Clevidipine

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Clevidipine
(RS)-Clevidipin Structural Formula V1.svg
Clevidipine 3D.png
Names
Trade namesCleviprex
  • (RS)-5-O-(Butanoyloxymethyl) 3-O-methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate
Clinical data
Drug classCalcium channel blocker (dihydropyridine)[1]
Main usesHigh blood pressure[1]
Side effectsHeadache, nausea[2]
Routes of
use
Intravenous
Onset of actionWith 4 min[1]
Duration of actionUp to 15 min[1]
External links
AHFS/Drugs.comMonograph
US NLMClevidipine
Legal
License data
Legal status
Pharmacokinetics
Bioavailability100% (used only IV)
Protein binding>99.5%
MetabolismBlood and tissue esterases
Elimination half-life1 minute
ExcretionUrine (63–74%), feces (7–22%)
Chemical and physical data
FormulaC21H23Cl2NO6
Molar mass456.32 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
  • O=C(OCOC(=O)CCC)\C1=C(\N/C(=C(/C(=O)OC)[C@H]1c2cccc(Cl)c2Cl)C)C

Clevidipine, sold under the brand name Cleviprex, is a medication used to treat high blood pressure.[1] This includes in hypertensive emergencies and around the time of surgery.[1] It is used by injection into a vein.[1] Effects begin within 4 minutes and last for up to 15 minutes.[1]

Common side effects include headache and nausea.[2] Other side effects may include low blood pressure, fast heart rate, and worsened heart failure.[2] It should not be used in those allergic to eggs or soy.[2] There are concerns that use during pregnancy may harm the baby.[4] It is a calcium channel blocker of the dihydropyridine type.[1]

Clevidipine was approved for medical use in the United States in 2008.[1] It is also available in a number of European countries.[5] In the United States 50 mg costs about 160 USD as of 2022.[6]

Medical uses

Dosage

Aseptic technique should be used when handling since it contains phospholipids and can support microbial growth.

Clevidipine is administered intravenously and should be titrated to achieve the desired blood pressure reduction. Blood pressure and heart rate should be monitored continually during infusion.

Clevidipine 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, 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 is 32 mg/hour. Most people 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 clevidipine infusion is recommended per 24 hours. In clinical studies, no significant changes occurred in serum triglyceride levels in the treated people. 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.

Side effects

Clevidipine 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 are stable. Patients who receive prolonged infusions and are not transitioned to other antihypertensive 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, nitroglycerin, or nicardipine in patients undergoing cardiac surgery.[7]

Clevidipine 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 if it is accompanied by hyperlipidemia; and in patients with severe aortic stenosis.

Hypotension and reflex tachycardia are potential consequences of rapid upward titration. In clinical trials, a similar increase in heart rate was observed in both clevidipine and comparator arms. Dihydropyridine calcium channel blockers can produce negative inotropic effects and exacerbate heart failure. Heart failure patients should be monitored carefully. Clevidipine gives no protection against the effects of abrupt beta-blocker withdrawal.

Most common adverse reactions (>2%) are headache, nausea, and vomiting.

Clevidipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Interactions

No clinical drug interaction studies were conducted. Clevidipine does not have the potential for blocking or inducing any CYP enzymes.

Pharmacological

Cleviprex is supplied in sterile, pre-mixed, ready-to-use 50 mL or 100 mL vials

Clevidipine is a dihydropyridine L-type calcium channel blocker, highly selective for vascular, as opposed to myocardial, smooth muscle and, therefore, has little or no effect on myocardial contractility or cardiac conduction. It reduces mean arterial blood pressure by decreasing systemic vascular resistance. 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 blood has been seen, confirming the absence of myocardial ischemia due to coronary steal.

Clevidipine is rapidly metabolized by esterases in the blood and extravascular tissues. Therefore, its elimination is unlikely to be affected by hepatic (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 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 (22.5 mg/mL), purified egg yolk phospholipids (12 mg/mL), and sodium hydroxide 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 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, ie a 1: 1 mixture of ( R ) – and the ( S ) - form:[8]

Enantiomers of clevidipine
(R)-Clevidipin Structural Formula V1.svg
CAS-Number: 167356-40-3
(S)-Clevidipin Structural Formula V1.svg
CAS-Number: 167356-39-0

Storage

Clevidipine 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 2-8oC (36-46°F). Clevidipine can be stored to controlled room temperature for up to 2 months. Clevidipine is photosensitive and storage in cartons protects against photodegradation. Protection from light during administration is not required.

Research

Clevidipine has been evaluated in 6 Phase III clinical studies including the perioperative and emergency department/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, clevidipine 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, clevidipine 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 clevidipine, nitroglycerin, sodium nitroprusside, or nicardipine, for the treatment of hypertension associated with cardiac surgery. The incidence of death, stroke, myocardial infarction (heart attack), and renal dysfunction at 30 days did not differ significantly between the pooled clevidipine 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

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 "Clevidipine Monograph for Professionals". Drugs.com. Archived from the original on 10 June 2021. Retrieved 5 January 2022.
  2. 2.0 2.1 2.2 2.3 "DailyMed - CLEVIPREX- clevidipine emulsion". dailymed.nlm.nih.gov. Archived from the original on 2 March 2021. Retrieved 5 January 2022.
  3. "Archive copy" (PDF). Archived (PDF) from the original on 2021-11-02. Retrieved 2021-10-31.{{cite web}}: CS1 maint: archived copy as title (link)
  4. "Clevidipine (Cleviprex) Use During Pregnancy". Drugs.com. Archived from the original on 26 November 2020. Retrieved 5 January 2022.
  5. "List of nationally authorised medicinal products" (PDF). Archived (PDF) from the original on 5 July 2019. Retrieved 5 January 2022.
  6. "Cleviprex Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 18 January 2021. Retrieved 5 January 2022.
  7. Deeks ED, Keating GM, Keam SJ (2009). "Clevidipine: a review of its use in the management of acute hypertension". American Journal of Cardiovascular Drugs : Drugs, Devices, and Other Interventions. 9 (2): 117–34. doi:10.2165/00129784-200909020-00006. PMID 19331440.
  8. Rote Liste Service GmbH (Hrsg.) (2017). Rote Liste 2017 – Arzneimittelverzeichnis für Deutschland (einschließlich EU-Zulassungen und bestimmter Medizinprodukte). Vol. Aufl. 57. Frankfurt/Main: Rote Liste Service GmbH. p. 171. ISBN 978-3-946057-10-9.

External links

Identifiers: