1

REVIEW OF THE AVAILABLE EVIDENCE ABOUT NIFEDIPINE IN THE

TREATMENT OF HYPERTENSION

Introduction

The aims of the present review were to make an evidence-based recommendation

regarding inclusion/exclusion of long-acting nifedipine (LAN) in the WHO Model List
of Essential Medicines (EML) and to consider possible alternatives.

Findings from a meta-analysis published in 1995 suggested that in the secondary

prevention of myocardial infarction, short-acting nifedipine in moderate to high doses
causes an increase in total mortality.1 Several plausible explanations for this adverse
outcome have been suggested, including a proischaemic effect, a negative inotropic
effect, marked hypotension, and proarrthythmic effects. A prohemorrhagic effect
attributed to antiplatelet and vasodilatory actions of calcium channel blockers has
also been reported.1 More recently, in two case-control studies an increased risk of
cardiovascular events in hypertensive patients treated with short-acting calcium
channel blockers was found.2,3 As a result, in 1997 the VI Report of the Joint National
US Committee on Prevention, Detection, Evaluation and Treatment of High Blood
Pressure recommended avoiding the use of short-acting calcium channel blockers in
patients with hypertension and angina pectoris.4 At that time, data for long-acting
calcium channel blockers were scarce, but in 1996-2004 several trials have been
published which deserve attention.

Specific objectives:
- To assess the efficacy and safety of LAN for the treatment of different types of
hypertension (essential, isolated systolic, hypertensive emergencies and
hypertension in pregnancy).
- To evaluate the existing evidence on the role of LAN in patients with common
comorbidities (heart failure, coronary heart disease, diabetes, and chronic
kidney disease) and in certain subgroups (advanced age and particular ethnic
origins).
- To assess the efficacy and safety of LAN as a tocolytic agent for preterm
labour.
- To evaluate the patent status of the existing LAN formulations.

For all these conditions, the efficacy and safety of possible alternatives was
assessed and was taken into consideration.

Methods

We made a bibliographic search through the computerised databases Medline and

Cochrane reviews, looking for the main clinical trials and meta-analyses on nifedipine
and on possible alternatives for the treatment of the different types of hypertension
(essential, isolated systolic, emergency and hypertension during pregnancy). The
available evidence on the treatment of patients with the commonest comorbidities
(heart failure, coronary heart disease, diabetes, and chronic kidney disease), and in
patients with common demographic characteristics (by age and by various ethnic
groups) was also reviewed. As nifedipine is also used as a tocolytic for preterm
labour, its efficacy in this condition was also evaluated.
 2

Evaluation of the efficacy and safety of nifedipine and possible alternatives in each
type of hypertension was based on total mortality and on the main cardiovascular
end points (myocardial infarction, stroke and heart failure) from studies. Other
assessed variables were doubling in serum creatinine concentration and
development of end-stage renal disease for diabetic patients and those with chronic
kidney disease, and length of pregnancy prolongation and perinatal mortality and
morbidity in the presentation of preterm labour.

The patent status of different formulations of nifedipine and their potential alternatives
was obtained from the FDA webpage (‘Orange Book’).

The following were the main clinical questions addressed in the present review:

• Is LAN effective and safe for the treatment of hypertension?

• Should an alternative or an additional dihydropyridine or other long-acting
calcium channel blocker be included in the EDL?
• Is there a dihydropyridine which is more effective and safe than nifedipine for
the treatment of essential hypertension?
• What is the efficacy and safety of nifedipine in other indications as
hypertension of pregnancy and as a tocolytic for preterm labour? Are there
other medicines or other dihydropyridines which can be preferable for the
treatment of these conditions?

Essential (systolic-diastolic) hypertension

The results of several randomised clinical trials showed that in comparison with
placebo, in patients with hypertension treatment with thiazide diuretics and/or β-
blockers reduce the risk of some major cardiovascular events (stroke, myocardial
infarction).5-7 Both groups of drugs (thiazide diuretics and β-blocker agents) are
generally regarded as first line treatment for patients with essential hypertension.4,8

For other antihypertensive drugs, namely new antihypertensive drugs (i.e., ACE
inhibitors, calcium channel blockers, α-blockers and angiotensin antagonists), results
of clinical trials have been available more recently. In general, these “new drugs”
have been compared in clinical trials to “old drugs”.

