Indapamide SR - A Review of Its Use AH - Drugs 2006

Drugs 2006; 66 (2): 257-271ADIS DRUG EVALUATION 0012-6667/06/0002-0257/$44.95/0

2006 Adis Data Information BV. All rights reserved.

Indapamide Sustained ReleaseA Review of its Use in the Treatment of Hypertension

Dean M. Robinson and Keri Wellington

Adis International Limited, Auckland, New Zealand

Various sections of the manuscript reviewed by:E. Ambrosioni, Divisione Medicina Interna, Policlinico S. Orsola, Universita di Bologna, Bologna, Italy; R.Asmar, L’Institut Cardiovasculaire, Paris, France; R. Donnelly, Derby City General Hospital, University ofNottingham, Derby, England; N.M. Kaplan, University of Texas, Southwestern Medical Center at Dallas,Dallas, Texas, USA; F.H.H. Leenen, University of Ottawa Heart Institute, Ottawa, Ontario, Canada; G.Leonetti, Department of Cardiology, Ospedale San Luca, Milan, Italy; H.F. McIntyre, Conquest Hospital,Hastings, England; P.A. Meredith, University Department of Medicine and Therapeutics, The WesternInfirmary, Glasgow, Scotland.

Data SelectionSources: Medical literature published in any language since 1980 on indapamide SR, identified using MEDLINE and EMBASE,supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists ofpublished articles. Bibliographical information, including contributory unpublished data, was also requested from the company developingthe drug.Search strategy: MEDLINE, EMBASE and AdisBase search terms were ‘indapamide SR’ or ‘indapamide sustained release’. Searcheswere last updated 9 Jan 2006.Selection: Studies in patients with hypertension who received indapamide SR. Inclusion of studies was based mainly on the methodssection of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevantpharmacodynamic and pharmacokinetic data are also included.Index terms: Indapamide SR, hypertension, left ventricular hypertrophy, microalbuminuria, pharmacodynamics, pharmacokinetics,therapeutic use.

ContentsSummary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2581. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2592. Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259

2.1 Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2592.1.1 Diuretic Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2602.1.2 Vasodilation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260

2.2 Effect on Vascular and Ventricular Hypertrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2602.3 Antihypertensive Effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2602.4 Metabolic Actions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261

3. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2623.1 Absorption and Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2623.2 Metabolism and Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263

4. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2634.1 Effects on Blood Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2644.2 Effects on Left Ventricular Hypertrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2664.3 Effects on Microalbuminuria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266

5. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266

258 Robinson & Wellington

6. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2677. Place of Indapamide Sustained Release in the Management of Hypertension . . . . . . . . . . . . . . . . . 268

SummaryA low-dose sustained-release (SR) formulation of the thiazide-type diureticAbstractindapamide, indapamide SR (Natrilix SR), retains the antihypertensive activityof the immediate-release (IR) formulation, with a smoother pharmacokineticprofile.

In well controlled 12- to 52-week clinical trials, indapamide SR 1.5 mg/daywas well tolerated and reduced blood pressure as effectively as therapeuticdosages of amlodipine, candesartan, enalapril, hydrochlorothiazide or indapamideIR. Indapamide SR was also more effective than enalapril in reducing leftventricular hypertrophy (LVH), and similar reductions in renal end-organ dam-age, assessed by microalbuminuria, were seen with indapamide SR- andenalapril-based antihypertensive strategies. Indapamide SR provides an effectiveoption for initial antihypertensive monotherapy and a basis for multidrugantihypertensive strategies.

Indapamide inhibits sodium chloride cotransport in the cortical diluting segmentPharmacologicalof the proximal distal tubule, as well as inhibiting a membrane-bound form ofPropertiescarbonic anhydrase.

Therapeutic dosages of indapamide have only a mild diuretic activity; theprimary antihypertensive activity of low-dose indapamide appears to occurthrough a direct vasodilatory effect. Indapamide also reduces vascular hypertro-phy and LVH in animal models of pressure overload.

Serum or plasma sodium and glucose levels in hypertensive patients wereunaffected by indapamide SR monotherapy over 12 to 52 weeks; modest reduc-tions in potassium and increases in uric acid levels have been observed.

Indapamide SR 1.5 mg/day for 7 days achieved a lower maximum bloodindapamide concentration (Cmax) than indapamide IR 2.5 mg/day (58 vs 154 µg/L) and took longer to reach Cmax (11.0 vs 0.8 hours), while total exposure (areaunder the concentration-time curve from time 0–24 hours corrected for dose; 726vs 690 µg • h/L) and minimum concentration (38 vs 41 µg/L) were similar.Indapamide undergoes extensive hepatic metabolism, and elimination occurs in abiphasic manner (terminal elimination half-life 15–24 hours), mainly throughrenal (≈70%) and biliary (≈22%) pathways.

In well controlled clinical trials of 12–52 weeks’ duration, indapamide SR 1.5 mg/Therapeutic Efficacyday reduced both mean supine systolic blood pressure (SBP) and diastolic bloodpressure (DBP). In patients with essential hypertension or isolated systolic hyper-tension, the reductions in mean supine SBP and DBP induced by indapamide SRwere significantly larger than those seen with placebo, and SBP reductions weregreater than those with enalapril 10 mg/day. Reductions in supine SBP and DBPwith indapamide SR were similar to those with amlodipine 5 mg/day, candesartan8 mg/day, indapamide IR 2.5 mg/day and enalapril 20 mg/day. In elderly patients(aged ≥65 years), reductions in mean supine SBP and DBP induced byindapamide SR were equivalent to those with amlodipine 5 mg/day orhydrochlorothiazide 25 mg/day.

2006 Adis Data Information BV. All rights reserved. Drugs 2006; 66 (2)

Indapamide SR in Hypertension: A Review 259

End-organ damage was also reduced by indapamide SR. LVH was reduced inindapamide SR 1.5 mg/day but not enalapril 20 mg/day recipients after 48 weeksof therapy in patients with essential hypertension. In patients with type 2 diabetesmellitus, multidrug indapamide SR 1.5 mg/day based and enalapril 10 mg/day-based antihypertensive strategies induced similar reductions in urinary albu-min : creatinine ratio and fractional albumin clearance; noninferiority was notdemonstrated in the reduction of albumin excretion rate.Indapamide SR 1.5 mg/day was generally well tolerated. Headache, back pain,Tolerabilitynausea and diarrhoea were observed at relatively low rates (0.2–1.6%), andorthostatic hypotension was observed in 0.4–8.6% of recipients. Hypokalaemia(serum potassium <3.4 mmol/L) occurred in 4–11% of indapamide SR recipients,while the incidence of moderate to severe hypokalaemia (<3.0 mmol/L) was0–1.5%.

