Emapalumab is an interferon gamma blocking antibody used for the treatment of primary hemophagocytic lymphohistiocytosis (HLH) in adult and pediatric patients with refractory, recurrent, or progressive disease or intolerance to conventional HLH therapy. Primary HLH is a rare and life-threatening condition that typically affects children. In patients with HLH, the body's immune cells do not function properly. The cells become overactive, leading to inflammation and damage to the body's organs, including the liver, brain, and bone marrow. Patients with primary HLH usually develop symptoms, which may include fever, enlarged liver or spleen, and cytopenia, within the first months or years of life. Emapalumab was studied in a clinical trial of 27 pediatric patients (median age 1 year old) with suspected or confirmed primary HLH with either refractory, recurrent, or progressive disease during conventional therapy or who were intolerant to conventional therapy. The overall response rate, defined as achievement of either a complete or partial response or HLH improvement, was 63% (95% CI: 0.42, 0.81; p = 0.013) at the end of treatment. Additionally, 70% (19/27) of patients proceeded to hematopoietic stem cell transplantation (HSCT). Infections were the most common adverse reaction reported during the clinical trial. Prior to treatment, evaluate patients for latent tuberculosis and administer prophylaxis to patients at risk for tuberculosis. Additionally, administer prophylaxis for Herpes Zoster, Pneumocystis jirovecii, and fungal infections prior to emapalumab initiation. During emapalumab treatment, routine monitoring for tuberculosis, adenovirus, Epstein-Barr virus, and cytomegalovirus is recommended.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Emetic Risk
-Minimal
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-Emapalumab is a clear to slightly opalescent, colorless to slightly yellow liquid. Do not administer if discolored or foreign particulate matter is present.
Intravenous Administration
-Administer as an intravenous (IV) infusion only. Do NOT administer as an IV push or bolus.
-Do not infuse emapalumab concomitantly with other agents; do not add any other product to the infusion bag or syringe.
Reconstitution
-Calculate the dose (mg/kg), total volume (mL), and the number of vials needed based on patient actual body weight.
-Withdraw the necessary amount of emapalumab solution and dilute with 0.9% NaCl Injection to a maximum concentration of 2.5 mg/mL. Do not dilute product to less than 0.25 mg/mL.
-Emapalumab vials are for single-use only; discard any unused portion left in the vial(s).
-Place diluted solution in either a syringe or an infusion bag, depending on the volume needed.
-Use a gamma irradiated, latex-free, polyvinyl chloride (PVC)-free syringe. Do not use with ethylene oxide-sterilized syringes.
-Use a non-PVC polyolefin infusion bag.
-Storage: Use the diluted solution immediately or store at 2 to 8 degrees C (36 to 46 degrees F) for no more than 4 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.
-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 requirement.
Intermittent IV Infusion
-Administer emapalumab diluted solution over 1 hour through an IV line containing a sterile, non-pyrogenic, low-protein binding 0.2 micron in-line filter.
Safety data was conducted in 34 patients with untreated primary hemophagocytic lymphohistiocytosis (HLH) and previously treated patients with primary HLH (median age 1 year; range: 0.1 to 13 years) receiving emapalumab 1 mg/kg/dose every 3 days with dose increases up to 10 mg/kg/dose. The median duration of treatment was 59 days (range: 4 to 425 days), and the median cumulative dose was 25 mg/kg (range: 4 to 254 mg/kg).
Mild to moderate infusion-related reactions, characterized by drug eruption, pyrexia, rash, erythema, and hyperhidrosis, were reported during emapalumab clinical trials in 27% of patients. In one-third of these patients, the infusion-related reaction occurred during the first infusion. Rash, separate from an infusion-related reaction, was reported in 12% of patients.
Infection, including viral, bacterial, fungal, and infections in which no pathogen was identified, was reported in 56% of patients during emapalumab clinical trials. Serious infections (32%) such as sepsis, pneumonia, bacteremia, disseminated histoplasmosis, necrotizing fasciitis, viral infections, and perforated appendicitis were also observed. The reported serious infections were viral (41%), bacterial (35%), fungal (9%), and unidentified pathogen (15%). Cytomegalovirus infection (12%), fever (24%), lymphocytosis (12%), cough (12%), and multiple organ dysfunction (more than 3%) were also reported. Disseminated histoplasmosis led to drug discontinuation in 1 patient. Fatal adverse reactions occurred in 2 (6%) patients; septic shock was 1 of the fatal adverse reactions.
