Indapamide Information
Indapamide () 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-Sulfamoylbenzamide, and its molecular weight is 365.84. The compound is a weak acid, pK=8.8, and is soluble in aqueous solutions of strong bases. It is a white to yellow-white crystalline (tetragonal) 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, and titanium dioxide. Additionally, the 1.25 mg product contains glyceryl triacetate and D&C Red No. 30 Aluminum Lake and the 2.5 mg product contains triacetin.
Indapamide () 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 the blood within 2 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 2 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 8 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 C-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 mg produced dose related antihypertensive effects. Doses of 5 mg and 10 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 mg and 10 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 mg and 5 mg produced dose related effects. Generally, doses of 2.5 mg and 5 mg were not distinguishable from each other although each was differentiated from placebo and from 0.5 mg or 1 mg Indapamide () . At daily doses of 2.5 mg and 5 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 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 mg, 2.5 mg and 5 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.
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.
Indapamide () Contraindications
Anuria. Known hypersensitivity to Indapamide () or to other sulfonamide-derived drugs.
Indapamide () Warnings
Severe cases of hyponatremia, accompanied by hypokalemia have been reported with recommended doses of Indapamide () . This occurred primarily in elderly females. (See .) This appears to be dose related. Also, a large case-controlled pharmacoepidemiology study indicates that there is an increased risk of hyponatremia with Indapamide () 2.5 mg and 5 mg doses. Hyponatremia considered possibly clinically significant (
Hypokalemia occurs commonly with diuretics (see ), and electrolyte monitoring is essential, particularly in patients who would be at increased risk from hypokalemia, such as those with cardiac arrhythmias or who are receiving concomitant cardiac glycosides.
In general, diuretics should not be given concomitantly with lithium because they reduce its renal clearance and add a high risk of lithium toxicity. Read prescribing information for lithium preparations before use of such concomitant therapy.
Indapamide () Precautions
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 ).
Indapamide () 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 (426 patients given Indapamide () 2.5 mg or 5 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.
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 8 weeks because of adverse reactions.
In controlled clinical trials of 6 to 8 weeks in duration, 20% of patients receiving Indapamide () 1.25 mg, 61% of patients receiving Indapamide () 5 mg, and 80% of patients receiving Indapamide () 10 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 6 to 8 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 (
Indapamide () had no adverse effects on lipids.
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.
Indapamide () 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.
Indapamide () Dosage And Administration
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 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 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 mg once a day.
Indapamide () How Supplied
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, unscored, round tablets debossed with on one side of the tablet and on the other side. They are available as follows:
NDC 21695-576-30bottles of 30 tablets
Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
Mylan Pharmaceuticals Inc.Morgantown, WV 26505
REVISED JANUARY 2010INDAP:R6
Repackaged by:
Rebel Distributors Corp
Thousand Oaks, CA 91320
Indapamide () Principal Display Panel
