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.

• 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.

Special populations

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 5.1 Pharmacodynamic properties, Clinical efficacy and safety].

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 5.2 Pharmacokinetics properties]. 

In general, the adverse reactions in HEMLIBRA-treated pediatric patients were similar in type to those seen in adult patients with hemophilia A [see 4.8 Undesirable effects].

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.

• 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.

• 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 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 in a single injection.

• 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 fulfilling the following criteria may be used: Stainless steel needle with Luer-Lock connection, sterile, 18 gauge, length 1 to 1½ inch, single bevel or semi-blunted tip, single-use, latex-free, 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 3/8 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.

• 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. 

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.

• 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 thromboembolism 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. 

• 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. Laboratory tests affected and unaffected by HEMLIBRA are shown in Table 1.

Table 1 Coagulation Test Results Affected and Unaffected by HEMLIBRA

*For important considerations regarding FVIII chromogenic activity assays, see section 4.5 Interaction with other medicinal products and other forms of interaction

• Hypercoagulability with Concomitant Use of aPCC, 

Clinical experience suggests that a drug interaction exists with HEMLIBRA and aPCC [see section 4.4 Special warnings and precautions for use and 4.8 Undesirable effects].

• Drug-Laboratory Test Interactions

HEMLIBRA restores the tenase cofactor activity of missing activated factor VIII (FVIIIa). Coagulation laboratory tests based on intrinsic clotting (i.e., 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 HEMLIBRA, 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; however, single-factor assays utilizing chromogenic or immuno-based methods are unaffected by HEMLIBRA and may be used to monitor coagulation parameters during treatment, with specific considerations for FVIII chromogenic activity assays as described below.

Chromogenic FVIII activity tests may be manufactured with either human or bovine coagulation proteins. Assays containing human coagulation factors are responsive to HEMLIBRA but may overestimate the clinical hemostatic potential of HEMLIBRA. In contrast, assays containing bovine coagulation factors are insensitive to HEMLIBRA (no activity measured) and can be used to monitor endogenous or infused FVIII activity, or to measure anti-FVIII inhibitors.

HEMLIBRA remains active in the presence of inhibitors against FVIII, so it will produce a false-negative result in clotting-based Bethesda assays for functional inhibition of FVIII. Instead, a chromogenic Bethesda assay utilizing a bovine-based FVIII chromogenic test that is insensitive to HEMLIBRA may be used.

Due to the long half-life of HEMLIBRA, effects on coagulation assays may persist for up to 6 months after the last dose [see section 5.2 Pharmacokinetics properties].

• 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.

• 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.

• Females and Males of Reproductive Potential

Contraception

Women of childbearing potential should use contraception while receiving HEMLIBRA.

There is no evidence that treatment with HEMLIBRA results in an increase in adverse reactions that might lead to the impairment of the ability to drive and use machines.

The following serious adverse reactions are described elsewhere in the labeling:

• Thrombotic Microangiopathy Associated with HEMLIBRA and aPCC [see section 4.4 Special warnings and precautions for use].

• Thromboembolism Associated with HEMLIBRA and aPCC [see section 4.4 Special warnings and precautions for use].

• 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, headache, and injection site reaction.

One patient withdrew from treatment after developing an anti-emicizumab-kxwh neutralizing antibody associated with loss of efficacy [see section 4.8 Undesirable effects].

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

* 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

* 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 creatine kinase without associated renal or musculoskeletal symptoms. In both instances, the event occurred following an increase in physical activity.

• 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. 

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.

To report any side effect(s):

•    Saudi Arabia:

•    Other GCC States:

There is limited experience with overdose of HEMLIBRA. Accidental overdose may result in hypercoagulability.

Patients who receive an accidental overdose should immediately contact their physician and be monitored closely. 

Pharmacodynamic properties

Pharmacotherapeutic group: Other systemic hemostatics, ATC code: B02BX06. 

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.

Pharmacodynamics

Hemophilia A is an X-linked hereditary disorder of blood coagulation due to a deficiency of functional FVIII and results in bleeding into joints, muscles or internal organs, either spontaneously or as result of accidental or surgical trauma.  Prophylactic therapy with HEMLIBRA shortens the aPTT and increases the reported FVIII activity (using a chromogenic assay with human coagulation factors).  These two pharmacodynamic markers do not reflect the true hemostatic effect of emicizumab in vivo (aPTT is overly shortened and reported FVIII activity may be overestimated) but provide a relative indication of the pro-coagulant effect of emicizumab.

