Hydrochlorothiazide

Description

Hydrochlorothiazide is a diuretic and antihypertensive agent, classified as the 3,4-dihydro derivative of chlorothiazide. Its chemical designation is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Hydrochlorothiazide, USP appears as a white or practically white crystalline powder. The compound exhibits very slight solubility in water, is freely soluble in sodium hydroxide solution, n-butylamine, and dimethylformamide, and is sparingly soluble in methanol. It is insoluble in ether, chloroform, and dilute mineral acids.

Each tablet intended for oral administration contains either 25 mg or 50 mg of hydrochlorothiazide, USP. The formulation also includes the following inactive ingredients: microcrystalline cellulose, NF; lactose anhydrous, NF; pregelatinized starch, NF; sodium lauryl sulfate, NF; silicon dioxide, NF; and magnesium stearate, NF.

Uses and Indications

Hydrochlorothiazide tablets are indicated as adjunctive therapy in the management of edema associated with various conditions, including congestive heart failure, hepatic cirrhosis, and corticosteroid or 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 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 The routine use of diuretics, including hydrochlorothiazide, during normal pregnancy is not recommended due to potential risks to both the mother and fetus. Diuretics do not prevent the development of toxemia of pregnancy, and there is insufficient evidence to support their efficacy in treating this condition. However, thiazides may be indicated in pregnancy when edema is due to pathological causes.

For dependent edema in pregnancy, which arises from venous return restriction by the gravid uterus, non-pharmacological measures such as elevating the lower extremities and using support stockings are recommended. In the absence of cardiovascular disease, hypervolemia during normal pregnancy is generally not harmful to the mother or fetus. If edema results in significant discomfort, increased recumbency may provide relief. In rare cases where extreme discomfort persists despite rest, a short course of diuretic therapy may be appropriate.

Dosage and Administration

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

In the management of hypertension, the usual initial dosage for adults is 25 mg daily, administered as a single dose. If necessary, the dosage may be increased to 50 mg daily, which can be given as a single dose or divided into two doses. Caution is advised when doses exceed 50 mg, as higher doses are often associated with significant reductions in serum potassium levels.

For pediatric patients, the typical dosage for diuresis and hypertension control is 0.5 to 1 mg per pound (1 to 2 mg/kg) per day, which can be given in a single dose or divided into two doses. It is important to note that the maximum dosage should not exceed 37.5 mg per day for infants up to 2 years of age, and 100 mg per day for children aged 2 to 12 years. In infants younger than 6 months, doses may need to be increased to 1.5 mg per pound (3 mg/kg) per day, administered in two divided doses, if clinically indicated.

Contraindications

Use of this product is contraindicated in patients with anuria due to the potential for exacerbating renal function. 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 hydrochlorothiazide requires careful consideration in patients with specific health conditions.

Renal Considerations Caution is advised when prescribing hydrochlorothiazide to patients with severe renal disease, as thiazides may precipitate azotemia. The cumulative effects of the drug can develop in individuals with impaired renal function, necessitating close monitoring.

Hepatic Function Thiazides should also be used with caution in patients with impaired hepatic function or progressive liver disease. Minor alterations in fluid and electrolyte balance in these patients may precipitate hepatic coma, highlighting the need for vigilant oversight.

Drug Interactions It is important to note that thiazides may enhance the effects of other antihypertensive medications. Therefore, healthcare professionals should monitor patients for potential additive effects.

Allergic Reactions Sensitivity reactions can occur in patients regardless of their allergy or bronchial asthma history. Clinicians should remain alert to the possibility of such reactions.

Systemic Lupus Erythematosus 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.

Lithium Interaction Lithium should generally not be co-administered with diuretics, including hydrochlorothiazide, due to the risk of increased lithium levels and potential toxicity.

Laboratory Monitoring Periodic determination of serum electrolytes is recommended to detect possible electrolyte imbalances. This monitoring should occur at appropriate intervals to ensure patient safety.

Emergency Medical Attention Hydrochlorothiazide, classified as a sulfonamide, may cause idiosyncratic reactions such as acute transient myopia and acute angle-closure glaucoma. Symptoms, including a sudden decrease in visual acuity or ocular pain, may arise within hours to weeks of initiating treatment. If these symptoms occur, it is critical to discontinue hydrochlorothiazide immediately. Untreated acute angle-closure glaucoma can lead to permanent vision loss, and prompt medical or surgical intervention may be necessary if intraocular pressure remains uncontrolled.

Discontinuation Instructions Patients should be advised to stop taking hydrochlorothiazide as rapidly as possible if they experience symptoms indicative of acute angle-closure glaucoma and to contact their healthcare provider without delay.

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.

Patients may experience metabolic disturbances, including electrolyte imbalances, hyperglycemia, glycosuria, and hyperuricemia. Urogenital effects such as impotence and transient visual disturbances, including blurred vision and xanthopsia, have been reported as well.

