HEMLIBRA 150mg/ml 150mg / 1ml injectible solution medication leaflet

Hemlibra 30 mg/mL solution for injection

Hemlibra 150 mg/mL solution for injection

Hemlibra 30 mg/mL solution for injection

Each mL of solution contains 30 mg of emicizumab*

Each vial of 0.4 mL contains 12 mg of emicizumab at a concentration of 30 mg/mL.

Each vial of 1 mL contains 30 mg of emicizumab at a concentration of 30 mg/mL.

Hemlibra 150 mg/mL solution for injection

Each mL of solution contains 150 mg of emicizumab*

Each vial of 0.4 mL contains 60 mg of emicizumab at a concentration of 150 mg/mL.

Each vial of 0.7 mL contains 105 mg of emicizumab at a concentration of 150 mg/mL.

Each vial of 1 mL contains 150 mg of emicizumab at a concentration of 150 mg/mL.

Each vial of 2 mL contains 300 mg of emicizumab at a concentration of 150 mg/mL.

* Emicizumab is a humanised monoclonal modified immunoglobulin G4 (IgG4) antibody producedusing recombinant DNA technology in mammalian Chinese Hamster Ovary (CHO) cells

For the full list of excipients, see section 6.1

Solution for injection.

Colourless to slightly yellow solution.

Hemlibra is indicated for routine prophylaxis of bleeding episodes in patients with haemophilia A(congenital factor VIII deficiency):● with factor VIII inhibitors● without factor VIII inhibitors who have:

- severe disease (FVIII < 1%)

- moderate disease (FVIII ≥ 1% and ≤ 5%) with severe bleeding phenotype.

Hemlibra can be used in all age groups.

Treatment should be initiated under the supervision of a physician experienced in the treatment ofhaemophilia and/or bleeding disorders.

Treatment (including routine prophylaxis) with bypassing agents (e.g. activated prothrombin complexconcentrate [aPCC] and activated recombinant human FVII [rFVIIa]) should be discontinued the daybefore starting Hemlibra therapy (see section 4.4).

Factor VIII (FVIII) prophylaxis may be continued for the first 7 days of Hemlibra treatment.

The recommended dose is 3 mg/kg once weekly for the first 4 weeks (loading dose), followed by amaintenance dose from week 5, of either 1.5 mg/kg once weekly, 3 mg/kg every two weeks, or6 mg/kg every four weeks, all doses administered as a subcutaneous injection.

The loading dose regimen is the same, irrespective of the maintenance dose regimen.

The maintenance dose regimen should be selected based on physician and patient/caregiver dosingregimen preference to support adherence.

The patient dose (in mg) and volume (in mL) should be calculated as follows:

● Loading dose (3 mg/kg) once weekly for the first 4 weeks:

Patient bodyweight (kg) x dose (3 mg/kg) = total amount (mg) of emicizumab to beadministered● Followed by a maintenance dose from week 5, of either 1.5 mg/kg once weekly, 3 mg/kg everytwo weeks or 6 mg/kg every four weeks:

Patient bodyweight (kg) x dose (1.5; 3 or 6 mg/kg) = total amount (mg) of emicizumab to beadministered

The total volume of Hemlibra to be injected subcutaneously is calculated as follows:

Total amount (mg) of emicizumab to be administered ÷ vial concentration (mg/mL) = total volume of

Hemlibra (mL) to be injected.

Different Hemlibra concentrations (30 mg/mL and 150 mg/mL) should not be combined in the samesyringe when making up the total volume to be administered.

A volume greater than 2 mL per injection should not be administered.

Examples:

Patient’s bodyweight of 16 kg, under a maintenance dose regimen of 1.5 mg/kg once weekly:● Loading dose (first 4 weeks) example: 16 kg x 3 mg/kg = 48 mg of emicizumab needed for theloading dose.● To calculate the volume to be administered divide calculated dose 48 mg by 150 mg/mL: 48 mgof emicizumab ÷ 150 mg/mL = 0.32 mL of 150 mg/mL Hemlibra concentration to be injected.● Choose appropriate dose and volume from vial strengths available.

● Maintenance dose (from week 5 on) example: 16 kg x 1.5 mg/kg = 24 mg of emicizumabneeded for the maintenance dose.● To calculate the volume to be administered divide calculated dose 24 mg by 30 mg/mL: 24 mgof emicizumab ÷ 30 mg/mL = 0.8 mL of 30 mg/mL Hemlibra concentration to be injected onceweekly.

● Choose appropriate dose and volume from vial strengths available.

Patient’s bodyweight of 40 kg, under a maintenance dose regimen of 3 mg/kg every two weeks:● Loading dose (first 4 weeks) example: 40 kg x 3 mg/kg = 120 mg of emicizumab needed for theloading dose.● To calculate the volume to be administered divide calculated dose 120 mg by 150 mg/mL:

120 mg of emicizumab ÷ 150 mg/mL = 0.8 mL of 150 mg/mL Hemlibra concentration to beinjected.

● Choose appropriate dose and volume from vial strengths available.

● Maintenance dose (from week 5 on) example: 40 kg x 3 mg/kg = 120 mg of emicizumab neededfor the maintenance dose.● To calculate the volume to be administered divide calculated dose 120 mg by 150 mg/mL:

120 mg of emicizumab ÷ 150 mg/mL = 0.8 mL of 150 mg/mL Hemlibra concentration to beinjected every two weeks.

● Choose appropriate dose and volume from vial strengths available.

Patient’s bodyweight of 60 kg, under a maintenance dose regimen of 6 mg/kg every four weeks:● Loading dose (first 4 weeks) example: 60 kg x 3 mg/kg = 180 mg of emicizumab needed for theloading dose.● To calculate the volume to be administered divide calculated dose 180 mg by 150 mg/mL:

180 mg of emicizumab ÷ 150 mg/mL = 1.20 mL of 150 mg/mL Hemlibra concentration to beinjected.

● Choose appropriate dose and volume from vial strengths available.

● Maintenance dose (from week 5 on) example: 60 kg x 6 mg/kg = 360 mg of emicizumab neededfor the maintenance dose.● To calculate the volume to be administered divide calculated dose 360 mg by 150 mg/mL:

360 mg of emicizumab ÷ 150 mg/mL = 2.4 mL of 150 mg/mL Hemlibra concentration to beinjected every four weeks.

● Choose appropriate dose and volume from vial strengths available.

Hemlibra is intended for long-term prophylactic treatment.

No dose adjustments of Hemlibra are recommended.

If a patient misses a scheduled subcutaneous injection of Hemlibra, the patient should be instructed totake the missed dose as soon as possible, up to a day before the day of the next scheduled dose. Thepatient should then administer the next dose on the usual scheduled dosing day. The patient should nottake two doses on the same day to make up for a missed dose.

Paediatric

No dose adjustments are recommended in paediatric patients (see section 5.2). There are no data inpatients less than 1 year of age.

No dose adjustments are recommended in patients ≥ 65 years of age (see sections 5.1 and 5.2). Thereare no data in patients over 77 years old.

No dose adjustments are recommended in patients with mild, renal or hepatic impairment (seesection 5.2). There are limited data available on the use of Hemlibra in patients with moderate renal orhepatic impairment. Emicizumab has not been studied in patients with severe renal or hepaticimpairment

Management in the perioperative setting

The safety and efficacy of emicizumab have not been formally evaluated in the surgical setting.

Patients have had surgical procedures without discontinuing emicizumab prophylaxis in clinicalstudies.

If bypassing agents (e.g. aPCC and rFVIIa) are required in the perioperative period, please refer to thedosing guidance on the use of bypassing agents in section 4.4. If FVIII is required in the perioperativeperiod, please refer to section 4.5.

When monitoring a patient’s underlying haemostatic activity, please refer to section 4.4 for laboratorytests unaffected by emicizumab.

Immune tolerance induction (ITI)

The safety and efficacy of emicizumab in patients receiving ongoing immune tolerance induction havenot yet been established. No data are available.

Hemlibra is for subcutaneous use only, and it should be administered using appropriate aseptictechnique (see section 6.6).

The injection should be restricted to the recommended injection sites: the abdomen, the upper outerarms and the thighs (see section 5.2).

Administration of Hemlibra subcutaneous injection in the upper outer arm should be performed by acaregiver or healthcare professional.

Alternating the site of injection may help prevent or reduce injection site reactions (see section 4.8).

Hemlibra subcutaneous injection should not be administered into areas where the skin is red, bruised,tender or hard, or areas where there are moles or scars.

During treatment with Hemlibra, other medicinal products for subcutaneous administration should,preferably, be injected at different anatomical sites.

Administration by the patient and/or caregiver

Hemlibra is intended for use under the guidance of a healthcare professional. After proper training insubcutaneous injection technique, a patient may self-inject Hemlibra, or the patient’s caregiver mayadminister it, if their physician determines that it is appropriate.

The physician and the caregiver should determine the appropriateness of the child self-injecting

Hemlibra. However, self-administration is not recommended for children below 7 years of age.

For comprehensive instructions on the administration of Hemlibra, see section 6.6 and package leaflet.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

In order to improve the traceability of biological medicinal products, the name and the batch numberof 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 for24 hours or more was administered (see section 4.8). Treatment for the TMA events includedsupportive care with or without plasmapheresis and haemodialysis. Evidence of improvement wasseen within one week following discontinuation of aPCC and interruption of Hemlibra. This rapidimprovement is distinct from the usual clinical course observed in atypical hemolytic uremicsyndrome and classic TMAs, such as thrombotic thrombocytopenic purpura (see section 4.8). Onepatient resumed Hemlibra following resolution of TMA and continued to be treated safely.

Patients receiving Hemlibra prophylaxis should be monitored for the development of TMA whenadministering aPCC. The physician should immediately discontinue aPCC and interrupt Hemlibratherapy if clinical symptoms and/or laboratory findings consistent with TMA occur, and manage asclinically indicated. Physicians and patients/caregivers should weigh the benefits and risks ofresuming Hemlibra prophylaxis following complete resolution of TMA on a case-by-case basis. Incase a bypassing agent is indicated in a patient receiving Hemlibra prophylaxis, see below for dosingguidance on the use of bypassing agents.

Caution should be used when treating patients who are at high risk for TMA (e.g. have a previousmedical history or family history of TMA), or those who are receiving concomitant medicinalproducts 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 Hemlibraprophylaxis when on average a cumulative amount of >100U/kg/24 hours of aPCC for 24 hours ormore was administered (see section 4.8). No cases required anticoagulation therapy. Followingdiscontinuation of aPCC and interruption of Hemlibra, evidence of improvement or resolution wasseen within one month (see section 4.8). One patient resumed Hemlibra following resolution ofthrombotic event and continued to be treated safely.

Patients receiving Hemlibra prophylaxis should be monitored for the development ofthromboembolism when administering aPCC. The physician should immediately discontinue aPCCand interrupt Hemlibra therapy if clinical symptoms, imaging, and/or laboratory findings consistentwith thrombotic events occur, and manage as clinically indicated. Physicians and patients/caregiversshould weigh the benefits and risks of resuming Hemlibra prophylaxis following complete resolutionof thrombotic events on a case-by-case basis. In case a bypassing agent is indicated in a patientreceiving 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 bypassingagents to use, if required while receiving Hemlibra prophylaxis.

Hemlibra increases the patient’s coagulation potential. The bypassing agent dose required maytherefore be lower than that used without Hemlibra prophylaxis. The dose and duration of treatmentwith bypassing agents will depend on the location and extent of bleeding, and the patient’s clinicalcondition. 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 exceed50 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 ofaPCC up to 50 U/kg, additional aPCC doses should be administered under medical guidance orsupervision with consideration made to laboratory monitoring for the diagnosis of TMA orthromboembolism and verification of bleeds prior to repeated dosing. The total aPCC dose should notexceed 100 U/kg in the first 24-hours of treatment. Treating physicians must carefully weigh the riskof TMA and thromboembolism against the risk of bleeding when considering aPCC treatment beyonda 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 inpatients receiving Hemlibra prophylaxis.

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

Development of neutralising anti-emicizumab antibodies with decreasing emicizumab concentrationleading to loss of efficacy has been uncommonly observed during clinical studies (see sections 4.8 and5.1). 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 consideredif 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 timeneeded for activation of FVIII to FVIIIa by thrombin. Such intrinsic pathway based tests will yieldoverly shortened clotting times with emicizumab, which does not require activation by thrombin. Theoverly shortened intrinsic clotting time will then disturb all single factor assays based on aPTT, suchas the one stage FVIII activity assay (see section 4.4, Table 1). However, single factor assays utilisingchromogenic or immuno-based methods are not affected by emicizumab and may be used to assesscoagulation parameters during treatment, with specific considerations for FVIII chromogenic activityassays as described below.

Chromogenic FVIII activity tests may be manufactured with either human or bovine coagulationproteins. Assays containing human coagulation factors are responsive to emicizumab but mayoverestimate the clinical haemostatic potential of emicizumab. In contrast, assays containing bovinecoagulation factors are insensitive to emicizumab (no activity measured) and can be used to monitorendogenous 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 falsenegative result in clotting based Bethesda assays for functional inhibition of FVIII. Instead, achromogenic Bethesda assay utilising a bovine based FVIII chromogenic test that is insensitive toemicizumab 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 relativeindication of the pro-coagulant effect of emicizumab.

In summary, intrinsic pathway clotting-based laboratory test results in patients treated with Hemlibrashould 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 basedlaboratory tests are used, as misinterpretation of their results may lead to under-treatment of patientsexperiencing 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 longhalf-life, these effects on coagulation assays may persist for up to 6 months after the last dose (seesection 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

- Bethesda assays (clotting-based) for FVIII FVIII inhibitor titersinhibitor 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)1For important considerations regarding FVIII chromogenic activity assays, see section 4.4.

There are no data in children < 1 year of age. The developing haemostatic system in neonates andinfants is dynamic and evolving, and the relative concentrations of pro- and anticoagulant proteins inthese patients should be taken into consideration when making a benefit-risk assessment, includingpotential 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 (seesections 4.4 and 4.8).

There is a possibility for hypercoagulability with rFVIIa or FVIII with emicizumab based onpreclinical experiments. Emicizumab increases coagulation potential, therefore the FVIIa or FVIIIdose 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 andinterrupt Hemlibra prophylaxis as clinically indicated. Further management should be tailored to theindividual 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 coagulationfactors, and testing for thrombophilic traits may be considered.

Experience with concomitant administration of anti-fibrinolytics with aPCC or rFVIIa in patientsreceiving Hemlibra prophylaxis is limited. However, the possibility of thrombotic events should beconsidered when systemic anti-fibrinolytics are used in combination with aPCC or rFVIIa in patientsreceiving emicizumab.

Women of childbearing potential receiving Hemlibra should use effective contraception during, andfor 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 havenot been conducted with Hemlibra. It is not known whether emicizumab can cause fetal harm whenadministered to a pregnant woman or can affect reproductive capacity. Hemlibra should be usedduring pregnancy only if the potential benefit for the mother outweighs the potential risk to the fetustaking into account that, during pregnancy and after parturition, the risk for thrombosis is increasedand that several pregnancy complications are linked to an increased risk for disseminated intravascularcoagulation (DIC).

It is not known whether emicizumab is excreted in human milk. No studies have been conducted toassess the impact of emicizumab on milk production or its presence in breast milk. Human IgG isknown to be present in human milk. A decision must be made whether to discontinue breast-feeding orto discontinue/abstain from Hemlibra therapy taking into account the benefit of breast-feeding for thechild 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 maleand female fertility is unknown.

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

The overall safety profile of Hemlibra is based on data from clinical studies and post-marketingsurveillance. The most serious adverse drug reactions (ADRs) reported from the clinical studies with

Hemlibra were thrombotic microangiopathy (TMA) and thrombotic events, including cavernous sinusthrombosis (CST) and superficial vein thrombosis contemporaneous with skin necrosis (see below andsection 4.4).

The most common ADRs reported in ≥ 10% of patients treated with at least one dose of Hemlibrawere: 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 fromtreatment due to ADRs, which were TMA, skin necrosis contemporaneous with superficialthrombophlebitis, and headache.

Tabulated list of adverse drug reactions

The following adverse drug reactions (ADRs) are based on data from post-marketing surveillance andpooled 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 Areceived at least one dose of Hemlibra as routine prophylaxis (see section 5.1). Three hundred andseven (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 studieswas 32 weeks (range: 0.1 to 94.3 weeks).

ADRs from the phase III clinical studies and post-marketing surveillance are listed by MedDRAsystem organ class (Table 2). The corresponding frequency categories for each ADR are based on thefollowing 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 estimatedfrom the available data).

Table 2 Summary of adverse drug reactions from pooled HAVEN clinical studies and post-marketing surveillance with Hemlibra

System Organ Class (SOC) Adverse reactions Frequency(preferred term, MedDRA)

Blood and lymphatic system disorders Thrombotic microangiopathy Uncommon

Nervous system disorders Headache Very common

Vascular disorders Thrombophlebitis superficial Uncommon

Cavernous sinus thrombosisa Uncommon

Gastrointestinal disorders Diarrhoea Common

Skin and subcutaneous tissue disorders Skin necrosis Uncommon

Angioedema Uncommon

Urticaria Common

Rash Common

Musculoskeletal and connective tissue Arthralgia Very commondisorders Myalgia Common

General disorders and administration Injection site reaction Very commonsite conditions

Pyrexia Common

Therapeutic response decreasedb UncommonaVascular disorders is a secondary SOC for cavernous sinus thrombosis.bLoss of efficacy (therapeutic response decreased) manifest as an increase in breakthrough bleedinghas been reported with neutralising anti-emicizumab antibodies with decreasing emicizumabconcentration (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) andin 9.7 % of patients (3/31) who received at least one dose of aPCC while being treated withemicizumab. All 3 TMAs occurred when on average a cumulative amount of > 100 U/Kg/24 hours ofaPCC for 24 hours or more was administered during a treatment event (see section 4.4). Patientspresented with thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury,without severe deficiencies in ADAMTS13 activity. One patient resumed Hemlibra followingresolution of TMA without recurrence.

In pooled phase III clinical studies, serious thrombotic events were reported in less than 1 % ofpatients (2/444) and in 6.5 % of patients (2/31) who received at least one dose of aPCC while beingtreated with emicizumab. Both serious thrombotic events occurred when on average a cumulativeamount of > 100 U/Kg/24 hours of aPCC for 24 hours or more was administered during a treatmentevent. 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 clinicalstudies

There were 82 instances of aPCC treatment* in patients receiving Hemlibra prophylaxis, of whicheight instances (10%) consisted of on average a cumulative amount of >100 U/kg/24 hours of aPCCfor 24 hours or more; two of the eight instances were associated with thrombotic events and three ofthe eight instances were associated with TMA (Table 3). No TMA or thrombotic events wereassociated 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

Average cumulative amount of aPCC over 24 hours

Duration of aPCC (U/kg/24 hours)treatment<50 50-100 >100<24 hours 9 47 1324-48 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 therewas a 36-hour treatment-free break. Includes all instances of aPCC treatment excluding those in the first 7 daysand those that occurred 30 days after the discontinuation of Hemlibra.a Thrombotic microangiopathyb Thrombotic event

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

In the pooled phase III clinical studies with Hemlibra, development of neutralising anti-emicizumabantibodies associated with decreasing emicizumab concentration was uncommon (see section 5.1).

One patient, who developed neutralising anti-emicizumab antibodies with decreasing emicizumabconcentration, experienced loss of efficacy (manifest as breakthrough bleeding) after five weeks oftreatment and later discontinued Hemlibra treatment (see sections 4.4 and 5.1).

The paediatric population studied comprises a total of 137 patients, of which 5 (3.6 %) were infantsand toddlers (1 month to less than 2 years of age), 71 (51.8 %) were children (from 2 to less than12 years of age) and 61 (44.5 %) were adolescents (from 12 to less than 18 years old). The safetyprofile of Hemlibra was overall consistent between infants, children, adolescents, and adults.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is limited experience with overdose of Hemlibra.

Accidental overdose may result in hypercoagulability.

Patients who receive an accidental overdose should immediately contact their physician and bemonitored closely.

Pharmacotherapeutic group: antihemorrhagics, other systemic hemostatics; ATC code: B02BX06

Emicizumab is a humanized monoclonal modified immunoglobulin G4 (IgG4) antibody with abispecific antibody structure.

Emicizumab bridges activated factor IX and factor X to restore the function of missing FVIIIa that isneeded for effective haemostasis.

Emicizumab has no structural relationship or sequence homology to FVIII and, as such, does notinduce or enhance the development of direct inhibitors to FVIII.

Prophylactic therapy with Hemlibra shortens the aPTT and increases the reported FVIII activity (usinga chromogenic assay with human coagulation factors). These two pharmacodynamic markers do notreflect the true haemostatic effect of emicizumab in vivo (aPTT is overly shortened and reported FVIIIactivity may be overestimated) but provide a relative indication of the pro-coagulant effect ofemicizumab.

The efficacy of Hemlibra for routine prophylaxis in patients with haemophilia A was evaluated in fiveclinical studies (three adult and adolescent studies in patients with haemophilia A with or without

FVIII inhibitors [HAVEN 1, HAVEN 3, and HAVEN 4], a paediatric study in patients withhaemophilia A with FVIII inhibitors [HAVEN 2] and an all-age group study in patients with mild ormoderate haemophilia A without FVIII inhibitors [HAVEN 6]).

Clinical studies in adult and adolescent patients with haemophilia A with or without FVIII inhibitors

Patients (aged ≥ 12 years old and > 40 kg) with haemophilia A without FVIII inhibitors (Study

BH30071 - HAVEN 3)

The HAVEN 3 study was a randomised, multicentre, open-label, phase III clinical study in 152 adultand adolescent males (aged ≥ 12 years and > 40 kg) with severe haemophilia A without FVIIIinhibitors who previously received either episodic (“on demand”) or prophylactic treatment with

FVIII. Patients received subcutaneous Hemlibra, 3 mg/kg once weekly for the first four weeksfollowed by either 1.5 mg/kg once weekly (Arms A and D) or 3 mg/kg every two weeks (Arm B)thereafter, or no prophylaxis (Arm C). Patients in Arm C could switch to Hemlibra (3 mg/kg everytwo weeks) after completing at least 24 weeks without prophylaxis. For Arms A and B dose up-titration to 3 mg/kg weekly was allowed after 24 weeks for patients who experienced two or morequalified bleeds (i.e., spontaneous and clinically significant bleeds occurring at steady state). Arm Dpatients could up-titrate after the second qualifying bleed. At the time of the primary analysis, fivepatients underwent up-titration of their maintenance dose.

Eighty-nine patients previously treated with episodic (“on demand”) FVIII were randomized in a 2:2:1ratio to receive Hemlibra either once weekly (Arm A; N = 36), every two weeks (Arm B; N = 35) orno prophylaxis (Arm C; N = 18), with stratification by prior 24-week bleed rate (< 9 or ≥ 9). Sixty-three patients previously treated with prophylactic FVIII were enrolled into Arm D to receive

Hemlibra (1.5 mg/kg once weekly).

The primary objective of the study was to evaluate in patients previously treated with episodic FVIIIthe efficacy of prophylactic Hemlibra weekly (Arm A) or every two weeks (Arm B) compared to noprophylaxis (Arm C) based on the number of bleeds requiring treatment with coagulation factors (see

Table 4). Other objectives of the study included evaluation of the randomised comparison of Arms Aor B and Arm C for the efficacy of Hemlibra prophylaxis in reducing the number of all bleeds,spontaneous bleeds, joint bleeds, and target joint bleeds (see Table 4), as well as assessing patienttreatment preference using a preference survey.

The efficacy of Hemlibra prophylaxis was also compared with previous prophylactic FVIII treatment(Arm D) in patients who had participated in a non-interventional study (NIS) prior to enrollment (see

Table 5). Only patients from the NIS were included in this comparison, because bleed and treatmentdata were collected with the same level of granularity as used in HAVEN 3. The NIS is anobservational study with the main objective of capturing detailed clinical data on the bleeding episodesand haemophilia medicinal product use of patients with haemophilia A outside of an interventionalstudy setting.

Patients (aged ≥ 12 years old) with haemophilia A with FVIII inhibitors (Study BH29884 - HAVEN 1)

The HAVEN 1 study was a randomised, multicentre, open-label clinical study in 109 adolescent andadult males (aged ≥ 12 years old) with haemophilia A with FVIII inhibitors who had previouslyreceived either episodic or prophylactic treatment with bypassing agents (aPCC and rFVIIa). In thestudy, patients received weekly Hemlibra prophylaxis (Arms A, C, and D) — 3 mg/kg once weeklyfor four weeks followed by 1.5 mg/kg once weekly thereafter — or no prophylaxis (Arm B). Patientsrandomised to Arm B could switch to Hemlibra prophylaxis after completing at least 24 weekswithout prophylaxis. Dose up-titration to 3 mg/kg once weekly was allowed after 24 weeks on

Hemlibra prophylaxis for patients who experienced two or more qualified bleeds (i.e., spontaneousand verified clinically significant bleeds occurring at steady state). At the time of the primary analysis,two patients underwent up-titration of their maintenance dose to 3 mg/kg once weekly.

Fifty-three patients previously treated with episodic (“on-demand”) bypassing agents were randomisedin a 2:1 ratio to receive Hemlibra prophylaxis (Arm A) or no prophylaxis (Arm B), with stratificationby prior 24-week bleed rate (< 9 or ≥ 9).

Forty-nine patients previously treated with prophylactic bypassing agents were enrolled in Arm C toreceive Hemlibra prophylaxis. Seven patients previously treated with episodic (“on-demand”)bypassing agents who had participated in the NIS prior to enrolment but were unable to enroll in

HAVEN 1 prior to the closure of Arms A and B were enrolled in Arm D to receive Hemlibraprophylaxis.

The primary objective of the study was to evaluate, among patients previously treated with episodic(“on-demand”) bypassing agents, the treatment effect of weekly Hemlibra prophylaxis compared withno prophylaxis (Arm A vs. Arm B) on the number of bleeds requiring treatment with coagulationfactors over time (minimum of 24 weeks or date of discontinuation) (see Table 6). Other secondaryobjectives of the randomised comparison of Arms A and B were the efficacy of weekly Hemlibraprophylaxis in reducing the number of all bleeds, spontaneous bleeds, joint bleeds and target jointbleeds (see Table 6), as well as assessing patients’ health-related quality of life (HRQoL) and healthstatus (see Tables 10 and 11). The mean exposure time (+SD) for all patients on study was21.38 weeks (12.01). For each treatment arm, the mean exposure times (+SD) were 28.86 weeks(8.37) for Arm A, 8.79 (3.62) for Arm B, 21.56 (11.85) for Arm C and 7.08 (3.89) for Arm D. Onepatient in Arm A withdrew from study prior to initiation of Hemlibra.

The study also evaluated the efficacy of weekly Hemlibra prophylaxis compared with previousepisodic (on-demand) and prophylactic bypassing agents (separate comparisons) in patients who hadparticipated in the NIS prior to enrolment (Arms A and C, respectively) (see Table 7).

Patients (aged ≥ 12 years old) with haemophilia A with or without FVIII inhibitors (Study

BO39182 - HAVEN 4)

Hemlibra was investigated in a single arm, multicentre, phase III clinical study in 41 adult andadolescent males (aged ≥ 12 years and > 40 kg) who have haemophilia A with FVIII inhibitors orsevere haemophilia A without FVIII inhibitors who previously received either episodic (“on demand”)or prophylactic treatment with bypassing agents or FVIII. Patients received Hemlibra prophylaxis -3 mg/kg once weekly for four weeks followed by 6 mg/kg every four weeks thereafter. The primaryobjective of the study was to evaluate the efficacy of Hemlibra prophylaxis given every four weeks inmaintaining adequate bleed control, based on treated bleeds. Other objectives were to evaluate theclinical efficacy of Hemlibra prophylaxis on all bleeds, treated spontaneous bleeds, treated joint bleedsand treated target joint bleeds (see Table 8). Patient treatment preference was also assessed using apreference survey.

Patients (all ages) with mild or moderate haemophilia A without FVIII inhibitors (Study BO41423 -

HAVEN 6)

The HAVEN 6 study was a multicentre, open-label, single-arm phase III clinical study in71 emicizumab-treated patients (all ages) with mild (n = 20 [28.2%]) or moderate (n = 51 [71.8%])haemophilia A without FVIII inhibitors for whom prophylaxis was indicated, as assessed by theinvestigator. Most patients were male (69 patients [97.2%]), and 2 were female (2.8%). At study entry,34 patients (47.9%) were on episodic and 37 patients (52.1%) were on prophylactic treatment with

FVIII. Patients received subcutaneous Hemlibra 3 mg/kg once weekly for the first four weeksfollowed by patient preference for one of the following maintenance regimens, from week 5:1.5 mg/kg once weekly (n = 24 [33.8%]), 3 mg/kg every two weeks (n = 39 [54.9%]) or 6 mg/kg everyfour weeks (n = 8 [11.3%]). Dose up-titration to 3 mg/kg weekly was allowed after 24 weeks forpatients who experienced two or more qualified bleeds (i.e., spontaneous and clinically significantbleeds occurring at steady state). At the time of interim analysis, no patients underwent up-titration oftheir maintenance dose.

The primary efficacy objective of the study was to evaluate the efficacy of Hemlibra prophylaxisbased on the number of bleeds requiring treatment with coagulation factors over time (i.e., bleed rateof treated bleeds, see Table 9). Other objectives were to evaluate the efficacy of Hemlibra prophylaxisbased on the number of all bleeds, spontaneous bleeds, joint bleeds, and target joint bleeds over time,as well as assessing patient reported HRQoL using the Comprehensive Assessment Tool of Challengesin Haemophilia (CATCH) questionnaire over time.

HAVEN 3

The efficacy results of Hemlibra prophylaxis compared with no prophylaxis with respect to rate oftreated bleeds, all bleeds, treated spontaneous bleeds, treated joint bleeds, and treated target jointbleeds are shown in Table 4.

Table 4 HAVEN 3 study: Annualised Bleed Rate for Hemlibra prophylaxis arm versus noprophylaxis arm in patients ≥ 12 years of age without FVIII inhibitors

Endpoint Arm B:

Arm C: Arm A:

Hemlibra

Hemlibra

No prophylaxis 3 mg/kg1.5 mg/kg weekly(N = 18) every 2 weeks(N = 36)(N = 35)

Treated bleeds

ABR (95% CI) 38.2 (22.9; 63.8) 1.5 (0.9; 2.5) 1.3 (0.8; 2.3)% reduction (RR), p-value

NA 96% (0.04),< 0.0001 97% (0.03), < 0.0001% patients with 0 bleeds(95% CI) 0.0 (0.0; 18.5) 55.6 (38.1; 72.1) 60.0 (42.1; 76.1)

Median ABR (IQR) 40.4 (25.3; 56.7) 0 (0; 2.5) 0 (0; 1.9)

All bleeds

ABR (95% CI) 47.6 (28.5; 79.6) 2.5 (1.6; 3.9) 2.6 (1.6; 4.3)% reduction (RR), p-value NA 95% (0.05 <0.0001 94% (0.06),<0.0001% patients with 0 bleeds 0 (0.0:18.5)(95% CI) 50 (32.9; 67.1) 40 (23.9; 57.9)

Treated spontaneous bleeds

ABR (95% CI) 15.6 (7.6; 31.9) 1.0 (0.5; 1.9) 0.3 (0.1; 0.8)% reduction (RR), p-value NA 94% (0.06), <0.0001 98% (0.02),<0.0001% patients with 0 bleeds 22.2 (6.4; 47.6)(95% CI) 66.7 (49.0; 81.4) 88.6 (73.3; 96.8)

Treated joint bleeds

ABR (95% CI) 26.5 (14.67; 47.79) 1.1 (0.59; 1.89) 0.9 (0.44; 1.67)% reduction (RR), p-value NA 96% (0.04), <0.0001 97% (0.03),<0.0001% patients with 0 bleeds 0 (0; 18.5)(95% CI) 58.3 (40.8; 74.5) 74.3 (56.7; 87.5)

Endpoint Arm B:

Arm C: Arm A:

Hemlibra

Hemlibra

No prophylaxis 3 mg/kg1.5 mg/kg weekly(N = 18) every 2 weeks(N = 36)(N = 35)

Treated target joint bleeds

ABR (95% CI) 13.0 (5.2; 32.3) 0.6 (0.3; 1.4) 0.7 (0.3; 1.6)% reduction (RR), p-value NA 95% (0.05), <0.0001 95% (0.05),<0.0001% patients with 0 bleeds 27.8 (9.7; 53.5)(95% CI) 69.4 (51.9; 83.7) 77.1 (59.9; 89.6)

Rate ratio, and confidence interval (CI) come from negative binomial regression (NBR) model and p-valuefrom Stratified Wald test, comparing bleed rate between specified arms.

Arm C: includes no prophylaxis period only.

Bleed definitions adapted based on ISTH criteria.

Treated bleeds = bleeds treated with FVIII

All bleeds = bleeds treated and not treated with FVIII.

Includes data before up-titration only, for patients whose dose was up-titrated.

Patients exposed to emicizumab started with a loading dose of 3 mg/kg/week for 4 weeks.

ABR= Annualised Bleed Rate; CI= confidence interval; RR= rate ratio; IQR= interquartile range, 25thpercentile to 75th percentile, NA=Not Applicable

In the HAVEN 3 clinical study intra-patient analysis, Hemlibra prophylaxis resulted in a statisticallysignificant (p<0.0001) reduction (68 %) in bleed rate for treated bleeds compared with previous FVIIIprophylaxis collected in the NIS prior to enrollment (see Table 5).

Table 5 HAVEN 3 study: Intra-patient comparison of Annualised Bleed Rate (treated bleeds)with Hemlibra prophylaxis versus previous FVIII prophylaxis

Endpoint Arm D NIS: Arm D:

Previous FVIII prophylaxis Hemlibra 1.5 mg/kg weekly(N = 48) (N = 48)

Median efficacy period (weeks) 30.1 33.7

Treated bleeds

ABR (95% CI) 4.8 (3.2; 7.1) 1.5 (1; 2.3)% reduction (RR), p-value 68% (0.32), <0.0001% patients with zero bleeds(95% CI) 39.6 (25.8; 54.7) 54.2 (39.2; 68.6)

Median ABR (IQR) 1.8 (0; 7.6) 0 (0; 2.1)

Rate ratio and confidence interval (CI) comes from negative binomial regression (NBR) model and p-value from Stratified Wald test, comparing ABR between specified arms.

Intra-patient comparator data from the NIS. Only patients who participated in the NIS and in study

HAVEN 3 are included.

Includes data before up-titration only, for patients whose dose was up-titrated.

Treated bleeds = bleeds treated with FVIII. Bleed definitions adapted based on ISTH criteria. ABR=

Annualised Bleed Rate; CI= confidence interval; RR= rate ratio; IQR=interquartile range, 25th percentileto 75th percentile

Although a higher adherence was observed with emicizumab prophylaxis than with prior FVIIIprophylaxis, no difference in ABR in patients with ≥80% or < 80% compliant doses on FVIII prophylaxisaccording to standard label requirements could be identified (data to be interpreted with caution due tosmall sample sizes).

Due to the short half-life of FVIII, no carryover effect is assumed after its discontinuation.

Only the first five emicizumab doses had to be administered under supervision to ensure safety andinjection technique proficiency. Similar to FVIII prophylaxis, self-administration at home was allowedfor all subsequent emicizumab doses.

All patients were treated by haemophilia experts who confirmed that adequate FVIII prophylaxis wasadministered to patients included in the intra-patient comparison, supporting equivalent usual prophylaxiscare across sites and patients.

HAVEN 1

The efficacy results of Hemlibra prophylaxis compared with no prophylaxis with respect to rate oftreated bleeds, all bleeds, treated spontaneous bleeds, treated joint bleeds, and treated target jointbleeds are shown in Table 6.

Table 6 HAVEN 1: Annualised Bleed Rate with Hemlibra prophylaxis arm versus noprophylaxis arm in patients ≥ 12 years of age with FVIII inhibitors

Endpoint Arm B: no prophylaxis Arm A: 1.5 mg/kg

Hemlibra weekly

N=18 N=35

Treated bleeds

ABR (95% CI) 23.3 (12.33; 43.89) 2.9 (1.69; 5.02)% reduction (RR), p-value 87% (0.13), < 0.0001% patients with 0 bleeds (95% CI) 5.6 (0.1; 27.3) 62.9 (44.9; 78.5)

Median ABR (IQR) 18.8 (12.97;35.08) 0 (0; 3.73)

All bleeds

ABR (95% CI) 28.3 (16.79; 47.76) 5.5 (3.58; 8.60)% reduction (RR), p-value 80% (0.20), < 0.0001% patients with 0 bleeds (95% CI) 5.6 (0.1; 27.3) 37.1 (21.5; 55.1)

Treated spontaneous bleeds

ABR (95% CI) 16.8 (9.94; 28.30) 1.3 (0.73; 2.19)% reduction (RR), p-value 92% (0.08), < 0.0001% patients with 0 bleeds (95% CI) 11.1 (1.4; 34.7) 68.6 (50.7; 83.1)

Treated joint bleeds

ABR (95% CI) 6.7 (1.99; 22.42) 0.8 (0.26; 2.20)% reduction (RR), p-value 89% (0.11), 0.0050% patients with 0 bleeds (95% CI) 50.0 (26.0; 74.0) 85.7 (69.7; 95.2)

Treated target joint bleeds

ABR (95% CI) 3.0 (0.96; 9.13) 0.1 (0.03; 0.58)% reduction (RR), p-value 95% (0.05), 0.0002% patients with 0 bleeds (95% CI) 50.0 (26.0; 74.0) 94.3 (80.8; 99.3)

Rate ratio, and confidence interval (CI) come from negative binomial regression (NBR) model and p-valuefrom Stratified Wald test, comparing bleed rate between specified arms.

Arm B: includes no prophylaxis period only.

Bleed definitions adapted based on ISTH criteria.

Treated bleeds = bleeds treated with bypassing agents.

All bleeds = bleeds treated and not treated with bypassing agents.

Includes data before up-titration only, for patients whose dose was up-titrated.

Patients exposed to emicizumab started with a loading dose of 3 mg/kg/week for 4 weeks.

ABR= Annualised Bleed Rate; CI= confidence interval; RR= rate ratio; IQR= interquartile range, 25thpercentile to 75th percentile.

In the HAVEN 1 intra-patient analysis, Hemlibra prophylaxis resulted in statistically significant(p = 0.0003) and clinically meaningful reduction (79 %) in bleed rate for treated bleeds compared withprevious bypassing agent prophylaxis collected in the NIS prior to enrolment (see Table 7).

Table 7 HAVEN 1: Intra-patient comparison of Annualised Bleed Rate (treated bleeds) with

Hemlibra prophylaxis versus previous bypassing agent prophylaxis (NIS patients)

Arm CNIS: previous bypassing agent Arm C: Hemlibra 1.5 mg/kg

Endpoint prophylaxis weekly

N=24 N=24

Treated bleeds

ABR (95% CI) 15.7 (11.08; 22.29) 3.3 (1.33; 8.08)% patients with 0 bleeds(95% CI) 12.5 (2.7; 32.4) 70.8 (48.9; 87.4)

Median ABR (IQR) 12.0 (5.73; 24.22) 0.0 (0.00; 2.23)% reduction 79%(RR), p-value (0.21), 0.0003

Rate ratio and confidence interval (CI) comes from negative binomial regression (NBR) model and p-valuefrom Stratified Wald test, comparing ABR between specified arms.

Intra-patient comparator data from the NIS.

Only patients who participated in the NIS and in study HAVEN 1 are included.

Includes data before up-titration only, for patients whose dose was up-titrated.

Treated bleeds = bleeds treated with bypassing agents.

Bleed definitions adapted based on ISTH criteria.

ABR= Annualised Bleed Rate; CI= confidence interval; RR= rate ratio; IQR=interquartile range, 25thpercentile to 75th percentile

Although a higher adherence was observed with emicizumab prophylaxis than with prior bypassing agent(BPA) prophylaxis, no difference in ABR in patients with ≥ 80% or < 80% compliant doses on BPAprophylaxis according to standard label requirements could be identified (data to be interpreted with cautiondue to small sample sizes).

Due to the short half-life of bypassing agents, no carryover effect is assumed after its discontinuation.

Only the first five emicizumab doses had to be administered under supervision to ensure safety and injectiontechnique proficiency. Similar to BPA prophylaxis, self-administration at home was allowed for all subsequentemicizumab doses.

HAVEN 4

Primary analysis efficacy results of Hemlibra prophylaxis every four weeks with respect to rate oftreated bleeds, all bleeds, treated spontaneous bleeds, treated joint bleeds, and treated target jointbleeds are shown in Table 8. Forty one patients ≥ 12 years old were evaluated for efficacy with amedian observation time of 25.6 weeks (range: 24.1-29.4).

Table 8 HAVEN 4: Annualised Bleed Rate with Hemlibra prophylaxis in patients ≥12 yearsof age with or without FVIII inhibitors

Hemlibra 6mg/kg Q4W

Endpoints aABR (95% CI) bMedian ABR (IQR) % Zero Bleeds(95%CI)

N 41 41 41

Treated bleeds 2.4 (1.4; 4.3) 0.0 (0.0; 2.1) 56.1 (39.7; 71.5)

All bleeds 4.5 (3.1; 6.6) 2.1 (0.0; 5.9) 29.3 (16.1; 45.5)

Treated spontaneous 0.6 (0.3;1.5) 0.0 (0.0; 0.0) 82.9 (67.9;92.8)bleeds

Treated joint bleeds 1.7 (0.8; 3.7) 0.0 (0.0; 1.9) 70.7 (54.5; 83.9)

Treated target joint 1.0 (0.3; 3.3) 0.0 (0.0;0.0) 85.4 (70.8; 94.4)bleedsa Calculated with negative binomial regression (NBR) modelb Calculated ABR

Bleed definitions adapted based on ISTH criteria

Treated bleeds: bleeds treated with FVIII or rFVIIa

All bleeds: bleeds treated and not treated with FVIII or rFVIIa

Patients exposed to emicizumab started with a loading dose of 3mg/kg/week for 4 weeks.

ABR=Annualised Bleed Rate, CI=confidence interval; IQR=interquartile range; 25th percentile to 75thpercentile ; Q4W=once every four week prophylaxis

HAVEN 6 (interim analysis)

Fifty-one patients with moderate haemophilia A aged 2 to 56 years old were evaluated for efficacywith a median observation time of 30.4 weeks (range: 17.4 - 61.7). Interim efficacy results of

Hemlibra prophylaxis in patients with moderate haemophilia A (see section 4.1) with respect to rate oftreated bleeds, all bleeds, treated spontaneous bleeds, treated joint bleeds, and treated target jointbleeds are shown in Table 9.

Table 9 HAVEN 6: Annualised Bleed Rate with Hemlibra prophylaxis in patients withmoderate haemophilia A without FVIII inhibitorscHemlibra 1.5 mg/kg QW, 3 mg/kg Q2W or 6 mg/kg Q4W

Endpoints aABR (95% CI) bMedian ABR (IQR) % Zero Bleeds(95%CI)

N 51 51 51

Treated bleeds 0.9 [0.43; 1.89] 0.0 [0.00; 0.00] 78.4 [64.7; 88.7]

All bleeds 2.6 [1.81; 3.81] 1.7 [0.00; 3.90] 43.1 [29.3; 57.8]

Treated spontaneous 0.1 [0.03; 0.30] 0.0 [0.00; 0.00] 94.1 [83.8; 98.8]bleeds

Treated joint bleeds 0.3 [0.10; 0.84] 0.0 [0.00; 0.00] 90.2 [78.6; 96.7]

Treated target joint 0.1 [0.02; 0.26] 0.0 [0.00; 0.00] 96.1 [86.5; 99.5]bleedsa Calculated with negative binomial regression (NBR) modelb Calculated ABR

Bleed definitions adapted based on ISTH criteria

Treated bleeds: bleeds treated with FVIII.

All bleeds: bleeds treated and not treated with FVIII.

Patients exposed to emicizumab started with a loading dose of 3 mg/kg/week for 4 weeks.

ABR=Annualised Bleed Rate, CI=confidence interval; IQR=interquartile range; 25th percentile to 75th percentile;

QW=once every week prophylaxis; Q2W=once every two weeks prophylaxis; Q4W=once every four weeks prophylaxisc 1.5 mg/kg QW (n = 16); 3 mg/kg Q2W (n = 30); 6 mg/kg Q4W (n = 5)

Health-related outcome measures

The HAVEN clinical studies evaluated HRQoL and health-status using clinical outcome assessmentmeasures. HAVEN 1 and 2 used the Haemophilia-Specific Quality of Life (Haem-A-QoL)questionnaire for adults (> 18 years) and its adolescent version (Haemo-QoL-SF, for 8 to <18 years),respectively, for which the Physical Health Score (i.e. painful swellings, presence of joint pain, painwith movement, difficulty walking far and needing more time to get ready) and Total Score (summaryof all scores) were protocol defined endpoints of interest. HAVEN 2 additionally used the Adapted

InhibQoL with Aspects of Caregiver Burden questionnaire to obtain caregiver-report of HRQoL inpaediatric patients < 12 years. HAVEN 6 assessed HRQoL in adult and paediatric patients, as well ascaregivers of paediatric patients, using the Comprehensive Assessment Tool of Challenges in

Haemophilia (CATCH) questionnaire. The domains of risk perception and impact of haemophilia ondaily activities, social activities, recreational activities, and work/school, as well as preoccupation andtreatment burden were examined. To measure change in health status, the Index Utility Score (IUS)and the Visual Analog Scale (VAS) from the EuroQoL Five-Dimension Five-Levels Questionnaire(EQ-5D-5L) were examined.

HAVEN 1 health-related outcomes

In this study baseline Total Scores (mean = 41.14 and 44.58, respectively) and Physical Health scalescores (mean = 52.41 and 57.19, respectively) were similar for Hemlibra prophylaxis and noprophylaxis. Table 10 provides a summary of the comparison between the Hemlibra prophylaxis arm(Arm A) and the no prophylaxis arm (Arm B) on the Haem-A-QoL Total Score and Physical Healthscale after 24 weeks of treatment adjusting for baseline. Weekly Hemlibra prophylaxis showed astatistically significant and clinically meaningful improvement compared with no prophylaxis in thepre-specified endpoints of Haem-A-QoL Physical Health Scale score at the Week 25 assessment.

Table 10 HAVEN 1: Change in Haem-A-QoL Physical Health and Total score with Hemlibraprophylaxis versus no prophylaxis in patients ≥ 18 years with FVIII inhibitors

Haem-A-QoL at week 25 Arm B: no prophylaxis Arm A: Hemlibra(N=14) 1.5 mg/kg weekly (N=25)

Physical health score (range 0 to 100)

Adjusted mean 54.17 32.61

Difference in adjusted means (95% CI) 21.55 (7.89, 35.22)p-value 0.0029

Total score (range 0 to 100)

Adjusted mean 43.21 29.2

Difference in adjusted means (95% CI) 14.01 (5.56, 22.45)

Arm B: includes no prophylaxis period only.

Includes data before up-titration only, for patients whose dose was up-titrated.

Patients exposed to emicizumab started with a loading dose of 3 mg/kg/week for 4 weeks.

Haem-A_QoL scales range from 0 to 100; lower scores are reflective of better HRQoL.

Clinically meaningful difference: Total score: 7 points; Physical Health: 10 points. Analyses are based ondata from individuals who provided responses at both baseline and Week 25 assessments.

HAVEN 1 health status outcomes

Table 11 provides a summary of the comparison between the Hemlibra prophylaxis arm (Arm A) andthe no prophylaxis arm (Arm B) on the EQ-5D-5L IUS and VAS after 24 weeks of treatment adjustingfor baseline.

Table 11 HAVEN 1: EQ-5D-5L scores in patients ≥ 12 years at week 25

EQ-5D-5L scores after 24 weeks Arm B: no prophylaxis Arm A: Hemlibra(N=16) 1.5 mg/kg weekly(N=29)

Visual Analogue Scale

Adjusted mean 74.36 84.08

Difference in adjusted means (95% CI) -9.72 (-17.62, -1.82)

Index Utility Score

Adjusted mean 0.65 0.81

Difference in adjusted means (95% CI) -0.16 (-0.25, -0.07)

Arm B: includes no prophylaxis period only.

Includes data before up-titration only, for patients whose dose was up-titrated.

Patients exposed to emicizumab started with a loading dose of 3 mg/kg/week for 4 weeks.

Higher scores indicate better quality of life.

Clinically meaningful difference: VAS: 7 points, Index Utility Score: 0.07 points

Analyses are based on data from individuals who provided responses at both baseline and Week 25assessments.

HAVEN 6 health-related outcomes

In HAVEN 6, HRQoL for patients of all ages with moderate haemophilia A was evaluated at week 25based on the CATCH questionnaire. The CATCH questionnaire (version 1.0) is a validated instrumentthat assesses the effect of haemophilia and its treatment. Different versions of the questionnaire existfor adult patients, paediatric patients and caregivers of paediatric patients.

Health-related quality of life on Hemlibra prophylaxis remained generally stable, with improvement inthe treatment burden domain of CATCH consistently observed across respondent groups.

Paediatric patients (age < 12 years old, or 12 to 17 years old weighing < 40 kg) with haemophilia Awith FVIII inhibitors (Study BH29992 - HAVEN 2)

Hemlibra weekly prophylaxis was evaluated in a single-arm, multicentre, open-label clinical study inpaediatric patients (age < 12 years old, or 12 to 17 years old weighing < 40 kg) with haemophilia Awith FVIII inhibitors. Patients received Hemlibra prophylaxis at 3 mg/kg once weekly for the first4 weeks followed by 1.5 mg/kg once weekly thereafter.

The study evaluated the pharmacokinetics (PK), safety, and efficacy including the efficacy of weekly

Hemlibra prophylaxis compared with previous episodic and prophylactic bypassing agent treatment inpatients who had participated in the NIS prior to enrolment (intra-patient comparison).

HAVEN 2 (interim analysis)

At the time of the interim analysis, efficacy was evaluated in 59 patients who were < 12 years old andhad been receiving weekly Hemlibra prophylaxis for at least 12 weeks, including four patients aged< 2 years old, 17 patients aged 2 to < 6 years, 38 patients aged 6 to < 12 years old. Annualised bleedrate and percent of patients with zero bleeds were calculated (see Table 12). The median observationtime for these patients was 29.6 weeks (range: 18.4 to 63.0 weeks).

Table 12 HAVEN 2: Overview of efficacy (interim analysis)

Endpoint aABR (95% CI) cMedian ABR (IQR) % Zero Bleeds(95% CI)bN = 59 bN = 59 bN = 59

Treated bleeds 0.3 (0.1; 0.5) 0 (0; 0) 86.4 (75; 94)

All bleeds 3.8 (2.2; 6.5) 0 (0; 3.4) 55.9 (42.4; 68.8)

Treated spontaneousbleeds 0 (0; 0.2) 0 (0; 0) 98.3 (90.9; 100)

Treated joint bleeds 0.2 (0.1; 0.4) 0 (0; 0) 89.8 (79.2; 96.2)

Treated target jointbleeds 0.1 (0; 0.7) 0 (0; 0) 96.6 (88.3; 99.6)

ABR = annualised bleed rate; CI = confidence interval; IQR = interquartile range, 25th percentile to 75thpercentilea Calculated with negative binomial regression (NBR) model.b Efficacy data from treated patients aged < 12 years who had been on study HAVEN 2 for at least 12 weeks(N = 59), as the study aimed to primarily investigate treatment effect based on age.c Calculated ABR

Bleed definitions adapted based on ISTH criteria.

Treated bleeds: bleeds treated with bypassing agents.

All bleeds: bleeds treated and not treated with bypassing agents.

Patients exposed to emicizumab started with a loading dose of 3 mg/kg/week for 4 weeks.

In the intra-patient analysis, Hemlibra weekly prophylaxis resulted in a clinically meaningfulreduction (98 %) in treated bleed rate in 18 paediatric patients who had at least 12 weeks of Hemlibraprophylaxis compared to their bleed rate collected in the NIS prior to enrolment (Table 13).

Table 13 HAVEN 2: Intra-patient comparison of Annualised Bleed Rate (treated bleeds) with

Hemlibra prophylaxis versus previous bypassing agent prophylaxis

Endpoint Previous bypassing agent Hemlibra prophylaxistreatment* (N = 18) (N = 18)

Treated bleeds

ABR (95% CI) 19.8 (15.3; 25.7) 0.4 (0.15; 0.88)98%% reduction (RR)(0.02)% patients with zero bleeds (95% 5.6 (0.1; 27.3)

CI) 77.8 (52.4; 93.6)

Median ABR (IQR) 16.2 (11.49; 25.78) 0 (0; 0)

* Previous prophylactic treatment for 15 of the 18 patients; previous episodic (on-demand) treatment for 3subject

Rate ratio and confidence interval (CI) comes from negative binomial regression (NBR) model and p-valuefrom Stratified Wald test, comparing ABR between specified arms.

Intra-patient comparator data from the NIS.

Only patients who participated in the NIS and in study HAVEN 2 are included.

Bleed definitions adapted based on ISTH criteria.

Treated bleeds: bleeds treated with bypassing agents.

Patients exposed to emicizumab started with a loading dose of 3 mg/kg/week for 4 weeks.

ABR= Annualised Bleed Rate; CI= confidence interval; RR= rate ratio; IQR=interquartile range, 25thpercentile to 75th percentile

Although a higher adherence was observed with emicizumab prophylaxis than with prior bypassing agent(BPA) prophylaxis, no difference in ABR in patients with ≥ 80% or < 80% compliant doses on BPAprophylaxis according to standard label requirements could be identified (data to be interpreted with cautiondue to small sample sizes).

Due to the short half-life of bypassing agents, no carryover effect is assumed after its discontinuation.

Only the first five emicizumab doses had to be administered under supervision to ensure safety and injectiontechnique proficiency. Similar to BPA prophylaxis, self-administration at home was allowed for all subsequentemicizumab doses.

Paediatric health-related outcomes results

HAVEN 2 health-related outcomes

In HAVEN 2, HRQoL for patients aged ≥ 8 to < 12 years was evaluated at week 25 based on the

Haemo-QoL-SF questionnaire for children (see Table 14). The Haemo-QoL-SF is a valid and reliablemeasure of HRQoL. HRQoL for patients aged < 12 years was also evaluated at week 25 based on the

Adapted InhibQoL with Aspects of Caregiver Burden questionnaire completed by caregivers (see

Table 14). The Adapted InhibQoL is a valid and reliable measure of HRQoL.

Table 14 HAVEN 2: Change from baseline to week 25 in the Physical Health score of patients(< 12 years of age) following treatment with Hemlibra prophylaxis as reported bypatients and caregivers

Haemo-QoL-SF

Physical health score (range 0 to 100)a

Mean baseline score (95% CI) (n = 18) 29.5 (16.4 - 42.7)

Mean change from baseline (95% CI) (n = 15) -21.7 (-37.1 - -6.3)

Adapted InhibQoL with aspects ofcaregiver burden

Physical health score (range 0 to 100)a

Mean baseline score (95% CI) (n = 54) 37.2 (31.5 - 42.8)

Mean change from baseline (95% CI) (n = 43) -32.4 (-38.6 - -26.2)a Lower scores (negative change scores) are reflective of better functioning.

Analyses are based on data from individuals who provided responses at both baseline and Week 25 assessments.

There is limited experience with bypassing agent or FVIII use during surgeries and procedures.

Bypassing agent or FVIII use during surgeries and procedures was determined by the investigator.

In the event of breakthrough bleeding, patients receiving emicizumab prophylaxis should be managedwith available therapies. For bypassing agent guidance refer to section 4.4.

As with all therapeutic proteins, there is the potential for an immune response in patients treated withemicizumab. A total of 739 patients were tested for anti-emicizumab antibodies in the pooled clinicalstudies. Thirty-six patients (4.9%) tested positive for anti-emicizumab antibodies. In 19 patients(2.6%), anti-emicizumab antibodies were neutralising in vitro. Of these 19 patients, the neutralisinganti-emicizumab antibodies did not have a clinically meaningful impact on the pharmacokinetics orefficacy of Hemlibra in 15 patients, while decreased emicizumab plasma concentrations wereobserved in four patients (0.5%). One patient (0.1%) with neutralising anti-emicizumab antibodies anddecreased emicizumab plasma concentrations experienced loss of efficacy after five weeks oftreatment and discontinued Hemlibra. Overall, the safety profile of Hemlibra was similar betweenthose patients with anti-emicizumab antibodies (including neutralising antibodies) and those without(see sections 4.4 and 4.8).

Use of Hemlibra in patients aged 65 and over with haemophilia A is supported by studies HAVEN 1,

HAVEN 3, HAVEN 4 and HAVEN 6. Based on limited data, there is no evidence to suggest adifference in efficacy or safety in patients aged 65 years or above.

The pharmacokinetics of emicizumab was determined via non-compartmental analysis in healthysubjects and using a population pharmacokinetic analysis on a database composed of 389 patients withhaemophilia A.

Following subcutaneous administration in haemophilia A patients, the absorption half-life was1.6 days.

Following multiple subcutaneous administrations of 3 mg/kg once weekly for the first 4 weeks inhaemophilia A patients, mean (±SD) trough plasma concentrations of emicizumab achieved52.6±13.6 µg/mL at Week 5.

The predicted mean (±SD) Ctrough ,and Cmax and ratios of Cmax/Ctrough at steady- state for therecommended maintenance doses of 1.5 mg/kg once weekly, 3 mg/kg every two weeks or 6 mg/kgevery four weeks are shown in Table 15 .

Table 15 Mean (± SD) steady-state emicizumab concentrations

Parameters 1.5 mg/kg QW 3 mg/kg Q2W 6 mg/kg Q4W

Cmax, ss (µg/mL) 54.9±15.9 58.1±16.5 66.8±17.7

Cavg, ss (µg/mL) 53.5 ±15.7 53.5 ±15.7 53.5 ±15.7

Ctrough, ss (µg/mL) 51.1±15.3 46.7±16.9 38.3±14.3

Cmax/Ctrough ratio 1.08±0.03 1.26±0.12 1.85±0.46

Cavg, ss = average concentration at steady state; Cmax, ss = maximum plasma concentration at steady state; Ctrough,ss = trough concentration at steady state; QW = once weekly; Q2W = every two weeks; Q4W = every fourweeks. Pharmacokinetic parameters derived from the population PK model.

Similar PK profiles were observed following once weekly dosing (3 mg/kg/week for 4 weeks followedby 1.5 mg/kg/week) in adults/adolescents (≥ 12 years) and children (< 12 years) (see Figure 1).

Figure 1: Mean (±95% CI) plasma emicizumab concentration versus time profiles forpatients ≥ 12 years (studies HAVEN 1 and HAVEN 3) compared withpatients < 12 years (study HAVEN 2)

In healthy subjects, the absolute bioavailability following subcutaneous administration of 1 mg/kg wasbetween 80.4% and 93.1% depending on the injection site. Similar pharmacokinetic profiles wereobserved following subcutaneous administration in the abdomen, upper arm, and thigh. Emicizumabcan be administered interchangeably at these anatomical sites (see section 4.2).

Following a single intravenous dose of 0.25 mg/kg emicizumab in healthy subjects, the volume ofdistribution at steady state was 106 mL/kg (i.e. 7.4 L for a 70-kg adult).

The apparent volume of distribution (V/F), estimated from the population PK analysis, in haemophilia

A patients following multiple subcutaneous doses of emicizumab was 10.4 L.

The metabolism of emicizumab has not been studied. IgG antibodies are mainly catabolised bylysosomal proteolysis and then eliminated from or reused by the body.

Following intravenous administration of 0.25 mg/kg in healthy subjects, the total clearance ofemicizumab was 3.26 mL/kg/day (i.e. 0.228 L/d for a 70-kg adult) and the mean terminal half-life was26.7 days.

Following single subcutaneous injection in healthy subjects, the elimination half-life wasapproximately 4 to 5 weeks.

Following multiple subcutaneous injections in haemophilia A patients, the apparent clearance was0.272 L/day and the elimination apparent half-life was 26.8 days.

Dose linearity

Emicizumab exhibited dose-proportional pharmacokinetics in patients with haemophilia A after thefirst dose of Hemlibra over a dose range from 0.3 to 6 mg/kg . The exposure (Cavg, ss) of multiple dosesis comparable between 1.5 mg/kg every week, 3mg/kg every 2 weeks and 6mg/kg dose every 4 weeks.

Paediatric

The effect of age on the pharmacokinetics of emicizumab was assessed in a populationpharmacokinetic analysis which included 5 infants (≥ 1 month to < 2 years), 55 children (lessthan 12 years) and 50 adolescents (12 to < 18 years) with haemophilia A. Age did not affect thepharmacokinetics of emicizumab in paediatric patients.

The effect of age on the pharmacokinetics of emicizumab was assessed in a populationpharmacokinetic analysis which included thirteen subjects aged 65 years and older (no subjects wereolder than 77 years of age). Relative bioavailability decreased with older age, but no clinicallyimportant differences were observed in the pharmacokinetics of emicizumab between subjects< 65 years and subjects ≥ 65 years.

Population pharmacokinetics analyses in patients with haemophilia A showed that race did not affectthe pharmacokinetics of emicizumab. No dose adjustment is required for this demographic factor.

Data in female patients are too limited for conclusion.

No dedicated studies of the effect of renal impairment on the pharmacokinetics of emicizumab havebeen conducted.

Most of the patients with haemophilia A in the population pharmacokinetic analysis had normal renalfunction (N = 332; creatinine clearance [CLcr] ≥ 90 mL/min) or mild renal impairment (N = 27; CLcrof 60-89 mL/min). Mild renal impairment did not affect the pharmacokinetics of emicizumab. Thereare limited data available on the use of Hemlibra in patients with moderate renal impairment (only 2patients with CLcr of 30-59 mL/min) and no data in patients with severe renal impairment. The impactof moderate and severe renal impairment on the pharmacokinetics of emicizumab cannot beconcluded.

Emicizumab is a monoclonal antibody and is cleared via catabolism rather than renal excretion and achange in dose is not expected to be required for patients with renal impairment.

No dedicated studies on the effect of hepatic impairment on the pharmacokinetics of emicizumab havebeen conducted. Most of the patients with haemophilia A in the population pharmacokinetic analysishad normal hepatic function (bilirubin and AST ≤ ULN, N = 300) or mild hepatic impairment(bilirubin ≤ ULN and AST > ULN or bilirubin from 1.0 to 1.5 × ULN and any AST, N = 51). Only6 patients had moderate hepatic impairment (1.5 × ULN < bilirubin ≤ 3 × ULN and any AST). Mildhepatic impairment did not affect the pharmacokinetics of emicizumab (see section 4.2). The safetyand efficacy of emicizumab have not been specifically tested in patients with hepatic impairment.

Patients with mild and moderate hepatic impairment were included in clinical studies. No data areavailable on the use of Hemlibra in patients with severe hepatic impairment.

Emicizumab is a monoclonal antibody and cleared via catabolism rather than hepatic metabolism anda change in dose is not expected to be required for patients with hepatic impairment.

Modelling shows that less frequent dosing in patients with hypoalbuminemia and low body weight fortheir age results in lower emicizumab exposures; simulations indicate that these patients would stillbenefit from clinically meaningful bleed control. No patients with such characteristics were enrolled inclinical studies.

Preclinical data reveal no special hazards for humans based on studies of acute and repeated dosetoxicity, including safety pharmacology endpoints and endpoints for reproductive toxicity.

Emicizumab did not cause any changes in the reproductive organs of male or female cynomolgusmonkeys up to the highest tested dose of 30 mg/kg/week (equivalent to 11 times the human exposureat the highest dose of 3 mg/kg/week, based on AUC).

No data are available with respect to potential side effects of emicizumab on embryo-foetaldevelopment.

Reversible haemorrhage, perivascular mononuclear cell infiltration, degeneration/necrosis of subcutisand swelling of endothelium in the subcutis was noted in animals after subcutaneous injection.

L-Arginine

L-Histidine

L-Aspartic acid

Poloxamer 188

Water for injections

No incompatibilities between Hemlibra and polypropylene or polycarbonate syringes and stainlesssteel needles have been observed.

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

Hemlibra 30 mg/mL solution for injection2 years.

Hemlibra 150 mg/mL solution for injection2 years.

Once removed from the refrigerator, unopened vials can be kept at room temperature (below 30°C) forup to 7 days.

After storage at room temperature, unopened vials may be returned to the refrigerator. If stored out ofand then returned to refrigeration, the total combined time out of refrigeration should not exceed 7days. The vials should never be exposed to temperatures above 30 °C. Vials that have been kept atroom temperature for more than 7 days or exposed to temperatures above 30 °C should be discarded.

Pierced vial and filled syringe

From a microbiological point of view, once transferred from the vial to the syringe, the medicinalproduct should be used immediately. If not used immediately, in-use storage times and conditions arethe responsibility of the user.

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

For storage conditions after first opening of the medicinal product, see section 6.3.

Hemlibra 30 mg/mL solution for injection3 mL clear glass type I vial with butyl rubber stopper laminated with a fluoro-resin film and crimpedwith an aluminium cap fitted with a grey plastic flip-off disk. Each vial contains 12 mg emicizumab in0.4 mL of solution for injection. Each carton contains one vial.

3 mL clear glass type I vial with butyl rubber stopper laminated with a fluoro-resin film and crimpedwith an aluminium cap fitted with a sky blue plastic flip-off disk. Each vial contains 30 mgemicizumab in 1 mL of solution for injection. Each carton contains one vial.

Hemlibra 150 mg/mL solution for injection3 mL clear glass type I vial with butyl rubber stopper laminated with a fluoro-resin film and crimpedwith an aluminium cap fitted with a purple plastic flip-off disk. Each vial contains 60 mg emicizumabin 0.4 mL of solution for injection. Each carton contains one vial.

3 mL clear glass type I vial with butyl rubber stopper laminated with a fluoro-resin film and crimpedwith an aluminium cap fitted with a turquoise plastic flip-off disk. Each vial contains 105 mgemicizumab in 0.7 mL of solution for injection. Each carton contains one vial.

3 mL clear glass type I vial with butyl rubber stopper laminated with a fluoro-resin film and crimpedwith an aluminium cap fitted with a brown plastic flip-off disk. Each vial contains 150 mgemicizumab in 1 mL of solution for injection. Each carton contains one vial.

3 mL clear glass type I vial with butyl rubber stopper laminated with a fluoro-resin film and crimpedwith an aluminium cap fitted with a yellow plastic flip-off disk. Each vial contains 300 mgemicizumab in 2 mL of solution for injection. Each carton contains one vial.

Not all pack sizes may be marketed.

Hemlibra solution is a sterile, preservative-free, and ready to use solution for subcutaneous injectionthat does not need to be diluted.

Hemlibra should be inspected visually to ensure there is no particulate matter or discolouration prior toadministration. Hemlibra is a colourless to slightly yellow solution. The solution should be discardedif particulate matter is visible or product is discoloured.

Do not shake.

Hemlibra solution for injection vials are for single-use only.

A syringe, a transfer needle with filter or a vial adapter with filter, and an injection needle are neededto withdraw Hemlibra solution from the vial and inject it subcutaneously.

Please see below recommended features:

A 1 mL syringe should be used for an injection up to 1 mL of Hemlibra solution, whereas a 2 to 3 mLsyringe should be used for an injection greater than 1 mL and up to 2 mL.

Refer to the Hemlibra “Instructions for Use” for handling instructions when combining vials in asyringe. Different Hemlibra vial concentrations (30 mg/mL and 150 mg/mL) should not be combinedin a single injection to administer the prescribed dose.

1 mL syringe

Criteria: Transparent polypropylene or polycarbonate syringe with Luer-lock tip, graduation 0.01 mL.

2 to 3 mL syringe

Criteria: Transparent polypropylene or polycarbonate syringe with Luer-lock tip, graduation 0.1 mL.

Transfer needle with filter

Criteria for transfer needle with filter: Stainless steel with Luer-lock connection, gauge 18 G, length35 mm (1½″), containing a 5 micrometre filter and preferably with semi-blunted tip.

Vial adapter with filter

Criteria for vial adapter with filter: Polypropylene with Luer-lock connection, integrating a 5micrometre filter, fitting 15 mm vial neck diameter.

Injection needle

Criteria: Stainless steel with Luer-lock connection, gauge 26 G (acceptable range: 25-27 gauge),length preferably 9 mm (3/8″) or maximally 13 mm (½″), preferably including needle safety feature.

Please see section 4.2 and package leaflet (section 7 Instructions for Use), for additional informationon administration.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Roche Registration GmbH

Emil-Barell-Strasse 179639 Grenzach-Wyhlen

Germany

Hemlibra 30 mg/mL solution for injection

EU/1/18/1271/006 (12 mg/0.4 mL)

EU/1/18/1271/001 (30 mg/1 mL)

Hemlibra 150 mg/mL solution for injection

EU/1/18/1271/002 (60 mg/0.4 mL)

EU/1/18/1271/003 (105 mg/0.7 mL)

EU/1/18/1271/004 (150 mg/1 mL)

EU/1/18/1271/005 (300 mg/2 mL)

Date of first authorisation: 23 February 2018

Date of latest renewal: 15 September 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.