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Medicines Q&As
UKMi Medicines Q&A 18.5
How do amlodipine and felodipine compare for the treatment
of hypertension or prophylaxis of stable angina?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
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Date published: 15th October 2012
Background
Clinical pharmacological differences between the ‘rate-limiting’ calcium channel blockers,
verapamil and diltiazem, and the dihydropyridine group are well recognised. Less well
recognised are the significant differences between agents within the dihydropyridine group.
These differences translate to distinct differences in the therapeutic profiles and may well
translate into differences in outcome during long-term treatment. The differences in
pharmacokinetic, pharmacodynamic and therapeutic profiles suggest that caution should be
exercised in assuming that all dihydropyridine calcium channel blockers licensed for oncedaily administration are equivalent in terms of their durations of action and overall
antihypertensive efficacy. (1)
Amlodipine and felodipine are dihydropyridine calcium channel blockers. The half-life of
amlodipine is reported as 35 – 50 hours, which is consistent with once daily dosing. (2)
Felodipine, in the modified release (m/r) formulation has an elimination half-life of
approximately 25 hours, which is also consistent with once daily dosing. (3)
Amlodipine (Istin®) has a number of licensed indications. It can be used to treat hypertension,
often in combination with a thiazide diuretic, alpha-blocker, beta-blocker or an ACE inhibitor.
Amlodipine is also licensed for the prophylaxis of chronic stable angina pectoris and is used
either as monotherapy or in combination with other antianginal drugs in patients with angina
that is refractory or nitrates and/or adequate doses of beta-blockers. Amlodipine can also be
used for Prinzmetal's (variant) angina when diagnosed by a cardiologist. Amlodipine is well
tolerated in patients with heart failure and a history of hypertension or ischaemic heart
disease but should be still be used cautiously in patients with heart failure. (2)
Felodipine m/r (Plendil®) is currently licensed for the management of hypertension and the
prophylaxis of chronic stable angina pectoris. Felodipine can be used in combination with
beta-blockers, ACE inhibitors or diuretics.
Felodipine is well tolerated in patients with
congestive heart failure but should be used with caution in patients with severe left ventricular
dysfunction. (3) There are no significant pharmacological differences between the effects of
amlodipine and felodipine on heart rate, myocardial contractility, cardiac output, or peripheral
vascular resistance. (4)
This Medicines Q&A aims to review the data available to assist decision-making when
choosing between the two agents.
Answer
Hypertension
Prospective comparisons of different drug classes have shown that differences in BP, rather
than differences between drug classes, have the over-riding influence on overall outcome. (5)
The blood pressure response to dihydropyridine calcium antagonists is less dependent on
From the NHS Evidence website www.evidence.nhs.uk
Medicines Q&As
patient factors such as age and race compared with other antihypertensive agents such as
ACE inhibitors.(6) Current advice from NICE recommends calcium channel blockers as
potential first line agents in older patients (over 55 years) or black patients of any age and as
potential second line adjunctive agent in younger non-black patients. No specific calcium
channel blocker is recommended. (7) The choice of calcium channel blocker may depend on
local recommendations, with the least expensive one being preferred. (8) For patients with
both hypertension and angina, amlodipine or felodipine are suitable choices. (8)
An open label, crossover, pharmacokinetic study conducted in 1997 compared the
pharmacokinetics of amlodipine 5mg and felodipine m/r 5mg daily in 28 hypertensive patients
(diastolic blood pressure (DBP) between 95 and 115 on 2 consecutive visits to a hypertension
clinic). (9) Subjects were given a single dose of the first test drug on day one of week one
followed by blood sample monitoring for 96 hours. The drug was then administered daily for
two weeks. Following a two-week placebo washout period the regimen was repeated for the
other test drug. The effect on blood pressure was measured only as a secondary parameter.
It was found that the inter-patient variability in the plasma concentration was less with
amlodipine than felodipine m/r. Similarly the peak-to-trough plasma concentration ratio was
more favourable for amlodipine compared to felodipine m/r. It was not established whether
these characteristics reflected ‘smoother and more consistent’ blood pressure control.
