General Administration Information
For storage information, see the specific product information within the How Supplied section.
-May administer in the morning to prevent disruption of sleep cycle.
-To minimize GI irritation, may administer with food or milk.
-For patients with difficulty swallowing, the tablets may be crushed and mixed with fluid or the oral suspension may be used.
Oral Liquid Formulations
-Oral suspension: Shake well before administering. Measure dosage with calibrated measuring device.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration.
-Reconstitution: Add 18 ml of sterile water for injection to the vial to form an isotonic solution for IV injection with a final concentration of 28 mg/ml.
-May be given by slow IV injection or by IV infusion.
-For single dose only. Contains no preservative; prepare a fresh solution immediately prior to use. Discard unused portion of the reconstituted solution.
-Compatible with dextrose or sodium chloride IV solutions. Avoid simultaneous administration with whole blood or its derivatives.
-Extravasation must be strictly avoided. Do not give by subcutaneous or intramuscular injection.
Adverse GI effects associated with chlorothiazide include abdominal pain, abdominal cramping, anorexia, constipation, diarrhea, gastric irritation (dyspepsia), nausea, vomiting, sialadenitis, and pancreatitis. Pancreatitis occurs rarely with thiazide diuretics; clinical manifestations frequently include abdominal pain, abdominal distention, vomiting, and low-grade fever. Pancreatitis can occur within 2 weeks of initiation of therapy or after several months of therapy. If signs and/or symptoms suggestive of pancreatitis develop in a patient receiving chlorothiazide, discontinue drug therapy.
Adverse central nervous system effects and whole body effects reported with chlorothiazide therapy may also be associated with fluid or electrolyte imbalance and include weakness, vertigo, paresthesias, dizziness, headache, restlessness, and muscle cramps.
Hypokalemia is one of the most common adverse effects associated with thiazide diuretic therapy, such as chlorothiazide, and can lead to cardiac arrhythmias. Patients receiving chlorothiazide may require supplemental potassium. Hypochloremia and metabolic alkalosis can be associated with hypokalemia during thiazide diuretic therapy; it is particularly likely to occur in patients with other losses of potassium and/or chloride such as through severe vomiting, diarrhea, excessive sweating, GI drainage, paracentesis, or potassium-losing renal diseases. Although any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be required in the treatment of metabolic alkalosis.
In addition to hypokalemia and hypochloremic alkalosis, thiazide diuretics can result in other fluid and electrolyte imbalances. Polyuria and hypovolemia, including symptoms of orthostatic hypotension, dizziness and/or syncope can occur during thiazide diuretic therapy. Patients receiving thiazide diuretics may also develop hypercalcemia, hypomagnesemia, or hyponatremia. Hypercalcemia may occur secondary to decreased urinary calcium excretion. The development of marked hypercalcemia may be evidence of hidden hyperparathyroidism. If hypercalcemia occurs, discontinue chlorothiazide therapy before carrying out tests for parathyroid function. Hypomagnesemia may develop secondary to increased urinary magnesium excretion. Patients receiving chlorothiazide can develop a dilutional hyponatremia, but it usually is asymptomatic and moderate. Withdrawal of the drug, fluid restriction, and potassium or magnesium supplementation typically will return the serum sodium concentration to normal, but severe hyponatremia can occur. Monitor patients receiving thiazide therapy for signs and symptoms of potential fluid and electrolyte disturbances including dizziness, fatigue, headache, lassitude, mental confusion, muscle cramps, paresthesias, restlessness, sinus tachycardia, thirst, vertigo, and/or weakness/asthenia.
Thiazide diuretics, such as chlorothiazide, have been associated with azotemia and interstitial nephritis, potentially resulting in reversible renal dysfunction or renal failure (unspecified). These effects have occurred mainly in patients with preexisting renal disease. Consider discontinuing chlorothiazide in patients who develop progressive renal impairment.
Chlorothiazide can produce glycosuria and hyperglycemia in diabetic patients, possibly due to potassium depletion. Assess blood and/or urine glucose concentrations more carefully in diabetic patients receiving chlorothiazide.
Hyperuricemia has been reported in patients receiving chlorothiazide. In predisposed individuals, acute gout may be precipitated.
Hypercholesterolemia and/or hypertriglyceridemia have been associated with thiazide diuretic therapy. Data from long-term studies in adults suggest diuretic-induced cholesterol changes are not clinically significant and do not contribute to coronary heart disease risk; the impact in pediatric patients has not been clearly defined. After approximately one year of treatment, total serum cholesterol concentrations in adults subside to baseline or lower, suggesting chlorothiazide-induced cholesterol changes are not a significant coronary heart disease risk factor.
