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. Its empirical formula is C7H5ClN3NaO4S2.

The 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. 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.

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. This approach can help minimize the risk of excessive response and subsequent 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. Intravenous use in infants and children is limited and generally not recommended.

When transitioning from intravenous to oral therapy, chlorothiazide tablets or oral suspension may be substituted, maintaining the same dosage schedule as for the parenteral route.

To prepare the solution for intravenous injection, add 18 mL of Sterile Water for Injection to the vial. It is essential to use no less than 18 mL to ensure the formation of an isotonic solution. Upon reconstitution with 18 mL of Sterile Water, the final concentration of Chlorothiazide Sodium for Injection, USP will be 28 mg per mL.

Contraindications

Use of this product is contraindicated in patients with anuria due to the inability to excrete the drug, which may lead to accumulation and toxicity. Additionally, hypersensitivity to any component of this product or to other sulfonamide-derived drugs is a contraindication, as it may result in 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 receiving diuretic therapy must be 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 recommended. While chloride deficits are typically mild and may not require specific 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, which may lead to hypomagnesemia. They may also decrease urinary calcium excretion, potentially causing intermittent and slight elevations in 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 determination of serum electrolytes is recommended to detect possible electrolyte imbalances at appropriate intervals during thiazide therapy.

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 may manifest as anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), and respiratory distress, which can include pneumonitis and pulmonary edema. Skin reactions can be severe, with reports of erythema multiforme, including Stevens-Johnson syndrome, and exfoliative dermatitis, including toxic epidermal necrolysis. Renal complications such as renal failure, renal dysfunction, and interstitial nephritis have also been noted, with hematuria reported following intravenous use.

Common adverse reactions include weakness, hypotension (including orthostatic hypotension), and various digestive issues such as diarrhea, vomiting, nausea, anorexia, cramping, constipation, and gastric irritation. 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 reported. Skin reactions may also include photosensitivity, fever, urticaria, rash, and purpura. Transient blurred vision and xanthopsia have been noted among special senses reactions, 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 with chlorothiazide sodium may lead to significant drug interactions, which can affect therapeutic outcomes and patient 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 engaging in activities that require alertness.

• Antidiabetic Drugs (Oral Agents and Insulin): The use of chlorothiazide sodium may necessitate dosage adjustments of antidiabetic medications to maintain glycemic control. Regular monitoring of blood glucose levels is recommended.

• Other Antihypertensive Drugs: The administration of chlorothiazide sodium alongside other antihypertensive agents may result in an additive effect or potentiation of blood pressure-lowering effects. Blood pressure should be monitored closely to avoid excessive hypotension.

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

• 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 in patients receiving chlorothiazide sodium.

• Skeletal Muscle Relaxants (Nondepolarizing, e.g., Tubocurarine): Increased responsiveness to nondepolarizing muscle relaxants may occur. Monitoring of neuromuscular function is advised during concurrent use.

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 concomitant use 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: Thiazide diuretics, including chlorothiazide sodium, 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 potential 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 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. Therefore, it remains unclear whether chlorothiazide can cause fetal harm when administered to pregnant patients. It is important to note that thiazides, including chlorothiazide, cross the placental barrier and are detectable in cord blood.

Chlorothiazide may also lead to nonteratogenic effects such as fetal or neonatal jaundice and thrombocytopenia, along with other adverse reactions that have been observed in adults. Given these considerations, chlorothiazide should be prescribed during pregnancy only if the potential 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 consideration of dosing adjustments and close observation for 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 mitigate potential risks. Adjustments to dosage may be necessary based on the severity of hepatic impairment and the patient's overall clinical status.

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 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

Teratogenic effects associated with chlorothiazide have been classified under 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 in 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 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.

In terms of nonteratogenic effects, 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 mutagenicity assessments, chlorothiazide was found to be non-mutagenic in vitro 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 across various 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 drugs.

Digestive: 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: 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: 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: Adverse events such as 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: 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 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

Healthcare providers should advise patients to be vigilant for signs of fluid or electrolyte imbalance, including conditions such as hyponatremia, hypochloremic alkalosis, and hypokalemia. It is essential to monitor serum and urine electrolyte levels, 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, 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.

Healthcare providers should emphasize that hypokalemia can develop, particularly in cases of brisk diuresis, severe cirrhosis, or prolonged therapy. Patients should be made aware that hypokalemia may lead to cardiac arrhythmias and can sensitize the heart to the toxic effects of digitalis. To prevent or treat 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 should be informed that dilutional hyponatremia can occur in edematous individuals during hot weather, and that water restriction is the appropriate therapy, except in rare cases of life-threatening hyponatremia. Conversely, in instances of actual salt depletion, appropriate salt replacement is the preferred treatment.

Patients receiving thiazides should be made aware of the potential for hyperuricemia or the precipitation of acute gout. Diabetic patients may require dosage adjustments of insulin or oral hypoglycemic agents. Additionally, the antihypertensive effects of the medication 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 excretion of magnesium, potentially leading to hypomagnesemia, while they may also decrease urinary calcium excretion, causing intermittent slight elevations in serum calcium levels in the absence of known calcium metabolism disorders. Marked hypercalcemia may indicate hidden hyperparathyroidism, and thiazides should be discontinued prior to conducting tests for parathyroid function.

Periodic monitoring of serum electrolytes is recommended to detect possible imbalances at appropriate intervals. 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. Finally, healthcare providers should discuss the potential for serious adverse reactions in nursing infants from chlorothiazide sodium for injection, prompting a decision on whether to discontinue nursing or the medication, considering the drug's importance to the mother.

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 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 Sagent Pharmaceuticals. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)