Hypokalemia, Hyponatremia, and Other Fluid and Electrolyte Imbalances
Periodic determinations of serum electrolytes should be
performed at appropriate intervals. In addition, patients should be observed
for clinical signs of fluid or electrolyte imbalance, such as hyponatremia,
hypochloremic alkalosis, or hypokalemia. Warning signs include dry mouth,
thirst, weakness, fatigue, lethargy, drowsiness, restlessness, muscle pains or
cramps, hypotension, oliguria, tachycardia, and gastrointestinal disturbance.
Electrolyte determinations are particularly important in patients who are
vomiting excessively or receiving parenteral fluids, in patients subject to
electrolyte imbalance (including those with heart failure, kidney disease, and
cirrhosis), and in patients on a salt-restricted diet.
The risk of hypokalemia secondary to diuresis and
natriuresis is increased when larger doses are used, when the diuresis is
brisk, when severe cirrhosis is present and during concomitant use of
corticosteroids or ACTH. Interference with adequate oral intake of electrolytes
will also contribute to hypokalemia. Hypokalemia can sensitize or exaggerate
the response of the heart to the toxic effects of digitalis, such as increased
Dilutional hyponatremia may occur in edematous patients; the
appropriate treatment is restriction of water rather than administration of
salt, except in rare instances when the hyponatremia is life threatening.
However, in actual salt depletion, appropriate replacement is the treatment of
choice. Any chloride deficit that may occur during treatment is generally mild
and usually does not require specific treatment except in extraordinary
circumstances as in liver or renal disease. Thiazide-like diuretics have been
shown to increase the urinary excretion of magnesium; this may result in
Hyperuricemia and Gout
Serum concentrations of uric acid increased by an average of 0.69 mg/100 mL
in patients treated with indapamide 1.25 mg, and by an average of 1.0 mg/100
mL in patients treated with indapamide 2.5 mg and 5.0 mg, and frank gout may
be precipitated in certain patients receiving indapamide (see ADVERSE
REACTIONS below). Serum concentrations of uric acid should, therefore,
be monitored periodically during treatment.
Indapamide, like the thiazides, should be used with caution
in patients with severe renal disease, as reduced plasma volume may exacerbate
or precipitate azotemia. If progressive renal impairment is observed in a
patient receiving indapamide, withholding or discontinuing diuretic therapy
should be considered. Renal function tests should be performed periodically
during treatment with indapamide.
Impaired Hepatic Function
Indapamide, like the 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
Latent diabetes may become manifest and insulin requirements
in diabetic patients may be altered during thiazide administration. A mean
increase in glucose of 6.47 mg/dL was observed in patients treated with
indapamide 1.25 mg, which was not considered clinically significant in these
trials. Serum concentrations of glucose should be monitored routinely during
treatment with Lozol (indapamide) .
Calcium excretion is decreased by diuretics pharmacologically
related to indapamide. After six to eight weeks of indapamide 1.25 mg treatment
and in long-term studies of hypertensive patients with higher doses of
indapamide, however, serum concentrations of calcium increased only slightly
with indapamide. Prolonged treatment with drugs pharmacologically related to
indapamide may in rare instances be associated with hypercalcemia and
hypophosphatemia secondary to physiologic changes in the parathyroid gland;
however, the common complications of hyperparathyroidism, such as renal
lithiasis, bone resorption, and peptic ulcer, have not been seen. Treatment
should be discontinued before tests for parathyroid function are performed.
Like the thiazides, indapamide may decrease serum PBI levels without signs of
Interaction With Systemic Lupus Erythematosus
Thiazides have exacerbated or activated systemic lupus
erythematosus and this possibility should be considered with indapamide as
Carcinogenesis, Mutagenesis, Impairment of Fertility
Both mouse and rat lifetime carcinogenicity studies were
conducted. There was no significant difference in the incidence of tumors
between the indapamide-treated animals and the control groups.
Pregnancy Category B. Reproduction studies have been performed
in rats, mice and rabbits at doses up to 6,250 times the therapeutic human dose
and have revealed no evidence of impaired fertility or harm to the fetus due to
Lozol® (indapamide). Postnatal development in rats and mice was unaffected by
pretreatment of parent animals during gestation. There are, however, no
adequate and well-controlled studies in pregnant women. Moreover, diuretics are
known to cross the placental barrier and appear in cord blood. Because animal
reproduction studies are not always predictive of human response, this drug
should be used during pregnancy only if clearly needed. There may be hazards
associated with this use such as fetal or neonatal jaundice, thrombocytopenia,
and possibly other adverse reactions that have occurred in the adult.
It is not known whether this drug is excreted in human milk.
Because most drugs are excreted in human milk, if use of this drug is deemed
essential, the patient should stop nursing.
Safety and effectiveness of indapamide in pediatric patients
have not been established.
Clinical studies of indapamide 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.
Severe cases of hyponatremia, accompanied by hypokalemia have been reported
with recommended doses of indapamide in elderly females (see WARNINGS).