prescription drugs [24:<1% of patients with severe or essential hypertension included: Cardiac: myocardial infarction, cardiac arrest Nervous system: syncope Respiratory: dyspnea 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. 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. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There 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 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)] . 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. 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. Pediatric Use The safety and effectiveness of Cleviprex in children under 18 years of age have not been established. 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. 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. Cleviprex 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. 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 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. 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. 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. Nonclinical Toxicology 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 1/4 th the MRHD); however, doses of up to 55 mg/kg/day did not affect mating performance or fertility. 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 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 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. 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. 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. How Supplied/Storage and Handling Cleviprex (clevidipine) injectable emulsion is supplied as a sterile, milky white liquid emulsion product in single-use glass vials at a concentration of 0.5 mg/mL of clevidipine. NDC 10122-610-10: 10 Single Use 50 mL Vials NDC 10122-611-10: 10 Single Use 100 mL Vials NDC 10122-612-04: 4 Single Use 250 mL Vials Storage Leave 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 2-8 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. 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. 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 a healthcare professional immediately for any of the following signs of a new hypertensive emergency: neurological symptoms, visual changes, or evidence of congestive heart failure. Manufactured by: Fresenius Kabi Austria GmbH, Graz, Austria Marketed by: Chiesi USA , Inc. Cary, NC 27518 For information call: 1-888-661-9260 Cleviprex is a registered trademark of Chiesi Farmaceutici S.p.A. US Patent 5,856,346 US Patent 5,739,152 CTCP-001-0816-00-SPL M088834/05 USA 0108002410/01 Package Label - Principal Display Panel - 25mg/50mL Vial Label Package Label - Principal Display Panel - 25mg/50mL Inner Carton Package Label - Principal Display Panel - 25mg/50mL Outer Carton Package Label - Principal Display Panel - 50mg/100mL Vial Label Package Label - Principal Display Panel - 50mg/100mL Inner Carton Package Label - Principal Display Panel - 50mg/100mL Outer Carton Package Label - Principal Display Panel - 125mg/250mL Vial Label Package Label - Principal Display Panel - 125mg/250mL Inner Carton Package Label - Principal Display Panel - 125mg/250mL Outer Carton Cleviprex clevipidine emulsion Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:10122-610 Route of Administration INTRAVENOUS DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CLEVIDIPINE (CLEVIDIPINE) CLEVIDIPINE 0.5 mg in 1 mL Inactive Ingredients Ingredient Name Strength SOYBEAN OIL GLYCERIN EGG PHOSPHOLIPIDS OLEIC ACID EDETATE DISODIUM SODIUM HYDROXIDE Product Characteristics Color WHITE (Milky) Score Shape Size Flavor Imprint Code Contains Packaging # Item Code Package Description 1 NDC:10122-610-10 10 CARTON in 1 CARTON 1 NDC:10122-610-01 1 VIAL, SINGLE-USE in 1 CARTON 1 50 mL in 1 VIAL, SINGLE-USE Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA022156 09/15/2008 Cleviprex clevipidine emulsion Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:10122-612 Route of Administration INTRAVENOUS DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CLEVIDIPINE (CLEVIDIPINE) CLEVIDIPINE 0.5 mg in 1 mL Inactive Ingredients Ingredient Name Strength SOYBEAN OIL GLYCERIN EGG PHOSPHOLIPIDS OLEIC ACID EDETATE DISODIUM SODIUM HYDROXIDE Product Characteristics Color WHITE (Milky) Score Shape Size Flavor Imprint Code Contains Packaging # Item Code Package Description 1 NDC:10122-612-04 4 CARTON in 1 CARTON 1 NDC:10122-612-01 1 VIAL, SINGLE-USE in 1 CARTON 1 250 mL in 1 VIAL, SINGLE-USE Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA022156 09/15/2008 Cleviprex clevipidine emulsion Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:10122-611 Route of Administration INTRAVENOUS DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CLEVIDIPINE (CLEVIDIPINE) CLEVIDIPINE 0.5 mg in 1 mL Inactive Ingredients Ingredient Name Strength SOYBEAN OIL GLYCERIN EGG PHOSPHOLIPIDS OLEIC ACID EDETATE DISODIUM SODIUM HYDROXIDE Product Characteristics Color WHITE (Milky) Score Shape Size Flavor Imprint Code Contains Packaging # Item Code Package Description 1 NDC:10122-611-10 10 CARTON in 1 CARTON 1 NDC:10122-611-01 1 VIAL, SINGLE-USE in 1 CARTON 1 100 mL in 1 VIAL, SINGLE-USE Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA022156 09/15/2008 Labeler - Chiesi USA, Inc. (088084228) Registrant - Chiesi USA, Inc. (088084228) Revised: 05/2017 Chiesi USA, Inc. Next Interactions Print this page Add to My Med List More about Cleviprex (clevidipine) Side Effects During Pregnancy Dosage Information Drug Interactions Support Group Pricing & Coupons En Español 0 Reviews Add your own review/rating Drug class: calcium channel blocking agents Consumer resources Cleviprex Cleviprex (Advanced Reading) Professional resources Cleviprex (AHFS Monograph) Related treatment guides High Blood Pressure Hypertensive Emergency ]} FEATURED: CAR-T Cell Therapy Overview Mechanism of Action KTE-C19 Studies KTE-C19 Cancer Targets Adverse Events Manufacturing Drug Status Rx Availability Prescription only C Pregnancy Category Risk cannot be ruled out N/A CSA Schedule Not a controlled drug 9 years Approval History FDA approved 2008 Manufacturer The Medicines Company Drug Class Calcium channel blocking agents Related Drugs calcium channel blocking agents amlodipine , diltiazem , Norvasc , nifedipine , verapamil , Cardizem Hypertensive Emergency hydralazine , enalapril , nifedipine , labetalol , captopril , Vasotec , Apresoline , methyldopa , Capoten , Normodyne , Trandate , nitroprusside , More... High Blood Pressure amlodipine , lisinopril , hydrochlorothiazide , furosemide , losartan , metoprolol , atenolol , Lasix , Norvasc , valsartan , More... Cleviprex Rating No Reviews - Be the first! No Reviews - Be the first! Not Rated - Be the first!} } all people
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