Chlorothiazide sodium

Description

Chlorothiazide Sodium for Injection, USP is a diuretic and antihypertensive agent. The chemical designation is 6-chloro-2 H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide monosodium salt, with a molecular weight of 317.71 g/mol. Its empirical formula is C₇H₅ClN₃NaO₄S₂.

This product is presented as a sterile lyophilized white powder, supplied in a vial containing chlorothiazide sodium equivalent to 500 mg of chlorothiazide, along with 250 mg of the inactive ingredient mannitol and sodium hydroxide for pH adjustment. Chlorothiazide itself is characterized as a white or practically white crystalline powder, with a molecular weight of 295.72 g/mol. It exhibits very slight solubility in water but is readily soluble in dilute aqueous sodium hydroxide. Additionally, chlorothiazide is soluble in urine to the extent of approximately 150 mg per 100 mL at pH 7.

Uses and Indications

Chlorothiazide Sodium for Injection, USP is indicated as adjunctive therapy in the management of edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. Additionally, this medication is beneficial in treating edema resulting from various forms of renal dysfunction, including nephrotic syndrome, acute glomerulonephritis, and chronic renal failure.

Limitations of Use: The routine use of diuretics 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 efficacy in treating this condition. During normal pregnancy, hypervolemia is typically not harmful to the mother or fetus in the absence of cardiovascular disease.

In cases of edema during pregnancy, it is essential to differentiate between pathologic causes and the physiological and mechanical effects of pregnancy. Thiazides may be indicated for treating edema due to pathologic causes, similar to their use in non-pregnant patients. For dependent edema resulting from venous return restriction by the gravid uterus, non-pharmacological measures such as elevating the lower extremities and using support stockings are recommended. If discomfort arises from such edema and is not alleviated by rest, a short course of diuretic therapy may be appropriate to provide relief.

Dosage and Administration

Chlorothiazide Sodium for Injection, USP is indicated for patients who are unable to take oral medication or in emergency situations. Therapy should be individualized based on patient response, utilizing the smallest effective dosage to achieve the desired therapeutic effect.

For adult patients, the usual dosage ranges from 500 mg to 1 g, administered once or twice daily. Many patients with edema may benefit from an intermittent dosing schedule, such as administration on alternate days or three to five days per week, which can help minimize the risk of excessive response and electrolyte imbalances.

Chlorothiazide Sodium for Injection, USP may be administered either by slow direct intravenous injection or by intravenous infusion. It is critical to avoid extravasation; the medication must not be given subcutaneously or intramuscularly.

For preparation, add 18 mL of Sterile Water for Injection to the vial to create an isotonic solution for intravenous injection. It is essential to use no less than 18 mL for reconstitution. When reconstituted with the appropriate volume of Sterile Water, the final concentration of Chlorothiazide Sodium for Injection, USP will be 28 mg per mL.

Intravenous use in infants and children is limited and generally not recommended. When patients are able to take oral medication, chlorothiazide tablets or oral suspension may be substituted for intravenous therapy, following the same dosage schedule as the parenteral route.

Contraindications

Use of this product is contraindicated in patients with anuria due to the potential for exacerbating renal impairment. Additionally, individuals with hypersensitivity to any component of this product or to other sulfonamide-derived drugs should not use this product, as it may lead to severe allergic reactions.

Warnings and Precautions

Intravenous administration of thiazides in infants and children is limited and generally not recommended due to safety concerns. Caution is advised when prescribing thiazides to patients with severe renal disease, as these medications may precipitate azotemia and lead to cumulative effects in individuals with impaired renal function. Additionally, thiazides should be used judiciously in patients with impaired hepatic function or progressive liver disease, as even minor alterations in fluid and electrolyte balance can precipitate hepatic coma.

Thiazides may enhance or potentiate the effects of other antihypertensive agents, necessitating careful monitoring of blood pressure and overall patient response. Sensitivity reactions can occur in patients regardless of prior allergy or bronchial asthma history. There is also a reported risk of exacerbation or activation of systemic lupus erythematosus in some patients. It is important to note that lithium should generally not be co-administered with diuretics due to potential interactions.

All patients undergoing diuretic therapy must be closely monitored for signs of fluid or electrolyte imbalance, including hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly critical in patients experiencing excessive vomiting or receiving parenteral fluids. Warning signs of fluid and electrolyte imbalance include dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle cramps, fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

Hypokalemia is a common concern, especially during brisk diuresis, in patients with severe cirrhosis, or after prolonged therapy. Inadequate oral electrolyte intake can exacerbate hypokalemia, which may lead to cardiac arrhythmias and increase the heart's sensitivity to digitalis toxicity. To mitigate hypokalemia, potassium-sparing diuretics or potassium-rich foods may be recommended. While chloride deficits are typically mild and may not require treatment, chloride replacement may be necessary in cases of metabolic alkalosis.

