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Fixed-Dose Combination Enalapril/Nitrendipine

A Review of its Use in Mild-to-Moderate Hypertension

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Summary

Abstract

The fixed-dose combination of enalapril 10mg with nitrendipine 20mg combines an ACE inhibitor with a calcium channel antagonist (CCA) and is indicated for the treatment of patients with mild-to-moderate hypertension whose blood pressure (BP) is inadequately controlled with enalapril or nitrendipine monotherapy. In randomised, double-blind clinical trials, enalapril/nitrendipine 10/20 mg/day was significantly more effective than its individual components in reducing diastolic BP (DBP) in patients with mild-to-moderate hypertension inadequately controlled with enalapril 10 mg/day or nitrendipine 20 mg/day. The fixed-dose combination was similar in efficacy at reducing DBP to amlodipine 10 mg/day in patients who failed to achieve BP control with amlodipine 5 mg/day, and to losartan/hydrochlo-rothiazide 50/12.5 mg/day in patients who received the combinations as first-line therapy. Enalapril/nitrendipine 10/20mg produced a consistent antihypertensive effect that persisted for the entire 24-hour dosage interval as shown by ambulatory BP monitoring.

Enalapril/nitrendipine 10/20mg was well tolerated in clinical trials where it was administered to patients with mild-to-moderate hypertension for up to 12 weeks. The adverse events were those expected of ACE inhibitors and CCAs and included cough, headache and flushing. Evidence from clinical trials, including a pooled analysis, suggests that the incidence of oedema may be significantly lower with the fixed-dose combination than with CCA monotherapy.

In conclusion, enalapril/nitrendipine 10/20mg is a well tolerated fixed-dose combination of two established antihypertensive agents administered once daily that effectively lowers BP throughout the 24-hour dosage interval. Importantly, the fixed-dose combination may have a lower incidence of oedema than CCA monotherapy. Enalapril/nitrendipine 10/20mg provides an additional treatment option for patients with mild-to-moderate hypertension for whom combination therapy is appropriate..

Pharmacodynamic Properties

Enalapril is an ACE inhibitor prodrug that is converted to the active moiety enalaprilat after absorption from the gastrointestinal tract. Nitrendipine is a dihydropyridine calcium channel antagonist (CCA).

In patients with hypertension, the single agents enalapril and nitrendipine as well as their combination effectively lower BP on a once-daily basis. Both have long-term beneficial effects on the cardiovascular system, improving left ventricular structure and function, with neutral and/or moderating effects on renal function, metabolic parameters and insulin sensitivity. Neither of these agents has any significant effect on electrolyte balance.

Enalapril/nitrendipine combination did not have any significant effect on heart rate (HR) in healthy volunteers..

Pharmacokinetic Properties

There were no clinically relevant differences in the area under the plasma concentration-time curve and maximum plasma concentration values of enalapril or nitrendipine after single-dose administration of the fixed-dose combination enalapril/nitrendipine 10/20mg, compared with those observed with single agent enalapril 10mg or nitrendipine 20mg. There was no other pharmacokinetic interaction between the two drugs when coadministered..

Therapeutic Efficacy

In two randomised, double-blind studies, patients with mild-to-moderate hypertension whose BP was not controlled with enalapril 10 mg/day or nitrendipine 20 mg/day monotherapies had significantly greater reductions in diastolic BP (DBP) with enalapril/nitrendipine 10/20 mg/day than those who continued on their respective monotherapies for 12 weeks. Pooled analysis of these two trials showed that the reduction in both systolic BP (SBP) and DBP with the combination therapy was significantly higher than that in patients receiving monotherapy (enalapril or nitrendipine). BP response rates were also significantly higher with enalapril/nitrendipine than those seen with the monotherapies in the pooled analysis, although one of the randomised trials did not show statistically significant differences between groups for SBP and DBP response rates.

After failure of amlodipine 5 mg/day to achieve BP control in patients with mild-to-moderate hypertension, enalapril/nitrendipine 10/20 mg/day was as effective as doubling the dosage of amlodipine in reducing DBP after 6 weeks. Although amlodipine 10 mg/day achieved significantly greater SBP reduction, there was no significant difference between the two treatments with respect to the proportions of patients achieving control of BP.

