FDA Label for Hemlibra

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 microangiopathy 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 with hemophilia A (congenital factor VIII deficiency) with factor VIII inhibitors.

2.1 Recommended Dosage

For subcutaneous use only.

The recommended dose is 3 mg/kg by subcutaneous injection once weekly for the first 4 weeks, followed by 1.5 mg/kg once weekly.

Other

Missed Dose

If a dose of HEMLIBRA is not administered on the scheduled day, administer as soon as possible before the day of the next scheduled dose, and then resume usual weekly dosing schedule. Do not double doses to make up for a missed dose.

Characterization of aPCC treatment in pooled clinical trials

There were 125 instances of aPCC treatment in 36 patients, of which 13 instances (10.4%) 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.

Injection Site Reactions

In total, 35 patients (19%) reported injection site reactions (ISRs). All ISRs observed in HEMLIBRA clinical trials were reported as mild to moderate intensity and 88% resolved without treatment. The commonly reported ISR symptoms were injection site erythema (7.4%), injection site pruritus (5.3%), and injection site pain (5.3%).

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.

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.

Contraception

Women of childbearing potential should use contraception while receiving HEMLIBRA.

Absorption

Following subcutaneous administration, the mean (± SD) absorption half-life was 1.7 ± 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 Dosage and Administration (2.2)].

Distribution

The mean apparent volume of distribution was 11.4 L (95% confidence interval (CI) [10.6, 12.1]).

Elimination

The mean apparent clearance (95% CI) was 0.24 L/day (0.22, 0.26) and the mean elimination apparent half-life (± SD) was 27.8 ± 8.1 days.

Specific Populations

The pharmacokinetics of emicizumab-kxwh are not influenced by age (3 years to 75 years), race (White 54%, Asian 30.5% and Black 8.5%), inhibitor status (inhibitor present, 92%), mild hepatic impairment (defined as total bilirubin 1× to ≤ 1.5× the upper limit of normal (ULN) and any aspartate transaminase (AST) level) and moderate hepatic impairment (defined as total bilirubin 1.5× to ≤ 3× the ULN and any AST level).

Body weight: The apparent clearance and volume of distribution of emicizumab-kxwh increased with increasing body weight (14.2 kg to 131 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.

HAVEN 1

The HAVEN 1 study (NCT02622321) was a randomized, multicenter, open-label, clinical trial in 109 adult and adolescent males (aged 12 to 75 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 weekly HEMLIBRA prophylaxis (Arms A, C, and D), 3 mg/kg once weekly for the first 4 weeks followed by 1.5 mg/kg once weekly thereafter, or no prophylaxis (Arm B). Dose up-titration to 3 mg/kg once weekly was allowed after 24 weeks on HEMLIBRA prophylaxis in case of suboptimal efficacy (i.e., ≥ 2 spontaneous and clinically significant bleeds). During the study, two patients underwent up-titration of their maintenance dose to 3 mg/kg once weekly.

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). Patients randomized to Arm B could switch to HEMLIBRA prophylaxis after completing at least 24 weeks without prophylaxis.

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 a non-interventional study (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 based on the annualized bleeding rate (ABR) requiring treatment with coagulation factors (minimum of 24 weeks or date of discontinuation) 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 trial also evaluated the randomized comparison of Arms A and B for the efficacy of weekly 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 study also evaluated the efficacy of weekly HEMLIBRA prophylaxis compared with previous episodic (on-demand) and prophylactic bypassing agents in patients who had participated in the NIS prior to enrollment (Arms A and C, respectively). Only patients from the NIS were included in this comparison, because bleed and treatment data were collected with the same level of granularity in both periods.

The efficacy results of HEMLIBRA prophylaxis compared with no prophylaxis in bleed rate for treated bleeds, all bleeds, treated spontaneous bleeds, treated joint bleeds and treated target joint bleeds are shown in Table 4.

In the 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 5).

The 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 aged ≥ 18 years. The weekly 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 6). The improvement in the Physical Health Score was further supported by the Total Score as measured by the Haem-A-QoL at Week 25.

HAVEN 2

The HAVEN 2 study (NCT02795767) was a single-arm, multicenter, open-label, clinical study 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 weekly thereafter.

