Ebanga

1 INDICATIONS AND USAGE EBANGA is indicated for the treatment of infection caused by Orthoebolavirus zairense (formerly Zaire ebolavirus) in adult and pediatric patients, including neonates born to a mother who is RT-PCR positive for Orthoebolavirus zairense infection [see Dosage and Administration (2.2) and Clinical Studies (14) ]. EBANGA (ansuvimab-zykl) is an Orthoebolavirus zairense glycoprotein (EBOV GP)-directed human monoclonal antibody indicated for the treatment of infection caused by Orthoebolavirus zairense in adult and pediatric patients, including neonates born to a mother who is RT-PCR positive for Orthoebolavirus zairense infection. ( 1 ) Limitation of Use • The efficacy of EBANGA has not been established for other species of the Orthoebolavirus and Orthomarburgvirus genera . • Orthoebolavirus zairense can change over time, and factors such as emergence of resistance or changes in viral virulence could diminish the clinical benefit of antiviral drugs. Consider available information on drug susceptibility patterns for circulating Orthoebolavirus zairense strains when deciding whether to use EBANGA. Limitations of Use: The efficacy of EBANGA has not been established for other species of the Orthoebolavirus and Orthomarburgvirus genera. Orthoebolavirus zairense can change over time, and factors such as emergence of resistance, or changes in viral virulence could diminish the clinical benefit of antiviral drugs. Consider available information on drug susceptibility patterns for circulating Orthoebolavirus zairense strains when deciding whether to use EBANGA.

2 DOSAGE AND ADMINISTRATION The recommended dose of EBANGA for adult and pediatric patients is 50 mg/kg reconstituted, further diluted, and administered as a single intravenous infusion over 60 minutes. ( 2.1 , 2.2 ) See Full Prescribing Information for instructions on preparation, dilution and administration of EBANGA injection. ( 2.2 ) 2.1 Recommended Dosage for Adult and Pediatric Patients The recommended dosage of EBANGA is 50 mg/kg administered as a single intravenous (IV) infusion over 60 minutes. EBANGA must be reconstituted with Sterile Water for Injection, USP then further diluted in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP prior to IV infusion [see Dosage and Administration (2.2) ] . 2.2. Preparation, Administration, and Storage Instructions EBANGA must be prepared and administered under the supervision of a health care professional. Reconstitution Instructions • Aseptically reconstitute and further dilute EBANGA prior to IV infusion. Do not administer as an IV push or bolus. • More than one vial may be needed for a full dose. Calculate the dose (mg) based on the patient’s actual weight in kg and the number of EBANGA vials required [see Dosage and Administration (2.1) ] . • Prior to reconstitution, allow EBANGA vial(s) to reach ambient temperature (15°C to 27°C [59°F to 81°F]) for approximately 20 minutes. If for any reason reconstitution cannot proceed immediately upon reaching ambient temperature, vials that have NOT been reconstituted may be kept at ambient temperature, protected from light, for no more than 24 hours. • Immediately upon reaching ambient temperature, use a sterile 10 mL syringe and an 18-gauge needle to withdraw 7.7 mL of Sterile Water for Injection, USP. Insert the needle tip into the EBANGA vial. Holding horizontally, angle the needle down at an approximate 45° angle, above the lyophilized powder, which has a cake-like appearance. Slowly inject the diluent along the wall of the vial and without any air to avoid foaming and bubbles. • Gently swirl (do NOT shake) for approximately 10 seconds; then set the vial down to rest for at least 10 seconds. Repeat until the cake is dissolved. This may take up to 20 minutes. • Upon reconstitution, one vial delivers 8 mL of solution that is clear to slightly opalescent and colorless to slightly yellow containing 50 mg/mL of ansuvimab-zykl. Do NOT administer and discard the vial if the reconstituted solution is discolored or contains visible particles. • Dilute the EBANGA solution immediately upon reconstitution. If needed, the reconstituted solution may be stored refrigerated at 2°C to 8°C (36°F to 46°F), protected from light, for up to 4 hours. This 4-hour window includes time required for further dilution and EBANGA solution should be infused immediately upon further dilution. Dilution Instructions • Following reconstitution, EBANGA must be further diluted prior to IV infusion. o Use an 18-20 gauge, 1-1.5” needle with an appropriately sized syringe up to 60 mL to perform the dilution steps. o Prepare the EBANGA IV dosing solution using an appropriately sized syringe up to 60 mL. • For patients weighing ≥ 2 kg, prepare the diluent using either a latex-free, di-ethylhexylphthalate (DEHP)-free 0.9% Sodium Chloride Injection USP infusion bag, or latex-free, DEHP-free 5% Dextrose Injection USP infusion bag. For patients weighing 0.5 to < 2 kg use a pump-compatible syringe ( Table 1 ). o For adult and pediatric patients, either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP can be used as the diluent. o The total volume of the infusion solution to be administered is based on the patient’s body weight and is specified in Table 1 . For patients weighing 0.5 to < 2 kg: - Use a 10 mL syringe compatible with the IV infusion pump. - Fill the 10 mL syringe with the appropriate amount of diluent ( Table 1 ). - Add the calculated volume of EBANGA to the 10 mL syringe ( Table 1 ). - Mix the diluted solution by gentle inversion (3 …

