HYDROCHLOROTHIAZIDE
DESCRIPTION:
ESIDREX* (Hydrochlorothiazide) is a diuretic and antihypertensive. It is the
3,4-dihydro derivative of chlorothiazide. Its chemical name is 6-chloro-3,4-
dihydro-2H- 1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical
formula is C7H8ClN3O4S2.
It is a white, or practically white, crystalline powder with a molecular weight
of 297.72, which is slightly soluble in water, but freely soluble in sodium
hydroxide solution.
ACTIONS/CLINICAL PHARMACOLOGY:
The mechanism of the antihypertensive effect of thiazides is unknown.
ESIDREX does not usually affect normal blood pressure.
ESIDREX affects the distal renal tubular mechanism of electrolyte
reabsorption. At maximal therapeutic dosage all thiazides are approximately
equal in their diuretic efficacy.
ESIDREX 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
ESIDREX 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 USAGE:
ESIDREX is indicated as adjunctive therapy in edema associated with
congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen
therapy.
ESIDREX has also been found useful in edema due to various forms of renal
dysfunction such as nephrotic syndrome, acute glomerulonephritis, and chronic
renal failure.
ESIDREX 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.
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 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 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--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
ESIDREX.
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 ESIDREX 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, 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 mcgm/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--Pregnancy Category B: Studies 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 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 children have not been established.
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--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
ESIDREX.
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 ESIDREX 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.
(See Also PRECAUTIONS)
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 hydrochlorothiazide is removed by hemodialysis
has not been established.
The oral LD50 of hydrochlorothiazide is greater than 10 g/kg in the mouse and
rat.
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 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.
************************************************************************