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

Hydrochlorothiazide 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 minimized, including those concurrently receiving ACE inhibitors.

The routine use of diuretics, including hydrochlorothiazide, in otherwise healthy pregnant women is not recommended, as it poses 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, 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. While this condition may lead to generalized edema, it is often manageable through increased recumbency.

In rare instances where edema causes significant discomfort that is unrelieved by 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.

Contraindications

Hydrochlorothiazide capsules are 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 include a sudden decrease in visual acuity or ocular pain, typically manifesting 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 the medication can affect glucose metabolism.

Renal Disease In patients with impaired renal function, the cumulative effects of thiazides can lead to the development of azotemia. It is crucial to monitor renal function in these patients, as thiazide therapy may exacerbate their condition.

Healthcare professionals are advised to remain vigilant for these potential adverse effects and to conduct appropriate monitoring to ensure patient safety while using hydrochlorothiazide.

Side Effects

Adverse reactions observed in patients include a range of serious and common effects, categorized by system involvement.

Serious adverse reactions encompass hematologic events such as aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia. Renal complications may also arise, including renal failure, renal dysfunction, and interstitial nephritis. Hypersensitivity reactions can be severe, with reports of anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), and respiratory distress, which may include pneumonitis and pulmonary edema. Additionally, skin reactions such as erythema multiforme, including Stevens-Johnson syndrome, and exfoliative dermatitis, including toxic epidermal necrolysis, have been documented.

Common adverse reactions reported by participants include weakness, hypotension (including orthostatic hypotension), and various digestive issues such as pancreatitis, jaundice (intrahepatic cholestatic jaundice), diarrhea, vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea, and anorexia. Neurological effects such as vertigo, paresthesia, dizziness, headache, and restlessness are also frequently noted. Musculoskeletal symptoms may include muscle spasms, while urogenital effects can manifest as impotence.

Patients may experience metabolic disturbances, including electrolyte imbalances, hyperglycemia, glycosuria, and hyperuricemia. Skin reactions may also include photosensitivity, fever, urticaria, rash, and purpura. Transient blurred vision and xanthopsia have been reported under special senses.

In addition to the above, it is important to note that hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer. A study conducted in the Sentinel System indicated that the increased risk was predominantly for squamous cell carcinoma (SCC), particularly in white patients receiving large cumulative doses. The overall population showed an approximate increase of 1 additional case of SCC per 16,000 patients per year, while white patients taking a cumulative dose of ≥50,000 mg had an increased risk of approximately 1 additional SCC case for every 6,700 patients per year.

Drug Interactions

The following drug interactions have been identified, categorized by their pharmacodynamic and pharmacokinetic effects, along with recommendations for dosage adjustments or monitoring where applicable.

Pharmacodynamic Interactions

• Alcohol, Barbiturates, and Narcotics: Concurrent use may potentiate orthostatic hypotension. Patients should be monitored for signs of hypotension and advised to avoid these substances if possible.

• Antidiabetic Drugs (Oral Agents and Insulin): Dosage adjustments of the antidiabetic medication may be necessary when used in conjunction with this drug. Regular monitoring of blood glucose levels is recommended.

• Other Antihypertensive Drugs: There is a potential for additive effects or potentiation of antihypertensive effects. Blood pressure should be monitored closely to avoid excessive hypotension.

• Corticosteroids and ACTH: These agents may lead to intensified electrolyte depletion, particularly hypokalemia. Electrolyte levels should be monitored regularly.

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

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

• 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. Lithium levels should be closely monitored if co-administration is unavoidable.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The administration of NSAIDs can diminish the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics. Patients should be observed closely 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 these agents to minimize interaction.

Drug & Laboratory Test Interactions

• Thiazides: It is recommended that thiazide diuretics 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 for potential adverse effects and adjust the dosage accordingly to optimize safety and therapeutic outcomes in geriatric patients.

Pregnancy

Hydrochlorothiazide has been studied in pregnant mice and rats during their major organogenesis periods at doses up to 3,000 mg/kg and 1,000 mg/kg, respectively, with no evidence of fetal harm observed. 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 cross the placental barrier and can be detected in cord blood. This raises concerns regarding potential risks to the fetus, including 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. 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

There is no information available regarding the use of this medication in patients with hepatic impairment. Consequently, there are no dosage adjustments, special monitoring requirements, or precautions specified for individuals with compromised liver function. Healthcare professionals should exercise caution and consider the lack of data when prescribing this medication to patients with liver problems.

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 from the body through hemodialysis has not been definitively established. 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, did not demonstrate any teratogenic effects on the fetus. 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 may also occur in adults.

In two-year feeding studies conducted by the National Toxicology Program (NTP), no evidence of carcinogenic potential was found 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 observe 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 noted only in the in vitro CHO Sister Chromatid Exchange assay and the 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 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 more pronounced 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, 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 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 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 may indicate the development of acute angle-closure glaucoma. Diabetic patients should be advised that latent diabetes mellitus may become manifest, potentially requiring 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), 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 below -20°C (-4°F). To maintain the integrity of the product, the container should remain tightly closed when not in use. Additionally, it is important to keep this product out of reach of children.

Additional Clinical Information

Thiazides should be discontinued prior to conducting tests for parathyroid function to ensure accurate results. Patients prescribed hydrochlorothiazide are advised to protect their skin from sun exposure and to participate in regular skin cancer screenings, as the medication is associated with an increased risk of non-melanoma skin cancer. Specifically, a study within the Sentinel System indicated a heightened risk for squamous cell carcinoma (SCC), particularly among white patients receiving large cumulative doses. The overall risk for SCC in the general population was estimated at approximately one additional case per 16,000 patients per year, while white patients with a cumulative dose of ≥50,000 mg faced an increased risk of about one additional SCC 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 Aurobindo Pharma Limited. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)