Class: Thiazide-like Diuretics
VA Class: CV701
Chemical Name: 3-(Aminosulfonyl)-4-chloro-N-(2,3-dihydro-2-methyl-1H-indol-1-yl)benzamide
Molecular Formula: C16H16ClN3O3S
CAS Number: 26807-65-8
Medically reviewed on March 2, 2017
Uses for Indapamide
JNC classifies indapamide as a thiazide-like drug with regard to management of hypertension; the drug’s efficacy in hypertensive patients is similar to that of the thiazide diuretics.14 18 21 24 500 501
Thiazide-type diuretics are recommended as one of several preferred agents for the initial management of hypertension; other options include ACE inhibitors, angiotensin II receptor antagonists, and calcium-channel blockers.501 502 503 504 While there may be individual differences with respect to specific outcomes, these antihypertensive drug classes all produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes.500 501 502 504 Individualize choice of therapy; consider patient characteristics (e.g., age, ethnicity/race, comorbidities, cardiovascular risk) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, cost).500 501 502 503 504 515
The optimum BP threshold for initiating antihypertensive drug therapy is controversial.501 504 505 506 507 508 515 523 530 Further study needed to determine optimum BP thresholds/goals; individualize treatment decisions.501 503 507 515 526 530
JNC 7 recommends initiation of drug therapy in all patients with uncomplicated hypertension and BP ≥140/90 mm Hg;500 JNC 8 panel recommends SBP threshold of 150 mm Hg for patients ≥60 years of age.501 Although many experts agree that SBP goal of <150 mm Hg may be appropriate for patients ≥80 years of age,502 504 505 530 application of this goal to those ≥60 years of age is controversial, especially for those at higher cardiovascular risk.501 502 505 506 508 511 515
In the past, initial antihypertensive drug therapy was recommended for patients with diabetes mellitus or chronic kidney disease who had BP ≥130/80 mm Hg;500 503 current hypertension management guidelines generally recommend a BP threshold of 140/90 mm Hg for these individuals (same as for the general population of patients without these conditions), although a goal of <130/80 mm Hg may still be considered.501 502 503 504 520 530 535 536 541
Black hypertensive patients generally tend to respond better to monotherapy with thiazide diuretics or calcium-channel blockers than to other antihypertensive drug classes (e.g., ACE inhibitors, angiotensin II receptor antagonists).82 200 500 501 504 However, diminished response to these other drug classes is largely eliminated when administered concomitantly with a thiazide diuretic or calcium-channel blocker.500 504
Thiazide-like diuretics may be preferred in hypertensive patients with osteoporosis. Secondary beneficial effect in hypertensive geriatric patients of reducing the risk of osteoporosis secondary to effect on calcium homeostasis and bone mineralization.
Edema in Heart Failure
Most experts state that all patients with symptomatic heart failure who have evidence for, or a history of, fluid retention generally should receive diuretic therapy in conjunction with moderate sodium restriction, an agent to inhibit the renin-angiotensin-aldosterone (RAA) system (e.g., ACE inhibitor, angiotensin II receptor antagonist, angiotensin receptor-neprilysin inhibitor [ARNI]), a β-adrenergic blocking agent (β-blocker), and in selected patients, an aldosterone antagonist.524 700 713
Diuretics produce rapid symptomatic benefits, relieving pulmonary and peripheral edema more rapidly (within hours or days) than cardiac glycosides, ACE inhibitors, or β-blockers (in weeks or months).70
Loop diuretics (e.g., bumetanide, ethacrynic acid, furosemide, torsemide) are diuretics of choice for most patients with heart failure.524
Edema in Pregnancy
Diuretics should not be used for routine therapy in pregnant women with mild edema who are otherwise healthy.a
Use of thiazide-like diuretics may be appropriate in the management of edema of pathologic origin during pregnancy when clearly needed; routine use of diuretics in otherwise healthy pregnant women is irrational.21 30
Dependent edema secondary to restriction of venous return by the expanded uterus should be managed by elevating the lower extremities and/or by wearing support hose; use of diuretics in these pregnant women is inappropriate.21 30
In rare cases when the hypervolemia associated with normal pregnancy results in edema that produces extreme discomfort, a short course of diuretic therapy may provide relief and may be considered when other methods (e.g., decreased sodium intake, increased recumbency) are ineffective.21 30 44
No substantial difference in clinical effects or toxicity of comparable thiazide or thiazide-like diuretics, except metolazone may be more effective in edema with renal impairment.a
Indapamide Dosage and Administration
BP Monitoring and Treatment Goals
When available, use evidence-based dosing information (i.e., dosages shown in randomized controlled trials to reduce complications of hypertension) to determine target dosages; target dosages usually can be achieved within 2–4 weeks but may take up to several months.501
If adequate BP response not achieved with a single antihypertensive agent, add a second drug with demonstrated benefit; if goal BP still not achieved with optimal dosages of 2 antihypertensive agents, add a third drug.501 May maximize dosage of the first drug before adding a second drug, or add a second drug before maximizing dosage of the initial drug.501
Goal is to achieve and maintain optimal control of BP; individualize specific target BP based on consideration of multiple factors, including patient age and comorbidities, and currently available evidence from clinical studies.500 501 (See Hypertension under Uses.)
