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.

The product is presented as a sterile lyophilized white powder, supplied in vials containing Chlorothiazide Sodium equivalent to 500 mg of Chlorothiazide. Inactive ingredients include 250 mg of 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, it is soluble in urine at a concentration 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, and there is insufficient evidence to support their efficacy in treating this condition.

In cases where edema during pregnancy is attributed to pathological causes, thiazides may be indicated, similar to their use in non-pregnant patients. However, dependent edema resulting from the mechanical effects of pregnancy should primarily be managed through non-pharmacological measures, such as elevating the lower extremities and utilizing support stockings.

It is important to note that hypervolemia during normal pregnancy is generally not harmful to the mother or fetus in the absence of cardiovascular disease. If edema leads to significant discomfort that is not alleviated by rest, a short course of diuretic therapy may be considered appropriate in rare instances.

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; therefore, 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/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, 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 could 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. 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 and may vary in severity and frequency.

Serious adverse reactions include hematologic events such as aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia. Hypersensitivity reactions can also be severe, manifesting as anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), and respiratory distress, which may include pneumonitis and pulmonary edema. Additionally, skin reactions such as erythema multiforme, including Stevens-Johnson syndrome, and exfoliative dermatitis, including toxic epidermal necrolysis, have been reported.

Common adverse reactions include weakness, hypotension (including orthostatic hypotension), and various digestive issues such as diarrhea, vomiting, nausea, and abdominal cramping. Patients may also experience metabolic disturbances, including electrolyte imbalances, hyperglycemia, glycosuria, and hyperuricemia. Musculoskeletal symptoms such as muscle spasms and nervous system effects including dizziness, vertigo, and headache have been noted.

Renal adverse reactions may include renal failure, renal dysfunction, interstitial nephritis, and hematuria, particularly following intravenous use. Urogenital effects such as impotence have also been reported.

In clinical trials and postmarketing experiences, it is important to monitor all patients receiving diuretic therapy for signs of fluid or electrolyte imbalance, including hyponatremia, hypochloremic alkalosis, and hypokalemia. Warning signs of these imbalances may include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle cramps, hypotension, and gastrointestinal disturbances. Hypokalemia may develop, especially with brisk diuresis or prolonged therapy, and hyperuricemia may occur, potentially precipitating acute gout in susceptible individuals.

In diabetic patients, dosage adjustments of insulin or oral hypoglycemic agents may be necessary, as thiazide diuretics can induce hyperglycemia and unmask latent diabetes mellitus. Furthermore, thiazides may increase urinary excretion of magnesium, leading to hypomagnesemia, and decrease urinary calcium excretion, which may result in slight elevations of serum calcium levels. Marked hypercalcemia could indicate hidden hyperparathyroidism, necessitating discontinuation of thiazides prior to parathyroid function tests.

Patients should be advised that increases in cholesterol and triglyceride levels may also be associated with thiazide diuretic therapy. Caution is advised in patients with severe renal disease, hepatic impairment, or a history of sensitivity reactions, as these factors may exacerbate adverse effects.

Drug Interactions

Concomitant use of thiazide diuretics with certain medications may lead to significant drug interactions, categorized primarily into pharmacodynamic and pharmacokinetic interactions.

Pharmacodynamic Interactions:

• Alcohol, Barbiturates, or Narcotics: The combination may potentiate orthostatic hypotension, necessitating careful monitoring of blood pressure and patient symptoms.

• Antidiabetic Drugs (Oral Agents and Insulin): Dosage adjustments of the antidiabetic medication may be required to maintain glycemic control.

• Other Antihypertensive Drugs: There is a potential for additive effects or potentiation of antihypertensive effects, which may require monitoring of blood pressure to avoid excessive hypotension.

• Corticosteroids and ACTH: These agents may intensify electrolyte depletion, particularly hypokalemia. Regular monitoring of electrolyte levels is advised.

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

• Skeletal Muscle Relaxants (Nondepolarizing, e.g., Tubocurarine): Increased responsiveness to muscle relaxants may occur, warranting careful monitoring of neuromuscular function.

