Hydrochlorothiazide

Description

Hydrochlorothiazide Capsules 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, with a molecular weight of 297.74. The structural formula is represented as follows:

Hydrochlorothiazide appears as a white or practically white crystalline powder that is slightly soluble in water and freely soluble in sodium hydroxide solution. The capsules are formulated for oral administration, each containing 12.5 mg of hydrochlorothiazide.

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 is 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 minimized, such as those receiving ACE inhibitors.

In the context of pregnancy, hydrochlorothiazide may be utilized when edema is attributable to pathological causes. However, the routine use of diuretics in otherwise healthy pregnant women is deemed inappropriate, as it poses unnecessary risks to both the mother and fetus. Diuretics do not prevent or treat toxemia of pregnancy, and there is insufficient evidence supporting their efficacy in managing developed toxemia.

Dependent edema during pregnancy, resulting from venous return restriction due to an expanded uterus, should be managed through non-pharmacological measures such as elevating the lower extremities and using support hose. The physiological hypervolemia associated with normal pregnancy is generally not harmful to the mother or fetus, provided there is no underlying cardiovascular disease, and is often accompanied by generalized edema.

In instances where edema during pregnancy causes significant discomfort and is unresponsive to rest, 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 the medication is taken consistently at the same time each day to maintain optimal therapeutic levels.

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 when prescribing this medication.

Acute Myopia and Secondary Angle-Closure Glaucoma Hydrochlorothiazide can induce an idiosyncratic reaction leading to acute transient myopia and acute angle-closure glaucoma. Symptoms may present as a sudden decrease in visual acuity or ocular pain, typically occurring within hours to weeks following the initiation of therapy. It is critical to recognize that untreated acute angle-closure glaucoma can result in permanent vision loss. The primary course of action is 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.

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 the development of azotemia. It is essential to monitor renal function closely in these patients, as thiazide diuretics may exacerbate existing renal impairment.

In summary, careful consideration of these warnings and precautions is essential for the safe use of hydrochlorothiazide, particularly in patients with a history of ocular issues, diabetes, or renal disease. Regular monitoring and prompt intervention are crucial to mitigate potential adverse effects.

Side Effects

Adverse reactions associated with the use of hydrochlorothiazide include a range of serious and common effects, which may necessitate dosage adjustment or discontinuation of therapy.

Serious adverse reactions include hypersensitivity reactions such as anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), and respiratory distress, which may manifest as pneumonitis or 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.

Patients may experience acute myopia and secondary angle-closure glaucoma, which can occur as an idiosyncratic reaction to hydrochlorothiazide. Symptoms typically arise within hours to weeks of initiating treatment and include acute onset of decreased visual acuity or ocular pain. If left untreated, acute angle-closure glaucoma can result in permanent vision loss, necessitating prompt discontinuation of the drug and potential medical or surgical intervention if intraocular pressure remains uncontrolled.

Common adverse reactions include weakness, hypotension (including orthostatic hypotension), and various digestive issues such as pancreatitis, jaundice (intrahepatic cholestatic jaundice), diarrhea, vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea, and anorexia. Neurological effects may include vertigo, paresthesia, dizziness, headache, and restlessness. Musculoskeletal symptoms such as muscle spasms and urogenital issues like impotence have also been reported.

Skin reactions can range from erythema multiforme, including Stevens-Johnson syndrome, to 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. Metabolic disturbances such as electrolyte imbalance, hyperglycemia, glycosuria, and hyperuricemia have been noted, particularly in patients with pre-existing conditions.

In clinical trials and postmarketing experiences, it is advised that whenever adverse reactions are moderate or severe, the dosage of hydrochlorothiazide should be reduced or therapy withdrawn. Additionally, latent diabetes mellitus may become manifest in patients, and those with diabetes may require adjustments to their insulin dosage when treated with thiazides. Cumulative effects of thiazides may develop in patients with impaired renal function, potentially precipitating azotemia.

Drug Interactions

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

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 required when used in conjunction with hydrochlorothiazide. Close monitoring of blood glucose levels is advised.

• Other Antihypertensive Drugs: The use of additional 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): Increased responsiveness to muscle relaxants such as tubocurarine may occur. Monitoring of neuromuscular function is recommended.

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

• 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.

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, 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.

If further titration of the dosage is necessary, increments of 12.5 mg should be employed. Careful monitoring of blood pressure and potential adverse effects is advised to ensure the safety and efficacy of treatment 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 fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have been observed in adults. Healthcare professionals 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 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

Overdosage may present with a range of symptoms primarily associated with electrolyte depletion and dehydration due to excessive diuresis. The most frequently observed signs include hypokalemia, hypochloremia, and hyponatremia. In cases where digitalis has been co-administered, hypokalemia can exacerbate the risk of cardiac arrhythmias.

In the event of an overdosage, it is crucial to implement symptomatic and supportive measures. Inducing emesis or performing gastric lavage is recommended to mitigate the effects of the overdose. Additionally, it is essential to correct any dehydration and electrolyte imbalances, as well as to address hepatic coma and hypotension using established medical procedures. Should respiratory impairment occur, the administration of oxygen or 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 margin of safety in these species. However, the efficacy of hemodialysis in removing hydrochlorothiazide has not been established, and its role in the management of overdose remains unclear.

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 may also occur in adults.

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.

In terms of mutagenicity, hydrochlorothiazide was not found to be genotoxic in vitro in the Ames mutagenicity assay using various strains of Salmonella typhimurium, nor in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. 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 at concentrations ranging from 43 to 1300 mcg/mL, as well as in the Aspergillus nidulans non-disjunction assay at an unspecified concentration.

Hydrochlorothiazide did not adversely affect the fertility of either male or female mice and rats in studies where these animals were exposed to dietary doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to conception and throughout gestation.

Postmarketing Experience

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. Hyperuricemia or acute gout has also been reported in certain individuals receiving 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, resulting in hypercalcemia and hypophosphatemia 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 placebo. For doses of 25 mg and greater, 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 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 spasm.

• 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 to monitor their blood pressure regularly while taking hydrochlorothiazide. It is important for patients to be informed about 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, such as dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances, including nausea and vomiting. Additionally, 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 immediately.

Patients should be advised that latent diabetes mellitus may become manifest during treatment, and diabetic patients may require adjustments to their insulin dosage. Those with renal disease should be cautioned about the cumulative effects of thiazides and the potential for azotemia. Furthermore, patients should be informed that thiazides can precipitate hyperuricemia or acute gout.

Patients should be advised to avoid alcohol, barbiturates, or narcotics while taking hydrochlorothiazide due to the risk of orthostatic hypotension. It is also important for patients to maintain adequate oral electrolyte intake to help prevent hypokalemia.

Patients should be informed that thiazides cross the placental barrier and may appear in breast milk; therefore, a decision should be made regarding whether to discontinue nursing or the medication based on the importance of the drug to the mother. Lastly, patients should be advised to start treatment with the lowest available dose of hydrochlorothiazide, particularly in the elderly, and to titrate the dosage as necessary.

Storage and Handling

Dispensed in a tight, light-resistant container as defined in the 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 temperatures below -20°C (-4°F). The container should remain tightly closed to maintain product integrity. 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 RedPharm Drug Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)