Drug: Cleviprex

Cleviprex is a sterile, milky-white emulsion containing 0.5 mg/mL of clevidipine suitable for intravenous administration. Clevidipine is a dihydropyridine calcium channel blocker. Chemically, the active substance,clevidipine,is butyroxymethyl methyl 4-(2',3'-dichlorophenyl)-l,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate. It is a racemic mixture with a molecular weight of 456.3 g/mol. Each enantiomer has equipotent antihypertensive activity. The structure and formula are: Clevidipineis practically insoluble in water and is formulated in an oil-in-water emulsion. In addition to the active ingredient, clevidipine, Cleviprex contains soybean oil(200 mg/mL), glycerin (22.5 mg/mL), purified egg yolk phospholipids (12 mg/mL),oleic acid (0.3 mg/mL), disodium edetate (0.05 mg/mL), and sodium hydroxide to adjust pH. Cleviprex has a pH of 6.0 - 8.0 and is a ready-to-use emulsion.

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The following risk is discussed elsewhere in the labeling:
  • Hypotension and Reflex Tachycardia [see WARNINGS AND PRECAUTIONS]
Clinical Trials Experience Cleviprex clinical development included 19 studies, with 99 healthy subjects and 1307 hypertensive patients who received at least one dose of clevidipine(1406 total exposures). Clevidipinewas evaluated in 15 studies in hypertensive patients: 1099 patients with perioperative hypertension, 126 with severe hypertension and 82 patients with essential hypertension. The desired therapeutic response was achieved at doses of 4-6 mg/hour. Cleviprex wasinfused for < 24 hours in the majority of patients (n=l 199); it was infused as a continuous infusion in an additional 93 patients for durations between 24 and 72 hours. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Perioperative Hypertension The placebo-controlled experience with Cleviprex in the perioperative setting was both small and brief (about 30 minutes). Table 2 shows treatment-emergent adverse reactions and the category of "any common adverse event" in ESCAPE-1 and ESCAPE-2 where the rate on Cleviprex exceeded the rate on placebo by at least 5% (common adverse reactions). Table 2.Common adverse reactions in placebo-controlled perioperative studies.
  ESCAPE-1 ESCAPE-2 CLV
N=53(%) PBO
N=51(%) CLV
N=61(%) PBO
N=49(%) Any common adverse event 27(51%) 21 (41%) 32(53%) 24(49%) Acute renal failure 5 (9%) 1 (2%) -- -- Atrial fibrillation -- -- 13(21%) 6(12%) Nausea -- -- 13(21%) 6(12%) Three randomized, parallel, open-label studies called ECLIPSE, with longer exposure in cardiac surgery patients define the adverse reactions for patients with perioperative hypertension.Each ECLIPSE study compared Cleviprex (n=752) to an active comparatonnitroglycerin (NTG, n=278), sodium nitroprusside (SNP, n=283), ornicardipine (NIC, n=193).The pooled mean maximum dose in these studies was 10 mg/hour and the mean duration of treatment was 8 hours. There were many adverse events associated with the operative procedure in the clinical studies of Cleviprex and relatively few plausibly related to the drugs used to lower blood pressure. Thus, the ability to differentiate the adverse event profile between treatments is limited. The adverse events observed within one hour of the end of the infusion were similar in patients who received Cleviprex and in those who received comparator agents.There was no adverse reaction that was more than 2% more common on Cleviprex than on the average of all comparators. Serious Adverse Events and Discontinuation - Perioperative Hypertension Studies The incidence of adverse events leading to study drug discontinuation in patients with perioperative hypertension receiving Cleviprex was 5.9% versus 3.2% for all active comparators.For patients receiving Cleviprex and all active comparators the incidence of serious adverse events within one hour of drug infusion discontinuation was similar. Severe Hypertension The adverse events for patients with severe hypertension are based on anuncontrolled study in patients with severe hypertension (VELOCITY,n=126). The common adverse reactions for Cleviprex in severe hypertension included headache (6.3%),nausea (4.8%), and vomiting (3.2%).The incidence of adverse events leading to study drug discontinuation for Cleviprex in severe hypertension was 4.8%. Less Common Adverse Reactions in Patients with Severe or Essential Hypertension Adverse reactions that were reported in < 1% of patients with severe or essential hypertension included: Cardiac: myocardial infarction, cardiac arrest Nervous system: syncope Respiratory: dyspnea Post-Marketing and Other Clinical Experience Because adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or to establish a casual relationship to drug exposure. The following adverse reactions have been identified during post-approval use of Cleviprex: increased blood triglycerides, ileus, hypersensitivity, hypotension, nausea, decreased oxygen saturation (possible pulmonary shunting) and reflex tachycardia. Read the Cleviprex (clevidipine butyrate) Side Effects Center for a complete guide to possible side effectsLearn More »

