Chlorothiazide

Description

Chlorothiazide sodium for injection, USP is a diuretic and antihypertensive agent. The chemical designation is 6-chloro-2-H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide monosodium salt, with a molecular weight of 317.71 and a structural formula of C₇H₅ClN₃NaO₄S₂. This 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 6-chloro-2-H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, with a molecular weight of 295.72 and a structural formula of C₇H₆ClN₃O₄S₂. It appears as a white or practically white crystalline powder, exhibiting very slight solubility in water, but is readily soluble in dilute aqueous sodium hydroxide. Additionally, chlorothiazide 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. Additionally, this medication is beneficial in treating edema resulting from various forms of renal dysfunction, including nephrotic syndrome, acute glomerulonephritis, and chronic renal failure.

Limitations of Use The routine use of diuretics during normal pregnancy is not recommended, as it poses unnecessary risks to both the mother and fetus. Diuretics do not prevent the development of toxemia of pregnancy, and there is insufficient evidence to support their efficacy in treating this condition.

In cases of edema during pregnancy, which may arise from pathological causes or the physiological and mechanical effects of pregnancy, thiazides may be indicated when the edema is due to pathological causes, similar to their use in non-pregnant individuals. Dependent edema resulting from venous return restriction by the gravid uterus should be managed through non-pharmacological measures such as elevation of the lower extremities and the use of support stockings.

During normal pregnancy, hypervolemia is typically not harmful to the mother or fetus in the absence of cardiovascular disease. If edema causes significant discomfort, increased recumbency may provide relief. In rare instances where edema leads to extreme discomfort unrelieved by rest, a short course of diuretic therapy may 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 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 dosing schedule, such as administration on alternate days or three to five days per week, to minimize the risk of excessive response and 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; the medication must not be given subcutaneously or intramuscularly.

For preparation, add 18 mL of Sterile Water for Injection to the vial to create an isotonic solution for intravenous use. It is essential to never add 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, chlorothiazide tablets or oral suspension may be substituted for intravenous therapy, following the same dosage schedule as the parenteral route.

Contraindications

Use of this product is contraindicated in patients with anuria due to the potential for exacerbating renal function. Additionally, it should not be administered to 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 this medication in infants and children is limited and not generally recommended due to safety concerns.

Caution is advised when prescribing this medication to patients with severe renal disease, as thiazides may precipitate azotemia in this population. The cumulative effects of the drug can develop in individuals with impaired renal function, necessitating careful monitoring of renal parameters.

In patients with impaired hepatic function or progressive liver disease, thiazides should be used judiciously. Minor alterations in fluid and electrolyte balance may lead to serious complications, including hepatic coma.

Thiazides have the potential to enhance the effects of other antihypertensive agents, which may necessitate adjustments in therapy and close monitoring of blood pressure.

Healthcare professionals should be aware that sensitivity reactions can occur in patients regardless of their allergy or bronchial asthma history. Additionally, there have been reports of exacerbation or activation of systemic lupus erythematosus associated with thiazide use.

It is important to note that lithium should generally not be co-administered with diuretics, as this combination may lead to increased lithium levels and toxicity. Regular monitoring of lithium levels is recommended in patients receiving both therapies.

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 their seriousness and frequency.

In the body as a whole, patients may experience weakness. Cardiovascular effects include hypotension, which may present as orthostatic hypotension and can be exacerbated by the concurrent use of alcohol, barbiturates, narcotics, or antihypertensive medications.

Digestive system reactions are notable and may include pancreatitis, jaundice (specifically intrahepatic cholestatic jaundice), diarrhea, vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea, and anorexia.

Hematologic adverse reactions can be serious and include aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia.

Hypersensitivity reactions may manifest as anaphylactic reactions, necrotizing angiitis (which encompasses vasculitis and cutaneous vasculitis), respiratory distress (including pneumonitis and pulmonary edema), photosensitivity, fever, urticaria, rash, and purpura.

From a metabolic perspective, patients may experience electrolyte imbalances, hyperglycemia, glycosuria, and hyperuricemia.

