Hydrochlorothiazide

Description

Hydrochlorothiazide Capsules, USP, 12.5 mg is the 3,4-dihydro derivative of chlorothiazide. The chemical name is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, with an empirical formula of C7H8ClN3O4S2 and a molecular weight of 297.74. The drug appears as a white, or practically white, crystalline powder that is slightly soluble in water but freely soluble in sodium hydroxide solution. Hydrochlorothiazide is supplied in 12.5 mg capsules for oral use. Inactive ingredients include colloidal silicon dioxide, corn starch, lactose monohydrate, and magnesium stearate. The gelatin capsules contain D&C Red No. 28, D&C Yellow No. 10, FD&C Blue No. 1, gelatin, and titanium dioxide. The capsules are printed with edible ink that includes black iron oxide, D&C Yellow No. 10, FD&C Blue No. 1, FD&C Blue No. 2, and FD&C Red No. 40.

Uses and Indications

Hydrochlorothiazide is 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, such as those concurrently receiving ACE inhibitors.

In the context of pregnancy, hydrochlorothiazide may be utilized when edema is attributable to pathological causes. However, the routine use of diuretics in otherwise healthy pregnant women is deemed inappropriate, as it poses unnecessary risks to both the mother and fetus. Diuretics do not prevent or effectively treat toxemia of pregnancy, and their use is not supported by satisfactory evidence in this regard.

Dependent edema during pregnancy, often resulting from venous return restriction due to an expanded uterus, should be managed through non-pharmacological measures such as elevating the lower extremities and employing support hose. The physiological hypervolemia associated with normal pregnancy is generally not harmful to the mother or fetus, provided there is no underlying cardiovascular disease, and is frequently accompanied by generalized edema.

In instances where edema causes significant discomfort that is unrelieved by rest, a short course of diuretics may be considered appropriate to provide relief.

Dosage and Administration

For the control of hypertension, the recommended initial dose of hydrochlorothiazide for adults is one capsule administered once daily. This dosage may be used alone 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 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 typically manifest as an acute onset of decreased visual acuity or ocular pain, occurring within hours to weeks following the initiation of therapy. It is critical to recognize that 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 intervention may be necessary. Patients with a history of sulfonamide or penicillin allergy may be at increased risk for developing acute angle-closure glaucoma.

Diabetes and Hypoglycemia Healthcare professionals should be aware that hydrochlorothiazide may unmask latent diabetes mellitus in some patients. Additionally, diabetic patients receiving 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. Therefore, careful monitoring of renal function is recommended in these individuals to prevent potential complications associated with thiazide use. Regular assessment of renal parameters is advised to ensure patient safety and effective management of therapy.

Side Effects

Adverse reactions associated with hydrochlorothiazide have been observed in clinical trials and postmarketing experiences, and they can be categorized by seriousness and frequency.

Serious adverse reactions include hematologic events such as aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia. Hypersensitivity reactions may manifest as anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), and respiratory distress, which can include pneumonitis and pulmonary edema. Renal complications such as renal failure, renal dysfunction, and interstitial nephritis have also been reported. Additionally, acute myopia and secondary angle-closure glaucoma can occur, presenting with acute onset of decreased visual acuity or ocular pain, typically within hours to weeks of initiating treatment. Untreated angle-closure glaucoma may lead to permanent vision loss.

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. Musculoskeletal symptoms such as muscle spasms, as well as nervous system effects like dizziness, vertigo, and headaches, have been noted. Skin reactions can include erythema multiforme, exfoliative dermatitis, and alopecia. Urogenital effects such as impotence and transient blurred vision or xanthopsia in the special senses have also been documented.

In postmarketing experience, hydrochlorothiazide has been associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC), especially in white patients receiving large cumulative doses. The risk for SCC in the general population is approximately 1 additional case per 16,000 patients per year, while for white patients taking a cumulative dose of ≥50,000 mg, the risk increases to approximately 1 additional case for every 6,700 patients per year.

Patients should be monitored for signs of fluid or electrolyte disturbances, including symptoms such as dryness of mouth, thirst, weakness, and gastrointestinal disturbances. Hypokalemia may develop, particularly in patients with severe cirrhosis or those receiving corticosteroids. Caution is advised in patients with impaired hepatic function, as thiazides can precipitate hepatic coma in severe liver disease. Additionally, prolonged thiazide therapy may lead to pathologic changes in the parathyroid glands, resulting in hypercalcemia and hypophosphatemia.

Drug Interactions

Thiazide diuretics may interact with various drug classes, leading to significant clinical effects that warrant careful consideration.

