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Emapalumab-lzsg Injection

TABLE OF CONTENTS

1. DESCRIPTION 7. DRUG INTERACTIONS
2. INDICATIONS AND USAGE 8. USE IN SPECIFIC POPULATIONS
3. DOSAGE AND ADMINISTRATION 10. MECHANISM OF ACTION
4. CONTRAINDICATIONS 11. PHARMACODYNAMICS
5. WARNINGS AND PRECAUTIONS 12. PHARMACOKINETICS
6. ADVERSE REACTIONS 13. HOW SUPPLIED/STORAGE AND HANDLING

 

1. DESCRIPTION

Emapalumab-lzsg is an interferon gamma (IFNγ) blocking antibody. Emapalumab-lzsg is produced in Chinese Hamster Ovary cells by recombinant DNA technology. Emapalumab-lzsg is an IgG1 immunoglobulin with a molecular weight of approximately 148 kDa.

Emapalumab-lzsg injection for intravenous use is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly yellow solution provided in single-dose vials that require dilution prior to intravenous infusion.

Each vial contains 10 mg/2 mL or 50 mg/10 mL emapalumab-lzsg at a concentration of 5 mg/mL. Each mL also contains the following inactive ingredients: L-Histidine (1.55 mg), L-Histidine monohydrochloride, monohydrate (3.14 mg), Polysorbate 80 (0.05 mg), sodium chloride (7.30 mg), and Water for Injection, USP.

2. INDICATIONS AND USAGE

Emapalumab-lzsg is indicated for the treatment of adult and pediatric (newborn and older) patients with primary hemophagocytic lymphohistiocytosis (HLH) with refractory, recurrent or progressive disease or intolerance with conventional HLH therapy.

3. DOSAGE AND ADMINISTRATION

3.1 Recommended Dosing

The recommended starting dose of emapalumab-lzsg is 1 mg/kg given as an intravenous infusion over 1 hour twice per week (every three to four days). Doses subsequent to the initial dose may be increased based on clinical and laboratory criteria [see Dosage and Administration (3.4)].

Administer emapalumab-lzsg until hematopoietic stem cell transplantation (HSCT) is performed or unacceptable toxicity. Discontinue emapalumab-lzsg when a patient no longer requires therapy for the treatment of HLH.

3.2 Monitoring to Assess Safety

Before Initiating Emapalumab-lzsg Treatment

Conduct testing for latent tuberculosis infections using the purified protein derivative (PPD) or IFNγ release assay and evaluate patients for tuberculosis risk factors prior to initiating emapalumab-lzsg. Administer tuberculosis prophylaxis to patients at risk for tuberculosis, or known to have a positive PPD test result, or positive IFNγ release assay.

During Emapalumab-lzsg Treatment

Monitor for tuberculosis, adenovirus, EBV and CMV every 2 weeks and as clinically indicated.

3.3 Pre-Medications and Concomitant Medication Information

Pre-Medications

Administer prophylaxis for Herpes Zoster, Pneumocystis jirovecii, and for fungal infections prior to emapalumab-lzsg administration.

Concomitant Medications For patients who are not receiving baseline dexamethasone treatment, begin dexamethasone at a daily dose of at least 5 to 10 mg/m2 the day before emapalumab-lzsg treatment begins. For patients who were receiving baseline dexamethasone, they may continue their regular dose provided the dose is at least 5 mg/m2. Dexamethasone can be tapered according to the judgment of the treating physician [see Clinical Studies].

3.4 Dose Modification Based on Response

The emapalumab-lzsg dose may be titrated up if disease response is unsatisfactory (see Table 1) [see Clinical Pharmacology]. After the patient’s clinical condition is stabilized, decrease the dose to the previous level to maintain clinical response.

Table 1: Dose Titration Criteria

3.5 Instructions for Preparation and Administration

Preparation emapalumab-lzsg vials are for single-use only. Prepare the solution for infusion as follows:

• Calculate the dose (mg/kg), total volume (mL) of emapalumab-lzsg required and the number of emapalumab-lzsg vials needed based on patient actual body weight [see Dosage and Administration (3.1)].

