CHLORTHALIDONE
DESCRIPTION:
Hythalton (chlorthalidone USP) is an antihypertensive/diuretic supplied as 15
or 25 mg tablets for oral use. It is a monosulfamyl diuretic that differs
chemically from thiazide diuretics in that a double ring system is incorporated
in its structure. It is a racemic mixture of 2-chloro-5-(1-hydroxy-3-oxo- 1-
isoindolinyl) benzenesulfonamide, with the following structural formula:
Chlorthalidone is practically insoluble in water, in ether and in chloroform;
soluble in methanol; slightly soluble in alcohol.
The inactive ingredients are colloidal silicon dioxide, lactose, magnesium
stearate, microcrystalline cellulose, povidone, sodium starch glycolate.
ACTIONS/CLINICAL PHARMACOLOGY:
Chlorthalidone is a long-acting oral diuretic with antihypertensive activity.
Its diuretic action commences a mean of 2.6 hours after dosing and continues for
up to 72 hours. The drug produces diuresis with increased excretion of sodium
and chloride. The diuretic effects of chlorthalidone and the benzothiadiazine
(thiazide) diuretics appear to arise from similar mechanisms and the maximal
effect of chlorthalidone and the thiazides appear to be similar. The site of the
action appears to be the distal convoluted tubule of the nephron. The diuretic
effects of chlorthalidone lead to decreased extracellular fluid volume, plasma
volume, cardiac output, total exchangeable sodium, glomerular filtration rate,
and renal plasma flow. Although the mechanism of action of chlorthalidone and
related drugs is not wholly clear, sodium and water depletion appear to provide
a basis for its antihypertensive effect. Like the thiazide diuretics,
chlorthalidone produces dose-related reductions in serum potassium levels,
elevations in serum uric acid and blood glucose, and it can lead to decreased
sodium and chloride levels.
The mean plasma half-life of chlorthalidone is about 40 to 60 hours. It is
eliminated primarily as unchanged drug in the urine. Non-renal routes of
elimination have yet to be clarified. In the blood, approximately 75% of the
drug is bound to plasma proteins.
Hythalton (chlorthalidone USP) has been formulated with PVP (povidone
polyvinylpyrrolidone), a bioavailability enhancer that provides 104% to 116%
bioavailability relative to an oral solution of chlorthalidone. Hythalton
cannot be substituted for other formulations of chlorthalidone and likewise,
other formulations of chlorthalidone cannot be substituted for Hythalton.
INDICATIONS AND USAGE:
Hythalton (chlorthalidone USP) is indicated in the management of hypertension
either alone or in combination with other antihypertensive drugs.
Chlorthalidone is indicated as adjunctive therapy in edema associated with
congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen
therapy.
Chlorthalidone has also been found useful in edema due to various forms of renal
dysfunction such as nephrotic syndrome, acute glomerulonephritis, and chronic
renal failure.
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. Chlorthalidone is
indicated in pregnancy when edema is due to pathologic causes just as it is in
the absence of pregnancy (however, see WARNINGS below). 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 that is harmful
to neither the fetus nor the mother (in the absence of cardiovascular disease)
but that is associated with edema, including generalized edema, in the majority
of pregnancy women. If this edema produces discomfort, increased recumbency will
often provide relief. In rare instances, this edema may cause extreme discomfort
that is not relieved by rest. In these cases, a short course of diuretics may
provide relief and may be appropriate.
CONTRAINDICATIONS:
Anuria. Known hypersensitivity to chlorthalidone or other sulfonamide-derived
drugs.
WARNINGS:
Hythalton (chlorthalidone USP) should be used with caution in severe renal
disease. In patients with renal disease, chlorthalidone or related drugs may
precipitate azotemia. Cumulative effects of the drug may develop in patients
with impaired renal function.
Chlorthalidone should be used with caution in patients with impaired hepatic
function or progressive liver disease, because minor alterations of fluid and
electrolyte balance may precipitate hepatic coma.
