Hemlibra

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ANNEX I 

 
SUMMARY OF PRODUCT CHARACTERISTICS 

 



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This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT  
 
Hemlibra 30 mg/mL solution for injection 
 
Hemlibra 150 mg/mL solution for injection 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Hemlibra 30 mg/mL solution for injection 
 
Each mL of solution contains 30 mg of emicizumab* 
 
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. 
 
* Emicizumab is a humanised monoclonal modified immunoglobulin G4 (IgG4) antibody produced 
using recombinant DNA technology in mammalian Chinese Hamster Ovary (CHO) cells 
 
For the full list of excipients, see section 6.1 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection. 
 
Colourless to slightly yellow solution. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Hemlibra is indicated for routine prophylaxis of bleeding episodes in patients with  
● haemophilia A (congenital factor VIII deficiency) with factor VIII inhibitors 
● severe haemophilia A (congenital factor VIII deficiency, FVIII < 1%) without factor VIII 

inhibitors.  
 
Hemlibra can be used in all age groups. 
 



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4.2 Posology and method of administration 
 
Treatment should be initiated under the supervision of a physician experienced in the treatment of 
haemophilia and/or bleeding disorders. 
 
Posology 
 
Treatment (including routine prophylaxis) with bypassing agents (e.g. aPCC and rFVIIa) should be 
discontinued the day before 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 
maintenance dose of either 1.5 mg/kg once weekly, 3 mg/kg every two weeks, or 6 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 dosing 
regimen 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 be 
administered 

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

 
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 same 
syringe 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 the 

loading dose. 
● To calculate the volume to be administered divide calculated dose 48 mg by 150 mg/mL: 48 mg 

of emicizumab ÷ 150 mg/mL = 0.32 mL of 150 mg/mL Hemlibra concentration to be injected. 
● Choose appropriate dosage and volume from vial strengths available. 
 
● Maintenance dose (from week 5 on) example: 16 kg x 1.5 mg/kg = 24 mg of emicizumab 

needed for the maintenance dose. 
● To calculate the volume to be administered divide calculated dose 24 mg by 30 mg/mL: 24 mg 

of emicizumab ÷ 30 mg/mL = 0.8 mL of 30 mg/mL Hemlibra concentration to be injected once 
weekly. 

● Choose appropriate dosage and volume from vial strength available.  
 



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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 the 

loading 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 be 
injected. 

● Choose appropriate dosage and volume from vial strengths available. 
 
● Maintenance dose (from week 5 on) example: 40 kg x 3 mg/kg = 120 mg of emicizumab needed 

for 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 be 
injected every two weeks. 

● Choose appropriate dosage and volume from vial strength 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 the 

loading 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 be 
injected. 

● Choose appropriate dosage and volume from vial strengths available.  
 
● Maintenance dose (from week 5 on) example: 60 kg x 6 mg/kg = 360 mg of emicizumab needed 

for 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 be 
injected every four weeks. 

● Choose appropriate dosage and volume from vial strengths available. 
 
Duration of treatment 
 
Hemlibra is intended for long-term prophylactic treatment.  
 
Dosage adjustments during treatment  
 
No dosage adjustments of Hemlibra are recommended. 
 
Delayed or missed doses  
 
If a patient misses a scheduled subcutaneous injection of Hemlibra, the patient should be instructed to 
take the missed dose as soon as possible, up to a day before the day of the next scheduled dose. The 
patient should then administer the next dose on the usual scheduled dosing day. The patient should not 
take two doses on the same day to make up for a missed dose. 
 
Special populations 
 
Paediatric  
 
No dose adjustments are recommended in paediatric patients (see section 5.2). There are no data in 
patients less than 1 year of age. 
 
Elderly 
 
No dose adjustments are recommended in patients ≥ 65 years of age (see sections 5.1 and 5.2).   There 
are no data in patients over 77 years old. 
 



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Renal and hepatic impairment 
 
No dose adjustments are recommended in patients with mild , renal or hepatic impairment (see 
section 5.2). There are limited data available on the use of Hemlibra in patients with moderate renal or 
hepatic impairment.  Emicizumab has not been studied in patients with severe renal or hepatic 
impairment 
 
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 clinical trials.  
 
If bypassing agents (e.g. aPCC and rFVIIa) are required in the perioperative period, please refer to the 
dosing guidance on the use of bypassing agents in section 4.4. 
If FVIII is required in the perioperative period, please refer to section 4.5. 
 
When monitoring a patients underlying hemostatic activity, please refer to section 4.4 for laboratory 
tests unaffected by emicizumab. 
 
Immune tolerance induction (ITI) 
 
The safety and efficacy of emicizumab in patients receiving ongoing immune tolerance induction have 
not yet been established. No data are available. 
 
Method of administration 
 
Hemlibra is for subcutaneous use only, and it should be administered using appropriate aseptic 
technique (see section 6.6). 
 
The injection should be restricted to the recommended injection sites: the abdomen, the upper outer 
arms and the thighs (see section 5.2).  
 
Administration of Hemlibra subcutaneous injection in the upper outer arm should be performed by a 
caregiver 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 in 
subcutaneous injection technique, a patient may self-inject Hemlibra, or the patient’s caregiver may 
administer 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. 
 
4.3 Contraindications  
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 



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4.4 Special warnings and precautions for use  
 
Traceability  
 
In order to improve 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 activated prothrombin complex 
concentrate 
 
Cases of thrombotic microangiopathy (TMA) were reported from a clinical trial in patients receiving 
Hemlibra prophylaxis when on average a cumulative amount of  >100U/kg/24 hours of activated 
prothrombin complex concentrate (aPCC) for 24 hours or more was administered (see section 4.8). 
Treatment for the TMA events included supportive care with or without plasmapheresis and 
haemodialysis. Evidence of improvement was seen within one week following discontinuation of 
aPCC and interruption of Hemlibra. This rapid improvement is distinct from the usual clinical course 
observed in atypical hemolytic uremic syndrome and classic TMAs, such as thrombotic 
thrombocytopenic purpura (see section 4.8). One patient resumed Hemlibra following resolution of 
TMA and continued to be treated safely. 
 
Patients receiving Hemlibra prophylaxis should be monitored for the development of TMA when 
administering aPCC. The physician should immediately discontinue aPCC and interrupt Hemlibra 
therapy if clinical symptoms and/or laboratory findings consistent with TMA occur, and manage as 
clinically indicated. Physicians and patients/caregivers should weigh the benefits and risks of 
resuming Hemlibra prophylaxis following complete resolution of TMA on a case-by-case basis. In 
case a bypassing agent is indicated in a patient receiving Hemlibra prophylaxis, see below for dosing 
guidance on the use of bypassing agents. 
 
Caution should be used when treating patients who are at high risk for TMA (e.g. have a previous 
medical history or family history of TMA), or those who are receiving concomitant medications 
known to be a risk factor for the development of TMA (e.g. ciclosporin, quinine, tacrolimus). 
 
Thromboembolism associated with Hemlibra and activated prothrombin complex concentrate  
 
Serious thrombotic events were reported from a clinical trial in patients receiving Hemlibra 
prophylaxis when on average a cumulative amount of >100U/kg/24 hours of aPCC for 24 hours or 
more was administered (see section 4.8). No cases required anticoagulation therapy. Following 
discontinuation of aPCC and interruption of Hemlibra, evidence of improvement or resolution was 
seen within one month (see section 4.8). One patient resumed Hemlibra following resolution of 
thrombotic event and continued to be treated safely.  
 
Patients receiving Hemlibra prophylaxis should be monitored for the development of 
thromboembolism when administering aPCC. The physician should immediately discontinue aPCC 
and interrupt Hemlibra therapy if clinical symptoms, imaging, and/or laboratory findings consistent 
with thrombotic events occur, and manage as clinically indicated. Physicians and patients/caregivers 
should weigh the benefits and risks of resuming Hemlibra prophylaxis following complete resolution 
of thrombotic events on a case-by-case basis. In case a bypassing agent is indicated in a patient 
receiving Hemlibra prophylaxis, see below for dosing guidance on the use of bypassing agents. 
 
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. 



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Physicians should discuss with all patients and/or caregivers the exact dose and schedule of bypassing 
agents to use, if required while receiving Hemlibra prophylaxis. 
 
Hemlibra increases the patient’s coagulation potential. The bypassing agent dose required may 
therefore be lower than that used without Hemlibra prophylaxis. The dose and duration of treatment 
with bypassing agents will depend on the location and extent of bleeding, and the patient’s clinical 
condition. Use of aPCC should be avoided unless no other treatment options/alternatives are available. 
If aPCC is indicated in a patient receiving Hemlibra prophylaxis, the initial dose should not exceed 
50 U/kg and laboratory monitoring is recommended (including but not restricted to renal monitoring, 
platelet testing, and evaluation of thrombosis). If bleeding is not controlled with the initial dose of 
aPCC up to 50 U/kg, additional aPCC doses should be administered under medical guidance or 
supervision with consideration made to laboratory monitoring for the diagnosis of TMA or 
thromboembolism and verification of bleeds prior to repeated dosing. The total aPCC dose should not 
exceed 100 U/kg in the first 24-hours of treatment. Treating physicians must carefully weigh the risk 
of TMA and thromboembolism against the risk of bleeding when considering aPCC treatment beyond 
a maximum of 100 U/kg in the first 24-hours. 
 
In clinical trials, no cases of TMA or thrombotic events were observed with use of activated 
recombinant human FVII (rFVIIa) alone in patients receiving Hemlibra prophylaxis. 
 
Bypassing agent dosing guidance should be followed for at least 6 months following discontinuation 
of Hemlibra prophylaxis (see section 5.2). 
 
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 monitor 
coagulation parameters during treatment, with specific considerations for FVIII chromogenic activity 
assays as described below. 
 
Chromogenic factor VIII activity tests may be manufactured with either human or bovine coagulation 
proteins. Assays containing human coagulation factors are responsive to emicizumab but may 
overestimate the clinical haemostatic potential of emicizumab. In contrast, assays containing bovine 
coagulation factors are insensitive to emicizumab (no activity measured) and can be used to monitor 
endogenous or infused factor VIII activity, or to measure anti FVIII inhibitors. 
 
Emicizumab remains active in the presence of inhibitors against factor VIII and so will produce a false 
negative result in clotting based Bethesda assays for functional inhibition of factor VIII. Instead, a 
chromogenic Bethesda assay utilising a bovine based factor VIII chromogenic test that is insensitive to 
emicizumab may be used. 
 
These two pharmacodynamic markers do not reflect the true haemostatic effect of emicizumab in vivo 
(aPTT is overly shortened and reported factor VIII activity may be overestimated) but provide a 
relative indication of the pro-coagulant effect of emicizumab. 
 



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In summary, intrinsic pathway clotting-based laboratory test results in patients treated with Hemlibra 
should not be used to monitor its activity, determine dosing for factor replacement or anti-coagulation, 
or measure factor VIII inhibitors titers. Caution should be taken if intrinsic pathway clotting based 
laboratory tests are used, as misinterpretation of their results may lead to under-treatment of patients 
experiencing bleeding episodes, which can potentially result in severe or life-threatening bleeds.  
 
Laboratory tests affected and unaffected by emicizumab are shown in Table 1 below. Due to its long 
half-life, these effects on coagulation assays may persist for up to 6 months after the last dose (see 
section 5.2). 
 
Table 1 Coagulation test results affected and unaffected by emicizumab 
 

Results Affected by emicizumab Results Unaffected by emicizumab 

- Activated partial thromboplastin time (aPTT) 
- Bethesda assays (clotting-based) for FVIII 
inhibitor titers  
- One-stage, aPTT-based, single-factor assays 
- aPTT-based activated protein C resistance 
(APC-R) 
- Activated clotting time (ACT) 

- Bethesda assays (bovine chromogenic) for FVIII 
inhibitor titers 
- Thrombin time (TT) 
- One-stage, prothrombin time (PT)-based, 
single-factor assays 
- Chromogenic-based single-factor assays other 
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. 
 
Paediatric population 
 
There are no data in children < 1 year of age. The developing hemostatic system in neonates and 
infants is dynamic and evolving, and the relative concentrations of pro- and anticoagulant proteins in 
these patients should be taken into consideration when making a benefit-risk assessment, including 
potential risk of thrombosis (e.g. central venous catheter-related thrombosis). 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No adequate or well-controlled drug-drug interaction studies have been conducted with emicizumab.  
 
Clinical experience indicates a drug interaction exists with emicizumab and aPCC (see sections 4.4 
and 4.8).  
 
There is a possibility for hypercoagulability with rFVIIa or FVIII with emicizumab based on 
preclinical experiments. Emicizumab increases coagulation potential, therefore the FVIIa or FVIII 
dose required to achieve hemostasis may be lower than when used without Hemlibra prophylaxis. 
 
In case of thrombotic complication, the physician should consider discontinuing rFVIIa or FVIII and 
interrupt Hemlibra prophylaxis as clinically indicated. Further management should be tailored to the 
individual clinical circumstances. 
● Decision about dose modifications should take into account the half-life of medications; 

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 



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considered when systemic anti-fibrinolytics are used in combination with aPCC or rFVIIa in patients 
receiving emicizumab. 
 
4.6 Fertility, pregnancy and lactation 
 
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. 
 
4.7 Effects on ability to drive and use machines 
 
Hemlibra has no influence on the ability to drive and use machines.  
 
4.8 Undesirable effects  
 
Summary of the safety profile  
 
The most serious adverse drug reactions (ADRs) reported from the clinical trials with Hemlibra were 
thrombotic microangiopathy (TMA) and thrombotic events, including cavernous sinus thrombosis 
(CST) and superficial vein thrombosis contemporaneous with skin necrosis (see below and 
section 4.4). 
 
The most common ADRs reported in ≥ 10% of patients treated with at least one dose of Hemlibra 
were: injection site reactions (20 %), arthralgia (15 %) and headache (14 %). 
 
In total three patients (0.8 %) in the clinical trials receiving Hemlibra prophylaxis withdrew from 
treatment due to ADRs, which were TMA, skin necrosis contemporaneous with superficial 
thrombophlebitis, and headache.  
 



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Tabulated list of adverse drug reactions  
 
The following adverse drug reactions (ADRs) are based on pooled data from four phase III clinical 
trials (adult and adolescent studies [BH29884 - HAVEN 1, BH30071 – HAVEN 3, and BO39182 – 
HAVEN 4] and a paediatric study BH29992 - HAVEN 2]), in which a total of 373 male patients with 
haemophilia A received at least one dose of Hemlibra as routine prophylaxis. Two hundred and sixty-
six (71 %) were adults, 47(13 %) were adolescents (≥ 12 to < 18 years), 55 (15 %) were children (≥ 2 
to < 12 years) and five (1 %) were infants and toddlers (1 month to < 2 years). The median duration of 
exposure across the studies was 33 weeks (range: 0.1 to 94.3 weeks).  
 
ADRs from the phase III clinical trials in patients who received Hemlibra are listed by MedDRA 
system organ class (Table 2). The corresponding frequency categories for each ADR are based on the 
following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to 
< 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) and not known (cannot be estimated 
from the available data).  
 
Table 2 Summary of adverse drug reactions from pooled HAVEN clinical trials with 

Hemlibra  
 
System Organ Class (SOC) Adverse reactions 

(preferred term, MedDRA) 
Frequency 

Blood and lymphatic system disorders Thrombotic microangiopathy Uncommon 

Nervous system disorders Headache Very common 

Vascular disorders Thrombophlebitis superficial Uncommon 

*Cavernous sinus thrombosis Uncommon 

Gastrointestinal disorders Diarrhoea  Common 

Skin and subcutaneous tissue disorders Skin necrosis Uncommon 

Musculoskeletal and connective tissue 
disorders 

Arthralgia Very common 

Myalgia Common 

General disorders and administration 
site conditions 

Injection site reaction Very common 

Pyrexia Common 
*Vascular disorders is a secondary SOC for cavernous sinus thrombosis. 
 
