Hydrochlorothiazide

Description

Hydrochlorothiazide, USP is a diuretic and antihypertensive agent, classified as the 3, 4-dihydro derivative of chlorothiazide. It is chemically designated as 6-chloro-3, 4-dihydro-2H-1, 2, 4-benzothiadiazine-7-sulfonamide 1, 1-dioxide. The structural formula of hydrochlorothiazide is provided in the accompanying documentation.

This compound appears as a white or practically white crystalline powder. It exhibits slight solubility in water, is freely soluble in sodium hydroxide solution, n-butylamine, and dimethylformamide, and is sparingly soluble in methanol. Hydrochlorothiazide is insoluble in ether, chloroform, and dilute mineral acids.

Each tablet intended for oral administration contains either 12.5 mg, 25 mg, or 50 mg of hydrochlorothiazide, USP. The formulation also includes inactive ingredients such as corn starch, FD&C Yellow #6, dibasic calcium phosphate, pregelatinized starch, colloidal silicon dioxide, lactose monohydrate, and magnesium stearate.

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. Hydrochlorothiazide is also indicated for the management of hypertension, either as a monotherapy or to enhance the efficacy of other antihypertensive agents in patients with more severe forms of hypertension.

Limitations of Use The routine use of diuretics, including hydrochlorothiazide, during normal pregnancy is not recommended, as it poses unnecessary risks to both the mother and fetus. Diuretics do not prevent the development of toxemia of pregnancy, and there is insufficient evidence supporting their efficacy in treating this condition. During normal pregnancy, hypervolemia is typically not harmful to the mother or fetus in the absence of cardiovascular disease.

Hydrochlorothiazide may be indicated in pregnancy when edema is due to pathological causes, similar to its use in non-pregnant patients. Dependent edema during pregnancy, often resulting from venous return restriction by the gravid uterus, should primarily be managed through non-pharmacological measures such as elevation of the lower extremities and the use of support stockings. If this edema leads to significant discomfort that is not alleviated by rest, a short course of diuretic therapy may be appropriate.

Dosage and Administration

The usual adult dosage for edema is 25 mg 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 3 to 5 days each week.

For the control of hypertension in adults, the initial recommended dose is 25 mg daily, given as a single dose. This dose may be increased to 50 mg daily, which can be administered as a single dose or divided into two doses. It is important to note that doses exceeding 50 mg are often associated with significant reductions in serum potassium levels.

In pediatric patients, the usual dosage for diuresis and control of hypertension is 0.5 mg to 1 mg per pound (1 to 2 mg/kg) per day, administered in either a single dose or two divided doses. The maximum daily dosage should not exceed 37.5 mg for infants up to 2 years of age or 100 mg for children aged 2 to 12 years. For 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, it is contraindicated in individuals with hypersensitivity to this product or to other sulfonamide-derived drugs, as this 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, as they may precipitate azotemia. Patients with impaired renal function are at risk for cumulative effects of the drug, necessitating close monitoring of renal parameters.

Hepatic Function In patients with impaired hepatic function or progressive liver disease, thiazides may disrupt fluid and electrolyte balance, potentially leading to hepatic coma. Caution is advised in this population, and monitoring of liver function may be warranted.

Drug Interactions Thiazides may enhance the effects of other antihypertensive medications. Healthcare professionals should be vigilant when prescribing thiazides alongside other antihypertensives to avoid excessive hypotension.

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

Systemic Lupus Erythematosus There have been reports of exacerbation or activation of systemic lupus erythematosus in patients taking thiazides. Clinicians should be aware of this potential risk and monitor patients with a history of lupus closely.

Lithium Interaction Lithium should generally be avoided in conjunction with diuretics, including thiazides, due to the risk of lithium toxicity. Regular monitoring of lithium levels is recommended for patients requiring both therapies.

Ocular Effects Hydrochlorothiazide, a sulfonamide, may cause idiosyncratic reactions such as acute transient myopia and acute angle-closure glaucoma. Symptoms may include a sudden decrease in visual acuity or ocular pain, typically occurring within hours to weeks of initiating treatment. If acute angle-closure glaucoma is suspected, immediate discontinuation of hydrochlorothiazide is essential, and prompt medical or surgical intervention may be necessary if intraocular pressure remains uncontrolled. Patients with a history of sulfonamide or penicillin allergy may be at increased risk for developing this condition.

Electrolyte Monitoring Periodic assessment of serum electrolytes is recommended to detect potential imbalances. Regular monitoring should be conducted at appropriate intervals to ensure patient safety and effective management of electrolyte levels.

Side Effects

Adverse reactions have been observed in patients receiving treatment, categorized by seriousness and frequency.