It is important to note that hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC) in white patients receiving large cumulative doses. The overall population faces 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 may see an increase of approximately 1 additional SCC case for every 6,700 patients per year.

Drug Interactions

The concomitant use of certain medications with hydrochlorothiazide may lead to significant drug interactions, which can affect therapeutic outcomes and safety.

Pharmacodynamic Interactions

• Alcohol, Barbiturates, or Narcotics: The combination of hydrochlorothiazide with these agents may potentiate orthostatic hypotension. Patients should be monitored for signs of hypotension and advised to exercise caution when standing up.

• Antidiabetic Drugs (Oral Agents and Insulin): The use of hydrochlorothiazide may necessitate dosage adjustments of antidiabetic medications to maintain glycemic control. Regular monitoring of blood glucose levels is recommended.

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

• Corticosteroids, ACTH: Co-administration may lead to intensified electrolyte depletion, particularly hypokalemia. Electrolyte levels should be monitored regularly.

• Skeletal Muscle Relaxants, Nondepolarizing (e.g., Tubocurarine): There is a potential for increased responsiveness to nondepolarizing muscle relaxants. Caution is advised when using these agents concurrently.

• Lithium: The use of hydrochlorothiazide with lithium is generally contraindicated due to the risk of reduced renal clearance of lithium, which may lead to toxicity. It is essential to consult the package insert for lithium preparations before considering their use with hydrochlorothiazide.

• Non-steroidal Anti-inflammatory Drugs (NSAIDs): The administration of NSAIDs may diminish the diuretic, natriuretic, and antihypertensive effects of hydrochlorothiazide. Patients should be closely observed to ensure the desired diuretic effect is achieved when these agents are used together.

Pharmacokinetic Interactions

• Cholestyramine and Colestipol Resins: The absorption of hydrochlorothiazide is significantly impaired when administered with anionic exchange resins. Single doses of cholestyramine or colestipol can reduce the absorption of hydrochlorothiazide by up to 85% and 43%, respectively. It is advisable to separate the administration of hydrochlorothiazide and these resins by at least 2 hours.

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

Additional Considerations

Thiazide diuretics, including hydrochlorothiazide, 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 exhibit increased sensitivity to the side effects of hydrochlorothiazide, including hypotension and electrolyte imbalances. Caution is advised when administering this medication to geriatric patients, particularly those with severe renal disease, as thiazides may precipitate azotemia and lead to cumulative effects in individuals with impaired renal function.

In patients with impaired hepatic function or progressive liver disease, thiazides should also be used with caution, as even minor alterations in fluid and electrolyte balance could precipitate hepatic coma. It is essential to monitor all patients receiving diuretic therapy for signs of fluid or electrolyte imbalance, such as hyponatremia, hypochloremic alkalosis, and hypokalemia. Periodic determination of serum electrolytes should be conducted at appropriate intervals to detect any potential imbalances.

If progressive renal impairment is observed, consideration should be given to withholding or discontinuing diuretic therapy. Additionally, in diabetic patients, dosage adjustments of insulin or oral hypoglycemic agents may be necessary to maintain glycemic control. The antihypertensive effects of hydrochlorothiazide may be enhanced in patients who have undergone sympathectomy, necessitating careful monitoring and potential dose adjustments in this population.

Pregnancy

Hydrochlorothiazide is classified as Pregnancy Category B. 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 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 can cross the placental barrier and are detectable in cord blood. The use of hydrochlorothiazide during pregnancy may be associated with risks such as fetal or neonatal jaundice, thrombocytopenia, and potentially other adverse reactions that have been observed in adults. Therefore, healthcare professionals should carefully weigh the benefits and risks when considering this medication 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 breastfeeding 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 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 consideration of dosing adjustments and close observation for 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 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 associated with 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 can be removed 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, 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 may also occur in adults.

Two-year feeding studies conducted by the National Toxicology Program (NTP) in mice and rats indicated 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 similar doses. 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, or 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.

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.

No additional specific details regarding animal pharmacology and toxicology are provided beyond those mentioned in the nonclinical toxicology section.

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 the risk of 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 that complies with the specifications outlined in the United States Pharmacopeia (USP) for controlled room temperature. It is essential to store the product at a temperature range of 20° to 25°C (68 to 77°F) to maintain its integrity and efficacy. Additionally, the container must be equipped with a child-resistant closure to ensure safety during handling and dispensing.

Additional Clinical Information

Periodic determination of serum electrolytes is recommended for patients to monitor potential electrolyte imbalances at appropriate intervals.

Postmarketing data indicate that hydrochlorothiazide is linked to an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC). This risk is notably higher in white patients receiving large cumulative doses. Specifically, the overall population faces an approximate risk of 1 additional case of SCC per 16,000 patients annually, while white patients with a cumulative dose of ≥50,000 mg may experience an increased risk of 1 additional SCC case for every 6,700 patients per year.

FDA Insert (PDF)

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

View full prescribing information (PDF)