Cardiovascular adverse reactions reported during emapalumab clinical trials include hypertension (41%), sinus tachycardia (12%), and bradycardia (less than 10%).
Gastrointestinal adverse reactions were reported during emapalumab clinical trials and included constipation (15%), abdominal pain (12%), diarrhea (12%), vomiting (less than 10%), and gastrointestinal hemorrhage (less than 10%). Fatal adverse reactions occurred in 2 (6%) patients; 1 of the adverse reactions was gastrointestinal hemorrhage.
Respiratory effects including tachypnea (12%) and dyspnea (less than 10%) were reported during emapalumab clinical trials.
Other adverse reactions reported during emapalumab clinical trials include hypokalemia (15%), asthenia (less than 10%), epistaxis (less than 10%), peripheral edema (less than 10%), irritability (12%), and acute kidney injury (less than 10%).
As with all therapeutic proteins, there is a potential for immunogenicity. A total of 64 patients were evaluated for anti-therapeutic antibody formation after emapalumab treatment. Anti-therapeutic antibodies (ATAs) were detected in 3/64 patients (5%) who received emapalumab. Treatment-emergent ATAs were detected in 1/33 patients (3%) in the primary hemophagocytic lymphohistiocytosis (HLH) clinical trial. The ATAs in this patient were found to have neutralizing ability. One patient receiving emapalumab through compassionate use developed transient non-neutralizing treatment-emergent ATAs. In both patients, ATAs occurred within the first 9 weeks after initiation of emapalumab treatment. Additionally, 1 healthy subject tested positive for ATAs after a single emapalumab dose. No evidence of an altered safety or efficacy profile was identified in the primary HLH patients who developed antibodies to emapalumab.
Emapalumab may increase the risk of fatal and serious infection, including mycobacteria, Herpes Zoster virus, and Histoplasma Capsulatum, all pathogens favored by interferon gamma neutralization. Do not administer emapalumab in patients with infections caused by these pathogens until appropriate treatment has been initiated. Administer prophylaxis for Herpes Zoster, Pneumocystis jirovecii, and fungal infections prior to emapalumab administration. Prior to treatment, evaluate patients for tuberculosis risk factors and test for latent tuberculosis infections using the purified protein derivative (PPD), polymerase chain reaction (PCR), or interferon gamma release assay. Administer tuberculosis prophylaxis to patients at risk for tuberculosis, or known to have a positive PPD test result or positive interferon gamma release assay. During emapalumab treatment, monitor for tuberculosis, adenovirus, Epstein-Barr virus, and cytomegalovirus every 2 weeks and as clinically indicated.
Vaccination with live or live attenuated vaccines is not recommended during emapalumab treatment and for at least 4 weeks after drug discontinuation. The safety of immunization with live vaccines during or after emapalumab therapy has not been studied.
Mild to moderate infusion-related reactions were reported during emapalumab clinical trials. In some patients, the infusion-related reaction occurred during the first infusion. Monitor patients for infusion-related symptoms including drug eruption, pyrexia, rash, erythema, and hyperhidrosis. Interrupt infusion for infusion reactions and institute appropriate medical management prior to continuing the infusion at a slower rate.
There are no available data regarding emapalumab use during pregnancy to inform a drug-associated risk. Animal data did not reveal evidence of harm to the fetus when a murine surrogate anti-mouse interferon gamma antibody was administered to mice throughout 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, but no maternal toxicity occurred, and there was no evidence of teratogenicity or effects on embryo-fetal survival or growth.
There are no data on the presence of emapalumab in human milk, the effects on a breast-fed infant, 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. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.
General dosing information:
-Prior to treatment, evaluate patients for tuberculosis risk factors and test for latent tuberculosis infections using the purified protein derivative (PPD), polymerase chain reaction (PCR), or interferon gamma release assay. Administer tuberculosis prophylaxis to patients at risk for tuberculosis, or known to have a positive PPD test result or positive interferon gamma release assay.
