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美国FDA批准The Medicines Company公司的丁酸氯维地平静脉注射用乳剂(clevidipine butyrate，Cleviprex)上市，用于降低不宜口服治疗或口服治疗无效的高血压。 本品系一新颖的静脉抗高血压药品，代表了目前治疗药品的1项新进展，为重症监护室医生提供了快速、精确控制血压的新武器。凭藉急救室、手术室和监护室所得数据，本品向医生提供了降血压重要的新观点。新近临床实践发现，控制血压紧急升高和降低不良反应出现的危险性间存在着重要的相关性。 本品起效快，作用消除也快，可递增剂量精确地控制血压。与目前许多静脉注射经肾和（或）肝代谢的抗高血压药不同，其在血液和组织中代谢，因而不在体内蓄积。 在近10年中，尚无静脉注射的抗高血压新药上市。本品是新一代静脉注射用二氢吡啶类钙通道阻滞药。本品最先在美国获准上市是基于其对1 406例治疗和手术患者6项Ⅲ期临床研究的结果。所有Ⅲ期临床研究均符合其主要终点指标。本品可引起全身性低血压和反射性心动过速，其最常见的不良反应（>2%）：头痛，恶心和呕吐。 商品名：Cleviprex 本品由英国阿斯利康公司(AstraZeneca)原研制。美国The Medicines Company拥有在除日本以外的全球市场开发和商业化授权，并于2008年8月11日首次在美国上市本品。 适应证 本品适用于在口服降压药不适用或无法取得满意疗效的情况下治疗高血压。 作用机制 本品为二氢吡啶L-型钙通道阻滞剂。在动脉平滑肌去极化过程中，L-型钙通道调节其钙流入。 在麻醉的大鼠和狗中进行的实验表明，本品可通过降低全身血管阻力使平均动脉压下降。本品不降低心脏充盈压(前负荷)，证明对静脉容量血管不起作用。 药效学 本品逐步增加剂量至获得预期降压效果的浓度。在基线收缩压的25％左右处，本品的效果达到坪值。达到半数有效浓度的输注速度约为10mg／小时。 起效：在围手术期患者中，以0.4μg/kg／分钟(约1～2mg/小时)的速度开始输注本品，2～4分钟后可使收缩压下降4％～5％。 药效的维持：在连续输注共计72小时的研究中，未显示耐量或滞后现象。 失效：在大部分患者，停止输注后5～15分钟内血压完全恢复。 在连续输注共计72小时的研究中，有证据表明，对于未转用其它抗高血压疗法的患者，在停止使用本品后出现反调性高血压。 血液动力学：本品可导致全身血管阻力呈剂量依赖性地下降。 心率：心率增加是血管舒张和血压下降的一种正常反应，在某些患者，心率的增加可能非常明显(见“注意事项”)。 电生理效应：在健康志愿者，本品或其主要羧酸代谢产物，在治疗浓度或高于治疗浓度(约为稳态浓度的2.8倍)时，不会延长心脏复极时间。 临床评价 围手术期高血压 2项在心脏外科手术患者中进行的随机双盲平行安慰剂对照的多中心临床研究对本品进行了评价，其中ESCAPE-1研究(n=105)在手术前用药，ESCAPE-2研究(n=110)在手术后用药。入选患者为接受冠状动脉搭桥术(伴或不伴瓣膜置换术)者。入选ESCAPE-1的患者收缩压≥160mmHg；而在ESCAPE-2研究中，入选标准为完成手术后4小时内收缩压≥140mmHg。ESCAPE-1研究中，平均基线血压为178/77mmHg；ESCAPE-2研究中，平均基线血压为150/71mmHg。2项研究中，女性占27％，65岁以上患者占47％。 ESCAPE-1研究中，本品于手术前输注30分钟，直至治疗失败或进行麻醉。在ESCAPE-2研究中，本品在手术后输注至少30分钟，除非需要改用其它疗法。ESCAPE研究中，允许的最长输注时间为60分钟。 两项研究中，输注本品的起始剂量为1～2mg/小时，并在可以耐受的情况下逐步增加剂量，以每90秒倍增的方式将输注速度增加至16mg/小时，从而达到获得预期降压效果的水平。超过16mg/小时后，增加的剂量为7mg/小时。ESCAPE-1研究中，本品平均输注速度为15.3 mg/小时；ESCAPE-2研究中为5.1mg/小时。两项研究中，本品治疗组患者的平均暴露时间为30分钟。在本品用药的前30分钟，ESCAPE-1研究中有4％的本品治疗组患者联用血管扩张剂，ESCAPE-2研究中则为4l％。 严重高血压 一项纳入126例严重高血压(收缩压>180mmHg或舒张压>115mmHg)患者的开放的非对照临床研究(VELOCITY)对本品进行了评价。本品的起始输注速度为2mg/小时，每3分钟增加1次剂量，倍增至最大输注速度32mg/小时，以达到30分钟内将血压降到目标范围(首要终点)的目的。对转用口服降压药的评估一直延续至停止输注本品后6小时。 口服降压药于本品输注停止前1小时开始使用。91％的患者(115/126)在停止本品输注的6小时内转用口服降压药获得成功。在转用口服降压药后，没有患者重新使用静脉输注降压药。 