Serious adverse reactions include hematologic events such as aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia. Additionally, hypersensitivity reactions may occur, including anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), and respiratory distress, which encompasses pneumonitis and pulmonary edema. Renal complications such as renal failure, renal dysfunction, and interstitial nephritis have also been reported, necessitating careful monitoring.

Common adverse reactions reported in clinical trials and postmarketing experiences 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 like muscle spasms, as well as nervous system/psychiatric effects such as vertigo, dizziness, headache, and restlessness, have been noted.

Skin reactions can manifest as erythema multiforme, including Stevens-Johnson Syndrome, exfoliative dermatitis, and alopecia. Patients may also report transient blurred vision and xanthopsia as special senses effects. Urogenital issues, including impotence, have been documented 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 receiving large cumulative doses. The overall risk for SCC in the population was approximately 1 additional case per 16,000 patients per year, while for white patients taking a cumulative dose of ≥ 50,000 mg, the risk increase was approximately 1 additional SCC case for every 6,700 patients per year.

Healthcare providers should remain vigilant for these adverse reactions and monitor patients accordingly.

Drug Interactions

Concomitant use of thiazide diuretics with certain medications may lead to significant drug interactions, categorized primarily into pharmacodynamic and pharmacokinetic interactions.

Pharmacodynamic Interactions:

• Alcohol, Barbiturates, or Narcotics: The combination may potentiate orthostatic hypotension, necessitating careful monitoring of blood pressure and patient symptoms.

• Antidiabetic Drugs (Oral Agents and Insulin): Dosage adjustments of the antidiabetic medication may be required to maintain glycemic control.

• Other Antihypertensive Drugs: There is a potential for additive effects or potentiation of antihypertensive activity, which may necessitate monitoring of blood pressure and possible dosage adjustments.

• Corticosteroids and ACTH: Concurrent use may lead to intensified electrolyte depletion, particularly hypokalemia, requiring regular monitoring of electrolyte levels.

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

• Skeletal Muscle Relaxants (Nondepolarizing, e.g., Tubocurarine): Increased responsiveness to muscle relaxants may occur, warranting careful monitoring of neuromuscular function.

Pharmacokinetic Interactions:

• Cholestyramine and Colestipol Resins: These anionic exchange resins can significantly impair the absorption of hydrochlorothiazide, reducing its gastrointestinal absorption by up to 85% and 43%, respectively. It is advisable to separate the administration of these agents from thiazide diuretics.

• Lithium: The use of diuretics with lithium is generally contraindicated due to the risk of reduced renal clearance of lithium, which can lead to toxicity. Consultation of the package insert for lithium preparations is recommended prior to co-administration.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): In some patients, NSAIDs may diminish the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics. Close observation is recommended to ensure the desired diuretic effect is achieved when these agents are used together.

Healthcare professionals should exercise caution and consider appropriate monitoring and dosage adjustments when prescribing thiazide diuretics alongside these interacting medications.

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 derived from empirical use and published literature concerning the treatment of hypertension in pediatric patients. For specific dosing recommendations, refer to the section on Dosage and Administration for infants and children.

Geriatric Use

Elderly patients may exhibit increased sensitivity to side effects when using this medication, necessitating cautious administration. It is essential to monitor these patients for potential electrolyte imbalances, particularly hypokalemia, which may be more pronounced in this population.

Dosage adjustments should be considered for elderly patients, especially those with reduced kidney function, as the cumulative effects of hydrochlorothiazide can develop in individuals with impaired renal function. Additionally, there is an increased risk of orthostatic hypotension in elderly patients, particularly when the medication is used in conjunction with other antihypertensive agents or substances such as alcohol, barbiturates, or narcotics. Regular monitoring and careful management are advised to mitigate these risks.

Pregnancy

Hydrochlorothiazide is classified as a Pregnancy Category B medication. Animal 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, have not demonstrated any evidence of teratogenic effects or harm to the fetus. 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, including hydrochlorothiazide, 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 other adverse reactions that may also occur in adults. Healthcare providers 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 the risks and benefits when advising lactating mothers. A decision should be made whether to discontinue nursing or to discontinue hydrochlorothiazide, taking into account the importance of the drug to the mother.

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 important to closely monitor these patients for any signs of deterioration in liver function and to assess their fluid and electrolyte status regularly. Adjustments to dosage may be necessary based on the severity of hepatic impairment and the patient's overall clinical condition.

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 is removed from the body through hemodialysis has not been definitively established. Furthermore, it is noteworthy that the oral LD50 of hydrochlorothiazide exceeds 10 g/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 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. Due to the limitations of animal reproduction studies in predicting human responses, 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.

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.

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 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 dietary 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 indicated 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 well-closed container as defined by the United States Pharmacopeia (USP) and must be dispensed with 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). Additionally, it is crucial to keep this product, along with all medications, out of reach of children to ensure safety.

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)