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Generic Name: Indapamide
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
An indoline diuretic and antihypertensive agent; pharmacologically similar to thiazide diuretics.83 500
Uses for Lozol
Used alone or in combination with other antihypertensive agents for all stages of hypertension.4 19 21 83 a 500
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
Management of edema and salt retention associated with heart failure.21 24 29 39 83
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
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
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
Lozol Dosage and Administration
BP Monitoring and Treatment Goals
Carefully monitor BP during initial titration or subsequent upward adjustment in dosage.500 501
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
Consider initiating antihypertensive therapy with a combination of drugs if patient's BP exceeds goal BP by >20/10 mm Hg.500 501 503 504
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.)
Administer orally as a single daily dose in the morning.21 83
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
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.)
Similar dosages to those employed for the management of edema associated with heart failure have been used in the management of edema from other causes†.29
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.4 24 83 (See Renal Impairment under Cautions.)
No specific dosage recommendations.83 (See Geriatric Use under Cautions.)
Cautions for Lozol
Known hypersensitivity to indapamide or other sulfonamide derivatives.21
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 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
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.21 28 44
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
Erythema multiforme and epidermal necrolysis63 reported rarely.c
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
Generally avoid or use with caution in hypertensive patients with a history of gout or elevated uric acid concentrations.500 502
Monitor serum uric acid concentrations periodically.83 Hyperuricemia and gout may be treated with a uricosuric agent.28 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
Use with caution in patients with hyperparathyroidism or thyroid disorders.21 Discontinue prior to performing parathyroid tests.21 83
Possible exacerbation or activation of systemic lupus erythematosus.21 83
Antihypertensive effect may be enhanced after sympathectomy.21
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
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
Diuretics are not recommended for prevention or management of gestational hypertension or preeclampsia.141 539 540
Not known whether distributed into human milk.83 Manufacturer states to discontinue nursing or the drug;83 however, considered to be compatible with breast-feeding.141
Safety and efficacy not established.83
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.21 24 39 (See Hypokalemia under Cautions.)
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
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.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 Lozol
Additive hypotensive effect;21 44 83 possible potentiation of postural hypotension21
Usually used to therapeutic advantage21 83
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
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
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
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 or antacids do not appear to affect absorption.20 24
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
Extensively metabolized in the liver, principally to glucuronide and sulfate conjugates.16 20 21 24 39
Excreted in urine (70%) mainly as metabolites and in feces (16–23%), probably including biliary elimination.20 21 25 39 83
Biphasic; terminal half-life is approximately 14–26 hours.16 20 21 24 39 83
Half-life is not prolonged in patients with impaired renal function.4 20 24
Not removed from circulation by hemodialysis.4
Tight, light-resistant containers at 20–25°C; avoid excessive heat.600
A sulfonamide diuretic; 12 24 pharmacologically and structurally related to thiazide diuretics.6 8 12 14 18 21 24 25 26 38 39 42
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.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
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 2017, 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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