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. withdraw beta-blockers 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.

ve 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. 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 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

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. use in perioperative hypertension the placebo-controlled experience with cleviprex in the perioperative setting was both small and brief (about 30 minutes). table 1 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 1. 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. use in 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.

g/hour respectively ( see data ). the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of major birth defects, loss, and other adverse outcomes. in the u.s. general population, the estimated major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and postpartum hemorrhage). hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. pregnant women with hypertension should be carefully monitored and managed accordingly. data animal data in pregnant rats, clevidipine caused a dose-related increase in mortality, length of gestation, and prolonged parturition at dose levels of 13, 35, and 55 mg/kg/day. clevidipine has been shown to cross the placenta in rats. no evidence of embryo-fetal malformation was found with continuous iv infusion of clevidipine during the period of organogenesis at doses up to 13 mg/kg/day in pregnant rats and 35 mg/kg/day in pregnant rabbits (2.8 to 7.6 times the expected human dose of 16 mg/hour). embryo-fetal toxicity was seen with continuous iv infusion of clevidipine during the period of major embryonic organogenesis at 35 mg/kg/day in pregnant rats and at 55 mg/kg/day in pregnant rabbits (7.6 to 12 times the expected maximum human dose of 16 mg/hour). there was no evidence that clevidipine was teratogenic at the highest dose levels studied in pregnant rats and rabbits. 8.2 lactation risk summary there are no data on the presence of clevidipine in human milk, the effects on the breastfed infant, or the effects on milk production. 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.

nancies have a background risk of major birth defects, loss, and other adverse outcomes. in the u.s. general population, the estimated major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and postpartum hemorrhage). hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. pregnant women with hypertension should be carefully monitored and managed accordingly. data animal data in pregnant rats, clevidipine caused a dose-related increase in mortality, length of gestation, and prolonged parturition at dose levels of 13, 35, and 55 mg/kg/day. clevidipine has been shown to cross the placenta in rats. no evidence of embryo-fetal malformation was found with continuous iv infusion of clevidipine during the period of organogenesis at doses up to 13 mg/kg/day in pregnant rats and 35 mg/kg/day in pregnant rabbits (2.8 to 7.6 times the expected human dose of 16 mg/hour). embryo-fetal toxicity was seen with continuous iv infusion of clevidipine during the period of major embryonic organogenesis at 35 mg/kg/day in pregnant rats and at 55 mg/kg/day in pregnant rabbits (7.6 to 12 times the expected maximum human dose of 16 mg/hour). there was no evidence that clevidipine was teratogenic at the highest dose levels studied in pregnant rats and rabbits.

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.

s 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.

the mrhd); however, doses of up to 55 mg/kg/day did not affect mating performance or fertility.

of up to 55 mg/kg/day did not affect mating performance or fertility.

he perioperative setting was both small and brief (about 30 minutes). table 1 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 1. 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. use in 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

um 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. 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) 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) 14.2 severe hypertension cleviprex was evaluated in an open-label, uncontrolled clinical 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 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 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. figure 5. mean percent change in sbp (%) during the first 30 minutes of infusion, velocity (severe hypertension) 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.

erature storage. handling maintain aseptic technique while handling cleviprex. cleviprex is a single-use parenteral product that contains 0.005% disodium edetate to inhibit the rate of growth of microorganisms, for up to 12 hours, in the event of accidental contamination. however, cleviprex can still support the growth of microorganisms, as it is not an antimicrobially preserved product under usp standards. do not use if contamination is suspected. once the stopper is punctured, use within 12 hours and discard any unused portion. cleviprex inhibits microbial growth for up to 12 hours, as demonstrated by test data for representative usp microorganisms, staphylococcus epidermidis and serratiamarcescens.