Chlorothiazide

West-ward Pharmaceutical Corp

CHLOROTHIAZIDE TABLETS, USP250 mg and 500 mg

FULL PRESCRIBING INFORMATION: CONTENTS*

• CHLOROTHIAZIDE DESCRIPTION
• CLINICAL PHARMACOLOGY
  • Pharmacokinetics and Metabolism
• CHLOROTHIAZIDE INDICATIONS AND USAGE
  • Use in Pregnancy
• CHLOROTHIAZIDE CONTRAINDICATIONS
• WARNINGS
• PRECAUTIONS
  • General
  • Laboratory Tests
  • Drug Interactions
  • Drug/Laboratory Test Interactions
  • Carcinogenesis, Mutagenesis, Impairment of Fertility
  • Pregnancy
  • Nursing Mothers
  • Pediatric Use
  • Geriatric Use
• CHLOROTHIAZIDE ADVERSE REACTIONS
• OVERDOSAGE
• CHLOROTHIAZIDE DOSAGE AND ADMINISTRATION
  • Adults
  • Infants and Children
• HOW SUPPLIED

FULL PRESCRIBING INFORMATION

Rx Only

CHLOROTHIAZIDE DESCRIPTION

Chlorothiazide is a diuretic and antihypertensive. It is 6-chloro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C₇H₆CIN₃O₄S₂ and its structural formula is:

It is a white, or practically white crystalline compound with a molecular weight of 295.72, which is very slightly soluble in water, but readily soluble in dilute aqueous sodium hydroxide. It is soluble in urine to the extent of about 150 mg per 100 mL at pH 7.

Chlorothiazide is supplied as 250 mg and 500 mg tablets, for oral use. Each tablet contains the following inactive ingredients: Anhydrous Lactose, Colloidal Silicon Dioxide, Magnesium Stearate, Microcrystalline Cellulose, Pregelatinized Starch, Polysorbate 80, and Sodium Starch Glycolate.

CLINICAL PHARMACOLOGY

The mechanism of the antihypertensive effect of thiazides is unknown. Chlorothiazide does not usually effect normal blood pressure.

Chlorothiazide affects the distal renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosage all thiazides are approximately equal in their diuretic efficacy.

Chlorothiazide increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate.

After oral use diuresis begins within 2 hours, peaks in about 4 hours, and lasts about 6 to 12 hours.

Pharmacokinetics and Metabolism

Chlorothiazide is not metabolized but is eliminated rapidly by the kidney. The plasma half-life of chlorothiazide is 45-120 minutes. After oral doses, 10 to 15 percent of the dose is excreted unchanged in the urine. Chlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.

CHLOROTHIAZIDE INDICATIONS AND USAGE

Chlorothiazide is indicated as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy.

Chlorothiazide has also been found useful in edema due to various forms of renal dysfunction such as nephrotic syndrome, acute glomerulonephritis, and chronic renal failure.

Chlorothiazide is indicated in the management of hypertension either as the sole therapeutic agent or to enhance the effectiveness of other antihypertensive drugs in the more severe forms of hypertension.

Use in Pregnancy

Routine use of diuretics during normal pregnancy is inappropriate and exposes mother and fetus to unnecessary hazard. Diuretics do not prevent development of toxemia of pregnancy and there is no satisfactory evidence that they are useful in the treatment of toxemia.

Edema during pregnancy may arise from pathologic causes or from the physiologic and mechanical consequences of pregnancy. Thiazides are indicated in pregnancy when edema is due to pathologic causes, just as they are in the absence of pregnancy (see PRECAUTIONS: Pregnancy). Dependent edema in pregnancy, resulting from restriction of venous return by the gravid uterus, is properly treated through elevation of the lower extremities and use of support stockings. Use of diuretics to lower intravascular volume in this instance is illogical and unnecessary. During normal pregnancy there is hypervolemia which is not harmful to the fetus or the mother in the absence of cardiovascular disease. However, it may be associated with edema, rarely generalized edema. If such edema causes discomfort, increased recumbency will often provide relief. Rarely this edema may cause extreme discomfort which is not relieved by rest. In these instances, a short course of diuretic therapy may provide relief and be appropriate.

