Sodium Diuril

Description

Intravenous Sodium DIURIL (chlorothiazide sodium) 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. Its empirical formula is C7H5ClN3NaO4S2. The product is presented as a sterile lyophilized white powder, supplied in a vial containing chlorothiazide sodium equivalent to 0.5 g of chlorothiazide.

Inactive ingredients include 0.25 g of mannitol, with sodium hydroxide included to adjust pH. DIURIL (chlorothiazide) is also characterized as 6-chloro-2 H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, with an empirical formula of C7H6ClN3O4S2 and a molecular weight of 295.72. This compound appears as a white or practically white crystalline powder, exhibiting very slight solubility in water, but is readily soluble in dilute aqueous sodium hydroxide. It is soluble in urine to the extent of approximately 150 mg per 100 mL at pH 7.

Uses and Indications

Intravenous Sodium DIURIL is indicated as adjunctive therapy in the management of edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. Additionally, it is useful 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 inappropriate, 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, it is essential to differentiate between pathologic causes and the physiologic and mechanical effects of pregnancy. Thiazides may be indicated for treating edema due to pathologic 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 elevating the lower extremities and using support stockings.

During normal pregnancy, hypervolemia is typically not harmful to the mother or fetus in the absence of cardiovascular disease. If edema causes discomfort, increased recumbency may provide relief. In rare instances where edema leads to significant discomfort unrelieved by rest, a short course of diuretic therapy may be considered appropriate.

Dosage and Administration

Intravenous Sodium DIURIL 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.

The usual adult dosage ranges from 0.5 to 1 g, administered once or twice daily. Many patients with edema may benefit from an intermittent dosing schedule, which involves 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.

Intravenous Sodium DIURIL may be administered slowly via direct intravenous injection or through intravenous infusion. It is critical to avoid extravasation during administration; the medication must not be given subcutaneously or intramuscularly.

In cases where oral medication is feasible, therapy with DIURIL tablets or oral suspension may be substituted for intravenous administration, adhering to the same dosage schedule as the parenteral route. It is important to note that intravenous use in infants and children is limited and generally not recommended.

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 can 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 is also a reported risk of exacerbation or activation of systemic lupus erythematosus in some patients. Furthermore, lithium should generally not be co-administered with diuretics due to the potential for adverse interactions.

All patients undergoing diuretic therapy must be closely monitored for signs of fluid or electrolyte imbalance, including hyponatremia, hypochloremic alkalosis, and hypokalemia. Regular 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 common concern, especially during brisk diuresis, in patients with severe cirrhosis, or after prolonged therapy. Inadequate 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 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, potentially leading to hypomagnesemia. They may also decrease urinary calcium excretion, resulting in intermittent and slight elevations of 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 treatment.

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.

Serious adverse reactions include hematologic events such as aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia. Additionally, hypersensitivity reactions can occur, manifesting 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, are significant and warrant attention.

Common adverse reactions reported 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. Neurological symptoms such as vertigo, paresthesias, dizziness, headache, and restlessness have been noted among patients. Musculoskeletal complaints, particularly muscle spasms, and urogenital issues like impotence have also been observed.

Patients may experience metabolic disturbances, including electrolyte imbalances, hyperglycemia, glycosuria, and hyperuricemia. Visual disturbances such as transient blurred vision and xanthopsia have been reported as well.

In cases where adverse reactions are moderate or severe, it is recommended that the thiazide dosage be reduced or therapy be withdrawn. Notably, in instances of overdose, the most common signs and symptoms are those resulting from electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration due to excessive diuresis. If digitalis has been administered concurrently, hypokalemia may exacerbate cardiac arrhythmias.

Healthcare professionals should monitor patients closely for these adverse reactions and manage them appropriately.

Drug Interactions

The concomitant use of Sodium DIURIL with certain medications may lead to significant drug interactions that require careful consideration.

Pharmacodynamic Interactions

• Alcohol, Barbiturates, and Narcotics: The combination of Sodium DIURIL with these substances may potentiate orthostatic hypotension. Patients should be monitored for signs of hypotension and advised to exercise caution when standing up.

• Antihypertensive Drugs: The use of Sodium DIURIL alongside other antihypertensive agents may result in an additive effect or potentiation of blood pressure-lowering effects. Blood pressure should be closely monitored, and dosage adjustments may be necessary.

• Corticosteroids and ACTH: Co-administration may lead to intensified electrolyte depletion, particularly hypokalemia. Regular monitoring of electrolyte levels is recommended.

• Skeletal Muscle Relaxants (e.g., Tubocurarine): There is a potential for increased responsiveness to nondepolarizing skeletal muscle relaxants. Caution is advised when using these agents concurrently.

• Pressor Amines (e.g., Norepinephrine): The response to pressor amines may be decreased when used with Sodium DIURIL; however, this interaction does not preclude their use. Clinical judgment should guide the use of pressor agents.

