Hydrochlorothiazide

Description

Hydrochlorothiazide Capsules USP 12.5 mg contain the active ingredient hydrochlorothiazide, which is the 3,4-dihydro derivative of chlorothiazide. The chemical name for hydrochlorothiazide is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. The empirical formula is C7H8ClN3O4S2, and the molecular weight is 297.74.

The capsules are presented as a white or practically white crystalline powder, which is slightly soluble in water and freely soluble in sodium hydroxide solution. Hydrochlorothiazide is formulated for oral administration, with each capsule containing 12.5 mg of the active ingredient.

Inactive ingredients in each capsule include docusate sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, and sodium benzoate. The gelatin capsules are colored with D&C Red #28, D&C Yellow #10, FD&C Blue #1, and contain gelatin and titanium dioxide.

Uses and Indications

Hydrochlorothiazide Capsules USP are indicated for the management of hypertension, either as a monotherapy or in combination with other antihypertensive agents. This medication is particularly suitable for patients in whom the risk of developing hyperkalemia must be avoided, including those concurrently receiving ACE inhibitors.

The routine use of diuretics, including hydrochlorothiazide, in otherwise healthy pregnant women is not recommended due to potential risks to both the mother and fetus. Diuretics do not prevent the onset of toxemia of pregnancy, nor is there sufficient evidence to support their efficacy in treating established toxemia.

However, diuretics may be indicated during pregnancy when edema is attributable to pathological causes, similar to their use in non-pregnant individuals. In cases of dependent edema during pregnancy, which arises from venous return restriction due to an enlarged uterus, non-pharmacological interventions such as elevating the lower extremities and utilizing support hose are preferred. The physiological hypervolemia associated with normal pregnancy is generally not harmful to the mother or fetus, provided there are no underlying cardiovascular conditions.

In instances where edema causes significant discomfort and is unresponsive to rest, a short course of diuretics may be warranted to alleviate symptoms.

Dosage and Administration

The adult initial dose of hydrochlorothiazide is one capsule administered once daily, regardless of whether it is used as monotherapy or in conjunction with other antihypertensive agents. It is important to note that total daily doses exceeding 50 mg are not recommended.

Healthcare professionals should ensure that patients are monitored for efficacy and tolerability, adjusting the dosage as necessary while adhering to the maximum recommended daily limit.

Contraindications

Hydrochlorothiazide is contraindicated in patients with anuria due to the lack of urine output, which may lead to severe complications. Additionally, use of this medication is contraindicated in individuals with hypersensitivity to hydrochlorothiazide or other sulfonamide-derived drugs, as this may result in serious allergic reactions.

Warnings and Precautions

Hydrochlorothiazide, a sulfonamide, is associated with several significant warnings and precautions that healthcare professionals must consider to ensure patient safety.

Acute Myopia and Secondary Angle-Closure Glaucoma Hydrochlorothiazide can induce an idiosyncratic reaction leading to acute transient myopia and acute angle-closure glaucoma. Symptoms typically manifest as an acute onset of decreased visual acuity or ocular pain, occurring within hours to weeks following the initiation of therapy. It is critical to recognize that untreated acute angle-closure glaucoma may result in permanent vision loss. The primary intervention is the immediate discontinuation of hydrochlorothiazide. If intraocular pressure remains uncontrolled, prompt medical or surgical interventions should be considered. Patients with a history of sulfonamide or penicillin allergy may be at increased risk for developing this condition.

Diabetes and Hypoglycemia Healthcare providers should be aware that hydrochlorothiazide may unmask latent diabetes mellitus in some patients. Additionally, diabetic patients receiving thiazide therapy may require adjustments to their insulin dosage to maintain glycemic control.

Renal Disease In patients with impaired renal function, the cumulative effects of thiazides can lead to adverse outcomes, including the potential for azotemia. It is essential to monitor renal function closely in these patients to mitigate risks associated with thiazide therapy. Regular assessment of renal parameters is recommended to ensure safe use of hydrochlorothiazide in this population.

Side Effects

Adverse reactions associated with the use of thiazide diuretics have been observed in clinical trials and postmarketing experiences. These reactions can be categorized by seriousness and frequency.

Serious adverse reactions include hypersensitivity reactions such as anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), and respiratory distress, which may manifest as pneumonitis and pulmonary edema. Additionally, patients may experience renal complications, including renal failure, renal dysfunction, and interstitial nephritis. Hematologic reactions such as aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia have also been reported.

Common adverse reactions encompass a range of systems. Patients may experience 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, including muscle spasms, and nervous system/psychiatric effects such as vertigo, paresthesia, dizziness, headache, and restlessness, have been noted as well.

