Hemlibra

— THERAPEUTIC DISORDERS TREATED —
  • Bleeding disorders
PAGE CONTENTS
  • Jump to Section
  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Hemlibra Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Emicizumab-kxwh 30mg/mL, 60mg/0.4mL, 105mg/0.7mL, 150mg/mL; per vial; soln for SC inj; preservative-free.

    Pharmacological Class

    Bispecific factor IXa- and factor X-directed antibody.

    How Supplied

    Single-dose vial—1

    How Supplied

    Hemlibra (emicizumab-kxwh) injection is available as a sterile, preservative-free, colorless to slightly yellow solution in 1 single-dose vial per carton in the following dosage strengths:

    • Strength 30 mg; Nominal Volume 1 mL; Concentration 30 mg/mL

    • Strength 60 mg; Nominal Volume 0.4 mL; Concentration 150 mg/mL

    • Strength 105 mg; Nominal Volume 0.7 mL; Concentration 150 mg/mL

    • Strength 150 mg; Nominal Volume 1 mL; Concentration 150 mg/mL

    Storage

    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.

    Manufacturer

    Genentech, Inc.

    Generic Availability

    NO

    Hemlibra Indications

    Indications

    Routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients with hemophilia A with or without factor VIII inhibitors.

    Hemlibra Dosage and Administration

    Adults and Children

    Do not inj into moles, scars, tender skin, bruised, red, hard or not intact skin areas. Give by SC inj into upper outer arms, thighs, or any abdomen quadrant; rotate inj sites. 3mg/kg once weekly for first 4 weeks, then 1.5mg/kg once weekly, or 3mg/kg once every 2 weeks, or 6mg/kg once every 4 weeks. Discontinue prophylactic use of bypassing agents the day before starting therapy; may continue FVIII prophylaxis during first week of Hemlibra.

    Other Modifications

    Females and Males of Reproductive Potential 

    • Contraception: Women of childbearing potential should use contraception while receiving Hemlibra.

    Hemlibra Contraindications

    Not Applicable

    Hemlibra Boxed Warnings

    Boxed Warning

    Thrombotic microangiopathy and thromboembolism.

    Boxed 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 (aPCC) 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.

    Hemlibra Warnings/Precautions

    Warnings/Precautions

    Thrombotic microangiopathy and thromboembolism can occur when average cumulative of >100U/kg per 24hrs of activated prothrombin complex concentrate (aPCC) was given for ≥24hrs. Advise females of reproductive potential to use effective contraception during treatment. Pregnancy. Nursing mothers.

    Warnings/Precautions

    Thrombotic Microangiopathy and Thromboembolism Associated with Hemlibra and aPCC

    • Thrombotic microangiopathy (TMA) and thrombotic events can occur when an average cumulative amount of >100 U/kg/24 hours of activated prothrombin complex concentrate (aPCC) was given for 24 hours or more.

    • Patients presented with thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury, without severe deficiencies in ADAMTS13 activity. No thrombotic event required anticoagulation therapy.

    • After discontinuing aPCC, evidence of improvement for TMA was observed within 1 week, and evidence of improvement or resolution for thrombotic events was observed within 1 month.

    • Consider benefits and risks if aPCC must be used in a patient receiving Hemlibra prophylaxis. The potential for an interaction between Hemlibra and an aPCC may persist for up to 6 months after the last dose of Hemlibra.

    • Monitor for TMA when administering aPCC.

    • Discontinue aPCC immediately and interrupt Hemlibra prophylaxis if clinical symptoms and/or laboratory findings consistent with TMA or thromboembolism occur and manage as clinically indicated. Consider the benefits and risks of resuming Hemlibra prophylaxis on a case-by-base basis.

    Immunogenicity

    • Hemlibra may induce anti-drug antibodies.

    • Monitor for clinical signs of loss of efficacy (eg, increase in breakthrough bleeding events) and if observed, promptly assess the cause and consider a change in treatment if neutralizing anti-emicizumab-kxwh antibodies are suspected.

    Laboratory Coagulation Test Interference

    • Do not use intrinsic pathway clotting-based laboratory tests to monitor Hemlibra activity, to determine dosing for factor replacement or anti-coagulation, or to measure FVIII inhibitor titers.

    • Coagulation test results affected by Hemlibra:

      • Activated partial thromboplastin time (aPTT)

      • Bethesda assays (clotting-based) for FVIII inhibitor titers

      • One-state, aPTT-based, single-factor assays

      • aPTT-based Activated Protein C Resistance (APC-R)

      • Activated clotting time (ACT)

    • Coagulation test results unaffected by Hemlibra:

      • 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 Immuno-based assays (i.e., ELISA, turbidimetric methods) 

      • Genetic tests of coagulation factors (e.g., Factor V Leiden, Prothrombin 20210)

    Pregnancy Considerations

    There are no available data on Hemlibra use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. 

    Only use during pregnancy if the potential benefit for the mother outweighs the risk to the fetus.

    Nursing Mother Considerations

    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.

    Consider the mother’s clinical need for Hemlibra and any potential adverse effects on the breastfed child from Hemlibra or from the underlying maternal condition.

    Pediatric Considerations

    The safety and efficacy of Hemlibra have been established in pediatric patients. Use in pediatric patients with hemophilia A is supported by two randomized trials (HAVEN 1 and HAVEN 3) and two single-arm trials (HAVEN 2 and HAVEN 4). All clinical trials included pediatric patients in the following age group: 47 adolescents (12 years up to less than 18 years). Only HAVEN 2 included pediatric patients in the following age groups: 55 children (2 years up to less than 12 years) and five infants (1 month up to less than 2 years). No differences in efficacy were observed between the different age groups

    Geriatric Considerations

    Clinical studies did not include a sufficient number of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

    Other Considerations for Specific Populations

    Females and Males of Reproductive Potential 

    • Contraception: Women of childbearing potential should use contraception while receiving Hemlibra.

    Hemlibra Pharmacokinetics

    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.

    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.

    Hemlibra Interactions

    Interactions

    Risk of thrombotic microangiopathy and thromboembolism with concomitant aPCC; monitor and immediately discontinue if occurs. May interfere with coagulation lab tests (eg, ACT, aPTT, aPTT-based assays, Bethesda assays [clotting-based] for FVIII inhibitor titers).

    Hemlibra Adverse Reactions

    Adverse Reactions

    Inj site reactions, headache, arthralgia, pyrexia, diarrhea; neutralizing antibody formation.

    Hemlibra Clinical Trials

    Clinical Trials

    Hemophilia A without FVIII Inhibitors

    The approval was based on data from two phase 3 clinical trials: HAVEN 3 and HAVEN 4. 

    In the HAVEN 3 study (N=89), patients 12 years of age and older with hemophilia A without factor VIII inhibitors who received Hemlibra prophylaxis 1.5 mg/kg once weekly or 3 mg/kg every 2 weeks experienced the following reductions in annualized bleed rates (ABR) compared with those who received no prophylaxis, respectively:

    • Treated Bleeds: 96% (95% CI, 92.5-98.0; P <.0001) and 97% (95% CI, 93.4-98.3; P <.0001)

    • All Bleeds: 95% (95% CI, 90.1-97; P <.0001) and 94% (95% CI, 89.7-97; P <.0001)

    • Treated Spontaneous Bleeds: 94% (95% CI, 84.9-97.5; P <.0001) and 98% (95% CI, 94.4-99.4; P <.0001)

    • Treated Joint Bleeds: 96% (95% CI, 91.5-98.1; P <.0001) and 97% (95% CI, 93-98.5; P <.0001)

    • Treated Target Joint Bleeds: 95% (95% CI, 85.7-98.4; P <.0001) and 95% (95% CI, 85.3-98.2; P <.0001)

    In the HAVEN 3 intra-patient analysis, Hemlibra prophylaxis achieved a statistically significant 68% reduction in bleed rate for treated bleeds compared with previous FVIII prophylaxis collected in the NIS prior to enrollment (P <.0001). 

    In the HAVEN 4 study, Hemlibra prophylaxis every 4 weeks (N=41) was associated with clinically meaningful control of bleeding in patients with hemophilia A without factor VIII inhibitors (ABR: 2.6; 95% CI: 1.5, 4.7).

     

    Hemophilia A with FVIII Inhibitors

    The approval of Hemlibra for routine prophylaxis in patients with hemophilia A with FVIII inhibitors was based on data from 3 clinical trials: [adult and adolescent studies (HAVEN 1 and HAVEN 4) and a pediatric study (HAVEN 2)].

    In the HAVEN 1 study (N=89), patients 12 years of age and older with hemophilia A with factor VIII inhibitors who received Hemlibra prophylaxis 1.5 mg/kg once weekly experienced the following reductions in annualized bleed rates (ABR) compared with those who received no prophylaxis:

    • Treated Bleeds: 87% (95% CI, 72.3-94.3; P <.0001)

    • All Bleeds: 80% (95% CI, 62.5-89.8; P <.0001)

    • Treated Spontaneous Bleeds: 92% (95% CI, 84.6-96.3; P <.0001)

    • Treated Joint Bleeds: 89% (48-97.5; P =.0050)

    • Treated Targeted Joint Bleeds: 95% (95% CI, 77.3-99.1; P =.0002)

    In the HAVEN 1 intra-patient analysis, Hemlibra prophylaxis achieved a statistically significant 79% reduction in bleed rate for treated bleeds compared with previous bypassing agent prophylaxis collected in the NIS prior to enrollment (P =.0003).

    In the HAVEN 2 study, patients less than 12 years of age or patients 12 to 17 years of age weighing less than 40kg were enrolled who had hemophilia A with FVIII inhibitors. At the time of interim analysis, there were 59 pediatric patients less than 12 years of age, including 38 who were 6 to less than 12 years, 17 who were 2 to less than 6 years, and 4 who were less than 2 years. Patients who received Hemlibra prophylaxis 1.5 mg/kg once weekly had the following ABRs:

    • Treated Bleeds: 0.3 (95% CI, 0.1-0.5)

    • All Bleeds: 3.8 (95% CI, 2.2-6.5)

    • Treated Spontaneous Bleeds: 0 (95% CI, 0-0.2)

    • Treated Joint Bleeds: 0.2 (95% CI, 0.1-0.4)

    • Treated Targeted Joint Bleeds: 0.1 (95% CI, 0-0.7)

    In the HAVEN 2 intra-patient analysis, 18 pediatric patients who had participated in the NIS had an ABR for treated bleeds of 19.8 (95% CI, 15.3-25.7]) on previous bypassing agent treatment (prophylactic treatment in 15 patients and on-demand treatment for 3 patients). Hemlibra prophylaxis resulted in an ABR for treated bleeds of 0.4 (95% CI, 0.2-0.9]) based on negative binomial regression, corresponding to a 98% reduction in bleed rate. On Hemlibra prophylaxis, 14 patients (77.8%) had zero treated bleeds. 

    In the HAVEN 4 study, 41 patients 12 years of age and older weighing at least 40 kg were enrolled who had hemophilia A with or without FVIII inhibitors and previously received either episodic (on demand) or prophylactic treatment with FVIII or bypassing agents. Patients received Hemlibra prophylaxis at 3 mg/kg once weekly for the first 4 weeks then 6 mg/kg once every 4 weeks thereafter. Treatment with Hemlibra prophylaxis every 4 weeks was associated with clinically meaningful control of bleeding in patients with hemophilia A with factor VIII inhibitors and without factor VIII inhibitors (ABR: 2.4; 95% CI, 1.4-4.3).

    Hemlibra Note

    Not Applicable

    Hemlibra Patient Counseling

    Patient Counseling

    Use of Bypassing Agents or FVIII

    • Inform the patient and/or caregiver that Hemlibra increases coagulation potential.

    • Advise to discontinue prophylactic use of bypassing agents the day before starting Hemlibra prophylaxis.

    • Advise that prophylactic use of FVIII may be continued for the first week of Hemlibra prophylaxis.

    Thrombotic Microangiopathy and Thromboembolism Associated with Hemlibra and aPCC 

    • Inform the patient and/or caregiver of the potential risk of thrombotic microangiopathy and thromboembolism if aPCC is administered while receiving Hemlibra prophylaxis.

    • Consult healthcare provider if aPCC is required in cumulative doses exceeding 100 U/kg.

    • Seek immediate medical attention if any signs or symptoms of thrombotic microangiopathy or thromboembolism occur.

    Immunogenicity

    • Promptly report clinical signs of loss of efficacy (e.g., increase in breakthrough bleeding events).

    Laboratory Coagulation Test Interference 

    • Inform patient and/or caregiver that Hemlibra interferes with some laboratory tests that measure blood clotting and may cause a false reading.

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