1. Introduction good tolerability.[8,9] There is also evidence that ithas cardiovascular protective properties[10] and

Hypertension is a highly prevalent risk factor for reduces indicators of end-organ damage such ascardiovascular disease (CVD) and is estimated to microalbuminuria[11] and left ventricular hypertro-cause 7.1 million premature deaths worldwide annu- phy (LVH).[12]

ally and 4.4% of the global disease burden.[1] Treat- In response to the recommendation for low-dos-ment of hypertension reduces the risk of stroke by age antihypertensive therapies[13] a sustained-release≈35–40%, while the risk of coronary heart disease (SR) formulation of indapamide, indapamide SR,1(CHD) is reduced by ≈20–25%.[2]

was developed and is the focus of this review.Recently revised guidelines[3-6] for the treatment

of hypertension recommend the initiation of antihy- 2. Pharmacodynamic Propertiespertensive therapy at a systolic blood pressure (SBP)

Indapamide SR is a hydrophilic, high viscosity,of ≥160[3] or 180mm Hg[5] and/or a diastolic bloodmethylhydroxypropylcellulose matrix formulationpressure (DBP) of ≥100[3] or 110mm Hg,[5] or at anof indapamide.[13] Most of the pharmacodynamicSBP/DBP of ≥140/90mm Hg in patients with otherdata presented herein were obtained from studiesrisk factors, including cardiovascular disease or oth-using an indapamide immediate-release (IR) formu-er target organ damage.[3,5] European and US guide-lation.lines recommend lifestyle interventions at threshold

pressures as low as SBP/DBP 120/80mm Hg.[5,6]

2.1 Mechanism of ActionThiazide-type diuretics have been recommended

as the primary treatment modality for hypertension, Despite the long clinical history of indapamide,with low doses improving tolerability,[4,6] and long- its mechanism of action remains to be fully deter-acting formulations recommended to improve com- mined, although some pharmacological properties,pliance, hypertensive control and cardiovascular including diuretic and vasoactive properties, haveprotection.[5,7] been described.[10,14] Indapamide appears to inhibit

Indapamide is a thiazide-type diuretic derived the Na+/Cl– cotransporter[15] in the cortical dilutingfrom chlorosulphonamide, which has a long clinical segment of the proximal distal tubule in a mannerhistory as an effective antihypertensive agent with similar to the thiazide diuretic metolazone.[14] How-

1 Natrilix SR, Natrilix LP, Natrilix Retard, Natrilix AP, Fludex LP, Fludex Retard, Fludex SR, Fludex

1.5mg, Tertensif SR, Tertensif Retard, Pretanix. The use of trade names is for product identification purposes onlyand does not imply endorsement.



ever, another major renal binding site of indapamide indapamide in vitro and in vivo have been attributedhas been identified as a membrane-bound form of to a variety of factors, including reductions in vascu-carbonic anhydrase with a dissociation constant of lar reactivity to angiotensin, angiotensin II, epineph-24 nmol/L and an inhibition constant of 400 nmol/ rine, norepinephrine, thromboxane A2 and pros-L.[14] Inhibition of carbonic anhydrase in the kidney taglandin (PG)F2.[10,15,21-23] Other properties of in-is thought to indirectly inhibit sodium/hydrogen ex- dapamide suggested to contribute to vasodilationchange and thereby decrease sodium chloride co- include free-radical scavenging[10] (reducing lowtransport.[14] It has also been proposed that carbonic density lipoprotein peroxidation,[24] increasing en-anhydrase inhibitors increase intracellular pH, there- dothelium-derived relaxing factor activity andby activating large-conductance calcium-activated preventing endothelial damage[10]) and elastin bind-potassium channels to hyperpolarise vascular ing, which may influence vessel rigidity.[10]

smooth muscle and reduce voltage-dependent calci- Data in humans are limited, but indapamide IRum influx causing vasorelaxation.[16] 2.5 mg/day for 4 weeks was significantly (p < 0.05)

In vitro data indicate that the lipid solubility of antihypertensive in anephric patients on long-termindapamide is 5- to 80-fold higher than that of other haemodialysis, an effect not associated with thethiazide-type diuretics and allows extensive ac- diuretic actions of indapamide.[25] Indapamide forcumulation of the drug in vascular smooth mus- 2–12 weeks also reduced vascular reactivity tocle,[17] and that indapamide reduces inward calcium norepinephrine, angiotensin II and phenylephrine,and sodium currents, outward potassium currents and increased the release of local acting vasodila-and calcium release from peripheral sarcoplasmic tors, including PGE2 and PGF2α.[10]

reticular stores, all factors associated with the con-2.2 Effect on Vascular andtraction of vascular smooth muscle.[18]

Ventricular Hypertrophy2.1.1 Diuretic ActivityAlthough indapamide is generally referred to as a In vitro, a reduction in cytosolic free calcium was

thiazide-type diuretic, data from both short-term and associated with indapamide-induced inhibition ofmedium-term studies indicate that at therapeutic proliferation in a vascular smooth-muscle cell cul-dosages (2.5 mg/day) indapamide IR has only mild ture,[26] while in vivo, in spontaneously hypertensivediuretic activity.[19] rats, indapamide 1 mg/kg/day reduced, but did not

normalise, mean cerebral arteriolar pressure and at-The diuretic action of indapamide occurs as atenuated increases in cerebral arteriolar wall thick-result of the inhibition of sodium reabsorption in theness and distensibility.[27]cortical segment of the distal tubule.[20] In animal

models, indapamide IR increased natriuresis 2- to In an in vivo rat model of pressure overload LVH,3-fold and kaliuresis 1.2-fold at a dose of 1 mg/kg; low-dose (1 mg/kg/day) but not high-dose (10 mg/higher doses did not affect natriuresis, but kaliuresis kg/day) indapamide led to regression of LVH inde-and the risk of hypokalaemia were increased.[15] pendent of blood-pressure lowering, probably

through downregulation of genes responsible forAlthough diuretic activity was observed in hyper-cardiac growth regulation, including ACE messen-tensive patients at an indapamide IR dosage of 5 mg/ger RNA.[28] The lack of effect of high-dose in-day, at 2.5 mg/day no significant effects were ob-dapamide was attributed to a countervailing activa-served in plasma volume or total body sodium ortion of the renin-angiotensin system.potassium, and only mild hypokalaemia, hyperuri-

caemia and weight loss occurred.[19]

2.3 Antihypertensive Effect2.1.2 VasodilationThe antihypertensive activity of low-dose in- Indapamide SR 1.5 mg/day was as effective in

dapamide may occur primarily through a direct reducing hypertension as indapamide SR 2.0 orvasodilatory effect.[10,15,21] The vascular effects of 2.5 mg/day or indapamide IR 2.5 mg/day in a



randomised, double-blind, 2-month, dose-finding als;[29,30] and the 2-month, dose-finding trial (sectiontrial in 285 patients aged 18–70 years with essential 2.3).[29]

hypertension (supine DBP of 95–114mm Hg).[29]Major concerns with the use of thiazide-type

Treatment with indapamide SR 1.5 mg/day reduced diuretics revolve around sodium and potassium de-supine SBP/DBP by significantly more than placebo pletion and uric acid and glucose accumulation.[36]

(reductions of 19/11mm Hg vs 9/5mm Hg; both Serum or plasma sodium and glucose levels werep ≤ 0.01). No significant linear dose trends across unaffected by indapamide SR treatment over 2–3the SR-treated groups were observed and reductions months, while modest reductions in potassium andwere similar to those induced by indapamide IR increases in uric acid levels were induced by in-2.5 mg/day (18/10mm Hg).[29]

dapamide SR[29,30,32] that were similar or less thanthose induced by indapamide IR (table I).[29]

2.4 Metabolic ActionsThe metabolic effects of longer-term exposure to

Changes in metabolic parameters with inindapamide SR are also moderate. In a nonblinddapamide SR 1.5 mg/day therapy have been ex- extension of the indapamide SR/IR equivalence tri-amined in large, randomised, comparative, double- al, mean serum uric acid levels returned to baselineblind, multicentre 12- to 52-week trials (see trial after 9 months,[34] while in a nonblind extension (n =design details in section 4);[29-33] nonblind, 9- to 354)[35] of the 3-month trial in elderly patients,[30]

12-month extensions[29,34,35] of two of these tri- small but significant (p < 0.05) declines from base-

Table I. Change in metabolic parameters induced by indapamide (IND) sustained release (SR). Mean change in serum[29-31] or plasma[32,33]

levels of biochemical parameters in intention-to-treat populations in randomised, double-blind, multicentre trials of IND SR,[29-32] INDimmediate release (IR),[29] amlodipine (AML)[30] or hydrochlorothiazide (HCTZ)[30] monotherapy, and IND SR-based and enalapril (ENA)-based multidrug antihypertensive strategies.[33] See table III for trial design details and inclusion criteria

