal function is recommended to mitigate this risk.

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 may include hematologic conditions such as aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia. Renal complications can manifest as renal failure, renal dysfunction, and interstitial nephritis. Hypersensitivity reactions may present as anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), and respiratory distress, which includes pneumonitis and pulmonary edema. Additionally, patients may experience severe skin reactions such as erythema multiforme, including Stevens-Johnson syndrome, and exfoliative dermatitis, including toxic epidermal necrolysis.

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.

In terms of postmarketing experience, hydrochlorothiazide has been associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC), especially in white patients receiving large cumulative doses. The risk for SCC in the general population is approximately one additional case per 16,000 patients per year, while for white patients taking a cumulative dose of ≥50,000 mg, the risk increases to approximately one additional case for every 6,700 patients per year.

Patients should be monitored for signs of fluid or electrolyte disturbances, including hypokalemia, which may occur, particularly with brisk diuresis or in the presence of severe cirrhosis. Warning signs of fluid and electrolyte imbalance include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle cramps, hypotension, and gastrointestinal disturbances.

Hydrochlorothiazide can also precipitate acute myopia and secondary angle-closure glaucoma, with symptoms typically occurring within hours to weeks of initiation. Prompt discontinuation of the drug is essential to prevent permanent vision loss. Furthermore, latent diabetes mellitus may become manifest in patients, necessitating adjustments in insulin dosage for those with diabetes.

Overall, careful monitoring and management of these adverse reactions are crucial for patient safety during hydrochlorothiazide therapy.

Drug Interactions

The following drug interactions have been identified with hydrochlorothiazide capsules, 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 exercise caution when standing up.

• Antidiabetic Drugs (Oral Agents and Insulin): Dosage adjustments of the antidiabetic medication may be necessary to maintain glycemic control. Regular 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 closely.

• Corticosteroids and ACTH: Co-administration may result in intensified electrolyte depletion, particularly hypokalemia. Electrolyte levels should be monitored regularly.

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

• Lithium: The use of diuretics, including hydrochlorothiazide, can reduce renal clearance of lithium, significantly increasing the risk of lithium toxicity. Caution is advised, and the package insert for lithium preparations should be consulted prior to co-administration.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): In some patients, NSAIDs may diminish the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics. Patients should be closely observed to ensure the desired diuretic effect is achieved.

Pharmacokinetic Interactions

• Cholestyramine and Colestipol Resins: These resins can bind hydrochlorothiazide, reducing its gastrointestinal 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. Clinical judgment should guide the use of pressor agents in patients receiving hydrochlorothiazide.

Drug & Laboratory Test Interactions

• Parathyroid Function Tests: Thiazides should be discontinued prior to conducting tests for parathyroid function to avoid interference with test results.

Healthcare professionals should remain vigilant for these interactions and adjust treatment regimens as necessary 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

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.

Should further titration be necessary, increments of 12.5 mg should be employed to ensure careful monitoring of both efficacy and tolerability. Healthcare providers should remain vigilant in assessing the response and any adverse effects in geriatric patients throughout the treatment process.

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 fetal harm. 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. There is a potential 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

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 may experience cumulative effects of thiazides due to reduced kidney function. It is important to monitor these patients closely, as thiazides can precipitate azotemia in this population. Dosing adjustments may be necessary to mitigate the risk of adverse effects associated with impaired renal clearance.

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 outlined 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 are not defined in the available information.

Overdosage

Overdosage of hydrochlorothiazide can lead to significant clinical manifestations primarily due to electrolyte depletion and dehydration. The most frequently observed signs and symptoms include hypokalemia, hypochloremia, and hyponatremia, which may result from excessive diuresis. In cases where digitalis has also been administered, the presence of hypokalemia can exacerbate the risk of cardiac arrhythmias.

In the event of an overdosage, it is crucial to implement symptomatic and supportive measures promptly. 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 potential complications such as hepatic coma and hypotension through established medical procedures. In instances of respiratory impairment, the administration of oxygen or the provision of 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 relatively high threshold for acute toxicity in these species. However, the extent to which hydrochlorothiazide can be removed from the body via hemodialysis remains to be established. Therefore, healthcare professionals should remain vigilant and prepared to manage the complications associated with overdosage effectively.

Nonclinical Toxicology

Studies evaluating the teratogenic effects of hydrochlorothiazide involved oral administration to pregnant mice and rats during critical periods of organogenesis, with doses reaching up to 3,000 mg/kg in mice and 1,000 mg/kg in rats. These studies did not demonstrate any evidence of fetal harm. However, it is important to note that there are no adequate and well-controlled studies in pregnant women. Given that 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 to the fetus or neonate, including the possibility of jaundice, thrombocytopenia, and other adverse reactions that have been observed in adults.

In terms of carcinogenicity, two-year feeding studies conducted by the National Toxicology Program (NTP) in mice and rats revealed no evidence of carcinogenic potential 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 for 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, in vivo assays involving mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene did not indicate genotoxicity. 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 1300 mcg/mL, as well as in the Aspergillus nidulans non-disjunction assay at an unspecified concentration.

Regarding 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

During post-approval use of hydrochlorothiazide, an adverse reaction has been identified. This reaction has been reported voluntarily from a population of uncertain size, making it impossible to reliably estimate its frequency or establish a causal relationship to drug exposure.

Patient Counseling

Patients taking hydrochlorothiazide should be instructed to protect their skin from sun exposure and to undergo regular skin cancer screenings. Healthcare providers should discuss the warning signs and symptoms of fluid and electrolyte imbalance with patients, 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.

It is important for healthcare providers to observe patients for signs of fluid or electrolyte disturbances, including hyponatremia, hypochloremic alkalosis, hypokalemia, and hypomagnesemia. Patients should be made aware that hypokalemia may develop, particularly with brisk diuresis in the presence of severe cirrhosis, during concomitant use of corticosteroids or adrenocorticotropic hormone (ACTH), or after prolonged therapy. Healthcare providers should advise patients that hypokalemia can be avoided or treated through potassium supplementation or by increasing the intake of potassium-rich foods.

Patients should be informed that dilutional hyponatremia is a life-threatening condition that may occur in edematous patients during hot weather. In such cases, appropriate therapy involves water restriction rather than salt administration, except in rare instances when hyponatremia is life-threatening.

Healthcare providers should caution patients that thiazides should be used with care in individuals with impaired hepatic function, as they can precipitate hepatic coma in patients with severe liver disease. It is also essential to inform patients that thiazides cross the placental barrier and may appear in cord blood, posing a risk of fetal or neonatal jaundice, thrombocytopenia, and potentially other adverse reactions that have been observed in adults.

Patients should be made aware that thiazides are excreted in breast milk, and a decision should be made regarding whether to discontinue nursing or to discontinue hydrochlorothiazide, considering the importance of the medication to the mother.

Finally, healthcare providers should advise elderly patients that they may experience a greater reduction in blood pressure and an increase in side effects. It is recommended to start treatment with the lowest available dose of hydrochlorothiazide (12.5 mg) for this population.

Storage and Handling

This product is supplied in a manner that ensures its integrity and efficacy. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP controlled room temperature guidelines. It is essential to protect the product from light and moisture, as well as from freezing conditions below -20°C (-4°F).

The container must remain tightly closed to maintain the product's stability. For dispensing, a tight, light-resistant container, as defined by the USP, is required. Additionally, it is crucial to keep this product out of reach of children to ensure safety.

Additional Clinical Information

During postmarketing surveillance of hydrochlorothiazide, an adverse reaction has been identified. It is important to note that this reaction is reported voluntarily from a population of uncertain size, which limits the ability to reliably estimate its frequency or establish a causal relationship to drug exposure. Clinicians should remain vigilant for this adverse reaction in patients using hydrochlorothiazide.

FDA Insert (PDF)

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

View full prescribing information (PDF)