The Chinese trial STONE (Shanghai Trial Of Nifedipine in the Elderly) compared a
long-acting formulation of nifedipine to placebo in patients with hypertension.9 The
results were favourable to nifedipine (see table 1) but the allocation of patients to the
treatment groups was alternative (not randomised), the distribution of certain
baseline clinical characteristics of patients to both groups of treatment was not
symmetrical, no blood pressure endpoint in the placebo group was set, and there
was no available pharmacokinetic information on the long-acting formulation of
nifedipine used in this study.

In a meta-analysis of four published trials (two with amlodipine, one with nisoldipine,
and one with nitrendipine) comparing a dihydropyridine with placebo in hypertensive
patients, the relative risks of total major cardiovascular events (stroke, coronary heart
disease, heart failure, or cardiovascular death) and of stroke were reduced by the
 3

calcium channel blockers (RR=0.82 [95%CI 0.71-0.95], and RR=0.62 [95%CI 0.47-
0.82], respectively), although the effect of drugs on heart failure was not clear
(RR=1.21 [95%CI 0.93-1.58]).10

In the INSIGHT (INtervention aS a Goal in Hyppertension Treatment) trial, a long-

acting formulation of nifedipine (GITS) was similarly effective to hydrochlorothiazide
plus amiloride in reducing a composite variable of cardiovascular events (see table
1). However, the results were also compatible with a 36% increase of the overall
cardiovascular end-points with nifedipine compared to the diuretic combination.11
More patients died of myocardial infarction and were admitted for heart failure in the
nifedipine group, but the number of events was small in both groups (see table 1).

Nifedipine retard was also compared with ACE inhibitors in a smaller clinical trial in
Japanese hypertensive patients (JMIC-B). No differences were observed between
both groups of treatment in reducing major cardiovascular end-points (see table 1).12

The ALLHAT (the Antihypertensive and Lipid-Lowering treatment to prevent Heart

Attack Trial) study is the largest trial up to now on the treatment of hypertension. The
primary outcome was CHD or non-fatal myocardial infarction. No difference between
amlodipine and chlortalidone was seen in the primary variable and in secondary
outcomes (stroke and total mortality) (see table 2). However, a higher rate of heart
failure was seen with amlodipine (RR=1.38 [95%CI 1.25-1.52]).13

Recently in the VALUE trial ( Valsartan Antihypertensive Long-term Use Evaluation)

no difference was seen between valsartan and amlodipine in the primary end-point (a
composite variable of cardiac mortality and morbidity). The relative risk was 1.04
(95%CI 0.94-1.15) (see table 2).14

The incidence of myocardial infarction and stroke was higher with valsartan and that
of heart failure was higher with amlodipine. However, it has been suggested that the
inequalities in blood pressure in favour of amlopidine, specially in the early period
(blood pressure 4.0/2.1 mm Hg lower with amlodipine compared to valsartan after
one month), hinder the comparison of cardiovascular outcomes.15

The HOT study (Hypertension Optimal Treatment) assessed the effects of intensive
lowering of blood pressure in patients with hypertension. Felodipine was given to all
patients, who were allocated to a target diastolic blood pressure of ≤90 mm Hg, ≤85,
or ≤80 mm Hg.16 The lowest incidence of major cardiovascular events occurred with
felodipine at a mean achieved diastolic blood pressure of 82.6 mm Hg. However,
41% and 28% of randomized patients received concomitant treatment with an ACE
inhibitor or a β-blocker, respectively. As felodipine was not compared to any other
antihypertensive class of drug, the results do not provide any evidence on the relative
benefits of this agent as an antihypertensive, and hence on their place in the
treatment of hypertension.

In the STOP-2 trial (Swedish Trial in Old Patients with hypertension-2), two
dihydrpyridines (felodipine or isradipine) were compared to ACE inhibitors (enalapril
or lisinopril) and to “conventional antihypertensives” (atenolol, metoprolol, pindolol or
hydrochlorothiazide plus amiloride).17 No differences in mortality were seen between
the different groups of treatment. However, the trial was powered only to compared
 4

“conventional” versus “newer antihypertensive drugs” (ie, ACE inhibitors plus calcium
channel blockers) (see table 2).

