Cleviprex ® (clevidipine) injectable emulsion

DESCRIPTION
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)-1,4-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.

Clevidipine is 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.

DRUG INTERACTIONS
At clinically relevant concentrations, clevidipine and its metabolites do not inhibit or induce any CYP450 enzymes. The potential of clevidipine 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.

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

• Maintain aseptic technique. Discard unused portion 124 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.

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.

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. 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 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

50 mL single-use vial with 0.5 mg/mL clevidipine
100 mL single-use vial with 0.5 mg/mL clevidipine

For information call: 888-977-MDCO (6326)

US Patent 5,856,346
US Patent 5,739,152

TMC PN 1220 (April 28, 2011)

Package Label - Principal Display Panel - 25mg/50mL Container