-Administer prophylaxis for Herpes Zoster, Pneumocystis jirovecii, and fungal infections prior to emapalumab administration.
-For patients not receiving baseline dexamethasone treatment, begin dexamethasone at a daily dose of at least 5 to 10 mg/m2 the day before emapalumab treatment begins. Patients receiving dexamethasone treatment may continue their regular dose of at least 5 mg/m2. Dexamethasone can be tapered according to the judgment of the treating physician.
-During emapalumab treatment, monitor for tuberculosis, adenovirus, Epstein-Barr virus, and cytomegalovirus every 2 weeks and as clinically indicated.
For the treatment of primary hemophagocytic lymphohistiocytosis (HLH) with refractory, recurrent, or progressive disease or intolerance with conventional HLH therapy:
Intravenous dosage:
Adults: 1 mg/kg/dose IV over 1 hour twice per week (every 3 to 4 days). A dose increase on day 3 (to 3 mg/kg/dose), days 6 to 8 (to 6 mg/kg/dose), and day 9 onwards (to 10 mg/kg/dose) may be necessary based on unsatisfactory improvement in clinical condition in addition to fever, thrombocytopenia, neutropenia, ferritin, fibrinogen, splenomegaly, or coagulopathy. Decrease the dose to the previous level once the patient's clinical condition has stabilized to maintain response. Administer dexamethasone concomitantly with emapalumab. Administer emapalumab until hematopoietic stem cell transplantation (HSCT) or unacceptable toxicity. Discontinue when the patient no longer requires therapy for the treatment of HLH.
Infants, Children, and Adolescents: 1 mg/kg/dose IV over 1 hour twice per week (every 3 to 4 days). A dose increase on day 3 (to 3 mg/kg/dose), days 6 to 8 (to 6 mg/kg/dose), and day 9 onwards (to 10 mg/kg/dose) may be necessary based on unsatisfactory improvement in clinical condition in addition to fever, thrombocytopenia, neutropenia, ferritin, fibrinogen, splenomegaly, or coagulopathy. Decrease the dose to the previous level once the patient's clinical condition has stabilized to maintain response. Administer dexamethasone concomitantly with emapalumab. Administer emapalumab until hematopoietic stem cell transplantation (HSCT) or unacceptable toxicity. Discontinue when the patient no longer requires therapy for the treatment of HLH.
Neonates: 1 mg/kg/dose IV over 1 hour twice per week (every 3 to 4 days). A dose increase on day 3 (to 3 mg/kg/dose), days 6 to 8 (to 6 mg/kg/dose), and day 9 onwards (to 10 mg/kg/dose) may be necessary based on unsatisfactory improvement in clinical condition in addition to fever, thrombocytopenia, neutropenia, ferritin, fibrinogen, splenomegaly, or coagulopathy. Decrease the dose to the previous level once the patient's clinical condition has stabilized to maintain response. Administer dexamethasone concomitantly with emapalumab. Administer emapalumab until hematopoietic stem cell transplantation (HSCT) or unacceptable toxicity. Discontinue when the patient no longer requires therapy for the treatment of HLH.
Therapeutic Drug Monitoring:
Criteria for Dose Increase
On day 3 (increase to 3 mg/kg/dose IV) and day 6 to 8 (increase to 6 mg/kg/dose IV), unsatisfactory improvement in clinical condition, as assessed by a healthcare provider AND at least 1 of the following:
-Fever: Persistence or recurrence.
-Platelet count: Baseline less than 50,000/mm3 and no improvement to more than 50,000/mm3, baseline more than 50,000/mm3 and less than 30% improvement, or baseline more than 100,000/mm3 and any decrease to less than 100,000/mm3.
-Neutrophil count: Baseline less than 500/mm3 and no improvement to more than 500/mm3, baseline more than 500 to 1,000/mm3 and decrease to less than 500/mm3, or baseline 1,000 to 1,500/mm3 and decrease to less than 1,000/mm3.
