CLINICAL TRIALS EXPERIENCE SECTION.


6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates may not reflect the rates observed in practice.Overall, 382 adult and pediatric subjects with Zaire ebolavirus infection received INMAZEB in one clinical trial (the PALM trial) and as part of an expanded access program conducted in the Democratic Republic of Congo during Zaire ebolavirus outbreak in 2018-2019. In the PALM trial, the safety of INMAZEB was evaluated in multi-center, open-label, randomized controlled trial, in which 154 subjects (115 adult subjects and 39 pediatric subjects) received INMAZEB [50 mg of atoltivimab, 50 mg of maftivimab, and 50 mg of odesivimab per kg (3 mL/kg)] intravenously as single infusion and 168 subjects received an investigational control [see Clinical Studies (14)]. All subjects received optimized standard of care treatment. During the same outbreak, INMAZEB [50 mg of atoltivimab, 50 mg of maftivimab, and 50 mg of odesivimab per kg (3 mL/kg)] was given to 228 subjects (190 adult subjects and 38 pediatric subjects) in the expanded access program.The safety data described below is derived from the PALM trial.Table summarizes adverse events that were reported during INMAZEB infusion. The evaluation of adverse events in subjects who received INMAZEB may have been confounded by the signs and symptoms of the underlying Zaire ebolavirus infection. The most common adverse events reported in at least 20% of subjects who received INMAZEB were pyrexia (or elevation in fever), chills, tachycardia, tachypnea, and vomiting. The adverse event profile in adult and pediatric subjects treated with INMAZEB was similar.Table 4: Adverse Events That Occurred during INMAZEB Infusion in >=10% of Adult and Pediatric Subjects in the PALM TrialAdverse EventAdverse events in this table were reported as preferred terms from list of pre-defined or other adverse events that occurred on the day of infusion, and included signs and symptoms that occurred during or immediately after infusion INMAZEB(N=154)%ControlInvestigational therapy administered as three separate infusions (N=168)%Pyrexia (Elevation in fever)5458Chills3933Tachycardia2032Tachypnea1928VomitingAdverse events that were not pre-specified 1923Hypotension1531Diarrhea 1118Hypoxia 1011The following pre-specified symptoms, which were assessed on daily basis while admitted to the treatment unit, were reported in 40% or more of subjects who received INMAZEB: diarrhea, pyrexia, and vomiting. Evaluation of these symptoms may have been confounded by the underlying Zaire ebolavirus infection.. Discontinuation and Infusion Rate Adjustments in the PALM TrialApproximately 99% of subjects who received INMAZEB in the PALM trial were able to complete their dose within three hours. Two subjects who received INMAZEB (1%) did not receive their complete infusion. One of the two subjects did not complete their INMAZEB infusion because of fever elevation [see Warnings and Precautions (5.1)].. Selected Laboratory Abnormalities in the PALM TrialTable presents selected laboratory abnormalities (worsening to Grade or compared to baseline) for adult and pediatric subjects in the PALM trial.Table 5: Selected Grade and Laboratory Abnormalities, Worsened Grade from Baseline for Adult and Pediatric Subjects in the PALM TrialLaboratory TestGraded per Division of AIDS (DAIDS) v2.1 INMAZEBN=154%ControlN=168%ULN upper limit of normalSodium, high >= 154 mmol/L94Sodium, low 125 mmol/L711Potassium, high >= 6.5 mmol/L1312Potassium, low 2.5 mmol/L98Creatinine (mg/dL) >= 1.8 ULNULN for creatinine was 1.2 mg/dL. Criterion for increase to >= 1.5 from baseline was applied if the worsening grade was higher. 1523Alanine aminotransferase (U/L) >= x ULN1014Aspartate aminotransferase (U/L) >= x ULN2118.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS. None.. None. (4).

ADVERSE REACTIONS SECTION.


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)] Hypersensitivity Reactions Including Infusion-Associated Events [see Warnings and Precautions (5.1)] The most common adverse events (incidence >=20%) were pyrexia, chills, tachycardia, tachypnea, and vomiting. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Regeneron at 1-844-734-6643 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 may not reflect the rates observed in practice.Overall, 382 adult and pediatric subjects with Zaire ebolavirus infection received INMAZEB in one clinical trial (the PALM trial) and as part of an expanded access program conducted in the Democratic Republic of Congo during Zaire ebolavirus outbreak in 2018-2019. In the PALM trial, the safety of INMAZEB was evaluated in multi-center, open-label, randomized controlled trial, in which 154 subjects (115 adult subjects and 39 pediatric subjects) received INMAZEB [50 mg of atoltivimab, 50 mg of maftivimab, and 50 mg of odesivimab per kg (3 mL/kg)] intravenously as single infusion and 168 subjects received an investigational control [see Clinical Studies (14)]. All subjects received optimized standard of care treatment. During the same outbreak, INMAZEB [50 mg of atoltivimab, 50 mg of maftivimab, and 50 mg of odesivimab per kg (3 mL/kg)] was given to 228 subjects (190 adult subjects and 38 pediatric subjects) in the expanded access program.The safety data described below is derived from the PALM trial.Table summarizes adverse events that were reported during INMAZEB infusion. The evaluation of adverse events in subjects who received INMAZEB may have been confounded by the signs and symptoms of the underlying Zaire ebolavirus infection. The most common adverse events reported in at least 20% of subjects who received INMAZEB were pyrexia (or elevation in fever), chills, tachycardia, tachypnea, and vomiting. The adverse event profile in adult and pediatric subjects treated with INMAZEB was similar.Table 4: Adverse Events That Occurred during INMAZEB Infusion in >=10% of Adult and Pediatric Subjects in the PALM TrialAdverse EventAdverse events in this table were reported as preferred terms from list of pre-defined or other adverse events that occurred on the day of infusion, and included signs and symptoms that occurred during or immediately after infusion INMAZEB(N=154)%ControlInvestigational therapy administered as three separate infusions (N=168)%Pyrexia (Elevation in fever)5458Chills3933Tachycardia2032Tachypnea1928VomitingAdverse events that were not pre-specified 1923Hypotension1531Diarrhea 1118Hypoxia 1011The following pre-specified symptoms, which were assessed on daily basis while admitted to the treatment unit, were reported in 40% or more of subjects who received INMAZEB: diarrhea, pyrexia, and vomiting. Evaluation of these symptoms may have been confounded by the underlying Zaire ebolavirus infection.. Discontinuation and Infusion Rate Adjustments in the PALM TrialApproximately 99% of subjects who received INMAZEB in the PALM trial were able to complete their dose within three hours. Two subjects who received INMAZEB (1%) did not receive their complete infusion. One of the two subjects did not complete their INMAZEB infusion because of fever elevation [see Warnings and Precautions (5.1)].. Selected Laboratory Abnormalities in the PALM TrialTable presents selected laboratory abnormalities (worsening to Grade or compared to baseline) for adult and pediatric subjects in the PALM trial.Table 5: Selected Grade and Laboratory Abnormalities, Worsened Grade from Baseline for Adult and Pediatric Subjects in the PALM TrialLaboratory TestGraded per Division of AIDS (DAIDS) v2.1 INMAZEBN=154%ControlN=168%ULN upper limit of normalSodium, high >= 154 mmol/L94Sodium, low 125 mmol/L711Potassium, high >= 6.5 mmol/L1312Potassium, low 2.5 mmol/L98Creatinine (mg/dL) >= 1.8 ULNULN for creatinine was 1.2 mg/dL. Criterion for increase to >= 1.5 from baseline was applied if the worsening grade was higher. 1523Alanine aminotransferase (U/L) >= x ULN1014Aspartate aminotransferase (U/L) >= x ULN2118. 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 study described below with the incidence of antibodies in other studies or to other atoltivimab, maftivimab, and odesivimab products may be misleading.The development of anti-atoltivimab, anti-maftivimab, and anti-odesivimab antibodies was evaluated in 24 healthy adults in single dose, randomized, double-blind, placebo-controlled, dose escalation study. Immunogenic responses against atoltivimab, maftivimab, and odesivimab were not detected at baseline or through 168 days post-dose in any subjects.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity, genotoxicity, and fertility studies have not been conducted with INMAZEB.

