Drug Evaluation

Clevidipine: a state-of-the-art
antihypertensive drug under the
scope
1.

Introduction

2.

The intravenous

Ilse M Espina & Joseph Varon

Dorrington Medical Associates, Houston, Texas, USA

Expert Opin. Pharmacother. Downloaded from informahealthcare.com by IBI Circulation - Ashley Publications Ltd on 08/07/12
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antihypertensive market and

clevidipine butyrate
3.

Clevidipine butyrate: the

compound

4.

Chemistry

5.

Pharmacodynamics

6.

Pharmacokinetics and
metabolism

7.

Clinical efficacy

8.

Safety and tolerability

9.

Regulatory affairs

10.

Conclusions

11.

Expert opinion

Introduction: Clevidipine butyrate is the first intravenous antihypertensive

drug to be approved by the FDA over the last decade. This medication is
approved for use in the USA, Australia and New Zealand, but is still pending
for approval in Europe. It is a new agent that might change the current management for severe acute hypertension in the critical care, emergency and
perioperative areas.
Areas covered: This systematic review summarizes the pharmacological and
clinical characteristics of this third-generation dihydropyridine intravenous
calcium channel blocker, and was done using the literature available from
the first publication in 1999 up until now, including the pivotal trials that
led to its approval.
Expert opinion: This agent is arterially selective, has an ultrashort half-life,
with no CYP-mediated interactions with other medications and is easily titratable. These characteristics place it in a unique category compared with other
commonly used antihypertensives. Clevidipine butyrate reaches target systolic
blood pressure in more than 90% of patients, within 30 min. It has a low incidence of adverse reactions and is generally well tolerated. The main goal of
this review is to provide healthcare providers with a comprehensive appraisal
of this promising medication.
Keywords: calcium channel blockers, clevidipine, clevidipine butyrate, hypertension,
hypertensive crisis, intravenous antihypertensives
Expert Opin. Pharmacother. (2012) 13(3):387-393

1.

Introduction

Hypertension is one of the most common chronic conditions throughout the world,
with an estimated 1 billion patients worldwide [1]. In the USA alone, 76 million
people suffer from this condition. Of them, 1% will develop a hypertensive crisis,
such as hypertensive emergencies [2]. If these events are not promptly assessed and
managed, they can lead to a number of conditions and complications that can seriously compromise health and life (i.e., hypertensive encephalopathy, stroke, subarachnoid and intraparenchymal brain hemorrhage, myocardial ischemia, acute
congestive heart failure and pulmonary edema, aortic dissection and acute renal
injury) [3]. The current available antihypertensive therapy remains less than ideal
for these clinical situations. As yet, there are no homogeneous treatment protocols,
and the present approach has been shown to have high rates of mortality and morbidity and a high incidence of recurrence, which increases the costs and use of
medical resources [4-6].
With some of the current treatment strategies, < 50% of patients have a decrease
in systolic blood pressure within 30 min, have an incidence of iatrogenic hypotension as high as 4% and, even though patients are successfully transitioned to oral
treatments, the recurrence rates exceed 30% [4]. One of the reasons for these issues
is that most of the intravenous agents used in the treatment of acute hypertension
10.1517/14656566.2012.651126 2012 Informa UK, Ltd. ISSN 1465-6566
All rights reserved: reproduction in whole or in part not permitted

387

Clevidipine butyrate

Box 1. Drug summary.

Drug name
Phase

Clevidipine butyrate
Launched (approved: USA, Australia, New Zealand;
EU submission pending approval)
Hypertension
L-type calcium channel blocker
Intravenous
C21H21Cl2NO6
ESCAPE 1 & 2, ECLIPSE, VELOCITY

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Indication
Pharmacology description/mechanism of action
Route of administration
Chemical structure
Pivotal trials

have slow onset and offset times [7,8]. In addition, these agents
tend to have interactions with other medications, or contraindications to most of the common comorbidities [7-9]. In
patients with acute hypertension, under- and inappropriate
management of hypertensive crises result equally dangerous
and can lead to high morbi-mortality [10].
2. The intravenous antihypertensive market
and clevidipine butyrate

