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Indapamide (Systemic)


VA CLASSIFICATION
Primary: CV701
Secondary: CV409

Commonly used brand name(s): Apo-Indapamide; Gen-Indapamide; Lozide; Lozol; Novo-Indapamide; Nu-Indapamide.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antihypertensive—

diuretic—

Indications

Accepted

Hypertension (treatment)—Indapamide is indicated, alone or in combination with other agents, for treatment of hypertension . {01} Indapamide is effective in treating hypertension in patients with renal function impairment, although its diuretic effect is reduced.

Edema (treatment)—Indapamide is indicated for treatment of salt and fluid retention associated with congestive heart failure. {01}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    365.83

pKa—
    8.8

Mechanism of action/Effect:

Antihypertensive—Not clearly understood, but may involve both renal and extrarenal effects. The diuretic effect (reduction of extracellular fluid and blood volume) probably contributes only minimally since indapamide decreases blood pressure at a dose well below the effective diuretic dose. The antihypertensive effect is thought to be the result of reduction in peripheral vascular resistance.

Diuretic—Indapamide inhibits reabsorption of water and electrolytes, primarily as a result of action on the cortical diluting segment of the distal tubule.

Protein binding:

High (71 to 79%), to plasma proteins. {01} {12} Also bound to elastin in vascular smooth muscle.

Biotransformation:

Hepatic (extensive). {12}

Half-life:

In whole blood—Approximately 14 hours. {01}

Terminal half-life of excretion of total radioactivity ( 14C-labeled indapamide)—26 hours. {04}

Onset of action:

Antihypertensive—Multiple dose: 1 to 2 weeks.

Time to peak concentration:

Within 2 hours. {01}

Peak serum concentration

Approximately 260 nanograms per mL after oral administration of 5 mg. {01}

Time to peak effect


Antihypertensive:

Single dose: Approximately 24 hours.

Multiple doses: 8 to 12 weeks.


Duration of action:

Antihypertensive—Multiple doses: Up to 8 weeks.

Elimination:
    Renal—60 to 70% (5 to 7% unchanged). {12}
    Fecal—20 to 23%. {12}


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to other sulfonamide-type medications may be sensitive to indapamide also.

Carcinogenicity/Tumorigenicity

Studies in rats and mice found no evidence of carcinogenicity or tumorigenicity.

Pregnancy/Reproduction
Fertility—
Studies in animals have not shown that indapamide causes adverse effects on the fetus at up to 6250 times the therapeutic human dose.

Pregnancy—
Adequate and well-controlled studies in humans have not been done. However, pregnant women should be advised to contact physician before taking this medication, since routine use of diuretics during normal pregnancy is inappropriate and exposes mother and fetus to unnecessary hazard. {01}

Studies in animals have not shown that indapamide causes adverse effects on the fetus at up to 6250 times the therapeutic human dose. {01}

FDA Pregnancy Category B. {01}

Breast-feeding

It is not known whether indapamide is excreted in breast milk. However, problems in humans have not been documented. {01}

Pediatrics

Appropriate studies on the relationship of age to the effects of indapamide have not been performed in the pediatric population. Safety and efficacy have not been established.


Geriatrics


Although appropriate studies on the relationship of age to the effects of indapamide have not been performed in the geriatric population, the elderly may be more sensitive to the hypotensive and electrolyte effects. In addition, elderly patients are more likely to have age-related renal function impairment, which may require caution in patients receiving indapamide.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Amiodarone    (concurrent use of indapamide with amiodarone may lead to an increased risk of arrhythmias associated with hypokalemia {07} {08})


Anticoagulants, coumarin- or indandione-derivative{06}    (effects may be decreased when these medications are used concurrently with indapamide, as a result of reduction of plasma volume leading to concentration of procoagulant factors in the blood; in addition, diuretic-induced improvement of hepatic congestion may lead to improved hepatic function resulting in increased procoagulant factor synthesis; dosage adjustments may be necessary)


» Digitalis glycosides    (concurrent use with indapamide may enhance the possibility of digitalis toxicity associated with hypokalemia {01} {08})


