Chlorothiazide sodium

Description

Chlorothiazide sodium is a diuretic and antihypertensive agent, chemically designated as 6-chloro-2 H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide monosodium salt, with a molecular weight of 317.71. Its molecular formula is C₇H₅ClN₃NaO₄S₂. Chlorothiazide sodium for injection, USP, is presented as a sterile lyophilized white powder, supplied in vials containing chlorothiazide sodium equivalent to 500 mg of chlorothiazide USP.

The formulation includes inactive ingredients such as mannitol (250 mg) and sodium hydroxide for pH adjustment. Chlorothiazide, the active component, is characterized as a white or practically white crystalline powder with a molecular weight of 295.72. It is insoluble in water but readily soluble in dilute aqueous sodium hydroxide and exhibits solubility in urine at approximately 150 mg per 100 mL at pH 7.

Uses and Indications

Chlorothiazide sodium for injection 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, including chlorothiazide sodium, during normal pregnancy is not recommended due to potential 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. In the absence of cardiovascular disease, the hypervolemia experienced during normal pregnancy is generally not harmful to the mother or fetus.

Chlorothiazide sodium may be indicated during pregnancy when edema is due to pathological causes, similar to its use in non-pregnant patients. For dependent edema resulting from venous return restriction by the gravid uterus, non-pharmacological measures such as elevation of the lower extremities and the use of support stockings are recommended. If edema during pregnancy leads to significant discomfort, increased recumbency may provide relief. In rare cases where extreme discomfort persists despite rest, a short course of diuretic therapy may be considered appropriate.

Dosage and Administration

Chlorothiazide sodium for injection 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 adults, the usual dosage ranges from 500 mg to 1 g, administered once or twice daily. Many patients with edema may benefit from an intermittent therapy schedule, such as administration on alternate days or three to five days per week, to minimize the risk of excessive response and electrolyte imbalances.

Chlorothiazide sodium for injection may be administered either slowly by direct intravenous injection or via intravenous infusion. It is critical to avoid extravasation; the medication must not be given subcutaneously or intramuscularly.

To prepare the solution for intravenous use, add 18 mL of Sterile Water for Injection to the vial to create an isotonic solution. It is essential to add no less than 18 mL. Upon reconstitution, the final concentration of chlorothiazide sodium is 28 mg/mL, and the solution should be clear and free from visible particles. Prior to administration, parenteral drug products should be visually inspected for particulate matter and discoloration whenever possible.

The reconstituted solution is compatible with dextrose or sodium chloride solutions for intravenous infusion. However, simultaneous administration of chlorothiazide solutions with whole blood or its derivatives should be avoided.

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, as it may exacerbate renal function impairment. Additionally, individuals with hypersensitivity to any component of this product or to other sulfonamide-derived drugs should not use this product due to the risk of 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 have also been reports 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 the risk of adverse 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 potential risk, especially during brisk diuresis, in patients with severe cirrhosis, or after prolonged therapy. Interference with adequate 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 utilized. While chloride deficits are typically mild and may not require treatment, chloride replacement may be necessary in cases of metabolic alkalosis, particularly in patients with liver or renal disease.

Dilutional hyponatremia may 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 where salt administration may be warranted. In cases of actual salt depletion, appropriate replacement therapy is indicated.

Patients receiving thiazides may experience hyperuricemia or acute gout, and diabetic patients may require dosage adjustments of insulin or oral hypoglycemic agents due to potential hyperglycemia. 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, increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.

Periodic determination of serum electrolytes is recommended to detect possible electrolyte imbalances at appropriate intervals during treatment.

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 their seriousness and frequency.

Serious adverse reactions include hematologic events such as aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia. Additionally, hypersensitivity reactions can manifest 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.

Common adverse reactions reported 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. Patients may also experience musculoskeletal symptoms like muscle spasms and nervous system/psychiatric effects, including vertigo, paresthesias, dizziness, headache, and restlessness.

Metabolic disturbances such as electrolyte imbalance, hyperglycemia, glycosuria, and hyperuricemia have been noted. Skin reactions may also include photosensitivity, fever, urticaria, rash, and purpura. Transient blurred vision and xanthopsia have been reported under special senses, while urogenital effects may include impotence.

In clinical trials and postmarketing experiences, it is advised that whenever adverse reactions are moderate or severe, the dosage of thiazide should be reduced or therapy withdrawn to mitigate risks.

Drug Interactions

The concomitant use of certain medications may lead to significant drug interactions that require careful consideration and management.

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): The use of this medication may necessitate dosage adjustments of the antidiabetic agent to maintain glycemic control. Close monitoring of blood glucose levels is recommended.

• Other Antihypertensive Drugs: There is a potential for an additive effect or potentiation of antihypertensive effects when used concurrently. Blood pressure should be monitored regularly to avoid excessive hypotension.

• Corticosteroids and ACTH: Co-administration may lead to intensified electrolyte depletion, particularly hypokalemia. Regular monitoring of electrolyte levels is advised.

