Hemlibra

Hemlibra

emicizumab

Manufacturer:

Roche

Distributor:

DKSH
Full Prescribing Info
Contents
Emicizumab.
Description
Active substance: emicizumab.
HEMLIBRA solution for subcutaneous injection is a colorless to slightly yellow solution, adjusted to pH 6.0. HEMLIBRA is supplied in single-use colorless glass vials containing 30 mg/1 mL (30 mg/mL), 60 mg/0.4 mL (150 mg/mL), 105 mg/0.7 mL (150 mg/mL) or 150 mg/1 mL (150 mg/mL) of emicizumab.
For preparation, use and other handling recommendations, see Special Instructions for Use, Handling and Disposal under Cautions for Usage.
Excipients/Inactive Ingredients: L-Histidine, L-Aspartic Acid, L-Arginine, Poloxamer 188, Water for Injection.
Action
Therapeutic/Pharmacologic Class of Drug: Emicizumab is a humanized monoclonal modified immunoglobulin G4 (IgG4) antibody with a bispecific antibody structure bridging factor IXa and factor X produced by recombinant DNA technology in Chinese hamster ovary (CHO) cells. ATC code: B02BX06.
Pharmacology: Mechanism of Action: Emicizumab bridges activated factor IX and factor X to restore the function of missing activated factor VIII that is needed for effective hemostasis.
Emicizumab has no structural relationship or sequence homology to FVIII and, as such, does not induce or enhance the development of direct inhibitors to FVIII.
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 Studies: The efficacy of HEMLIBRA for routine prophylaxis in patients with hemophilia A with or without inhibitors to FVIII was evaluated in four clinical studies (three adult and adolescent studies [HAVEN 3, HAVEN 1, and HAVEN 4] and a pediatric study [HAVEN 2]).
Clinical Studies in Adult and Adolescent Patients: HAVEN 3: The HAVEN 3 study was a randomized, multicenter, open-label, phase III clinical study 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 subcutaneous HEMLIBRA, 3 mg/kg once weekly for the first four weeks followed by either 1.5 mg/kg once weekly (Arms A and D) or 3 mg/kg every two weeks (Arm B) thereafter, or no prophylaxis (Arm C).
Patients in Arm C could switch to HEMLIBRA (3 mg/kg every two weeks) after completing at least 24 weeks without prophylaxis. For Arms A and B dose up-titration to 3 mg/kg weekly was allowed after 24 weeks for patients who experienced two or more qualified bleeds (i.e., spontaneous and clinically significant bleeds occurring at steady state). Arm D patients could up-titrate after the second qualifying bleed. At the time of the analysis, five patients underwent up-titration of their maintenance dose.
Eighty-nine patients previously treated with episodic (''on demand'') FVIII were randomized in a 2:2:1 ratio to receive HEMLIBRA either once weekly (Arm A; N = 36), every two weeks (Arm B; N = 35) or no prophylaxis (Arm C; N = 18), 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 (1.5 mg/kg once weekly).
The primary objective of the study was to evaluate in patients previously treated with episodic FVIII the efficacy of prophylactic HEMLIBRA weekly (Arm A) or every two weeks (Arm B) compared to no prophylaxis (Arm C) based on the number of bleeds requiring treatment with coagulation factors (see Table 1). Other objectives of the study included evaluation of the randomized comparison of Arms A or B and Arm C for the efficacy of HEMLIBRA prophylaxis in reducing the number of all bleeds, spontaneous bleeds, joint bleeds, and target joint bleeds (see Table 2). Patient treatment preference was also assessed using a preference survey.
The efficacy of HEMLIBRA prophylaxis was also compared with previous prophylactic FVIII treatment (Arm D) in patients who had participated in a non-interventional study (NIS) prior to enrollment (see Table 3). Only patients from the NIS were included in this comparison, because bleed and treatment data were collected with the same level of granularity as used in HAVEN 3.
HAVEN 1: The HAVEN 1 study was a randomized, multicenter, open-label clinical study in 109 adolescent and adult males (aged ≥ 12 years old and ≥ 40 kg) with hemophilia A with factor VIII inhibitors who had previously received either episodic (''on demand') or prophylactic treatment with bypassing agents. In the study, patients received weekly HEMLIBRA prophylaxis (Arms A, C, and D) – 3 mg/kg once weekly for 4 weeks followed by 1.5 mg/kg once weekly thereafter – or no prophylaxis (Arm B). Patients randomized to Arm B could switch to HEMLIBRA prophylaxis after completing at least 24 weeks without prophylaxis. Dose up-titration to 3 mg/kg once weekly 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 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).
Forty-nine patients previously treated with prophylactic bypassing agents were enrolled in 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 in Arm D to receive HEMLIBRA prophylaxis.
The primary objective of the study was to evaluate among patients previously treated with episodic (on-demand) bypassing agents the treatment effect of weekly HEMLIBRA prophylaxis compared with no prophylaxis (Arm A vs. Arm B) on the number of bleeds requiring treatment with coagulation factors over time (minimum of 24 weeks or date of discontinuation) (see Table 1). Other secondary objectives of the randomized comparison of Arms A and B were the efficacy of weekly HEMLIBRA prophylaxis in reducing the number of all bleeds, spontaneous bleeds, joint bleeds and target joint bleeds (see Table 4), as well as assessing patient-reported health-related quality of life (HRQoL) and health status (see Tables 8 and 9).
The efficacy of weekly HEMLIBRA prophylaxis compared with previous prophylactic bypassing agents was also evaluated in patients who had participated in the NIS prior to enrollment (Arms C) (see Table 5). 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.
HAVEN 4: HEMLIBRA was investigated in a single arm, multicenter, phase III clinical study 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 – 3 mg/kg once weekly for four weeks followed by 6 mg/kg every four weeks thereafter.
The primary objective of the study was to evaluate the efficacy of HEMLIBRA prophylaxis in maintaining adequate bleed control, given every four weeks based on treated bleeds (see Table 1). Other objectives were to evaluate the clinical efficacy of HEMLIBRA prophylaxis on all bleeds, treated spontaneous bleeds, treated joint bleeds and treated target joint bleeds (see Table 7). Patient treatment preference was also assessed using a preference survey.
Adult and Adolescent Efficacy Results: The efficacy results of HEMLIBRA prophylaxis with respect to rate of treated bleeds are shown in Table 1. (See Table 1.)

