Professional Information — Indapamide

Indications and Usage

Indapamide tablets are indicated for the treatment of hypertension, alone or in combination with other antihypertensive drugs.

Indapamide tablets are also indicated for the treatment of salt and fluid retention associated with congestive heart failure.

Usage in Pregnancy: The routine use of diuretics in an otherwise healthy woman is inappropriate and exposes mother and fetus to unnecessary hazard (see PRECAUTIONS below).


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. Indapamide is indicated in pregnancy when edema is due to pathologic causes, just as it is in the absence of pregnancy (however, see PRECAUTIONS 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 which is not harmful to either the fetus or the mother (in the absence of cardiovascular disease), but which 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 which is not relieved by rest. In these cases, a short course of diuretics may provide relief and may be appropriate.

Dosage and Administration

Hypertension: The adult starting indapamide dose for hypertension is 1.25 mg as a single daily dose taken in the morning. If the response to 1.25 mg is not satisfactory after 4 weeks, the daily dose may be increased to 2.5 mg taken once daily. If the response to 2.5 mg is not satisfactory after 4 weeks, the daily dose may be increased to 5.0 mg taken once daily, but adding another antihypertensive should be considered.

Edema of Congestive Heart Failure: The adult starting indapamide dose for edema of congestive heart failure is 2.5 mg as a single daily dose taken in the morning. If the response to 2.5 mg is not satisfactory after one week, the daily dose may be increased to 5.0 mg taken once daily.

If the antihypertensive response to indapamide is insufficient, indapamide may be combined with other antihypertensive drugs, with careful monitoring of blood pressure. It is recommended that the usual dose of other agents be reduced by 50% during initial combination therapy. As the blood pressure response becomes evident, further dosage adjustments may be necessary.

In general, doses of 5.0 mg and larger have not appeared to provide additional effects on blood pressure or heart failure, but are associated with a greater degree of hypokalemia. There is minimal clinical trial experience in patients with doses greater than 5.0 mg once a day.

Contraindications

Anuria.
 

Known hypersensitivity to indapamide or to other sulfonamide-derived drugs.

Adverse Reactions

Most adverse effects have been mild and transient. The clinical adverse reactions listed in Table 1 represent data from Phase II/III placebo-controlled studies (306 patients given indapamide 1.25 mg). The clinical adverse reactions listed in Table 2 represent data from Phase II placebo-controlled studies and long-term controlled clinical trials (426patients given indapamide 2.5 mg or 5.0 mg). The reactions are arranged into two groups: 1) a cumulative incidence equal to or greater than 5%; 2)a cumulative incidence less than 5%. Reactions are counted regardless of relation to drug.

All other clinical adverse reactions occurred at an incidence of <1%.
Approximately 4% of patients given indapamide 1.25 mg compared to 5% of the patients given placebo discontinued treatment in the trials of up to eight weeks because of adverse reactions.
In controlled clinical trials of six to eight weeks in duration, 20% of patients receiving indapamide 1.25 mg, 61% of patients receiving indapamide 5.0 mg, and 80% of patients receiving indapamide 10.0 mg had at least one potassium value below 3.4 mEq/L. In the indapamide 1.25 mg group, about 40% of those patients who reported hypokalemia as a laboratory adverse event returned to normal serum potassium values without intervention. Hypokalemia with concomitant clinical signs or symptoms occurred in 2% of patients receiving indapamide 1.25 mg.

Because most of these data are from long-term studies (up to 40 weeks of treatment), it is probable that many of the adverse experiences reported are due to causes other than the drug. Approximately 10% of patients given indapamide discontinued treatment in long-term trials because of reactions either related or unrelated to the drug.
Hypokalemia with concomitant clinical signs or symptoms occurred in 3% of patients receiving indapamide 2.5 mg q.d. and 7% of patients receiving indapamide 5 mg q.d. In long-term controlled clinical trials comparing the hypokalemic effects of daily doses of indapamide and hydrochlorothiazide, however, 47% of patients receiving indapamide 2.5 mg, 72% of patients receiving indapamide 5 mg, and 44% of patients receiving hydrochlorothiazide 50 mg had at least one potassium value (out of a total of 11 taken during the study) below 3.5 mEq/L. In the indapamide 2.5 mg group, over 50% of those patients returned to normal serum potassium values without intervention.

In clinical trials of six to eight weeks, the mean changes in selected values were as shown in the tables below.

No patients receiving indapamide 1.25 mg experienced hyponatremia considered possibly clinically significant (< 125 mEq/L).

The following reactions have been reported with clinical usage of indapamide: jaundice (intrahepatic cholestatic jaundice), hepatitis, pancreatitis and abnormal liver function tests. These reactions were reversible with discontinuance of the drug. Also reported are erythema multiforme, Stevens-Johnson Syndrome, bullous eruptions, purpura, photosensitivity, fever, pneumonitis, anaphylactic reactions, agranulocytosis, leukopenia, thrombocytopenia and aplastic anemia. Other adverse reactions reported with antihypertensive/diuretics are necrotizing angiitis, respiratory distress, sialadenitis, xanthopsia.

Postmarketing Experience
Eye Disorders: Choroidal effusion, acute myopia, and angle-closure glaucoma (frequency not known).<sup>1

1</sup>Module 2.5 SER-indapamide-choroidal effusion-acute myopia and angleclosure glaucoma-Jul2020

To report SUSPECTED ADVERSE REACTIONS, contact Rising Pharma Holdings, Inc. at 1-844-874-7464 or FDA at 1-800-FDA-1088 or www. fda.gov/medwatch.

