Clevidipine (
INN
Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway. Before the advent of motorized transportation, they also provided accomm ...
,
trade name Cleviprex) is a dihydropyridine
calcium channel blocker
Calcium channel blockers (CCB), calcium channel antagonists or calcium antagonists are a group of medications that disrupt the movement of calcium () through calcium channels. Calcium channel blockers are used as antihypertensive drugs, i.e., as ...
indicated for the reduction of blood pressure when oral therapy is not feasible or not desirable. Clevidipine is used IV only and practitioners titrate this drug to lower blood pressure. It has a half-life of approximately one minute. It is rapidly inactivated by esterases.
It was approved by the United States
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
on August 1, 2008.
Basic chemical and pharmacological properties
Clevidipine is a dihydropyridine L-type calcium channel blocker, highly selective for
vascular Vascular can refer to:
* blood vessels, the vascular system in animals
* vascular tissue
Vascular tissue is a complex transporting tissue, formed of more than one cell type, found in vascular plants. The primary components of vascular tissue ...
, as opposed to
myocardial
Cardiac muscle (also called heart muscle or myocardium) is one of three types of vertebrate muscle tissues, the others being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that constitutes the main tissue of the wall of ...
, smooth muscle and, therefore, has little or no effect on myocardial
contractility
Contractility refers to the ability for self- contraction, especially of the muscles or similar active biological tissue
*Contractile ring in cytokinesis
*Contractile vacuole
*Muscle contraction
**Myocardial contractility
*See contractile cell fo ...
or
cardiac conduction. It reduces
mean arterial blood pressure by decreasing
systemic vascular resistance
Vascular resistance is the resistance that must be overcome for blood to flow through the circulatory system. The resistance offered by the systemic circulation is known as the systemic vascular resistance or may sometimes be called by another ter ...
. Clevidipine does not reduce cardiac filling pressure (
pre-load), confirming lack of effects on the venous capacitance vessels. No increase in myocardial
lactate production in
coronary sinus
The coronary sinus () is the largest vein of the heart. It drains over half of the deoxygenated blood from the heart muscle into the right atrium. It begins on the backside of the heart, in between the left atrium, and left ventricle; it begi ...
blood has been seen, confirming the absence of
myocardial ischemia
Coronary artery disease (CAD), also called coronary heart disease (CHD), or ischemic heart disease (IHD), is a type of heart disease involving the reduction of blood flow to the cardiac muscle due to a build-up of atheromatous plaque in the a ...
due to
coronary steal.
Clevidipine is rapidly metabolized by
esterase
In biochemistry, an esterase is a class of enzyme that splits esters into an acid and an alcohol in a chemical reaction with water called hydrolysis (and as such, it is a type of hydrolase).
A wide range of different esterases exist that differ ...
s in the blood and extravascular tissues. Therefore, its elimination is unlikely to be affected by
hepatic
The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
(liver) or
renal (kidney) dysfunction. Clevidipine does not accumulate in the body, and its
clearance is independent of body weight.
The initial phase
half-life Half-life is a mathematical and scientific description of exponential or gradual decay.
Half-life, half life or halflife may also refer to:
Film
* Half-Life (film), ''Half-Life'' (film), a 2008 independent film by Jennifer Phang
* ''Half Life: ...
is approximately 1 minute and the terminal half-life is approximately 15 minutes. Clevidipine will still be rapidly metabolized in
pseudocholinesterase-deficient patients.
Clevidipine is formulated as a lipid emulsion in 20% soybean oil (Intralipid) and contains approximately 0.2 g of fat per mL (2.0 kcal/ml). Clevidipine also contains
glycerin
Glycerol () is a simple triol compound. It is a colorless, odorless, sweet-tasting, viscous liquid. The glycerol backbone is found in lipids known as glycerides. It is also widely used as a sweetener in the food industry and as a humectant in pha ...
(22.5 mg/mL), purified egg yolk
phospholipid
Phospholipids are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...
s (12 mg/mL), and
sodium hydroxide
Sodium hydroxide, also known as lye and caustic soda, is an inorganic compound with the formula . It is a white solid ionic compound consisting of sodium cations and hydroxide anions .
Sodium hydroxide is a highly corrosive base (chemistry), ...
to adjust pH. Clevidipine has a pH of 6.0–8.0
In the perioperative patient population Clevidipine produces a 4–5% reduction in
systolic blood pressure
Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "blood pressure" r ...
within 2–4 minutes after starting a 1–2 mg/hour
IV infusion.
In studies up to 72 hours of continuous infusion, there was no evidence of tolerance.
