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 gamifant. 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 ( 2.2 )] . administer prophylaxis for herpes zoster, pneumocystis jirovecii , and fungal infection to mitigate the risk to patients while receiving gamifant. employ surveillance testing during treatment with gamifant. closely monitor patients receiving gamifant 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 vaccine do not administer live or live attenuated vaccines to patients receiving gamifant and for at least 4 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 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. 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.

ister 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 tuberculosis, adenovirus, ebv and cmv every 2 weeks and as clinically indicated. 2.3 pre-medications and concomitant medication information pre-medications administer prophylaxis for herpes zoster, pneumocystis jirovecii , and for fungal infections prior to gamifant 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/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/m 2 . dexamethasone can be tapered according to the judgment of the treating physician [see clinical studies ( 14 )] . 2.4 dose modification based on response the gamifant dose may be titrated up if disease response is unsatisfactory (see table 1 ) [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 1: dose titration criteria treatment day gamifant dose criteria for dose increase day 1 starting dose of 1 mg/kg n/a on day 3 increase to 3 mg/kg unsatisfactory improvement in clinical condition, as assessed by a healthcare provider and at least one of the following: from day 6 onwards increase to 6 mg/kg 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 -1000/mm 3 and decrease to < 500/mm 3 if baseline 1000-1500/mm 3 and decrease to < 1000/mm 3 ferritin (ng/ml) if baseline ≥ 3000 ng/ml and < 20% decrease if baseline < 3000 ng/ml and any increase to > 3000 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 9 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 2.5 instructions for preparation and administration preparation gamifant vials are for single-use only. 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 )] . inspect gamifant vials visually for particulate matter and discoloration prior to dilution. 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 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 gamifant 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 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.

reases 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 2 . table 2: adverse reactions reported in ≥ 10% of patients with primary hlh adverse reactions gamifant (%) (n = 34) infections includes viral, bacterial, fungal, and infections in which no pathogen was identified 56 hypertension includes secondary hypertension 41 infusion-related reactions includes events of drug eruption, pyrexia, rash, erythema, and hyperhidrosis 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 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. 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 gamifant. atas were detected in 3/64 subjects (5%) who received gamifant. 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 gamifant 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 gamifant treatment. in addition, one healthy subject tested positive for atas following a single dose of gamifant. no evidence of an altered safety or efficacy profile was identified in the primary hlh patients who developed antibodies to emapalumab-lzsg.

e 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 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, newborn and older, with primary hlh that is reactivated or refractory to conventional therapies. use of gamifant 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 ( 14 )] . 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.

ted 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.

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 ( 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 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, gamifant 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 gamifant.

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, gamifant 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 gamifant.

ts had to have evidence of active disease as assessed by treating physician. patients had to fulfill one of the following criteria as assessed by the treating physician: having not responded or not achieved a satisfactory response or not maintained a satisfactory response to conventional hlh therapy, or intolerance to conventional hlh treatments. patients with active infections caused by specific pathogens favored by ifnγ neutralization were excluded from the trial (e.g., mycobacteria and histoplasma capsulatum ). 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 1 year after hsct or after the last gamifant infusion (ni-0501-05; nct02069899). the study treatment duration was up to 8 weeks after which patients could continue treatment on the extension study. all patients received an initial starting dose of gamifant of 1 mg/kg every 3 days. subsequent doses could be increased to a maximum of 10 mg/kg based on clinical and laboratory parameters interpreted as unsatisfactory response. forty-four percent of patients remained at a dose of 1 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 a dose increase in the first week of treatment. all patients received dexamethasone as background hlh treatment with doses between 5 to 10 mg/m 2 /day. cyclosporine a 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 1 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 2 (19%). the hlh mutations in the population enrolled are described in table 3 . table 3: hlh mutations in patients with primary hlh with prior therapy gamifant (n=27) hlh genetic confirmation 22 (82) fhl3 – unc13d 7 (26) fhl2 – prf1 5 (19) griscelli syndrome type 2 (rab27a) 5 (19) fhl5 – stxbp2 (unc18b) 2 (7.4) fhl4 – stx11 1 (3.7) x-linked lymphoproliferative disorder 1 1 (3.7) x-linked lymphoproliferative disorder 2 1 (3.7) all patients received previous hlh treatments. patients received a median of 3 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 x 10 9 cells/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 ifnγ 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 a 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 > 1x10 9 /l, platelets > 100x10 9 /l, ferritin < 2,000 μg/l, fibrinogen > 1.50 g/l, d-dimer < 500 μg/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 4: overall response rate at end of treatment gamifant (n=27) overall response rate n (%) 17 (63) (95% ci) (0.42, 0.81) p-value p-value based on exact binomial test at a one-sided significance level of 2.5% comparing proportion of patients with overall response to hypothesized null hypothesis of 40%. 0.013 overall response by category complete response, n (%) 7 (26) partial response 8 (30) hlh improvement 2 (7.4) ci = confidence interval the 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.