• Inspect emapalumab-lzsg vials visually for particulate matter and discoloration prior to dilution. Emapalumab-lzsg is a clear to slightly opalescent, colorless to slightly yellow liquid. Do not administer if discolored or foreign particulate matter is present.

• Withdraw the necessary amount of emapalumab-lzsg solution and dilute with 0.9% Sodium Chloride Injection, USP to a maximum concentration of 2.5 mg/mL. Do not dilute product to less than 0.25 mg/mL.

• Discard any unused portion left in the vial(s).

• The diluted solution can be placed in either a syringe or an infusion bag, depending on the volume needed.

• Use a gamma irradiated latex-free, polyvinyl chloride (PVC)-free syringe. Do not use with ethylene oxide-sterilized syringes.

• Use a non-PVC polyolefin infusion bag.

Administration

• Administer emapalumab-lzsg diluted solution intravenously over 1 hour through an intravenous line containing a sterile, non-pyrogenic, low-protein binding 0.2 micron in-line filter.

• Do not infuse emapalumab-lzsg concomitantly with other agents and do not add any other product to the infusion bag or syringe.

• Do not store any unused portion of the infusion solution for reuse. Any unused product or waste material should be disposed of in accordance with local requirements.

Storage of Diluted Solution

This product does not contain a preservative.

If not administered immediately:

• Store the diluted solution of emapalumab-lzsg under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 4 hours from the time of dilution.

• If refrigerated, allow the diluted solution to come to room temperature prior to administration.

• Do not freeze. Do not shake.

4. CONTRAINDICATIONS

None.

5. WARNINGS AND PRECAUTIONS

5.1 Infections

Emapalumab-lzsg may increase the risk of fatal and serious infections to include specific pathogens favored by IFNγ neutralization, including mycobacteria, Herpes Zoster virus, and Histoplasma Capsulatum.

Do not administer emapalumab-lzsg in patients with infections caused by these pathogens until appropriate treatment has been initiated.

In 32% of patients receiving emapalumab-lzsg in clinical trials, serious infections such as sepsis, pneumonia, bacteremia, disseminated histoplasmosis, necrotizing fasciitis, viral infections, and perforated appendicitis were observed. The reported infections were viral (41%), bacterial (35%), fungal (9%), and the pathogen was not identified in 15% of cases.

Evaluate patients for tuberculosis risk factors and test for latent infection (PPD testing, PCR, or IFNγ release assay) prior to initiating emapalumab-lzsg. Administer tuberculosis prophylaxis to patients at risk for tuberculosis or known to have a positive purified protein derivative (PPD) test result [see Dosage and Administration (3.2)].

Administer prophylaxis for Herpes Zoster, Pneumocystis jirovecii, and fungal infection to mitigate the risk to patients while receiving emapalumab-lzsg. Employ surveillance testing during treatment with emapalumab-lzsg.

Closely monitor patients receiving emapalumab-lzsg for signs or symptoms of infection, promptly initiate a complete diagnostic workup appropriate for an immunocompromised patient, and initiate appropriate antimicrobial therapy.

5.2 Increased Risk of Infection with Use of Live Vaccines

Do not administer live or live attenuated vaccines to patients receiving emapalumab-lzsg and for at least 4 weeks after the last dose of emapalumab-lzsg. The safety of immunization with live vaccines during or following emapalumab-lzsg therapy has not been studied.

5.3 Infusion-Related Reactions

Infusion-related reactions including drug eruption, pyrexia, rash, erythema, and hyperhidrosis were reported with emapalumab-lzsg treatment in 27% of patients. In one-third of these patients, the infusion-related reaction occurred during the first infusion.

All infusion related reactions were reported as mild to moderate. Monitor patients for infusion-related reactions. Interrupt infusion for infusion reactions and institute appropriate medical management prior to continuing infusion at a slower rate.

6. ADVERSE REACTIONS

The following adverse reactions are described elsewhere in the labeling:

• Infections [see Warnings and Precautions (5.1)]

• Infusion-Related Reactions [see Warnings and Precautions (5.3)]

6.1 Clinical Trial 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 safety data described in this section reflect exposure to emapalumab-lzsg in which 34 patients with untreated primary HLH and previously treated patients with primary HLH (NCT01818492) received emapalumab-lzsg at a starting dose of 1 mg/kg every 3 days with dose increases up to 10 mg/kg [see Dosage and Administration (3.1) and Clinical Studies]. The median duration of treatment with emapalumab-lzsg was 59 days (range: 4 to 245 days) and the median cumulative dose was 25 mg/kg (range: 4 to 254 mg/kg).

The median age of study population was 1 year (range: 0.1 to 13 years), 53% were female, and 65% were Caucasian.

Serious adverse reactions were reported in 53% of patients. The most common serious adverse reactions (≥ 3%) included infections, gastrointestinal hemorrhage, and multiple organ dysfunction. Fatal adverse reactions occurred in two (6%) of patients and included septic shock and gastrointestinal hemorrhage.

Disseminated histoplasmosis led to drug discontinuation in one patient. The most commonly reported adverse reactions (≥ 20%) were infections, hypertension, infusion-related reactions, and pyrexia. Adverse reactions reported in ≥ 10% of patients during treatment with emapalumab-lzsg are presented in Table 2.

Table 2: Adverse Reactions Reported in ≥ 10% of Patients with Primary HLH

a Includes viral, bacterial, fungal, and infections in which no pathogen was identified

b Includes secondary hypertension

c Includes events of drug eruption, pyrexia, rash, erythema, and hyperhidrosis

Additional selected adverse reactions (all grades) that were reported in less than 10% of patients treated with emapalumab-lzsg included: vomiting, acute kidney injury, asthenia, bradycardia, dyspnea, gastro-intestinal hemorrhage, epistaxis, and peripheral edema.

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other emapalumab products may be misleading.

The immunogenicity of emapalumab-lzsg has been evaluated using an electrochemiluminescence-based immunoassay (ECLIA). A total of 64 subjects were evaluated for anti-therapeutic antibodies (ATAs) to emapalumab-lzsg after treatment with emapalumab-lzsg. ATAs were detected in 3/64 subjects (5%) who received emapalumab-lzsg.

Treatment-emergent ATAs were detected in 1/33 (3%) of patients in the primary HLH clinical trial. The ATAs in this patient were found to have neutralizing ability. One patient receiving emapalumab-lzsg through compassionate use developed transient non-neutralizing treatment-emergent ATAs. In both of these patients, ATAs occurred within the first 9 weeks following the initiation of emapalumab-lzsg treatment. In addition, one healthy subject tested positive for ATAs following a single dose of emapalumab-lzsg. No evidence of an altered safety or efficacy profile was identified in the primary HLH patients who developed antibodies to emapalumab-lzsg.

7. DRUG INTERACTIONS

7.1 Effect of Emapalumab-lzsg on Cytochrome P450 Substrates

The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (such as IFNγ) during chronic inflammation. By neutralizing IFNγ, use of emapalumab-lzsg may normalize CYP450 activities which may reduce the efficacy of drugs that are CYP450 substrates due to increased metabolism.

Upon initiation or discontinuation of concomitant emapalumab-lzsg, monitor for reduced efficacy and adjust dosage of CYP450 substrate drugs as appropriate.

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no available data on emapalumab-lzsg use in pregnant women to inform a drug-associated risk of adverse developmental outcomes. In an animal reproduction study, a murine surrogate anti-mouse IFNγ antibody administered to pregnant mice throughout gestation crossed the placental barrier, and no fetal harm was observed (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

In a mouse embryo-fetal development study, a murine surrogate anti-mouse IFNγ antibody was administered every 3-4 days throughout organogenesis and late gestation at doses of 0, 30, 75 or 150 mg/kg/occasion. The surrogate antibody was detected in the plasma of all treated pregnant mice and their corresponding fetuses. No maternal toxicity occurred and there was no evidence of teratogenicity or effects on embryo-fetal survival or growth.

8.2 Lactation

Risk Summary

There is no information regarding the presence of emapalumab-lzsg in human milk, the effects on the breastfed child, or the effects on milk production. Published data suggest that only limited amounts of therapeutic antibodies are found in breast milk and they do not enter the neonatal and infant circulations in substantial amounts.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for emapalumab-lzsg and any potential adverse effects on the breastfed child from emapalumab-lzsg or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness of emapalumab-lzsg have been established in pediatric patients, newborn and older, with primary HLH that is reactivated or refractory to conventional therapies. Use of emapalumab-lzsg is supported by a single-arm trial in 27 pediatric patients with reactivated or refractory primary HLH. This study included pediatric patients in the following age groups: 5 patients newborn to 6 months, 10 patients 6 months to 2 years, and 12 patients from 2 years to 13 years [see Clinical Studies].

8.5 Geriatric Use

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

10. MECHANISM OF ACTION

Emapalumab-lzsg is a monoclonal antibody that binds to and neutralizes interferon gamma (IFNγ). Nonclinical data suggest that IFNγ plays a pivotal role in the pathogenesis of HLH by being hypersecreted.

11. PHARMACODYNAMICS

IFNγ Inhibition

Emapalumab-lzsg reduces the plasma concentrations of CXCL9, a chemokine induced by IFNγ.

Cardiac Electrophysiology

At a dose of 3 mg/kg emapalumab-lzsg does not prolong the QT interval to any clinically relevant extent.

12. PHARMACOKINETICS

The pharmacokinetics of emapalumab-lzsg were evaluated in healthy adult subjects and in patients with primary HLH.

Following a 1 mg/kg emapalumab-lzsg dose, median steady state peak concentration was 44 mcg/mL, which was 2.9 times higher than after the first dose. The median steady state trough concentration was 25 mcg/mL, which was 4.3 times higher than after the first dose. Emapalumab-lzsg 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.

Emapalumab-lzsg exhibits target-mediated clearance dependent on IFNγ production, which can vary between and within patients as a function of time and can affect the recommended dosage [see Dosage and Administration (3.2)]. Emapalumab-lzsg steady state is achieved by the 7th infusion when the IFNγ production is moderate. At high IFNγ production, steady-state is reached earlier due to a shorter half-life.

Distribution

The central and peripheral volumes of distribution in a subject with body weight of 70 kg are 4.2 and 5.6 L, respectively.

Elimination

Emapalumab-lzsg elimination half-life is approximately 22 days in healthy subjects, and ranged from 2.5 to 18.9 days in HLH patients.

Emapalumab-lzsg clearance is approximately 0.007 L/h in healthy subjects.

In patients, the total clearance of emapalumab-lzsg was significantly influenced by the production of IFNγ, demonstrating target mediated clearance of emapalumab-lzsg.

Metabolism

The metabolic pathway of emapalumab-lzsg has not been characterized. Like other protein therapeutics, emapalumab-lzsg is expected to be degraded into small peptides and amino acids via catabolic pathways.

Specific Populations

Body weight (2 to 82 kg) was a significant covariate of emapalumab-lzsg pharmacokinetics, supporting body weight-based dosing.

No clinically significant differences in the pharmacokinetics of emapalumab-lzsg were observed based on age (0.02 to 56 year), sex (53% Females), race (71.4% Caucasian, 12.2% Asian and 8.2% Black), renal impairment including dialysis, or hepatic impairment (mild, moderate, and severe).

Drug Interaction Studies

No drug-drug interaction studies have been conducted with emapalumab-lzsg.

13. HOW SUPPLIED/STORAGE AND HANDLING

How Supplied:

GAMIFANT (emapalumab-lzsg) injection is a sterile, clear to slightly opalescent, colorless to slightly yellow solution supplied in the following packaging configuration:

NDC 72171-501-01 – containing one 10 mg/2 mL (5 mg/mL) single-dose vial

NDC 72171-505-01 – containing one 50 mg/10 mL (5 mg/mL) single-dose vial

Storage and Handling:

Store in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF) in original carton to protect from light. Do not freeze or shake. This product contains no preservative.

Rx only

Rev 11/18