Hydrochlorothiazide

Description

Hydrochlorothiazide, USP is a diuretic and antihypertensive agent, chemically identified as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. It is the 3,4-dihydro derivative of chlorothiazide, with the empirical formula C7H8ClN3O4S2 and a molecular weight of 297.74. Hydrochlorothiazide appears as a white, or practically white, crystalline powder. It exhibits slight solubility in water and is freely soluble in sodium hydroxide solution. Each tablet for oral administration contains 12.5 mg of hydrochlorothiazide, USP, along with inactive ingredients that include calcium stearate, corn starch, FD&C Yellow #6 (Sunset Yellow), lactose monohydrate, pregelatinized starch, sodium lauryl sulfate, and stearic acid.

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, this medication is effective in treating edema resulting from various forms of renal dysfunction, including nephrotic syndrome, acute glomerulonephritis, and chronic renal failure.

In the management of hypertension, hydrochlorothiazide is indicated either as a monotherapy or as an adjunct to enhance the efficacy of other antihypertensive agents, particularly in cases of more severe hypertension.

Limitations of Use: Routine use of diuretics, including hydrochlorothiazide, during normal pregnancy is not recommended, as it may pose unnecessary 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 use 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.

Dependent edema during pregnancy, which arises from venous return restriction by the gravid uterus, should primarily be managed through non-pharmacological measures such as elevating the lower extremities and utilizing support stockings. The use of diuretics to reduce intravascular volume in this context is considered illogical and unnecessary, as hypervolemia during normal pregnancy is not harmful in the absence of cardiovascular disease. In rare cases where edema causes significant discomfort not alleviated by rest, a short course of diuretic therapy may be appropriate.

Dosage and Administration

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

In the case of hypertension, the usual initial dose for adults is 25 mg daily, administered as a single dose. This dose may be increased to 50 mg daily, which can be given as either a single dose or divided into two doses.

For infants and children, the typical dosage for diuresis and hypertension control 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. In infants younger than 6 months, 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 thiazide diuretics requires careful consideration in patients with severe renal disease, as these agents may precipitate azotemia and lead to cumulative effects in individuals with impaired renal function. Caution is also advised in patients with impaired hepatic function or progressive liver disease, as even minor alterations in fluid and electrolyte balance can trigger hepatic coma. Additionally, thiazides may enhance the effects of other antihypertensive medications, necessitating close monitoring of blood pressure and overall treatment response.

Sensitivity reactions can occur in patients regardless of prior allergy or bronchial asthma history. There have been reports of exacerbation or activation of systemic lupus erythematosus associated with thiazide use. It is important to note that lithium should generally not be co-administered with diuretics due to potential interactions.

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 of initiating therapy. If acute angle-closure glaucoma occurs, immediate discontinuation of hydrochlorothiazide is essential, and prompt medical or surgical intervention may be required if intraocular pressure remains uncontrolled. Patients with a history of sulfonamide or penicillin allergy may be at increased risk for developing this condition.

All patients undergoing diuretic therapy should be monitored for signs of fluid or electrolyte imbalance, including hyponatremia, hypochloremic alkalosis, and hypokalemia. Regular serum and urine electrolyte assessments are particularly critical in cases of excessive vomiting or when patients are receiving parenteral fluids. Warning signs of fluid and electrolyte imbalance include dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle cramps, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

Hypokalemia may develop, particularly with brisk diuresis, in patients with severe cirrhosis or after prolonged therapy. Inadequate oral electrolyte intake can exacerbate hypokalemia, which may lead to cardiac arrhythmias and increase the heart's sensitivity to digitalis toxicity. To mitigate hypokalemia, potassium-sparing diuretics or potassium-rich foods may be utilized. While chloride deficits are typically mild and may not require treatment, chloride replacement may be necessary in cases of metabolic alkalosis, especially in patients with liver or renal disease.

Dilutional hyponatremia can occur in edematous patients during hot weather; in such cases, water restriction is the preferred management strategy, except in rare instances of life-threatening hyponatremia. In cases of actual salt depletion, appropriate salt replacement is indicated. Hyperuricemia and acute gout may be precipitated in certain patients receiving thiazides.

Diabetic patients may require dosage adjustments of insulin or oral hypoglycemic agents, as thiazide diuretics can induce hyperglycemia and potentially unmask latent diabetes mellitus. The antihypertensive effects of thiazides may be amplified in patients who have undergone sympathectomy. If progressive renal impairment is observed, it may be necessary to withhold or discontinue diuretic therapy.

Thiazides are known to increase urinary magnesium excretion, which can lead to hypomagnesemia. They may also decrease urinary calcium excretion, resulting in intermittent and slight elevations of serum calcium levels in the absence of known calcium metabolism disorders. Marked hypercalcemia may indicate hidden hyperparathyroidism, and thiazides should be discontinued prior to conducting parathyroid function tests. Additionally, thiazide therapy may be associated with increases in cholesterol and triglyceride levels.

Periodic monitoring of serum electrolytes is recommended to detect potential electrolyte imbalances during treatment.

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. Renal complications, including renal failure, renal dysfunction, and interstitial nephritis, have also been reported and warrant attention (see WARNINGS). 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 documented.

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, such as muscle spasms, and nervous system/psychiatric effects, including vertigo, dizziness, headache, and restlessness, have been noted.

Skin reactions such as photosensitivity, rash, urticaria, and purpura are also common. Transient blurred vision and xanthopsia have been reported under special senses. Urogenital effects, including impotence, have been observed as well.

Postmarketing data indicate 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.

