HYDROCHLOROTHIAZIDE Edema during pregnancy may arise from patho­ irritability). Hypokalemia may be avoided or treated logic causes or from the physiologic and mechanical by use of potassium sparing diuretics or potassium TABLETS, USP consequences of pregnancy. Thiazides are indicated supplements such as foods with a high potassium 12.5 mg, 25 mg and 50 mg in pregnancy when edema is due to pathologic content. causes, just as they are in the absence of pregnan­ Although any chloride deficit is generally mild and cy (see PRECAUTIONS: Pregnancy). Dependent usually does not require specific treatment except edema in pregnancy, resulting from restriction of under extraordinary circumstances (as in liver dis­ DESCRIPTION: Hydrochlorothiazide is a diuretic venous return by the gravid uterus, is properly treat­ ease or renal disease), chloride replacement may and antihypertensive. It is the 3,4-dihydro derivative ed through elevation of the lower extremities and be required in the treatment of metabolic alkalosis. of chlorothiazide. It is chemically designated as 6­ use of support stockings. Use of diuretics to lower Dilutional hyponatremia may occur in edematous chloro-3,4-dihydro-2 H-1,2,4-benzothiadiazine-7-sul­ intravascular volume in this instance is illogical and patients in hot weather; appropriate therapy is water fonamide 1,1-dioxide and has the following structural unnecessary. During normal pregnancy there is restriction, rather than administration of salt, except formula: hypervolemia which is not harmful to the fetus or the in rare instances when the hyponatremia is life mother in the absence of cardiovascular disease. threatening. In actual salt depletion, appropriate However, it may be associated with edema, rarely replacement is the therapy of choice. generalized edema. If such edema causes discom­ fort, increased recumbency will often provide relief. Hyperuricemia may occur or acute gout may be Rarely this edema may cause extreme discomfort precipitated in certain patients receiving thiazides. which is not relieved by rest. In these instances, a In diabetic patients dosage adjustments of insulin short course of diuretic therapy may provide relief or oral hypoglycemic agents may be required. HCTZT:R2 and be appropriate. Hyper glycemia may occur with thiazide diuretics. Thus latent diabetes mellitus may become manifest C7H8ClN3O4S2 M.W. 297.74 CONTRAINDICATIONS: Anuria. during thiazide therapy. Hydrochlorothiazide, USP is a white, or practically Hypersensitivity to this product or to other sulfon­ The antihypertensive effects of the drug may be white, crystalline powder which is slightly soluble in amide-derived drugs. enhanced in the post-sympathectomy patient. water, freely soluble in sodium hydroxide solution, in WARNINGS: Use with caution in severe renal dis­ If progressive renal impairment becomes evi­ n-butylamine, and in dimethylformamide; sparingly ease. In patients with renal disease, thiazides may dent, consider withholding or discontinuing diuretic soluble in methanol; insoluble in ether, in chloroform, precipitate azotemia. Cumulative effects of the drug therapy. and in dilute mineral acids. Each tablet for oral may develop in patients with impaired renal function. Thiazides have been shown to increase the uri­ administration contains 12.5 mg, 25 mg or 50 mg Thiazides should be used with caution in patients nary excretion of magnesium; this may result in hydrochlorothiazide, USP. In addition, each tablet with impaired hepatic function or progressive liver hypomagnesemia. contains the following inactive ingredients: colloidal disease, since minor alterations of fluid and elec­ Thiazides may decrease urinary calcium excre­ silicon dioxide, magnesium stearate, microcrystalline trolyte balance may precipitate hepatic coma. cellulose, pregelatinized starch, and sodium lauryl tion. Thiazides may cause intermittent and slight ele­ Thiazides may add to or potentiate the action of sulfate. vation of serum calcium in the absence of known other antihypertensive drugs. disorders of calcium metabolism. Marked hypercal­ CLINICAL PHARMACOLOGY: The mechanism of Sensitivity reactions may occur in patients with or cemia may be evidence of hidden hyperparathy­ the antihypertensive effect of thiazides is unknown. without a history of allergy or bronchial asthma. roidism. Thiazides should be discontinued before Hydrochlorothiazide does not usually affect normal The possibility of exacerbation or activation of sys­ carrying out