Hypotension-producing medications, other (See Appendix II )    (antihypertensive and/or diuretic effects may be increased when these medications are used concurrently with indapamide; although some antihypertensive and/or diuretic combinations are used frequently for therapeutic advantage, dosage adjustment may be necessary during concurrent use {01})


» Lithium    (concurrent use with indapamide is not recommended, as it may provoke lithium toxicity because of reduced renal clearance; in addition, lithium has nephrotoxic effects {01} {05})


Neuromuscular blocking agents, nondepolarizing    (indapamide may induce hypokalemia, which may enhance the blockade of nondepolarizing neuromuscular blocking agents; serum potassium determinations may be necessary prior to administration of nondepolarizing neuromuscular blocking agents; careful postoperative monitoring of the patient may be necessary following concurrent or sequential use, especially if there is a possibility of incomplete reversal of neuromuscular blockade {08})


Sympathomimetics    (antihypertensive effects of indapamide may be reduced when it is used concurrently with sympathomimetics; the patient should be carefully monitored to confirm that the desired effect is being obtained {01})

    (indapamide may decrease arterial responsiveness to norepinephrine, but does not usually significantly interfere with its clinical effects {01})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Calcium and
Protein-bound iodine (PBI)    (serum concentrations may be slightly decreased {01})


Plasma renin activity (PRA)    (may be increased)


Potassium and
Sodium    (serum concentrations may be decreased but usually remain within normal limits {01})


Uric acid    (serum concentrations may be increased but usually remain within normal limits {01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Anuria or severe renal function impairment    (diuretic effect reduced; may precipitate azotemia {01})


Diabetes mellitus    (possible impaired glucose tolerance {01})


Gout, history of or
Hyperuricemia    (serum uric acid concentrations may be elevated {01})


Hepatic function impairment    (risk of dehydration, which may precipitate hepatic coma and death {01})


Sensitivity to indapamide or other sulfonamide-type medications{01}
Sympathectomy    (antihypertensive effects may be enhanced {01})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Blood glucose concentration and{01}
Blood urea nitrogen (BUN) concentration and{01}
Uric acid concentration, serum    (determinations recommended prior to initiation of therapy and at periodic intervals during therapy {01})


» Blood pressure measurements    (recommended at periodic intervals in patients being treated for hypertension; selected patients may be trained to perform blood pressure measurements at home and report the results at regular physician visits)


Electrolyte concentrations, serum    (determinations recommended at periodic intervals for patients on long-term therapy, especially if they are also taking cardiac glycosides or systemic steroids, or when severe cirrhosis is present {01})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence rare {01}
    
Allergic reaction (skin rash, itching, or hives)
    
electrolyte imbalance, specifically hyponatremia, hypochloremic alkalosis, or hypokalemia (dryness of mouth; increased thirst; irregular heartbeat; mood or mental changes; muscle cramps or pain; nausea or vomiting; unusual tiredness or weakness; weak pulse)

Note: Electrolyte imbalance is dose-related ( hypokalemia occurs fairly frequently) but is not usually symptomatic. {01}




Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent or rare {01}
    
Anorexia (loss of appetite)
    
diarrhea
    
headache
    
orthostatic hypotension as a result of volume depletion (dizziness or lightheadedness, especially when getting up from a lying or sitting position)
    
trouble in sleeping
    
stomach upset





Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Treatment of overdose
Indapamide overdose should be treated by immediate evacuation of the stomach followed by supportive, symptomatic treatment and monitoring of serum electrolyte concentrations and renal function. {01}


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Indapamide (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to indapamide or other sulfonamide-type medications

Pregnancy—Routine use not recommended





Use in the elderly—Increased sensitivity to hypotensive and electrolyte effects
Other medications, especially digitalis glycosides or lithium
Other medical problems, especially anuria or severe renal function impairment

Proper use of this medication
Diuretic effects of the medication and timing of doses to minimize inconvenience of diuresis

Compliance with therapy; taking medication at the same time each day to maintain the therapeutic effect

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

For use as an antihypertensive
Possible need for control of weight and diet, especially sodium intake

