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Perindopril/Indapamide 2/0.625 mg/day

A Review of its Place in the Management of Hypertension

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Summary

Abstract

The fixed low-dose combination of the ACE inhibitor perindopril and the non-thiazide diuretic indapamide has been evaluated in the management of patients with mild to moderate hypertension. Combination therapy aims to improve overall therapeutic efficacy while minimising adverse effects.

In well-designed multicentre clinical trials, perindopril/indapamide at doses ranging from 2/0.625 to 8/2.5 mg/day was significantly more effective than placebo in achieving adequate blood pressure (BP) control. A similar reduction in supine BP was observed when combined perindopril/indapamide 2/0.625 mg/day was compared with losartan 50 mg/day or atenolol 50 mg/day. Similar reductions in 24-hour ambulatory BP were also seen with perindopril/indapamide 2/0.625 mg/day and irbesartan 150 mg/day. However, response and normalisation rates were significantly higher with combination therapy than with losartan or irbesartan monotherapy.

Combined perindopril/indapamide 2/0.625 mg/day therapy effectively reduced BP in elderly patients aged 65 to 85 years to a significantly greater extent than either atenolol 50 mg/day or placebo. Supine BP was also normalised in approximately two-thirds of patients in a small noncomparative trial in patients with hypertension and renal impairment.

Low-dose perindopril/indapamide 2/0.625 mg/day was well tolerated in clinical trials; the most common adverse events were headache and cough. Hypokalaemia, associated with the use of diuretics, occurred with a higher incidence with combined perindopril/indapamide 2/0.625 mg/day therapy than with either atenolol 50 mg/day or placebo.

Perindopril/indapamide 2/0.625 mg/day has shown efficacy in well designed comparative trials with atenolol, losartan and irbesartan including elderly patients and patients with renal impairment. Studies comparing this dosage of perindopril/indapamide with other combination therapies would be beneficial in allowing the place of perindopril/indapamide to be more accurately determined. The fixed-low dose combination of perindopril/indapamide provides a promising and well tolerated treatment option in the management of patients with mild to moderate hypertension.

Pharmacodynamic Profile

The pharmacodynamic profile of the fixed low-dose combination of perindopril/ indapamide has been largely investigated in animal models of hypertension: limited human data are available.

In a 12-month randomised, double-blind trial in 471 patients with hypertension perindopril/indapamide 2/0.625 mg/day produced a significantly greater decrease in brachial and central arterial pulse pressure and delayed carotid wave reflection, resulting in a significant decrease in Aix intensity (augmentation index by applanation tonometry) compared with an increase with atenolol 50mg treatment.

In spontaneously hypertensive rats (SHR), perindopril/indapamide at combined total doses of 0.3, 1 or 3 mg/kg administered daily for 6 weeks effectively reduced systolic blood pressure (SBP), without affecting heart rate in comparison with vehicle-treated animals; 1 mg/kg/day perindopril/indapamide reduced SBP to a greater extent than animals administered either perindopril 0.76 mg/kg/day or indapamide 0.24 mg/kg/day monotherapy. In SHR administered perindopril/ indapamide 0.25/0.08 to 1/0.31 mg/kg daily for 5 weeks, the change in SBP was significantly correlated with plasma renin activity.

Conduit and small arterial endothelial dysfunction are implicated in the development of hypertension. Endothelium-dependent relaxation was normalised with perindopril/indapamide 4.5/1.44 mg/kg/day and indapamide monotherapy 1.44 mg/kg/day compared with vehicle-treated hypertensive Dahl salt-sensitive (DS) rats. Endothelin-1 excretion in the urine (correlated with renal injury) was significantly reduced in 6-week-old hypertensive DS rats administered perindopril/indapamide 4.5/1.44 mg/kg/day or indapamide (but not perindopril) monotherapy compared with vehicle-treated hypertensive DS rats. In addition, perindopril/ indapamide therapy and indapamide therapy normalised nitric oxide synthase (NOS) activity in 6-week-old hypertensive DS rats.

