Emapalumab – Uses, Dosage, Side Effects, Interaction

Emapalumab (em” a pal’ ue mab) is a recombinant, human IgG1 monoclonal antibody to gamma interferon, which inhibits its binding to cell surface interferon receptors and the subsequent activation of intracellular proinflammatory signaling pathways. Gamma interferon levels are known to be elevated in patients with hemophagocytic lymphohistiocytosis (HLH), a life-threatening inflammatory syndrome marked by fever, enlargement of liver and spleen, macrophage update of red blood cells (hemophagocytosis) in bone marrow, spleen and lymph nodes, low natural killer cell activity and high levels of serum ferritin, triglycerides and multiple cytokines.

Emapalumab is an interferon-gamma-blocking antibody used to treat primary hemophagocytic lymphohistiocytosis.

Emapalumab, also known as NI-0501, is a fully human monoclonal antibody that targets interferon-gamma. Emapalumab development was sponsored by NovImmune SA, further developed by Sobi, and FDA-approved on November 20, 2018.[rx,rx] The approval of emapalumab was followed by the designation of an orphan drug, priority review, and breakthrough therapy.[rx] As well, emapalumab was given the status of PRIME by the EMA.[rx]

Mechanism of action

Emapalumab acts by binding and neutralizing interferon-gamma.[rx] The specific interaction between emapalumab and interferon-gamma produces an inhibition in the interaction between interferon-gamma and its cognate receptor on T-cells which produces the neutralizing activity.[rx] It is important to consider that emapalumab inhibits both free and IFNGR1-bound interferon-gamma as well as the interaction with IFNGR1 and IFNGR2 at the cell surface.[rx]

HLH is an immune dysregulation syndrome in which several cytokines are involved but it has been reported that interferon-gamma plays a pivotal role in the development of this disease as studies have shown a vast increase in the interferon-gamma levels in HLH patients.[rx]

In phase 2/3 clinical trials, emapalumab administered concomitantly with dexamethasone reported an overall response in 63% of the patients. The overall response was defined as the achievement of complete or partial response or HLH improvement.[rx] In this trial and as proof of interferon-gamma neutralization, there was registered a sharp decrease in serum CXCL9 and to avoid QT prolongation in the presence of low doses of emapalumab.[rx]

Indications

  • Emapalumab is indicated for the treatment of pediatric and adult patients with primary hemophagocytic lymphohistiocytosis (HLH) with refractory, recurrent, or progressive disease or intolerance to conventional HLH therapy.[rx]
  • The HLH condition is a hyperinflammatory status characterized by the overwhelming activation of normal T lymphocytes and macrophages which can lead to disturbances in the hematology profile and even death. As part of the condition profile, there have been reports proving a massive overexpression of interferon-gamma which is thought to drive the immune hyperactivation leading to organ failure.[rx] This condition is usually developed and presents the symptomatic profile within the first months or years of life. These symptoms consist of fever, enlarged liver or spleen, and a lower number of blood cells.[rx]
  • Progressive, refractory, primary intolerance with conventional therapy, recurrent Hemophagocytic Lymphohistiocytosis
  • Emapalumab is used to treat primary hemophagocytic lymphohistiocytosis (HLH) with refractory, recurrent, or progressive disease or intolerance with conventional HLH therapy.
  • For the treatment of primary hemophagocytic lymphohistiocytosis (HLH) with refractory, recurrent, or progressive disease or intolerance with conventional HLH therapy

Use in Cancer

Emapalumab-lzsg is approved to treat:

Emapalumab-lzsg is also being studied in the treatment of other conditions.

Contraindications

  • active tuberculosis
  • shingles
  • a type of fungal lung infection called histoplasmosis
  • an infection due to a fungus
  • pneumonia with a fungus called Pneumocystis jirovecii

Dosage

Strengths: lzsg 5 mg/mL

Histiocytosis

  • Initial dose: 1 mg/kg IV over 1 hour 2 times a week (every 3 to 4 days)
  • Doses after the initial dose may be increased stepwise to 10 mg/kg based on clinical and laboratory criteria (see Dose Adjustments).
  • Duration of therapy: Until hematopoietic stem cell transplantation (HSCT) is performed or unacceptable toxicity; discontinue when a patient no longer requires treatment of HLH.

Premedication/Concomitant Medication:

  • For patients who are not receiving baseline dexamethasone: Begin dexamethasone at a daily dose of at least 5 to 10 mg/m2 the day before initiation of this drug.
  • For patients who were receiving baseline dexamethasone: They may continue their regular dose provided the dose is at least 5 mg/m2.
  • Dexamethasone can be tapered according to the judgment of the physician.
  • Test for latent TB using the purified protein derivative (PPD) or IFNy release assay and evaluate patients for TB risk factors.
  • Administer TB prophylaxis to patients at risk, or known to have a positive PPD test result or positive IFNy release assay.
  • Administer prophylaxis for herpes zoster, Pneumocystis jirovecii, and fungal infections prior to therapy initiation.
  • During therapy monitor for TB, adenovirus, EBV, and CMV every 2 weeks and as clinically indicated.

Pediatric Dose for Histiocytosis

  • Initial dose: 1 mg/kg IV over 1 hour 2 times a week (every 3 to 4 days)
  • Doses after the initial dose may be increased stepwise to 10 mg/kg based on clinical and laboratory criteria (see Dose Adjustments).
  • Duration of therapy: Until hematopoietic stem cell transplantation (HSCT) is performed or unacceptable toxicity; discontinue when a patient no longer requires treatment of HLH.

Premedication/Concomitant Medication:

  • For patients who are not receiving baseline dexamethasone: Begin dexamethasone at a daily dose of at least 5 to 10 mg/m2 the day before initiation of this drug.
  • For patients who were receiving baseline dexamethasone: They may continue their regular dose provided the dose is at least 5 mg/m2.
  • Dexamethasone can be tapered according to the judgment of the physician.
  • Test for latent TB using the purified protein derivative (PPD) or IFNy release assay and evaluate patients for TB risk factors.
  • Administer TB prophylaxis to patients at risk, or known to have a positive PPD test result or positive IFNy release assay.
  • Administer prophylaxis for herpes zoster, Pneumocystis jirovecii, and fungal infections prior to therapy initiation.
  • During therapy monitor for TB, adenovirus, EBV, and CMV every 2 weeks and as clinically indicated.

Dose Adjustments

Dose Modification Based on Response:

  • Day 1: Starting dose of 1 IV mg/kg
  • Increase the dose to 3 mg/kg IV on Day 3 for unsatisfactory improvement
  • Increase the dose to 6 mg/kg IV on Day 6 onwards for unsatisfactory improvement
  • Increase dose to 10 mg/kg IV from Day 9 onwards

NOTE: UNSATISFACTORY IMPROVEMENT ON DAY 3 AND DAY 6 IS DEFINED AS ASSESSED BY A HEALTHCARE PROVIDER AND AT LEAST ONE OF THE FOLLOWING:
FEVER: Persistent or recurring
PLATELET COUNT:

  • If the baseline is less than 50,000/mm3 and no improvement to greater than 50,000/mm3
  • If the baseline is greater than 50,000/mm3 and less than 30% improvement
  • If the baseline is greater than 100,000/mm3 and decreases to less than 100,000/mm3

NEUTROPHIL COUNT:

  • If the baseline is less than 500/mm3 and no improvement to greater than 500/mm3
  • If a baseline is greater than 500 to 1000/mm3 and decreases to less than 500/mm3 -If the baseline is 1000 to 1500/mm3 and decreases to less than 1000/ mm3

FERRITIN (ng/mL):

  • If the baseline is 3000 ng/mL or greater and less than a 20% decrease
  • If the baseline is less than 3000 ng/mL and any increase to greater than 3000 ng/mL SPLENOMEGALY: Any worsening

COAGULOPATHY (both D-Dimer and Fibrinogen must apply):

  • D-Dimer: If abnormal at baseline and no improvement
  • Fibrinogen (mg/dL): If baseline levels are 100 mg/dL or less and no improvement
  • If baseline levels are greater than 100 mg/dL) and any decrease to less than 100 mg/dL

NOTE: UNSATISFACTORY IMPROVEMENT ON DAY 9 IS DEFINED AS:

  • Assessment by a healthcare provider that based on initial signs of response, a further increase in the dose can be of benefit.

Administration advice:

  • Administer diluted solution IV over 1 hour through an IV line containing a sterile, non-pyrogenic, low-protein binding 0.2-micron in-line filter.
  • Do not infuse this drug concomitantly with other agents and do not add any other product to the infusion bag or syringe.

Side Effects

The Most Common

  • constipation
  • nose bleeds
  • fast, slow, or irregular heartbeat
  • fast breathing
  • muscle cramps
  • numbness and tingling
  • bloody or black, tarry stools
  • vomiting blood or brown material that resembles coffee grounds
  • decreased urination
  • swelling in the hands, feet, ankles, or lower legs