tests for parathyroid function. blood pressure. temic lupus erythematosus has been reported. Increases in cholesterol and triglyceride levels Hydrochlorothiazide affects the distal renal tubular Lithium generally should not be given with diuret­ may be associated with thiazide diuretic therapy. mechanism of electrolyte reabsorption. At maximal ics (see PRECAUTIONS: Drug Interactions). Laboratory Tests: Periodic determination of serum therapeutic dosage all thiazides are approximately electrolytes to detect possible electrolyte imbalance equal in their diuretic efficacy. Acute Myopia and Secondary Angle-Closure Glaucoma: Hydrochlorothiazide, a sulfonamide, should be done at appropriate intervals. Hydrochlorothiazide increases excretion of sodi­ can cause an idiosyncratic reaction, resulting in Drug Interactions: When given concurrently the um and chloride in approximately equivalent acute transient myopia and acute angle-closure following drugs may interact with thiazide diuretics. amounts. Natriuresis may be accompanied by some glaucoma. Symptoms include acute onset of loss of potassium and bicarbonate. Alcohol, Barbiturates, or Narcotics: Potentiation decreased visual acuity or ocular pain and typically of orthostatic hypotension may occur. After oral use diuresis begins within 2 hours, occur within hours to weeks of drug initiation. Antidiabetic Drugs (Oral Agents and Insulin): peaks in about 4 hours and lasts about 6 to 12 Untreated acute angle-closure glaucoma can lead to Dosage adjustment of the antidiabetic drug may be hours. permanent vision loss. The primary treatment is to required. Pharmacokinetics and Metabolism: Hydro­ discontinue hydrochlorothiazide as rapidly as possi­ chlorothiazide is not metabolized but is eliminated ble. Prompt medical or surgical treatments may Other Antihypertensive Drugs: Additive effect or rapidly by the kidney. When plasma levels have been need to be considered if the intraocular pressure potentiation. followed for at least 24 hours, the plasma half-life remains uncontrolled. Risk factors for developing Cholestyramine and Colestipol Resins: has been observed to vary between 5.6 and 14.8 acute angle-closure glaucoma may include a history Absorption of hydrochlorothiazide is impaired in the hours. At least 61% of the oral dose is eliminated of sulfonamide or penicillin allergy. presence of anionic exchange resins. Single doses unchanged within 24 hours. Hydrochlorothiazide of either cholestyramine or colestipol resins bind the crosses the placental but not the blood-brain barrier PRECAUTIONS: General: All patients receiving hydrochlorothiazide and reduce its absorption from and is excreted in breast milk. diuretic therapy should be observed for evidence of the gastrointestinal tract by up to 85% and 43%, fluid or electrolyte imbalance: namely, hyponatrem­ respectively. INDICATIONS AND USAGE: Hydrochlorothiazide ia, hypochloremic alkalosis, and hypokalemia. Corticosteroids, ACTH: Intensified electrolyte tablets are indicated as adjunctive therapy in edema Serum and urine electrolyte determinations are par­ depletion, particularly hypokalemia. associated with congestive heart failure, hepatic cir­ ticularly important when the patient is vomiting rhosis, and corticosteroid and estrogen therapy. excessively or receiving parenteral fluids. Warning Pressor Amines (e.g., Norepinephrine): Possible Hydrochlorothiazide tablets have also been found signs or symptoms of fluid and electrolyte imbal­ decreased response to pressor amines but not suffi­ useful in edema due to various forms of renal dys­ ance, irrespective of cause, include dryness of cient to preclude their use. function such as nephrotic syndrome, acute mouth, thirst, weakness, lethargy, drowsiness, rest­ Skeletal Muscle Relaxants, Nondepolarizing glomerulonephritis, and chronic renal failure. lessness, confusion, seizures, muscle pains or (e.g., Tubocurarine): Possible increased respon­ Hydrochlorothiazide tablets are indicated in the cramps, muscular fatigue, hypotension, oliguria, siveness to the muscle relaxant. management of hypertension either as the sole ther­ tachycardia, and gastrointestinal disturbances such Lithium: Generally should not be given with diuret­ apeutic agent or to enhance the effectiveness of as nausea and vomiting. ics. Diuretic agents reduce the renal clearance of other antihypertensive drugs in the more severe Hypokalemia may develop, especially with brisk lithium and add a high risk of lithium toxicity. Refer