Musculoskeletal effects may include muscle spasms.

In the nervous system/psychiatric domain, participants have reported vertigo, paresthesias, dizziness, headache, and restlessness.

Skin reactions can be severe, with reports of erythema multiforme (including Stevens-Johnson syndrome), exfoliative dermatitis (including toxic epidermal necrolysis), and alopecia.

Special senses may be affected, leading to transient blurred vision and xanthopsia.

Renal complications include renal failure, renal dysfunction, interstitial nephritis (as noted in the warnings), and hematuria, particularly following intravenous administration.

In the urogenital system, impotence has been reported.

It is important to note that in cases where adverse reactions are moderate or severe, the dosage of thiazide should be reduced or therapy should be withdrawn to mitigate risks.

Drug Interactions

The concomitant use of certain medications may lead to significant drug interactions that require careful consideration and monitoring.

Pharmacodynamic Interactions

• Alcohol, Barbiturates, or Narcotics: The combination of these agents 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 in conjunction with other agents. Close monitoring of blood glucose levels is recommended to ensure effective glycemic control.

• Other Antihypertensive Drugs: The use of additional 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, ACTH: Co-administration may lead to intensified electrolyte depletion, particularly hypokalemia. Regular monitoring of electrolyte levels is advised.

• Skeletal Muscle Relaxants (Nondepolarizing, e.g., Tubocurarine): There may be an increased responsiveness to nondepolarizing muscle relaxants. Monitoring of neuromuscular function is recommended during concurrent use.

Pharmacokinetic Interactions

• Lithium: The use of diuretics in patients receiving lithium is generally contraindicated due to the potential for reduced renal clearance of lithium, which increases the risk of lithium toxicity. Close monitoring of lithium levels is essential.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): In some patients, NSAIDs may diminish the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics. When chlorothiazide sodium is used with NSAIDs, patients should be closely observed to ensure the desired diuretic effect is achieved.

Testing Considerations

• Thiazides: It is recommended that thiazide diuretics 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 (chlorothiazide sodium), the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Safety and effectiveness of chlorothiazide sodium for injection in pediatric patients have not been established. Therefore, caution is advised when considering its use in this population. Further studies are necessary to determine appropriate dosing and potential outcomes in children and adolescents.

Geriatric Use

Clinical studies of chlorothiazide sodium for injection did not include a sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. However, other reported clinical 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 decreased renal function, careful consideration should be given to dose selection. Monitoring of renal function may be beneficial to ensure safety and efficacy in this population.

Pregnancy

Chlorothiazide is classified as a Pregnancy Category C medication. Reproduction studies conducted in rabbits, rats, and mice at doses of 50 mg/kg/day, 60 mg/kg/day, and 500 mg/kg/day, respectively, did not demonstrate external fetal abnormalities or impairments in growth and survival. However, these studies did not include comprehensive evaluations for visceral and skeletal abnormalities.

The potential for chlorothiazide to cause fetal harm in pregnant patients is not fully understood, as thiazides are known to cross the placental barrier and can be detected in cord blood. Therefore, chlorothiazide should only be administered during pregnancy if the potential benefits clearly outweigh the risks.

Clinicians should be aware that chlorothiazide may lead to fetal or neonatal complications, including jaundice and thrombocytopenia, as well as other adverse reactions that have been observed in adults. Careful consideration and monitoring are advised when prescribing this medication to women of childbearing potential.

Lactation

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

Renal Impairment

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

Hepatic Impairment

Patients with hepatic impairment should use thiazides with caution. In individuals with impaired hepatic function or progressive liver disease, minor alterations in fluid and electrolyte balance may precipitate hepatic coma. Therefore, careful monitoring of liver function and electrolyte levels is recommended in this population to 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 administered concurrently, hypokalemia may exacerbate the risk of cardiac arrhythmias.