In most patients, full recovery of blood pressure is achieved in 5–15 minutes after the infusion is stopped.
Stereochemistry
Clevidipine contains a stereocenter and consists of two enantiomers. This is a
racemate
In chemistry, a racemic mixture or racemate () is a mixture that has equal amounts (50:50) of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as r ...
, ie a 1: 1 mixture of ('' R '') – and the ('' S '') - form:
Dosage and administration
Aseptic technique
Asepsis is the state of being free from disease-causing micro-organisms (such as pathogenic bacteria, viruses, pathogenic fungi, and parasites). There are two categories of asepsis: medical and surgical. The modern day notion of asepsis is deri ...
should be used when handling Cleviprex since it contains phospholipids and can support microbial growth.
Cleviprex is
administered intravenously and should be titrated to achieve the desired blood pressure reduction.
Blood pressure
Blood pressure (BP) is the pressure of Circulatory system, circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term ...
and
heart rate
Heart rate is the frequency of the cardiac cycle, heartbeat measured by the number of contractions of the heart per minute (''beats per minute'', or bpm). The heart rate varies according to the body's Human body, physical needs, including the nee ...
should be monitored continually during infusion.
Cleviprex is a single use product that should not be diluted and should not be administered in the same line as other medications. Once the stopper is punctured, Cleviprex should be used within 12 hours and any unused portion remaining in the vial should be discarded. Change IV lines in accordance with hospital protocol.
An IV infusion at 1–2 mg/hour is recommended for initiation and should be titrated by doubling the dose every 90 seconds. As the blood pressure approaches goal, the infusion rate should be increased in smaller increments and titrated less frequently. The maximum infusion rate for Cleviprex is 32 mg/hour. Most patients in clinical trials were treated with doses of 16 mg/hour or less.
Because of lipid load restrictions, no more than 1000 mL (or an average of 21 mg/hour) of Cleviprex infusion is recommended per 24 hours. In clinical studies, no significant changes occurred in serum
triglyceride
A triglyceride (from '' tri-'' and '' glyceride''; also TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids.
Triglycerides are the main constituents of body fat in humans and other vertebrates ...
levels in the Cleviprex treated patients. There is little experience with infusion durations beyond 72 hours at any dose. The infusion can be reduced or discontinued to achieve desired blood pressure while appropriate oral therapy is established.
Safety information
Cleviprex is intended for intravenous use. Titrate drug depending on the response of the individual patient to achieve the desired blood pressure reduction. Monitor blood pressure and heart rate continually during infusion, and then until
vital signs
Vital signs (also known as vitals) are a group of the four to six most crucial medical signs that indicate the status of the body's vital (life-sustaining) functions. These measurements are taken to help assess the general physical health of ...
are stable. Patients who receive prolonged Cleviprex infusions and are not transitioned to other
antihypertensive
Antihypertensives are a class of drugs that are used to treat hypertension (high blood pressure). Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke, heart failure, kidney failure and myocardial infa ...
therapies should be monitored for the possibility of
rebound hypertension for at least 8 hours after the infusion is stopped.
In clinical trials, the safety profile of clevidipine was generally similar to
sodium nitroprusside
Sodium nitroprusside (SNP), sold under the brand name Nitropress among others, is a medication used to lower blood pressure. This may be done if the blood pressure is very high and resulting in symptoms, in certain types of heart failure, and ...
,
nitroglycerin
Nitroglycerin (NG) (alternative spelling nitroglycerine), also known as trinitroglycerol (TNG), nitro, glyceryl trinitrate (GTN), or 1,2,3-trinitroxypropane, is a dense, colorless or pale yellow, oily, explosive liquid most commonly produced by ...
, or
nicardipine in patients undergoing
cardiac surgery.
Cleviprex is contraindicated in patients with allergies to soybeans, soy products, eggs, or egg products; defective lipid metabolism such as pathologic hyperlipemia (rare genetic disorders characterized by abnormal triglyceride metabolism),
lipoid nephrosis, or
acute pancreatitis
Acute pancreatitis (AP) is a sudden inflammation of the pancreas. Causes include a gallstone impacted in the common bile duct or the pancreatic duct, heavy alcohol use, systemic disease, trauma, elevated calcium levels, hypertriglyceridemia (w ...
if it is accompanied by
hyperlipidemia
Hyperlipidemia is abnormally high levels of any or all lipids (e.g. fats, triglycerides, cholesterol, phospholipids) or lipoproteins in the blood. citing: and The term ''hyperlipidemia'' refers to the laboratory finding itself and is also use ...
