, Volume 59, Issue 1, pp 141-157
Date: 15 Oct 2012

Felodipine/Metoprolol

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Summary

Abstract

The main objective of fixed dose combination therapy for hypertension is to improve blood pressure (BP) control with lower, better tolerated dosages of 2 antihypertensives rather than higher dosages of a single agent. Felodipine and metoprolol lower BP via different, but complementary, mechanisms and controlled release formulations of these 2 drugs are available as a fixed dose combination, felodipine/metoprolol.

In clinical trials in patients with hypertension, felodipine/metoprolol was significantly more effective than placebo and the respective monotherapies administered at the same dosages. Mean BP was reduced to <155/90mm Hg in patients treated with combination therapy and controlled in ≈70% of patients. In one study that titrated dosages to effect, fewer felodipine/metoprolol than felodipine or metoprolol monotherapy recipients required dosage increases to achieve BP control (45 vs 60 and 67%, respectively).

Data from double blind comparative studies show that the antihypertensive efficacy of felodipine/metoprolol 5 to 10/50 to 100 mg/day is significantly greater than that of enalapril monotherapy or captopril plus hydrochlorothiazide and equivalent to nifedipine/atenolol and amlodipine.

In comparisons with enalapril, fewer felodipine/metoprolol than enalapril recipients required dosage titration to achieve BP control.

Compared with amlodipine, felodipine/metoprolol significantly reduced mean 24-hour average BP (8.9/5.5 vs 14.4/9.5mm Hg after 6 weeks; p < 0.001). Both treatments preserved diurnal rhythm.

Long term follow-up studies show that the antihypertensive effect of felodipine/metoprolol occurs mostly during the first month of treatment with small additional decreases in BP being observed in the second and third months, and a relatively constant effect thereafter.

According to a validated questionnaire, quality of life was relatively similar during 12 weeks treatment with felodipine/metoprolol, enalapril or placebo.

In a retrospective pharmacoeconomic analysis conducted in Sweden, felodipine/metoprolol was more cost effective than enalapril as initial treatment for hypertension.

Peripheral oedema, headache and flushing were the most commonly reported adverse events with felodipine/metoprolol and felodipine monotherapy, whereas dizziness, fatigue, headache and respiratory infection were more frequent with metoprolol monotherapy. Dose-dependent adverse events such as oedema may occur less often in patients taking lower dosages in combination than in those taking higher dosages of felodipine monotherapy.

Thus, patients with hypertension treated with felodipine/metoprolol experience greater control of BP, with less need for dosage titration, than those treated with felodipine, metoprolol or enalapril monotherapy. Importantly this greater efficacy does not appear to be associated with a higher incidence of adverse events relative to monotherapy. Additionally, in short term studies felodipine/metoprolol had a similar (minimal) effect on QOL to enalapril monotherapy but was more cost effective.

Pharmacodynamic Properties

This review evaluates the antihypertensive efficacy of a fixed dose controlled release formulation of felodipine and metoprolol, felodipine/metoprolol. Felodipine is a vascular selective dihydropyridine calcium channel blocker which lowers arterial BP by decreasing peripheral vascular resistance. It dilates systemic but not pulmonary arterioles and has no effect on venous vessels. Felodipine is also selective for vascular smooth muscle over myocardial tissue, and thus has no direct effect on cardiac contractility or conduction at therapeutic dosages.

Metoprolol is a β1-blocker with no intrinsic sympathomimetic activity and essentially no membrane stabilising properties. Competitive antagonism of β1-adrenoceptors by metoprolol produces a negative chronotropic effect, with resulting decreases in cardiac output and systolic BP (SBP) after acute drug administration.

The combined effects of felodipine and metoprolol on haemodynamic parameters may provide some additional benefit compared with the 2 drugs as monotherapy. Reflex tachycardia induced by felodipine may be prevented by metoprolol, and decreases in cardiac output resulting from metoprolol administration may be counteracted by felodipine. Potential increases in peripheral vascular resistance caused by β-blockers may readily be compensated for by the effects of calcium channel blockers on this parameter.

Pharmacokinetic Properties

Concomitant use of felodipine and metoprolol does not appear to produce clinically significant changes in the pharmacokinetic parameters [maximum plasma concentrations (Cmax), minimum plasma concentrations, time to Cmax(tmax), area under the plasma concentration-time curve and terminal elimination half-life] of either drug.

Design of the controlled release felodipine/metoprolol combination tablet is based on the principles used for the individual drug preparations, namely felodipine ER and metoprolol CR/ZOK and the 2 drugs have similar pharmacokinetic profiles when administered as separate controlled release dosage forms or when administered as the combined fixed dose, controlled release formulation.

Therapeutic Efficacy

Preliminary data from a large cohort indicate felodipine/metoprolol is effective in patients with inadequately treated hypertension [insufficient BP control (n =1350) or experiencing adverse events (n = 193)]. The combination elicited BP response in 84.4% of patients.

In all comparative studies, felodipine/metoprolol reduced mean BP to less than 155/90mm Hg and elicited BP control in 63 to 76% of patients. The combination was significantly more effective than placebo or each drug as monotherapy. Combination therapy acheived BP control in 71 or 73% of patients compared with 44 to 49% in felodipine monotherapy recipients and 34 to 59% of metoprolol monotherapy recipients (p < 0.05).

