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Mavani et al Journal of Drug Delivery & Therapeutics. 2022; 12(4-S):181-191
ISSN: 2250-1177 [181] CODEN (USA): JDDTAO
Available online on 15.08.2022 at http://jddtonline.info
Journal of Drug Delivery and Therapeutics
Open Access to Pharmaceutical and Medical Research
Copyright © 2011-2022 The Author(s): This is an open-access article distributed under the terms of the CC BY-NC 4.0
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Open Access Full Text Article Review Article
Nicardia® XL (Nifedipine Extended Release): Technologically Advanced
GITS Formulation Ensures Robust Efficacy and Assured Safety
Siddharth Mavani1, Abi Abraham M2, Arvind Conjeevaram3, Shivendra Singh4, Vaibhav Revandkar5*, Ashish
Birla5
1 Consultant Nephrologist & Transplant Physician, Mavani Kidney Care, Ahmedabad, India.
2 Director, Nephrology & Chief of Renal Transplant Services, Lakeshore Hospital, Kochi, India.
3 Senior Nephrologist & Transplant physician, Bangalore Hospital, Bengaluru, India.
4 Consultant Nephrologist & Transplant Physician, Institute of Medical Sciences, BHU, Varanasi, India.
5 Medical Affairs, J. B. Chemicals and Pharmaceuticals Ltd, Mumbai, India.
Article Info:
_____________________________________________
Article History:
Received 18 June 2022
Reviewed 23 July 2022
Accepted 29 July 2022
Published 15 August 2022
_____________________________________________
Cite this article as:
Mavani S, Abraham M A, Conjeevaram A, Singh S,
Revandkar V, Birla A, Nicardia® XL (Nifedipine
Extended Release): Technologically Advanced
GITS Fo rmulation Ensures Robust Efficacy and
Assured Safety, Journal of Drug Delivery and
Therapeutics. 2022; 12(4-S):181-191
DOI: http://dx.doi.org/10.22270/jddt.v12i4 -s.5483
_____________________________________________
*Address for Correspondence:
Vaibhav Revandkar, Medical Affairs, J. B.
Chemicals and Pharmaceuticals Ltd, Cnergy,
Prabhadevi, Mumbai, Maharashtra, India
Abstract
___________________________________________________________________________________________________________________
Nifedipine is a classical dihydropyridine calcium channel blocker (CCB) indicated for the management
of hypertension, vasospastic angina and chronic stable angina. Prestigious regulatory bodies like
USFDA, EMA, CDSCO and TGA have approved long-acting Nifedipine for the management of
hypertension and angina. Nifedipine was 1st introduced in United States as Adalat® (Bayer) in 1981
and in India as Nicardia® (J. B. Chemicals & Pharmaceuticals) in 1985.
Conventional Nifedipine shows the rapid onset and short duration of action which results in prompt
and marked hypotensive effect but exhibits reflex SNS activation leading to flushing, tachycardia,
worsening myocardial ischemia, and cerebrovascular ischemia. Nifedipine gastrointestinal
therapeutic system (GITS) formulation addresses many of the concerns surrounding the older
formulations of Nifedipine. Nifedipine GITS is a gold standard once-daily formulation of Nifedipine
which allows relatively constant plasma drug concentrations over 24 hours. Nifedipine GITS provides
a controlled release and gradual onset of action of Nifedipine, avoiding the reflex SNS activation
resulting in improved tolerability and compliance.
Clinical studies suggest that long-acting formulations of Nifedipine have slightly greater
antihypertensive actions than Amlodipine. Nifedipine was also found to be more efficient than other
CCBs like Amlodipine, Nicardipine, and Isradipine in resistant hypertensive patients. The addition of
Nifedipine GITS to the conventional treatment of angina pectoris is safe and reduces the need for
coronary angiography and interventions.
Several landmark trials have demonstrated that long-acting Nifedipine improves endothelial function
and arterial stiffness and reduces albuminuria, LV hypertrophy, atherosclerotic plaques and
cardiovascular and cerebrovascular complications.
This comprehensive review focuses on the superiority of the Nifedipine GITS formulation over the
conventional Nifedipine and elaborates on the role of long-acting Nifedipine as a CCB of choice for the
management of hypertension, resistant hypertension, angina pectoris and coronary artery disease.
Keywords – Calcium Channel Blockers, Nifedipine, Long-Acting Nifedipine, Nifedipine GITS,
Nifedipine Extended Release, Nicardia XL.
HYPERTENSION – AN EVER-GROWING BURDEN
Hypertension is one of the leading health-related risk factors
in India, with the largest contribution to the burden of disease
and mortality
1
. An astonishing 1 out of every 3 adults in India
is affected by hypertension, making it one of the highly
prevalent diseases in the country
2
. The number of people
living with hypertension world-wide has doubled to 1.3 billion
since 1990
3
. Globally, hypertension accounts for a staggering
10.4 million deaths every year
4
. Hypertension is diagnosed
when blood pressure is consistently ≥130 and/or ≥80 mm Hg
5
.
