Emicizumab

Q: What should I know before taking Emicizumab?

5 WARNINGS AND PRECAUTIONS Immunogenicity: Anti-emicizumab antibodies (including neutralizing antibodies) have developed in HEMLIBRA-treated patients. In case of clinical signs of loss of efficacy, promptly assess the etiology and consider a change in treatment if neutralizing antibodies are suspected. ( 5.3 , 12.6 , 14.3 ) Laboratory Coagulation Test Interference: HEMLIBRA interferes with activated clotting time (ACT), activated partial thromboplastin time (aPTT), and coagulation laboratory tes

Q: Is Emicizumab available over the counter?

Emicizumab is a prescription medication. You will need a valid prescription from a licensed healthcare provider.

Prescription

Ticari adlar: Hemlibra

Farmasötik Form

Injection

Uygulama Yolu

SUBCUTANEOUS

Üretici

Genentech, Inc.

About This Medication

11 DESCRIPTION Emicizumab-kxwh is a humanized monoclonal modified immunoglobulin G4 (IgG4) bispecific antibody binding factor IXa and factor X. Emicizumab-kxwh has an approximate molecular weight of 145.6 kDa and is produced in genetically engineered mammalian (Chinese hamster ovary) cells. Emicizumab-kxwh has no structural relationship or sequence homology to FVIII and, as such, does not induce or enhance the development of direct inhibitors to FVIII. HEMLIBRA (emicizumab-kxwh) injection is a sterile, preservative-free, colorless to slightly yellow solution for subcutaneous injection supplied in single-dose vials containing emicizumab-kxwh at 12 mg/0.4 mL, 30 mg/mL, 60 mg/0.4 mL, 105 mg/0.7 mL, 150 mg/mL, or 300 mg/2 mL. Each single-dose 12 mg vial contains a 0.4 mL solution of emicizumab-kxwh (12 mg), L-arginine (10.5 mg), L-histidine (1.2 mg), and poloxamer 188 (0.2 mg), adjusted to pH 6.0 with L-aspartic acid. Each single-dose 30 mg vial contains a 1 mL solution of emicizumab-kxwh (30 mg), L-arginine (26.1 mg), L-histidine (3.1 mg), and poloxamer 188 (0.5 mg), adjusted to pH 6.0 with L-aspartic acid. Each single-dose 60 mg vial contains a 0.4 mL solution of emicizumab-kxwh (60 mg), L-arginine (10.5 mg), L-histidine (1.2 mg), and poloxamer 188 (0.2 mg), adjusted to pH 6.0 with L-aspartic acid. Each single-dose 105 mg vial contains a 0.7 mL solution of emicizumab-kxwh (105 mg), L-arginine (18.3 mg), L-histidine (2.2 mg), and poloxamer 188 (0.4 mg), adjusted to pH 6.0 with L-aspartic acid. Each single-dose 150 mg vial contains a 1 mL solution of emicizumab-kxwh (150 mg), L-arginine (26.1 mg), L-histidine (3.1 mg), and poloxamer 188 (0.5 mg), adjusted to pH 6.0 with L-aspartic acid. Each single-dose 300 mg vial contains a 2 mL solution of emicizumab-kxwh (300 mg), L-arginine (52.3 mg), L-histidine (6.2 mg), and poloxamer 188 (1 mg), adjusted to pH 6.0 with L-aspartic acid.

Etken Maddeler

Bileşen	Güç
Emicizumab	-

Endikasyonlar ve Kullanım

1 INDICATIONS AND USAGE HEMLIBRA is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients ages newborn and older with hemophilia A (congenital factor VIII deficiency) with or without factor VIII inhibitors. HEMLIBRA is a bispecific factor IXa- and factor X-directed antibody indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients ages newborn and older with hemophilia A (congenital factor VIII deficiency) with or without factor VIII inhibitors. ( 1 )

Nasıl çalışır

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.

Dozaj ve Uygulama

2 DOSAGE AND ADMINISTRATION Recommended loading dose is 3 mg/kg by subcutaneous injection once weekly for the first 4 weeks, followed by a maintenance dose of: 1.5 mg/kg once every week, or 3 mg/kg once every two weeks, or 6 mg/kg once every four weeks. ( 2.1 ) See Full Prescribing Information for important preparation and administration instructions. ( 2.2 ) 2.1 Recommended Dosage For subcutaneous use only. The recommended loading dose is 3 mg/kg by subcutaneous injection once weekly for the first 4 weeks, followed by a maintenance dose of: 1.5 mg/kg once every week, or 3 mg/kg once every two weeks, or 6 mg/kg once every four weeks. The selection of a maintenance dose should be based on healthcare provider preference with consideration of regimens that may increase patient adherence. Discontinue the prophylactic use of bypassing agents the day before starting HEMLIBRA prophylaxis. The prophylactic use of factor VIII (FVIII) products may be continued during the first week of HEMLIBRA prophylaxis. Missed Dose If a dose of HEMLIBRA is missed administer as soon as possible and then resume usual dosing schedule. Do not administer two doses on the same day to make up for a missed dose. 2.2 Preparation and Administration HEMLIBRA is intended for use under the guidance of a healthcare provider. After proper training in subcutaneous injection technique, a patient may self-inject, or the patient's caregiver may administer HEMLIBRA, if a healthcare provider determines that it is appropriate. Self-administration is not recommended for children less than 7 years of age. 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 with filter and an injection needle are needed to withdraw HEMLIBRA solution from the vial and inject it subcutaneously. Refer to the HEMLIBRA " Instructions for Use " for handling instructions when combining vials. Do not combine HEMLIBRA vials of different concentrations (i.e. 30 mg/mL and 150 mg/mL) in a single injection. Please see below the selection criteria for the recommended device options: Administer doses of HEMLIBRA up to 1 mL with a 1 mL syringe. A 1 mL syringe fulfilling the following criteria may be used: Transparent polypropylene or polycarbonate syringe with Luer-Lock tip, graduation 0.01 mL, sterile, for injection only, single-use, latex-free and non-pyrogenic, commercially available in the US. Administer doses of HEMLIBRA greater than 1 mL and up to 2 mL with a 2 mL or 3 mL syringe. A 2 mL or 3 mL syringe fulfilling the following criteria may be used: Transparent polypropylene or polycarbonate syringe with Luer-Lock tip, graduation 0.1 mL, sterile, for injection only, single-use, latex-free, and non-pyrogenic, commercially available in the US. A transfer needle with a filter fulfilling the following criteria should be used: Stainless steel needle with Luer-Lock connection, sterile, 18 gauge, length 1 to 1½ inch, single bevel or semi-blunted tip, single-use, latex-free, containing a 5-micron filter and non-pyrogenic, commercially available in the US. An injection needle fulfilling the following criteria may be used: Stainless steel with Luer-Lock connection, sterile, 26 gauge (acceptable range: 25 – 27 gauge), length preferably ⅜ inch or maximal length ½ inch, single-use, latex-free and non-pyrogenic, including needle safety feature, commercially available in the US. Administer each injection at a different anatomic location (upper outer arms, thighs, or any quadrant of abdomen) than the previous injection. An injection should never be given into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact. Administration of HEMLIBRA in the upper outer arm should only be performed by a caregiver or healthcare provider. Discard any unused HEMLIBRA remaining in the single-dose vial.

Side Effects Overview

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) ] Most common adverse reactions (incidence ≥ 10%) are injection site reactions, headache, and arthralgia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following adverse reactions are based on pooled data from two randomized trials in adult and adolescent patients (HAVEN 1 and HAVEN 3), one single-arm trial in adult and adolescent patients (HAVEN 4), one single-arm trial in pediatric patients (HAVEN 2), and one dose-finding trial, in which a total of 391 male patients with hemophilia A received at least one dose of HEMLIBRA as routine prophylaxis. Two hundred eighty-one patients (72%) were adults (18 years and older), 50 (13%) were adolescents (12 years up to less than 18 years), 55 (14%) were children (2 years up to less than 12 years), and five (1%) were infants (1 month up to less than 2 years). The median duration of exposure across the studies was 34.1 weeks (0.1 to 224.4 weeks). The most frequently reported adverse reactions observed in ≥ 10% of patients treated with HEMLIBRA were injection site reactions, headache, and arthralgia. Four patients (1%) in the clinical trials receiving HEMLIBRA prophylaxis withdrew from treatment due to adverse reactions, which were thrombotic microangiopathy, skin necrosis and superficial thrombophlebitis, headache, and injection site reaction. Adverse reactions observed in patients who received HEMLIBRA are shown in Table 2 . Table 2 Adverse Reactions Reported in ≥ 5% of Patients from Pooled Clinical Trials with HEMLIBRA Body System Adverse Reaction Number of Patients n (%) (N = 391) General Disorders and Administration Site Conditions Injection site reaction Includes injection site bruising, injection site discomfort, injection site erythema, injection site hematoma, injection site induration, injection site pain, injection site pruritus, injection site rash, injection site reaction, injection site swelling, injection site urticaria, and injection site warmth. 85 (22%) Pyrexia 23 (6%) Nervous System Disorders Headache 57 (15%) Gastrointestinal Disorders Diarrhea 22 (6%) Musculoskeletal and Connective Tissue Disorders Arthralgia 59 (15%) Characterization of aPCC treatment in pooled clinical trials There were 130 instances of aPCC treatment in 37 patients, of which 13 instances (10%) consisted of on average a cumulative amount of >100 U/kg/24 hours of aPCC for 24 hours or more; two of the 13 were associated with thrombotic events and three of the 13 were associated with TMA ( Table 3 ). No TMA or thrombotic events were associated with the remaining instances of aPCC treatment. Table 3 Characterization of aPCC Treatment An instance of aPCC treatment is defined as all doses of aPCC received by a patient, for any reason, until there was a 36-hour treatment-free break. in Pooled Clinical Trials Duration of aPCC treatment Average cumulative amount of aPCC over 24 hours (U/kg/24 hours) < 50 50 – 100 > 100 < 24 hours 11 76 18 24 – 48 hours 0 6 3 Thrombotic event. > 48 hours 1 5 10 , Thrombotic microangiopathy. , , Injection Site Reactions In total, 85 patients (22%) reported injection site reactions (ISRs). All ISRs observed in HEMLIBRA clinical trials were reported as mild to moderate intensity and 93% resolved without treatment. The commonly reported ISR symptoms were injection site erythema (11%), injection site pain (4%), and injection site pruritus (4%). Other Less Common (<1%) Reactions Rhabdomyolysis Rhabdomyolysis was reported in two adult patients with asymptomatic elevations in serum creatine kinase without associated renal or musculoskeletal symptoms. In both instances, the event occurred following an increase in physical activity. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of HEMLIBRA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and subcutaneous tissue disorders : rash, urticaria, angioedema. Immune system disorders : hypersensitivity.

Uyarılar ve Önlemler

5 WARNINGS AND PRECAUTIONS Immunogenicity: Anti-emicizumab antibodies (including neutralizing antibodies) have developed in HEMLIBRA-treated patients. In case of clinical signs of loss of efficacy, promptly assess the etiology and consider a change in treatment if neutralizing antibodies are suspected. ( 5.3 , 12.6 , 14.3 ) Laboratory Coagulation Test Interference: HEMLIBRA interferes with activated clotting time (ACT), activated partial thromboplastin time (aPTT), and coagulation laboratory tests based on aPTT, including one-stage aPTT-based single-factor assays, aPTT-based Activated Protein C Resistance (APC-R), and Bethesda assays (clotting-based) for factor VIII (FVIII) inhibitor titers. Intrinsic pathway clotting-based laboratory tests should not be used. ( 5.4 , 7.2 ) 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 0.8% of patients (3/391) and in 8.1% of patients (3/37) who received at least one dose of aPCC. Patients presented with thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury, without severe deficiencies in ADAMTS13 activity. Evidence of improvement was seen within one week following discontinuation of aPCC. One patient resumed HEMLIBRA following resolution of TMA. Consider the benefits and risks if aPCC must be used in a patient receiving HEMLIBRA prophylaxis. Due to the long half-life of HEMLIBRA, the potential for an interaction with aPCC may persist for up to 6 months after the last dose. 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 0.5% of patients (2/391) and in 5.4% of patients (2/37) who received at least one dose of aPCC. No thrombotic event required anticoagulation therapy. Evidence of improvement or resolution was seen within one month following discontinuation of aPCC. One patient resumed HEMLIBRA following resolution of thrombotic event. Consider the benefits and risks if aPCC must be used in a patient receiving HEMLIBRA prophylaxis. Due to the long half-life of HEMLIBRA, the potential for an interaction with aPCC may persist for up to 6 months after the last dose. 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 Immunogenicity Treatment with HEMLIBRA may induce anti-drug antibodies. Anti-emicizumab-kxwh antibodies were reported in 5.1% of patients (34/668) treated with HEMLIBRA in clinical trials. Most patients with anti-emicizumab-kxwh antibodies did not experience a change in HEMLIBRA plasma concentrations or an increase in bleeding events; however, in uncommon cases (incidence < 1%), the presence of neutralizing antibodies with decreasing plasma concentration may be associated with loss of efficacy [see Clinical Pharmacology (12.6) , Clinical Studies (14.3) ] . Monitor for clinical signs of loss of efficacy (e.g., increase in breakthrough bleeding events) and if observed, promptly assess the etiology and consider a change in treatment if neutralizing anti-emicizumab-kxwh antibodies are suspected. 5.4 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 . Table 1 Coagulation Test Results Affected and Unaffected by HEMLIBRA Results Affected by HEMLIBRA Results Unaffected by HEMLIBRA Activated partial thromboplastin time (aPTT) Bethesda assays (clotting-based) for FVIII inhibitor titers One-stage, aPTT-based, single-factor assays aPTT-based Activated Protein C Resistance (APC-R) Activated clotting time (ACT) Bethesda assays (bovine chromogenic) for FVIII inhibitor titers Thrombin time (TT) One-stage, prothrombin time (PT)-based, single-factor assays Chromogenic-based single-factor assays other than FVIII For important considerations regarding FVIII chromogenic activity assays, see Drug Interactions (7.2) . Immuno-based assays (i.e., ELISA, turbidimetric methods) Genetic tests of coagulation factors (e.g., Factor V Leiden, Prothrombin 20210)

Kontrendikasyonlar

4 CONTRAINDICATIONS None. None ( 4 )

Farmakokinetik

12.3 Pharmacokinetics Emicizumab-kxwh exhibited dose-proportional pharmacokinetics over a dose range of 0.3 mg/kg (0.1 times approved recommended starting dosage) to 6 mg/kg following subcutaneous administration. Following multiple subcutaneous administrations of a loading dose of 3 mg/kg emicizumab-kxwh once weekly for the first 4 weeks in hemophilia A patients, mean (± SD) trough plasma concentrations of 52.6 ± 13.6 μg/mL was achieved at Week 5. Sustained mean (± SD) plasma concentrations of emicizumab-kxwh at steady-state with the recommended maintenance doses are shown in Table 4 . Table 4 Mean (± SD) Steady-State Concentrations after emicizumab-kxwh Loading Dose by Maintenance Dose Regimen Maintenance Dose Parameters 1.5 mg/kg once every week 3 mg/kg once every two weeks 6 mg/kg once every four weeks AUC ss,τ = area under the concentration time curve at steady-state over the dosing interval (τ = 1, 2, or 4 weeks); C max, ss = maximum plasma concentration at steady state; C trough, ss = trough concentration at steady state. C max, ss (µg/mL) 55.1 ± 15.9 58.3 ± 16.4 67 ± 17.7 AUC ss,τ (µg/mL*day) 376 ± 109 752 ± 218 1503 ± 437 C trough, ss (µg/mL) 51.2± 15.2 46.9 ± 14.8 38.5 ± 14.2 C max / C trough ratio (µg/mL) 1.08 ± 0.03 1.26 ± 0.12 1.85 ± 0.47 Absorption Following subcutaneous administration, the mean (± SD) absorption half-life was 1.6 ± 1 day. The absolute bioavailability following subcutaneous administration of 1 mg/kg was between 80.4% and 93.1%. Similar pharmacokinetic profiles were observed following subcutaneous administration in the abdomen, upper arm, and thigh [see Dosage and Administration (2.2) ] . Distribution The mean apparent volume of distribution (% coefficient of variation [%CV]) was 10.4 L (26.0%). Elimination The mean apparent clearance (%CV) was 0.27 L/day (28.4%) and the mean elimination apparent half-life (± SD) was 26.9 ± 9.1 days. Specific Populations The pharmacokinetics of emicizumab-kxwh are not influenced by age (1 year to 77 years), race (White 62.7%, Asian 22.9%, and Black 8%), inhibitor status (inhibitor present, 50%), mild hepatic impairment (defined as total bilirubin 1× to ≤1.5× the upper limit of normal (ULN) and any aspartate transaminase (AST) level), moderate hepatic impairment (defined as total bilirubin 1.5× to ≤3× the ULN and any AST level), mild renal impairment (defined as creatinine clearance (CrCl) of 60 – 89 mL/min), and moderate renal impairment (defined as CrCl of 30 – 59 mL/min). Emicizumab-kxwh has not been studied in patients with severe hepatic or renal impairment. In pediatric patients less than 6 months old, the predicted concentrations of emicizumab-kxwh were 19% to 33% lower than the older patients, especially with the 3 mg/kg once every two weeks or 6 mg/kg once every four weeks maintenance dose. Body weight : The apparent clearance and volume of distribution of emicizumab-kxwh increased with increasing body weight (9 kg to 156 kg). Dosing in mg/kg provides similar emicizumab-kxwh exposure across body weight range. Drug Interaction Studies No drug-drug interaction studies have been conducted with HEMLIBRA.

Frequently Asked Questions

1 INDICATIONS AND USAGE HEMLIBRA is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients ages newborn and older with hemophilia A (congenital factor VIII deficiency) with or without factor VIII inhibitors. HEMLIBRA is a bispecific factor IXa- and factor X-directed antibody indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients ages newborn and older with hemophilia A (congenital factor VIII deficiency) …

2 DOSAGE AND ADMINISTRATION Recommended loading dose is 3 mg/kg by subcutaneous injection once weekly for the first 4 weeks, followed by a maintenance dose of: 1.5 mg/kg once every week, or 3 mg/kg once every two weeks, or 6 mg/kg once every four weeks. ( 2.1 ) See Full Prescribing Information for important preparation and administration instructions. ( 2.2 ) 2.1 Recommended Dosage For subcutaneous use only. The recommended loading dose is 3 mg/kg by subcutaneous injection once weekly …

5 WARNINGS AND PRECAUTIONS Immunogenicity: Anti-emicizumab antibodies (including neutralizing antibodies) have developed in HEMLIBRA-treated patients. In case of clinical signs of loss of efficacy, promptly assess the etiology and consider a change in treatment if neutralizing antibodies are suspected. ( 5.3 , 12.6 , 14.3 ) Laboratory Coagulation Test Interference: HEMLIBRA interferes with activated clotting time (ACT), activated partial thromboplastin time (aPTT), and coagulation laboratory tests based on aPTT, including one-stage aPTT-based single-factor assays, aPTT-based Activated Protein C Resistance (APC-R), …

4 CONTRAINDICATIONS None. None ( 4 )

Emicizumab is a prescription medication. You will need a valid prescription from a licensed healthcare provider.

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References & Data Sources

• DailyMed — Emicizumab drug label (National Library of Medicine)
• openFDA — Emicizumab label data (U.S. Food & Drug Administration)
• RxNorm — RXCUI 1989799 (NLM Normalized Drug Names)
• NDC Directory — Emicizumab (FDA National Drug Code)

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