Study (acronym) Duration Treatment No. Sodium Potassium Uric acid Glucose Cholesterol(mg/day) of (mmol/L) (mmol/L) (µmol/L) (mmol/L) (mmol/L)

pts. baseline change baseline change baseline change baseline change baseline change

Ambrosioni et al.[29] 2moa IND SR 1.5 57 141.3 –0.4 4.28 –0.43b 288 +40 5.2 0.0 5.9 0.0

IND IR 2.5 59 141.7 –0.4 4.16 –0.42 284 +71 5.2 +0.2 6.2 +0.2

3moc IND SR 1.5 200 140.8 –0.3 4.18 –0.25d**311 +34* 5.4 +0.1 6.2 0.0

IND IR 2.5 205 141.1 –0.7 4.20 –0.40d 316 +51 5.6 +0.1 5.9 +0.2

Emeriau et al.[30] 12wk IND SR 1.5 178 NR +37 NR +0.3 NR +0.2

HCTZ 25 175 NR +27 NR +0.2 NR +0.1

AML 5 171 NR –7 NR –0.1 NR –0.1

Gosse et al.[31] ef 48wk IND SR 1.5 252 341 +13 5.6 –0.1 6.0 –0.2(LIVE)

London et al.[32] f 12wk IND SR 1.5 440 4.29 –0.21(X-CELLENT)

Marre et al.[33] 52wk IND SR 1.5g 283 139.8 –0.9 4.4 –0.2** 336 +30** 8.9 +0.8 5.2 +0.2*

(NESTOR) ENA 10g 286 139.8 –0.9 4.4 +0.1 335 +6 9.3 +0.3 5.4 –0.1

a Dose-ranging trial. Metabolic parameters not reported for IND SR 2.0 and 2.5 mg/day dosages.[29]

b After 4 weeks of treatment.

c SR/IR equivalence trial.

d After 6 weeks of treatment.

e Data obtained from Weidmann.[34]

f Metabolic parameters for comparators not reported.

g Plus AML 5 or 10 mg/day and/or atenolol 50 or 100 mg/day as required to achieve systolic/diastolic blood pressure ≤140/85mm Hg.

LIVE = Left ventricular hypertrophy regression: Indapamide Versus Enalapril trial; NESTOR = Natrilix SR versus Enalapril Study in Type 2diabetic hypertensives with micrOalbuminuRia; NR = not reported; X-CELLENT = NatriliX SR versus CandEsartan and amLodipine in thereduction of systoLic blood prEssure in hyperteNsive patienTs trial. * p < 0.05, ** p ≤ 0.001 vs comparator.



Table II. Pharmacokinetic characteristics of indapamide. Mean data from double-blind, randomised, crossover trials in healthy volunteersaged 18–37 years after a single dose of IND immediate release (IR) or sustained release (SR) under fed (fd) or fasted (fs) conditions(n = 12), and after repeated-dose administration for 7 days (n = 12)[37]

Treatment Cmax Cmax tmax Cmin t0.75 AUCb AUCb CLR t1/2β(µg/L) dose correcteda (h) (µg/L) (h) (µg • h/L) dose correcteda (mL/min) (h)

(µg/L) (µg • h/L)

Single dose

IND IR 2.5mg (fs) 98 39 0.8 1.8 1409 564 18.4

IND SR 1.5mg (fs) 26* 18* 12.3 15.3* 839 559 14.8

IND SR 1.5mg (fd) 34*† 22* 9.8 11.6* 983 653† 20.6

Repeated dose

IND IR 2.5 mg/day 154 62 0.8 41 1.5 1726 690 2.1 24.2

IND SR 1.5 mg/day 58** 39 11.0 38 16.4* 1089 726 2.1 19.2

a Normalised to 1mg or 1 mg/day.

b In the single-dose trial, AUC from time zero to infinity; in the repeated dose trial, AUC from time zero to 24 hours on day 7.

AUC = area under the concentration-time curve; Cmax = maximum blood concentration; Cmin = minimum blood concentration 24h after adose; ClR = renal clearance; tmax = time to reach Cmax; t0.75 = time during which IND concentration exceeded 75% of Cmax; t1/2β = terminalelimination half-life; * p < 0.01, ** p < 0.001 vs IND IR; † p < 0.01 vs IND SR 1.5 mg (fs).

line in mean serum sodium (1.6 mmol/L) and potas- 3.1 Absorption and Distributionsium (0.26 mmol/L) levels and rises in mean uric

Compared with the indapamide IR 2.5mg formu-acid levels (36 µmol/L) were observed at 15lation, use of indapamide SR 1.5mg was associatedmonths.[35]

with a reduced and delayed peak blood indapamideIn double-blind, 48-[31] and 52-week[33] trials in concentration, with similar total exposure and mini-

hypertensive patients with LVH[31] or type 2 diabe- mum concentration (table II).[37] Single-dose admin-tes mellitus,[33] indapamide SR did not alter mean istration of indapamide SR 1.5mg resulted in a sig-

nificantly lower maximum blood indapamide con-serum or plasma sodium or glucose levels (tablecentration (Cmax) than after single-doseI).[31,34] However, modest differences were inducedadministration of indapamide IR 2.5mg, while thein mean plasma potassium, uric acid and total cho-time to reach Cmax (tmax) and the time during whichlesterol levels in the 52-week trial (table I).[33] Athe blood indapamide concentration exceeded 75%greater increase in mean glycated haemoglobin oc-of Cmax (t0.75) were prolonged (table II). The two

curred in indapamide SR (from 7.4% at baseline toformulations were bioequivalent, with an SR : IR

8.4% after 1 year) than enalapril recipients (from ratio for dose-corrected area under the concentra-7.7% at baseline to 7.9% after 1 year; p = 0.0006); tion-time curve from time zero to infinity (AUC∞)however, diabetes control was not a primary objec- of 1.00 (90% CI 0.88, 1.14). Indapamide Cmax andtive of the trial.[33] dose-corrected AUC∞ were higher by a small mar-

gin in fed versus fasted conditions, but food did notaffect other pharmacokinetic parameters[37] and is3. Pharmacokinetic Propertiesnot considered clinically relevant.[38]

Repeated administration of the indapamide SRThe pharmacokinetic properties of indapamide

formulation resulted in a smoothed indapamideSR 1.5 mg/day have been compared with those of blood profile compared with the higher-dose IRindapamide IR 2.5 mg/day after single-dose or re- formulation, with a significant reduction in peak-to-peated oral administration in two groups of 12 trough fluctuations in drug concentration (161% vshealthy volunteers aged 18–37 years in randomised, 40%; p < 0.001).[37] After repeated indapamide SRdouble-blind, crossover trials (table II).[13,37] 1.5 mg/day administration, the Cmax was signifi-



cantly lower than that after indapamide IR 2.5 mg/ ly through renal (≈70%) and biliary (≈22%) path-day, while t0.75 was significantly prolonged (table ways as inactive metabolites.[39,40]

II). Steady state was achieved after 5 days and the4. Therapeutic Efficacyminimum blood concentration and AUC from 0 to

24 hours corrected for dose did not differ betweenThe efficacy of indapamide SR 1.5 mg/day in theformulations.[37]

treatment of hypertension has been examined in fiveIndapamide is widely distributed, with an appar-large (n = 405–1758), randomised, comparative,ent volume of distribution of 25L,[39] while plasmadouble-blind, multicentre trials of 12- to 52-weeks’protein binding is reported to be 76–79%.[39,40] Otherduration.[29-33] Trials were conducted in patientsparameters, such as complete gastrointestinal ab-with essential hypertension[29-33] or isolated systolicsorption and almost 100% bioavailability, do nothypertension (ISH).[30,32] Efficacy data fromdiffer between formulations.[40] Indapamide is high-noncomparative 9-[29] and 12-month[35] extensionsly bound to red blood cells (80%), specifically toof two of these trials,[29,30] and a large noncompara-carbonic anhydrase (98%).[38]

tive trial,[41] confirm the findings of these compara-tive studies and are not discussed further.3.2 Metabolism and Elimination