Studies have shown that most hypertensive patients on
conventional treatment have uncontrolled blood pressure
6
,
7
.
Globally, nearly 1 billion individuals are living with
uncontrolled hypertension with a proportion of 66.8% and
61.6% in developed and developing countries respectively6.
Resistant hypertension is defined as hypertension that
remains uncontrolled with three antihypertensives (including
one diuretic) or blood pressure that is controlled on four
medications, while refractory hypertension is the one which
remains uncontrolled on five or more antihypertensives of
different classes including a diuretic and a mineralocorticoid
receptor antagonist
8
. Uncontrolled hypertension is one of the
most important cardiovascular risk factors and contributes to
an elevated risk of stroke, myocardial infarction, heart failure,
and renal failure
9
.
Mavani et al Journal of Drug Delivery & Therapeutics. 2022; 12(4-S):181-191
ISSN: 2250-1177 [182] CODEN (USA): JDDTAO
Hypertension is managed by a combination of lifestyle
changes and pharmacological therapy. Some effective life-style
strategies include decreasing salt intake, increasing potassium
intake from vegetables and fruits, weight control, limiting
alcohol intake, and quitting smoking. The drugs commonly
used for the treatment of hypertension either alone or in
combination include calcium channel blockers (CCBs),
angiotensin receptor blockers (ARBs), angiotensin-converting
enzyme inhibitors (ACEi), beta-blockers, alpha-blockers and
diuretics
10
.
CALCIUM CHANNEL BLOCKERS – A PROVEN
ANTI-HYPERTENSIVE THERAPY
Calcium channel blockers, also called as calcium channel
antagonists, are a popular class of antihypertensive drugs.
CCBs are the 1st line drugs for the management of
hypertension. CCBs are the only class of agents deemed
desirable for combination with all the other four classes of
antihypertensive drugs including ARB, ACEi, Beta-blocker and
Diuretics
11
.
These agents are classified into two major categories, non-
dihydropyridines or dihydropyridines. The non-
dihydropyridines include Verapamil and Diltiazem while the
dihydropyridines include drugs like Nifedipine, Amlodipine,
Cilnidipine, Azelnidipine, Benidipine etc. (Table 1).
Calcium channel antagonists block the inward movement of
calcium by binding to the L-type “long-acting” voltage-gated
calcium channels in the heart, vascular smooth muscle, and
pancreas.
Table 1 - Classification of Calcium Channel Blockers
Non-dihydropyridines
Dihydropyridines
Verapamil
Diltiazem
Nifedipine
Amlodipine
Cilnidipine
Azelnidipine
Benidipine
The non-dihydropyridines have inhibitory effects on the
sinoatrial, and atrioventricular nodes which result in slowing
of cardiac conduction and contractility. This allows for the
treatment of hypertension, reduces oxygen demand, and helps
to control the rate of tachydysrhythmias. The
dihydropyridines have a little direct effect on the myocardium,
and instead, are more often peripheral vasodilators
12
.
Dihydropyridine CCBs have been determined to be
appropriate for first-line therapy in patients with
hypertension, particularly in those with left ventricular
hypertrophy, asymptomatic atherosclerosis, angina pectoris,
permanent atrial fibrillation, peripheral artery disease,
isolated systolic hypertension, metabolic syndrome, and
pregnancy
13
.
It is important to note that not all CCBs are alike. CCBs are a
heterogenous class of antihypertensives. Therefore, each
agent needs to be considered individually.
CONVENTIONAL NIFEDIPINE – A CLASSICAL CCB
Nifedipine is the prototype dihydropyridine CCB first
introduced in 1975 initially for the prevention of angina
symptoms and later for the treatment of hypertension.
Nifedipine was 1st introduced in United States as Adalat®
(Bayer) in 1981 and in India as Nicardia® (J. B. Chemicals &
Pharmaceuticals) in 1985.
Nifedipine is a short-acting, potent vasodilator, which relaxes
vascular smooth muscle by its inhibitory effect on the
transmembrane influx of calcium. Nifedipine is indicated in
the treatment of essential hypertension, angina resulting from
coronary artery spasms, and chronic stable angina. Nifedipine
exerts its effect on hypertension, as well as angina, by acting as
an arterial vasodilator. Nifedipine is also very effective in the
treatment of severe hypertension and hypertensive
emergency. Other potential uses of Nifedipine in certain
subclasses of patients include treatment of Raynaud's
phenomenon, congestive heart failure, and prevention of
atherosclerosis, although it must be emphasised that these are
not approved indications.
