Hydrochlorothiazide

Description

Hydrochlorothiazide (hydrochlorothiazide, USP 12.5 mg) 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 empirical 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, which 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.

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 minimized, including those receiving ACE inhibitors.

Limitations of Use: The routine use of diuretics in otherwise healthy pregnant women is not recommended, as it poses unnecessary risks to both the mother and fetus. Hydrochlorothiazide does not prevent or treat toxemia of pregnancy, and there is insufficient evidence to support its efficacy in cases of developed toxemia.

Diuretics may be indicated during pregnancy when edema is attributable to pathological causes, similar to their use in non-pregnant individuals. However, 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 use of diuretics to reduce intravascular volume in this context is considered illogical and unnecessary.

It is important to note that hypervolemia is a normal physiological condition during pregnancy and is not harmful to the mother or fetus in the absence of cardiovascular disease, despite being associated with edema in many pregnant women. If edema causes discomfort, increased recumbency may provide relief. In rare cases where edema leads to significant discomfort not alleviated by rest, a short course of diuretics may be appropriate for symptom management.

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 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 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 can lead to the development of azotemia. Caution is advised when prescribing hydrochlorothiazide to this patient population, and renal function should be monitored closely.

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 impairment. Regular monitoring and prompt intervention are critical to mitigate potential adverse effects.

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 include hematologic events such as aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia. Renal complications may manifest as renal failure, renal dysfunction, and interstitial nephritis. Hypersensitivity reactions can be severe, including anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), and respiratory distress, which may present as pneumonitis and pulmonary edema. Additionally, patients may experience acute myopia and secondary angle-closure glaucoma, which can lead to permanent vision loss if untreated. Symptoms of this condition typically arise within hours to weeks of initiating treatment and include acute onset of decreased visual acuity or ocular pain.

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. Skin reactions may range from erythema multiforme, including Stevens-Johnson syndrome, to exfoliative dermatitis and alopecia. Transient blurred vision and xanthopsia have been reported as effects on special senses.

Postmarketing data indicate an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC), in patients taking hydrochlorothiazide. The risk is notably higher in white patients receiving large cumulative doses, with an estimated increase of approximately 1 additional case of SCC per 16,000 patients per year in the general population, and 1 additional case for every 6,700 patients per year in those taking a cumulative dose of ≥50,000 mg.

Patients with a history of sulfonamide or penicillin allergy may be at increased risk for developing acute angle-closure glaucoma. Furthermore, latent diabetes mellitus may become apparent in some patients, necessitating adjustments in insulin dosage for those with diabetes. In patients with impaired renal function, thiazides may precipitate azotemia due to cumulative effects.

Drug Interactions

The following drug interactions have been identified for 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 increased hypotensive effects.

• 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 advised.

• 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 regularly.

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

• Skeletal Muscle Relaxants (Nondepolarizing, e.g., Tubocurarine): Increased responsiveness to muscle relaxants may occur. Monitoring of neuromuscular function is recommended.

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

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): 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. Administration of hydrochlorothiazide should be separated from these agents 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. Monitoring of blood pressure response is advisable.

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 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 begins with the lowest available dose of hydrochlorothiazide, which is 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 course of treatment.

Pregnancy

Hydrochlorothiazide has been evaluated in animal studies for teratogenic effects, with no evidence of harm to the fetus observed when administered 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. Therefore, the use of hydrochlorothiazide during pregnancy should be considered only if clearly needed, as animal reproduction studies may not always 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, 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 and risks when prescribing hydrochlorothiazide to pregnant patients and monitor for any adverse effects in both the mother and the fetus.

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. It is important to monitor these patients closely, as thiazides can precipitate azotemia in individuals with impaired renal function. Dosing adjustments may be necessary to mitigate these risks and ensure safe and effective use of the medication.

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 and consider the overall clinical context when prescribing this medication to patients with hepatic impairment, as individual responses may vary.

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 dehydration and any 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 threshold for toxicity. 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 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 indicated 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 genotoxic effects 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 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 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, the following adverse 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 has been associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC). Data from a study conducted in the Sentinel System indicate that the increased risk is predominantly observed in white patients who are taking large cumulative doses of the medication. Specifically, the overall population shows an approximate increase of 1 additional case of SCC per 16,000 patients per year. For white patients receiving a cumulative dose of ≥50,000 mg, the risk escalates to approximately 1 additional case of SCC 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 monitor 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 patients with 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. In such cases, appropriate therapy involves water restriction rather than salt administration, except in rare instances when 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 dose.

Thiazides should be used with caution in patients with impaired hepatic function, as they can precipitate hepatic coma in those with severe liver disease. Additionally, patients should be encouraged to consult their healthcare provider before taking any new medications, including over-the-counter drugs, due to the potential for interactions with thiazide diuretics.

Storage and Handling

The product is supplied in a tight, 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), 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 product integrity, the container must be kept tightly closed at all times.

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 of the medication. 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 ScieGen Pharmaceuticals Inc. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)