Description of selected adverse drug reactions 
 
Thrombotic microangiopathy 
 
In pooled phase III clinical trials, thrombotic microangiopathy (TMA) events were reported in less 
than 1 % of patients (3/373) and in 9.7 % of patients (3/31) who received at least one dose of aPCC 
while being treated with emicizumab. All 3 TMAs occurred when on average a cumulative amount 
of > 100 U/Kg/24 hours of aPCC for 24 hours or more was administered during a treatment event (see 
section 4.4). Patients presented with thrombocytopenia, microangiopathic hemolytic anemia, and acute 
kidney injury, without severe deficiencies in ADAMTS13 activity. One patient resumed Hemlibra 
following resolution of TMA without recurrence. 
 
Thrombotic events 
 
In pooled phase III clinical trials, serious thrombotic events were reported in less than 1 % of patients 
(2/373) and in 6.5 % of patients (2/31) who received at least one dose of aPCC while being treated 
with emicizumab. Both serious thrombotic events occurred when on average a cumulative amount 
of > 100 U/Kg/24 hours of aPCC for 24 hours or more was administered during a treatment event. One 



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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 trials  
 
There were 82 instances of aPCC treatment* in patients receiving Hemlibra prophylaxis, of which 
eight instances (10%) consisted of on average a cumulative amount of >100 U/kg/24 hours of aPCC 
for 24 hours or more; two of the eight instances were associated with thrombotic events and three of 
the eight instances were associated with TMA (Table 3). No TMA or thrombotic events were 
associated with the remaining instances of aPCC treatment. Of all instances of aPCC treatment, 68 % 
consisted of only one infusion < 100 U/kg. 
 
Table 3 Characterisation of aPCC treatment* in the pooled phase III clinical studies  
 

Duration of aPCC 
treatment  

Average cumulative amount of aPCC over 24 hours 
(U/kg/24 hours) 

<50 50–100 >100 

<24 hours 9 47 13 
24-48 hours 0 3 1b 
>48 hours 1 1 7a,a,a,b 

 

* An instance of aPCC treatment is defined as all doses of aPCC received by a patient, for any reason, until there 
was a 36-hour treatment-free break. Includes all instances of aPCC treatment excluding those in the first 7 days 
and those that occurred 30 days after the discontinuation of Hemlibra. 
a Thrombotic microangiopathy 
b Thrombotic event 
 
Injection site reactions 
 
Injection site reactions (ISRs) were reported very commonly (20 %) from clinical trials. All ISRs 
observed in the Hemlibra clinical trials were reported as being non-serious and mild to moderate in 
intensity, and 95 % resolved without treatment. The most commonly reported ISR symptoms were 
injection site erythema (11  %), injection site pain (4 %) and injection site pruritus (3 %). 
 
Paediatric population 
 
The paediatric population studied comprises a total of 107 patients, of which 5 (5 %) were infants and 
toddlers (1 month to less than 2 years of age), 55 (51 %) were children (from 2 to less than 12 years of 
age) and 47 (44 %) were adolescents (from 12 to less than 18 years old). The safety profile of 
Hemlibra was overall consistent between infants, children, adolescents, and adults. 
 
Reporting 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.  
 
4.9 Overdose 
 
There is limited experience with overdose of Hemlibra. 
 
Symptoms 
 
Accidental overdose may result in hypercoagulability.  
 

https://www.ema.europa.eu/documents/template-form/appendix-v-adverse-drug-reaction-reporting-details_en.doc


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Management 
 
Patients who receive an accidental overdose should immediately contact their physician and be 
monitored closely.  
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: antihemorrhagics, other systemic hemostatics; ATC code: B02BX06 
 
Mechanism of action  
 
Emicizumab is a humanized monoclonal modified immunoglobulin G4 (IgG4) antibody with a 
bispecific antibody structure. 
 
Emicizumab bridges activated factor IX and factor X to restore the function of missing activated factor 
VIII that is needed for effective haemostasis. 
 
Emicizumab has no structural relationship or sequence homology to factor VIII and, as such, does not 
induce or enhance the development of direct inhibitors to factor VIII. 
 
Pharmacodynamics 
 
Prophylactic therapy with Hemlibra shortens the aPTT and increases the reported factor VIII activity 
(using a chromogenic assay with human coagulation factors). These two pharmacodynamic markers 
do not reflect the true haemostatic effect of emicizumab in vivo (aPTT is overly shortened and 
reported factor VIII activity may be overestimated) but provide a relative indication of the pro-
coagulant effect of emicizumab. 
 
Clinical efficacy and safety 
 
The efficacy of Hemlibra for routine prophylaxis in patients with hemophilia A with or without FVIII 
inhibitors was evaluated in four clinical studies (three adult and adolescent studies [HAVEN 3, 
HAVEN 1, and HAVEN 4] and a paediatric study [HAVEN 2]). 
 
Clinical studies in adults and adolescents 
 
Patients (aged ≥ 12 years old and > 40 kg) with hemophilia A without FVIII inhibitors (Study 
BH30071 – HAVEN 3) 
 
The HAVEN 3 study was a randomized, multicenter, open-label, phase III clinical study in 152 adult 
and adolescent males (aged ≥ 12 years and > 40 kg) with severe hemophilia A without FVIII inhibitors 
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 weeks followed 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 every two 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 more qualified bleeds (i.e., 
spontaneous and clinically significant bleeds occurring at steady state).  Arm D patients could up-
titrate after the second qualifying bleed.  At the time of the primary analysis, five patients underwent 
up-titration of their maintenance dose. 
 
Eighty-nine patients previously treated with episodic (“on demand”) FVIII were randomized in a 2:2:1 
ratio to receive Hemlibra either once weekly (Arm A; N = 36), every two weeks (Arm B; N = 35) or 
no prophylaxis (Arm C; N = 18), with stratification by prior 24-week bleed rate (< 9 or ≥ 9).  Sixty-



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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 FVIII 
the efficacy of prophylactic Hemlibra weekly (Arm A) or every two weeks (Arm B) compared to no 
prophylaxis (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 randomized comparison of Arms A 
or 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 patient 
treatment 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 treatment 
data were collected with the same level of granularity as used in HAVEN 3. The NIS is an 
observational study with the main objective of capturing detailed clinical data on the bleeding episodes 
and haemophilia medication use of patients with haemophilia A outside of an interventional trial 
setting. 
 
Patients (aged ≥ 12 years old) with haemophilia A with factor VIII inhibitors (Study BH29884 – 
HAVEN 1) 
 
The HAVEN 1 study was a randomised, multicentre, open-label clinical study in 109 adolescent and 
adult males (aged ≥  12 years old) with haemophilia A with factor VIII inhibitors who had previously 
received either episodic or prophylactic treatment with bypassing agents (aPCC and rFVIIa). In the 
study, patients received weekly Hemlibra prophylaxis (Arms A, C, and D) — 3 mg/kg once weekly 
for four weeks followed by 1.5 mg/kg once weekly thereafter — or no prophylaxis (Arm B). Patients 
randomized to Arm B could switch to Hemlibra prophylaxis after completing at least 24 weeks 
without 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.  spontaneous 
and 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 randomised 
in a 2:1 ratio to receive Hemlibra prophylaxis (Arm A) or no prophylaxis (Arm B), with stratification 
by prior 24-week bleed rate (< 9 or ≥ 9). 
 
Forty-nine patients previously treated with prophylactic bypassing agents were enrolled in Arm C to 
receive 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 Hemlibra 
prophylaxis.  
 
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 with 
no prophylaxis (Arm A vs. Arm B) on the number of bleeds requiring treatment with coagulation 
factors over time (minimum of 24 weeks or date of discontinuation) (see Table 6). Other secondary 
objectives of the randomised comparison of Arms A and B were the efficacy of weekly Hemlibra 
prophylaxis in reducing the number of all bleeds, spontaneous bleeds, joint bleeds and target joint 
bleeds (see Table 6), as well as assessing patients’ HRQoL and health status (see Tables 9 and 10). 
The mean exposure time (+SD) for all patients on study was 21.38 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. One patient in Arm A withdrew from study prior 
to initiation of Hemlibra. 
 



14 
 

The study also evaluated the efficacy of weekly Hemlibra prophylaxis compared with previous 
episodic (on-demand) and prophylactic bypassing agents (separate comparisons) in patients who had 
participated 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 factor VIII inhibitors (Study 
BO39182 – HAVEN 4) 
 
Hemlibra was investigated in a single arm, multicenter, phase III clinical study in 41 adult and 
adolescent males (aged ≥ 12 years and > 40 kg) who have hemophilia A with FVIII inhibitors or 
severe hemophilia 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 primary 
objective of the study was to evaluate the efficacy of Hemlibra prophylaxis given every four weeks in 
maintaining adequate bleed control, based on treated bleeds.  Other objectives were to evaluate the 
clinical efficacy of Hemlibra prophylaxis on all bleeds, treated spontaneous bleeds, treated joint bleeds 
and treated target joint bleeds (see Table 8).  Patient treatment preference was also assessed using a 
preference survey. 
 
Adults and Adolescents Efficacy Results 
 
HAVEN 3 
 
The efficacy results of Hemlibra prophylaxis compared with no prophylaxis with respect to rate of 
treated bleeds, all bleeds, treated spontaneous bleeds, treated joint bleeds, and treated target joint 
bleeds are shown in Table 4. 
 
Table 4 HAVEN 3 study: Annualised Bleed Rate for Hemlibra prophylaxis arm versus no 

prophylaxis arm in patients ≥ 12 years of age without factor VIII inhibitors 
 

 Endpoint 
Arm C: 

No Prophylaxis 
(N = 18) 

Arm A: 
Hemlibra 

1.5 mg/kg weekly 
(N = 36) 

Arm B: 
Hemlibra 
3 mg/kg 

every 2 weeks 
(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 
(95% CI) 

0 (0.0:18.5) 50 (32.9; 67.1) 40 (23.9; 57.9) 



15 
 

 Endpoint 
Arm C: 

No Prophylaxis 
(N = 18) 

Arm A: 
Hemlibra 

1.5 mg/kg weekly 
(N = 36) 

Arm B: 
Hemlibra 
3 mg/kg 

every 2 weeks 
(N = 35) 

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 
(95% CI) 

22.2 (6.4; 47.6) 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 
(95% CI) 

0 (0; 18.5) 58.3 (40.8; 74.5) 74.3 (56.7; 87.5) 

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 
(95% CI) 

27.8 (9.7; 53.5) 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-value from 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, 25th percentile to 75th 
percentile, NA=Not Applicable 

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



16 
 

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:  

Previous FVIII Prophylaxis 
(N = 48) 

Arm D:  
Hemlibra 1.5 mg/kg weekly 
(N = 48) 

Median Efficacy Period (weeks) 30.1 33.7 
Treated Bleeds 
ABR (95% CI) a 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 percentile 
to 75th percentile 
Although a higher adherence was observed with emicizumab prophylaxis than with prior FVIII 
prophylaxis, no difference in ABR in patients with ≥80% or < 80% compliant doses on FVIII prophylaxis 
according to standard label requirements could be identified (data to be interpreted with caution due to 
small sample sizes). 
Due to  the short half-life of FVIII, no carryover effect is assumed after it's discontinuation.  
Only the first five emicizumab doses had to be administered under supervision to ensure safety and 
injection technique proficiency. Similar to FVIII prophylaxis, self administration at home was allowed for 
all subsequent emicizumab doses.   
All patients were treated by hemophilia experts who confirmed that adequate FVIII propylaxis was 
administered to patients included in the intra-patient comparison, supporting equivalent usual prophylaxis 
care across sites and patients. 

 
HAVEN 1 
 
The efficacy results of Hemlibra prophylaxis compared with no prophylaxis with respect to rate of 
treated bleeds, all bleeds, treated spontaneous bleeds, treated joint bleeds, and treated target joint 
bleeds are shown in Table 6. 
 



17 
 

Table 6 HAVEN 1: Annualised Bleed Rate with Hemlibra prophylaxis arm versus no 
prophylaxis arm in patients ≥ 12 years of age with factor VIII 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-value from 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, 25th 

percentile to 75th percentile. 
 



18 
 

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 with 
previous 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) 
 

 Endpoint 
Arm CNIS: previous bypassing agent 

prophylaxis 
Arm C: Hemlibra 1.5 mg/kg 

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 
(RR), p-value 

79% 
(0.21), 0.0003 

 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 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, 25th 
percentile 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 BPA 
prophylaxis according to standard label requirements could be identified  (data to be interpreted with caution 
due to small sample sizes). 

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

Only the first five emicizumab doses had to be administered under supervision to ensure safety and injection 
technique proficiency. Similar to BPA prophylaxis, self administration at home was allowed for all subsequent 
emicizumab doses.   
 
HAVEN 4 
 
Primary analysis efficacy results of Hemlibra prophylaxis every four weeks with respect to rate of 
treated bleeds, all bleeds, treated spontaneous bleeds, treated joint bleeds, and treated target joint 
bleeds are shown in Table 8. Forty one patients ≥ 12 years old were evaluated for efficacy with a 
median observation time of 25.6 weeks (range: 24.1-29.4).  
 



19 
 

Table 8 HAVEN 4: Annualised Bleed Rate with Hemlibra prophylaxis in patients ≥12 years 
of age with or without factor VIII 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 
Bleeds 

0.6 (0.3;1.5) 0.0 (0.0; 0.0) 82.9 (67.9;92.8) 

Treated Joint Bleeds 1.7 (0.8; 3.7) 0.0 (0.0; 1.9) 70.7 (54.5; 83.9) 
Treated Target Joint 
Bleeds                                                                                                                                                                

1.0 (0.3; 3.3) 0.0 (0.0;0.0) 85.4 (70.8; 94.4) 

a Calculated with negative binomial regression (NBR) model 
b 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=Annualized Bleed Rate, CI=confidence interval; IQR=interquartile range; 25th percentile to 75th 
percentile ; Q4W=once every four week prophylaxis 
 
 
Adults and Adolescents Health-Related outcome measures 
 
The HAVEN adult and adolescent clinical studies evaluated patient-reported hemophilia-related 
quality of life outcomes with 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), the Physical 
Health Score (i.e. painful swellings, presence of joint pain, pain with movement, difficulty walking far 
and needing more time to get ready) and Total Score (summary of all scores) were protocol defined 
endpoints of interest.  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) was 
examined. 
 
HAVEN 1 health-related outcomes 
 
In this study baseline Total Scores (mean = 41.14 and 44.58, respectively) and Physical Health scale 
scores (mean = 52.41 and 57.19, respectively) were similar for Hemlibra prophylaxis and no 
prophylaxis. Table 9 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 Health 
scale after 24 weeks of treatment adjusting for baseline. Weekly Hemlibra prophylaxis showed a 
statistically significant and clinically meaningful improvement compared with no prophylaxis in the 
pre-specified endpoints of Haem-A-QoL Physical Health Scale score at the Week 25 assessment. 
 



20 
 

Table 9 HAVEN 1: Change in Haem-A-QoL Physical Health and Total score with Hemlibra 
prophylaxis versus no prophylaxis in patients ≥ 18 years with factor VIII inhibitors  

 

Haem-A-QoL at week 25 Arm B: no prophylaxis  
(N=14) 

Arm A: Hemlibra 
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 on data from 
individuals who provided responses at both baseline and Week 25 assessments. 

