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| {{DrugProjectFormSinglePage
| | #REDIRECT [[Factor VIIa complex]] |
| |authorTag={{SS}}
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| |genericName=prothrombin, coagulation factor vii, coagulation factor ix, coagulation factor x, protein c, protein s
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| |aOrAn=an
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| |drugClass=Anti-coagulant
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| |indication=acute major bleeding, need for an urgent surgery/invasive procedure
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| |hasBlackBoxWarning=Yes
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| |adverseReactions=a list of adverse reactions, separated by commas.
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| |blackBoxWarningTitle=<span style="color:#FF0000;">WARNING: ARTERIAL AND VENOUS THROMBOEMBOLIC COMPLICATIONS</span>
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| |blackBoxWarningBody=Patients being treated with Vitamin K antagonists (VKA) therapy have underlying disease states that predispose them to thromboembolic events. Potential benefits of reversing VKA should be weighed against the potential risks of thromboembolic events, especially in patients with the history of a thromboembolic event. Resumption of anticoagulation should be carefully considered as soon as the risk of thromboembolic events outweighs the risk of acute bleeding.
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| * Both fatal and non-fatal arterial and venous thromboembolic complications have been reported with Kcentra in clinical trials and post marketing surveillance. Monitor patients receiving Kcentra for signs and symptoms of thromboembolic events.
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| * Kcentra was not studied in subjects who had a thromboembolic event, myocardial infarction, disseminated intravascular coagulation, cerebral vascular accident, transient ischemic attack, unstable angina pectoris, or severe peripheral vascular disease within the prior 3 months. Kcentra may not be suitable in patients with thromboembolic events in the prior 3 months. (5.2)
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| |fdaLIADAdult======Urgent Reversal of Acquired Coagulation Factor Deficiency=====
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| * Dosing Information
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| :* Individualize Kcentra dosing based on the patient's current pre-dose International Normalized Ratio (INR) value, and body weight (see [[Kcentra#Administration and Monitoring|Administration and Monitoring]]).
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| |contraindications=Kcentra is contraindicated in:
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| * Patients with known [[anaphylactic]] or severe systemic reactions to Kcentra or any components in Kcentra including [[heparin]], Factors II, VII, IX, X, [[Proteins C]] and S, [[Antithrombin]] III and human [[albumin]].
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| * Patients with [[disseminated intravascular coagulation]] ([[DIC]]).
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| * Patients with known [[heparin-induced thrombocytopenia]] ([[HIT]]). Kcentra contains [[heparin]] [see Description (11)].
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| |warnings======Hypersensitivity Reactions=====
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| [[Hypersensitivity]] reactions including [[flushing]], [[urticaria]], [[tachycardia]], [[anxiety]], [[angioedema]], [[wheezing]], [[nausea]], [[vomiting]], [[hypotension]], [[tachypnea]], [[dyspnea]], [[pulmonary edema]], and [[bronchospasm]] have been observed with Kcentra.
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| If severe allergic reaction or anaphylactic type reactions occur, immediately discontinue administration, and institute appropriate treatment.
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| =====Thromboembolic Risk/Complications=====
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| Both fatal and non-fatal arterial thromboembolic events (including [[acute myocardial infarction]] and [[arterial thrombosis]]), and venous thromboembolic events (including [[pulmonary embolism]] and [[venous thrombosis]]) and disseminated [[intravascular coagulation]] have been reported with Kcentra in clinical trials and post marketing surveillance [see Adverse Reactions (6) and Clinical Studies (14)]. Patients being treated with VKA therapy have underlying disease states that predispose them to thromboembolic events. Reversing VKA therapy exposes patients to the thromboembolic risk of their underlying disease. Resumption of [[anticoagulation]] should be carefully considered following administration of Kcentra and Vitamin K once the risk of thromboembolic events outweighs the risk of bleeding.
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| Thromboembolic events occurred more frequently following Kcentra compared to plasma in a randomized, plasma controlled trial in subjects requiring urgent reversal of VKA [[anticoagulation]] due to acute major bleeding, and the excess in thromboembolic events was more pronounced among subjects who had a history of prior thromboembolic event, although these differences were not statistically significant [see Adverse Reactions (6.1), Clinical Studies (14)]. Potential benefits of treatment with Kcentra should be weighed against the potential risks of thromboembolic events [see Adverse Reactions (6)]. Patients with a history of thrombotic events, [[myocardial infarction]], cerebral vascular accident, [[transient ischemic attack]], [[unstable angina pectoris]], severe peripheral vascular disease, or [[disseminated intravascular coagulation]], within the previous 3 months were excluded from participating in the plasma-controlled RCT. Kcentra may not be suitable in patients with thromboembolic events in the prior 3 months. Because of the risk of thromboembolism associated with reversal of [[VKA]], closely monitor patients for signs and symptoms of [[thromboembolism]] during and after administration of Kcentra. [see 17 Patient Counseling Information]
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| =====Transmissible Infectious Agents=====
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| Because Kcentra is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and, theoretically, the Creutzfeldt-Jakob disease agent. There is also the possibility that unknown infectious agents may be present in such products. Despite the use of two dedicated virus reduction steps in manufacturing to reduce risks, such products may still potentially transmit disease.
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| Reports of suspected virus transmission of [[hepatitis]] A, B, C, and [[HIV]] were generally confounded by concomitant administration of blood/blood components and/or other plasma-derived products. No causal relationship to Kcentra administration was established for any of these reports since introduction of a virus filtration step in 1996.
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| All infections thought by a physician to have been possibly transmitted by Kcentra should be reported by the physician or other healthcare provider to the CSL Behring Pharmacovigilance Department at 1-866-915-6958 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
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| |clinicalTrials=The most common adverse reactions (ARs) (frequency ≥ 2.8%) observed in subjects receiving Kcentra were [[headache]], [[nausea]]/[[vomiting]], [[hypotension]], and [[anemia]].
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| The most serious ARs were thromboembolic events including [[stroke]], [[pulmonary embolism]], and [[deep vein thrombosis]].
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| The following serious adverse reactions are described below and/or elsewhere in the labeling:
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| * [[Hypersensitivity]] Reactions [see Warnings and Precautions (5.1)]
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| * Arterial and venous thromboembolic complications [see Boxed Warning and Warnings and Precautions (5.2)]
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| * Possible transmission of infectious agents [see Warnings and Precautions (5.3)]
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| =====Clinical Trials Experience=====
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| Because clinical studies 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.
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| ''Randomized, Plasma-Controlled Trial in Acute Major Bleeding''
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| In a prospective, randomized, open-label, active-controlled multicenter non-inferiority trial, 212 subjects who required urgent reversal of [[VKA]] therapy due to acute major bleeding were enrolled and randomized to treatment; 103 were treated with Kcentra and 109 with plasma. Subjects with a history of a thrombotic event, [[myocardial infarction]], cerebral vascular accident, [[transient ischemic attack]], [[unstable angina pectoris]], severe peripheral vascular disease, or [[disseminated intravascular coagulation]], within the previous 3 months were excluded from participating. Subjects ranged in age from 26 years to 96 years.
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| ''Randomized, Plasma-Controlled Trial in Urgent Surgery/Invasive Procedures''
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| In a prospective, randomized, open-label, active-controlled, multicenter non-inferiority trial, 176 subjects who required urgent reversal of [[VKA]] therapy due to the need for an urgent surgical or urgent invasive procedure were enrolled; 88 were treated with Kcentra and 88 with plasma. Subjects ranged in age from 27 years to 94 years.
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| Adverse reactions are summarized for Kcentra and plasma in the Acute Major Bleeding and Urgent Surgery/Invasive Procedures RCTs (see Table 3).
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| Adverse Reactions are defined as adverse events that began during or within 72 hours of test product infusion plus adverse events considered possibly/probably related or related to study treatment according to the investigator, sponsor, or the blinded safety adjudication board (SAB), and with at least a 1.3‐fold difference between treatments.
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| [[File：Kcentra_adverse_01.jpg|thumb|none|400px]]
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| Serious adverse reactions in subjects receiving Kcentra in both RCTs included ischemic cerebrovascular accident (stroke), [[DVT]], [[thrombosis]], and [[venous insufficiency]]. Serious adverse reactions in both RCTs for plasma included [[myocardial ischemia]], [[myocardial infarction]], fluid overload, embolic cerebral infarction, [[pulmonary edema]], [[respiratory failure]], and [[DVT]].
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| There were a total of 10 subjects (9.7%) who died in the Kcentra group (1 additional death occurred on day 46 just after completion of the study reporting period) and 5 (4.6%) who died in the plasma group in the plasma-controlled RCT in acute major bleeding. The 95% confidence interval for the Kcentra minus plasma between-group difference in deaths ranged from -2.7% to 13.5%. From the plasma-controlled RCT in urgent surgery/invasive procedures, there were a total of 3 subjects (3.4%) who died in the Kcentra group (1 additional death occurred on day 48 after completion of the study reporting period) and 8 (9.1%) who died in the Plasma group. The 95% confidence interval for the Kcentra minus plasma between-group difference in deaths in this trial ranged from -14.6% to 2.7%. One death in the Kcentra group in the RCT in Acute Major Bleeding and one death in the plasma group in the RCT in urgent surgery/invasive procedures were considered possibly related to study treatment according to an assessment of masked data by an independent safety adjudication board. No factors common to all deaths were identified, except for the frequent findings of a high comorbidity burden, advanced age, and death after being placed on comfort care. Although, a greater proportion of subjects in the RCT in acute major bleeding than in the RCT in surgery/invasive procedure received the highest two recommended doses of Kcentra because more subjects in the trial in acute major bleeding had a baseline INR in the ranges of 4–6 and > 6.0, an analysis of deaths and factor levels in subjects with major bleeding revealed that subjects who died had similar median factor levels to subjects that did not die. Additionally, outliers with supraphysiologic factor levels did not have a mortality rate out of proportion to the overall population.
