Chlorothiazide sodium

Uses and Indications

Chlorothiazide sodium for injection is indicated as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. It has also been found useful in edema due to various forms of renal dysfunction, including nephrotic syndrome, acute glomerulonephritis, and chronic renal failure.

Limitations of Use

Routine use of diuretics during normal pregnancy is inappropriate and exposes both the mother and fetus to unnecessary hazards. Diuretics do not prevent the development of toxemia of pregnancy, and there is no satisfactory evidence that they are useful in its treatment. During normal pregnancy, hypervolemia is not harmful to the fetus or the mother in the absence of cardiovascular disease.

Nonteratogenic Effects

Edema during pregnancy may arise from pathologic causes or from the physiologic and mechanical consequences of pregnancy. Thiazides are indicated in pregnancy when edema is due to pathologic causes, just as they are in the absence of pregnancy. Dependent edema in pregnancy, resulting from restriction of venous return by the gravid uterus, is properly treated through elevation of the lower extremities and the use of support stockings. If such edema causes discomfort, increased recumbency will often provide relief. Rarely, this edema may cause extreme discomfort that is not relieved by rest; in these instances, a short course of diuretic therapy may provide relief and be 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 necessary to achieve the desired therapeutic effect. The usual adult dosage ranges from 500 mg to 1 g, administered once or twice daily. Many patients with edema may benefit from intermittent therapy, which involves administration on alternate days or three to five days per week, thereby reducing the risk of excessive response and electrolyte imbalances.

Intravenous administration of chlorothiazide sodium may be performed either by slow direct intravenous injection or by intravenous infusion. It is crucial to avoid extravasation; the drug should not be administered 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, following the same dosage schedule as for the parenteral route.

For preparation, 18 mL of Sterile Water for Injection should be added to the vial to create an isotonic solution for intravenous use. It is essential to never add less than 18 mL. Upon reconstitution with 18 mL of Sterile Water, the final concentration of chlorothiazide sodium is 28 mg/mL. The reconstituted solution should be clear and free from visible particles. Parenteral drug products must be visually inspected for particulate matter and discoloration prior to use whenever possible.

Due to the absence of preservatives in chlorothiazide sodium for injection, a fresh solution should be prepared immediately before each administration, and any unused portion should be discarded. The solution is compatible with dextrose or sodium chloride solutions for intravenous infusion; however, simultaneous administration with whole blood or its derivatives should be avoided.

Contraindications

Use of this product is contraindicated in patients with anuria. Additionally, it is contraindicated in individuals with hypersensitivity to any component of this product or to other sulfonamide-derived drugs.

Warnings and Precautions

Intravenous use of thiazide diuretics, including Chlorothiazide Sodium, is limited in infants and children and is not generally recommended. Caution is advised when administering these medications to patients with severe renal disease, as thiazides may precipitate azotemia and cumulative effects can develop in those with impaired renal function. Additionally, thiazides should be used cautiously in patients with impaired hepatic function or progressive liver disease, as even minor alterations in fluid and electrolyte balance may lead to hepatic coma.

Serious Warnings

• Thiazides may enhance the effects of other antihypertensive drugs.

• Sensitivity reactions can occur in patients with or without a history of allergy or bronchial asthma.

• There is a reported possibility of exacerbation or activation of systemic lupus erythematosus.

• Lithium should generally not be administered with diuretics.

General Precautions

All patients receiving diuretic therapy should be monitored for signs of fluid or electrolyte imbalance, including:

• Hyponatremia

• Hypochloremic alkalosis

• Hypokalemia

Serum and urine electrolyte determinations are particularly important for patients who are vomiting excessively or receiving parenteral fluids. Warning signs of fluid and electrolyte imbalance may include:

• Dryness of mouth

• Thirst

• Weakness

• Lethargy

• Drowsiness

• Restlessness

• Confusion

• Seizures

• Muscle pains or cramps

• Muscular fatigue

• Hypotension

• Oliguria

• Tachycardia

• Gastrointestinal disturbances such as nausea and vomiting

Hypokalemia may develop, especially with brisk diuresis, severe cirrhosis, or prolonged therapy. It can lead to cardiac arrhythmias and may sensitize the heart to the toxic effects of digitalis. Hypokalemia can be managed with potassium-sparing diuretics or potassium-rich foods.

