Dave is an associate professor at Duquesne University School of Pharmacy and emergency medicine pharmacist at UPMC Mercy Hospital. He completed residency training at The Johns Hopkins Hospital and Maimonides Medical Center in Brooklyn, NY. His practice interests include medication dosing in patients that are obese and pain management in the ED. Find him on Twitter @DEZ_EM_Pharm
The Pre-brief
Whether you are a new student, resident, or experienced clinician, you probably have heard of “PCC” or “Kcentra®” and used it a couple of times for anticoagulation reversal. But what exactly is it? How is it prepared? What are some of the “fun” pharmacy intricacies with it? Well, have no fear, this post will give a background tutorial on Kcentra® from a friendly pharmacist perspective.
So, what is it exactly?
Prothrombin Complex Concentrate (PCC) human is the technical generic name for Kcentra® (Kcentra® is much cooler and easier to say). It was first approved by the FDA in 2013 and is indicated for urgent reversal of vitamin K antagonist (e.g., warfarin) in adults with acute major bleeding or need for an urgent surgery/invasive procedure. It is known as a 4-Factor PCC as it contains Factors II, VII, IX, and X. What a coincidence as those are the vitamin K-dependent factors that warfarin inhibits! Kcentra® is not the first PCC to come to the market. We have had 3-Factor PCC’s that are approved for Factor deficiencies related to hemophilia (brand names such as Profilnine®, etc..). These products primarily contain Factors II, IX, and X. One of the key things to remember though is the factors are inactivated and require activation by the coagulation cascade. I point this out because there are other products out there, like NovoSeven® that have activated VIIa and FEIBA® (or aPCC) which has Factors II, VIIa, IX, X where factor VII is activated (denoted with an “a” next to the number).
How is it made?
Kcentra® is prepared from human U.S. Source Plasmas (i.e. human blood) and undergoes purification, heat-treated, nano-filtered, and lyophilized. Couple of questions that I get about this fact:
- Do I have to type & screen the patient?
- Answer: Nope, the end product is simply the factors and other components listed in Table 1.
- Is there a risk of transmission of viruses?
- Answer: Technically yes but the manufacturing process includes multiple steps in <almost> eliminating this concern but it can’t be entirely ruled out.
What is in Kcentra®?
Kcentra® has Factors II, VII, IX, and X and that is why it’s known as a 4-factor PCC but that is not all that it has. See Table 1 adapted from the Prescribing Information (PI) for all of the components.
Two important points: 1) Note the inclusion of Protein C, Protein S, and antithrombin III & their role in the coagulation cascade. 2) More importantly though, is the inclusion of heparin to prevent activation of the clotting factors. This means if you have a patient with a history of heparin-induced thrombocytopenia (HIT) then Kcentra® is contraindicated and an alternative reversal strategy should be used. I never thought I would have to use Kcentra® in a patient with a history of HIT until it actually happened. So, make sure you are aware or know where to find your institution’s alternative reversal strategy. Some options include A) 3-factor PCC + VIIa B) 3-factor PCC by itself C) Fresh frozen plasma or D) FEIBA (aPCC)
How is Kcentra® dosed?
Kcentra® has many factors in each vial so what is the dosing based off of? The dosing is actually based upon the Factor IX content and is labeled on the vial. The FDA labeled dosing for warfarin reversal is based upon the patient’s weight (capped at 100kg) and the patient’s INR (INR 2 – <4 = 25 units/kg – max of 2,500 units; INR 4-6 = 35 units/kg- max of 3,500 units, and INR >6 = 50 units/kg, max of 5,000 units). There is a legitimate debate for using the package labeled dosing vs flat dosing for warfarin reversal, reversal of anti-Xa inhibitors, and use in other coagulable conditions but that is beyond this summary.
Fun pharmacy fact though, Kcentra® is prepared in two vial sizes: 500 units and 1,000 units, but these are not exact amounts and differ from one lot to the next. The 500-unit vial ranges from 400-620 units/vial and the 1,000 unit ranges from 800-1,240 units/vial.1 Why do I point this out? If your institution prepares Kcentra® in a central pharmacy they may be allowed to round the dose based upon the vial lots for cost savings (ex: you order 2,500 units but the end product is 2,621 units). Lastly, there are some institutions that may use off-label “flat dosing” like 1,000 or 1,500 units. So, it’s more likely than not they are not getting that exact amount. Does that matter? Probably not, but it is important to know the vials differ in potency from one lot to the next.
How is Kcentra®administered?
Kcentra® is administered via IV infusion and there isn’t compatibility data with other medications. The PI recommends a rate of 0.12 mL/kg/min (~3 units/kg/min) up to a maximum of 8.4 mL/min (~210 units/min). This can get a little confusing as the unit/mL depends on the lot. At my institution, we simplified the infusion time so it is always over 25 minutes regardless of the dose and given via IV pump. Since the maximum dose is 5,000 units and the maximum rate is 210 units/min that would be ~24 mins and under the recommended max rate. Hypersensitivity reactions can occur with Kcentra® but are fortunately very rare. Other adverse reactions to be aware of are thromboembolic events such as stroke, pulmonary embolism, and deep vein
The Debrief
- Kcentra® is a 4-factor PCC that is FDA approved for the reversal of warfarin
- Kcentra® contains factors II, VII, IX, and X but also contain other components like heparin, Antithrombin III, protein C, and Protein S
- Kcentra is dosed based off of the Factor IX content and this can vary to a small extent from one lot to the next
References
- Kcentra. Package insert. CSL Behring; 2018.
- Profilnine SD. Package insert. Grifols Biologicals; 2018.
- NovoSeven RT. Package insert. Novo Nordisk; 2020.
- FEIBA. Package Insert. Baxalta US; 2020.
