GAMIFANT

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 ) 5.1 Infections GAMIFANT may increase the risk of fatal and serious infections to include specific pathogens favored by IFNγ neutralization, including mycobacteria, herpes zoster virus, and Histoplasma capsulatum . Do not administer 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 Still’s 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 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 )] . 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 a complete diagnostic workup appropriate for an immunocompromised patient, and initiate appropriate antimicrobial therapy. 5.2 Increased Risk of Infection with Use of Live Vaccines Do not administer live or live attenuated vaccines to patients receiving 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 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 Still’s 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 a slower rate.

6 ADVERSE REACTIONS The following adverse reactions are described elsewhere in the labeling: Infections [see Warnings and Precautions ( 5.1 )] Increased Risk of Infection with Use of Live Vaccines [see Warnings and Precautions ( 5.2 )] Infusion-Related Reactions [see Warnings and Precautions ( 5.3 )] In patients with primary HLH, the most common adverse reactions (≥ 20%) were: infections, hypertension, infusion-related reactions, and pyrexia. ( 6.1 ) In patients with HLH/MAS in Still’s disease, the most common adverse reactions (≥20%) were: viral infections, including cytomegalovirus infection or reactivation, and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact 1-866-773-5274 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Primary HLH The safety data described in this section reflect exposure to GAMIFANT in which 34 patients with untreated primary HLH and previously treated patients with primary HLH ( NCT01818492 ) received GAMIFANT at a starting dose of 1 mg/kg every 3 days with dose increases up to 10 mg/kg [see Dosage and Administration ( 2.1 ) and Clinical Studies ( 14 )] . The median duration of treatment with GAMIFANT was 59 days (range: 4 to 245 days) and the median cumulative dose was 25 mg/kg (range: 4 to 254 mg/kg). The median age of study population was 1 year (range: 0.1 to 13 years), 53% were female, and 65% were Caucasian. Serious adverse reactions were reported in 53% of patients. The most common serious adverse reactions (≥3%) included infections, gastrointestinal hemorrhage, and multiple organ dysfunction. Fatal adverse reactions occurred in two (6%) of patients and included septic shock and gastrointestinal hemorrhage. Disseminated histoplasmosis led to drug discontinuation in one patient. The most commonly reported adverse reactions (≥20%) were infections, hypertension, infusion-related reactions, and pyrexia. Adverse reactions reported in ≥10% of patients during treatment with GAMIFANT are presented in Table 4. Table 4 : Adverse Reactions Reported in 10% of Patients with Primary HLH Adverse Reactions GAMIFANT (%) (N = 34) Infections a 56 Hypertension b 41 Infusion-related reactions c 27 Pyrexia 24 Hypokalemia 15 Constipation 15 Rash 12 Abdominal pain 12 Cytomegalovirus infection 12 Diarrhea 12 Lymphocytosis 12 Cough 12 Irritability 12 Tachycardia 12 Tachypnea 12 a Includes viral, bacterial, fungal, and infections in which no pathogen was identified b Includes secondary hypertension c Includes events of drug eruption, pyrexia, rash, erythema, and hyperhidrosis Additional selected adverse reactions (all grades) that were reported in less than 10% of patients treated with GAMIFANT included: vomiting, acute kidney injury, asthenia, bradycardia, dyspnea, gastro-intestinal hemorrhage, epistaxis, and peripheral edema. HLH/MAS The safety of GAMIFANT was evaluated in two open-label clinical studies in patients with HLH/MAS in Stills disease, including sJIA [see Clinical Studies ( 14.2 )] . The pooled safety data from these two studies included 39 patients who received an initial dose of 6 mg/kg followed by 3 mg/kg every 3 days until Day 16, and then twice weekly thereafter. The median duration of treatment with GAMIFANT was 29 days (range: 7 to 220 days) and the median cumulative dose was 33 mg/kg (range: 12 to 175 mg/kg). Serious adverse reactions were reported in 12 patients (31%), with the most common serious adverse reaction being pneumonia (5%). Fatal adverse reactions occurred in two patients (5%) and included multiple organ dysfunction and circulatory shock. Pneumonia led to drug discontinuation in one patient (3%). The most common adverse reactions (≥20%) were viral infections, including cytomegalovirus infection or reactivation, and rash. Adverse reactions reported in ≥ 10% of patients in the pooled safety analysis up to Week 8 during treatment with GAMIFANT are presented in Table 5. Table 5: Adverse Reactions Reported in ≥10% of Patients with HLH/MAS in Still's disease Adverse Reactions GAMIFANT (%) (N = 39) Viral infection a Cytomegalovirus infection or reactivation 44 36 Rash b 21 Anemia c 18 Leukopenia d 15 Thrombosis 15 Bacterial infection 13 Headache 13 Hyperglycemia 13 Infusion-related reactions e 13 Abdominal pain 10 Hypertension 10 Pyrexia 10 Thrombocytopenia 10 a Includes: Cytomegalovirus infection reactivation, Cytomegalovirus infection, Adenovirus test positive, Cytomegalovirus test positive, BK polyomavirus test positive, Respirovirus test positive, Parainfluenzae virus infection, COVID-19, Rhinovirus infection, gastroenteritis Rotavirus, Adenovirus infection, Human herpesvirus 6 infection reactivation, Adenovirus reactivation b Includes: rash maculo-papular, rash erythematous, rash pruritic, urticaria c Includes: anemia macrocytic, and hypochromic anemia d Includes: granulocytopenia, neutropenia e Infusion-related reactions were defined as any event reported to have occurred within 24 hours after the start of infusion and assessed as related to study treatment

<table border="1" cellspacing="0" cellpadding="0"><thead><tr styleCode="First Last"><td valign="top"><paragraph styleCode="C-BodyText First"><content styleCode="bold">Adverse Reactions</content></paragraph></td><td valign="top"><paragraph styleCode="C-BodyText First"><content styleCode="bold">GAMIFANT</content></paragraph><paragraph styleCode="C-BodyText"><content styleCode="bold">(%)</content></paragraph><paragraph styleCode="C-BodyText"><content styleCode="bold">(N = 34)</content></paragraph></td></tr></thead><tbody><tr><td valign="top"><paragraph>Infections^a</paragraph></td><td valign="top"><paragraph> 56</paragraph></td></tr><tr><td valign="top"><paragraph>Hypertension^b</paragraph></td><td valign="top"><paragraph> 41</paragraph></td></tr><tr><td valign="top"><paragraph>Infusion-related reactions^c</paragraph></td><td valign="top"><paragraph> 27</paragraph></td></tr><tr><td valign="top"><paragraph>Pyrexia</paragraph></td><td valign="top"><paragraph> 24</paragraph></td></tr><tr><td valign="top"><paragraph>Hypokalemia</paragraph></td><td valign="top"><paragraph> 15</paragraph></td></tr><tr><td valign="top"><paragraph>Constipation</paragraph></td><td valign="top"><paragraph> 15</paragraph></td></tr><tr><td valign="top"><paragraph>Rash</paragraph></td><td valign="top"><paragraph> 12</paragraph></td></tr><tr><td valign="top"><paragraph>Abdominal pain</paragraph></td><td valign="top"><paragraph> 12</paragraph></td></tr><tr><td valign="top"><paragraph>Cytomegalovirus infection</paragraph></td><td valign="top"><paragraph> 12</paragraph></td></tr><tr><td valign="top"><paragraph>Diarrhea</paragraph></td><td valign="top"><paragraph> 12</paragraph></td></tr><tr><td valign="top"><paragraph>Lymphocytosis</paragraph></td><td valign="top"><paragraph> 12</paragraph></td></tr><tr><td valign="top"><paragraph>Cough</paragraph></td><td valign="top"><paragraph> 12</paragraph></td></tr><tr><td valign="top"><paragraph>Irritability </paragraph></td><td valign="top"><paragraph> 12</paragraph></td></tr><tr><td valign="top"><paragraph>Tachycardia</paragraph></td><td valign="top"><paragraph> 12</paragraph></td></tr><tr><td valign="top"><paragraph>Tachypnea </paragraph></td><td valign="top"><paragraph> 12</paragraph></td></tr></tbody></table>

<table border="1" cellspacing="0" cellpadding="0"><thead><tr styleCode="First Last"><td valign="top"><paragraph><content styleCode="bold">Adverse Reactions</content></paragraph></td><td valign="top"><paragraph><content styleCode="bold">GAMIFANT</content></paragraph><paragraph><content styleCode="bold">(%)</content></paragraph><paragraph><content styleCode="bold">(N = 39)</content></paragraph></td></tr></thead><tbody><tr><td><paragraph>Viral infection^a</paragraph><paragraph> Cytomegalovirus infection or reactivation</paragraph></td><td><paragraph> 44</paragraph><paragraph> 36</paragraph></td></tr><tr><td><paragraph>Rash^b</paragraph></td><td><paragraph> 21</paragraph></td></tr><tr><td><paragraph>Anemia^c</paragraph></td><td><paragraph> 18</paragraph></td></tr><tr><td><paragraph>Leukopenia^d</paragraph></td><td><paragraph> 15</paragraph></td></tr><tr><td><paragraph>Thrombosis</paragraph></td><td><paragraph> 15</paragraph></td></tr><tr><td><paragraph>Bacterial infection</paragraph></td><td><paragraph> 13</paragraph></td></tr><tr><td><paragraph>Headache</paragraph></td><td><paragraph> 13</paragraph></td></tr><tr><td><paragraph>Hyperglycemia</paragraph></td><td><paragraph> 13</paragraph></td></tr><tr><td><paragraph>Infusion-related reactions^e</paragraph></td><td><paragraph> 13</paragraph></td></tr><tr><td><paragraph>Abdominal pain</paragraph></td><td><paragraph> 10</paragraph></td></tr><tr><td><paragraph>Hypertension</paragraph></td><td><paragraph> 10</paragraph></td></tr><tr><td><paragraph>Pyrexia</paragraph></td><td><paragraph> 10</paragraph></td></tr><tr><td><paragraph>Thrombocytopenia</paragraph></td><td><paragraph> 10</paragraph></td></tr></tbody></table>