Indapamide Sustained Release

A low-dose sustained-release (SR) formulation of the thiazide-type diuretic indapamide, indapamide SR (Natrilix® SR), retains the antihypertensive activity of the immediate-release (IR) formulation, with a smoother pharmacokinetic profile.

In well controlled 12- to 52-week clinical trials, indapamide SR 1.5 mg/day was well tolerated and reduced blood pressure as effectively as therapeutic dosages of amlodipine, candesartan, enalapril, hydrochlorothiazide or indapamide IR. Indapamide SR was also more effective than enalapril in reducing left ventricular hypertrophy (LVH), and similar reductions in renal end-organ damage, assessed by microalbuminuria, were seen with indapamide SR- and enalapril-based antihypertensive strategies. Indapamide SR provides an effective option for initial antihypertensive monotherapy and a basis for multidrug antihvpertensive strategies.

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

Therapeutic dosages of indapamide have only a mild diuretic activity; the primary antihypertensive activity of low-dose indapamide appears to occur through a direct vasodilatory effect. Indapamide also reduces vascular hypertrophy and LVH in animal models of pressure overload.

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

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

In well controlled clinical trials of 12–52 weeks’ duration, indapamide SR 1.5 mg/ day reduced both mean supine systolic blood pressure (SBP) and diastolic blood pressure (DBP). In patients with essential hypertension or isolated systolic hypertension, the reductions in mean supine SBP and DBP induced by indapamide SR were significantly larger than those seen with placebo, and SBP reductions were greater than those with enalapril 10 mg/day. Reductions in supine SBP and DBP with indapamide SR were similar to those with amlodipine 5 mg/day, candesartan 8 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 by indapamide SR were equivalent to those with amlodipine 5 mg/day or hydrochlorothiazide 25 mg/day.

End-organ damage was also reduced by indapamide SR. LVH was reduced in indapamide SR 1.5 mg/day but not enalapril 20 mg/day recipients after 48 weeks of therapy in patients with essential hypertension. In patients with type 2 diabetes mellitus, multidrug indapamide SR 1.5 mg/day based and enalapril 10 mg/day-based antihypertensive strategies induced similar reductions in urinary albumin: creatinine ratio and fractional albumin clearance; noninferiority was not demonstrated in the reduction of albumin excretion rate.

Indapamide SR 1.5 mg/day was generally well tolerated. Headache, back pain, nausea and diarrhoea were observed at relatively low rates (0.2–1.6%), and orthostatic 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) was 0–1.5%.