Sensitivity reactions may occur in patients with a history of allergy or
bronchial asthma.
The possibility of exacerbation or activation of systemic lupus erythematosus
has been reported with thiazide diuretics which are structurally related to
chlorthalidone. However, systemic lupus erythematosus has not been reported
following chlorthalidone administration.
PRECAUTIONS:
GENERAL Hypokalemia and other electrolyte abnormalities, including hyponatremia
and hypochloremic alkalosis, are common in patients receiving chlorthalidone.
These abnormalities are dose-related but may occur even at the lowest marketed
doses of chlorthalidone. Serum electrolytes should be determined before
initiating therapy and at periodic intervals during therapy. Serum and urine
electrolyte determinations are particularly important when the patient is
vomiting excessively or receiving parenteral fluids. All patients taking
chlorthalidone should be observed for clinical signs of electrolyte imbalance,
including dryness of mouth, thirst, weakness, lethargy, drowsiness,
restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria,
tachycardia, palpitations and gastrointestinal disturbances, such as nausea and
vomiting. Digitalis therapy may exaggerate metabolic effects of hypokalemia
especially with reference to myocardial activity.
Any chloride deficit is generally mild and usually does not require specific
treatment except under extraordinary circumstances (as in liver disease or renal
disease). 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
cases of actual salt depletion, appropriate replacement is the therapy of
choice.
Thiazide-like diuretics have been shown to increase the urinary excretion of
magnesium; this may result in hypomagnesemia.
Calcium excretion is decreased by thiazide-like drugs. Pathological changes in
the parathyroid gland with hypercalcemia and hypophosphatemia have been observed
in a few patients on thiazide therapy. The common complications of
hyperparathyroidism such as renal lithiasis, bone resorption and peptic
ulceration have not been seen.
URIC ACID Hyperuricemia may occur or frank gout may be precipitated in certain
patients receiving chlorthalidone.
OTHER Increases in serum glucose may occur and latent diabetes mellitus may
become manifest during chlorthalidone therapy (see PRECAUTIONS Drug
Interactions). Chlorthalidone and related drugs may decrease serum PBI levels
without signs of thyroid disturbance.
INFORMATION FOR PATIENTS Patients should inform their doctor if they have: 1)
had an allergic reaction to chlorthalidone or other diuretics or have asthma 2)
kidney disease 3) liver disease 4) gout 5) systemic lupus erythematosus, or 6)
been taking other drugs such as cortisone, digitalis, lithium carbonate, or
drugs for diabetes.
Patients should be cautioned to contact their physician if they experience any
of the following symptoms of potassium loss: excess thirst, tiredness,
drowsiness, restlessness, muscle pains or cramps, nausea, vomiting or increased
heart rate or pulse.
Patients should also be cautioned that taking alcohol can increase the chance of
dizziness occurring.
LABORATORY TESTS Periodic determination of serum electrolytes to detect possible
electrolyte imbalance should be performed at appropriate intervals.
All patients receiving chlorthalidone should be observed for clinical signs 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.
DRUG INTERACTIONS: Chlorthalidone may add to or potentiate the action of other
antihypertensive drugs.
Insulin requirements in diabetic patients may be increased, decreased or
unchanged. Higher dosage of oral hypoglycemic agents may be required.
Chlorthalidone and related drugs may increase the responsiveness to
tubocurarine.
Chlorthalidone and related drugs may decrease arterial responsiveness to
norepinephrine. This diminution is not sufficient to preclude effectiveness of
the pressor agent for therapeutic use.
Lithium renal clearance is reduced by chlorthalidone, increasing the risk of
lithium toxicity.
DRUG/LABORATORY TEST INTERACTIONS Chlorthalidone and related drugs may decrease
serum PBI levels without signs of thyroid disturbance.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY: No information is
available.
PREGNANCY/TERATOGENIC EFFECTS PREGNANCY CATEGORY B: Reproduction studies have
been performed in the rat and the rabbit at doses up to 420 times the human dose
and have revealed no evidence of harm to the fetus due to chlorthalidone. 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.
