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warnings and cautions
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 ) 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 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 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.
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 )] 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 a 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 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 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.