Chlorothiazide

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 structural formula is represented as 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-2H-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 the extent 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 or 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 teratogenic effects, which may pose 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, it is essential to differentiate between pathologic causes and the physiological changes associated with pregnancy. Thiazides may be indicated for treating edema due to pathologic causes, similar to their use in non-pregnant patients. However, dependent edema resulting from venous return restriction by the gravid uterus should be managed through non-pharmacological measures, such as elevating the lower extremities and using support stockings. The use of diuretics to reduce intravascular volume in this context is generally illogical and unnecessary, as hypervolemia during normal pregnancy is typically not harmful to the mother or fetus in the absence of cardiovascular disease. If edema causes significant discomfort that 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. Intermittent therapy, such as administration on alternate days or three to five days per week, may be beneficial for patients with edema, as it reduces the risk of excessive response and electrolyte imbalances.

Chlorothiazide sodium for injection may be administered slowly via direct intravenous injection or through 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 oral administration is feasible, chlorothiazide tablets or oral suspension may be substituted for intravenous therapy, following the same dosage schedule as the parenteral route.

Preparation of the solution 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 prepare the isotonic solution for intravenous injection, add 18 mL of Sterile Water for Injection to the vial. It is essential 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 possible.

The reconstituted 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 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 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 patients.

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. Skin reactions such as erythema multiforme, including Stevens-Johnson syndrome, and exfoliative dermatitis, including toxic epidermal necrolysis, have also been reported. Renal complications, including renal failure, renal dysfunction, and interstitial nephritis, as well as hematuria following intravenous use, are significant concerns.

Common adverse reactions reported include weakness, hypotension (including orthostatic hypotension), and various digestive issues such as diarrhea, vomiting, nausea, and abdominal cramping. Patients may also experience sialadenitis, constipation, gastric irritation, and anorexia. Neurological effects such as vertigo, paresthesias, dizziness, headache, and restlessness have been noted, along with musculoskeletal symptoms like muscle spasm.

Metabolic disturbances, including electrolyte imbalance, hyperglycemia, glycosuria, and hyperuricemia, have been observed. Skin reactions may also include photosensitivity, fever, urticaria, rash, and purpura. Transient blurred vision and xanthopsia have been reported under special senses. Urogenital effects, such as impotence, have also been documented.

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 may lead to significant drug interactions that require careful consideration and monitoring.

Pharmacodynamic Interactions

• Alcohol, Barbiturates, and Narcotics: The combination of these substances may potentiate orthostatic hypotension. Patients should be monitored for signs of hypotension and advised to avoid activities that require alertness until they are aware of how these substances affect them.

• 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 and ACTH: These agents may lead to intensified electrolyte depletion, particularly hypokalemia. Regular monitoring of electrolyte levels is advised to prevent complications associated with electrolyte imbalances.

• Skeletal Muscle Relaxants (Nondepolarizing): There may be an increased responsiveness to nondepolarizing muscle relaxants, such as tubocurarine. Monitoring of neuromuscular function is recommended to adjust dosages accordingly.

Pharmacokinetic Interactions

• Lithium: The use of diuretics in patients receiving lithium is generally contraindicated, as diuretics can reduce renal clearance of lithium, increasing the risk of toxicity. Patients should be closely monitored for signs of lithium toxicity, and alternative therapies should be considered.

• 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 administered with NSAIDs, patients should be observed closely to ensure the desired diuretic effect is achieved.

Testing Considerations

• Thiazide Diuretics: 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 should be exercised 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 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 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 abnormalities or impairments in growth and survival of the fetus. However, these studies did not include comprehensive evaluations for visceral and skeletal abnormalities, leaving some uncertainty regarding potential teratogenic effects.

It remains unknown whether chlorothiazide can cause fetal harm when administered to pregnant patients. Notably, thiazides, including chlorothiazide, are known to cross the placental barrier and can be detected in cord blood. Therefore, chlorothiazide should be prescribed during pregnancy only if the potential benefits clearly outweigh the risks. Healthcare professionals are advised to carefully consider the necessity of this medication in pregnant patients.

Lactation

There are no specific statements regarding the use of this medication in lactating mothers or its effects on breastfed infants. Healthcare professionals should consider the absence of data when advising lactating mothers about the use of this medication.

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.

Nonclinical Toxicology

Chlorothiazide has been evaluated for teratogenic effects in reproduction studies involving 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 in the fetus or impair 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 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 have been reported voluntarily or through surveillance programs, categorized by system and listed in order of decreasing severity.

In the Body as a Whole category, weakness has been noted. Cardiovascular events include hypotension, with specific mention of orthostatic hypotension, which may be exacerbated by alcohol, barbiturates, narcotics, or antihypertensive medications.

Digestive system reactions encompass pancreatitis, jaundice (specifically intrahepatic cholestatic jaundice), diarrhea, vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea, and anorexia. Hematologic events reported include aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia.

Hypersensitivity reactions have been documented, including anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress (such as pneumonitis and pulmonary edema), photosensitivity, fever, urticaria, rash, and purpura.

Metabolic disturbances reported include electrolyte imbalance, hyperglycemia, glycosuria, and hyperuricemia. Musculoskeletal reactions consist of muscle spasms.

Nervous system and psychiatric events include vertigo, paresthesias, dizziness, headache, and restlessness. Skin reactions reported are erythema multiforme (including Stevens-Johnson syndrome), exfoliative dermatitis (including toxic epidermal necrolysis), and alopecia.

Special senses reactions include transient blurred vision and xanthopsia. Renal 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 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 the warning signs and symptoms associated with 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, water restriction is the recommended therapy, rather than salt administration, unless the hyponatremia is life-threatening. For patients with actual salt depletion, appropriate salt replacement should be emphasized as the preferred treatment.

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, it may be necessary to adjust the dosage of insulin or oral hypoglycemic agents, as thiazide diuretics can lead to hyperglycemia and potentially unmask latent diabetes mellitus.

In cases where progressive renal impairment is observed, healthcare providers should consider the possibility of withholding or discontinuing diuretic therapy. Thiazides are known to increase urinary excretion of magnesium, which may result in hypomagnesemia, and 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 could indicate hidden hyperparathyroidism, and thiazides should be discontinued prior to conducting tests for parathyroid function.

Patients should be advised that thiazide diuretic therapy may be associated with increases in cholesterol and triglyceride levels. Regular monitoring of serum electrolytes is recommended to detect any potential electrolyte imbalances, and patients should be encouraged to report any adverse reactions, including weakness, hypotension, gastrointestinal disturbances, or signs of hypersensitivity.

Storage and Handling

The lyophilized powder should be stored at temperatures between 2°C and 25°C (36°F and 77°F). It is supplied as a single dose only. 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)