原发性高血压 一项在61例轻至中度原发性高血压患者中进行的随机安慰剂对照的单盲平行72小时持续输注研究对本品进行了评价。患者的平均基线血压为15l/86mmHg。 研究中，患者随机接受安慰剂或本品(2mg/小时、4mg/小时、8mg/小时或6mg/小时)治疗。对于接受2mg/小时以上剂量治疗者，起始剂量均为2mg/小时，每3分钟倍增1次剂量，直至达到目标剂量。输注期间，对患者血压、心率和本品血药浓度进行测量。输注停止后，对本品血药浓度监测1小时；对血压和心率监测8小时，并在96小时后再监测1次。收缩压的降压效果与本品浓度相关，并在较高测量浓度时达坪，估计的最大降压效果为将收缩压降至基线值的25％，估计获得半数最大降压效果的输注速度约为10mg/小时。 用法与用量 监测 在输注本品时，应不断监测患者血压和心率，直至患者体征稳定。对于长时间持续输注本品且未转用其它降压药的患者，应在输注结束后进行至少8小时的反跳性高血压监测。此类患者在血压控制中可能需要随访调整。 推荐剂量 本品为静脉用药制剂，使用过程中应逐步调整剂量以达到理想的降压效果。具体的用药剂量取决于预期达到的降压效果和患者的反应。 起始剂量：本品静脉输注的起始剂量为l～2mg/小时。 剂量调整：可以短时间(90秒)间隔地翻倍增加剂量。当接近目标降压效果时，增加的剂量应低于一倍，调整剂量的时间间隔也应延长至5～10分钟。一般来说，剂量每增加1～2mg/小时，就可使收缩压进一步下降2～4mmHg。 维持剂量：大多数患者在计量达到4～6mg/小时，获得理想的治疗应答。而对于严重高血压患者，可能需要将剂量增至32mg/小时，但是这一剂量的临床经验有限。 最大剂量：大多数患者的最大剂量不超过16mg/小时。32mg/小时剂量的短期用药经验有限。由于受到脂质摄入量的限制，建议24小时内本品的输注量不超过1000m1或平均21mg/小时。在临床研究中，有55例高血压患者在24小时内输注本品的量超过500m1。几乎没有输注本品(所有剂量)超过72小时的用药经验。 转用其它降压药：当确定适当的口服降压药时，可停用本品或逐步降低本品用药量。使用口服降压药初期，应考虑口服药物起效的延滞时间。在达到预期效果前应继续监测血压。 特殊人群：尚未针对特殊人群进行本品的研究。在临床研究中，有78例肝功能异常患者(出现下列情况中的至少1种：血清胆红素升高、AST/SGOT升高、ALT/SGPT升高)和12l例中至重度肾损伤患者接受本品的治疗。在此类患者中，本品的起始输注剂量宜控制在1～2mg/小时。 用药说明 使用本品时应保持无菌操作。本品为一次性使用肠外用药产品，含有磷脂，可支持微生物生长。如果怀疑本品已受污染，则不能使用。一旦其瓶塞被刺穿，则应在4小时内使用，过时则应丢弃任何未使用的部分，包括正在输注的药物。 本品为预混合即用型50ml或100ml小玻璃瓶装无菌产品。在使用前应轻轻来回倒置药瓶数次，保证乳剂的均匀一致。在溶液和容器允许的情况下，用药前应检查肠外用药产品的颗粒物和变色情况。本品给药时应使用可标明输注速度的输注器械。市售的标准塑料套管可用于本品输注。应沿管子的中心线或边缘线给药。 本品不应与其它药物在同一线上给药。 本品不能稀释，但可以与下列产品联用： 注射用水，USP 氯化钠注射液(0.9％)，USP 葡萄糖注射液(5％)，USP 葡萄糖(5％)氯化钠(0.9％)注射液，USP 葡萄糖(5％)乳酸林格氏液注射剂，USP 乳酸林格氏液注射剂，USP 10％氨基酸 制剂 乳白色静脉输注用无菌注射乳剂，一次性使用小玻璃瓶装，50ml/瓶和100ml/瓶，含本品0.5mg/ml。 1 INDICATIONS AND USAGE Cleviprex is indicated for the reduction of blood pressure when oral therapy is not feasible or not desirable. 2 DOSAGE AND ADMINISTRATION 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.
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:
3 DOSAGE FORMS AND STRENGTHS Cleviprex is a sterile, milky white injectable emulsion for intravenous use, available in the following two configurations:
