ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are described elsewhere in the labeling:Infections [see Warnings and Precautions (5.1)] Infusion-Related Reactions [see Warnings and Precautions (5.3)] Infections [see Warnings and Precautions (5.1)] Infusion-Related Reactions [see Warnings and Precautions (5.3)] The most common adverse reactions (>= 20%) were: infections, hypertension, infusion-related reactions, and pyrexia. (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.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 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 2.Table 2: Adverse Reactions Reported in >= 10% of Patients with Primary HLHAdverse ReactionsGAMIFANT(%)(N 34)InfectionsIncludes viral, bacterial, fungal, and infections in which no pathogen was identified 56HypertensionIncludes secondary hypertension 41Infusion-related reactionsIncludes events of drug eruption, pyrexia, rash, erythema, and hyperhidrosis 27Pyrexia24Hypokalemia15Constipation15Rash12Abdominal pain12Cytomegalovirus infection12Diarrhea12Lymphocytosis12Cough12Irritability12Tachycardia12Tachypnea12Additional 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). 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 weeks following the initiation of GAMIFANT treatment. In addition, one healthy subject tested positive for ATAs following 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.

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 primary 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 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 4.2 and 5.6 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.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 IFN, demonstrating target mediated clearance of emapalumab-lzsg.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 (2 to 82 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 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 StudiesNo drug-drug interaction studies have been conducted with GAMIFANT.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 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 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 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 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 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 3.Table 3: 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 >= HLH abnormalities. HLH improvement was defined as >= HLH abnormalities improved by at least 50% from baseline.Table 4: Overall Response Rate at End of TreatmentGAMIFANT(N=27)Overall Response Rate (%)17 (63) (95% CI)(0.42, 0.81) p-valuep-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%. 0.013Overall Response by Category Complete response, (%)7 (26) Partial response8 (30) HLH improvement2 (7.4)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.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. For intravenous infusion only:Recommended starting dosage: mg/kg as an intravenous infusion over hour twice per week. (2.1)Administer dexamethasone concomitantly with GAMIFANT. (2.3). Recommended starting dosage: mg/kg as an intravenous infusion over hour twice per week. (2.1). Administer dexamethasone concomitantly with GAMIFANT. (2.3). 2.1 Recommended Dosing. The recommended starting dose of GAMIFANT is mg/kg given as an 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 (2.4)].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 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 tuberculosis, adenovirus, EBV and CMV every weeks and as clinically indicated.. 2.3 Pre-Medications and Concomitant Medication Information. Pre-MedicationsAdminister prophylaxis for Herpes Zoster, Pneumocystis jirovecii, and for fungal infections prior to GAMIFANT administration.Concomitant MedicationsFor patients who are not receiving baseline dexamethasone treatment, begin dexamethasone at daily dose of at least 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)].. 2.4 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 patients clinical condition is stabilized, decrease the dose to the previous level to maintain clinical response.Table 1: Dose Titration CriteriaTreatmentDayGAMIFANT DoseCriteria for Dose IncreaseDay 1Starting Dose of mg/kgN/AOn Day 3Increase to mg/kgUnsatisfactory improvement in clinical condition, as assessed by healthcare provider AND at least one of the following:From Day onwardsIncrease to mg/kgFever persistence or recurrencePlatelet count If 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 -1000/mm3 and decrease to 500/mm3 If baseline 1000-1500/mm3 and decrease to 1000/ mm3 Ferritin (ng/mL)If baseline >= 3000 ng/mL and 20% decreaseIf baseline 3000 ng/mL and any increase to 3000 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 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 count If 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 -1000/mm3 and decrease to 500/mm3 If baseline 1000-1500/mm3 and decrease to 1000/ mm3 If baseline 500/mm3 and no improvement to 500/mm3 If baseline 500 -1000/mm3 and decrease to 500/mm3 If baseline 1000-1500/mm3 and decrease to 1000/ mm3 Ferritin (ng/mL)If baseline >= 3000 ng/mL and 20% decreaseIf baseline 3000 ng/mL and any increase to 3000 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-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 D-DimerIf abnormal at baseline and no improvement 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. 2.5 Instructions for Preparation and Administration. PreparationGAMIFANT 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 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 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 syringe or an infusion bag, depending on the volume needed.Use gamma irradiated latex-free, polyvinyl chloride (PVC)-free syringe. Do not use with ethylene oxide-sterilized syringes.Use non-PVC polyolefin infusion bag.AdministrationAdminister GAMIFANT diluted solution intravenously over hour through an 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 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)].. Inspect GAMIFANT vials visually for particulate matter and discoloration prior to dilution. 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 to 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 syringe or an infusion bag, depending on the volume needed.. Use gamma irradiated latex-free, polyvinyl chloride (PVC)-free syringe. Do not use with ethylene oxide-sterilized syringes.. Use non-PVC polyolefin infusion bag.. Administer GAMIFANT diluted solution intravenously over hour through an 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 prior to administration.. Do not freeze. Do not shake.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of emapalumab-lzsg were evaluated in healthy adult subjects and in patients with primary 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 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 4.2 and 5.6 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.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 IFN, demonstrating target mediated clearance of emapalumab-lzsg.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 (2 to 82 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 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 StudiesNo drug-drug interaction studies have been conducted with GAMIFANT.

