ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following risk is discussed elsewhere in the labeling:Hypotension and Reflex Tachycardia [see Warnings and Precautions (5.2)] 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 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 drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Perioperative HypertensionThe placebo-controlled experience with Cleviprex in the perioperative setting was both small and brief (about 30 minutes). Table 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 event27 (51%) 21 (41%) 32 (53%) 24 (49%) Acute renal failure5 (9%) (2%) -- -- Atrial fibrillation-- -- 13 (21%) (12%) Nausea-- -- 13 (21%) (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 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 StudiesThe 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 HypertensionThe 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 HypertensionAdverse 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 population of uncertain size, it is not always possible to estimate reliably their frequency or to establish 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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, metabolite of clevidipine, known genotoxicant in vitro and 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 24 hours) on body surface area basis. Female rats demonstrated pseudopregnancy and changes in estrus cycle at doses as low as 13 mg/kg/day (about 1/4 th the MRHD); however, doses of up to 55 mg/kg/day did not affect mating performance or fertility.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Clevidipine is 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 4-5% reduction in systolic blood pressure within 2-4 minutes after starting 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 dose-dependent decrease in systemic vascular resistance. Heart Rate:An increase in heart rate is 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 very short half life. The arterial blood concentration of clevidipine declines in multi-phasic pattern following termination of the infusion. The initial phase half-life is approximately 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 37C. 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 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 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.

CLINICAL STUDIES SECTION.

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 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 drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Perioperative HypertensionThe placebo-controlled experience with Cleviprex in the perioperative setting was both small and brief (about 30 minutes). Table 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 event27 (51%) 21 (41%) 32 (53%) 24 (49%) Acute renal failure5 (9%) (2%) -- -- Atrial fibrillation-- -- 13 (21%) (12%) Nausea-- -- 13 (21%) (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 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 StudiesThe 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 HypertensionThe 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 HypertensionAdverse reactions that were reported in <1% of patients with severe or essential hypertension included: Cardiac: myocardial infarction, cardiac arrest Nervous system: syncope Respiratory: dyspnea.

DOSAGE & ADMINISTRATION SECTION.

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- 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 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 agents 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 is guideline for dosing conversion from mg/hour to mL/hour.Table 1. Dose conversion Dose (mg/hour) Dose (mL/hour) 2 4 8 12 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 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 central line or 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, USPSodium Chloride (0.9%) Injection, USPDextrose (5%) Injection, USPDextrose (5%) in Sodium Chloride (0.9%) Injection, USPDextrose (5%) in Ringers Lactate Injection, USPLactated Ringers Injection, USP10% amino acid. 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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Cleviprex (clevidipine) injectable emulsion is supplied as sterile, milky white liquid emulsion product in single-use glass vials at concentration of 0.5 mg/mL of clevidipine.NDC 65293-005-50: 50 mL vial NDC 65293-005-00: 100 mL vial NDC 65293-005-25: 250 mL vial StorageLeave vials in cartons until use. Clevidipine is photosensitive and storage in cartons protects against photodegradation. Protection from light during administration is not required. Store vials refrigerated at 2-8C (36-46F). Do not freeze. Vials in cartons may be transferred to 25C (77F, USP controlled room temperature) for period not to exceed 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 months after this date or the labeled expiration date (whichever date comes first). Do not return to refrigerated storage after beginning room temperature storage. Handling Maintain aseptic technique while handling Cleviprex. Cleviprex is 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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise patients with underlying hypertension that they require continued follow up for their medical condition, and, if applicable, encourage patients to continue taking their oral antihypertensive medication(s) as directed.Advise patients to contact healthcare professional immediately for any of the following signs of new hypertensive emergency: neurological symptoms, visual changes, or evidence of congestive heart failure.Manufactured by: Fresenius Kabi Austria GmbH, Graz, Austria Marketed by: The Medicines Company Parsippany, New Jersey 07054 For information call: 888-977-MDCO (6326)US Patent 5,856,346 US Patent 5,739,152 TMC [PN 1220-3 (November 08, 2013)] M088834/04 USA. Advise patients with underlying hypertension that they require continued follow up for their medical condition, and, if applicable, encourage patients to continue taking their oral antihypertensive medication(s) as directed.. Advise patients to contact healthcare professional immediately for any of the following signs of new hypertensive emergency: neurological symptoms, visual changes, or evidence of congestive heart failure.

