Approved Drug Label (PDF)
5
Warnings and Precautions
5.3 Immunogenicity
New subsection
added
Treatment with HEMLIBRA may induce anti-drug antibodies.
Anti-emicizumab-kxwh antibodies were reported in 5.1% of patients (34/668)
treated with HEMLIBRA in clinical trials. Most patients with
anti-emicizumab-kxwh antibodies did not experience a change in HEMLIBRA plasma
concentrations or an increase in bleeding events; however, in uncommon cases
(incidence < 1%), the presence of neutralizing antibodies with decreasing
plasma concentration may be associated with loss of efficacy [see Adverse
Reactions (6.1, 6.2)].
Monitor for clinical signs of loss of efficacy
(e.g., increase in breakthrough bleeding events) and if observed, promptly
assess the etiology and consider a change in treatment if neutralizing anti-
emicizumab-kxwh antibodies are suspected.
6
Adverse Reactions
Addition of the following to the bulleted line listing:
• Immunogenicity
[see Warnings and Precautions (5.3)
6.2 Immunogenicity
Additions and/or revisions underlined
…
The immunogenicity of HEMLIBRA was evaluated using an
enzyme-linked immunosorbent assay (ELISA) or an electrochemiluminescence (ECL)
assay for anti-emicizumab-kxwh antibodies. In the 7 phase III clinical trials,
antibody positive samples were further evaluated for neutralizing
anti-emicizumab-kxwh antibodies using a modified FVIII chromogenic assay. A total
of 668 patients were tested for anti-emicizumab-kxwh antibodies. In the pooled
phase III clinical trials, 5.1% of patients (34/668) tested positive for
anti-emicizumab-kxwh antibodies and 2.7% of patients (18/668) developed
anti-emicizumab-kxwh antibodies that were neutralizing in vitro. The
anti-emicizumab antibody positive rate may be under-reported due to the
limitation of the assay. Of these 18 patients, the neutralizing
anti-emicizumab-kxwh antibodies did not have a clinically meaningful impact on
the pharmacokinetics or efficacy of HEMLIBRA in 14 patients, while decreased
emicizumab-kxwh plasma concentrations were observed in four patients (0.6%).
One patient (0.2%) from HAVEN 2, who developed neutralizing
anti-emicizumab-kxwh antibodies and decreased emicizumab-kxwh plasma
concentrations, experienced loss of efficacy (manifest as breakthrough
bleeding) after 5 weeks of treatment and discontinued HEMLIBRA treatment.
Overall, the safety profile of HEMLIBRA was similar between those patients with
anti-emicizumab-kxwh antibodies (including neutralizing antibodies) and those
without [see Warnings and Precautions (5.3), Adverse Reactions (6.1)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING
INFORMATION
Additions
underlined
![]()
…
Immunogenicity
Inform
the patient and/or caregiver of the uncommon occurrence (incidence < 1%) of
loss of efficacy while receiving HEMLIBRA prophylaxis due to immunogenicity
(neutralizing anti- emicizumab-kxwh antibodies). Instruct the patient and/or
caregiver to promptly report clinical signs of loss of efficacy (e.g., increase
in breakthrough bleeding events) [see
Warnings and Precautions (5.3)].
…
MEDICATION GUIDE
Additions
underlined
What is the most
important information I should know about HEMLIBRA?
…
Your body may make
antibodies against HEMLIBRA, which may stop HEMLIBRA from working properly.
Contact your healthcare provider immediately if you notice that HEMLIBRA has
stopped working for you (e.g. increase in bleeds).
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Thrombotic Microangiopathy Associated with HEMLIBRA and aPCC
(Additions
and/or revisions are underlined)
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 microangiopathy 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.
…
5.2 Thromboembolism Associated with HEMLIBRA and aPCC
(Additions and/or revisions
are underlined)
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.
…
6
Adverse Reactions
6.1 Clinical Trials Experience
(Additions and/or revisions are
underlined)
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). populationThe 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, headache,
and injection site reaction.