» Patients may not experience symptoms of hypertension; importance of taking medication even if feeling well

» Does not cure but helps control hypertension; possible need for lifelong therapy; checking with physician before discontinuing therapy; serious consequences of untreated hypertension

Precautions while using this medication
Making regular visits to physician to check progress

» Possibility of hypokalemia; possible need for additional potassium in diet; not changing diet without first checking with physician

To prevent dehydration, checking with physician if severe nausea, vomiting, or diarrhea occurs and continues

For use as an antihypertensive
» Not taking other medications, especially nonprescription sympathomimetics, unless discussed with physician


Side/adverse effects
Signs of potential side effects, especially allergic reaction and electrolyte imbalance


General Dosing Information
The lowest effective dosage should be utilized to minimize potential electrolyte imbalance.

When used to promote diuresis, a single daily dose is preferably taken on arising in order to minimize the effect of increased frequency of urination on sleep. Intermittent dosage schedules (drug-free days) may reduce the possibility of electrolyte imbalance or hyperuricemia resulting from therapy.

Concurrent administration of potassium supplements or potassium-sparing diuretics may be indicated in patients considered to be at higher risk for developing hypokalemia. Caution in administering potassium supplements is recommended, however, since loss of potassium is not clinically significant in most patients, and supplementation leads to a risk of development of hyperkalemia.

Recent evidence suggests that withdrawal of antihypertensive therapy prior to surgery is not necessary, but that the anesthesiologist must be aware of such therapy.


Oral Dosage Forms

INDAPAMIDE TABLETS

Usual adult dose
Diuretic
Oral, 2.5 mg once a day, adjusted according to response after one (for edema) to four (for hypertension) weeks up to 5 mg once a day. {01} {04}


Note: Geriatric patients may be more sensitive to the effects of the usual adult dose.


Usual pediatric dose
Safety and efficacy have not been established.

Strength(s) usually available
U.S.—


1.25mg [Lozol][Generic]{15}


2.5 mg (Rx) [Lozol (lactose)][Generic]{15}

Canada—


1.25 mg [Lozide]{14}


2.5 mg (Rx) [Lozide] [Apo-Indapamide] [Gen-Indapamide] [Novo-Indapamide] [Nu-Indapamide][Generic]{14}

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer. Protect from light.

Note: Check refill frequency to determine compliance in hypertensive patients.




Revised: 08/18/1998



References

Note: All references used in the development and earlier revisions of this monograph have not yet been incorporated into the computer database and, therefore, are not listed below. Citations for information not yet referenced in the monograph will be provided upon request.

  1. Lozol package insert, Rorer (U.S.), rev 5/88, rec 11/88.
  1. Arch Intern Med 1984 May; 144: 1045-57.
  1. The 1988 Report of the Joint National Committee on Distribution, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1988; 148: 1023-38.
  1. Lozol product information, PDR 1992.
  1. Hanna M, Lobao C, Stewart J. Severe lithium toxicity associated with indapamide therapy. J Clin Psychopharmacol 1990; 10[5]: 379.
  1. Drug Information Facts, 1990 Edition.
  1. Cordarone product information (Wyeth—US), rec 9/90, rec 2/91.
  1. Retain these drug interactions per panel consensus, 1991 ballot.
  1. International Olympic Committee (IOC) Medical Commission Doping classes, methods, and restrictions, 1991.
  1. United States Olympic Committee. Drug education handbook 1989 to 1992.
  1. The National Collegiate Athletic Association (NCAA) Drug testing/education programs 1990/1991.
  1. Thomas JR. A review of 10 years of experience with indapamide as an antihypertensive agent. Hypertension 1985; 7 (Suppl 2): II152-6.
  1. The fifth report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC V). Arch Intern Med 1993; 153(2): 154-83.
  1. Health Canada Drug Product Database (DPD) [online database]. Cited June 22, 1998. Available from: URL: http://www.hc-sc.gc.ca/english/search.htm.
  1. Red book 1998. Montvale, NJ: Medical Economics Company; 1998. p. 363.
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