Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium
ELREXFIO is indicated as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, who have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody and have demonstrated disease progression on the last therapy.
Treatment should be initiated and supervised by physicians experienced in the treatment of multiple myeloma.
ELREXFIO should be administered via subcutaneous injection by a healthcare professional with adequately trained medical personnel and appropriate medical equipment to manage severe reactions, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) (see section 4.4).
Prior to initiating treatment, complete blood count should be performed. Any possibility of active infections and/or pregnancy in women of child-bearing potential should be ruled out (see sections 4.4 and 4.6).
The recommended doses are step-up doses of 12 mg on day 1 and 32 mg on day 4, followed by a full treatment dose of 76 mg weekly from week 2 to week 24 (see Table 1).
For patients who have received at least 24 weeks of treatment and have achieved a response, the dosing interval should transition to an every two-week schedule.
ELREXFIO should be administered according to the step-up dosing schedule in Table 1 to reduce the incidence and severity of CRS and ICANS. Due to the risk of CRS and ICANS, patients should be monitored for signs and symptoms for 48 hours after administration of each of the 2 step-up doses and instructed to remain within proximity of a healthcare facility (see section 4.4).
Table 1. ELREXFIO dosing schedule:
| Dosing schedule | Week/day | Dose | |
|---|---|---|---|
| Step-up dosinga,b | Week 1: day 1 | Step-up dose 1 | 12 mg |
| Week 1: day 4 | Step-up dose 2 | 32 mg | |
| Weekly dosinga,c,d | Week 2-24: day 1 | Full treatment dose | 76 mg once weekly |
| Every 2 weeks dosingd,e | Week 25 onward: day 1 | Full treatment dose | 76 mg once every two weeks |
a Pre-treatment medicinal products should be administered prior to the first three doses of ELREXFIO.
b A minimum of 2 days should be maintained between step-up dose 1 (12 mg) and step-up dose 2 (32 mg).
c A minimum of 3 days should be maintained between step-up dose 2 (32 mg) and the first full treatment (76 mg) dose.
d A minimum of 6 days should be maintained between doses.
e For patients who have achieved a response.
Note: See Table 5 for recommendations on restarting ELREXFIO after dose delays.
The following pre-treatment medicinal products should be administered approximately 1 hour prior to the first three doses of ELREXFIO, which includes step-up dose 1, step-up dose 2, and the first full treatment dose as described in Table 1 to reduce the risk of CRS (see section 4.4):
Prophylactic antimicrobials and anti-virals should be considered according to local institutional guidelines (see section 4.4).
Dose reductions of ELREXFIO are not recommended. Dose delays may be required to manage toxicities (see section 4.4).
See Tables 2 and 3 for recommended actions for adverse reactions of CRS and ICANS, respectively.
See Table 4 for recommended actions for other adverse reactions.
CRS should be identified based on clinical presentation (see section 4.4). Patients should be evaluated and treated for other causes of fever, hypoxia, and hypotension. Supportive therapy for CRS (including but not limited to anti-pyretic agents, intravenous fluid support, vasopressors, IL-6 or IL-6 receptor inhibitors, supplemental oxygen, etc.) should be administered as appropriate. Laboratory testing to monitor for disseminated intravascular coagulation (DIC), haematology parameters, as well as pulmonary, cardiac, renal, and hepatic function should be considered.