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. INMAZEB is an antiviral drug combination of three recombinant human IgG1 monoclonal antibodies (atoltivimab, maftivimab, and odesivimab) that inhibit Zaire ebolavirus [see Microbiology (12.4) ].. 12.2 Pharmacodynamics. Atoltivimab, maftivimab, and odesivimab exposure-response relationships and the time course of pharmacodynamic response are unknown.. 12.3 Pharmacokinetics. No pharmacokinetic data are available in patients with Zaire ebolavirus infection. The pharmacokinetics of atoltivimab, maftivimab, and odesivimab in 18 healthy subjects 21 to 60 years of age are linear and dose-proportional over the range of mg of atoltivimab, mg of maftivimab, and mg of odesivimab per kg to 50 mg of atoltivimab, 50 mg of maftivimab, and 50 mg of odesivimab per kg (0.02 to times the approved recommended dosage) of INMAZEB following single intravenous (IV) infusion. Pharmacokinetic parameters for the individual antibodies of INMAZEB are provided in Table 6.Table 6: Pharmacokinetic Parameters of INMAZEB Administered IV in Healthy SubjectsAtoltivimab50 mg/kgINMAZEB was administered at total dose of 50 mg of atoltivimab, 50 mg of maftivimab, and 50 mg of odesivimab per kg in 1:1:1 ratio. Maftivimab50 mg/kg Odesivimab50 mg/kg Systemic Exposure (n=6)Mean (SD) Cmax, mg/L1,220 (101)1,280 (68.0)1,260 (81.2)Mean (SD) AUCinf, mg day/L17,100 (4,480)18,700 (4,100)25,600 (5,040)DistributionMean (SD) Volume of Distribution at Steady State, mL/kg58.2 (2.66)57.6 (3.89)56.0 (3.16)EliminationMean (SD) Elimination Half-Life (days)21.2 (3.36)22.3 (3.09)25.3 (3.86)Mean (SD) Clearance (mL/day/kg)3.08 (0.719)2.78 (0.558)2.02 (0.374). Specific PopulationsThe effect of age (< 21 or 60), renal impairment, or hepatic impairment on the pharmacokinetics of atoltivimab, maftivimab, and odesivimab is unknown.. 12.4 Microbiology. Mechanism of ActionINMAZEB is combination of three recombinant human IgG1 monoclonal antibodies each targeting the Zaire ebolavirus glycoprotein (GP). Zaire ebolavirus encodes sole envelope protein, the glycoprotein, which mediates virus attachment and membrane fusion with the host cell membranes. In addition, GP is expressed on the surface of Zaire ebolavirus infected host cells making it target for antibodies that can mediate killing of these cells by antibody dependent cellular cytotoxicity and/or other effector functions. The antibodies that make up the combination can bind the GP simultaneously. The mean KD values for atoltivimab, odesivimab, and maftivimab were 7.84 nM, 8.26 nM, and 3.34 nM, respectively, as determined by surface plasmon resonance. Maftivimab is neutralizing antibody that blocks entry of the virus into susceptible cells. Odesivimab is non-neutralizing antibody that induces antibody-dependent effector function through FcyRIIIa signaling when bound to its target. Odesivimab also binds to the soluble form of Zaire ebolavirus glycoprotein (sGP). Atoltivimab combines both neutralization and FcyRIIIa signaling activities.. Antiviral ActivityIn live virus infection assay on Vero cells, maftivimab neutralized Mayinga, Kikwit, and Makona strains of Zaire ebolavirus, with concentration between 0.2 and 1.2 nM (0.03 and 0.18 ug/mL) providing 80% inhibition of viral infection in plaque-reduction neutralization test (PRNT-80). Atoltivimab and odesivimab did not demonstrate any neutralizing activity in this assay. Effector function activity of INMAZEB individual antibodies was assessed with an EBOV Makona-GP expressing cell line and Jurkat/NFAT-Luc/FcRIIIa reporter effector cells. The EC50 values of atoltivimab and odesivimab were 2.9 nM and 1.6 nM, respectively, whereas maftivimab did not exhibit any FcRIIIa signaling activity at the maximum concentration tested, 40 nM.Treatment of Zaire ebolavirus infected rhesus macaques with single intravenous dose of INMAZEB (50 mg of atoltivimab, 50 mg of maftivimab, and 50 mg of odesivimab per kg) generally protected infected animals from Zaire ebolavirus mediated death when drug was administered days post-infection.. ResistanceNo clinical data are available on the development of EBOV resistance to INMAZEB. The cell culture development of EBOV resistance to INMAZEB has not been assessed to date. GPE280G amino acid substitution identified by routine surveillance in the Democratic Republic of the Congo resulted in loss of neutralization activity of at least 134-fold mediated by the single human monoclonal antibody atoltivimab in lentivirus-based pseudovirus system. GPE564K substitution identified in an infected NHP PK study resulted in loss of neutralization activity of at least 215-fold mediated by the single human monoclonal antibody maftivimab in lentivirus-based pseudovirus system. The clinical significance of these substitutions is unknown.. Immune ResponseInteraction studies with recombinant live EBOV vaccines and INMAZEB have not been conducted [see Drug Interactions (7.1)].

