Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Traceability
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Thrombotic microangiopathy associated with Hemlibra and aPCC

Cases of thrombotic microangiopathy (TMA) were reported from a clinical study in patients receiving Hemlibra prophylaxis when on average a cumulative amount of >100U/kg/24 hours of aPCC for 24 hours or more was administered (see section 4.8). Treatment for the TMA events included supportive care with or without plasmapheresis and haemodialysis. Evidence of improvement was seen within one week following discontinuation of aPCC and interruption of Hemlibra. This rapid improvement is distinct from the usual clinical course observed in atypical hemolytic uremic syndrome and classic TMAs, such as thrombotic thrombocytopenic purpura (see section 4.8). One patient resumed Hemlibra following resolution of TMA and continued to be treated safely.

Patients receiving Hemlibra prophylaxis should be monitored for the development of TMA when administering aPCC. The physician should immediately discontinue aPCC and interrupt Hemlibra therapy if clinical symptoms and/or laboratory findings consistent with TMA occur, and manage as clinically indicated. Physicians and patients/caregivers should weigh the benefits and risks of resuming Hemlibra prophylaxis following complete resolution of TMA on a case-by-case basis. In case a bypassing agent is indicated in a patient receiving Hemlibra prophylaxis, see below for dosing guidance on the use of bypassing agents.

Caution should be used when treating patients who are at high risk for TMA (e.g. have a previous medical history or family history of TMA), or those who are receiving concomitant medicinal products known to be a risk factor for the development of TMA (e.g. ciclosporin, quinine, tacrolimus).

Thromboembolism associated with Hemlibra and aPCC

Serious thrombotic events were reported from a clinical study in patients receiving Hemlibra prophylaxis when on average a cumulative amount of >100U/kg/24 hours of aPCC for 24 hours or more was administered (see section 4.8). No cases required anticoagulation therapy. Following discontinuation of aPCC and interruption of Hemlibra, evidence of improvement or resolution was seen within one month (see section 4.8). One patient resumed Hemlibra following resolution of thrombotic event and continued to be treated safely.

Patients receiving Hemlibra prophylaxis should be monitored for the development of thromboembolism when administering aPCC. The physician should immediately discontinue aPCC and interrupt Hemlibra therapy if clinical symptoms, imaging, and/or laboratory findings consistent with thrombotic events occur, and manage as clinically indicated. Physicians and patients/caregivers should weigh the benefits and risks of resuming Hemlibra prophylaxis following complete resolution of thrombotic events on a case-by-case basis. In case a bypassing agent is indicated in a patient receiving Hemlibra prophylaxis, see below for dosing guidance on the use of bypassing agents.

Guidance on the use of bypassing agents in patients receiving Hemlibra prophylaxis 
Treatment with bypassing agents should be discontinued the day before starting Hemlibra therapy.


Physicians should discuss with all patients and/or caregivers the exact dose and schedule of bypassing agents to use, if required while receiving Hemlibra prophylaxis.

Hemlibra increases the patient’s coagulation potential. The bypassing agent dose required may therefore be lower than that used without Hemlibra prophylaxis. The dose and duration of treatment with bypassing agents will depend on the location and extent of bleeding, and the patient’s clinical condition. Use of aPCC should be avoided unless no other treatment options/alternatives are available.
If aPCC is indicated in a patient receiving Hemlibra prophylaxis, the initial dose should not exceed 50 U/kg and laboratory monitoring is recommended (including but not restricted to renal monitoring, platelet testing, and evaluation of thrombosis). If bleeding is not controlled with the initial dose of aPCC up to 50 U/kg, additional aPCC doses should be administered under medical guidance or supervision with consideration made to laboratory monitoring for the diagnosis of TMA or thromboembolism and verification of bleeds prior to repeated dosing. The total aPCC dose should not exceed 100 U/kg in the first 24-hours of treatment. Treating physicians must carefully weigh the risk of TMA and thromboembolism against the risk of bleeding when considering aPCC treatment beyond a maximum of 100 U/kg in the first 24-hours.

In clinical studies, no cases of TMA or thrombotic events were observed with use of rFVIIa alone in patients receiving Hemlibra prophylaxis.

Bypassing agent dosing guidance should be followed for at least 6 months following discontinuation of Hemlibra prophylaxis (see section 5.2).

Immunogenicity

Development of neutralising anti-emicizumab antibodies with decreasing emicizumab concentration leading to loss of efficacy has been uncommonly observed during clinical studies (see sections 4.8 and 5.1). Patients with clinical signs of loss of efficacy (e.g. increase in breakthrough bleeding events), should be promptly evaluated to assess the etiology and other therapeutic options should be considered if neutralising anti-emicizumab antibodies are suspected.

Effects of emicizumab on coagulation tests

Emicizumab restores the tenase cofactor activity of missing activated factor VIII (FVIIIa).
Coagulation laboratory tests based on intrinsic clotting, including the activated clotting time (ACT), activated partial thromboplastin time (e.g. aPTT), measure the total clotting time including time needed for activation of FVIII to FVIIIa by thrombin. Such intrinsic pathway based tests will yield overly shortened clotting times with emicizumab, which does not require activation by thrombin. The overly shortened intrinsic clotting time will then disturb all single factor assays based on aPTT, such as the one stage FVIII activity assay (see section 4.4, Table 1). However, single factor assays utilising chromogenic or immuno-based methods are not affected by emicizumab and may be used to assess coagulation parameters during treatment, with specific considerations for FVIII chromogenic activity assays as described below.

Chromogenic FVIII activity tests may be manufactured with either human or bovine coagulation proteins. Assays containing human coagulation factors are responsive to emicizumab but may overestimate the clinical haemostatic potential of emicizumab. In contrast, assays containing bovine coagulation factors are insensitive to emicizumab (no activity measured) and can be used to monitor endogenous or infused FVIII activity, or to measure anti FVIII inhibitors.

Emicizumab remains active in the presence of inhibitors against FVIII and so will produce a false negative result in clotting based Bethesda assays for functional inhibition of FVIII. Instead, a chromogenic Bethesda assay utilising a bovine based FVIII chromogenic test that is insensitive to emicizumab may be used.

These two pharmacodynamic markers do not reflect the true haemostatic effect of emicizumab in vivo (aPTT is overly shortened and reported FVIII activity may be overestimated) but provide a relative indication of the pro-coagulant effect of emicizumab.

In summary, intrinsic pathway clotting-based laboratory test results in patients treated with Hemlibra should not be used to monitor its activity, determine dosing for factor replacement or anti-coagulation, or measure FVIII inhibitors titers. Caution should be taken if intrinsic pathway clotting based laboratory tests are used, as misinterpretation of their results may lead to under-treatment of patients experiencing bleeding episodes, which can potentially result in severe or life-threatening bleeds.

Laboratory tests affected and unaffected by emicizumab are shown in Table 1 below. Due to its long half-life, these effects on coagulation assays may persist for up to 6 months after the last dose (see section 5.2).

Table 1      Coagulation test results affected and unaffected by emicizumab 
Results affected by emicizumab                      Results unaffected by emicizumab 
- Activated partial thromboplastin time (aPTT)     - Bethesda assays (bovine chromogenic) for FVIII - Bethesda assays (clotting-based) for FVIII       inhibitor titers inhibitor titers                                   - Thrombin time (TT) - One-stage, aPTT-based, single-factor assays      - One-stage, prothrombin time (PT)-based, - aPTT-based activated protein C resistance        single-factor assays (APC-R)                                            - Chromogenic-based single-factor assays other - Activated clotting time (ACT)                    than FVIII1
- Immuno-based assays (e.g. ELISA,
turbidimetric methods)
- Genetic tests of coagulation factors (e.g. Factor
V Leiden, Prothrombin 20210)
1
For important considerations regarding FVIII chromogenic activity assays, see section 4.4.

Paediatric population

There are no data in children <1 year of age. The developing haemostatic system in neonates and infants is dynamic and evolving, and the relative concentrations of pro- and anticoagulant proteins in these patients should be taken into consideration when making a benefit-risk assessment, including potential risk of thrombosis (e.g. central venous catheter-related thrombosis).

Effects on Driving

4.7    Effects on ability to drive and use machines

Hemlibra has no or negligible influence on the ability to drive and use machines.