NONCLINICAL TOXICOLOGY SECTION.

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, metabolite of clevidipine, known genotoxicant in vitro and 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 24 hours) on body surface area basis. Female rats demonstrated pseudopregnancy and changes in estrus cycle at doses as low as 13 mg/kg/day (about 1/4 th 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 1/4 th the maximum recommended human dose of 504 mg/day (21 mg/hour 24 hours) on body surface area basis). When offspring of these dams were mated, they had 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 body surface area basis).

PHARMACODYNAMICS SECTION.

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 4-5% reduction in systolic blood pressure within 2-4 minutes after starting 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 dose-dependent decrease in systemic vascular resistance. Heart Rate:An increase in heart rate is 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.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Clevidipine is rapidly distributed and metabolized resulting in very short half life. The arterial blood concentration of clevidipine declines in multi-phasic pattern following termination of the infusion. The initial phase half-life is approximately 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 37C. 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 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 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.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Category CThere are no adequate and well-controlled studies of Cleviprex use in pregnant women. In animal studies, clevidipine caused increases in maternal and fetal mortality and length of gestation. Cleviprex should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. There was decreased fetal survival when pregnant rats and rabbits were treated with clevidipine during organogenesis at doses 0.7 times (on body surface area basis) the maximum recommended human dose (MRHD) in rats and 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 conception rate lower than that of controls. Clevidipine has been shown to cross the placenta in rats [see Nonclinical Toxicology (13.3)].

STORAGE AND HANDLING SECTION.

StorageLeave vials in cartons until use. Clevidipine is photosensitive and storage in cartons protects against photodegradation. Protection from light during administration is not required. Store vials refrigerated at 2-8C (36-46F). Do not freeze. Vials in cartons may be transferred to 25C (77F, USP controlled room temperature) for period not to exceed 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 months after this date or the labeled expiration date (whichever date comes first). Do not return to refrigerated storage after beginning room temperature storage. Handling Maintain aseptic technique while handling Cleviprex. Cleviprex is 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pediatric use: Safety and effectiveness of Cleviprex in children under 18 years of age have not been established. (8.4) 8.1 Pregnancy. Pregnancy Category CThere are no adequate and well-controlled studies of Cleviprex use in pregnant women. In animal studies, clevidipine caused increases in maternal and fetal mortality and length of gestation. Cleviprex should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. There was decreased fetal survival when pregnant rats and rabbits were treated with clevidipine during organogenesis at doses 0.7 times (on body surface area basis) the maximum recommended human dose (MRHD) in rats and 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 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 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Maintain aseptic technique. Discard unused portion 12 hours after stopper puncture. (5.1) Hypotension and reflex tachycardia are potential consequences of rapid upward titration of Cleviprex. (5.2) Dihydropyridine calcium channel blockers can produce negative inotropic effects and exacerbate heart failure. Monitor heart failure patients carefully. (5.4) Cleviprex gives no protection against the effects of abrupt beta-blocker withdrawal. (5.5) 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 hours after the infusion is stopped. (5.6) Maintain aseptic technique. Discard unused portion 12 hours after stopper puncture. (5.1) Hypotension and reflex tachycardia are potential consequences of rapid upward titration of Cleviprex. (5.2) Dihydropyridine calcium channel blockers can produce negative inotropic effects and exacerbate heart failure. Monitor heart failure patients carefully. (5.4) Cleviprex gives no protection against the effects of abrupt beta-blocker withdrawal. (5.5) 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 hours after the infusion is stopped. (5.6) 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 treatment for Cleviprex-induced tachycardia. Beta-blocker use for this purpose is not recommended. 5.3 Lipid Intake. Cleviprex contains approximately 0.2 of lipid per mL (2.0 kcal). Lipid intake restrictions may be necessary for patients with significant disorders of lipid metabolism. For these patients, 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 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 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 hours after the infusion is stopped.. 5.7 Pheochromocytoma. There is no information to guide use of Cleviprex in treating hypertension associated with pheochromocytoma.

CLINICAL TRIALS EXPERIENCE SECTION.