HEMLIBRA Solution for injection Ref.[8987] Active ingredients: Emicizumab

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:

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).

No adequate or well-controlled interaction studies have been conducted with emicizumab.

Clinical experience indicates a medicinal product 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 haemostasis 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.

• Decision about dose modifications should take into account the half-life of medicinal products; specifically, interruption of emicizumab may not have an immediate effect.
• Monitoring using a FVIII chromogenic assay may guide the administration of coagulation factors, and testing for thrombophilic traits may be considered.

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/Contraception

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).

Pregnancy

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).

Breast-feeding

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.

Fertility

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 or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The overall safety profile of Hemlibra is based on data from clinical studies and post-marketing surveillance. The most serious adverse drug reactions (ADRs) reported from the clinical studies 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 (19.4%), arthralgia (14.2%) and headache (14.0%).

In total three patients (0.7%) in the clinical studies receiving Hemlibra prophylaxis withdrew from treatment due to ADRs, which were TMA, skin necrosis contemporaneous with superficial thrombophlebitis, and headache.

Tabulated list of adverse drug reactions

The following adverse drug reactions (ADRs) are based on data from post-marketing surveillance and pooled data from five phase III clinical studies (adult and adolescent studies [BH29884 – HAVEN 1, BH30071 – HAVEN 3, and BO39182 – HAVEN 4], an all-age group study [BO41423 – HAVEN 6], and a paediatric study [BH29992 – HAVEN 2]), in which a total of 444 patients with haemophilia A received at least one dose of Hemlibra as routine prophylaxis (see section 5.1). Three hundred and seven (69.1%) of the clinical study participants were adults (of which two were female), 61 (13.7%) were adolescents (≥12 to <18 years), 71 (16.0%) were children (≥2 to <12 years) and five (1.1%) were infants and toddlers (1 month to <2 years). The median duration of exposure across the studies was 32 weeks (range: 0.1 to 94.3 weeks).

ADRs from the phase III clinical studies and post-marketing surveillance 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 studies and post-marketing surveillance with Hemlibra:

^a Vascular disorders is a secondary SOC for cavernous sinus thrombosis.
^b Loss of efficacy (therapeutic response decreased) manifest as an increase in breakthrough bleeding has been reported with neutralising anti-emicizumab antibodies with decreasing emicizumab concentration (see Description of selected adverse drug reactions and sections 4.4 and 5.1).

Description of selected adverse drug reactions

Thrombotic microangiopathy

In pooled phase III clinical studies, TMA events were reported in less than 1% of patients (3/444) 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.

Thrombotic events

In pooled phase III clinical studies, serious thrombotic events were reported in less than 1% of patients (2/444) 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).

Characterization of the interaction between emicizumab and aPCC treatment in pivotal clinical studies

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:

^* 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

Injection site reactions (ISRs) were reported very commonly (19.4%) from the pooled phase III clinical studies. All ISRs observed in the Hemlibra clinical studies were reported as being non-serious and mild to moderate in intensity, and 94.9% resolved without treatment. The most commonly reported ISR symptoms were injection site erythema (10.6%), injection site pain (4.1%), injection site pruritus (2.9%) and injection site swelling (2.7%).

Immunogenicity

In the pooled phase III clinical studies with Hemlibra, development of neutralising anti-emicizumab antibodies associated with decreasing emicizumab concentration was uncommon (see section 5.1). One patient, who developed neutralising anti-emicizumab antibodies with decreasing emicizumab concentration, experienced loss of efficacy (manifest as breakthrough bleeding) after five weeks of treatment and later discontinued Hemlibra treatment (see sections 4.4 and 5.1).

Paediatric population

The paediatric population studied comprises a total of 137 patients, of which 5 (3.6%) were infants and toddlers (1 month to less than 2 years of age), 71 (51.8%) were children (from 2 to less than 12 years of age) and 61 (44.5%) 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 of suspected adverse reactions

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 and stainless steel needles have been observed.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.