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Options For a FDA View of this Label, click here RxNorm NamesNot yet provided hydrochlorothiazide (Hydrochlorothiazide) tablet DESCRIPTIONHydrochlorothiazide is a diuretic and antihypertensive. It is the 3,4-dihydro derivative of chlorothiazide. It is chemically designated as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide and has the following structural formula:  C7H8CIN3O4S2M.W. 297.74 Hydrochlorothiazide is a white, or practically white, crystalline powder which is slightly soluble in water, but freely soluble in sodium hydroxide solution. Each tablet for oral administration contains 25 mg or 50 mg hydrochlorothiazide. In addition, each tablet contains the following inactive ingredients: corn starch, FD&C yellow #6, dibasic calcium phosphate, lactose monohydrate and magnesium stearate. CLINICAL PHARMACOLOGYThe mechanism of the antihypertensive effect of thiazides is unknown. Hydrochlorothiazide does not usually affect normal blood pressure. Hydrochlorothiazide affects the distal renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosage all thiazides are approximately equal in their diuretic ef'cacy. Hydrochlorothiazide 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 MetabolismHydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. At least 61 percent of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk. INDICATIONS AND USAGEHydrochlorothiazide is indicated as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. Hydrochlorothiazide has also been found useful in edema due to various forms of renal dysfunction such as nephrotic syndrome, acute glomerulonephritis, and chronic renal failure. Hydrochlorothiazide 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 PregnancyRoutine 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 (seePRECAUTIONS, 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. CONTRAINDICATIONSAnuria. Hypersensitivity to this product or to other sulfonamide-derived drugs. WARNINGSUse 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 'uid 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 (seePRECAUTIONS, Drug Interactions). PRECAUTIONSGeneralAll patients receiving diuretic therapy should be observed for evidence of 'uid 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 'uids. Warning signs or symptoms of 'uid 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 arrhythmia 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 de'cit 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 TestsPeriodic determination of serum electrolytes to detect possible electrolyte imbalance should be done at appropriate intervals. Drug InteractionsWhen given concurrently the following drugs may interact with thiazide diuretics. Alcohol, Barbiturates, or NarcoticsPotentiation of orthostatic hypotension may occur. Antidiabetic Drugs-(oral agents and insulin)Dosage adjustment of the antidiabetic drug may be required. Other Antihypertensive DrugsAdditive effect or potentiation. Cholestyramine and Colestipol ResinsAbsorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 percent, respectively. Corticosteroids, ACTHIntensified electrolyte depletion, particularly hypokalemia. Pressor Amines (e.g., norepinephrine)Possible decreased response to pressor amines but not suf'cient to preclude their use. Skeletal Muscle Relaxants, Nondepolarizing (e.g., turbocurarine)Possible increased responsiveness to the muscle relaxant. LithiumGenerally 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 hydrochlorothiazide. Non-steroidal Anti-inflammatory DrugsIn some patients, the administration of a non-steroidal anti-in'ammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when hydrochlorothiazide and non-steroidal anti-in'ammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained. Drug/Laboratory Test InteractionsThiazides should be discontinued before carrying out tests for parathyroid function (seePRECAUTIONS, General). Carcinogenesis, Mutagenesis, Impairment of FertilityTwo-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in male and female rats (at doses of up to approximately 100 mg/kg/day). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay ofSalmonella typhimuriumstrains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, orin vivoin assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and theDrosophilasex-linked recessive lethal trait gene. Positive test results were obtained only in thein vitroCHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide from 43 to 1300 µg/mL, and in theAspergillus nidulansnon-disjunction assay at an unspeci'ed concentration. Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg, respectively, prior to conception and throughout gestation. PregnancyTeratogenic EffectsPregnancy category BStudies in which hydrochlorothiazide was orally administered to pregnant mice and rats during their respective periods of major organogenesis at doses up to 3000 and 1000 mg hydrochlorothiazide/kg, respectively, provided no evidence of harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nonteratogenic EffectsThiazides cross the placental barrier and appear in cord blood. There is a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults. Nursing MothersThiazides are excreted in breast milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue hydrochlorothiazide, taking into account the importance of the drug to the mother. Pediatric UseThere 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. (SeeDOSAGE AND ADMINISTRATION, Infants and Children). ADVERSE REACTIONSThe following adverse reactions have been reported and, within each category, are listed in order of decreasing severity. Body as a WholeWeakness CardiovascularHypotension including orthostatic hypotension (may be aggravated by alcohol, barbiturates, narcotics or antihypertensive drugs) DigestivePancreatitis, jaundice (intrahepatic cholestatic jaundice), diarrhea, vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea, anorexia HematologicAplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia HypersensitivityAnaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress including pneumonitis and pulmonary edema, photosensitivity, fever, urticaria, rash, purpura MetabolicElectrolyte imbalance (seePRECAUTIONS), hyperglycemia, glycosuria, hyperuricemia MusculoskeletalMuscle spasm Nervous System/PsychiatricVertigo, paresthesias, dizziness, headache, restlessness. RenalRenal failure, renal dysfunction, interstitial nephritis (seeWARNINGS) SkinErythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis, alopecia Special SensesTransient blurred vision, xanthopsia UrogenitalImpotence Whenever adverse reactions are moderate or severe, thiazide dosage should be reduced or therapy withdrawn. OVERDOSAGEThe 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 hydrochlorothiazide is removed by hemodialysis has not been established. The oral LD50of hydrochlorothiazide is greater than 10 g/kg in the mouse and rat. DOSAGE AND ADMINISTRATIONTherapy should be individualized according to patient response. Use the smallest dosage necessary to achieve the required response. AdultsFor EdemaThe usual adult dosage is 25 to 100 mg daily as a single or divided dose. 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 HypertensionThe usual initial dose in adults is 25 mg daily given as a single dose. The dose may be increased to 50 mg daily, given as a single or two divided doses. Doses above 50 mg are often associated with marked reductions in serum potassium (see alsoPRECAUTIONS). Patients usually do not require doses in excess of 50 mg of hydrochlorothiazide daily when used concomitantly with other antihypertensive agents. Infants and ChildrenFor Diuresis and For Control of HypertensionThe usual pediatric dosage is 0.5 to 1 mg per pound (1 to 2 mg/kg) per day in single or two divided doses, not to exceed 37.5 mg per day in infants up to 2 years of age or 100 mg per day in children 2 to 12 years of age. In infants less than 6 months of age, doses up to 1.5 mg per pound (3 mg/kg) per day in two divided doses may be required. (SeePRECAUTIONS, Pediatric Use) HOW SUPPLIEDHydrochlorothiazide Tablets USP are available as round, light orange, bisected tablets, debossed with company logo and 2083, containing 25 mg of hydrochlorothiazide USP, packaged in bottles of 90, 100, 1000, 5000 and unit-dose boxes of 100 tablets. Hydrochlorothiazide Tablets USP are available as round, light orange, bisected tablets, debossed with company logo and 2089, containing 50 mg of hydrochlorothiazide USP, packaged in bottles of 100, 1000, 5000 and unit-dose boxes of 100 tablets. PHARMACIST: Dispense in a well closed container as defined in the USP. Use child-resistant closure (as required). Store at 20° to 25°C(68° to 77°F) [See USP Controlled Room Temperature]. PE1802 Manufactured In Ireland By: 0172 IVAX PHARMACEUTICALS IRELAND 06/06 Waterford, Ireland B18 Manufactured For: IVAX PHARMACEUTICALS, INC. Miami, FL 33137 Distributed By: TEVA PHARMACEUTICALS USA Sellersville, PA 18960 74327IN-2800 Rev. 00 Iss. 6/2006
Revised: 08/2008Ivax Pharmaceuticals, Inc.
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