HYDROCHLOROTHIAZIDE

Hydrochlorothiazide, USP is a diuretic and antihypertensive. It is the 3,4-dihydro derivative of chlorothiazide. Its chemical name is 6-chloro-3,4-dihydro-2 H -1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its molecular formula is C 7 H 8 CIN 3 O 4 S 2 and its structural formula is: It is a white, or practically white, crystalline powder with a molecular weight of 297.74 which is slightly soluble in water, freely soluble in sodium hydroxide solution, in n-butylamine and in dimethylformamide; sparingly soluble in methanol; insoluble in ether, in chloroform and in dilute mineral acids. Each tablet for oral administration contains 12.5 mg, 25 mg and 50 mg of hydrochlorothiazide respectively. In addition, each tablet contains following inactive ingredients: anhydrous lactose, D&C Yellow No.10 aluminum lake, FD&C Red No. 40 aluminum lake, magnesium stearate, pregelatinized starch and sodium starch glycolate. image description

Hydrochlorothiazide tablets are indicated as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. Hydrochlorothiazide tablets have also been found useful in edema due to various forms of renal dysfunction such as nephrotic syndrome, acute glomerulonephritis, and chronic renal failure. Hydrochlorothiazide tablets are 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.

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 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 Hypertension The 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 also PRECAUTIONS ). Patients usually do not require doses in excess of 50 mg of hydrochlorothiazide daily when used concomitantly with other antihypertensive agents. Infants and Children For Diuresis and For Control of Hypertension The 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. (See PRECAUTIONS , Pediatric Use.)

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

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. Musculosketetal: 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. Postmarketing Experience Non-melanoma Skin Cancer Hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer. In a study conducted in the Sentinel System, increased risk was predominantly for squamous cell carcinoma (SCC) and in white patients taking large cumulative doses. The increased risk for SCC in the overall population was approximately 1 additional case per 16,000 patients per year, and for white patients taking a cumulative dose of ≥50,000 mg the risk increase was approximately 1 additional SCC case for every 6,700 patients per year. Call your doctor for medical advice about side effects. To report SUSPECTED ADVERSE REACTION, contact Chartwell RX, LLC. at 1-845-232-1683or FDA at 1-800-FDA-1088 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 -Absorption 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, 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 Hydrochlorothiazide. 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 Hydrochlorothiazide 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 Two-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 of Salmonella typhimurium strains TA 98, TA100, TA 1535, TA 1537, and TA 1538 and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or in vivo in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide from 43 to 1300 mcg/mL, and in the Aspergillus nidulans non-disjunction assay at an unspecified 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.