The study evaluated the efficacy of weekly HEMLIBRA prophylaxis, including the efficacy of weekly 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 23 pediatric patients who were < 12 years old and had been receiving weekly HEMLIBRA prophylaxis for at least 12 weeks, including 19 patients age 6 to < 12 years and 4 patients age 2 to < 6 years.

Annualized bleed rate (ABR) and percent of patients with zero bleeds were calculated for 23 patients (Table 7). The median observation time for these patients was 38.1 weeks (12.7 – 41.6 weeks).

In the intra-patient analysis, 13 pediatric patients who had participated in the NIS had an ABR of 17.2 (95% CI [12.4, 23.8]) on previous bypassing agent treatment (prophylactic treatment in 12 patients and on-demand treatment for one patient). Weekly HEMLIBRA prophylaxis resulted in an ABR for treated bleeds of 0.2 (95% CI [0.1, 0.8]) based on negative binomial regression, corresponding to a 99% reduction in bleed rate. On HEMLIBRA prophylaxis, 11 patients (84.6%) had zero treated bleeds.

How Supplied

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:

Use of Bypassing Agents

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. Discuss the use of bypassing agents with the patient and/or caregiver prior to starting HEMLIBRA prophylaxis [see Adverse Reactions (6.1)].

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.

HEMLIBRA^® [emicizumab-kxwh]

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
©2017 Genentech, Inc. All rights reserved.

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 aged less than 7 years old. The HEMLIBRA "Instructions for Use" contains more detailed instructions on the preparation and administration of HEMLIBRA [see Instructions for Use].

• 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.

3 Dosage Forms And Strengths

HEMLIBRA is available as a colorless to slightly yellow solution in single-dose vials.

Injection:

• 30 mg/mL
• 60 mg/0.4 mL
• 105 mg/0.7 mL
• 150 mg/mL

4 Contraindications

None.

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 microangiopathy was reported in 1.6% of patients (3/189) and in 8.3% of patients (3/36) 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 1.1% of patients (2/189) and in 5.6% of patients (2/36) 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.

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

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 a randomized trial (HAVEN 1), single-arm trial (HAVEN 2), and a dose-finding trial, in which a total of 189 male patients with hemophilia A received at least one dose of HEMLIBRA as routine prophylaxis. Ninety-four patients (50%) were adults (18 years and older), 38 (20%) were adolescents (12 years up to less than 18 years), 55 (29%) were children (2 years up to less than 12 years), and two (1%) were infants (1 month up to less than 2 years). Seven of the 189 patients (4%) included in the safety population were patients without FVIII inhibitors from the dose-finding trial. The median duration of exposure across the studies was 38 weeks (0.8 to 177.2 weeks).

The most frequently reported adverse reactions observed in ≥ 10% of patients treated with at least one dose of HEMLIBRA were injection site reactions, headache, and arthralgia.

Four patients (2.1%) 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.

Adverse reactions observed in patients who received HEMLIBRA are shown in Table 2.

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. No patients tested positive for anti-emicizumab antibodies in HAVEN 1 and HAVEN 2 (n = 171). Four patients tested positive for anti-emicizumab antibodies in the dose-finding trial (n = 18). The anti-emicizumab antibody positive rate may be under-reported due to the limitation of the assay.

7.1 Hypercoagulability With Concomitant Use Of Apcc, Rfviia, Or Fviii

Clinical experience suggests that a drug interaction exists with HEMLIBRA and aPCC [see Warnings and Precautions (5.1, 5.2)].

There is a possibility for hypercoagulability with rFVIIa or FVIII with HEMLIBRA based on preclinical experiments.

7.2 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 Clinical Pharmacology (12.3)].

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 with FVIII inhibitors is supported by a randomized trial (HAVEN 1) and a single-arm trial (HAVEN 2). HAVEN 1 included pediatric patients in the following age group: 38 adolescents (12 years 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 two 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 general, the adverse reactions in HEMLIBRA-treated pediatric patients were similar in type to those seen in adult patients with hemophilia A with FVIII inhibitors [see Adverse Reactions (6.1)].

