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Cleviprex

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Cleviprex

Cleviprex

CLINICAL PHARMACOLOGY

Mechanism of Action

Clevidipine is a dihydropyridine L-type calcium channel blocker. L-type calcium channels mediate the influx of calcium during depolarization in arterialsmooth muscle. Experiments in anesthetized rats and dogs show that clevidipinereduces mean arterial blood pressure by decreasing systemic vascular resistance.Clevidipinedoes 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, Cleviprexproduces a 4-5% reduction in systolic blood pressurewithin 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 [see WARNINGS AND PRECAUTIONS].

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

Pharmacokinetics

Clevidipineis rapidly distributed and metabolized resulting in a very short half-life. The arterial blood concentration of clevidipinedeclines 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 clevidipineelimination. 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 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 metabolitesarethe carboxylic acid metabolite and formaldehydeformed 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 primarydihydropyridine metabolite is 0.03 L/h/kg and the terminal half-life is approximately 9 hours.

In vitro studies show that clevidipineand 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.

Developmental Toxicology

When pregnant rats were dosed with clevidipine during late gestation and lactation, there were dose-related increases in mortality, length of gestation and prolonged parturition at dose levels as low as 13 mg/kg/day (about 1/4th the maximum recommended human dose of 504 mg/day (21 mg/hour x 24 hours) on a body surface area basis).When offspring of these dams were mated, they had a conception rate lower than that of controls.Clevidipine crosses the placental membrane in this species and doses of 35 or more mg/kg/day (about 0.7 times the MRHD) administered during organogenesis adversely affected fetal survival.Fetal survival was also adversely affected when pregnant rabbits were treated during organogenesis with 55 mg/kg/day (about twice the MRHD on a body surface area basis).

Clinical Studies

Perioperative Hypertension

Cleviprexwas evaluated in twodouble-blind, randomized, parallel, placebo-controlled, multicenter trials of cardiac surgery patients—pre-operative use in ESCAPE-1 (n=105) and post-operative use in ESCAPE-2 (n=l 10).Patients were undergoingcoronary artery bypass grafting, with or without valve replacement.Inclusion in ESCAPE-1 requireda systolic pressure ≥ 160 mmHg.In ESCAPE-2, the entry criterion was systolic pressure of ≥ 140 mmHg within 4 hours of the completed surgery.The mean baseline blood pressure was 178/77mmHg in ESCAPE -1 and 150/71 mmHg in ESCAPE 2.The population of both studies included 27% females and 47% patients older than age 65.

Cleviprex was infused in ESCAPE-1 preoperatively for 30 minutes, until treatment failure, or until induction of anesthesia, whichever came first.Cleviprex was infused in ESCAPE-2 postoperatively for a minimum of 30 minutes unless alternative therapy was required.The maximum infusion time allowed in the ESCAPE studies was 60 minutes.

In both studiesinfusion of Cleviprex was started at a dose of 1- 2 mg/hourand was titrated upwards, as tolerated, in doubling increments every 90 seconds up to an infusion rate of 16 mg/hourin 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/hourand in ESCAPE-2 it was 5.1 mg/hour.The mean duration of exposure in the same ESCAPE studies was 30 minutes for the Cleviprex treated patients.

Approximately 4% of Cleviprex-treated subjects in ESCAPE-1 and 41% in ESCAPE-2 were on concomitant vasodilators during the first 30 minutes of Cleviprex administration.

Cleviprex lowered blood pressure within 2-4 minutes.The change in systolic blood pressure over 30 minutes for ESCAPE-1 (preoperative) and ESCAPE-2 (postoperative) are shown in Figure 1 and 2.

Figure 1. Mean change in systolic blood pressure (mmHg) during 30-minute infusion, ESCAPE-1 (preoperative)

Mean change in systolic blood pressure (mmHg) during 30-minute infusion, ESCAPE-1 (preoperative) - Illustration

Figure 2. Mean change in systolic blood pressure (mmHg) during 30-minute infusion, ESCAPE-2 (postoperative)

Mean change in systolic blood pressure (mmHg) during 30-minute infusion, ESCAPE-2 (postoperative) - Illustration

The change in heart rate over 30 minutes for ESCAPE-1 (preoperative) and ESCAPE-2 (postoperative) are shown in Figure 3 and 4.

Figure 3. Mean change in heart rate(bpm) during 30-minute infusion, ESCAPE-1 (preoperative)

Mean change in heart rate(bpm) during 30-minute infusion, ESCAPE-1 (preoperative) - Illustration

Figure 4. Mean change in heart rate (bpm)during 30-minute infusion, ESCAPE-2 (postoperative)

Mean change in heart rate (bpm)during 30-minute infusion, ESCAPE-2 (postoperative) - Illustration

In three Phase 3 open-label clinical trials (ECLIPSE), 1512 patients 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 in the ECLIPSE studies 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

Cleviprexwas evaluated in an open-label, uncontrolledclinical trial (VELOCITY) in 126 patients with severe hypertension (SBP > 180 mmHg or diastolic blood pressure [DBP] > 115 mmHg). 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 toachieve a prespecified target blood pressure range within 30 minutes (primary endpoint). The transition to oral antihypertensive therapy was assessed for up to 6hours following cessation of Cleviprex infusion.

The blood pressure effect in this study is shown in Figure 5. The average infusion rate was9.5 mg/hour.The mean duration of Cleviprex exposure was 21 hours.

Figure 5.Mean percent change in SBP (%) during the first 30 minutes of infusion, VELOCITY (severe hypertension)

Mean percent change in SBP (%) during the first 30 minutes of infusion, VELOCITY (severe hypertension) - Illustration

Oral antihypertensive therapy was instituted 1 hour prior to the anticipated cessation of Cleviprex infusion. Transition to oral antihypertensive therapy within 6 hours after discontinuing Cleviprex infusion was successful in 91% (115/126) of patients. No patient had IV antihypertensive therapy reinstituted following transition to oral therapy.

Essential Hypertension

Cleviprex was evaluated ina randomized, placebo-controlled, single-blind, parallel 72-hour continuous infusion study in 61 mild to moderate essential hypertensives.The mean baseline blood pressure was 151/86 mmHg.

Subjects were randomized to placebo or to 2, 4, 8, or 16 mg/hour. Doses above 2 mg/hour were started at 2 mg/hour and force-titrated in 2-fold increments at 3-minute intervals.Blood pressure, heart rate,and blood levels of clevidipinewere measured during the infusion period. Blood levels were monitored 1 hour after the infusion was discontinued. Blood pressure and heart rate were monitored for 8 hours and also at 96 hoursafter the termination of infusion. Systolic blood pressure effect was relatedto the concentration of clevidipine and plateaued at higher measured concentrations, with the maximal effect estimated at 25% of baseline systolic blood pressure. The estimated infusion rate necessary to achieve half of this maximal effect was approximately 10 mg/hour.

Last reviewed on RxList: 1/4/2012
This monograph has been modified to include the generic and brand name in many instances.

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