Conventional Nifedipine has a rapid onset and short duration
of action. The hypotensive effect of the conventional form of
Nifedipine is observed maximally at 1 hour after
administration and disappears within 7 hours. As a result,
Nifedipine has been shown to exert a prompt and marked
hypotensive effect when administered to hypertensive
patients
14
. Rapid and profound vasodilation by short-acting
Nifedipine has been associated with reflex sympathetic
nervous system (SNS) activation leading to flushing,
tachycardia, worsening myocardial ischemia, and
cerebrovascular ischemia14. It has been suggested that a
higher incidence of cardiovascular events associated with
Nifedipine may be due to reflex activation of the SNS20.
Also, due to the short duration of action, a q.i.d. administration
of the conventional Nifedipine is essential for the maintenance
of a hypotensive effect. Therefore, physicians and patients
found it difficult to use the conventional form of Nifedipine for
the treatment of mild to moderate hypertension.
EVOLUTION OF NIFEDIPINE FORMULATIONS
The administration of the original formulation of Nifedipine
(immediate-release capsules) was associated with a profound
reflex increases in heart rate and activation of the sympathetic
nervous system. The Nifedipine immediate-release capsules
needed a q.i.d. administration for maintenance of a
hypotensive effect.
Nifedipine retard formulation was developed to overcome the
limitations of the Nifedipine immediate-release capsules. The
retard formulation of Nifedipine blunted the peak
concentration and sustained the measurable drug levels over a
longer period. The Nifedipine retard required a twice-daily
administration. There was a more sustained reduction in
blood pressure with Nifedipine retard, but there was still a
significant increase in heart rate.
Hence, it was desirable to develop a long-acting form of
Nifedipine to overcome the disadvantages observed with
Nifedipine immediate-release capsule and Nifedipine retard. It
was recognized that the rate of delivery of Nifedipine into the
systemic circulation was a direct determinant of the rate of
onset of vasodilator effect and extent of the reflex sympathetic
activation. As a result, modified-release formulations of
Nifedipine were then developed.
The development of the GITS formulation finally resulted in a
formulation that delayed and flattened the attainment of the
peak plasma concentrations of Nifedipine and thereafter
sustained these levels at a relatively constant level for 24
hours. This results in a smoother, more gradual onset of the
antihypertensive effect, sustained throughout 24 hours with
no discernible cardioacceleration.
Mavani et al Journal of Drug Delivery & Therapeutics. 2022; 12(4-S):181-191
ISSN: 2250-1177 [183] CODEN (USA): JDDTAO
Figure 1 :– Evolution of Nifedipine Formulations
NIFEDIPINE GASTROINTESTINAL THERAPEUTIC
SYSTEM (GITS) – A NOVEL DRUG DELIVERY
SYSTEM
Nifedipine gastrointestinal therapeutic system (GITS)
technology is the latest advancement in the Nifedipine drug
delivery system which allows relatively constant plasma drug
concentrations over 24 hours. Nifedipine GITS is regarded as
the gold standard once-daily formulation of Nifedipine. The
GITS formulation provides drug concentration which reaches
a plateau within 6 hours after administration of a single
Nifedipine dose and continue at that concentration until at
least 24 hours after administration16.
This device utilizes a proprietary mechanism involving a
'push-pull' osmotic pump process. An osmotic pump method
used in the formulation of the Nifedipine GITS, allows for
nearly zero-order drug administration. The osmotic push-pull
technology-based Nifedipine GITS formulation comprises a
bilayer core containing Nifedipine and an osmotically active
but pharmacologically inert polymer wrapped by a
semipermeable membrane (Figure 2). The pill absorbs water
after entering the gastrointestinal tract, resulting in a
Nifedipine suspension in the drug reservoir. The medication
suspension is then extruded through the precision-drilled
pore at a controlled rate over 24 hours as the polymer swells
and the osmotic pressure rises. Until the formulation is
exhausted, this unique osmotic delivery method releases
Nifedipine into the gastrointestinal system and thus into the
systemic circulation at a constant (zero-order) rate
15
,
16
. This
process does not depend upon pH or intestinal motility,
therefore drug distribution out of the system does not vary
with gastrointestinal contents or function.
Figure 2: Diagrammatic representation of the Nifedipine gastrointestinal therapeutic system (GITS). (Image sourced from a
paper by Peter A Meredith11)
Nifedipine
Immediate-release
capsules
Nifedipine
Retard
Nifedipine
GITS
Mavani et al Journal of Drug Delivery & Therapeutics. 2022; 12(4-S):181-191
ISSN: 2250-1177 [184] CODEN (USA): JDDTAO
Nifedipine GITS provided relatively constant plasma
concentrations over >18 hours intervals in a clinical study
done on 23 healthy human volunteers (Figure 3). The results
of this study suggest that Nifedipine drug release and
absorption are zero-order within the human GI tract, and that
once-daily administration appears to be reasonable with the
device
17
.
Figure 3:- Mean plasma Nifedipine concentration-time profiles in healthy volunteers (n = 23) after single doses of a
Nifedipine GITS tablet (60mg) or immediate- release Nifedipine capsules (2 x 10mg)17 (Graph sourced from a study by Chung
M et al.17)
Nifedipine GITS formulation allows controlled release of the
drug and thus prolongs the duration of action and reduces the
risk of adverse events as compared to conventional Nifedipine.
