DESCRIPTION

The Clevipidine Molecule

Clevidipine ButyrateCleviprex is supplied as a sterile, milky white, ready-to-use lipid emulsion that contains clevidipine butyrate, soybean oil, glycerin, purified egg yolk phospholipids, and sodium hydroxide to adjust pH.1 Cleviprex is formulated and administered in a lipid emulsion because clevidipine butyrate is practically insoluble in water.1

Rapidly Metabolized by Tissue and Blood Esterases

Cleviprex is rapidly metabolized by hydrolysis of the ester linkage, primarily by esterases in the blood and extravascular tissues, making its elimination unlikely to be affected by hepatic or renal dysfunction1 In vitro studies show that Cleviprex and its metabolite, at the concentrations achieved in clinical practice, will not inhibit or induce any cytochrome P (CYP) enzyme1 The potential of Cleviprex to interact with other drugs is low1

Metabolism in Blood and Extravascular Tissues2

Figure adapted from Ericsson H et al. Anesthesiology. 2000;92:993-1001.

Hemodynamics

A New Dynamic for Targeted BP Control

Cleviprex is a vascular and arterial selective dihydropyridine L-type calcium antagonist that mediates the influx of calcium during depolarization in vascular smooth muscle.1 It reduces mean arterial BP by decreasing systemic vascular resistance (SVR) while increasing cardiac output (CO) and stroke volume (SV).2 As a pure afterload reducer, Cleviprex has no effect on venous return or cardiac filling pressure (preload).1

Cleviprex Lowers BP With Targeted Hemodynamics*

*Studied in 9 postoperative cardiac bypass graft patients. This graph shows the effects at the highest Cleviprex dose (3 micrograms/kg/min); +P<.001; ++P<.05. BP=blood pressure; CO=cardiac output; MAP=mean arterial pressure; SBP=systolic blood pressure; SV=stroke volume; SVR=systemic vascular resistance.

Figure adapted from Kieler-Jensen N et al. Acta Anaesthesiol Scand. 2000;44:186-193.

Efficacy of Cleviprex

Rapid On, Rapid Off: A Predictable Performance

Cleviprex has a rapid onset and offset of BP-lowering effects for a predictable pharmacologic response, and an ultrashort half-life of approximately 1 minute provides rapid-acting control. Cleviprex demonstrates a dose-dependent BP-lowering response. The onset of effect is seen within 2 to 4 minutes after infusion, and full recovery of BP is achieved 5 to 15 minutes after the infusion is stopped in most patients.

Safety Profile

Demonstrated Safety in Clinical Trials in More Than 1,800 Patients

Drug-drug interactions

• The potential of Cleviprex to interact with other drugs is low
• Cleviprex does not have the potential for blocking or inducing any CYP enzyme

• The most common adverse reactions (>2%) with Cleviprex are headache, nausea, and vomiting

• No adjustment of initial dosage necessary in patients with renal or hepatic dysfunction
• In geriatric patients, doses should be titrated cautiously, starting at the low end of the dosing range. In clinical tirals, no overall differences in safety or effectiveness were observed between these and younger patients with Cleviprex

• Cleviprex is photosensitive and storage in cartons protects against photodegradation. Protection from light during administration is not required
• Store vials refrigerated at 2 to 8�C (36-46�F). Do not freeze
• Cleviprex should not be administered in the same line as other medications

CLINICAL TRIALS

Cleviprex has been evaluated in 19 clinical studies, including more than 1,400 Cleviprex-treated patients in a variety of clinical settings, including the emergency department, operating room, and critical care unit.

Cleviprex Phase 3 Clinical Trial Program


BP=blood pressure; ECLIPSE=Evaluation of CLevidipine In the Perioperative Treatment of Hypertension Assessing Safety Events; ESCAPE= Efficacy Study of Clevidipine Assessing Its Preoperative/Postoperative Antihypertensive Effect in Cardiac Surgery; NIC=nicardipine; NTG=nitroglycerin; SNP=sodium nitroprusside; VELOCITY=EValuation of the Effect of ULtra-ShOrt-Acting Clevidipine In the Treatment of Patients With Severe HYpertension.

ESCAPE Trials

In Perioperative Patients Requiring Rapid Reduction of Blood Pressure, Rapid Control That�s on Target

Cleviprex rapidly reduced blood pressure (BP) to target levels in cardiac surgery patients requiring preoperative or postoperative BP control in the ESCAPE-1 (Efficacy Study of Clevidipine Assessing Its Preoperative Antihypertensive Effect in Cardiac Surgery-1) and ESCAPE-2 (Efficacy Study of Clevidipine Assessing Its Postoperative Antihypertensive Effect in Cardiac Surgery-2) trials.1,2

The ESCAPE trials were phase 3, randomized, double-blind, placebo-controlled, multicenter trials evaluating the efficacy and tolerability of Cleviprex in a total of 215 cardiac surgery patients requiring preoperative (ESCAPE-1) or postoperative (ESCAPE-2) BP control.1,2

ESCAPE-1=Efficacy Study of Clevidipine Assessing Its Preoperative Antihypertensive Effect in Cardiac Surgery-1; ESCAPE-2=Efficacy Study of Clevidipine Assessing Its Postoperative Antihypertensive Effect in Cardiac Surgery-2; HTN=hypertension; SBP=systolic blood pressure.

