Hydrochlorothiazide

Description

Hydrochlorothiazide, a thiazide diuretic, 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. The empirical formula is C7H8ClN3O4S2, and it has a molecular weight of 297.74. The structural formula is represented as follows:

Hydrochlorothiazide is presented as a white or practically white crystalline powder, which exhibits slight solubility in water and is freely soluble in sodium hydroxide solution. Hydrochlorothiazide capsules, USP, are formulated for oral administration, containing 12.5 mg of the active ingredient.

Inactive ingredients in the capsules include 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, 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, 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, and there is insufficient 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. It is important to note that 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 physiological hypervolemia associated with normal pregnancy is generally not harmful to the mother or fetus, provided there are no underlying cardiovascular conditions, and is often accompanied by edema in many pregnant women.

In instances where edema causes significant discomfort and is unresponsive to increased recumbency, a short course of diuretics may be warranted to provide relief.

Dosage and Administration

The adult initial dose of hydrochlorothiazide capsules, USP, 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.

Healthcare professionals should ensure that patients are monitored for efficacy and tolerability, adjusting the dosage as necessary while adhering to the maximum recommended daily limit.

Contraindications

Hydrochlorothiazide is contraindicated in patients with anuria due to the lack of urine output, which may lead to severe complications. Additionally, use of this product 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 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 providers 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 thiazides can affect glucose metabolism.

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 renal function should be monitored regularly.

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 mitigate potential adverse effects.

Side Effects

Adverse reactions associated with the use of hydrochlorothiazide have been observed in clinical trials and postmarketing experiences. These reactions can be categorized by seriousness and frequency.

Serious adverse reactions include hematologic events such as aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia. Additionally, hypersensitivity reactions may occur, including anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), and respiratory distress, which can manifest as 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 body systems. Patients may experience weakness, hypotension (including orthostatic hypotension), and gastrointestinal disturbances such as diarrhea, vomiting, nausea, cramping, constipation, and anorexia. Other common reactions include muscle spasms, dizziness, vertigo, paresthesia, and headaches. Skin reactions may present as erythema multiforme, exfoliative dermatitis, and alopecia.

In terms of metabolic effects, patients may experience electrolyte imbalances, hyperglycemia, glycosuria, and hyperuricemia. Urogenital issues such as impotence have also been noted. Transient blurred vision and xanthopsia are reported under special senses.

Postmarketing data indicate an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma, in white patients receiving large cumulative doses of hydrochlorothiazide.

Warnings associated with hydrochlorothiazide include the potential for acute myopia and secondary angle-closure glaucoma, which may occur as an idiosyncratic reaction. Patients with latent diabetes mellitus may find that their condition becomes manifest, necessitating adjustments in insulin dosage for those already diagnosed with diabetes. Furthermore, patients with impaired renal function may experience cumulative effects from thiazide therapy.

Warning signs of fluid and electrolyte imbalance include dryness of the mouth, 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 concurrent use of corticosteroids or adrenocorticotropic hormone (ACTH), or following prolonged therapy.

Drug Interactions

The concomitant use of certain medications with hydrochlorothiazide 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. Patients should be monitored for signs of hypotension and advised to use caution when standing up.

• Antidiabetic Drugs (Oral Agents and Insulin): Dosage adjustments of the antidiabetic medication may be necessary to maintain glycemic control. Close monitoring of blood glucose levels is recommended.

• 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: There is a risk of intensified electrolyte depletion, particularly hypokalemia. Electrolyte levels should be monitored, and potassium supplementation may be required.

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

• Pressor Amines (e.g., Norepinephrine): There may be a decreased response to pressor amines; however, this interaction does not preclude their use. Clinical response should be assessed.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The administration of NSAIDs may reduce 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. Administration of hydrochlorothiazide should be separated from these agents to minimize interaction.

• Lithium: The use of diuretics with lithium is generally contraindicated due to the potential for reduced renal clearance of lithium, significantly increasing the risk of toxicity. It is essential to refer to the package insert for lithium preparations before co-administration.

Drug/Laboratory Test Interactions:

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 until further data is available.

Geriatric Use

Elderly patients, specifically 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 begin with the lowest available dose of hydrochlorothiazide, which is 12.5 mg.

If further titration of the dosage is necessary, increments of 12.5 mg should be employed. Healthcare providers should closely monitor elderly patients for both therapeutic efficacy and potential adverse effects throughout the treatment process.

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, 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, necessitating careful monitoring and consideration of dosing adjustments. It is essential for healthcare professionals to evaluate renal function regularly in patients receiving thiazide therapy 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 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

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 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 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 of 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, and since animal reproduction studies may not always 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 nonteratogenic effects, including the risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have been observed in adults.

Two-year feeding studies conducted by the National Toxicology Program (NTP) in mice and rats did not demonstrate any carcinogenic potential of 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. 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. In vivo assays involving mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene also showed no genotoxicity. 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 1300 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 doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to conception and throughout gestation.

Postmarketing Experience

Adverse reactions have been identified during the post-approval use of hydrochlorothiazide. These reactions have been reported voluntarily from a population of uncertain size, making it impossible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer. Data from a study conducted in the Sentinel System indicate that the increased risk is predominantly for squamous cell carcinoma (SCC), particularly among white patients who are taking large cumulative doses. The overall increased risk for SCC in the population is estimated to be approximately 1 additional case per 16,000 patients per year. For white patients receiving a cumulative dose of ≥50,000 mg, the risk increase is approximately 1 additional SCC case for every 6,700 patients per year.

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 observe patients for signs of fluid or electrolyte disturbances, including hyponatremia, hypochloremic alkalosis, hypokalemia, and hypomagnesemia.

Patients should be made aware of warning signs or symptoms 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. It is important to note 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. 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. The appropriate management for this condition is water restriction rather than salt administration, except in rare cases where hyponatremia is life-threatening.

Patients should be instructed to report any signs of acute myopia or ocular pain, as these symptoms may indicate the development of acute angle-closure glaucoma. Diabetic patients should be advised that latent diabetes mellitus may become manifest, necessitating an adjustment of 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 informed that thiazides cross the placental barrier and can appear in cord blood, posing a risk of fetal or neonatal jaundice, thrombocytopenia, and potentially other adverse reactions.

Nursing mothers 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.

Storage and Handling

The product is supplied in a tightly sealed, light-resistant container, as specified by the United States Pharmacopeia (USP). It is essential to store the product at a controlled room temperature of 20° to 25°C (68° to 77°F) and to protect it from light, moisture, and freezing conditions (below -20°C / -4°F). To ensure the integrity of the product, the container must remain tightly closed at all times. Additionally, it is crucial to keep this product out of reach of children.

Additional Clinical Information

Postmarketing experience has revealed an adverse reaction associated with hydrochlorothiazide, specifically an increased risk of non-melanoma skin cancer. This risk, primarily for squamous cell carcinoma (SCC), has been observed predominantly in white patients receiving large cumulative doses. Data from a study conducted in the Sentinel System indicate that the overall increased risk for SCC is approximately 1 additional case per 16,000 patients per year. For white patients who have taken a cumulative dose of ≥50,000 mg, the risk escalates to approximately 1 additional SCC case for every 6,700 patients per year. It is important to note that these reactions are reported voluntarily from a population of uncertain size, making it challenging to reliably estimate frequency or establish a causal relationship to drug exposure.

FDA Insert (PDF)

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

View full prescribing information (PDF)