HYDROCHLOROTHIAZIDE

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-Administer in the morning to prevent disruption of sleep cycle.
-For patients with difficulty swallowing, the tablets may be crushed and mixed with fluid.

Adverse gastrointestinal reactions associated with thiazides, like hydrochlorothiazide, include abdominal pain, anorexia, gastric irritation, nausea, vomiting, cramps, diarrhea, constipation, sialadenitis, and pancreatitis.

Adverse central nervous system reactions associated with thiazides, like hydrochlorothiazide, include dizziness, headache, paresthesias, restlessness, and vertigo.

As a result of the mechanism of action of hydrochlorothiazide, polyuria is expected. Monitor patients receiving hydrochlorothiazide closely for signs of electrolyte imbalance including hyponatremia, hypokalemia, hypomagnesemia, and hypochloremia. Patients should be aware of the symptoms of these disturbances (e.g., lassitude, mental confusion, fatigue, faintness, dizziness, cramps, tachycardia, headache, paresthesia, thirst, anorexia, nausea, or vomiting), and report these signs immediately. Patients receiving hydrochlorothiazide can develop a dilutional hyponatremia; it usually is asymptomatic and moderate, but severe hyponatremia can occur. Withdrawal of the drug, fluid restriction, and potassium or magnesium supplementation typically will return the serum sodium concentration to normal. In addition, thiazide diuretics may induce metabolic alkalosis associated with hypokalemia and hypochloremia; this acid/base imbalance is effectively treated with potassium chloride replacement. 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. Hypokalemia occurs in 30-50% of adults taking thiazide diuretics and can lead to cardiac arrhythmias. Hyperaldosteronism, secondary to cirrhosis or nephrosis, can predispose patients to hypokalemia when hydrochlorothiazide is administered. Low dietary-potassium intake, potassium-wasting states, or administration of potassium-wasting drugs also can predispose patients to hydrochlorothiazide-induced hypokalemia. Patients receiving hydrochlorothiazide therapy may require supplemental potassium to prevent hypokalemia or metabolic alkalosis. Thiazides also can decrease urinary calcium excretion, resulting in hypercalcemia. The development of marked hypercalcemia may be evidence of hidden hyperparathyroidism. If hypercalcemia occurs, discontinue hydrochlorothiazide therapy before carrying out tests for parathyroid function.

Complications of thiazide diuretic therapy may include intravascular volume depletion (hypovolemia), with potential for development of pre-renal azotemia. Hydrochlorothiazide reportedly has caused azotemia and interstitial nephritis, resulting in renal dysfunction and renal failure (unspecified). These effects have occurred mainly in patients with preexisting renal disease. If progressive renal impairment occurs, consider discontinuing diuretic therapy.

Hydrochlorothiazide can produce glycosuria and hyperglycemia. Latent diabetes mellitus may become manifest during thiazide therapy. Monitor blood and/or urine glucose concentrations more carefully in diabetic patients receiving hydrochlorothiazide.

Hyperuricemia has been reported in up to 40% of adult men taking thiazide diuretics, like hydrochlorothiazide, and less frequently in women ; the incidence in pediatric patients is not known. Thiazide diuretics appear to interfere with proximal tubule secretion of uric acid; because thiazides are organic acids, they compete with uric acid for binding at this site. Because thiazides reduce the clearance of uric acid, acute gout may be precipitated by thiazide diuretics in some patients. Serum uric acid concentrations return to pretreatment concentrations upon discontinuation of therapy.

Hypercholesterolemia and/or hypertriglyceridemia have been associated with thiazide diuretic therapy (e.g., hydrochlorothiazide). 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 the pediatric population 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.

Orthostatic hypotension may occur during treatment with thiazide diuretics. 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.

Thiazide diuretics, like hydrochlorothiazide, have been associated with intrahepatic cholestatic jaundice (rare). Caution should be used when hydrochlorothiazide is administered to infants at risk for jaundice; thiazide diuretics may displace bilirubin from albumin binding sites.

Agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, and thrombocytopenia have been reported with hydrochlorothiazide use ; the incidences are unknown but are thought to be low.

General adverse effects reported with hydrochlorothiazide include muscle spasm (muscle cramps), fever, and weakness.

Adverse dermatologic reactions have been reported with hydrochlorothiazide use. These reactions include purpura, photosensitivity, rash (unspecified), alopecia, urticaria, erythema multiforme including Stevens-Johnson syndrome, and exfoliative dermatitis including toxic epidermal necrolysis (TEN).

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in transient myopia and acute angle-closure glaucoma; the incidence of this reaction in pediatric patients is unknown. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. Discontinue hydrochlorothiazide as rapidly as possible and consider prompt medical or surgical treatment if the ocular hypertension remains uncontrolled. Transient blurred vision and xanthopsia have also been reported during hydrochlorothiazide therapy.

Anaphylactoid reactions and necrotizing angiitis (vasculitis and cutaneous vasculitis) have occurred with the administration of hydrochlorothiazide (incidence unknown).

Pneumonitis and pulmonary edema have been reported with the use of hydrochlorothiazide (incidence unknown).

Hydrochlorothiazide has been associated with an increased risk of non-melanoma skin cancer. An FDA Sentinel Initiative study found that increased risk was mostly for squamous cell carcinoma and in White patients taking large cumulative doses. The increased risk for the overall population was approximately 1 additional case per 16,000 patients per year. For White patients taking a cumulative dose more than 50,000 mg, the risk increased to approximately 1 additional case per 6,700 patients per year.

Thiazide diuretics are contraindicated in patients with known thiazide diuretic hypersensitivity. According to the manufacturer, hydrochlorothiazide 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 which 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). Also, patients with a history of sulfonamide hypersensitivity or penicillin hypersensitivity who receive hydrochlorothiazide may be at increased risk for the development of an idiosyncratic reaction resulting in transient myopia and acute angle-closure glaucoma. Discontinue hydrochlorothiazide promptly if this reaction occurs.

Hydrochlorothiazide is contraindicated in patients with anuria. Use hydrochlorothiazide with caution in patients with renal disease such as severe renal impairment or renal failure; the drug can precipitate azotemia in these patients. Discontinue or interrupt therapy if renal impairment worsens, as evidenced by an increase in concentrations of BUN or serum creatinine. With the exception of metolazone, thiazide diuretics are considered ineffective when the creatinine clearance is less than 30 ml/minute.

Avoid thiazides, like hydrochlorothiazide, in neonates with jaundice. Thiazide-induced hyperbilirubinemia is greater in this patient population. In addition, use hydrochlorothiazide with caution in patients with hepatic disease; minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Patients with pre-existing significant hyponatremia, hypokalemia, hypomagnesemia, and/or hypercalcemia should have their electrolyte imbalances corrected before hydrochlorothiazide is initiated. Initiation of thiazide diuretics in patients with electrolyte imbalances such as hypokalemia or hyponatremia can produce life-threatening situations such as cardiac arrhythmias, decreased blood pressure, and seizures. Hydrochlorothiazide has been shown to increase the urinary excretion of magnesium and potassium. Thiazide diuretics may induce metabolic alkalosis associated with hypokalemia and hypochloremia; this acid/base imbalance is effectively treated with potassium chloride replacement. Hydrochlorothiazide can also increase serum calcium concentrations by decreasing excretion of urinary calcium. Monitor patients receiving diuretics closely for clinical signs of fluid or electrolyte imbalance.

Patients with pre-existing hypovolemia or hypotension should have their condition corrected before diuretics are initiated. Orthostatic hypotension may occur during treatment with thiazide diuretics like hydrochlorothiazide. 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, impaired glucose tolerance, and glycosuria can occur during hydrochlorothiazide therapy. Assess blood and/or urine glucose concentrations more carefully in patients with diabetes mellitus who are receiving hydrochlorothiazide. Adjustment of insulin and/or oral hypoglycemic agents may be required.