to forms of hypertension. diuresis, when severe cirrhosis is present or after the package insert for lithium preparations before Use in Pregnancy: Routine use of diuretics during prolonged therapy. use of such preparations with hydrochlorothiazide. normal pregnancy is inappropriate and exposes Interference with adequate oral electrolyte intake Non-Steroidal Anti-Inflammatory Drugs: In mother and fetus to unnecessary hazard. Diuretics will also contribute to hypokalemia. Hypokalemia some patients, the administration of a non-steroidal do not prevent development of toxemia of pregnancy may cause cardiac arrhythmia and may also sensi­ anti-inflammatory agent can reduce the diuretic, and there is no satisfactory evidence that they are tize or exaggerate the response of the heart to the natriuretic, and antihypertensive effects of loop, useful in the treatment of toxemia. toxic effects of digitalis (e.g., increased ventricular potassium-sparing and thiazide diuretics. Therefore,

Reference ID: 3001472 when hydrochlorothiazide and non-steroidal anti­ cramping, constipation, gastric irritation, nausea, The 12.5 mg tablets are white to off-white, round, inflammatory agents are used concomitantly, the anorexia. unscored tablets debossed with M on one side of patient should be observed closely to determine if Hematologic: Aplastic anemia, agranulocytosis, the tablet and H3 on the other side. They are avail­ the desired effect of the diuretic is obtained. leukopenia, hemolytic anemia, thrombocytopenia. able as follows: Drug/Laboratory Test Interactions: Thiazides Hypersensitivity: Anaphylactic reactions, necrotiz­ NDC 0378-3603-01 should be discontinued before carrying out tests ing angiitis (vasculitis and cutaneous vasculitis), res­ bottles of 100 tablets for parathyroid function (see PRECAUTIONS: piratory distress including pneumonitis and pul­ General). NDC 0378-3603-10 monary edema, photosensitivity, fever, urticaria, bottles of 1000 tablets Carcinogenesis, Mutagenesis, Impairment of rash, purpura. Fertility: Two year feeding studies in mice and rats Metabolic: Electrolyte imbalance (see PRECAU­ The 25 mg tablets are white to off-white, round, conducted under the auspices of the National TIONS), hyperglycemia, glycosuria, hyperuricemia. scored tablets debossed with M on one side of the tablet and H to the left of the score and 1 to the right Toxicology Program (NTP) uncovered no evidence Musculoskeletal: Muscle spasm. of a carcinogenic potential of hydrochlorothiazide of the score on the other side. They are available as in female mice (at doses of up to approximately Nervous System/Psychiatric: Vertigo, paresthe­ follows: sias, dizziness, headache, restlessness. 600 mg/kg/day) or in male and female rats (at NDC 0378-3601-01 doses of up to approximately 100 mg/kg/day). The Renal: Renal failure, renal dysfunction, interstitial bottles of 100 tablets NTP, however, found equivocal evidence for hepa­ nephritis (see WARNINGS). tocarcinogenicity in male mice. Skin: Erythema multiforme including Stevens- NDC 0378-3601-10 bottles of 1000 tablets Hydrochlorothiazide was not genotoxic in vitro in Johnson Syndrome, exfoliative dermatitis including the Ames mutagenicity assay of Salmonella toxic epidermal necrolysis, alopecia. The 50 mg tablets are white to off-white, round, typhimurium strains TA 98, TA 100, TA 1535, TA Special Senses: Transient blurred vision, xan­ scored tablets debossed with M on one side of the 1537, and TA 1538 and in the Chinese Hamster thopsia. tablet and H to the left of the score and 2 to the right of the score on the other side. They are available as Ovary (CHO) test for chromosomal aberrations, or Urogenital: Impotence. follows: in vivo in assays using mouse germinal cell chromo­ Whenever adverse reactions are moderate or somes, Chinese hamster bone marrow chromo­ severe, thiazide dosage should be reduced or thera­ NDC 0378-3602-01 somes, and the Drosophila sex-linked recessive py withdrawn. bottles of 100 tablets lethal trait gene. Positive test results were obtained NDC 0378-3602-10 only in the in vitro CHO Sister Chromatid Exchange OVERDOSAGE: The most common signs and bottles of 1000 tablets (clastogenicity) and in the Mouse Lymphoma Cell symptoms observed are those caused by elec­ (mutagenicity) assays, using concentrations of trolyte depletion (hypokalemia, hypochloremia, Store at 20° to 25°C (68° to 77°F). [See USP hydrochlorothiazide from 43 to 1300 mcg/mL, and in hyponatremia) and dehydration resulting