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 slight solubility in water and is freely soluble in sodium hydroxide solution, n-butylamine, and dimethylformamide. It is sparingly soluble in methanol and 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 inactive ingredients such as corn starch, FD&C Yellow #6, dibasic calcium phosphate, pregelatinized starch, colloidal silicon dioxide, 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 effective 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 where edema during pregnancy is due to pathological causes, thiazides may be indicated, 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 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 may lead to 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 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 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 thiazides, including hydrochlorothiazide, necessitates caution in specific patient populations and conditions due to potential adverse effects and interactions.

Renal and Hepatic Considerations Thiazides should be administered with caution in patients with severe renal disease, as they may precipitate azotemia and lead to cumulative effects in those with impaired renal function. Additionally, caution is warranted in patients with impaired hepatic function or progressive liver disease, as even minor alterations in fluid and electrolyte balance can precipitate hepatic coma.

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

Allergic Reactions and Autoimmune Considerations Sensitivity reactions can occur in patients regardless of prior allergy or bronchial asthma history. Furthermore, there have been reports of exacerbation or activation of systemic lupus erythematosus in some patients.

Lithium Interaction It is generally advised that lithium not be co-administered with diuretics due to the potential for increased lithium levels and toxicity.

Ocular Effects Hydrochlorothiazide, as a sulfonamide, may cause idiosyncratic reactions leading to 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, 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 determination of serum electrolytes is recommended to detect potential electrolyte imbalances. Regular monitoring should be conducted at appropriate intervals to ensure patient safety and effective management of therapy.

Side Effects

Adverse reactions associated with the use of this medication have been observed across various body systems, with some reactions categorized by seriousness and frequency.

Serious adverse reactions include hematologic events such as aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia. Renal complications may manifest as renal failure, renal dysfunction, and interstitial nephritis. Hypersensitivity reactions can be severe, including anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), and respiratory distress, which may present as pneumonitis and pulmonary edema. Additionally, skin reactions such as erythema multiforme, including Stevens-Johnson Syndrome, and exfoliative dermatitis, including toxic epidermal necrolysis, have been reported.

Common adverse reactions 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. Neurological symptoms such as dizziness, vertigo, paresthesias, and headaches have been noted, along with musculoskeletal complaints like muscle spasms. Urogenital effects, including impotence, and transient visual disturbances such as blurred vision and xanthopsia, have also been reported.

In clinical trials and postmarketing experiences, it is important to note that adverse reactions may be exacerbated by concomitant use of alcohol, barbiturates, narcotics, or antihypertensive drugs. In patients with renal disease, thiazides may precipitate azotemia, and cumulative effects of the drug may develop in those with impaired renal function. Caution is advised when prescribing to patients with severe renal disease or impaired hepatic function, as minor alterations in fluid and electrolyte balance may precipitate hepatic coma.

Sensitivity reactions can occur in patients with or without a history of allergy or bronchial asthma. Furthermore, there have been reports of exacerbation or activation of systemic lupus erythematosus. Hydrochlorothiazide, a sulfonamide, may cause an idiosyncratic reaction leading to acute transient myopia and acute angle-closure glaucoma, characterized by a rapid onset of decreased visual acuity or ocular pain. This condition typically arises within hours to weeks of initiating treatment and can result in permanent vision loss if untreated. The primary management involves the prompt discontinuation of hydrochlorothiazide, with consideration for medical or surgical intervention if intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma include a history of sulfonamide or penicillin allergy.

Whenever adverse reactions are moderate or severe, it is recommended that the thiazide dosage be reduced or therapy withdrawn.

Drug Interactions

Concomitant use of thiazide diuretics with certain medications may lead to significant drug interactions, categorized primarily into pharmacodynamic and pharmacokinetic interactions.

Pharmacodynamic Interactions:

• Alcohol, Barbiturates, and Narcotics: The combination with thiazide diuretics 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 thiazide diuretics may necessitate dosage adjustments of antidiabetic medications due to potential alterations in glycemic control. Regular monitoring of blood glucose levels is recommended.

• Other Antihypertensive Drugs: The concurrent administration may result in an additive effect or potentiation of antihypertensive effects. Blood pressure should be monitored closely to avoid excessive hypotension.

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

• Pressor Amines (e.g., Norepinephrine): Thiazide diuretics may decrease the 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 thiazide diuretics is generally contraindicated with lithium due to the risk of reduced renal clearance and potential lithium toxicity. Caution is advised, and the package insert for lithium preparations should be consulted prior to co-administration.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): In some patients, NSAIDs may diminish the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics. Close observation is warranted 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, with reductions in absorption of up to 85% and 43%, respectively. It is advisable to separate the administration of these agents to minimize interaction.

Drug/Laboratory Test Interactions:

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 currently 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. For specific dosing recommendations, refer to the section on Dosage and Administration for infants and children.

Geriatric Use

Elderly patients should be treated with caution, particularly those aged 65 and older, due to the increased likelihood of renal and hepatic impairment. In patients with severe renal disease, thiazides may precipitate azotemia, and the cumulative effects of the drug can develop in individuals with impaired renal function. Therefore, careful monitoring of renal status is essential, and if progressive renal impairment becomes evident, consideration should be given to withholding or discontinuing diuretic therapy.

Thiazides should also be used cautiously in geriatric patients with impaired hepatic function or progressive liver disease, as even minor alterations in fluid and electrolyte balance may lead to hepatic coma. Additionally, there is a reported possibility of exacerbation or activation of systemic lupus erythematosus in this population.

Hypokalemia may develop, particularly with brisk diuresis, in patients with severe cirrhosis or after prolonged therapy. To mitigate the risk of electrolyte imbalances, periodic determination of serum electrolytes should be conducted at appropriate intervals.