Administer hydrochlorothiazide cautiously to patients with gout or hyperuricemia; thiazide diuretics can reduce the clearance of uric acid.

Hydrochlorothiazide has been reported to activate or exacerbate systemic lupus erythematosus (SLE).

Instruct patients taking hydrochlorothiazide to avoid excessive sunlight (UV) exposure and undergo regular skin cancer screening. Hydrochlorothiazide has been associated with an increased risk of non-melanoma skin cancer. An FDA Sentinel Initiative study found that increased risk was mostly for squamous cell carcinoma and in White patients taking large cumulative doses. The increased risk for the overall population was approximately 1 additional case per 16,000 patients per year. For White patients taking a cumulative dose more than 50,000 mg, the risk increased to approximately 1 additional case per 6,700 patients per year. Photosensitivity has also been reported with thiazide diuretics like hydrochlorothiazide; discontinue if phototoxicity occurs.

Description: Hydrochlorothiazide (HCTZ) is a thiazide diuretic used in the management of edema and hypertension. The American Academy of Pediatrics recommends diuretics, such as hydrochlorothiazide, be used as add-on therapy in pediatric patients uncontrolled on other antihypertensives. Thiazide diuretics are often the preferred second agent for pediatric hypertension because of the salt and water retention that occurs with many antihypertensive medications. They may also be considered an alternative first line antihypertensive agent. Hydrochlorothiazide also has been used to treat nephrogenic diabetes insipidus and hypercalciuria, although these are not FDA-approved indications. Unlike the loop diuretics, thiazide's efficacy is diminished in patients with renal insufficiency. Hydrochlorothiazide tablets are FDA-approved in pediatric patients as young as neonates.

For the treatment of hypertension:
Oral dosage:
Neonates and Infants younger than 6 months: 1 to 3 mg/kg/day PO given in 1 to 2 divided doses is recommended by the FDA-approved labeling; however, doses up to 3.3 mg/kg/day PO given in 2 divided doses have been recommended by some pediatric experts.
Infants 6 to 11 months: 1 to 2 mg/kg/day PO given in 1 to 2 divided doses (Max: 37.5 mg/day).
Children younger than 2 years: 1 mg/kg/day PO given once daily, titrated as needed up to 3 mg/kg/day PO (Max: 50 mg/day) based on clinical response is recommended by the American Academy of Pediatrics (AAP). FDA-approved labeling recommends 1 to 2 mg/kg/day PO given in 1 to 2 divided doses (Max: 37.5 mg/day).
Children 2 to 12 years: 1 mg/kg/day PO given once daily, titrated as needed up to 3 mg/kg/day PO (Max: 50 mg/day) based on clinical response is recommended by the American Academy of Pediatrics (AAP). FDA-approved labeling recommends 1 to 2 mg/kg/day PO given in 1 to 2 divided doses (Max: 100 mg/day).
Adolescents: 1 mg/kg/day PO given once daily, titrated as needed up to 3 mg/kg/day PO (Max: 50 mg/day) based on clinical response is recommended by the American Academy of Pediatrics (AAP). An initial dose of 25 mg PO once daily increased, if necessary, up to 50 mg/day PO given in 1 to 2 divided doses is recommended by the FDA-approved labeling.

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)
Oral dosage:
Neonates and Infants < 6 months: 1-3 mg/kg/day PO given in 1-2 divided doses, is recommended by the manufacturer ; however, doses up to 3.3 mg/kg/day PO, given in 2 divided doses, have been recommended by some pediatric experts.
Infants and Children 6 months to < 2 years: 1-2 mg/kg/day PO given in 1-2 divided doses (Max: 37.5 mg/day PO).
Children 2-12 years: 1-2 mg/kg/day PO given in 1-2 divided doses (Max: 100 mg/day PO).
Adolescents: 25-100 mg/day PO given in 1-2 divided doses. Many patients with edema respond to intermittent therapy (e.g., every other day or 3-5 days each week).