In rats with experimentally induced hypertension, myocardial hypertrophy is associated with significant increases in arteriolar density and significant decreases in capillary density. Reductions in ventricular collagen density, and aortic and carotid media collagen density were significant in SHR administered perindopril/ indapamide 1 mg/kg/day, relative to untreated animals. Combination treatment also resulted in significantly increased aortic elastin density and improved carotid arterial compliance. Myocardial arteriolar and capillary density was normalised in Wistar rats with experimentally induced renovascular hypertension administered perindopril/indapamide 1 mg/kg daily for 4 weeks.

Perindopril/indapamide 1 mg/kg and perindopril monotherapy 0.76 mg/kg administered daily for 4 weeks significantly reduced both total heart and left ventricular (LV) weight in Wistar rats with experimentally induced hypertension. In hypertensive DS rats perindopril/indapamide 4.5/1.44 mg/kg/day normalised the reduced aortic constitutive NOS activity (cNOS) seen in this model.

In hypertensive DS rats with renal damage perindopril/indapamide 4.5/1.44 mg/kg administered daily for 8 weeks significantly reduced the glomerular injury score and normalised urinary protein excretion compared with perindopril or indapamide monotherapy. Long term administration of perindopril/indapamide 1 mg/kg administered daily for 6 weeks to SHR resulted in marked renal vasodilation without significantly affecting renal function.

Pharmacokinetic Profile

Peak plasma concentrations (Cmax) of perindoprilat and indapamide (4.9 and 17 μg/L, respectively) were reached 6 and 1.5 hours after administration of perindopril/indapamide 4/1.25mg to 18 healthy male volunteers in a randomised crossover trial; areas under the concentration-time curve (AUC) were 191 and 294 μg/L · h. The combined formulation demonstrated bioequivalence with its individual components.

The elimination half-lives of perindoprilat and indapamide (50.7 and 14.6 hours, respectively) after oral administration of perindopril/indapamide 4/2.5 mg/day for 7 days to 18 healthy male volunteers were not significantly different from those reported after administration of each drug separately. Renal clearance of each agent was statistically significantly lower after combination therapy than after monotherapy (p < 0.05 for both drugs), as was the fraction of perindopril excreted in the urine over 24 hours.

The pharmacokinetics of combined perindopril/indapamide in patients with renal failure or in elderly patients were consistent with those reported for its individual components. In a short term, noncontrolled trial, the AUC24 value was increased for perindoprilat and reduced for indapamide in patients with severe renal dysfunction treated with a combined dosage [which ranged from 2/0.625mg every second day (for this regimen n = 2) to 4/1.25 mg/day]. Cmax and AUC for indapamide, but not perindoprilat, increased with age in 36 perindopril/indapamide (2/0.625 mg/day) recipients in a 12-week, noncontrolled trial.

Therapeutic Efficacy

The fixed low-dose combination of perindopril/indapamide has been evaluated in randomised, double-blind clinical trials in patients with mild to moderate hypertension. In clinical trials the dosage of perindopril/indapamide was 2/0.625 mg/day unless otherwise stated.

Comparison with placebo: In comparison with placebo, perindopril/indapamide, at doses ranging from 2/0.625 to 8/2.5 mg/day for 2 to 3 months, significantly reduced supine SBP and DBP in patients with essential hypertension. Over this dose range the response rate for perindopril/indapamide was 50 to 81 % compared with 30 and 49% for placebo. Both standing and 24-hour ambulatory BP were also significantly reduced with perindopril/indapamide treatment compared with placebo. Three months of treatment with perindopril/indapamide normalised BP in a greater proportion of patients, aged 65 to 85 years, with essential or isolated systolic hypertension compared with placebo (74.1 vs 42.1%); at 15 months the normalisation rate for perindopril/indapamide was 83% (placebo normalisation rates were not measured). Increasing the perindopril or perindopril/indapamide dosage reduced BP in a linear fashion, although increasing the dosage from 4/1.25 to 8/1.25 did not result in further clinically significant reductions.

