The most common adverse reactions (ARs) (frequency ≥ 2.8%) observed in subjects receiving Kcentra were headache, nausea/vomiting, arthralgia, and hypotension.
The most serious ARs were thromboembolic events including stroke, pulmonary embolism, and deep vein thrombosis.
The following serious adverse reactions are described below and/or elsewhere in the labeling:
- Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]
- Arterial and venous thromboembolic complications [see BOXED WARNING and WARNINGS AND PRECAUTIONS]
- Possible Transmission of Infectious Agents [see WARNINGS AND PRECAUTIONS]
Clinical Trials Experience
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.
Randomized, Plasma-Controlled Trial in Acute Major Bleeding
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.
Randomized, Plasma-Controlled Trial in Urgent Surgery/Invasive Procedures
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.
Adverse reactions are summarized for Kcentra and plasma in the Acute Major Bleeding RCT (see Table 3).
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.
Table 3: Adverse Reactions Reported in 3 or more Subjects ( ≥ 2.8%) Following Kcentra or Plasma Administration in Acute Major Bleeding RCT
|No. (%) of subjects|
(N = 103)
(N = 109)
|General disorders and administration site conditions|
|Chest pain||1 (1.0%)||3 (2.8%)|
|Nervous system disorders|
|Headache||8 (7.8%)||2 (1.8%)|
|Hemorrhage intracranial||3 (2.9%)||0|
|Respiratory, thoracic, and mediastinal disorders|
|Respiratory distress/dyspnea/hypoxia||2 (1.9%)||4 (3.7%)|
|Breath sounds abnormal/rates||1 (1.0%)||3 (2.8%)|
|Pulmonary edema||0||4 (3.7%)|
|Nausea/vomiting||4 (3.9%)||1 (0.9%)|
|Constipation||2 (1.9%)||6 (5.5%)|
|Tachycardia||3 (2.9%)||1 (0.9%)|
|International normalized ratio increased*||3 (2.9%)||0|
|Metabolism and nutrition disorders|
|Hypokalemia||2 (1.9%)||5 (4.6%)|
|Fluid overload†||1 (1.0%)||6 (5.5%)|
|Mental status changes||3 (2.9%)||0|
|Insomnia||1 (1.0%)||3 (2.8%)|
|Musculoskeletal and connective tissue disorders|
|Hypotension‡||5 (4.9%)||3 (2.8%)|
|Blood pressure increased/hypertension||3 (2.9%)||0|
|Injury, poisoning, and procedural complications|
|Skin laceration/contusion/subcutaneous hematoma||3 (2.9%)||1 (0.9%)|
|Transfusion reaction§||0||4 (3.7%)|
|Blood and lymphatic disorders|
|* Two subjects experienced an INR correction that was not sustained past 3 hours; One subject received a lower than protocol specified Kcentra dose.
† Includes fluid overload and cardiac failure congestive
‡ Includes orthostatic hypotension, hypotension, and hemorrhagic shock
§ Includes transfusion reaction, allergic transfusion reaction
|| Includes anemia, hemoglobin decreased, and hematocrit decreased
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.
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%. In a preliminary analysis of data from the plasmacontrolled RCT in urgent surgery/invasive procedures, there were a total of 3 subjects (3.4%) who died in the Kcentra group 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.
There were 6 subjects (5.8%, all non-related by investigator assessment) in the Kcentra group who experienced fluid overload in the plasma-controlled RCT in acute major bleeding and 14 (12.8%, 7 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 -15.8% to 1.8%.
Post-hoc subgroup analyses of the RCT in acute major bleeding were conducted according to whether subjects had a prior history of congestive heart failure (Table 4). The incidence of fluid overload events was 8.7% in the Kcentra group and 25% in the plasma group in the subgroup of subjects with a history of prior congestive heart failure. The 95% confidence interval (CI) for the Kcentra minus Plasma between-group difference in fluid overload in subjects with a prior history of congestive heart failure ranged from -33.0% to 0.9%. In subjects without a history of congestive heart failure, the Kcentra minus Plasma between-group difference in fluid overload was – 1.1% (95% CI -10.7 to 9.1%).
Table 4: Subjects with Fluid Overload Events by Prior History of Congestive Heart Failure in Plasma-Controlled Trial in Subjects with Acute Major Bleeding
|Subgroup||Major Bleeding Study|
|N||Fluid Overload N (%)||N||Fluid Overload N (%)|
|All subjects||103||6 (5.8)||109||14 (12.8)|
|With history of CHF||46||4 (8.7)||44||11 (25.0)|
|Without history of CHF||57||2 (3.5)||65||3 (4.6)|
There were 9 subjects (8.7%) in the Kcentra group who experienced possible thromboembolic events (TEEs) in the plasma-controlled RCT in acute major bleeding and 6 (5.5%) who had TEEs in the plasma group. The 95% confidence interval for the Kcentra minus Plasma between-group difference in possible TEE incidence ranged from -4.7% to 11.5%. 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 5 (4.9%) in the Kcentra group and 3 (2.8%) in the plasma group. When also considering the events which began during or within 72 hours of test product infusion, the incidence was 5 (4.9%) in the Kcentra group and 4 (3.7%) in the plasma group (95% confidence interval) for the Kcentra minus plasma difference ranged from -5.6% to 8.3%. TE events observed in the major bleeding study are shown in Table 5.
Table 5: Adverse Reactions (TEEs only) Following Kcentra or Plasma Administration in the Acute Major Bleeding RCT
|System Organ Class||No. (%) of subjects|
(N = 103)
(N = 109)
|Any possible TEE*||9 (8.7%)||6 (5.5%)|
|TEE Adverse reactions||6 (5.5%)‡||4 (3.7%)|
|Myocardial infarctiont||0||1 (0.9%)|
|Myocardial ischemia||0||2 (1.8%)|
|Nervous system disorders|
|Ischemic cerebrovascular accident (stroke)}||2 (1.9%)||0|
|Cerebrovascular disorder§||0||1 (0.9%)|
|Venous thrombosis calf||1 (1.0%)||0|
|Deep vein thrombosis (DVT) ||||1 (1.0%)||0|
|Fistula Clot||1 (1.0%)||0|
|Unknown Cause of Death (not confirmed TEE)|
|Sudden death||1 (1.0%)||0|
|* The tabulation of possible TEEs includes subjects with confirmed TEEs as well as 3 subjects in the Kcentra group that died of unknown causes on days 7, 31, and 38. The death on day 7 was considered possibly related to study product by the SAB and is tabulated as an adverse reaction. One additional subject who had received Kcentra, not listed in the table, had an upper extremity venous thrombosis in association with an indwelling catheter.
† One subject who had received plasma had an acute myocardial infarction (d1) rated moderate in severity, not considered serious.
‡ One subject, included in the tabulation, had an ischemic cerebrovascular accident on day 43 that was considered unrelated by the SAB.
§ One subject who had received plasma had a cerebrovascular disorder (d1) not considered serious, and
|| One Kcentra subject had two DVTs, both considered related by SAB.
Post-hoc subgroup analyses of the RCT in acute major bleeding were conducted according to whether subjects had a prior history of a thromboembolic event. Among subjects who received Kcentra, the incidence of TE events was 11.6% (95% confidence interval 6.0 –21.2%) in the subgroup of subjects with a history of prior TE event compared to 2.9% (95% confidence interval 0.5 – 14.9%) in the subgroup without such history. The incidence of TE events in the plasma group was 3.8% (95% confidence interval 1.3 – 10.6%) in the subgroup of subjects with a history of prior TE event compared to 10.0% (95% confidence interval 3.5 – 25.6%) in the subgroup without such history.
Table 6 shows treatment-emergent TE events by randomized treatment subgroup according to whether subjects had a prior history of TE event.
Table 6: Subjects with Thromboembolic Events by Prior History of TE Event in Plasma-Controlled RCT in Acute Major Bleeding Acute Major Bleeding
|Acute Major Bleeding Study|
|N||TE Events† N (%)||N||TE Events N (%)|
|All subjects||103||9 (8.7)||109||6 (5.5)|
|With history of TE event*||69||8 (11.6)||79||3 (3.8)|
|Without history of TE event||34||1 (2.9)||30||3 (10.0)|
|* History of prior TE event.
† One additional subject who had received Kcentra, not listed in the table, had an upper extremity venous thrombosis in association with an indwelling catheter.
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 events 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.
Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure.
The following adverse reactions have been identified and reported during postmarketing use of Kcentra outside the US since 1996.
- Hypersensitivity or Allergic reactions: flushing, urticaria, tachycardia, anxiety, angioedema, wheezing, nausea, vomiting, hypotension, tachypnea, dyspnea, pulmonary edema, and bronchospasm.
- Thromboembolic complications: arterial thromboembolic events (including acute myocardial infarction and arterial thrombosis), venous thromboembolic events (including pulmonary embolism and venous thrombosis), and disseminated intravascular coagulation.