Table 2. Recommendations for management of CRS:
| Gradea | Presenting symptoms | Actions |
|---|---|---|
| Grade 1 | Temperature ≥38°Cb | • Withhold treatment until CRS resolves.c • Provide supportive therapy. |
| Grade 2 | Temperature ≥38°C with either: • Hypotension responsive to fluid and not requiring vasopressors, and/or • Oxygen requirement of low-flow nasal cannulad or blow-by | • Withhold treatment until CRS resolves.c • Provide supportive therapy. • Monitor patients daily for 48 hours following the next dose of ELREXFIO. Instruct patients to remain within proximity of a healthcare facility. |
| Grade 3 (First occurrence) | Temperature ≥38°C with either: • Hypotension requiring one vasopressor with or without vasopressin, and/or • Oxygen requirement of high-flow nasal cannulad, facemask, non-rebreather mask, or Venturi mask | • Withhold treatment until CRS resolves.c • Provide supportive therapy, which may include intensive care. • Administer pre-treatment medicinal products prior to the next dose of ELREXFIO. • Monitor patients daily for 48 hours following the next dose of ELREXFIO. Instruct patients to remain within proximity of a healthcare facility. |
| Grade 3 (Recurrent) | Temperature ≥38°C with either: • Hypotension requiring one vasopressor with or without vasopressin, and/or • Oxygen requirement of high-flow nasal cannulad, facemask, non-rebreather mask, or Venturi mask | • Permanently discontinue therapy. • Provide supportive therapy, which may include intensive care. |
| Grade 4 | Temperature ≥38°C with either: • Hypotension requiring multiple vasopressors (excluding vasopressin), and/or • Oxygen requirement of positive pressure (e.g., continuous positive airway pressure [CPAP], bilevel positive airway pressure [BiPAP], intubation, and mechanical ventilation) | • Permanently discontinue therapy. • Provide supportive therapy, which may include intensive care. |
a Based on American society for transplantation and cellular therapy (ASTCT) 2019 grading for CRS.
b Attributed to CRS. Fever may not always be present concurrently with hypotension or hypoxia as it may be masked by interventions such as antipyretics or anti-cytokine therapy.
c See Table 5 for recommendations on restarting ELREXFIO after dose delays.
d Low-flow nasal cannula is ≤6 L/min, and high-flow nasal cannula is >6 L/min.
Other causes of neurologic symptoms should be ruled out. Patients should be immediately evaluated and treated based on severity. Supportive therapy, which may include intensive care, for severe or life-threatening neurologic toxicities, should be provided. Patients who experience Grade 2 or higher ICANS with the previous dose of ELREXFIO should be instructed to remain within proximity of a healthcare facility and be monitored for signs and symptoms daily for 48 hours following the next dose.
Table 3. Recommendations for management of ICANS:
| Gradea | Presenting symptomsb | Actions |
|---|---|---|
| Grade 1 | ICE score 7-9c Or depressed level of consciousnessd: awakens spontaneously. | • Withhold treatment until ICANS resolves.e • Monitor neurologic symptoms and consider consultation with a neurologist for further evaluation and management. • Consider non-sedating, anti-seizure medicinal products (e.g., levetiracetam) for seizure prophylaxis. |
| Grade 2 | ICE score 3-6c Or depressed level of consciousnessd: awakens to voice. | • Withhold treatment until ICANS resolves.e • Administer dexamethasonef 10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. • Monitor neurologic symptoms and consider consultation with a neurologist and other specialists for further evaluation and management. • Consider non-sedating, anti-seizure medicinal products (e.g., levetiracetam) for seizure prophylaxis. • Monitor patients daily for 48 hours following the next dose of ELREXFIO. Instruct patients to remain within proximity of a healthcare facility. |
| Grade 3 (First occurrence) | ICE score 0-2c or depressed level of consciousnessd: awakens only to tactile stimulus, or seizuresd, either: • any clinical seizure, focal or generalised, that resolves rapidly, or • non-convulsive seizures on electroencephalogram (EEG) that resolve with intervention, or raised intracranial pressure: focal/local oedema on neuroimagingd | • Withhold treatment until ICANS resolves.e • Administer dexamethasonef 10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. • Monitor neurologic symptoms and consider consultation with a neurologist and other specialists for further evaluation and management. • Consider non-sedating, anti-seizure medicinal products (e.g., levetiracetam) for seizure prophylaxis. • Provide supportive therapy, which may include intensive care. • Monitor patients daily for 48 hours following the next dose of ELREXFIO. Instruct patients to remain within proximity of a healthcare facility. |