Trial design details of the trials are presented inElimination of indapamide after single or repeat- table III. Four of the trials compared the efficacy of

ed doses of IR and SR formulations was biphasic, indapamide SR 1.5 mg/day with placebo,[32] in-with a mean terminal elimination half-life of 15–24 dapamide IR 2.5 mg/day,[29] the long-actinghours that did not differ among treatment groups dihydropyridine calcium-channel antagonist am-(table II).[37] Renal clearance on day 7 was indistin- lodipine 5 mg/day,[30,32] the thiazide diureticguishable between the SR and IR formulations. In- hydrochlorothiazide 25 mg/day,[30] the angiotensindapamide undergoes extensive hepatic metabolism II receptor antagonist candesartan 8 mg/day,[32] or(only 5–7% of a dose is excreted in the urine as the ACE inhibitor enalapril 10 mg/day.[31] The useunchanged drug[38,39]) and elimination occurs main- of other antihypertensive medication was not per-

Table III. Trial design details for five randomised, comparative, double-blind, multicentre trials[29-33] examining the efficacy of indapamide(IND) sustained release in patients (pts) with hypertension

Study Inclusion criteria Selected exclusion Age No. of Comparators Durationa Primary endpoints(acronym) (BP mm Hg) criteria (y) pts

Ambrosioni et al.[29] DBP 95–114 Hypokalaemia 18–70 405 IND IR 3mo DBP

Emeriau et al.[30] SBP 161–209, DBP 95–114; Orthostatic hypotension, ≥65 524 AML, HCTZ 12wk SBP, DBPSBP 161–209, DBP <95 hypokalaemia, uraemia

Gosse et al.[31] SBP 161–209, LVHb Cardiovascular disease >20 411 ENA 48wk LVMI(LIVE)

London et al.[32] SBP 150–179, DBP 95–114; Cardiovascular disease 40–80 1758 AML, CAN, 12wk SBP(X-CELLENT) SBP 160–179, DBP <90 PL

Marre et al.[33] SBP 140–180, DBP <110, Cardiovascular disease, 35–80 569 ENA 52wk UACR, AER, FAC(NESTOR) T2 diabetes, hypokalaemia, uraemia

microalbuminuriac

a Following a 1-month[29] or 2-[31] or 4-week[30,32,33] washout period.

b LVMI; men >120, women >110 g/m2.

c AER 20–200 µg/min.

AER = albumin excretion rate; AML = amlodipine; BP = blood pressure; CAN = candesartan; DBP = supine diastolic BP; ENA = enalapril;FAC = fractional albumin clearance; HCTZ = hydrochlorothiazide; IR = immediate release; LIVE = Left ventricular hypertrophy regression:Indapamide Versus Enalapril trial; LVH = left ventricular hypertrophy; LVMI = left ventricular mass index; NESTOR = Natrilix SR versusEnalapril Study in Type 2 diabetic hypertensives with micrOalbuminuRia; PL = placebo; SBP = supine systolic BP; T2 diabetes = type 2diabetes mellitus; UACR = urinary albumin : creatinine ratio; X-CELLENT = NatriliX SR versus CandEsartan and amLodipine in thereduction of systoLic blood prEssure in hyperteNsive patienTs trial.



Table IV. Effect of indapamide (IND) sustained release (SR) on blood pressure in patients (pts) with hypertension. Mean change in supinesystolic (SBP) and diastolic (DBP) blood pressure in intention-to-treat[29,30,32,33] and per-protocol populations[31] in randomised, double-blind,comparative, multicentre trials of IND SR.[29,30,32,33] See table III for trial design details and inclusion criteria

Study (acronym) Duration Treatment No. SBP (mm Hg) DBP (mm Hg)

(mg/day) of pts baseline decline baseline decline

Ambrosioni et al.[29] 3mo IND SR 1.5 200 162 15*‡ 101 11*‡a

IND IR 2.5 205 164 18* 102 11*a

Emeriau et al.[30] 12wk IND SR 1.5 178 174 23‡‡a 98 12‡‡a

AML 5 175 175 22a 98 11a

HCTZ 25 171 174 19a 98 11a

Gosse et al.[31] 48wkb IND SR 1.5 205c 172 25**‡‡ 101 13**‡‡

(LIVE) ENA 20 206c 172 25** 102 12**

London et al.[32] 12wk IND SR 1.5 440 164 17††a 97 7††

(X-CELLENT) AML 5 444 165 16††a 97 9††

CAN 8 435 164 16††a 97 8††

PL 439 165 7a 96 4

Marre et al.[33] 52wk IND SR 1.5d 283 161 24† 94 13

(NESTOR) ENA 10d 286 160 21 94 12

a Primary endpoint.

b Median exposure 11 months.

c Patient receiving monotherapy.

d Plus AML 5 or 10 mg/day and atenolol 50 or 100 mg/day as required to achieve SBP/DBP ≤140/85mm Hg.

AML = amlodipine; CAN = candesartan; ENA = enalapril; HCTZ = hydrochlorothiazide; IR = immediate release; PL = placebo. * p ≤ 0.01,** p < 0.001 vs baseline; † p < 0.05 vs ENA,[33] †† p < 0.0001 vs PL;[32] ‡ equivalence p < 0.05 (between-group difference <2mm Hg in SBP/DBP, with a SBP 95% confidence interval [CI] within ±9.5mm Hg and a DBP 95% CI within ±5mm Hg[29]) vs IND IR; ‡‡ equivalencep < 0.001 (between-group difference 95% CI ±9.5mm Hg for SBP and ±5mm Hg for DBP[30] or 90% CI ±8mm Hg for SBP and ±4mm Hg forDBP[31]) vs comparators.

mitted in these trials and patients with poorly con- damage, such as LVH (section 4.2)[31] ormicroalbuminuria (section 4.3),[33] as surrogatetrolled BP were withdrawn[30,32] or their data notendpoints (see table III).reported.[31]

No significant differences in baseline patientIn the other trial (NESTOR[33]), patients not re-characteristics between treatment groups were re-sponding adequately (supine SBP/DBP >140/ported in any of the trials.[29-33]

84mm Hg) to treatment with indapamide SR 1.5 mg/day or the comparator, enalapril 20 mg/day, by

4.1 Effects on Blood Pressureweek 6 received additional, progressive treatment at6-week intervals with amlodipine 5 mg/day, Indapamide SR reduced mean supine SBP andamlodipine 10 mg/day, amlodipine 10 mg/day plus DBP during treatment of 12–52 weeks’ durationatenolol 50 mg/day and finally amlodipine 10 mg/ (table IV).[29-33] In an indapamide SR/IR equiva-day plus atenolol 100 mg/day.[33]) This trial is there- lence trial,[29] reductions from baseline in mean su-fore considered as a comparison of indapamide SR- pine DBP and SBP with indapamide SR therapyand enalapril-based antihypertensive strategies. (table IV) were equivalent (p < 0.05) to those in-

The primary goal of antihypertensive therapy is duced by indapamide IR (difference, SBPthe reduction of cardiovascular morbidity and mor- 2.3mm Hg; 90% CI –0.52, +5.16: DBP 0.4mm Hg;