 
HAVEN 1 Health Status Outcomes 
 
Table 10 provides a summary of the comparison between the Hemlibra prophylaxis arm (Arm A) and 
the no prophylaxis arm (Arm B) on the EQ-5D-5L index utility scale and visual analog scale after 
24 weeks of treatment adjusting for baseline.  
 
Table 10 HAVEN 1: EQ-5D-5L scores in patients ≥ 12 years at week 25 
 

EQ-5D-5L scores after 24 weeks Arm B: no prophylaxis 
(N=16) 

Arm A: Hemlibra 
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 25 assessments. 
 

 



21 
 

Clinical study in paediatric patients 
 
Paediatric patients (age < 12 years old, or 12 to 17 years old weighing < 40 kg) with haemophilia A 
with factor VIII inhibitors (Study BH29992 – HAVEN 2) 
 
Hemlibra weekly prophylaxis was evaluated in a single-arm, multicentre, open-label clinical study in 
paediatric patients (age < 12 years old, or 12 to 17 years old weighing < 40 kg) with haemophilia A 
with factor VIII inhibitors. Patients received Hemlibra prophylaxis at 3 mg/kg once weekly for the 
first 4 weeks followed by 1.5 mg/kg once weekly thereafter.  
 
The study evaluated the pharmacokinetics, safety, and efficacy including the efficacy of weekly 
Hemlibra prophylaxis compared with previous episodic and prophylactic bypassing agent treatment in 
patients who had participated in the NIS prior to enrolment (intra-patient comparison). 
 
HAVEN 2 paediatric Efficacy Results (Interim Analysis) 
 
At the time of the interim analysis, efficacy was evaluated in 59 patients who were < 12 years old and 
had 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. Annualized bleed 
rate and percent of patients with zero bleeds were calculated (see Table 11). The median observation 
time for these patients was 29.6 weeks (range: 18.4 to 63.0 weeks).  
 

 Table 11 HAVEN 2: Overview of efficacy (interim analysis) 
 
Endpoint aABR (95% CI) 

 
bN = 59 

cMedian ABR (IQR) 
 

bN = 59 

% Zero Bleeds  
(95% CI) 

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 spontaneous 
bleeds 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 joint 
bleeds 0.1 (0; 0.7) 0 (0; 0) 96.6 (88.3; 99.6) 

ABR = annualized bleed rate; CI = confidence interval; IQR = interquartile range, 25th percentile to 75th 
percentile 
  a 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. 
  bCalculated 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 meaningful 
reduction (98 %) in treated bleed rate in 18 paediatric patients who had at least 12 weeks of Hemlibra 
prophylaxis compared to their bleed rate collected in the NIS prior to enrolment (Table 12).  
 



22 
 

Table 12 HAVEN 2: Intra-patient comparison of Annualised Bleed Rate (treated 
bleeds) with Hemlibra prophylaxis versus previous bypassing agent 
prophylaxis 

 
Endpoint Previous bypassing agent 

treatment* (N = 18) 
Hemlibra prophylaxis 

(N = 18) 
Treated bleeds 
ABR (95% CI) 19.8 (15.3; 25.7) 0.4 (0.15; 0.88) 

% reduction (RR) 
98% 

 

 (0.02) 
 

% patients with zero bleeds (95% 
CI) 

5.6 (0.1; 27.3) 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 3 
subject 
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 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, 25th percentile 
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 BPA prophylaxis 
according to standard label requirements could be identified (data to be interpreted with caution due to small 
sample sizes). 
Due to the short half-life of bypassing agents,  no carryover effect is assumed after it's discontinuation. 
Only the first five emicizumab doses had to be administered under supervision to ensure safety and injection 
technique proficiency. Similar to BPA prophylaxis, self administration at home was allowed for all subsequent 
emicizumab doses. 
 
 
Pediatric 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 13).  The Haemo-QoL-SF is a valid and reliable 
measure 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 13). The Adapted InhibQoL is a valid and reliable measure of HRQoL.  
 



23 
 

Table 13 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 by patients 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 of 
caregiver 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 managed 
with available therapies.  For bypassing agent guidance refer to section 4.4.  
 
Immunogenicity  
 
As with all therapeutic proteins, there is the potential for an immune response in patients treated with 
emicizumab. A total of 398 patients were tested for anti-emicizumab antibodies in the HAVEN 1-4 
clinical trials. Less than 5 % of patients tested positive for anti-emicizumab antibodies and < 1 % of 
patients had anti-emicizumab antibodies with neutralizing potential (based on declining 
pharmacokinetics). Loss of efficacy was reported in 1 out of 398 patients. . 
 
In case of clinical signs of loss of efficacy, a change of treatment should be considered. 
 
Elderly population 
 
Use of Hemlibra in patients aged 65 and over with haemophilia A is supported by adult and adolescent 
studies HAVEN 1, HAVEN 3, and HAVEN 4. Based on limited data, there is no evidence to suggest a 
difference in efficacy or safety in patients aged 65 years or above.  
 
5.2 Pharmacokinetic properties  
 
The pharmacokinetics of emicizumab was determined via non-compartmental analysis in healthy 
subjects and using a population pharmacokinetic analysis on a database composed of 389 patients with 
haemophilia A. 
 
Absorption  
 
Following subcutaneous administration in haemophilia A patients, the absorption half-life was 
1.6 days.  
 
Following multiple subcutaneous administrations of 3 mg/kg once weekly for the first 4 weeks in 
haemophilia A patients, mean (±SD) trough plasma concentrations of emicizumab achieved 
52.6±13.6 µg/mL at Week 5. 
 



24 
 

The predicted mean (±SD) Ctrough ,and Cmax and ratios of Cmax/Ctrough at steady- state for the 
recommended maintenance doses of 1.5 mg/kg once weekly, 3 mg/kg every two weeks or 6 mg/kg 
every four weeks are shown in Table 14 . 
 
Table 14 Mean (± SD) steady-state emicizumab concentrations 
 
 Maintenance dose 

Parameters 1.5 mg/kg once weekly 3 mg/kg every two 
weeks 

6 mg/kg every four 
weeks 

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 four weeks.  
Pharmacokinetic parameters derived from the population PK model. 

 
Similar PK profiles were observed following once weekly dosing (3 mg/kg/week for 4 weeks followed 
by 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 for 

patients ≥ 12 years (studies HAVEN 1 and HAVEN 3) compared with 
patients < 12 years (study HAVEN 2) 

 

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



25 
 

Distribution  
 
Following a single intravenous dose of 0.25 mg/kg emicizumab in healthy subjects, the volume of 
distribution 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. 
 
Metabolism 
 
The metabolism of emicizumab has not been studied. IgG antibodies are mainly catabolised by 
lysosomal proteolysis and then eliminated from or reused by the body. 
 
Elimination  
 
Following intravenous administration of 0.25 mg/kg in healthy subjects, the total clearance of 
emicizumab was 3.26 mL/kg/day (i.e. 0.228 L/d for a 70-kg adult) and the mean terminal half-life was 
26.7 days. 
 
Following single subcutaneous injection in healthy subjects, the elimination half-life was 
approximately 4 to 5 weeks. 
 
Following multiple subcutaneous injections in haemophilia A patients, the apparent clearance was 
0.272 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 the 
first dose of Hemlibra over a dose range from 0.3 to 6 mg/kg . The exposure (Cavg, ss) of multiple doses 
is comparable between 1.5 mg/kg every week, 3mg/kg every 2 weeks and 6mg/kg dose every 4 weeks. 
 
Special populations  
 
Paediatric 
 
The effect of age on the pharmacokinetics of emicizumab was assessed in a population 
pharmacokinetic analysis which included 5 infants (≥ 1 month to < 2 years), 55 children (less 
than 12 years) and 50 adolescents (12 to < 18 years) with haemophilia A.  Age did not affect the 
pharmacokinetics of emicizumab in paediatric patients.  
 
Elderly 
 
The effect of age on the pharmacokinetics of emicizumab was assessed in a population 
pharmacokinetic analysis which included thirteen subjects aged 65 years and older (no subjects were 
older than 77 years of age). Relative bioavailability decreased with older age, but no clinically 
important differences were observed in the pharmacokinetics of emicizumab between subjects 
< 65 years and subjects ≥ 65 years.  
 
Race 
 
Population pharmacokinetics analyses in patients with haemophilia A showed that race did not affect 
the pharmacokinetics of emicizumab. No dose adjustment is required for this demographic factor.   
 



26 
 

Renal impairment 
 
No dedicated studies of the effect of renal impairment on the pharmacokinetics of emicizumab have 
been conducted.  
 
Most of the patients with hemophilia A in the population pharmacokinetic analysis had normal renal 
function (N = 332; creatinine clearance [CLcr] ≥ 90 mL/min) or mild renal impairment (N = 27; CLcr 
of 60-89 mL/min).  Mild renal impairment did not affect the pharmacokinetics of emicizumab. There 
are limited data available on the use of Hemlibra in patients with moderate renal impairment (only 2 
patients with CLcr of 30-59 mL/min) and no data in patients with severe renal impairment. The impact 
of moderate and severe renal impairment on the pharmacokinetics of emicizumab cannot be 
concluded. 
 
Emicizumab is a monoclonal antibody and is cleared via catabolism rather than renal excretion and a 
change in dose is not expected to be required for patients with renal impairment. 
 
Hepatic impairment 
 
No dedicated studies on the effect of hepatic impairment on the pharmacokinetics of emicizumab have 
been conducted. Most of the patients with haemophilia A in the population pharmacokinetic analysis 
had 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). Only 
6 patients had moderate hepatic impairment (1.5 × ULN <  bilirubin ≤ 3 × ULN and any AST).  Mild 
hepatic impairment did not affect the pharmacokinetics of emicizumab (see section 4.2). The safety 
and efficacy of emicizumab have not been specifically tested in patients with hepatic impairment. 
Patients with mild and moderate hepatic impairment were included in clinical trials. No data are 
available on the use of Hemlibra in patients with severe hepatic impairment.  
 
Emicizumab is a monoclonal antibody and cleared via catabolism rather than hepatic metabolism and 
a change in dose is not expected to be required for patients with hepatic impairment. 
 
Other special populations 
 
Modelling shows that less frequent dosing in patients with hypoalbuminemia and low body weight for 
their age results in lower emicizumab exposures; simulations indicate that these patients would still 
benefit from clinically meaningful bleed control. No patients with such characteristics were enrolled in 
clinical trials. 
 
5.3 Preclinical safety data 
 
Preclinical data reveal no special hazards for humans based on studies of acute and repeated dose 
toxicity, including safety pharmacology endpoints and endpoints for reproductive toxicity.  
 
Fertility 
 
Emicizumab did not cause any changes in the reproductive organs of male or female cynomolgus 
monkeys up to the highest tested dose of 30 mg/kg/week (equivalent to 11 times the human exposure 
at the highest dose of 3 mg/kg/week, based on AUC). 
 
Teratogenicity 
 
No data are available with respect to potential side effects of emicizumab on embryo-foetal 
development.  
 



27 
 

Injection site reactions 
 
Reversible hemorrhage, perivascular mononuclear cell infiltration, degeneration/necrosis of subcutis 
and swelling of endothelium in the subcutis was noted in animals after subcutaneous injection. 
 
 
6. PHARMACEUTICAL PARTICULARS  
 
6.1 List of excipients 
 
L-Arginine 
L-Histidine 
L-Aspartic acid 
Poloxamer 188 
Water for injections 
 
6.2 Incompatibilities 
 
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. 
 
6.3 Shelf life 
 
Unopened vial 
 
Hemlibra 30 mg/mL solution for injection 
 
2 years. 
 
Hemlibra 150 mg/mL solution for injection 
 
2 years. 
 
Once removed from the refrigerator, unopened vials can be kept at room temperature (below 30°C) for 
up to 7 days.  
 
After storage at room temperature, unopened vials may be returned to the refrigerator. If stored out of 
and then returned to refrigeration, the total combined time out of refrigeration should not exceed 7 
days. The vials should never be exposed to temperatures above 30 °C. Vials that have been kept at 
room 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 medicinal 
product should be used immediately. If not used immediately, in-use storage times and conditions are 
the responsibility of the user. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C to 8°C). 
 
Do not freeze. 
 
Keep the vial in the outer carton in order to protect from light. 



28 
 

 
For storage conditions after first opening of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container  
 
Hemlibra 30 mg/mL solution for injection 
 
3 mL clear glass type I vial with butyl rubber stopper laminated with a fluoro-resin film and crimped 
with an aluminium cap fitted with a plastic flip-off disk. Each vial contains 30 mg emicizumab in 
1 mL of solution for injection. Each carton contains one vial. 
 
Hemlibra 150 mg/mL solution for injection 
 
3 mL clear glass type I vial with butyl rubber stopper laminated with a fluoro-resin film and crimped 
with an aluminium cap fitted with a plastic flip-off disk. Each vial contains 60 mg emicizumab in 
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 crimped 
with an aluminium cap fitted with a plastic flip-off disk. Each vial contains 105 mg emicizumab 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 crimped 
with an aluminium cap fitted with a plastic flip-off disk. Each vial contains 150 mg emicizumab in 
1 mL of solution for injection. Each carton contains one vial. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
Hemlibra solution is a sterile, preservative-free, and ready to use solution for subcutaneous injection 
that does not need to be diluted. 
 
Hemlibra should be inspected visually to ensure there is no particulate matter or discolouration prior to 
administration. Hemlibra is a colourless to slightly yellow solution. The solution should be discarded 
if 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 and an injection needle are needed to 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 mL 
syringe 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 a 
syringe. Different Hemlibra vial concentrations (30 mg/mL and 150 mg/mL) should not be combined 
in 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. 
 



29 
 

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, length 
35 mm (1½″), containing a 5 µm filter and preferably with semi-blunted tip. 
 
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 information 
on administration. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements.  
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH 
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen  
Germany  
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/18/1271/001 (30 mg/1 ml) 
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) 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 23 February 2018 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
  

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


30 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 

MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE  
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 

 



31 
 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturer of the biological active substance  
 
Chugai Pharma Manufacturing Co., Ltd. 
5-1, Ukima 5-Chome 
Kita-Ku, Tokyo 
115-8543 
Japan 
 
Name and address of the manufacturers responsible for batch release 
 
Roche Austria GmbH 
Engelhorngasse 3 
1211 Wien 
Austria 
 
Roche Pharma AG 
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 

 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription. 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  
 
● Periodic safety update reports  
 

The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
The marketing authorisation holder shall submit the first periodic safety update report for this product 
within 6 months following authorisation. 

 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 
● Risk Management Plan (RMP) 
 

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the  
agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent 
updates of the RMP. 
 



32 
 

An updated RMP should be submitted: 
● At the request of the European Medicines Agency; 
● Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached.  

 
● Additional risk minimisation measures  

 
Prior to launch of Hemlibra in each Member State the Marketing Authorisation Holder (MAH) must 
agree about the content and format of the educational programme, including communication media, 
distribution modalities, and any other aspects of the programme, with the National Competent 
Authority.  
 
The educational programme is aimed at increasing communication and medical and patient education 
around the important identified risks of thromboembolic events and thrombotic microangiopathy 
associated with the concomitant use of emicizumab and activated prothrombin complex concentrate 
(aPCC), and the important potential risk of life-threatening bleeding due to misinterpretation of the 
standard coagulation tests (unreliable in patients treated with emicizumab) and provide information on 
how to manage them. 
 
The MAH shall ensure that in each Member State where Hemlibra is marketed, all healthcare 
professionals, patients/carers who are expected to prescribe, dispense or use Hemlibra, and laboratory 
professionals, have access to/are provided with the following educational package: 
● Physician educational material 
● Patient/Carer educational material 
● Laboratory professionals educational material 
 
The physician educational material should contain: 
● The Summary of Product Characteristics  
● Guide for healthcare professionals 
● Patient alert card 
 
● The guide for healthcare professionals shall contain the following key elements: 

- Brief introduction to emicizumab (chemical class, mode of action, pharmacodynamics 
and indication) 

- Relevant information (e.g. seriousness, severity, frequency, time to onset, reversibility as 
applicable) of the following safety concerns associated with the use of Hemlibra: 
- thromboembolic events associated with the concomitant use of emicizumab and 

activated prothrombin complex concentrate (aPCC),  
- thrombotic microangiopathy associated with the concomitant use of emicizumab 

and aPCC 
- life-threatening bleeding due to misinterpretation of the standard coagulation tests 

(unreliable in patients treated with emicizumab)  
- Guidance on the use of bypassing agents concomitantly with emicizumab, including the 

following information: 
- Treatment with prophylactic bypassing agents should be discontinued the day 

before starting emicizumab therapy; 
- Physicians should discuss with all patients and/or caregivers the exact dose and 

schedule of bypassing agents to use, if required while receiving emicizumab 
prophylaxis; 



33 
 

- Emicizumab increases the patient’s coagulation potential and the dose and duration 
of treatment with bypassing agents may require adjustment depending on the 
location and extent of bleeding and on the patient’s clinical conditions; 

- For all coagulation agents (aPCC, rFVIIa, FVIII, etc.), consideration should be 
given to verifying bleeds prior to repeated dosing; 

- Use of aPCC should be avoided unless no other treatment options/alternatives are 
available and aPCC dosing recommendations in case aPCC is the only option. 

- Treating physicians must carefully weigh the risk of TMA and thromboembolism 
against the risk of bleeding when considering aPCC treatment. 

- Information on emicizumab’s interference with certain laboratory coagulation tests which 
will affect their reliability in the emicizumab setting and warning that these tests should 
not be used to monitor for emicizumab activity, determine need for factor replacement 
dosing, or measure FVIII inhibitors.  

- Information on assays and methods not affected by emicizumab that may be used to 
monitor coagulation parameters during treatment, with specific considerations for FVIII 
chromogenic activity assays; 

- Listing of laboratory tests unaffected by emicizumab; 
- Reminder that all patients receiving treatment with emicizumab should be given a Patient 

Alert Card and reminded to carry it at all times and show it to any healthcare 
professionals who may treat them and to laboratory professionals that will perform their 
coagulation testing; 

- Reminder to report any adverse events associated with the use of emicizumab. 
 

● The patient alert card shall contain the following key messages:  
- Instructions for patients to carry the card at any time, including in conditions of 

emergency and to present the card at visits to doctors, hospital clinics, carers, laboratory 
professionals or pharmacists to inform on emicizumab treatment and risks; 

- Information on serious, life-threatening thromboembolic events or thrombotic 
microangiopathy events that have been observed with the concomitant use of emicizumab 
with activated prothrombin complex concentrate (aPCC) in patients on emicizumab 
prophylaxis; 

- Guidance on the use of bypassing agents concomitantly with emicizumab and on the 
dosing recommendations for patients requiring treatment with bypassing agents in the 
perioperative setting; 

- Warning on emicizumab’s interference with certain laboratory coagulation tests which 
will affect their reliability and information that single-factor assays utilizing chromogenic 
or immuno-based methods are not affected by emicizumab and may be used to monitor 
coagulation parameters during treatment, with specific consideration for factor VIII 
chromogenic activity assays; 

- Contact details of the patient’s emicizumab prescriber. 
 

The patient/carer educational material should contain: 
● The package leaflet  
● Guide for patients/carers 
● The guide for patients/carers shall contain the following key messages:  

- What is emicizumab, how emicizumab has been tested, and how to use emicizumab; 
- Warning on the risks associated with the concomitant use of bypassing agents and 

Hemlibra and to discuss with their doctor if they are receiving activated prothrombin 
complex concentrate (aPCC) when being prescribed  or while receiving Hemlibra; 



34 
 

- Description of the signs and symptoms of the following safety concerns and reminder of 
the importance of immediately stopping using Hemlibra and aPCC and notifying their 
treating physician if symptoms occur : 
- Destruction of red blood cells (thrombotic microangiopathy) 
- Blood clots (thromboembolism) 

- Information that they should be given a Patient Alert Card and reminder to carry it at all 
times and to show it to any healthcare professionals who may treat them; 

- Information on emicizumab’s interference with certain laboratory coagulation tests which 
will affect their reliability and on the importance to show the patient alert card to any 
healthcare professionals who may treat them and to laboratory professionals that will 
perform their coagulation testing; 

- Reminder to report any adverse events to their treating doctor. 
 

The laboratory professional educational material should contain: 
● The Summary of Product Characteristics  
● Guide for Laboratory Professionals 
● The guide for laboratory professionals shall contain the following key messages:  

- Chemical class, mode of action, pharmacodynamics and indication for emicizumab 
- Information on emicizumab’s interference with certain laboratory coagulation tests which 

will affect their reliability and not accurately reflect the patient’s underlying hemostatic 
status during emicizumab prophylaxis. Warning that these tests should not be used to 
monitor for emicizumab activity, determine need for factor replacement dosing, or 
measure FVIII inhibitors; 

- Information on assays and methods not affected by emicizumab and that may be used to 
monitor coagulation parameters during treatment, with specific considerations for FVIII 
chromogenic activity assays; 

- Listing of laboratory tests unaffected by emicizumab; 
- Recommendation that the laboratory director contact the patient’s treating physician to 

discuss any abnormal test results. 
  



35 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



36 
 

 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



37 
 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Hemlibra 30 mg/mL solution for injection 
emicizumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial of 1 mL contains 30 mg of emicizumab at a concentration of 30 mg/mL. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: L-Arginine, L-Histidine, L-Aspartic acid, Poloxamer 188, water for injections. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection 
 
1 vial  
30 mg/1mL 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For subcutaneous use 
Read the package leaflet before use 
Do not shake 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



38 
 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator  
Do not freeze 
Keep the vial in the outer carton in order to protect from light 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH 
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen  
Germany  
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/18/1271/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
hemlibra 30 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN:  
NN:  
  



39 
 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Hemlibra 30 mg/mL solution for injection 
emicizumab 
For subcutaneous use 
 
 
2. METHOD OF ADMINISTRATION 
 
Do not shake. 
 
 
3. EXPIRY DATE  
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
30 mg/1mL 
 
 
6. OTHER 
 
  



40 
 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Hemlibra 150 mg/mL solution for injection 
emicizumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial of 0.4 mL contains 60 mg of emicizumab at a concentration of 150 mg/mL. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: L-Arginine, L-Histidine, L-Aspartic acid, Poloxamer 188, water for injections. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection 
 
1 vial  
60 mg/0.4 mL 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For subcutaneous use 
Read the package leaflet before use 
Do not shake 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



41 
 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator  
Do not freeze 
Keep the vial in the outer carton in order to protect from light 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH 
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen  
Germany  
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/18/1271/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
hemlibra 60 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN:  
NN:  
  



42 
 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Hemlibra 150 mg/mL solution for injection 
emicizumab 
For subcutaneous use 
 
 
2. METHOD OF ADMINISTRATION 
 
Do not shake. 
 
 
3. EXPIRY DATE  
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
60 mg/0.4 mL 
 
 
6. OTHER 
 
  



43 
 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Hemlibra 150 mg/mL solution for injection 
emicizumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial of 0.7 mL contains 105 mg of emicizumab at a concentration of 150 mg/mL. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: L-Arginine, L-Histidine, L-Aspartic acid, Poloxamer 188, water for injections. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection 
 
1 vial  
105 mg/0.7 mL 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For subcutaneous use 
Read the package leaflet before use 
Do not shake 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



44 
 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator  
Do not freeze 
Keep the vial in the outer carton in order to protect from light 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH 
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen  
Germany  
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/18/1271/003 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
hemlibra 105 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN:  
NN:  
  



45 
 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Hemlibra 150 mg/mL solution for injection 
emicizumab 
For subcutaneous use 
 
 
2. METHOD OF ADMINISTRATION 
 
Do not shake 
 
 
3. EXPIRY DATE  
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
105 mg/0.7 mL 
 
 
6. OTHER 
 
  



46 
 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Hemlibra 150 mg/mL solution for injection 
emicizumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial of 1 mL contains 150 mg of emicizumab at a concentration of 150 mg/mL. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: L-Arginine, L-Histidine, L-Aspartic acid, Poloxamer 188, water for injections. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection 
 
1 vial  
150 mg/1 mL 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For subcutaneous use 
Read the package leaflet before use 
Do not shake 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



47 
 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator 
Do not freeze 
Keep the vial in the outer carton in order to protect from light 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH 
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen  
Germany  
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/18/1271/004 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
hemlibra 150 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN:  
NN:  
  



48 
 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Hemlibra 150 mg/mL solution for injection 
emicizumab 
For subcutaneous use 
 
 
2. METHOD OF ADMINISTRATION 
 
Do not shake 
 
 
3. EXPIRY DATE  
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
150 mg/1 mL 
 
 
6. OTHER 
 
  



49 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
  



50 
 

Package leaflet: Information for the user 
 

Hemlibra 30 mg/mL solution for injection 
 

emicizumab 
 

 
 This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects.  
 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
 
● Keep this leaflet. You may need to read it again.  
● If you have any further questions, ask your doctor, pharmacist or nurse.  
● This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.   
● If you get any side effects, talk to your doctor, pharmacist or nurse.  This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Hemlibra is and what it is used for  
2. What you need to know before you use Hemlibra 
3. How to use Hemlibra 
4. Possible side effects 
5. How to store Hemlibra 
6. Contents of the pack and other information 
7. Instructions for use 
 
 
1. What Hemlibra is and what it is used for 
 
What Hemlibra is 
 
Hemlibra contains the active substance “emicizumab”. This belongs to a group of medicines called 
“monoclonal antibodies”. Monoclonal antibodies are a type of protein that recognise and bind to a 
target in the body. 
 
What Hemlibra is used for 
 
Hemlibra is a medicine used for treating patients of all ages with  
● either haemophilia A who have developed factor VIII inhibitors  
● or with severe haemophilia A who have not developed factor VIII inhibitors (the FVIII blood 

level is less than 1%). 
 
Haemophilia A is an inherited condition caused by a lack of factor VIII, an essential substance 
required for blood to clot and stop any bleeding. 
 
The medicine prevents bleeding or reduces bleeding episodes in people with this condition. 
 
Some patients with haemophilia A can develop factor VIII inhibitors (antibodies against factor VIII) 
which stop the replacement factor VIII from working. 
 



51 
 

How Hemlibra works 
 
Hemlibra restores the function of missing activated factor VIII that is needed for effective blood 
clotting. Its structure is different from factor VIII, therefore Hemlibra is not affected by factor VIII 
inhibitors.  
 
 
2. What you need to know before you use Hemlibra  
 
Do not use Hemlibra: 
 
● if you are allergic to emicizumab or any of the other ingredients of this medicine (listed in 

section 6). If you are not sure, talk to your doctor, pharmacist or nurse before using Hemlibra. 
 
Warnings and precautions  
 
Before you start using Hemlibra, it is very important to talk to your doctor about using 
“bypassing agents” (medicines that help blood clot but which work in a different way from factor 
VIII). This is because treatment with bypassing agents may need to change while receiving 
Hemlibra. Examples of bypassing agents include activated prothrombin complex concentrate (aPCC) 
and recombinant FVIIa (rFVIIa). Serious and potentially life-threatening side effects can occur when 
aPCC is used in patients who are also receiving Hemlibra:  
 
Potentially serious side effects of using aPCC while receiving Hemlibra  
 
● Destruction of red blood cells (thrombotic microangiopathy) 

- This is a serious and potentially life-threatening condition.  
- When people have this condition, the lining of the blood vessels can be damaged and 

blood clots may develop in small blood vessels. In some cases, this can cause damage to 
the kidneys and other organs.  

- Be cautious if you are at high risk for this condition (have had this condition in the past, 
or a member of your family have suffered from it), or if you are taking medicines that can 
increase the risk of developing this condition, such as ciclosporin, quinine or tacrolimus. 

- It is important to know the symptoms of thrombotic microangiopathy, in case you 
develop the condition (see section 4, “Possible side effects” for a list of symptoms).  

 
Stop using Hemlibra and aPCC, and talk to a doctor immediately if you or your caregiver notices 
any symptoms of thrombotic microangiopathy. 

 
● Blood clots (thromboembolism) 

- In rare cases, a blood clot can form inside blood vessels and block them, which may be 
life-threatening.  

- It is important to know the symptoms of such internal blood clots, in case they develop 
(see section 4, “Possible side effects” for a list of symptoms). 

 
Stop using Hemlibra and aPCC, and talk to a doctor immediately if you or your caregiver notices 
any symptoms of blood clots in blood vessels.     



52 
 

 
Children below the age of 1 year 
 
In children less than one year of age, the blood system is still developing. If your child is less than one 
year old, your doctor may prescribe Hemlibra only after carefully weighing the expected benefits and 
risks of using this product.  
 
Other medicines and Hemlibra 
 
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. 
 
● Using a bypassing agent while receiving Hemlibra 

- Before you start using Hemlibra, talk to your doctor and carefully follow their 
instructions on when to use a bypassing agent and the dose and schedule you should 
use. Hemlibra increases the ability of your blood to clot. Therefore, the dose of bypassing 
agent required may be lower than the dose you used before starting Hemlibra.  

- Use aPCC only if no other treatment can be used.  If aPCC is required, talk to your doctor 
in case you feel you need a total of more than 50 units/kg of aPCC. For more information 
on using aPCC while receiving Hemlibra, see in section 2: “Potentially serious side 
effects of using aPCC while receiving Hemlibra”.  

- Despite limited experience with concomitant administration of anti-fibrinolytics with 
aPCC or rFVIIa in patients treated with Hemlibra, you should know that there may be a 
possibility of thrombotic events using anti-fibrinolytics administered intravenously in 
combination with aPCC or rFVIIa. 

 
Laboratory tests 
 
Tell your doctor if you are using Hemlibra before you have laboratory tests to measure how well your 
blood is clotting. This is because Hemlibra in the blood may interfere with some laboratory tests, 
leading to inaccurate results. 
 
Pregnancy and breast-feeding 
 
● You should use an effective method of birth control (contraception) during treatment with 

Hemlibra and for 6 months after your last injection of Hemlibra. 
● If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, 

ask your doctor or pharmacist for advice before using this medicine. Your doctor will consider 
the benefit of you taking Hemlibra against the risk to your baby. 

 
Driving and using machines 
 
This medicine is not likely to affect your ability to drive or use machines. 
 
 
3. How to use Hemlibra 
 
Hemlibra is provided in single-use vials as ready to use solution which does not need to be diluted. 
A doctor qualified to care for patients with haemophilia will start you on treatment with Hemlibra. 
Always use this medicine exactly as your doctor has told you. Check with your healthcare provider if 
you are not sure.  
 
Keeping a record 
 
Each time you use Hemlibra, record the name and batch number of the medicine. 
 



