HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. GAMIFANT (emapalumab-lzsg) injection is sterile, clear to slightly opalescent, colorless to slightly yellow solution supplied in the following packaging configuration:NDC 66658-501-01 containing one 10 mg/2 mL (5 mg/mL) single-dose vialNDC 66658-505-01 containing one 50 mg/10 mL (5 mg/mL) single-dose vialNDC 66658-510-01 containing one 100 mg/20 mL (5 mg/mL) single-dose vialNDC 66658-522-01 containing one 50 mg/2 mL (25 mg/mL) single-dose vialNDC 66658-523-01 containing one 100 mg/4 mL (25 mg/mL) single-dose vialNDC 66658-524-01 containing one 250 mg/10 mL (25 mg/mL) single-dose vialNDC 66658-525-01 containing one 500 mg/20 mL (25 mg/mL) single-dose vialStore GAMIFANT in 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.

ADVERSE REACTIONS SECTION.

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)] 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 Stills 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 drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Primary HLHThe 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 starting dose of mg/kg every 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: to 245 days) and the median cumulative dose was 25 mg/kg (range: to 254 mg/kg).The median age of study population was 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 HLHAdverse ReactionsGAMIFANT(%)(N 34)Infectionsa 56Hypertensionb 41Infusion-related reactionsc 27Pyrexia 24Hypokalemia 15Constipation 15Rash 12Abdominal pain 12Cytomegalovirus infection 12Diarrhea 12Lymphocytosis 12Cough 12Irritability 12Tachycardia 12Tachypnea 12aIncludes viral, bacterial, fungal, and infections in which no pathogen was identifiedbIncludes secondary hypertensioncIncludes events of drug eruption, pyrexia, rash, erythema, and hyperhidrosisAdditional 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/MASThe 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 mg/kg followed by mg/kg every days until Day 16, and then twice weekly thereafter. The median duration of treatment with GAMIFANT was 29 days (range: 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 during treatment with GAMIFANT are presented in Table 5.Table 5: Adverse Reactions Reported in >=10% of Patients with HLH/MAS in Stills diseaseAdverse ReactionsGAMIFANT(%)(N 39)Viral infectiona Cytomegalovirus infection or reactivation 44 36Rashb 21Anemiac 18Leukopeniad 15Thrombosis 15Bacterial infection 13Headache 13Hyperglycemia 13Infusion-related reactionse 13Abdominal pain 10Hypertension 10Pyrexia 10Thrombocytopenia 10aIncludes: 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 infection reactivation, Adenovirus reactivationbIncludes: rash maculo-papular, rash erythematous, rash pruritic, urticariacIncludes: anemia macrocytic, and hypochromic anemia dIncludes: granulocytopenia, neutropeniaeInfusion-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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No carcinogenicity or genotoxicity studies have been conducted with emapalumab-lzsg.No studies have been conducted to evaluate the effects of emapalumab-lzsg on fertility; however, no adverse effects on male or female reproductive organs were observed in the 8- or 13-week repeat-dose toxicity studies in cynomolgus monkeys.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Emapalumab-lzsg is monoclonal antibody that binds to and neutralizes interferon gamma (IFN). Nonclinical data suggest that IFN plays pivotal role in the pathogenesis of HLH by being hypersecreted.. 12.2 Pharmacodynamics. IFN InhibitionEmapalumab-lzsg reduces the plasma concentrations of CXCL9, chemokine induced by IFN.. Cardiac ElectrophysiologyAt dose of mg/kg GAMIFANT does not prolong the QT interval to any clinically relevant extent.. 12.3 Pharmacokinetics. The pharmacokinetics of emapalumab-lzsg were evaluated in healthy adult subjects and in patients with HLH.Following 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 and mg/kg doses, and less than proportionally at 3, 6, and 10 mg/kg doses.Emapalumab-lzsg exhibits target-mediated-like clearance dependent on IFN production, which can vary between and within patients as 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 IFN production is moderate. At high IFN production, steady-state is reached earlier due to shorter half-life.. DistributionThe central and peripheral volumes of distribution in subject with body weight of 70 kg are 2.8 and 4.4 L, respectively.. EliminationEmapalumab-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 IFN within the patient, demonstrating target mediated clearance-like mechanism. The elimination half-life of emapalumab-lzsg is reduced as the concentration of IFN increases.Emapalumab-lzsg clearance is approximately 0.007 L/h in healthy subjects.. MetabolismThe 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 PopulationsBody weight (3 to 80 kg) was 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 StudiesNo drug-drug interaction studies have been conducted with GAMIFANT.. 12.4 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). Treatment-emergent anti-drug antibodies (ADAs) were detected in 1/33 (3%) of patients in the primary HLH clinical trial. The ADAs in this patient were found to have neutralizing ability. Treatment-emergent ADAs were detected in 5/35 patients (14%) in the two HLH/MAS clinical trials. None of the ADAs in these patients were found to have neutralizing ability. No evidence of an altered pharmacokinetic, safety or efficacy profile was identified in primary HLH or HLH/MAS patients who developed antibodies to emapalumab-lzsg.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Primary Hemophagocytic Lymphohistiocytosis. The efficacy of GAMIFANT was evaluated in multicenter, open-label, single-arm trial NI-0501-04 (NCT01818492) in 27 pediatric patients with suspected or confirmed primary Hemophagocytic lymphohistiocytosis (HLH) with either refractory, recurrent, or progressive disease during conventional HLH therapy or who were intolerant of conventional HLH therapy.Patients were required to fulfill the following criteria for enrollment: primary HLH based on molecular diagnosis or family history consistent with primary HLH or five out of the criteria fulfilled: fever, splenomegaly, cytopenias affecting of lineages in the peripheral blood (hemoglobin 9, platelets 100 109/L, neutrophils 1 109/L), hypertriglyceridemia (fasting triglycerides 3 mmol/L or >=265 mg/dL) and/or hypofibrinogenemia (<=1.5 g/L), hemophagocytosis in bone marrow, spleen, or lymph nodes with no evidence of malignancy, low or absent NK-cell activity, ferritin >=500 mcg/L, soluble CD25 >=2400 U/mL. Patients had to have evidence of active disease as assessed by the treating physician. Patients had to fulfill one of the following criteria as assessed by the treating physician: having not responded or not achieved satisfactory response or not maintained satisfactory response to conventional HLH therapy, or intolerance to conventional HLH treatments. Patients with active infections caused by specific pathogens favored by IFN neutralization were excluded from the trial (e.g., mycobacteria and Histoplasma apsulatum). Patients received prophylaxis for herpes zoster, Pneumocystis jirovecii, and fungal infections.Twenty-seven patients enrolled and received treatment in the study and twenty patients (74%) completed the study. Seven patients (26%) were prematurely withdrawn. Twenty-two patients (81%) enrolled onto the open-label extension study which monitored patients for up to year after HSCT or after the last GAMIFANT infusion (NI-0501-05; NCT02069899).The study treatment duration was up to weeks after which patients could continue treatment on the extension study. All patients received an initial starting dose of GAMIFANT of mg/kg every days. Subsequent doses could be increased to maximum of 10 mg/kg based on clinical and laboratory parameters interpreted as unsatisfactory response. Forty-four percent of patients remained at dose of mg/kg, 30% of patients increased to 3-4 mg/kg and 26% of patients increased to 6-10 mg/kg. The median time to dose increase was 27 days (range: 3-31 days) with 22% of patients requiring dose increase in the first week of treatment.All patients received dexamethasone as background HLH treatment with doses between to 10 mg/m2/day. Cyclosporine was continued if administered prior to screening. Patients receiving methotrexate and glucocorticoids administered intrathecally at baseline could continue these treatments.In Study NI-0501-04, the median patient age was year (0.2 to 13). Fifty-nine percent of the patients were female, 63% were Caucasian, 11% were Asian, and 11% were Black.A genetic mutation known to cause HLH was present in 82% of patients. The most frequent causative mutations were FHL3-UNC13D (MUNC 13-4) (26%), FHL2-PRF1 (19%), and Griscelli Syndrome type (19%).The HLH mutations in the population enrolled are described in Table 6Table 6: HLH Mutations in Patients with Primary HLH with Prior TherapyGAMIFANT(N=27)HLH Genetic Confirmation22 (82)FHL3-UNC13D7 (26)FHL2-PRF15 (19)Griscelli Syndrome type (RAB27A)5 (19)FHL5-STXBP2 (UNC18B)2 (7.4)FHL4-STX111 (3.7)X-linked Lymphoproliferative Disorder 11 (3.7)X-linked Lymphoproliferative Disorder 21 (3.7)All patients received previous HLH treatments. Patients received median of prior agents before enrollment into the trial. Prior regimens included combinations of the following agents: dexamethasone, etoposide, cyclosporine A, and anti-thymocyte globulin.At baseline entry into the study, 78% of patients had elevated ferritin levels, thrombocytopenia (70% with platelet count of 100 109cells/L), hypertriglyceridemia (67%) with triglyceride level >3 mmol/L. Central nervous system findings were present in 37% of patients. Forty-one percent of patients had active infections not due to specific pathogens favored by IFN neutralization at the time of GAMIFANT initiation.The efficacy of GAMIFANT was based upon overall response rate (ORR) at the end of treatment, defined as achievement of either complete or partial response or HLH improvement. ORR was evaluated using an algorithm that included the following objective clinical and laboratory parameters: fever, splenomegaly, central nervous system symptoms, complete blood count, fibrinogen and/or D-dimer, ferritin, and soluble CD25 (also referred to as soluble interleukin-2 receptor) levels. Complete response was defined as normalization of all HLH abnormalities (i.e., no fever, no splenomegaly, neutrophils >1x109/L, platelets >100x109/L, ferritin <2,000 ug/L, fibrinogen >1.50 g/L, D-dimer <500 ug/L, normal CNS symptoms, no worsening of sCD25 >2-fold baseline). Partial response was defined as normalization of >=3 HLH abnormalities. HLH improvement was defined as >=3 HLH abnormalities improved by at least 50% from baseline.Table 7: Overall Response Rate at End of TreatmentGAMIFANT(N=27)Overall Response RateN (%)17 (63)(95% CI)(0.42, 0.81) p-value+0.013Overall Response by CategoryComplete response, (%)7 (26)Partial response8 (30)HLH improvement2 (7.4)+p-value based on Exact Binomial Test at one-sided significance level of 2.5% comparing proportion of patients with overall response to hypothesized null hypothesis of 40%.CI confidence intervalThe median duration of first response, defined as time from achievement of first response to loss of first response, is