HEMLIBRA

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 emicizumab-kxwh at 12 mg/0.4 mL, 30 mg/mL, 60 mg/0.4 mL, 105 mg/0.7 mL, 150 mg/mL, or 300 mg/2 mL.

Each single-dose 12 mg vial contains a 0.4 mL solution of emicizumab-kxwh (12 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 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.

Each single-dose 300 mg vial contains a 2 mL solution of emicizumab-kxwh (300 mg), L-arginine (52.3 mg), L-histidine (6.2 mg), and poloxamer 188 (1 mg), adjusted to pH 6.0 with L-aspartic acid.

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.

HEMLIBRA is a bispecific factor

• 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. 12.3 Pharmacokinetics Emicizumab-kxwh exhibited dose-proportional pharmacokinetics over a dose range of 0.3 mg/kg (0.1 times approved recommended starting dosage) to 6 mg/kg following subcutaneous administration.

Following multiple subcutaneous administrations of a loading dose of 3 mg/kg emicizumab-kxwh once weekly for the first 4 weeks in hemophilia A patients, mean (± SD) trough plasma concentrations of 52.6 ± 13.6 μg/mL was achieved at Week 5.

Sustained mean (± SD) plasma concentrations of emicizumab-kxwh at steady-state with the recommended maintenance doses are shown in Table 4.

Table 4 Mean (± SD) Steady-State Concentrations after emicizumab-kxwh Loading Dose by Maintenance Dose Regimen Maintenance Dose Parameters 1.5 mg/kg once every week 3 mg/kg once every two weeks 6 mg/kg once every four weeks AUC ss,τ = area under the concentration time curve at steady-state over the dosing interval (τ = 1, 2, or 4 weeks); C max, ss = maximum plasma concentration at steady state; C trough, ss = trough concentration at steady state.

C max, ss (µg/mL) 55.1 ± 15.9 58.3 ± 16.4 67 ± 17.7 AUC ss,τ (µg/mL*day) 376 ± 109 752 ± 218 1503 ± 437 C trough, ss (µg/mL) 51.2± 15.2 46.9 ± 14.8 38.5 ± 14.2 C max / C trough ratio (µg/mL) 1.08 ± 0.03 1.26 ± 0.12 1.85 ± 0.47 Absorption Following subcutaneous administration, the mean (± SD) absorption half-life was 1.6 ± 1 day. The absolute bioavailability following subcutaneous administration of 1 mg/kg was between 80.4% and 93.1%.

Similar pharmacokinetic profiles were observed following subcutaneous administration in the abdomen, upper arm, and thigh.

The mean apparent volume of distribution (% coefficient of variation [%CV]) was 10.4 L (26.0%).

The mean apparent clearance (%CV) was 0.27 L/day (28.4%) and the mean elimination apparent half-life (± SD) was 26.9 ± 9.1 days.

The pharmacokinetics of emicizumab-kxwh are not influenced by age (1 year to 77 years), race (White 62.7%, Asian 22.9%, and Black 8%), inhibitor status (inhibitor present, 50%), mild hepatic impairment (defined as total bilirubin 1× to ≤1.5× the upper limit of normal (ULN) and any aspartate transaminase (AST) level), moderate hepatic impairment (defined as total bilirubin 1.5× to ≤3× the ULN and any AST level), mild renal impairment (defined as creatinine clearance (CrCl) of 60 – 89 mL/min), and moderate renal impairment (defined as CrCl of 30 – 59 mL/min).

Emicizumab-kxwh has not been studied in patients with severe hepatic or renal impairment.

In pediatric patients less than 6 months old, the predicted concentrations of emicizumab-kxwh were 19% to 33% lower than the older patients, especially with the 3 mg/kg once every two weeks or 6 mg/kg once every four weeks maintenance dose.

Body weight

The apparent clearance and volume of distribution of emicizumab-kxwh increased with increasing body weight (9 kg to 156 kg).

Dosing in mg/kg provides similar emicizumab-kxwh exposure across body weight range.

No drug-drug interaction studies have been conducted with HEMLIBRA. 12.6 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay.

Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of HEMLIBRA or of other emicizumab products.

In the clinical trials with

HEMLIBRA, 5.1% of patients (34/668) tested positive for anti-emicizumab-kxwh antibodies.

Participants were exposed to emicizumab-kxwh for a median interquartile range (IQR) of 103.1 (82.4 – 148.1) weeks.

Samples testing for anti-drug antibodies were obtained at baseline and at trough periodically throughout the studies duration.

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. 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.

Of these, 2.7% of patients (18/668), the neutralizing anti-emicizumab-kxwh antibodies did not have a clinically meaningful impact on the pharmacokinetics of HEMLIBRA in 2.1% of patients (14/668), while decreased emicizumab-kxwh plasma concentrations were observed in 0.6% of patients (4/668).

One patient (1/668; 0.1%) developed neutralizing anti-emicizumab-kxwh antibodies and had decreased emicizumab-kxwh plasma concentrations, and experienced loss of efficacy (manifest as breakthrough bleeding) after 5 weeks of treatment and discontinued HEMLIBRA treatment. .

The following serious adverse reactions are described elsewhere in the labeling: Thrombotic Microangiopathy Associated with HEMLIBRA and aPCC Thromboembolism Associated with HEMLIBRA and aPCC Most common adverse reactions (incidence ≥ 10%) are injection site reactions, headache, and arthralgia.fda.gov/medwatch. 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 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, headache, and injection site reaction.

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 Body System Adverse Reaction Number of Patients n (%) (N = 391) General.