SPL MEDGUIDE SECTION.

MEDICATION GUIDEGAMIFANT(R) (gam fant) (emapalumab-lzsg)injection, for intravenous use What is the most important information should know about GAMIFANTGAMIFANT 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, 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 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 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 will 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 adults and children (newborn and older) with primary hemophagocytic lymphohistiocytosis (HLH) whose disease has come back or progressed, or other medicines have not worked well enough or cannot be tolerated.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 attenuated-live 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.GAMIFANT is given 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.GAMIFANT is used with another prescription medicine called dexamethasone. You can ask your healthcare provider for information about dexamethasone.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 are common with GAMIFANT, and can also be severe. Infusion reactions can happen during or shortly after treatment with GAMIFANT. Your healthcare provider may temporarily stop your infusion and treat your symptoms before continuing your infusion if you have severe infusion reactions. Tell your healthcare provider right away if you get any of the following symptoms:skin rednessitchingfeverrashexcessive sweatingchillschest painshortness of breathnausea or vomitinglightheadedness or dizziness The most common side effects of GAMIFANT include: high blood pressure (hypertension) and fever.These are not all of 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 yourhealthcare 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, andWater for Injection, USP Manufactured at: Patheon Italia S.p.A. Trav. SX Via Morolense, 5, 03013-Ferentino Italy Manufactured by: Swedish Orphan Biovitrum AB (publ), Stockholm, Sweden, U.S. License Number 1859 Distributed by: Sobi Inc., 890 Winter Street, Waltham, MA 02451 Product of the United Kingdom For more information call 1-866-773-5274 or go to www.gamifant.com This Medication Guide has been approved by the U.S. Food and Drug Administration.Issued: 05/2019. test you for TB before you start treatment with GAMIFANT.. treat you with medicine for TB if you 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 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.. 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 attenuated-live 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.. GAMIFANT is given 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.. GAMIFANT is used with another prescription medicine called dexamethasone. You can ask your healthcare provider for information about dexamethasone.. See What is the most important information should know about GAMIFANT. Infusion reactions. Infusion reactions are common with GAMIFANT, and can also be severe. Infusion reactions can happen during or shortly after treatment with GAMIFANT. Your healthcare provider may temporarily stop your infusion and treat your symptoms before continuing your infusion if you have severe infusion reactions. Tell your healthcare provider right away if you get any of the following symptoms:skin rednessitchingfeverrashexcessive sweatingchillschest painshortness of breathnausea or vomitinglightheadedness or dizziness skin redness. itching. fever. rash. excessive sweating. chills. chest pain. shortness of breath. nausea or vomiting. lightheadedness or dizziness.

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.DataAnimal 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, newborn and older, with primary HLH that is reactivated or refractory to conventional therapies. Use of GAMIFANT is supported by single-arm trial in 27 pediatric patients with reactivated or refractory primary HLH. This study included pediatric patients in the following age groups: patients newborn to months, 10 patients months to years, and 12 patients from 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Infections: Monitor patients for signs and symptoms and treat promptly. Test for latent tuberculosis. Administer prophylactic treatment against Herpes Zoster, Pneumocystis jiroveci 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 severe infusion reactions and institute appropriate medical management. (5.3). Infections: Monitor patients for signs and symptoms and treat promptly. Test for latent tuberculosis. Administer prophylactic treatment against Herpes Zoster, Pneumocystis jiroveci 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 severe 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 32% of patients receiving GAMIFANT in clinical trials, serious infections such as sepsis, pneumonia, bacteremia, disseminated histoplasmosis, necrotizing fasciitis, viral infections, and perforated appendicitis were observed. The reported infections were viral (41%), bacterial (35%), fungal (9%), and the pathogen was not identified in 15% of cases.Evaluate patients for tuberculosis risk factors and test for latent infection (PPD testing, PCR, or 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)].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 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 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 slower rate.