Hydrochlorothiazide

Description

Hydrochlorothiazide USP is the 3,4-dihydro derivative of chlorothiazide, chemically designated as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. It appears as a white, or practically white, crystalline powder. Hydrochlorothiazide USP is slightly soluble in water and freely soluble in sodium hydroxide solution, n-butylamine, and dimethylformamide. It is sparingly soluble in methanol and insoluble in ether, chloroform, and dilute mineral acids. Each tablet for oral administration contains 12.5 mg, 25 mg, or 50 mg of hydrochlorothiazide USP. The tablets also include inactive ingredients such as FD&C yellow #6, lactose anhydrous, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, and stearic acid.

Uses and Indications

Hydrochlorothiazide tablets USP are indicated as adjunctive therapy in the management of edema associated with various conditions, including congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. Additionally, these tablets are beneficial in treating edema resulting from renal dysfunction, such as nephrotic syndrome, acute glomerulonephritis, and chronic renal failure.

In the management of hypertension, hydrochlorothiazide tablets USP may be utilized either as a sole therapeutic agent or to enhance the effectiveness of other antihypertensive medications in patients with more severe forms of hypertension.

Limitations of use include the routine use of diuretics during normal pregnancy, which is inappropriate and poses unnecessary risks to both the mother and fetus. Hydrochlorothiazide does not prevent or effectively treat toxemia of pregnancy. Thiazides may be indicated in pregnancy only when edema is due to pathological causes, similar to their use in non-pregnant patients.

Dependent edema during pregnancy, resulting from venous return restriction by the gravid uterus, should be managed through non-pharmacological measures such as elevation of the lower extremities and the use of support stockings. The use of diuretics to reduce intravascular volume in cases of dependent edema during pregnancy is considered illogical and unnecessary, as hypervolemia is typically not harmful in the absence of cardiovascular disease. While this hypervolemia may occasionally be associated with discomfort due to edema, increased recumbency often alleviates such discomfort. In rare cases where edema causes extreme discomfort unrelieved by rest, a short course of diuretic therapy may be appropriate.

Dosage and Administration

Therapy should be individualized according to patient response. Healthcare professionals are advised to utilize the smallest dosage necessary to achieve the required therapeutic effect. Regular assessment of the patient's response is essential to determine the appropriate dosage adjustments.

Contraindications

Use of this product is contraindicated in patients with anuria due to the potential for exacerbating renal impairment. Additionally, hypersensitivity to this product or to other sulfonamide-derived drugs is a contraindication, as it may lead to severe allergic reactions.

Warnings and Precautions

Use of thiazide diuretics requires careful consideration in patients with specific health conditions.

Renal Considerations Thiazides should be administered with caution in individuals with severe renal disease. In such patients, the use of thiazides may precipitate azotemia, and the cumulative effects of the drug can become pronounced in those with impaired renal function. Regular monitoring of renal function is advised to mitigate potential risks.

Hepatic Function Patients with impaired hepatic function or progressive liver disease should also be closely monitored when using thiazides. Minor alterations in fluid and electrolyte balance in these individuals may lead to hepatic coma, necessitating vigilant oversight of liver function parameters.

Drug Interactions Thiazides may enhance the effects of other antihypertensive medications. Healthcare professionals should be aware of this potential interaction and adjust treatment regimens accordingly to avoid excessive hypotension.

Allergic Reactions Sensitivity reactions can occur in patients regardless of their allergy history, including those with bronchial asthma. Clinicians should remain alert for signs of allergic responses and be prepared to manage them appropriately.

Systemic Lupus Erythematosus There have been reports of exacerbation or activation of systemic lupus erythematosus in patients taking thiazides. Monitoring for symptoms indicative of this condition is recommended.

Lithium Interaction The concomitant use of lithium with diuretics, including thiazides, is generally contraindicated due to the risk of lithium toxicity. Regular serum lithium levels should be monitored in patients receiving both therapies.