Enalapril/nitrendipine 10/20 mg/day was generally similar to a fixed-dose combination of losartan/hydrochlorothiazide (HCTZ) 50/12.5 mg/day in reducing BP in patients with mild-to-moderate hypertension as indicated by the reductions in office, 24-hour, daytime or night-time SBP/DBP measured by ambulatory BP monitoring (ABPM). Response rates were high and similar for both treatments. The only significant difference between the two treatments was with respect to office SBP control rates in favour of enalapril/nitrendipine.

The values of mean trough-to-peak ratios and the smoothness indices for the two treatments estimated during ABPM showed that the antihypertensive effects of both treatments persisted for the entire 24-hour dosage interval.

Pharmacoeconomic analyses of enalapril/nitrendipine therapy are limited to a modelled cost-effectiveness analysis conducted in Spain. Results indicated that enalapril/nitrendipine may provide a cost-effective treatment option in the treatment of hypertension.

Tolerability

Enalapril/nitrendipine 10/20 mg/day was well tolerated in clinical trials, with the well known adverse effects of ACE inhibitors (e.g. cough) or CCAs (e.g. oedema, flushing and headache) being the most commonly reported adverse events.

The combination was at least as well tolerated as its individual components, and better tolerated than amlodipine 10 mg/day as shown by the incidence of adverse events considered to be at least possibly treatment-related, especially that of oedema. The incidence of oedema associated with enalapril/nitrendipine combination was two to three times lower than that observed with either nitrendipine 20 mg/day or amlodipine 10 mg/day. Adverse events observed with enalapril/ nitrendipine were generally similar in nature and incidence to those seen with losartan/HCTZ 50/12.5 mg/day.

Enalapril/nitrendipine had a neutral or a mild positive effect on the HR in clinical trials in patients with mild-to-moderate hypertension.

Adverse events were an infrequent cause of discontinuation of treatment with enalapril/nitrendipine in clinical trials. No deaths or serious adverse events related to study medication were reported in any of the trials.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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    M. Asif A. Siddiqui & Greg L. Plosker

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Correspondence to M. Asif A. Siddiqui.

Additional information

Various sections of the manuscript reviewed by: F. Antoñanzas, Departamento de Economía y Empresa, Universidad de la Rioja, Logroño, Spain; A. de la Sierra, Hypertension Unit, Department of Internal Medicine, Hospital Clínic, Barcelona, Spain; P.W. de Leeuw, Department of Medicine, University Hospital, Universiteit Maastricht, Maastricht, The Netherlands; R. Fagard, Hypertension and Cardiovascular Rehabilitation Unit, Katholieke Universiteit Leuven, Leuven, Belgium; G. Leonetti, Istituto di Medicina Cardiovascolare, Università degli Studi di Milano, Milan, Italy; R. Marín, Hospital de Covadonga, Oviedo, Spain; G.T. McInnes, Division of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom; A. Roca-Cusachs, Department of Internal Medicine, Hospital de la Santa Creu i St Pau, Universitat Autonoma de Barcelona, Barcelona, Spain; J. Wang, Hypertension and Cardiovascular Rehabilitation Unit, Katholieke Universiteit Leuven, Leuven, Belgium; J. Webster, Department of Pharmacy, Grampian Health Board, Aberdeen, United Kingdom; A. Zanchetti, Centro di Fisiologia Clinica e Ipertensione, Università degli Studi di Milano, Milan, Italy.

Data Selection

Sources: Medical literature published in any language since 1980 on enalapril/nitrendipine, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: Medline search terms were ‘enalapril nitrendipine’ or ‘enalapril’ or ‘nitrendipine’. EMBASE search terms were ‘enalapril nitrendipine’ or ‘enalapril’ or ‘nitrendipine’. AdisBase search terms were ‘enalapril nitrendipine’ or ‘enalapril’ or ‘nitrendipine’. Searches were last updated 20 April 2004.

Selection: Studies in patients with essential hypertension who received enalapril/nitrendipine. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Enalapril/nitrendipine, hypertension, pharmacodynamics, pharmacokinetics, therapeutic use, adverse events.

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Siddiqui, M.A.A., Plosker, G.L. Fixed-Dose Combination Enalapril/Nitrendipine. Drugs 64, 1135–1148 (2004). https://doi.org/10.2165/00003495-200464100-00009

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