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Indapamide

Pronunciation

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
Brands: Lozol

Introduction

An indoline diuretic and antihypertensive agent; pharmacologically similar to thiazide diuretics.83 84

Uses for Indapamide

Hypertension

Used alone or in combination with other antihypertensive agents for all stages of hypertension.1 4 19 21 48 66 83 84 a b

The JNC 7 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.1 14 18 21 24 48 66 84

Thiazide-like drugs have well-established benefits, can be useful in achieving goal BP alone or combined with other antihypertensive drugs, enhance the antihypertensive efficacy of multidrug regimens, and are more affordable than other agents.84 a b

JNC 7 recommends that thiazide-like drugs be used as initial therapy for the treatment of uncomplicated hypertension in most patients, either alone or combined with other classes of antihypertensive drugs with demonstrated benefit (e.g., ACE inhibitors, angiotensin II receptor antagonists, β-blockers, calcium-channel blockers).b

Most hypertension outcome studies have involved thiazide-like drugs, which generally have been unsurpassed in preventing cardiovascular complications of hypertension and are relatively inexpensive and well tolerated.b

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The principal goal of preventing and treating hypertension is to reduce the risk of cardiovascular and renal morbidity and mortality, including target organ damage.b The higher the baseline BP, the more likely the development of MI, heart failure, stroke, and renal disease.b

Effective antihypertensive therapy reduces the risk of stroke by about 34–40%, MI by about 20–25%, and heart failure by more than 50%.b

Antihypertensive drug therapy is recommended for all patients with SBP/DBP ≥140/90 mm Hg who fail to respond to life-style/behavioral modifications.b

Initial antihypertensive therapy with drugs generally is recommended for anyone with diabetes mellitus, chronic renal impairment, or heart failure having SBP ≥130 mm Hg or DBP ≥80 mm Hg.b

Black hypertensive patients generally tend to respond better to monotherapy with diuretics or calcium-channel blockers than to monotherapy with ACE inhibitors, angiotensin II receptor antagonists, or β-blockers.b

Diuretics largely eliminate the diminished response in blacks to ACE inhibitors, angiotensin II receptor antagonists, or β-blockers.b

Thiazide-like drugs are preferred in hypertensive patients with osteoporosis.b Secondary beneficial effect in hypertensive geriatric patients of reducing the risk of osteoporosis secondary to effect on calcium homeostasis and bone mineralization.b

Although hypertension during pregnancy responds well to thiazide-like drugs, and the drugs had been used widely in the past for preeclampsia and eclampsia,a d such use no longer is recommended and other antihypertensives (e.g., methyldopa, hydralazine, labetolol) currently are preferred.b

Edema in CHF

Management of edema and salt retention associated with CHF.21 24 29 39 83

Used in conjunction with moderate sodium restriction (≤3 g of sodium daily), an ACE inhibitor, and usually a β-adrenergic blocking agent, with or without a cardiac glycoside.70

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 CHF.70

Edema in Pregnancy

Diuretics should not be used for routine therapy in pregnant women with mild edema who are otherwise healthy.b d

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

Use of diuretics for the management of edema of physiologic and mechanical origin during pregnancy generally is not warranted.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

Diuretics will not prevent the development of toxemia, nor is there evidence that diuretics have a beneficial effect on the overall course of established toxemia.21 30

Edema (General)

Management of edema resulting from various causes.24 29 39

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

Administration

Administer orally as a single daily dose in the morning.21 83

Dosage

Individualize dosage according to individual requirements and response.1 66

Adults

Hypertension
BP Monitoring and Treatment Goals

Carefully monitor BP during initial titration or subsequent upward adjustment in dosage.a

Avoid large or abrupt reductions in BP.a

Adjust dosage at approximately monthly intervals (more aggressively in high-risk patients [stage 2 hypertension, comorbid conditions]) if BP control is inadequate at a given dosage; it may take months to control hypertension adequately while avoiding adverse effects of therapy.a

SBP is the principal clinical end point, especially in middle-aged and geriatric patients.a Once the goal SBP is attained, the goal DBP usually is achieved.a

The goal is to achieve and maintain a lifelong SBP <140 mm Hg and a DBP <90 mm Hg if tolerated.a

The goal in hypertensive patients with diabetes mellitus or renal impairment is to achieve and maintain a SBP <130 mm Hg and a DBP <80 mm Hg.a

Monotherapy
Oral

Initially, 1.25 mg once daily in the morning.83

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 24 29 39 83 (See Hypokalemia under Cautions.)