The steady-state plasma trough concentrations of emicizumab-kxwh were comparable in adult and pediatric patients at equivalent weight-based doses [see Clinical Pharmacology (12.3)].

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.

11 Description

Emicizumab-kxwh is a humanized monoclonal modified immunoglobulin G4 (IgG4) antibody with a bispecific antibody structure 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 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.

12.1 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 3 mg/kg once weekly following subcutaneous administration. Following multiple subcutaneous administrations of 3 mg/kg once weekly for the first 4 weeks in hemophilia A patients, mean (± SD) trough plasma concentrations of emicizumab-kxwh increased to achieve 54.6 ± 14.3 μg/mL at Week 5. Trough plasma concentrations above 50 μg/mL were sustained thereafter with the recommended weekly dosage of 1.5 mg/kg; the mean (± SD) trough plasma concentrations of emicizumab-kxwh at steady-state was 52.8 ± 13.5 µg/mL.

13.1 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.

14 Clinical Studies

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

Storage And Handling

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.

17 Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Spl Medguide

Instructions For Use

Instructions for Use
HEMLIBRA^® (hem-lee-bruh)
(emicizumab-kxwh)
injection, for subcutaneous use

Be sure that you read, understand, and follow the Instructions for Use before injecting HEMLIBRA. Your healthcare provider should show you how to prepare, measure, and inject HEMLIBRA properly before you use it for the first time. Ask your healthcare provider if you have any questions.

Important Information:

• Do not inject yourself or someone else unless you have been shown how to by your healthcare provider.
• Make sure the name HEMLIBRA appears on the box and vial label.
• Before opening the vial, read the vial label to make sure you have the medicine strength(s) needed to give the dose prescribed by your healthcare provider.
• HEMLIBRA comes in four strengths. Depending on your dose, you may need to use more than one vial to give your total prescribed dose. Your healthcare provider will determine your dose in milliliters (mL) that you will need to give based on your body weight. Do not use different HEMLIBRA vials of different concentrations when combining vials to achieve the prescribed dose.
• Check the expiration date on the box and vial label. Do not use if the expiration date has passed.
• Only use the vial one time. After you inject your dose, dispose of (throw away) any unused HEMLIBRA left in the vial. Do not save unused HEMLIBRA in the vial for later use.
• Only use the syringes, transfer needles, and injection needles that your healthcare provider prescribes.
• Only use the syringes, transfer needles and injection needles one time. Dispose of (throw away) any used syringes and needles.
• If your prescribed dose is more than 2 mL, you will need to give more than one injection of HEMLIBRA.

Storing 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.
• Take the vial out of the refrigerator 15 minutes before use and allow it to reach room temperature before preparing an injection.
• Before giving the injection, unopened vials of HEMLIBRA may be stored out of the refrigerator and then returned to the refrigerator. HEMLIBRA should not be stored out of the refrigerator:
  • for more than 7 days or
  • at a temperature greater than 86^°F (30^°C)

  Keep HEMLIBRA and all medicines out of the reach of children.

  Inspecting the HEMLIBRA vial and your supplies:

  • Collect all supplies listed below to prepare and give your injection.
  • Check the expiration date on the box, on the vial label, and on the supplies listed below. Do not use if the expiration date has passed.
  • Inspect the supplies for damage. Do not use if they appear damaged or if they have been dropped.
  • Place the supplies on a clean, well-lit flat work surface.

  HEMLIBRA is colorless to slightly yellow in color. Do not use the vial if:

  • the medicine is cloudy, hazy, or colored.
  • the medicine contains particles.
  • the cap covering the stopper is missing.

  Included in the box:
  	Figure - hemlibra 01	Vial containing HEMLIBRA
  		HEMLIBRA Instructions for Use

  Not included in the box:
  		Alcohol wipes Note: If you need to use more than one vial to inject your prescribed dose, you must use a new alcohol wipe for each vial. Gauze Cotton Ball
  		Syringe Note: For injection amount up to 1 mL, use a 1 mL syringe. For injection amount between 1 mL and 2 mL, use a 2 mL or 3 mL syringe.
  		18G Transfer Needle Note: If you need to use more than one vial to inject your prescribed dose, you must use a new transfer needle for each vial. Do not use the transfer needle to inject HEMLIBRA.
  		26G Injection Needle with safety shield Do not use the injection needle to withdraw HEMLIBRA from vial.
  		Sharps disposal container

  Get ready: Before use, allow the vial(s) to warm up to room temperature for about 15 minutes on a clean flat surface away from direct sunlight. Do not try to warm the vial by any other way. Wash your hands well with soap and water.