One patient withdrew from treatment after
developing an anti-emicizumab-kxwh neutralizing antibody associated with loss
of efficacy.
Table 2 has been revised, please refer to the
label.
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
6.2 Immunogenicity
(Additions and/or revisions are
underlined)
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.
8
Use in Specific Populations
8.4 Pediatric Use
(Additions
and/or revisions are underlined)
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.
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.
In general, the adverse reactions in HEMLIBRA-treated pediatric
patients were similar in type to those seen in adult patients with hemophilia
A.
8.5 Geriatric Use
(Additions and/or revisions are underlined)
Clinical studies of HEMLIBRA did not include a sufficient number
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 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Additions and/or revisions are
underlined)
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.
….
MEDICATION GUIDE
(Additions
and/or revisions are underlined)
What is the most important
information I should know about HEMLIBRA?
HEMLIBRA increases the potential for your blood to clot. Carefully follow your healthcare provider’s instructions
regarding when to use an on-demand
bypassing agent or factor
VIII (FVIII) and the recommended
dose and schedule to use for breakthrough bleed treatment.
HEMLIBRA may cause the following
serious side effects when used
with activated prothrombin complex concentrate (aPCC; FEIBA®),
including:
Thrombotic microangiopathy (TMA). This is a condition involving blood clots and
injury to small blood vessels that may cause harm to your kidneys, brain, and
other organs. …
What is HEMLIBRA?
HEMLIBRA is a prescription medicine used for routine prophylaxis
to prevent or reduce the frequency of bleeding episodes in adults and children,
ages newborn and older, with hemophilia A with or without factor
VIII inhibitors.
…
How should I use HEMLIBRA?
See the detailed “Instructions for Use” that comes with your HEMLIBRA
for information on how to prepare and
inject a dose of HEMLIBRA, and how to properly throw away (dispose of) used needles and syringes.
Use HEMLIBRA exactly as prescribed by your
healthcare provider.
Stop (discontinue) prophylactic use of
bypassing agents the day before starting HEMLIBRA prophylaxis.
You may continue prophylactic use of FVIII for
the first week of HEMLIBRA prophylaxis.
HEMLIBRA is given as an injection under your
skin (subcutaneous injection) by you or a caregiver.
Your healthcare provider should show you or
your caregiver how to prepare, measure, and inject your dose of HEMLIBRA before
you inject yourself for the first time.
Do not attempt to inject yourself or another
person unless you have been taught how to do so by a healthcare provider.
Your healthcare provider will prescribe your
dose based on your weight. If your weight changes, tell your healthcare
provider.
You will receive HEMLIBRA 1 time a week for the first four
weeks. Then you will receive a maintenance dose as prescribed by
your healthcare provider.
If
you miss a dose of HEMLIBRA on your scheduled day, you should give the dose as
soon as you remember. You must give the missed dose as soon as possible before
the next scheduled dose, and then continue with your normal dosing schedule. Do
not give two doses on the same day to make up for a missed dose.
HEMLIBRA
may interfere with laboratory tests that measure how well your blood is
clotting and may cause a false reading. Talk to your healthcare provider about
how this may affect your care.
…
How should I store HEMLIBRA?
Store HEMLIBRA in the refrigerator at 36°F to
46°F (2°C to 8°C). Do not freeze.
Store HEMLIBRA in the original carton to
protect the vials from light.
Do not shake HEMLIBRA.
f needed, unopened vials of HEMLIBRA can be
stored out of the refrigerator and then returned to the refrigerator. HEMLIBRA
should not be stored out of the refrigerator for more than a total of 7 days or at a temperature
greater than 86°F (30°C).
After HEMLIBRA is transferred from the vial to
the syringe, HEMLIBRA should be used right away.
Throw away (dispose of) any unused HEMLIBRA
left in the vial.
Keep HEMLIBRA and all medicines out of the
reach of children.