Drug Interactions

The concomitant use of thiazide diuretics with certain drug classes may lead to significant interactions that require careful consideration.

Pharmacodynamic Interactions:

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

• Corticosteroids and ACTH: These agents may exacerbate electrolyte depletion, particularly hypokalemia, when administered alongside thiazide diuretics. Regular monitoring of electrolyte levels is recommended.

• Other Antihypertensive Drugs: The use of additional 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.

• Non-depolarizing Skeletal Muscle Relaxants (e.g., Tubocurarine): Increased responsiveness to these agents may occur when used with thiazide diuretics. Monitoring of neuromuscular function is advisable.

• Pressor Amines (e.g., Norepinephrine): There may be a decreased response to pressor amines when used in conjunction with thiazide diuretics; however, this does not contraindicate their use. Clinical judgment should guide therapy.

• Non-steroidal Anti-inflammatory Drugs (NSAIDs): The effectiveness of thiazide diuretics may be diminished by NSAIDs, which can reduce diuretic, natriuretic, and antihypertensive effects. Close observation of blood pressure and fluid status is warranted.

Pharmacokinetic Interactions:

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

• Lithium: The use of lithium with diuretics is generally contraindicated due to the risk of lithium toxicity resulting from decreased renal clearance. Monitoring of lithium levels is essential if co-administration is necessary.

Dosage Adjustments:

• Antidiabetic Drugs: Dosage adjustments of antidiabetic medications may be required when used in conjunction with thiazide diuretics. Blood glucose levels should be monitored to ensure adequate glycemic control.

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 due to the potential for adverse effects and the need for careful monitoring. In patients aged 65 and older, thiazides should be used with caution, particularly in those with severe renal disease, as these medications may precipitate azotemia and lead to cumulative effects in individuals with impaired renal function.

Additionally, thiazides should be administered with caution in patients with impaired hepatic function or progressive liver disease, as even minor alterations in fluid and electrolyte balance can precipitate hepatic coma. The possibility of exacerbation or activation of systemic lupus erythematosus has also been reported in this population.

Elderly patients are at risk for acute myopia and secondary angle-closure glaucoma, which can occur as an idiosyncratic reaction to hydrochlorothiazide. Symptoms, including acute onset of decreased visual acuity or ocular pain, may manifest within hours to weeks after initiation of therapy.

Monitoring for signs or symptoms of fluid and electrolyte imbalance is crucial, as elderly patients may present with non-specific symptoms such as dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances like nausea and vomiting. Hypokalemia may develop, particularly with brisk diuresis, in cases of severe cirrhosis, or after prolonged therapy.

If progressive renal impairment is observed, healthcare providers should consider withholding or discontinuing diuretic therapy. It is recommended that periodic determination of serum electrolytes be conducted at appropriate intervals to detect any potential electrolyte imbalances in geriatric patients.

Pregnancy

Hydrochlorothiazide has been studied in pregnant mice and rats during their major organogenesis periods at doses up to 3,000 mg/kg and 1,000 mg/kg, respectively, with no evidence of teratogenic effects observed in these animal studies. However, there are no adequate and well-controlled studies in pregnant women, and animal reproduction studies are not always predictive of human response. Therefore, 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. 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. Healthcare professionals should weigh the potential benefits against the 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 consideration of dosing adjustments and close observation for potential adverse effects.

Hepatic Impairment

Patients with hepatic impairment should use thiazides with caution. In individuals with impaired liver function or progressive liver disease, minor alterations in fluid and electrolyte balance may precipitate hepatic coma. Therefore, careful monitoring of these patients is recommended to avoid potential complications. No specific dosage adjustments are provided; however, clinicians should assess the patient's overall condition and liver function regularly to ensure safe and effective use of thiazides in this population.

Overdosage

In cases of overdose, the most frequently observed signs and symptoms include electrolyte depletion, specifically hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis.

Management of Overdose 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 during an overdose, healthcare professionals should provide supplemental oxygen or initiate artificial respiration as necessary to ensure adequate oxygenation.

Toxicological Information The oral LD50 of hydrochlorothiazide has been determined to be greater than 10 g/kg in both mice and rats. It is important to note that the extent to which hydrochlorothiazide is removed from the body via hemodialysis has not been established, indicating that supportive care may be necessary in managing overdose cases.

Nonclinical Toxicology

Two-year feeding studies conducted by the National Toxicology Program (NTP) in mice and rats revealed 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 for hepatocarcinogenicity in male mice.

In terms of genotoxicity, hydrochlorothiazide was not found to be genotoxic in vitro in the Ames mutagenicity assay using Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538, nor in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. Additionally, in vivo assays involving mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene did not indicate genotoxicity. Positive results were observed only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and Mouse Lymphoma Cell (mutagenicity) assays, which utilized hydrochlorothiazide concentrations ranging from 43 to 1,300 μg/mL, as well as in the Aspergillus nidulans non-disjunction assay at an unspecified concentration.

Hydrochlorothiazide did not demonstrate any adverse effects on fertility in studies involving mice and rats of both sexes. These studies involved dietary exposure to doses of up to 100 mg/kg for mice and 4 mg/kg for rats 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 most pronounced 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. 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

Dispense the product in a well-closed container as defined in the United States Pharmacopeia (USP). It is essential to keep the container tightly closed to maintain product integrity. The product must be protected from light, moisture, and freezing conditions, specifically at temperatures below -20°C (-4°F).

For optimal storage, maintain the product at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines.

Additional Clinical Information

Clinicians should conduct periodic determinations of serum electrolytes in patients to monitor for potential electrolyte imbalances. This assessment should be performed 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 Actavis Pharma, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)