The diameter of the pre-drilled opening limits the rate at
which the drug exits the system, thus preventing a dose-
dumping effect. The prevention of dose dumping by GITS
technology also contributes to smooth BP management.
Another important advantage of the Nifedipine GITS is that the
trough/peak (T/P) effect ratio following once-daily
administration is maintained above 50%, as recommended by
the United States Food and Drug Administration16. Studies
with the Nifedipine GITS have reported T/P ratios between 66
and 98.6%16.
Further, the extended 24-hours duration of action reduces the
frequency of drug intake from two or three tablets (in
conventional Nifedipine) to once daily. Once-daily dose
administration with Nifedipine GITS would help improve
patient compliance and the long-term treatment outcomes.
With respect to age, no or only slight differences were found in
Nifedipine GITS pharmacokinetic parameters after single or
multiple doses in young and elderly volunteers, and thus no
dosage adjustment is apparently necessary16. Similarly,
impaired renal function in patients does not appear to
significantly affect the plasma concentrations of Nifedipine
even following multiple doses of the Nifedipine GITS, and thus
dosage adjustment seems unnecessary16.
It should be noted that, in GITS systems, the tablet shell does
not dissolve but passes through the gastrointestinal system
intact and is expelled upon defecation.
LONG-ACTING NIFEDIPINE – THE NEXT-GEN
REVAMPED CCB
Recently, long-acting formulations of Nifedipine were
developed and made available to the clinicians. These newer
formulations were designed to address many of the concerns
raised by earlier formulations of Nifedipine. Long-acting
formulations of Nifedipine have a longer duration of action,
greater bioavailability, and lesser incidences of adverse events
than the conventional preparations
18
. Regulatory bodies like
USFDA, EMA, CDSCO and TGA have approved long acting
Nifedipine for hypertension and angina. Numerous extended-
release formulations of Nifedipine are available worldwide
and have been shown to be equally efficacious as compared to
other antihypertensives such as ARBs, β-blockers, and
diuretics in the management of hypertension13.
Mavani et al Journal of Drug Delivery & Therapeutics. 2022; 12(4-S):181-191
ISSN: 2250-1177 [185] CODEN (USA): JDDTAO
Table 2: Comparative Analysis of Conventional Nifedipine and Long acting Nifedipine Over Various Pharmacological
Parameters
Parameters
Conventional Nifedipine
Long-Acting Nifedipine
1. Technology
Normal tablet
Osmotically controlled drug release oral
delivery system (OROS)
2. Drug release
Rapidly releases the active drug
Slow and sustained release of active drug
3. Onset of action
Rapid
Slow
4. Duration of action
Short
Long (24 hours)
5. Half-life
1.7 hours
7 hours
6. Bioavailability
45%–68%
75% - 85%
7. Dosing
Twice daily
Once daily
8. Blood Pressure
Rapidly decreases blood pressure
Smoother, more gradual decrease in blood
pressure
9. Norepinephrine (NE) level
Increases significantly both acutely
and chronically, reaching peak 3
hours after drug administration
Decreases plasma NE levels significantly 6
hours after the dose and the effect is
maintained throughout the dosing interval
10. Heart Rate (HR)
Increases HR
No significant change in HR
11. Edema
High incidence
Low incidence
12. Side-effects
SNS activation
Flushing
Tachycardia
Worsens myocardial &
cerebrovascular ischemia
Lesser side-effects as compared to short-acting
formulations
LONG-ACTING NIFEDIPINE – INSIGHTS FROM
CLINICAL TRIALS
According to AHA Scientific Statement, dihydropyridine CCBs
such as Nifedipine extended release and Amlodipine are the
most studied in the setting of hypertension
19
. Till date, a
staggering >24,000 publications and >2700 clinical trials are
being published on Nifedipine in the scientific journals.
In adults with essential hypertension, monotherapy with
modified-release Nifedipine (irrespective of formulation) for
≥8 weeks led to similar reductions in systolic and diastolic BP,
and achieved similar response rates, to those seen with
comparator agents, including Amlodipine, Lacidipine,
extended-release Verapamil, Enalapril, Lisinopril, Losartan
(with or without Hydrochlorothiazide) and Nebivolol36.
The extended-release formulation of Nifedipine significantly
reduced SBP and DBP due to its longer duration of action (24
hours)
20
,
21
. The Nifedipine GITS formulation was associated
with a more gradual decrease in BP without an increase in NE,
potentially due to the fact that plasma drug levels were lower
than those obtained by Nifedipine retard20.
Clinical studies suggest that long-acting formulations of
Nifedipine have slightly greater antihypertensive actions than
Amlodipine
22
,
23
,
24
. In a study conducted by Keisuke Kuga et al.,
the total anti-hypertensive power of Nifedipine coat-core,
measured by the hypobaric area, was found to be 1.69 times
more potent than that of Amlodipine23.
