HEMLIBRA ® (emicizumab-kxwh) injection

HEMLIBRA ® (emicizumab-kxwh) injection

HEMLIBRA ® (emicizumab-kxwh) injection

Emicizumab-kxwh is a humanized monoclonal modified immunoglobulin G4 (IgG4) bispecific antibody binding factor IXa and factor X. Emicizumab-kxwh has an approximate molecular weight of 145.6 kDa and is produced in genetically engineered mammalian (Chinese hamster ovary) cells. Emicizumab-kxwh has no structural relationship or sequence homology to FVIII and, as such, does not induce or enhance the development of direct inhibitors to FVIII.

HEMLIBRA (emicizumab-kxwh) injection is a sterile, preservative-free, colorless to slightly yellow solution for subcutaneous injection supplied in single-dose vials containing emicizumab­kxwh at 30 mg/mL, 60 mg/0.4 mL, 105 mg/0.7 mL, or 150 mg/mL.

Each single-dose 30 mg vial contains a 1 mL solution of emicizumab-kxwh (30 mg), L-arginine (26.1 mg), L-histidine (3.1 mg), and poloxamer 188 (0.5 mg), adjusted to pH 6.0 with L-aspartic acid.

Each single-dose 60 mg vial contains a 0.4 mL solution of emicizumab-kxwh (60 mg), L-arginine (10.5 mg), L-histidine (1.2 mg), and poloxamer 188 (0.2 mg), adjusted to pH 6.0 with L-aspartic acid.

Each single-dose 105 mg vial contains a 0.7 mL solution of emicizumab-kxwh (105 mg), L-arginine (18.3 mg), L-histidine (2.2 mg), and poloxamer 188 (0.4 mg), adjusted to pH 6.0 with L-aspartic acid.

Each single-dose 150 mg vial contains a 1 mL solution of emicizumab-kxwh (150 mg), L-arginine (26.1 mg), L-histidine (3.1 mg), and poloxamer 188 (0.5 mg), adjusted to pH 6.0 with L-aspartic acid.

Indications and usage

HEMLIBRA is a bispecific factor IXa- and factor X-directed antibody 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.

Mechanism of Action

HEMLIBRA bridges activated factor IX and factor X to restore the function of missing activated factor VIII that is needed for effective hemostasis.

Dosage and administration

For subcutaneous use only.
The recommended loading dose is 3 mg/kg by subcutaneous injection once weekly for the first
4 weeks, followed by a maintenance dose of:

  • 1.5 mg/kg once every week, or
  • 3 mg/kg once every two weeks, or
  • 6 mg/kg once every four weeks.

The selection of a maintenance dose should be based on health care provider preference with
consideration of regimens that may increase patient adherence.
Discontinue the prophylactic use of bypassing agents the day before starting HEMLIBRA
prophylaxis.

The prophylactic use of factor VIII (FVIII) products may be continued during the first week of
HEMLIBRA prophylaxis.

Missed Dose

If a dose of HEMLIBRA is missed administer as soon as possible and then resume usual dosing
schedule. Do not administer two doses on the same day to make up for a missed dose.

WARNINGS AND PRECAUTIONS

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 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.

Evidence of improvement was seen within one week following discontinuation of aPCC. One
patient resumed HEMLIBRA following resolution of TMA.

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.

Immunogenicity

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

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

DRUG INTERACTIONS

Hypercoagulability with Concomitant Use of aPCC: Clinical experience suggests that a drug interaction exists with HEMLIBRA and aPCC

USE IN SPECIFIC POPULATIONS

Pregnancy: 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.

Lactation: 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.

Contraception: Women of childbearing potential should use contraception while receiving HEMLIBRA.

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

Geriatric Use: 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.

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