Active ingredient and strength
Indapamide hemihydrate 2.5mg
Excipients: Sodium lauryl sulphate, lactose, microcrystalline cellulose,
magnesium stearate, hypromellose, titanium dioxide, polyethylene glycol,
carmine BPC Aluminium lake, sunset yellow aluminium lake, indigo carmine
Mechanism of Action
Indapamide is an indoline antihypertensive/diuretic. Chemically indapamide
has a sulphonamide group in common with other diuretics but also has an
indoline moiety. The N-N bond has similarities to hydralazine that is a
direct vasodilator. It does not have a thiazide ring.
In clinical trials daily doses of indapamide between 0.5 mg and 5.0 mg
produce dose-related antihypertensive effects. Generally, doses of 2.5 mg
and 5.0 mg are indistinguishable but are distinguishable from placebo and
doses of 0.5 mg and 1.0 mg.
The effect of indapamide at doses of 2.5 mg daily are approximately equal to
those obtained with conventional doses of other anti-hypertensive/diuretics.
The antihypertensive action appears to predominantly involve extra-renal
mechanisms including normalisation of vascular hyperreactivity to
vasopressor amines and a reduction in peripheral resistance. There is little
cardiac: inotropic, chronotropic, output or rhythm effect. Indapamide does
not provoke glucose intolerance and has no adverse effect upon
triglycerides, LDL-cholesterol, or LDL/HDL cholesterol ratio.
Indapamide is rapidly and completely absorbed from the gastrointestinal
tract after oral administration, estimates of the degree of absorption
ranging from 80-93%. Peak plasma concentrations are achieved at
approximately 3.5 hours. It is preferentially and reversibly taken up by the
erythrocytes in blood, the whole blood/ plasma ratio being approximately 6:1
at peak concentration decreasing to 3.5:1 after eight hours.
Within the red cell, indapamide is almost completely bound to carbonic
anhydrase, however, the activity of the enzyme is not inhibited by this
binding. Red cell binding has been shown in-vitro to be substantially
decreased by chlorthalidone and acetazolamide. These latter two agents have
greater affinity for the binding site than indapamide. Within plasma
indapamide is approximately 76-79% bound to human plasma proteins, however,
the specific proteins involved have not been identified.
Volume of distribution for indapamide is large, having been estimated as
25-27 I from blood concentrations and 110 I from plasma concentrations. The
major route of elimination in man is the urine where up to 60-70% of a dose
is excreted within 48 hours. Between 5- 7% is excreted unchanged, the rest
being metabolised. Up to 19 metabolites have been identified although the
majority are minor.
Hydroxylation of the indoline ring gives rise to the major metabolite. It is
thought to be active, however, this remains to be confirmed. 18% of the
metabolites in urine appear as conjugates, 14% as conjugates with glucuronic
acid and 4% as conjugates with sulphate.
The renal clearance of unchanged indapamide is low, being estimated at 0.3
l/h while systemic clearance is approximately 1.2 1/h. This reflects the
importance of hepatic clearance. Approximately 16-23% of a dose is
eliminated in the faeces. The plasma elimination half-life has been
estimated to be between 14-18 hours.
The bioavailability of indapamide is not significantly altered by
administration with food or magnesium hydroxide or aluminium hydroxide.
Renal failure, however, increases plasma concentrations by about 20%. Little
is known about the effect of age or impaired hepatic function.
Hypersensitivity to indapamide or other sulphonamide-derived agents. Severe
renal or hepatic impairment. Pregnancy and breast feeding. Recent
Most adverse effects have been mild and transient. Serum potassium may fall
although it usually remains within the normal range. The fall may be
sufficient, however, to cause hypokalaemia in some patients, Serum urate
levels may rise slightly but gout has rarely been reported. Asthenia,
headache, gastrointestinal disturbances and rash have also been reported.
Thiazide and related diuretics may decrease urinary calcium excretion and
cause a slight and transitory rise in plasma calcium, however hypercalcaemia
from this cause is extremely rare. Frank hypercalcaemia if it arises may be
due to previously unrecognised hyperparathyroidism. Treatment with
indapamide should be withdrawn before the investigation of parathyroid
function. An increase in blood glucose may occur during treatment, however,
indapamide does not appear to adversely affect glucose tolerance or alter
glucose metabolism, even in diabetic hypertensive patients.
Warnings and Precautions
Hypokalaemia 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 hyponatraemia, hypochloraemic
alkalosis, or hypokalaemia. 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 hypokalaemia 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 hypokalaemia. Hypokalaemia can sensitise or exaggerate the response of
the heart to the toxic effects of digitalis, such as increased ventricular
Dilutional hyponatraemia may occur in oedematous patients; the appropriate
treatment is restriction of water rather than administration of salt, except
in rare instances when the hyponatraemia 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.
Hyperuricaemia and Gout: Serum concentrations of uric acid
increased by an average of 1.0mg/100mL in patients treated with indapamide,
and frank gout may be precipitated in certain patients receiving indapamide.
Serumconcentrations of uric acid should, therefore, be monitored
periodically during treatment.
Renal Impairment: Indapamide, like the thiazides, should be used
with caution in patients with severe renal disease, as reduced plasma volume
may exacerbate or precipitate azotaemia. 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 coma.
Calcium Excretion: Calcium excretion is decreased by diuretics
pharmacologically related to indapamide. In long-term studies of
hypertensive patients, however, serum concentrations of calcium increased
only slightly with indapamide.
Prolonged treatment with medicines pharmacologically related to
indapamide may in rare instances be associated with hypercalcaemia and
hypophosphataemia 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 thyroid disturbance.
Interaction with Systemic Lupus Erythematosus: Thiazides have
exacerbated or activated systemic lupus erythematosus and this possibility
should be considered with indapamide as well.
Indapamide is a drug substance that may induce a positive reaction during
antidoping control tests. Athletes may need to be cautious about taking