Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous [preservative free]:
Gamifant: emapalumab-lzsg 10 mg/2 mL (2 mL); emapalumab-lzsg 50 mg/10 mL (10 mL) [contains polysorbate 80]
Pharmacology
Mechanism of Action
Emapalumab is an interferon gamma (IFNγ) blocking monoclonal antibody. IFNγ is hypersecreted in hemophagocytic lymphohistiocytosis (HLH); emapalumab binds to IFNγ and neutralizes it.
Pharmacokinetics/Pharmacodynamics
Distribution
Vd (based on a 70 kg patient): Central: 4.2 L; Peripheral: 5.6 L
Metabolism
Emapalumab is likely degraded into small peptides and amino acids via catabolic pathways.
Half-Life Elimination
Healthy subjects: ~22 days; Patients with hemophagocytic lymphohistiocytosis (HLH): 2.5 to 18.9 days
Use in Specific Populations
Special Populations Note
Body weight: Body weight (2 to 82 kg) was a significant covariate of emapalumab pharmacokinetics (therefore supporting body weight-based dosing).
Use: Labeled Indications
Primary hemophagocytic lymphohistiocytosis: Treatment of primary hemophagocytic lymphohistiocytosis (HLH) in adult and pediatric (newborn and older) patients with refractory, recurrent or progressive disease or intolerance to conventional HLH therapy.
Contraindications
There are no contraindications listed in the manufacturer's labeling.
Dosage and Administration
Dosing: Adult
Note: Test for latent tuberculosis (using purified protein derivative [PPD] or IFNγ release assay) and evaluate for tuberculosis risk factors prior to emapalumab treatment. Monitor for tuberculosis, adenovirus, Epstein-Barr virus, and cytomegalovirus every 2 weeks (and as clinically indicated) during emapalumab treatment. Premedication is recommended (see below). Dosing should be based on actual body weight.
Primary hemophagocytic lymphohistiocytosis: IV: Initial: 1 mg/kg twice a week (every 3 or 4 days); subsequent doses may be increased based on clinical and laboratory criteria. After the clinical condition is stabilized, decrease dose to the previous level to maintain clinical response. Continue until hematopoietic stem cell transplantation (HSCT) or unacceptable toxicity; discontinue when therapy is no longer required for hemophagocytic lymphohistiocytosis.
Dosage modification:
Treatment day and dose:
Day 1 initial dose: 1 mg/kg
Day 3: May increase to 3 mg/kg if meet criteria for dose increase
Day 6 and beyond: Increase to 6 mg/kg if meet criteria for dose increase
Day 9 and beyond: Increase to 10 mg/kg if (based on initial signs of response) assessment by health care provider indicates that a further increase in emapalumab dose may be of benefit
Criteria for dose increase:
Unsatisfactory improvement in clinical condition (assessed by health care provider) AND at least one of the following:
Fever (persistent or recurrent)
Platelets: Baseline <50,000/mm3 without improvement to >50,000/mm3or baseline >50,000/mm3 and <30% improvement, or baseline >100,000/mm3 and any decrease to <100,000/mm3
Neutrophils: Baseline <500/mm3 without improvement to >500/mm3or baseline >500 to 1,000/mm3 and decrease to <500/mm3or baseline 1,000 to 1,500/mm3 and decrease to <1,000/mm3
Ferritin: Baseline ≥3,000 ng/mL and <20% decrease or baseline <3,000 ng/mL and any increase to >3,000 ng/mL.
Splenomegaly (any worsening)
Coagulopathy (both D-dimer and fibrinogen must apply): D-Dimer: Abnormal at baseline and no improvement; Fibrinogen: Baseline levels ≤100 mg/dL and no improvement or baseline levels >100 mg/dL and any decrease to <100 mg/dL.
Premedication and concomitant therapy: Administer prophylaxis for herpes zoster, pneumocystis jirovecii, and for fungal infections prior to emapalumab administration. Administer tuberculosis prophylaxis to patients at risk for tuberculosis, or known to have a positive PPD test result or a positive IFNγ release assay. For patients not receiving baseline dexamethasone treatment, begin dexamethasone at a dose of at least 5 to 10 mg/m2/day beginning 1 day prior to initiation of emapalumab. For patients receiving baseline dexamethasone, continue the regular dexamethasone dose, as long as the dose is at least 5 mg/m2/day. Dexamethasone may be tapered according to clinical judgement.
Dosing: Geriatric
Refer to adult dosing.
Dosing: Pediatric
Note: Tuberculosis screening should be completed prior to emapalumab therapy. Dose should be based on actual body weight.
