Hydrochlorothiazide

Description

Hydrochlorothiazide, USP is a diuretic and antihypertensive agent. It is the 3,4-dihydro derivative of chlorothiazide and is chemically designated as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, with the empirical formula C7H8ClN3O4S2 and a molecular weight of 297.74. Hydrochlorothiazide, USP 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. It is insoluble in ether, chloroform, and dilute mineral acids. Each tablet for oral administration contains 12.5 mg, 25 mg, or 50 mg of hydrochlorothiazide, USP, along with inactive ingredients that include corn starch, dibasic calcium phosphate dihydrate, FD&C Yellow No. 6 Aluminum Lake, 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, nor is there sufficient evidence to support their use 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, which may result from mechanical factors such as the gravid uterus restricting venous return, is best managed through non-pharmacological measures such as elevating the lower extremities and using 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 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 inability to excrete the drug, which may lead to accumulation and toxicity. Additionally, it is contraindicated in individuals with hypersensitivity to this product or to other sulfonamide-derived drugs, as this may result in 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 is also a reported risk of exacerbation or activation of systemic lupus erythematosus. It is important to note that lithium should generally not be co-administered with diuretics due to potential interactions.

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 determinations are particularly critical in patients experiencing excessive vomiting or receiving parenteral fluids. Warning signs of fluid and electrolyte imbalance may 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 is a potential complication, especially in cases of brisk diuresis, severe cirrhosis, or prolonged therapy. Inadequate oral electrolyte intake can exacerbate this condition, which may lead to cardiac arrhythmias and increased sensitivity to digitalis toxicity. To mitigate hypokalemia, potassium-sparing diuretics or potassium-rich foods may be beneficial. While chloride deficits are typically mild and may not require treatment, chloride replacement may be necessary in cases of metabolic alkalosis.

Dilutional hyponatremia can occur in edematous patients during hot weather; in such cases, water restriction is the preferred management strategy, with salt replacement reserved for rare, life-threatening situations. Hyperuricemia and acute gout may also be precipitated in certain patients receiving thiazides.

In diabetic patients, dosage adjustments for insulin or oral hypoglycemic agents may be necessary, as thiazide therapy 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 prudent 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 elevations of serum calcium levels. Marked hypercalcemia could indicate underlying hyperparathyroidism, and thiazides should be discontinued prior to parathyroid function testing. Additionally, thiazide therapy may be associated with increases in cholesterol and triglyceride levels.

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

Healthcare professionals should be vigilant for symptoms indicative of acute angle-closure glaucoma, such as a sudden decrease in visual acuity or ocular pain, which may arise within hours to weeks of initiating therapy. If these symptoms occur, hydrochlorothiazide should be discontinued immediately, and prompt medical or surgical intervention may be necessary to control intraocular pressure and prevent permanent vision loss.

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 such as renal failure, renal dysfunction, and interstitial nephritis have also been reported. 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 pancreatitis, jaundice (intrahepatic cholestatic jaundice), diarrhea, vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea, and anorexia. Patients may also experience musculoskeletal symptoms like muscle spasms and nervous system/psychiatric effects, including vertigo, paresthesias, dizziness, headache, and restlessness.

Metabolic disturbances such as electrolyte imbalance, hyperglycemia, glycosuria, and hyperuricemia have been noted. Skin reactions may include photosensitivity, fever, urticaria, rash, and purpura. Transient blurred vision and xanthopsia have been reported under special senses, while urogenital effects such as impotence have also been observed.

In postmarketing experience, there is an association between hydrochlorothiazide and an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC). Data from a study conducted in the Sentinel System indicate that the increased risk is predominantly observed in white patients taking large cumulative doses. The overall risk for SCC in the population is approximately 1 additional case per 16,000 patients per year, while for white patients with a cumulative dose of ≥ 50,000 mg, the risk increases to approximately 1 additional SCC case for every 6,700 patients per year.

Drug Interactions

Thiazide diuretics may interact with several drug classes, leading to significant clinical effects that warrant careful consideration.

Pharmacodynamic Interactions

• The concomitant use of thiazide diuretics with alcohol, barbiturates, or narcotics may potentiate orthostatic hypotension. Clinicians should monitor patients for signs of hypotension and consider dose adjustments as necessary.

• When thiazide diuretics are used alongside other antihypertensive agents, there may be an additive effect or potentiation of blood pressure-lowering effects. Monitoring blood pressure is recommended to avoid excessive hypotension.

• Corticosteroids and adrenocorticotropic hormone (ACTH) can lead to intensified electrolyte depletion, particularly hypokalemia, when administered with thiazide diuretics. Regular monitoring of electrolyte levels is advised.

• Non-depolarizing skeletal muscle relaxants, such as tubocurarine, may exhibit increased responsiveness when used in conjunction with thiazide diuretics. Clinicians should be aware of this potential interaction during surgical procedures.

• Pressor amines, including norepinephrine, may have a diminished response when used with thiazide diuretics; however, this does not contraindicate their use. Careful monitoring of hemodynamic response is recommended.

Pharmacokinetic Interactions

• Cholestyramine and colestipol resins can significantly impair the absorption of hydrochlorothiazide, with reductions of up to 85% and 43%, respectively. It is advisable to separate the administration of these agents to minimize interaction.