4 CONTRAINDICATIONS 4.1 Known Allergy Cleviprex is contraindicated in patients with allergies to soybeans, soy products, eggs, or egg products. 4.2 Defective Lipid Metabolism Cleviprex is contraindicated in patients with defective lipid metabolism such as pathologic hyperlipemia, lipoid nephrosis, or acute pancreatitis if it is accompanied by hyperlipidemia. 4.3 Severe Aortic Stenosis Cleviprex is contraindicated in patients with severe aortic stenosis because afterload reduction can be expected to reduce myocardial oxygen delivery. 5 WARNINGS AND PRECAUTIONS 5.1 Need for Aseptic Technique Use aseptic technique and discard any unused product within 12 hours of stopper puncture [see Dosage and Administration (2.3)]. 5.2 Hypotension and Reflex Tachycardia Cleviprex may produce systemic hypotension and reflex tachycardia. If either occurs, decrease the dose of Cleviprex. There is limited experience with short-duration therapy with beta-blockers as a treatment for Cleviprex-induced tachycardia. Beta-blocker use for this purpose is not recommended. 5.3 Lipid Intake Cleviprex contains approximately 0.2 g of lipid per mL (2.0 kcal). Lipid intake restrictions may be necessary for patients with significant disorders of lipid metabolism. For these patients, a reduction in the quantity of concurrently administered lipids may be necessary to compensate for the amount of lipid infused as part of the Cleviprex formulation. 5.4 Negative Inotropy Dihydropyridine calcium channel blockers can produce negative inotropic effects and exacerbate heart failure. Monitor heart failure patients carefully. 5.5 Beta-Blocker Withdrawal Cleviprex is not a beta-blocker, does not reduce heart rate, and gives no protection against the effects of abrupt beta-blocker withdrawal. Beta-blockers should be withdrawn only after a gradual reduction in dose. 5.6 Rebound Hypertension 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. 5.7 Pheochromocytoma There is no information to guide use of Cleviprex in treating hypertension associated with pheochromocytoma. 6 ADVERSE REACTIONS The following risk is discussed elsewhere in the labeling:
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).
