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FDA Alerts

Pharmacist's Applications to Practice

HOPA, through the Publications Committee, will review new drug updates and provide analysis and research on the application of these new drugs or indications.

The letters “PAP” after drugs listed below indicates that they include this additional analysis.  


November 16, 2017

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761083s000lbl.pdf

On November 16, 2017, the Food and Drug Administration approved emicizumab-kxwh (HEMLIBRA®, Genentech, Inc.) 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.

Approval was based on data from two clinical trials—an adult and adolescent trial (HAVEN 1) and a pediatric trial (HAVEN 2). HAVEN 1 (NCT02622321) was a randomized, multicenter, open-label, phase 3 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 on prior episodic treatment were randomized 2:1 to weekly emicizumab-kxwh prophylaxis (3 mg/kg once weekly for the first 4 weeks followed by 1.5 mg/kg once weekly, thereafter) or no prophylaxis. Patients randomized to no prophylaxis could switch to emicizumab-kxwh prophylaxis after 24 weeks. For patients receiving emicizumab-kxwh prophylaxis, the annualized bleeding rate (ABR) requiring treatment with coagulation factors was 2.9 (95% CI; 1.7, 5.0) compared with 23.3 (95% CI: 12.3, 43.9) for patients not receiving prophylaxis corresponding to an 87% ABR reduction (95% CI: 72.3%, 94.3%), p<0.0001. In addition, improvements in patient-reported hemophilia-related symptoms and physical functioning in patients receiving emicizumab-kxwh prophylaxis were observed.

HAVEN 2 (NCT02795767) was a single-arm, multicenter, open-label, clinical trial in pediatric males (age < 12 years, or 12-17 years who weigh <40 kg) with hemophilia A with FVIII inhibitors. Patients received emicizumab-kxwh prophylaxis at the dose and schedule described above. In 23 patients evaluated at the interim analysis, ABR for treated bleeds was 0.2 (95% CI: 0.1, 0.6). ABR for all bleeds was 2.9 (95% CI: 1.8, 4.9).

The most common adverse reactions (occurring in ≥ 10% of patients taking emicizumab-kxwh) are injection site reactions, headache, and arthralgia. 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 emicizumab-kxwh prophylaxis. The prescribing information contains a boxed warning to monitor for thrombotic microangiopathy and thrombotic events when aPCC is administered. If symptoms occur, aPCC should be discontinued and emicizumab-kxwh should be suspended.

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

Full prescribing information is available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761083s000lbl.pdf

Emicizumab-kxwh was approved 3.3 months prior to the assigned regulatory action date. FDA granted Priority Review, Breakthrough Therapy designation, and Orphan Drug designation for this indication. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

 


Pharmacist's Applications to Practice

Emicizumab-kxwh (Hemlibra) for Routine Prophylaxis in Patients with Hemophilia A with Factor VIII Inhibitors

Authors: Payal Kakadiya, PharmD BCPS
PGY-2 Internal Medicine Pharmacy Resident
VCU Health
Richmond, VA

Cady Noda, PharmD BCPS
Pediatric Hematology/Oncology Clinical Pharmacist
VCU Health
Richmond, VA

What is the potential role for emicizumab-kxwh in the treatment of hemophilia A with factor VIII (FVIII) inhibitors?1,2,3

  • The U.S. Food and Drug Administration (FDA) granted emicizumab-kxwh approval as an orphan drug and breakthrough therapy on November 16, 2017, for the prevention or reduction in frequency of bleeding episodes in adult and pediatric patients with hemophilia A with factor VIII inhibitors.
  • The approval was granted by the FDA based on data from two trials:
    • HAVEN I (N = 109) was a phase 3 randomized multicenter open-label trial conducted to evaluate the efficacy, study, and pharmacokinetics of once-weekly emicizumab-kxwh prophylaxis compared to no prophylaxis for a duration of 24 weeks in patients who were 12 years of age and older with hemophilia A with inhibitors.
      • The primary end point, annualized bleeding rate, was significantly reduced by 87% (2.9 vs. 23.3 events, risk ratio = .13; p < .001) in those receiving emicizumab-kxwh, compared to placebo.
        • The annualized bleeding rate was defined as the difference in the rate of treated bleeding events over a period of at least 24 weeks between those receiving prophylaxis versus no prophylaxis.
      • The results of using emicizumab-kxwh also showed a statistically significant reduction of 79% (95% confidence interval [CI]: 51.4–91.1; p = .0003) of annual treated bleeds in a cohort of 24 patients who had previously received prophylaxis with a bypassing agent.
      • Overall, emicizumab-kxwh prophylaxis showed a reduction in all bleeds (80%, p < .0001), treated spontaneous bleeds (92%, p < .0001), and treated joint bleeds (89%, p < .005).
      • The results showed improvement in the Physical Health Score in the Hemophilia-Specific Quality of Life Index at the end of 24 weeks for patients receiving emicizumab-kxwh compared to the placebo group.
      • Common adverse events reported in the emicizumab-kxwh group included injection-site reaction (15%), headache (12%), upper respiratory tract infection (9%), fatigue (6%), and arthralgia (6%).
    • HAVEN II is an ongoing single-arm multicenter open-label study including children younger than 12 years of age with hemophilia A with FVIII inhibitors (N = 23) to evaluate the efficacy, safety, and pharmacokinetics of once-weekly emicizumab-kxwh prophylaxis. The interim analysis was conducted after 12 weeks of treatment.
      • Nearly 87% (95% CI: 66.4–97.2) of patients who received emicizumab-kxwh for prophylaxis reported zero bleeding events.
      • In the intrapatient analysis of 13 patients, the annualized bleeding rate was 0.2 (95% CI: 0.1–0.8) in patients on emicizumab-kxwh prophylaxis compared to 17.2 (95% CI: 12.4–23.8) in patients on previous treatment with bypassing agents as prophylaxis or on demand.
  • Emicizumab-kxwh is currently the only bispecific factor IXa- and factor X-directed monoclonal antibody designed to bridge factor IXa and factor X to restore function of missing factor VIII.
    • Other products that can be used in the setting of high-titer inhibitors are the bypassing agents, which include factor VII products, fresh frozen plasma, cryoprecipitate, and desmopressin.
    • Bypassing agents are often used during severe, spontaneous bleeds or when a patient’s baseline factor activity is unknown. However, they are only a temporary solution because they have short half-lives and need to be redosed quite frequently.

What role can the pharmacist play in the management of patients on emicizumab-kxwh? 4

  • Patients are given a loading dose followed by a maintenance dose via subcutaneous injection.
    • Loading: 3 mg/kg once weekly for 4 weeks
    • Maintenance: 1.5 mg/kg once weekly
      • The HAVEN 1 protocol allowed for a dose increase to 3 mg/kg once weekly in those who experience 2 or more spontaneous and clinically significant bleeds after the loading dose and a minimum of 24 weeks of treatment on 1.5 mg/kg injections.  Notably, the FDA label does not include this dosing.
  • If a dose is missed, it should be administered as soon as possible before the next scheduled dose, and then the usual weekly schedule should be resumed.
  • Pharmacists can help in educating patients about the subcutaneous self-injection technique because the medication is approved for self-injection in patients over the age of 7 years.
    • Sites of self-injection include thighs or abdomen. The upper outer arm should be used only if the patient has a caregiver to administer the injection.
  • Subcutaneous injections can result in injection-site reactions. To ease these reactions, apply pressure after administration of the injection and, if bruising occurs, apply an ice pack to the site of the injection.
  • Emicizumab-kxwh comes with a black-box warning for thrombotic microangiopathy and thrombotic events when used concomitantly with activated prothrombin complex concentrate (aPCC) doses of greater than 100 U/kg/24 hr.
    • Pharmacists can play a role in checking for administration of aPCC within the previous 24 hours before the administration of emicizumab-kxwh.
  • Genentech offers two options for financial assistance to help patients afford emicizumab-kxwh,

Clinical Pearls1-4

  • Emicizumab-kxwh is not expected to induce the new development of inhibitors or be affected by existing factor VIII inhibitors.
  • Unused vials should be stored in the refrigerator at a temperature of 2–8 °C and protected from light.
    • Unopened vials may be stored in or out of refrigeration at temperatures less than 30 °C for up to 7 days.
  • Emicizumab-kxwh can interfere with the activated clotting time, activated partial thromboplastin time, Bethesda assays for factor VIII inhibitor titers, and activated protein C resistance test.
  • Emicizumab-kxwh is indicated for patients with hemophilia A with high-titer inhibitors (5 Bethesda units or greater) and is not recommended for hemophilia A patients without inhibitors at this time.

References

  1. Emicizumab-kxwh. U.S. Food and Drug Administration: FDA News Release. November 16, 2017. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm585567.htm. Accessed January 21, 2018.
  2. Oldenburg J, Mahlangu JN, Kim B, et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med. 2017;377(9): 809-818
  3. U.S. National Library of Medicine. clinicaltrials.gov. A study of emicizumab administered subcutaneously in pediatric participants with hemophilia A and factor VIII inhibitors (HAVEN 2). June 10, 2016. https://clinicaltrials.gov/ct2/show/NCT02795767. Accessed January 21, 2018.
  4. Hemlibra (emicizumab-kxwh) [package insert]. San Francisco, CA: Genentech, Inc.; November 2017.
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