Hydrochlorothiazide

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Hydrochlorothiazide Prescribing Information

Hydrochlorothiazide capsules, USP are indicated in the management of hypertension either as the sole therapeutic agent, or in combination with other antihypertensives. Unlike potassium sparing combination diuretic products, hydrochlorothiazide capsules, USP may be used in those patients in whom the development of hyperkalemia cannot be risked, including patients taking ACE inhibitors.

Usage in Pregnancy:

The routine use of diuretics in an otherwise healthy woman 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 developed toxemia.

Edema during pregnancy may arise from pathological causes or from the physiologic and mechanical consequences of pregnancy. Diuretics are indicated in pregnancy when edema is due to pathologic causes, just as they are in the absence of pregnancy. Dependent edema in pregnancy resulting from restriction of venous return by the expanded uterus is properly treated through elevation of the lower extremities and use of support hose; use of diuretics to lower intravascular volume in this case is illogical and unnecessary. There is hypervolemia during normal pregnancy which is harmful to neither the fetus nor the mother (in the absence of cardiovascular disease), but which is associated with edema, including generalized edema in the majority of pregnant women. If this edema produces discomfort, increased recumbency will often provide relief. In rare instances this edema may cause extreme discomfort which is not relieved by rest. In these cases a short course of diuretics may provide relief and may be appropriate.

The adverse reactions associated with hydrochlorothiazide have been shown to be dose related. In controlled clinical trials, the adverse events reported with doses of 12.5 mg hydrochlorothiazide once daily were comparable to placebo. The following adverse reactions have been reported for doses of hydrochlorothiazide 25 mg and greater and, within each category, are listed in the 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

Electrolyte and Fluid Balance Status:

In published studies, clinically significant hypokalemia has been consistently less common in patients who received 12.5 mg of hydrochlorothiazide than in patients who received higher doses. Nevertheless, periodic determination of serum electrolytes should be performed in patients who may be at risk for the development of hypokalemia. Patients should be observed for signs of fluid or electrolyte disturbances, i.e., hyponatremia, hypochloremic alkalosis, and hypokalemia and hypomagnesemia.

Warning signs or symptoms of fluid and electrolyte imbalance include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, 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, during concomitant use of corticosteroid or adrenocorticotropic hormone (ACTH) or after prolonged therapy. Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia and hypomagnesemia can provoke ventricular arrhythmias or sensitize or exaggerate the response of the heart to the toxic effects of digitalis. Hypokalemia may be avoided or treated by potassium supplementation or increased intake of potassium rich foods.

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

Hyperuricemia:

Hyperuricemia or acute gout may be precipitated in certain patients receiving thiazide diuretics.

Impaired Hepatic Function:

Thiazides should be used with caution in patients with impaired hepatic function. They can precipitate hepatic coma in patients with severe liver disease.

Parathyroid Disease:

Calcium excretion is decreased by thiazides, and pathologic changes in the parathyroid glands, with hypercalcemia and hypophosphatemia, have been observed in a few patients on prolonged thiazide therapy.

Information for Patients:

Non-melanoma Skin Cancer:

Instruct patients taking hydrochlorothiazide to protect skin from the sun and undergo regular skin cancer screening.

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:

Cholestyramine and colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 percent, respectively.

Corticosteroid, 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 greatly increase the risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such preparations with hydrochlorothiazide capsules.

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. When hydrochlorothiazide capsules and non-steroidal anti-inflammatory agents are used concomitantly, the patients 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 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, TA 100, 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.

Pregnancy:

Teratogenic Effects:

Studies in which hydrochlorothiazide was orally administered to pregnant mice and rats during their respective periods of major organogenesis at doses up to 3,000 mg and 1,000 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 Effects:

Thiazides 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 Mothers:

Thiazides 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 Use:

Safety and effectiveness in pediatric patients have not been established.

Elderly Use:

A greater blood pressure reduction and an increase in side effects may be observed in the elderly (i.e., > 65 years) with hydrochlorothiazide. Starting treatment with the lowest available dose of hydrochlorothiazide (12.5 mg) is therefore recommended. If further titration is required, 12.5 mg increments should be utilized.

), hyperglycemia, glycosuria, hyperuricemia.

Musculoskeletal:

Muscle spasm.

Nervous System/Psychiatric:

Vertigo, paresthesia, dizziness, headache, restlessness.

Renal:

Renal failure, renal dysfunction, interstitial nephritis (see

WARNINGS

Acute Myopia and Secondary Angle-Closure Glaucoma:

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. 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. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Diabetes and Hypoglycemia:

Latent diabetes mellitus may become manifest and diabetic patients given thiazides may require adjustment of their insulin dose.

Renal Disease:

Cumulative effects of the thiazides may develop in patients with impaired renal function. In such patients, thiazides may precipitate azotemia.

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.

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:

Cholestyramine and colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 percent, respectively.

Corticosteroid, 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:

Non-steroidal anti-inflammatory drugs:

Drug/Laboratory Test Interactions:

Thiazides should be discontinued before carrying out tests for parathyroid function (see

PRECAUTIONS

Electrolyte and Fluid Balance Status:

Hyperuricemia:

Hyperuricemia or acute gout may be precipitated in certain patients receiving thiazide diuretics.

Impaired Hepatic Function:

Thiazides should be used with caution in patients with impaired hepatic function. They can precipitate hepatic coma in patients with severe liver disease.

Parathyroid Disease:

Information for Patients:

Non-melanoma Skin Cancer:

Instruct patients taking hydrochlorothiazide to protect skin from the sun and undergo regular skin cancer screening.

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:

Cholestyramine and colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 percent, respectively.

Corticosteroid, 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:

Non-steroidal anti-inflammatory drugs:

Drug/Laboratory Test Interactions:

Thiazides should be discontinued before carrying out tests for parathyroid function (see

PRECAUTIONS

General

Carcinogenesis, Mutagenesis, Impairment of Fertility:

in vitro

in the Ames mutagenicity assay of

Salmonella typhimurium

strains TA 98, TA 100, 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.

Pregnancy:

Teratogenic Effects:

Nonteratogenic Effects:

Thiazides 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 Mothers:

Pediatric Use:

Safety and effectiveness in pediatric patients have not been established.

Elderly Use:

General

Hydrochlorothiazide (hydrochlorothiazide, USP 12.5 mg) is the 3,4-dihydro derivative of chlorothiazide. Its chemical name is 6-chloro-3,4-dihydro-2

-1,2,4-benzothiadiazine-7- sulfonamide 1,1-dioxide. Its empirical formula is C
₇H
₈ClN
₃O
₄S
₂; its molecular weight is 297.74; and its structural formula is:

It is a white, or practically white, crystalline powder which is slightly soluble in water, but freely soluble in sodium hydroxide solution.

Hydrochlorothiazide capsules, USP are supplied as 12.5 mg capsules for oral use.

Inactive ingredients:

colloidal silicon dioxide, corn starch, lactose monohydrate, magnesium stearate. The hard gelatin shell consists of gelatin, titanium dioxide, sodium lauryl sulfate, FD&C Blue #1, FD&C Red #3. The capsules are printed with black ink containing shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, black iron oxide, and potassium hydroxide.

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