Intrahepatic cholestatic jaundice has been reported during chlorothiazide therapy. Caution should be used when chlorothiazide is administered to infants with jaundice due to the risk of hyperbilirubinemia; chlorothiazide has been shown to displace bilirubin from albumin binding sites.
Rare blood dyscrasias including agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, and thrombocytopenia have been reported during therapy with chlorothiazide.
Ocular effects reported during therapy with chlorothiazide include transient blurred vision and xanthopsia.
Adverse dermatologic reactions associated with thiazide diuretics are uncommon, but may occur in some patients. Reactions reported with chlorothiazide include alopecia, erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis (TEN), photosensitivity, polyarteritis nodosa, purpura, rash (unspecified), and urticaria. Hypersensitivity or anaphylactoid reactions including necrotizing angiitis (vasculitis and cutaneous vasculitis), and respiratory distress including pneumonitis and pulmonary edema, have been reported during chlorothiazide therapy.
Extravasation must be strictly avoided during IV administration of chlorothiazide to prevent tissue necrosis. Do not give by intramuscular (IM) or subcutaneous (SC) administration.
Thiazide diuretics are contraindicated in patients with known thiazide diuretic hypersensitivity. According to the manufacturer, chlorothiazide is specifically contraindicated in patients with sulfonamide hypersensitivity. Although thiazide diuretics are sulfonamide derivatives, sulfonamide cross-sensitivity has been rarely documented. Until further data are available, use thiazide diuretics with caution in patients with sulfonamide hypersensitivity. Thiazide diuretics do not contain the N4-aromatic amine or the N1-substituent that are present in sulfonamide antibiotics. Non-arylamine sulfonamide derivatives, such as thiazide diuretics, have been proposed to have a lower risk of allergic reactions in patients with sulfonamide allergy, presumably due to lack of an arylamine group at the N4 position (a proposed structural site of action for sulfonamide allergy).
Chlorothiazide is contraindicated in patients with anuria and should not be used in patients with renal failure; thiazide diuretics are ineffective when the creatinine clearance is less than 30 ml/minute. Use chlorothiazide cautiously in patients with renal disease resulting in severe renal impairment because the drug decreases the glomerular filtration rate and may precipitate azotemia in these patients. Chlorothiazide is eliminated renally; accumulation may occur if the drug is used in patients with renal impairment.
Use chlorothiazide with caution in patients with jaundice, particularly neonates; chlorothiazide can displace bilirubin from albumin-binding sites. In addition, use chlorothiazide with caution in patients with hepatic disease; minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
Patients with pre-existing significant hyponatremia, hyperkalemia, hypokalemia, hypochloremic metabolic alkalosis, hypomagnesemia, or hypercalcemia should have their electrolyte imbalance and/or acid/base imbalance corrected before chlorothiazide is initiated. Initiation of thiazide diuretics in patients with electrolyte imbalances such as hypokalemia can produce life-threatening situations such as cardiac arrhythmias. Thiazide diuretics may induce metabolic alkalosis associated with hypokalemia and hypochloremia; this acid/base imbalance is effectively treated with potassium chloride replacement. Thiazide diuretics have been shown to increase the urinary excretion of magnesium and decrease urinary calcium excretion. Thiazides may also worsen dilutional hyponatremia. Monitor patients receiving diuretics for clinical signs of acid/base, fluid, or electrolyte imbalances.
Patients with pre-existing hypovolemia or hypotension should have their condition corrected before diuretics are initiated. Orthostatic hypotension may occur during treatment with chlorothiazide. Orthostatic hypotension can be exacerbated by concurrent use of alcohol, narcotics, or antihypertensive drugs. Excessive hypotension during thiazide diuretic therapy can result in syncope. In addition, the antihypertensive effects of thiazides may be enhanced in other patients predisposed for orthostatic hypotension, including the post-sympathectomy patient.
Hyperglycemia or impaired glucose tolerance can occur during therapy with thiazide diuretics. In patients with diabetes mellitus who are receiving chlorothiazide, monitor blood glucose concentrations. Adjustment of insulin and/or oral hypoglycemic agents may be required.
Administer chlorothiazide cautiously to patients with gout or hyperuricemia; thiazide diuretics can reduce the clearance of uric acid.
Thiazide diuretics, such as chlorothiazide, have been reported to activate or exacerbate systemic lupus erythematosus (SLE).
Extravasation must be strictly avoided during IV administration of chlorothiazide to prevent tissue necrosis. Do not give by intramuscular administration or subcutaneous administration.
Photosensitivity has been reported with thiazide diuretics, such as chlorothiazide. Patients should avoid excessive sunlight (UV) exposure and therapy should be discontinued if phototoxicity occurs.