Skin reactions can include erythema multiforme (including Stevens-Johnson syndrome), exfoliative dermatitis (including toxic epidermal necrolysis), and alopecia. Patients may also experience transient blurred vision and xanthopsia as part of the special senses adverse reactions. Urogenital effects, such as impotence, have been reported.

Warnings associated with thiazide use include the potential for acute myopia and secondary angle-closure glaucoma, which can occur within hours to weeks of initiation and may lead to permanent vision loss if untreated. Additionally, latent diabetes mellitus may manifest, necessitating insulin dose adjustments in diabetic patients. Cumulative effects may develop in patients with impaired renal function, potentially precipitating azotemia.

In cases where adverse reactions are moderate or severe, it is recommended that thiazide dosage be reduced or therapy withdrawn. Overdosage may lead to electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration due to excessive diuresis, with particular caution advised for patients also receiving digitalis, as hypokalemia may exacerbate cardiac arrhythmias.

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, and Narcotics: The combination of hydrochlorothiazide with these agents may potentiate orthostatic hypotension. Patients should be monitored for signs of excessive hypotension.

• Antidiabetic Drugs (Oral Agents and Insulin): Dosage adjustments of antidiabetic medications may be necessary when used in conjunction with hydrochlorothiazide. Close monitoring of blood glucose levels is recommended.

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

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

• Skeletal Muscle Relaxants (Nondepolarizing, e.g., Tubocurarine): There may be an increased responsiveness to muscle relaxants when used with hydrochlorothiazide. Monitoring of neuromuscular function is advised.

• Lithium: The use of hydrochlorothiazide with lithium is generally contraindicated due to the potential for reduced renal clearance of lithium, which significantly increases the risk of lithium toxicity. Refer to the package insert for lithium preparations for specific guidance.

• 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.

Pharmacokinetic Interactions

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

• 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.

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

Safety and effectiveness in pediatric patients have not been established. Therefore, the use of this medication in children, infants, and adolescents should be approached with caution until further data is available.

Geriatric Use

Elderly patients, specifically those aged 65 years and older, may experience a greater reduction in blood pressure and an increased incidence of side effects when treated with hydrochlorothiazide. Due to these considerations, it is recommended that treatment in this population begin with the lowest available dose of hydrochlorothiazide, which is 12.5 mg.

Should further titration be necessary, increments of 12.5 mg should be employed to ensure careful monitoring of both efficacy and tolerability. Healthcare providers should remain vigilant for potential adverse effects and adjust the dosage accordingly to optimize patient safety and therapeutic outcomes in geriatric patients.

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. This raises concerns regarding potential risks to the fetus, including the possibility of fetal or neonatal jaundice, thrombocytopenia, and other adverse reactions that may also occur in adults. Healthcare providers should carefully weigh the benefits and 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 may experience cumulative effects of thiazides due to reduced kidney function. It is important to monitor these patients closely, as thiazides can precipitate azotemia in this population. Dosing adjustments may be necessary to mitigate the risk of adverse effects associated with impaired renal clearance.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

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 artificial respiration may be necessary.

The extent to which hydrochlorothiazide can be removed from the body through hemodialysis has not been definitively established. For reference, the oral LD50 of hydrochlorothiazide is greater than 10 g/kg in both mouse and rat models, indicating a high threshold for acute toxicity 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 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 such as fetal or neonatal jaundice, thrombocytopenia, and other adverse reactions that may also occur in adults.

In nonclinical toxicology assessments, two-year feeding studies conducted by the National Toxicology Program (NTP) in mice and rats demonstrated 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 of approximately 100 mg/kg/day. However, the NTP did find equivocal evidence of hepatocarcinogenicity in male mice.

Hydrochlorothiazide was not found to be genotoxic in vitro, as evidenced by the Ames mutagenicity assay using various strains of Salmonella typhimurium and 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 showed no genotoxic effects. Positive results were observed only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and Mouse Lymphoma Cell (mutagenicity) assays, with hydrochlorothiazide concentrations ranging from 43 to 1300 mcg/mL, as well as in the Aspergillus nidulans non-disjunction assay at an unspecified concentration.

Furthermore, studies indicated that hydrochlorothiazide did not adversely affect the fertility of either male or female mice and rats when 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 events associated with hydrochlorothiazide, reported voluntarily or through surveillance programs.