In two other large clinical trials, one with diltiazem and the other with a controlled-
onset extended-release formulation of verapamil, similar results were obtained with
the calcium channel blockers compared with a thiazide or a β-blocker.18,19

Finally, in a meta-analysis of clinical trials with more than 1,000 patients where a
calcium channel blocker was compared with a thiazide diuretic and/or a β-blocker, no
major differences were found between both groups of treatment in all variables
(stroke, coronary heart disease, cardiovascular death and total mortality), except a
higher rate of heart failure in patients randomized to calcium channel blockers
(RR=1.33 [95%CI 1.21-1.47]).10

Isolated systolic hypertension

Two major trials on the treatment of isolated systolic hypertension have been
published.

In the SHEP trial (Systolic Hypertension in the Elderly Program),5 treatment with
chlorthalidone reduced the risk of fatal and non-fatal stroke (RR=0.64 [95%CI, 0.50-
0.82]) and of major cardiovascular events (RR=0.68 [95%CI, 0.58-0.79]) in
comparison to matching placebo.

The Syst-Eur trial (Systolic hypertension in Europe) was the largest study where a
dihydropyridine was compared with placebo, in patients with isolated systolic
hypertension.20 In this trial, nitrendipine reduced the risk of stroke (RR=0.58 [95%CI,
0.40-0.83]) and of a composite variable of cardiac end-points (heart failure and
myocardial infarction) (RR=0.74 [95%CI, 0.56-0.0.97]) in comparison to placebo.
However, 36.5% of patients assigned to the active treatment concomitantly received
other antihypertensive drugs (enalapril and/or hydrochlorothiazide), while patients
assigned to placebo received more placebo as second step, and a third placebo as a
third step if blood pressure was not controlled. On the other hand, the decision of
investigators to continue with a placebo group despite the publication of the positive
SHEP results was also of concern.21

Favourable results to the nitrendipine treatment compared with placebo were also
observed in the Syst-China (Systolic Hypertension in China) trial, but the less
orthodox method of allocation (alternative) used in this study, limited the
interpretation of results.22

Recently in a substudy of the LIFE trial (Losartan Intervention For End-point

reduction), in elderly patients with isolated systolic hypertension and
electrocardiographically documented left ventricular hypertrophy, losartan, an
angiotensin receptor blocker (ARB), was superior to atenolol in reducing a composite
end point of cardiovascular death, stroke or myocardial infarction (RR=0.71 [95%CI,
0.53-0.95]).23 The main limitations in this trial were that more than 60% of patients in
each group received concomitant treatment with hydrochlorothiazide, and β-bockers
were a suboptimal control group, because they are not first choice in the elderly and
because their efficacy in isolated systolic hypertension is not proven.24
 5

Hypertensive crises

In a hypertensive emergency, immediate blood pressure control to limit or to

prevent target organ damage (hypertensive encephalopathy, intracraneal
haemorrhage, unstable angina, acute myocardial infarction, etc.) is required.
Treatment with certain parenteral antihypertensive agents (sodium nitroprusside,
labetalol, nitroglycerin or enalaprilat) is generally recommended for most of these
situations.4 In a hypertensive urgency (hypertension with optic disc edema, severe
perioperative hypertension…) it is desirable to achieve a blood pressure reduction
within a few hours. Treatment with oral doses of drugs with relatively fast onset of
action (i.e., loop diuretics, β-blockers, ACE inhibitors) is recommended for these
situations and for isolated elevated blood pressure, in the absence of symptoms,
although results from randomised clinical studies are lacking.4 Sublingual
administration of short-acting nifedipine has been used for this purpose, but there is
no evidence of its benefit and several serious adverse effects (including myocardial
ischaemia) have been reported.25,26 In addition, the inability to control the degree of
fall in blood pressure make this agent unacceptable.4

Special populations and situations

Ethnic variability in the natural history of hypertension

The prevalence, severity and individual impact of hypertension are increased in black
people. In clinical trials, black patients have shown reduced blood pressure
responses to monotherapy with β-blockers and ACE inhibitors, compared with
diuretics or calcium channel blockers.27 Renin concentrations tend to be lower in
black people compared to white people.28 Antihypertensive agents that inhibit the
renin-angiotensin system (RAS) have been less effective as initial treatment in
reducing blood pressure values than other alternatives.29 In some studies, this less
marked response has been overcome by using increased doses of thiazide diuretics.