As noted above, hypertension is a common disease that is

often complicated with hypertensive emergencies that require
effective and rapid intravenous therapy. These are everyday
situations, found not only in emergency departments but
also in medical wards, intensive care units and in perioperative
settings [11]. Many agents have been used in these settings over
decades and are still commonly found in American and
European guidelines, without any one of them being a gold
standard [4,12]. The use of an intravenous antihypertensive
that is easily titratable and does not require invasive blood
pressure monitoring is ideal in these situations [13-15].
Clevidipine butyrate (Box 1) is a relatively new antihypertensive medication that has progressively made its way into
the emergency and preoperative settings in the last few years.
This drug has a wide range of possible uses and applications.
Besides its role in the management of hypertensive emergencies and cardiovascular surgery, several clinical trials are being
conducted in other settings (i.e., neurosurgery) [16].
3.

Clevidipine butyrate: the compound

Clevidipine butyrate is a synthetic intravenous antihypertensive

that comes as an injectable oil-in-water emulsion. It is white
with a very similar appearance to that of propofol [17,18]. It is
almost insoluble in water (0.1 mg/ml) and is prepared with
egg yolk and soybean phospholipids [19,20]. It can be classified
as an arterially selective, short-acting vasodilator. It belongs
to the group of third-generation synthetic dihydropyridine
calcium channel blockers [20,21].
4.

Chemistry

The chemical name of clevidipine butyrate is butyroxymethyl

methyl 4-(2, 3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl388

3,5-pyridinedicarboxylate. It has a molecular weight of

456.3 g/mol [18,22,23].
Clevidipine butyrate is a racemic compound composed of
two enantiomers, R-clevidipine and S-clevidipine. These
have comparable half-lifes and are equipotent [24,25]. Its chemical composition is similar to that of felodipine, except that it
contains an ester linkage, which allows for a rapid metabolism
owing to esterases in the blood and tissues [21,26]. Its composition can be compared to other medications from the same
group of dihydropyridine calcium channel blockers (i.e.,
nifedipine, nicardipine, amlodipine) [27].
5.

Pharmacodynamics

Clevidipine butyrates mechanism of action consists of blocking

of the voltage dependent L-type calcium channels and, thus,
inhibiting the transmembrane calcium influx. This, in turn,
results in an inhibition of cell depolarization and consequently
preventing the arterial smooth muscle contraction, diminishing
the peripheral vascular resistance without affecting venous
capacitance, thus considered arterially selective. [27-30]. Clevidipine butyrate allows for a selective decrease in the afterload,
causing a reduction in the mean arterial pressure values without
affecting the cardiac filling pressures [28]. The initial onset of
action in humans is observed about 2 -- 4 min, with a mean
reduction of 5.9% in systolic blood pressure after 3 min of
infusion [7]. The mean arterial pressure experiences a reduction
of 10 mmHg on average, after the infusion of clevidipine butyrate is started with a systolic blood pressure reduction of 15%
after a mean time of 5 -- 10 min [7,25,31]. The stabilization of
the effect of clevidipine butyrate can be observed 15 min after
the infusion has been started, with a decrease in the blood pressure and minimal elevation of the heart rate. Once the infusion
is discontinued, the blood pressure and heart rate values return
to their baseline after approximately the same amount of
time [25].
With the use of other intravenous calcium channel blockers, heart rate increases progressively with continuous infusions, with an average elevation of 2 -- 3% for every 3 min.
With clevidipine butyrate, however, this elevation stabilizes
after 15 min with pulse elevations remaining below 14%
from baseline [7]. Its hemodynamic properties are dosedependent and follow a linear response regarding the decrease
in systemic vascular resistance [7,28,32,33]. This unique

Expert Opin. Pharmacother. (2012) 13(3)

Espina & Varon

18

achieved. Most commonly, therapeutic success is achieved

with doses of 4 -- 6 mg/h. The usual maximal dose is
16 mg/h; it has been used up to 32 mg/h, but there is limited
clinical experience at this dose; no more than 1000 ml or
21 ml/h in a 24-h period is recommended because of
increased lipid load [23] (see Figure 1).

Recommended
16

Therapeutic

14

90 seconds

12

Time 0

10
8

7.