Individualize dosage according to individual requirements and response.600
For the management of fluid retention (e.g., edema) associated with heart failure, experts state that diuretics should be administered at a dosage sufficient to achieve optimal volume status and relieve congestion without inducing an excessively rapid reduction in intravascular volume, which could result in hypotension, renal dysfunction, or both.524
JNC 8 expert panel recommends initial dosage of 1.25 mg once daily and target dosage of 1.25–2.5 mg once daily based on dosages used in randomized controlled studies.501
Manufacturer recommends initial dosage of 1.25 mg once daily in the morning; if response is inadequate, dosage may be increased at 4-week intervals to 2.5 mg daily and subsequently to 5 mg daily.83
Dosages >5 mg daily do not appear to result in further improvement in BP and increase the risk of hypokalemia.83 (See Hypokalemia under Cautions.)
If adequate response is not achieved with monotherapy, add another antihypertensive agent.501
If concomitant therapy with other antihypertensive agents is required, the usual dose of the other agent may need to be reduced initially by up to 50%; subsequent dosage adjustments should be based on BP response.44 83 Dosage reduction of both drugs may be required.39
If intolerable adverse effects occur, consider dosage reduction; if adverse effects worsen or fail to resolve, may need to discontinue and switch to another antihypertensive drug class.501
Edema in Heart Failure
Initially, 2.5 mg once daily in the morning.83
Dosages >5 mg daily do not appear to result in further improvement in heart failure or BP and are associated with increased risk of hypokalemia;24 29 39 83 such dosages have been employed only in a limited number of clinical studies.24 29 39 83
No specific dosage recommendations.83 (See Hepatic Impairment under Cautions.)
No specific dosage recommendations.83 (See Geriatric Use under Cautions.)
Cautions for Indapamide
Severe hyponatremia (serum sodium concentration <120 mEq/L), accompanied by hypokalemia, occurs rarely.51 52 53 54 55 56 57 58 59 60 61 Do not administer sodium chloride unless the hyponatremia is life threatening or actual sodium depletion is documented.21 If sodium chloride is administered, initially only correct to a state of mild hyponatremia; avoid early overcorrection to normonatremia or hypernatremia (risk of central pontine myelinolysis).52 55 60 62
Possible dilutional hyponatremia; occurs most commonly in patients with edema.21 51 54 Usually asymptomatic and managed by fluid intake restriction (e.g., 500 mL/day)21 and withdrawal of the diuretic.51 54
Hypokalemia occurs commonly.9 21 24 28 47 Increased risk of hypokalemia, especially with brisk diuresis; large dosages (i.e., ≥5 mg daily);21 24 29 39 40 83 inadequate oral electrolyte intake; in presence of severe cirrhosis, hyperaldosteronism, or potassium-losing renal diseases; or during concomitant use of corticosteroids or ACTH.21 24 83
Generally, do not use with lithium salts.21 (See Specific Drugs under Interactions.)
Rash (e.g., erythematous, maculopapular, morbilliform), urticaria, pruritus, and vasculitis reported.21 63 In some cases, rash was accompanied by fever and/or dysuria.63 Rash generally resolves within 2 weeks after drug discontinuance, usually without specific therapy.63 64 May be treated with antihistamines.63
Fluid and Electrolyte Imbalance
Risk of electrolyte disturbances (e.g., hyponatremia, hypokalemia, hypochloremic alkalosis, hypomagnesemia).21 (See Hyponatremia and also Hypokalemia under Cautions.)
