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. Its empirical formula is C7H8ClN3O4S2, and it has a molecular weight of 297.74. The compound appears as a white, or practically white, crystalline powder that is slightly soluble in water and freely soluble in sodium hydroxide solution.

Hydrochlorothiazide is formulated as 12.5 mg capsules for oral administration. The inactive ingredients include colloidal silicon dioxide, pregelatinized starch, lactose monohydrate, and magnesium stearate. The gelatin capsules are colored with D&C Red # 28, D&C Yellow # 10, and FD&C Blue # 1, and contain gelatin and titanium dioxide. The capsules are printed with edible ink that includes black iron oxide and pharmaceutical glaze.

Uses and Indications

Hydrochlorothiazide capsules, USP 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.

However, diuretics may be indicated during pregnancy when edema is attributable to pathological causes, similar to their use in non-pregnant individuals. In cases of dependent edema during pregnancy, which arises from venous return restriction due to an enlarged uterus, non-pharmacological interventions such as elevating the lower extremities and utilizing 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.

In instances where edema causes significant discomfort and is unresponsive to rest, a short course of diuretics may be warranted to alleviate symptoms.

Dosage and Administration

For the control of hypertension, the recommended initial dose of hydrochlorothiazide capsules for adults is one capsule administered once daily. This dosage may be used alone 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 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, 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 an increased risk for developing acute angle-closure glaucoma.

Diabetes and Hypoglycemia Healthcare providers 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

Patients may experience a range of adverse reactions while using this medication, categorized by seriousness and frequency.

Serious adverse reactions include hypersensitivity reactions such as anaphylaxis, necrotizing angiitis (vasculitis and cutaneous vasculitis), and respiratory distress, which may manifest as pneumonitis or pulmonary edema. Additionally, renal complications such as renal failure, renal dysfunction, and interstitial nephritis have been reported. Patients may also experience hematologic issues, including aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia.

Acute myopia and secondary angle-closure glaucoma are significant concerns, as hydrochlorothiazide can induce an idiosyncratic reaction leading to these conditions. Symptoms typically arise within hours to weeks of initiating treatment and may include acute onset of decreased visual acuity or ocular pain. If left untreated, acute angle-closure glaucoma can result in permanent vision loss. Immediate discontinuation of the medication is essential, and further medical or surgical intervention may be necessary if intraocular pressure remains uncontrolled.

Common adverse reactions reported in clinical trials and postmarketing experiences 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. Musculoskeletal symptoms like muscle spasms, as well as nervous system effects such as dizziness, vertigo, and headaches, have also been noted.

Skin reactions can range from mild to severe, including erythema multiforme (such as 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 with the medication.

In terms of postmarketing data, there is an increased risk of non-melanoma skin cancer associated with hydrochlorothiazide, particularly squamous cell carcinoma (SCC) in white patients taking 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 with a cumulative dose of ≥50,000 mg, the risk increases to approximately one additional case for every 6,700 patients per year.

Patients with a history of diabetes may experience latent diabetes mellitus, necessitating adjustments in insulin dosage. Furthermore, those with renal disease should be monitored closely, as thiazides can exacerbate renal impairment and precipitate azotemia.

Drug Interactions

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

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 the antidiabetic medication may be required to maintain glycemic control.

• 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 lead to intensified 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 management.

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

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): In some patients, NSAIDs may reduce the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics. Close observation is warranted 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. Administration of thiazides should be timed appropriately to avoid this interaction.

• Lithium: Thiazide diuretics are generally contraindicated with lithium due to the reduction in renal clearance of lithium, significantly increasing the risk of lithium toxicity. Consultation of the package insert for lithium preparations is advised prior to concurrent use.

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 to support its use in these populations.

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 studied in pregnant mice and rats during critical periods of organogenesis, with doses up to 3,000 mg/kg and 1,000 mg/kg, respectively, showing no evidence of teratogenic effects. However, there are no adequate and well-controlled studies in pregnant women. Therefore, the use of hydrochlorothiazide during pregnancy should be considered only if clearly needed, as animal reproduction studies may not accurately predict human outcomes.

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, such as fetal or neonatal jaundice and thrombocytopenia, as well as other adverse reactions that may occur in adults. Healthcare professionals should weigh the benefits against the 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, lactating mothers should make a decision regarding whether to discontinue breastfeeding or to discontinue hydrochlorothiazide. This decision should take into account the importance of the medication to the mother.

Renal Impairment

Patients with renal impairment may experience cumulative effects of thiazides due to reduced kidney function. In this population, the use of thiazides can precipitate azotemia, necessitating careful monitoring and consideration of dosing adjustments. It is essential for healthcare professionals to evaluate renal function regularly and adjust treatment as needed to mitigate potential adverse effects.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in clinical trials for this medication. Consequently, there is no available information regarding 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 warranted based on clinical judgment.

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 oral LD50 of hydrochlorothiazide has been determined to be greater than 10 gm/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 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, 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, 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.

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 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 patients with severe cirrhosis, during the 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 management involves water restriction rather than salt administration, except in rare instances where hyponatremia is life-threatening. Caution should be exercised when prescribing thiazides to patients with impaired hepatic function, as these medications can precipitate hepatic coma in individuals with severe liver disease.

Patients should be made aware that thiazides cross the placental barrier and can appear in cord blood, posing risks such as fetal or neonatal jaundice, thrombocytopenia, and potentially other adverse reactions that have been observed in adults. A careful decision should be made regarding whether to discontinue nursing or to discontinue hydrochlorothiazide, considering the importance of the medication to the mother.

It is essential to inform patients that the use of diuretics in otherwise healthy women during pregnancy is inappropriate and may expose both the mother and fetus to unnecessary risks. Additionally, patients should be advised that hydrochlorothiazide may precipitate hyperuricemia or acute gout. Finally, it is important to communicate that hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC), in white patients who are taking large cumulative doses.

Storage and Handling

The product is supplied in a configuration that ensures optimal preservation of its integrity. 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, moisture, and freezing conditions, specifically temperatures below -20°C (-4°F). To maintain the quality of the product, the container must be kept tightly closed at all times.

Additional Clinical Information

Thiazides should be discontinued prior to conducting tests for parathyroid function to ensure accurate results. The recommended initial dose of hydrochlorothiazide capsules for adults is one capsule taken once daily, either alone or in conjunction with other antihypertensive medications. It is advised that total daily doses exceeding 50 mg are not recommended.

Clinicians should counsel patients on the importance of protecting their skin from sun exposure and encourage regular skin cancer screenings. Hydrochlorothiazide has been linked to an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC), especially in white patients receiving high cumulative doses. Data from the Sentinel System indicate that the overall risk for SCC is approximately one additional case per 16,000 patients per year, while for white patients with a cumulative dose of ≥50,000 mg, the risk increases to about one additional 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 Alembic Pharmaceuticals Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)