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HEMLIBRA ® (emicizumab-kxwh) injection, for subcutaneous use
Initial U.S. Approval: 2017
BRIEF SUMMARY: Please see package insert for full prescribing information.
WARNING: THROMBOTIC MICROANGIOPATHY AND THROMBOEMBOLISM
Cases of thrombotic microangiopathy and thrombotic events were reported when on average a cumulative
amount of >100 U/kg/24 hours of activated prothrombin complex concentrate was administered for 24 hours or
more to patients receiving HEMLIBRA prophylaxis. Monitor for the development of thrombotic microangi opathy
and thrombotic events if aPCC is administered. Discontinue aPCC and suspend dosing of HEMLIBRA if
symptoms occur.
1 INDICATIONS AND USAGE
HEMLIBRA is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in
adult and pediatric patients ages newborn and older with hemophilia A (congenital factor VIII deficiency) with
or without factor VIII inhibitors.
4 CONTRAINDICATIONS
None.
5 WARNINGS AND PRECAUTIONS
5.1 Thrombotic Microangiopathy Associated with HEMLIBRA and aPCC Cases of thrombotic microangiopathy
(TMA) were reported from clinical trials when on average a cumulative amount of >100 U/kg/24 hours of
activated prothrombin complex concentrate (aPCC) was administered for 24 hours or more to patients
receiving HEMLIBRA prophylaxis. In clinical trials, thrombotic microangi opathy was reported in 0.8% of
patients (3/391) and in 8.1% of patients (3/37) who received at least one dose of aPCC. Patients presented
with thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury, without severe
deficiencies in ADAMTS13 activity.
Evidence of improvement was seen within one week following discontinuation of aPCC. One patient resumed
HEMLIBRA following resolution of TMA.
Consider the benefits and risks if aPCC must be used in a patient receiving HEMLIBRA prophylaxis. Monitor for
the development of TMA when administering aPCC. Immediately discontinue aPCC and interrupt HEMLIBRA
prophylaxis if clinical symptoms and/or laboratory findings consistent with TMA occur, and manage as
clinically indicated. Consider the benefits and risks of resuming HEMLIBRA prophylaxis following complete
resolution of TMA on a case-by-case basis.
5.2 Thromboembolism Associated with HEMLIBRA and aPCC Thrombotic events were reported from clinical
trials when on average a cumulative amount of >100 U/kg/24 hours of aPCC was administered for 24 hours or
more to patients receiving HEMLIBRA prophylaxis. In clinical trials, thrombotic events were reported in 0.5%
of patients (2/391) and in 5.4% of patients (2/37) who received at least one dose of aPCC.
No thrombotic event required anticoagulation therapy. Evidence of improvement or resolution was seen within
one month following discontinuation of aPCC. One patient resumed HEMLIBRA following resolution of
thrombotic event.
Consider the benefits and risks if aPCC must be used in a patient receiving HEMLIBRA prophylaxis. Monitor
for the development of thromboembolism when administering aPCC. Immediately discontinue aPCC and
interrupt HEMLIBRA prophylaxis if clinical symptoms, imaging, or laboratory findings consistent with
thrombo embolism occur, and manage as clinically indicated. Consider the benefits and risks of resuming
HEMLIBRA prophylaxis following complete resolution of thrombotic events on a case-by-case basis.
5.3 Laboratory Coagulation Test Interference HEMLIBRA affects intrinsic pathway clotting-based laboratory
tests, including activated clotting time (ACT), activated partial thromboplastin time (aPTT), and all assays
based on aPTT, such as one-stage factor VIII (FVIII) activity (Table 1). Therefore, intrinsic pathway clotting-
based laboratory test results in patients treated with HEMLIBRA should not be used to monitor HEMLIBRA
activity, determine dosing for factor replacement or anti-coagulation, or measure FVIII inhibitor titers [see
Drug Interactions (7.2) in the full prescribing information]. Laboratory tests affected and unaffected by
HEMLIBRA are shown in Table 1.
Table 1 Coagulation Test Results Affected and Unaffected by HEMLIBRA
Results Affected by HEMLIBRA
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)
Results Unaffected by HEMLIBRA
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 FVIII*
Immuno-based assays (i.e., ELISA, turbidimetric methods)
Genetic tests of coagulation factors (e.g., Factor V Leiden,
Prothrombin 20210)
*For important considerations regarding FVIII chromogenic activity assays, see Drug Interactions (7.2) in the full
prescribing information
6 ADVERSE REACTIONS
The following serious adverse reactions are described elsewhere in the labeling:
• Thrombotic Microangiopathy Associated with HEMLIBRA and aPCC [see Warnings and Precautions (5.1)]
• Thromboembolism Associated with HEMLIBRA and aPCC [see Warnings and Precautions (5.2)]
6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse
reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
of another drug and may not reflect the rates observed in practice. The following adverse reactions are based
on pooled data from two randomized trials in adult and adolescent patients (HAVEN 1 and HAVEN 3), one
single-arm trial in adult and adolescent patients (HAVEN 4), one single-arm trial in pediatric patients (HAVEN 2),
and one dose-finding trial, in which a total of 391 male patients with hemophilia A received at least one dose of
HEMLIBRA as routine prophylaxis. Two hundred eighty-one patients (72%) were adults (18 years and older),
50 (13%) were adolescents (12 years up to less than 18 years), 55 (14%) were children (2 years up to less
than 12 years), and five (1%) were infants (1 month up to less than 2 years). The median duration of exposure
across the studies was 34.1 weeks (0.1 to 224.4 weeks). The most frequently reported adverse reactions
observed in ≥ 10% of patients treated with HEMLIBRA were injection site reactions, headache, and arthralgia.