Primary hemophagocytic lymphohistiocytosis (HLH): Infants, Children, and Adolescents: IV: Initial dose: 1 mg/kg/dose twice weekly (ie, every 3 to 4 days); subsequent doses may be increased based on clinical and laboratory criteria. After the clinical condition is stabilized, decrease dose to the previous level to maintain clinical response. Continue until hematopoietic stem cell transplantation (HSCT) or unacceptable toxicity; discontinue when therapy is no longer required for HLH.
Dose modification: If inadequate response (see Criteria for dose increase), titrate dose as follows:
Day 3: May increase dose to 3 mg/kg/dose if meets criteria for dose increase
Day 6 and beyond: May increase dose to 6 mg/kg/dose if meets criteria for dose increase
Day 9 and beyond: May increase dose to 10 mg/kg/dose if (based on initial signs of response) assessment by health care provider indicates that a further increase in emapalumab dose may be of benefit.
Criteria for dose increase: Inadequate response as determined by health care provider assessment and at least one of the following criteria:
Fever (persistent or recurrent)
Platelets: Baseline <50,000/mm3 without improvement to >50,000/mm3or baseline >50,000/mm3 and <30% improvement, or baseline >100,000/mm3 and any decrease to <100,000/mm3
Neutrophils: Baseline <500/mm3 without improvement >500/mm3or baseline >500 to 1,000/mm3 and decrease to <500/mm3or baseline 1,000 to 1,500/mm3 and decrease to <1,000/mm3
Ferritin: Baseline ≥3,000 ng/mL and <20% decrease or baseline <3,000 ng/mL and any increase to >3,000 ng/mL
Splenomegaly (any worsening)
Coagulopathy (both D-dimer and fibrinogen criteria must apply): D-Dimer: Abnormal at baseline and no improvement AND Fibrinogen: Baseline levels ≤100 mg/dL and no improvement or baseline levels >100 mg/dL and any decrease to <100 mg/dL
Premedication and concomitant therapy: Administer prophylaxis for herpes zoster, Pneumocystis jirovecii, and for fungal infections prior to emapalumab administration. Administer tuberculosis prophylaxis to patients at risk for tuberculosis or known to have a positive purified protein derivative (PPD) test result or a positive interferon gamma (IFNγ) release assay. If patient is not receiving baseline dexamethasone treatment (≥5 mg/m2/day), begin dexamethasone at a dose of at least 5 to 10 mg/m2/day beginning 1 day prior to initiation of emapalumab. For patients receiving baseline dexamethasone, continue the regular dexamethasone dose, as long as the dose is at least 5 mg/m2/day. Dexamethasone may be tapered according to clinical judgement.
Dosing: Adjustment for Toxicity
Infusion reaction: If an infusion reaction occurs, interrupt infusion and manage appropriately, then continue with the infusion rate reduced.
Reconstitution
Calculate the mg/kg dose based on actual body weight. Withdraw the necessary amount of emapalumab from the vial(s) and dilute with sodium chloride 0.9% to a maximum concentration of 2.5 mg/mL. Do not dilute to a concentration <0.25 mg/mL. Do not shake the diluted solution. Depending on the volume needed, the diluted solution can be dispensed either in a syringe or in an infusion bag. If dispensing in a syringe, use a gamma irradiated latex-free, polyvinyl chloride (PVC)-free syringe; do not use with ethylene oxide-sterilized syringes. If dispensing in an infusion bag, use a non-PVC polyolefin bag.
Administration
IV: Infuse over 1 hour through an IV line containing a sterile, non-pyrogenic, low-protein binding 0.2 micron inline filter. Do not shake. Allow solution to reach room temperature prior to infusion. Do not infuse with other medications. If an infusion reaction occurs, interrupt infusion and manage appropriately, then continue with the infusion rate reduced.
Storage
Store intact vials at 2ºC to 8ºC (36ºF to 46ºF); do not freeze. Store in original carton to protect from light. Do not shake. Solutions diluted for infusion should be used immediately after preparation; however, diluted solutions may be stored at 2ºC to 8ºC (36ºF to 46ºF) for a maximum of 4 hours from the time of dilution; do not freeze; allow diluted solution to reach room temperature prior to infusion.