In a 10-week, multi-center, double-blind study, 102 patients
received Nifedipine GITS 30 or 60 mg daily,
Hydrochlorothiazide 25 or 50 mg daily, or placebo. Both
treatments, Nifedipine GITS and Hydrochlorothiazide were
found to be significantly better than placebo in decreasing SBP
and DBP with 71% of the Hydrochlorothiazide group and 67%
of the Nifedipine group achieving a sitting DBP<90 mmHg.
This study concluded that Nifedipine GITS monotherapy
decreases BP with efficacy similar to that of
Hydrochlorothiazide
25
.
In another double-blind study, patients received Nifedipine
GITS or sustained-release Propranolol for 8 weeks. In this
study, sitting SBP has decreased a mean of 15.9 mmHg in the
Nifedipine group compared to 5.7 mmHg in the Propranolol
group (p<0.001). The proportion of patients receiving
Nifedipine who achieved target sitting and standing SBP was
61% and 52%, respectively, as compared to 25% and 28% in
the Propranolol group
26
.
Mavani et al Journal of Drug Delivery & Therapeutics. 2022; 12(4-S):181-191
ISSN: 2250-1177 [186] CODEN (USA): JDDTAO
Figure 4 :- Changes in hemodynamic parameters with Nifedipine GITS (Graph sourced from a study by Jidong Zhang et al.)20
LONG-ACTING NIFEDIPINE – CCB OF CHOICE IN
DIFFICULT TO CONTROL/ RESISTANT
HYPERTENSION/ REFRACTORY HYPERTENSION
Resistant hypertension can be managed with appropriate
lifestyle modifications and escalation of antihypertensive
medications. In patients with uncontrolled BP on the triple
combination, it is important to first replace the existing on-
going drugs with other potent molecules from the same class,
before adding new drugs. For examples, the existing CCB can
be replaced with a more potent CCB like long-acting
Nifedipine. According to an expert review paper published in
the Clinical Journal of the American Society of Nephrology,
long-acting Nifedipine or Amlodipine should be the preferred
CCBs for managing resistant hypertensive patients
27
.
In several clinical trials done in refractory hypertensive
patients, the high potent antihypertensive action of a single
dose of long-acting Nifedipine was found to be much more
efficient than two or more doses of Amlodipine, Nicardipine,
and Isradipine24,22,
28
.
Landmark MONICA Study compared the efficacy of Valsartan
80 mg + Amlodipine 5 mg per day with Valsartan 80 mg +
Nifedipine controlled release (CR) 20 mg per day in thirty-five
patients with uncontrolled blood pressure for 16 weeks. If the
patient did not reach the target office BP at 8 weeks, they
received double doses of CCBs. In the Valsartan + Nifedipine
group, morning diastolic BP was found to be significantly
lower than the respective values in the Valsartan + Amlodipine
group at 8 weeks. The percentage of patients who required a
double dose of CCB in the Valsartan + Nifedipine group was
significantly lower than that in the Valsartan + Amlodipine
group. Urinary albumin/creatinine at 16 weeks was
significantly less than that at 0 weeks in the Valsartan +
Nifedipine group. The authors concluded that, combination
therapy with Valsartan and Nifedipine CR may help to control
morning BP and protect the kidneys24.
In another study done in patients with an inadequate response
to Candesartan, Atenolol or Diuretic monotherapy, the
addition of modified release Nifedipine formulations led to
significant reductions in BP36.
According to the ESC/ESH guidelines for managing severe
hypertension during pregnancy, drug treatment with IV
Labetalol, oral Methyldopa, or Nifedipine is recommended
29
.
Joshua Adeniyi Adebayo et al. compared Nifedipine versus
Hydralazine in the management of severe hypertension in
pregnancy. Both oral Nifedipine and intravenous Hydralazine
were found to be equally efficacious for acute control of BP in
severe hypertension in pregnancy without adverse maternal
and perinatal effects. However, the average number of dosages
needed to control the BP was lower in the Nifedipine arm
30
.
LONG-ACTING NIFEDIPINE – BENEFITS BEYOND
BLOOD PRESSURE CONTROL
Long-acting formulations of Nifedipine have been shown to
exert several beneficial effects along with blood pressure
reduction.
Nifedipine has been shown to decrease albuminuria in
hypertensive patients. MONICA study, showed that,
Mavani et al Journal of Drug Delivery & Therapeutics. 2022; 12(4-S):181-191
ISSN: 2250-1177 [187] CODEN (USA): JDDTAO
combination therapy consisting of Valsartan and Nifedipine CR
is more useful for controlling morning BP and protecting the
kidneys than the combination of Valsartan and Amlodipine.
Valsartan + Nifedipine was found to significantly reduce the
urinary albumin/creatinine after 16 weeks of treatment24.
