Dosing and Safety for Emicizumab plus aPCC
JANUARY 02, 2019
MD Magazine Staff
Meera B. Chitlur, MD: The major complications associated with emicizumab treatment were the development of thrombotic episodes as well as TMA, or thrombotic microangiopathy. These were unexpected complications, especially the TMA, in patients who were treated with emicizumab. It was noted only in those patients who received aPCCs in large doses over a prolonged period of time. The thought process is that there’s potentially a significant increase in thrombin generation associated with background emicizumab and the addition of activated PCCs and that prolonged treatment in these situations resulted in excessive thrombin generation, which resulted in TMAs as well as thrombotic episodes. There were also some episodes that were questioned as being thrombotic but were treated as bleeds, which potentially led to worsening of thrombin generation and worsening of thrombosis. TMA and thrombosis are the major complications associated with emicizumab administration.
Since both TMAs and thrombotic episodes were seen in patients who received excessive or high doses of aPCCs for prolonged periods of time—specifically greater than 100 u/kg per day, typically for more than 24 hours—the black box warning includes that we should not use doses that exceed 100 u/kg per day and try to restrict the use to less than 24 hours. If higher doses or prolonged use of aPCCs are required in the setting of a patient who’s on emicizumab, it is recommended that patients be followed very closely by the hematologist and even considered for admission to the hospital, so that they can be monitored for the development of TMAs as well as thrombosis.
The combination of emicizumab and aPCCs may be required in some patients. It is well recognized that there are patients who do not necessarily respond to recombinant factor VIIa, but it is still recommended that we try recombinant factor VIIa as the first drug of choice for management of breakthrough bleeding. If this does not work in a patient, or if the bleed is severe or significant such that the recombinant VIIa is not working, we should consider the use of aPCCs, which should be managed by a hematologist who’s well versed with the associated complications in this situation.
The development of TMAs and thrombotic episodes was seen in patients who use high doses of aPCCs with emicizumab. If these complications occur, the first thing to do of course is not to give the next dose of emicizumab. But in addition to that, most of these are managed symptomatically with supportive care. TMAs especially might require hydration and monitoring of the hemolysis that is being observed in these patients. They may require inpatient hydration and monitoring for worsening of renal failure or development of CNS [central nervous system] pathology.
In terms of thrombotic episodes, they may require anticoagulant therapy. But so far, I do not believe that any of these patients have been treated with anticoagulation while receiving emicizumab. Supportive care has been found to be effective, but that will also depend on the location of the thrombotic episode and would need to be determined on a case-by-case basis.
Breakthrough bleeding in the setting of emicizumab should be handled individually on a patient-by-patient basis, as well as on a bleed-by-bleed basis. Severe bleeding should be treated like it was treated before, in that you should immediately use clotting factor concentrates. The noninhibitor population would be treated with doses that they used previously. In the inhibitor population, on the other hand, we should be careful about the doses we use. If you’re using an aPCC, our doses should not exceed 100 u/kg per day. In the noninhibitor population, this is not as much of a concern because the factor VIII would replace the emicizumab as soon as it is infused. We do not anticipate that there would be any complications related to the concomitant use of recombinant factor VIII with emicizumab. Most of these complications would only occur in patients who are using aPCCs in conjunction with emicizumab.
Minor bleeding episodes, on the other hand, may not require any treatment in these patients because emicizumab may provide effective clotting potential. Small bleeds may be monitored without treatment and only be treated if any worsening of symptoms occurs.
Transcript edited for clarity.