SIZE XSSIZE SMSIZE MDSIZE LG

The following information helps you to find FDA Alerts and Pharmacist’s Applications to Practice quickly and easily. In cooperation with the Food and Drug Administration (FDA), and as a service to our members, HOPA periodically distributes information about newly approved therapies for cancer patients from FDA’s Office of Oncology Drug Products Director, Dr. Richard Pazdur to inform oncologists and professionals in oncology-related fields in a timely manner. Links to product labels will take you to relevant clinical information on the indication, contraindications, dosing, and safety. In sending this information, HOPA does not endorse any product or therapy and does not take any position on the safety or efficacy of the product or therapy described.

Along with HOPA’s Publications Committee, members also review new drug updates and provide analysis and research on the application of these new drugs or indications. Pharmacist’s Applications to Practice, or PAP, are listed after drugs that include the additional analysis. If you are interested in helping the Publications Committee with creating a Pharmacist's Application to Practice, please contact Jeff Price at jprice@hoparx.org.

You can also find additional information on FDA Alerts and Updates by listening to FDA Drug Safety Podcasts.

November 20, 2018, with PAP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761107lbl.pdf

On November 20, 2018, the Food and Drug Administration approved emapalumab (GAMIFANT, Novimmune SA), a monoclonal antibody that binds and neutralizes interferon gamma, for adult and pediatric (newborn and older) patients with primary hemophagocytic lymphohistiocytosis (HLH) with refractory, recurrent or progressive disease or intolerance with conventional HLH therapy.

Approval was based on a multicenter, open-label, single-arm trial NI-0501-04 (NCT01818492) in 27 pediatric patients with suspected or confirmed primary HLH with either refractory, recurrent, or progressive disease during conventional HLH therapy or who were intolerant of conventional HLH therapy. All patients received an initial starting emapalumab dose of 1 mg/kg every 3 days. All patients received dexamethasone as background HLH treatment with doses between 5 to 10 mg/m2/day. Patients received prophylaxis for Herpes Zoster, Pneumocystis jirovecii, and fungal infections prior to emapalumab administration.

The overall response rate at the end of treatment, defined as achievement of either a complete or partial response or HLH improvement, was 63% (95% CI: 0.42, 0.81; p=0.013). There were 7 complete and 8 partial responses, and 2 patients had HLH improvement, defined as ≥ 3 HLH abnormalities improved by at least 50% from baseline.

The most common adverse reactions occurring in ≥ 20% of patients were infections, hypertension, infusion-related reactions, and pyrexia.

The recommended starting emapalumab dose is 1 mg/kg as an intravenous infusion over 1 hour twice per week. Doses subsequent to the initial dose may be increased based on clinical and laboratory criteria.

View full prescribing information for GAMIFANT.

FDA granted this application priority review. FDA expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

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

Emapalumab-lzsg for Treatment of Adult and Pediatric Patients with Primary Hemophagocytic Lymphohistiocytosis with Refractory, Recurrent, or Progressive Disease or Intolerance with Conventional Therapy

Author: Kaley Hughes, PharmD
PGY2 Oncology Pharmacy Resident
Norton Children’s Hospital
Louisville, KY

What is the potential role for emapalumab-lzsg in the treatment of hemophagocytic lymphohistiocytosis (HLH)?

  • Emapalumab-lzsg is an interferon gamma (IFNγ)–blocking antibody indicated for the treatment of adult and pediatric patients who have primary HLH with refractory, recurrent, or progressive disease or intolerance to conventional HLH therapy.1 Emapalumab is the first treatment to be approved by the U.S. Food and Drug Administration (FDA) for primary HLH.2
  • The initial treatment for primary HLH generally consists of immunosuppressive and chemotherapeutic agents, such as dexamethasone and etoposide, with or without cyclosporine.3-5 For patients with familial, persistent, or recurrent disease, the aim of therapy is often clinical remission, with 8 weeks of initial therapy followed by continuation therapy until hematopoietic stem cell transplant (HSCT), because this remains the only curative treatment to date.5,6
  • Patients who develop reactivation may respond to intensification of initial therapy. However, no standard of care has been established for patients with refractory, recurrent, or progressive disease requiring salvage therapy.3,5 Examples of salvage therapy include the following:
    • Alemtuzumab is a therapeutic monoclonal antibody directed against CD52, which is expressed on lymphocytes such as T cells, natural killer cells, and B cells. In a retrospective review of 22 pediatric and adult patients receiving alemtuzumab for refractory HLH, 14 patients had an overall partial response, defined as at least a 25% improvement in two or more symptoms or laboratory markers of HLH. Alemtuzumab is associated with infectious complications, and procurement does not follow standard distribution practices, making obtainment difficult.7
    • Success with infliximab, a chimeric monoclonal antibody against tumor necrosis factor (TNF) alpha, or etanercept, a TNF inhibitor, in treating refractory HLH is limited to case report experiences.8,9
  • The safety, tolerability, and efficacy of emapalumab-lzsg in controlling disease activity in patients with primary HLH was assessed in an open-label single-arm multicenter phase 2/3 study. The study included patients 18 years of age or younger with a diagnosis of primary HLH who were treatment-naïve or had failed previous conventional therapy. The treatment intervention included emapalumab-lzsg starting at 1 mg/kg intravenously every 3–4 days in addition to dexamethasone 5–10 mg/m2/day. Subsequent emapalumab-lzsg doses could be increased incrementally up to a maximum of 10 mg/kg on the basis of the evolution of clinical and laboratory response parameters. The primary efficacy endpoint was overall response at the end of treatment, defined as normalization, or at least 50% improvement from baseline factors such as fever, splenomegaly, cytopenias, and/or central nervous system abnormalities. In all patients treated (N = 34) and in the subset of patients failing conventional therapy (n = 27), the overall response rates were 64.7% (95% confidence interval [CI]: 46%–80%) and 63% (95% CI: 42%–81%), respectively.10

What role can the pharmacist play in the management of patients on emapalumab-lzsg?

  • The recommended initial dose of emapalumab-lzsg is 1 mg/kg intravenously twice a week, or every 3–4 days. Subsequent doses may be increased on the basis of clinical and laboratory criteria to a maximum of 10 mg/kg/dose.
    • Criteria for dose increases include the following1:
      • Persistent or recurrent fever
      • Platelet count
        • Baseline of <50,000/mm3 and no improvement to >50,000/mm3
          or
        • Baseline of >50,000/mm3 and less than 30% improvement
          or
        • Baseline of >100,000/mm3 and decrease to <100,000/mm3
      • Neutrophil count
        • Baseline of <500/mm3 and no improvement to >500/mm3
          or
        • Baseline of >500–1,000/mm3 and decrease to <500/mm3
          or
        • Baseline of 1,000–1,500/mm3 and decrease to <1,000/mm3
      • Ferritin
        • Baseline is greater than or equal to 3,000 ng/mL and <20% decrease
          or
        • Baseline <3,000 ng/mL and any increase to >3,000 ng/mL
      • Worsening splenomegaly
      • D-dimer abnormal at baseline with no improvement and fibrinogen abnormalities
        • Fibrinogen baseline is less than or equal to 100 mg/dL and no improvement
          or
        • Fibrinogen >100 mg/dL and any decrease to <100 mg/dL)
    • The recommended dose increases if the criteria above apply are based on the treatment day:
      • On day 3, increase to 3 mg/kg .
      • From day 6 onward, increase to 6 mg/kg.
      • From day 9 onward, increase to 10 mg/kg.
  • No dosage adjustments are provided for renal or hepatic impairment. The trial that led to FDA approval of emapalumab-lzsg excluded patients with concomitant disease or malformation severely affecting the cardiovascular, pulmonary, liver, or renal function.10
  • No drug-drug interaction studies have been conducted with emapalumab-lzsg.1
  • The most prevalent adverse events reported were infections (56%), hypertension (41%), infusion-related reactions (27%), and pyrexia (24%).10,11 Emapalumab-lzsg is an immunosuppressant; thus patients who are initiating therapy should be started on prophylaxis for herpes zoster, Pneumocystis jirovecci, and fungal infections per institutional standards. For patients with infusion-related reactions, the infusion should be interrupted and continued at a slower rate after instituting appropriate medical management.1
  • Serious adverse reactions were reported in 53% of patients and most commonly included infections, gastrointestinal hemorrhage, and multiple organ dysfunction. Other adverse reactions (though they occurred less frequently) included acute kidney injury, asthenia, bradycardia, and peripheral edema. Discontinuation of therapy may be warranted, depending on the serious adverse reaction.1
  • Monitor for clinical improvement on the basis of platelet counts, neutrophil counts, ferritin, D-dimer and fibrinogen, fever, and signs and symptoms of splenomegaly.
  • Monitor for signs and symptoms of infection. Specifically, test for tuberculosis prior to initiating therapy with emapalumab-lzsg, and monitor for adenovirus, Epstein-Barr virus, and cytomegalovirus every 2 weeks during therapy. Monitor for infusion-related reactions while administering emapalumab-lzsg, and check blood pressure periodically during the therapy.

Clinical Pearls

  • Emapalumab-lzsg is supplied as a single-dose vial as either 10 mg/2 mL or 50 mg/10 mL (5 mg/mL) and should be stored under refrigeration. When one is preparing this medication, it should be diluted with 0.9% sodium chloride injection to a concentration between 0.25 mg/mL and 2.5 mg/mL.
  • Emapalumab-lzsg should be dispensed in either a gamma-irradiated, latex-free, polyvinyl chloride (PVC)–free syringe or a non-PVC polyolefin infusion bag. Administer emapalumab-lzsg over 1 hour with a low-protein-binding 0.2 micron in-line filter.1
  • Once diluted, emapalumab-lzsg should be administered immediately or may be stored under refrigeration for up to 4 hours.1
  • Dose adjustments may be made on the basis of clinical or laboratory assessments, which include fever, platelet count, neutrophil count, ferritin, splenomegaly, and/or coagulopathy.1
  • Serious infections have been reported with emapalumab-Lzsg. Patients should be evaluated for tuberculosis and started on adequate antimicrobial prophylaxis prior to initiation of therapy. Avoid live vaccines during therapy and for at least 4 weeks after the last dose of emapalumab-lzsg.1
  • In the pivotal trial leading to FDA approval, treatment duration was typically 8 weeks, with possible extension up to the time of allogeneic HSCT, if needed.1,10
  • Pharmacists should monitor clinical and laboratory parameters with the healthcare team to help identify criteria that may warrant a dose adjustment. Careful monitoring will help optimize the safety and efficacy of emapalumab-lzsg therapy and will help with estimating appropriate drug inventory.
  • Published data are currently limited to pediatric patients with primary HLH, and the majority of patients had previously treated disease. The role of emapalumab-lzsg in upfront therapy is less clear.1,10
  • In addition to studies of primary HLH, ongoing clinical trials are evaluating the role of emapalumab-lzsg in treating patients with systemic juvenile idiopathic arthritis who develop macrophage activation syndrome or secondary HLH. Pharmacists should be aware of other indications under investigation in order to play an active role in the expanded use of emapalumab-lzsg.
  • Emapalumab-lzsg is available through either the manufacturer’s specialty pharmacy or two specialty distributors, though the patient’s insurance coverage may dictate how this medication should be procured.12

References

  1. Gamifant (emapalumab-lzsg) [package insert]. Geneva, Switzerland: Novimmune SA; 2018.
  2. FDA approves Gamifant® (emapalumab), the first and only treatment for primary haemophagocytic lymphohistiocytosis (HLH). Available at https://www.novimmune.com/en/swiss-biopharmaceutical-company/news/2018/fda-approves-gamifantreg-emapalumab-first-and-only-treatment-primary-haemophagocytic-lymphohistiocytosis-hlh.html. Accessed January 31, 2019.
  3. Henter JI, Horne A, Arico M, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48:124-131.
  4. Marsh RA, Haddad E. How I treat primary haemophagocytic lymphohistiocytosis. Br J Haematol. 2018;182:185-199.
  5. Ramachandran S, Zaidi F, Aggarwal A, Gera R. Recent advances in diagnostic and therapeutic guidelines for primary and secondary hemophagocytic lymphohistiocytosis. Blood Cells Mol Dis. 2017;64:53-57.
  6. Trottestam H, Horne A, Arico M, et al. Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol. Blood. 2011;118:4577-4584.
  7. Marsh RA, Allen CE, McClain KL, et al. Salvage therapy of refractory hemophagocytic lymphohistiocytosis with alemtuzumab. Pediatr Blood Cancer. 2013;60:101-109.
  8. Henzan T, Nagafuji K, Tsukamoto H, et al. Success with infliximab in treating refractory hemophagocytic lymphohistiocytosis. Am J Hematol. 2006;81:59-61.
  9. Takahashi N, Naniwa T, Banno S. Successful use of etanercept in the treatment of acute lupus hemophagocytic syndrome. Mod Rheumatol. 2008;18:72-75.
  10. Locatelli F, Jordan MB, Allen CE, et al. Safety and efficacy of emapalumab in pediatric patients with primary hemophagocytic lymphohistiocytosis. Blood. 2018;132:LBA6.
  11. Al-Salama ZT. Emapalumab: first global approval. Drugs. 2019;79:99-103.
  12. Gamifant (emapalumab-lzsg). Gamifant website. Available at https://gamifant.com. Accessed February 6, 2019.
xs
sm
md
lg