Clevidipine

1 INDICATIONS AND USAGE Cleviprex is indicated for the reduction of blood pressure when oral therapy is not feasible or not desirable. Cleviprex is a dihydropyridine calcium channel blocker indicated for the reduction of blood pressure when oral therapy is not feasible or not desirable. (1)

2 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) 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 >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: 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 (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 2.3 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, or 250 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

6 ADVERSE REACTIONS The following risk is discussed elsewhere in the labeling: Hypotension and Reflex Tachycardia [see Warnings and Precautions (5.2)] Most common adverse reactions (>2%) are headache, nausea, and vomiting. (6.1) 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. 6.1 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). Clevidipine was 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 was infused for <24 hours in the majority of patients (n=1199); 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 comparator: nitroglycerin (NTG, n=278), sodium nitroprusside (SNP, n=283), or nicardipine (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 an uncontrolled 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 6.2 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 causal 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.

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