Emapalumab (Gamifant) is a fully human monoclonal immunoglobulin of the IgG-1 subtype that non-competitively inhibits Interferon Gamma. It is used in the treatment of primary hemophagocytic lymphohistiocytosis syndrome that is characterized by immune dysregulation and multiple organ dysfunction.

Emapalumab (Gamifant) Uses:

• 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.

Adult dose:

 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.
• However, premedication is recommended (see below). Dosing ought to be based on actual body weight.

Emapalumab (Gamifant) dose in Primary hemophagocytic lymphohistiocytosis:

• IV: Initial: 1 mg/kg twice a week (every 3 or 4 days);
• based on clinical and laboratory criteria subsequent doses may be increased.
• Decrease dose to the previous level to maintain the clinical response after the clinical condition is stabilized.
• 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: It may increase to 3 mg/kg if meet criteria for a dose increase
    • Day 6 and beyond: Increase to 6 mg/kg if meet criteria for a 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 a health care provider) AND at least one of the following:

    • Fever (persistent or recurrent)
    • Platelets:
      • Baseline <50,000/mm³ without improvement to >50,000/mm³ or 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/mm³ or baseline >500 to 1,000/mm³ and decrease to <500/mm³ or 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 who are not receiving baseline dexamethasone treatment, begin dexamethasone at a dose of at least 5 to 10 mg/m /day beginning 1 day prior to initiation of emapalumab.
    • Though, for patients receiving baseline dexamethasone, continue the regular dexamethasone dose, as long as the dose is at least 5 mg/m /day. Dexamethasone may be tapered according to clinical judgment.

Dose in children:

 Note:

• Tuberculosis screening should be completed before emapalumab therapy.
• The dose has to be based on actual body weight.

Emapalumab (Gamifant) Dose in the treatment of Primary Hemophagocytic Lymphohistiocytosis (HLH):

• Infants, Children, and Adolescents:

  • IV: Initial dose: 1 mg/kg/dose twice a week (e.g. every 3 to 4 days);
  • however, subsequent doses may be increased based on clinical and laboratory criteria.
  • Decrease dose to the previous level to maintain the clinical response when the clinical condition is stabilized.
  • Continue until hematopoietic stem cell transplantation (HSCT) or unacceptable toxicity; though discontinue when therapy is no longer required for HLH.

  • Dose modification: If an inadequate response (see Criteria for dose increase) titrate dose as follows:

    • Day 3:
      • It may increase dose to 3 mg/kg/dose if meets criteria for a dose increase
    • Day 6 and beyond:
      • It may increase dose to 6 mg/kg/dose if meets criteria for a dose increase
    • Day 9 and beyond:
      • It may increase dose to 10 mg/kg/dose if (based on initial signs of response) assessment by health care provider refers 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/mm³ or 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/mm³ or baseline >500 to 1,000/mm³ and decrease to <500/mm³ or 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 before 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.
    • In case, if the patient is not having baseline dexamethasone treatment (≥5 mg/m² /day), begin dexamethasone at a dose of at least 5 to 10 mg/m² /day beginning 1 day before initiation of emapalumab.
    • However, 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 judgment.

Pregnancy Risk Category: N (Not assigned)

• • • Animal reproduction studies did not show any adverse events.

Emapalumab use during breastfeeding:

• • It is not known if breast milk contains emapalumab.
  • According to the manufacturer, breastfeeding during therapy should be considered in light of the risks to infants, the benefits to the mother, and the benefits to the mother.

Emapalumab (Gamifant) Dose in Kidney disease:

No dosage adjustments are provided in the manufacturer's labeling; however, renal impairment (including dialysis) had no clinically meaningful effect on emapalumab pharmacokinetics. 

Emapalumab (Gamifant) Dose in Liver disease:

No dosage adjustments are provided in the manufacturer's labeling; however, mild, moderate, or severe hepatic impairment had no clinically meaningful effect on emapalumab pharmacokinetics.

Common Side Effects of Emapalumab (Gamifant):

• Cardiovascular:

  • Hypertension
  • tachycardia

• Central nervous system:

  • Irritability

• Dermatologic:

  • Skin rash

• Endocrine & metabolic:

  • Hypokalemia

• Gastrointestinal:

  • Appendicitis
  • constipation
  • abdominal pain
  • diarrhea

• Hematologic & oncologic:

  • Lymphocytosis

• Infection:

  • Infection
  • viral infection
  • bacterial infection
  • bacteremia
  • histoplasmosis
  • necrotizing fasciitis
  • sepsis
  • cytomegalovirus disease

• Respiratory:

  • Pneumonia
  • cough
  • tachypnea

• Miscellaneous:

  • Infusion related reaction
  • fever

Less Common Side Effects of Emapalumab (Gamifant):

• Cardiovascular:

  • Bradycardia
  • peripheral edema

• Gastrointestinal:

  • Gastrointestinal hemorrhage
  • vomiting

• Immunologic:

  • Antibody development

• Infection:

  • Fungal infection

• Neuromuscular & skeletal:

  • Asthenia

• Renal:

  • Acute renal failure

• Respiratory:

  • Dyspnea
  • epistaxis

• Miscellaneous:

  • Multi-organ failure

Contraindications to Emapalumab (Gamifant):

The manufacturer's label does not contain any contraindications.

Warnings and precautions

• • Infection

    • It is possible to contract an infection frequently.
    • Emapalumab can increase the chance of serious and fatal infections in patients with certain pathogens that are favored by IFNg neutrization (mycobacteria and herpes virus). However, emapalumab should not be administered to patients with these infections until appropriate treatment has been started.
    • Nearly one-third of patients who received emapalumab during clinical trials were diagnosed with serious infections such as pneumonia, bacteremia and sepsis.
    • Most infections reported were viral and bacterial. However, fungal infections and infections with unidentified pathogens also occurred.
    • Before you start emapalumab treatment, assess for tuberculosis risk factors. Also, test for latent infections by using purified protein derivative (PPD), polymerase chain reaction, or IFNg release assay.
    • Patients at high risk of developing tuberculosis, or those with positive PPD tests, should be given tuberculosis prevention.
    • During emapalumab therapy, you should administer prophylaxis for herpes, pneumocystis, and fungal infections.
    • Surveillance testing should be performed during treatment.
    • Watch out for any signs or symptoms of infection and immediately initiate an appropriate diagnostic workup for immunocompromised patients.

  • Infusion reactions

    • Over one-fourth (or more) of patients who received emapalumab have reported experiencing infusion-related reactions. These include drug eruptions, rash, erythema and hyperhidrosis.
    • Infusion-related reactions were observed in one-third of the patients who received their first infusion.
    • Mild to moderate infusion reactions were possible.
    • Monitoring should be done for infusion-related reactions.
    • If an infusion reaction occurs during infusion, stop the infusion and treat it appropriately. Then, reduce the rate of infusion.

Emapalumab: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

  Risk Factor C (Monitor therapy).
  Coccidioides immitis Skin Test	Coccidioides immitis Skin Test may be affected by immunosuppressants.
  Denosumab	Might increase the toxic/adverse effects of Immunosuppressants. In particular, there may be an increase in the risk of serious infections.
  Ocrelizumab	May increase the immunosuppressive effects of Immunosuppressants.
  Pidotimod	Pidotimod's therapeutic effects may be diminished by immunosuppressants.
  Siponimod	Siponimod's immunosuppressive effects may be enhanced by taking immunosuppressants.
  Tertomotide	Tertomotide's therapeutic effects may be diminished by immunosuppressants.
  Trastuzumab	May increase the neutropenic effects of Immunosuppressants.
  Risk Factor D (Regard therapy modification)
  Echinacea	Might decrease the therapeutic effects of Immunosuppressants.
  Baricitinib	Baricitinib's immunosuppressive effects may be enhanced by immunosuppressants. Baricitinib should not be used in combination with immunosuppressants like azathioprine and cyclosporine. It is permissible to use methotrexate antirheumatically or nonbiologic disease-modifying antirheumatic drug (DMARDs), concurrently.
  Fingolimod	Fingolimod may be immunosuppressed by immunosuppressants. When possible, avoid the use of fingolimod with other immunosuppressants. Patients should be closely monitored for any additive immunosuppressant effects, such as infections, if they are used together.
  Leflunomide	Leflunomide's toxic/adverse effects may be exacerbated by immunosuppressants. The risk of hematologic toxicities such as pancytopenia and agranulocytosis may increase. Patients on immunosuppressants should not be given a leflunomide loading dosage. Patients who are receiving leflunomide or another immunosuppressant must be checked for bone marrow suppression at minimum monthly.
  Nivolumab	Nivolumab's therapeutic effects may be diminished by immunosuppressants.
  Roflumilast	May increase the immunosuppressive effects of Immunosuppressants.
  Sipuleucel-T	Sipuleucel T therapy may be affected by immunosuppressants. Treatment: Patients should be evaluated to determine if they are able to stop or reduce their use of immunosuppressants before initiating sipuleucel T therapy.
  Tofacitinib	Tofacitinib's immunosuppressive effects may be enhanced by immunosuppressants. Management: It is permissible to use methotrexate (or nonbiologic disease-modifying antirheumatic drug (DMARDs), concurrently with antirheumatic doses. This warning appears to be particularly targeted at more potent immunosuppressants.
  Vaccines (Inactivated)	Immunosuppressants can reduce the therapeutic effects of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. All age-appropriate vaccines must be completed at least two weeks before you start an immunosuppressant. Re-vaccinate anyone who was vaccinated while on immunosuppressant therapy.
  Risk Factor X (Avoid Combination)
  BCG (Intravesical).	The therapeutic effects of BCG (Intravesical) may be diminished by immunosuppressants
  Cladribine	May increase the immunosuppressive effects of Immunosuppressants.
  Natalizumab	Natalizumab's toxic/adverse effects may be exacerbated by immunosuppressants. Particularly, concurrent infections may increase.
  Pimecrolimus	May increase the toxic/adverse effects of Immunosuppressants
  Tacrolimus (Topical)	May increase the toxic/adverse effects of Immunosuppressants
  Vaccines (Live)	Immunosuppressants can increase the toxic/adverse effects of Vaccines (Live). Immunosuppressants can decrease the therapeutic effects of Vaccines. Management: Live-attenuated vaccines should be avoided for at least three months following immunosuppressants.

Monitoring parameters:

• Monitor for clinical improvement that is based on platelet counts, neutrophil counts, ferritin, D-dimer and fibrinogen, fever, and signs/symptoms of splenomegaly.
• Evaluate for tuberculosis risk factors and test for latent infection by purified protein derivative (PPD) testing, PCR, or IFNγ release assay, before initiating emapalumab.
• 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 ought to be utilized during treatment.
• Monitor closely for signs/symptoms of an infection; promptly initiate a complete diagnostic workup appropriate for an immunocompromised patient. However, monitor for infusion-related reactions.

How to administer Emapalumab (Gamifant)?

IV: Infuse over 1 hour through an IV line containing a sterile, non-pyrogenic, low-protein binding 0.2-micron inline filter. Need not to shake. Before infusion allows the solution to reach room temperature. Do not infuse with other medications. Though in case an infusion reaction occurs, interrupt the infusion and manage appropriately, then continue with the infusion rate reduced. 

Mechanism of action of Emapalumab (Gamifant):

Emapalumab (IFNg) is a monoclonal, interferon-gamma blocking antibody. Hemophagocytic lymphohistiocytosis (HLH) causes IFNg to be hypersecreted. emapalumab binds with IFNg and neutralizes it. Metabolism

• Emapalumab will likely be degraded via catabolic pathways into small peptides or amino acids.

Half-life elimination:

• Healthy subjects: 22 Days
• Patients with hemophagocytic Lymphohistiocytosis: 2.5 to 18.9 days

International Brand Names of Emapalumab:

• Gamifant

Emapalumab Brand Names in Pakistan:

• No Brands are Available in Pakistan.