General Information

Cleviprex is an intravenous short acting dihydropyridine calcium channel antagonist. Clevidipine acts by selectively relaxing smooth muscle cells that line small arteries. This results in widening of the arterial lumen and reduction of blood pressure since the small arterioles are the primary resistance vessel within the vasculature.

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

Cleviprex is supplied as a sterile liquid emulsion designed for intravenous administration. The recommended initial dose of the drug is 1-2 mg/hour until the desired blood pressure reduction is achieved.

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.

Maintenance dose: The desired therapeutic response for most patients occurs at doses of 4-6 mg/hour.

Maximum dose: Most patients were treated with maximum doses of 16 mg/hour or less. 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.

Mechanism of Action

Cleviprex is an intravenous short acting dihydropyridine calcium channel antagonist. Clevidipine acts by selectively relaxing smooth muscle cells that line small arteries. This results in widening of the arterial lumen and reduction of blood pressure since the small arterioles are the primary resistance vessel within the vasculature. Clevidipine butyrate does not reduce cardiac filling pressure (pre-load), confirming lack of effects on the venous capacitance vessels.

Side Effects

Adverse events associated with the use of Cleviprex in the perioperative setting may include, but are not limited to, the following:

• Acute renal failure
• Atrial fibrillation
• Nausea

Adverse events associated with the use of Cleviprex for patients with severe hypertension may include, but are not limited to, the following:

• Headache
• Nausea
• Vomiting

Adverse events associated with the use of Cleviprex for patients with severe or essential hypertension may include, but are not limited to, the following:

• Myocardial infarction
• Cardiac arrest
• Syncope
• Dyspnea

Clinical Trial Results

The FDA approval of Cliviprex for perioperative hypertension was based on the results of two clinical trials. These double-blind, randomized, parallel, placebo controlled, multicenter trials enrolled cardiac surgery patients undergoing coronary artery bypass grafting, with or without valve replacement.

ESCAPE-1
This study evaluated the pre-operative use of Cleviprex. Inclusion required a systolic pressure >160 mmHg and the mean baseline blood pressure was 178/77 mmHg. Cleviprex was infused preoperatively for 30 minutes, until treatment failure, or until induction of anesthesia, whichever came first. The maximum infusion time was 60 minutes. Cleviprex was started at a dose of 1-2 mg/hour and was titrated upwards, as tolerated, in doubling increments every 90 seconds up to an infusion rate of 16 mg/hour in order to achieve the desired blood pressure-lowering effect. At doses above 16 mg/hour increments were 7 mg/hour. The average Cleviprex infusion rate in ESCAPE-1 was 15.3 mg/hour. The subjects treated with clevidipine achieved treatment success (at least a 15% reduction in blood pressure) 92.5% of the time, compared to 17.3% in the placebo arm. Cleviprex lowered blood pressure within 2-4 minutes.

ESCAPE-2
This study evlauated the post-operative use of Cleviprex. Inclusion required a systolic pressure of >140 mmHg within 4 hours of the completed surgery. The mean baseline blood pressure was 150/71 mmHg. Cleviprex was infused postoperatively for a minimum of 30 minutes unless alternative therapy was required. Infusion of Cleviprex was started at a dose of 1-2 mg/hour and was titrated upwards, as tolerated, in doubling increments every 90 seconds up to an infusion rate of 16 mg/hour in order to achieve the desired blood pressure-lowering effect. At doses above 16 mg/hour increments were 7 mg/hour. The average Cleviprex infusion rate was 5.1 mg/hour. Treatment success was achieved in 91.8% of clevidipine-treated patients compared with 20.4% of placebo-treated patients. Median time to achieving target SBP was 5.3 min with cleviprex.

ECLIPSE Studies
These three phase III open label studies enrolled 1,512 subjects who were randomized to receive Cleviprex, nitroglycerin (perioperative hypertension), sodium nitroprusside (perioperative hypertension), or nicardipine (postoperative hypertension), for the treatment of hypertension in cardiac surgery. The mean exposure was 8 hours at 4.5 mg/hour for the 752 patients who were treated with Cleviprex. Blood pressure control was assessed by measuring the magnitude and duration of SBP excursions outside the predefined pre- and post-operative SBP target range of 75-145 mmHg and the predefined intra-operative SBP range of 65-135 mmHg. In general, blood pressure control was similar with the four treatments.

Severe Hypertension
Cleviprex was evaluated in an open-label, uncontrolled clinical trial dubbed VELOCITY in 126 patients with severe hypertension. Cleviprex infusion was initiated at 2 mg/hour and up-titrated every 3 minutes, doubling up to a maximum dose of 32 mg/hour as required to achieve a prespecified target blood pressure range within 30 minutes (primary endpoint). The transition to oral antihypertensive therapy was assessed for up to 6 hours following cessation of Cleviprex infusion. The average infusion rate was 9.5 mg/hour. The mean duration of Cleviprex exposure was 21 hours. Transition to oral antihypertensive therapy within 6 hours after discontinuing Cleviprex infusion was successful in 91% of patients. Infusion of clevidipine reduced systolic blood pressure by 6% (12 mmHg) within 3 minutes, by 15% after 9.5 minutes and by 27% (55 mmHg) at 18 hours. Target blood pressure was reached in a median time of 10.9 minutes and 89% of patients achieved their target within 30 minutes.