Management of overdosage should focus on symptomatic and supportive measures. Healthcare professionals are advised to correct dehydration and address any electrolyte imbalances, hepatic coma, and hypotension using established medical procedures. In instances of respiratory impairment, the administration of oxygen or the provision of artificial respiration may be necessary.

The extent to which chlorothiazide sodium can be removed through hemodialysis has not been definitively established. Additionally, it is noteworthy that the intravenous LD50 of chlorothiazide in mice is reported to be 1.1 g/kg, which may provide context for understanding the potential toxicity of the drug in overdose situations.

Nonclinical Toxicology

Chlorothiazide has been evaluated for teratogenic effects in reproduction studies conducted in rabbits, rats, and mice. Doses of 50 mg/kg/day in rabbits, 60 mg/kg/day in rats, and 500 mg/kg/day in mice did not reveal any external abnormalities of the fetus or impairments in growth and survival. However, these studies did not include comprehensive examinations for visceral and skeletal abnormalities. The potential for chlorothiazide to cause fetal harm when administered to a pregnant woman is not established; 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.

In terms of nonteratogenic effects, chlorothiazide may lead to fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have been observed in adults.

Carcinogenicity studies have not been conducted with chlorothiazide. In mutagenicity assessments, chlorothiazide was not found to be 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, it did not induce mitotic nondisjunction in diploid strains of Aspergillus nidulans.

Chlorothiazide did not exhibit adverse effects on fertility in female rats at doses up to 60 mg/kg/day, nor did it affect fertility 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.

No further specific details regarding animal pharmacology and toxicology are available beyond the fertility studies mentioned.

Postmarketing Experience

Adverse reactions have been reported in the postmarketing experience, including the following:

Body as a Whole: Weakness.

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

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

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

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

Metabolic: Electrolyte imbalance, hyperglycemia, glycosuria, and hyperuricemia.

Musculoskeletal: Muscle spasm.

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

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

Special Senses: Transient blurred vision and xanthopsia.

Renal: Renal failure, renal dysfunction, interstitial nephritis, and hematuria following intravenous use.

Urogenital: Impotence.

In cases where adverse reactions are moderate or severe, it is recommended that thiazide dosage be reduced or therapy withdrawn.

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 inform patients about warning signs or symptoms of these imbalances, 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 important to note that hypokalemia may develop, particularly in patients experiencing brisk diuresis, those with 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. 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.

Patients with edematous conditions may experience dilutional hyponatremia, especially in hot weather. In such cases, healthcare providers should recommend water restriction as the appropriate therapy, rather than salt administration, unless the hyponatremia is life-threatening. In instances of actual salt depletion, appropriate replacement therapy should be emphasized.

Healthcare providers should also inform patients that hyperuricemia may occur, and acute gout may be precipitated in certain individuals receiving thiazide diuretics. 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.

If progressive renal impairment is observed, healthcare providers should consider the need to withhold or discontinue diuretic therapy. Additionally, thiazides can increase urinary excretion of magnesium, potentially resulting in hypomagnesemia, while they may decrease urinary calcium excretion and cause 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.

Patients should be made aware that thiazide diuretic therapy may be associated with increases in cholesterol and triglyceride levels. Periodic monitoring of serum electrolytes is recommended to detect possible imbalances at appropriate intervals. When chlorothiazide sodium is used concomitantly with non-steroidal anti-inflammatory agents, patients should be observed closely 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. A careful decision should be made regarding whether to discontinue nursing or the medication, considering the importance of the drug to the mother.

Storage and Handling

The lyophilized powder is supplied in single-dose vials. It should be stored at temperatures between 2°C and 25°C (36°F and 77°F). Upon reconstitution, the solution must be used immediately. Any unused portion of the reconstituted solution should be discarded.

Additional Clinical Information

Periodic determination of serum electrolytes is recommended for patients to detect potential electrolyte imbalances at appropriate intervals. This monitoring is essential for ensuring patient safety and effective management during treatment. No further information is available regarding abuse, administration routes, patient counseling, or postmarketing experiences.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Chlorothiazide as submitted by Fresenius Kabi USA, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)