not reached (range: 4-56+ days). Seventy percent (19/27) of patients proceeded to HSCT.. 14.2 Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (MAS) in Stills disease (including sJIA). The efficacy of GAMIFANT was evaluated in two open-label, single arm, multicenter studies which enrolled total of 39 patients with hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) in Stills disease, including systemic Juvenile Idiopathic Arthritis (sJIA), with an inadequate response to high-dose glucocorticoid treatment.In each study, patients were required to fulfill the following criteria for enrollment: confirmed or suspected diagnosis of sJIA or AOSD; diagnosis of active MAS with ferritin >684 ng/mL and any of these laboratory criteria: platelet count <=181x109/L, AST >48 U/L, triglycerides >156 mg/dL, or fibrinogen levels <=360 mg/dL; an inadequate response to high-dose IV glucocorticoids. Patients with active infections caused by specific pathogens favored by IFN neutralization were excluded from the trial (e.g., mycobacteria and Histoplasma capsulatum).In each study, GAMIFANT was administered at an initial dose of mg/kg, followed by at least mg/kg every days until Day 16, and then twice weekly thereafter. Glucocorticoids and anakinra (<4 mg/kg/d) could be co-administered for the treatment of Stills disease.Pooled DataThe pooled analysis includes all patients from Study NI-0501-06 (NCT03311854) and Study NI-0501-14 (NCT05001737). These two studies enrolled 39 patients who received GAMIFANT, and 37 patients completed the studies (95%). The majority of patients were female (80%) and the median age was 12.0 years (range: 0.9 to 64 years). The racial distribution was White (74%), Asian (10%), Black or African American (5%), and Other (3%), with patients not reporting race (8%). Ethnicity was only collected in Study NI-0501-14 in which 88% reported Not Hispanic or Latino with patients not reporting ethnicity (12%). At baseline, patients had elevated ferritin levels (median 6833 ug/L), elevated ALT (median 259 U/L), and elevated LDH (median 954 U/L).The efficacy of GAMIFANT was based on complete response (CR), composite endpoint consisting of clinical resolution of MAS signs and symptoms (a visual analogue scale (VAS), of <=1 cm [range to 10 cm]) and the following laboratory parameter endpoints: WBC count and platelet count above the lower limit of normal (LLN), LDH, AST and ALT below 1.5xthe upper limit of normal (ULN), fibrinogen >100 mg/dL, and ferritin levels decreased >=80% from values at screening or baseline (whichever was higher) or <2000 ng/mL, whichever was lower (see Table 8).Table - Pooled Efficacy ResultsComposite endpoint and individual components at Week 8n/N% of patients95% CIa Complete response (CR)21/3953.837.2, 69.9Clinical MAS remission (VAS <= cm)b 32/3982.166.5, 92.5Ferritin reduction to 2000 ng/mL or an 80% decreasec 33/3984.669.5, 94.1Platelet count above the LLN34/3987.272.6, 95.7ALT below 1.5x ULN34/3987.272.6, 95.7AST below 1.5xULN37/3994.982.7, 99.4Fibrinogen 100 mg/dL35/3989.775.8, 97.1WBC above the LLN36/3992.379.1, 98.4LDH below 1.5xULN26/3966.749.8, 80.9aClopper-Pearson confidence interval is presented: two-sided 95% confidence intervalbClinical MAS remission was assessed using visual analogue scale (VAS) where cm referred to no clinical signs or symptoms of MAS and 10 cm referred to the worst possible clinical signs and symptoms of MASc80% decrease calculated from values at screening or baseline (whichever was highest) or 2000 ng/mL, whichever was lowest.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None. (4). None. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Emapalumab-lzsg is an interferon gamma (IFN) neutralizing antibody. Emapalumab-lzsg is produced in Chinese Hamster Ovary cells by recombinant DNA technology. Emapalumab-lzsg is an IgG1 immunoglobulin with molecular weight of approximately 148 kDa.GAMIFANT (emapalumab-lzsg) injection for intravenous use is sterile, preservative-free, clear to slightly opalescent, colorless to slightly yellow solution provided in single-dose vials that require dilution prior to intravenous infusion.. GAMIFANT mg/mL (2 mL, 10 mL and 20 mL)Each vial contains 10 mg/2 mL, 50 mg/10 mL, or 100 mg/20 mL emapalumab-lzsg at concentration of 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.. GAMIFANT 25 mg/mL (2 mL, mL, 10 mL and 20 mL)Each vial contains 50 mg/2 mL, 100 mg/4 mL, 250 mg/10 mL or 500 mg/20 mL emapalumab- lzsg at concentration of 25 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.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. For intravenous infusion only:Primary HLH recommended starting dosage: mg/kg as an intravenous infusion over hour twice per week. (2.1)HLH/MAS in Stills disease recommended dosage schedule: mg/kg, followed by mg/kg every days for doses, then mg/kg twice per week. Given as an intravenous infusion over hour. (2.2)For both indications, the dose may be titrated up to maximum of 10 mg/kg. (2.5, 2.6). Primary HLH recommended starting dosage: mg/kg as an intravenous infusion over hour twice per week. (2.1). HLH/MAS in Stills disease recommended dosage schedule: mg/kg, followed by mg/kg every days for doses, then mg/kg twice per week. Given as an intravenous infusion over hour. (2.2). For both indications, the dose may be titrated up to maximum of 10 mg/kg. (2.5, 2.6). 