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 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: 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. 7 DRUG INTERACTIONS No clinical drug interaction studies were conducted. Clevidipine and its major dihydropyridine metabolite do not have the potential for blocking or inducing any CYP enzyme. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There was decreased fetal survival when pregnant rats and rabbits were treated with clevidipine during organogenesis at doses 0.7 times (on a body surface area basis) the maximum recommended human dose (MRHD) in rats and 2 times the MRHD in rabbits. In pregnant rats dosed with clevidipine during late gestation and lactation, there were dose-related increases in maternal mortality, length of gestation and prolonged parturition at doses greater than or equal to 1/6 of the MRHD based on body surface area. When offspring of these dams were mated, they had a conception rate lower than that of controls. Clevidipine has been shown to cross the placenta in rats [see Nonclinical Toxicology (13.3)]. 8.2 Labor and Delivery Cleviprex in the labor and delivery setting has not been established as safe and effective. Other calcium channel blockers suppress uterine contractions in humans. Pregnant rats treated with clevidipine during late gestation had an increased rate of prolonged parturition. 8.3 Nursing Mothers It is not known whether clevidipine is excreted in human milk. Because many drugs are excreted in human milk, consider possible infant exposure when Cleviprex is administered to a nursing woman. 8.4 Pediatric Use The safety and effectiveness of Cleviprex in children under 18 years of age have not been established. 8.5 Geriatric Use Of the 1406 subjects (1307 with hypertension) treated with Cleviprex in clinical studies, 620 were ≥65 years of age and 232 were ≥75 years of age. No overall differences in safety or effectiveness were observed between these and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, for an elderly patient doses should be titrated cautiously, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. 10 OVERDOSAGE There has been no experience of overdosage in human clinical trials. In clinical trials, doses of Cleviprex up to 106 mg/hour or 1153 mg maximum total dose were administered. The expected major effects of overdose would be hypotension and reflex tachycardia. Discontinuation of Cleviprex leads to a reduction in antihypertensive effects within 5 to 15 minutes [see Clinical Pharmacology (12.2)]. In case of suspected overdosage, Cleviprex should be discontinued immediately and the patient’s blood pressure should be supported. 11 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. The structure and formula are: 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. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Clevidipine 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 reduces mean arterial blood pressure by decreasing systemic vascular resistance. Clevidipine does not reduce cardiac filling pressure (pre-load), confirming lack of effects on the venous capacitance vessels. 12.2 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 [see Warnings and Precautions (5.2)]. 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 prolong cardiac repolarization. 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. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Clevidipine displayed positive genotoxic potential in vitro in the Ames test, mouse lymphoma thymidine kinase locus assay, and chromosomal aberration assay but not in vivo in the mouse micronucleus test. Formaldehyde, a metabolite of clevidipine, a known genotoxicant in vitro and a probable human carcinogen, appears to be at least partially responsible for the positive in vitro results. Long-term studies for evaluation of carcinogenic potential have not been performed with clevidipine due to the intended short-term duration of human use. There were no adverse effects on fertility or mating behavior of male rats at clevidipine doses of up to 55 mg/kg/day, approximately equivalent to the maximum recommended human dose (MRHD) of 504 mg/day (21 mg/hour x 24 hours) on a body surface area basis. Female rats demonstrated pseudopregnancy and changes in estrus cycle at doses as low as 13 mg/kg/day (about 1/4th the MRHD); however, doses of up to 55 mg/kg/day did not affect mating performance or fertility. 13.3 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). 14 CLINICAL STUDIES 14.1 Perioperative Hypertension Cleviprex was evaluated in two double-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=110). Patients were undergoing coronary artery bypass grafting, with or without valve replacement. Inclusion in ESCAPE-1 required a 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 178/77 mmHg 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 studies 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 in ESCAPE-1 was 15.3 mg/hour and 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) Figure 2. Mean change in systolic blood pressure (mmHg) during 30-minute infusion, ESCAPE-2 (postoperative) 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) Figure 4. Mean change in heart rate (bpm) during 30-minute infusion, ESCAPE-2 (postoperative) 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. 14.2 Severe Hypertension The blood pressure effect in this study is shown in Figure 5. The average infusion rate was 9.5 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) 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. 14.3 Essential Hypertension Cleviprex was evaluated in a 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 clevidipine were 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 hours after the termination of infusion. Systolic blood pressure effect was related to 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. 16 HOW SUPPLIED/STORAGE AND HANDLING Cleviprex (clevidipine) 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. NDC 65293-005-50: 50 mL vial Storage 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