Dilutional hyponatremia can occur in edematous patients during hot weather; in such cases, water restriction is the preferred management strategy, except in rare instances of life-threatening hyponatremia. In cases of actual salt depletion, appropriate salt replacement is the treatment of choice. Hyperuricemia and acute gout may be precipitated in certain patients receiving thiazides.

Diabetic patients may require dosage adjustments of insulin or oral hypoglycemic agents, as thiazide diuretics can induce hyperglycemia and potentially unmask latent diabetes mellitus. The antihypertensive effects of thiazides may be enhanced in patients who have undergone sympathectomy. If progressive renal impairment is observed, it may be necessary to withhold or discontinue diuretic therapy.

Thiazides have been shown to increase urinary magnesium excretion, potentially leading to hypomagnesemia. They may also decrease urinary calcium excretion, resulting in intermittent and slight elevations of serum calcium levels in the absence of known calcium metabolism disorders. Marked hypercalcemia may indicate hidden hyperparathyroidism, and thiazides should be discontinued prior to parathyroid function testing. Additionally, thiazide therapy may be associated with increases in cholesterol and triglyceride levels.

Periodic monitoring of serum electrolytes is essential to detect possible imbalances during thiazide therapy.

Side Effects

Adverse reactions associated with the use of this medication have been observed across various systems in patients.

Serious adverse reactions include hematologic events such as aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia. Additionally, hypersensitivity reactions can occur, manifesting as anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), and respiratory distress, which may include pneumonitis and pulmonary edema. Skin reactions such as erythema multiforme, including Stevens-Johnson syndrome, and exfoliative dermatitis, including toxic epidermal necrolysis, have also been reported. Renal complications, including renal failure, renal dysfunction, and interstitial nephritis, are significant and warrant attention, particularly in cases of hematuria following intravenous use.

Common adverse reactions reported in clinical trials and postmarketing experiences include weakness, hypotension (including orthostatic hypotension), and various digestive issues such as diarrhea, vomiting, cramping, constipation, gastric irritation, nausea, and anorexia. Patients may also experience metabolic disturbances, including electrolyte imbalances, hyperglycemia, glycosuria, and hyperuricemia. Musculoskeletal symptoms such as muscle spasms, as well as nervous system and psychiatric effects like vertigo, paresthesias, dizziness, headache, and restlessness, have been noted.

Skin reactions such as alopecia and photosensitivity, along with transient blurred vision and xanthopsia affecting special senses, have been documented. Urogenital effects, including impotence, have also been reported.

It is important to note that in cases where adverse reactions are moderate or severe, a reduction in thiazide dosage or withdrawal of therapy should be considered to mitigate risks.

Drug Interactions

Concomitant use of certain medications may lead to significant drug interactions that can affect therapeutic outcomes. The following interactions have been identified:

Pharmacodynamic Interactions:

• Alcohol, Barbiturates, and Narcotics: The combination of these substances may potentiate orthostatic hypotension. Patients should be monitored for signs of hypotension and advised to avoid these substances when possible.

• Antidiabetic Drugs (Oral Agents and Insulin): Dosage adjustments of antidiabetic medications may be necessary when used in conjunction with this drug. Regular monitoring of blood glucose levels is recommended to ensure effective glycemic control.

• 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 closely monitored to avoid excessive hypotension.

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

• Skeletal Muscle Relaxants (Nondepolarizing, e.g., Tubocurarine): There may be an increased responsiveness to muscle relaxants. Caution is advised when using these agents concurrently.

• Lithium: The use of diuretics with lithium is generally contraindicated due to the potential for reduced renal clearance of lithium, which increases the risk of toxicity. It is essential to refer to the package insert for lithium preparations before considering their use with chlorothiazide sodium.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): In some patients, NSAIDs may diminish the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics. Close observation is warranted to ensure that the desired diuretic effect is achieved when these agents are used together.

Pharmacokinetic Interactions:

• Pressor Amines (e.g., Norepinephrine): There is a potential for decreased response to pressor amines; however, this interaction does not preclude their use. Monitoring of hemodynamic parameters is advisable.

Drug/Laboratory Test Interactions:

• Thiazides: It is recommended that thiazide diuretics 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 Chlorothiazide Sodium, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Safety and effectiveness of chlorothiazide sodium for injection in pediatric patients have not been established. Therefore, caution should be exercised when considering its use in this population. Further studies are needed to determine appropriate dosing and outcomes in children and adolescents.