2.1 Recommended Dosage for Primary Hemophagocytic Lymphohistiocytosis. The recommended starting dose of GAMIFANT is mg/kg given as central or peripheral intravenous infusion over 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 patient no longer requires therapy for the treatment of HLH.. 2.2 Recommended Dosage for Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome. GAMIFANT is administered as central or peripheral intravenous infusion over 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 patient no longer requires therapy for the treatment of HLH/MAS.Table 1. GAMIFANT Dosage in Patients with HLH/MASTreatment DayGAMIFANT DosageDay 16 mg/kgDays to 163 mg/kg every days for dosesFrom Day 19 onward3 mg/kg twice per week (i.e., every to days). 2.3 Monitoring to Assess Safety. Before Initiating GAMIFANT TreatmentConduct testing for latent tuberculosis infections using the purified protein derivative (PPD) or IFN 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 positive PPD test result, or positive IFN release assay.During GAMIFANT TreatmentMonitor for herpes zoster infection, adenovirus, EBV and CMV as clinically indicated.. 2.4 Prophylaxis and Concomitant Medication Information. ProphylaxisConsider prophylaxis for herpes zoster, Pneumocystis jirovecii, and for fungal infections prior to GAMIFANT administration.Concomitant MedicationsFor primary HLH patients who are not receiving baseline dexamethasone treatment, begin dexamethasone at daily dose of at least mg/m2 to 10 mg/m2 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 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 patients clinical condition is stabilized, decrease the dose to the previous level to maintain clinical response.Table 2: Dose Titration CriteriaTreatment DayGAMIFANT DoseCriteria for Dose IncreaseDay 1Starting Dose of mg/kgN/AFrom Day onwardsIncrease to mg/kgUnsatisfactory improvement in clinical condition, as assessed by healthcare provider AND at least one of the following:Fever persistence or recurrencePlatelet countIf baseline 50,000/mm3 and no improvement to 50,000/mm3 If baseline 50,000/mm3 and less than 30% improvementIf baseline 100,000/mm3 and decrease to 100,000/mm3 Neutrophil countIf baseline 500/mm3 and no improvement to 500/mm3 If baseline 500/mm3 to 1,000/mm3 and decrease to 500/mm3 If baseline 1,000/mm3 to 1,500/mm3 and decrease to 1,000/mm3 Ferritin (ng/mL)If baseline >=3,000 ng/mL and 20% decreaseIf baseline 3,000 ng/mL and any increase to 3,000 ng/mL Splenomegaly any worseningCoagulopathy (both D-Dimer and Fibrinogen must apply)D-DimerIf abnormal at baseline and no improvement Fibrinogen (mg/dL)If baseline levels <=100 mg/dL and no improvementIf baseline levels 100 mg/dL and any decrease to 100 mg/dL From Day onwardsIncrease to mg/kgFrom Day 10 onwardsIncrease to 10 mg/kgAssessment by healthcare provider that based on initial signs of response, further increase in GAMIFANT dose can be of benefit. Fever persistence or recurrence. Platelet countIf baseline 50,000/mm3 and no improvement to 50,000/mm3 If baseline 50,000/mm3 and less than 30% improvementIf baseline 100,000/mm3 and decrease to 100,000/mm3 If baseline 50,000/mm3 and no improvement to 50,000/mm3 If baseline 50,000/mm3 and less than 30% improvement. If baseline 100,000/mm3 and decrease to 100,000/mm3 Neutrophil countIf baseline 500/mm3 and no improvement to 500/mm3 If baseline 500/mm3 to 1,000/mm3 and decrease to 500/mm3 If baseline 1,000/mm3 to 1,500/mm3 and decrease to 1,000/mm3 If baseline 500/mm3 and no improvement to 500/mm3 If baseline 500/mm3 to 1,000/mm3 and decrease to 500/mm3 If baseline 1,000/mm3 to 1,500/mm3 and decrease to 1,000/mm3 Ferritin (ng/mL)If baseline >=3,000 ng/mL and 20% decreaseIf baseline 3,000 ng/mL and any increase to 3,000 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-DimerIf abnormal at baseline and no improvement D-Dimer. If abnormal at baseline and no improvement. Fibrinogen (mg/dL)If baseline levels <=100 mg/dL and no improvementIf baseline levels 100 mg/dL and any decrease to 100 mg/dL If baseline levels <=100 mg/dL and no improvement. If baseline levels 100 mg/dL and any decrease to 100 mg/dL. 2.6 Dose Modification Based on Response for Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome. Table 3: Dosage Adjustment CriteriaTreatment DayGAMIFANT DoseDose AdjustmentsDay 1Initial dose of mg/kgIf unsatisfactory improvement in clinical condition, as assessed by healthcare provider, the dose of GAMIFANT may be increased to:a maximum cumulative dose of 10 mg/kg over daysAND the frequency may be increased to:every days or once dailyAfter the patients 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 to 163 mg/kg every days for dosesFrom Day 19 onwards3 mg/kg twice per week (i.e., every to days). maximum cumulative dose of 10 mg/kg over days. every days or once daily. 2.7 Instructions for Preparation and Administration. PreparationGAMIFANT vials are for single dose only.Do not mix GAMIFANT 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 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 mg/mL vials:Dilute to 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 syringe or an infusion bag, depending on the volume needed.When using syringe, use gamma irradiated or ethylene oxide sterilized latex-free, polyvinyl chloride (PVC)-free syringe.When using an infusion bag, use non-PVC polyolefin infusion bag. For GAMIFANT 25 mg/mL vials:Dilute to maximum concentration of 12.5 mg/mL. Do not dilute product to less than 1.25 mg/mL.Use non-PVC polyolefin infusion bag made from either polyethylene or ethylene/propylene copolymer. Discard any unused portion left in the vial(s).AdministrationAdminister GAMIFANT diluted solution intravenously over hour through central or peripheral intravenous line containing 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 SolutionThis product does not contain preservative.If not administered immediately:Store the diluted solution of GAMIFANT under refrigeration at 2C to 8C (36F to 46F) for no more than hours from the time of dilution. If refrigerated, allow the diluted solution to come to room temperature, typically 20C to 25C (68F to 77F), prior to administration.Do not freeze. Do not shake.. 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 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 mg/mL vials:Dilute to 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 syringe or an infusion bag, depending on the volume needed.When using syringe, use gamma irradiated or ethylene oxide sterilized latex-free, polyvinyl chloride (PVC)-free syringe.When using an infusion bag, use non-PVC polyolefin infusion bag. For GAMIFANT 25 mg/mL vials:Dilute to maximum concentration of 12.5 mg/mL. Do not dilute product to less than 1.25 mg/mL.Use non-PVC polyolefin infusion bag made from either polyethylene or ethylene/propylene copolymer. For GAMIFANT mg/mL vials:Dilute to 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 syringe or an infusion bag, depending on the volume needed.When using syringe, use gamma irradiated or ethylene oxide sterilized latex-free, polyvinyl chloride (PVC)-free syringe.When using an infusion bag, use non-PVC polyolefin infusion bag. Dilute to 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 syringe or an infusion bag, depending on the volume needed.. When using syringe, use gamma irradiated or ethylene oxide sterilized latex-free, polyvinyl chloride (PVC)-free syringe.. When using an infusion bag, use non-PVC polyolefin infusion bag.. For GAMIFANT 25 mg/mL vials:Dilute to maximum concentration of 12.5 mg/mL. Do not dilute product to less than 1.25 mg/mL.Use non-PVC polyolefin infusion bag made from either polyethylene or ethylene/propylene copolymer. Dilute to maximum concentration of 12.5 mg/mL. Do not dilute product to less than 1.25 mg/mL.. Use non-PVC polyolefin infusion bag made from either polyethylene or ethylene/propylene copolymer.. Discard any unused portion left in the vial(s).. Administer GAMIFANT diluted solution intravenously over hour through central or peripheral intravenous line containing 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.. Store the diluted solution of GAMIFANT under refrigeration at 2C to 8C (36F to 46F) for no more than hours from the time of dilution. If refrigerated, allow the diluted solution to come to room temperature, typically 20C to 25C (68F to 77F), prior to administration.. Do not freeze. Do not shake.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. GAMIFANT is clear to slightly opalescent, colorless to slightly yellow preservative-free solution available as:Injection:o 10 mg/2 mL (5 mg/mL) in single-dose vialo 50 mg/10 mL (5 mg/mL) in single-dose vialo 100 mg/20 mL (5 mg/mL) in single-dose vialo 50 mg/2 mL (25 mg/mL) in single-dose vialo 100 mg/4 mL (25 mg/mL) in single-dose vialo 250 mg/10 mL (25 mg/mL) in single-dose vialo 500 mg/20 mL (25 mg/mL) in single-dose vial. Injection:o 10 mg/2 mL (5 mg/mL) solution in single-dose vial (3)o 50 mg/10 mL (5 mg/mL) solution in single-dose vial (3)o 100 mg/20 mL (5 mg/mL) solution in single-dose vial (3)o 50 mg/2 mL (25 mg/mL) solution in single-dose vial (3)o 100 mg/4 mL (25 mg/mL) solution in single-dose vial (3)o 250 mg/10 mL (25 mg/mL) solution in single-dose vial (3)o 500 mg/20 mL (25 mg/mL) solution in single-dose vial (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. 7.1 Effect of GAMIFANT on Cytochrome P450 Substrates. The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (such as IFN) during chronic inflammation. By neutralizing IFN, use of GAMIFANT 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 GAMIFANT, monitor for reduced efficacy and adjust dosage of CYP450 substrate drugs as appropriate.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of GAMIFANT 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.

IMMUNOGENICITY.

12.4 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). Treatment-emergent anti-drug antibodies (ADAs) were detected in 1/33 (3%) of patients in the primary HLH clinical trial. The ADAs in this patient were found to have neutralizing ability. Treatment-emergent ADAs were detected in 5/35 patients (14%) in the two HLH/MAS clinical trials. None of the ADAs in these patients were found to have neutralizing ability. No evidence of an altered pharmacokinetic, safety or efficacy profile was identified in primary HLH or HLH/MAS patients who developed antibodies to emapalumab-lzsg.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. GAMIFANT is indicated for the treatment of:adult and pediatric patients with primary hemophagocytic lymphohistiocytosis (HLH) with refractory, recurrent or progressive disease or intolerance with conventional HLH therapy.adult and pediatric patients with HLH/macrophage activation syndrome (MAS) in known or suspected Stills disease, including systemic Juvenile Idiopathic Arthritis (sJIA), with an inadequate response or intolerance to glucocorticoids, or with recurrent MAS. adult and pediatric patients with primary hemophagocytic lymphohistiocytosis (HLH) with refractory, recurrent or progressive disease or intolerance with conventional HLH therapy.. adult and pediatric patients with HLH/macrophage activation syndrome (MAS) in known or suspected Stills disease, including systemic Juvenile Idiopathic Arthritis (sJIA), with an inadequate response or intolerance to glucocorticoids, or with recurrent MAS. GAMIFANT is an interferon gamma (IFN) neutralizing antibody indicated for the treatment of:adult and pediatric patients with primary hemophagocytic lymphohistiocytosis (HLH) with refractory, recurrent or progressive disease or intolerance with conventional HLH therapy. (1)adult and pediatric patients with HLH/macrophage activation syndrome (MAS) in known or suspected Stills disease, including systemic Juvenile Idiopathic Arthritis (sJIA), with an inadequate response or intolerance to glucocorticoids, or with recurrent MAS. (1). adult and pediatric patients with primary hemophagocytic lymphohistiocytosis (HLH) with refractory, recurrent or progressive disease or intolerance with conventional HLH therapy. (1). adult and pediatric patients with HLH/macrophage activation syndrome (MAS) in known or suspected Stills disease, including systemic Juvenile Idiopathic Arthritis (sJIA), with an inadequate response or intolerance to glucocorticoids, or with recurrent MAS. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide).. InfectionsInform patients and their caregivers of the risk of developing infections during treatment with GAMIFANT, and to report any symptoms of infection [see Warnings and Precautions (5.1)] .. VaccinationsAdvise patients and their caregivers that the patient should not receive live or live attenuated vaccines during GAMIFANT treatment [see Warnings and Precautions (5.2)] .. Infusion-Related ReactionsAdvise patients and their caregivers of the potential for developing infusion-related reactions during treatment with GAMIFANT [see Warnings and Precautions (5.3)].Manufactured by:Swedish Orphan Biovitrum AB (publ) Stockholm, Sweden U.S. License Number 1859Distributed by:Sobi Inc. 77 Fourth Avenue, rdFloor Waltham, MA 02451-7559Manufactured at:Patheon Italia S.p.A Trav. SX Via Morolense, 03013-Ferentino ItalyProduct of the United Kingdom.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere 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 mothers clinical need for GAMIFANT and any potential adverse effects on the breastfed child from GAMIFANT or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

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

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No carcinogenicity or genotoxicity studies have been conducted with emapalumab-lzsg.No studies have been conducted to evaluate the effects of emapalumab-lzsg on fertility; however, no adverse effects on male or female reproductive organs were observed in the 8- or 13-week repeat-dose toxicity studies in cynomolgus monkeys.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Consider contacting the Poison Help line (1-800-222-1222) or medical toxicologist for additional overdose management recommendations.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Principal Display Panel 10 mg/2 mL Carton LabelNDC 66658-501-01Gamifant(R) (emapalumab-lzsg) Injection10 mg/2 mL(5 mg/mL)For intravenous infusion only.Requires dilution prior to administration.Single-dose vial. Discard unused portion.Rx onlyDispense the enclosed Medication Guide to each patient.. image description.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness of GAMIFANT have been established in pediatric patients with primary HLH that is reactivated or refractory to conventional therapies and with HLH/MAS in Stills Disease (including sJIA) with an inadequate response to glucocorticoids [see Clinical Studies (14)]. Use of GAMIFANT is supported by single-arm trials which included 57 pediatric patients: 27 with primary HLH and 30 with HLH/MAS in Stills disease. These studies included pediatric patients in the following age groups: patients newborn to months, 13 patients months to years, 27 patients from years to <12 years, and 12 patients from 12 years to <17 years.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. IFN InhibitionEmapalumab-lzsg reduces the plasma concentrations of CXCL9, chemokine induced by IFN.. Cardiac ElectrophysiologyAt dose of mg/kg GAMIFANT does not prolong the QT interval to any clinically relevant extent.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of emapalumab-lzsg were evaluated in healthy adult subjects and in patients with HLH.Following 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 and mg/kg doses, and less than proportionally at 3, 6, and 10 mg/kg doses.Emapalumab-lzsg exhibits target-mediated-like clearance dependent on IFN production, which can vary between and within patients as 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 IFN production is moderate. At high IFN production, steady-state is reached earlier due to shorter half-life.. DistributionThe central and peripheral volumes of distribution in subject with body weight of 70 kg are 2.8 and 4.4 L, respectively.. EliminationEmapalumab-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 IFN within the patient, demonstrating target mediated clearance-like mechanism. The elimination half-life of emapalumab-lzsg is reduced as the concentration of IFN increases.Emapalumab-lzsg clearance is approximately 0.007 L/h in healthy subjects.. MetabolismThe 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 PopulationsBody weight (3 to 80 kg) was 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 StudiesNo drug-drug interaction studies have been conducted with GAMIFANT.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere are no available data on GAMIFANT use in pregnant women to inform drug-associated risk of adverse developmental outcomes. In an animal reproduction study, murine surrogate anti-mouse IFN 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 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 to 4% and 15 to 20%, respectively.. Data. Animal DataIn mouse embryo-fetal development study, murine surrogate anti-mouse IFN 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.

RECENT MAJOR CHANGES SECTION.

RECENT MAJOR CHANGES. Indications and Usage (1) 6/2025Dosage and Administration (2.2, 2.3) 6/2025Warnings and Precautions (5.1, 5.3) 03/2026.

SPL MEDGUIDE SECTION.