Pharmacodynamic Interactions

• Alcohol, Barbiturates, and Narcotics: The concomitant use of thiazide diuretics with alcohol, barbiturates, or narcotics may potentiate orthostatic hypotension. Patients should be monitored for signs of hypotension and advised to use caution when standing up.

• Antidiabetic Drugs: The use of thiazide diuretics in conjunction with oral antidiabetic agents or insulin may necessitate dosage adjustments. Blood glucose levels should be closely monitored to ensure effective glycemic control.

• Other Antihypertensive Agents: When thiazide diuretics are used with other antihypertensive medications, an additive effect may occur. Blood pressure should be regularly monitored to avoid excessive hypotension.

• Corticosteroids and ACTH: The combination of thiazide diuretics with corticosteroids or adrenocorticotropic hormone (ACTH) may exacerbate electrolyte depletion, particularly hypokalemia. Electrolyte levels should be monitored, and potassium supplementation may be required.

• Pressor Amines: The response to pressor amines, such as norepinephrine, may be diminished when used with thiazide diuretics; however, this does not contraindicate their use. Clinicians should be aware of this potential interaction when managing patients.

• Non-Depolarizing Skeletal Muscle Relaxants: Thiazide diuretics may enhance the responsiveness to non-depolarizing skeletal muscle relaxants, such as tubocurarine. Monitoring of neuromuscular function is advised during concurrent use.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The effectiveness of thiazide diuretics may be reduced by NSAIDs, which can diminish diuretic, natriuretic, and antihypertensive effects. Close observation of blood pressure and fluid status is recommended.

Pharmacokinetic Interactions

• Cholestyramine and Colestipol Resins: These resins can significantly bind hydrochlorothiazide, leading to reduced absorption (up to 85% with cholestyramine and 43% with colestipol). It is advisable to separate the administration of these agents from thiazide diuretics to minimize interaction.

• Lithium: The use of lithium with thiazide diuretics is generally contraindicated due to the potential for reduced renal clearance of lithium, which increases the risk of toxicity. Monitoring of lithium levels is essential if these drugs must be used together.

Testing Considerations

Thiazide diuretics should be discontinued prior to conducting tests for parathyroid function to prevent 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 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. Due to the limitations of animal reproduction studies in predicting human response, hydrochlorothiazide should be used during pregnancy only if clearly needed.

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 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 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 this population. Dosing adjustments may be necessary to mitigate the risk of adverse effects associated with impaired renal clearance.

Hepatic Impairment

There is no information available regarding hepatic impairment, including dosage adjustments, special monitoring, or precautions for patients with compromised liver function. Therefore, no specific recommendations can be made for the use of this medication in patients with hepatic impairment. It is advised that healthcare professionals exercise caution and consider individual patient circumstances 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.

Management of Overdosage In the event of an overdose, it is essential to implement symptomatic and supportive measures. This may include the induction of emesis or performing gastric lavage to mitigate the effects of the overdose.

Healthcare professionals should also focus on correcting dehydration and addressing any electrolyte imbalances, hepatic coma, and hypotension through established medical procedures. In instances of respiratory impairment due to overdose, the administration of oxygen or artificial respiration may be necessary.

Toxicity Information The oral LD50 of hydrochlorothiazide has been determined to be greater than 10 gm/kg in both mouse and rat models. It is important to note that the extent to which hydrochlorothiazide can be removed from the body via hemodialysis has not been established, indicating that additional supportive care may be required in severe cases of 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, did not demonstrate any evidence of teratogenic effects on the fetus. However, there are no adequate and well-controlled studies in pregnant women, and due to the limitations of animal reproduction studies in predicting 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 nonclinical toxicology assessments, two-year feeding studies conducted by the National Toxicology Program (NTP) 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. 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 (clastogenicity) and 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 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 identified. Reports of these reactions have been received 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. 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

Healthcare providers should instruct patients taking hydrochlorothiazide to take precautions to protect their skin from sun exposure. This includes wearing protective clothing, using sunscreen with a high SPF, and avoiding prolonged sun exposure, especially during peak hours.

Additionally, healthcare providers should emphasize the importance of regular skin cancer screenings for patients on this medication. Patients should be made aware of the potential increased risk of skin cancer associated with hydrochlorothiazide and encouraged to report any unusual skin changes or lesions to their healthcare provider promptly.

Storage and Handling

The product is supplied in a tight, light-resistant container as defined by the United States Pharmacopeia (USP). It is essential to store the product at a controlled room temperature of 20°C to 25°C (68°F to 77°F). Care should be taken to protect the product from light, moisture, and freezing temperatures below -20°C (-4°F). The container must remain tightly closed to maintain the integrity of the product. Additionally, it is crucial to keep the product out of reach of children to ensure safety.

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 Actavis Pharma, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)