Description: Chlorothiazide is an oral and parenteral thiazide diuretic. Chlorothiazide is indicated for the treatment of hypertension and as adjunctive therapy for edema associated with congestive heart failure, hepatic cirrhosis, corticosteroids, or renal dysfunction. Off-label uses in pediatric patients include the management of chronic lung disease, hypercalciuria, hypoglycemia due to hyperinsulinism, and diabetes insipidus. The IV preparation should be used only in patients who are unable to take oral medication. At maximal therapeutic dosage, thiazide diuretics are moderately potent diuretics and are approximately equal in diuretic efficacy. Chlorothiazide oral formulations are FDA-approved in pediatric patients as young as neonates; the IV formulation is not FDA approved in pediatric patients.
For the treatment of hypertension:
Neonates and Infants younger than 6 months: 10 to 20 mg/kg/dose PO twice daily is a commonly used dosage range. FDA-approved labeling recommends 10 to 30 mg/kg/day PO given in 1 to 2 divided doses.
Infants and Children 6 months to younger than 2 years: 10 to 20 mg/kg/day PO given in 1 to 2 divided doses (Max: 375 mg/day) is recommended by FDA-approved labeling. Some authors have suggested doses as high as 20 mg/kg/dose PO given every 8 to 12 hours may be required.
Children 2 to 12 years: 10 to 20 mg/kg/day PO given in 1 to 2 divided doses (Max: 1,000 mg/day PO) is recommended by FDA-approved labeling. Some authors have suggested doses as high as 20 mg/kg/dose PO given every 8 to 12 hours may be required.
Adolescents: 500 to 1,000 mg/day PO given in 1 to 2 divided doses (Max: 2,000 mg/day).
For the adjunctive treatment of edema:
(including edema due to congestive heart failure, hepatic cirrhosis (ascites), corticosteroid therapy, or renal dysfunction such as nephrotic syndrome, acute glomerulonephritis, and chronic renal failure)
Neonates and Infants < 6 months: 10 to 20 mg/kg/dose PO twice daily is a commonly used dosage range. The manufacturer recommends 10 to 30 mg/kg/day PO given in 1 to 2 divided doses.
Infants >= 6 months and Children < 2 years: 10 to 20 mg/kg/day PO given in 1 to 2 divided doses (Max: 375 mg/day) is recommended by the manufacturer. Some authors have suggested doses as high as 20 mg/kg/dose PO given every 8 to 12 hours may be needed for some pediatric patients.
Children 2 to 12 years: 10 to 20 mg/kg/day PO given in 1 to 2 divided doses (Max: 1,000 mg/day PO) is recommended by the manufacturer. Some authors have suggested doses as high as 20 mg/kg/dose PO given every 8 to 12 hours may be needed for some for pediatric patients.
Adolescents: 500 to 1,000 mg/day PO given in 1 to 2 divided doses. Many patients with edema respond to intermittent therapy (e.g., every other day or 3 to 5 days each week). With an intermittent schedule, excessive diuresis and associated electrolyte imbalances are less likely to occur.
Infants and Children: Safety and efficacy have not been established; limited data available. 5 to 10 mg/kg/dose IV every 12 hours has been recommended for children with decompensated heart failure. Reserve IV chlorothiazide for patients unable to take oral medication or for emergency situations.
Adolescents: Safety and efficacy have not been established; limited data available. 5 to 10 mg/kg/dose IV every 12 hours has been recommended for children with decompensated heart failure. The usual adult dosage is 500 to 1,000 mg IV given once or twice daily (Max: 2,000 mg/day). Reserve IV chlorothiazide for patients unable to take oral medication or for emergency situations.
For the management of chronic lung disease (CLD)*:
Neonates and Infants: 20 mg/kg/dose PO twice daily has been used in preterm and term neonates and infants in combination with spironolactone (1.5 to 2 mg/kg/dose PO twice daily). Pulmonary function, airway resistance, and compliance improved, but the duration of supplemental oxygen when compared to placebo was not reduced.
For the treatment of hypercalciuria*:
Neonates, Infants, and Children: 20 mg/kg/day PO given in 1 to 2 divided doses has been used for idiopathic hypercalciuria in infants and children and for the treatment and prevention of renal calcifications in neonates receiving furosemide. In 1 case series of 2 infants with idiopathic hypercalciuria, doses as high as 40 to 50 mg/kg/day divided twice daily were required. Chlorothiazide once daily, in addition to dietary restrictions (salt restriction plus limiting whole milk intake to 8 ounces per day), was effective in reducing the urine calcium/urine creatinine ratio to below baseline (less than 0.21) in all patients in a small retrospective study in children (n = 14, 3 to 10 years of age). Serum calcium concentrations were similar before and during treatment. After treatment discontinuation, the urine calcium/urine creatinine ratio increased back to at least 0.21 in 8 of the children.