Renal function was better preserved with Nifedipine GITS than
with Co-amilozide in hypertensive patients in the INSIGHT
study, while in the J-MIND study, Nifedipine had a similar
effect on urinary albumin excretion (UAE) rate after 2 years to
that seen with Enalapril in hypertensive diabetic patients36.
Nifedipine has been shown to improve endothelial function by
the virtue of its anti-hypertensive action. An improvement in
endothelial function by Nifedipine GITS was demonstrated in
the ENCORE study by a significant reduction in acetylcholine-
induced vasoconstriction in the coronary arteries
31
.
A prospective, double-blind INSIGHT trial by Brown and
colleagues evaluated the cardiovascular and cerebrovascular
outcomes following Nifedipine GITS 30 mg or Co-amilozide
(HCTZ 25 mg/amiloride 2.5 mg) daily therapy. The primary
outcome was reported in 6.3% of patients in the Nifedipine
group compared to 5.8% in the Co-amilozide group (p = 0.34).
There was no significant difference in event rates between
groups. The authors concluded that both agents were equally
efficacious in preventing cardiovascular and cerebrovascular
complications.
32
One sub-analysis of the INSIGHT study
showed that, Nifedipine and diuretics offer similar protection
against cardiovascular events
33
. Another sub-analysis of the
INSIGHT study showed that, Nifedipine GITS and diuretics are
equally efficacious in the treatment of patients with isolated
systolic hypertension
34
.
In the STONE study, Nifedipine was found to significantly
reduce the risk of major clinical events compared with placebo
in elderly hypertensive patients while in the JMIC-B study,
Nifedipine had similar efficacy to ACE-inhibitor therapy in
terms of reducing major cardiac events in patients with both
hypertension and coronary artery disease36.
Landmark INTACT trial provided evidence that, relative to
placebo, Nifedipine GITS significantly reduced the
development of new lesions (stenoses > 20% or occlusions) in
patients with mild coronary artery disease (CAD) over a 3-
year trial period
35
. In patients with CAD, Nifedipine GITS
significantly improved coronary endothelial function by
increasing artery diameter.42
In patients with chronic stable angina pectoris, modified-
release Nifedipine significantly increased the time to onset of
0.1mV ST-segment depression during exercise testing
compared with baseline. Improvements were similar to those
seen with Atenolol, Carvedilol or Diltiazem
36
. In another study,
modified-release Nifedipine was as effective as modified-
release Isosorbide dinitrate or Nisoldipine coat-core in
patients with variant angina36.
Landmark ACTION trial was a large, double-blind trial in
which patients were randomized to receive Nifedipine GITS
30–60 mg once daily (n = 3825) or placebo (n = 3840) in
addition to standard treatment and followed up for a mean of
4.9 years. ACTION trial showed that the addition of Nifedipine
GITS to conventional treatment of angina pectoris is safe and
reduces the need for coronary angiography and
interventions
37
. The mean heart rate was higher by 1 bpm in
the Nifedipine GITS group versus the placebo group. The risk
of meeting the primary efficacy endpoint (a composite of
major events including death from any cause, MI, refractory
angina, new overt heart failure, debilitating stroke, peripheral
revascularization), or primary safety endpoint (a composite of
any death, MI or debilitating stroke) was similar for recipients
of Nifedipine GITS and placebo37. Looking at secondary
endpoints, there was no difference for ‘any cardiovascular
event’, but the composite endpoint ‘any death, cardiovascular
event or procedure’ and the ‘any vascular event’ endpoint
were significantly reduced by 11% and 9% with Nifedipine
GITS compared with placebo37 (Figure 5). This was largely
because fewer Nifedipine GITS recipients needed coronary
angiography or coronary bypass surgery (hazard ratios 0.82
[p < 0.0001] and 0.79 [p = 0.0021]). Nifedipine GITS
significantly reduced the incidence of any stroke or transient
ischemic attack and the need for coronary angiography by
21% in normotensives and 16% in hypertensives. Nifedipine
GITS prolonged the mean cardiovascular event and procedure-
free survival by 41 days.
Figure 5 :- Effect of Nifedipine GITS on Cardiovascular (CV) Outcomes in Patients With Chronic Stable Angina37 (Forest Plot
sourced from the ACTION study37)
Mavani et al Journal of Drug Delivery & Therapeutics. 2022; 12(4-S):181-191
ISSN: 2250-1177 [188] CODEN (USA): JDDTAO
The PRESERVE trial demonstrated the effectiveness of
Nifedipine GITS in reducing LV hypertrophy. This study
compared once-daily Enalapril or long-acting Nifedipine, plus
adjunctive Hydrochlorothiazide and Atenolol when needed to
control blood pressure. Both once-daily Enalapril and long-
acting Nifedipine had moderately beneficial and statistically
indistinguishable effects on regression of LV hypertrophy
38
.
