Hydrochlorothiazide

Description

Hydrochlorothiazide 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. The structural formula of hydrochlorothiazide is provided in the relevant documentation.

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 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 dibasic calcium phosphate dihydrate, FD & C yellow, lactose monohydrate, magnesium stearate, pregelatinized starch (starch 1500), 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. 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.

In cases of edema during pregnancy, thiazides may be indicated when the edema is due to pathological causes, similar to their use in non-pregnant patients. Dependent edema 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 discomfort arises from such edema and is not alleviated by rest, a short course of diuretic therapy may be appropriate to provide relief.

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 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. Typically, doses exceeding 50 mg of hydrochlorothiazide daily are not necessary when used in conjunction with other antihypertensive agents.

In pediatric patients, the usual dosage for diuresis and control of hypertension ranges from 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 potential for exacerbating renal impairment. Additionally, hypersensitivity to this product or to other sulfonamide-derived drugs is a contraindication, as it 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. In such patients, the use of thiazides may precipitate azotemia, and the cumulative effects of the drug can become pronounced in those with impaired renal function.

Hepatic Function 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 the risk of hepatic coma.

Drug Interactions Thiazides may enhance the effects of other antihypertensive medications, necessitating careful monitoring of blood pressure and overall treatment response.

Allergic Reactions Sensitivity reactions can occur in patients regardless of their allergy history, including those with bronchial asthma. Healthcare professionals should remain vigilant for signs of such reactions.

Systemic Lupus Erythematosus There have been reports of exacerbation or activation of systemic lupus erythematosus in patients taking thiazides, warranting close observation in susceptible individuals.

Lithium Interaction The concomitant use of lithium with diuretics is generally not recommended due to the potential for increased lithium levels and toxicity.

Ocular Effects Hydrochlorothiazide, a sulfonamide, has been associated with an idiosyncratic reaction leading to acute myopia and secondary angle-closure glaucoma. Symptoms may include a sudden decrease in visual acuity or ocular pain, typically manifesting within hours to weeks after initiation of therapy. 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.

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

Side Effects

Adverse reactions have been observed in patients receiving treatment, categorized by seriousness and frequency as follows:

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 include weakness, hypotension (including orthostatic hypotension), and various digestive issues such as diarrhea, vomiting, nausea, anorexia, cramping, constipation, gastric irritation, and sialadenitis. Patients may also experience metabolic disturbances, including electrolyte imbalance, hyperglycemia, glycosuria, and hyperuricemia. Musculoskeletal symptoms like muscle spasms, as well as nervous system and psychiatric effects such as dizziness, vertigo, 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 part of their experience. Urogenital effects, such as impotence, have been documented as well.

In the postmarketing experience, an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC), has been associated with hydrochlorothiazide. This risk appears to be more pronounced in white patients receiving large cumulative doses. Data from a study conducted in the Sentinel System indicate that the overall risk for SCC 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 consider them when prescribing treatment.

Drug Interactions

Concomitant use of certain medications may lead to significant drug interactions with hydrochlorothiazide, necessitating careful consideration and monitoring.

Pharmacodynamic Interactions:

• Alcohol, Barbiturates, or Narcotics: The combination 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 antidiabetic medications may be required to maintain glycemic control. Regular monitoring of blood glucose levels is recommended.

• Other Antihypertensive Drugs: There is a potential for additive effects or potentiation of antihypertensive effects. Blood pressure should be monitored closely to avoid excessive hypotension.

• Corticosteroids, ACTH: The use of these agents may lead to intensified electrolyte depletion, particularly hypokalemia. Electrolyte levels should be monitored regularly.

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

• Skeletal Muscle Relaxants (Nondepolarizing, e.g., Tubocurarine): Increased responsiveness to muscle relaxants may occur. Monitoring of neuromuscular function is advisable.

• Lithium: The use of diuretics, including hydrochlorothiazide, can reduce renal clearance of lithium, increasing the risk of lithium toxicity. Caution is advised, and renal function and lithium levels should be monitored closely.

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

Pharmacokinetic Interactions:

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

Drug/Laboratory Test Interactions:

• Parathyroid Function Tests: Thiazides 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. Healthcare professionals should refer to the Dosage and Administration section for specific guidance on dosing in infants and children. Caution is advised when prescribing to this population due to the lack of robust clinical trial data.

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 cautiously in geriatric patients with impaired hepatic function or progressive liver disease, as even minor alterations in fluid and electrolyte balance can precipitate hepatic coma. It is important to monitor these patients closely for any signs of renal impairment; if progressive renal impairment becomes evident, consideration should be given to withholding or discontinuing diuretic therapy.

Periodic determination of serum electrolytes is recommended to detect possible electrolyte imbalances, particularly hypokalemia, which may develop with brisk diuresis, severe cirrhosis, or prolonged therapy. Hypokalemia poses a risk of cardiac arrhythmias and may sensitize the heart to the toxic effects of digitalis, increasing the risk of ventricular irritability.

In diabetic elderly patients, dosage adjustments of insulin or oral hypoglycemic agents may be necessary to maintain glycemic control. Furthermore, it is important to note that hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer, especially in patients receiving large cumulative doses. Therefore, healthcare providers should exercise caution and conduct regular assessments to ensure the safety and efficacy of thiazide therapy in geriatric patients.

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 teratogenic effects or harm to the fetus. However, there are no adequate and well-controlled studies in pregnant women, and the predictive value of animal studies for human response is limited. Therefore, hydrochlorothiazide should be used during pregnancy only if the potential benefits justify the potential risks to the fetus.

It is important to note that thiazides, including hydrochlorothiazide, cross the placental barrier and can be detected in cord blood. This raises concerns regarding nonteratogenic effects, such as the risk of fetal or neonatal jaundice and thrombocytopenia, as well as other adverse reactions that may occur in adults. Healthcare professionals should carefully consider these risks when prescribing hydrochlorothiazide to pregnant patients.

Lactation

Thiazides are excreted in breast milk. Due to the potential for serious adverse reactions in nursing infants, lactating mothers should make a decision regarding whether to discontinue nursing or to discontinue hydrochlorothiazide, considering the importance of the medication 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 reduced kidney function, thiazides may precipitate azotemia. Additionally, the cumulative effects of the drug may develop in patients with impaired renal function, necessitating careful monitoring and potential dosing adjustments.

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 the provision of 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 threshold for toxicity in these species. However, the extent to which hydrochlorothiazide can be removed from the body through hemodialysis remains to be fully established.

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. Given that 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 adult populations.

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 encouraged to report any new or unusual skin changes to their healthcare provider promptly.

Storage and Handling

The product is supplied in a tight, light-resistant container, compliant with the United States Pharmacopeia (USP) standards, and features a child-resistant closure. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP guidelines for Controlled Room Temperature.

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 Accord Healthcare Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)