The results of the AASK (African American Study of Kidney Disease) trial have
shown that RAS blockade can provide significant clinical benefits in Afro-American
patients with hypertensive renal disease.30 On the other hand, the greater differences
observed in the ALLHAT study in black versus nonblack patients for combined CVD
and stroke, along with a similar trend for heart failure and lesser blood pressure
lowering with lisinopril, are in accord with the reports of poorer blood pressure
response with ACE inhibitors in black patients.13 In the ALLHAT study, ACE
inhibitors-induced angioedema occurred 2 to 4 times more frequently in black
patients with hypertension than in other groups.13

Diabetes

No major clinical trial has been performed to assess the effect of blood pressure
lowering on cardiovascular morbidity and mortality in hypertensive patients with
diabetes. Most comparisons have been made in relatively small studies, or in
substudies or subgroups analyses of larger trials. ACE inhibitors have a favourable
effect on cardiovascular outcomes as demonstrated in the MICRO-HOPE (Heart
Outcomes Prevention Evaluation) study.31
 6

In the UKPDS (UK Prospective Diabetes Study), no differences between an ACE

inhibitor and a β-blocker were found.32 In the subgroup of diabetic patients included
in the LIFE trial, losartan reduced the composite endpoint of cardiovascular death,
stroke or myocardial infarction compared to atenolol (RR=0.76 [95%CI, 0.58-0.98]).33
The same limitations quoted above regarding the LIFE study apply to the
interpretation of these results, plus the fact that β-blockers are not of choice in
diabetic patients.

In the ALLHAT trial, no differences in cardiovascular outcomes in the 12,063 patients

with type 2 diabetes included were seen between chlortalidone, amlodipine, and
lisinopril.

On the other hand, there are a number of studies showing that ACE inhibitors and,
more recently, some angiotensin receptor blockers, retard the development and
progression of diabetic nephropathy.34-37 In albuminuric patients with type I diabetes,
captopril reduced the risk of doubling serum creatinine concentration in comparison
to placebo (RR=0.57 [95%CI, 0.35-0.94])34. More recently, in hypertensive patients
with nephropathy due to type 2 diabetes, losartan reduced the risk of the composite
variable (doubling serum creatinine concentration, development of end stage renal
disease or death) in comparison to placebo (RR=0.84 [95% CI, 0.72-0.98]),35 and
irbesartan reduced the same composite variable in comparison to placebo (RR=0.81
[95%CI, 0.67-0.99]) and to amlodipine (RR=0.76 [95%CI, 0.63-0.92]).36

Chronic kidney disease

ACE inhibitors have also shown a favourable effect on the progression of non-
diabetic renal disease in patients with hypertension.38 A recent meta-analysis of 11
trials comparing the efficacy of antihypertensive regimens including ACE inhibitors to
the efficacy of regimens without ACE inhibitors in predominantly nondiabetic renal
disease, showed a greater mean decrease of urinary protein excretion (of 0.46g/L;
95% CI, 0.33-0.59), end-stage renal disease (RR=0.69 [95%CI, 0.51-0.94]) and the
combined outcome of doubling the baseline serum creatinine concentration or end-
stage renal disease (RR=0.70 [95%CI, 0.55-0.88]) with antihypertensive regimens
including ACE inhibitors.38 Finally, the results of the AASK trial suggest that an ACE
inhibitor (ramipril) is more effective than a β-blocker (atenolol) or a dihydropyridine
calcium channel blocker (amlodipine) in slowing the decline of glomerular filtration
rate in Afro-American hypertensive patients with nephrosclerosis.30

Heart failure

ACE inhibitors (at doses higher than those used in hypertension), β-blockers, and
anti-aldosterone compounds have well established efficacy for prevention of
cardiovascular events and mortality in patients with heart failure when added to
furosemide.39-41 ARBs may be a sound alternative for patients who are intolerant to
ACE inhibitors.42,43