53 
 

How much Hemlibra to use 
 
The dose of Hemlibra depends on your weight and your doctor will calculate the amount (in mg) and 
corresponding amount of Hemlibra solution (in mL) to be injected: 
 
● Loading dose regimen: Weeks 1 to 4: The dose is 3 milligrams for every 1 kilogram you weigh, 

injected once a week. 
 
● Maintenance dose regimen: Week 5 and onwards: The dose is either 1.5 milligrams for every 

1 kilogram you weigh, injected once a week, 3 milligrams for every 1 kilogram you weigh, 
injected every 2 weeks, or 6 milligrams for every 1 kilogram you weigh, injected every 4 weeks.  

 
The decision, to use either the 1.5 mg/kg once weekly, 3 mg/kg every two weeks, or 6 mg/kg every 
four weeks maintenance dose, should be made in consultation with your doctor and, where applicable, 
with your caregiver. 
 
Different Hemlibra concentrations (30 mg/mL and 150 mg/mL) should not be combined in a single 
injection when making up the total volume to be injected. 
 
The amount of Hemlibra solution given in each injection must not be more than 2 mL.  
 
How Hemlibra is given 
 
If you inject Hemlibra yourself or if your caregiver injects it, you or your caregiver must 
carefully read and follow the instructions in section 7, “Instructions for use”. 
 
● Hemlibra is given by injection under the skin (subcutaneously). 
● Your doctor or nurse will show you how to inject Hemlibra. 
● Once you have been trained, you should be able to inject this medicine at home, by yourself or 

with the help of a caregiver.  
● To correctly insert the needle under the skin, pinch a fold of loose skin at the clean injection site 

with your free hand. Pinching the skin is important to ensure that you inject under the skin (into 
fatty tissue) but not any deeper (into muscle). Injecting into a muscle could cause discomfort. 

● Prepare and give the injection in clean and germ-free conditions using aseptic technique. Your 
doctor or nurse will give more information about this. 

 
Where to inject Hemlibra  
 
● Your doctor will show you which areas of the body are suitable for injecting Hemlibra.  
● The recommended places to give an injection are: the front of the waist (lower abdomen), upper 

outer arms, or the front of the thighs. Use only recommended places for injection.  
● For each injection, use a different area of the body to the one you used last time.  
● Do not give injections where the skin is red, bruised, tender, hard, or areas where there are 

moles or scars. 
● When using Hemlibra, any other medicine injected under the skin should be given in a different 

area. 
 
Using syringes and needles 
 
● A syringe, a transfer needle with 5 micrometre filter, and an injection needle are used to draw 

up the Hemlibra solution from the vial into the syringe and to inject it under the skin.  
● Syringes, transfer needles with filter and injection needles are not provided in this pack. For 

more information, see in section 6 “What is needed for Hemlibra administration and is not 
contained in this pack”.  

● Make sure that you use a new injection needle for each injection and dispose of it after a single 
use. 

● A 1 mL syringe should be used for an injection up to 1 mL of Hemlibra solution. 



54 
 

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

 
Use in children and adolescents 
 
Hemlibra can be used in adolescents and children of all ages.  
● A child can self-inject the medicine provided the child’s healthcare provider and the parent or 

caregiver agree. Self-injection for children below the age of 7 years is not recommended.  
 
If you use more Hemlibra than you should 
 
If you use more Hemlibra than you are supposed to, tell your doctor immediately. This is because you 
may be at risk of developing side effects such as blood clots. Always use Hemlibra exactly as your 
doctor has told you, and check with your doctor, pharmacist or nurse if you are not sure. 
 
If you forget to use Hemlibra 
 
● If you forget your scheduled injection, inject the forgotten dose as soon as possible before the 

day of the next scheduled dose. Then, continue to inject the medicine as scheduled. Do not 
inject two doses on the same day to make up for a forgotten dose. 

● If you are not sure what to do, ask your doctor, pharmacist or nurse. 
 
If you stop using Hemlibra 
 
Do not stop using Hemlibra without talking to your doctor. If you stop using Hemlibra, you may no 
longer be protected against bleeding. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Serious side effects of using aPCC while receiving Hemlibra 
 
Stop using Hemlibra and aPCC and talk to a doctor immediately if you or your caregiver notices 
any of the following side effects:  
● Destruction of red blood cells (thrombotic microangiopathy):  

- confusion, weakness, swelling of arms and legs, yellowing of skin and eyes, vague belly 
(abdominal) or back pain, feeling sick (nausea), being sick (vomiting) or urinating less – 
these symptoms may be signs of thrombotic microangiopathy. 

● Blood clots (thromboembolism):   
- swelling, warmth, pain or redness – these symptoms may be signs of a blood clot in a 

vein near the surface of the skin. 
- headache, numbness in your face, eye pain or swelling or problems with your vision – 

these symptoms may be signs of a blood clot in a vein behind your eye. 
- blackening of the skin – this symptom may be a sign of severe damage to the skin tissue. 

 
Other side effects when using Hemlibra 
 
Very common: may affect more than 1 in 10 people 
● a reaction in the area where the injection is given (redness, itching, pain) 
● headache  
● joint pain 
 



55 
 

Common: may affect up to 1 in 10 people 
● fever 
● muscle aches 
● diarrhoea 
 
Uncommon: may affect up to 1 in 100 people 
● destruction of red blood cells (thrombotic microangiopathy) 
● blood clot in a vein behind your eye (cavernous sinus thrombosis) 
● severe damage of the skin tissue (skin necrosis) 
● blood clot in a vein near the surface of the skin (superficial thrombophlebitis) 
 
Reporting of side effects 
 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects, you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Hemlibra 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and the vial label after 
“EXP”. The expiry date refers to the last day of that month.  
 
Store in a refrigerator (2°C to 8°C). Do not freeze.  
 
Store in the original pack in order to protect from light. 
 
Once removed from the refrigerator, unopened vials may be kept at room temperature (below 30°C) 
for up to 7 days. After storage at room temperature, unopened vials may be returned back to the 
refrigerator. The total time the medicine is stored at room temperature should not be more than 7 days. 
 
Discard vials that have been kept at room temperature for more than 7 days or exposed to temperatures 
above 30°C. 
 
Once transferred from the vial to the syringe, use Hemlibra straight away. Do not refrigerate the 
solution in the syringe.  
 
Before using the medicine, check the solution for particles or discoloration. The solution should be 
colourless to slightly yellow. Do not use this medicine if it is cloudy, discoloured, or contains visible 
particles. 
 
Throw away any unused solution appropriately. Do not throw away any medicines via wastewater or 
household waste. Ask your pharmacist how to throw away medicines you no longer use. These 
measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Hemlibra contains  
 
● The active substance is emicizumab. Each vial of Hemlibra contains 30 mg (1 mL at a 

concentration of 30 mg/mL) of emicizumab. 
● The other ingredients are L-arginine, L-histidine, L-aspartic acid, poloxamer 188 and water for 

injections. 

https://www.ema.europa.eu/documents/template-form/appendix-v-adverse-drug-reaction-reporting-details_en.doc


56 
 

 
What Hemlibra looks like and contents of the pack 
 
Hemlibra is a solution for injection. It is a colourless to slightly yellow liquid.  
 
Each pack of Hemlibra contains 1 glass vial. 
 
What is needed for Hemlibra administration and is not contained in this pack 
A syringe, a transfer needle and an injection needle are needed to withdraw the Hemlibra solution 
from the vial to a syringe and inject it under the skin (see section 7, “Instructions for use”).  
 
Syringes  
 
● 1 mL syringe: Transparent polypropylene or polycarbonate syringe with Luer-lock tip, 

graduation 0.01 mL or 
● 2 to 3 mL syringe: Transparent polypropylene or polycarbonate syringe with Luer-lock tip, 

graduation 0.1 mL. 
 
Needles 
 
● Transfer needle with filter: Stainless steel with Luer-lock connection, gauge 18 G, length 

35 mm (1½″), containing a 5 micrometre filter and preferably with semi-blunted tip, and 
● Injection needle: 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. 

 
Marketing Authorisation Holder  
 
Roche Registration GmbH 
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen  
Germany  
 
Manufacturers 
 
Roche Pharma AG 
Emil-Barell-Strasse 1 
D-79639 Grenzach-Wyhlen 
Germany 
 
Roche Austria GmbH 
Engelhorngasse 3  
A-1211 Wien 
Austria 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
N.V. Roche S.A. 
Tél/Tel: +32 (0) 2 525 82 11 
 

Lietuva 
UAB “Roche Lietuva” 
Tel: +370 5 2546799 
 

България 
Рош България ЕООД 
Тел: +359 2 818 44 44 
 

Luxembourg/Luxemburg 
(Voir/siehe Belgique/Belgien) 
 
 



57 
 

Česká republika 
Roche s. r. O. 
Tel: +420 - 2 20382111 

Magyarország 
Roche (Magyarország) Kft. 
Tel: +36 - 23 446 800 

 
Danmark 
Roche a/s 
Tlf: +45 - 36 39 99 99 
  

 
Malta 
(See Ireland) 
 
 

Deutschland 
Roche Pharma AG 
Tel: +49 (0) 7624 140  

Nederland 
Roche Nederland B.V. 
Tel: +31 (0) 348 438050 
 

Eesti 
Roche Eesti OÜ 
Tel: + 372 - 6 177 380  
 

Norge 
Roche Norge AS 
Tlf: +47 - 22 78 90 00 
 

Ελλάδα 
Roche (Hellas) A.E. 
Τηλ: +30 210 61 66 100 
 

Österreich 
Roche Austria GmbH 
Tel: +43 (0) 1 27739 
 

España 
Roche Farma S.A. 
Tel: +34 - 91 324 81 00 
 

Polska 
Roche Polska Sp.z o.o. 
Tel: +48 - 22 345 18 88 
 

France 
Roche 
Tél: +33 (0) 1 47 61 40 00 
 

Portugal 
Roche Farmacêutica Química, Lda 
Tel: +351 - 21 425 70 00 
 

Hrvatska 
Roche d.o.o. 
Tel: +385 1 4722 333 
 
Ireland 
Roche Products (Ireland) Ltd. 
Tel: +353 (0) 1 469 0700 
 

România 
Roche România S.R.L. 
Tel: +40 21 206 47 01 
 
Slovenija 
Roche farmacevtska družba d.o.o. 
Tel: +386 - 1 360 26 00 
 

Ísland 
Roche a/s 
c/o Icepharma hf 
Sími: +354 540 8000 
 

Slovenská republika 
Roche Slovensko, s.r.o. 
Tel: +421 - 2 52638201 
 

Italia 
Roche S.p.A. 
Tel: +39 - 039 2471 
 

Suomi/Finland 
Roche Oy 
Puh/Tel: +358 (0) 10 554 500 
 

Κύπρος 
Γ.Α.Σταμάτης & Σια Λτδ. 
Τηλ: +357 - 22 76 62 76 
 

Sverige 
Roche AB 
Tel: +46 (0) 8 726 1200 
 

Latvija 
Roche Latvija SIA 
Tel: +371 - 6 7039831 
 

United Kingdom 
Roche Products Ltd. 
Tel: +44 (0) 1707 366000 
 

 



58 
 

This leaflet was last revised in  
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 
 

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


59 
 

 

7. Instructions for use 
 

Transfer Needle with Filter 
(For transfer of HEMLIBRA from vial to syringe) 

 
 
 
 
 
 
 

 
 
 
 

Instructions for Use 
Hemlibra 
Injection 

Single-Dose Vial(s) 
 

You must read, understand and follow the Instructions for Use before injecting Hemlibra. Your 
healthcare provider should show you how to prepare, measure, and inject Hemlibra properly before 
you use it for the first time. Ask your healthcare provider if you have any questions. 
 
Important Information: 
 
● Do not inject yourself or someone else unless you have been shown how to by your healthcare 

provider. 
 
● Make sure the name Hemlibra is on the box and vial label.  
 
● Before opening the vial, read the vial label to make sure you have the correct medicine 

strength(s) to give the dose prescribed for you. You may need to use more than 1 vial to give 
yourself the correct dose. 

 
● Check the expiry date on the box and vial label. Do not use if the expiry date has passed. 
 
● Only use the vial once. After you inject your dose, throw away any unused Hemlibra left in the 

vial. Do not save unused medicine in the vial for later use.  
 
● Only use the syringes, transfer needles and injection needles that your healthcare provider 

prescribes. 
 
● Use the syringes, transfer needles and injection needles only once. Throw away any used 

syringes and needles. 
 
● If your prescribed dose is more than 2 mL, you will need to have more than one subcutaneous 

injection of Hemlibra; contact your healthcare provider for the injection instructions. 
 
●  You must inject Hemlibra only under the skin. 
 
Storing Hemlibra vials, needles and syringes: 
 
● Keep the vial in the original box to protect the medicine from light. 
 
● Keep the vials, needles and syringes out of the sight and reach of children. Store the vial in the 

refrigerator. 



60 
 

 
● Do not freeze. 
 
● Do not shake the vial. 
 
● Take the vial out of the refrigerator 15 minutes before use and allow it to reach room 

temperature (below 30°C) before preparing an injection. 
 
● Once removed from the refrigerator, the unopened vial can be kept at room temperature for up 

to 7 days. After storage at room temperature unopened vials may be returned to the refrigerator. 
The total amount of time outside cold storage and at room temperature should not exceed 
7 days. 

 
● Discard vials that have been kept at room temperature for more than 7 days or have been in 

temperatures above 30°C. 
 
● Keep the transfer needle, injection needle and syringe dry. 
 
Inspecting the medicine and your supplies: 
 
● Collect all supplies listed below to prepare and give your injection. 
 
● Check the expiry date on the box, on the vial label and on the supplies listed below. Do not use 

if the expiry date has passed. 
 
● Do not use the vial if: 

- the medicine is cloudy, hazy or coloured. 
- the medicine contains particles. 
- the cap covering the stopper is missing. 

 
● Inspect the supplies for damage. Do not use if they appear damaged or if they have been 

dropped. 
 
● Place the supplies on a clean, well-lit flat work surface. 
 
 
INCLUDED IN THE BOX: 

 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 

● Vial containing the medicine 
 
 
 
 
 
 
 
 
 
 

● HEMLIBRA Instructions for Use 
 
 
 
 
 
 



61 
 

NOT INCLUDED IN THE BOX: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 

 
 
 
 
 
 
 
 
 
 
 

 
 
 

● Alcohol wipes  
Note: If you need to use more than 1 vial to 
inject your prescribed dose, you must use a 
new alcohol wipe for each vial. 

● Gauze 
● Cotton Ball 

 
 
 

● Syringe 
Note: For injection amount up to 1 mL use a 
1 mL syringe. 

For injection amount between 1 mL 
and 2 mL use a 2 mL or 3 mL 
syringe. 

 
 
 
 
 

● 18G Transfer needle with 
5 micrometre filter 

Note: If you need to use more than 1 vial to 
inject your prescribed dose, you must use a 
new transfer needle for each vial.  
Do not use the transfer needle to inject the 
medicine. 
 
 
 
 

● 26G Injection needle with safety 
shield 

Do not use the injection needle to withdraw 
medicine from vial. 
 
 
 
 
 
 

● Sharps disposal container  
 

 



62 
 

Figure A 

Figure B 

Get ready: 
 

● Before use, allow the vial(s) to reach room temperature for about 
15 minutes on a clean flat surface away from direct sunlight.  

 
● Do not try to warm the vial by any other way. 
 
● Wash your hands well with soap and water.   