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Monitoring Monitor blood pressure and heart rate continually during infusion,and then until vital signs are stable.Patients who receive prolonged Cleviprex 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. These patients may need follow-up adjustments in blood pressure control. Recommended Dosing Cleviprex is intended for intravenous use.Titrate drug to achieve the desired blood pressure reduction. Individualize dosage depending on the blood pressure to be obtained and theresponse of the patient. Initial dose Initiate the intravenous infusion of Cleviprex at 1-2 mg/hour. Dose titration The dose may be doubled at short (90 second) intervals initially. As the blood pressure approaches goal, the increase in doses should be less than doubling and the time between dose adjustments should be lengthened to every 5-10 minutes. An approximately 1-2 mg/hour increase will generally produce an additional 2-4 mmHg decrease in systolic pressure. Maintenance dose The desired therapeutic response for most patients occurs at doses of 4-6 mg/hour. Patients with severe hypertension may require doses up to 32 mg/hour, but there is limited experience at this dose rate. Maximum dose Most patients were treated with maximum doses of 16 mg/hour or less.There is limited short-term experience with doses up to 32 mg/hour.Because of lipid load restrictions, no more than 1000 mL or an average of 21 mg/hour of Cleviprex infusion is recommended per 24 hour period. In clinical trials, 55 hypertensive patients were treated with > 500mL of Cleviprex infusion per 24 hour period.There is little experience with infusion durations beyond 72 hours at any dose. Transition to an oral antihypertensive agent Discontinue Cleviprex or titrate downward while appropriate oral therapy is established. When an oral antihypertensive agent is being instituted, consider the lag time of onset of the oral agent's effect. Continue blood pressure monitoring until desired effect is achieved. Special populations Special populations were not specifically studied.In clinical trials, 78 patients with abnormal hepatic function(one or more of the following: elevatedserum bilirubin, AST/SGOT, ALT/SGPT) and 121patients with moderate to severe renalimpairment were treated with Cleviprex. An initial Cleviprex infusion rate of 1-2 mg/hour is appropriate in these patients. Table 1 is a guideline for dosing conversion from mg/hour to mL/hour. Table 1. Dose conversion
Dose (mg/hour) Dose (mL/hour) 1 2 2 4 4 8 6 12 8 16 10 20 12 24 14 28 16 32 18 36 20 40 22 44 24 48 26 52 28 56 30 60 32 64 Instructions for Administration Maintainaseptic technique while handling Cleviprex. Cleviprex is a single-use parenteral product. Do not use if contamination is suspected. Once the stopper is punctured, use within 12 hours and discard any unused portion. Cleviprex is supplied in sterile, pre-mixed, ready-to-use 50 mL or 100 mL vials. Invert vial gently several times before use to ensure uniformity of the emulsion prior to administration. Inspect parenteral drug products for particulate matter and discoloration prior to administration whenever solution and container permit. Administer Cleviprex using aninfusion device allowing calibrated infusion rates. Commercially available standard plastic cannulae may be used to administer the infusion. Administer Cleviprex by a central line or a peripheral line. Cleviprex should not be administered in the same line as other medications. Cleviprex should not be diluted, but it can be administered with the following:
  • Water for Injection, USP
  • Sodium Chloride (0.9%) Injection, USP
  • Dextrose (5%) Injection, USP
  • Dextrose (5%) in Sodium Chloride (0.9%) Injection, USP
  • Dextrose (5%) in Ringers Lactate Injection, USP
  • Lactated Ringers Injection, USP
  • 10% amino acid

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No clinical drug interactionstudies were conducted. Clevidipine and its major dihydropyridine metabolite do not have the potential for blocking or inducing any CYP enzyme. Read the Cleviprex Drug Interactions Center for a complete guide to possible interactions Learn More »

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Cleviprex is indicated for the reduction of blood pressure when oral therapy is not feasible or not desirable.

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Known Allergy Cleviprex is contraindicated in patients with allergies to soybeans, soy products, eggs, or egg products. Defective Lipid Metabolism Cleviprex is contraindicated in patients with defective lipid metabolism such as pathologic hyperlipemia, lipoid nephrosis, or acute pancreatitis if it is accompanied by hyperlipidemia. Severe Aortic Stenosis Cleviprex is contraindicated in patients with severeaortic stenosis because afterload reduction can be expected to reduce myocardial oxygen delivery. Last reviewed on RxList: 1/4/2012
This monograph has been modified to include the generic and brand name in many instances.

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There has been no experience of overdosage in human clinical trials. In clinical trials, doses of Cleviprex up to 106 mg/hour or 1153 mg maximum total dose were administered. The expected major effects of overdose would be hypotension and reflex tachycardia. Discontinuation of Cleviprex leads to a reduction in antihypertensive effects within 5 to 15 minutes [see CLINICAL PHARMACOLOGY]. In case of suspected overdosage, Cleviprex should be discontinued immediately and the patient's blood pressure should be supported.

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Dosage Forms and Strengths Cleviprex is a sterile, milky white injectable emulsion for intravenous use, available in the following two configurations:
  • 50 mL single use vial with 0.5 mg/mL clevidipine
  • 100 mL single use vial with 0.5 mg/mL clevidipine
Cleviprex (clevidipine)injectable emulsion is supplied as a sterile, milky white liquid emulsion product in single-use 50 mL or 100 mL glass vials at a concentration of 0.5 mg/mL of clevidipine. NDC 65293-005-50: 50 mL vial
NDC 65293-005-00: 100 mL vial Storage Leave vials in cartons until use. Clevidipineis photosensitive and storage in cartons protects against photodegradation. Protection from light during administration is not required. Store vials refrigerated at 2-8°C (36-46°F). Do notfreeze. Vials in cartons may be transferred to 25°C (77°F, USP controlled room temperature) for a period not to exceed 2 months.Upon transfer to room temperature, mark vials in cartons "This product was removed from the refrigerator on _/_/_ date.lt must be used or discarded 2 months after this date or the labeled expiration date (whichever date comes first)."Do not return to refrigerated storage after beginning room temperature storage. Handling Maintain aseptic technique while handling Cleviprex. Cleviprex is a single-use parenteral product that contains 0.005% disodium edetate to inhibit the rate of growth of microorganisms, for up to 12 hours, in the event of accidental contamination. However, Cleviprex can still support the growth of microorganisms, as it is not an antimicrobially preserved product under USP standards. Do not use if contamination is suspected. Once the stopper is punctured, use within 12 hours and discard any unused portion. Cleviprex inhibits microbial growth for up to 12 hours, as demonstrated by test data for representative USP microorganisms, staphylococcus epidermidis and serratiamarcescens. Manufactured by: Fresenius KabiAustria GmbH, Graz, Austria. Marketed by: The Medicines Company, Parsippany, New Jersey07054. For information call: 888-977-MDCO (6326). Revised: 07/2011Last reviewed on RxList: 1/4/2012
This monograph has been modified to include the generic and brand name in many instances.