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| <u>Fluid Overload</u>
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| There were 9 subjects (4.7%, all non-related by investigator assessment) in the Kcentra group who experienced fluid overload in the plasma-controlled RCTs in acute major bleeding and urgent surgery/invasive procedures and 25 (12.7%, 13 events related by investigator assessment) who had fluid overload in the plasma group. The 95% confidence interval for the Kcentra minus Plasma between-group difference in fluid overload event incidence ranged from -14.1% to -2.0%.
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| Subgroup analyses of the RCTs in acute major bleeding and urgent surgery/invasive procedures according to whether subjects with fluid overload events had a prior history of congestive [[heart failure]] are presented in Table 4.
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| [[File：Kcentra_adverse_02.jpg|thumb|none|400px]]
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| <u>Thromboembolic Events400px]]</u>
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| In RCTs, there were 13 subjects (6.8%) in the Kcentra group who experienced possible thromboembolic events (TEEs) and 14 (7.1%) who had TEEs in the plasma group. The incidence of thromboembolic (TE) adverse reactions assessed as at least possibly related to study treatment by the Investigator or, in the case of serious thromboembolic events, the blinded safety adjudication board (SAB) was 9 (4.7%) in the Kcentra group and 7 (3.6%) in the plasma group. When also considering the events which began during or within 72 hours of test product infusion, the incidence was 9 (4.7%) in the Kcentra group and 8 (4.1%) in the plasma group.
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| TE events observed in the acute major bleeding and the urgent surgery/invasive procedures RCTs are shown in Table 5.
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| [[File：Kcentra_adverse_03.jpg|thumb|none|400px]]
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| Subgroup analyses of the RCTs according to whether subjects with thromboembolic events had a prior history of a thromboembolic event are presented in Table 6.
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| [[File：Kcentra_adverse_04.jpg|thumb|none|400px]]
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| The European Bleeding and Surgical Study: In a prospective, open label, single-arm, multicenter safety and efficacy trial, 17 subjects who required urgent reversal of [[VKA]] due to acute bleeding were enrolled and 26 subjects who required urgent reversal of [[Vitamin K antagonist]] due to the need for an urgent surgical/invasive procedure were enrolled, all were treated with Kcentra. Subjects ranged in age from 22 years to 85 years. Serious adverse reactions considered possibly related to Kcentra included a suspected [[pulmonary embolism]] which occurred in one subject following a second dose of Kcentra. A single non-fatal TE event occurred in another Kcentra-treated subject in that trial.
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| |postmarketing=No adverse reactions other than those addressed in Warnings And Precautions (5) and Adverse Reactions (6) have been observed in the postmarketing use of Kcentra outside the US since 1996.
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| |FDAPregCat=C
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| |useInPregnancyFDA=Pregnancy Category C. Animal reproduction studies have not been conducted with Kcentra. It is also not known whether Kcentra can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Kcentra should be prescribed for a pregnant woman only if clearly needed.
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| |useInPregnancyAUS=(Description)
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| |useInLaborDelivery=Kcentra has not been studied for use during labor and delivery. Safety and effectiveness in labor and delivery have not been established.
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| |useInNursing=It is not known whether Kcentra is excreted in human milk. Because many drugs are excreted in human milk, use Kcentra only if clearly needed when treating a nursing woman.
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| |useInPed=The safety and efficacy of Kcentra in the pediatric population has not been studied.
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| |useInGeri=Of the total number of subjects (431) with acute major bleeding or with the need for an urgent surgery/invasive procedure treated to reverse [[VKA]] [[anticoagulation]] in three clinical studies, 66% were 65 years old or greater and 39% were 75 years old or greater. There were no clinically significant differences between the safety profile of Kcentra and plasma in any age group.
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| |useInGender=(Description)
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| |useInRace=(Description)
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| |useInRenalImpair=(Description)
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| |useInHepaticImpair=(Description)
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| |useInReproPotential=(Description)
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| |useInImmunocomp=(Description)
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| |othersTitle=Congenital Factor Deficiencies
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| |useInOthers=Kcentra has not been studied in patients with congenital factor deficiencies.