5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions Including Infusion-Associated Events: Hypersensitivity reactions including infusion-associated events have been reported with EBANGA. These may include acute, life- threatening reactions during and after the infusion. Monitor patients and in the case of severe or life-threatening hypersensitivity reactions, discontinue the administration of EBANGA immediately and administer appropriate emergency care. ( 5.1 ) 5.1 Hypersensitivity Reactions Including Infusion-Associated Events Hypersensitivity reactions including infusion-associated events have been reported with EBANGA. These may include acute, life-threatening reactions during and after the infusion. Monitor all patients for signs and symptoms including, but not limited to, hypotension, chills and elevation of fever, during and following EBANGA infusion. In the case of severe or life-threatening hypersensitivity reactions, discontinue the administration of EBANGA immediately and administer appropriate emergency care [see Adverse Reactions (6.1) ]. Infusion could not be completed in 1% of participants who received EBANGA due to infusion-associated adverse events. The rate of infusion of EBANGA may be slowed or interrupted if the patient develops any signs of infusion-associated events or other adverse events [see Adverse Reactions (6.1) ].

4 CONTRAINDICATIONS None . None.

7 DRUG INTERACTIONS Interaction with live vaccine indicated for prevention of Orthoebolavirus zairense infection: No vaccine interaction studies have been performed. EBANGA may reduce the efficacy of the live vaccine. The interval between administration of EBANGA therapy and live vaccination should be in accordance with current vaccination guidelines. ( 7.1 ) 7.1 Vaccine Interactions No vaccine-therapeutic interaction studies have been performed in human participants using EBANGA. However, because of the potential for EBANGA to inhibit replication of a live vaccine virus indicated for prevention of Orthoebolavirus zairense infection and possibly reduce the efficacy of the vaccine, avoid the concurrent administration of a live vaccine during treatment with EBANGA. The interval between administration of EBANGA therapy and live vaccination should be in accordance with current vaccination guidelines. The efficacy of EBANGA among participants who reported receipt of a recombinant live vaccine prior to their enrollment in the PALM trial was similar to participants who did not report receiving a vaccine prior to enrollment.