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HAVEN 3: The efficacy results of HEMLIBRA prophylaxis 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 as follows in Table 2. (See Table 2.)

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In the HAVEN 3 clinical study 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 3).

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HAVEN 1: The efficacy results of HEMLIBRA prophylaxis 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. (See Table 4.)

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Additional analyses for HAVEN 1 to assess long term control of bleeds with HEMLIBRA prophylaxis were conducted using 12-week treatment intervals up to week 72. When ABR for treated bleeds was assessed over 12-week intervals the mean ABRs decreased over time and the improvement was sustained up to week 72, while the median remained consistently at zero (see Table 5). These data demonstrate the long term efficacy of HEMLIBRA prophylaxis. The mean and median calculated ABRs for treated bleeds are shown in Table 5. (See Table 5.)

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In the HAVEN 1 clinical study 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 (see Table 6).

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HAVEN 4: Efficacy results for the HAVEN 4 clinical study are summarized as follows. Forty-one patients ≥12 years old were evaluated for efficacy with a median observation time of 25.6 weeks (range: 24.1 - 29.4 weeks). The efficacy results of HEMLIBRA prophylaxis 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 7. (See Table 7.)

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Adults and Adolescents Health-Related Outcome Measures: The HAVEN adult and adolescent clinical studies evaluated patient-reported outcomes with several measures. The Haemophilia-Specific Quality of Life (Haem-A-QoL) questionnaire for adults (≥ 18 years) and its adolescent version (Haemo-QoL-SF, for 8 to <18 years) assessed hemophilia-related quality of life in patients. For the Haem-A-QoL and Haemo-QoL-SF, the Physical Health Score (i.e., painful swellings, presence of joint pain, pain with movement, difficulty walking far and needing more time to get ready) and Total Score (summary of all scores) were protocol defined endpoints of interest. To measure change in health status, the Index Utility Score (IUS) and the Visual Analog Scale (VAS) from the EuroQoL Five-Dimension-Five Levels Questionnaire (EQ-5D-5L) was examined.
In HAVEN 3 and 4, an assessment of patient preference for treatment, the Emicizumab Preference Survey (EmiPref), was used.
Adult and Adolescent Health-Related Outcomes Results: HAVEN 1 Health-Related Outcomes: In HAVEN 1, health-related quality of life (HRQoL) for patients aged ≥ 18 years was evaluated at week 25 based on the Haem-A-QoL questionnaire for adults (see Table 8). The Haem-A-QoL is a valid and reliable measure of HRQoL. (See Table 8.)

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HAVEN 1 Health Status Outcomes: In HAVEN 1, patients' health status was assessed according to EQ-5D-5L. EQ-5D-5L is a valid and reliable measure of health status (see Table 9).

