Chlorothiazide sodium

Description

Chlorothiazide sodium for injection, USP is a diuretic and antihypertensive agent. The chemical designation is 6-chloro-2H-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. 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 to 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. This medication is also beneficial in treating edema resulting from various forms of renal dysfunction, including nephrotic syndrome, acute glomerulonephritis, and chronic renal failure.

In pregnant patients, chlorothiazide sodium for injection may be indicated when edema is due to pathologic causes. However, routine use of diuretics during normal pregnancy is inappropriate, as it poses unnecessary risks to both the mother and fetus. Diuretics do not prevent the development of toxemia of pregnancy, nor is there satisfactory evidence supporting their efficacy in treating this condition. It is important to note that hypervolemia during normal pregnancy is not harmful in the absence of cardiovascular disease.

For dependent edema in pregnancy, which may arise 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 discomfort from such edema occurs, increased recumbency may provide relief. In rare cases where extreme discomfort persists and is not alleviated by 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, which involves administration on alternate days or three to five days each week. This approach can help minimize the risk of excessive response and subsequent electrolyte imbalances.

Chlorothiazide sodium for injection may be administered slowly via direct intravenous injection or through intravenous infusion. It is important to note that intravenous use in infants and children is limited and generally not recommended. When oral administration is feasible, chlorothiazide tablets or oral suspension can be substituted for intravenous therapy, following the same dosage schedule as the parenteral route.

Preparation of the injection requires aseptic technique. Chlorothiazide sodium for injection contains no preservatives; therefore, a fresh solution should be prepared immediately prior to each administration, with any unused portion discarded. To reconstitute, add 18 mL of Sterile Water for Injection to the vial to create an isotonic solution for intravenous injection. It is critical 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 use, parenteral drug products should be visually inspected for particulate matter and discoloration whenever the solution and container permit. 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.

Contraindications

Use of this product is contraindicated in patients with anuria due to the potential for exacerbating renal impairment. Additionally, it is contraindicated in individuals with hypersensitivity to any component of this product or to other sulfonamide-derived drugs, as this 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. In individuals with impaired renal function, the cumulative effects of thiazides can lead to significant complications.

Thiazides should also be used judiciously in patients with impaired hepatic function or progressive liver disease. Minor alterations in fluid and electrolyte balance in these patients may precipitate hepatic coma, necessitating careful monitoring.

When thiazides are used in conjunction with other antihypertensive agents, there is a potential for additive or potentiated effects, which may require adjustments in therapy. Additionally, sensitivity reactions can occur in patients regardless of their allergy or bronchial asthma history, warranting close observation.

There have been reports of exacerbation or activation of systemic lupus erythematosus associated with thiazide use, which should be considered when evaluating treatment options. Furthermore, lithium should generally not be co-administered with diuretics due to the risk of increased lithium levels and toxicity.

To ensure patient safety, periodic determination of serum electrolytes is recommended to detect possible electrolyte imbalances. Monitoring should be conducted at appropriate intervals to manage any potential complications effectively.

Side Effects

Adverse reactions observed in patients receiving the treatment include a range of serious and common effects, categorized by system involvement.

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. Renal complications such as renal failure, renal dysfunction, and interstitial nephritis have also been reported, with hematuria noted following intravenous use. Patients experiencing moderate to severe adverse reactions may require a reduction in thiazide dosage or withdrawal of therapy.

Common adverse reactions encompass a variety of symptoms across different systems. Patients may experience weakness, hypotension—including orthostatic hypotension, which can be exacerbated by alcohol, barbiturates, narcotics, or antihypertensive medications. Digestive issues such as pancreatitis, jaundice (intrahepatic cholestatic jaundice), diarrhea, vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea, and anorexia have been reported.

Nervous system and psychiatric effects include vertigo, paresthesias, dizziness, headache, and restlessness. Musculoskeletal symptoms may present as muscle spasms. Skin reactions can range from erythema multiforme, including Stevens-Johnson syndrome, to exfoliative dermatitis, including toxic epidermal necrolysis and alopecia.

Metabolic disturbances such as electrolyte imbalance, hyperglycemia, glycosuria, and hyperuricemia have also been observed. Patients may report transient blurred vision and xanthopsia as part of the special senses adverse reactions. Urogenital effects include impotence.

It is important for healthcare providers to monitor patients for these adverse reactions and manage them appropriately to ensure patient safety and treatment efficacy.

Drug Interactions

The concomitant use of certain medications with chlorothiazide sodium may lead to significant drug interactions, which can affect therapeutic outcomes and safety.

Pharmacodynamic Interactions:

• Alcohol, Barbiturates, and Narcotics: The combination of chlorothiazide sodium with these substances may potentiate orthostatic hypotension. Patients should be monitored for signs of hypotension and advised to use caution when standing up.

• Antidiabetic Drugs (Oral Agents and Insulin): Dosage adjustments of antidiabetic medications may be necessary when used alongside chlorothiazide sodium. Close monitoring of blood glucose levels is recommended to ensure effective glycemic control.

• Other Antihypertensive Drugs: The use of chlorothiazide sodium with other antihypertensive agents may result in an additive effect or potentiation of blood pressure-lowering effects. 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.

• Pressor Amines (e.g., Norepinephrine): There may be a decreased response to pressor amines when used with chlorothiazide sodium; however, this interaction does not preclude their use. Clinical judgment should guide the use of pressor agents.