• Skeletal Muscle Relaxants (Nondepolarizing): Increased responsiveness to muscle relaxants, such as tubocurarine, may occur. Monitoring of neuromuscular function is recommended.

• Lithium: The use of diuretics with lithium is generally contraindicated due to the risk of reduced renal clearance of lithium, which can lead to toxicity. It is essential to refer to the package insert for lithium preparations before co-administration.

• 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. Patients should be closely observed to ensure the desired diuretic effect is achieved when these agents are used together.

Pharmacokinetic Interactions

• Pressor Amines (e.g., Norepinephrine): There may be a decreased response to pressor amines; however, this interaction does not preclude their use. Monitoring of blood pressure and response to treatment 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

The safety and effectiveness of chlorothiazide sodium in pediatric patients have not been established. Therefore, caution is advised when considering its use in this population. Further studies are necessary to determine appropriate dosing and potential outcomes in children and adolescents.

Geriatric Use

Clinical studies of chlorothiazide sodium 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 renal impairment, careful consideration should be given to dose selection. Monitoring of renal function may be beneficial to ensure safe and effective use of this medication in the geriatric 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. The potential for chlorothiazide to cause fetal harm in pregnant patients remains unknown, as thiazides are known to cross the placental barrier and can be detected in cord blood. Therefore, chlorothiazide should only be administered during pregnancy if the potential benefits clearly outweigh the risks.

Additionally, chlorothiazide may lead to nonteratogenic effects such as fetal or neonatal jaundice and thrombocytopenia, along with other adverse reactions that have been observed in adults. Healthcare professionals should carefully consider these risks when prescribing chlorothiazide to women of childbearing potential and during pregnancy.

Lactation

Because of the potential for serious adverse reactions in nursing infants from chlorothiazide sodium, 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 important to closely monitor these patients 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 concurrently administered, 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, which may provide context for understanding the potential toxicity of the drug in overdose situations.

Nonclinical Toxicology

Carcinogenicity studies have not been conducted with chlorothiazide. In vitro studies indicate that chlorothiazide was not mutagenic in the Ames microbial mutagen test, utilizing a maximum concentration of 5 mg/plate with Salmonella typhimurium strains TA98 and TA100. Additionally, chlorothiazide did not exhibit mutagenic properties or induce mitotic nondisjunction in diploid strains of Aspergillus nidulans.

Chlorothiazide demonstrated no adverse effects on fertility in female rats at doses up to 60 mg/kg/day, and similarly, no adverse effects were observed in male rats at doses up to 40 mg/kg/day. These doses correspond to 1.5 and 1 times the recommended maximum human dose, respectively, when adjusted for body weight.

Postmarketing Experience

The following adverse reactions have been reported in postmarketing experience, derived from voluntary reports and surveillance programs:

Weakness has been noted as a general adverse reaction. Cardiovascular events include hypotension, with specific mention of orthostatic hypotension, which may be exacerbated by the concurrent use 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, including anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress such as pneumonitis and pulmonary edema, photosensitivity, fever, urticaria, rash, and purpura. Metabolic disturbances reported include electrolyte imbalances, hyperglycemia, glycosuria, and hyperuricemia.

Musculoskeletal reactions consist of muscle spasms. Nervous system and psychiatric events 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 reactions include transient blurred vision and xanthopsia. Renal adverse events consist of renal failure, renal dysfunction, interstitial nephritis, and hematuria following intravenous use. Urogenital reactions include impotence.

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

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.

Hypokalemia is a potential risk, especially 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, the use of potassium-sparing diuretics or potassium-rich foods may be recommended.

In edematous patients, particularly during hot weather, dilutional hyponatremia may occur. Patients should be advised that the appropriate management for this condition is water restriction, rather than salt administration, except in rare cases where hyponatremia is life-threatening. In instances of actual salt depletion, appropriate replacement therapy is essential.

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

If progressive renal impairment is observed, healthcare providers should consider withholding or discontinuing diuretic therapy. Thiazides are known to increase urinary excretion of magnesium, which may lead to hypomagnesemia. They may also decrease urinary calcium excretion, resulting in intermittent and slight elevations of serum calcium in the absence of known calcium metabolism disorders. Marked hypercalcemia could indicate hidden hyperparathyroidism, necessitating the discontinuation of thiazides prior to parathyroid function tests.

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. Patients should be encouraged to report any adverse reactions, including weakness, hypotension, gastrointestinal disturbances, and any signs of hypersensitivity reactions.

Storage and Handling

The lyophilized powder is supplied in a single-dose configuration. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15° and 30°C (59° and 86°F) in accordance with USP Controlled Room Temperature guidelines.

Upon reconstitution, the solution must be used immediately. Any unused portion of the reconstituted solution should be discarded.

Additional Clinical Information

Clinicians should conduct periodic determinations of serum electrolytes in patients to monitor for potential electrolyte imbalances. This assessment should occur at appropriate intervals to ensure timely identification and management of any imbalances that may arise.

FDA Insert (PDF)

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

View full prescribing information (PDF)