Hydrochlorothiazide

Description

Hydrochlorothiazide (hydrochlorothiazide, USP 12.5 mg) is the 3,4-dihydro derivative of chlorothiazide. Its chemical name is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. The empirical formula is C7H8ClN3O4S2, and the molecular weight is 297.74. Hydrochlorothiazide appears as a white, or practically white, crystalline powder that is slightly soluble in water but freely soluble in sodium hydroxide solution. Hydrochlorothiazide capsules, USP, are supplied as 12.5 mg capsules for oral use. Inactive ingredients 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 that contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, black iron oxide, and potassium hydroxide.

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 avoided, 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.

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 provide relief.

Dosage and Administration

The adult initial dose of hydrochlorothiazide capsules, USP, is one capsule administered once daily. This dosage is applicable whether the medication is prescribed as 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 monitor patients 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 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 typically manifest as an acute onset of decreased visual acuity or ocular pain, occurring within hours to weeks following the initiation of therapy. If left untreated, acute angle-closure glaucoma may result in permanent vision loss. The primary course of action is to discontinue hydrochlorothiazide immediately. 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 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 thiazides can affect glucose metabolism and potentially lead to hypoglycemia.

Renal Disease In patients with impaired renal function, the cumulative effects of thiazides can be exacerbated, potentially leading to azotemia. It is crucial to monitor renal function closely in these patients to prevent adverse outcomes associated with thiazide therapy. Regular assessment of renal parameters is recommended to ensure safe use of hydrochlorothiazide in this population.

Side Effects

Adverse reactions associated with the use of the medication include a range of serious and common effects, which are categorized below.

Serious adverse reactions may include hematologic conditions such as aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia. Renal complications such as renal failure, renal dysfunction, and interstitial nephritis 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, severe skin reactions such as erythema multiforme, including Stevens-Johnson syndrome, exfoliative dermatitis, and toxic epidermal necrolysis, have been observed.

Common adverse reactions reported in clinical trials and postmarketing experiences 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. Patients may also experience musculoskeletal symptoms like muscle spasms and nervous system/psychiatric effects including vertigo, paresthesia, dizziness, headache, and restlessness.

Metabolic disturbances such as electrolyte imbalance, hyperglycemia, glycosuria, and hyperuricemia have been noted. Skin reactions may also include photosensitivity, fever, urticaria, rash, and purpura. Transient blurred vision and xanthopsia have been reported under special senses, while urogenital effects may include impotence.

It is important to note that hydrochlorothiazide has been associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC). A study conducted in the Sentinel System indicated that the increased risk was predominantly observed in white patients taking large cumulative doses. The overall population showed an approximate risk increase of 1 additional case of SCC per 16,000 patients per year, while white patients receiving 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 concomitant use of thiazide diuretics with certain drug classes may lead to significant interactions that require careful consideration.

Pharmacodynamic Interactions:

• Alcohol, Barbiturates, and Narcotics: The use of these agents alongside thiazide diuretics may potentiate orthostatic hypotension. Patients should be monitored for signs of hypotension, and dosage adjustments may be necessary.

• Antidiabetic Drugs: Both oral antidiabetic agents and insulin may necessitate dosage adjustments when administered with thiazide diuretics due to potential alterations in glycemic control.

• Other Antihypertensive Agents: The combination of thiazide diuretics with other antihypertensive medications may result in an additive effect. Blood pressure should be closely monitored to avoid excessive hypotension.

• Corticosteroids and ACTH: These agents can exacerbate electrolyte depletion, particularly hypokalemia, when used in conjunction with thiazide diuretics. Regular monitoring of electrolyte levels is advised.

• Pressor Amines (e.g., Norepinephrine): There may be a diminished response to pressor amines when used with thiazide diuretics; however, this does not contraindicate their use. Clinical judgment should guide therapy.

• Nondepolarizing Skeletal Muscle Relaxants (e.g., Tubocurarine): Increased responsiveness may occur when these relaxants are used with thiazide diuretics. Monitoring of neuromuscular function is recommended.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The effectiveness of thiazide diuretics may be reduced when used with NSAIDs, impacting diuretic, natriuretic, and antihypertensive effects. Close observation of blood pressure and fluid status is warranted.