Comparison with losartan, atenolol or irbesartan: Losartan 50 mg/day, atenolol 50 mg/day and perindopril/indapamide combination therapy resulted in similar reductions in supine BP after 3 months’ treatment. However, both response (91 vs 81.8%) and normalisation (75.4 vs 60%) rates and the mean reduction in night-time BP were significantly higher with perindopril/indapamide therapy than with losartan. Similar response rates (81 vs 84%) and reductions in 1- and 3-minute standing BP were seen with perindopril/indapamide and atenolol therapy. Preliminary data shows similar reductions in 24-hour ambulatory BP for perindopril/indapamide therapy versus irbesartan 150 mg/day; although both response and normalisation rates were significantly higher with combination therapy.

Elderly patients: In patients aged 65 to 85 years, perindopril/indapamide significantly reduced supine BP to a greater extent than either placebo (SBP and DBP) or atenolol 50 mg/day (SBP) in multicentre, randomised, double-blind trials.

Patients with renal impairment: In patients with renal impairment [creatinine clearance < 4.5 L/h/1.73m2 (<75 ml/min/1.73m2)] and mild to moderate hypertension, perindopril/indapamide 2/0.625 to 4/1.25 mg/day significantly reduced supine BP relative to baseline. The responder and normalisation rates were 81 and 65%, respectively for the intention-to-treat groups.

Tolerability

Fixed low-dose perindopril/indapamide was well tolerated by patients with hypertension; in a well-designed trial, most adverse events were mild to moderate in severity and corresponded to those expected for each drug administered as monotherapy. Perindopril/indapamide had a tolerability profile similar to that of placebo in a 1-year, randomised double-blind trial in 199 elderly patients with hypertension; cough, headache and orthostatic hypotension were the most common adverse events irrespective of treatment.

The incidence of adverse events in trials of 3 months’ duration comparing perindopril/indapamide with losartan 50 mg/day or atenolol 50 mg/day was ≤5%. Cough occurred only in patients receiving combination therapy. Asthenia occurred with a similar incidence in patients receiving the combination or losartan; however, asthenia, orthostatic hypotension and bradycardia all occurred with a higher incidence in atenolol recipients relative to those treated with the combination.

Hypokalaemia occurred with a higher incidence with perindopril/indapamide therapy (2/0.625 mg/day for 1 year) than placebo in a well-controlled trial in 308 elderly patients with hypertension (5 versus 2%, p-values were not indicated), although serum potassium levels did not fall below 3.1 mmol/L in any patient.

Mean uric acid levels increased with treatment with perindopril/indapamide in well-controlled trials; however, the increase with perindopril/indapamide 2/0.625 mg/day for 1 year was not significantly different from that reported with placebo (20.0 versus 15.2 mmol/L) in elderly patients with hypertension in a randomised, double-blind trial.

Dosage and Administration

Based on the French prescribing information, fixed low-dose perindopril/indapamide 2/0.625mg is recommended once daily for adult and elderly patients with essential hypertension and should be taken in the morning before food. If initial BP control is unsatisfactory, the dosage may be doubled.

Low-dose perindopril/indapamide is contraindicated in women who are pregnant or lactating, and in patients with renal impairment [creatinine clearance <1.8 L/h (<30 ml/min)], hypokalaemia, severe hepatic impairment or hepatic encephalopathy, a history of angioedema linked with treatment with an ACE inhibitor, or hereditary or idiopathic angioedema. Several drugs (including lithium, potassium-sparing diuretics, anaesthetics, cytostatic or immunosuppressant agents, and nonantiarrhythmic drugs which cause torsades de pointe) should not be coadministered with perindopril/indapamide because of the potential for significant drug interactions with either component of the combined dose.

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Notes

  1. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.

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  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    Anna J. Matheson, Susan M. Cheer & Karen L. Goa

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  1. Anna J. Matheson
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Matheson, A.J., Cheer, S.M. & Goa, K.L. Perindopril/Indapamide 2/0.625 mg/day. Drugs 61, 1211–1229 (2001). https://doi.org/10.2165/00003495-200161080-00018

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