Drug Interactions

Other Antihypertensives: Indapamide may add to or potentiate the action of other antihypertensive drugs. In limited controlled trials that compared the effect of indapamide combined with other antihypertensive drugs with the effect of the other drugs administered alone, there was no notable change in the nature or frequency of adverse reactions associated with the combined therapy.

Lithium: See WARNINGS .

Post-Sympathectomy Patient: The antihypertensive effect of the drug may be enhanced in the post-sympathectomized patient.

Norepinephrine: Indapamide, like the thiazides, may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use.

Overdosage

Symptoms of overdosage include nausea, vomiting, weakness, gastrointestinal disorders and disturbances of electrolyte balance. In severe instances, hypotension and depressed respiration may be observed. If this occurs, support of respiration and cardiac circulation should be instituted. There is no specific antidote. An evacuation of the stomach is recommended by emesis and gastric lavage after which the electrolyte and fluid balance should be evaluated carefully.

Description

Indapamide is an oral antihypertensive/diuretic. Its molecule contains both a polar sulfamoyl chlorobenzamide moiety and a lipid-soluble methylindoline moiety. It differs chemically from the thiazides in that it does not possess the thiazide ring system and contains only one sulfonamide group. The chemical name of indapamide is 4-chloro-N-(2-methyl-1-indolinyl)-3-sulfamoyl benzamide, and its molecular weight is 365.8. The compound is a weak acid, pKa=9.35±0.60, and is soluble in methanol, in acetonitrile, in glacial acetic acid, and in ethyl acetate; very slightly soluble in ether and in chloroform; practically insoluble in water. It is a white to off- white, crystalline powder.

Each tablet, for oral administration, contains 1.25 mg or 2.5 mg of indapamide, USP and the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, pregelatinized starch, sodium lauryl sulfate, titanium dioxide and triacetin. Additionally, the 1.25 mg product contains D&C Red# 30/ Helendon pink aluminum lake.

Clinical Pharmacology

Indapamide is the first of a new class of antihypertensive/diuretics, the indolines. The oral administration of 2.5 mg (two 1.25 mg tablets) of indapamide to male subjects produced peak concentrations of approximately 115 ng/mL of the drug in blood within two hours. The oral administration of 5 mg (two 2.5 mg tablets) of indapamide to healthy male subjects produced peak concentrations of approximately 260 ng/mL of the drug in the blood within two hours. A minimum of 70% of a single oral dose is eliminated by the kidneys and an additional 23% by the gastrointestinal tract, probably including the biliary route. The half-life of indapamide in whole blood is approximately 14 hours.

Indapamide is preferentially and reversibly taken up by the erythrocytes in the peripheral blood. The whole blood/plasma ratio is approximately 6:1 at the time of peak concentration and decreases to 3.5:1 at eight hours. From 71 to 79% of the indapamide in plasma is reversibly bound to plasma proteins.

Indapamide is an extensively metabolized drug, with only about 7% of the total dose administered, recovered in the urine as unchanged drug during the first 48 hours after administration. The urinary elimination of ¹⁴C-labeled indapamide and metabolites is biphasic with a terminal half-life of excretion of total radioactivity of 26 hours.

In a parallel design double-blind, placebo controlled trial in hypertension, daily doses of indapamide between 1.25 mg and 10.0 mg produced dose related antihypertensive effects. Doses of 5.0 and 10.0 mg were not distinguishable from each other although each was differentiated from placebo and 1.25 mg indapamide. At daily doses of 1.25 mg, 5.0 mg and 10.0 mg, a mean decrease of serum potassium of 0.28, 0.61 and 0.76 mEq/L, respectively, was observed and uric acid increased by about 0.69 mg/100 mL.

In other parallel design, dose-ranging clinical trials in hypertension and edema, daily doses of indapamide between 0.5 and 5.0 mg produced dose related effects. Generally, doses of 2.5 and 5.0 mg were not distinguishable from each other although each was differentiated from placebo and from 0.5 or 1.0 mg indapamide. At daily doses of 2.5 and 5.0 mg a mean decrease of serum potassium of 0.5 and 0.6 mEq/Liter, respectively, was observed and uric acid increased by about 1.0 mg/100 mL.

At these doses, the effects of indapamide on blood pressure and edema are approximately equal to those obtained with conventional doses of other antihypertensive/diuretics.

In hypertensive patients, daily doses of 1.25, 2.5 and 5.0 mg of indapamide have no appreciable cardiac inotropic or chronotropic effect. The drug decreases peripheral resistance with little or no effect on cardiac output, rate or rhythm. Chronic administration of indapamide to hypertensive patients has little or no effect on glomerular filtration rate or renal plasma flow.

Indapamide had an antihypertensive effect in patients with varying degrees of renal impairment, although in general, diuretic effects declined as renal function decreased.

In a small number of controlled studies, indapamide taken with other antihypertensive drugs such as hydralazine, propranolol, guanethidine and methyldopa, appeared to have the additive effect typical of thiazide-type diuretics.

How Supplied / Storage and Handling

Indapamide Tablets, USP are available containing 1.25 mg or 2.5 mg of indapamide, USP.

The 1.25 mg tablets are pink, film coated, round, biconvex, beveled edge tablet debossed with “875” on one side of the tablet and plain on the other side. They are available as follows:

NDC 16571-875-01
bottles of 100 tablets

The 2.5 mg tablets are white, film coated, round, biconvex, beveled edge tablet debossed with “876” on one side of the tablet and plain on the other side. They are available as follows:

NDC 16571-876-01
bottles of 100 tablets

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Avoid excessive heat.

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

Manufactured for:
Rising Pharma Holdings, Inc.
East Brunswick, NJ 08816

Revised: 04/2023

200653

PIR87610-01