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6
4
2
0
Initial dose

Maximal

Initial increase Maintainance

Figure 1. Graphic overview of the different dosing ranges at

different times of infusion.

propriety has also led to postulation that clevidipine butyrate

might have protective proprieties against ischemic and
reperfusion injury [34-36].
6.

Pharmacokinetics and metabolism

Clevidipine butyrate has a high tendency for protein binding

with > 99.5% in males and females and a mean volume of distribution of 0.17 liters/min/kg in arterial blood [18,37]. Its arterial
half-life is ~ 1 min [21,28,38]. It is rapidly metabolized through
blood and tissue esterases, which hydrolyze the compound by
cleavage of the ester linkage [37,39]. This mechanism of hydrolysis
allows a metabolism free of renal or hepatic involvement [18,19,25].
Therefore, no dose adjustments are needed for those with liver or
kidney dysfunction, and there is no risk of cytochromeP450-associated drug interactions. This has been demonstrated
in vitro by induction solely of CYP3A4 and not of CYP1A2
and CYP2C9 in hepatocytes [40]. The primary metabolite
obtained from this first-order reaction is H152/81, an inactive
carboxylic acid, which according to animal studies does not
have vasodilatory properties [18,37,41]. This carboxylic acid is further metabolized through glucuronidation and oxidation to a
pyridine derivate with a terminal half-life of 9 h and a clearance
rate of 0.03 liters/kg [18]. It is excreted through renal and biliary
routes [42].
In vitro investigations were done using fresh, diluted
human blood from both genders at three different temperatures. The half-lifes were: 5.8 min at 37 C, 10.7 min at
30.5 C and 40.1 min at 18 C [37]. Additionally, some
in vitro studies have shown that patients with pseudoesterase
deficiency have longer clearance times because of delayed
metabolism, though this may not be clinically relevant owing
to the short half-life [37].
The recommended initial dose is 1 -- 2 mg/h; the dose can
be increased every 90 s initially until target blood pressure is

Clinical efficacy

The clinical efficacy of clevidipine butyrate has been proved in

numerous observational and experimental studies in animal
models and humans. Ericsson and colleagues, in 1999,
described the pharmacokinetics in rat, rabbit and dog,
and demonstrated the blood-pressure-lowering capability in
dogs [41].
The ESCAPE (efficacy study of clevidipine assessing its
postoperative antihypertensive effect in cardiac surgery)-1 trial
was the first randomized trial of significance, done to evaluate
the effect of clevidipine butyrate in preoperative hypertension.
This trial included 105 patients that were randomized before
cardiac surgery to receive either clevidipine butyrate or placebo infusions; resulting in 92.5% of successful treatment
with clevidipine butyrate, compared with 17.3% in placebo [43]. This study was followed by a double-blind,
placebo-controlled, randomized clinical trial that further analyzed its efficacy in postoperative cardiac surgery [31]. In this
trial, ESCAPE-2, 206 patients received either clevidipine
butyrate or placebo infusions. The success rate for clevidipine
butyrate was significantly higher with 91.8 versus 20.4%. The
efficacy of the medication was observed further with a median
time to reach target systolic blood pressure of 5.3 min and a
maximal decrease in the mean arterial pressure of 28.9% [31].
The ECLIPSE trial reported by 2008 by Aronson and coworkers, compared the effectiveness of clevidipine butyrate versus nitroglycerine, sodium nitroprusside and nicardipine in
1512 cardiac surgery patients with acute hypertension [44].
This prospective study demonstrated that clevidipine butyrate
was safe and effective, without difference in the incidence of
myocardial infarction, renal dysfunction and stroke than the
other drugs, and has lower mortality rates when compared
with sodium nitroprusside. Additionally, this drug proved
successfully to reduce blood pressure and maintain blood
pressure boundaries in narrower ranges [44].
Clevidipine butyrates utility in the emergency department
and intensive care unit were shown in the VELOCITY trial [7].
In this trial in patients with acute severe hypertension, a
success rate of 88.9% in achieving target blood pressure
within 30 min of infusion was demonstrated (median time
10.9 min). Moreover, 92.3% of subjects were successfully
transitioned to oral medication once the crises were controlled. This trial evaluated 126 patients, of which a great
majority presented with multiple comorbidities and end
organ injury (81%). Although not all the patients had true
hypertensive emergencies, clevidipine butyrate showed good
success and tolerability rates [7].