Geriatric Use

Clinical studies of chlorothiazide sodium for injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. However, other reported clinical experience has not identified significant differences in responses between elderly patients and younger patients.

In general, dose selection for geriatric patients should be approached with caution. It is advisable to start at the low end of the dosing range, taking into account the increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies. Chlorothiazide sodium is substantially excreted by the kidneys, which raises the risk of toxic reactions, particularly in patients with impaired renal function.

Given that elderly patients are more prone to decreased renal function, careful consideration should be given to dose selection. Monitoring of renal function may be beneficial to ensure safety and efficacy in this population.

Pregnancy

Chlorothiazide is classified as a Pregnancy Category C medication. Reproduction studies conducted in rabbits, rats, and mice at doses of 50 mg/kg/day, 60 mg/kg/day, and 500 mg/kg/day, respectively, did not demonstrate external fetal abnormalities or impairments in growth and survival. However, these studies did not include comprehensive evaluations for visceral and skeletal abnormalities. Therefore, it remains unclear whether chlorothiazide poses a risk of fetal harm when administered to pregnant patients. It is important to note that thiazides, including chlorothiazide, can cross the placental barrier and are detectable in cord blood. Consequently, chlorothiazide should be prescribed during pregnancy only when the potential benefits outweigh the risks.

Additionally, chlorothiazide may lead to nonteratogenic effects such as fetal or neonatal jaundice and thrombocytopenia, as well as other adverse reactions that have been observed in adults. Healthcare professionals should carefully consider these potential risks when treating pregnant patients with chlorothiazide.

Lactation

Because of the potential for serious adverse reactions in nursing infants from chlorothiazide sodium for injection, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Renal Impairment

Patients with renal impairment should use this medication with caution, particularly in cases of severe renal disease. In individuals with renal disease, thiazides may precipitate azotemia, necessitating careful monitoring of renal function. Additionally, the cumulative effects of the drug may develop in patients with impaired renal function, warranting dose adjustments and vigilant oversight to mitigate potential adverse effects.

Hepatic Impairment

Patients with hepatic impairment should use thiazides with caution due to the potential for minor alterations in fluid and electrolyte balance, which may precipitate hepatic coma. It is essential to monitor these patients closely for any signs of deterioration in liver function and to assess their fluid and electrolyte status regularly. Adjustments to dosage may be necessary based on the severity of hepatic impairment and the patient's overall clinical condition.

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 administered concurrently, hypokalemia may exacerbate the risk of cardiac arrhythmias.

Management of overdosage should focus on symptomatic and supportive measures. Healthcare professionals are advised to correct dehydration and address any electrolyte imbalances, hepatic coma, and hypotension using established medical procedures. In instances of respiratory impairment, the administration of oxygen or the provision of artificial respiration may be necessary.

The extent to which chlorothiazide sodium can be removed through hemodialysis has not been definitively established. Additionally, it is noteworthy that the intravenous LD50 of chlorothiazide in mice is reported to be 1.1 g/kg.

Nonclinical Toxicology

Chlorothiazide has been classified as a Pregnancy Category C medication. Reproduction studies conducted in rabbits, rats, and mice at doses of 50 mg/kg/day, 60 mg/kg/day, and 500 mg/kg/day, respectively, did not reveal any external fetal abnormalities or impairments in growth and survival. However, these studies did not include comprehensive evaluations for visceral and skeletal abnormalities. The potential for chlorothiazide to cause fetal harm when administered to pregnant women remains unknown, although it is noted that thiazides can cross the placental barrier and are detectable in cord blood. Therefore, chlorothiazide should be used during pregnancy only if clearly necessary.

Chlorothiazide may be associated with fetal or neonatal jaundice, thrombocytopenia, and potentially other adverse reactions that have also been observed in adults.

Carcinogenicity studies have not been performed with chlorothiazide. In mutagenicity assessments, chlorothiazide did not demonstrate mutagenic properties in vitro in the Ames microbial mutagen test, utilizing a maximum concentration of 5 mg/plate with Salmonella typhimurium strains TA98 and TA100. Additionally, it did not induce mitotic nondisjunction in diploid strains of Aspergillus nidulans.

In terms of fertility, chlorothiazide exhibited no adverse effects in female rats at doses up to 60 mg/kg/day and in male rats at doses up to 40 mg/kg/day. These doses correspond to 1.5 and 1.0 times the recommended maximum human dose, respectively, when adjusted for body weight.