Primary End Point

• Antihypertensive efficacy, as evaluated by comparing the incidence of treatment failure between Cleviprex and placebo over the 30-minute study drug infusion period. Treatment failure was defined as discontinuation of study drug for any reason or failure to decrease systolic blood pressure (SBP) by >=15% before the end of the 30-minute treatment period

• Time to target BP (first decrease of SBP by >=15% from baseline); change in mean arterial pressure from baseline; change in heart rate. The incidence of adverse events (AEs) was recorded starting from study drug initiation through hospital discharge or 7 days, whichever came first

• Safety, as assessed by the incidence of death, myocardial infarction, stroke, and renal dysfunction from the start of study drug infusion through postoperative Day 30

• Efficacy (BP control) of Cleviprex compared with that of NTG, SNP, and NIC during the first 24 hours or removal of arterial line, whichever came first

• There was no difference between the pooled Cleviprex population and the pooled comparator population for any of the 30-day safety outcome measures

• Efficacy: percentage of patients in whom SBP fell within the SBP initial target range (ITR) within 30 minutes of initiating infusion
• Safety: percentage of patients whose SBP fell below the lower limit of the SBP ITR within 3 minutes of initiating infusion

• Efficacy: time to achieve the 30-minute SBP ITR
• Safety: proportion of patients successfully transitioned to oral antihypertensive therapy (defined as SBP within the last specified target range at 6 hours after discontinuation of Cleviprex infusion); safety of prolonged continuous infusion of Cleviprex (>=18 hours)

• The probability of achieving the prespecified SBP target range by 30 minutes (N=117; modified intent-to-treat patients) was 91.4%, according to Kaplan-Meier analysis

• Cleviprex was initiated at 2 mg/h and titrated as needed in doubling increments every 3 minutes up to 32 mg/h over a 30-minute period
• Titratable BP control reduces the risk of overshoot and reduces the need for a rescue agent
  - 2 patients (1.6%) fell below the lower SBP ITR limit within the first 3 minutes of drug infusion
• 99% of patients (125 of 126) were safely and effectively managed with BP cuff monitoring throughout the infusion and did not require an arterial line
• Median time to achieve target BP was 10.9 minutes (95% confidence interval: 9.0, 15.0)
  - Median time to achieve a 15% reduction in SBP was 9.5 minutes (post-hoc analysis)

• Patients achieving target BP within 30 minutes continued infusion up to 32 mg/h for a protocol-specified duration of at least 18 hours and up to 96 hours, with dosing adjustments as needed to maintain desired blood pressure

• More than 90% of patients maintained BP control on Cleviprex monotherapy, eliminating the need for additional intravenous antihypertensive therapy
• Headache (6.3%; 8 of 126), nausea (4.8%; 6 of 126), chest discomfort (3.2%; 4 of 126), and vomiting (3.2%; 4 of 126) were the most common AEs
• Cleviprex did not raise serum triglyceride levels
  - Median percentage change in concentration of serum triglyceride levels was zero at 6 hours after cessation of therapy
  - No relationship between change in triglyceride levels and total dose of Cleviprex received (Pearson�s correlation coefficient = -0.0269)

• 98% (115 of 118) of eligible patients successfully transitioned to oral therapy to a predefined target BP within 6 hours of discontinuing Cleviprex
• Patients were maintained on a steady infusion of Cleviprex without evidence of tachyphylaxis, drug accumulation, or rebound hypertension on discontinuation

DOSING AND ADMINISTRATION

Predictable BP Control With Convenient Dosing

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 an infusion 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

• 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

• Most patients will achieve desired therapeutic response at 4-6 mg/h

• Most patients have received maximum doses of 16 mg/h or less
• Because of lipid load restrictions, no more than 1000 mL, or an average of 21 mg/h, is recommended per 24-hour period
• There is little experience with infusions beyond 72 hours at any dose

• 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 monitoring BP until desired effect is achieved

• Leave Cleviprex vials in cartons until administration to protect from light
  - Protection from light during administration is not required
• Vials should be stored refrigerated at 2-8�C (36-46�F). Do not freeze
• Vials in cartons may be transferred to 25�C (77�F, USP controlled room temperature) for a period not to exceed 2 months, indicated by the "Discard By" Date marked by the dispensing pharmacist, and should not be returned to refrigerated storage after beginning room temperature storage

PRESCRIBING INFORMATION

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use Cleviprex safely and effectively. See full prescribing information for Cleviprex. Cleviprex (clevidipine butyrate) injectable emulsion, for intravenous use Initial U.S. Approval: 2008

INDICATIONS AND USAGE

Cleviprex is a dihydropyridine calcium channel blocker indicated for the reduction of blood pressure when oral therapy is not feasible or not desirable.