Ocular Effects Hydrochlorothiazide, a sulfonamide, has been associated with acute myopia and secondary angle-closure glaucoma. This idiosyncratic reaction may present with a sudden decrease in visual acuity or ocular pain, typically occurring within hours to weeks after initiation of the drug. If these symptoms arise, hydrochlorothiazide should be discontinued 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, warranting careful assessment prior to treatment initiation.

Side Effects

Adverse reactions associated with the use of the medication include a range of serious and common effects, as observed in clinical trials and postmarketing experiences.

Serious adverse reactions may include hematologic conditions such as aplastic anemia, agranulocytosis, leucopenia, 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, and exfoliative dermatitis, including toxic epidermal necrolysis, have been noted.

Common adverse reactions reported by patients include weakness, hypotension (including orthostatic hypotension), and various digestive issues such as diarrhea, vomiting, cramping, constipation, gastric irritation, nausea, and anorexia. 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 including vertigo, paresthesias, dizziness, headache, and restlessness, have been documented. Urogenital effects, specifically impotence, have also been reported.

In terms of skin reactions, patients may experience photosensitivity, fever, urticaria, rash, and purpura. Special senses may be affected, leading to transient blurred vision and xanthopsia.

Postmarketing experience has indicated an association between hydrochlorothiazide and an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC). In a study conducted within the Sentinel System, the increased risk was predominantly observed in white patients receiving large cumulative doses. The overall population exhibited an approximate risk 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

Thiazide diuretics may interact with several classes of drugs, leading to various clinical effects that warrant consideration.

Pharmacodynamic Interactions

• Alcohol, Barbiturates, and Narcotics: The concomitant use of these agents with thiazide diuretics may potentiate orthostatic hypotension. Monitoring for signs of hypotension is advised when these medications are used together.

• Antidiabetic Drugs: The use of thiazide diuretics may necessitate dosage adjustments of antidiabetic medications due to potential alterations in glycemic control. Regular monitoring of blood glucose levels is recommended.

• Corticosteroids and ACTH: These agents may exacerbate electrolyte depletion, particularly hypokalemia, when administered alongside thiazide diuretics. Electrolyte levels should be monitored closely.

• Other Antihypertensive Drugs: The combination of thiazide diuretics with other antihypertensive agents may result in an additive effect or potentiation of blood pressure-lowering effects. Blood pressure should be monitored to avoid excessive hypotension.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The effectiveness of thiazide diuretics may be diminished in some patients when used concurrently with NSAIDs, potentially reducing diuretic, natriuretic, and antihypertensive effects. Monitoring of blood pressure and fluid status is recommended.

• Pressor Amines (e.g., Norepinephrine): The response to pressor amines may be decreased when used with thiazide diuretics; however, this does not contraindicate their use. Clinical judgment should guide the use of these agents.

Pharmacokinetic Interactions

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

Testing 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

There are no well-controlled clinical trials conducted in pediatric patients. Dosing information for this age group is primarily derived from empirical use and published literature concerning the treatment of hypertension in pediatric patients. Caution is advised when prescribing, as the safety and efficacy of the medication in children have not been established through rigorous clinical trials.

Geriatric Use

Elderly patients may require special consideration when using thiazide diuretics, particularly those aged 65 and older. Caution is advised in patients with severe renal disease, as thiazides can precipitate azotemia and lead to cumulative effects due to impaired renal function. In cases of progressive renal impairment, it may be necessary to withhold or discontinue diuretic therapy.

Thiazides should also be used with caution in geriatric patients who have impaired hepatic function or progressive liver disease, as even minor alterations in fluid and electrolyte balance can precipitate hepatic coma. Additionally, there have been reports of exacerbation or activation of systemic lupus erythematosus in some patients.

Elderly patients typically do not require doses exceeding 50 mg of hydrochlorothiazide daily when used in conjunction with other antihypertensive agents. However, hypokalemia may develop, particularly with brisk diuresis, in the presence of severe cirrhosis or after prolonged therapy.