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Table 1. Comparison of the results in the Phase III trials [7,31,43,44].

Trial

Dosage

Onset of action

Results

VELOCITY
Severe hypertension

2 mg/h, titrated by doubling the

dose every 3 min to maximum of
32 mg/h

2 -- 4 min

Target blood pressure was reached in

a median time of 10.9 min and 89%
of patients achieved their target within
30 min

ESCAPE -1
Pre-operative hypertension

1 -- 2 mg/h, doubling every 90 s

up to an infusion rate of 16 mg/h

2 -- 4 min

Treatment success (at least a 15%

reduction in blood pressure) in 92.5%
of patients.

ESCAPE 2
Post-operative hypertension

1 -- 2 mg/h, doubling every 90 s

up to an infusion rate of 16 mg/h

5.3 min

Target blood pressure achieved in

91.8% of clevidipine butyrate-treated
patients

ECLIPSE
Perioperative hypertension

Initial rate at 0.4 g/kg/min titrated

every 90 s doubling increments up
to 3.2 g/kg/min

N/A

Clevidipine butyrate was more effective in

maintaining blood pressure within the
specified range. There was no difference
in the incidence of myocardial infarction,
stroke or renal dysfunction compared
with the other treatments

Table 2. Comparison of the most frequently observed

adverse events in the pivotal Phase III clinical
trials [7,31,43,44].
Most common adverse events

Percentage

Atrial fibrillation
Nausea
Headache
Vomiting
Chest discomfort

13.2 -- 33.6%
5 -- 21%
6%
3.2%
3.2%

In most of these studies, clevidipine butyrate has shown a

reduction of 15% in systolic blood pressure after a median
time of 5 -- 10 min and reached successful treatment targets
in > 91% of patients [7,31,43,44] (see Table 1).
8.

Safety and tolerability

Clevidipine butyrate seems to be a safe medication in situations in

which there are multiple comorbidities. Owing to its esterasebased metabolism, clevidipine butyrate is a safe medication
because of the lack cytochrome-P450-associated drug interactions [40]. Clevidipine butyrate has been shown to have few
adverse effects and is generally well tolerated [45]. In < 2% of cases,
the blood pressure decreased under desirable ranges; however, no
adverse events due to hypotension have been reported [7,46]. Even
though, the studies have not shown significant complications
related to this drug, it is important to consider that, like any other
antihypertensive, it entails a risk to develop hypotensive events
with serious complications (i.e., ischemia).
Overall, < 20% of severe adverse events were reported,
during the Phase III studies evaluating this calcium channel
390

blocker [31,44]. There is no statistically significant evidence

that these adverse events are directly drug related; the most
common adverse effects presented during most of the trials
were nausea with an incidence fluctuating around 5 -- 20%,
headache and vomiting [7,31].
Atrial fibrillation has been observed in percentages varying from 13.2% up to 33.6% of patients receiving clevidipine butyrate. However, this event was observed in the
trials evaluating cardiac surgery patients and no mention
of such adverse reaction was found in noncardiac
patients [7,31,44]. There is only one case reported, in which
clevidipine butyrate had to be discontinued as a result of
this adverse event, and it resolved on its own without
sequelae [31] (see Table 2).
Owing to its mechanism of action, clevidipine butyrate
may lead to reflex tachycardia during its infusion, with seldom
elevations over 15% from baseline [7,43].
No evidence of tachyphylaxis or drug accumulation has
been observed under prolonged infusion times (> 18 h),
unlike that experienced with sodium nitroprusside and other
intravenous antihypertensives [7,44,47].
Caution must be taken in patients with significant
alterations in the lipid metabolism. Since clevipirex is
manufactured with a high concentration of phospholipids
as a vehicle, it would be good practice to measure triglyceride levels before and after the drug infusion in such
patients. However, in all clevidipine-butyrate-treated
patients observed, increases in triglyceride concentrations from baseline were transient, independent of type
of hypertension, and were not associated with clinical
sequelae [7,48].
All deaths in clinical trials were considered to be unrelated to
clevidipine butyrate. Even though during the studies < 3%