For the treatment of secondary hypoglycemia* due to congenital hyperinsulinemia*:
Neonates and Infants: 7 to 10 mg/kg/day PO divided twice daily in combination with diazoxide (5 to 20 mg/kg/day PO divided into 3 daily doses). Chlorothiazide provides additive hyperglycemic effects and helps minimize fluid retention associated with diazoxide.
For the management of central diabetes insipidus*:
Neonates and Infants: An initial dose of 5 mg/kg/dose PO twice daily adjusted to a urine osmolality of 100 to 150 mOsm/L in combination with a diet of breast milk or a low renal solute load formula has been recommended.
Maximum Dosage Limits:
30 mg/kg/day PO is recommended by the manufacturer; up to 40 mg/kg/day PO has been used off-label for chronic lung disease. Safety and efficacy have not been established for IV formulation.
1 to 5 months: 30 mg/kg/day PO is recommended by the manufacturer; however, up to 40 mg/kg/day PO has been used off-label. Safety and efficacy of IV formulation have not been established; doses up to 20 mg/kg/day IV have been used off-label.
6 to 11 months: 20 mg/kg/day PO is recommended by the manufacturer; however, up to 40 mg/kg/day PO has been used off-label. Safety and efficacy of IV formulation have not been established; doses up to 20 mg/kg/day IV have been used off-label.
1 year: 20 mg/kg/day PO (Max: 375 mg/day) is recommended by the manufacturer; however, up to 40 mg/kg/day has been used off-label. Safety and efficacy of IV chlorothiazide have not been established; doses up to 20 mg/kg/day IV have been used off-label.
2 to 12 years: 20 mg/kg/day PO (Max: 1,000 mg/day) is recommended by the manufacturer; however, up to 40 mg/kg/day has been used off-label. Safety and efficacy of IV chlorothiazide have not been established; doses up to 20 mg/kg/day IV have been used off-label.
2,000 mg/day PO for hypertension or 1,000 mg/day PO for edema. Safety and efficacy of IV chlorothiazide have not been established; doses up to 20 mg/kg/day IV (Max: 2,000 mg/day IV) have been used off-label.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed. Use diuretics with caution in patients with hepatic disease since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
Patients with Renal Impairment Dosing
CrCl >= 30 ml/min/1.73m2: No dosage adjustment needed.
CrCl < 30 ml/min/1.73m2: Do not use, thiazide diuretics are generally not effective in this setting.
Chlorothiazide is not recommended in patients with CrCl < 30 ml/min/1.73m2; thiazide diuretics are generally not effective in this setting. The degree to which chlorothiazide is removed by hemodialysis is unknown.
Monograph content under development
Mechanism of Action: Thiazide diuretics increase the excretion of water by inhibiting the reabsorption of sodium and chloride ions at the distal renal tubule. The natriuretic effects are accompanied by a secondary loss of potassium and bicarbonate which can cause a mild hypokalemic, hypochloremic, metabolic alkalosis. Thiazides also decrease the elimination of calcium and uric acid. Thiazides diuretics usually do not affect normal blood pressure. When chronically administered, diuretics decrease peripheral vascular resistance. The exact mechanism responsible for the lowered peripheral resistance is not known; however, excretion of urinary sodium by the kidneys is required to achieve blood pressure reduction. Initially, diuretics lower blood pressure by decreasing cardiac output, plasma volume and extracellular fluid volume. Cardiac output eventually returns to normal, plasma and extracellular fluid values return to slightly less than normal, but peripheral vascular resistance is reduced, resulting in lower blood pressure. Thiazide diuretics also decrease the glomerular filtration rate, which contributes to the drug's lower efficacy in patients with renal impairment. The changes in plasma volume induce an elevation in plasma renin activity and aldosterone secretion, which contributes to the potassium losses associated with thiazide diuretics. In general, diuretics can worsen glucose tolerance and lipid abnormalities.
Pharmacokinetics: Chlorothiazide is administered intravenously or orally. The drug is not metabolized but is rapidly eliminated by the kidneys. In general, the plasma half-life of chlorothiazide is 45-120 minutes. Chlorothiazide does not cross the blood-brain barrier. Data suggest that chlorothiazide can displace bilirubin from albumin binding sites.
Affected cytochrome P450 isoenzymes: none
After oral administration, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6-12 hours. Chlorothiazide absorption from the GI tract is saturable. A single 250 or 500 mg dose achieves similar systemic absorption after oral administration. Absorption of chlorothiazide is approximately doubled when taken with food. After oral doses, 10-15% of the dose is excreted unchanged in the urine.
After IV administration, the onset of the diuretic action occurs in 15 minutes and the peak effect occurs at 30 minutes. Approximately 96% of an IV dose is excreted unchanged in the urine within 23 hours.