Periodic determinations of serum electrolyte concentrations (particularly potassium, sodium, chloride, and bicarbonate) should be performed and are especially important in patients at increased risk from hypokalemia (e.g., geriatric patients, those with cardiac arrhythmias, receiving concomitant cardiac glycosides, and/or with a history of ventricular arrhythmias),21 24 39 and those with diabetes mellitus, vomiting, diarrhea, parenteral fluid therapy, or expectations of other electrolyte imbalance (e.g., heart failure, renal disease, cirrhosis, restricted sodium intake, advanced age).21 83
Observe carefully for manifestations of fluid and electrolyte depletion (e.g., dryness of mouth, thirst, weakness, fatigue, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, arrhythmia, GI disturbance).21 83 Measures to maintain normal serum concentrations should be instituted if necessary.21 83
Risk of hyperuricemia, especially in patients with a history of gout, family predisposition to gout, or chronic renal failure.4 10 12 17 25 28 29 39 47 Usually asymptomatic and rarely leads to clinical gout.19 21 24 28 29 39
Risk of increased blood glucose, hyperglycemia, glycosuria, and impaired glucose tolerance;15 21 24 28 precipitation of diabetes mellitus rarely reported in patients with a history of impaired glucose tolerance (latent diabetes).21
Monitor blood glucose concentrations periodically, especially in patients with known or suspected (e.g., marginally impaired glucose tolerance) diabetes mellitus.21
May decrease calcium urinary excretion; slight intermittent serum calcium increases reported;83 clinically important changes in serum total or ionic calcium concentrations have not been reported.20 21 24
Antihypertensive effect may be enhanced after sympathectomy.21
Diuretics are considered second-line agents for control of chronic hypertension in pregnant women;142 500 if initiation of antihypertensive therapy is necessary during pregnancy, other antihypertensives (i.e., methyldopa, nifedipine, labetalol) are preferred.142 540
Safety and efficacy not established.83
Increased risk of hypochloremic alkalosis associated with hypokalemia.21
Increased risk of hypochloremic alkalosis associated with hypokalemia.21
Evaluate renal function (e.g., BUN, Scr) periodically.21
Common Adverse Effects
Hypokalemia,9 21 24 28 47 headache,3 21 24 28 dizziness,3 21 24 28 29 fatigue,3 21 24 weakness,21 29 lethargy,21 tiredness,21 malaise,21 muscle cramps or spasm,3 21 24 29 numbness of the extremities,21 nervousness,21 24 tension, anxiety, irritability, agitation.21 83
Interactions for Indapamide
If concomitant therapy with other antihypertensive agents is required, dose of the other agent may need to be reduced initially by up to 50%; subsequent dosage adjustments should be based on BP response;44 83 dosage reduction of both drugs may be required39
Monitor for possible postural hypotension21
Possible electrolyte disturbances (e.g., hypokalemia, hypomagnesemia) may predispose to digitalis toxicity; possibly fatal cardiac arrhythmias21
Monitor electrolytes; correct hypokalemia21
Diuretics, potassium-sparing (e.g., amiloride, triamterene)
Concomitant therapy not fully evaluated40
Safety and efficacy of concurrent use for the prevention of hypokalemia have not been fully determined40
Monitor blood glucose concentrations periodically, especially in patients with known or suspected (e.g., marginally impaired glucose tolerance) diabetes mellitus21
Concomitant use generally contraindicated21
Potassium-depleting drugs (e.g., corticosteroids, corticotropin, amphotericin B)
Additive hypokalemic effects21
Monitor electrolytes; correct hypokalemia83
Vasopressors (e.g., norepinephrine, phenylephrine)
Unlikely to be clinically important21
Plasma Protein Binding
Not removed from circulation by hemodialysis.4
Tight, light-resistant containers at 20–25°C; avoid excessive heat.600
Precise mechanism of hypotensive action has not been determined, but postulated that diuretics lower BP mainly by reducing plasma and extracellular fluid volume41 44 and by decreasing peripheral vascular resistance possibly secondary to sodium depletion43 and/or vascular autoregulatory feedback mechanisms;41 however, part of the hypotensive effect of indapamide may be caused by direct arteriolar dilation.5 6 21 24 25 27 39
Advice to Patients
Importance of informing patients of the signs and symptoms of electrolyte imbalance and instructing them to contact their clinician if dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, oliguria, hypotension, tachycardia, GI disturbance, or muscle pains or cramps occur.21
Importance of informing patients with diabetes mellitus that blood glucose and urine glucose concentrations may increase.83
Advise hypertensive patients of importance of continuing lifestyle/behavioral modifications that include weight reduction (for those who are overweight or obese), dietary changes to include foods that are rich in potassium and calcium and moderately restricted in sodium (adoption of the Dietary Approaches to Stop Hypertension [DASH] eating plan), increased physical activity, smoking cessation, and moderation of alcohol intake.500
Advise that lifestyle/behavioral modifications reduce BP, enhance antihypertensive drug efficacy, and decrease cardiovascular risk and remain an indispensable part of the management of hypertension.500
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.83
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.83
Importance of informing patients of other important precautionary information. (See Cautions.)
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
AHFS DI Essentials. © Copyright 2018, Selected Revisions March 2, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
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