Emapalumab-lzsg (Monograph)

Brand name: Gamifant
Drug class: Immunosuppressive Agents

Medically reviewed by Drugs.com on Feb 10, 2024. Written by ASHP.

Introduction

Immunosuppressive agent; interferon gamma (IFNγ) blocking antibody.

Uses for Emapalumab-lzsg

Primary Hemophagocytic Lymphohistiocytosis

Treatment of primary hemophagocytic lymphohistiocytosis (HLH) in adults and pediatric patients (newborn and older) with refractory, recurrent, or progressive disease or intolerance to conventional HLH therapy. Designated an orphan drug by FDA for this use.

A working group of the Histiocyte Society has published recommendations on the management of HLH. These experts state that emapalumab-lzsg may be a salvage option with better tolerability compared to etoposide; however, experience with emapalumab-lzsg in adults is limited.

Emapalumab-lzsg Dosage and Administration

General

Pretreatment Screening

Evaluate patients for tuberculosis risk factors and test for latent infection using purified protein derivative (PPD) testing, polymerase chain reaction (PCR), or interferon gamma (IFNγ) release assay prior to initiating emapalumab-lzsg.

Patient Monitoring

Monitor patients for tuberculosis, adenovirus, Epstein-Barr virus, and cytomegalovirus every 2 weeks and as clinically indicated during treatment with emapalumab-lzsg.
Closely monitor patients for signs or symptoms of infection throughout treatment with emapalumab-lzsg.
Monitor patients for infusion-related reactions; interrupt infusion when infusion reactions occur and institute appropriate medical management prior to continuing infusion at a slower rate.

Premedication and Prophylaxis

Administer tuberculosis prophylaxis to patients at risk for tuberculosis and patients with a positive PPD test or positive IFNγ release assay.
Administer prophylaxis for herpes zoster, Pneumocystis jirovecii, and fungal infections prior to administration of emapalumab-lzsg.
For patients who are not receiving dexamethasone treatment at baseline, begin dexamethasone at a dose of at least 5–10 mg/m² the day before emapalumab-lzsg treament begins; for patients receiving baseline dexamethasone, continue the regular dose as long as it is at least 5 mg/m².

Administration

IV Administration

Administer by IV infusion.

Commercially available as an injection concentrate that must be diluted prior to IV administration.

Calculate dose, total volume required, and number of vials of emapalumab-lzsg needed based on patient's actual body weight.

Emapalumab-lzsg injection is perservative-free; discard any unused portion in accordance with local requirements.

Dilution

Prior to dilution, inspect vials visually; do not administer if solution is discolored or if foreign particulate matter is present (solution should be clear to slightly opalescent and colorless to slightly yellow).

To prepare the diluted infusion solution, withdraw necessary amount of emapalumab-lzsg solution from the single-use vial and dilute with 0.9% sodium chloride injection, to a maximum concentration of 2.5 mg/mL. Do not dilute to a concentration <0.25 mg/mL.

Depending on the volume needed, the diluted solution can either be placed in a gamma irradiated, latex-free, PVC-free syringe or a non-PVC polyolefin infusion bag; do not use with ethylene oxide-sterilized syringes.

Use the diluted solution immediately after preparation or store under refrigeration at 2 to 8°C for no longer than 4 hours from the time of dilution; do not freeze or shake. If refrigerated, allow the diluted solution to come to room temperature prior to administration.

Rate of Administration

Administer diluted solution via IV infusion over 1 hour through an IV line containing a sterile, nonpyrogenic, low-protein binding 0.2 micron in-line filter.

Dosage

Pediatric Patients

Primary HLH

IV

Initial dose of 1 mg/kg administered by IV infusion over 1 hour every 3–4 days (twice weekly); administer until hematopoietic stem cell transplantation (HSCT) is performed or unacceptable toxicity occurs.

May titrate dose if unsatisfactory response.

Discontinue when therapy is no longer required to treat HLH.

For patients not receiving dexamethasone at baseline, begin dexamethasone at a daily dosage of at least 5–10 mg/m² the day before emapalumab-lzsg treatment begins. For patients receiving dexamethasone at baseline, continue regular dose as long as it is at least 5 mg/m². Dexamethasone may be tapered at the discretion of the treating physician.

Adults

Primary HLH

IV

Initial dose of 1 mg/kg administered by IV infusion over 1 hour every 3–4 days (twice weekly); administer until HSCT is performed or unacceptable toxicity occurs.

May titrate dose if unsatisfactory response.

Discontinue when therapy is no longer required to treat HLH.

Dosage Modification Based on Response

Dose may be increased in patients with unsatisfactory clinical improvement (as assessed by a healthcare provider) and at least 1 of the following:

Persistent or recurrent fever
Baseline platelet count <50,000/mm³ and no improvement to >50,000/mm³
Baseline platelet count >50,000/mm³ and <30% improvement
Baseline platelet count >100,000/mm³ and decrease to <100,000/mm³
Baseline neutrophil count <500/mm³ and no improvement to >500/mm³
Baseline neutrophil count >500–1000/mm³ and decrease to <500/mm³
Baseline neutrophil count 1000–1500/mm³ and decease to <1000/mm³
Baseline ferritin ≥3000 ng/mL and <20% decrease
Baseline ferritin <3000 ng/mL and any increase to >3000 ng/mL
Worsening splenomegaly
Coagulopathy (both D-dimer and fibrinogen must apply):
Abnormal D-dimer at baseline and no improvement
Baseline fibrinogen levels ≤100 mg/dL and no improvement
Baseline fibrinogen levels >100 mg/dL and any decrease to <100 mg/dL

If the dose titration criteria is met, dose may be increased on day 3 to 3 mg/kg. If unsatisfactory improvement in clinical condition on emapalumab-lzsg 3 mg/kg, increase dose to 6 mg/kg from day 6 onwards. If unsatisfactory improvement in clinical condition on emapalumab-lzsg 6 mg/kg and healthcare provider determines a further dose increase may benefit the patient, increase dose to 10 mg/kg from day 9 onwards. Once clinical condition is stabilized, decrease dose to previous level to maintain clinical response.

Special Populations

Hepatic Impairment

No specific dosage recommendations.

Renal Impairment

No specific dosage recommendations.

Geriatric Patients

No specific dosage recommendations.

Cautions for Emapalumab-lzsg

Contraindications

None.

Warnings/Precautions

Infections

Increased risk of serious, sometimes fatal infections from pathogens favored by neutralization of iIFNγ, including mycobacteria, herpes zoster, and Histoplasma Capsulatum.

Do not administer emapalumab-lzsg in patients with infections caused by mycobacteria, herpes zoster, or Histoplasma Capsulatum until after initiation of appropriate treatment.

Evaluate patients for tuberculosis risk factors and test for latent infection prior to starting emapalumab-lzsg; administer tuberculosis prophylaxis to patients at risk for tuberculosis and patients with a positive PPD test result or positive IFNγ release assay.

Administer prophylaxis for herpes zoster, Pneumocystis jirovecii, and fungal infections; employ surveillance testing.

Closely monitor patients for signs or symptoms of infection; if any infections occur, promptly initiate complete diagnostic workup appropriate for an immunocompromised patient and initiate antimicrobial therapy.

Increased Risk of Infection with Use of Live Vaccine

Safety of immunization with live vaccines during or following treatment with emapalumab-lzsg not studied.

Do not administer live or live attenuated vaccines during emapalumab-lzsg treatment or for at least 4 weeks after discontinuation.

Infusion-Related Reactions

Mild to moderate infusion-related reactions, including drug eruption, pyrexia, rash, erythema, and hyperhidrosis, occur.

Monitor patients for infusion-related reactions; if such reactions occur, interrupt infusion, institute appropriate medical management, and reinitate infusion at a slower rate.

Immunogenicity

Potential for immunogenicity. Anti-therapeutic antibodies detected within the first 9 weeks following treatment initiation. No evidence of altered safety or efficacy identified in patients who developed antibodies to emapalumab-lzsg.

Specific Populations

Pregnancy

No data available to inform a drug-associated risk of adverse developmental outcomes with use in pregnancy. No fetal harm observed in animal studies.

Lactation

Not known whether emapalumab-lzsg is distributed into human milk. Effects on breast-fed infants and on milk production also unknown.

Consider developmental and health benefits of breast-feeding, mother's clinical need for emapalumab-lzsg, and potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.

Pediatric Use

Safety and effectiveness of emapalumab-lzsg established in pediatric patients.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.

Hepatic Impairment

Hepatic impairment not expected to substantially affect pharmacokinetics.

Renal Impairment

Renal impairment not expected to substantially affect pharmacokinetics.

Common Adverse Effects

Adverse effects (≥20%): infections, hypertension, infusion-related reactions, pyrexia.

Drug Interactions

No formal drug-drug interaction studies conducted.

Drugs Affecting or Affected by Hepatic Microsomal Enzymes

In patients with chronic inflammation, formation of CYP enzymes may be suppressed by increased levels of cytokines such as IFNγ. Emapalumab's neutralizing effect on IFNγ may normalize CYP activities, thus reducing efficacy of CYP substrates via increased metabolism.

Monitor for reduced efficacy of CYP substrate drugs upon initiation and discontinuation of concomitant emapalumab-lzsg; adjust dosage as necessary.

Emapalumab-lzsg Pharmacokinetics

Absorption

Bioavailability

AUC increases slightly more than proportionally between 1 and 3 mg/kg doses, and less than proportionally at 3, 6, and 10 mg/kg doses.

Exhibits target-mediated clearance dependent on production of IFNγ; clearance varies between and within patients as a function of time and affects recommended dosage and time to steady state.

Steady-state is reached earlier at times of high IFNγ production and by the seventh infusion when IFNγ production is moderate.

Distribution

Extent

Only limited amounts of therapeutic antibodies expected in breast milk; therapeutic antibodies do not enter the neonatal/infant circulation in substantial amounts.

Elimination

Metabolism

Metabolic pathway not characterized; expected to be degraded into small peptides and amino acids via catabolic pathways.

Elimination Route

Exhibits target-mediated clearance dependent on production of IFNγ; clearance varies between and within patients as a function of time.

Half-life

Healthy subjects: 22 days

Patients with HLH: 2.5–18.9 days

Special Populations

Body weight (2–82 kg) is a significant covariate affecting pharmacokinetics.

No significant difference in pharmacokinetics observed based on age, sex, race, renal impairment including dialysis, or hepatic impairment.

Stability

Storage

Parenteral

Injection concentrate

Store unopened vials under refrigeration at 2–8°C in the original carton to protect from light; do not freeze or shake.

Use diluted solution immediately after preparation. If not used immediately, store diluted solution between 2–8°C for ≤4 hours from time of dilution. Do not freeze or shake.

Actions

Fully human recombinant IgG monoclonal antibody.
Binds to and neutralizes IFNγ, an inflammatory cytokine produced by T-cells and natural killer cells.
Hemophagocytic lymphohistiocytosis (HLH) is caused by excessive IFNγ and overactivation of lymphocytes and macrophages.

Advice to Patients

Inform patients and their caregivers of the risk of developing infections during treatment with emapalumab-lzsg, and to report any symptoms of infection.
Advise patients and their caregivers that the patient should not receive live or live attenuated vaccines during emapalumab-lzsg treatment.
Advise patients and their caregivers of the potential for developing infusion-related reactions during treatment with emapalumab-lzsg.
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.