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Espina & Varon

(55/1844) of fatal cases occurred overall, regardless of treatment,

and 2.5% (25/987) for all clevidipine-butyrate-treated patients
from Phase II and III studies, these were probably related to
complications from the parallel procedures, and medical
issues [7,31,43,44].
Additionally, analyses have shown that clevidipine
butyrate is safe in patients with severe hypertension
suffering from congestive heart failure and acute renal
dysfunction [49,50].
The administration of this medication is contraindicated in
patients with known allergies to egg or egg products, soy or
any of its components; this should be seriously taken into
account in the emergency setting, where administration
should be cautiously considered [18,48].
9.

Regulatory affairs

11.

Clevidipine butyrate was approved by the FDA on 1 August

2008 under the brand name Cleviprex by The Medicines
Co. with the NDA no. 022156 [51]. This is the first new
intravenous antihypertensive drug to be approved in the
last ten years [52]. This medication is approved for use in
the USA, Australia and New Zealand but is still pending
for approval in Europe [53].
10.

use is uncertain, although the risk of egg-allergy crossreaction should not be overlooked, and its administration
should be cautious.
Clevidipine butyrate is a good alternative to other intravenous antihypertensives. This medication is easily titratable
because of its very short half-life and quick onset and offset
times, which makes it superior to similar therapies. This
drug could change the initial management of acute severe
hypertension, providing a safer treatment with better control
and more successful rates of transition to oral medication.
More trials are needed to establish if clevidipine butyrate is
effective and can be applied in pediatric populations and other
settings like neurosurgery where tight blood pressure control
is desirable.

Conclusions

Clevidipine butyrate is a good option for hypertensive crises

in the perioperative, critical care and emergency settings. It
is effective in decreasing the systolic blood pressure in short
periods of time without leading the patients to dangerous
hypotension and additional complications. Its ultrashort
half-life grants it safety characteristics appraisable in highrisk situations. It is easily titratable, has few adverse effects
and no known interactions with other medications. It has
been proved to be safe in patients with multiple comorbidities, end organ damage and critical or emergent situations.
Owing to its non-weight-based dosing protocol, it is ideal
for emergency situations in which hemodynamic stability
is compromised, an accurate weight of the patient is not
easily available and underlying pathologies or medication

Expert opinion

Clevidipine butyrate has a good pharmacological profile

and is a good alternative to other intravenous antihypertensives. This medication is easily titratable, has a very short
half-life and a quick onset and offset.
Clevidipine butyrate will probably modify initial management of hypertensive crises by allowing tight control of
blood pressure and higher success rate of transition to
oral medications.
Healthcare providers caring for patients in the emergency
department, perioperative arenas and intensive care units
will be the ones to benefit from this agents unique properties. Other settings such as neurosurgery, in which tight
blood pressure control is desirable, will also find this
drug useful.
Clinical trials are still needed to ascertain if clevidipine
butyrate is also effective in pediatric populations.

Declaration of interest
J Varon was the principal investigator for the VELOCITY
trial, sponsored by The Medicines Co., and research
grant monies were obtained from this trial. He is also
a consultant for Baxter, The Medicines Co. and
EKR Pharma.

Expert Opin. Pharmacother. (2012) 13(3)

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Affiliation
Ilse M Espina1,2 MS &
Joseph Varon1,3,4,5 MD FACP FCCP FCCM

Author for correspondence

1
Dorrington Medical Associates,
2219 Dorrington Street,
Houston, Texas 77030, USA
Tel: +1 713 669 1670; Fax: +1 713 669 1671;
E-mail: Joseph.Varon@uth.tmc.edu
2
Universidad Popular Autonoma
del Estado de Puebla, Puebla, Mexico
3
University General Hospital,
Houston, Texas, USA
4
The University of Texas Health Science Center
at Houston,
Houston, Texas, USA
5
The University of Texas Medical Branch at
Galveston, Houston,
Texas, USA

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