If adequate response is not achieved with the 5-mg daily dosage, add or substitute another antihypertensive agent.83 84

Although JNC previously recommended a usual dosage range of 1.25–5 mg daily,66 these experts currently (JNC 7) recommend a lower usual dosage range of 1.25–2.5 mg daily.84

Maintenance
Oral

In patients whose BP is controlled adequately with 2.5 or 5 mg daily, reduction in dosage, including alternate-day therapy, may be attempted.1 24 48 66

Dosage reduction should be gradual and deliberate and under close medical supervision.1 48 66

Combination Therapy
Oral

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

Edema in CHF
Oral

Initially, 2.5 mg once daily in the morning.83

If response is inadequate after 1 week, dosage may be increased to 5 mg daily given as a single dose in the morning.21 83

Dosages >5 mg daily do not appear to result in further improvement in heart failure and increase the risk of hypokalemia.83 24 29 39 83 (See Hypokalemia under Cautions.)

Edema (General)
Oral

Similar dosages to those employed for the management of edema associated with CHF have been used in the management of edema from other causes.29

Prescribing Limits

Adults

Oral

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

Special Populations

Hepatic Impairment

No specific dosage recommendations.83 (See Hepatic Impairment under Cautions.)

Renal Impairment

No specific dosage recommendations.4 24 83 (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations.83 (See Geriatric Use under Cautions.)

Cautions for Indapamide

Contraindications

  • Anuria.21

  • Known hypersensitivity to indapamide or other sulfonamide derivatives.21

Warnings/Precautions

Warnings

Hyponatremia

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

Risk of hyponatremia appears to be dose related;51 52 53 54 55 56 61 83 risk is greater in patients receiving a daily dosage of 2.5 or 5 mg.83

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

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.1 21 24 83

Risk of hypochloremic alkalosis associated with hypokalemia, especially in patients with renal or liver disease; usually mild.21 Specific therapy generally not required.21

Supplemental potassium chloride (including potassium-containing salt substitutes) may be necessary to prevent or treat hypokalemia and/or metabolic alkalosis.1 21 28 44

Lithium

Generally, do not use with lithium salts.21 (See Specific Drugs under Interactions.)

Sensitivity Reactions

Dermatologic Reactions

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

Erythema multiforme and epidermal necrolysis63 reported rarely.c

General Precautions

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),1 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

Hyperuricemia

Risk of hyperuricemia, especially in patients with a history of gout, family predisposition to gout, or chronic renal failure.1 4 10 12 17 25 28 29 39 47 Usually asymptomatic and rarely leads to clinical gout.1 19 21 24 28 29 39

Generally avoid or use with caution in hypertensive patients with a history of gout or elevated uric acid concentrations.b

Monitor serum uric acid concentrations periodically.83 Hyperuricemia and gout may be treated with a uricosuric agent.1 28 39

Endocrine Effects

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

Hypercalcemia

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

Use with caution in patients with hyperparathyroidism or thyroid disorders.21 Discontinue prior to performing parathyroid tests.21 83

Lupus Erythematosus

Possible exacerbation or activation of systemic lupus erythematosus.21 83

Sympathectomy

Antihypertensive effect may be enhanced after sympathectomy.21

Fetal/Neonatal Morbidity

Diuretics cross the placental barrier and appear in cord blood.83 Use with caution; possibility of fetal or neonatal jaundice, thrombocytopenia, and other adverse effects reported in adults.83

Specific Populations

Pregnancy

Category B.83

Lactation

Not known whether distributed into human milk.83 Discontinue nursing or the drug.83

Pediatric Use

Safety and efficacy not established.83

Geriatric Use

Use with caution in geriatric patients, especially females who are underweight; increased risk of dilutional hyponatremia.51 52 53 54 55 56 61 (See Hyponatremia under Cautions.)

Increased risk of hypokalemia; close monitoring recommended.1 21 24 39 (See Hypokalemia under Cautions.)