90% CI –1.05, +1.93).[29]tality; however, differences in these endpointsmay take years or decades to manifest. Therefore, Equivalent reductions in mean supine SBP andstudies use changes in blood pressure (BP) [section DBP were induced in an elderly population (mean4.1][29-33] or measures of end-organ adaptation or age 72 years) by indapamide SR, amlodipine (differ-



ence, SBP 0.9mm Hg; 90% CI –3.4, 1.7: DBP supine SBP ≥20mm Hg[31,32] or DBP1.0mm Hg; 90% CI –2.5, +0.4) and hydrochloroth- ≥10mm Hg[29,31,32]) with indapamide SR (61%,[32]

iazide (difference, SBP 3.3mm Hg; 90% CI –5.8, 66%[29] or 71%[31]), indapamide IR (69%),[29]

–0.7: DBP 1.0mm Hg; 90% CI –2.5, +0.4) [table enalapril (72%),[31] candesartan (59%) and amlodip-IV].[30] The ITT equivalence result was supported by ine (61%);[32] 35% of placebo recipients respond-per-protocol analysis, indicating that reductions in- ed.[32] Normalisation of BP (supine SBP/DBP ≤160/duced by indapamide SR in mean SBP/DBP (24/ 90mm Hg,[31] DBP ≤90mm Hg[29,30] or SBP12mm Hg) were equivalent to those induced by ≤160mm Hg in patients with ISH[30]) was achievedamlodipine (23/11mm Hg) and hydrochlorothiazide by a majority of indapamide SR (57%,[29] 60%[31] or(19/11mm Hg). 75%[30]), indapamide IR (61%),[29] amlodipine

In the X-CELLENT trial,[32] the reductions in (67%), enalapril (61%)[31] and hydrochlorothiazidemean supine SBP and DBP induced by indapamide (67%) recipients.[30]

SR were larger than those with placebo and similarA subgroup analysis of patients with ISH

to those induced by amlodipine or candesartan (dif-(n = 388) in the X-CELLENT trial, revealed reduc-

ferences between active comparators were not sig-tions in mean supine SBP from baseline in in-nificant).dapamide SR, candesartan and amlodipine recipi-

Results of analyses of secondary endpoints sup- ents (17, 16 and 16mm Hg, respectively), whichport the primary analyses. In the LIVE study,[31]

were significantly (p < 0.05) larger than those in-78% of indapamide SR recipients and 79% of

duced by placebo (9mm Hg), and which were simi-enalapril recipients required only monotherapy to

lar between active comparators.[32] Changes fromachieve a treatment response (decrease in supine

baseline in mean supine DBP in candesartanSBP <20mm Hg or DBP <10mm Hg) and the reduc-(–3mm Hg) and amlodipine (–3mm Hg) but nottions in mean supine SBP and DBP induced byindapamide SR (+1mm Hg) ISH treatment groupsindapamide SR 1.5 mg/day in those patients werewere significantly (p < 0.05) different from thatequivalent (p < 0.001) to those induced by enalaprilobserved in the placebo group (+2mm Hg), with a20 mg/day.significant (p = 0.02) difference between in-

In NESTOR,[33] 49% of indapamide SR versusdapamide SR and amlodipine recipients.[32]

43% of enalapril recipients required only monother-Equivalent (p < 0.01) reductions in mean supineapy to achieve a treatment response (decrease inSBP/DBP were also seen in elderly patients withsupine SBP/DBP ≤140/84mm Hg), while 39% ver-ISH (n = 128) who received indapamide SR,sus 42% required additional amlodipine, 3% versusamlodipine or hydrochlorothiazide (22/5, 22/5 or2% additional atenolol and 8% versus 12% required20/5mm Hg).[30]

amlodipine plus atenolol. The reduction from base-line in mean supine SBP induced by indapamide Reductions in mean systolic 24-hour ambulatorySR-based therapy was superior to that induced by BP monitoring (ABPM) were similar between in-enalapril-based therapy (table IV), while reductions dapamide SR, candesartan and amlodipine treat-from baseline in mean supine DBP were similar ment groups (8, 9, and 8mm Hg, respectively), andbetween treatment groups.[33] significantly (p < 0.0001) greater than with placebo

Compared with placebo, indapamide SR, can- (0mm Hg) in a subgroup analysis (n = 576) of the X-desartan and amlodipine significantly (p < 0.0001) CELLENT trial.[32] All three agents induced signifi-reduced mean pulse pressure (4mm Hg vs 9, 8 and cantly (p < 0.0001) larger reductions in mean dias-7mm Hg, respectively), and differences between tolic 24h-ABPM than placebo (4, 6 and 5mm Hg,active comparators were not significant.[32] respectively, vs 0mm Hg), although the reduction

induced by indapamide SR was less than that in-The majority of patients achieved a response totreatment (BP <140/90mm Hg,[32] a reduction in duced by candesartan (p = 0.039).



In NESTOR, supine mean arterial pressure(MAP) declined from baseline in both indapamideSR and enalapril recipients (17 and 15mm Hg), andno significant between-group differences in meansupine MAP, or in MAP over 24 hours (0.6mm Hg)in those (n = 99) who underwent 24h-ABPM moni-toring, were observed.[33]

4.2 Effects on Left Ventricular Hypertrophy

Indapamide SR 1.5 mg/day, but not enalapril20 mg/day, induced a reduction in left ventricularmass index (LVMI) after 48 weeks of monotherapyin patients with essential hypertension and LVH.[31]

Mean LVMI was significantly (one-sided t-test with90% CI) reduced from 144.0 to 135.7 g/m2 after 48weeks of therapy in indapamide SR but not enalapril(137.8 vs 135.9 g/m2) recipients, and the between-group difference was significant whether adjusted(4.3 g/m2, 90% CI –8.6, 0.0; p = 0.049) or unadjust-ed (6.5 g/m2, 90% CI –11.3, –1.7; p = 0.013) for

0 24 48

Week

Indapamide SREnalapril

*

*

−15

−10

−5

0

Cha

nge

in L

VM

I (g/

m2 )

Fig. 1. Effect of indapamide sustained release (SR) on left ventricu-lar hypertrophy. Mean (standard error) change in left ventricularmass index (LVMI) in a subgroup of patients who had evaluableechocardiograms at weeks 0, 24 and 48 during therapy with in-dapamide SR 1.5 mg/day (n = 130) or enalapril 20 mg/day (n = 139)in a randomised, double-blind trial.[31] Left ventricular mass wascalculated from end-diastolic M-mode echocardiographic measure-ments of left ventricular internal diameter, intraventricular septumthickness and posterior wall thickness, and divided by body surfacearea to determine LVMI (reproduced from Gosse et al.[31] with per-mission. Copyright 2000, Lippincott Williams & Wilkins). *p < 0.05 vs week 0.baseline values.[31] In a subgroup of indapamide SR

(n = 130) and enalapril (n = 139) recipients who hadminuria.[33] From a geometric mean baseline ofevaluable echocardiograms at weeks 0, 24 and 48, a6.16–6.17 mg/mmol the decline in urinary albu-significant reduction in LVMI with respect to base-min : creatinine ratio (2.13 vs 2.43 mg/mmol) in-line was observed at week 24 in both treatmentduced by indapamide SR was noninferior (one-sidedgroups. By week 48, the reduction remained signifi-t-test with a noninferiority limit of 35%; p < 0.025)cant only in indapamide SR recipients (figure 1).[31]

to that induced by enalapril, as was the reductionSecondary endpoint data generally supported pri-from the mean baseline fractional albumin clearancemary analyses. Absolute left ventricular mass wasof 10.98–11.06 × 10–6 (3.41 vs 4.14 × 10–6). How-reduced significantly more in indapamide SR thanever, the noninferiority of the reduction from a meanenalapril recipients (14.2 vs 3.0g; p = 0.044). Abaseline albumin excretion rate of 58.0–58.4 µg/minreduction in posterior wall thickness occurred ininduced by indapamide SR versus enalapril was notboth enalapril and indapamide SR recipients (2.0%demonstrated (21.5 vs 25.9 µg/min; p = 0.0616).[33]

and 1.6%; p < 0.01 and p < 0.05 vs baseline), whilechanges in intraventricular septum thickness and left