-Ferritin: Baseline 3,000 ng/mL or more and less than 20% decrease or baseline less than 3,000 ng/mL and any increase to more than 3,000 ng/mL.
-Splenomegaly: Any worsening.
-Coagulopathy (both D-Dimer and Fibrinogen must apply): D-Dimer is abnormal at baseline and no improvement. Fibrinogen: Baseline 100 mg/dL or less and no improvement or baseline more than 100 mg/dL and any decrease to less than 100 mg/dL.
From Day 9 onwards (increase to 10 mg/kg/dose IV), assessment by a healthcare provider that based on initial signs of response, a further increase in emapalumab dose can be of benefit.
Maximum Dosage Limits:
-Adults
10 mg/kg/dose IV twice per week.
-Geriatric
10 mg/kg/dose IV twice per week.
-Adolescents
10 mg/kg/dose IV twice per week.
-Children
10 mg/kg/dose IV twice per week.
-Infants
10 mg/kg/dose IV twice per week.
-Neonates
10 mg/kg/dose IV twice per week.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Alfentanil: (Moderate) Monitor for decreased efficacy of alfentanil and adjust the dose as needed during coadministration with emapalumab. Alfentanil is a CYP3A4 substrate with a narrow therapeutic range. Emapalumab may normalize CYP450 activity, which may decrease the efficacy of drugs that are CYP450 substrates due to increased metabolism.
Bacillus Calmette-Guerin Vaccine, BCG: (Major) Do not administer live or live attenuated vaccines to patients receiving emapalumab and for at least 4 weeks after the last dose of emapalumab. The safety of immunization with live vaccines during or after emapalumab therapy has not been studied.
Carbamazepine: (Moderate) Monitor for decreased efficacy of carbamazepine and adjust the dose as needed during coadministration with emapalumab. Carbamazepine is a CYP3A4, CYP1A2, and CYP2C8 substrate with a narrow therapeutic index. Emapalumab may normalize CYP450 activity, which may decrease the efficacy of drugs that are CYP450 substrates due to increased metabolism.
Chikungunya Vaccine, Live: (Major) Do not administer live or live attenuated vaccines to patients receiving emapalumab and for at least 4 weeks after the last dose of emapalumab. The safety of immunization with live vaccines during or after emapalumab therapy has not been studied.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Cisapride: (Moderate) Monitor for decreased efficacy of cisapride and adjust the dose as needed during coadministration with emapalumab. Cisapride is a CYP3A4 substrate with a narrow therapeutic range. Emapalumab may normalize CYP450 activity, which may decrease the efficacy of drugs that are CYP450 substrates due to increased metabolism.
Cyclosporine: (Moderate) Monitor for decreased efficacy of cyclosporine and adjust the dose as needed during coadministration with emapalumab. Cyclosporine is a CYP3A4 substrate with a narrow therapeutic index. Emapalumab may normalize CYP450 activity, which may decrease the efficacy of drugs that are CYP450 substrates due to increased metabolism.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Dextromethorphan; Quinidine: (Moderate) Monitor for decreased efficacy of quinidine and adjust the dose as needed during coadministration with emapalumab. Quinidine is a CYP3A4 substrate with a narrow therapeutic range. Emapalumab may normalize CYP450 activity, which may decrease the efficacy of drugs that are CYP450 substrates due to increased metabolism.
Ethosuximide: (Moderate) Monitor for decreased efficacy of ethosuximide and adjust the dose as needed during coadministration with emapalumab. Ethosuximide is a CYP3A4 substrate with a narrow therapeutic index. Emapalumab may normalize CYP450 activity, which may decrease the efficacy of drugs that are CYP450 substrates due to increased metabolism.
Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if treatment with emapalumab is initiated for a patient on chronic everolimus therapy. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate. During chronic inflammation, increased levels of certain cytokines can decrease the formation of CYP450 enzymes. Thus, the formation of CYP3A4 could be normalized during emapalumab administration. The addition of emapalumab to everolimus therapy may increase the metabolism of everolimus and decrease everolimus blood concentrations.