Chloride deficits are generally mild but may require replacement in cases of metabolic alkalosis. Dilutional hyponatremia may occur in edematous patients during hot weather; water restriction is the preferred therapy, except in life-threatening situations. Hyperuricemia and acute gout may be precipitated in some patients receiving thiazides.

In diabetic patients, dosage adjustments of insulin or oral hypoglycemic agents may be necessary, as hyperglycemia can occur, potentially revealing latent diabetes mellitus. The antihypertensive effects of thiazides may be enhanced in postsympathectomy patients. If progressive renal impairment is observed, consideration should be given to withholding or discontinuing diuretic therapy.

Thiazides can increase urinary excretion of magnesium, leading to hypomagnesemia, and may decrease urinary calcium excretion. They can cause slight elevations in serum calcium, which may indicate hidden hyperparathyroidism; thiazides should be discontinued before parathyroid function tests. Increases in cholesterol and triglyceride levels may also be associated with thiazide therapy.

Laboratory Tests

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

Side Effects

Patients receiving Chlorothiazide Sodium may experience a range of adverse reactions, which can be categorized by seriousness and frequency.

Serious Adverse Reactions

• Hematologic: Aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia.

• Hypersensitivity: Anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress including pneumonitis and pulmonary edema.

• Renal: Renal failure, renal dysfunction, interstitial nephritis; hematuria (following intravenous use).

Common Adverse Reactions

• Body as a Whole: Weakness.

• Cardiovascular: Hypotension including orthostatic hypotension (may be aggravated by alcohol, barbiturates, narcotics, or antihypertensive drugs).

• Digestive: Pancreatitis, jaundice (intrahepatic cholestatic jaundice), diarrhea, vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea, anorexia.

• Metabolic: Electrolyte imbalance (see PRECAUTIONS), hyperglycemia, glycosuria, hyperuricemia.

• Musculoskeletal: Muscle spasm.

• Nervous System/Psychiatric: Vertigo, paresthesias, dizziness, headache, restlessness.

• Skin: Erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis, alopecia.

• Special Senses: Transient blurred vision, xanthopsia.

• Urogenital: Impotence.

Additional Notes

• Whenever adverse reactions are moderate or severe, thiazide dosage should be reduced or therapy withdrawn.

• The most common signs and symptoms observed in overdosage are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias.

• Patients should be monitored for evidence of fluid or electrolyte imbalance, including signs of hyponatremia, hypochloremic alkalosis, and hypokalemia. Warning signs include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

• In diabetic patients, dosage adjustments of insulin or oral hypoglycemic agents may be required, as hyperglycemia may occur with thiazide diuretics.

Drug Interactions

When chlorothiazide sodium or Sodium Diuril is administered, several drug interactions may occur, which can be categorized into pharmacodynamic and pharmacokinetic interactions.

Pharmacodynamic Interactions

• Alcohol, Barbiturates, or Narcotics: The concomitant use of these substances may potentiate orthostatic hypotension.

• Antidiabetic Drugs (Oral Agents and Insulin): Dosage adjustments of antidiabetic medications may be necessary when used alongside thiazide diuretics.

• Other Antihypertensive Drugs: There may be an additive effect or potentiation of antihypertensive effects when used with other antihypertensive agents.

• Corticosteroids and ACTH: These agents can lead to intensified electrolyte depletion, particularly hypokalemia.

• Pressor Amines (e.g., Norepinephrine): There is a potential for decreased response to pressor amines, although this does not preclude their use.

• Skeletal Muscle Relaxants (Nondepolarizing, e.g., Tubocurarine): Increased responsiveness to muscle relaxants may occur.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The administration of NSAIDs may reduce the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics. Close monitoring is advised to ensure the desired diuretic effect is achieved.

Pharmacokinetic Interactions

• Lithium: The use of diuretics, including thiazides, is generally not recommended with lithium due to the reduction in renal clearance of lithium, which increases the risk of lithium toxicity. It is advised to refer to the package insert for lithium preparations before concurrent use.

Drug/Laboratory Test Interactions

• Parathyroid Function Tests: Thiazides should be discontinued prior to conducting tests for parathyroid function to avoid interference with test results.

These interactions highlight the importance of careful monitoring and potential dosage adjustments when thiazide diuretics are used in conjunction with other medications.

