Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Roche Registration GmbH, Emil-Barell-Strasse 1, 79639, Grenzach-Wyhlen, Germany
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
In order to improve traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Cases of thrombotic microangiopathy (TMA) were reported from a clinical trial in patients receiving Hemlibra prophylaxis when on average a cumulative amount of >100U/kg/24 hours of activated prothrombin complex concentrate (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 medications known to be a risk factor for the development of TMA (e.g. ciclosporin, quinine, tacrolimus).
Serious thrombotic events were reported from a clinical trial 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.
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 trials, no cases of TMA or thrombotic events were observed with use of activated recombinant human FVII (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).
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 monitor coagulation parameters during treatment, with specific considerations for FVIII chromogenic activity assays as described below.
Chromogenic factor VIII 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 factor VIII activity, or to measure anti FVIII inhibitors.
Emicizumab remains active in the presence of inhibitors against factor VIII and so will produce a false negative result in clotting based Bethesda assays for functional inhibition of factor VIII. Instead, a chromogenic Bethesda assay utilising a bovine based factor VIII 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 factor VIII 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 factor VIII 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 inhibitor titers |
| Bethesda assays (clotting-based) for FVIII inhibitor titers | Thrombin time (TT) |
| One-stage, aPTT-based, single-factor assays | One-stage, prothrombin time (PT)-based, single-factor assays |
| aPTT-based activated protein C resistance (APC-R) | Chromogenic-based single-factor assays other than FVIII1 |
| Activated clotting time (ACT) | 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.
There are no data in children <1 year of age. The developing hemostatic 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).
No adequate or well-controlled drug-drug interaction studies have been conducted with emicizumab.
Clinical experience indicates a drug interaction exists with emicizumab and aPCC (see sections 4.4 and 4.8).
There is a possibility for hypercoagulability with rFVIIa or FVIII with emicizumab based on preclinical experiments. Emicizumab increases coagulation potential, therefore the FVIIa or FVIII dose required to achieve hemostasis may be lower than when used without Hemlibra prophylaxis.
In case of thrombotic complication, the physician should consider discontinuing rFVIIa or FVIII and interrupt Hemlibra prophylaxis as clinically indicated. Further management should be tailored to the individual clinical circumstances.
Experience with concomitant administration of anti-fibrinolytics with aPCC or rFVIIa in patients receiving Hemlibra prophylaxis is limited. However, the possibility of thrombotic events should be considered when systemic anti-fibrinolytics are used in combination with aPCC or rFVIIa in patients receiving emicizumab.
Women of childbearing potential receiving Hemlibra should use effective contraception during, and for at least 6 months after cessation of Hemlibra treatment (see section 5.2).
There are no clinical studies of emicizumab use in pregnant women. Animal reproduction studies have not been conducted with Hemlibra. It is not known whether emicizumab can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Hemlibra should be used during pregnancy only if the potential benefit for the mother outweighs the potential risk to the fetus taking into account that, during pregnancy and after parturition, the risk for thrombosis is increased and that several pregnancy complications are linked to an increased risk for disseminated intravascular coagulation (DIC).
It is not known whether emicizumab is excreted in human milk. No studies have been conducted to assess the impact of emicizumab on milk production or its presence in breast milk. Human IgG is known to be present in human milk. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Hemlibra therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). No fertility data are available in humans. Thus, the effect of emicizumab on male and female fertility is unknown.
Hemlibra has no influence on the ability to drive and use machines.
The most serious adverse drug reactions (ADRs) reported from the clinical trials with Hemlibra were thrombotic microangiopathy (TMA) and thrombotic events, including cavernous sinus thrombosis (CST) and superficial vein thrombosis contemporaneous with skin necrosis (see below and section 4.4).
The most common ADRs reported in ≥10% of patients treated with at least one dose of Hemlibra were: injection site reactions (20%), arthralgia (15%) and headache (14%).
In total three patients (0.8%) in the clinical trials receiving Hemlibra prophylaxis withdrew from treatment due to ADRs, which were TMA, skin necrosis contemporaneous with superficial thrombophlebitis, and headache.