In a study conducted by Houston MC, Nifedipine GITS
significantly increased HDL, HDL2, and apolipoprotein A-I and
A-II levels in patients with mild-to-moderate hypertension
39
.
In other 2 studies, Nifedipine GITS significantly reduced
apolipoprotein E levels, the LDL:HDL-cholesterol ratio and the
apolipoprotein B:A-I ratio in hypertensive patients
40
,
41
.
Nifedipine GITS was also shown to non-significantly reduce
serum triglyceride levels39,41.
In a single-center, prospective, Phase IV study, Jidong Zhang et
al., evaluated the early intervention impact of Nifedipine GITS
on arterial stiffness and pulse wave velocity (PWV) in mild
hypertensive patients. Nifedipine GITS was found to
significantly reduce 24-hour ambulatory BP and brachial–
ankle pulse wave velocity, indicating improvement in arterial
stiffness as early as 4 weeks21.
In animal studies, Nifedipine retarded and reversed the
development of atherosclerotic plaque and improved
endothelial function. Several animal studies have indicated
that Nifedipine may reduce the accumulation of components
of atherosclerotic plaque and, therefore, retard the
development of lesions in rats, rabbits and primates. Plaque
formation was inhibited dose-dependently in Nifedipine-
treated (50 mg/kg) rats fed a cholesterol-enriched diet by up
to 61% relative to controls
42
. In humans, Nifedipine GITS has
been shown to slow the progression of various markers of
early atherosclerosis, including intimal thickening, vascular
calcification and luminal narrowing42.
LONG-ACTING NIFEDIPINE – PROVEN SAFETY &
TOLERABILITY
Extended release Nifedipine appears to be relatively well
tolerated, particularly compared with other antihypertensives
because it does not cause depression of the central nervous
system or orthostasis25. The extended-release formulation of
Nifedipine possesses clinically significant benefits since reflex
activation of the SNS correlates with the rate of increase in
plasma drug levels. Thus, the gradual rise in drug
concentrations decreases SNS activation, in turn reducing
adverse events associated with short-acting Nifedipine
43
,
44
.
The most common types of adverse events seen, irrespective
of formulation, are those relating to its vasodilatory
properties, such as headache, peripheral edema not associated
with heart failure, flushing and palpitations36. The most
significant adverse effect, edema, is dose-related and occurs in
10% to 30% of patients receiving 180 mg Nifedipine. When
compared with placebo, headache and edema were more
common in the Nifedipine extended-release group.
When the GITS formulation was compared to prolonged action
and capsule formulations, Nifedipine GITS was better
tolerated with respect to overall adverse events, particularly
headache and dizziness. Only vomiting was more common in
the Nifedipine GITS arm compared to the other formulations44.
A study by Wenzel and colleagues showed that, there was no
significant change in HR in the Nifedipine GITS group
compared to baseline
45
.
In the EXACT trial, adverse events were most commonly
reported during the first few weeks of the Nifedipine GITS
treatment period, and then decreased in frequency
46
.
Figure 6:– Effect of Different Nifedipine Formulations on Heart Rate and Plasma Noradrenaline Level11 (Graphs sourced from
a paper by Peter A Meredith11)
Table 3:- Long-Acting Nifedipine Brands Available Globally
Brand
Strength
Manufacturer
Adalat CC
30 mg, 60 mg, 90 mg
Bayer
Adipine XL
30 mg, 60 mg
Chiesi
Procardia XL
30 mg, 60 mg, 90 mg
Pfizer
Afeditab CR
30 mg, 60 mg
Actavis
Mavani et al Journal of Drug Delivery & Therapeutics. 2022; 12(4-S):181-191
ISSN: 2250-1177 [189] CODEN (USA): JDDTAO
Table 4:- Long-Acting Nifedipine Brands Available in India
Brand
Strength
Manufacturer
Nicardia XL
30 mg, 60 mg
J. B. Chemicals and
Pharmaceuticals
Folcardia XL
30 mg
Folarix
Table 5 :– Long-Acting Nifedipine Indication and Dosage
Indications
Hypertension
Vasospastic Angina
Chronic Stable Angina
Dosage
30 or 60 mg once daily
DISCUSSION & CONCLUSION
Hypertension is the number one risk factor for death, affecting
more than 1 billion people globally. It has been found that,
despite the availability of standard medicines, most
hypertensive patients on conventional treatment have
uncontrolled blood pressure. CCBs are the 1st line drugs for
the management of hypertension and the only class of agents
deemed desirable for combination with all the other four
classes of antihypertensive drugs including ARB, ACEi, Beta-
blockers, and Diuretics.
Nifedipine is a classical dihydropyridine CCB introduced
initially for the prevention of angina symptoms and later for
the treatment of hypertension. Conventional Nifedipine had a
rapid onset and short duration of action which results in
prompt and marked hypotensive effect but exhibits reflex SNS
activation leading to flushing, tachycardia, worsening
myocardial ischemia, and cerebrovascular ischemia.