On the contrary, in the PRAISE trial (Prospective Randomized Amlodipine Survival

Evaluation study), the larger published study with a dihydropyridine-type calcium
antagonist in patients with heart failure, amlodipine did not differ from placebo in
 7

cardiovascular morbidity or mortality.44 More recently, in the ALLHAT trial, amlodipine

was associated with a higher rate of heart failure than chlortalidone or lisinopril.13
Similar results were reported from a meta-analysis of the main clinical trials
comparing dihydropyridine or non-dihydropyridine-type calcium channel blockers
versus diuretics/β-blockers (RR=1.33 [95%CI, 1.21-1.47]) or versus ACE inhibitors in
patients with hypertension (RR=1.18 [95%CI, 1.8-1.27]).10

Coronary heart disease

In patients who have suffered myocardial infarction, β-blockers, ACE inhibitors, and
recently aldosterone antagonists have proven to be the most beneficial drugs.45-48 In
patients with hypertension and stable angina pectoris, the first drug of choice is
usually a β-blocker. Short-acting calcium channel blockers are not recommended and
long-acting calcium antagonists are usually recommended as second or third line
therapy in combination with a β-blocker. The results of more recently published trials
seem to confirm this recommendation.

In the ALLHAT study, amlodipine had the same efficacy as other antihypertensive
agents in preventing coronary events in hypertensive patients.13

In the INVEST trial (The International Verapamil-Trandolapril study), treatment with

sustained release verapamil and trandolapril showed an efficacy similar to atenolol or
hydrochlorothiazide in reducing a composite variable of death, non-fatal myocardial
infarction and non-fatal stroke in patients with hypertension and coronary artery
disease.49

Recently, in the ACTION trial (A Coronary disease Trial Investigating Outcome with
Nifedipine gastrointestinal therapeutic system), the addition of nifedipine GITS to the
conventional treatment of angina pectoris showed no effect on major cardiovascular
events in comparison to placebo, but reduced the need for coronary angiography and
interventions (see table 1).52

It has been suggested that these results are less convincing than those obtained with
ACE inhibitors in the HOPE53 and EUROPA (EURopean trial On reduction of cardiac
events with Perindopril in stable coronary Artery disease)54 trials.55 However,
compared with these two other studies, in the ACTION trial a higher percentage of
patients were concomitantly treated with β-blockers (80%, 39% and 62%,
respectively) and with lipid-lowering drugs (68%, 28% and 57%).

Hypertension in pregnancy

It is generally agreed that for the treatment of mild-to-moderate pregnancy

hypertension which started before pregnancy, if taken before pregnancy, diuretics
and most other antihypertensive agents, except ACE inhibitors and angiotensin II
receptor blockers, may be continued.4,54 Methyldopa is the most extensively
evaluated antihypertensive agent in pregnancy. It is recommended as first choice
when hypertension is diagnosed for the first time during pregnancy.54 β-blockers are
considered safe in the later part of pregnancy; however, their use in early pregnancy
may be associated with fetal growth retardation.
 8

The results of a recently published meta-analysis suggest that treatment-induced

falls in maternal blood pressure may adversely affect fetal growth. Given the small
maternal benefit derived from therapy, the authors have suggested that in order to
evaluate benefits and risks of oral antihypertensive drug treatment of mild-to
moderate pregnancy hypertension, data from new clinical trials are needed.55

For the treatment of severe pregnancy hypertension, hydralazine, labetalol, and

nifedipine have been evaluated in clinical trials. However, the results of a recent
meta-analysis indicate that, compared to other antihypertensive drugs, hydralazine is
associated with a higher incidence of adverse effects on the mother and on the
fetus.56 Labetalol has consequently been suggested as a more favourable
alternative, although adequately powered clinical trials are needed.57

Combination therapy

In most hypertensive patients, therapy should be started gradually and target blood
pressure values should be achieved progressively, but to reach such target blood
pressures a large proportion of patients will require combination therapy with more
than one agent.58 The results of several clinical trials indicate that monotherapy is
successful in only 25-40% of patients,59 and in some groups (such as diabetics) an
average of 2.5 to 3 drugs will be required in order to achieve adequate blood
pressure control.35,36

On the other hand, only a limited number of two-drug combinations are safe and
effective in reducing blood pressure values and are therefore recommended. In
general, a dihydropyridine-type calcium antagonist can be combined with almost all
the other antihypertensive drugs, even with a β-blocker.

