Indapamide

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Indapamide
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gerald Chi

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Overview

Indapamide is a thiazide-like diuretic that is FDA approved for the {{{indicationType}}} of hypertension and salt and fluid retention associated with congestive heart failure. Common adverse reactions include hypokalemia, cramp, asthenia, dizziness, headache, lethargy, numbness, fatigue, and malaise.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Hypertension
  • Dosing Information
  • 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 four 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 four weeks, the daily dose may be increased to 5 mg taken once daily, but adding another antihypertensive should be considered.
Edema Of Congestive Heart Failure
  • Dosing Information
  • 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.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Indapamide in adult patients.

Non–Guideline-Supported Use

Hypercalciuria
  • Dosing Information
Neurohypophyseal diabetes insipidus
  • Dosing Information

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

  • Safety and effectiveness of indapamide in pediatric patients have not been established.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Indapamide in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Indapamide in pediatric patients.

Contraindications

Warnings

  • Severe cases of hyponatremia, accompanied by hypokalemia, have been reported with recommended doses of indapamide. This occurred primarily in elderly females. 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 (< 125 mEq/L) has not been observed in clinical trials with the 1.25 mg dosage. Thus, patients should be started at the 1.25 mg dose and maintained at the lowest possible dose.
  • Hypokalemia occurs commonly with diuretics, 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.

Precautions

  • 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 mg/100 mL in patients treated with indapamide 2.5 mg and 5 mg, and frank gout may be precipitated in certain patients receiving indapamide. Serum concentrations 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 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
  • Glucose Tolerance
  • 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 indapamide.
  • Calcium Excretion
  • 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 thyroid disturbance.
  • The antihypertensive effect of the drug may be enhanced in the post-sympathectomized patient.

Adverse Reactions

Clinical Trials Experience

  • 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.
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  • 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 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.
This image is provided by the National Library of Medicine.
  • 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.
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  • No patients receiving indapamide 1.25 mg experienced hyponatremia considered possibly clinically significant (<125 mEq/L).
  • Indapamide had no adverse effects on lipids.
This image is provided by the National Library of Medicine.

Postmarketing Experience

There is limited information regarding Postmarketing Experience of Indapamide in the drug label.

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.
  • 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.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

  • 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 indapamide. Postnatal development in rats and mice was unaffected by pre-treatment 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.
  • 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. Indapamide is indicated in pregnancy when edema is due to pathologic causes, just as it is in the absence of pregnancy. 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.


Pregnancy Category (AUS):

  • Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Indapamide in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Indapamide during labor and delivery.

Nursing Mothers

  • 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.

Pediatric Use

  • Safety and effectiveness of indapamide in pediatric patients have not been established.

Geriatic Use

  • 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.

Gender

There is no FDA guidance on the use of Indapamide with respect to specific gender populations.

Race

There is no FDA guidance on the use of Indapamide with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Indapamide in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Indapamide in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Indapamide in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Indapamide in patients who are immunocompromised.

Administration and Monitoring

Administration

  • Oral

Monitoring

IV Compatibility

There is limited information regarding IV Compatibility of Indapamide in the drug label.

Overdosage

Acute Overdose

Signs and Symptoms

Management

  • 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.

Chronic Overdose

There is limited information regarding Chronic Overdose of Indapamide in the drug label.

Pharmacology

Indapamide.png
Indapamide
Systematic (IUPAC) name
4-chloro-N-(2-methyl-2,3-dihydroindol-1-yl)- 3-sulfamoyl-benzamide
Identifiers
CAS number 26807-65-8
ATC code C03BA11
PubChem 3702
DrugBank DB00808
Chemical data
Formula C16H16ClN3O3S 
Mol. mass 365.835 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability ?
Protein binding 71–79%
Metabolism Hepatic
Half life 14–18 hours
Excretion ?
Therapeutic considerations
Pregnancy cat.

B(US), C (Aus)

Legal status

POMt

Routes Oral tablet

Mechanism of Action

  • Indapamide is the first of a new class of antihypertensive/diuretics, the indolines.

Structure

  • 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, pKa=8.8, and is soluble in aqueous solutions of strong bases. It is a white to yellow-white crystalline (tetragonal) powder, and has the following structural formula:
This image is provided by the National Library of Medicine.
  • Each tablet, for oral administration, contains 1.25 mg or 2.5 mg of indapamide. In addition, each tablet contains the following inactive ingredients: corn starch, hypromellose, lactose monohydrate, magnesium stearate, maltodextrin, microcrystalline cellulose, polydextrose, polyethylene glycol, talc, titanium dioxide, triacetin. The 1.25 mg tablet also contains FD&C yellow #6 aluminum lake (sunset yellow lake).

Pharmacodynamics

  • 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.
  • 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 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 and 5 mg produced dose-related effects. Generally, doses of 2.5 and 5 mg were not distinguishable from each other although each was differentiated from placebo and from 0.5 or 1 mg indapamide. At daily doses of 2.5 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, 2.5 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.

Pharmacokinetics

  • 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.

Nonclinical Toxicology

  • 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.

Clinical Studies

There is limited information regarding Clinical Studies of Indapamide in the drug label.

How Supplied

  • Indapamide Tablets, USP are available as follows:
1.25 mg — Each orange, round, compound cup, film-coated tablet imprinted with c8144390-figure-02 on one side and 597 on the other side contains 1.25 mg of indapamide, USP. Tablets are supplied in bottles of 100 (NDC 0228-2597-11) and 1000 (NDC 0228-2597-96).
2.5 mg — Each white, round, compound cup, film-coated tablet imprinted with c8144390-figure-03 on one side and 571 on the other side contains 2.5 mg of indapamide, USP. Tablets are supplied in bottles of 100 (NDC 0228-2571-11) and 1000 (NDC 0228-2571-96).
  • Keep tightly closed.
  • Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP]. Avoid excessive heat.
  • Dispense in a tight, light-resistant container as defined in the USP.

Storage

There is limited information regarding Indapamide Storage in the drug label.

Images

Drug Images

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Drug Label Author:

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Package and Label Display Panel

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This image of the FDA label is provided by the National Library of Medicine.
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This image of the FDA label is provided by the National Library of Medicine.

Patient Counseling Information

There is limited information regarding Patient Counseling Information of Indapamide in the drug label.

Precautions with Alcohol

  • Alcohol-Indapamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

Look-Alike Drug Names

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

  1. Borghi, L. (1993). "Randomized prospective study of a nonthiazide diuretic, indapamide, in preventing calcium stone recurrences". Journal of Cardiovascular Pharmacology. 22 Suppl 6: –78-86. ISSN 0160-2446. PMID 7508066. Unknown parameter |coauthors= ignored (help)
  2. Lemieux, G. (1986-07-15). "Treatment of idiopathic hypercalciuria with indapamide". CMAJ: Canadian Medical Association journal = journal de l'Association medicale canadienne. 135 (2): 119–121. ISSN 0820-3946. PMC 1491209. PMID 3719496.
  3. Tetiker, T. (1999-09-27). "Efficacy of indapamide in central diabetes insipidus". Archives of Internal Medicine. 159 (17): 2085–2087. ISSN 0003-9926. PMID 10510995. Unknown parameter |coauthors= ignored (help)
  4. "INDAPAMIDE tablet, film coated".
  5. "http://www.ismp.org". External link in |title= (help)

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