Hepatic Impairment

Use with caution in hepatic impairment or progressive liver disease (particularly with associated potassium deficiency); electrolyte and fluid imbalance may precipitate hepatic coma.21 83

Increased risk of hypochloremic alkalosis associated with hypokalemia.21

Renal Impairment

Use with caution in patients with severe renal disease; reduced plasma volume may exacerbate or precipitate azotemia.4 21 83

Increased risk of hypochloremic alkalosis associated with hypokalemia.21

Risk of hyperuricemia in patients with chronic renal failure.1 4 10 12 17 25 28 29 39 47

Diuretic effect declines with decreasing renal function.4 21 83

Evaluate renal function (e.g., BUN, Scr) periodically.21

Consider interruption or discontinuance if progressive renal impairment (rising nonprotein nitrogen, BUN, or Scr) occurs.21 83

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

Specific Drugs

Drug

Interaction

Comments

Antihypertensive agents

Additive hypotensive effect;21 44 83 possible potentiation of postural hypotension21

Usually used to therapeutic advantage1 21 83 84

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

Digitalis glycosides

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

Insulin

Possible precipitation of diabetes mellitus21 and altered insulin requirements83 (see Endocrine Effects under Cautions)

Monitor blood glucose concentrations periodically, especially in patients with known or suspected (e.g., marginally impaired glucose tolerance) diabetes mellitus21

Lithium

Reduced renal clearance of lithium and increased risk of lithium toxicity21 23 24

Concomitant use generally contraindicated21

If concomitant therapy is necessary, monitor serum lithium concentrations and reduce lithium dosage by about 50%23 35

Potassium-depleting drugs (e.g., corticosteroids, corticotropin, amphotericin B)

Additive hypokalemic effects21

Monitor electrolytes; correct hypokalemia83

Vasopressors (e.g., norepinephrine, phenylephrine)

Possible decrease in arterial responsiveness to vasopressors21 24 27 39

Unlikely to be clinically important21

Indapamide Pharmacokinetics

Absorption

Bioavailability

Rapidly and completely absorbed following oral administration, with peak plasma concentration usually attained within 2–2.5 hours.16 20 21 24 39 83

Food

Food or antacids do not appear to affect absorption.20 24

Distribution

Extent

Lipophilic; widely distributed into most tissues.16 20 24

Not known whether indapamide crosses the placenta or is distributed into milk.21 40

Preferentially and reversibly distributes into erythrocytes;20 21 25 39 83 whole blood/plasma ratio is about 6 during peak concentration20 21 24 and about 3.5 eight hours after administration.21 83

Competitively and reversibly binds to carbonic anhydrase in erythrocytes, but does not appreciably inhibit the enzyme.24 39

Plasma Protein Binding

Approximately 71–79%.20 21 24 39 83

Elimination

Metabolism

Extensively metabolized in the liver, principally to glucuronide and sulfate conjugates.16 20 21 24 39

Elimination Route

Excreted in urine (70%) mainly as metabolites and in feces (16–23%), probably including biliary elimination.20 21 25 39 83

Half-life

Biphasic; terminal half-life is approximately 14–26 hours.16 20 21 24 39 83

Special Populations

Half-life is not prolonged in patients with impaired renal function.4 20 24

Not removed from circulation by hemodialysis.4

Stability

Storage

Oral

Tablets

Tight containers at 20–25°C; avoid excessive heat.83

Actions

  • A sulfonamide diuretic; 12 24 pharmacologically and structurally related to thiazide diuretics.6 8 12 14 18 21 24 25 26 38 39 42 d

  • Enhances excretion of sodium, chloride, and water by interfering with the transport of sodium ions across the renal tubular epithelium.12 20 24 25 26 39

  • Exact tubular mechanism(s) of action is not known;25 principal site of action appears to be the cortical diluting segment of the distal convoluted tubules of the nephron.20 21 25 26 39

  • Appears to indirectly increase potassium excretion by increasing the sodium load at the distal renal tubular site of sodium-potassium exchange.20 24

  • Increases proximal calcium reabsorption and does not inhibit distal calcium reabsorption in the renal tubules.20 21 24 25

  • Decreases free water clearance during hydration20 24 but not during dehydration.20

  • Decreases urinary uric acid excretion.24 25 28 39

  • No substantial effect on GFR or renal blood flow.4 20 21 24

  • May increase plasma renin activity and urinary aldosterone secretion.2 24 27

  • Hypotensive activity in hypertensive patients;19 20 21 24 28 also augments the action of other hypotensive agents.1 21

  • 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

  • Reduces total peripheral resistance.20 21 24

  • Usually no effect on cardiac output20 21 or left ventricular function12 13 in hypertensive patients.21 24

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

  • 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.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Indapamide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

1.25 mg*

Lozol

Aventis

2.5 mg*

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Indapamide 1.25MG Tablets (MYLAN): 90/$15.99 or 180/$19.97

Indapamide 2.5MG Tablets (MYLAN): 30/$13.99 or 90/$19.97

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 1, 2006. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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