Hydrochlorothiazide

Description

Hydrochlorothiazide 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 molecular formula is C7H8ClN3O4S2, and it has a molecular weight of 297.74 g/mol. Hydrochlorothiazide appears as a white, or practically white, crystalline powder. It is slightly soluble in water, freely soluble in sodium hydroxide solution, n-butylamine, and dimethylformamide; 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, respectively. The tablets also contain the following inactive ingredients: anhydrous lactose, D&C Yellow No.10 aluminum lake, FD&C Red No. 40 aluminum lake, magnesium stearate, pregelatinized starch, and sodium starch glycolate.

Uses and Indications

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

In the context of hypertension, hydrochlorothiazide tablets are indicated for use either as a monotherapy or to enhance the effectiveness of other antihypertensive agents in patients with more severe forms of hypertension.

Limitations of use include the routine administration of diuretics during normal pregnancy, which is deemed inappropriate and poses unnecessary risks to both the mother and fetus. Diuretics do not prevent the development of toxemia of pregnancy, nor is there satisfactory evidence supporting their efficacy in treating this condition. Thiazides may be indicated during pregnancy when edema is due to pathological causes, similar to their use in non-pregnant individuals.

Dependent edema in 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.

It is important to note that hypervolemia during normal pregnancy is not harmful to the mother or fetus 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, utilizing the smallest dosage necessary to achieve the desired effect.

In adults, for the management of edema, the usual dosage ranges from 25 to 100 mg daily, which may be administered as a single dose or divided into multiple doses. Many patients with edema may benefit from intermittent therapy, which involves administration on alternate days or on three to five days each week.

For the control of hypertension in adults, the usual initial dose is 25 mg daily, administered as a single dose. This dose may be increased to 50 mg daily, which can be given as a single dose or divided into two doses. Typically, patients do not require doses exceeding 50 mg of hydrochlorothiazide daily when used in conjunction with other antihypertensive agents.

In infants and children, for diuresis and the control of hypertension, the usual pediatric dosage is 0.5 to 1 mg per pound (1 to 2 mg/kg) per day, administered in a single dose or divided into two doses. The maximum dosage should not exceed 37.5 mg per day for infants up to 2 years of age or 100 mg per day for children aged 2 to 12 years. In infants less than 6 months of age, doses may be increased to 1.5 mg per pound (3 mg/kg) per day, administered in two divided doses if necessary.

Contraindications

Use of this product is contraindicated in patients with anuria due to the potential for exacerbating renal impairment. Additionally, individuals with hypersensitivity to this product or to other sulfonamide-derived drugs should not use it, as this may lead to severe allergic reactions.

Warnings and Precautions

Use of thiazides requires careful consideration in patients with severe renal disease, as these medications may precipitate azotemia. The cumulative effects of thiazides can become pronounced in individuals with impaired renal function, necessitating close monitoring of renal parameters.

In patients with impaired hepatic function or progressive liver disease, thiazides should be administered with caution. Minor alterations in fluid and electrolyte balance in these patients may lead to hepatic coma, highlighting the need for vigilant observation of liver function.

Thiazides have the potential to enhance the effects of other antihypertensive agents. Therefore, healthcare professionals should be aware of this interaction when prescribing thiazides in conjunction with other antihypertensive medications.

Sensitivity reactions may occur in patients regardless of their allergy history, including those with bronchial asthma. Clinicians should remain alert to the possibility of such reactions and monitor patients accordingly.

There have been reports of exacerbation or activation of systemic lupus erythematosus associated with thiazide use. Patients with a history of this condition should be monitored closely for any signs of worsening symptoms.

Lithium administration is generally contraindicated with diuretics, including thiazides, due to the risk of lithium toxicity. Healthcare providers should consider alternative therapies when managing patients requiring both medications.

Hydrochlorothiazide, classified as a sulfonamide, may lead to idiosyncratic reactions such as acute transient myopia and acute angle-closure glaucoma. Symptoms typically manifest within hours to weeks of initiating treatment and include a sudden decrease in visual acuity or ocular pain. If acute angle-closure glaucoma occurs, it is critical 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.

To ensure patient safety, periodic determination of serum electrolytes is recommended to detect potential electrolyte imbalances. Monitoring should occur at appropriate intervals to facilitate timely intervention if imbalances are identified.

Side Effects

Adverse reactions observed in patients include a range of serious and common effects across various body systems.

Serious adverse reactions encompass hematologic conditions 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, presenting as 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, exfoliative dermatitis, and toxic epidermal necrolysis, have been reported.

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. Musculoskeletal symptoms like muscle spasm and nervous system/psychiatric effects, including vertigo, paresthesias, dizziness, headache, and restlessness, have also been noted.