Tocolytic treatment for preterm labour

In most countries, β-agonists are the reference tocolytic drugs. Their efficacy in
prolonging pregnancy in threatened premature labour compared to placebo is
proven, but no benefit on neonatal morbidity or mortality has been demonstrated.60,61
Despite this weak evidence on their efficacy, some clinicians remain convinced that,
in selected pregnancies the fetus will benefit by being enabled to remain in utero a bit
longer by use of a tocolytic agent. β-agonists have some contraindications, and
serious adverse effects such as pulmonary edema have been reported. Ritodrine is
the drug with more evidence of efficacy in this indication, but salbutamol and
terbutaline may be equally effective.

Calcium channel blockers (especially nifedipine)62 have been compared with ritodrine
in randomised trials. In a meta-analysis of randomised clinical trials, nifedipine was
associated with longer pregnancy and fewer maternal side-effects that ritodrine.63
However, nifedipine has not been compared with placebo in any randomised trial.

Atosiban, an oxytocin antagonist which can only be given by infusion, was associated
with a higher percentage of withdrawals from some studies, due to lack of efficacy in
comparison to ritodrine.64,65 Atosiban is expensive, patent-protected and difficult to
use, ans its marginal efficacy is uncertain.
 9

Patent status of LAN formulations and other dihydropyridines

Several generic preparations of LAN , amlodipine and nitrendipine are available in

certain countries. The patent of the LAN formulation used in the two biggest trials
with nifedipine (nifedipine GITS) will expire during the first trimester of 2005 and that
of felopidine has not yet expired (see table 3).

Discussion

1. Is long-acting nifedipine effective and safe for the treatment of

hypertension?

The available evidence on long-acting nifedipine (LAN) for the treatment of

hypertension is limited, but the results of a few studies suggest that it can be quite
safe, especially if administered in combination and/or as a second or third line
therapy.

In hypertensive patients nifedipine has been compared to diuretics in a large clinical

trial, to ACE inhibitors in a smaller one, and to placebo in a less orthodox study. In
the first clinical trial, more patients died of myocardial infarction or were admitted for
heart failure with nifedipine than with diuretics. However, the numbers of events in
each group were small, and the incidence of overall cardiovascular events was
similarly reduced with nifedipine and diuretics. A recently published clinical trial
showed that the addition of LAN to the standard treatment of angina pectoris (β-
blockers, statins, aspirin) did not reduce major cardiovascular events in comparison
to placebo, although less coronary angiographies and interventions were needed in
the dihydropyridine group. On the other hand, the positive results obtained with other
long-acting dihydropyridines in their respective large clinical trials (with nitrendipine
and, especially, with amlodipine) and in the meta-analyses of clinical trials comparing
calcium channel blockers with diuretics/β-blockers or with ACE inhibitors, suggest
that in patients with hypertension treatment with calcium channel blockers is
reasonably safe, except in those with heart failure.

2) Should some dihydropyridine or other long-acting calcium channel blocker

be included in the EDL?

Several reasons suggest that a dihydropyridine calcium channel blocker should be

kept in the in the EDL:

1) A high percentage of patients with hypertension need treatment with a

combination of two or three different classes of antihypertensive drugs to
achieve the target blood pressure values. As hypertension affects at least 25%
of the adult population, patients in need of three antihypertensive agents are
common, and thus combined antihypertensive treatment should be seen as
“essential”.
2) Only a few two-drug combinations are safe and effective. The dihydropyridine-
type calcium channel blockers can be combined with almost all the other
antihypertensive classes of drugs, even with a β-blocker.
 10

3) In black people, calcium channel blockers can be more effective than some
other antihypertensive drugs in lowering blood pressure.

3) Is there more effective and safer dihydropyridine than nifedipine for the
treatment of essential hypertension?