Pharmacokinetic Interactions:

• Cholestyramine and Colestipol Resins: These resins can significantly reduce the absorption of hydrochlorothiazide, by up to 85% and 43%, respectively. It is advisable to separate the administration of these agents from thiazide diuretics to minimize interaction.

• Lithium: The use of lithium with diuretics is generally contraindicated due to the potential for reduced renal clearance and an increased risk of lithium toxicity. Monitoring of lithium levels is essential if co-administration is unavoidable.

Additional Considerations:

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.

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.

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 to optimize therapeutic outcomes while minimizing potential risks.

Pregnancy

Hydrochlorothiazide has been studied in pregnant mice and rats during their major organogenesis periods, with doses up to 3,000 mg/kg and 1,000 mg/kg, respectively, showing no 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 cross the placental barrier and can be detected in cord blood. There is a potential risk of 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 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. 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 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.

Management of overdosage should involve the implementation of symptomatic and supportive measures. This may include the induction of emesis or the performance of gastric lavage to mitigate the effects of the overdose.

It is crucial to address any complications that arise, such as dehydration, electrolyte imbalances, hepatic coma, and hypotension, by following established medical procedures. In instances where respiratory impairment occurs due to overdose, the administration of oxygen or the provision of artificial respiration may be necessary.

Toxicological data indicate that the oral LD50 of hydrochlorothiazide exceeds 10 g/kg in both mouse and rat models, underscoring the importance of prompt and effective management in cases of suspected overdosage.

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, demonstrated 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 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.

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 reported equivocal evidence for 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 observed only in the in vitro CHO Sister Chromatid Exchange assay and the 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

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

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 to discuss the potential interactions with other medications, as certain drugs may affect the efficacy and safety of hydrochlorothiazide.

Patients should be made aware that concurrent use of alcohol, barbiturates, or narcotics may lead to an increased risk of orthostatic hypotension. Additionally, when taking antidiabetic medications, including both oral agents and insulin, dosage adjustments may be necessary. The use of other antihypertensive drugs can result in an additive effect or potentiation, which should be monitored.

Providers should inform patients that cholestyramine and colestipol resins can significantly reduce the absorption of hydrochlorothiazide, with reductions of up to 85% and 43%, respectively. Caution should also be exercised when using corticosteroids or ACTH, as these may intensify electrolyte depletion, particularly hypokalemia.

Patients should be advised that the response to pressor amines, such as norepinephrine, may be decreased, although this does not preclude their use. Furthermore, the use of non-depolarizing skeletal muscle relaxants, like tubocurarine, may lead to increased responsiveness to these agents.

It is critical to inform patients that lithium should generally not be used in conjunction with diuretics, as diuretics can reduce renal clearance of lithium and significantly increase the risk of lithium toxicity. Healthcare providers should refer to the package insert for lithium preparations before considering their use alongside hydrochlorothiazide.

Patients should also be monitored closely if non-steroidal anti-inflammatory drugs (NSAIDs) are prescribed concurrently, as these agents may diminish the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics.

Finally, thiazides should be discontinued prior to conducting tests for parathyroid function. Patients should be made aware of the increased risk of non-melanoma skin cancer associated with hydrochlorothiazide, particularly squamous cell carcinoma (SCC). The risk is notably higher in white patients taking large cumulative doses, with an estimated increase of one additional case of SCC for every 6,700 patients per year for those receiving a cumulative dose of ≥50,000 mg.

Storage and Handling

This product should be kept out of reach of children. It is recommended to store the product at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP controlled room temperature guidelines. The product must be protected from light and moisture, and it should not be exposed to freezing temperatures or temperatures below -20°C (-4°F).

To ensure the integrity of the product, the container must be kept tightly closed. When dispensing, it is essential to use a tight, light-resistant container as defined by the USP.

Additional Clinical Information

The postmarketing experience for hydrochlorothiazide has revealed an adverse reaction that has been identified during its use after approval. Due to the voluntary nature of these reports from a population of uncertain size, it is not feasible to reliably estimate the frequency of this reaction or to establish a causal relationship with drug exposure.

FDA Insert (PDF)

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

View full prescribing information (PDF)