Hydrochlorothiazide

Description

Hydrochlorothiazide is a diuretic and antihypertensive agent, specifically the 3,4-dihydro derivative of chlorothiazide. The chemical name for hydrochlorothiazide is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, with a molecular formula of C7H8ClN3O4S2 and a molecular weight of 297.74.

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

For oral administration, each tablet contains 12.5 mg, 25 mg, or 50 mg of hydrochlorothiazide. The tablets also include inactive ingredients such as 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 efficacy of other antihypertensive agents in patients with more severe forms of hypertension.

Limitations of Use: Routine use of diuretics, including hydrochlorothiazide, during normal pregnancy is 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 only when edema is due to pathological causes, similar to their use in non-pregnant patients.

For dependent edema in pregnancy, which arises from venous return restriction by the gravid uterus, treatment should focus on non-pharmacological measures such as elevating the lower extremities and utilizing support stockings. The use of diuretics to reduce intravascular volume in cases of dependent edema during normal 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 instances where edema causes extreme discomfort unrelieved by rest, a short course of diuretic therapy may be appropriate.

Dosage and Administration

The usual adult dosage for edema is 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 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 either as a single dose or divided into two doses.

In pediatric patients, the usual dosage for diuresis and control of hypertension is 0.5 to 1 mg per pound (1 to 2 mg/kg) per day, administered in either a single dose or two divided 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. 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 thiazides requires careful consideration in patients with severe renal disease, as these medications may precipitate azotemia. In individuals with impaired renal function, the cumulative effects of thiazides can develop, necessitating close monitoring of renal parameters.

Caution is also advised when prescribing thiazides to patients with impaired hepatic function or progressive liver disease. Minor alterations in fluid and electrolyte balance in these patients may lead to hepatic coma, highlighting the need for vigilant oversight of liver function.

Thiazides have the potential to enhance the effects of other antihypertensive agents, which may necessitate adjustments in therapy to avoid excessive hypotension. Additionally, sensitivity reactions can occur in patients regardless of their allergy or bronchial asthma history, warranting careful observation for any signs of adverse reactions.

There have been reports of exacerbation or activation of systemic lupus erythematosus in some patients, which should be taken into account when evaluating the risk-benefit profile of thiazide therapy.

Lithium administration is generally contraindicated in conjunction with diuretics due to the risk of lithium toxicity.

Hydrochlorothiazide, classified as a sulfonamide, carries the risk of idiosyncratic reactions, including acute transient myopia and acute angle-closure glaucoma. Symptoms such as a sudden decrease in visual acuity or ocular pain may manifest within hours to weeks following initiation of the drug. 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 be conducted at appropriate intervals to facilitate timely intervention if abnormalities are identified.

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 can occur, manifesting as anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), and respiratory distress, which may include 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 effects such as vertigo, dizziness, headache, and restlessness, have been noted.

Skin reactions can range from erythema multiforme, including Stevens-Johnson syndrome, to exfoliative dermatitis, including toxic epidermal necrolysis and alopecia. Patients may also report transient blurred vision and xanthopsia as special senses effects. Urogenital issues, such as impotence, have been documented as well.

In postmarketing experience, there is an increased risk of non-melanoma skin cancer associated with hydrochlorothiazide, particularly squamous cell carcinoma (SCC) in white patients receiving large cumulative doses. The overall 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.

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

Drug Interactions

The following drug interactions have been identified with hydrochlorothiazide, categorized by interaction type and clinical significance.

Pharmacodynamic Interactions

• Alcohol, Barbiturates, and Narcotics: Concurrent use may potentiate orthostatic hypotension. Patients should be monitored for signs of hypotension and advised to use caution when standing up.

• Antidiabetic Drugs (Oral Agents and Insulin): Dosage adjustments of the antidiabetic medication may be necessary to maintain glycemic control. Close monitoring of blood glucose levels is recommended.

• Other Antihypertensive Drugs: The use of additional antihypertensive agents may lead to an additive effect or potentiation of blood pressure-lowering effects. Blood pressure should be monitored regularly.

• Corticosteroids and ACTH: There is a risk of intensified electrolyte depletion, particularly hypokalemia. Electrolyte levels should be monitored, and potassium supplementation may be required.

• Skeletal Muscle Relaxants (Nondepolarizing, e.g., Tubocurarine): There may be an increased responsiveness to nondepolarizing muscle relaxants. Monitoring of neuromuscular function is advised.

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

Pharmacokinetic Interactions

• Cholestyramine and Colestipol Resins: The absorption of hydrochlorothiazide is significantly impaired in the presence of these anionic exchange resins, with reductions in absorption of up to 85% and 43%, respectively. It is advisable to separate the administration of hydrochlorothiazide and these resins by at least 2 hours.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The concomitant use of NSAIDs may reduce the diuretic, natriuretic, and antihypertensive effects of hydrochlorothiazide. Patients should be closely observed to ensure the desired diuretic effect is achieved.

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

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 exhibit increased sensitivity to side effects, necessitating cautious use of this medication in this population. It is essential to monitor these patients for signs of fluid or electrolyte imbalance, especially considering that many elderly individuals may have reduced kidney function.

Dosage adjustments should be made carefully, as geriatric patients often require lower doses to achieve the desired therapeutic effect. Additionally, the cumulative effects of the drug must be considered in elderly patients with impaired renal function, as this may lead to azotemia.

Periodic determination of serum electrolytes is particularly important in elderly patients to detect possible electrolyte imbalances, ensuring their safety and the efficacy of treatment.

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 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, thrombocytopenia, and other adverse reactions that may also occur in adults. Healthcare professionals should weigh the potential benefits against the risks when considering the use of hydrochlorothiazide in pregnant patients.

Lactation

There are no specific statements regarding nursing mothers or lactation in the provided text. Therefore, the effects of the medication on breastfed infants and the excretion of the drug in human milk remain undetermined. 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 be treated with caution, particularly those with severe renal disease. In this population, 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. 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

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 artificial respiration may be necessary.

The oral LD50 of hydrochlorothiazide has been determined to be greater than 10 g/kg in both mouse and rat models, indicating a significant margin of safety in these species. However, the extent to which hydrochlorothiazide can be removed from the body through hemodialysis remains to be established.

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. 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, 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.

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

Hydrochlorothiazide has been associated with 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 adherence to these storage conditions is essential for maintaining the quality of the product.

Additional Clinical Information

Clinicians should conduct periodic determinations of serum electrolytes in patients to detect any potential electrolyte imbalances. This monitoring should occur at appropriate intervals to ensure patient safety and effective management of treatment.

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)