Three dihydropyridine-type calcium channel blockers have been evaluated in large

clinical trials. In the Sys-Eur trial, nitrendipine showed favourable results on
cardiovascular end-points but it was only compared to placebo, and only in patients
with isolated systolic hypertension. In the HOT trial, treatment with felodipine showed
the benefits of lowering diastolic blood pressure down to 90 mm Hg. However,
felodipine was not compared to any other antihypertensive agent. The STOP-2 trial
was not powered to compare felodipine alone with “conventional antihypertensive
drugs” (diuretics or β-blockers). Finally, in the ALLHAT study, the efficacy of
amlodipine was similar to that of chlortalidone in reducing total mortality and the
incidence of coronary heart disease, although the incidence of heart failure was
marginally higher with amlodipine. It has been suggested that amlodipine is now the
best evaluated dihydropyridine in the treatment of essential hypertension and it is
recommended as third or four line therapy (after diuretics, β-blockers and ACE
inhibitors). However, no information is available on amlodipine for treatment of
hypertension during pregnancy or as a tocolytic .

4) What is the efficacy and safety of nifedipine in other indications such as

hypertension of pregnancy and as a tocolytic for preterm labour? Should other
medicines or other dihydropyridines be preferred for the treatment of these
indications?

In a recent overview of comparative trials on the treatment of severe hypertension in

pregnancy, hydralazine has been associated with a higher percentage of adverse
reactions to the mother and the fetus than other antihypertensive drugs. Labetalol
and nifedipine are possibly safer alternatives, but nifedipine can be preferable for
patients with contraindications or who can not tolerate treatment with a β-blocker. On
the other hand, the beneficial effect of tocolytic agents in preterm labour seems
scarce. New data from clinical trials with a placebo control group in selected patients
at risk of preterm labour are needed. Meanwhile, nifedipine can be an alternative for
patients with contraindications or in those intolerant to ritodrine treatment (e.g., with
asthma).

Several generic preparations of LAN, amlodipine and nitrendipine are available in

certain markets and the patent of nifedipine GITS (used in the two biggest published
trials with nifedipine) will expire during the first trimester of 2005. The patent of
felodipine has not yet expired.

Conclusions

1. Results from a limited number of studies suggests that treatment with long-acting
nifedipine formulations can be quite safe, especially in combination with other
antihypertensives and/or as a second or third line therapy.
 11

2. Other quite safe long-acting dihydropyridines are nitrendipine and amlodipine. At

present amlodipine should be considered as the dihydropyridine calcium channel
blocker with the most extensive experience from a clinical trial (the ALLHAT
study). However, nitrendipine has only been evaluated against placebo in isolated
systolic hypertension, and amlodipine showed a marginally lower benefit/risk ratio
with respect to diuretics in the ALLHAT trial.

3. It seems necessary to keep a long-acting dihydropyridine channel blocker as a

antihypertensive agent in the EML, because a significant proportion of
hypertensive patients need treatment with a combination of two or more
antyhypertensives, and because the dihydropyridine-type calcium channel
blockers can be combined with almost all other classes of antihypertensives
(even β-blockers). Finally, in black people calcium channel blockers can lower
blood pressure values more effectively than some other antihypertensives.

4. Nifedipine has been extensively evaluated as a tocolytic agent and for the
treatment of severe hypertension in pregnancy.

5. There are several generic preparations of LAN and of amlodipine in certain

countries, and the patent of nifedipine GITS (the formulation used in the biggest
published trials with nifedipine) will expire in a few months.

WHO Collaborating Centre

Pharmacotherapy Teaching & Training
Fundació Institut Català de Farmacología
Spain
2 November 2004

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 12

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Table 3. Patent status in the US of LAN formulations and other dihydropyridines

(FDA webpage, “Orange book”).

Brand Name* Producer Strengh (s) Patent(s) expiration date

(year)
Nifedipine:
Adalat CC Bayer Pharma 30, 60, 90 mg 2008 / 2010
Procardia XL Pfizer 30, 60, 90 mg 2003 / 2010
Nifedipine Biovail 30, 60, 90 mg Expired
Nifedipine Elan Pharm 30, 60, 90 mg Expired

Amlodipine:
Norvasc Pfizer 10 mg 2006 / 2007

Felodipine:
Plendil Astrazeneca 2,5, 5, 10 mg 2007
* nitrendipine is not available in the United States. Its patent has expired in some European
countries.