5. Tolerabilityventricular internal diameter were significant in in-dapamide SR (–1.8% and –1.7%; p < 0.05 and p < Withdrawals due to adverse events or for medical0.01 vs baseline) but not enalapril (+0.1% and reasons occurred in 2%,[32] 4%,[30] 5%,[33] 6%[29] or–0.3%) recipients.[31]

9%[31] of indapamide SR recipients, and in 3% ofindapamide IR,[29] 3%[32] or 7%[30] of amlodipine,4.3 Effects on Microalbuminuria5% of enalapril 10 mg/day[31] and 8% of enalapril 20mg/day,[33] 4% of hydrochlorothiazide,[30] 2% ofMicroalbuminuria was reduced by 52 weeks ofcandesartan and 2% of placebo recipients.[32]treatment with either indapamide SR 1.5 mg/day or

enalapril 10 mg/day in patients with essential hyper- Indapamide SR 1.5 mg/day was generally welltension, type 2 diabetes and persistent microalbu- tolerated in the 12- to 52-week trials discussed in



0

1

2

3

4

5

Headache Back pain Nausea Diarrhoea Peripheraloedema

Hot flushes

Indapamide SRCandesartanAmlodipinePlacebo

Pat

ient

s (%

)

Fig. 2. Tolerability of indapamide sustained release (SR). Incidence of emergent adverse events occurring in >4% of patients, or withdiffering frequencies, in patients with hypertension receiving indapamide SR 1.5 mg/day (n = 440), candesartan 8 mg/day (n = 436),amlodipine 5 mg/day (n = 444) or placebo (n = 440) for 12 weeks in a randomised, double-blind trial.[32] Statistical analyses were notreported.

section 4.[29,30,32,33] In the indapamide SR/IR equiva- zide 25 mg/day and 0% of amlodipine 5 mg/dayrecipients.[30]lence study, 23% of indapamide SR and 24% of

Orthostatic hypotension was observed in 0.4% ofindapamide IR recipients experienced adverse ef-indapamide SR and 0.7% of enalapril recipients infects,[29] while in the elderly population trial, ad-NESTOR[33] and in 8.6% of indapamide SR, 10.5%verse events were reported in 20% of indapamideof amlodipine and 11.3% of hydrochlorothiazideSR, 38% of amlodipine and 26% of hydrochloroth-recipients in the indapamide SR/IR equivalence tri-iazide recipients.[30]

al.[30]

Hypokalaemia (serum or plasma potassium Headache, back pain, nausea and diarrhoea werelevels <3.4 mmol/L) occurred in 4–11% of in- observed at relatively low rates in indapamide SRdapamide SR 1.5 mg/day recipients[29,30,32,33] and, recipients (figure 2),[32] whereas some adversewhere reported, 0–1.5% of these patients exper- events observed in recipients of active comparators,ienced more severe hypokalaemia (potassium levels peripheral oedema and hot flushes, were not ob-

served in indapamide SR recipients.<3.0 mmol/L).[29,30,32] Of note was a significantlylower incidence of hypokalaemia in patients receiv-

6. Dosage and Administrationing indapamide SR than in those receiving the IRformulation (9% vs 24%; p ≤ 0.001);[29] the inci-

Indapamide SR is approved in the UK[42] anddence of more severe hypokalaemia was similar for

most other European countries for the treatment ofpatients in both groups (1.5% vs 3.0%). By way of essential hypertension at a dosage of 1.5 mg/day.[20]

comparison, hypokalaemia was observed in 10% The indapamide SR tablet is orally administered andof hydrochlorothiazide 25 mg/day and 2% of should not be divided, crushed or chewed.amlodipine 5 mg/day recipients in the elderly popu- Local prescribing information should be con-lation trial,[30] and 1% of enalapril 10 mg/day recipi- sulted for dosage reduction guidelines in patientsents during NESTOR.[33] More severe hypokalaemia experiencing toxicity, dosage recommendations inwas observed in elderly patients in 1% of in- special populations, contraindications and precau-dapamide SR 1.5 mg/day, 2% of hydrochlorothia- tions.



7. Place of Indapamide Sustained in chlorthalidone recipients, while combined cardio-Release in the Management vascular disease and stroke rate was lower inof Hypertension chlorthalidone than lisinopril recipients. These dif-

ferences, along with the lower cost of thiazide-typeCardiovascular disease is a leading cause of mor- diuretics, led the ALLHAT investigators to suggest

tality and morbidity worldwide, causing approxi- thiazide-type diuretics as the primary treatment formately 29% of deaths annually,[43] and 62% of cer- hypertension.[48]

ebrovascular disease and 49% of ischaemic heart Recently revised guidelines[3-5] for the treatmentdisease cases are attributed to suboptimal BP.[1]

of hypertension suggest that there is a continuousModest reductions in DBP of 5–6mm Hg over relationship between BP level and cardiovascular

2–3 years are associated with a 42% reduction in the risk, and thus classification is based on total cardio-incidence of stroke and a 14% reduction in CHD.[2]

vascular risk. Although current US guidelines, theIn the multinational HOT (Hypertension Optimal 7th report of the Joint National Committee on theTreatment) trial in 18 790 patients with moderately prevention, detection, evaluation and treatment ofelevated DBP (100–115mm Hg), intensive treat- high BP (JNC7), classify risk solely on the basis ofment was maximally protective when SBP was low- BP values,[6] the American Society of Hypertensionered to ≤140mm Hg and DBP to ≤85mm Hg.[44]

(ASH) has proposed a revised definition of hyper-However, mortality rates over 20 years in treated tension that also emphasises the total cardiovascularhypertensive patients are still higher than those in risk.[50]

normotensive volunteers, particularly as a result ofBritish Hypertension Society guidelines[3] advo-ischaemic heart disease (2-fold higher) and stroke

cate the initiation of antihypertensive therapy if sus-(2.5-fold higher), as shown in a large, prospective,tained SBP/DBP is ≥160/100mm Hg, although inpopulation-based study.[45]

patients with cardiovascular disease or other targetMeta-analysis suggests that the reduction in riskorgan damage the thresholds should be lowered toof major cardiovascular events is highly dependent≥140/90mm Hg. However, WHO guidelines recom-on the magnitude of BP reduction, particularly SBPmend a lower threshold for therapy of ≥140mm/reduction, with no significant differences among90mm Hg,[4] and the European Society of Hyperten-different antihypertensive strategies (ACE inhibi-sion/European Society of Cardiology (ESH/ESC)tors, calcium channel antagonists, angiotensin-re-and JNC7 recommend lifestyle intervention atceptor antagonists, diuretics and β-adrenoceptor an-threshold pressures of ≥120/80mm Hg.[5,6]

tagonists).[46] In addition, the importance of promptLifestyle modifications are the initial treatmentcontrol of BP in optimising cardiovascular risk re-

modality for hypertension and should be started induction has been emphasised recently.[47]

all patients considered hypertensive[3-6] or prehyper-In the 6-year ALLHAT (Antihypertensive andtensive.[6] These lifestyle interventions includeLipid-Lowering treatment to prevent Heart Attacksmoking cessation, weight loss, increased physicalTrial) in 33 357 patients receiving a thiazide-typeactivity, moderation of alcohol intake, reduced diet-diuretic (chlorthalidone), a calcium-channel antago-ary intake of saturated fats and sodium, and annist (amlodipine), an α-adrenoceptor antagonistincreased intake of dietary potassium and fresh fruit(doxazosin) or an ACE inhibitor (lisinopril), theand vegetables.[3-6]

