chlorthalidone tablet Monarch Pharmaceuticals, Inc.
Thalitone® (chlorthalidone tablets, USP) 15 mg
Thalitone® (chlorthalidone USP) is
an antihypertensive/diuretic supplied as 15 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.
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.
Thalitone® (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. Thalitone® cannot be substituted for other formulations of chlorthalidone and
likewise, other formulations of chlorthalidone cannot be substituted
INDICATIONS AND USAGE
Thalitone® (chlorthalidone USP) is
indicated in the management of hypertension either alone or in combination
with other antihypertensive drugs.
is indicated as adjunctive therapy in edema associated with congestive
heart failure, hepatic cirrhosis, and corticosteroid and estrogen
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 pregnant
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.
Anuria. Known hypersensitivity to chlorthalidone
or other sulfonamide-derived drugs.
Thalitone® (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
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.
reactions may occur in patients with a history of allergy or bronchial
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
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.
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.
diuretics have been shown to increase the urinary excretion of magnesium;
this may result in hypomagnesemia.
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.
Hyperuricemia may occur or frank gout may be precipitated in certain
patients receiving chlorthalidone.
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.
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.
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.
Interactions Chlorthalidone may add to or potentiate the
action of other antihypertensive drugs.
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
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.
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.
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.
Geriatric Use Clinical studies of Thalitone® did not include sufficient
numbers of subjects aged 65 and over to determine whether they respond
differently from younger subjects. Other reported clinical experience
has not identified differences in responses between the elderly and
younger patients. In general, dose selection for an elderly patient
should be cautious, usually starting at the low end of the dosing
range, reflecting the greater frequency of decreased hepatic, renal
or cardiac function, and of concomitant disease or other drug therapy.
This drug is known to be substantially excreted by the
kidney, and the risk of toxic reactions to this drug may be greater
in patients with impaired renal function. Because elderly patients
are more likely to have decreased renal function, care should be taken
in dose selection, and it may be useful to monitor renal function.
The following adverse reactions have been observed,
but there is not enough systematic collection of data to support an
estimate of their frequency.
adverse reactions are moderate or severe, chlorthalidone dosage should
be reduced or therapy withdrawn.
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
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
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.
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.
White, kidney-shaped, compressed tablets coded M/024
containing 15 mg of chlorthalidone in bottles of 100 (NDC 61570-024-01).
below 30°C (86°F).
Information as of January 2004.
Inc., Bristol, TN 37620
(A wholly owned subsidiary
of King Pharmaceuticals, Inc.)