  

 
Selecting and preparing an injection site: 
 

● Clean the chosen injection site area using an alcohol wipe.  
 

● Let the skin dry for about 10 seconds. Do not touch, fan or 
blow on the cleaned area before your injection. 

 
For injection, you can use your: 

 
● Thigh (front and middle). 
 
● Stomach area (abdomen), except for 5 cm around the navel 

(belly button). 
 
● Outer area of the upper arm (only if a caregiver is giving 

the injection). 
 
● You should use a different injection site for each injection, 

at least 2.5 cm away from the area you used for your 
previous injection. 

 
● Do not inject into areas that could be irritated by a belt or 

waistband. Do not inject into moles, scars, bruises, or areas 
where the skin is tender, red, hard or the skin is broken. 
 

 

 
Preparing the syringe for injection: 
 

● Do not touch exposed needles or place them on a surface once the cap has been removed. 
 
● Once the syringe has been filled with the medicine, the injection must be given immediately. 
 
● Once the injection needle cap has been removed, the medicine in the syringe must be injected 

under the skin within 5 minutes. Do not use the syringe if the needle touches any surface. 
 

● Throw away any used vial(s), needles, vial or injection needle caps and used syringes in a 
sharps or puncture-proof container. 

 



63 
 

Important information after the injection: 
 

● Do not rub the injection site after injection. 
 
● If you see drops of blood at the injection site, you can press a sterile cotton ball or gauze 

over the injection site for at least 10 seconds, until bleeding has stopped. 
 
● If you have bruising (small area of bleeding under the skin), an ice pack can also be pressed 

gently on the site. If bleeding does not stop, please contact your healthcare provider. 
 
Disposing of the medicine and supplies: 
 
Important: Always keep the sharps disposal container out of reach of children. 
 

● Put your used needles and syringes in a sharps disposal container straight away after use. Do not 
throw away any loose needles and syringes in your household waste. 

 
● If you do not have a sharps disposal container, you may use a household container that is: 

- made of heavy-duty plastic. 
- can be closed with a tight-fitting, puncture resistant lid, without sharps being able to come 

out. 
- upright and stable during use. 
- leak-resistant. 
- properly labelled to warn of hazardous waste inside the container. 

 
● When your sharps disposal container is almost full, you will need to follow your local 

guidelines for the right way to  dispose of your sharps disposal container.   
 
● Do not throw away any used sharps disposal container in your household waste unless your local 

guidelines permit this. Do not recycle your used sharps disposal container. 



 

64 
 

1. PREPARATION 
 
Step 1. Remove vial cap and clean 
top 
 

 

 

 

 

 

 

 
 

● Take the cap off the vial(s). 
 
● Throw away the vial cap(s) into the sharps 

disposal container. 
 

 
 
 
 

● Clean the top of the vial(s) stopper with an 
alcohol wipe.  

 
 

 

 

Step 2. Attach transfer needle with filter 
to syringe 
 
 
 
 
 

 

 

 

 

 

 

 

 

● Push and twist the transfer needle with 
filter clockwise on to the syringe until it is 
fully attached. 

 
 
 
 
 
 
 
 
 
 
 

● Slowly pull back on the plunger and draw air 
into the syringe that is the same amount as 
your prescribed dose. 

 
 
 
 



 

65 
 

 
 
 

 

Step 3. Uncap transfer needle 
 

 

 
 

● Hold the syringe by the barrel with the transfer needle 
pointing up. 

 
● Carefully pull the transfer needle cap straight off and away 

from your body. Do not throw the cap away. Place the 
transfer needle cap down on a clean flat surface. You 
will need to recap the transfer needle after transferring the 
medicine. 

 

● Do not touch the needle tip or place it on a surface after 
the needle cap has been removed. 

 

Step 4. Inject air into vial 
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 
 

● Keep the vial on the flat working surface and insert the 
transfer needle and syringe straight down into the centre 
of the vial stopper. 

 
 
 
 
 
 
 
 
 
 

● Keep the needle in the vial and turn the vial upside down. 
 

 

 

 

 

 

 

 



 

66 
 

 

 

 

 

 

 

 

 

 

● With the needle pointing upwards, push on the plunger to 
inject the air from the syringe above the medicine. 

 
● Keep your finger pressed down on the syringe plunger. 

 
● Do not inject air into the medicine as this could create air 

bubbles or foam in the medicine. 
 

 
 
 
Step 5. Transfer medicine to syringe 

 
 

 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 

● Slide the tip of the needle down so that it is 
within the medicine. 

 
● Slowly pull back the plunger to prevent air 

bubbles/foam. 
Fill the syringe with more than the amount 
of medicine needed for your prescribed 
dose. 

 
● Be careful not to pull the plunger out of the 

syringe. 
 
 
 
Important: If your prescribed dose is more than 

the amount of medicine in the vial, 
withdraw all of the medicine and go to the 
“Combining Vials” section now. 

 
 

 
Step 6. Remove air bubbles 
 
 
 
 
 
 
 
 
 

 
 

● Keep the needle in the vial and check the 
syringe for larger air bubbles. Large air 
bubble can reduce the dose you receive. 

 
● Remove the larger air bubbles by gently 

tapping the syringe barrel with your fingers 
until the air bubbles rise to the top of the 
syringe. Move the tip of the needle above 
the medicine and slowly push the plunger 
up to push the air bubbles out of the syringe. 

 



 

67 
 

 
 

 
 
 
 
 
 
 
 
 
 
 
 

 
 
● If the amount of medicine in the syringe is 

now at or below your prescribed dose, move 
the tip of the needle to within the medicine 
and slowly pull back the plunger until you 
have more than the amount of medicine 
needed for your prescribed dose. 

 
● Be careful not to pull the plunger out of the 

syringe. 
 
● Repeat the steps above until you have 

removed the larger air bubbles. 
 
 

Note: Ensure you have enough medicine in the 
syringe to complete your dose before moving onto 
the next step.  If you cannot remove all medicine, 

turn the vial upright to reach the remaining amount 
 

 

 Do not use the transfer needle to inject medicine as this may cause pain and bleeding.  
 
2. INJECTION 

Step 7. Recap transfer needle 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 

● Remove the syringe and transfer needle from 
the vial. 

 
● Using one hand, slide the transfer needle 

into the cap and scoop upwards to cover the 
needle. 

 
● Once the needle is covered, push the transfer 

needle cap towards the syringe to fully attach 
it with one hand to prevent accidentally 
injuring yourself with the needle.    

 

Step 8. Clean injection site 
 
 

 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 

● Select and clean your injection site with an 
alcohol wipe. 



 

68 
 

 
 
 

Step 9. Remove transfer needle 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 

● Remove the transfer needle from the syringe 
by twisting anticlockwise and gently pulling. 

 
● Throw away the used transfer needle into a 

sharps disposal container. 

 
Step 10. Attach injection needle to 
syringe 
 
 
 
 
 
 

 
 
 
 
 
 

 
 
 
 
 
 
 

● Push and twist the injection needle 
clockwise onto the syringe until it is 
fully attached. 

 
Step 11. Move safety shield 

 
 
 
 
 
 
 
 
 
 

 
 
 

● Move the safety shield away from the 
needle and towards the syringe 
barrel. 

 
  

 
 
 
 
 
 
 
 
 
 
 
  



 

69 
 

Step 12. Uncap injection needle 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 

 
 

● Carefully pull the injection needle 
cap straightaway from the syringe. 

 
● Throw away the cap into a sharps 

disposal container. 
 

● Do not touch the needle tip or allow 
it to touch any surface. 

 
● After the injection needle cap has 

been removed, the medicine in the 
syringe must be injected within 
5 minutes. 

 
Step 13. Adjust plunger to prescribed dose 

 
 

 
 
 
 
 

● Hold the syringe with the needle 
pointing up and slowly push the 
plunger to your prescribed dose. 
 

● Check your dose, ensure the top 
rim of the plunger is in line with 
the mark on the syringe for your 
prescribed dose. 

 
 
 
 
 
 
 
 
  

 
 
Step 14. Subcutaneous (under the skin) 
injection  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 

● Pinch the selected injection site and fully insert the 
needle at a 45° to 90° angle with a quick, firm action. 
Do not hold or push on the plunger while inserting the 
needle. 

 
 

● Hold the position of the syringe and let go of the 
pinched injection site. 

 
. 
 
 



 

70 
 

 
 
 

Step 15. Inject the medicine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 

● Slowly inject all of the medicine by gently pushing the 
plunger all the way down. 

 
● Remove the needle and syringe from the injection site 

at the same angle as inserted. 

3 . DISPOSAL 
 
Step 16. Cover needle with safety shield 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 

 
 

● Move the safety shield forward 
90°, away from the syringe barrel. 

 
● Holding the syringe with one 

hand, press the safety shield 
down against a flat surface with a 
firm, quick motion until you hear a 
“click”. 

 
 
 
 
 
 
 

● If you do not hear a click, look to 
see that the needle is fully covered 
by the safety shield. 

 
● Keep your fingers behind the 

safety shield and away from the 
needle at all times. 

 
● Do not detach injection needle 

 
 
 
 

 



 

71 
 

Step 17. Throw away the syringe and 
needle. 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 

● Put your used needles and syringes in a sharps 
disposal container right away after use. For further 
information refer to the section “Disposing of the 
medicine and supplies”. 

 
● Do not try to remove the used injection needle from 

the used syringe. 
 

● Do not recap the injection needle with the cap. 
 

● Important: Always keep the sharps disposal 
container out of reach of children. 

 
● Throw away any used caps, vial(s), needles and 

syringes in a sharps or puncture-proof container 
 

 
 
Combining Vials 
 
If you need to use more than 1 vial to get to your prescribed dose, follow these steps after you have drawn up the 
medicine from the first vial: 
 
Step A. Recap transfer needle 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 

● Remove the syringe and transfer needle from the 
first vial. 
 

● Using one hand, slide the transfer needle into the 
cap and scoop upwards to cover the needle. 
 

● Once the needle is covered, push the transfer 
needle cap toward the syringe to fully attach it with 
one hand to prevent accidentally injuring yourself 
with the needle.  

 

 
 
Step B. Remove transfer needle 

 
 
 
 
 
 
 
 

 
 
 

● Remove the transfer needle from the syringe by 
twisting anticlockwise and gently pulling. 

 
● Throw away the used transfer needle into a sharps 

disposal container. 
 
 
 



 

72 
 

  
 
Step C. Attach a new transfer needle with 
filter to syringe 

 

 
 
 
Note: You must use a new transfer needle with filter each time 
you withdraw medicine from a new vial. 

 
● Push and twist a new transfer needle clockwise on 

to the syringe until it is fully attached. 
 

● Slowly pull back the plunger and draw some air 
into the syringe.  

 
 
 
 
 

 
 
Step D. Uncap transfer needle 
 
 
 

 

 
 

● Hold the syringe by the barrel with the transfer 
needle cap pointing up. 

 
● Carefully pull the transfer needle cap straight off 

and away from your body. Do not throw the cap 
away. You will need to recap the transfer needle 
after drawing up the medicine.  

 
● Do not touch the needle tip. 

 
 

 
 



 

73 
 

Step E. Inject air into vial 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 

● With the new vial on the flat working surface, 
insert the new transfer needle and syringe, straight 
down into the centre of the vial stopper.  

 
 
 
 
 
 
 

 
● Keep the transfer needle in the vial and turn the 

vial upside down.  
  
 
 
 
 
 
 
 
 
 
 

● With the needle pointing upwards, inject the air 
from the syringe above the medicine. 

 
 

● Keep your finger pressed down on the syringe 
plunger. 

 
● Do not inject air into the medicine as this could 

create air bubbles or foam in the medicine. 
 

 



 

74 
 

Step F. Transfer medicine to syringe 
 
 
 
 
 

 
 
 
 

● Slide the tip of the needle down so that it is within 
the medicine. 

 
 

● Slowly pull back the plunger to prevent air 
bubbles/foam.  
Fill the syringe barrel more than the amount of 
medicine needed for your prescribed dose.  

 
● Be careful not to pull the plunger out of the 

syringe. 
 
 

Note: Ensure you have enough medicine in the syringe to 
complete your dose before moving onto the next steps. If you 
cannot remove all medicine, turn the vial upright to reach the 

remaining amount 
 

     
 

        Do not use the transfer needle to inject medicine as this may cause harm such as pain and 
bleeding. 
 

 
Repeat steps A to F with each additional vial until you have more than 

your prescribed dose. Once completed, keep the transfer needle  inserted 
in the vial and return to Step 6. Continue with the remaining steps. 

  
 



 

75 
 

Package leaflet: Information for the user 
 

Hemlibra 150 mg/mL solution for injection 
 

emicizumab 
 

 
 This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects.  
 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
 
● Keep this leaflet. You may need to read it again.  
● If you have any further questions, ask your doctor, pharmacist or nurse.  
● This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.   
● If you get any side effects, talk to your doctor, pharmacist or nurse.  This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Hemlibra is and what it is used for  
2. What you need to know before you use Hemlibra 
3. How to use Hemlibra 
4. Possible side effects 
5. How to store Hemlibra 
6. Contents of the pack and other information 
7. Instructions for use 
 
 
1. What Hemlibra is and what it is used for 
 
What Hemlibra is 
 
Hemlibra contains the active substance “emicizumab”. This belongs to a group of medicines called 
“monoclonal antibodies”. Monoclonal antibodies are a type of protein that recognise and bind to a 
target in the body. 
 
What Hemlibra is used for 
 
Hemlibra is a medicine used for treating patients of all ages with  
● either haemophilia A who have developed factor VIII inhibitors  
● or with severe haemophilia A who have not developed factor VIII inhibitors (the FVIII blood 

level is less than 1%). 
 
Haemophilia A is an inherited condition caused by a lack of factor VIII, an essential substance 
required for blood to clot and stop any bleeding. 
 
The medicine prevents bleeding or reduces bleeding episodes in people with this condition. 
 
Some patients with haemophilia A can develop factor VIII inhibitors (antibodies against factor VIII) 
which stop the replacement factor VIII from working. 
 



 

76 
 

How Hemlibra works 
 
Hemlibra restores the function of missing activated factor VIII that is needed for effective blood 
clotting Its structure is different from factor VIII, therefore Hemlibra is not affected by factor VIII 
inhibitors.  
 
 
2. What you need to know before you use Hemlibra  
 
Do not use Hemlibra: 
 
● if you are allergic to emicizumab or any of the other ingredients of this medicine (listed in 

section 6). If you are not sure, talk to your doctor, pharmacist or nurse before using Hemlibra. 
 
Warnings and precautions  
 
Before you start using Hemlibra, it is very important to talk to your doctor about using 
“bypassing agents” (medicines that help blood clot but which work in a different way from factor 
VIII). This is because treatment with bypassing agents may need to change while receiving 
Hemlibra. Examples of bypassing agents include activated prothrombin complex concentrate (aPCC) 
and recombinant FVIIa (rFVIIa). Serious and potentially life-threatening side effects can occur when 
aPCC is used in patients who are also receiving Hemlibra:  
 
Potentially serious side effects of using aPCC while receiving Hemlibra  
 
● Destruction of red blood cells (thrombotic microangiopathy) 

- This is a serious and potentially life-threatening condition.  
- When people have this condition, the lining of the blood vessels can be damaged and 

blood clots may develop in small blood vessels. In some cases, this can cause damage to 
the kidneys and other organs.  

- Be cautious if you are at high risk for this condition (have had this condition in the past, 
or a member of your family have suffered from it), or if you are taking medicines that can 
increase the risk of developing this condition, such as ciclosporin, quinine or tacrolimus. 