For diabetic elderly patients, dosage adjustments of insulin or oral hypoglycemic agents may be necessary, as thiazide diuretics can induce hyperglycemia and potentially unmask latent diabetes mellitus. It is recommended that periodic determination of serum electrolytes be conducted at appropriate intervals to monitor for possible electrolyte imbalances.

Pregnancy

Hydrochlorothiazide has been studied in pregnant mice and rats during their major organogenesis periods, with doses up to 3000 mg/kg and 1000 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. The use of this medication during pregnancy may be associated with risks, including fetal or neonatal jaundice and thrombocytopenia, as well as other adverse reactions that have been observed in adults. Healthcare professionals should weigh the potential benefits against these risks when considering hydrochlorothiazide for 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 should use this medication with caution, particularly in cases of severe renal disease. In individuals with reduced kidney function, thiazides may precipitate azotemia. Additionally, the cumulative effects of the drug may develop in patients with impaired renal function, necessitating careful monitoring and potential dosing adjustments.

Hepatic Impairment

Patients with hepatic impairment should use thiazides with caution. In individuals with impaired hepatic function or progressive liver disease, minor alterations in fluid and electrolyte balance may precipitate hepatic coma. Therefore, careful monitoring of liver function and electrolyte levels is recommended in this population to mitigate potential risks. Adjustments to dosage may be necessary based on the severity of hepatic impairment and the patient's overall clinical status.

Overdosage

The most common signs and symptoms associated with overdose include electrolyte depletion, specifically hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis.

In the event of an overdose, it is recommended to induce emesis or perform gastric lavage to mitigate the effects of the ingested substance. Additionally, it is crucial to correct any dehydration and electrolyte imbalances through established medical procedures.

Should respiratory impairment occur as a result of the overdose, it is essential to provide supplemental oxygen or initiate artificial respiration as necessary to ensure adequate oxygenation.

The oral LD50 of hydrochlorothiazide has been determined to be greater than 10 g/kg in both mice and rats, indicating a significant margin of safety in these animal models. However, clinical management of overdose should always be approached with caution and in accordance with established medical guidelines.

Nonclinical Toxicology

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, revealed no 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 nonteratogenic effects, including the 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 did not demonstrate any carcinogenic potential of hydrochlorothiazide in female mice at doses up to approximately 600 mg/kg/day or in male and female rats at doses up to 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, and 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.

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

Postmarketing experience has identified an association between hydrochlorothiazide and 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 predominantly observed in white patients who are administered large cumulative doses of the medication.

In the overall population, the estimated increase in risk for SCC is approximately one additional case per 16,000 patients per year. Notably, for white patients receiving a cumulative dose of 50,000 mg or more, the risk escalates to approximately one additional case of SCC for every 6,700 patients per year.

Patient Counseling

Patients taking hydrochlorothiazide should be advised to take precautions to protect their skin from sun exposure. This includes wearing protective clothing and using sunscreen to minimize the risk of skin damage. Additionally, healthcare providers should recommend that patients undergo regular skin cancer screenings to monitor for any potential issues.

Patients should be informed about the importance of reporting any side effects they experience while on hydrochlorothiazide. They should be encouraged to contact their healthcare provider for medical advice regarding any adverse effects. Furthermore, patients can report side effects to the FDA at 1-800-FDA-1088 or to Leading Pharma, LLC at 1-844-740-7500.

Storage and Handling

The product is supplied in a well-closed container that meets the specifications outlined in the United States Pharmacopeia (USP), featuring a child-resistant closure as required. It is essential 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.

Healthcare professionals are reminded to keep this product, along with all medications, out of the reach of children to ensure safety.

Additional Clinical Information

Periodic determination of serum electrolytes is recommended for patients to detect potential electrolyte imbalances at appropriate intervals. Clinicians should counsel patients taking hydrochlorothiazide about the risk of non-melanoma skin cancer, advising them to protect their skin from sun exposure and to undergo regular skin cancer screenings.

FDA Insert (PDF)

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

View full prescribing information (PDF)