MEDICATION GUIDE GAMIFANT(R) (gam fant) (emapalumab-lzsg) injection, for intravenous use What is the most important information should know about GAMIFANT GAMIFANT can cause serious side effects including: Infections. GAMIFANT is medicine that affects your immune system and may lower the ability of your immune system to fight infections. GAMIFANT may increase your risk of serious infections that can lead to death. These infections include tuberculosis (TB), histoplasmosis, pneumonia, cytomegalovirus infection or reactivation of infection, sepsis, herpes zoster infection (shingles) and other infections caused by viruses, fungi or bacteria that can spread throughout the body. Your healthcare provider will: test you for TB before you start treatment with GAMIFANT.treat you with medicine for TB if you are at risk for TB or if you have known positive TB test. Infections are common in people treated with GAMIFANT. Before starting GAMIFANT, tell your healthcare provider if you: had TB in the past, or if you or member of your family have been in recent close contact with someone with TB.have ever had positive TB skin test (PPD).currently have or have had history of infections, including histoplasmosis, cytomegalovirus, or herpes zoster (shingles).are being treated for an active infection.have symptoms of an infection, such as fever, sweat and chills, cough, breathing problems, blood in mucus (phlegm), warm, red, or painful skin or sores on your body. Your healthcare provider may give you medicine to help prevent certain infections before you receive GAMIFANT. After starting GAMIFANT, tell your healthcare provider if:new symptoms of an infection appear.symptoms of an infection that you already had when starting GAMIFANT worsen. Your healthcare provider will monitor you closely for signs and symptoms of infections during treatment with GAMIFANT. See What are the possible side effects of GAMIFANT for more information about side effects.What is GAMIFANTGAMIFANT is prescription medicine used for the treatment of hemophagocytic lymphohistiocytosis (HLH) in adults and children with:primary HLH whose disease has come back or progressed, or other medicines have not worked well enough or cannot be tolerated.HLH/macrophage activation syndrome (MAS) in known or suspected Stills disease, including systemic Juvenile Idiopathic Arthritis (sJIA), when glucocorticoids have not worked well enough or cannot be tolerated, or with MAS that has come back.Before you receive GAMIFANT, tell your healthcare provider about all of your medical conditions including if you:have an infection (see What is the most important information should know about GAMIFANT)have received or are scheduled to receive an immunization (vaccine). You should not receive live or live attenuated vaccines during your treatment with GAMIFANT and for at least weeks after the last dose of GAMIFANT.are pregnant or plan to become pregnant. It is not known if GAMIFANT can harm your unborn baby.are breastfeeding or plan to breastfeed. It is not known if GAMIFANT passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with GAMIFANT.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How will receive GAMIFANTYou will receive GAMIFANT through vein by intravenous (IV) infusion over hour.Your healthcare provider will monitor you during the infusion for side effects.For primary HLH: GAMIFANT is given times week (every to days). GAMIFANT is used with another prescription medicine called dexamethasone. You can ask your healthcare provider for information about dexamethasone. For HLH/MAS in Stills disease, after your first dose, GAMIFANT is given every days for doses, then times week (every to days).Your healthcare provider will do blood tests during your treatment with GAMIFANT to see how well you respond to treatment. What are the possible side effects of GAMIFANTGAMIFANT can cause serious side effects, including:See What is the most important information should know about GAMIFANTInfusion reactions. Infusion reactions, including severe reactions, can happen during or within 24 hours after the start of your GAMIFANT infusion. Your healthcare provider may temporarily stop your infusion and treat your symptoms before continuing your infusion at slower rate if you get severe infusion reactions. Tell your healthcare provider right away if you get any of the following symptoms: skin redness chills itching chest pain fever shortness of breath rash nausea or vomiting excessive sweating lightheadedness or dizziness headache tingling, burning, or numbness bone pain cold hands, arms, legs or feet generally feeling unwell increased heart rate feeling hot The most common side effects of GAMIFANT in people with primary HLH include: infections, high blood pressure (hypertension), infusion reactions, and fever.The most common side effects of GAMIFANT in people with HLH/MAS in Stills disease include: viral infection, including cytomegalovirus infection or reactivation, and rash.These are not all the possible side effects of GAMIFANT.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of GAMIFANT. Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. You can ask your healthcare provider or pharmacist for information about GAMIFANT that is written for health professionals.What are the ingredients in GAMIFANTActive ingredient: emapalumab-lzsg Inactive ingredients: L-Histidine, L-Histidine monohydrochloride, monohydrate, Polysorbate 80, sodium chloride, and Water for InjectionManufactured by: Swedish Orphan Biovitrum AB (publ), Stockholm, Sweden, U.S. License Number 1859Distributed by: Sobi Inc., 77 Fourth Avenue, 3rd Floor, Waltham, MA 02451-7559Manufactured at: Patheon Italia S.p.A. Trav. SX Via Morolense, 5, 03013-Ferentino ItalyProduct of the United KingdomFor more information call 1-866-773-5274 or go to www.gamifant.comThis Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: 03/2026. test you for TB before you start treatment with GAMIFANT.. treat you with medicine for TB if you are at risk for TB or if you have known positive TB test.. had TB in the past, or if you or member of your family have been in recent close contact with someone with TB.. have ever had positive TB skin test (PPD).. currently have or have had history of infections, including histoplasmosis, cytomegalovirus, or herpes zoster (shingles).. are being treated for an active infection.. have symptoms of an infection, such as fever, sweat and chills, cough, breathing problems, blood in mucus (phlegm), warm, red, or painful skin or sores on your body.. new symptoms of an infection appear.. symptoms of an infection that you already had when starting GAMIFANT worsen.. primary HLH whose disease has come back or progressed, or other medicines have not worked well enough or cannot be tolerated.. HLH/macrophage activation syndrome (MAS) in known or suspected Stills disease, including systemic Juvenile Idiopathic Arthritis (sJIA), when glucocorticoids have not worked well enough or cannot be tolerated, or with MAS that has come back.. have an infection (see What is the most important information should know about GAMIFANT). have received or are scheduled to receive an immunization (vaccine). You should not receive live or live attenuated vaccines during your treatment with GAMIFANT and for at least weeks after the last dose of GAMIFANT.. are pregnant or plan to become pregnant. It is not known if GAMIFANT can harm your unborn baby.. are breastfeeding or plan to breastfeed. It is not known if GAMIFANT passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with GAMIFANT.. You will receive GAMIFANT through vein by intravenous (IV) infusion over hour.. Your healthcare provider will monitor you during the infusion for side effects.. For primary HLH:. For HLH/MAS in Stills disease, after your first dose, GAMIFANT is given every days for doses, then times week (every to days).. Your healthcare provider will do blood tests during your treatment with GAMIFANT to see how well you respond to treatment.

SPL UNCLASSIFIED SECTION.

2.1 Recommended Dosage for Primary Hemophagocytic Lymphohistiocytosis. The recommended starting dose of GAMIFANT is mg/kg given as central or peripheral intravenous infusion over 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 patient no longer requires therapy for the treatment of HLH.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThere are no available data on GAMIFANT use in pregnant women to inform drug-associated risk of adverse developmental outcomes. In an animal reproduction study, murine surrogate anti-mouse IFN 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 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 to 4% and 15 to 20%, respectively.. Data. Animal DataIn mouse embryo-fetal development study, murine surrogate anti-mouse IFN 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 SummaryThere 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 mothers clinical need for GAMIFANT and any potential adverse effects on the breastfed child from GAMIFANT or from the underlying maternal condition.. 8.4 Pediatric Use. Safety and effectiveness of GAMIFANT have been established in pediatric patients with primary HLH that is reactivated or refractory to conventional therapies and with HLH/MAS in Stills Disease (including sJIA) with an inadequate response to glucocorticoids [see Clinical Studies (14)]. Use of GAMIFANT is supported by single-arm trials which included 57 pediatric patients: 27 with primary HLH and 30 with HLH/MAS in Stills disease. These studies included pediatric patients in the following age groups: patients newborn to months, 13 patients months to years, 27 patients from years to <12 years, and 12 patients from 12 years to <17 years.. 8.5 Geriatric Use. Clinical studies of GAMIFANT 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Infections: Monitor patients for signs and symptoms and treat promptly. Test for latent tuberculosis. Consider administering prophylactic treatment against herpes zoster, Pneumocystis jirovecii and fungal infections. (5.1)Live Vaccines: Do not administer live or live attenuated vaccines to patients receiving GAMIFANT. (5.2)Infusion-Related Reactions: Monitor patients for infusion-related reactions. Interrupt infusion for infusion reactions and institute appropriate medical management. (5.3). Infections: Monitor patients for signs and symptoms and treat promptly. Test for latent tuberculosis. Consider administering prophylactic treatment against herpes zoster, Pneumocystis jirovecii and fungal infections. (5.1). Live Vaccines: Do not administer live or live attenuated vaccines to patients receiving GAMIFANT. (5.2). Infusion-Related Reactions: Monitor patients for infusion-related reactions. Interrupt infusion for infusion reactions and institute appropriate medical management. (5.3). 5.1 Infections. GAMIFANT may increase the risk of fatal and serious infections to include specific pathogens favored by IFN neutralization, including mycobacteria, herpes zoster virus, and Histoplasma capsulatum.Do not administer GAMIFANT in patients with infections caused by these pathogens until appropriate treatment has been initiated.In patients with primary HLH receiving GAMIFANT in clinical trials, serious infections such as sepsis, pneumonia, bacteremia, disseminated histoplasmosis, necrotizing fasciitis, viral infections, and perforated appendicitis were observed in 32% of patients. The reported infections were viral (41%), bacterial (35%), fungal (9%), and the pathogen was not identified in 15% of cases.In patients with HLH/MAS in Stills disease receiving GAMIFANT in clinical trials, serious infections such as pneumonia, cytomegalovirus infection, cytomegalovirus infection reactivation, and sepsis were observed in 13% of patients. The reported infections were viral (44%), bacterial (13%), fungal (3%) and the pathogen was not identified in (13%) of patients.In the GAMIFANT clinical trials, additional infections were reported in patients treated with GAMIFANT including herpes zoster (2.4%) and mycobacterial infections (2.4%).Evaluate patients for tuberculosis risk factors and test for latent infection (PPD testing, PCR, or IFN release assay) prior to initiating GAMIFANT. Administer tuberculosis prophylaxis to patients at risk for tuberculosis or known to have positive purified protein derivative (PPD) test result [see Dosage and Administration (2.2)].Consider prophylaxis for herpes zoster, Pneumocystis jirovecii,and fungal infection to mitigate the risk to patients while receiving GAMIFANT [see Dosage and Administration (2.3)].Employ surveillance testing during treatment with GAMIFANT.Closely monitor patients receiving GAMIFANT for signs or symptoms of infection, promptly initiate 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 GAMIFANT and for at least weeks after the last dose of GAMIFANT. The safety of immunization with live vaccines during or following GAMIFANT therapy has not been studied.. 5.3 Infusion-Related Reactions. Infusion-related reactions in patients with primary HLH, including drug eruption, pyrexia, rash, erythema, and hyperhidrosis, were reported with GAMIFANT treatment in 27% of patients. In one-third of these patients, the infusion-related reaction occurred during the first infusion.Infusion-related reactions in patients with HLH/MAS in Stills disease, including pyrexia, headache, paresthesia, bone pain, pruritic rash, and peripheral coldness, were reported with GAMIFANT treatment in 13% of patients. Infusion-related reactions were reported as mild in 8% of patients and as moderate in 5% of patients.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 GAMIFANT.In the GAMIFANT clinical trials, additional infusion-related reactions that were reported in less than 3% of patients treated with GAMIFANT included: malaise, sinus tachycardia, feeling hot, and acute respiratory failure.Monitor patients for infusion-related reactions which can be severe. Interrupt the infusion for infusion reactions and institute appropriate medical management prior to continuing infusion at slower rate.