Pharmacokinetic Interactions:

• Lithium: Thiazide diuretics generally should not be used concurrently with lithium due to the risk of reduced renal clearance of lithium, which can lead to lithium toxicity. Consultation of the package insert for lithium preparations is recommended prior to co-administration.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The use of NSAIDs may reduce the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics in some patients. Close observation is necessary to ensure the desired diuretic effect is achieved when these agents are used together.

In summary, careful consideration and monitoring are essential when thiazide diuretics are used in conjunction with the aforementioned drug classes to mitigate potential adverse effects and ensure therapeutic efficacy.

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 is advised when considering its use in this population. Further studies are necessary to determine appropriate dosing and outcomes in children and adolescents.

Geriatric Use

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

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. 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.

Healthcare professionals should be aware that chlorothiazide may lead to fetal or neonatal complications, including jaundice and thrombocytopenia, as well as other adverse reactions that have been observed in adults. Therefore, chlorothiazide sodium for injection should be administered during pregnancy only when the benefits clearly outweigh the risks.

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. In individuals with impaired hepatic function or progressive liver disease, minor alterations in fluid and electrolyte balance may precipitate hepatic coma. Therefore, careful monitoring of liver function and electrolyte levels is recommended in this population to prevent potential complications. No specific dosage adjustments are provided; however, clinicians should assess the risks and benefits of thiazide therapy in patients with compromised liver function.

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 remains undetermined. Additionally, it is noteworthy that the intravenous LD50 of chlorothiazide in mice is recorded at 1.1 g/kg, which may serve as a reference point for assessing potential toxicity in clinical scenarios.

Nonclinical Toxicology

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

Chlorothiazide may lead to fetal or neonatal jaundice, thrombocytopenia, and potentially other adverse reactions that have been observed in adults.

Carcinogenicity studies have not been performed with chlorothiazide. In vitro testing, specifically the Ames microbial mutagen test using a maximum concentration of 5 mg/plate and Salmonella typhimurium strains TA98 and TA100, indicated that chlorothiazide was not mutagenic. Additionally, it did not 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 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

Adverse reactions reported during postmarketing surveillance include a range of events across multiple systems.

Body as a Whole: Weakness has been noted.

Cardiovascular: Instances of hypotension, including orthostatic hypotension, have been reported, with potential aggravation from alcohol, barbiturates, narcotics, or antihypertensive medications.

Digestive System: Reports include pancreatitis, intrahepatic cholestatic jaundice, diarrhea, vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea, and anorexia.

Hematologic: Cases of aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia have been documented.

Hypersensitivity Reactions: Anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress (including pneumonitis and pulmonary edema), photosensitivity, fever, urticaria, rash, and purpura have been observed.

Metabolic Effects: Electrolyte imbalances, hyperglycemia, glycosuria, and hyperuricemia have been reported.

Musculoskeletal: Muscle spasms have been noted.

Nervous System/Psychiatric: Reports include vertigo, paresthesias, dizziness, headache, and restlessness.

Skin Reactions: Erythema multiforme (including Stevens-Johnson syndrome), exfoliative dermatitis (including toxic epidermal necrolysis), and alopecia have been documented.

Special Senses: Transient blurred vision and xanthopsia have been reported.

Renal Effects: Instances of renal failure, renal dysfunction, interstitial nephritis, and hematuria (following intravenous use) have been noted.

Urogenital: Impotence has been reported.

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 American Regent at 1-800-734-9236 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.

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 cases of metabolic alkalosis, chloride replacement may be necessary. Patients with dilutional hyponatremia, particularly those who are edematous and in hot weather, should be advised that water restriction is the appropriate therapy, except in rare cases where hyponatremia is life-threatening. Conversely, in instances of actual salt depletion, appropriate salt replacement is the preferred treatment.

Patients receiving thiazide diuretics should be informed that hyperuricemia may occur, potentially precipitating acute gout. 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. 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 imbalances, and patients should be encouraged to report any adverse reactions, including weakness, hypotension, gastrointestinal disturbances, and hypersensitivity reactions.

Storage and Handling

The product is supplied as a lyophilized powder, which 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 intended for single-dose use only. The reconstituted solution should be utilized immediately after preparation, and any unused portion must be discarded to ensure safety and efficacy.

Additional Clinical Information

Clinicians should conduct periodic determinations of serum electrolytes in patients to monitor for potential electrolyte imbalances. This assessment should be performed 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 American Regent, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)