For the prevention of nephrolithiasis* (calcium-containing renal calculus*) due to hypercalciuria*:
Oral dosage:
Neonates, Infants, Children, and Adolescents: 1 to 2 mg/kg/day PO (Max: 100 mg/day). Treatment with hydrochlorothiazide led to resolution of hypercalciuria in 10 of 19 pediatric patients (15 days to 5 years of age) with urolithiasis. Of those 10 patients, 4 became stone-free and 1 experienced a decrease in calculus size.

For the treatment of nephrogenic diabetes insipidus*:
Oral dosage:
Infants, Children, and Adolescents: 2-3 mg/kg/day PO given in 1-3 divided doses has been used in a limited number of patients. Although a maximum dose has not been specified, the manufacturer recommends maximum doses of 37.5 mg/day PO in infants and children < 2 years of age and 100 mg/day PO in children >= 2 years of age and adolescents for other indications.

Maximum Dosage Limits:
-Neonates
3 mg/kg/day PO per FDA-approved labeling; up to 3.3 mg/kg/day PO is recommended by some experts for hypertension.
-Infants
1 to 5 months: 3 mg/kg/day PO per FDA-approved labeling; up to 3.3 mg/kg/day PO is recommended by some experts for hypertension.
6 to 11 months: 2 mg/kg/day PO (Max: 37.5 mg/day).
-Children
1 year : 2 mg/kg/day PO (Max: 37.5 mg/day).
2 to 12 years: 2 mg/kg/day PO (Max: 100 mg/day).
-Adolescents
50 mg/day PO for hypertension; 100 mg/day PO for edema.

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.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Thiazide diuretics increase the excretion of sodium, chloride, and water by inhibiting sodium ion transport across the renal tubular epithelium. Although thiazides may have more than one action, the major mechanism responsible for diuresis is to inhibit active chloride reabsorption at the distal portion of the ascending limb or, more likely, the early part of the distal tubule (i.e., the cortical diluting segment). Exactly how chloride transport is impaired is unknown. Thiazides also increase the excretion of potassium and bicarbonate, and they decrease the urinary excretion of calcium and uric acid. By increasing the sodium load at the distal renal tubule, hydrochlorothiazide indirectly increases potassium excretion via the sodium-potassium exchange mechanism. Hypochloremia and hypokalemia can cause mild metabolic alkalosis. The diuretic efficacy of hydrochlorothiazide is not affected by the acid-base balance of the patient. Hydrochlorothiazide is not an aldosterone antagonist, and its main action is independent of carbonic anhydrase inhibition.

The antihypertensive mechanism of hydrochlorothiazide is unknown. It usually does not affect normal blood pressure. Initially, diuretics lower blood pressure by decreasing cardiac output and reducing plasma 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. These 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 is increased, contributing to the potassium loss associated with thiazide diuretic therapy.

Pharmacokinetics: Hydrochlorothiazide is administered orally. The drug does not cross the blood-brain barrier. Hydrochlorothiazide is not significantly metabolized and is excreted unchanged in the urine. At least 61% of the oral dose is eliminated unchanged within 24 hours. The elimination half-life ranges from 5.6-14.8 hours.

Affected cytochrome P450 isoenzymes: none


-Route-Specific Pharmacokinetics
Oral Route
Hydrochlorothiazide absorption from the GI tract varies depending on the formulation, dose, and presence of concomitant disease states. Absorption is reduced in patients with hepatic, cardiac, and/or renal disease. The bioavailability is approximately 60-70%. The onset of action is 2 hours after oral administration with peak effects occurring at approximately 4 hours. The duration of action ranges from 6-12 hours.


-Special Populations
Renal Impairment
Results from a study in adult patients evaluating the pharmacokinetics of hydrochlorothiazide in relation to renal function indicate the elimination half life increases with varying degrees of renal failure, from 6.4 hours for patients with normal renal function to 11.5 hours for patients with mild renal impairment (30-90 ml/min) to 20.7 hours in patients with CrCl < 30 ml/min.