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| |administration='''For intravenous use only.'''
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| =====Dosage=====
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| * Measurement of INR prior to treatment and close to the time of dosing is important because [[coagulation factors]] may be unstable in patients with acute major bleeding or an urgent need for surgery and other invasive procedures.
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| * Individualize Kcentra dosing based on the patient's current pre-dose [[International Normalized Ratio]] [[(INR]]) value, and body weight (see Table 1).
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| * The actual potency per vial of Factors II, VII, IX and X, Proteins C and S is stated on the carton.
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| * Administer [[Vitamin K]] concurrently to patients receiving Kcentra. [[Vitamin K]] is administered to maintain Vitamin K-dependent clotting factor levels once the effects of Kcentra have diminished.
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| * The safety and effectiveness of repeat dosing have not been established and is not recommended.
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| * Dose ranging within pre-treatment [INR]] groups has not been studied in randomized clinical trials of Kcentra.
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| |monitoring======Condition 1=====
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| (Description regarding monitoring, from ''Warnings'' section)
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| =====Condition 2=====
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| (Description regarding monitoring, from ''Warnings'' section)
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| =====Condition 3=====
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| (Description regarding monitoring, from ''Warnings'' section)
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| |IVCompat====Solution===
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| ====Compatible====
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| * Solution 1
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| * Solution 2
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| * Solution 3
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| ====Not Tested====
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| * Solution 1
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| * Solution 2
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| * Solution 3
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| ====Variable====
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| * Solution 1
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| * Solution 2
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| * Solution 3
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| ====Incompatible====
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| * Solution 1
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| * Solution 2
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| * Solution 3
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| ===Y-Site===
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| ====Compatible====
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| * Solution 1
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| * Solution 2
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| * Solution 3
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| ====Not Tested====
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| * Solution 1
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| * Solution 2
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| * Solution 3
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| ====Variable====
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| * Solution 1
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| * Solution 2
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| * Solution 3
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| ====Incompatible====
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| * Solution 1
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| * Solution 2
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| * Solution 3
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| ===Admixture===
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| ====Compatible====
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| * Solution 1
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| * Solution 2
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| * Solution 3
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| ====Not Tested====
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| * Solution 1
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| * Solution 2
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| * Solution 3
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| ====Variable====
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| * Solution 1
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| * Solution 2
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| * Solution 3
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| ====Incompatible====
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| * Solution 1
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| * Solution 2
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| * Solution 3
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| ===Syringe===
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| ====Compatible====
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| * Solution 1
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| * Solution 2
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| * Solution 3
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| ====Not Tested====
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| * Solution 1
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| * Solution 2
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| * Solution 3
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| ====Variable====
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| * Solution 1
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| * Solution 2
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| * Solution 3
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| ====Incompatible====
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| * Solution 1
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| * Solution 2
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| * Solution 3
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| ===TPN/TNA===
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| ====Compatible====
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| * Solution 1
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| * Solution 2
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| * Solution 3
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| ====Not Tested====
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| * Solution 1
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| * Solution 2
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| * Solution 3
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| ====Variable====
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| * Solution 1
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| * Solution 2
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| * Solution 3
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| ====Incompatible====
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| * Solution 1
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| * Solution 2
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| * Solution 3
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| |overdose====Acute Overdose===
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| ====Signs and Symptoms====
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| (Description)
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| ====Management====
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| (Description)
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| ===Chronic Overdose===
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| ====Signs and Symptoms====
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| (Description)
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| ====Management====
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| (Description)
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| |drugBox={{Drugbox2
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| | verifiedrevid =
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| | IUPAC_name =
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| | image =
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| | pregnancy_AU =
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| | legal_status =
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| | routes_of_administration =
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| <!--Pharmacokinetic data-->
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| <!--Chemical data-->
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| | C= | H= | N= | O=
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| |mechAction=(Description)
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| |structure=(Description with picture)
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| |PD=(Description)
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| |PK=(Description)
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| |nonClinToxic=(Description)
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| |clinicalStudies======Condition 1=====
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| (Description)
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| =====Condition 2=====
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| (Description)
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| =====Condition 3=====
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| (Description)
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| |howSupplied=(Description)
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| |fdaPatientInfo=(Patient Counseling Information)
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| |nlmPatientInfo=(Link to patient information page)
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| |lookAlike=* (Paired Confused Name 1a) — (Paired Confused Name 1b)
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| * (Paired Confused Name 2a) — (Paired Confused Name 2b)
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| * (Paired Confused Name 3a) — (Paired Confused Name 3b)
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| |drugShortage=Drug Shortage
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| }}
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