CHLOROTHIAZIDE CONTRAINDICATIONS

Anuria.

Hypersensitivity to this product or to other sulfonamide-derived drugs.

WARNINGS

Use with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function.

Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Thiazides may add to or potentiate the action of other antihypertensive drugs.

Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma.

The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.

Lithium generally should not be given with diuretics (see PRECAUTIONS: Drug Interactions).

PRECAUTIONS

General

All patients receiving diuretic therapy should be observed for evidence of fluid or electrolyte imbalance: namely, hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause, include dryness of mouth, 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 may develop, especially with brisk diuresis, when severe cirrhosis is present or after prolonged therapy.

Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may cause cardiac arrhythmias and may also sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability). Hypokalemia may be avoided or treated by use of potassium sparing diuretics or potassium supplements such as foods with a high potassium content.

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.

Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt, except in rare instances when the hyponatremia is life-threatening. In actual salt depletion, appropriate replacement is the therapy of choice.

Hyperuricemia may occur or acute gout may be precipitated in certain patients receiving thiazides.

In diabetic patients dosage adjustments of insulin or oral hypoglycemic agents may be required. Hyperglycemia may occur with thiazide diuretics. Thus latent diabetes mellitus may become manifest during thiazide therapy.

The antihypertensive effects of the drug may be enhanced in the post-sympathectomy patient.

If progressive renal impairment becomes evident, consider withholding or discontinuing diuretic therapy.

Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.

Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.

Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.

Laboratory Tests

Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be done at appropriate intervals.

Drug Interactions

When given concurrently the following drugs may interact with thiazide diuretics.

Alcohol, barbiturates, or narcotics - potentiation of orthostatic hypotension may occur.

Antidiabetic drugs (oral agents and insulin) - dosage adjustment of the antidiabetic drug may be required.

Other antihypertensive drugs - additive effect or potentiation.

Cholestyramine and colestipol resins - both cholestyramine and colestipol resins have the potential of binding thiazide diuretics and reducing diuretic absorption from the gastrointestinal tract.

Corticosteroids, ACTH - intensified electrolyte depletion, particularly hypokalemia.

Pressor amines (e.g., norepinephrine) - possible decreased response to pressor amines but not sufficient to preclude their use.

Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine) - possible increased responsiveness to the muscle relaxant.

Lithium - generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such preparations with Chlorothiazide.

Non-steroidal Anti-inflammatory Drugs - In some patients, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when Chlorothiazide and non-steroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.

Drug/Laboratory Test Interactions

Thiazides should be discontinued before carrying out tests for parathyroid function (see PRECAUTIONS: General).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity and mutagenicity studies have not been conducted with chlorothiazide.

Chlorothiazide was not mutagenic in vitro in the Ames microbial mutagen test (using a maximum concentration of 5 mg/plate and Salmonella typhimurium strains TA98 and TA100) and was not mutagenic and did not induce mitotic non-disjunction in diploid-strains of Aspergillus nidulans.

Chlorothiazide had no adverse effects on fertility in female rats at doses up to 60 mg/kg/day and no adverse effects on fertility in male rats at doses up to 40 mg/kg/day. These doses are 1.5 and 1.0 times** the recommended maximum human dose, respectively, when compared on a body weight basis.