DOSAGE AND ADMINISTRATION

For intravenous use: Cleviprex is intended for intravenous use. Titrate Cleviprex to achieve the desired blood pressure reduction. Individualize dosage depending on the blood pressure response of the patient and the goal blood pressure. (2.2)

Monitoring: Monitor blood pressure and heart rate during infusion, and until vital signs stabilize. (2.1) Initial dose: Initiate intravenous infusion of Cleviprex at 1-2 mg/hour. (2.2)

Dose titration: Double the dose at short (90 second) intervals initially. As the blood pressure approaches goal, increase the dose by less than doubling and lengthen the time between dose adjustments to every 5-10 minutes. An approximately 1-2 mg/hour increase will generally produce an additional 2-4 mmHg decrease in systolic pressure. (2.2)

Maintenance dose: Most patients will achieve the desired therapeutic response at approximately 4-6 mg/hour. Severe hypertension is likely to require higher doses. (2.2)

Maximum dose: Most patients have received maximum doses of 16 mg/hour or less. There is limited experience with short-term dosing as high as 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. There is little experience beyond 72 hours at any dose. (2.2)

DOSAGE FORMS AND STRENGTHS

Single-use vials: 50 mL or 100 mL. Concentration is 0.5 mg/mL. (3)

CONTRAINDICATIONS

Cleviprex is contraindicated in patients with:

• Allergy to soy or eggs (4.1)
• Defective lipid metabolism (4.2)
• Severe aortic stenosis (4.3)
  WARNINGS AND PRECAUTIONS
  • Maintain aseptic technique. Discard unused portion 4 hours after stopper puncture. (5.1)
  • Hypotension and reflex tachycardia are potential consequences of rapid upward titration of Cleviprex. (5.2)
  • Dihydropyridine calcium channel blockers can produce negative inotropic effects and exacerbate heart failure. Monitor heart failure patients carefully. (5.4)
  • Cleviprex gives no protection against the effects of abrupt beta-blocker withdrawal. (5.5)
  • 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. (5.6)

1 INDICATIONS AND USAGE

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

2 DOSAGE AND ADMINISTRATION

2.1 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.

2.2 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 the response 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 > 500 mL 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: elevated serum bilirubin, AST/SGOT, ALT/SGPT) and 121 patients with moderate to severe renal impairment 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 Dose
(mg/hour) (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

• 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

3 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 butyrate
• 100 mL single-use vial with 0.5 mg/mL clevidipine butyrate

4 CONTRAINDICATIONS

Cleviprex is a sterile, milky white injectable emulsion for intravenous use,

4.1 Known Allergy

Cleviprex is contraindicated in patients with allergies to soybeans, soy products, eggs, or egg products.

4.2 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.

4.3 Severe Aortic Stenosis

Cleviprex is contraindicated in patients with severe aortic stenosis because afterload reduction can be expected to reduce myocardial oxygen delivery.

5 WARNINGS AND PRECAUTIONS

5.1 Need for Aseptic Technique Use aseptic technique and discard any unused product�including product being infused�within 4 hours of stopper puncture [see Dosage and Administration (2.3)].

5.2 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 Cleviprexinduced tachycardia. Beta-blocker use for this purpose is not recommended.

5.3 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.

5.4 Negative Inotropy

Dihydropyridine calcium channel blockers can produce negative inotropic effects and exacerbate heart failure. Monitor heart failure patients carefully.

5.5 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. Betablockers should be withdrawn only after a gradual reduction in dose.

5.6 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.

5.7 Pheochromocytoma

There is no information to guide use of Cleviprex in treating hypertension associated with pheochromocytoma.

6 ADVERSE REACTIONS

The following risk is discussed elsewhere in the labeling:

• Hypotension and Reflex Tachycardia [see Warnings and Precautions (5.2)]

7 DRUG INTERACTIONS

No clinical drug interaction studies were conducted. Clevidipine butyrate and its major dihydropyridine metabolite do not have the potential for blocking or inducing any CYP enzyme.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of Cleviprex use in pregnant women. In animal studies, clevidipine butyrate 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 butyrate 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 butyrate 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 butyrate has been shown to cross the placenta in rats [see Nonclinical Toxicology (13.3)].

8.2 Labor and Delivery

Cleviprex in the labor and delivery setting has not been established as safe and effective. Other calcium channel blockers suppress uterine contractions in humans. Pregnant rats treated with clevidipine butyrate during late gestation had an increased rate of prolonged parturition.