The following adverse drug reactions (ADRs) are based on pooled data from four phase III clinical trials (adult and adolescent studies [BH29884 – HAVEN 1, BH30071 – HAVEN 3, and BO39182 – HAVEN 4] and a paediatric study BH29992 – HAVEN 2]), in which a total of 373 male patients with haemophilia A received at least one dose of Hemlibra as routine prophylaxis. Two hundred and sixty-six (71%) were adults, 47 (13%) were adolescents (≥12 to <18 years), 55 (15%) were children (≥2 to <12 years) and five (1%) were infants and toddlers (1 month to <2 years). The median duration of exposure across the studies was 33 weeks (range: 0.1 to 94.3 weeks).
ADRs from the phase III clinical trials in patients who received Hemlibra are listed by MedDRA system organ class (Table 2). The corresponding frequency categories for each ADR are based on the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).
Table 2. Summary of adverse drug reactions from pooled HAVEN clinical trials with Hemlibra:
Uncommon: Thrombotic microangiopathy
Very common: Headache
Uncommon: Thrombophlebitis superficial, *Cavernous sinus thrombosis
Common: Diarrhoea
Uncommon: Skin necrosis
disorders
Very common: Arthralgia
Common: Myalgia
Very common: Injection site reaction
Common: Pyrexia
* Vascular disorders is a secondary SOC for cavernous sinus thrombosis.
In pooled phase III clinical trials, thrombotic microangiopathy (TMA) events were reported in less than 1% of patients (3/373) and in 9.7% of patients (3/31) who received at least one dose of aPCC while being treated with emicizumab. All 3 TMAs occurred when on average a cumulative amount of >100 U/Kg/24 hours of aPCC for 24 hours or more was administered during a treatment event (see section 4.4). Patients presented with thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury, without severe deficiencies in ADAMTS13 activity. One patient resumed Hemlibra following resolution of TMA without recurrence.
In pooled phase III clinical trials, serious thrombotic events were reported in less than 1% of patients (2/373) and in 6.5% of patients (2/31) who received at least one dose of aPCC while being treated with emicizumab. Both serious thrombotic events occurred when on average a cumulative amount of >100 U/Kg/24 hours of aPCC for 24 hours or more was administered during a treatment event. One patient resumed Hemlibra following resolution of the thrombotic event without recurrence (see section 4.4).
There were 82 instances of aPCC treatment* in patients receiving Hemlibra prophylaxis, of which eight instances (10%) consisted of on average a cumulative amount of >100 U/kg/24 hours of aPCC for 24 hours or more; two of the eight instances were associated with thrombotic events and three of the eight instances were associated with TMA (Table 3). No TMA or thrombotic events were associated with the remaining instances of aPCC treatment. Of all instances of aPCC treatment, 68% consisted of only one infusion <100 U/kg.
Table 3. Characterisation of aPCC treatment* in the pooled phase III clinical studies:
| Duration of aPCC treatment | Average cumulative amount of aPCC over 24 hours (U/kg/24 hours)) | ||
|---|---|---|---|
| <50 | 50–100 | >100 | |
| <24 hours | 9 | 47 | 13 |
| 24-48 hours | 0 | 3 | 1b |
| >48 hours | 1 | 1 | 7a,a,a,b |
* An instance of aPCC treatment is defined as all doses of aPCC received by a patient, for any reason, until there was a 36-hour treatment-free break. Includes all instances of aPCC treatment excluding those in the first 7 days and those that occurred 30 days after the discontinuation of Hemlibra.
a Thrombotic microangiopathy
b Thrombotic event
Injection site reactions (ISRs) were reported very commonly (20%) from clinical trials. All ISRs observed in the Hemlibra clinical trials were reported as being non-serious and mild to moderate in intensity, and 95% resolved without treatment. The most commonly reported ISR symptoms were injection site erythema (11%), injection site pain (4%) and injection site pruritus (3%).
The paediatric population studied comprises a total of 107 patients, of which 5 (5%) were infants and toddlers (1 month to less than 2 years of age), 55 (51%) were children (from 2 to less than 12 years of age) and 47 (44%) were adolescents (from 12 to less than 18 years old). The safety profile of Hemlibra was overall consistent between infants, children, adolescents, and adults.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
No incompatibilities between Hemlibra and polypropylene or polycarbonate syringes , polycarbonate vial adapters and stainless steel needles have been observed.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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