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. 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 supplied in 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 minimized, including those receiving ACE inhibitors.

The routine use of diuretics, including hydrochlorothiazide, in otherwise healthy pregnant women is not recommended due to potential teratogenic effects, which may pose unnecessary 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, it is important to note that 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 means, 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 relief.

Dosage and Administration

For the control of hypertension, the recommended initial dose of hydrochlorothiazide capsules for adults is one capsule administered once daily. This can be prescribed as a 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 is contraindicated in patients with anuria due to the lack of urine output, which may lead to severe complications. Additionally, use of this medication 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 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, which can be categorized by seriousness and frequency.

Serious adverse reactions include renal failure, renal dysfunction, and interstitial nephritis. Hematologic effects such as aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia have also been reported. Hypersensitivity reactions can manifest as anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), and respiratory distress, which may include pneumonitis and pulmonary edema. Additionally, patients may experience acute myopia and secondary angle-closure glaucoma, which can lead to permanent vision loss if not treated promptly.

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 such as muscle spasms, as well as nervous system effects like vertigo, dizziness, headache, and restlessness, have been noted.

Skin reactions can include erythema multiforme (including Stevens-Johnson syndrome), exfoliative dermatitis (including toxic epidermal necrolysis), and alopecia. Patients may also report transient blurred vision and xanthopsia as special senses effects. Urogenital issues, such as impotence, have been documented as well.

In cases of overdose, the most common signs and symptoms are related to electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration due to excessive diuresis. If digitalis has been administered concurrently, hypokalemia may exacerbate cardiac arrhythmias.

Patients should be monitored for these adverse reactions, and appropriate management strategies should be employed as necessary.

Drug Interactions

Concomitant use of thiazide diuretics with certain medications may lead to significant 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 the antidiabetic medication may be required to maintain glycemic control.

• Other Antihypertensive Drugs: There is a potential for additive effects or potentiation of antihypertensive activity, which may require monitoring of blood pressure to avoid excessive hypotension.

• Corticosteroids and ACTH: These agents may intensify electrolyte depletion, particularly hypokalemia, necessitating regular monitoring of electrolyte levels.

• Skeletal Muscle Relaxants (Nondepolarizing, e.g., Tubocurarine): Increased responsiveness to muscle relaxants may occur, warranting caution in dosing.

• Pressor Amines (e.g., Norepinephrine): There may be a decreased response to pressor amines; however, this interaction is not sufficient to contraindicate their use.

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 minimize this interaction.

• Lithium: Thiazide diuretics generally should not be co-administered with lithium due to the reduction in renal clearance of lithium, which significantly increases the risk of lithium toxicity. Consultation of the package insert for lithium preparations is advised prior to concurrent use.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): In some patients, NSAIDs may diminish the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics. Close observation is recommended to ensure the desired diuretic effect is achieved when these agents are used together.

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, as there is insufficient data to support its use in these populations. Healthcare professionals are advised to consider this lack of established safety and efficacy when making treatment decisions for pediatric patients.

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. Healthcare providers should closely monitor elderly patients for both therapeutic efficacy and potential side effects throughout the treatment process.

Pregnancy

Hydrochlorothiazide is classified as Pregnancy Category B. Animal studies involving the oral administration of hydrochlorothiazide to pregnant mice and rats during critical periods of organogenesis, at doses up to 3000 mg/kg and 1000 mg/kg respectively, have not demonstrated any 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 can cross the placental barrier and are detectable in cord blood. This raises concerns regarding potential risks to the fetus, including the possibility of fetal or neonatal jaundice, thrombocytopenia, and other adverse reactions that may also occur in adults. Healthcare professionals should carefully weigh the benefits and 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. 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 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

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 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

Pregnancy Category B studies involving the oral administration of hydrochlorothiazide to pregnant mice and rats during their major organogenesis periods, at doses up to 3000 mg/kg and 1000 mg/kg respectively, demonstrated no evidence of fetal harm. However, there are no adequate and well-controlled studies in pregnant women, and since animal reproduction studies may not reliably predict human responses, the use of this drug during pregnancy should be considered only when clearly necessary.

Thiazides are known to cross the placental barrier and can be detected in cord blood. This raises concerns regarding the potential 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 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.

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 genotoxic effects. Positive results were observed only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and Mouse Lymphoma Cell (mutagenicity) assays, with hydrochlorothiazide concentrations ranging from 43 to 1300 mcg/mL, as well as in the Aspergillus nidulans non-disjunction assay at an unspecified concentration.