; and in patients with severe
aortic stenosis
Aortic stenosis (AS or AoS) is the narrowing of the exit of the left ventricle of the heart (where the aorta begins), such that problems result. It may occur at the aortic valve as well as above and below this level. It typically gets worse o ...
.
Hypotension
Hypotension, also known as low blood pressure, is a cardiovascular condition characterized by abnormally reduced blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood and is ...
and
reflex tachycardia
Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal ( ...
are potential consequences of rapid upward titration of Cleviprex. In
clinical trial
Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...
s, a similar increase in heart rate was observed in both Cleviprex and comparator arms. Dihydropyridine calcium channel blockers can produce negative
inotropic
An inotrope or inotropic is a drug or any substance that alters the force or energy of muscular contractions. Negatively inotropic agents weaken the force of muscular contractions. Positively inotropic agents increase the strength of muscular co ...
effects and exacerbate
heart failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to Cardiac cycle, fill with and pump blood.
Although symptoms vary based on which side of the heart is affected, HF ...
. Heart failure patients should be monitored carefully. Cleviprex gives no protection against the effects of abrupt
beta-blocker
Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage abnormal heart rhythms ( arrhythmia), and to protect the heart from a second heart attack after a first heart attack (secondary prevention) ...
withdrawal.
Most common adverse reactions (>2%) are headache, nausea, and vomiting.
Cleviprex should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Maintain aseptic technique while handling Cleviprex. Cleviprex contains phospholipids and can support microbial growth. Do not use if contamination is suspected. Once the stopper is punctured, use or discard within 12 hours.
Drug interactions
No clinical drug interaction studies were conducted. Cleviprex does not have the potential for blocking or inducing any
CYP enzymes.
Storage
Cleviprex is available in ready-to-use 50 and 100 mL glass vials at a concentration of 0.5 mg/mL of clevidipine butyrate. Vials should be refrigerated at . Cleviprex can be stored to controlled room temperature for up to 2 months. Cleviprex is photosensitive and storage in cartons protects against
photodegradation
Photodegradation is the alteration of materials by light. Commonly, the term is used loosely to refer to the combined action of sunlight and air, which cause oxidation and hydrolysis. Often photodegradation is intentionally avoided, since it dest ...
. Protection from light during administration is not required.
Phase III clinical trial results
Cleviprex has been evaluated in 6
Phase III clinical studies including the perioperative and
emergency department
An emergency department (ED), also known as an accident and emergency department (A&E), emergency room (ER), emergency ward (EW) or casualty department, is a medical treatment facility specializing in emergency medicine, the Acute (medicine), ...
/intensive care settings. These include ESCAPE-1, ESCAPE-2, ECLIPSE, and VELOCITY trials.
ESCAPE-1 was a double-blind, randomized, placebo-controlled efficacy trial of 105 cardiac surgery patients. In ESCAPE-1, Cleviprex had a significantly lower rate of treatment failure when compared with placebo (7.5% vs 82.7%) and a 92.5% rate of success in lowering systolic blood pressure (SBP) by ≥15%. The median time to reduce SBP ≥15% from baseline was 6 minutes.
ESCAPE-2 was a double-blind, randomized, placebo-controlled efficacy trials of 110 cardiac surgery patients. In ESCAPE-2, Cleviprex had a significantly lower rate of treatment failure when compared with placebo (8.2% vs 79.6%) and a 91.8% treatment success rate. The median time to reduce SBP ≥15% from baseline was 5.3 minutes.
The ECLIPSE trials consisted of three safety trials in which 1506 patients were randomized to receive Cleviprex, nitroglycerin, sodium nitroprusside, or nicardipine, for the treatment of hypertension associated with cardiac surgery. The incidence of death,
stroke
Stroke is a medical condition in which poor cerebral circulation, blood flow to a part of the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemor ...
,
myocardial infarction
A myocardial infarction (MI), commonly known as a heart attack, occurs when Ischemia, blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom ...
(heart attack), and renal dysfunction at 30 days did not differ significantly between the pooled Cleviprex and comparator treatment arms.
VELOCITY was an open-label trial of 126 patients with severe hypertension (BP > 180/115 mmHg) in the emergency department and intensive care unit. In VELOCITY, 104 out of 117 patients (88.9%) achieved a target SBP mean decrease of 21.1% at 30 minutes.
References
Further reading
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External links
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{{Calcium channel blockers
Calcium channel blockers
Dihydropyridines
Chloroarenes
Carboxylate esters
Butyrate esters
Formals