CLEVIPREX (clevidipine butyrate) injectable emulsion

Usual Diluents

Standard Dilution [Amount of drug] [Infusion volume] [Infusion rate]

Dosage and administration. / Storage.

Stability / Miscellaneous

CLINICAL PHARMACOLOGY
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.

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/hr).

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.

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 Return to article top
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.
Monitoring: Monitor blood pressure and heart rate during infusion, and until vital signs stabilize.
Initial dose: Initiate intravenous infusion of Cleviprex at 1- 2 mg/hour.
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.
Maintenance dose: Most patients will achieve the desired therapeutic response at approximately 4-6 mg/hour. Severe hypertension is likely to require higher doses.
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.

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.

Instructions for Administration
Maintain aseptic technique while handling Cleviprex. Cleviprex is a single-use parenteral product that contains phospholipids and can support microbial growth. Do not use if contamination is suspected. Once the stopper is punctured, use within 4 hours and discard any unused portion including that which is currently being infused.

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 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

DOSAGE FORMS AND STRENGTHS
Single-use vials: 50 mL or 100 mL. Concentration is 0.5 mg/mL.

CONTRAINDICATIONS
Cleviprex is contraindicated in patients with:

• Allergy to soy or eggs
• Defective lipid metabolism
• Severe aortic stenosis

WARNINGS AND PRECAUTIONS:

• Maintain aseptic technique. Discard unused portion 4 hours after stopper puncture.
• Hypotension and reflex tachycardia are potential consequences of rapid upward titration of Cleviprex.
• Dihydropyridine calcium channel blockers can produce negative inotropic effects and exacerbate heart failure. Monitor heart failure patients carefully
• Cleviprex gives no protection against the effects of abrupt beta-blocker withdrawal.
• 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.

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

To report SUSPECTED ADVERSE REACTIONS, contact The Medicines Company at 1-888-977-MDCO (6326) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

DRUG INTERACTIONS
At clinically relevant concentrations, clevidipine butyrate and its metabolites do not inhibit or induce any CYP450 enzymes. The potential of clevidipine butyrate to interact with other drugs is low.

USE IN SPECIFIC POPULATIONS
Pediatric use: Safety and effectiveness of Cleviprex in children under 18 years of age have not been established.

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 Return to article top
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.

Reference(s)

Marketed by:
The Medicines Company
Parsippany, New Jersey 07054

For information call: 888-977-MDCO (6326)
TMC PN 1611 (August 1, 2008)

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