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 g/mol.

The product appears as a white or practically white crystalline powder that is slightly soluble in water and freely soluble in sodium hydroxide solution. Hydrochlorothiazide is formulated as capsules for oral administration, each 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. It is important to note that dependent edema resulting from venous return restriction due to an expanded uterus should be managed through non-pharmacological measures, such as elevating the lower extremities and utilizing support hose. 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 increased recumbency, a short course of diuretics may be considered appropriate for relief.

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 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 course of action is to discontinue hydrochlorothiazide immediately. 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 professionals 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 the development of azotemia. It is essential to monitor renal function closely in these patients, as thiazide therapy may exacerbate their condition. Regular assessment of renal parameters is recommended to mitigate potential complications.

Side Effects

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

In the Body as a Whole, patients may experience weakness. Cardiovascular effects include hypotension, which may present as orthostatic hypotension and can be exacerbated by the concurrent use of alcohol, barbiturates, narcotics, or antihypertensive medications.

Digestive system reactions are notable and may include pancreatitis, jaundice (specifically intrahepatic cholestatic jaundice), diarrhea, vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea, and anorexia.

Hematologic adverse reactions can be serious, including aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia.

Hypersensitivity reactions may manifest as anaphylactic reactions, necrotizing angiitis (which includes vasculitis and cutaneous vasculitis), respiratory distress (including pneumonitis and pulmonary edema), photosensitivity, fever, urticaria, rash, and purpura.

Metabolic disturbances may occur, such as electrolyte imbalances, hyperglycemia, glycosuria, and hyperuricemia. In the Musculoskeletal system, muscle spasms have been reported.

Nervous System/Psychiatric effects include vertigo, paresthesia, dizziness, headache, and restlessness. Renal complications can arise, including renal failure, renal dysfunction, and interstitial nephritis.

Skin reactions may be severe, with reports of erythema multiforme (including Stevens-Johnson syndrome), exfoliative dermatitis (including toxic epidermal necrolysis), and alopecia.

In terms of Special Senses, patients may experience transient blurred vision and xanthopsia. Urogenital effects include impotence.

Warnings associated with this medication include the potential for acute myopia and secondary angle-closure glaucoma, which can occur as an idiosyncratic reaction to hydrochlorothiazide, a sulfonamide. Symptoms may present as an acute onset of decreased visual acuity or ocular pain, typically occurring within hours to weeks of initiation. Untreated, acute angle-closure glaucoma can lead to permanent vision loss.

Additionally, latent diabetes mellitus may become manifest in patients, and those with diabetes may require adjustments to their insulin dosage when treated with thiazides. In patients with renal disease, cumulative effects of thiazides may precipitate azotemia, particularly in those with impaired renal function.

It is important to note that if adverse reactions are moderate or severe, the dosage of thiazide should be reduced or therapy withdrawn. In cases of overdosage, the most common signs and symptoms are related to electrolyte depletion (such as hypokalemia, hypochloremia, and hyponatremia) and dehydration due to excessive diuresis. If digitalis has also been administered, 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 specific lithium preparations before co-administration.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The concurrent use 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.

Laboratory Test Interactions

Thiazide diuretics, including hydrochlorothiazide, 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, as there is insufficient data to support its use in these populations. Healthcare professionals are advised to consider the potential risks and benefits before prescribing this medication to pediatric patients.

Geriatric Use

Elderly patients, defined as 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 begins with the lowest available dose of hydrochlorothiazide, specifically 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 in assessing the response and any adverse effects in geriatric patients throughout the course of treatment.

Pregnancy

Hydrochlorothiazide is classified as Pregnancy Category B. Animal studies involving the oral administration of hydrochlorothiazide to pregnant mice and rats during major organogenesis at doses up to 3000 mg/kg and 1000 mg/kg, respectively, have shown no evidence of harm to the fetus. However, there are no adequate and well-controlled studies in pregnant women. Due to the limitations of animal reproduction studies in predicting human response, 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 fetal or neonatal complications, including the risk of 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 the risks and benefits when advising lactating mothers. A decision should be made whether to discontinue nursing or to discontinue hydrochlorothiazide, taking into account the importance of the drug to the mother.

Renal Impairment

Patients with renal impairment 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 individuals with impaired renal function. Dosing adjustments may be necessary to mitigate these risks and ensure safe and effective use of the medication.

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 outlined 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 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 established.

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, did not demonstrate any 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 have been observed in adults.

In nonclinical toxicology assessments, 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 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 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 (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 may include a sudden decrease in visual acuity or ocular pain, typically occurring within hours to weeks after initiation of therapy. If untreated, acute angle-closure glaucoma can result in permanent vision loss, necessitating rapid discontinuation of the medication and potential medical or surgical intervention if intraocular pressure remains uncontrolled. Risk factors for this condition may include a history of sulfonamide or penicillin allergy.

In diabetic patients, latent diabetes mellitus may become apparent, and adjustments to insulin dosing may be required for those receiving thiazides. 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. Warning signs of fluid and electrolyte imbalance include symptoms such as dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle cramps, hypotension, oliguria, tachycardia, and gastrointestinal disturbances.

Hyperuricemia or acute gout may occur in certain patients 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 also been associated with decreased calcium excretion and pathologic changes in the parathyroid glands, leading to hypercalcemia and hypophosphatemia in some 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 placebo. However, at doses of 25 mg and above, the following adverse reactions have been documented:

• 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, 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 discontinued.

Patient Counseling

Patients should be advised to monitor their blood pressure regularly while taking hydrochlorothiazide. It is important for patients to understand the potential for electrolyte imbalances, including hypokalemia, and the necessity of periodic serum electrolyte monitoring.

Patients should be instructed to report any signs of fluid or electrolyte disturbances. Symptoms to watch for include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

Patients should be made aware that hydrochlorothiazide can cause acute myopia and acute angle-closure glaucoma. They should report any sudden changes in vision or ocular pain to their healthcare provider promptly.

It is essential to inform patients that latent diabetes mellitus may become manifest during treatment, and diabetic patients may require adjustments to their insulin dosage.

Patients should be cautioned about the risk of hyperuricemia or acute gout while taking thiazide diuretics. Additionally, patients should be informed that thiazides are excreted in breast milk, and a decision should be made regarding whether to discontinue nursing or to discontinue hydrochlorothiazide, taking into account the importance of the medication to the mother.

Patients should be advised to avoid excessive alcohol, barbiturates, or narcotics, as these substances may potentiate orthostatic hypotension. Furthermore, patients should be instructed to take hydrochlorothiazide in the morning to minimize the risk of nocturia.

Finally, patients should be informed that hydrochlorothiazide should not be used if they have anuria or hypersensitivity to sulfonamide-derived drugs.

Storage and Handling

This product is supplied in a tight, light-resistant container as defined by the United States Pharmacopeia (USP). It should be stored at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines.

To ensure the integrity of the product, it must be protected from moisture, freezing, and excessive heat. Healthcare professionals are advised to inspect the bottle seal prior to use; the product should not be used if the seal is not intact. After each use, the cap on the bottle should be securely tightened to maintain product stability.

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.

FDA Insert (PDF)

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

View full prescribing information (PDF)