It is important to note that the antihypertensive effects of the drug may be enhanced in patients who have undergone sympathectomy. Generally, elderly patients do not require doses exceeding 50 mg of hydrochlorothiazide daily when used in conjunction with other antihypertensive agents.

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 any evidence of teratogenic effects or harm to the fetus. However, there are no adequate and well-controlled studies in pregnant women, and it is important to note that animal reproduction studies may not always predict human responses.

Thiazides, including hydrochlorothiazide, are known to cross the placental barrier and can be detected in cord blood. Consequently, there is a potential risk of fetal or neonatal complications, including jaundice and thrombocytopenia, as well as other adverse reactions that have been observed in adult populations. Therefore, hydrochlorothiazide should be used during pregnancy only if the potential benefits clearly outweigh the risks. Healthcare professionals are advised to carefully consider the necessity of this medication in pregnant patients and to monitor for any adverse effects in both the mother and the fetus.

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 nursing 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 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 extent to which hydrochlorothiazide is removed from the body 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, it is important to note that there are no adequate and well-controlled studies in pregnant women. Given that 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 nonteratogenic effects, including the risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have been observed in adults.

In two-year feeding studies conducted by the National Toxicology Program (NTP), no evidence of carcinogenic potential was found 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 identify equivocal evidence for 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, 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 assay, at concentrations ranging from 43 to 1300 mcg/mL, as well as in the Aspergillus nidulans non-disjunction assay at an unspecified concentration.

Furthermore, 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

Postmarketing experience has identified several adverse reactions associated with hydrochlorothiazide, reported voluntarily or through surveillance programs.

Acute myopia and secondary angle-closure glaucoma have been noted as idiosyncratic reactions, characterized by an acute onset of decreased visual acuity or ocular pain, typically occurring within hours to weeks of initiating treatment. Untreated cases may lead to permanent vision loss, necessitating prompt discontinuation of hydrochlorothiazide and potential medical or surgical intervention if intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma include a history of sulfonamide or penicillin allergy.

The following adverse reactions have been reported, categorized by system and listed in order of decreasing severity:

• Body as a Whole: Weakness.

• Cardiovascular: Hypotension, including orthostatic hypotension, which may be exacerbated by alcohol, barbiturates, narcotics, or antihypertensive medications.

• Digestive: Pancreatitis, jaundice (intrahepatic cholestatic jaundice), diarrhea, vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea, and anorexia.

• Hematologic: Aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia.

• Hypersensitivity: Anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress (including pneumonitis and pulmonary edema), photosensitivity, fever, urticaria, rash, and purpura.

• Metabolic: Electrolyte imbalance, hyperglycemia, glycosuria, and hyperuricemia.

• Musculoskeletal: Muscle spasm.

• Nervous System/Psychiatric: Vertigo, paresthesias, dizziness, headache, and restlessness.

• Renal: Renal failure, renal dysfunction, and interstitial nephritis.

• Skin: Erythema multiforme (including Stevens-Johnson Syndrome), exfoliative dermatitis (including toxic epidermal necrolysis), and alopecia.

• Special Senses: Transient blurred vision and xanthopsia.

• Urogenital: Impotence.

In cases where adverse reactions are moderate or severe, it is recommended that the thiazide dosage be reduced or therapy withdrawn.

Patient Counseling

Patients should be observed for evidence of fluid or electrolyte imbalance. Healthcare providers should discuss with patients the importance of recognizing signs such as dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances, including nausea and vomiting.

It is essential to inform patients that hypokalemia may develop, particularly with brisk diuresis, in cases of severe cirrhosis, or after prolonged therapy. Patients should be made aware that hypokalemia can lead to cardiac arrhythmias and may sensitize or exaggerate the heart's response to the toxic effects of digitalis. Healthcare providers should advise patients on strategies to avoid or treat hypokalemia, such as the use of potassium-sparing diuretics or potassium supplements, including foods rich in potassium.

Patients should be cautioned that thiazides may increase urinary excretion of magnesium, potentially resulting in hypomagnesemia. Additionally, it is important to inform patients that thiazides may decrease urinary calcium excretion, which can lead to intermittent and slight elevations of serum calcium in the absence of known disorders of calcium metabolism. Healthcare providers should advise patients that marked hypercalcemia may indicate hidden hyperparathyroidism, and thiazides should be discontinued prior to conducting tests for parathyroid function.

Patients should also be informed that thiazide diuretic therapy may be associated with increases in cholesterol and triglyceride levels. Furthermore, healthcare providers should emphasize the need for patients to monitor their blood glucose levels, as hyperglycemia may occur with thiazide diuretics, necessitating dosage adjustments of insulin or oral hypoglycemic agents for diabetic patients.

It is crucial to inform patients that thiazides cross the placental barrier and can appear in cord blood, posing a risk of fetal or neonatal jaundice, thrombocytopenia, and potentially other adverse reactions. Nursing mothers should be advised that thiazides are excreted in breast milk, and they should consider the potential for serious adverse reactions in nursing infants when deciding whether to continue breastfeeding or to discontinue hydrochlorothiazide.

Storage and Handling

The product is supplied in a well-closed container as defined by the United States Pharmacopeia (USP). 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. Additionally, a child-resistant closure is required for dispensing to ensure safety.

Additional Clinical Information

Periodic determination of serum electrolytes is recommended for patients to detect potential electrolyte imbalances at appropriate intervals. No further information is available regarding abuse, administration routes, patient counseling, or postmarketing experiences.

FDA Insert (PDF)

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

View full prescribing information (PDF)