| Grade 3 (Recurrent) | ICE score 0-2c or depressed level of consciousnessd: awakens only to tactile stimulus, or seizuresd, either: • any clinical seizure, focal or generalised, that resolves rapidly, or • non-convulsive seizures on electroencephalogram (EEG) that resolve with intervention, or raised intracranial pressure: focal/local oedema on neuroimagingd | • Permanently discontinue treatment. • Administer dexamethasonef 10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. • Monitor neurologic symptoms and consider consultation with a neurologist and other specialists for further evaluation and management. • Consider non-sedating, anti-seizure medicinal products (e.g., levetiracetam) for seizure prophylaxis. • Provide supportive therapy, which may include intensive care. |
| Grade 4 | ICE score 0c Or, depressed level of consciousnessd either: • patient is unarousable or requires vigorous or repetitive tactile stimuli to arouse, or • stupor or coma, or seizuresd, either: • life-threatening prolonged seizure (>5 minutes), or • repetitive clinical or electrical seizures without return to baseline in between, or motor findingsd: • deep focal motor weakness such as hemiparesis or paraparesis, or raised intracranial pressure/cerebral oedemad, with signs/symptoms such as: • diffuse cerebral oedema on neuroimaging, or • decerebrate or decorticate posturing, or • cranial nerve VI palsy, or • papilloedema, or • Cushing’s triad | • Permanently discontinue treatment. • Administer dexamethasonef 10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. • Alternatively, consider administration of methylprednisolone 1 000 mg per day intravenously for 3 days. • Monitor neurologic symptoms and consider consultation with a neurologist and other specialists for further evaluation and management. • Consider non-sedating, anti-seizure medicinal products (e.g., levetiracetam) for seizure prophylaxis. • Provide supportive therapy, which may include intensive care. |
Abbreviations: Immune effector cell-associated encephalopathy (ICE).
a Based on American society for transplantation and cellular therapy (ASTCT) 2019 grading for ICANS.
b Management is determined by the most severe event, not attributable to any other cause.
c If patient is arousable and able to perform ICE assessment, assess: Orientation (oriented to year, month, city, hospital=4 points); Naming (name 3 objects, e.g., point to clock, pen, button=3 points); Following commands (e.g., “show me 2 fingers” or “close your eyes and stick out your tongue”=1 point); Writing (ability to write a standard sentence=1 point); and Attention (count backwards from 100 by ten=1 point). If patient is unarousable and unable to perform ICE assessment (Grade 4 ICANS)=0 points.
d Not attributable to any other cause.
e See Table 5 for recommendations on restarting ELREXFIO after dose delays.
f All references to dexamethasone administration are dexamethasone or equivalent medicinal products.
Table 4. Recommended actions for other adverse reactions:
| Adverse reactions | Severity | Actions |
|---|---|---|
| Haematologic adverse reactions (see section 4.8) | Absolute neutrophil count less than 0.5 × 109/L | • Withhold treatment until absolute neutrophil count is 0.5 × 109/L or higher.b |
| Febrile neutropenia | • Withhold treatment until absolute neutrophil count is 1 × 109/L or higher and fever resolves.b | |
| Haemoglobin less than 8 g/dL | • Withhold treatment until haemoglobin is 8 g/dL or higher.b | |
| Platelet count less than 25 000/mcL Platelet count between 25 000/mcL and 50 000/mcL with bleeding | • Withhold treatment until platelet count is 25 000/mcL or higher and no evidence of bleeding.b | |
| Other* non-haematologic adverse reactionsa (see section 4.8) | Grade 3 or 4 | • Withhold treatment until recovery to Grade 1 or less or baseline.b • Permanently discontinue if recovery does not occur. |
a Based on National cancer institute common terminology criteria for adverse events (NCI-CTCAE), Version 5.0.
b See Table 5 for recommendations on restarting ELREXFIO after dose delays (see section 4.2).
* Other than CRS and ICANS.
If a dose is delayed, therapy should be restarted based on the recommendations listed in Table 5, and therapy should be resumed according to the dosing schedule (see Table 1). Pre-treatment medicinal products should be administered as indicated in Table 5.