Drug Interactions
Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification
BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination
Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination
Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy
Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification
Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination
Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification
Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy
Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification
Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification
Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination
Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy
Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy
Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination
Adverse Reactions
>10%:
Cardiovascular: Hypertension (41%), tachycardia (12%)
Central nervous system: Irritability (12%)
Dermatologic: Skin rash (12%)
Endocrine & metabolic: Hypokalemia (15%)
Gastrointestinal: Appendicitis (≤32%), constipation (15%), abdominal pain (12%), diarrhea (12%)
Hematologic & oncologic: Lymphocytosis (12%)
Infection: Infection (56%), viral infection (32% to 41%), bacterial infection (35%), bacteremia (≤32%), histoplasmosis (≤32%), necrotizing fasciitis (≤32%), sepsis (≤32%), cytomegalovirus disease (12%)
Respiratory: Pneumonia (≤32%), cough (12%), tachypnea (12%)
Miscellaneous: Infusion related reaction (27%), fever (24%)
1% to 10%:
Cardiovascular: Bradycardia (<10%), peripheral edema (<10%)
Gastrointestinal: Gastrointestinal hemorrhage (<10%), vomiting (<10%)
Immunologic: Antibody development (3% to 5%)
Infection: Fungal infection (9%)
Neuromuscular & skeletal: Asthenia (<10%)
Renal: Acute renal failure (<10%)
Respiratory: Dyspnea (<10%), epistaxis (<10%)
Miscellaneous: Multi-organ failure (≥3%)
Warnings/Precautions
Concerns related to adverse effects:
- Infection: Infections may commonly occur. Emapalumab may increase the risk of fatal and serious infections including specific pathogens favored by IFNγ neutralization (mycobacteria, herpes zoster virus, and Histoplasma capsulatum); do not administer emapalumab to patients with infections caused by these pathogens until appropriate treatment has been initiated. Serious infections such as pneumonia, bacteremia, sepsis, disseminated histoplasmosis, necrotizing fasciitis, viral infections, and perforated appendicitis were observed in nearly one-third of patients receiving emapalumab in clinical trials. Reported infections were predominantly viral and bacterial, although fungal infections and infections with an unidentified pathogen also occurred. Prior to initiating emapalumab, evaluate for tuberculosis risk factors and test for latent infection by purified protein derivative (PPD) testing, polymerase chain reaction (PCR), or IFNγ release assay. Administer tuberculosis prophylaxis to patients at risk for tuberculosis or known to have a positive PPD test result. Prophylaxis for herpes zoster, pneumocystis jirovecii, and fungal infection should also be administered during emapalumab treatment. Utilize surveillance testing during treatment. Monitor closely for signs/symptoms of infection; promptly initiate a complete diagnostic workup appropriate for an immunocompromised patient and initiate appropriate antimicrobial therapy.
- Infusion reactions: Infusion-related reactions (including drug eruption, pyrexia, rash, erythema, and hyperhidrosis) have been reported in over one-fourth of patients treated with emapalumab. Infusion-related reactions occurred during the first infusion in one-third of these patients. Infusion reactions were mild to moderate. Monitor for infusion-related reactions. If an infusion reaction occurs, interrupt infusion and manage appropriately, then continue with the infusion rate reduced.
Concurrent drug therapy issues:
- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
- Immunizations: Do not administer live or live attenuated vaccines to patients receiving emapalumab and for at least 4 weeks following the last emapalumab dose (safety of immunization with live vaccines during or following emapalumab has not been studied).
Dosage form specific issues:
- Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.
Monitoring Parameters
Monitor for clinical improvement based on platelet counts, neutrophil counts, ferritin, D-dimer and fibrinogen, fever, and signs/symptoms of splenomegaly.
Prior to initiating emapalumab, evaluate for tuberculosis risk factors and test for latent infection by purified protein derivative (PPD) testing, PCR, or IFNγ release assay. Monitor for tuberculosis, adenovirus, Epstein-Barr virus, and cytomegalovirus every 2 weeks (and as clinically indicated) during emapalumab treatment. Surveillance testing for herpes zoster, pneumocystis jirovecii, and fungal infection should be utilized during treatment.
Monitor closely for signs/symptoms of infection; promptly initiate a complete diagnostic workup appropriate for an immunocompromised patient. Monitor for infusion-related reactions.
Pregnancy
Pregnancy Considerations
Adverse events were not observed in animal reproduction studies.
Patient Education
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience constipation, diarrhea, loss of strength and energy, irritability, or nosebleed. Have patient report immediately to prescriber signs of infusion reaction; signs of infection; signs of low potassium (muscle pain or weakness, muscle cramps, or an abnormal heartbeat); signs of kidney problems (unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain); severe headache; dizziness; passing out; vision changes; fast heartbeat; slow heartbeat; fast breathing; black, tarry, or bloody stools; vomiting blood; severe abdominal pain; severe nausea; or vomiting (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