  Selecting and preparing an injection site:

  Clean the chosen injection site area using an alcohol wipe. Let the skin dry for about 10 seconds. Do not touch, fan, or blow on the cleaned area before your injection. You can use your: Thigh (front and middle). Stomach area (abdomen), except for 2 inches around the navel (belly button). Outer area of the upper arm (only if a caregiver is giving the injection). You should use a different injection site each time you give an injection, at least 1 inch away from the area you used for your previous injection. Do not inject into areas that could be irritated by a belt or waistband. Do not inject into moles, scars, bruises, or areas where the skin is tender, red, hard, or the skin is broken.

  Preparing the syringe for injection:

  • HEMLIBRA must not be stored in the syringe.
  • HEMLIBRA in the syringe must be injected under the skin (subcutaneous injection) immediately.
  • Dispose of (throw away) any used vial(s), needles, vial and injection needle caps, and used syringes in a sharps or puncture-proof container.

  Important information after the injection:

  • Do not rub the injection site after an injection.
  • If you see drops of blood at the injection site, you can press a sterile cotton ball or gauze over the injection site for at least 10 seconds, until bleeding has stopped.
  • If you have bruising (small area of bleeding under the skin), an ice pack can also be applied with gentle pressure to the site. If bleeding does not stop, please contact your healthcare provider.

  Disposing of used HEMLIBRA vial(s), needles, and syringes:

  • Put your used needles and syringes in a FDA-cleared sharps disposal container right away after use. Do not dispose of (throw away) any loose needles and syringes in your household trash.
  • If you do not have a FDA-cleared sharps disposal container, you may use a household container that is:
    • made of heavy-duty plastic.
    • can be closed with a tight-fitting, puncture resistant lid, without sharps being able to come out.
    • upright and stable during use.
    • leak-resistant.
    • properly labeled to warn of hazardous waste inside the container.
    • When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal.
    • Do not dispose of (throw away) any used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.

    Important: Always keep the sharps disposal container out of reach of children.

    1. PREPARATION

    Step 1. Remove vial cap and clean top
    	Take the cap off the vial(s).
    	Clean the top of the vial(s) stopper with an alcohol wipe. Dispose of (throw away) the vial cap(s) into the sharps disposal container.
    Step 2. Attach transfer needle to syringe
    	Push and twist the transfer needle clockwise on to the syringe until it is fully attached.
    	Slowly pull back on the plunger and draw air into the syringe that is the same amount for your prescribed dose.
    Step 3. Uncap transfer needle
    	Hold the syringe by the barrel with the transfer needle pointing up. Carefully pull the transfer needle cap straight off and away from your body. Do not throw the cap away. Place the transfer needle cap down on a clean flat surface. You will need to recap the transfer needle after transferring the medicine. Do not touch the needle tip or place it on a surface after the needle cap has been removed.
    Step 4. Inject air into vial
    	Keep the vial on the flat working surface and insert the transfer needle and syringe straight down into the center of the vial stopper.
    	Keep the needle in the vial and turn the vial upside down.
    	With the needle pointing upwards, push on the plunger to inject the air from the syringe above the medicine. Keep your finger pressed down on the syringe plunger. Do not inject air into the medicine.
    Step 5. Transfer HEMLIBRA to syringe
    	Slide the tip of the needle down so that it is within the medicine. Slowly pull back the plunger to fill the syringe with more than the amount of HEMLIBRA needed for your prescribed dose. Be careful not to pull the plunger out of the syringe.
    	Important: If your prescribed dose is more than the amount of HEMLIBRA in the vial, withdraw all HEMLIBRA and go to the "Combining Vials" section now.
    Step 6. Remove air bubbles
    	Keep the needle in the vial and check the syringe for larger air bubbles. Too large an air bubble can reduce the dose you receive. Remove the larger air bubbles by gently tapping the syringe barrel with your fingers until the air bubbles rise to the top of the syringe. Move the tip of the needle above the medicine and slowly push the plunger up to push the air bubbles out of the syringe. If the amount of HEMLIBRA in the syringe is now at or below your prescribed dose, move the tip of the needle to within the medicine and slowly pull back the plunger until you have more than the amount of HEMLIBRA needed for your prescribed dose. Be careful not to pull the plunger out of the syringe. Repeat the steps above until you have removed the larger air bubbles.
    	Note: Ensure you have enough HEMLIBRA in the syringe to complete your dose before moving on to the next step. If you cannot remove all of HEMLIBRA, turn the vial upright to reach the remaining amount.

    Do not use the transfer needle to inject HEMLIBRA as this may cause harm such as pain and bleeding.

    2. INJECTION

    Step 7. Recap transfer needle
    	Remove the syringe and transfer needle from the vial. Using one hand, slide the transfer needle into the cap and scoop upwards to cover the needle. Once the needle is covered, push the transfer needle cap towards the syringe to fully attach it with one hand to prevent accidentally sticking yourself with the needle.
    Step 8. Clean injection site
    	Select and clean your injection site with an alcohol wipe. Let the skin dry for about 10 seconds. Do not touch, fan, or blow on the cleaned area before your injection.
    Step 9. Remove transfer needle
    	Remove the transfer needle from the syringe by twisting counter-clockwise and gently pulling. Dispose of (throw away) the used transfer needle into a sharps disposal container.
    Step 10. Attach injection needle to syringe
    	Push and twist the injection needle clockwise on to the syringe until it is fully attached.
    Step 11. Move safety shield
    	Move the safety shield away from the needle and towards the syringe barrel.
    Step 12. Uncap injection needle
    	Carefully pull the injection needle cap away from the syringe. Dispose of (throw away) the cap into a sharps disposal container. Do not touch the needle tip or allow it to touch any surface. After the injection needle cap has been removed, HEMLIBRA in the syringe must be injected immediately.
    Step 13. Adjust plunger to prescribed dose
    	Slowly push the plunger to your prescribed dose. Ensure the top rim of the plunger is in line with the mark on the syringe for your prescribed dose.
    Step 14. Subcutaneous (under the skin) injection
    	Pinch the selected injection site and fully insert the needle at a 45° to 90° angle with a quick, firm action. Do not hold or push on the plunger while inserting the needle. Hold the position of the syringe and let go of the pinched injection site.
    Step 15. Inject HEMLIBRA
    	Slowly inject all of HEMLIBRA by gently pushing the plunger all the way down. Remove the needle and syringe from the injection site at the same angle as inserted.

    3. DISPOSAL

    Step 16. Cover needle with safety shield
    	Move the safety shield forward 90°, away from the syringe barrel. Holding the syringe with one hand, press the safety shield down against a flat surface with a firm, quick motion until you hear a "click".
    	If you do not hear a click, look to see that the needle is fully covered by the safety shield. Keep your fingers behind the safety shield and away from the needle at all times. Do not remove the injection needle from the syringe.
    Step 17. Dispose of (throw away) the used HEMLIBRA vial(s), needle, and syringe
    	Put your used needles and syringes in a FDA-cleared sharps disposal container right away after use. For further information, refer to the section "Disposing of used HEMLIBRA vial(s), needles, and syringes". Do not try to remove the used injection needle from the used syringe. Do not recap the injection needle with the cap. Important: Always keep the sharps disposal container out of reach of children. Dispose of (throw away) any used vial(s), needles, vial and injection needle caps, and used syringes in a sharps or puncture-proof container.