Metabolic disturbances such as electrolyte imbalance, hyperglycemia, glycosuria, and hyperuricemia are of concern. Urogenital effects, particularly impotence, and transient visual disturbances, including blurred vision and xanthopsia, have been reported as well.

In postmarketing experience, 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 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

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 these agents with 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 require dosage adjustments when administered alongside thiazide diuretics due to potential alterations in glycemic control.

• Corticosteroids and ACTH: The use of corticosteroids or ACTH in conjunction with thiazide diuretics may exacerbate electrolyte depletion, particularly hypokalemia. Regular monitoring of electrolyte levels is advised.

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

• Pressor Amines (e.g., Norepinephrine): Thiazide diuretics may diminish the response to pressor amines; however, this does not contraindicate their use. Clinicians should be aware of this interaction when managing patients requiring pressor support.

• Non-Depolarizing Skeletal Muscle Relaxants (e.g., Tubocurarine): Increased responsiveness to non-depolarizing skeletal muscle relaxants may occur when used with thiazide diuretics. Monitoring of neuromuscular function is recommended.

• 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 impair the gastrointestinal absorption of hydrochlorothiazide, reducing its absorption by up to 85% and 43%, respectively. It is advisable to separate the administration of these resins and thiazide diuretics by several hours to minimize this 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 these agents must be used together.

In summary, careful monitoring and potential dosage adjustments are necessary when thiazide diuretics are used in conjunction with the aforementioned drug classes to mitigate the risk of adverse effects and ensure therapeutic efficacy.

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. For specific dosing recommendations, refer to the DOSAGE AND ADMINISTRATION section, particularly for infants and children.

Geriatric Use

Elderly patients should be treated with caution due to the potential for reduced kidney function and increased sensitivity to side effects. It is essential to monitor these patients for electrolyte imbalances, particularly hypokalemia, which may be more pronounced in this population.

Dosage adjustments may be necessary based on renal function, as elderly patients often exhibit impaired renal clearance. Additionally, the antihypertensive effects of the medication may be enhanced in elderly patients, necessitating careful monitoring of both blood pressure and renal function.

Periodic determination of serum electrolytes is particularly important for elderly patients receiving diuretic therapy to ensure safety and efficacy.

Pregnancy

Hydrochlorothiazide has been evaluated in animal studies, where it was administered orally to pregnant mice and rats during critical periods of organogenesis at doses up to 3,000 mg/kg and 1,000 mg/kg, respectively. These studies did not demonstrate any evidence of teratogenic effects on the fetus. However, there are no adequate and well-controlled studies in pregnant women, and the absence of such data necessitates caution. 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, 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 and thrombocytopenia, as well as other adverse reactions that may occur in adults. Healthcare professionals should weigh the benefits against the risks when considering the use of hydrochlorothiazide in pregnant patients.

Lactation

There are no specific statements regarding nursing mothers or lactation considerations in the provided text. Therefore, the effects of the drug on breastfed infants and the excretion of the drug in human milk are not addressed. Healthcare professionals should consider the lack of data when advising lactating mothers on the use of this medication.

Renal Impairment

Patients with renal impairment should use this medication with caution, particularly in cases of severe renal disease. In individuals with renal disease, thiazides may precipitate azotemia, necessitating careful monitoring of renal function. Additionally, the cumulative effects of the drug may develop in patients with impaired renal function, warranting dose adjustments and vigilant oversight to mitigate potential adverse effects.

Hepatic Impairment

Patients with hepatic impairment should use thiazides with caution due to the potential for minor alterations in fluid and electrolyte balance, which may precipitate hepatic coma. It is essential to monitor these patients closely for any signs of deterioration in liver function or fluid status. Adjustments to dosage may be necessary based on the severity of hepatic impairment and the patient's overall clinical condition. Regular assessment of liver function tests is recommended to ensure safe and effective use of thiazides in this population.

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. Established procedures should be followed to manage complications such as hepatic coma and hypotension. In instances of respiratory impairment due to overdose, the administration of oxygen or the provision of artificial respiration may be necessary.

Toxicity Information The oral LD50 of hydrochlorothiazide has been determined to be greater than 10 g/kg in both mouse and rat models. However, the extent to which hydrochlorothiazide can be removed from the body through hemodialysis has not been clearly established, indicating that further evaluation may be required in cases of significant overdose.

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, 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 demonstrated 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 up to 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 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 (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 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

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 to ensure its integrity and efficacy. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15°C to 30°C (59°F to 86°F) in accordance with USP Controlled Room Temperature guidelines. Proper storage conditions are essential for maintaining the quality of the product.

Additional Clinical Information

Clinicians should conduct periodic determinations of serum electrolytes in patients to monitor for potential electrolyte imbalances. This assessment should occur at appropriate intervals to ensure timely identification and management of any imbalances that may arise.

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)