Other
INSTRUCTIONS FOR USE
(Instructions
for Use has been added, please refer to the label)
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Thrombotic Microangiopathy Associated with HEMLIBRA and aPCC
(Additions
and/or revisions are underlined)
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 microangiopathy 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.
…
5.2 Thromboembolism Associated with HEMLIBRA and aPCC
(Additions and/or revisions
are underlined)
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.
…
8
Use in Specific Populations
8.4 Pediatric Use
(Additions
and/or revisions are underlined)
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.
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.
In general, the adverse reactions in HEMLIBRA-treated pediatric
patients were similar in type to those seen in adult patients with hemophilia
A.
8.5 Geriatric Use
(Additions and/or revisions are underlined)
Clinical studies of HEMLIBRA did not include a sufficient number
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 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Additions and/or revisions are
underlined)
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.
….
MEDICATION GUIDE
(Additions
and/or revisions are underlined)
What is the most important
information I should know about HEMLIBRA?
HEMLIBRA increases the potential for your blood to clot. Carefully follow your healthcare provider’s instructions
regarding when to use an on-demand
bypassing agent or factor
VIII (FVIII) and the recommended
dose and schedule to use for breakthrough bleed treatment.
HEMLIBRA may cause the following
serious side effects when used
with activated prothrombin complex concentrate (aPCC; FEIBA®),
including:
Thrombotic microangiopathy (TMA). This is a condition involving blood clots and
injury to small blood vessels that may cause harm to your kidneys, brain, and
other organs. …
What is HEMLIBRA?
HEMLIBRA is a prescription medicine used for routine prophylaxis
to prevent or reduce the frequency of bleeding episodes in adults and children,
ages newborn and older, with hemophilia A with or without factor
VIII inhibitors.
…
How should I use HEMLIBRA?
See the detailed “Instructions for Use” that comes with your HEMLIBRA
for information on how to prepare and
inject a dose of HEMLIBRA, and how to properly throw away (dispose of) used needles and syringes.
Use HEMLIBRA exactly as prescribed by your
healthcare provider.
Stop (discontinue) prophylactic use of
bypassing agents the day before starting HEMLIBRA prophylaxis.
You may continue prophylactic use of FVIII for
the first week of HEMLIBRA prophylaxis.
HEMLIBRA is given as an injection under your
skin (subcutaneous injection) by you or a caregiver.
Your healthcare provider should show you or
your caregiver how to prepare, measure, and inject your dose of HEMLIBRA before
you inject yourself for the first time.
Do not attempt to inject yourself or another
person unless you have been taught how to do so by a healthcare provider.
Your healthcare provider will prescribe your
dose based on your weight. If your weight changes, tell your healthcare
provider.
You will receive HEMLIBRA 1 time a week for the first four
weeks. Then you will receive a maintenance dose as prescribed by
your healthcare provider.
If
you miss a dose of HEMLIBRA on your scheduled day, you should give the dose as
soon as you remember. You must give the missed dose as soon as possible before
the next scheduled dose, and then continue with your normal dosing schedule. Do
not give two doses on the same day to make up for a missed dose.
HEMLIBRA
may interfere with laboratory tests that measure how well your blood is
clotting and may cause a false reading. Talk to your healthcare provider about
how this may affect your care.
…
How should I store HEMLIBRA?
Store HEMLIBRA in the refrigerator at 36°F to
46°F (2°C to 8°C). Do not freeze.
Store HEMLIBRA in the original carton to
protect the vials from light.
Do not shake HEMLIBRA.
f needed, unopened vials of HEMLIBRA can be
stored out of the refrigerator and then returned to the refrigerator. HEMLIBRA
should not be stored out of the refrigerator for more than a total of 7 days or at a temperature
greater than 86°F (30°C).
After HEMLIBRA is transferred from the vial to
the syringe, HEMLIBRA should be used right away.
Throw away (dispose of) any unused HEMLIBRA
left in the vial.
Keep HEMLIBRA and all medicines out of the
reach of children.
Other
INSTRUCTIONS FOR USE
(Instructions
for Use has been added, please refer to the label)
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