Disorders and Administration Site Conditions Injection site reaction 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 urticaria, and injection site warmth. 85 (22%) Pyrexia 23 (6%) Nervous System.

Disorders Headache 57 (15%) Gastrointestinal.

Disorders Diarrhea 22 (6%) Musculoskeletal and Connective Tissue.

Disorders Arthralgia 59 (15%) 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 were associated with thrombotic events and three of the 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 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. 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 Thrombotic event. > 48 hours 1 5 10, 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%).

Common (<1%) Reactions Rhabdomyolysis Rhabdomyolysis was reported in two adult patients with asymptomatic elevations in serum creatine kinase without associated renal or musculoskeletal symptoms.

In both instances, the event occurred following an increase in physical activity. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of HEMLIBRA.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and subcutaneous tissue disorders: rash, urticaria, angioedema.

Immune system disorders: hypersensitivity.

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.

Information for important preparation and administration instructions. 2.1 Recommended Dosage 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 healthcare 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. 2.2 Preparation and Administration HEMLIBRA is intended for use under the guidance of a healthcare provider.

After proper training in subcutaneous injection technique, a patient may self-inject, or the patient's caregiver may administer HEMLIBRA, if a healthcare provider determines that it is appropriate.

Self-administration is not recommended for children less than 7 years of age.

HEMLIBRA "Instructions for Use" contains more detailed instructions on the preparation and administration of HEMLIBRA.

Visually inspect

HEMLIBRA for particulate matter and discoloration before administration.

HEMLIBRA for subcutaneous administration is a colorless to slightly yellow solution.

Do not use if particulate matter is visible or product is discolored.

A syringe, a transfer needle with filter and an injection needle are needed to withdraw HEMLIBRA solution from the vial and inject it subcutaneously.

Refer to the

HEMLIBRA " Instructions for Use " for handling instructions when combining vials.

Do not combine

HEMLIBRA vials of different concentrations (i.e. 30 mg/mL and 150 mg/mL) in a single injection.

Please see below the selection criteria for the recommended device options: Administer doses of HEMLIBRA up to 1 mL with a 1 mL syringe.

A 1 mL syringe fulfilling the following criteria may be used: Transparent polypropylene or polycarbonate syringe with Luer-Lock tip, graduation 0.01 mL, sterile, for injection only, single-use, latex-free and non-pyrogenic, commercially available in the US.

Administer doses of

HEMLIBRA greater than 1 mL and up to 2 mL with a 2 mL or 3 mL syringe.

A 2 mL or 3 mL syringe fulfilling the following criteria may be used: Transparent polypropylene or polycarbonate syringe with Luer-Lock tip, graduation 0.1 mL, sterile, for injection only, single-use, latex-free, and non-pyrogenic, commercially available in the US.

A transfer needle with a filter fulfilling the following criteria should be used: Stainless steel needle with Luer-Lock connection, sterile, 18 gauge, length to 1½ inch, single bevel or semi-blunted tip, single-use, latex-free, containing a 5-micron filter and non-pyrogenic, commercially available in the US.

An injection needle fulfilling the following criteria may be used: Stainless steel with Luer-Lock connection, sterile, 26 gauge (acceptable range: 25 – 27 gauge), length preferably ⅜ inch or maximal length ½ inch, single-use, latex-free and non-pyrogenic, including needle safety feature, commercially available in the US.

Administer each injection at a different anatomic location (upper outer arms, thighs, or any quadrant of abdomen) than the previous injection.

An injection should never be given into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact.

Administration of

HEMLIBRA in the upper outer arm should only be performed by a caregiver or healthcare provider.

Discard any unused

HEMLIBRA remaining in the single-dose vial.

HEMLIBRA (emicizumab-kxwh) injection is available as a sterile, preservative-free, colorless to slightly yellow solution in single-dose vials in the following dosage strengths: Strength Nominal Volume Concentration Package Size (per carton) Cap Color NDC 12 mg 0.4 mL 30 mg/mL 1 vial Grey 50242-927-01 30 mg 1 mL 30 mg/mL 1 vial Sky Blue 50242-920-01 60 mg 0.4 mL 150 mg/mL 1 vial Purple 50242-921-01 105 mg 0.7 mL 150 mg/mL 1 vial Turquoise 50242-922-01 150 mg 1 mL 150 mg/mL 1 vial Brown 50242-923-01 300 mg 2 mL 150 mg/mL 1 vial Yellow 50242-930-01 Storage and Handling Store HEMLIBRA vials in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.

Do not freeze.

Do not shake.

Prior to administration, if needed, unopened vials of HEMLIBRA may be stored out of and then returned to refrigeration.

The temperature and total combined time out of refrigeration should not exceed 30°C (86°F) and 7 days (at a temperature below 30°C [86°F]), respectively.

Once removed from the vial, discard HEMLIBRA if not used immediately.

Discard any unused

HEMLIBRA vials in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.

Do not freeze.

Do not shake.

Prior to administration, if needed, unopened vials of HEMLIBRA may be stored out of and then returned to refrigeration.

The temperature and total combined time out of refrigeration should not exceed 30°C (86°F) and 7 days (at a temperature below 30°C [86°F]), respectively.

Once removed from the vial, discard HEMLIBRA if not used immediately.

Discard any unused

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.

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 and HAVEN 3) and two single-arm trials (HAVEN and HAVEN 4).

All clinical trials included pediatric patients in the following: 47 adolescents (12 years up to less than 18 years).

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.

Clinical studies of

HEMLIBRA did not include a sufficient number of patients aged 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.