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HAVEN 3 and 4 Patient Preference: In HAVEN 3 and HAVEN 4, patients who received HEMLIBRA (once weekly, every two weeks or every four weeks) reported whether they preferred subcutaneous HEMLIBRA, their prior IV treatment or had no preference at week 17. Of the patients in HAVEN 3 who responded to the preference questionnaire, 89 of 95 patients (93.7%) reported preferring HEMLIBRA to their prior IV treatment, and specifically 45 of 46 patients (97.8%) preferred HEMLIBRA to their prior prophylactic FVIII treatment. In HAVEN 4, all 41 patients (100%) responded to the preference questionnaire and reported preferring HEMLIBRA to their prior IV treatment.
In HAVEN 3 and 4, the two reasons most frequently ranked by patients as the most important for their preference for HEMLIBRA were that the route of administration was easier and the frequency of treatments was lower.
Clinical Study in Pediatric Patients: HAVEN 2 (Interim Analysis): HEMLIBRA weekly prophylaxis was evaluated in a single-arm, multicenter, open-label clinical study in pediatric patients (age < 12 years old, or 12 to 17 years old weighing < 40 kg) with hemophilia A with factor VIII inhibitors. Patients received HEMLIBRA prophylaxis at 3 mg/kg once weekly for the first four weeks followed by 1.5 mg/kg once weekly thereafter.
The study evaluated the pharmacokinetics, safety, and efficacy including the efficacy of weekly HEMLIBRA prophylaxis compared with previous episodic and prophylactic bypassing agent treatment in patients who had participated in the NIS prior to enrollment (intra-patient comparison).
HAVEN 2 Efficacy Results (Interim 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 weekly 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 < 2 years old. Annualized bleed rate and percent of patients with zero bleeds were calculated for 59 patients (see Table 10). The median observation time for these patients was 29.6 weeks (range: 18.4 - 63). (See Table 10.)

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In the intra-patient interim analysis, weekly HEMLIBRA prophylaxis resulted in a clinically meaningful (98%) reduction in bleed rate for treated bleeds in 18 pediatric patients who had at least 12 weeks of HEMLIBRA prophylaxis compared to their bleed rate collected in the NIS prior to enrollment (see Table 11).

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Pediatric Health-Related Outcomes Results: HAVEN 2 Health-Related Outcomes: In HAVEN 2, HRQoL for patients aged ≥ 8 to < 12 years was evaluated at week 25 based on the Haemo-QoL-SF questionnaire for children. The Haemo-QoL-SF is a valid and reliable measure of HRQoL (see Table 12).

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In HAVEN 2, HRQoL for patients ages < 12 years was also evaluated at week 25 based on the Adapted InhibQoL with Aspects of Caregiver Burden questionnaire completed by caregivers. The Adapted InhibQoL is a valid and reliable measure of HRQoL (see Table 13).

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Surgeries and Procedures in the HAVEN Clinical Studies: There is limited experience on bypassing agent or FVIII use during surgeries and procedures in patient receiving HEMLIBRA prophylaxis. In the clinical studies, bypassing agent or FVIII use during surgeries and procedures was determined by the investigator.
Immunogenicity: As with all therapeutic proteins, there is the potential for an immune response in patients treated with HEMLIBRA. In pooled phase III clinical trials, < 5% of patients tested positive for anti-drug antibodies (ADAs) and < 1% of patients developed ADAs with neutralizing potential (based on declining pharmacokinetics). The presence of ADAs with neutralizing potential may be associated with loss of efficacy; one patient who developed ADAs with neutralizing potential experienced loss of efficacy after 5 weeks of treatment and discontinued emicizumab treatment. A similar safety profile was observed in patients with or without ADAs. Patients who tested positive for ADAs did not experience hypersensitivity/anaphylaxis or changes in levels of endogenous FIX or FX and there was no trend towards increased frequency and severity of injection site reactions after patients tested positive for ADAs.
The data reflect the number of patients whose test results were considered positive for antibodies to emicizumab using an enzyme-linked immunosorbent assay (ELISA). Immunogenicity assay results may be influenced by several factors including assay sensitivity and specificity, sample handling, timing of sample collection, concomitant medicinal products and underlying disease. For these reasons, comparison of incidence of antibodies to emicizumab with the incidence of antibodies to other products may be misleading.
Pharmacokinetics: The pharmacokinetics of emicizumab were determined via a non-compartmental analysis in healthy subjects and using a population pharmacokinetic analysis on a database composed of 389 patients with hemophilia A.
Absorption: Following subcutaneous administration in hemophilia A patients, the absorption half-life was 1.6 days.
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 achieved 52.6±13.6 μg/mL at week 5. Sustained mean trough plasma concentrations of emicizumab at steady-state were 51.2 μg/mL, 46.9 μg/mL and 38.5 μg/mL with the recommended maintenance doses of 1.5 mg/kg once weekly, 3 mg/kg every two weeks or 6 mg/kg every four weeks, respectively (see Figure 1).

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The mean (±SD) Ctrough, Cmax and ratios of Cmax/Ctrough at steady-state for the recommended maintenance doses of 1.5 mg/kg once weekly, 3 mg/kg every two weeks or 6 mg/kg every four weeks are shown in Table 14. (See Table 14.)

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Similar PK profiles were observed following once weekly dosing (3 mg/kg/week for 4 weeks followed by 1.5 mg/kg/week) in adults/adolescents (≥ 12 years) and children (< 12 years) (see Figure 2).

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In healthy subjects, the absolute bioavailability following subcutaneous administration of 1 mg/kg was between 80.4% and 93.1% depending on the injection site. Similar pharmacokinetic profiles were observed following subcutaneous administration in the abdomen, upper arm, and thigh. Emicizumab can be administered interchangeably at these anatomical sites (see Dosage & Administration).
Distribution: Following a single intravenous dose of 0.25 mg/kg emicizumab in healthy subjects, the volume of distribution at steady state was 106 mL/kg (i.e., 7.4 L for a 70-kg adult). Emicizumab is not intended for intravenous use (see Dosage & Administration).
The apparent volume of distribution (V/F), estimated from the population PK analysis, in hemophilia A patients following multiple subcutaneous doses of emicizumab was 10.4 L.
Metabolism: The metabolism of emicizumab has not been studied. IgG antibodies are mainly catabolized by lysosomal proteolysis and then eliminated from or reused by the body.
Elimination: Following intravenous administration of 0.25 mg/kg in healthy subjects, the total clearance of emicizumab was 3.26 mL/kg/day (i.e. 0.228 L/d for a 70-kg adult) and the mean terminal half-life was 26.7 days.
Following single subcutaneous injection in healthy subjects, the elimination half-life was approximately 4 to 5 weeks.
Following multiple subcutaneous injections in hemophilia A patients, the apparent clearance was 0.271 L/day and the elimination apparent half-life was 26.9 days.
Dose Linearity: Emicizumab exhibited dose-proportional pharmacokinetics in patients with hemophilia A over a dose range from 0.3 to 6 mg/kg once weekly following subcutaneous administration.
Pharmacokinetics in Special Populations: Renal impairment: No dedicated studies on the effect of renal impairment on the pharmacokinetics of emicizumab have been conducted. Most of the patients with hemophilia A in the population pharmacokinetic analysis had normal renal function (N = 332; creatinine clearance [CLcr] ≥90 mL/min) or mild renal impairment (N = 27; CLcr of 60-89 mL/min). Only 2 patients had moderate renal impairment (CLcr of 30-59 mL/min). No patients had severe renal impairment. Mild or moderate renal impairment did not appear to have an impact on the pharmacokinetics of emicizumab (see also Special Dosage Instructions under Dosage & Administration).
Hepatic impairment: No dedicated studies on the effect of hepatic impairment on the pharmacokinetics of emicizumab have been conducted. Most of the patients with hemophilia A in the population pharmacokinetic analysis had normal hepatic function (bilirubin and AST ≤ ULN, N = 300) or mild hepatic impairment (bilirubin ≤ ULN and AST > ULN or bilirubin from 1.0 to 1.5 × ULN and any AST, N = 51). Only 6 patients had moderate hepatic impairment (1.5 × ULN < bilirubin ≤ 3 × ULN and any AST). Mild or moderate hepatic impairment did not affect the pharmacokinetics of emicizumab (see also Special Dosage Instructions under Dosage & Administration). Hepatic impairment was defined by the National Cancer Institute (NCI) criteria for hepatic dysfunction.
Pediatrics: The effect of age on the pharmacokinetics of emicizumab was assessed in a population pharmacokinetic analysis which included 5 infants (≥ 1 month to < 2 years), 55 children (≥ 2 years to < 12 years) and 50 adolescents (12 to < 18 years) with hemophilia A. Age did not affect the pharmacokinetics of emicizumab in pediatric patients (see Special Dosage Instructions under Dosage & Administration).
Geriatrics: The effect of age on the pharmacokinetics of emicizumab was assessed in a population pharmacokinetic analysis which included 13 patients aged 65 years and older (no patients were older than 77 years of age). Relative bioavailability decreased with older age, but no clinically important differences were observed in the pharmacokinetics of emicizumab between patients < 65 years and patients ≥ 65 years.
Race: Population pharmacokinetics analyses in patients with hemophilia A showed that race did not affect the pharmacokinetics of emicizumab.
Toxicology: Preclinical Safety: Preclinical data reveal no special hazards for humans based on studies of acute and repeated dose toxicity, including safety pharmacology endpoints and endpoints for reproductive toxicity.
Carcinogenicity: No carcinogenicity studies have been performed to establish the carcinogenic potential of emicizumab.
Genotoxicity: No studies have been performed to establish the mutagenic potential of emicizumab.
Impairment of Fertility: Emicizumab 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.
Reproductive Toxicity: No data are available with respect to potential side effects of emicizumab on embryo-fetal development.
Other: In an in vitro study of cytokine release that used the whole blood of healthy adults, the levels of cytokines induced by emicizumab were comparable to those induced by other low-risk antibodies.
Indications/Uses
HEMLIBRA is indicated for routine prophylaxis to prevent bleeding or reduce the frequency of bleeding episodes in adults and children with hemophilia A (congenital factor VIII deficiency) with or without factor VIII inhibitors.
HEMLIBRA can be used in all age groups.
Dosage/Direction for Use
General: Substitution by any other biological medicinal product requires the consent of the prescribing physician.
Treatment should be initiated under the supervision of a physician experienced in the treatment of hemophilia and/or bleeding disorders.
Treatment with bypassing agents should be discontinued the day before starting HEMLIBRA therapy (see Precautions). FVIII prophylaxis may be continued for the first 7 days of HEMLIBRA treatment.
Recommended dosage (all patients): The recommended loading dose is 3 mg/kg administered as a subcutaneous injection once weekly for the first 4 weeks, followed by a maintenance dose of either: 1.5 mg/kg once weekly, or 3 mg/kg every two weeks, or 6 mg/kg every four weeks.
The maintenance dose regimen should be selected based on physician and patient/caregiver dosing regimen preference to support adherence.
Method of administration: HEMLIBRA is for subcutaneous use only. HEMLIBRA should be administered using appropriate aseptic technique (see Special Instructions for Use, Handling and Disposal under Cautions for Usage).
The injection should be restricted to the recommended injection sites: the abdomen, the upper outer arms and the thighs (see Pharmacology: Pharmacokinetics: Absorption under Actions). No data are available on injection at other sites of the body.
Administration of HEMLIBRA subcutaneous injection in the upper outer arm should be performed by a caregiver or healthcare professional.
Alternating the site of injection may help prevent or reduce injection site reactions (see Clinical Trials under Adverse Reactions). HEMLIBRA subcutaneous injection should not be administered into areas where the skin is red, bruised, tender or hard, or areas where there are moles or scars.
During treatment with HEMLIBRA, other medicinal products for subcutaneous administration should, preferably, be injected at different anatomical sites.
Administration by the patient and/or caregiver: HEMLIBRA is intended for use under the guidance of a healthcare professional. After proper training in subcutaneous injection technique, a patient may self-inject HEMLIBRA, or the patient's caregiver may administer HEMLIBRA, if their physician determines that it is appropriate.
The physician and the caregiver should determine the appropriateness of a child self-injecting HEMLIBRA. However, self-administration is not recommended for children below 7 years of age.
Duration of treatment: HEMLIBRA is intended for long-term prophylactic treatment.
Dosage adjustments during treatment: No dosage adjustments of HEMLIBRA are recommended.
Delayed or missed doses: If a patient misses a scheduled subcutaneous injection of HEMLIBRA, the patient should be instructed to take the missed dose as soon as possible, before the day of the next scheduled dose. The patient should then administer the next dose on the usual scheduled dosing day. The patient should not take two doses on the same day to make up for a missed dose.
Special Dosage Instructions: Pediatric use: No dose adjustments are recommended in pediatric patients. Currently available data are described in Pharmacology: Pharmacodynamics: Clinical/Efficacy Studies and Pharmacokinetics: Pharmacokinetics in Special Populations under Actions.
Geriatric use: No dose adjustments are recommended in patients ≥ 65 years of age (see Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions).
Renal impairment: No dose adjustments are recommended in patients with renal impairment (see Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions).
Hepatic impairment: No dose adjustments are recommended in patients with hepatic impairment (see Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions).
Overdosage
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.
Contraindications
HEMLIBRA is contraindicated in patients with known hypersensitivity to emicizumab or to any of the excipients.
Special Precautions
General: In order to improve traceability of biological medicinal products, the tradename and the batch number of the administered product should be clearly recorded (or stated) in the patient file.
Advise patients/caregivers to record the batch number of the product whenever HEMLIBRA is administered outside of a healthcare setting.
Thrombotic microangiopathy associated with HEMLIBRA and activated prothrombin complex concentrate: Cases of thrombotic microangiopathy (TMA) were reported from a clinical trial in patients receiving HEMLIBRA prophylaxis when on average a cumulative amount of > 100 U/kg/24 hours of activated prothrombin complex concentrate (aPCC) for 24 hours or more were administered (see Clinical Trials under Adverse Reactions). Treatment for the TMA events included supportive care with or without plasmapheresis and hemodialysis. Evidence of improvement was seen within one week following discontinuation of aPCC. This rapid clinical improvement is distinct from the usual clinical course observed in atypical hemolytic uremic syndrome and classic TMAs such as thrombotic thrombocytopenic purpura (see Clinical Trials under Adverse Reactions).
Patients receiving HEMLIBRA prophylaxis should be monitored for the development of TMA when administering aPCC. The physician should immediately discontinue aPCC and interrupt HEMLIBRA therapy if clinical symptoms and/or laboratory findings consistent with TMA occur, and manage as clinically indicated. Physicians and patients/caregivers should weigh the benefits and risks of resuming HEMLIBRA prophylaxis following complete resolution of TMA on a case-by-case basis. In case a bypassing agent is indicated in a patient receiving HEMLIBRA prophylaxis, see subsection as follows for dosing recommendations for the use of bypassing agents.
Thromboembolism associated with HEMLIBRA and activated prothrombin complex concentrate: Thrombotic events were reported from a clinical trial in patients receiving HEMLIBRA prophylaxis when on average a cumulative amount of >100 U/kg/24 hours of aPCC for 24 hours or more were administered (see Clinical Trials under Adverse Reactions). No cases required anticoagulation therapy, which is distinct from the usual treatment of thrombotic events. Evidence of improvement or resolution was seen after discontinuation of aPCC (see Clinical Trials under Adverse Reactions).
Patients receiving HEMLIBRA prophylaxis should be monitored for the development of thromboembolism when administering aPCC. The physician should immediately discontinue aPCC and interrupt HEMLIBRA therapy if clinical symptoms, imaging, and/or laboratory findings consistent with thrombotic events occur, and manage as clinically indicated. Physicians and patients/caregivers should weigh the benefits and risks of resuming HEMLIBRA prophylaxis following complete resolution of thrombotic events on a case-by-case basis. In case a bypassing agent is indicated in a patient receiving HEMLIBRA prophylaxis, see subsection as follows for dosing recommendations for the use of bypassing agents.
Guidance on the use of bypassing agents in patients receiving HEMLIBRA prophylaxis: Treatment with bypassing agents should be discontinued the day before starting HEMLIBRA therapy.
Physicians should discuss with all patients and/or caregivers the exact dose and schedule of bypassing agents to use, if required, while receiving HEMLIBRA prophylaxis.
HEMLIBRA increases the patient's coagulation potential. The bypassing agent dose required may therefore be lower than that used without HEMLIBRA prophylaxis. The dose and duration of treatment with bypassing agents will depend on the location and extent of bleeding and on the patient's clinical condition. Avoid use of aPCC unless no other treatment options/alternatives are available. If aPCC is indicated in a patient receiving HEMLIBRA prophylaxis the initial dose should not exceed 50 U/kg. If bleeding is not controlled with the initial dose of aPCC up to 50 U/kg, additional aPCC doses should be administered under medical guidance or supervision, and the total aPCC dose should not exceed 100 U/kg in the first 24-hours of treatment. Treating physicians must carefully weigh the risk of TMA and thromboembolism against the risk of bleeding when considering aPCC treatment beyond a maximum of 100 U/kg in the first 24-hours.
In clinical trials, no cases of TMA or thrombotic events were observed with use of activated recombinant human FVII (rFVIIa) alone in patients receiving HEMLIBRA prophylaxis.
Bypassing agent dosing guidance should be followed for at least 6 months following discontinuation of HEMLIBRA prophylaxis (see Pharmacology: Pharmacokinetics: Elimination under Actions).
Laboratory coagulation test interference: HEMLIBRA affects intrinsic pathway clotting-based laboratory tests, including the activated clotting time (ACT), activated partial thromboplastin time (aPTT) and all assays based on aPTT, such as one-stage factor VIII activity (see Table 15 as follows). 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 factor VIII inhibitor titers. Laboratory tests affected and unaffected by HEMLIBRA are shown in Table 15 as follows (see Interactions). (See Table 15.)