Hydrochlorothiazide has been associated with idiosyncratic reactions, leading to acute transient myopia and acute angle-closure glaucoma. Symptoms typically manifest within hours to weeks of initiating therapy and may include a sudden decrease in visual acuity or ocular pain. If left untreated, acute angle-closure glaucoma can result in permanent vision loss. The primary intervention is the rapid discontinuation of hydrochlorothiazide, with prompt medical or surgical treatment considered if intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

In diabetic patients, latent diabetes mellitus may become apparent, necessitating adjustments to insulin dosages. Additionally, patients with impaired renal function may experience cumulative effects from thiazides, potentially leading to azotemia.

Clinically significant hypokalemia has been reported to be less common in patients receiving a lower dose of 12.5 mg of hydrochlorothiazide compared to those on higher doses. Hyperuricemia or acute gout may also be precipitated in certain individuals taking thiazide diuretics. Caution is advised when prescribing thiazides to patients with impaired hepatic function, as they may precipitate hepatic coma in those with severe liver disease.

Prolonged thiazide therapy has been associated with decreased calcium excretion and pathologic changes in the parathyroid glands, including hypercalcemia and hypophosphatemia, observed in a limited number of patients.

Adverse reactions related to hydrochlorothiazide have been shown to be dose-dependent. In controlled clinical trials, adverse events reported with a daily dose of 12.5 mg were comparable to those observed with placebo. However, doses of 25 mg and above have been linked to a range of adverse reactions, including:

• Body as a Whole: Weakness.

• Cardiovascular: Hypotension, including orthostatic hypotension, which may be exacerbated by alcohol, barbiturates, narcotics, or other 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 imbalances, hyperglycemia, glycosuria, and hyperuricemia.

• Musculoskeletal: Muscle spasms.

• Nervous System/Psychiatric: Vertigo, paresthesia, 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 be withdrawn.

Patient Counseling

Patients should be advised that hydrochlorothiazide can lead to idiosyncratic reactions, which may result in acute transient myopia and acute angle-closure glaucoma. Symptoms of these conditions include an acute onset of decreased visual acuity or ocular pain, typically occurring within hours to weeks after initiating the medication. It is crucial for patients to discontinue hydrochlorothiazide as quickly as possible if they experience any symptoms indicative of acute angle-closure glaucoma.

Healthcare providers should observe patients for signs of fluid or electrolyte disturbances, such as hyponatremia, hypochloremic alkalosis, hypokalemia, and hypomagnesemia. Patients should be informed about warning signs or symptoms of fluid and electrolyte imbalance, which may include dryness of the mouth, increased thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances like nausea and vomiting.

Patients should be made aware that hypokalemia may develop, particularly during brisk diuresis in the presence of severe cirrhosis, when corticosteroids or adrenocorticotropic hormone (ACTH) are used concurrently, or after prolonged therapy. To mitigate the risk of hypokalemia, patients may be advised to consider potassium supplementation or to increase their intake of potassium-rich foods.

It is important to caution patients that dilutional hyponatremia can be life-threatening and may occur in edematous patients, especially in hot weather. The appropriate management for this condition is water restriction rather than salt administration, except in rare cases where hyponatremia is life-threatening.

Patients should also be informed that thiazides should be used with caution in individuals with impaired hepatic function, as they can precipitate hepatic coma in patients with severe liver disease. Additionally, thiazides cross the placental barrier and may appear in cord blood, posing risks of fetal or neonatal jaundice, thrombocytopenia, and potentially other adverse reactions.

Nursing mothers should be informed that thiazides are excreted in breast milk, and a decision should be made regarding whether to discontinue nursing or to stop hydrochlorothiazide, considering the importance of the medication to the mother.

Patients should be advised that elderly individuals may experience a greater reduction in blood pressure and an increase in side effects. Therefore, it is recommended to initiate treatment with the lowest available dose of hydrochlorothiazide (12.5 mg). If patients experience moderate or severe adverse reactions, they should be informed that the thiazide dosage may need to be reduced or therapy withdrawn.

Storage and Handling

Dispensed in a tight, light-resistant container as defined by the United States Pharmacopeia (USP), this product must be stored at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines. It is essential to protect the product from light, moisture, and freezing conditions, specifically avoiding temperatures below -20°C (-4°F). The container should remain tightly closed to maintain the integrity of the product. Additionally, it is crucial to keep this product out of reach of children to ensure safety.

Additional Clinical Information

Thiazides should be discontinued prior to conducting tests for parathyroid function to ensure accurate results. For adults, the initial dose of hydrochlorothiazide is one capsule administered once daily, regardless of whether it is used alone or in conjunction with other antihypertensive medications. It is important to note that total daily doses exceeding 50 mg are not recommended.

FDA Insert (PDF)

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

View full prescribing information (PDF)