8.3 Nursing Mothers It is not known whether clevidipine butyrate 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.

8.4 Pediatric Use

The safety and effectiveness of Cleviprex in children under 18 years of age have not been established.

8.5 Geriatric Use

Of the 1406 subjects (1307 with 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 be titrated 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.

10 OVERDOSAGE

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 (12.2)]. In case of suspected overdosage, Cleviprex should be discontinued immediately and the patient�s blood pressure should be supported.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Clevidipine butyrate is a dihydropyridine L-type calcium channel blocker. L-type calcium channels mediate the influx of calcium during depolarization in arterial smooth muscle. Experiments in anesthetized rats and dogs show that clevidipine butyrate reduces mean arterial blood pressure by decreasing systemic vascular resistance. Clevidipine butyrate does not reduce cardiac filling pressure (pre-load), confirming lack of effects on the venous capacitance vessels.

12.2 Pharmacodynamics

Cleviprex is titrated to the desired reduction in blood pressure. The effect of Cleviprex appears to plateau at approximately 25% of baseline systolic pressure. The infusion rate for which half the maximal effect is observed is approximately 10 mg/hour.

Onset of Effect: In the perioperative patient population, Cleviprex produces a 4-5% reduction in systolic blood pressure within 2-4 minutes after starting a 0.4 mcg/kg/min infusion (approximately 1-2 mg/hour).

Maintenance of Effect: In studies up to 72 hours of continuous infusion, there was no evidence of tolerance or hysteresis.

Offset of Effect: In most patients, full recovery of blood pressure is achieved in 5-15 minutes after the infusion is stopped.

In studies up to 72 hours of continuous infusion, in patients that were not transitioned to other antihypertensive therapies, there was some evidence of rebound hypertension following Cleviprex discontinuation.

Hemodynamics: Cleviprex causes a dose-dependent decrease in systemic vascular resistance.

Heart Rate: An increase in heart rate is a normal response to vasodilation and decrease in blood pressure; in some patients these increases in heart rate may be pronounced [see Warnings and Precautions (5.2)].

Electrophysiologic Effects: In healthy volunteers, clevidipine butyrate or its major carboxylic acid metabolite, at therapeutic and supratherapeutic concentrations (approximately 2.8 times steady-state), did not prolong cardiac repolarization.

12.3 Pharmacokinetics

Clevidipine butyrate is rapidly distributed and metabolized resulting in a very short half-life. The arterial blood concentration of clevidipine butyrate declines in a multiphasic pattern following termination of the infusion. The initial phase half-life is approximately 1 minute, and accounts for 85-90% of clevidipine butyrate elimination. The terminal half-life is approximately 15 minutes.

Distribution: Clevidipine butyrate is >99.5% bound to proteins in plasma at 37�C.

The steady-state volume of distribution was determined to be 0.17 L/kg in arterial blood.

Metabolism and Elimination: Clevidipine butyrate is rapidly metabolized by hydrolysis of the ester linkage, primarily by esterases in the blood and extravascular tissues, making its elimination unlikely to be affected by hepatic or renal dysfunction. The primary metabolites are the carboxylic acid metabolite and formaldehyde formed by hydrolysis of the ester group. The carboxylic acid metabolite is inactive as an antihypertensive. This metabolite is further metabolized by glucuronidation or oxidation to the corresponding pyridine derivative. The clearance of the primary dihydropyridine metabolite is 0.03 L/h/kg and the terminal half-life is approximately 9 hours. In vitro studies show that clevidipine butyrate and its metabolite at the concentrations achieved in clinical practice will not inhibit or induce any CYP enzyme.

In a clinical study with radiolabeled clevidipine butyrate, 83% of the drug was excreted in urine and feces. The major fraction, 63-74% is excreted in the urine, 7-22% in the feces. More than 90% of the recovered radioactivity is excreted within the first 72 hours of collection.

16 HOW SUPPLIED/STORAGE AND HANDLING

Cleviprex (clevidipine butyrate) 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 butyrate.

NDC 65293-002-50: 50 mL vial
NDC 65293-002-00: 100 mL vial

Storage

Leave vials in cartons until use. Clevidipine butyrate is 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 not freeze. 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. It 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.

17 PATIENT COUNSELING INFORMATION

• Advise patients with underlying hypertension that they require continued follow up for their medical condition, and, if applicable, encourage patients to continue taking their oral antihypertensive medication(s) as directed.
• Advise patients to contact a healthcare professional immediately for any of the following signs of a new hypertensive emergency: neurological symptoms, visual changes, or evidence of congestive heart failure.

The Medicines Company

Cleviprex is a registered trademark of The Medicines Company.

©2008, The Medicines Company, All rights reserved.

December 2008