from Controlled Room Temperature.] the Aspergillus nidulans non-disjunction assay at excessive diuresis. If digitalis has also been admin­ Dispense in a tight, light-resistant container as an unspecified concentration. istered, hypokalemia may accentuate cardiac defined in the USP using a child-resistant closure. Hydrochlorothiazide had no adverse effects on the arrhythmias. fertility of mice and rats of either sex in studies In the event of overdosage, symptomatic and wherein these species were exposed, via their diet, supportive measures should be employed. Emesis to doses of up to 100 and 4 mg/kg, respectively, should be induced or gastric lavage performed. prior to conception and throughout gestation. Correct dehydration, electrolyte imbalance, hepatic Pregnancy: Teratogenic Effects. Pregnancy coma and hypotension by established procedures. Category B: Studies in which hydrochlorothiazide If required, give oxygen or artificial respiration for was orally administered to pregnant mice and rats respiratory impairment. The degree to which hydro ­ during their respective periods of major organogene­ chlorothiazide is removed by hemodialysis has not sis at doses up to 3000 and 1000 mg hydrochloro­ been established. The oral LD50 of hydro ­ thiazide/kg, respectively, provided no evidence of chlorothiazide is greater than 10 g/kg in the mouse harm to the fetus. and rat. Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A. There are, however, no adequate and well con­ DOSAGE AND ADMINISTRATION: Therapy trolled studies in pregnant women. Because animal should be individualized according to patient reproduction studies are not always predictive of response. Use the smallest dosage necessary to REVISED MAY 2011 human response, this drug should be used during achieve the required response. HCTZT:R2 pregnancy only if clearly needed. Adults: For Edema: The usual adult dosage is Nonteratogenic Effects: Thiazides cross the pla­ 25 mg to 100 mg daily as a single or divided dose. cental barrier and appear in cord blood. There is a Many patients with edema respond to intermittent risk of fetal or neonatal jaundice, thrombocytopenia, therapy, i.e., administration on alternate days or on and possibly other adverse reactions that have 3 to 5 days each week. With an intermittent sched­ occurred in adults. ule, excessive response and the resulting undesir­ Nursing Mothers: Thiazides are excreted in breast able electrolyte imbalance are less likely to occur. milk. Because of the potential for serious adverse For Control of Hypertension: The usual initial reactions in nursing infants, a decision should be dose in adults is 25 mg daily given as a single dose. made whether to discontinue nursing or to discontin­ The dose may be increased to 50 mg daily, given as ue hydrochlorothiazide, taking into account the a single or two divided doses. Doses above 50 mg importance of the drug to the mother. are often associated with marked reductions in Pediatric Use: There are no well controlled clinical serum potassium (see also PRECAUTIONS). trials in pediatric patients. Information on dosing in Patients usually do not require doses in excess of this age group is supported by evidence from empir­ 50 mg of hydrochlorothiazide daily when used con­ ic use in pediatric patients and published literature comitantly with other antihypertensive agents. regarding the treatment of hypertension in such Infants and Children: For Diuresis and for patients. (See DOSAGE AND ADMINISTRATION: Control of Hypertension: The usual pediatric Infants and Children.) dosage is 0.5 mg to 1 mg per pound (1 to 2 mg/kg) per day in single or two divided doses, not to ADVERSE REACTIONS: The following adverse exceed 37.5 mg per day in infants up to 2 years of reactions have been reported and, within each cate­ age or 100 mg per day in children 2 to 12 years of gory, are listed in order of decreasing severity. age. In infants less than 6 months of age, doses Body as a Whole: Weakness. up to 1.5 mg per pound (3 mg/kg) per day in two Cardiovascular: Hypotension including orthostatic divided doses may be required. (See PRECAU­ hypotension (may be aggravated by alcohol, barbitu­ TIONS: Pediatric Use.) rates, narcotics or antihypertensive drugs). HOW SUPPLIED: Hydrochlorothiazide tablets, USP Digestive: Pancreatitis, jaundice (intrahepatic are available containing 12.5 mg, 25 mg and 50 mg cholestatic jaundice), diarrhea, vomiting, sialadenitis, hydrochlorothiazide, USP.

Reference ID: 3001472