Clinical efficacy and safety (Clinical studies)

Hemophilia A without FVIII Inhibitors

The efficacy of HEMLIBRA for routine prophylaxis in patients with hemophilia A without FVIII inhibitors was evaluated in two clinical trials [adult and adolescent studies (HAVEN 3 and HAVEN 4)].

HAVEN 3 (Adult and Adolescent Patients)

The HAVEN 3 study (NCT02847637) was a randomized, multicenter, open-label, clinical trial in 152 adult and adolescent males (aged ≥ 12 years and ≥ 40 kg) with hemophilia A without FVIII inhibitors who previously received either episodic (on demand) or prophylactic treatment with FVIII. Patients received HEMLIBRA prophylaxis, 3 mg/kg once weekly for the first 4 weeks followed by either 1.5 mg/kg once every week [Arms A and D] or 3 mg/kg once every two weeks [Arm B] thereafter, or no prophylaxis (Arm C). Patients in Arm C could switch to HEMLIBRA prophylaxis (3 mg/kg once every two weeks) after completing at least 24 weeks without prophylaxis. For Arms A and B, dose up-titration to 3 mg/kg once every week was allowed after 24 weeks on HEMLIBRA prophylaxis for patients who experienced two or more qualified bleeds (i.e., spontaneous and clinically significant bleeds occurring at steady state). For Arm D patients, dose up-titration was allowed after the second qualifying bleed. During the study, five patients underwent up-titration of their maintenance dose; however, this study was not designed to investigate the 3 mg/kg once every week dosing regimen.

Eighty-nine patients previously treated with episodic (on demand) FVIII were randomized in a 2:2:1 ratio to receive HEMLIBRA prophylaxis 1.5 mg/kg once every week (Arm A), 3 mg/kg once every two weeks (Arm B), or no prophylaxis (Arm C), with stratification by prior 24-week bleed rate (< 9 or ≥ 9). Sixty-three patients previously treated with prophylactic FVIII were enrolled into Arm D to receive HEMLIBRA prophylaxis (1.5 mg/kg once every week).

Efficacy was evaluated after a minimum of 24 weeks of follow-up based on the bleed rate for bleeds requiring treatment with coagulation factors among patients previously treated with episodic (on-demand) FVIII who were randomized to HEMLIBRA prophylaxis 1.5 mg/kg once every week (Arm A) or 3 mg/kg once every two weeks (Arm B) compared with those receiving no prophylaxis (Arm C). The study also evaluated the randomized comparison of Arms A and C and Arms B and C for the efficacy of HEMLIBRA prophylaxis in reducing the number of all bleeds, spontaneous bleeds, joint bleeds, and target joint bleeds.

The efficacy of HEMLIBRA prophylaxis compared with previous prophylactic FVIII was also evaluated in patients who had participated in a non-interventional study (NIS) prior to enrollment (Arm D). Only patients from the NIS were included in this comparison, because bleed and treatment data were collected with the same level of granularity as that used in HAVEN 3.

The efficacy results of HEMLIBRA prophylaxis (1.5 mg/kg once every week and 3 mg/kg once every two weeks) 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 Annualized Bleed Rate with HEMLIBRA Prophylaxis versus No Prophylaxis in Patients ≥ 12 Years of Age without Factor VIII Inhibitors 

ABR = annualized bleed rate; CI = confidence interval; IQR = interquartile range, 25th percentile to 75th percentile.

a Based on negative binomial regression model.

In the HAVEN 3 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).

Table 5 Intra-Patient Comparison of Annualized Bleed Rate with HEMLIBRA Prophylaxis versus Previous FVIII Prophylaxis

ABR = annualized bleed rate; CI = confidence interval; IQR = interquartile range, 25th percentile to 75th percentile.

a Based on negative binomial regression model.

HAVEN 4 (Adult and Adolescent Patients)

The HAVEN 4 study (NCT03020160) was a single-arm, multicenter, open-label, clinical trial in 41 adult and adolescent males (aged ≥ 12 years and ≥ 40 kg) with hemophilia A with or without FVIII inhibitors who previously received either episodic (on demand) or prophylactic treatment with FVIII or bypassing agents. Patients received HEMLIBRA prophylaxis at 3 mg/kg once weekly for the first 4 weeks followed by 6 mg/kg once every four weeks thereafter. 

Efficacy was evaluated in a subgroup of 36 patients with hemophilia A without FVIII inhibitors based on the bleed rate for bleeds requiring treatment with coagulation factors. The study also evaluated the efficacy of HEMLIBRA prophylaxis on all bleeds, treated spontaneous bleeds, treated joint bleeds, and treated target joint bleeds.

The efficacy results of HEMLIBRA prophylaxis 6 mg/kg once 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 6. The median observation time was 25.6 weeks (range 24.1 – 29.4 weeks).

Table 6 Annualized Bleed Rate with HEMLIBRA Prophylaxis 6 mg/kg Once Every Four Weeks in Patients ≥ 12 Years of Age without Factor VIII Inhibitors

ABR = annualized bleed rate; CI = confidence interval; IQR = interquartile range, 25th percentile to 75th percentile.

a Based on negative binomial regression model.

Hemophilia A with FVIII Inhibitors

The efficacy of HEMLIBRA for routine prophylaxis in patients with hemophilia A with FVIII inhibitors was evaluated in three clinical trials [adult and adolescent studies (HAVEN 1 and HAVEN 4) and a pediatric study (HAVEN 2)].

HAVEN 1 (Adult and Adolescent Patients)

The HAVEN 1 study (NCT02622321) was a randomized, multicenter, open-label, clinical trial in 109 adult and adolescent males (aged ≥ 12 years and ≥ 40 kg) with hemophilia A with FVIII inhibitors who previously received either episodic (on-demand) or prophylactic treatment with bypassing agents. Patients received HEMLIBRA prophylaxis (Arms A, C, and D), 3 mg/kg once weekly for the first 4 weeks followed by 1.5 mg/kg once every week thereafter, or no prophylaxis (Arm B). Patients in Arm B could switch to HEMLIBRA prophylaxis after completing at least 24 weeks without prophylaxis. Dose up-titration to 3 mg/kg once every week was allowed after 24 weeks on HEMLIBRA prophylaxis for patients who experienced two or more qualified bleeds (i.e., spontaneous and clinically significant bleeds occurring at steady state). During the study, two patients underwent up-titration of their maintenance dose; however, this study was not designed to investigate the 3 mg/kg once every week dosing regimen.

Fifty-three patients previously treated with episodic (on-demand) bypassing agents were randomized 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 into Arm C to receive HEMLIBRA prophylaxis. Seven patients previously treated with episodic (on-demand) bypassing agents who had participated in the NIS prior to enrollment, but were unable to enroll into HAVEN 1 prior to the closure of Arms A and B, were enrolled into Arm D to receive HEMLIBRA prophylaxis.

Efficacy was evaluated after a minimum of 24 weeks of follow-up based on the bleed rate for bleeds requiring treatment with coagulation factors among patients previously treated with episodic bypassing agents who were randomized to HEMLIBRA prophylaxis (Arm A) compared with those receiving no prophylaxis (Arm B). The study also evaluated the randomized comparison of Arms A and B for the efficacy of HEMLIBRA prophylaxis in reducing the number of all bleeds, spontaneous bleeds, joint bleeds, and target joint bleeds, as well as patient-reported symptoms and physical functioning.

The efficacy of HEMLIBRA prophylaxis compared with previous prophylactic bypassing agents was also evaluated in patients who had participated in the NIS prior to enrollment (Arm C). Only patients from the NIS were included in this comparison, because bleed and treatment data were collected with the same level of granularity as that used in HAVEN 1.

The efficacy results of HEMLIBRA prophylaxis 1.5 mg/kg once every week 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 7.

Table 7 Annualized Bleed Rate with HEMLIBRA Prophylaxis versus No Prophylaxis in Patients ≥ 12 Years of Age with Factor VIII Inhibitors 

ABR = annualized bleed rate; CI = confidence interval; IQR = interquartile range, 25th percentile to 75th percentile.

a Based on negative binomial regression model.

Descriptive analyses were conducted to assess HEMLIBRA prophylaxis once every week using 12-week treatment intervals up to Week 72. The descriptive mean ABRs for treated bleeds are shown in Table 8.

Table 8 Annualized Bleed Rate with HEMLIBRA Prophylaxis Once Every Week per 12-Week Intervals in Patients ≥ 12 Years of Age with Factor VIII Inhibitors

ABR = annualized bleed rate; CI = confidence interval based on Poisson distribution; N = number of patients who contributed data for analyses at each time interval.

In the HAVEN 1 intra-patient analysis, HEMLIBRA prophylaxis resulted in a statistically significant (p = 0.0003) reduction (79%) in bleed rate for treated bleeds compared with previous bypassing agent prophylaxis collected in the NIS prior to enrollment (Table 9).

Table 9 Intra-Patient Comparison of Annualized Bleed Rate with HEMLIBRA Prophylaxis versus Previous Bypassing Agent Prophylaxis

ABR = annualized bleed rate; CI = confidence interval; IQR = interquartile range, 25th percentile to 75th percentile.

a Based on negative binomial regression model.

The HAVEN 1 study evaluated patient-reported hemophilia-related symptoms (painful swellings and presence of joint pain) and physical functioning (pain with movement and difficulty walking far) using the Physical Health Score of the Haemophilia-specific Quality of Life (Haem-A-QoL) questionnaire for patients ≥ 18 years of age. The HEMLIBRA prophylaxis arm (Arm A) showed an improvement compared with the no prophylaxis arm (Arm B) in the Haem-A-QoL Physical Health Subscale score at the Week 25 assessment (Table 10). The improvement in the Physical Health Score was further supported by the Total Score as measured by the Haem-A-QoL at Week 25.

Table 10 Change in Haem-A-QoL Physical Health Score with HEMLIBRA Prophylaxis versus No Prophylaxis in Patients (≥ 18 Years of Age) with Factor VIII Inhibitors at Week 25

a Number of patients ≥ 18 years who completed the Haem-A-QoL questionnaire.

b Lower scores are reflective of better functioning.

c Adjusted for baseline, and baseline by treatment group interaction.

HAVEN 2 (Pediatric Patients)

The HAVEN 2 study (NCT02795767) was a single-arm, multicenter, open-label, clinical trial in pediatric males (age < 12 years, or 12 − 17 years who weigh < 40 kg) with hemophilia A with FVIII inhibitors. Patients received HEMLIBRA prophylaxis at 3 mg/kg once weekly for the first 4 weeks followed by 1.5 mg/kg once every week thereafter.

The study evaluated the efficacy of HEMLIBRA prophylaxis, including the efficacy of HEMLIBRA prophylaxis compared with previous episodic (on-demand) and prophylactic bypassing agent treatment in patients who had participated in a non-interventional study (NIS) prior to enrollment (intra-patient analysis).

At the time of the interim analysis, efficacy was evaluated in 59 pediatric patients who were < 12 years of age and had been receiving HEMLIBRA prophylaxis for at least 12 weeks, including 38 patients age 6 to < 12 years, 17 patients age 2 to < 6 years, and four patients age < 2 years.

Annualized bleed rate (ABR) and percent of patients with zero bleeds were calculated for 59 patients (Table 11). The median observation time for these patients was 29.6 weeks (range 18.4 – 63 weeks). 

Table 11 Annualized Bleed Rate with HEMLIBRA Prophylaxis 1.5 mg/kg Once Every Week in Pediatric Patients < 12 Years of Age with Factor VIII Inhibitors (Interim Analysis)

ABR = annualized bleed rate; CI = confidence interval; IQR = interquartile range, 25th percentile to 75th percentile.

a Based on negative binomial regression model.

In the intra-patient analysis, 18 pediatric patients who had participated in the NIS had an ABR for treated bleeds of 19.8 (95% CI [15.3, 25.7]) on previous bypassing agent treatment (prophylactic treatment in 15 patients and on-demand treatment for 3 patients). HEMLIBRA prophylaxis resulted in an ABR for treated bleeds of 0.4 (95% CI [0.2, 0.9]) based on negative binomial regression, corresponding to a 98% reduction in bleed rate. On HEMLIBRA prophylaxis, 14 patients (77.8%) had zero treated bleeds. 

The HAVEN 2 study evaluated patient-reported hemophilia-related symptoms (painful swellings and presence of joint pain) and physical functioning (pain with movement) using the Physical Health Score of the Hemophilia-specific Quality of Life Short Form (Haemo-QoL-SF) questionnaire for patients ≥ 8 to < 12 years of age. HEMLIBRA prophylaxis showed improvement from baseline in the Haemo-QoL-SF Physical Health Subscale score at the Week 25 assessment.

HAVEN 4 (Adult and Adolescent Patients)

The HAVEN 4 study (NCT03020160) was a single-arm, multicenter, open-label, clinical trial in 41 adult and adolescent males (aged ≥ 12 years and ≥ 40 kg) with hemophilia A with or without FVIII inhibitors who previously received either episodic (on demand) or prophylactic treatment with FVIII or bypassing agents. Patients received HEMLIBRA prophylaxis at 3 mg/kg once weekly for the first 4 weeks followed by 6 mg/kg once every four weeks thereafter. 

Efficacy was evaluated in a subgroup of 5 patients with hemophilia A with FVIII inhibitors based on the bleed rate for bleeds requiring treatment with coagulation factors. The median observation time was 26.1 weeks (range 24.4 – 28.6 weeks). HEMLIBRA prophylaxis resulted in an ABR (95% CI) for treated bleeds of 1.2 (0.1, 14.8) based on negative binomial regression. On HEMLIBRA prophylaxis, 4 patients had zero treated bleeds.

The efficacy results of HEMLIBRA prophylaxis (1.5 mg/kg once every week, 3 mg/kg once every two weeks, and 6 mg/kg once every four weeks) with respect to rate of treated bleeds are shown in Table 12.

Table 12 Annualized Bleed Rate (Treated Bleeds) with HEMLIBRA Prophylaxis in Patients with or without Factor VIII Inhibitors

ABR = annualized bleed rate; CI = confidence interval; IQR = interquartile range, 25th percentile to 75th percentile; HAVEN 1 = adult and adolescent patients with factor VIII inhibitors; HAVEN 2 = pediatric patients with factor VIII inhibitors; HAVEN 3 = adult and adolescent patients without factor VIII inhibitors; HAVEN 4 = adult and adolescent patients with or without factor VIII inhibitors. 

a Based on negative binomial regression model.

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 13.

Table 13 Mean (± SD) Steady-State Concentrations after emicizumab-kxwh Loading Dose by Maintenance Dose Regimen 

AUCss,τ  = area under the concentration time curve at steady-state over the dosing interval (τ = 1, 2, or 4 weeks); Cmax, ss = maximum plasma concentration at steady state; Ctrough, ss = trough concentration at steady state.

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 [see section 4.2 Posology and method of administration].

Distribution

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

Elimination

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.

Specific Populations

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 1x to 1.5x the upper limit of normal (ULN) and any aspartate transaminase (AST) level), moderate hepatic impairment (defined as total bilirubin 1.5x to 3x 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).

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.

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. 

Drug Interaction Studies

No drug-drug interaction studies have been conducted with HEMLIBRA.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies in animals investigating the carcinogenic effects of emicizumab-kxwh have not been conducted. In vitro and in vivo testing of emicizumab-kxwh for genotoxicity was not conducted. 

Animal fertility studies have not been conducted; however, emicizumab-kxwh did not cause any toxicological changes in the reproductive organs of male or female cynomolgus monkeys at doses of up to 30 mg/kg/week in subcutaneous general toxicity studies of up to 26-week duration and at doses of up to 100 mg/kg/week in a 4-week intravenous general toxicity study.

L-Arginine

L-Histidine

L-aspartic acid

Poloxamer 188

Water for injection

No incompatibilities between Hemlibra and the recommended syringes and needles (see section 6.6) have been observed.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

• 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.

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:

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 aged less than 7 years old. 

• 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, 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 use different HEMLIBRA vials of different concentrations when combining vials to administer prescribed dose.

• 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-Lok™ 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-Lok™ tip, graduation 0.1 mL, sterile, for injection only, single-use, latex-free, and non-pyrogenic, commercially available in the US.

• A transfer needle fulfilling the following criteria may be used: Stainless steel needle with Luer-Lok™ connection, sterile, 18 gauge, length 1½ inch, semi-blunted tip, single-use, latex-free, and non-pyrogenic, commercially available in the US.

• An injection needle fulfilling the following criteria may be used: Stainless steel with Luer-Lok™ connection, sterile, 26 gauge, 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.