Table 5. Recommendations for restarting therapy with ELREXFIO after dose delay:
| Last administered dose | Duration of delay from the last administered dose | Action |
|---|---|---|
| Step-up dose 1 (12 mg) | 2 weeks or less (≤14 days) | Restart at step-up dose 2 (32 mg).a If tolerated, increase to 76 mg 4 days later. |
| Greater than 2 weeks (>14 days) | Restart step-up dosing schedule at step-up dose 1 (12 mg).a | |
| Step-up dose 2 (32 mg) | 2 weeks or less (≤14 days) | Restart at 76 mg.a |
| Greater than 2 weeks to less than or equal to 4 weeks (15 days and ≤28 days) | Restart at step-up dose 2 (32 mg).a If tolerated, increase to 76 mg 1 week later. | |
| Greater than 4 weeks (>28 days) | Restart step-up dosing schedule at step-up dose 1 (12 mg).a | |
| Any full treatment dose (76 mg) | 6 weeks or less (≤42 days) | Restart at 76 mg. |
| Greater than 6 weeks to less or equal to 12 weeks (43 days to ≤84 days) | Restart at step-up dose 2 (32 mg).a If tolerated, increase to 76 mg 1 week later. | |
| Greater than 12 weeks (>84 days) | Restart step-up dosing schedule at step-up dose 1 (12 mg).a |
a Administer pre-treatment medicinal products prior to the ELREXFIO dose.
Treatment should be continued until disease progression or unacceptable toxicity.
If a dose is missed, the dose should be administered as soon as possible, and the dosing schedule should be adjusted to maintain the dosing interval as needed (see Table 1).
No dose adjustment is necessary (see sections 5.1 and 5.2).
No dose adjustment is recommended in patients with mild to moderate renal impairment (estimated glomerular filtration rate [eGFR] >30 mL/min/1.73 m²). Limited data are available from patients with severe renal impairment, see section 5.2).
No dose adjustments are required for mild hepatic impairment (total bilirubin >1 to 1.5 × ULN and any AST, or total bilirubin ≤ ULN and AST > ULN, see section 5.2).
There is no relevant use of ELREXFIO in the paediatric population for the treatment of multiple myeloma.
ELREXFIO is for subcutaneous injection only and should be administered by a healthcare professional.
The required dose should be injected into the subcutaneous tissue of the abdomen (preferred injection site). Alternatively, it may be injected into the subcutaneous tissue of the thigh.
ELREXFIO should not be injected into areas where the skin is red, bruised, tender, hard, or areas where there are scars.
For instructions on handling of the medicinal product before administration, see section 6.6.
There has been no experience of overdose in clinical studies. The maximum tolerated dose of elranatamab has not been determined. In clinical studies, doses up to 76 mg once weekly have been administered.
In the event of an overdose, the patient should be monitored for any signs or symptoms of adverse reactions and appropriate supportive treatment should be instituted immediately.
Unopened vial:
2 years.
Prepared syringe:
Chemical and physical in-use stability has been demonstrated for 24 hours at 30°C.
From a microbiological point of view, unless the method of opening precludes the risks of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.
Store in a refrigerator (2°C to 8°C).
Do not freeze.
Store in the original carton in order to protect from light.
For storage conditions after first opening of the medicinal product, see section 6.3.
ELREXFIO 40 mg/mL solution for injection: 1.1 mL solution in a vial (Type 1 glass) with a stopper (butyl rubber) and an aluminium seal with a flip-off cap containing 44 mg of elranatamab. Pack size of 1 vial.
ELREXFIO 40 mg/mL solution for injection: 1.9 mL solution in a vial (Type 1 glass) with a stopper (butyl rubber) and an aluminium seal with a flip-off cap containing 76 mg of elranatamab. Pack size of 1 vial.
ELREXFIO 40 mg/mL solution for injection is supplied as a ready-to-use solution that does not need dilution prior to administration. Do not shake.
ELREXFIO is a clear to slightly opalescent, and colourless to pale brown solution. The solution should not be administered if it is discoloured or contains particulate matter.
Aseptic technique should be used to prepare and administer ELREXFIO.
ELREXFIO 40 mg/mL solution for injection vials are for single use only.
ELREXFIO should be prepared following the instructions below (see Table 9) depending on the required dose. It is suggested to use a 44 mg/1.1 mL (40 mg/mL) single dose vial for each one of the step-up doses.
Table 9. Preparation instructions for ELREXFIO:
| Required dose | Dose volume |
|---|---|
| 12 mg (Step-up dose 1) | 0.3 mL |
| 32 mg (Step-up dose 2) | 0.8 mL |
| 76 mg (Full treatment dose) | 1.9 mL |
Once punctured, the vial and dosing syringe should be used immediately. If the prepared dosing syringe is not used immediately, store syringe between 2°C to 30°C for a maximum of 24 hours.
The vial and any remaining contents should be discarded after a single use. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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