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Drug Abuse And Dependence: HEMLIBRA does not have the potential for abuse and dependence.
Renal Impairment: The safety and efficacy of HEMLIBRA have not been specifically tested in patients with renal impairment. There are limited data available on the use of HEMLIBRA in patients with mild to moderate renal impairment. No data are available on the use of HEMLIBRA in patients with severe renal impairment. HEMLIBRA is a monoclonal antibody and is cleared via catabolism rather than by renal excretion and a change in dose is not expected to be required for patients with renal impairment (see Special Dosage Instructions under Dosage & Administration and Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions).
Hepatic Impairment: The safety and efficacy of HEMLIBRA have not been specifically tested in patients with hepatic impairment. Patients with mild and moderate hepatic impairment were included in clinical trials. No data are available on the use of HEMLIBRA in patients with severe hepatic impairment. HEMLIBRA is a monoclonal antibody and is cleared via catabolism rather than by hepatic metabolism and a change in dose is not expected to be required for patients with hepatic impairment (see Special Dosage Instructions under Dosage & Administration and Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions).
Ability to Drive And Use Machines: 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.
Use in Children: The safety and efficacy of HEMLIBRA have been established in pediatric patients. Use of HEMLIBRA in pediatric patients with hemophilia A (with or without FVIII inhibitors) is supported by two randomized studies (HAVEN 3 and HAVEN 1) and two single-arm studies (HAVEN 4 and HAVEN 2).
These four clinical studies included a total of 107 pediatric patients in the following age groups: 47 adolescents (12 years to < 18 years), 55 children (2 years to < 12 years) and 5 infants (1 month to < 2 years) (see Pharmacology: Pharmacodynamics: Clinical/Efficacy Studies under Actions). Safety and efficacy results were consistent with those observed for adults (see Special Dosage Instructions under Dosage & Administration, Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions and Clinical Trials under Adverse Reactions).
The steady-state plasma trough concentrations of emicizumab were comparable in adult and pediatric patients at equivalent weight-based doses (Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions).
Use in Elderly: The safety and efficacy of HEMLIBRA have not been specifically tested in a geriatric population. Clinical studies of HEMLIBRA included 13 patients aged 65 and over. Relative bioavailability decreased with older age, but no clinically important differences were observed in the pharmacokinetics of emicizumab between patients < 65 years and patients ≥ 65 years (see Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions).
Use In Pregnancy & Lactation
Females and Males of Reproductive Potential: Fertility: No text (see Pharmacology: Toxicology: Preclinical Safety: Impairment of Fertility under Actions).
Pregnancy Testing: No text.
Contraception: Women of childbearing potential receiving HEMLIBRA should use effective contraception during, and for at least 6 months after cessation of HEMLIBRA treatment (see Pharmacology: Pharmacokinetics: Elimination under Actions).
Pregnancy:
There are no clinical studies of HEMLIBRA use in pregnant women. Animal reproduction studies have not been conducted with HEMLIBRA. It is not known whether HEMLIBRA can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. HEMLIBRA should be used during pregnancy only if the potential benefit for the mother outweighs the potential risk to the fetus.
Labor and delivery: The safe use of HEMLIBRA during labor and delivery has not been established.
Lactation: It is not known whether emicizumab is excreted in human milk. No studies have been conducted to assess the impact of emicizumab on milk production or its presence in breast milk. 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 infant from HEMLIBRA or from the underlying maternal condition.
Adverse Reactions
Clinical Trials: The following adverse drug reactions (ADRs) are based on pooled data from four phase III clinical trials (three adult and adolescent studies [HAVEN 1, HAVEN 3, and HAVEN 4] and a pediatric study [HAVEN 2]), in which a total of 373 male patients with hemophilia A received at least one dose of HEMLIBRA as routine prophylaxis. Two hundred and sixty-six (71%) patients were adults (≥ 18 years), 47 (13%) were adolescents (≥ 12 to < 18 years), 55 (15%) were children (≥ 2 to < 12 years) and five were infants (≥ 1 month to < 2 years). The median duration of exposure across the studies was 34.1 weeks (range: 0.1 to 94.3 weeks).
Three patients (0.8%) in the pooled phase III clinical trials receiving HEMLIBRA prophylaxis withdrew from treatment due to ADRs, which were thrombotic microangiopathy, skin necrosis contemporaneous with superficial thrombophlebitis, and headache.
Adverse drug reactions from the pooled phase III clinical trials in patients who received HEMLIBRA are listed by MedDRA system organ class (see Table 16 as follows). The corresponding frequency categories for each ADR are based on the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), and uncommon (≥ 1/1,000 to < 1/100). (See Table 16.)

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Description of selected adverse drug reactions: The most serious adverse drug reactions reported from the pooled phase III clinical trials with HEMLIBRA were TMA and thrombotic events, including cavernous sinus thrombosis and superficial vein thrombosis contemporaneous with skin necrosis (see as follows and Precautions).
Thrombotic microangiopathy: In the pooled phase III clinical trials, thrombotic microangiopathy events were reported in <1% of patients (3/373) and in 9.7% of patients (3/31) who received at least one dose of aPCC. Each patient was reported to have received on average a cumulative amount of > 100 U/kg/24 hours of aPCC for 24 hours or more while receiving HEMLIBRA prophylaxis prior to the development of TMA events (presenting with thrombocytopenia, microangiopathic hemolytic anemia and acute kidney injury, without severe deficiencies in ADAMTS13 activity). One patient resumed HEMLIBRA following resolution of TMA without recurrence (see Precautions).
Thrombotic events: In the pooled phase III clinical trials, serious thrombotic events were reported in <1% of patients (2/373) and in 6.5% of patients (2/31) who received at least one dose of aPCC. Each patient was reported to have received on average a cumulative amount of > 100 U/kg/24 hours of aPCC for 24 hours or more while receiving HEMLIBRA prophylaxis, prior to the development of the thrombotic events. One patient resumed HEMLIBRA following resolution of the thrombotic event without recurrence (see Precautions).
Characterization of aPCC Treatment (in the pooled phase III clinical trials): There were 82 instances of aPCC treatment*, of which 8 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 8 instances were associated with thrombotic events and three of the 8 instances were associated with TMA (see Table 17). No TMA or thrombotic events were associated with the remaining instances of aPCC treatment. Of all instances of aPCC treatment, 68% consisted of a single infusion ≤ 100 U/kg. (See Table 17.)

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Injection site reactions: Injection site reactions (ISRs) were reported very commonly (21%) from clinical trials. All ISRs observed in the HEMLIBRA clinical trials were reported as being non-serious and mild to moderate in intensity, and 95% resolved without treatment. The most commonly reported ISR symptoms were injection site erythema (11%); injection site pain (4%) and injection site pruritus (3%).
Post Marketing: No data to report.
Drug Interactions
No adequate or well-controlled drug-drug interaction studies have been conducted with HEMLIBRA.
Clinical experience suggests that a drug interaction exists with HEMLIBRA and aPCC (see Precautions and Clinical Trials under Adverse Reactions).
There is a possibility for hypercoagulability with rFVIIa or FVIII with HEMLIBRA based on preclinical experiments. Emicizumab increases coagulation potential, therefore the coagulation factor dose required to achieve hemostasis may be lower than when used without HEMLIBRA prophylaxis.
Effect of HEMLIBRA on coagulation tests: HEMLIBRA restores the tenase cofactor activity of missing activated factor VIII (FVIIIa). Coagulation laboratory tests based on intrinsic clotting (e.g., 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 (see Table 15 under Precautions). 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 as follows.
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 and so 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 Pharmacology: Pharmacokinetics: Elimination under Actions).
Caution For Usage
Special Instructions for Use, Handling and Disposal: HEMLIBRA solution is a sterile, preservative-free, and ready-to-use solution for subcutaneous injection that does not need to be diluted.
HEMLIBRA solution should be inspected visually to ensure there is no particulate matter or discoloration prior to administration. HEMLIBRA is a colorless to slightly yellow solution. HEMLIBRA solution should be discarded if particulate matter is visible or the product is discolored.
HEMLIBRA solution for injection vials are for single-use only.
A syringe, a transfer needle (or vial adapter) and an injection needle are needed to withdraw HEMLIBRA solution from the vial and inject it subcutaneously.
A 1 mL syringe should be used for an injection up to 1 mL of HEMLIBRA solution. Administer doses of HEMLIBRA greater than 1 mL and up to 2 mL with a 2 mL to 3 mL syringe.
Refer to the HEMLIBRA "Instructions for Use" for handling instructions when combining vials in a syringe. Do not use different HEMLIBRA vial concentrations in a single syringe when combining vials to administer the prescribed dose.
Recommendation criteria for syringes, needles and vial adaptor are defined to ensure correct and safe administration of HEMLIBRA. These criteria are based on handling considerations (e.g., dosing accuracy, subcutaneous injection), HEMLIBRA characteristics (e.g., viscosity), and compatibility between HEMLIBRA and device materials.
1 mL syringe: Criteria: Transparent polypropylene or polycarbonate syringe with Luer-Lock tip (in case not locally available, a syringe with Luer Slip tip can be used), graduation 0.01 mL, sterile, for injection only, single-use, latex-free and non-pyrogenic. When used together with a vial adapter, a low dead space plunger 1 mL syringe fulfilling the previously mentioned criteria must be used.
2 to 3 mL syringe: Criteria: Transparent polypropylene or polycarbonate syringe with Luer-Lock tip (in case not locally available, a syringe with Luer Slip tip can be used), graduation 0.1 mL, sterile, for injection only, single-use, latex-free and non-pyrogenic. When used together with a vial adapter, a low dead space plunger 3 mL syringe fulfilling the previously mentioned criteria must be used.
Transfer needle or vial adapter: Criteria for transfer needle: Stainless steel with Luer-Lock connection (in case not locally available, a needle with Luer Slip connection can be used), sterile, gauge 18 G, length 1" to 1½", blunt (single-bevelled) or semi-blunt tip, single-use, latex-free and non-pyrogenic.
Criteria for vial adapter: Polycarbonate with Luer-Lock connection, sterile, fitting 15 mm vial neck outer diameter, single-use, latex-free and non-pyrogenic.
Injection needle: Criteria: Stainless steel with Luer-Lock connection (in case not locally available, an injection needle with Luer Slip connection can be used), sterile, gauge 26 G (acceptable range: 25-27 G), length preferably 3/8" or maximally ½", single-use, latex-free and non-pyrogenic, preferably including needle safety feature.
Once transferred from the vial to the syringe, the medicinal product should be used immediately since it does not contain any antimicrobial preservative.
Incompatibilities: No incompatibilities between HEMLIBRA and the recommended syringes, vial adaptors and needles have been observed.
Disposal of syringes/sharps: The following procedures should be strictly adhered to regarding the use and disposal of syringes: Needles, syringes and vial adaptors should never be reused.
Place all used needles, syringes and vial adaptors into a sharps container (puncture-proof disposable container).
Disposal of unused/expired medicines: The release of pharmaceuticals in the environment should be minimized. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided. Use established "collection systems", if available in the location. Local requirements should be followed for the disposal process of unused/expired medicines.
Storage
Store at 2°C-8°C.
Do not freeze.
Do not shake.
Keep the vial in the outer carton in order to protect from light.
Once removed from the refrigerator, unopened vials can be kept at room temperature (below 30°C) for up to 7 days.
After storage at room temperature, unopened vials may be returned to the refrigerator. Cumulative storage time at room temperature should not exceed 7 days.
MIMS Class
ATC Classification
B02BX06 - emicizumab ; Belongs to the class of other systemic hemostatics. Used in the treatment of hemorrhage.
Presentation/Packing
Soln for inj (vial, colorless to slightly yellow, sterile) 30 mg/mL x 1's. 60 mg/0.4 mL x 1's. 105 mg/0.7 mL x 1's. 150 mg/mL x 1's.
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