In 1 study, upward dosage titration (in patients not achieving BP control) was required in fewer felodipine/metoprolol (45%) than felodipine (60%) or metoprolol (67%) monotherapy recipients.

In direct comparisons, felodipine/metoprolol reduced DBP to a significantly greater extent than enalapril monotherapy, captopril plus hydrochlorothiazide and nifedipine/atenolol, but not amlodipine. SBP was reduced by a significantly greater extent relative to enalapril monotherapy and captopril plus hydrochlorothiazide, but not nifedipine/atenolol or amlodipine.

Studies comparing felodipine/metoprolol with enalapril allowed upward dosage titration in cases where BP was not controlled (as defined above). This was required in ≈one-third fewer felodipine/metoprolol than enalapril recipients.

In a study evaluating 24-hour BP control, ambulatory BP was reduced to a greater extent with felodipine/metoprolol than with amlodipine.

Data from 1 to 2 year follow-up studies show that the optimal antihypertensive effect of felodipine/metoprolol therapy is generally attained within the first month of treatment, with small additional effects during the second and third months of treatment. BP remained relatively constant during subsequent months. The response rate to treatment with felodipine/metoprolol and the percentage of patients experiencing BP control exceeded 90% in 2 of these studies.

At end-point, 49 to 70% of patients remained on the lowest dosage of felodipine/metoprolol; 23 to 30% required the higher dosage and, where permitted, 17 to 25% required the addition of hydrochlorothiazide (12.5 to 25 mg/day) to achieve BP control.

In the Logiq study, health-related quality of life in patients with hypertension was similar at baseline and changed little during 12 weeks’ treatment with felodipine/metoprolol 5 to 10/50 to 100 mg/day, enalapril 10 to 20 mg/day or placebo.

A retrospective pharmacoeconomic conducted in Sweden found that, in terms of cost per millimetre of mercury reduction in BP (SEK198/mm Hg vs SEK328/mm Hg) and the number of patients reaching the goal DBP (≤90mm Hg)[SEK3776 vs SEK5756 per patient], felodipine/metoprolol was more cost effective than enalapril treatment.

Tolerability

Comparative studies show that the overall incidence of adverse events in patients receiving felodipine/metoprolol was similar to that observed in individuals taking felodipine and metoprolol as monotherapy. No differences were observed between the 3 groups in terms of withdrawal rates. Tolerability profiles, however, varied between the 3 treatment groups; most adverse events were described as mild. Overall, peripheral oedema, headache and flushing were the most commonly reported events with felodipine and felodipine/metoprolol, whereas dizziness, fatigue, headache and respiratory infection were the most frequently observed adverse events in metoprolol recipients. Patient withdrawals in most studies resulted from vasodilatory effects. Other contributory events included fatigue, and nausea and vomiting.

In long term studies (1 to 2 years), most adverse events were reported during the first 3 to 6 months of therapy, and decreased thereafter. Typically, peripheral oedema was most commonly described; headache and dizziness occurred less frequently.

Felodipine and metoprolol are metabolised by hepatic microsomal cytochrome P-450 (CYP) isoenzymes; predominantly CYP2D6 (metoprolol) and CYP3A4 (felodipine). Any drug that induces or inhibits these isoenzymes has the potential to affect plasma felodipine and/or metoprolol concentrations.

Dosage and Administration

Felodipine/metoprolol is available as 5/50 and 10/100mg tablets. Therapy should be initiated at a dosage of 5/50mg administered once daily in the morning and increased to 10/100 mg/day if required. Tablets should be swallowed whole; they must not be divided, crushed or chewed.

Various sections of the manuscript reviewed by: C. Bengtsson, Department of Primary Health Care, Göteborgs Universitet, Vasa Hospital, Gothenburg, Sweden; A.H. Gradman, Division of Cardiovascular Diseases, The Western Pennsylvania Hospital, Pittsburgh, Pennsylvania, USA; M.J. Kendall, University of Birmingham Department of Medicine, Queen Elizabeth Hospital, Birmingham, England; T.O. Morgan, Department of Physiology, The University of Melbourne, Parkville, Victoria, Australia; H. Pardell, Hypertension Unit, Department of Internal Medicine, Hospital de la Creu Roja, Barcelona, Spain; L.M. Ruilope, Unidad de Hipertension, Hospital 12 de Octubre, Madrid, Spain; P.S. Sever, Department of Clinical Pharmacology, Imperial College School of Medicine, St. Mary’s Hospital, London, England; L. Wing, Flinders Medical Centre, Bedford Park, South Australia, Australia.

Data Selection

Sources: Medical literature published in any language since 1966 on Felodipine.Metoprolol, identified using AdisBase (a proprietary database of Adis International, Auckland, New Zealand), Medline and EMBASE. 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: AdisBase search terms were ‘Felodipine.Metoprolol’. Medline search terms were ‘Felodipine-Metoprolol’ or ‘Metoprolol-Felodipine’. EMBASE search terms were ‘Felodipine-Metoprolol’. Searches were last updated 23 Dec 1999.
Selection: Studies in patients with hypertension who received felodipine/metoprolol. 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: pharmacodynamics, pharmacokinetics, therapeutic use.