Postmarketing Experience

The following adverse reactions have been reported through voluntary reporting and surveillance programs:

Weakness has been noted as a general body reaction. Cardiovascular events include hypotension, specifically orthostatic hypotension, which may be exacerbated by the consumption of alcohol, barbiturates, narcotics, or antihypertensive medications. Digestive system reactions encompass pancreatitis, intrahepatic cholestatic jaundice, diarrhea, vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea, and anorexia.

Hematologic adverse events reported include aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia. Hypersensitivity reactions have been documented, such as anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress (including pneumonitis and pulmonary edema), photosensitivity, fever, urticaria, rash, and purpura.

Metabolic disturbances include electrolyte imbalances, hyperglycemia, glycosuria, and hyperuricemia. Musculoskeletal issues reported consist of muscle spasms. Nervous system and psychiatric reactions include vertigo, paresthesias, dizziness, headache, and restlessness. Skin reactions reported are erythema multiforme (including Stevens-Johnson syndrome), exfoliative dermatitis (including toxic epidermal necrolysis), and alopecia.

Special senses may be affected, with reports of transient blurred vision and xanthopsia. Renal adverse events include renal failure, renal dysfunction, interstitial nephritis, and hematuria following intravenous use. Urogenital reactions have included impotence.

In cases where adverse reactions are moderate or severe, it is recommended that thiazide dosage be reduced or therapy be withdrawn. For reporting suspected adverse reactions, individuals are encouraged to contact Sagent Pharmaceuticals, Inc. at 1-866-625-1618 or the FDA at 1-800-FDA-1088 or visit www.fda.gov/medwatch.

Patient Counseling

Patients should be closely monitored for signs of fluid or electrolyte imbalance, including conditions such as hyponatremia, hypochloremic alkalosis, and hypokalemia. Healthcare providers are encouraged to perform serum and urine electrolyte determinations, particularly in patients experiencing excessive vomiting or those receiving parenteral fluids.

Patients should be informed about warning signs and symptoms indicative of fluid and electrolyte imbalance. These may include dryness of the mouth, increased thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

It is important to note that hypokalemia may develop, particularly in cases of brisk diuresis, severe cirrhosis, or prolonged therapy. Patients should be made aware that hypokalemia can lead to cardiac arrhythmias and may heighten the heart's sensitivity to the toxic effects of digitalis. To prevent or manage hypokalemia, healthcare providers may recommend the use of potassium-sparing diuretics or potassium supplements, including foods rich in potassium.

In cases of metabolic alkalosis, chloride replacement may be necessary. Patients with edematous conditions in hot weather should be informed that dilutional hyponatremia may occur, and that appropriate management typically involves water restriction rather than salt administration, except in rare cases of life-threatening hyponatremia. Conversely, in instances of actual salt depletion, appropriate replacement therapy is essential.

Patients receiving thiazide diuretics should be aware that hyperuricemia may occur, potentially precipitating acute gout in certain individuals. Diabetic patients may require dosage adjustments of insulin or oral hypoglycemic agents, as hyperglycemia can manifest during thiazide therapy, potentially revealing latent diabetes mellitus.

Healthcare providers should consider withholding or discontinuing diuretic therapy if progressive renal impairment is observed. Thiazides are known to increase urinary excretion of magnesium, which may lead to hypomagnesemia. Additionally, thiazides may decrease urinary calcium excretion and can cause intermittent, slight elevations in serum calcium levels in the absence of known calcium metabolism disorders. Marked hypercalcemia may indicate hidden hyperparathyroidism, necessitating the discontinuation of thiazides prior to parathyroid function testing.

Patients should be advised that thiazide diuretics may be associated with increases in cholesterol and triglyceride levels. Periodic monitoring of serum electrolytes is recommended to detect potential electrolyte imbalances at appropriate intervals. Lastly, patients should be encouraged to report any signs of adverse reactions, including weakness, hypotension, gastrointestinal disturbances, and hypersensitivity reactions.

Storage and Handling

The product is supplied as a single-dose container, which is sterile, nonpyrogenic, and preservative-free. It is essential to use the solution immediately after reconstitution and to discard any unused portion of the reconstituted solution.

Storage conditions require the product to be maintained at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines. Additionally, the container closure is designed without the use of natural rubber latex, ensuring compatibility for individuals with latex sensitivities.

Additional Clinical Information

Clinicians should conduct periodic determinations of serum electrolytes in patients to identify any potential electrolyte imbalances. This monitoring should occur at appropriate intervals to ensure patient safety and effective management.

FDA Insert (PDF)

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

View full prescribing information (PDF)