A number of clinical studies have compared the use of once daily amlodipine and felodipine
m/r in mild to moderate hypertension. These studies are summarised in table 1 below. The
trial durations were relatively short compared to how the products would be used in a clinical
setting. The primary efficacy measures varied between the trials.
In general, it would appear that that amlodipine is associated with a higher response rate,
better toleration of dihydropyridine adverse effects, and a better control of BP following
missed doses than felodipine m/r.
From the NHS Evidence website www.evidence.nhs.uk
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Table 1: Summary of Clinical Trials Comparing Amlodipine and Felodipine m/r for Hypertension
Patient
population
Study Design
Essential
hypertension
(DBP 95 – 114
mmHg).
Randomised, double blind, parallel group study
following a 4-week placebo washout phase. Patients
were asked to miss 2 consecutive doses at 12
weeks (no placebo used) to test the hypothesis that
skipping the dose of the antihypertensive for 1 or 2
days would have no/less effect on BP when taking
amlodipine compared to felodipine m/r.
Patients aged 27
to 75 years
(n=48).(10)
Essential
hypertension
(DBP 95 – 114
mmHg). Patients
aged 21-75 years
(n=83).(11)
Drug & Dose
The primary efficacy measure: Mean 24 hour
ambulatory systolic BP (SDP) and DBP after the
first and second missed doses at week 12.
Single centre, randomised, parallel group forced
titration with a 2-4 week washout period.
(All patients were Caucasian).
The objective was to evaluate the 24hour
antihypertensive efficacy and duration of action of
felodipine m/r compared with amlodipine and
nifedipine GITS.
Felodipine m/r 5mg (n=24) vs.
amlodipine 5mg (n=24) for 12
weeks.
Dose doubled to 10mg od if
the sitting casual DBP was
95mmHg.
Basic Results
After missing the first dose, blood pressure increased significantly
in the felodipine m/r group but not in the amlodipine group. This
difference in blood pressure change was statistically significantly
in favour of amlodipine (p<0.05 for DBP). However after missing
the second dose the difference in blood pressure change was no
longer statistically significant.
With respect to occasional missed doses, amlodipine is
theoretically more effective at maintaining BP than felodipine m/r if
1 or 2 consecutive doses are forgotten.
A limitation of the study is that patients were aware of the missed
doses.
Amlodipine 5mg (n=28) vs.
felodipine m/r 5mg (n=28) vs.
nifedipine GITS 30mg (n=27)
for 4 weeks, then double
dose for 4 weeks (not double
blinded).
Significant but not statistically different mean reductions from
baseline in DBP and SBP seen with all three treatments. Mean
daytime DBP <90mm Hg was only achieved when the highest
doses were used. A wide variation in the trough-to-peak ratios
was seen depending on the calculation method, however the study
did demonstrate that the three treatments exhibited comparable
reduction in clinic and ambulatory BP during all 24-hour periods.
From the NHS Evidence website www.evidence.nhs.uk
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Patient
population
Primary
hypertension
(DBP 95 – 115
mmHg).
Mean patient age
53 years (n=216).
(12)
Hypertension
(DBP 95 – 114
mmHg).
Patients aged 1875 years (n=193).
(13)
Study Design
Drug & Dose
Single blind, multicentre randomised parallel group
study. 4-week washout phase prior to active study
and patients were not blinded to the drug they
received.
The primary efficacy variable was the decrease in
mean diastolic BP in the last 4 hours of the 24 hours
ambulatory blood pressure monitoring (ABPM) after
4 weeks of treatment
Multicentre, randomised, double blind parallel-group
study with a 4-week washout phase preceding the
active phase.
The primary efficacy endpoint was to determine
whether treatment was successful (defined as
‘patient responded with DBP 90mm Hg or a
decrease of at least 10mm Hg from baseline, with
no serious/severe adverse events’) or unsuccessful
(Defined as ‘patient did not respond or had
serious/severe adverse events’).
Amlodipine 5mg (n=108) vs.
felodipine m/r 5mg (n=108)
for 4 weeks. Doses were
increased to 10mg for the last
4 weeks if they had not
reached the target DBP90
mmgHg.
Basic Results
Daytime BP control was similar for both treatments however nighttime control appeared to be better in amlodipine users. After 4
weeks of treatment, 50% of patients in the amlodipine group
reached their target BP compared with 33% in the felodipine m/r
group (p=0.013). After 8 weeks of treatment the percentages
were 82% and 69% respectively (p=0.036).