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES. The efficacy of INMAZEB was evaluated in PALM, multi-center, open-label, randomized controlled trial sponsored by the National Institute of Allergy and Infectious Diseases (NIAID; NCT03719586). The trial was conducted in the Democratic Republic of Congo, where an outbreak began in August 2018, and enrolled 681 subjects of all ages, including pregnant women, with documented Zaire ebolavirus infection and symptoms of any duration who were receiving optimized standard of care (oSOC). Subjects were randomized to receive INMAZEB (50 mg of atoltivimab, 50 mg of maftivimab, and 50 mg of odesivimab per kg) intravenously as single infusion, an investigational control 50 mg/kg intravenously every third day, for total of doses, or other investigational drugs. Eligible subjects had positive reverse transcriptase-polymerase chain reaction (RT-PCR) for the nucleoprotein (NP) gene of Zaire ebolavirus and had not received other investigational treatments (with the exception of experimental vaccines) within the previous 30 days. Neonates <=7 days of age were eligible if the mother had documented infection. Neonates born to mother who had cleared Zaire ebolavirus following course of her assigned investigational medication were also eligible to be enrolled at investigator discretion regarding the likelihood that the neonate was infected. Randomization was stratified by reverse transcription-PCR cycle threshold calculated using NP targets (CtNP <=22.0 vs >22.0; corresponding to high and low viral load, respectively) and Ebola Treatment Unit (ETU) site. All subjects received oSOC consisting of minimum of intravenous fluids, daily clinical laboratory testing, correction of hypoglycemia and electrolyte imbalances, and broad-spectrum antibiotics and antimalarials, as indicated .The primary efficacy endpoint was 28-day mortality. The primary analysis population includes all subjects who were randomized and concurrently eligible to receive either INMAZEB or the investigational control during the same time period of the trial.The demographics and baseline characteristics are provided in Table below.Table 7: Demographics and Baseline Characteristics in PALM TrialParameterINMAZEB(N=154)Control(N=153)CtNP cycle threshold calculated using NP targets; IQR interquartile range; AST=Aspartate aminotransferase; ALT=Alanine aminotransferase; ETU=Ebola treatment unitMean age (years)2831Age <1 month (%)1 (1%)2 (1%)Age month to <1 year (%)4 (3%)1 (1%)Age year to 6 years (%)18 (12%)13 (8%)Age years to <12 years (%)8 (5%)4 (3%)Age 12 years to <18 years (%)8 (5%)8 (5%)Age 18 years to <50 years (%)93 (60%)105 (69%)Age 50 years to <65 years (%)17 (11%)18 (12%)Age >=65 years (%)5 (3%)2 (1%)Female (%)90 (58%)80 (52%) Positive result on pregnancy testPregnancy positive test was calculated based on subjects who had pregnancy test result., (%)2/67 (3%)4/61 (7%)RT-PCR CtNP cycle threshold <=22, n6664Median RT-PCR CtNP (IQR)22.7 (20.1, 28.1)22.9 (18.8, 26.4)Median creatinine (IQR)1.0 (0.7, 4.0)1.1 (0.7, 3.2)Median AST (IQR)225.5 (98.0, 941.0)351.0 (109, 1404.0)Median ALT (IQR)165.0 (56.0, 418.0)223.5 (47.0, 564.0)Median days from onset of symptoms to randomization (IQR)5.0 (3.0, 7.0)5.0 (3.0, 7.0)Reported Vaccination with rVSV-ZEBOV vaccine, (%)34 (22%)41 (27%) <10 days before ETU admission20/34 (59%)21/41 (51%) >=10 days before ETU admission14/34 (41%)18/41 (44%) Timing unknown0/34 (0%)2/41 (5%)The PALM trial was stopped early on the basis of pre-specified interim analysis showing statistically significant reduction in mortality for INMAZEB compared to control.Mortality efficacy results are shown in Table 8.Table 8: Mortality Rates in PALM TrialEfficacy EndpointsINMAZEBBoth INMAZEB and Control were administered with optimized standard of care (N=154)Control (N=153)Overall28-day mortality, (%)52 (34%)78 (51%)Mortality rate difference relative to control (95% CI)-17.2 (-28.4, -2.6)p-ValueThe result is significant according to the interim stopping boundary, p<0.028 0.0024Baseline Viral LoadHigh viral load (CtNP <= 22)Cepheid GeneXpert Ebola(R) Assay used for detection of Zaire ebolavirus RNAn=66n=6428-day mortality, (%)42 (64%)56 (88%)Mortality rate difference relative to control (95% CI)-23.9 (-43.8, -6.4)Low viral load (CtNP 22)n=88n=8828-day mortality, (%)10 (11%)22 (25%)Mortality rate difference relative to control (95% CI)-13.6 (-31.8, -1.4)Age groupAdults (age >=18 years)39/115 (34%)67/125 (54%)12 to 18 years of age2/8 (25%)4/8 (50%)6 to 12 years of age1/8 (13%)1/4 (25%)< years of age10/23 (43%)6/16 (38%)SexMale21/64 (33%)31/73 (42%)Female31/90 (34%)47/80 (59%)Figure 1: Kaplan-Meier Curve for Overall Mortality. Figure 1.

DESCRIPTION SECTION.