• Thiazide diuretics can reduce the renal clearance of lithium, thereby increasing the risk of lithium toxicity. Monitoring lithium levels is essential when these medications are used concurrently.

• Non-steroidal anti-inflammatory drugs (NSAIDs) may diminish the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics. Close monitoring of blood pressure and renal function is recommended during co-administration.

Additional Considerations

• Thiazide diuretics should be discontinued prior to tests for parathyroid function to avoid interference with test results.

In summary, careful monitoring and potential dosage adjustments are necessary when thiazide diuretics are used in combination with the aforementioned drug classes to mitigate risks and ensure patient safety.

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. Healthcare professionals should refer to the Dosage and Administration section for specific guidance on dosing in infants and children.

Geriatric Use

Elderly patients may require special consideration when using thiazide diuretics, particularly those aged 65 and older. Caution is advised in this population, especially in individuals with severe renal disease, as thiazides can precipitate azotemia and lead to cumulative effects due to impaired renal function.

In patients with impaired hepatic function or progressive liver disease, thiazides should also be used with caution. Minor alterations in fluid and electrolyte balance in these patients may precipitate hepatic coma, necessitating careful monitoring.

There is a reported possibility of exacerbation or activation of systemic lupus erythematosus in geriatric patients, which should be taken into account during treatment. Additionally, hypokalemia may develop, particularly with brisk diuresis, in patients with severe cirrhosis or after prolonged therapy.

If progressive renal impairment is observed, it is advisable to consider withholding or discontinuing diuretic therapy. Regular monitoring of serum electrolytes is recommended to detect potential electrolyte imbalances at appropriate intervals.

Typically, elderly patients do not require doses exceeding 50 mg of hydrochlorothiazide daily when used in conjunction with other antihypertensive agents, which may help mitigate the risk of adverse effects.

Pregnancy

Hydrochlorothiazide has been studied in pregnant mice and rats during their major organogenesis periods, with doses up to 3000 mg/kg and 1000 mg/kg, respectively, showing no 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 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 possibly other adverse reactions that have been observed in adults. Healthcare professionals should weigh the 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 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 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 should involve the implementation of symptomatic and supportive measures. This may include the induction of emesis or the performance of gastric lavage to mitigate the effects of the overdose. It is crucial to address any resultant dehydration and electrolyte imbalances, as well as complications such as hepatic coma and hypotension, by following established medical procedures.

In instances where respiratory impairment occurs due to overdose, the administration of oxygen or the provision of artificial respiration may be necessary to ensure adequate respiratory function.

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 system through hemodialysis remains to be established. Therefore, healthcare professionals should exercise caution and monitor patients closely in cases of suspected overdosage.

Nonclinical Toxicology

Studies evaluating the teratogenic effects of hydrochlorothiazide involved oral administration to pregnant mice and rats during critical periods of organogenesis, with doses reaching up to 3000 mg/kg in mice and 1000 mg/kg in rats. These studies did not demonstrate any evidence of fetal harm. However, it is important to note that there are no adequate and well-controlled studies in pregnant women, and since animal reproduction studies may not reliably 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 to the fetus, including the possibility of fetal or neonatal jaundice, thrombocytopenia, and other adverse reactions that have been observed in adults.

In terms of carcinogenicity, 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 of hepatocarcinogenicity in male mice.

Regarding 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. In vivo assays involving mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene also showed no genotoxic effects. Positive results were observed only in the in vitro CHO Sister Chromatid Exchange assay and the Mouse Lymphoma Cell mutagenicity assay 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.

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 the heightened risk is predominantly observed in white patients who are administered large cumulative doses of the medication. Specifically, the overall population exhibits an approximate increase of 1 additional case of SCC per 16,000 patients per year. In contrast, white patients receiving a cumulative dose of 50,000 mg or more demonstrate a significantly higher risk, with an estimated 1 additional case of SCC for every 6,700 patients per year.

Healthcare professionals and patients are encouraged to report any suspected adverse events related to hydrochlorothiazide. Reports can be made to Teva at 1-888-838-2872, to the FDA at 1-800-FDA-1088, or through the FDA's MedWatch website at http://www.fda.gov/medwatch for voluntary reporting of adverse reactions.

Patient Counseling

Healthcare providers should instruct patients taking hydrochlorothiazide to take precautions to protect their skin from sun exposure. This includes wearing protective clothing and using sunscreen to minimize the risk of skin damage. Additionally, patients should be advised to undergo regular skin cancer screenings as part of their healthcare routine.

It is also important for healthcare providers to inform patients about the necessity of periodic determination of serum electrolytes. This monitoring is essential to detect any potential electrolyte imbalances that may arise during treatment. Providers should emphasize the importance of attending these follow-up appointments to ensure the patient's safety and well-being while on hydrochlorothiazide.

Storage and Handling

The product is supplied in a well-closed container that meets the specifications outlined in the United States Pharmacopeia (USP), featuring 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), in accordance with USP Controlled Room Temperature guidelines.

Healthcare professionals are advised to ensure that this product, along with all medications, is kept out of the reach of children to prevent accidental ingestion or misuse.

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 SCC case 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. Clinicians are encouraged to report any suspected adverse events to Teva at 1-888-838-2872 or to the FDA at 1-800-FDA-1088 or via http://www.fda.gov/medwatch for voluntary reporting of adverse reactions.

FDA Insert (PDF)

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

View full prescribing information (PDF)