Fentanyl: (Moderate) Monitor for decreased efficacy of fentanyl and adjust the dose as needed during coadministration with emapalumab. Fentanyl is a CYP3A4 substrate with a narrow therapeutic range. Emapalumab may normalize CYP450 activity, which may decrease the efficacy of drugs that are CYP450 substrates due to increased metabolism.
Intranasal Influenza Vaccine: (Major) Do not administer live or live attenuated vaccines to patients receiving emapalumab and for at least 4 weeks after the last dose of emapalumab. The safety of immunization with live vaccines during or after emapalumab therapy has not been studied.
Live Vaccines: (Major) Do not administer live or live attenuated vaccines to patients receiving emapalumab and for at least 4 weeks after the last dose of emapalumab. The safety of immunization with live vaccines during or after emapalumab therapy has not been studied.
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Major) Do not administer live or live attenuated vaccines to patients receiving emapalumab and for at least 4 weeks after the last dose of emapalumab. The safety of immunization with live vaccines during or after emapalumab therapy has not been studied.
Measles/Mumps/Rubella Vaccines, MMR: (Major) Do not administer live or live attenuated vaccines to patients receiving emapalumab and for at least 4 weeks after the last dose of emapalumab. The safety of immunization with live vaccines during or after emapalumab therapy has not been studied.
Paclitaxel: (Moderate) Monitor for decreased efficacy of paclitaxel and adjust the dose as needed during coadministration with emapalumab. Paclitaxel is a CYP2C8 substrate with a narrow therapeutic range. Emapalumab may normalize CYP450 activity, which may decrease the efficacy of drugs that are CYP450 substrates due to increased metabolism.
Phenytoin: (Moderate) Monitor for decreased efficacy of phenytoin and adjust the dose as needed during coadministration with emapalumab. Phenytoin is a CYP2C9 and CYP2C19 substrate with a narrow therapeutic index. Emapalumab may normalize CYP450 activity, which may decrease the efficacy of drugs that are CYP450 substrates due to increased metabolism.
Pimozide: (Moderate) Monitor for decreased efficacy of pimozide and adjust the dose as needed during coadministration with emapalumab. Pimozide is a CYP3A4 and CYP2D6 substrate with a narrow therapeutic range. Emapalumab may normalize CYP450 activity, which may decrease the efficacy of drugs that are CYP450 substrates due to increased metabolism.
Quinidine: (Moderate) Monitor for decreased efficacy of quinidine and adjust the dose as needed during coadministration with emapalumab. Quinidine is a CYP3A4 substrate with a narrow therapeutic range. Emapalumab may normalize CYP450 activity, which may decrease the efficacy of drugs that are CYP450 substrates due to increased metabolism.
Rotavirus Vaccine: (Major) Do not administer live or live attenuated vaccines to patients receiving emapalumab and for at least 4 weeks after the last dose of emapalumab. The safety of immunization with live vaccines during or after emapalumab therapy has not been studied.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Major) Do not administer live or live attenuated vaccines to patients receiving emapalumab and for at least 4 weeks after the last dose of emapalumab. The safety of immunization with live vaccines during or after emapalumab therapy has not been studied.
Smallpox Vaccine, Vaccinia Vaccine: (Major) Do not administer live or live attenuated vaccines to patients receiving emapalumab and for at least 4 weeks after the last dose of emapalumab. The safety of immunization with live vaccines during or after emapalumab therapy has not been studied.
Tacrolimus: (Moderate) Monitor for decreased efficacy of tacrolimus and adjust the dose as needed during coadministration with emapalumab. Tacrolimus is a CYP3A4 substrate with a narrow therapeutic index. Emapalumab may normalize CYP450 activity, which may decrease the efficacy of drugs that are CYP450 substrates due to increased metabolism.
Theophylline, Aminophylline: (Moderate) Monitor for decreased efficacy of theophylline and adjust the dose as needed during coadministration with emapalumab. Theophylline is a CYP1A2 substrate with a narrow therapeutic index. Emapalumab may normalize CYP450 activity, which may decrease the efficacy of drugs that are CYP450 substrates due to increased metabolism.