11 DESCRIPTION. Atoltivimab, maftivimab, and odesivimab-ebgn is combination of Zaire ebolavirus glycoprotein (GP) directed recombinant human IgG1 human monoclonal antibodies of similar structure. The human monoclonal antibodies, atoltivimab, maftivimab, and odesivimab are produced by recombinant DNA technology in Chinese hamster ovary (CHO) cell suspension culture and have an approximate molecular weight of 145 kDa, 146 kDa and 144 kDa, respectively.INMAZEB (atoltivimab, maftivimab, and odesivimab-ebgn) injection for intravenous use is sterile, preservative-free, clear to slightly opalescent, colorless to pale yellow solution, that is free from visible particulates.INMAZEB injection is supplied as two strength presentations:16.67 mg/16.67 mg/16.67 mg per mL: Each vial contains 241.7 mg of atoltivimab, 241.7 mg of maftivimab, and 241.7 mg of odesivimab in 14.5 mL. Each mL contains 16.67 mg of atoltivimab, 16.67 mg of maftivimab, 16.67 mg of odesivimab, and L-histidine (0.74 mg), L-histidine monohydrochloride monohydrate (1.09 mg), polysorbate 80 (1 mg), sucrose (100 mg), and Water for Injection, USP with pH of 6.0.33.33 mg/33.33 mg/33.33 mg per mL: Each vial contains 483.3 mg of atoltivimab, 483.3 mg of maftivimab, and 483.3 mg of odesivimab in 14.5 mL. Each mL contains 33.33 mg of atoltivimab, 33.33 mg of maftivimab, 33.33 mg of odesivimab, and L-histidine (0.74 mg), L-histidine monohydrochloride monohydrate (1.09 mg), polysorbate 80 (1 mg), sucrose (100 mg), and Water for Injection, USP with pH of 6.0.. 16.67 mg/16.67 mg/16.67 mg per mL: Each vial contains 241.7 mg of atoltivimab, 241.7 mg of maftivimab, and 241.7 mg of odesivimab in 14.5 mL. Each mL contains 16.67 mg of atoltivimab, 16.67 mg of maftivimab, 16.67 mg of odesivimab, and L-histidine (0.74 mg), L-histidine monohydrochloride monohydrate (1.09 mg), polysorbate 80 (1 mg), sucrose (100 mg), and Water for Injection, USP with pH of 6.0.. 33.33 mg/33.33 mg/33.33 mg per mL: Each vial contains 483.3 mg of atoltivimab, 483.3 mg of maftivimab, and 483.3 mg of odesivimab in 14.5 mL. Each mL contains 33.33 mg of atoltivimab, 33.33 mg of maftivimab, 33.33 mg of odesivimab, and L-histidine (0.74 mg), L-histidine monohydrochloride monohydrate (1.09 mg), polysorbate 80 (1 mg), sucrose (100 mg), and Water for Injection, USP with pH of 6.0.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION. The recommended dosage of INMAZEB is 50 mg of atoltivimab, 50 mg of maftivimab, and 50 mg of odesivimab per kg diluted and administered as single intravenous infusion. (2.1)Refer to the Full Prescribing Information for information on preparation and administration. (2.2). 2.1Recommended Dosage. INMAZEB is combination of three human monoclonal antibodies co-formulated in 1:1:1 ratio of atoltivimab, maftivimab, and odesivimab. INMAZEB is available as two different strength presentations, containing either 16.67 mg of each antibody per mL or 33.33 mg of each antibody per mL [see Dosage Forms and Strengths (3)].The recommended dosage of INMAZEB is 50 mg of atoltivimab, 50 mg of maftivimab, and 50 mg of odesivimab per kg diluted and administered as single intravenous infusion as shown in Table [see Dosage and Administration (2.2)].. 2.2Preparation and Administration. INMAZEB must be prepared and administered under the supervision of healthcare provider. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. INMAZEB should be clear to slightly opalescent, colorless to pale yellow solution that is free from visible particulates. Discard the vial if the solution is cloudy, discolored or contains particulate matter.. Preparation for Intravenous InfusionThe recommended dosage is based on 50 mg of atoltivimab, 50 mg of maftivimab, and 50 mg of odesivimab per kg. For example, patient weighing 50 kg the recommended dosage is 2,500 mg of atoltivimab, 2,500 mg of maftivimab, and 2,500 mg of odesivimab.Determine the number of vials needed based on the calculated dose in volume (mL). -The number of vials needed depends on the INMAZEB strength used. Refer to Table for the corresponding volume per kg needed to withdraw from each available strength presentation to prepare dose.-Multiple INMAZEB vials may be needed. Each vial contains 14.5 mL of INMAZEB solution, regardless of the strength presentation. For example, for 50 kg patient, the volume of INMAZEB needed is 150 mL (11 vials) if using the 16.67 mg/16.67 mg/16.67 mg per mL solution or 75 mL (5 vials) if using the 33.33 mg/33.33 mg/33.33 mg per mL solution. Table 1: INMAZEB Dosage (Volume per kg) for Intravenous Infusion PreparationWhen Using theWhen Using the241.7 mg of atoltivimab, 241.7 mg of maftivimab, and 241.7 mg of odesivimab per 14.5 mL483.3 mg of atoltivimab, 483.3 mg of maftivimab, and 483.3 mg of odesivimab per 14.5 mL(16.67 mg /16.67 mg /16.67 mg per mL) Solution(33.33 mg/33.33 mg /33.33 mg per mL) SolutionWithdraw mL of solution per kg to prepare the doseWithdraw 1.5 mL of solution per kg to prepare the doseDo not shake the vial.Prior to intravenous infusion, INMAZEB must be further diluted in an intravenous PVC infusion bag containing either 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP, or Lactated Ringers Injection, USP. For neonates, the INMAZEB solution should be diluted in 5% Dextrose Injection, USP (see Table 2). The total volume of the infusion solution to be administered is based on the patients body weight and is specified in Table 2. Select diluent solution infusion bag of appropriate fill volume based on the patients body weight (see Table 2). Withdraw and discard from the bag volume of diluent solution equal to the calculated dose in volume (mL) of INMAZEB. Then add the calculated volume of INMAZEB to the bag. For example:-When using the 16.67 mg/16.67 mg/16.67 mg per mL solution for 50 kg patient, withdraw and discard 150 mL of diluent from 500 mL infusion bag. Then add 150 mL of INMAZEB to obtain total infusion volume of 500 mL.-When using the 33.33 mg/33.33 mg/33.33 mg per mL solution for 50 kg patient, withdraw and discard 75 mL of diluent from 500 mL infusion bag. Then add 75 mL of INMAZEB to obtain total infusion volume of 500 mL. Table 2: INMAZEB Infusion Volumes and Times by Body WeightBody Weight (kg)Total Infusion Volume After Dilution (mL)The recommended infusion volume ensures the final concentration of the diluted solution is 9.5 mg/mL to 23.7 mg/mL for the 16.67 mg/16.67 mg/16.67 mg per mL solution and 9.5 mg/mL to 30 mg/mL for the 33.33 mg/33.33 mg/33.33 mg per mL solution. 5% Dextrose Injection, USP is recommended for neonates. Infusion Time0.5 to less than 174 hours1 to 1.9152 to 3.9253 hours to 7508 to 1510016 to 382502 hours 39 to 7950080 to 1491,000150 and above2,0004 hoursMix the diluted solution by gentle inversion. Do not shake.INMAZEB does not contain preservatives. It is always recommended to administer intravenous medication immediately after preparation when possible. Store the diluted INMAZEB solution as specified in Table 3.Do not freeze the diluted solution.Discard any unused medicinal product or waste material.Table 3: Diluted INMAZEB Solution Storage ConditionsDiluent Used to Prepare Solution for InfusionDiluted INMAZEB Solution Storage Conditions0.9% Sodium Chloride Injection, USPStore at room temperature up to 25C (77F) for no more than hours or refrigerated at 2C to 8C (36F to 46F) for no more than 24 hours.5% Dextrose Injection, USP or Lactated Ringers Injection, USPStore at room temperature up to 25C (77F) for no more than hours or refrigerated at 2C to 8C (36F to 46F) for no more than hours.. The recommended dosage is based on 50 mg of atoltivimab, 50 mg of maftivimab, and 50 mg of odesivimab per kg. For example, patient weighing 50 kg the recommended dosage is 2,500 mg of atoltivimab, 2,500 mg of maftivimab, and 2,500 mg of odesivimab.. Determine the number of vials needed based on the calculated dose in volume (mL). -The number of vials needed depends on the INMAZEB strength used. Refer to Table for the corresponding volume per kg needed to withdraw from each available strength presentation to prepare dose.-Multiple INMAZEB vials may be needed. Each vial contains 14.5 mL of INMAZEB solution, regardless of the strength presentation. For example, for 50 kg patient, the volume of INMAZEB needed is 150 mL (11 vials) if using the 16.67 mg/16.67 mg/16.67 mg per mL solution or 75 mL (5 vials) if using the 33.33 mg/33.33 mg/33.33 mg per mL solution. -The number of vials needed depends on the INMAZEB strength used. Refer to Table for the corresponding volume per kg needed to withdraw from each available strength presentation to prepare dose.. -Multiple INMAZEB vials may be needed. Each vial contains 14.5 mL of INMAZEB solution, regardless of the strength presentation. For example, for 50 kg patient, the volume of INMAZEB needed is 150 mL (11 vials) if using the 16.67 mg/16.67 mg/16.67 mg per mL solution or 75 mL (5 vials) if using the 33.33 mg/33.33 mg/33.33 mg per mL solution.. Do not shake the vial.. Prior to intravenous infusion, INMAZEB must be further diluted in an intravenous PVC infusion bag containing either 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP, or Lactated Ringers Injection, USP. For neonates, the INMAZEB solution should be diluted in 5% Dextrose Injection, USP (see Table 2). The total volume of the infusion solution to be administered is based on the patients body weight and is specified in Table 2. Select diluent solution infusion bag of appropriate fill volume based on the patients body weight (see Table 2). Withdraw and discard from the bag volume of diluent solution equal to the calculated dose in volume (mL) of INMAZEB. Then add the calculated volume of INMAZEB to the bag. For example:-When using the 16.67 mg/16.67 mg/16.67 mg per mL solution for 50 kg patient, withdraw and discard 150 mL of diluent from 500 mL infusion bag. Then add 150 mL of INMAZEB to obtain total infusion volume of 500 mL.-When using the 33.33 mg/33.33 mg/33.33 mg per mL solution for 50 kg patient, withdraw and discard 75 mL of diluent from 500 mL infusion bag. Then add 75 mL of INMAZEB to obtain total infusion volume of 500 mL. -When using the 16.67 mg/16.67 mg/16.67 mg per mL solution for 50 kg patient, withdraw and discard 150 mL of diluent from 500 mL infusion bag. Then add 150 mL of INMAZEB to obtain total infusion volume of 500 mL.. -When using the 33.33 mg/33.33 mg/33.33 mg per mL solution for 50 kg patient, withdraw and discard 75 mL of diluent from 500 mL infusion bag. Then add 75 mL of INMAZEB to obtain total infusion volume of 500 mL.. Mix the diluted solution by gentle inversion. Do not shake.. INMAZEB does not contain preservatives. It is always recommended to administer intravenous medication immediately after preparation when possible. Store the diluted INMAZEB solution as specified in Table 3.. Do not freeze the diluted solution.. Discard any unused medicinal product or waste material.. AdministrationINMAZEB must be administered by healthcare provider.Allow the diluted infusion solution to come to room temperature prior to administration.Administer the diluted infusion solution intravenously through an intravenous line containing sterile, in-line or add-on 0.2-micron filter.The infusion rate is based on the patients body weight and prepared infusion volume. Select an appropriate infusion rate for the diluted infusion solution (see Table 2). It is important to follow the infusion time outlined in Table based on the patients weight.The rate of infusion of INMAZEB may be slowed or interrupted if the patient develops any signs of infusion-associated events or other adverse events [see Warnings and Precautions (5.1)].Do not mix other medications with INMAZEB.Compatibility studies of INMAZEB have not been performed when co-administering other drugs simultaneously through the same infusion line.. INMAZEB must be administered by healthcare provider.. Allow the diluted infusion solution to come to room temperature prior to administration.. Administer the diluted infusion solution intravenously through an intravenous line containing sterile, in-line or add-on 0.2-micron filter.. The infusion rate is based on the patients body weight and prepared infusion volume. Select an appropriate infusion rate for the diluted infusion solution (see Table 2). It is important to follow the infusion time outlined in Table based on the patients weight.. The rate of infusion of INMAZEB may be slowed or interrupted if the patient develops any signs of infusion-associated events or other adverse events [see Warnings and Precautions (5.1)].. Do not mix other medications with INMAZEB.. Compatibility studies of INMAZEB have not been performed when co-administering other drugs simultaneously through the same infusion line.

DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS. INMAZEB is clear to slightly opalescent and colorless to pale yellow solution available as:Injection: 241.7 mg of atoltivimab, 241.7 mg of maftivimab, and 241.7 mg of odesivimab per 14.5 mL (16.67 mg/16.67 mg/16.67 mg per mL) in single-dose vial.Injection: 483.3 mg of atoltivimab, 483.3 mg of maftivimab, and 483.3 mg of odesivimab per 14.5 mL (33.33 mg/33.33 mg/33.33 mg per mL) in single-dose vial.. Injection: 241.7 mg of atoltivimab, 241.7 mg of maftivimab, and 241.7 mg of odesivimab per 14.5 mL (16.67 mg/16.67 mg/16.67 mg per mL) in single-dose vial.. Injection: 483.3 mg of atoltivimab, 483.3 mg of maftivimab, and 483.3 mg of odesivimab per 14.5 mL (33.33 mg/33.33 mg/33.33 mg per mL) in single-dose vial.. Injection:241.7 mg of atoltivimab, 241.7 mg of maftivimab, and 241.7 mg of odesivimab per 14.5 mL (16.67 mg/16.67 mg/16.67 mg per mL) in single-dose vial. (3)483.3 mg of atoltivimab, 483.3 mg of maftivimab, and 483.3 mg of odesivimab per 14.5 mL (33.33 mg/33.33 mg/33.33 mg per mL) in single-dose vial. (3). 241.7 mg of atoltivimab, 241.7 mg of maftivimab, and 241.7 mg of odesivimab per 14.5 mL (16.67 mg/16.67 mg/16.67 mg per mL) in single-dose vial. (3). 483.3 mg of atoltivimab, 483.3 mg of maftivimab, and 483.3 mg of odesivimab per 14.5 mL (33.33 mg/33.33 mg/33.33 mg per mL) in single-dose vial. (3).