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Need for Aseptic Technique Use aseptic technique and discard any unused productwithin 12 hours of stopper puncture [see DOSAGE AND ADMINISTRATION]. Hypotension and Reflex Tachycardia Cleviprex may produce systemic hypotension and reflex tachycardia.If either occurs, decrease the dose of Cleviprex. There is limited experience with short-duration therapy with beta-blockers as a treatment for Cleviprex-induced tachycardia.Beta-blocker use for this purpose is not recommended. Lipid Intake Cleviprex contains approximately 0.2 g of lipid per mL (2.0 kcal). Lipid intake restrictions may be necessary for patients with significant disorders of lipid metabolism. For these patients, a reduction in the quantity of concurrently administered lipids may be necessary to compensate for the amount of lipid infused as part of the Cleviprex formulation. Negative Inotropy Dihydropyridine calcium channel blockers can produce negative inotropic effects andexacerbateheart failure.Monitor heart failure patients carefully. Beta-Blocker Withdrawal Cleviprex is not a beta-blocker, does not reduce heart rate, and gives no protection against the effects of abrupt beta-blocker withdrawal. Beta-blockers should bewithdrawn only aftera gradual reduction indose. Rebound Hypertension Patients who receive prolonged Cleviprex 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. Pheochromocytoma There is no information to guide use of Cleviprex in treating hypertension associated with pheochromocytoma. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Clevidipine displayed positive genotoxic potentials in vitro in the Ames test, mouse lymphoma thymidine kinase locus assay, and chromosomal aberration assay but not in vivo in the mouse micronucleus test. Formaldehyde, a metabolite of clevidipine, a known genotoxicant in vitro and a probable human carcinogen, appears to be at least partially responsible for the positives in vitro results. Long-term studies for evaluation of carcinogenic potential have not been performed with clevidipine due to the intended short-term duration of human use. There were no adverse effects on fertility or mating behavior of male rats at clevidipine doses of up to 55 mg/kg/day, approximately equivalent to the maximum recommended human dose (MRHD) of 504 mg/day (21 mg/hour x 24 hours) on a body surface area basis. Female rats demonstrated pseudopregnancy and changes in estrus cycle at doses as low as 13 mg/kg/day (about 1/4th the MRHD); however, doses of up to 55 mg/kg/day did not affect mating performance or fertility. Use In Specific Populations Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of Cleviprex use in pregnant women. In animal studies, clevidipine caused increases in maternal and fetal mortality and length of gestation.Cleviprex should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. There was decreased fetal survival when pregnant rats and rabbits were treated with clevidipine during organogenesis at doses 0.7 times (on a body surface area basis) the maximum recommended human dose (MRHD) in rats and 2 times the MRHD in rabbits. In pregnant rats dosed with clevidipine during late gestation and lactation, there were dose-related increases in maternal mortality, length of gestation and prolonged parturition at doses greater than or equal to 1/6 of the MRHD based on body surface area. When offspring of these dams were mated, they had a conception rate lower than that of controls. Clevidipine has been shown to cross the placenta in rats [see Nonclinical Toxicology]. Labor and Delivery Cleviprex in the labor and delivery setting has not been establishedassafe and effective.Other calcium channel blockers suppress uterine contractions in humans.Pregnant rats treated with clevidipine during late gestation had an increased rate of prolonged parturition. Nursing Mothers It is not known whether clevidipine is excreted in human milk. Because many drugs are excreted in human milk, consider possible infant exposure when Cleviprex is administered to a nursing woman. Pediatric Use The safety and effectiveness of Cleviprex in children under 18 years of age have not been established. Geriatric Use Of the 1406 subjects (1307with hypertension) treated with Cleviprex in clinical studies, 620 were ≥ 65 years of age and 232 were ≥ 75 years of age. No overall differences in safety or effectiveness were observed between these and younger patients.Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, for an elderly patient doses should betitrated cautiously, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. Last reviewed on RxList: 1/4/2012
This monograph has been modified to include the generic and brand name in many instances.

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