Pharmacokinetic Interactions

• Antidiabetic Drugs (Oral Agents and Insulin): Dosage adjustments of antidiabetic medications may be required when used in conjunction with Sodium DIURIL. Blood glucose levels should be monitored closely.

• Lithium: The use of diuretics, including Sodium DIURIL, is generally contraindicated with lithium due to the potential for reduced renal clearance of lithium, increasing the risk of toxicity. It is essential to refer to the package insert for lithium preparations before co-administration.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The administration of NSAIDs may diminish the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics. Patients should be observed closely to ensure the desired diuretic effect is achieved when these agents are used together.

Laboratory Test Interactions

• 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 Sodium Diuril (chlorothiazide sodium), the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Safety and effectiveness of Intravenous Sodium DIURIL in pediatric patients have not been established. Therefore, caution is advised when considering its use in this population. Further studies are needed to determine appropriate dosing and outcomes in children and adolescents.

Geriatric Use

Clinical studies of Intravenous Sodium DIURIL 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 experiences have 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. Given that this drug is substantially excreted by the kidneys, the risk of toxic reactions may be heightened in patients with impaired renal function.

Elderly patients are more prone to have decreased renal function; therefore, careful consideration should be given to dose selection. It may be beneficial to monitor renal function in this population to ensure safety and efficacy.

Pregnancy

Chlorothiazide has been studied for teratogenic effects in animal models, with doses of 50 mg/kg/day in rabbits, 60 mg/kg/day in rats, and 500 mg/kg/day in mice revealing no external abnormalities or impairment of growth and survival of the fetus. However, these studies did not include comprehensive examinations for visceral and skeletal abnormalities. The potential for chlorothiazide to cause fetal harm in pregnant patients remains unknown, as thiazides are known to cross the placental barrier and can be detected in cord blood. Therefore, DIURIL should be administered during pregnancy only if the benefits clearly outweigh the risks.

In addition to potential teratogenic effects, chlorothiazide may lead to nonteratogenic complications such as fetal or neonatal jaundice and thrombocytopenia. These adverse reactions have been observed in adults and may also occur in the fetus or neonate. Healthcare professionals should carefully consider these risks when prescribing chlorothiazide to women of childbearing potential and during pregnancy.

Lactation

Because of the potential for serious adverse reactions in nursing infants from Intravenous Sodium DIURIL, 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 associated with 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

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 is unknown; it is noted that thiazides can cross the placental barrier and are detectable in cord blood. Therefore, DIURIL should be used during pregnancy only if clearly needed.

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 performed with chlorothiazide. In vitro studies indicate that chlorothiazide is not mutagenic, as demonstrated in the Ames microbial mutagen test using 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 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.

Postmarketing Experience

Adverse reactions reported in the postmarketing experience include a range of events categorized by severity.

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: 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 skin reactions 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: Cases of renal failure, renal dysfunction, interstitial nephritis, and hematuria (following intravenous use) have been noted.

Urogenital: Impotence has been reported.

The most frequently observed signs and symptoms are associated with electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration due to excessive diuresis. In cases where digitalis has been administered, hypokalemia may exacerbate cardiac arrhythmias.

To report suspected adverse reactions, individuals are encouraged to contact Oak Pharmaceuticals, 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.

Hypokalemia is a potential risk, especially in cases of brisk diuresis, severe cirrhosis, or prolonged therapy. It is important to communicate 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 may recommend potassium-sparing diuretics or dietary potassium supplements.

In cases of metabolic alkalosis, chloride replacement may be necessary. Patients should be made aware that dilutional hyponatremia can occur in edematous individuals during hot weather, and that the appropriate management is water restriction rather than salt administration, except in rare, life-threatening situations. Conversely, in cases of actual salt depletion, appropriate replacement therapy is essential.

Healthcare providers should inform patients that hyperuricemia may develop, or acute gout may be triggered in certain individuals receiving thiazide diuretics. For diabetic patients, dosage adjustments of insulin or oral hypoglycemic agents may be required, as thiazide diuretics can lead to hyperglycemia and potentially unmask latent diabetes mellitus.

If progressive renal impairment is observed, it may be necessary to consider withholding or discontinuing diuretic therapy. Thiazides are known to increase urinary magnesium excretion, which can result in 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 parathyroid function testing.

Patients should be informed that thiazide diuretic therapy may be associated with increases in cholesterol and triglyceride levels. Periodic monitoring of serum electrolytes is recommended to detect potential imbalances at appropriate intervals.

When Sodium DIURIL is used in conjunction with non-steroidal anti-inflammatory agents, patients should be observed closely to ensure that the desired diuretic effect is achieved. Furthermore, due to the risk of serious adverse reactions in nursing infants from intravenous Sodium DIURIL, healthcare providers should discuss with patients the need to either discontinue nursing or the medication, weighing the importance of the drug to the mother.

Storage and Handling

The product is supplied as a single-dose formulation. It is essential to use the solution immediately after reconstitution. Any unused portion of the reconstituted solution must be discarded to ensure safety and efficacy.

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 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 Sodium Diuril as submitted by Akorn. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)