Twice as many patients on felodipine m/r therapy (10 patients)
discontinued treatment due to adverse effects, compared with
amlodipine (5 patients). However this was not significant.
Limitations were the lack of blinding and power calculation in the
trial.
Amlodipine (n=101) and
felodipine m/r (n=92) 5mg for
12 weeks.
The dose was doubled to
10mg if after 4 or 8 weeks of
treatment the DBP was
95mmHg. If the DBP was
still 90mmHg after 4 weeks
of 10mg therapy, the dose
was halved and lisinopril 5mg
added.
No significant difference in efficacy between the two groups seen.
A statistically significant greater number of patients on felodipine
m/r reported more adverse events than the amlodipine arm but the
between-group difference in withdrawal due to adverse events
was not significant. More patients on amlodipine (68%) met predetermined BP lowering target than those on felodipine m/r (53%).
No power calculation was carried out.
From the NHS Evidence website www.evidence.nhs.uk
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Patient
population
Elderly
hypertensives
(DBP 90 – 115
mmHg).
Patients aged
over 65 years
(n=534). (14)
Hypertension
(Diastolic BP 95
– 115 mmHg)
(n=118). (15)
Hypertension
(DBP 95 – 115
mmHg)
Patients aged
over 18 years
(n=118). (16)
Study Design
Drug & Dose
Felodipine m/r 2.5mg (n=265)
vs. amlodipine 5mg (n=269)
for 9 weeks.
Multicentre, double blind, parallel group study with
3-week placebo washout phase.
The primary objective was to compare the
tolerability of felodipine m/r with amlodipine in
elderly hypertensive patients.
Multicentre, randomised double blind, double
dummy, parallel group study preceded by 2-week
drug free and 2-week placebo washout phases.
The objective was to compare the efficacies in
lowering BP, response rates 24 hours after dose
and tolerability of the two drugs.
Double blind, double dummy randomised study with
an 8 week run in period without any active
antihypertensive therapy.
The objective was to evaluate 24-hour BP control.
Patients were reassessed
after 3 and 6 weeks, and
doses were increased to
felodipine 5mg then 10mg or
amlodipine 10mg if BP
remained above 160/90
mmHg.
Felodipine m/r 5mg (n=59) vs.
amlodipine 5mg (n=59).
(Doses increased to 10mg if
DBP 90mmHg after 2
weeks) for 6 weeks.
Felodipine m/r 5,10 or 20mg
(n=57) vs. amlodipine 5-10mg
(n=61) for 12 weeks.
Basic Results
32% of felodipine m/r patients and 43% of amlodipine patients
reported vasodilatory adverse events (p=0.001).
Both drugs provided effective control of BP though amlodipine
may have produced greater mean reductions in both SBP and
DBP due to patients receiving a higher average daily dose of
amlodipine (7.3mg) when compared to felodipine m/r (5.5mg).
The differences in antihypertensive effect between treatments
were marginal and not statistically or clinically significant at weeks
2 and 6. Both agents were well tolerated.
No power calculation was carried out.
Comparisons between 24-hour ABPM were made for baseline,
day 1 of treatment and at the end of the study.
Amlodipine and felodipine m/r had a similar effect on office BP;
however ABPM demonstrated a greater effect of amlodipine on
SBP when compared with felodipine m/r (p=0.0014). This may be
due to the slightly higher ABPM baseline value in the amlodipine
group. Amlodipine seemed to be more potent on a mg-for-mg
basis in reducing BP – the average effective dose of felodipine
was 11.2mg compared with 7.4mg for amlodipine.
Both drugs were equally well tolerated.
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Patient
population
Hypertension
(Diastolic BP 95
– 115 mmHg).
Mean age 53
years, Chinese
population
(n=76).(17)
Hypertension
(DBP 90 – 109
mmHg)
Mean age 53.2
years (n=110).
(18)
Study Design
Randomised double blind and parallel group study
with a preceding 2-week placebo washout.
The aim of the study was to compare the efficacy
and safety of amlodipine with felodipine in the
Chinese population, as well as the effect of two
missed doses.