DRUG INTERACTIONS SECTION.


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

GERIATRIC USE SECTION.


8.5 Geriatric Use. Clinical studies of INMAZEB did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 154 subjects with Zaire ebolavirus infection who received INMAZEB in the randomized controlled trial, (3.2%) were 65 years or older. The limited clinical experience has not identified differences in responses between the elderly and younger subjects.

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING. INMAZEB (atoltivimab, maftivimab, and odesivimab-ebgn) injection is clear to slightly opalescent and colorless to pale yellow solution. It is supplied in carton containing one single dose vial of:241.7 mg of atoltivimab, 241.7 mg of maftivimab, and 241.7 mg of odesivimab per 14.5 mL (16.67 mg/16.67 mg/16.67 mg per mL) (NDC 61755-018-01)483.3 mg of atoltivimab, 483.3 mg of maftivimab, and 483.3 mg of odesivimab per 14.5 mL (33.33 mg/33.33 mg/33.33 mg per mL) (NDC 61755-019-01). 241.7 mg of atoltivimab, 241.7 mg of maftivimab, and 241.7 mg of odesivimab per 14.5 mL (16.67 mg/16.67 mg/16.67 mg per mL) (NDC 61755-018-01). 483.3 mg of atoltivimab, 483.3 mg of maftivimab, and 483.3 mg of odesivimab per 14.5 mL (33.33 mg/33.33 mg/33.33 mg per mL) (NDC 61755-019-01). Prior to dilutionStore INMAZEB vial refrigerated at 2C to 8C (36F to 46F) in the original carton to protect from light. Do not freeze or shake.. After dilutionINMAZEB does not contain preservatives. It is always recommended to administer intravenous medication immediately after preparation when possible. Store the diluted INMAZEB solution as specified according to Table below. Do not freeze the diluted solution [see Dosage and Administration (2.2)]. Table 9: Diluted INMAZEB Solution Storage ConditionsDiluent Used to Prepare Solution for InfusionDiluted INMAZEB Solution Storage Conditions0.9% Sodium Chloride Injection, USPStore at room temperature up to 25C (77F) for no more than hours or refrigerated at 2C to 8C (36F to 46F) for no more than 24 hours.5% Dextrose Injection, USP or Lactated Ringers Injection, USPStore at room temperature up to 25C (77F) for no more than hours or refrigerated or at 2C to 8C (36F to 46F) for no more than hours.

IMMUNOGENICITY.


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 study described below with the incidence of antibodies in other studies or to other atoltivimab, maftivimab, and odesivimab products may be misleading.The development of anti-atoltivimab, anti-maftivimab, and anti-odesivimab antibodies was evaluated in 24 healthy adults in single dose, randomized, double-blind, placebo-controlled, dose escalation study. Immunogenic responses against atoltivimab, maftivimab, and odesivimab were not detected at baseline or through 168 days post-dose in any subjects.

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE. INMAZEB is indicated for the treatment of infection caused by Zaire ebolavirus in adult and pediatric patients, including neonates born to mother who is RT-PCR positive for Zaire ebolavirus infection [see Dosage and Administration (2.2), and Clinical Studies (14)].. INMAZEB is combination of Zaire ebolavirus glycoprotein-directed human monoclonal antibodies (atoltivimab, maftivimab, and odesivimab), indicated for the treatment of infection caused by Zaire ebolavirus in adult and pediatric patients, including neonates born to mother who is RT-PCR positive for Zaire ebolavirus infection. (1)Limitation of UseThe efficacy of INMAZEB has not been established for other species of the Ebolavirus and Marburgvirus genera. Zaire ebolavirus 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 Zaire ebolavirus strains when deciding whether to use INMAZEB.. The efficacy of INMAZEB has not been established for other species of the Ebolavirus and Marburgvirus genera. Zaire ebolavirus 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 Zaire ebolavirus strains when deciding whether to use INMAZEB.. Limitations of UseThe efficacy of INMAZEB has not been established for other species of the Ebolavirus and Marburgvirus genera.Zaire ebolavirus 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 Zaire ebolavirus strains when deciding whether to use INMAZEB.

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION. Hypersensitivity Reactions Including Infusion-Associated EventsInform patients that hypersensitivity reactions including infusion-associated events have been reported during and post-infusion with INMAZEB and to immediately report if they experience any symptoms of systemic hypersensitivity reactions [see Warnings and Precautions (5.1) ].. LactationInstruct patients with Zaire ebolavirus infection not to breastfeed because of the risk of passing Zaire ebolavirus to the baby [see Use in Specific Populations (8.2)].

LACTATION SECTION.


8.2 Lactation. Risk SummaryThe Centers for Disease Control and Prevention recommend that patients with confirmed Zaire ebolavirus not breastfeed their infants to reduce the risk of postnatal transmission of Zaire ebolavirus infection.There are no data on the presence of atoltivimab, maftivimab, and odesivimab-ebgn in human or animal milk, the effects on the breastfed infant, or the effects on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to atoltivimab, maftivimab, or odesivimab-ebgn are unknown.

MECHANISM OF ACTION SECTION.


12.1 Mechanism of Action. INMAZEB is an antiviral drug combination of three recombinant human IgG1 monoclonal antibodies (atoltivimab, maftivimab, and odesivimab) that inhibit Zaire ebolavirus [see Microbiology (12.4) ].

MICROBIOLOGY SECTION.


12.4 Microbiology. Mechanism of ActionINMAZEB is combination of three recombinant human IgG1 monoclonal antibodies each targeting the Zaire ebolavirus glycoprotein (GP). Zaire ebolavirus encodes sole envelope protein, the glycoprotein, which mediates virus attachment and membrane fusion with the host cell membranes. In addition, GP is expressed on the surface of Zaire ebolavirus infected host cells making it target for antibodies that can mediate killing of these cells by antibody dependent cellular cytotoxicity and/or other effector functions. The antibodies that make up the combination can bind the GP simultaneously. The mean KD values for atoltivimab, odesivimab, and maftivimab were 7.84 nM, 8.26 nM, and 3.34 nM, respectively, as determined by surface plasmon resonance. Maftivimab is neutralizing antibody that blocks entry of the virus into susceptible cells. Odesivimab is non-neutralizing antibody that induces antibody-dependent effector function through FcyRIIIa signaling when bound to its target. Odesivimab also binds to the soluble form of Zaire ebolavirus glycoprotein (sGP). Atoltivimab combines both neutralization and FcyRIIIa signaling activities.. Antiviral ActivityIn live virus infection assay on Vero cells, maftivimab neutralized Mayinga, Kikwit, and Makona strains of Zaire ebolavirus, with concentration between 0.2 and 1.2 nM (0.03 and 0.18 ug/mL) providing 80% inhibition of viral infection in plaque-reduction neutralization test (PRNT-80). Atoltivimab and odesivimab did not demonstrate any neutralizing activity in this assay. Effector function activity of INMAZEB individual antibodies was assessed with an EBOV Makona-GP expressing cell line and Jurkat/NFAT-Luc/FcRIIIa reporter effector cells. The EC50 values of atoltivimab and odesivimab were 2.9 nM and 1.6 nM, respectively, whereas maftivimab did not exhibit any FcRIIIa signaling activity at the maximum concentration tested, 40 nM.Treatment of Zaire ebolavirus infected rhesus macaques with single intravenous dose of INMAZEB (50 mg of atoltivimab, 50 mg of maftivimab, and 50 mg of odesivimab per kg) generally protected infected animals from Zaire ebolavirus mediated death when drug was administered days post-infection.. ResistanceNo clinical data are available on the development of EBOV resistance to INMAZEB. The cell culture development of EBOV resistance to INMAZEB has not been assessed to date. GPE280G amino acid substitution identified by routine surveillance in the Democratic Republic of the Congo resulted in loss of neutralization activity of at least 134-fold mediated by the single human monoclonal antibody atoltivimab in lentivirus-based pseudovirus system. GPE564K substitution identified in an infected NHP PK study resulted in loss of neutralization activity of at least 215-fold mediated by the single human monoclonal antibody maftivimab in lentivirus-based pseudovirus system. The clinical significance of these substitutions is unknown.. Immune ResponseInteraction studies with recombinant live EBOV vaccines and INMAZEB have not been conducted [see Drug Interactions (7.1)].

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity, genotoxicity, and fertility studies have not been conducted with INMAZEB.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANEL 14.5 mL Vial Carton. NDC 61755-018-01Rx onlyInmazeb(TM)(atoltivimab, maftivimab, and odesivimab ebgn)Injection241.7 mg 241.7 mg 241.7 mg per 14.5 mL (16.67 mg 16.67 mg 16.67 mg per mL)For Intravenous Infusion after DilutionSingle-Dose VialDiscard unused portion.Do not use vial if seal is broken or missing.One 14.5 mL Vial. PRINCIPAL DISPLAY PANEL 14.5 mL Vial Carton.

PEDIATRIC USE SECTION.


8.4 Pediatric Use. The safety and effectiveness of INMAZEB for the treatment of infection caused by Zaire ebolavirus have been established in pediatric patients from birth to less than 18 years of age. Use of INMAZEB for this indication is supported by evidence from multi-center, open label, randomized controlled trial of INMAZEB in adults and pediatric subjects that included 39 pediatric subjects birth to less than 18 years of age, including neonates born to mother who is RT-PCR positive for Zaire ebolavirus infection. The 28-day mortality and safety in adult and pediatric subjects treated with INMAZEB were similar [see Adverse Reactions (6.1) and Clinical Studies (14)]. An additional 38 pediatric subjects from birth to less than 18 years of age received INMAZEB in an expanded access program.

PHARMACODYNAMICS SECTION.


12.2 Pharmacodynamics. Atoltivimab, maftivimab, and odesivimab exposure-response relationships and the time course of pharmacodynamic response are unknown.

PHARMACOKINETICS SECTION.