Pediatric Use

Safety and effectiveness of chlorothiazide sodium, available in forms such as injection, powder, and lyophilized solution, have not been established in pediatric patients. This includes both intravenous and other formulations of chlorothiazide sodium. No specific age ranges or dosing recommendations are provided due to the lack of established safety and efficacy in this population.

Geriatric Use

Clinical studies of chlorothiazide sodium and intravenous Sodium Diuril did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients. However, other reported clinical experience has not identified significant differences in responses between elderly and younger patients.

In general, dose selection for elderly patients should be approached with caution, typically starting at the low end of the dosing range. This cautious approach reflects the increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies in this population.

Chlorothiazide sodium is substantially excreted by the kidneys, and the risk of toxic reactions may be heightened 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, and it may be beneficial to monitor renal function regularly.

Pregnancy

Chlorothiazide is classified as a Pregnancy Category C medication. 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 have shown no external abnormalities of the fetus or impairment of growth and survival. However, these studies did not include comprehensive examinations for visceral and skeletal abnormalities. Therefore, it remains uncertain whether chlorothiazide can cause fetal harm when administered to pregnant patients. Notably, thiazides are known to cross the placental barrier and can be detected in cord blood.

Chlorothiazide should only be used during pregnancy if clearly needed. Potential nonteratogenic effects include the risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have been observed in adults. Healthcare providers are advised to weigh the benefits against the risks when considering the use of chlorothiazide in pregnant patients.

Lactation

Due to the potential for serious adverse reactions in breastfed infants, lactating mothers using chlorothiazide sodium, including its forms such as injection, powder, and lyophilized solution, should carefully consider whether to discontinue breastfeeding or to discontinue the medication. This decision should take into account the importance of the drug to the mother’s health.

Healthcare providers are advised to discuss the risks and benefits with lactating mothers, emphasizing the need for close monitoring of breastfed infants for any adverse effects if the medication is continued.

Renal Impairment

In patients with renal impairment, caution is advised when administering Chlorothiazide Sodium and its formulations, including injection, powder, and lyophilized forms. The use of thiazide diuretics in this population may precipitate azotemia, particularly in those with severe renal disease.

It is important to note that cumulative effects of the drug can develop in patients with impaired renal function, necessitating careful monitoring of renal status and potential adjustments in dosing. Regular assessment of kidney function is recommended to mitigate risks associated with the use of this medication in individuals with compromised renal capacity.

Hepatic Impairment

Patients with hepatic impairment should use thiazides, such as Chlorothiazide Sodium, with caution. Minor alterations in fluid and electrolyte balance in these patients may precipitate hepatic coma. There are no specific dosage adjustments or monitoring parameters provided for patients with hepatic impairment; however, close monitoring of fluid and electrolyte status is recommended to prevent complications.

Overdosage

In cases of overdosage with chlorothiazide sodium, the most common signs and symptoms are primarily due to electrolyte depletion, including hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis. If digitalis has been administered concurrently, hypokalemia may exacerbate the risk of cardiac arrhythmias.

Management of overdosage should involve symptomatic and supportive measures. It is essential to correct dehydration and any electrolyte imbalances, as well as to address 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 effectiveness of hemodialysis in removing chlorothiazide sodium has not been established. The intravenous LD50 of chlorothiazide in mice is reported to be 1.1 g/kg, which may provide a reference point for assessing the severity of an overdose. Continuous monitoring of the patient's condition is recommended to ensure appropriate interventions are implemented.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

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 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.

Teratogenic Effects

Reproduction studies involving chlorothiazide at doses of 50 mg/kg/day in rabbits, 60 mg/kg/day in rats, and 500 mg/kg/day in mice revealed no external abnormalities of the fetus or impairment of 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; 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 needed.

Nonteratogenic Effects

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

Storage and Handling

Chlorothiazide Sodium is supplied in the following forms: Injection, Powder, and Lyophilized for Solution. The lyophilized powder should be stored at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15° and 30°C (59° and 86°F) as per USP Controlled Room Temperature guidelines.

For all forms, the product is intended for single-dose use only. The solution must be used immediately after reconstitution, and any unused portion of the reconstituted solution should be discarded.

The product is sterile, nonpyrogenic, and preservative-free. Additionally, the container closure is not made with natural rubber latex.