Randomised, double blind study preceded by 3
weeks of no antihypertensive therapy.
The aim of the study was to evaluate the 24-hour
antihypertensive effects of various calcium channel
blockers and assess the drugs effects on 24-hour
BP variability.
Drug & Dose
Basic Results
Felodipine m/r 5mg (n=36) vs.
amlodipine 5mg (n=40) for 12
weeks followed by a 2-day
drug holiday. The dose was
increased to 10mg after 6
weeks if DBP was not 90
mmHg.
Both drugs equally effective and safe. BP was better controlled in
the amlodipine group 24-48 hours after the missed dose. After
the missed doses both 24-hour ambulatory SBP and DBP showed
no statistical changes in the amlodipine but did in the felodipine
group. Plasma fluctuations in the felodipine m/r group were
significantly worse than the amlodipine group.
No power calculation was carried out.
Felodipine m/r 5-10mg od
(n=15) vs. amlodipine 10mg
od (n=20) vs. other calcium
channel blockers for 4
months.
Neither amlodipine nor felodipine altered circadian variations in
BP. Four months of treatment with amlodipine, but not felodipine
m/r, significantly reduced 24-hour SBP. Amlodipine, but not
felodipine, induced a significant and homogenous reduction of BP.
Only amlodipine produced a significant decrease in the slope of
BP rise in the morning hours.
No power calculation was carried.
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Patient
population
Essential
hypertension
(DBP 90105mmHg,
SBP<190mmHg)
Mean age: older
group 67 years
(n=35), younger
group 41 years
(n=28). (19)
Study Design
Drug & Dose
Basic Results
Younger patients showed no BP response after the first dose of
either calcium channel blocker (CCB) but after 8 weeks of
treatment, decreases of approximately 10mmHg in both SBPand
DBPs were seen. The decrease in BP lasted <24 hours as
responses had disappeared by 24 hours after the last dose of both
CCBs.
Randomised, double blind, placebo-controlled and
parallel group study with a preceding 4-week
placebo run-in period.
The aim of the study was to evaluate the impact of
age on pharmacokinetics and BP in patients after
the first dose and after chronic treatment with
amlodipine or felodipine or placebo.
Felodipine-ER 5mg od vs.
amlodipine 5mg od vs.
placebo for 8 weeks for each
of the two age groups (older
group: 60-80 years; younger
group: 21-50 years)
Older patients showed clear responses in the felodipine-ER group,
SBP had decreased by 10mmHg after the first dose and by
20mmHg after the last dose, but this decrease largely disappeared
at 24 hours post-last dose. In the amlodipine group, SBP
reductions were 16-18mmHg after the first dose and 20mmHg
after the last dose. Reductions were sustained at 24 hours postlast dose and remained decreased by 10mmHg up to 120 hours
after the last dose and by7mmHg one week later.
The two age groups were small (n=28+35) and the number of
patients randomised to each treatment within the groups was not
stated. All patients were Caucasian and results may not be
replicated in larger, multi-ethnicity studies. No power calculation
was carried out.
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Medicines Q&As
Angina
Calcium channel blockers are generally as effective as beta-blockers in reducing angina symptoms.
When adequate control of angina symptoms are not achieved with a beta-blocker a dihydropyridine
calcium channel blocker should be added. (20) A long-acting dihydropyridine calcium channel
blocker such as amlodipine, or a modified release formulation of a short-acting one such as
felodipine, are should be used in order to minimise fluctuations of plasma concentrations and
increased cardiovascular effects. They are suitable options if the person is intolerant of betablockers or if beta-blockers are contra-indicated. (21)
In general, amlodipine appears to be as effective as felodipine m/r for stable angina based on
clinical symptoms, exercise tests and 24 hour electrocardiogram (ECG) monitoring. Studies
comparing the two treatments (see table 2) were small and definitive conclusions cannot be drawn
from them.
Table 2: Summary of Clinical Trials Comparing Amlodipine and Felodipine m/r for
Stable Angina
Diagnosis
Exercise induced
angina pectoris
and myocardial
ischaemia. (22)
47 patients aged
between 30 and
80 years.