occurrence of fatal CHD or nonfatal myocardialinfarction did not differ among treatment Specific pharmacotherapeutic recommendationsgroups,[48,49] although the superiority of chlorthali- are not made in two of the guidelines,[3,5] althoughdone over doxazosin in terms of combined cardio- the use of long-acting drugs or preparations requir-vascular events led to early termination of the dox- ing only once-daily administration is recommendedazosin treatment arm.[49] SBP and rates of heart by ESH/ESC.[5] However, despite noting the gener-failure were higher in amlodipine and lisinopril than ally similar efficacy of most classes of antihyperten-



sive agents[4] and the common requirement for mul- in indapamide IR 2.5 mg/day recipients (section 5),tidrug therapy to achieve BP goals,[6] both the JNC7 while moderate to severe hypokalaemia was ob-and WHO guidelines recommend, in the absence of served in 0–1.5% of indapamide SR recipients.a compelling indication for another drug class, the Further studies are needed to clarify the mecha-first-choice use of a low-dose diuretic, particularly nism of action of indapamide, to fully examine theof the thiazide type, on the basis of equivalent additive benefits of indapamide SR as a basis forefficacy, good tolerability and generally lower multidrug therapy and to evaluate the pharmacoeco-cost.[4,6] nomics of indapamide SR. An ongoing trial of in-

dapamide SR in patients aged ≥80 years is intendedIndapamide is a thiazide-type diuretic that inhib-to examine the possibility that the positive relation-its sodium chloride cotransport in the cortical dilut-ship between BP reduction and cardiovascular mor-ing segment of the proximal distal tubule, as well astality is reversed in the very elderly (HYVET;inhibiting a membrane-bound form of carbonicHypertension in the Very Elderly Trial).[51]anhydrase (section 2). Therapeutic dosages of in-

In conclusion, in well controlled 12- to 52-weekdapamide have only a mild diuretic activity and theclinical trials, indapamide SR 1.5 mg/day was wellprimary antihypertensive activity of low-dose in-tolerated and reduced blood pressure as effectivelydapamide is through a direct vasodilatory effect. Itas therapeutic dosages of amlodipine, candesartan,also reduces vascular hypertrophy and LVH inenalapril, hydrochlorothiazide or indapamide IR. In-animal models of pressure overload.dapamide SR was also more effective than enalaprilIndapamide SR 1.5mg retains the activity of thein reducing LVH, and similar reductions in renaloriginal indapamide IR 2.5mg formulation alongend-organ damage, assessed by microalbuminuria,with a similar total drug exposure, with a smootherwere seen with indapamide SR- and enalapril-basedblood profile and a 75% reduction in peak-to-troughantihypertensive strategies. Indapamide SR pro-fluctuations in drug concentration (section 3).vides an effective option for initial antihypertensive

In well controlled, 12-week or 3-month,monotherapy and a basis for multidrug antihyper-

monotherapy trials, indapamide SR 1.5 mg/day in-tensive strategies.

duced reductions in mean supine SBP and DBP thatwere significantly larger than those seen with place-

Disclosurebo, and similar to those induced by amlodipine5 mg/day, candesartan 8 mg/day, indapamide IR

During the peer review process, the manufacturer2.5 mg/day and hydrochlorothiazide 25 mg/dayof the agent under review was offered an opportuni-(section 4.1). In 48- and 52-week trials, indapamidety to comment on this article; changes based on anySR 1.5 mg/day induced reductions in supine SBPcomments received were made on the basis of scien-and DBP equivalent to those induced by enalapriltific and editorial merit.20 mg/day, and SBP reductions superior to those

induced by enalapril 10 mg/day.ReferencesEnd-organ damage was also improved by in-

1. World Health Organization. The World Health Report 2002.dapamide SR 1.5 mg/day, with a 48-week period of Reducing risks, promoting healthy life [online]. Availabletreatment inducing a reduction in LVH that was not from URL: http://www.who.int/whr/2002/en/index.html [Ac-

cessed 2004 Jun 13]observed after enalapril 20 mg/day therapy (section2. Collins R, Peto R, MacMahon S, et al. Blood pressure, stroke,

4.2), while indapamide SR 1.5 mg/day for 52 weeks and coronary heart disease. Part 2, short-term reductions inblood pressure: overview of randomised drug trials in theirwas similar to enalapril 10 mg/day in reducingepidemiological context. Lancet 1990 Apr 7; 335 (8693):microalbuminuria (section 4.3). 827-38

3. Williams B, Poulter NR, Brown MJ, et al. Guidelines forIndapamide SR was generally well tolerated,management of hypertension: report of the fourth workingwith hypokalaemia occurring in indapamide SR party of the British Hypertension Society, 2004-BHS IV. J

1.5 mg/day recipients (4–11%) at a lower rate than Hum Hypertens 2004 Mar; 18 (3): 139-85



4. World Health Organization International Society of Hyperten- 23. Kyncl J, Oheim K, Seki T, et al. Antihypertensive action ofsion Writing Group. 2003 World Health Organization (WHO)/ indapamide: comparative studies in several experimental mod-International Society of Hypertension (ISH) statement on man- els. Arzneimittelforschung 1975 Oct; 25 (10): 1491-5agement of hypertension. J Hypertens 2003 Nov; 21 (11): 24. Breugnot C, Iliou JP, Privat S, et al. In vitro and ex vivo1983-92 inhibition of the modification of low-density lipoprotein by

5. European Society of Hypertension-European Society of Cardi- indapamide. J Cardiovasc Pharmacol 1992 Sep; 20 (3): 340-7ology Guidelines Committee. 2003 European Society of Hy- 25. Acchiardo SR, Skoutakis VA. Clinical efficacy, safety, andpertension-European Society of Cardiology guidelines for the pharmacokinetics of indapamide in renal impairment. Ammanagement of arterial hypertension. J Hypertens 2003 Jun; Heart J 1983 Jul; 106 (1 Pt 2): 237-4421 (6): 1011-53 26. Ganado P, Ruiz E, Del Rio M, et al. Growth inhibitory activity

6. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of of indapamide on vascular smooth muscle cells. Eur Jthe Joint National Committee on prevention, detection, evalua- Pharmacol 2001 Sep 28; 428 (1): 19-27tion, and treatment of high blood pressure. Hypertension 2003 27. Chillon JM, Baumbach GL. Effects of indapamide, a thiazide-Dec; 42 (6): 1206-52 like diuretic, on structure of cerebral arterioles in hypertensive

7. The sixth report of the Joint National Committee on prevention, rats. Hypertension 2004 May; 43 (5): 1092-7detection, evaluation, and treatment of high blood pressure.

28. Bocker W, Hupf H, Grimm D, et al. Effects of indapamide inArch Intern Med 1997 Nov 24; 157: 2413-46rats with pressure overload left ventricular hypertrophy. J

8. Chaffman M, Heel RC, Brogden RN, et al. Indapamide: a Cardiovasc Pharmacol 2000 Oct; 36 (4): 481-6review of its pharmacodynamic properties and therapeutic

29. Ambrosioni E, Safar M, Degaute JP, et al. on behalf of theefficacy in hypertension. Drugs 1984 Sep; 28 (3): 189-235European study group. Low-dose antihypertensive therapy

9. Ames RP. A comparison of blood lipid and blood pressurewith 1.5 mg sustained-release indapamide: results of

responses during the treatment of systemic hypertension withrandomised double-blind controlled studies. J Hypertens 1998

indapamide and with thiazides. Am J Cardiol 1996 1996; 77Nov; 16 (11): 1677-84

(6): 12-16b30. Emeriau JP, Knauf H, Pujadas JO, et al. A comparison of10. Campbell DB, Brackman F. Cardiovascular protective proper-

indapamide SR 1.5 mg with both amlodipine 5 mg andties of indapamide. Am J Cardiol 1990 May 2; 65: 11-27Hhydrochlorothiazide 25 mg in elderly hypertensive patients: a