PREGNANCY/NON-TERATOGENIC EFFECTS: Thiazides cross the placental barrier and
appear in cord blood. The use of chlorthalidone and related drugs in pregnant
women requires that the anticipated benefits of the drug be weighed against
possible hazards to the fetus. These hazards include fetal or neonatal jaundice,
thrombocytopenia, and possibly other adverse reactions that have occurred in the
adult.
NURSING MOTHERS Thiazides are excreted in human milk. Because of the potential
for serious adverse reactions in nursing infants from chlorthalidone, a decision
should be made whether to discontinue nursing or to discontinue the drug, taking
into account the importance of the drug to the mother.
PEDIATRIC USE Safety and effectiveness in children have not been established.
DRUG INTERACTIONS:
Chlorthalidone may add to or potentiate the action of other antihypertensive
drugs.
Insulin requirements in diabetic patients may be increased, decreased or
unchanged. Higher dosage of oral hypoglycemic agents may be required.
Chlorthalidone and related drugs may increase the responsiveness to
tubocurarine.
Chlorthalidone and related drugs may decrease arterial responsiveness to
norepinephrine. This diminution is not sufficient to preclude effectiveness of
the pressor agent for therapeutic use.
Lithium renal clearance is reduced by chlorthalidone, increasing the risk of
lithium toxicity.
(See Also PRECAUTIONS.)
ADVERSE REACTIONS:
The following adverse reactions have been observed, but there is not enough
systematic collection of data to support an estimate of their frequency.
Gastrointestinal System Reactions: anorexia, gastric irritation, nausea,
vomiting, cramping, diarrhea, constipation, jaundice (intrahepatic cholestatic
jaundice), pancreatitis.
Central Nervous System Reactions: dizziness, vertigo, paresthesias, headache,
xanthopsia.
Hematologic Reactions: leukopenia, agranulocytosis, thrombocytopenia, aplastic
anemia.
Dermatologic-Hypersensitivity Reactions: purpura, photosensitivity, rash,
urticaria, necrotizing angiitis (vasculitis) (cutaneous vasculitis), Lyell's
syndrome (toxic epidermal necrolysis).
Cardiovascular Reaction: Orthostatic hypotension may occur and may be aggravated
by alcohol, barbiturates or narcotics.
Other Adverse Reactions: hyperglycemia, glycosuria, hyperuricemia, muscle spasm,
weakness, restlessness, impotence.
Whenever adverse reactions are moderate or severe, chlorthalidone dosage should
be reduced or therapy withdrawn.
OVERDOSAGE:
Symptoms of acute overdosage include nausea, weakness, dizziness and
disturbances of electrolyte balance. The oral LD50 of the drug in the mouse and
the rat is more than 25,000 mg/kg body weight. The minimum lethal dose (MLD) in
humans has not been established. There is no specific antidote but gastric
lavage is recommended, followed by supportive treatment. Where necessary, this
may include intravenous dextrose-saline with potassium, administered with
caution.
DOSAGE AND ADMINISTRATION:
Therapy should be initiated with the lowest possible dose, then titrated
according to individual patient response. A single dose given in the morning
with food is recommended; divided doses are unnecessary.
HYPERTENSION Therapy in most patients should be initiated with a single daily
dose of 15 mg. If the response is insufficient after a suitable trial, the
dosage may be increased to 30 mg and then to a single daily dose of 45-50 mg. If
additional control is required, the addition of a second antihypertensive drug
is recommended. Increases in serum uric acid and decreases in serum potassium
are dose-related over the 15-50 mg/day range and beyond.
EDEMA INITIATION: Adults, initially 30 to 60 mg daily or 60 mg on alternate
days. Some patients may require 90 to 120 mg at these intervals or up to 120 mg
daily. Dosages above this level, however, do not usually produce a greater
response.
MAINTENANCE: Maintenance doses may often be lower than initial doses and should
be adjusted according to the individual patient. Effectiveness is well sustained
during continued use.
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