Study Design
Prospective, randomised, double blind, double
dummy, crossover study preceded by a 9 day run in
with placebo and long acting nitrates. The primary
efficacy parameter was the number of ST-segment
depressions during 24 hour ECG monitoring.
Treatment: Felodipine m/r 5mg od vs. amlodipine
5mg od over 8 weeks with cross over at week 4.
Doses were increased to 10mg after one week of
each therapy.
Randomised double blind, double dummy, parallel
group study preceded by a 7 day wash out period
with placebo and rescue GTN throughout.
Stable exertional
angina. (23)
30 patients aged
over 18 years.
The aim of the study was to compare the antianginal and anti-ischaemic effects of amlodipine
and felodipine 4 hours after the first dose (acute
effect) and 23 hours after the last dose (chronic
effect).
Basic Results
Both agents appear to be equally effective
in reducing the number and duration of
ischaemic episodes as well as the mean
maximal ST-segment depression compared
with baseline. No differences in tolerability
were noted between the two treatments.
Both drugs reduced frequency of angina
attacks and were well tolerated.
Acute effects showed that felodipine m/r
had a quicker onset of action than
amlodipine. Chronic effects showed that
felodipine m/r had greater improvements in
exercise tolerance than amlodipine.
Treatment: Felodipine m/r 10mg (n=15) vs.
amlodipine 10mg (n=15) for 4 weeks.
From the NHS Evidence website www.evidence.nhs.uk
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Mixed or
exertional angina
pectoris
24 patients aged
from 44 to 73
years. (24)
Multicentre, double blind, double dummy, crossover
study preceded by a 7-day washout with placebo
and rescue GTN.
The aim was to compare the safety and efficacy of
felodipine m/r with amlodipine.
Treatment: Felodipine m/r 10mg vs. amlodipine
10mg od for 8 weeks with cross over at week 4.
The time to exercise test termination
showed an increase with both drugs, which
attained statistical significance only with
felodipine m/r. The duration of ischemia
showed a greater decrease that was more
evident with felodipine m/r. The decrease in
the duration of angina pain also attained
statistical significance with felodipine m/r
but not with amlodipine.
Adverse reactions considered as treatment
related occurred in 8.3% of felodipine m/r
cases and 25% of amlodipine cases.
No power calculation carried out.
From the NHS Evidence website www.evidence.nhs.uk
Medicines Q&As
Safety
Contraindications are comparable between felodipine m/r and amlodipine: unstable angina,
cardiogenic shock, clinically significant aortic stenosis, post-MI, sensitivity to dihydropyridine
calcium channel blockers and pregnancy. (2;3) Amlodipine should be used cautiously in patients
with impaired liver function. (2) Grapefruit juice can increase the plasma levels of both amlodipine
and felodipine so concurrent intake should be avoided. (2;3) Substances that affect the cytochrome
P450 3A4 enzyme system may affect plasma concentrations of felodipine. Enzyme inhibitors such
as erythromycin and cimetidine impair the elimination of felodipine and therefore the felodipine dose
may need to be reduced. Conversely, powerful enzyme inducing agents such as some
anticonvulsants can increase felodipine elimination. (3) Additional information on interactions can be
found in the Summary of Product Characteristics (http://emc.medicines.org.uk/) for both products.
Conversion from amlodipine to felodipine m/r and vice versa
Data are available for the conversion of amlodipine to felodipine m/r in hypertensive patients. A
USA based retrospective study involving 283 hypertensive males taking amlodipine looked at the
impact on patient satisfaction and tolerability after switching to felodipine m/r. Economical impact
was a secondary objective in this study and the authors suggested that 10mg amlodipine was
similar in efficacy to 10mg felodipine m/r. Although BP was lower after the change, the study was
not powered to determine a true difference in BP changes. The authors concluded that long-term
BP control was comparable with the two agents. Based on this small study, the authors also state
that dosage homogeny with regards to the switch was not apparent and patients only required extra
clinic visits following the switch for monitoring and titration purposes. (25)
The comparative costs for the drugs alone can be misleading since costs may also be incurred as a
result of converting patients from one agent to the other. The majority of cost effectiveness studies
following conversion from amlodipine to felodipine m/r are USA based retrospective and limited to
hypertensive patients. (26) Recommendations for hypertension treatment in the USA are not the
same as those advised in the UK. In the UK, most patients with hypertension or stable angina will
be on a combination of drug therapies (according to current best practice).