11. Molyneaux LM, Willey KA, Yue DK. Indapamide is as effec- randomized double-blind controlled study. J Hypertens 2001tive as captopril in the control of microalbuminuria in diabetes. Feb; 19 (2): 343-50J Cardiovasc Pharmacol 1996 Mar; 27 (3): 424-7

31. Gosse P, Sheridan DJ, Zannad F, et al. Regression of left12. Carey PA, Sheridan DJ, de Cordoue A, et al. Effect of in-ventricular hypertrophy in hypertensive patients treated withdapamide on left ventricular hypertrophy in hypertension: aindapamide SR 1.5 mg versus enalapril 20 mg: the LIVEmeta-analysis. Am J Cardiol 1996; 77 (6): 17-19bstudy. J Hypertens 2000 Oct; 18 (10): 1465-75

13. Damien G, Huet de Barochez B, Schiavi P. Galenic develop-32. London GM, Schmieder R, Calvo C, et al. on behalf of the X-ment and pharmacokinetic profile of indapamide sustained

CELLENT study investigators. Indapamide SR versusrelease 1.5mg. Clin Pharmacokinet 1999; 37 (Suppl. 1): 13-9candesartan and amlodipine in hypertension: the X-CELLENT

14. Schaeffer P, Vigne P, Frelin C, et al. Identification and pharma-study. Am J Hypertens 2006 Jan; 19 (113-21)

cological properties of binding sites for the atypical thiazide33. Marre M, Garcia Puig J, Kokot F, et al. Equivalence of in-diuretic, indapamide. Eur J Pharmacol 1990 Jul 17; 182 (3):

dapamide SR and enalapril on microalbuminuria reduction in503-8hypertensive patients with type 2 diabetes: the NESTOR study.15. Bataillard A, Schiavi P, Sassard J. Pharmacological propertiesJ Hypertens 2004 Aug; 22 (8): 1613-22of indapamide: rationale for use in hypertension. Clin

34. Weidmann P. Metabolic profile of indapamide sustained-releasePharmacokinet 1999; 37 (Suppl. 1): 7-12in patients with hypertension: data from three randomised16. Pickkers P, Garcha RS, Schachter M, et al. Inhibition of carbon-double-blind studies. Drug Saf 2001; 24 (15): 1155-65ic anhydrase accounts for the direct vascular effects of

35. Leonetti G, Emeriau JP, Knauf H, et al. Evaluation of long-termhydrochlorothiazide. Hypertension 1999 Apr; 33 (4): 1043-8efficacy and acceptability of indapamide SR in elderly hyper-17. Pruss T, Wolf PS. Preclinical studies of indapamide, a new 2-tensive patients. Curr Med Res Opin 2005 Jan; 21 (1): 37-46methylindoline antihypertensive diuretic. Am Heart J 1983 Jul;

36. Greenberg A. Diuretic complications. Am J Med Sci 2000 Jan;106 (1 Pt 2): 208-11319 (1): 10-2418. Mironneau J, Savineau JP, Mironneau C. Effect of indapamide

37. Schiavi P, Jochemsen R, Guez D. Pharmacokinetics of sustainedon the electromechanical properties of rat myometrium and ratand immediate release formulations of indapamide after singleportal vein. J Pharmacol Exp Ther 1986 Feb; 236 (2): 519-25and repeated oral administration in healthy volunteers.19. Thomas JR. A review of 10 years of experience with in-Fundam Clin Pharmacol 2000 Mar-Apr; 14: 139-46dapamide as an antihypertensive agent. Hypertension 1985

38. Servier Laboratories (NZ) Ltd. Data Sheet. Natrilix SR in-Nov-Dec; 7 (6 Pt 2): II152-6 1985 Nov-Dec; 7 (6 Pt 2): II152-dapamide hemihydrate 1.5 mg [online]. Available from URL:156http://www.medsafe.govt.nz/Profs/Datasheet/n/NatrilixSR20. Servier Laboratories Ltd. Natrilix SR [online]. Available fromtab.htm [Accessed 2005 Jun 9]URL: http://emc.medicines.org.uk [Accessed 2005 May 12]

39. Caruso FS, Szabadi RR, Vukovich RA. Pharmacokinetics and21. Calder JA. Mechanism of antihypertensive action of thiazideclinical pharmacology of indapamide. Am Heart J 1983 Jul;diuretics and related drugs: direct vascular effects. J Drug Dev106 (1 Pt 2): 212-201992 Apr; 4 (4): 189-98

22. Rendu F, Bachelot C, Molle D, et al. Indapamide inhibits human 40. Leonetti G. Clinical positioning of indapamide sustained releaseplatelet aggregation in vitro: comparison with hydrochloroth- 1.5mg in management protocols for hypertension. Drugs 2000;iazide. J Cardiovasc Pharmacol 1993; 22 (Suppl. 6): S57-63 59 (Suppl. 2): 27-38



41. Fusgen I, Schutz D. Use of indapamide SR in elderly patients in inhibitor or calcium channel blocker vs diuretic: the An-general practice: results of a prospective study of 3034 elderly tihypertensive and Lipid-Lowering Treatment to Prevent Heartmultimorbid patients [in German]. Eur J Ger 2001; 3 (4): 196- Attack Trial (ALLHAT). JAMA 2002 Dec 18; 288 (23): 2981-200 97

42. British National Formulary. Available from URL: http:// 49. ALLHAT Officers and Coordinators for the ALLHAT Collabo-www.bnf.org [Accessed 2005 Jun 1] rative Research Group. Major cardiovascular events in hyper-

43. World Health Organization. The World Health Report 2003: tensive patients randomized to doxazosin vs chlorthalidone:shaping the future [online]. Available from URL: http:// the antihypertensive and lipid-lowering treatment to preventwww.who.int/whr/2003 [Accessed 2005 Sep 9] heart attack trial (ALLHAT). JAMA 2000 Apr 19; 283 (15):

44. Hansson L, Zanchetti A, Carruthers SG, et al. for the HOT Study 1967-75Group. Effects of intensive blood-pressure lowering and low-

50. Writing Group of the American Society of Hypertension. Medi-dose aspirin in patients with hypertension: principal results ofcal experts redefine hypertension. Writing group urges expan-the Hypertension Optimal Treatment (HOT) randomised trial.sion of the definition of hypertension: move paves the way forLancet 1998 Jun 13; 351 (9118): 1755-62new avenues in disease management and research efforts [me-45. Andersson OK, Almgren T, Persson B, et al. Survival in treateddia release] [online]. Available from URL: http://www.ash-hypertension: follow up study after two decades. BMJ 1998 Julus.org/annual_meeting/2005/press/0514057.htm [Accessed18; 317 (7152): 167-712005 Jun 10]46. Turnbull F. Effects of different blood-pressure-lowering regi-

mens on major cardiovascular events: results of prospectively- 51. Bulpitt C, Fletcher A, Beckett N, et al. Hypertension in the Verydesigned overviews of randomised trials. Lancet 2003 Nov 8; Elderly Trial (HYVET): protocol for the main trial. Drugs362 (9395): 1527-35 Aging 2001; 18 (3): 151-64

47. Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hyperten-sive patients at high cardiovascular risk treated with regimensbased on valsartan or amlodipine: the VALUE randomised Correspondence: Dean M. Robinson, Adis Internationaltrial. Lancet 2004 Jun 19; 363 (9426): 2022-31

Limited, 41 Centorian Drive, Private Bag 65901, Mairangi48. ALLHAT Officers and Coordinators for the ALLHAT Collabo-Bay, Auckland 1311, New Zealand.rative Research Group. Major outcomes in high-risk hyperten-

sive patients randomized to angiotensin-converting enzyme E-mail: [email protected]


Indapamide SR - A Review of Its Use AH - Drugs 2006

Documents

Transcript of Indapamide SR - A Review of Its Use AH - Drugs 2006