Thioridazine: (Moderate) Monitor for decreased efficacy of thioridazine and adjust the dose as needed during coadministration with emapalumab. Thioridazine is a CYP2D6 substrate with a narrow therapeutic range. Emapalumab may normalize CYP450 activity, which may decrease the efficacy of drugs that are CYP450 substrates due to increased metabolism.
Tizanidine: (Moderate) Monitor for decreased efficacy of tizanidine and adjust the dose as needed during coadministration with emapalumab. Tizanidine is a CYP1A2 substrate with a narrow therapeutic range. Emapalumab may normalize CYP450 activity, which may decrease the efficacy of drugs that are CYP450 substrates due to increased metabolism.
Typhoid Vaccine: (Major) Do not administer live or live attenuated vaccines to patients receiving emapalumab and for at least 4 weeks after the last dose of emapalumab. The safety of immunization with live vaccines during or after emapalumab therapy has not been studied.
Varicella-Zoster Virus Vaccine, Live: (Major) Do not administer live or live attenuated vaccines to patients receiving emapalumab and for at least 4 weeks after the last dose of emapalumab. The safety of immunization with live vaccines during or after emapalumab therapy has not been studied.
Warfarin: (Moderate) Monitor for decreased efficacy of warfarin and adjust the dose as needed during coadministration with emapalumab. Warfarin is a CYP2C9 substrate with a narrow therapeutic index. Emapalumab may normalize CYP450 activity, which may decrease the efficacy of drugs that are CYP450 substrates due to increased metabolism.
Yellow Fever Vaccine, Live: (Major) Do not administer live or live attenuated vaccines to patients receiving emapalumab and for at least 4 weeks after the last dose of emapalumab. The safety of immunization with live vaccines during or after emapalumab therapy has not been studied.
Emapalumab is a monoclonal antibody that binds to and neutralizes interferon gamma. Nonclinical data suggest it plays a pivotal role in the pathogenesis of hemophagocytic lymphohistiocytosis (HLH) by being hypersecreted.
Emapalumab is administered intravenously. In a 70 kg patient, the central and peripheral volumes of distribution are 4.2 and 5.6 L, respectively. The elimination half-life is approximately 22 days in healthy subjects and ranges from 2.5 to 18.9 days in hemophagocytic lymphohistiocytosis (HLH) patients. In healthy patients, clearance is approximately 0.007 L/hour. Total emapalumab clearance is significantly influenced by the production of interferon gamma, which demonstrates target mediated clearance of emapalumab. The metabolic pathway of emapalumab has not been characterized. Like other protein therapeutics, emapalumab is expected to be degraded into small peptides and amino acids via catabolic pathways.
Affected cytochrome P450 isoenzymes or drug transporters: CYP450 substrates
The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines (such as interferon gamma) during chronic inflammation. By neutralizing interferon gamma, use of emapalumab may normalize CYP450 activities which may reduce the efficacy of drugs that are CYP450 substrates due to increased metabolism.
-Route-Specific Pharmacokinetics
Intravenous Route
After an emapalumab 1 mg/kg 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 AUC increases slightly more than proportionally between 1 and 3 mg/kg doses, and less than proportionally at 3, 6, and 10 mg/kg doses. Emapalumab exhibits target-mediated clearance dependent on interferon gamma production, which can vary between and within patients as a function of time and can affect the recommended dosage. Emapalumab steady state is reached by the 7th infusion when the interferon gamma production is moderate. At high interferon gamma production, steady-state is reached earlier due to a shorter half-life. Body weight (2 to 82 kg) is a significant covariate of emapalumab pharmacokinetics, supporting body weight-based dosing.
-Special Populations
Hepatic Impairment
Hepatic impairment (mild, moderate, and severe) had no significant impact on the pharmacokinetic parameters of emapalumab.
Renal Impairment
Renal impairment (including dialysis) had no significant impact on the pharmacokinetic parameters of emapalumab.
Gender Differences
Gender (53% females) had no significant impact on the pharmacokinetic parameters of emapalumab.
Ethnic Differences
Race (71.4% Caucasian, 12.2% Asian, and 8.2% Black) had no significant impact on the pharmacokinetic parameters of emapalumab.
Other
Age (0.02 to 56 years) had no significant impact on the pharmacokinetic parameters of emapalumab.