Summary





Amlodipine and felodipine m/r are both effective in the treatment of mild to moderate
hypertension and prevention of angina pectoris.
The larger comparative studies have demonstrated that amlodipine has a greater
antihypertensive effect than felodipine m/r, whilst some smaller ones have shown an equal
antihypertensive effect. Given the pharmacokinetics of the two drugs, it has also been
suggested that if patients are intermittently compliant then, in theory, amlodipine may be a
more suitable drug because its antihypertensive effects are longer lasting. The plasma levels
of amlodipine also fluctuate less during 24 hours.
In angina, two studies have shown a more favourable effect on exercise tolerance for
felodipine m/r compared to amlodipine, whilst one trial concluded that both agents were
equally effective. However, these trials were conducted in a very small number of patients.
There is inconsistency between studies as far as tolerability is concerned, and no clear
conclusions can be drawn.
The decision on whether to choose amlodipine or felodipine m/r depends on a number of
issues that will include local prescribing initiatives and cost, as well as efficacy, tolerability and
potential drug interactions. It is important to monitor and review regularly new patients taking
either drug.
Limitations

This review does not include cost effectiveness data.
From the NHS Evidence website www.evidence.nhs.uk
Medicines Q&As


The population size and quality of the studies involving head to head comparisons of
amlodipine and felodipine m/r differ widely such that it is not possible to develop any metaanalysis given the variations in BP assessment, patient randomisation, blinding, etc.
There are only a few trials, incorporating small numbers of patients, comparing amlodipine
and felodipine m/r in angina. Therefore, only limited conclusions can be drawn when
comparing these two agents for this condition.
References
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From the NHS Evidence website www.evidence.nhs.uk
Medicines Q&As
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(21) Angina - stable - management. Which calcium channel blocker is recommended? Last
revised September 2009. Clinical Knowledge Summaries
http://www.cks.nhs.uk/angina/management/prescribing_information/calcium_channel_block
ers/drug_interactions#-390593
(22) Koenig W, Hoher M. Felodipine and amlodipine in stable angina pectoris: results of a
randomized, double-blind crossover trial. J Cardiovasc Pharmacol 1997; 29(4):520-524.
(23) Achilli F, Buono G, di Fraia S et al. Acute and chronic effects of felodipine extended release
and amlodipine in patients with exertional angina: a double-masked, clinical comparison.
Curr Ther Res Clin Exp 1996; 57(7):523-536.
(24) Corradi L, Colombo G, Ravera R et al. Clinical interest of once-daily felodipine extendedrelease in patients with mixed and exertional angina. Results of a double-blind crossover
study versus amlodipine. Clin Drug Invest 1996; 9(6):324-333.
(25) Manzo B, Matalka MS, Ravnan SL. Evaluation of a therapeutic conversion from amlodipine
to felodipine. Pharmacotherapy 2003; 23(11):1508-1512.
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From the NHS Evidence website www.evidence.nhs.uk
Medicines Q&As
Quality Assurance
Prepared by
Varinder Rai (Senior Medicines Information Pharmacist) London Medicines Information (Northwick
Park Hospital)
Date Prepared
October 2012
Checked by
Alexandra Denby (Medicines Information Pharmacist) London Medicines Information (Northwick
Park Hospital)
Date of check
15th October 2012
Contact
[email protected]
Search strategy
Medline: [AMLODIPINE/ AND FELODIPINE/] AND [ANGINA PECTORIS/ OR HYPERTENSION/].
Limit to publication year 2010-current.
Embase: AMLODIPINE/cm [cm=Drug Comparison] OR AMLODIPINE BESYLATE/cm [cm=Drug
Comparison] OR AMLODIPINE MALEATE/cm [cm=Drug Comparison] AND
FELODIPINE/cm [cm=Drug Comparison] AND [HYPERTENSION/ OR ANGINA
PECTORIS/]. Limit to publication year 2010-current.
Micromedex (amlodipine/felodipine comparison)
Cochrane library (amlodipine; felodipine)
From the NHS Evidence website www.evidence.nhs.uk