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 an empirical formula of C7H5ClN3NaO4S2 and a molecular weight of 317.71. The 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 mannitol at 250 mg 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 at a concentration of 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 associated with normal pregnancy is 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 discomfort arises from such edema and is not alleviated by rest, a short course of diuretic therapy may be appropriate to provide relief.

Dosage and Administration

Chlorothiazide Sodium for Injection 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 subsequent electrolyte imbalances.

Chlorothiazide Sodium for Injection 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 suitable for intravenous administration. It is essential to add no less than 18 mL. Upon reconstitution with 18 mL of Sterile Water, the final concentration of intravenous chlorothiazide sodium 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, therapy with Chlorothiazide tablets or oral suspension may be substituted for intravenous therapy, adhering to the same dosage schedule as for the parenteral route.

Contraindications

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

Warnings and Precautions

Intravenous administration of thiazides in infants and children is limited and generally not recommended due to safety concerns. Caution is advised when prescribing thiazides to patients with severe renal disease, as these agents 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 medications, 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 been reports of exacerbation or activation of systemic lupus erythematosus associated with thiazide use. Furthermore, 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 levels should be assessed, particularly 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, 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 may exacerbate hypokalemia, which can 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, 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. In cases of actual salt depletion, appropriate salt replacement is indicated. 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 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 monitoring of serum electrolytes is essential to detect potential imbalances during thiazide therapy.

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 seriousness and frequency.

In clinical trials and postmarketing experiences, patients have reported serious adverse reactions, including hematologic events such as aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia. Hypersensitivity reactions have also been noted, including anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), and respiratory distress, which may manifest as pneumonitis and pulmonary edema. Additionally, skin reactions such as erythema multiforme, including Stevens-Johnson syndrome, exfoliative dermatitis, and alopecia have been documented. Renal complications, including renal failure, renal dysfunction, and interstitial nephritis, have been reported, with hematuria occurring following intravenous use.

Common adverse reactions 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, as well as nervous system and psychiatric effects, including vertigo, paresthesias, dizziness, headache, and restlessness.

Metabolic disturbances such as electrolyte imbalance, hyperglycemia, glycosuria, and hyperuricemia have been observed. In terms of special senses, transient blurred vision and xanthopsia have been reported. Urogenital effects, including impotence, have also been noted.

It is important to monitor patients closely, as moderate to severe adverse reactions may necessitate a reduction in thiazide dosage or withdrawal of therapy.

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 engaging in activities that require alertness.

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

• Other Antihypertensive Drugs: The use 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 considered if hypokalemia occurs.

• 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 this diuretic.

• Skeletal Muscle Relaxants (Nondepolarizing, e.g., Tubocurarine): Increased responsiveness to nondepolarizing muscle relaxants may occur. Caution is advised when administering these agents concurrently, and monitoring for enhanced neuromuscular blockade is recommended.

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 concurrent 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 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 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 in patients with impaired renal function. Given that elderly patients are more likely to experience decreased renal function, careful consideration should be given to dose selection. Monitoring of renal function may be beneficial in this population to mitigate potential risks associated with the use of this medication.

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. Healthcare professionals are advised to carefully evaluate the necessity of chlorothiazide in pregnant patients and to monitor for any potential adverse effects on fetal outcomes.

Lactation

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

Renal Impairment

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

Hepatic Impairment

Patients with hepatic impairment should use thiazides with caution due to the potential for minor alterations in fluid and electrolyte balance, which may precipitate hepatic coma. It is 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 remains undetermined. For reference, the intravenous LD50 of chlorothiazide in mice is reported to be 1.1 g/kg.

Nonclinical Toxicology

Chlorothiazide has been evaluated in reproduction studies involving rabbits, rats, and mice at doses of 50 mg/kg/day, 60 mg/kg/day, and 500 mg/kg/day, respectively. These studies did not reveal any external abnormalities in the fetus or impairments in growth and survival attributable to chlorothiazide. However, it is important to note that 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 uncertain, although it is known 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 conducted 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 mitotic nondisjunction in diploid strains of Aspergillus nidulans.

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

Postmarketing Experience

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 by 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: Reports of electrolyte imbalance, hyperglycemia, glycosuria, and hyperuricemia have been received.

Musculoskeletal: Muscle spasms have been reported.

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

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

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

Renal: Cases of renal failure, renal dysfunction, interstitial nephritis, and hematuria (following intravenous use) have been documented.

Urogenital: Impotence has been reported.

In instances 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 Akorn, Inc. at 1-800-932-5676 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 advised to conduct serum and urine electrolyte determinations, particularly in patients experiencing excessive vomiting or those receiving parenteral fluids.

Patients should be informed about warning signs and symptoms indicative of fluid and electrolyte imbalance. These may include dryness of the mouth, increased thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. It is important to note that hypokalemia may develop, 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 edematous conditions in hot weather may experience dilutional hyponatremia, for which water restriction is the preferred therapy, except in rare instances of life-threatening hyponatremia. In situations of actual salt depletion, appropriate salt replacement is the recommended treatment.

Healthcare providers should inform patients that hyperuricemia may occur, and acute gout may be precipitated in certain individuals receiving thiazides. For diabetic patients, dosage adjustments of insulin or oral hypoglycemic agents may be required. 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. Thiazides have been shown to increase urinary excretion of magnesium, potentially leading 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, 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, patients should be observed closely to ensure the desired diuretic effect is achieved.

Due to the potential for serious adverse reactions in nursing infants from Chlorothiazide Sodium for Injection, healthcare providers should discuss with patients the need to either discontinue nursing or the medication, weighing the importance of the drug to the mother. Clinical studies of Chlorothiazide Sodium for Injection have not included sufficient numbers of subjects aged 65 and older to determine if they respond differently than younger subjects. Therefore, dose selection for elderly patients should be approached with caution, typically starting at the lower end of the dosing range, considering the increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies.

Storage and Handling

The product is supplied as a single-dose formulation. It is essential to use the solution immediately after reconstitution to ensure optimal 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 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 Akorn. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)