Four patients (1%) in the clinical trials receiving HEMLIBRA prophylaxis withdrew from treatment due to
adverse reactions, which were thrombotic microangiopathy, skin necrosis and superficial thrombophlebitis,
and injection site reaction. One patient withdrew from treatment after developing an anti-emicizumab-kxwh
neutralizing antibody associated with loss of efficacy [see Adverse Reactions (6.2)].
Adverse reactions observed in patients who received HEMLIBRA are shown in Table 2.
Table 2 Adverse Reactions Reported in ≥ 5% of Patients from Pooled Clinical Trials with HEMLIBRA
Number of Patients
Body System
Adverse Reaction
n (%)
(N = 189)
Injection site reaction*
85 (22%)
General Disorders and
Administration Site Conditions
Pyrexia
23 (6%)
Nervous System Disorders
Headache
57 (15%)
Gastrointestinal Disorders
Diarrhea
22 (6%)
Musculoskeletal and Connective Tissue Disorders
Arthralgia
59 (15%)
* Includes injection site bruising, injection site discomfort, injection site erythema, injection site hematoma,
injection site induration, injection site pain, injection site pruritus, injection site rash, injection site reaction,
injection site swelling, injection site urticarial, and injection site warmth.
Characterization of aPCC treatment in pooled clinical trials There were 130 instances of aPCC treatment in
37 patients, of which 13 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 13 were associated with thrombotic events and three of the 13 were
associated with TMA (Table 3). No TMA or thrombotic events were associated with the remaining instances of
aPCC treatment.
Table 3 Characterization of aPCC Treatment* in Pooled Clinical Trials
Duration of aPCC treatment
Average cumulative amount of aPCC over 24 hours (U/kg/24 hours)
< 50 50 – 100 > 100
< 24 hours 11 76 18
24 – 48 hours 0 6 3 a
> 48 hours 1 5 10 a,b,b,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. a Thrombotic event. b Thrombotic microangiopathy.
Injection Site Reactions In total, 85 patients (22%) reported injection site reactions (ISRs). All ISRs observed in
HEMLIBRA clinical trials were reported as mild to moderate intensity and 93% resolved without treatment. The
commonly reported ISR symptoms were injection site erythema (11%), injection site pain (4%), and injection
site pruritus (4%). Other Less Common (<1%) Reactions • Rhabdomyolysis
Rhabdomyolysis was reported in two adult patients with asymptomatic elevations in serum creatinine kinase
without associated renal or musculoskeletal symptoms. In both instances, the event occurred following an
increase in physical activity.
6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The detection
of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the
observed incidence of antibody positivity in an assay may be influenced by several factors, including assay
methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease.
For these reasons, comparison of the incidence of antibodies to emicizumab-kxwh in the studies described
below with the incidence of antibodies in other studies or to other products may be misleading.
The immunogenicity of HEMLIBRA was evaluated using an enzyme-linked immunosorbent assay (ELISA) or
an electrochemiluminescence (ECL) assay. In the dose-finding trial (n = 18), four patients tested positive for
anti-emicizumab-kxwh antibodies. In the pooled HAVEN clinical trials, 3.5% of patients (14/398) tested
positive for anti-emicizumab-kxwh antibodies and <1% of patients (3/398) developed anti-emicizumab-kxwh
antibodies with neutralizing potential (based on declining pharmacokinetics). One patient from HAVEN 2, who
developed an anti-emicizumab-kxwh neutralizing antibody, experienced loss of efficacy after 5 weeks of
treatment.
There was no clinically apparent impact of the presence of anti-emicizumab-kxwh antibodies on safety.
7 DRUG INTERACTIONS
7.1 Hypercoagulability with Concomitant Use of aPCC Clinical experience suggests that a drug interaction
exists with HEMLIBRA and aPCC [see Warnings and Precautions (5.1, 5.2)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy Risk Summary There are no available data on HEMLIBRA use in pregnant women to inform a
drug-associated risk of major birth defects and miscarriage. Animal reproduction studies have not been
conducted with emicizumab-kxwh. It is not known whether HEMLIBRA can cause fetal harm when
administered to a pregnant woman or can affect reproduction capacity. HEMLIBRA should be used during
pregnancy only if the potential benefit for the mother outweighs the risk to the fetus. All pregnancies have a
background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major
birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the
estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is
2 – 4% and 15 – 20%, respectively.