More common

  • Agitation
  • back pain
  • black, tarry stools
  • bloating or swelling of the face, arms, hands, lower legs, or feet
  • bloody stools
  • blurred vision
  • chest pain, discomfort, or tightness
  • chills
  • confusion
  • cough
  • decreased awareness or responsiveness
  • decreased urine
  • depression
  • difficult or labored breathing
  • dry mouth
  • fast, pounding, or irregular heartbeat or pulse
  • feeling of warmth
  • fever
  • headache
  • hoarseness
  • hostility
  • increased thirst
  • irritability
  • lightheadedness, dizziness, or fainting
  • loss of appetite
  • loss of consciousness
  • lower back or side pain
  • mood changes
  • muscle pain, cramps, or twitching
  • nausea
  • nervousness
  • nosebleed
  • numbness or tingling in the hands, feet, or lips
  • painful or difficult urination
  • pounding in the ears
  • rapid weight gain
  • rapid, shallow breathing
  • redness of the face, neck, arms and occasionally, upper chest
  • seizures
  • severe sleepiness
  • slow heartbeat
  • swollen glands
  • unusual drowsiness, dullness, tiredness, weakness, or feeling of sluggishness
  • unusual weight gain or loss
  • vomiting
  • vomiting of blood or material that looks like coffee grounds

Rare

  • fever, chills, night sweats;
  • loss of appetite, weight loss;
  • feeling very tired;
  • warmth, redness, or painful sores on your skin;
  • cough, trouble breathing;
  • mouth and throat ulcers;
  • cough with bloody mucus; or
  • any other new or worsening signs of infection.
  • fever; or
  • increased blood pressure.

Drug Interaction

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Pregnancy and Lactation

US FDA pregnancy category: Not assigned.

Pregnancy

The manufacturer makes no recommendation regarding use during pregnancy. There are no available data on the use of this drug in pregnant women to inform a drug-associated risk of adverse developmental outcomes. In animal studies, a murine surrogate anti-mouse antibody administered to pregnant mice throughout gestation crossed the placental barrier, and no fetal harm was observed.

Lactation

Safety has not been established.
Excreted into human milk: Unknown
Excreted into animal milk: Data not available
The effects in the nursing infant are unknown. Available 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.

How should this medicine be used?

Emapalumab-lzsg comes as a liquid to be injected into a vein over 1 hour by a doctor or nurse in a hospital or medical facility. It is usually given 2 times per week, every 3 or 4 days, for as long as your doctor recommends that you receive treatment.

Your doctor may start you on a low dose of emapalumab-lzsg injection and gradually increase your dose, not more than once every 3 days.

Emapalumab-lzsg injection may cause a severe reaction during or shortly after the infusion of the medication. A doctor or nurse will monitor you carefully while you are receiving the medication. If you experience any of the following symptoms, tell your doctor immediately: skin redness, itching, fever, rash, excessive sweating, chills, nausea, vomiting, lightheadedness, dizziness, chest pain, or shortness of breath.

Your doctor or pharmacist will give you the manufacturer’s patient information sheet (Medication Guide) when you begin treatment with emapalumab-lzsg injection and each time you receive the medication. Read the information carefully and ask your doctor or pharmacist if you have any questions. You can also visit the Food and Drug Administration (FDA) website (http://www.fda.gov/Drugs/DrugSafety/ucm085729.htm) or the manufacturer’s website to obtain the Medication Guide.

What special precautions should I follow?

Before receiving emapalumab-lzsg injection,

  • tell your doctor and pharmacist if you are allergic to emapalumab-lzsg, any other medications, or any of the ingredients in emapalumab-lzsg injection. Ask your pharmacist or check the Medication Guide for a list of the ingredients.
  • tell your doctor if you have or have ever had any medical condition.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while receiving emapalumab-lzsg injection, call your doctor.
  • you should know that emapalumab-lzsg injection may decrease your ability to fight infection from bacteria, viruses, and fungi and increase the risk that you will get a serious or life-threatening infection. Tell your doctor if you often get any type of infection or if you have or think you may have any type of infection now. This includes minor infections (such as open cuts or sores), infections that come and go (such as herpes or cold sores), and chronic infections that do not go away. If you experience any of the following symptoms during or shortly after your treatment with emapalumab-lzsg injection, call your doctor immediately: fever, sweats, or chills; muscle aches; cough; bloody mucus; shortness of breath; sore throat or difficulty swallowing; warm, red, or painful skin or sores on your body; diarrhea; stomach pain; frequent, urgent, or painful urination; or other signs of infection.
  • you should know that receiving emapalumab-lzsg injection increases the risk that you will develop tuberculosis (TB; a serious lung infection), especially if you are already infected with TB but do not have any symptoms of the disease. Tell your doctor if you have or have ever had TB, if you have lived in a country where TB is common, or if you have been around someone who has TB. Your doctor will check you for TB before starting treatment with emapalumab-lzsg injection and may treat you for TB if you have a history of TB or have active TB. If you have any of the following symptoms of TB or if you develop any of these symptoms during your treatment, call your doctor immediately: cough, coughing up blood or mucus, weakness or tiredness, weight loss, loss of appetite, chills, fever, or night sweats.
  • do not have any vaccinations without talking to your doctor during your treatment with emapalumab-lzsg injection and for at least 4 weeks after your final dose.

References