    Combining Vials

    If you need to use more than one vial to get to your total prescribed dose, follow these steps after you have drawn up HEMLIBRA from the first vial:

    Step A. Recap transfer needle
    	Remove the syringe and transfer needle from the first vial. Using one hand, slide the transfer needle into the cap and scoop upwards to cover the needle. Once the needle is covered, push the transfer needle cap toward the syringe to fully attach it with one hand to prevent accidentally sticking yourself with the needle.
    Step B. Remove transfer needle
    	Remove the transfer needle from the syringe by twisting counter- clockwise and gently pulling. Dispose of (throw away) the used transfer needle into a sharps disposal container.
    Step C. Attach a new transfer needle to syringe
    	Note: You must use a new transfer needle each time you withdraw HEMLIBRA from a new vial. Push and twist a new transfer needle clockwise on to the syringe until it is fully attached. Slowly pull back the plunger and draw some air into the syringe.
    Step D. Uncap transfer needle
    	Hold the syringe by the barrel with the transfer needle cap pointing up. Carefully pull the transfer needle cap straight off and away from your body. Do not throw the cap away. You will need to recap the transfer needle after drawing up the medicine. Do not touch the needle tip.
    Step E. Inject air into vial
    	With the new vial on the flat working surface, insert the new transfer needle and syringe, straight down into the center of the vial stopper.
    	Keep the transfer needle in the vial and turn the vial upside down.
    	With the needle pointing upwards, inject the air from the syringe above the medicine. Keep your finger pressed down on the syringe plunger. Do not inject air into the medicine.
    Step F. Transfer HEMLIBRA to syringe
    	Slide the tip of the needle down so that it is within the medicine. Slowly pull back the plunger to fill the syringe barrel more than the amount of HEMLIBRA needed for your prescribed dose. Be careful not to pull the plunger out of the syringe.
    	Note: Ensure you have enough HEMLIBRA in the syringe to complete your dose before moving onto the next steps. If you cannot remove all of HEMLIBRA, turn the vial upright to reach the remaining amount.

    Do not use the transfer needle to inject HEMLIBRA as this may cause harm such as pain and bleeding.

    Repeat steps A to F with each additional vial until you have more than the amount of HEMLIBRA needed for your prescribed dose. Once completed, keep the transfer needle inserted in the vial and return to Step 6. Continue with the remaining steps.

    For more information, go to www.HEMLIBRA.com or call 1-866-HEMLIBRA.

    HEMLIBRA^® [emicizumab-kxwh]

    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
    ©2017 Genentech, Inc. All rights reserved.

    Representative sample of labeling (see the HOW SUPPLIED section for complete listing):

    
    

Principal Display Panel - 30 Mg Vial Carton

NDC 50242-920-01
Hemlibra^®
(emicizumab-kxwh)
Injection

30 mg/mL

For Subcutaneous Use.
Single-Dose Vial.
Discard Unused Portion.

ATTENTION: Dispense the enclosed
Medication Guide to each patient.

Rx only

1 vial
Genentech

10195119

PRINCIPAL DISPLAY PANEL - 30 mg Vial Carton - hemlibra 42

Principal Display Panel - 60 Mg Vial Carton

NDC 50242-921-01
Hemlibra^®
(emicizumab-kxwh)
Injection

60 mg/0.4 mL

For Subcutaneous Use.
Single-Dose Vial.
Discard Unused Portion.

ATTENTION: Dispense the enclosed
Medication Guide to each patient.

Rx only

1 vial
Genentech

10195122

PRINCIPAL DISPLAY PANEL - 60 mg Vial Carton - hemlibra 43

Principal Display Panel - 105 Mg Vial Carton

NDC 50242-922-01
Hemlibra^®
(emicizumab-kxwh)
Injection

105 mg/0.7 mL

For Subcutaneous Use.
Single-Dose Vial.
Discard Unused Portion.

ATTENTION: Dispense the enclosed
Medication Guide to each patient.

Rx only

1 vial
Genentech

10195123

PRINCIPAL DISPLAY PANEL - 105 mg Vial Carton - hemlibra 44

Principal Display Panel - 150 Mg Vial Carton

NDC 50242-923-01
Hemlibra^®
(emicizumab-kxwh)
Injection

150 mg/mL

For Subcutaneous Use.
Single-Dose Vial.
Discard Unused Portion.

ATTENTION: Dispense the enclosed
Medication Guide to each patient.

Rx only

1 vial
Genentech

10195121

PRINCIPAL DISPLAY PANEL - 150 mg Vial Carton - hemlibra 45