In studies assessing fertility, hydrochlorothiazide did not adversely affect the reproductive capabilities of mice and rats of either sex when 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

Postmarketing experience with hydrochlorothiazide has revealed several adverse events reported voluntarily or through surveillance programs.

Hydrochlorothiazide, a sulfonamide, has been associated with idiosyncratic reactions leading to acute transient myopia and acute angle-closure glaucoma. Symptoms typically manifest within hours to weeks of initiating therapy and include acute onset of decreased visual acuity or ocular pain. If left untreated, acute angle-closure glaucoma may result in permanent vision loss. The primary intervention is the rapid discontinuation of hydrochlorothiazide, with prompt medical or surgical treatment considered if intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma include a history of sulfonamide or penicillin allergy.

In diabetic patients, latent diabetes mellitus may become apparent, necessitating adjustments to insulin dosages. Additionally, patients with impaired renal function may experience cumulative effects from thiazides, potentially leading to azotemia. Electrolyte imbalances, hyperglycemia, glycosuria, and hyperuricemia have also been reported. Hyperuricemia or acute gout may be precipitated in certain individuals receiving thiazide diuretics.

Caution is advised when prescribing thiazides to patients with impaired hepatic function, as they may precipitate hepatic coma in those with severe liver disease. Prolonged thiazide therapy has been associated with decreased calcium excretion and pathologic changes in the parathyroid glands, resulting in hypercalcemia and hypophosphatemia in a limited number of patients.

Adverse reactions associated with hydrochlorothiazide have been shown to be dose-related. In controlled clinical trials, adverse events reported with a daily dose of 12.5 mg were comparable to placebo. For doses of 25 mg and greater, the following adverse reactions have been documented, listed in order of decreasing severity within each category:

• Body as a Whole: Weakness.

• Cardiovascular: Hypotension, including orthostatic hypotension, which may be exacerbated by alcohol, barbiturates, narcotics, or antihypertensive medications.

• Digestive: Pancreatitis, jaundice (intrahepatic cholestatic jaundice), diarrhea, vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea, and anorexia.

• Hematologic: Aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia.

• Hypersensitivity: Anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress (including pneumonitis and pulmonary edema), photosensitivity, fever, urticaria, rash, and purpura.

• Metabolic: Electrolyte imbalance, hyperglycemia, glycosuria, and hyperuricemia.

• Musculoskeletal: Muscle spasm.

• Nervous System/Psychiatric: Vertigo, paresthesia, dizziness, headache, and restlessness.

• Renal: Renal failure, renal dysfunction, and interstitial nephritis.

• Skin: Erythema multiforme (including Stevens-Johnson syndrome), exfoliative dermatitis (including toxic epidermal necrolysis), and alopecia.

• Special Senses: Transient blurred vision and xanthopsia.

• Urogenital: Impotence.

In cases where adverse reactions are moderate or severe, it is recommended that thiazide dosage be reduced or therapy withdrawn.

Patient Counseling

Patients should be advised to contact their healthcare provider for medical advice regarding any side effects they may experience. They are encouraged to report side effects to the FDA at 1-800-FDA-1088.

Healthcare providers should observe patients for signs of fluid or electrolyte disturbances, which may include symptoms such as dryness of the mouth, increased thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances like nausea and vomiting.

Patients should be informed that hypokalemia may develop, particularly with brisk diuresis in cases of severe cirrhosis, during concomitant use of corticosteroids or adrenocorticotropic hormone (ACTH), or following prolonged therapy. They should be advised that hypokalemia can be avoided or treated through potassium supplementation or by increasing the intake of potassium-rich foods.

It is important to inform patients that dilutional hyponatremia is a life-threatening condition that 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 cautioned that thiazides should be used with caution in individuals with impaired hepatic function, as they may precipitate hepatic coma in patients with severe liver disease. Additionally, 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.

Patients should be advised to consider whether to discontinue nursing or to discontinue hydrochlorothiazide, weighing the importance of the medication to the mother. Furthermore, it is essential to inform patients that a greater reduction in blood pressure and an increase in side effects may be observed in elderly patients (aged over 65 years) taking hydrochlorothiazide, and starting treatment with the lowest available dose (12.5 mg) is recommended.

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. No further information is available regarding abuse, administration routes, patient counseling, or postmarketing experiences.

FDA Insert (PDF)

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

View full prescribing information (PDF)