• Skeletal Muscle Relaxants (Nondepolarizing, e.g., Tubocurarine): Increased responsiveness to muscle relaxants may occur. Caution is advised when administering these agents concurrently.

Pharmacokinetic Interactions:

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

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The administration of NSAIDs may diminish the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics. Patients should be closely observed to ensure that the desired diuretic effect is achieved when these agents are used together.

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 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 for injection have not been established in pediatric patients. 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 these elderly patients respond differently from younger individuals. However, other reported clinical experiences have not identified significant differences in responses between geriatric patients and their younger counterparts.

In general, dose selection for elderly 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, and it may be beneficial to monitor renal function closely in this population.

Pregnancy

Chlorothiazide should be used during pregnancy only if clearly needed, as it is not known whether this medication can cause fetal harm when administered to pregnant patients. 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 external abnormalities of the fetus or impairments in growth and survival. However, these studies did not include comprehensive examinations for visceral and skeletal abnormalities.

It is important to note that thiazides, including chlorothiazide, cross the placental barrier and can be detected in cord blood. 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 weigh the potential risks and benefits when considering the use of chlorothiazide in pregnant patients.

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 be treated with caution, particularly those with severe renal disease. In this population, 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 or fluid status. Adjustments to dosage may be necessary based on the severity of hepatic impairment and the patient's overall clinical condition. Regular assessment of liver function tests is recommended to ensure safe and effective use of thiazides in this population.

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 care. 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

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 induce mutagenicity or 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 in the postmarketing experience include a range of events categorized by severity.

In the category of Body as a Whole, weakness has been noted. Cardiovascular events include hypotension, with specific mention of orthostatic hypotension, which may be exacerbated by the 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, such as anaphylactic reactions, necrotizing angiitis (including 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 reactions consist of muscle spasms. Nervous system and psychiatric events reported include vertigo, paresthesias, dizziness, headache, and restlessness. Skin reactions include 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 reported are 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. For reporting suspected adverse reactions, individuals are encouraged to contact Gland Pharma Limited at 864-879-9994 or the FDA at 1-800-FDA-1088 or visit www.fda.gov/medwatch.

Patient Counseling

Patients receiving diuretic therapy should be advised to monitor for signs of fluid or electrolyte imbalance, including conditions such as hyponatremia, hypochloremic alkalosis, and hypokalemia. Healthcare providers should emphasize the importance of 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 of fluid and electrolyte imbalance, which 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 crucial to note that hypokalemia may develop, especially during brisk diuresis, in the presence of severe cirrhosis, or after 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, resulting in increased ventricular irritability.

To prevent or manage hypokalemia, healthcare providers should discuss the potential use of potassium-sparing diuretics or potassium supplements, including dietary sources rich in potassium. While chloride deficits are generally mild and may not require specific treatment, patients with metabolic alkalosis, particularly those with liver or renal disease, may need chloride replacement.

Patients should be cautioned that dilutional hyponatremia can occur in edematous patients during hot weather, and that water restriction is the appropriate therapy, rather than salt administration, unless the hyponatremia is life-threatening. In cases of actual salt depletion, appropriate replacement therapy should be implemented.

Healthcare providers should inform patients that hyperuricemia or acute gout may be precipitated in some individuals receiving thiazides. For diabetic patients, dosage adjustments of insulin or oral hypoglycemic agents may be necessary, as thiazide diuretics can lead to hyperglycemia and potentially unmask latent diabetes mellitus.

The antihypertensive effects of the drug may be enhanced in patients who have undergone postsympathectomy. If progressive renal impairment is observed, healthcare providers should consider withholding or discontinuing diuretic therapy. It is important to note that thiazides can increase urinary magnesium excretion, potentially leading to hypomagnesemia, and may decrease urinary calcium excretion, causing intermittent and slight elevations of serum calcium. Marked hypercalcemia may indicate hidden hyperparathyroidism, and thiazides should be discontinued prior to parathyroid function tests.

Patients should be monitored for increases in cholesterol and triglyceride levels associated with thiazide diuretic therapy, and periodic serum electrolyte determinations should be conducted to detect possible imbalances.

When chlorothiazide sodium is used in conjunction with non-steroidal anti-inflammatory agents, close observation is necessary to ensure the desired diuretic effect is achieved. Patients should be informed of the potential for chlorothiazide to cause fetal or neonatal jaundice, thrombocytopenia, and other adverse reactions that may also occur in adults. The decision to continue nursing while on chlorothiazide sodium should be made with consideration of the drug's importance to the mother and the potential for serious adverse reactions in nursing infants.

The safety and effectiveness of chlorothiazide sodium for injection in pediatric patients have not been established. Additionally, clinical studies have not included sufficient numbers of subjects aged 65 and over to determine if they respond differently from younger patients. Therefore, dose selection for elderly patients should be approached with caution, typically starting at the lower end of the dosing range due to the increased likelihood of decreased hepatic, renal, or cardiac function, as well as concomitant diseases or other drug therapies.

Given that this drug is primarily excreted by the kidneys, the risk of toxic reactions may be heightened in patients with impaired renal function. As elderly patients are more likely to have decreased renal function, careful dose selection and monitoring of renal function are recommended.

Storage and Handling

The product is supplied as a single-dose formulation. It is essential to use the solution immediately after reconstitution to ensure efficacy. Any unused portion of the reconstituted solution must be discarded.

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. Proper adherence to these storage conditions is crucial for maintaining the integrity of the product.

Additional Clinical Information

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

FDA Insert (PDF)

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

View full prescribing information (PDF)