KCENTRA Powder for solution for infusion, lyophilized Ref.[50986] Active ingredients: Coagulation factor IX complex Protein C Protein S

5.1 Hypersensitivity Reactions

Hypersensitivity reactions including flushing, urticaria, tachycardia, anxiety, angioedema, wheezing, nausea, vomiting, hypotension, tachypnea, dyspnea, pulmonary edema, and bronchospasm have been observed with KCENTRA.

If severe allergic reaction or anaphylactic type reactions occur, immediately discontinue administration, and institute appropriate treatment.

5.2 Thromboembolic Risk/Complications

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.

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) and Clinical Studies (14)].

In a postmarketing observational study, there was no significant difference in the risk of post-treatment thromboembolic events after receiving KCENTRA compared with plasma therapy for VKA-associated acute major bleeding [see Adverse Reactions (6.2)].

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].

5.3 Transmissible Infectious Agents

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 (CJD) 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.

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.

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.

The most common adverse reactions (ARs) (frequency ≥2.8%) observed in subjects receiving KCENTRA were headache, nausea/vomiting, hypotension, and anemia.

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 (5.1)]
• Arterial and venous thromboembolic complications [see Boxed Warning and Warnings and Precautions (5.2)]
• Possible transmission of infectious agents [see Warnings and Precautions (5.3)]

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 and Urgent Surgery/Invasive Procedures RCTs (see Table 2).

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 2. Adverse Reactions Reported in more than 5 Subjects (≥2.8%) Following KCENTRA or Plasma Administration in RCTs:

^* Includes fluid overload and cardiac failure congestive
^† Includes orthostatic hypotension, hypotension, and hemorrhagic shock
^‡ 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%. 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.

Fluid Overload

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%.

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 3.

Table 3. Subjects with Fluid Overload Events by Prior History of Congestive Heart Failure in RCTs:

Thromboembolic Events

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.

TE events observed in the acute major bleeding and the urgent surgery/invasive procedures RCTs are shown in Table 4.

Table 4. Adverse Reactions (TEEs only) Following KCENTRA or Plasma Administration in RCTs:

^* The tabulation of possible TEEs includes subjects with confirmed TEEs as well as 3 subjects in the Acute Major Bleeding RCT KCENTRA group that died of unknown causes on days 7, 31, and 38 and 1 subject in the Urgent Surgery/Invasive Procedures RCT plasma group that died of unknown causes on day 18. The death on day 7 was considered possibly related to study product by the SAB and is tabulated as an adverse reaction.

Subgroup analyses of the RCTs according to whether subjects with thromboembolic events had a prior history of a thromboembolic event are presented in Table 5.

Table 5. Subjects with Thromboembolic Events by Prior History of TE Event in RCTs:

^* One additional subject in the Acute Major Bleeding RCT who had received KCENTRA, not listed in the table, had an upper extremity venous thrombosis in association with an indwelling catheter. Two additional subjects in the Urgent Surgery/Invasive Procedures RCT who had received KCENTRA, not listed in the table, had non-intravascular events (catheter-related/IVC filter insertion).
^† History of prior TE event greater than 3 months from study entry (TE event within 3 months not studied).

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.

In a postmarketing observational study, the risk of TEEs was assessed using Kaiser Permanente’s databases in a matched, real-world cohort of hospitalized adults receiving either KCENTRA or plasma for VKA-associated major bleeding. For the primary analysis, 1119 KCENTRA patients and 1119 historical plasma patients with no recent history of TEEs were grouped in 1:1 individually matched cohort based on propensity scores. During the 45-day follow-up after acute VKA reversal, there was no statistically significant difference in the adjusted risk of TEEs between KCENTRA-treated patients and plasma-treated patients. . In a secondary analysis, 101 KCENTRA patients and 101 historical plasma patients with a recent history of TEEs diagnosed ≤90 days before study entry were also grouped in 1:1 individually matched cohort based on propensity scores. During the 45-day follow-up after acute VKA reversal, there was no statistically significant difference in the adjusted risk of TEEs between KCENTRA-treated patients and plasma-treated patients.

Risk Summary

There are no data with KCENTRA use in pregnancy to inform on drug-associated risk. Animal reproduction studies have not been conducted with KCENTRA. It is 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.

In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Risk Summary

There is no information regarding the excretion of KCENTRA in human milk, the effect on the breastfed infant, or the effects on milk production. Because many drugs are excreted in human milk, use KCENTRA only if clearly needed when treating a nursing woman.

The safety and efficacy of KCENTRA in the pediatric population has not been studied.

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.

8.6 Congenital Factor Deficiencies

KCENTRA has not been studied in patients with congenital factor deficiencies.