**Calculations based on a human body weight of 50 kg.

Pregnancy

Teratogenic Effects - Pregnancy Category C

Although reproduction studies performed with chlorothiazide doses of 50 mg/kg/day in rabbits, 60 mg/kg/day in rats and 500 mg/kg/day in mice revealed no external abnormalities of the fetus or impairment of growth and survival of the fetus due to chlorothiazide, such studies did not include complete examinations for visceral and skeletal abnormalities. It is not known whether chlorothiazide can cause fetal harm when administered to a pregnant woman; however, thiazides cross the placental barrier and appear in cord blood. Chlorothiazide should be used during pregnancy only if clearly needed (see INDICATIONS AND USAGE).

Nonteratogenic Effects

Chlorothiazide may cause fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions which have occurred in the adult.

Nursing Mothers

Because of the potential for serious adverse reactions in nursing infants from Chlorothiazide, 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.

Pediatric Use

There are no well-controlled clinical trials in pediatric patients. Information on dosing in this age group is supported by evidence from empiric use in pediatric patients and published literature regarding the treatment of hypertension in such patients. (See DOSAGE AND ADMINISTRATION: Infants and Children.)

Geriatric Use

Clinical studies of chlorothiazide did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease of other drug therapy.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see WARNINGS).

CHLOROTHIAZIDE ADVERSE REACTIONS

The following adverse reactions have been reported and, within each category, are listed in order of decreasing severity.

Body as a whole: Weakness.

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

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

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

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

Metabolic: Electrolyte imbalance (see PRECAUTIONS), hyperglycemia, glycosuria, hyperuricemia.

Musculoskeletal: Muscle spasm.

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

Renal: Renal failure, renal dysfunction, interstitial nephritis (see WARNINGS).

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

Special Senses: Transient blurred vision, xanthopsia.

Urogenital: Impotence

Whenever adverse reactions are moderate or severe, thiazide dosage should be reduced or therapy withdrawn.

OVERDOSAGE

The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias.

In the event of overdosage, symptomatic and supportive measures should be employed. Emesis should be induced or gastric lavage performed. Correct dehydration, electrolyte imbalance, hepatic coma and hypotension by established procedures. If required, give oxygen or artificial respiration for respiratory impairment.

The degree to which chlorothiazide sodium is removed by hemodialysis has not been established.

The oral LD₅₀ of chlorothiazide is 8.5 g/kg, greater than 10 g/kg, and greater than 1 g/kg, in the mouse, rat and dog respectively.

CHLOROTHIAZIDE DOSAGE AND ADMINISTRATION

Therapy should be individualized according to patient response. Use the smallest dosage necessary to achieve the required response.

Adults

For Edema

The usual adult dosage is 500 mg to 1000 mg once or twice a day. Many patients with edema respond to intermittent therapy, i.e., administration on alternate days or on three to five days each week. With an intermittent schedule, excessive response and the resulting undesirable electrolyte imbalance are less likely to occur.

For Control of Hypertension

The usual adult starting dosage is 500 mg to 1000 mg a day as a single or divided dose. Dosage is increased or decreased according to blood pressure response. Rarely some patients may require up to 2000 mg a day in divided doses.

Infants and Children

For Diuresis and For Control of Hypertension

The usual pediatric dosage is 5 to 10 mg per pound (10 to 20 mg/kg) per day in single or two divided doses, not to exceed 375 mg per day in infants up to 2 years of age or 1000 mg per day in children 2 to 12 years of age. In infants less than 6 months of age, doses up to 15 mg per pound (30 mg/kg) per day in two divided doses may be required.

HOW SUPPLIED

Chlorothiazide Tablets USP 250 mg: White, round, scored, compressed tablets imprinted "West-ward 209".

Bottles of 100 tablets.

Bottles of 1000 tablets.

Chlorothiazide Tablets USP 500 mg: White, round, scored, compressed tablets imprinted "West-ward 210".

Bottles of 100 tablets.

Bottles of 1000 tablets.

Store at 20-25°C (68-77°F) [See USP Controlled Room Temperature]. Protect from light and moisture.

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

Manufactured By:

West-ward Pharmaceutical Corp.

Eatontown, NJ 07724

Revised September 2005