Nifedipine GITS formulation addresses many of the concerns
surrounding the older formulations of Nifedipine. Nifedipine
GITS is a gold standard once-daily formulation of Nifedipine
which allows relatively constant plasma drug concentrations
over 24 hours. Nifedipine GITS provides a controlled release
and gradual onset of action of Nifedipine, avoiding the
baroreceptor-mediated reflex activation of the SNS observed
with conventional Nifedipine. This once-daily, long-acting
formulation improves tolerability and compliance in patients
with hypertension.
Esteemed regulatory bodies like USFDA, EMA, CDSCO, and
TGA have approved long acting Nifedipine for hypertension
and angina. Numerous extended-release formulations of
Nifedipine are available worldwide and have been shown to be
equally efficacious as compared to other antihypertensives
such as ARBs, β-blockers, and diuretics in the management of
hypertension.
According to AHA Scientific Statement, among CCBs,
Nifedipine extended release and Amlodipine are the most
studied in the setting of hypertension. Till date, >24,000
publications and >2700 clinical trials are being published on
Nifedipine in scientific journals. Clinical studies suggest that
long-acting formulations of Nifedipine have slightly greater
antihypertensive actions than Amlodipine. In a study
conducted by Keisuke Kuga et al., the total anti-hypertensive
power of Nifedipine coat-core, measured by the hypobaric
area, was found to be 1.69 times more potent than that of
Amlodipine. In several clinical trials done in resistant
hypertensive patients, the high potent antihypertensive action
of a single dose of long-acting Nifedipine was found to be
much more efficient than two or more doses of Amlodipine,
Nicardipine, and Isradipine.
Long-acting formulations of Nifedipine have been shown to
exert several beneficial effects along with blood pressure
reduction. In the MONICA trial, Nifedipine was found to
significantly reduce the urinary albumin/creatinine after 16
weeks of treatment while in the J-MIND study, Nifedipine had
a similar effect on urinary albumin excretion (UAE) rate as
Enalapril in hypertensive diabetic patients after 2 years of
treatment.
An improvement in endothelial function by Nifedipine GITS
was demonstrated in the ENCORE study while the landmark
INSIGHT trial showed the role of Nifedipine in preventing
cardiovascular and cerebrovascular complications. STONE and
JMIC-B trials also showed Nifedipine to significantly reduce
the risk of major clinical events in elderly hypertensive
patients and to reduce the major cardiac events in patients
with both hypertension and coronary artery disease
respectively.
Landmark INTACT trial provided evidence that, relative to
placebo, Nifedipine GITS significantly reduced the
development of new lesions in patients with mild coronary
artery disease over a 3-year trial period. ACTION trial showed
that, the addition of Nifedipine GITS to conventional treatment
of angina pectoris is safe and reduces the need for coronary
angiography and interventions. Nifedipine GITS prolonged the
mean cardiovascular event and procedure-free survival by 41
days. The PRESERVE trial demonstrated the effectiveness of
Nifedipine GITS in reducing LV hypertrophy. A prospective,
Phase IV study by Jidong Zhang et al. showed that, early
intervention with Nifedipine GITS significantly reduces
brachial–ankle pulse wave velocity, and arterial stiffness in
mild hypertensive patients.
In animal studies, Nifedipine retarded and reversed the
development of atherosclerotic plaque and improved
endothelial function while in humans, Nifedipine GITS has
been shown to slow the progression of various markers of
early atherosclerosis, including intimal thickening, vascular
calcification and luminal narrowing.
Extended release Nifedipine has been proven to be safe and
tolerable in several clinical trials. When the GITS formulation
was compared to prolonged action and capsule formulations,
Nifedipine GITS was better tolerated with respect to overall
adverse events. A study by Wenzel and colleagues showed
that, there was no significant change in HR in the Nifedipine
GITS group compared to baseline.
Thus, to conclude, long-acting formulations of Nifedipine have
a longer duration of action, greater bioavailability, and lesser
incidences of adverse events than the conventional
preparations. With a diminished concern for reflex SNS
activation, long-acting Nifedipine has the potential to play a
larger role in the management of hypertension and angina.
Combination therapy, which combines long acting Nifedipine
with an ACE inhibitor or ARB, and/or a thiazide diuretic, can
be a game-changer in cases where traditional Nifedipine is
ineffective. Nifedipine GITS can be used safely for the long-
term treatment of patients with hypertension, resistant
hypertension, angina pectoris, and coronary diseases.
Nifedipine GITS can also be preferred in hypertensive patients
with high cardiovascular risk because of its proven potential
to prevent cardiovascular and cerebrovascular complications.
CONFLICTS OF INTEREST
The authors declare no conflict of interest.
Mavani et al Journal of Drug Delivery & Therapeutics. 2022; 12(4-S):181-191
ISSN: 2250-1177 [190] CODEN (USA): JDDTAO
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