Emapalumab-Lzsg

1 INDICATIONS AND USAGE GAMIFANT 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. adult and pediatric ( newborn and older) patients with HLH/macrophage activation syndrome (MAS) in known or suspected Still’s disease, including systemic Juvenile Idiopathic Arthritis (sJIA), with an inadequate response or intolerance to glucocorticoids, or with recurrent MAS. GAMIFANT is an interferon gamma (IFNγ) neutralizing antibody 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. ( 1 ) adult and pediatric (newborn and older) patients with HLH/macrophage activation syndrome (MAS) in known or suspected Still’s disease, including systemic Juvenile Idiopathic Arthritis (sJIA), with an inadequate response or intolerance to glucocorticoids, or with recurrent MAS. ( 1 )

2 DOSAGE AND ADMINISTRATION For intravenous infusion only: Primary HLH recommended starting dosage: 1 mg/kg as an intravenous infusion over 1 hour twice per week. ( 2.1 ) HLH/MAS in Still’s disease recommended starting dose: 6 mg/kg, followed by 3 mg/kg every 3 days for 5 doses, then 3 mg/kg twice per week. Given as an intravenous infusion over 1 hour. ( 2.2 ) For both indications, the dose may be titrated up to a maximum of 10 mg/kg. ( 2.5 , 2.6 ) 2.1 Recommended Dosage for Primary Hemophagocytic Lymphohistiocytosis The recommended starting dose of GAMIFANT is 1 mg/kg given as a central or peripheral 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 ( 2.5 )] . Administer GAMIFANT until hematopoietic stem cell transplantation (HSCT) is performed or unacceptable toxicity. Discontinue GAMIFANT when a patient no longer requires therapy for the treatment of HLH. 2.2 Recommended Dosage for Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome GAMIFANT is administered as a central or peripheral intravenous infusion over 1 hour according to the dosage schedule in Table 1. Doses may be increased based on clinical and laboratory criteria [see Dosage and Administration ( 2.6 )] . Discontinue GAMIFANT when a patient no longer requires therapy for the treatment of HLH/MAS. Table 1. GAMIFANT Dosage in Patients with HLH/MAS Treatment Day GAMIFANT Dosage Day 1 6 mg/kg Days 4 to 16 3 mg/kg every 3 days for 5 doses From Day 19 onward 3 mg/kg twice per week (i.e., every 3 to 4 days) 2.3 Monitoring to Assess Safety Before Initiating GAMIFANT 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 GAMIFANT. Administer tuberculosis prophylaxis to patients at risk for tuberculosis, or known to have a positive PPD test result, or positive IFNγ release assay. During GAMIFANT Treatment Monitor for Herpes Zoster infection, adenovirus, EBV and CMV as clinically indicated. 2.4 Prophylaxis and Concomitant Medication Information Prophylaxis Consider prophylaxis for Herpes Zoster, Pneumocystis jirovecii , and for fungal infections prior to GAMIFANT administration. Concomitant Medications For primary HLH patients who are not receiving baseline dexamethasone treatment, begin dexamethasone at a daily dose of at least 5 mg/m 2 to 10 mg/m 2 the day before GAMIFANT 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 ( 14 )]. 2.5 Dose Modification Based on Response for Primary Hemophagocytic Lymphohistiocytosis The GAMIFANT dose may be titrated up if disease response is unsatisfactory (see Table 2) [see Clinical Pharmacology ( 12.3 )] . After the patient's clinical condition is stabilized, decrease the dose to the previous level to maintain clinical response. Table 2: Dose Titration Criteria Treatment Day GAMIFANT Dose Criteria for Dose Increase Day 1 Starting Dose of 1 mg/kg N/A From Day 4 onwards Increase to 3 mg/kg Unsatisfactory improvement in clinical condition, as assessed by a healthcare provider AND at least one of the following: Fever - persistence or recurrence Platelet count If baseline < 50,000/mm 3 and no improvement to > 50,000/mm 3 If baseline > 50,000/mm 3 and less than 30% improvement If baseline > 100,000/mm 3 and decrease to < 100,000/mm 3 Neutrophil count If baseline < 500/mm 3 and no improvement to > 500/mm 3 If baseline > 500/mm 3 to 1,000/mm 3 and decrease to < 500/mm 3 If baseline 1,000/mm 3 to 1,500/mm 3 and decrease to < 1,000/mm 3 Ferritin (ng/mL) If baseline ≥3,000 ng/mL and < 20% decrease If baseline < 3,000 ng/mL and any increase to > 3,000 ng/mL Splenomegaly - any worsening Coagulopathy (both D-Dimer and Fibrinogen must apply) D-Dimer If abnormal at baseline and no improvement Fibrinogen (mg/dL) If baseline levels ≤100 mg/dL and no improvement If baseline levels > 100 mg/dL and any decrease to < 100 mg/dL From Day 7 onwards Increase to 6 mg/kg From Day 10 onwards Increase to 10 mg/kg Assessment by a healthcare provider that based on initial signs of response, a further increase in GAMIFANT dose can be of benefit 2.6 Dose Modification Based on Response for Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome Table 3: Dosage Adjustment Criteria Treatment Day GAMIFANT Dose Dose Adjustments Day 1 Initial dose of 6 mg/kg If unsatisfactory improvement in clinical condition, as assessed by a healthcare provider, the dose of GAMIFANT may be increased to: a maximum cumulative dose of 10 mg/kg over 3 days AND the frequency may be increased to: every 2 days or once daily After the patient’s clinical condition has improved, consider decreasing the dose to the previous level and assess whether clinical response is maintained. If the clinical condition is not stabilized while receiving the maximum dosage, consider discontinuing GAMIFANT. Days 4 to 16 3 mg/kg every 3 days for 5 doses From Day 19 onwards 3 mg/kg twice per week (i.e., every 3 to 4 days) 2.7 Instructions for Preparation and Administration Preparation GAMIFANT vials are for single dose only. Do not mix GAMIFANT 5 mg/mL and 25 mg/mL vials together. Prepare the solution for infusion as follows: Calculate the dose (mg/kg), total volume (mL) of GAMIFANT required and the number of GAMIFANT vials needed based on patient actual body weight [see Dosage and Administration ( 2.1 )] . Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. GAMIFANT 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 GAMIFANT solution and dilute with 0.9% Sodium Chloride Injection, USP. For GAMIFANT 5 mg/mL vials: Dilute to a maximum concentration of 2.5 mg/mL. Do not dilute product to less than 0.25 mg/mL. The diluted solution can be placed in either a syringe or an infusion bag, depending on the volume needed. When using a syringe, use a gamma irradiated or ethylene oxide sterilized latex-free, polyvinyl chloride (PVC)-free syringe. When using an infusion bag, use a non-PVC polyolefin infusion bag. For GAMIFANT 25 mg/mL vials: Dilute to a maximum concentration of 12.5 mg/mL. Do not dilute product to less than 1.25 mg/mL. Use a non-PVC polyolefin infusion bag made from either polyethylene or ethylene/propylene copolymer. Discard any unused portion left in the vial(s). Administration Administer GAMIFANT diluted solution intravenously over 1 hour through a central or peripheral intravenous line containing a sterile, non-pyrogenic, low-protein binding 0.2 micron in-line filter. Do not infuse GAMIFANT 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 GAMIFANT 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.

6 ADVERSE REACTIONS The following adverse reactions are described elsewhere in the labeling: Infections [see Warnings and Precautions ( 5.1 )] Increased Risk of Infection with Use of Live Vaccines [see Warnings and Precautions ( 5.2 )] Infusion-Related Reactions [see Warnings and Precautions ( 5.3 )] In patients with primary HLH, the most common adverse reactions (≥ 20%) were: infections, hypertension, infusion-related reactions, and pyrexia. ( 6.1 ) In patients with HLH/MAS in Still’s disease, the most common adverse reactions (≥20%) were:viral infections, including cytomegalovirus infection or reactivation, and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact 1-866-773-5274 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. Primary HLH The safety data described in this section reflect exposure to GAMIFANT in which 34 patients with untreated primary HLH and previously treated patients with primary HLH ( NCT01818492 ) received GAMIFANT at a starting dose of 1 mg/kg every 3 days with dose increases up to 10 mg/kg [see Dosage and Administration ( 2.1 ) and Clinical Studies ( 14 )] . The median duration of treatment with GAMIFANT 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 GAMIFANT are presented in Table 4. Table 4 : Adverse Reactions Reported in 10% of Patients with Primary HLH Adverse Reactions GAMIFANT (%) (N = 34) Infections a 56 Hypertension b 41 Infusion-related reactions c 27 Pyrexia 24 Hypokalemia 15 Constipation 15 Rash 12 Abdominal pain 12 Cytomegalovirus infection 12 Diarrhea 12 Lymphocytosis 12 Cough 12 Irritability 12 Tachycardia 12 Tachypnea 12 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 GAMIFANT included: vomiting, acute kidney injury, asthenia, bradycardia, dyspnea, gastro-intestinal hemorrhage, epistaxis, and peripheral edema. HLH/MAS The safety of GAMIFANT was evaluated in two open-label clinical studies in patients with HLH/MAS in Stills disease, including sJIA [see Clinical Studies ( 14.2 )] . The pooled safety data from these two studies included 39 patients who received an initial dose of 6 mg/kg followed by 3 mg/kg every 3 days until Day 16, and then twice weekly thereafter. The median duration of treatment with GAMIFANT was 29 days (range: 7 to 220 days) and the median cumulative dose was 33 mg/kg (range: 12 to 175 mg/kg). Serious adverse reactions were reported in 12 patients (31%), with the most common serious adverse reaction being pneumonia (5%). Fatal adverse reactions occurred in two patients (5%) and included multiple organ dysfunction and circulatory shock. Pneumonia led to drug discontinuation in one patient (3%). The most common adverse reactions (≥20%) were viral infections, including cytomegalovirus infection or reactivation, and rash. Adverse reactions reported in ≥ 10% of patients in the pooled safety analysis up to Week 8 during treatment with GAMIFANT are presented in Table 5. Table 5: Adverse Reactions Reported in ≥10% of Patients with HLH/MAS in Stills disease Adverse Reactions GAMIFANT (%) (N = 39) Viral infection a Cytomegalovirus infection or reactivation 44 36 Rash b 21 Anemia c 18 Leukopenia d 15 Thrombosis 15 Bacterial infection 13 Headache 13 Hyperglycemia 13 Infusion-related reactions e 13 Abdominal pain 10 Hypertension 10 Pyrexia 10 Thrombocytopenia 10 a Includes: Cytomegalovirus infection reactivation, Cytomegalovirus infection, Adenovirus test positive, Cytomegalovirus test positive, BK polyomavirus test positive, Respirovirus test positive, Parainfluenzae virus infection, COVID-19, Rhinovirus infection, gastroenteritis Rotavirus, Adenovirus infection, Human herpesvirus 6 infection reactivation, Adenovirus reactivation b Includes: rash maculo-papular, rash erythematous, rash pruritic, urticaria c Includes: anemia macrocytic, and hypochromic anemia d Includes: granulocytopenia, neutropenia e Infusion-related reactions were defined as any event reported to have occurred within 24 hours after the start of infusion and assessed as related to study treatment

12.3 Pharmacokinetics The pharmacokinetics of emapalumab-lzsg were evaluated in healthy adult subjects and in patients with 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-like 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 ( 2.2 )] . 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 2.8 and 4.4 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. In patients with HLH, the elimination half-life of emapalumab-lzsg was significantly influenced by the amount of IFNγ within the patient, demonstrating a target mediated clearance-like mechanism. The elimination half-life of emapalumab-lzsg is reduced as the concentration of IFNγ increases. Emapalumab-lzsg clearance is approximately 0.007 L/h in healthy subjects. Metabolism The metabolic pathway of emapalumab-lzsg has not been characterized. Like other protein therapeutics, GAMIFANT is expected to be degraded into small peptides and amino acids via catabolic pathways. Specific Populations Body weight (3 to 80 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 64 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 GAMIFANT.