8.2 Lactation Risk Summary There is no information regarding the presence of emicizumab-kxwh in human
milk, the effects on the breastfed child, or the effects on milk production. Human IgG is known to be present
in human milk. The developmental and health benefits of breastfeeding should be considered along with the
mother’s clinical need for HEMLIBRA and any potential adverse effects on the breastfed child from HEMLIBRA
or from the underlying maternal condition.
8.3 Females and Males of Reproductive Potential Contraception Women of childbearing potential should
use contraception while receiving HEMLIBRA.
8.4 Pediatric Use The safety and efficacy of HEMLIBRA have been established in pediatric patients. Use of
HEMLIBRA in pediatric patients with hemophilia A is supported by two randomized trials (HAVEN 1 and
HAVEN 3) and two single-arm trials (HAVEN 2 and HAVEN 4). All clinical trials included pediatric patients in
the following age group: 47 adolescents (12 years up to less than 18 years). Only HAVEN 2 included pediatric
patients in the following age groups: 55 children (2 years up to less than 12 years) and five infants (1 month
up to less than 2 years). No differences in efficacy were observed between the different age groups [see
Clinical Studies (14) in the full prescribing information].
The steady-state plasma trough concentrations of emicizumab-kxwh were comparable in adult and pediatric
patients older than 6 months at equivalent weight-based doses. Lower concentrations of emicizumab-kxwh
were predicted in pediatric patients less than 6 months old [see Clinical Pharmacology (12.3) in the full
prescribing information].
In general, the adverse reactions in HEMLIBRA-treated pediatric patients were similar in type to those seen in
adult patients with hemophilia A [see Adverse Reactions (6.1)].
8.5 Geriatric Use Clinical studies of HEMLIBRA did not include sufficient numbers of patients aged 65 and
over to determine whether they respond differently from younger patients. Other reported clinical experience
has not identified differences in responses between the elderly and younger patients.
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
Use of Bypassing Agents or FVIII
Inform the patient and/or caregiver that HEMLIBRA increases coagulation potential. Advise the patient and/or
caregiver to discontinue prophylactic use of bypassing agents the day before starting HEMLIBRA prophylaxis.
Advise the patient and/or caregiver that prophylactic use of FVIII may be continued for the first week of
HEMLIBRA prophylaxis. Discuss the appropriate dosing of concomitant agents such as bypassing agents or
FVIII with the patient and/or caregiver prior to starting HEMLIBRA prophylaxis [see Warnings and Precautions
(5.1, 5.2) and Drug Interactions (7.1)].
Thrombotic Microangiopathy Associated with HEMLIBRA and aPCC
Inform the patient and/or caregiver of the potential risk of thrombotic microangiopathy if aPCC is
administered while receiving HEMLIBRA prophylaxis. Instruct the patient and/or caregiver to consult their
healthcare provider if aPCC is required in cumulative doses exceeding 100 U/kg. Advise the patient and/or
caregiver to seek immediate medical attention if any signs or symptoms of thrombotic microangiopathy occur
[see Warnings and Precautions (5.1)].
Thromboembolism Associated with HEMLIBRA and aPCC
Inform the patient and/or caregiver of the potential risk of thromboembolism if aPCC is administered while
receiving HEMLIBRA prophylaxis. Instruct the patient and/or caregiver to consult their healthcare provider if
aPCC is required in cumulative doses exceeding 100 U/kg. Advise the patient and/or caregiver to seek
immediate medical attention if any signs or symptoms of thromboembolism occur [see Warnings and
Precautions (5.2)].
Laboratory Coagulation Test Interference
Inform the patient and/or caregiver that HEMLIBRA interferes with some laboratory tests that measure blood
clotting and may cause a false reading. Advise the patient and/or caregiver that they should notify any
healthcare provider about this possibility prior to any blood tests or medical procedures [see Warnings and
Precautions (5.3)].
Instruction on Injection Technique
HEMLIBRA is intended for use under the guidance of a healthcare provider. If a patient or caregiver is to
administer subcutaneous HEMLIBRA, instruct him/her in injection techniques and assess his/her ability to
inject subcutaneously to ensure proper administration of subcutaneous HEMLIBRA and the suitability for
home use [see Instructions for Use].
Advise the patient to follow the recommendations in the FDA-approved patient labeling regarding proper
sharps disposal.
Manufactured by:
Genentech, Inc.
A Member of the Roche Group
1 DNA Way
South San Francisco, CA 94080-4990
U.S. License No. 1048
HEMLIBRA ® is a registered trademark of
Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
©2018 Genentech, Inc. All rights reserved.
EMI/031218/0041(1) 01/19