- It is important to know the symptoms of thrombotic microangiopathy, in case you 
develop the condition (see section 4, “Possible side effects” for a list of symptoms).  

 
Stop using Hemlibra and aPCC, and talk to a doctor immediately if you or your caregiver notices 
any symptoms of thrombotic microangiopathy. 

 
● Blood clots (thromboembolism) 

- In rare cases, a blood clot can form inside blood vessels and block them, which may be 
life-threatening.  

- It is important to know the symptoms of such internal blood clots, in case they develop 
(see section 4, “Possible side effects” for a list of symptoms). 

 
Stop using Hemlibra and aPCC, and talk to a doctor immediately if you or your caregiver notices 
any symptoms of blood clots in blood vessels.     



 

77 
 

 
Children below the age of 1 year 
 
In children less than one year of age, the blood system is still developing. If your child is less than one 
year old, your doctor may prescribe Hemlibra only after carefully weighing the expected benefits and 
risks of using this product.  
 
Other medicines and Hemlibra 
 
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. 
 
● Using a bypassing agent while receiving Hemlibra 

- Before you start using Hemlibra, talk to your doctor and carefully follow their 
instructions on when to use a bypassing agent and the dose and schedule you should 
use. Hemlibra increases the ability of your blood to clot. Therefore, the dose of bypassing 
agent required may be lower than the dose you used before starting Hemlibra.  

- Use aPCC only if no other treatment can be used.  If aPCC is required, talk to your doctor 
in case you feel you need a total of more than 50 units/kg of aPCC. For more information 
on using aPCC while receiving Hemlibra, see in section 2: “Potentially serious side 
effects of using aPCC while receiving Hemlibra”.  

- Despite limited experience with concomitant administration of anti-fibrinolytics with 
aPCC or rFVIIa in patients treated with Hemlibra, you should know that there may be a 
possibility of thrombotic events using anti-fibrinolytics administered intravenously in 
combination with aPCC or rFVIIa. 

 
Laboratory tests 
 
Tell your doctor if you are using Hemlibra before you have laboratory tests to measure how well your 
blood is clotting. This is because Hemlibra in the blood may interfere with some laboratory tests, 
leading to inaccurate results. 
 
Pregnancy and breast-feeding 
 
● You should use an effective method of birth control (contraception) during treatment with 

Hemlibra and for 6 months after your last injection of Hemlibra. 
● If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, 

ask your doctor or pharmacist for advice before using this medicine. Your doctor will consider 
the benefit of you taking Hemlibra against the risk to your baby. 

 
Driving and using machines 
 
This medicine is not likely to affect your ability to drive or use machines. 
 
 
3. How to use Hemlibra 
 
Hemlibra is provided in single-use vials as ready to use solution which does not need to be diluted. 
A doctor qualified to care for patients with haemophilia will start you on treatment with Hemlibra. 
Always use this medicine exactly as your doctor has told you. Check with your healthcare provider if 
you are not sure.  
 
Keeping a record 
 
Each time you use Hemlibra, record the name and batch number of the medicine. 
 



 

78 
 

How much Hemlibra to use 
 
The dose of Hemlibra depends on your weight and your doctor will calculate the amount (in mg) and 
corresponding amount of Hemlibra solution (in mL) to be injected: 
 
● Loading dose regimen: Weeks 1 to 4: The dose is 3 milligrams for every 1 kilogram you weigh, 

injected once a week. 
 
● Maintenance dose regimen: Week 5 and onwards: The dose is either 1.5 milligrams for every 

1 kilogram you weigh, injected once a week, 3 milligrams for every 1 kilogram you weigh, 
injected every 2 weeks, or 6 milligrams for every 1 kilogram you weigh, injected every 4 weeks.  

 
The decision, to use either the 1.5 mg/kg once weekly, 3 mg/kg every two weeks, or 6 mg/kg every 
four weeks maintenance dose, should be made in consultation with your doctor and, where applicable, 
with your caregiver. 
  
Different Hemlibra concentrations (30 mg/mL and 150 mg/mL) should not be combined in a single 
injection when making up the total volume to be injected. 
 
The amount of Hemlibra solution given in each injection must not be more than 2 mL.  
 
How Hemlibra is given 
 
If you inject Hemlibra yourself or if your caregiver injects it, you or your caregiver must 
carefully read and follow the instructions in section 7, “Instructions for use”. 
 
● Hemlibra is given by injection under the skin (subcutaneously). 
● Your doctor or nurse will show you how to inject Hemlibra. 
● Once you have been trained, you should be able to inject this medicine at home, by yourself or 

with the help of a caregiver.  
● To correctly insert the needle under the skin, pinch a fold of loose skin at the clean injection site 

with your free hand. Pinching the skin is important to ensure that you inject under the skin (into 
fatty tissue) but not any deeper (into muscle). Injecting into a muscle could  cause discomfort. 

● Prepare and give the injection in clean and germ-free conditions using aseptic technique. Your 
doctor or nurse will give more information about this. 

 
Where to inject Hemlibra  
 
● Your doctor will show you which areas of the body  are suitable for injecting Hemlibra.  
● The recommended places to give an injection are: the front of the waist (lower abdomen), upper 

outer arms, or the front of the thighs. Use only recommended places for injection.  
● For each injection, use a different area of the body to the one you used last time.  
● Do not give injections where the skin is red, bruised, tender, hard, or areas where there are 

moles or scars. 
● When using Hemlibra, any other medicine injected under the skin should be given in a different 

area. 
 
Using syringes and needles 
 
● A syringe, a transfer needle with 5 micrometre filter, and an injection needle are used to draw 

up the Hemlibra solution from the vial into the syringe and to inject it under the skin.  
● Syringes, transfer needles with filter and injection needles are not provided in this pack. For 

more information, see in section 6 “What is needed for Hemlibra administration and is not 
contained in this pack”.  

● Make sure that you use a new injection needle for each injection and dispose of it after a single 
use. 

● A 1 mL syringe should be used for an injection up to 1 mL of Hemlibra solution. 



 

79 
 

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

 
Use in children and adolescents 
 
Hemlibra can be used in adolescents and children of all ages.  
● A child can self-inject the medicine provided the child’s healthcare provider and the parent or 

caregiver agree. Self-injection for children below the age of 7 years is not recommended.  
 
If you use more Hemlibra than you should 
 
If you use more Hemlibra than you are supposed to, tell your doctor immediately. This is because you 
may be at risk of developing side effects such as blood clots. Always use Hemlibra exactly as your 
doctor has told you, and check with your doctor, pharmacist or nurse if you are not sure. 
 
If you forget to use Hemlibra 
 
● If you forget your scheduled injection, inject the forgotten dose as soon as possible before the 

day of the next scheduled dose. Then, continue to inject the medicine as scheduled. Do not 
inject two doses on the same day to make up for a forgotten dose. 

● If you are not sure what to do, ask your doctor, pharmacist or nurse. 
 
If you stop using Hemlibra 
 
Do not stop using Hemlibra without talking to your doctor. If you stop using Hemlibra, you may no 
longer be protected against bleeding. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Serious side effects of using aPCC while receiving Hemlibra 
 
Stop using Hemlibra and aPCC and talk to a doctor immediately if you or your caregiver notices 
any of the following side effects:  
● Destruction of red blood cells (thrombotic microangiopathy):  

- confusion, weakness, swelling of arms and legs, yellowing of skin and eyes, vague belly 
(abdominal) or back pain, feeling sick (nausea), being sick (vomiting) or urinating less – 
these symptoms may be signs of thrombotic microangiopathy.      

● Blood clots (thromboembolism):   
- swelling, warmth, pain or redness – these symptoms may be signs of a blood clot in a 

vein near the surface of the skin. 
- headache, numbness in your face, eye pain or swelling or problems with your vision – 

these symptoms may be signs of a blood clot in a vein behind your eye. 
- blackening of the skin – this symptom may be a sign of severe damage to the skin tissue. 

 
Other side effects when using Hemlibra 
 
Very common: may affect more than 1 in 10 people 
● a reaction in the area where the injection is given (redness, itching, pain) 
● headache 
● joint pain 
 



 

80 
 

Common: may affect up to 1 in 10 people 
● fever 
● muscle aches 
● diarrhoea 
 
Uncommon: may affect up to 1 in 100 people 
● destruction of red blood cells (thrombotic microangiopathy) 
● blood clot in a vein behind your eye (cavernous sinus thrombosis) 
● severe damage of the skin tissue (skin necrosis) 
● blood clot in a vein near the surface of the skin (superficial thrombophlebitis) 
 
Reporting of side effects 
 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects, you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Hemlibra 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and the vial label after 
“EXP”. The expiry date refers to the last day of that month.  
 
Store in a refrigerator (2°C to 8°C). Do not freeze.  
 
Store in the original pack in order to protect from light. 
 
Once removed from the refrigerator, unopened vials may be kept at room temperature (below 30°C) 
for up to 7 days. After storage at room temperature, unopened vials may be returned back to the 
refrigerator. The total time the medicine is stored at room temperature should not be more than 7 days. 
 
Discard vials that have been kept at room temperature for more than 7 days or exposed to temperatures 
above 30°C. 
 
Once transferred from the vial to the syringe, use Hemlibra straight away. Do not refrigerate the 
solution in the syringe.  
 
Before using the medicine, check the solution for particles or discoloration. The solution should be 
colourless to slightly yellow. Do not use this medicine if it is cloudy, discoloured, or contains visible 
particles. 
 
Throw away any unused solution appropriately. Do not throw away any medicines via wastewater or 
household waste. Ask your pharmacist how to throw away medicines you no longer use. These 
measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Hemlibra contains  
 
● The active substance is emicizumab. Each vial of Hemlibra contains 60 mg (0.4 mL at a 

concentration of 150 mg/mL), 105 mg (0.7 mL at a concentration of 150 mg/mL) or 150 mg 
(1 mL at a concentration of 150 mg/mL) of emicizumab. 

https://www.ema.europa.eu/documents/template-form/appendix-v-adverse-drug-reaction-reporting-details_en.doc


 

81 
 

● The other ingredients are L-arginine, L-histidine, L-aspartic acid, poloxamer 188 and water for 
injections. 

 
What Hemlibra looks like and contents of the pack 
 
Hemlibra is a solution for injection. It is a colourless to slightly yellow liquid.  
 
Each pack of Hemlibra contains 1 glass vial. 
 
What is needed for Hemlibra administration and is not contained in this pack 
A syringe, a transfer needle  and an injection needle are needed to withdraw the Hemlibra solution 
from the vial to a syringe and inject it under the skin (see section 7, “Instructions for use”).  
 
Syringes  
 
● 1 mL syringe: Transparent polypropylene or polycarbonate syringe with Luer-lock tip, 

graduation 0.01 mL or 
● 2 to 3 mL syringe: Transparent polypropylene or polycarbonate syringe with Luer-lock tip, 

graduation 0.1 mL. 
 
Needles 
 
● Transfer needle with filter: Stainless steel with Luer-lock connection, gauge 18 G, length 

35 mm (1½″), containing a 5 micrometre filter and preferably with semi-blunted tip, and 
● Injection needle: 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. 

 
Marketing Authorisation Holder  
 
Roche Registration GmbH 
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen  
Germany  
 
Manufacturers 
 
Roche Pharma AG 
Emil-Barell-Strasse 1 
D-79639 Grenzach-Wyhlen 
Germany 
 
Roche Austria GmbH 
Engelhorngasse 3  
A-1211 Wien 
Austria 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
N.V. Roche S.A. 
Tél/Tel: +32 (0) 2 525 82 11 
 

Lietuva 
UAB “Roche Lietuva” 
Tel: +370 5 2546799 
 

България 
Рош България ЕООД 
Тел: +359 2 818 44 44 

Luxembourg/Luxemburg 
(Voir/siehe Belgique/Belgien) 
 



 

82 
 

 
Česká republika 
Roche s. r. O. 
Tel: +420 - 2 20382111 

Magyarország 
Roche (Magyarország) Kft. 
Tel: +36 - 23 446 800 
 

Danmark 
Roche a/s 
Tlf: +45 - 36 39 99 99 
  

Malta 
(See Ireland) 
 
 

Deutschland 
Roche Pharma AG 
Tel: +49 (0) 7624 140  

Nederland 
Roche Nederland B.V. 
Tel: +31 (0) 348 438050 
 

Eesti 
Roche Eesti OÜ 
Tel: + 372 - 6 177 380  
 

Norge 
Roche Norge AS 
Tlf: +47 - 22 78 90 00 
 

Ελλάδα 
Roche (Hellas) A.E. 
Τηλ: +30 210 61 66 100 
 

Österreich 
Roche Austria GmbH 
Tel: +43 (0) 1 27739 
 

España 
Roche Farma S.A. 
Tel: +34 - 91 324 81 00 
 

Polska 
Roche Polska Sp.z o.o. 
Tel: +48 - 22 345 18 88 
 

France 
Roche 
Tél: +33 (0) 1 47 61 40 00 
 

Portugal 
Roche Farmacêutica Química, Lda 
Tel: +351 - 21 425 70 00 
 

Hrvatska 
Roche d.o.o. 
Tel: +385 1 4722 333 
 
Ireland 
Roche Products (Ireland) Ltd. 
Tel: +353 (0) 1 469 0700 
 

România 
Roche România S.R.L. 
Tel: +40 21 206 47 01 
 
Slovenija 
Roche farmacevtska družba d.o.o. 
Tel: +386 - 1 360 26 00 
 

Ísland 
Roche a/s 
c/o Icepharma hf 
Sími: +354 540 8000 
 

Slovenská republika 
Roche Slovensko, s.r.o. 
Tel: +421 - 2 52638201 
 

Italia 
Roche S.p.A. 
Tel: +39 - 039 2471 
 

Suomi/Finland 
Roche Oy 
Puh/Tel: +358 (0) 10 554 500 
 

Κύπρος 
Γ.Α.Σταμάτης & Σια Λτδ. 
Τηλ: +357 - 22 76 62 76 
 

Sverige 
Roche AB 
Tel: +46 (0) 8 726 1200 
 

Latvija 
Roche Latvija SIA 
Tel: +371 - 6 7039831 
 

United Kingdom 
Roche Products Ltd. 
Tel: +44 (0) 1707 366000 
 

  
 



 

83 
 

This leaflet was last revised in  
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 
 

  

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


 

84 
 

 

7. Instructions for use 

Transfer Needle with Filter 
 (For transfer of HEMLIBRA from vial to syringe) 

 
 
 

 
 
 
 

 
 
 

Instructions for Use 
Hemlibra 
Injection 

Single-Dose Vial(s) 
 

You must read, understand and follow the Instructions for Use before injecting Hemlibra. Your 
healthcare provider should show you how to prepare, measure, and inject Hemlibra properly before 
you use it for the first time. Ask your healthcare provider if you have any questions. 
 
Important Information: 
 
● Do not inject yourself or someone else unless you have been shown how to by your healthcare 

provider. 
 
● Make sure the name Hemlibra  is on the box and vial label.  
 
● Before opening the vial, read the vial label to make sure you have the correct medicine 

strength(s) to give the dose prescribed for you. You may need to use more than 1 vial to give 
yourself the correct dose. 

 
● Check the expiry date on the box and vial label. Do not use if the expiry date has passed. 
 
● Only use the vial once. After you inject your dose, throw away any unused Hemlibra left in the 

vial. Do not save unused medicine in the vial for later use.  
 
● Only use the syringes, transfer needles, and injection needles that your healthcare 

provider prescribes. 
 