12.3 Pharmacokinetics. No pharmacokinetic data are available in patients with Zaire ebolavirus infection. The pharmacokinetics of atoltivimab, maftivimab, and odesivimab in 18 healthy subjects 21 to 60 years of age are linear and dose-proportional over the range of mg of atoltivimab, mg of maftivimab, and mg of odesivimab per kg to 50 mg of atoltivimab, 50 mg of maftivimab, and 50 mg of odesivimab per kg (0.02 to times the approved recommended dosage) of INMAZEB following single intravenous (IV) infusion. Pharmacokinetic parameters for the individual antibodies of INMAZEB are provided in Table 6.Table 6: Pharmacokinetic Parameters of INMAZEB Administered IV in Healthy SubjectsAtoltivimab50 mg/kgINMAZEB was administered at total dose of 50 mg of atoltivimab, 50 mg of maftivimab, and 50 mg of odesivimab per kg in 1:1:1 ratio. Maftivimab50 mg/kg Odesivimab50 mg/kg Systemic Exposure (n=6)Mean (SD) Cmax, mg/L1,220 (101)1,280 (68.0)1,260 (81.2)Mean (SD) AUCinf, mg day/L17,100 (4,480)18,700 (4,100)25,600 (5,040)DistributionMean (SD) Volume of Distribution at Steady State, mL/kg58.2 (2.66)57.6 (3.89)56.0 (3.16)EliminationMean (SD) Elimination Half-Life (days)21.2 (3.36)22.3 (3.09)25.3 (3.86)Mean (SD) Clearance (mL/day/kg)3.08 (0.719)2.78 (0.558)2.02 (0.374). Specific PopulationsThe effect of age (< 21 or 60), renal impairment, or hepatic impairment on the pharmacokinetics of atoltivimab, maftivimab, and odesivimab is unknown.

PREGNANCY SECTION.


8.1 Pregnancy. Risk SummaryZaire ebolavirus 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 and an expanded access program in which pregnant women with Zaire ebolavirus infection were treated with INMAZEB demonstrate the high rate of maternal and fetal/neonatal morbidity consistent with published literature regarding the risk associated with underlying maternal Zaire ebolavirus infection. These data are insufficient to evaluate for drug-associated risk of major birth defects, miscarriage, or adverse maternal/fetal outcome. Animal reproduction studies with INMAZEB have not been conducted. Human monoclonal antibodies, such as INMAZEB, are transported across the placenta; therefore, INMAZEB 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 Zaire ebolavirus. The majority of such pregnancies result in maternal death with miscarriage, stillbirth, or neonatal death. Treatment should not be withheld due to pregnancy.

RECENT MAJOR CHANGES SECTION.


Dosage and Administration, Recommended Dosage (2.1)07/2021Dosage and Administration, Preparation and Administration (2.2)07/2021.

SPL UNCLASSIFIED SECTION.


Limitations of UseThe efficacy of INMAZEB has not been established for other species of the Ebolavirus and Marburgvirus genera.Zaire ebolavirus 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 Zaire ebolavirus strains when deciding whether to use INMAZEB.

STORAGE AND HANDLING SECTION.


Prior to dilutionStore INMAZEB vial refrigerated at 2C to 8C (36F to 46F) in the original carton to protect from light. Do not freeze or shake.

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS. Lactation: Patients infected with Zaire ebolavirus should be instructed not to breastfeed due to the potential for Zaire ebolavirus transmission. (8.2). 8.1 Pregnancy. Risk SummaryZaire ebolavirus 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 and an expanded access program in which pregnant women with Zaire ebolavirus infection were treated with INMAZEB demonstrate the high rate of maternal and fetal/neonatal morbidity consistent with published literature regarding the risk associated with underlying maternal Zaire ebolavirus infection. These data are insufficient to evaluate for drug-associated risk of major birth defects, miscarriage, or adverse maternal/fetal outcome. Animal reproduction studies with INMAZEB have not been conducted. Human monoclonal antibodies, such as INMAZEB, are transported across the placenta; therefore, INMAZEB 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 Zaire ebolavirus. The majority of such pregnancies result in maternal death with miscarriage, stillbirth, or neonatal death. Treatment should not be withheld due to pregnancy.. 8.2 Lactation. Risk SummaryThe Centers for Disease Control and Prevention recommend that patients with confirmed Zaire ebolavirus not breastfeed their infants to reduce the risk of postnatal transmission of Zaire ebolavirus infection.There are no data on the presence of atoltivimab, maftivimab, and odesivimab-ebgn in human or animal milk, the effects on the breastfed infant, or the effects on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to atoltivimab, maftivimab, or odesivimab-ebgn are unknown.. 8.4 Pediatric Use. The safety and effectiveness of INMAZEB for the treatment of infection caused by Zaire ebolavirus have been established in pediatric patients from birth to less than 18 years of age. Use of INMAZEB for this indication is supported by evidence from multi-center, open label, randomized controlled trial of INMAZEB in adults and pediatric subjects that included 39 pediatric subjects birth to less than 18 years of age, including neonates born to mother who is RT-PCR positive for Zaire ebolavirus infection. The 28-day mortality and safety in adult and pediatric subjects treated with INMAZEB were similar [see Adverse Reactions (6.1) and Clinical Studies (14)]. An additional 38 pediatric subjects from birth to less than 18 years of age received INMAZEB in an expanded access program.. 8.5 Geriatric Use. Clinical studies of INMAZEB did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 154 subjects with Zaire ebolavirus infection who received INMAZEB in the randomized controlled trial, (3.2%) were 65 years or older. The limited clinical experience has not identified differences in responses between the elderly and younger subjects.

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS. Hypersensitivity Reactions Including Infusion-Associated Events: Hypersensitivity reactions including infusion-associated events have been reported during and post-infusion with INMAZEB. 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 INMAZEB immediately and administer appropriate emergency care. (5.1). 5.1Hypersensitivity Reactions Including Infusion-Associated Events. Hypersensitivity reactions including infusion-associated events have been reported during and post-infusion with INMAZEB. 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 INMAZEB infusion. In the case of severe or life-threatening hypersensitivity reactions, discontinue the administration of INMAZEB immediately and administer appropriate emergency care [see Adverse Reactions (6.1)].Infusion could not be completed in 1% of subjects who received INMAZEB due to infusion-associated adverse events. The rate of infusion of INMAZEB may be slowed or interrupted if the patient develops any signs of infusion-associated events or other adverse events [see Adverse Reactions (6.1)].