8.1 Pregnancy Risk Summary Orthoebolavirus zairense infection is life-threatening for both the mother and fetus and treatment should not be withheld due to pregnancy (see Clinical Considerations ) . Available data from the PALM trial in which pregnant women with Orthoebolavirus zairense infection were treated with EBANGA demonstrate the high rate of maternal and fetal/neonatal morbidity consistent with published literature regarding the risk associated with underlying maternal Orthoebolavirus zairense infection. These data are insufficient to evaluate for a drug associated risk of major birth defects, miscarriage, or adverse maternal/fetal outcome. Animal reproduction studies with ansuvimab-zykl have not been conducted. Monoclonal antibodies, such as EBANGA, are transported across the placenta; therefore, EBANGA has the potential to be transferred from the mother to the developing fetus. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Maternal, fetal and neonatal outcomes are poor among pregnant women infected with Orthoebolavirus zairense . The majority of such pregnancies result in maternal death with miscarriage, stillbirth, or neonatal death. Treatment should not be withheld due to pregnancy.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Hypersensitivity Reactions Including Infusion-Associated Events [see Warnings and Precautions (5.1) ] The most frequently reported adverse events (≥ 5%) after administration of EBANGA were pyrexia, tachycardia, diarrhea, vomiting, hypotension, tachypnea, and chills. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Emergent BioSolutions at 1-800-768-2304 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice. Overall, 424 adult and pediatric participants with Orthoebolavirus zairense infection received EBANGA in one clinical trial and as part of an expanded access program during the 2018 Orthoebolavirus zairense outbreak in the Democratic Republic of Congo (DRC). In the PALM trial, the safety of EBANGA was evaluated in a multi-center, open-label, randomized controlled trial, in which 173 participants (119 adults and 54 pediatric participants) with confirmed Orthoebolavirus zairense infection received EBANGA as a single 50 mg/kg IV infusion and 168 participants received an investigational control [see Clinical Studies (14) ] . All participants received optimized standard of care treatment (oSOC). The median age of the study population that received EBANGA was 26 years (range: 1 day to 85 years) and 55% were female. During the same outbreak, 251 participants (173 adults and 78 pediatric participants) with laboratory-confirmed Orthoebolavirus zairense infection received EBANGA under an expanded access program, 57% of whom were female. Ages ranged from 6 days to 80 years, with a median age of 25 years. Common Adverse Events Table 2 summarizes the adverse events that were reported in the PALM trial from a pre-defined list of signs and symptoms that occurred during EBANGA infusion. The evaluation of adverse events in participants who received EBANGA may have been confounded by the signs and symptoms of the underlying Orthoebolavirus zairense infection. Twenty nine percent (n=51) of participants who received EBANGA in the PALM Trial experienced a pre-specified infusion-related adverse event. The most common pre-specified infusion-related adverse event reported in at least 10% of participants who received EBANGA was fever ( Table 2 ). The adverse event profile in adult and pediatric participants treated with EBANGA was similar. Table 2 Adverse Events That Occurred During Infusion in >10% of Adult and Pediatric Participants in the PALM Trial Adverse Event a EBANGA (N=173) % Control b (N=168) % a Adverse events in this table were reported on the day of infusion, and included signs and symptoms that occurred during or immediately after infusion b Investigational therapy administered as three separate infusions c Adverse events that occurred during infusion but were not pre-specified. d The term chills includes other similar adverse events including rigors and tremors Pyrexia 17 58 Tachycardia 9 32 Diarrhea c 9 18 Vomiting c 8 23 Hypotension 8 31 Tachypnea 6 28 Chills d 5 33 Hypoxia c 3 11 The following pre-specified symptoms, which were assessed on a daily basis during admission while admitted to the treatment unit, were reported in ≥40% of participants who received EBANGA: diarrhea, pyrexia, abdominal pain, and vomiting. Evaluation of these symptoms may have been confounded by the underlying Orthoebolavirus zairense infection. Discontinuation and Infusion Rate Adjustments Approximately 99% of participants who received EBANGA in the PALM trial were able to complete their dose within one hour. Two participants who received EBANGA (1%) did not receive their complete infusion. In eight participants (5%) the EBANGA infusion rate was decreased due to an AE [see Warnings and Precautions (5.1) ] . Selected Laboratory Abnormaliti…