● Use the syringes, transfer needles and injection needles only once. Throw away any used 

syringes and needles. 
 
● If your prescribed dose is more than 2 mL, you will need to  have more than one subcutaneous 

injection of Hemlibra; contact your healthcare provider for the injection instructions. 
 
●  You must inject Hemlibra only under the skin. 
 
Storing Hemlibra vials, needles and syringes: 
 
● Keep the vial in the original box to protect the medicine from light. 
 
● Keep the vials, needles and syringes out of the sight and reach of children. Store the vial in the 

refrigerator. 
 
● Do not freeze. 



 

85 
 

 
● Do not shake the vial. 
 

● Take the vial out of the refrigerator 15 minutes before use and allow it to reach room 
temperature (below 30°C) before preparing an injection. 

 
● Once removed from the refrigerator, the unopened vial can be kept at room temperature for up 

to 7 days. After storage at room temperature unopened vials may be returned to the refrigerator. 
The total amount of time outside cold storage and at room temperature should not exceed 
7 days. 

 
● Discard vials that have been kept at room temperature for more than 7 days or have been in 

temperatures above 30°C. 
 
● Keep the transfer needle, injection needle and syringe dry. 
 
Inspecting the medicine and your supplies: 
 
● Collect all supplies listed below to prepare and give your injection. 
 
● Check the expiry date on the box, on the vial label and on the supplies listed below. Do not use 

if the expiry date has passed. 
 
● Do not use the vial if: 

- the medicine is cloudy, hazy or coloured. 
- the medicine contains particles. 
- the cap covering the stopper is missing. 

 
● Inspect the supplies for damage. Do not use if they appear damaged or if they have been 

dropped. 
 
● Place the supplies on a clean, well-lit flat work surface. 
 
 
INCLUDED IN THE BOX: 

 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 

● Vial containing the medicine 
 
 
 
 
 
 
 
 
 
 

● HEMLIBRA Instructions for Use 
 
 
 
 
 
 



 

86 
 

NOT INCLUDED IN THE BOX: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 

 
 
 
 
 
 
 
 
 
 
 

 
 
 

● Alcohol wipes  
Note: If you need to use more than 1 vial to 
inject your prescribed dose, you must use a 
new alcohol wipe for each vial. 

● Gauze 
● Cotton Ball 

 
 
 

● Syringe 
Note: For injection amount up to 1 mL use a 
1 mL syringe. 

For injection amount between 1 mL 
and 2 mL use a 2 mL or 3 mL 
syringe. 

 
 
 
 
 

● 18G Transfer needle with 
5 micrometre filter 

Note: If you need to use more than 1 vial to 
inject your prescribed dose, you must use a 
new transfer needle for each vial.  
Do not use the transfer needle to inject the 
medicine. 
 
 
 
 

● 26G Injection needle with safety 
shield 

Do not use the injection needle to withdraw 
medicine from vial. 
 
 
 
 
 
 

● Sharps disposal container  
 

 



 

87 
 

Figure A 

Figure B 

Get ready: 
 

● Before use, allow the vial(s) to reach room temperature for about 
15 minutes on a clean flat surface away from direct sunlight.  

 
● Do not try to warm the vial by any other way. 
 
● Wash your hands well with soap and water.   

  

 
Selecting and preparing an injection site: 
 

● Clean the chosen injection site area using an alcohol wipe.  
 

● Let the skin dry for about 10 seconds. Do not touch, fan or 
blow on the cleaned area before your injection. 

 
For injection, you can use your: 

 
● Thigh (front and middle). 
 
● Stomach area (abdomen), except for 5 cm around the navel 

(belly button). 
 
● Outer area of the upper arm (only if a caregiver is giving 

the injection). 
 
● You should use a different injection site for each injection, 

at least 2.5 cm away from the area you used for your 
previous injection. 

 
● Do not inject into areas that could be irritated by a belt or 

waistband. Do not inject into moles, scars, bruises, or areas 
where the skin is tender, red, hard or the skin is broken. 
 

 

 
Preparing the syringe for injection: 
 

● Do not touch exposed needles or place them on a surface once the cap has been removed. 
 
● Once the syringe has been filled with the medicine,  the injection must be given immediately. 
 
● Once the injection needle cap has been removed, the medicine in the syringe must be injected 

under the skin within 5 minutes. Do not use the syringe if the needle touches any surface. 
 

● Throw away any used vial(s), needles, vial or injection needle caps and used syringes in a 
sharps or puncture-proof container. 

 



 

88 
 

Important information after the injection: 
 

● Do not rub the injection site after injection. 
 

● If you see drops of blood at the injection site, you can press a sterile cotton ball or gauze 
over the injection site for at least 10 seconds, until bleeding has stopped. 

 
● If you have bruising (small area of bleeding under the skin), an ice pack can also be  pressed 

gently on the site. If bleeding does not stop,  please contact your healthcare provider. 
 
Disposing of the medicine and supplies: 
 
Important: Always keep the sharps disposal container out of reach of children. 
 

● Put your used needles and syringes in a sharps disposal container straight away after use. Do not 
throw away any loose needles and syringes in your household waste. 

 
● If you do not have a sharps disposal container, you may use a household container that is: 

- made of heavy-duty plastic. 
- can be closed with a tight-fitting, puncture resistant lid, without sharps being able to come 

out. 
- upright and stable during use. 
- leak-resistant. 
- properly labelled to warn of hazardous waste inside the container. 

 
● When your sharps disposal container is almost full, you will need to follow your local 

guidelines for the right way to  dispose of your sharps disposal container.   
 
● Do not throw away any used sharps disposal container in your household waste unless your 

local guidelines permit this. Do not recycle your used sharps disposal container. 



 

89 
 

1.  PREPARATION 
Step 1. Remove vial cap and clean top 
 

 

 

 

 

 

 

 
● Take the cap off the vial(s). 
 
● Throw away the vial cap(s) into the sharps disposal 

container. 
 

 
 
 
 

● Clean the top of the vial(s) stopper with an alcohol 
wipe.  

 

 

Step 2. Attach transfer needle with filter 
to syringe 
 
 
 
 
 

 

 

 

 

 

 

 

 

● Push and twist the transfer needle with 
filter clockwise on to the syringe until it is 
fully attached. 

 
 
 
 
 
 
 
 
 
 
 

● Slowly pull back on the plunger and draw air 
into the syringe that is the same amount as 
your prescribed dose. 

 
 
 
 
 
 
 



 

90 
 

 

 

Step 3. Uncap transfer needle 
 

 

 
 

● Hold the syringe by the barrel with the transfer 
needle pointing up. 

 
● Carefully pull the transfer needle cap straight off and 

away from your body. Do not throw the cap away. 
Place the transfer needle cap down on a clean flat 
surface. You will need to recap the transfer needle 
after transferring the medicine. 

 

● Do not touch the needle tip or place it on a surface 
after the needle cap has been removed. 

 



 

91 
 

Step 4. Inject air into vial 
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 
 

● Keep the vial on the flat working surface and insert the 
transfer needle and syringe straight down into the centre 
of the vial stopper. 

 
 
 
 
 
 
 
 
 
 

● Keep the needle in the vial and turn the vial upside 
down. 

 

 

 

 

 

 

 

 

 

 

● With the needle pointing upwards, push on the plunger 
to inject the air from the syringe above the medicine. 

 
● Keep your finger pressed down on the syringe plunger. 

 
● Do not inject air into the medicine as this could create 

air bubbles or foam in the medicine. 
 

 



 

92 
 

 
Step 5. Transfer medicine to syringe 

 
 

 
 
 
 
 
 
 
 
 
 
 
 

 
 
 

● Slide the tip of the needle down so that it is 
within the medicine. 

 
● Slowly pull back the plunger to prevent air 

bubbles/foam. 
Fill the syringe with more than the amount of 
medicine needed for your prescribed dose. 

 
● Be careful not to pull the plunger out of the 

syringe. 
 

Important: If your prescribed dose is more than the 
amount of medicine in the vial, withdraw all of the 
medicine and go to the “Combining Vials” section 

now. 
 
 

 
Step 6. Remove air bubbles 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 

 
 

● Keep the needle in the vial and check the syringe 
for larger air bubbles. Large air bubble can 
reduce the dose you receive. 

 
● Remove the larger air bubbles by gently 

tapping the syringe barrel with your fingers until 
the air bubbles rise to the top of the syringe. 
Move the tip of the needle above the medicine 
and slowly push the plunger up to push the air 
bubbles out of the syringe. 

 
 
 
 
 
 
 
 
● If the amount of medicine in the syringe is now 

at or below your prescribed dose, move the tip 
of the needle to within the medicine and slowly 
pull back the plunger until you have more than 
the amount of medicine needed for your 
prescribed dose. 

 
● Be careful not to pull the plunger out of the 

syringe. 
 



 

93 
 

 
 

● Repeat the steps above until you have removed 
the larger air bubbles. 

 
 
Note: Ensure you have enough medicine in the syringe 

to complete your dose before moving onto the next step.  
If you cannot remove all medicine, turn the vial upright 

to reach the remaining amount 
 

 

 Do not use the transfer needle to inject medicine as this may cause pain and bleeding.  
 
2 INJECTION 

 
Step 7. Recap transfer needle 

 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 

● Remove the syringe and transfer needle 
from the vial. 

 
● Using one hand, slide the transfer needle 

into the cap and scoop upwards to cover 
the needle. 

 
● Once the needle is covered, push the 

transfer needle cap towards the syringe to 
fully attach it with one hand to prevent 
accidentally injuring yourself with the 
needle.    

 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



 

94 
 

Step 8. Clean injection site 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 

● Select and clean your injection site with 
an alcohol wipe. 

 
 

Step 9. Remove transfer needle 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 

● Remove the transfer needle from the 
syringe by twisting anticlockwise and 
gently pulling. 

 
● Throw away the used transfer needle into 

a sharps disposal container. 

 



 

95 
 

Step 10. Attach injection needle to syringe 
 
 
 
 
 
 

 
 
 
 
 
 

 
 
 
 
 
 
 

● Push and twist the injection 
needle clockwise onto the 
syringe until it is fully attached. 

 
Step 11. Move safety shield 

 
 
 
 
 
 
 
 
 
 

 
 
 

● Move the safety shield away 
from the needle and towards the 
syringe barrel. 

 
  

 
 

Step 12. Uncap injection needle 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 

 
 
 

● Carefully pull the injection 
needle cap straightaway from the 
syringe. 

 
● Throw away the cap into a 

sharps disposal container. 
 

● Do not touch the needle tip or 
allow it to touch any surface. 

 
● After the injection needle cap 

has been removed, the medicine 
in the syringe must be injected 
within 5 minutes. 



 

96 
 

 
Step 13. Adjust plunger to prescribed dose 

 
 

 
 
 
 
 

● Hold the syringe with the needle 
pointing up and slowly push the 
plunger to your prescribed dose. 
 

● Check your dose, ensure the top 
rim of the plunger is in line with 
the mark on the syringe for your 
prescribed dose. 

 
 
 
 
 
 
 
 
  

 
 
Step 14. Subcutaneous (under the skin) injection  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 

● Pinch the selected injection site and fully insert the 
needle at a 45° to 90° angle with a quick, firm 
action. Do not hold or push on the plunger while 
inserting the needle. 

 
 

● Hold the position of the syringe and let go of the 
pinched injection site. 

 
. 
 
 

 
Step 15. Inject the medicine 

 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 

● Slowly inject all of the medicine by gently pushing 
the plunger all the way down. 

 
● Remove the needle and syringe from the injection 

site at the same angle as inserted. 

  



 

97 
 

3.DISPOSAL 
Step 16. Cover needle with safety shield 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 

 
 

● Move the safety shield forward 
90°, away from the syringe 
barrel. 

 
● Holding the syringe with one 

hand, press the safety shield 
down against a flat surface with 
a firm, quick motion until you 
hear a “click”. 

 
 
 
 

● If you do not hear a click, look 
to see that the needle is fully 
covered by the safety shield. 

 
● Keep your fingers behind the 

safety shield and away from the 
needle at all times. 

 
● Do not detach injection needle 

 
 
 
 

 
Step 17. Throw away the syringe and needle. 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 

● Put your used needles and syringes in a sharps 
disposal container right away after use. For further 
information refer to the section “Disposing of the 
medicine and supplies”. 

 
● Do not try to remove the used injection needle from 

the used syringe. 
 

● Do not recap the injection needle with the cap. 
 

● Important: Always keep the sharps disposal 
container out of reach of children. 

 
● Throw away any used caps, vial(s),  needles and 

syringes in a sharps or puncture-proof container. 
 
 

 
 



 

98 
 

 
Combining Vials 
 
If you need to use  more than 1 vial to get to your prescribed dose, follow these steps after you have drawn up the 
medicine from the first vial: 
 
Step A. Recap transfer needle 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 

● Remove the syringe and transfer needle from the 
first vial. 
 

● Using one hand, slide the transfer needle into the 
cap and scoop upwards to cover the needle. 
 

● Once the needle is covered, push the transfer 
needle cap toward the syringe to fully attach it 
with one hand to prevent accidentally  injuring 
yourself with the needle.  

 

 
 
Step B. Remove transfer needle 

 
 
 
 
 
 
 
 
 

 
 
 

● Remove the transfer needle from the syringe by 
twisting anticlockwise and gently pulling. 

 
● Throw away the used transfer needle into a 

sharps disposal container. 
 
 
 
 

 
Step C. Attach a new transfer needle with 
filter to syringe 

 

 
 
 
Note: You must use a new transfer needle with filter each time 
you withdraw medicine from a new vial. 

 
● Push and twist a new transfer needle clockwise 

on to the syringe until it is fully attached. 
 

● Slowly pull back the plunger and draw some air 
into the syringe.  

 
 
 
 
 



 

99 
 

 
 
Step D. Uncap transfer needle 
 
 
 

 

 
 

● Hold the syringe by the barrel with the transfer 
needle cap pointing up. 

 
● Carefully pull the transfer needle cap straight off 

and away from your body. Do not throw the cap 
away. You will need to recap the transfer needle 
after drawing up the medicine.  

 
● Do not touch the needle tip. 

 
 

 
 
Step E. Inject air into vial 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 

● With the new vial on the flat working surface, 
insert the new transfer needle and syringe, 
straight down into the centre of the vial stopper.  

 
 
 
 
 
 
 

 
● Keep the transfer needle in the vial and turn the 

vial upside down.  
  
 
 
 
 
 
 
 
 
 
 

● With the needle pointing upwards, inject the air 
from the syringe above the medicine. 

 
 

● Keep your finger pressed down on the syringe 
plunger. 

 
● Do not inject air into the medicine as this could 

create air bubbles or foam in the medicine. 
 

 
       Step F. Transfer medicine to syringe 

 
 

 
 



 

100 
 

  
● Slide the tip of the needle down so that it is within 

the medicine. 
 
 

● Slowly pull back the plunger to prevent air 
bubbles/foam. 
Fill the syringe barrel more than the amount of 
medicine needed for your prescribed dose.  

 
● Be careful not to pull the plunger out of the 

syringe. 
 
 

Note: Ensure you have enough medicine in the syringe to 
complete your dose before moving onto the next steps. If you 
cannot remove all medicine, turn the vial upright to reach the 

remaining amount 
 

     
 

        Do not use the transfer needle to inject medicine as this may cause harm such as pain and 
bleeding. 
 

 
Repeat steps A to F with each additional vial until you have more than 

your prescribed dose. Once completed, keep the transfer needle inserted 
in the vial and return to Step 6. Continue with the remaining steps. 

  
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION 
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET