Hydrochlorothiazide

Description

Hydrochlorothiazide 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 but freely soluble in sodium hydroxide solution. It is supplied in 12.5 mg capsules for oral administration. Each capsule contains inactive ingredients including colloidal silicon dioxide, corn starch, lactose monohydrate, and magnesium stearate. The hard gelatin shell is composed of gelatin, titanium dioxide, sodium lauryl sulfate, FD&C Blue #1, D&C Red #28, D&C Yellow #10, black iron oxide, and shellac.

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 concurrently receiving ACE inhibitors.

The routine use of diuretics, including hydrochlorothiazide, in otherwise healthy pregnant women is not recommended due to potential risks to both the mother and fetus. 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 the mechanical effects of pregnancy, such as venous return restriction due to an expanded uterus, should be managed through non-pharmacological measures, including elevation of the lower extremities and the use of support hose. The physiological hypervolemia associated with normal pregnancy is generally not harmful to the mother or fetus, provided there are no underlying cardiovascular conditions.

In instances where edema causes significant discomfort and is unresponsive to rest, a short course of diuretics may be considered appropriate for symptom relief.

Dosage and Administration

For the control of hypertension, the recommended initial dose of hydrochlorothiazide for adults is one capsule administered once daily. This can be used 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 ensure that patients are monitored for efficacy and tolerability, adjusting the treatment regimen as necessary while adhering to the established dosing limits.

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 when prescribing this medication.

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. If left untreated, acute angle-closure glaucoma can result in permanent vision loss. The primary course of action is 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.

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

Renal Disease In patients with impaired renal function, the cumulative effects of thiazides may lead to the development of azotemia. Caution is advised when prescribing hydrochlorothiazide to individuals with renal impairment, and monitoring of renal function is recommended to mitigate potential adverse effects.

In summary, careful consideration of these warnings and precautions is essential for the safe use of hydrochlorothiazide, particularly in patients with a history of ocular issues, diabetes, or renal disease. Regular monitoring and prompt intervention are critical to prevent serious complications associated with this medication.

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 can occur, manifesting as anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), and respiratory distress, which may include pneumonitis and pulmonary edema. Renal complications such as renal failure, renal dysfunction, and interstitial nephritis have also been reported.

Common adverse reactions encompass a range of symptoms affecting various systems. Patients may experience weakness, hypotension (including orthostatic hypotension), and gastrointestinal disturbances such as diarrhea, vomiting, cramping, constipation, gastric irritation, nausea, and anorexia. Musculoskeletal symptoms may include muscle spasms, while nervous system effects can manifest as vertigo, paresthesia, dizziness, headache, and restlessness. Skin reactions may present as erythema multiforme (including Stevens-Johnson syndrome), exfoliative dermatitis (including toxic epidermal necrolysis), and alopecia. Patients may also report transient blurred vision and xanthopsia as part of their experience.

Metabolic disturbances such as electrolyte imbalance, hyperglycemia, glycosuria, and hyperuricemia have been noted. Urogenital effects, including impotence, have also been reported.

In the postmarketing experience, an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC), has been associated with hydrochlorothiazide. This risk appears to be more pronounced in white patients receiving large cumulative doses. Specifically, the overall population shows an increased risk of approximately 1 additional case of SCC per 16,000 patients per year, while white patients taking a cumulative dose of ≥50,000 mg may experience an increase of approximately 1 additional SCC case for every 6,700 patients per year.

Drug Interactions

Concomitant use of certain medications may lead to significant drug interactions with hydrochlorothiazide, necessitating careful consideration and monitoring.

Pharmacodynamic Interactions:

• Alcohol, Barbiturates, and Narcotics: The combination of hydrochlorothiazide with these agents may potentiate orthostatic hypotension. Patients should be monitored for signs of increased hypotension.

• Antidiabetic Drugs (Oral Agents and Insulin): Dosage adjustments of antidiabetic medications may be required when used in conjunction with hydrochlorothiazide. Close monitoring of blood glucose levels is advised.

• Other Antihypertensive Drugs: The use of additional antihypertensive agents may result in an additive effect or potentiation of blood pressure-lowering effects. Blood pressure should be monitored regularly.

• Corticosteroids and ACTH: Co-administration may lead to intensified electrolyte depletion, particularly hypokalemia. Electrolyte levels should be monitored frequently.

• Skeletal Muscle Relaxants (Nondepolarizing, e.g., Tubocurarine): There may be an increased responsiveness to muscle relaxants. 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, significantly increasing the risk of toxicity. Refer to the package insert for lithium preparations before 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 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 to minimize interaction.

• 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.

Laboratory Test Interactions:

• Parathyroid Function Tests: Thiazides 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. Further studies are necessary to determine appropriate dosing and potential outcomes in this population.

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 to ensure safety and minimize the risk of adverse effects. Careful monitoring of blood pressure and side effects is advised during treatment in geriatric patients to optimize therapeutic outcomes while maintaining patient safety.

Pregnancy

Hydrochlorothiazide has been evaluated in animal studies for teratogenic effects, with no evidence of harm to the fetus observed when administered orally to pregnant mice and rats during major organogenesis at doses up to 3,000 mg/kg and 1,000 mg/kg, respectively. 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, 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 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 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

In cases of overdosage, the most frequently observed signs and symptoms are primarily attributed to 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 the provision of artificial respiration may be necessary.

The extent to which hydrochlorothiazide can be removed through hemodialysis remains undetermined. Furthermore, it is noteworthy that the oral LD50 of hydrochlorothiazide exceeds 10 gm/kg in both mouse and rat models, indicating a significant margin of safety in these species.

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 have been observed in adults.

In nonclinical toxicology assessments, two-year feeding studies conducted by the National Toxicology Program (NTP) demonstrated 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 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.

Animal studies indicated that hydrochlorothiazide did not adversely affect the fertility of mice and rats of either sex when administered via diet at doses 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 derived from a study conducted within the Sentinel System indicate that this increased risk is notably observed in white patients who have received 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 who have taken a cumulative dose of 50,000 mg or more, 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. Hypokalemia may develop, particularly with brisk diuresis in the presence of severe cirrhosis, during concomitant use of corticosteroids or adrenocorticotropic hormone (ACTH), or following prolonged therapy. Patients should be advised that hypokalemia can be avoided or treated through potassium supplementation or by increasing the intake of potassium-rich foods.

Healthcare providers should inform patients that dilutional hyponatremia, which can be life-threatening, may occur in edematous patients during hot weather. In such cases, appropriate therapy involves water restriction rather than salt administration, except in rare instances where hyponatremia is life-threatening. Patients should also be instructed to report any signs of acute myopia or ocular pain, as these may indicate the development of acute angle-closure glaucoma.

Diabetic patients should be advised that latent diabetes mellitus may become manifest, necessitating potential adjustments to their insulin dosage. Additionally, 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 be counseled to avoid alcohol, barbiturates, or narcotics, as these substances may exacerbate orthostatic hypotension.

Healthcare providers should instruct patients to monitor for signs of pancreatitis, jaundice, or other gastrointestinal disturbances. Patients should also be informed about the potential for increased sensitivity to muscle relaxants while taking hydrochlorothiazide. Finally, patients should be advised to consult their healthcare provider before taking non-steroidal anti-inflammatory drugs, as these medications can reduce the diuretic effects of hydrochlorothiazide.

Storage and Handling

The product is supplied in a tightly sealed, light-resistant container as defined by the USP. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15° to 30°C (59° to 86°F) in accordance with USP Controlled Room Temperature guidelines.

It is essential to protect the product from light, moisture, and freezing conditions. The product must not be frozen or stored at temperatures below -20°C (-4°F). Additionally, the container should remain tightly closed to maintain the integrity of the product.

To ensure safety, this product should be kept out of reach of children.

Additional Clinical Information

Thiazides should be discontinued prior to conducting tests for parathyroid function to ensure accurate results. The initial adult dose of hydrochlorothiazide is one capsule administered once daily, either alone or in conjunction with other antihypertensive medications.

Clinicians should counsel patients on the importance of sun protection and regular skin cancer screenings while taking hydrochlorothiazide. Notably, postmarketing data indicate an increased risk of non-melanoma skin cancer associated with hydrochlorothiazide, particularly squamous cell carcinoma (SCC) in white patients receiving high cumulative doses. The overall risk for SCC is estimated at one additional case per 16,000 patients annually, with a significantly higher risk of one additional case per 6,700 patients per year for those taking cumulative doses of 50,000 mg or more.

FDA Insert (PDF)

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

View full prescribing information (PDF)