ELREXFIO Solution for injection Ref.[107897] Active ingredients: Elranatamab

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered medicinal product should be clearly recorded.

Cytokine release syndrome (CRS)

CRS, including life-threatening or fatal reactions, may occur in patients receiving ELREXFIO. Clinical signs and symptoms of CRS may include, but are not limited to, fever, hypoxia, chills, hypotension, tachycardia, headache, and elevated liver enzymes (see section 4.8).

Therapy should be initiated according to the step-up dosing schedule to reduce risk of CRS and patients should be monitored following administration of ELREXFIO accordingly. Pre-treatment medicinal products should be administered prior to the first three doses to reduce risk of CRS (see section 4.2).

Patients should be counselled to seek urgent medical attention should signs or symptoms of CRS occur.

At the first sign of CRS, ELREXFIO should be withheld and patients should be immediately evaluated for hospitalisation. CRS should be managed according to the recommendations in section 4.2, and further management should be considered per local institutional guidelines. 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.

Neurologic toxicities, including ICANS

Serious or life-threatening neurologic toxicities, including ICANS, may occur following treatment with ELREXFIO (see section 4.8). Patients should be monitored for signs and symptoms (e.g., decrease level of consciousness, seizures and/or motor weakness) of neurologic toxicities during treatment.

Patients should be counselled to seek urgent medical attention should signs or symptoms of neurologic toxicity occur.

At the first sign of neurologic toxicity, including ICANS, ELREXFIO should be withheld and neurology evaluation should be considered. General management for neurologic toxicity (e.g., ICANS) is summarised in Table 3 (see section 4.2).

Due to the potential for ICANS, patients should be advised not to drive or operate heavy or potential dangerous machinery during the step-up dosing schedule and for 48 hours after completing each of the 2 step-up doses and in the event of new onset of any neurological symptoms (see sections 4.2 and 4.7).

Infections

Severe, life-threatening, or fatal infections have been reported in patients receiving ELREXFIO (see section 4.8). New or reactivated viral infections occurred during therapy with ELREXFIO. Progressive multifocal leukoencephalopathy (PML) has also occurred during therapy with ELREXFIO.

Treatment should not be initiated in patients with active infections. Patients should be monitored for signs and symptoms of infection prior to and during treatment with ELREXFIO and treated appropriately. ELREXFIO should be withheld based on the severity of the infection as indicated in Table 4 for other non-haematologic adverse reactions (see section 4.2).

Prophylactic antimicrobials (e.g., prevention of pneumocystis jirovecii pneumonia) and anti-virals (e.g., prevention of herpes zoster reactivation) should be administered according to local institutional guidelines.

Neutropenia

Neutropenia and febrile neutropenia have been reported in patients receiving ELREXFIO (see section 4.8).

Complete blood cell counts should be monitored at baseline and periodically during treatment. Treatment with ELREXFIO should be withheld as indicated in Table 4 (see section 4.2). Patients with neutropenia should be monitored for signs of infection. Supportive therapy should be provided according to local institutional guidelines.

Hypogammaglobulinaemia

Hypogammaglobulinemia has been reported in patients receiving ELREXFIO (see section 4.8).

Immunoglobulin levels should be monitored during treatment. Treatment with subcutaneous or intravenous immunoglobulin (IVIG) should be considered if IgG levels fall below 400 mg/dL and patients should be treated according to local institutional guidelines, including infection precautions and antimicrobial prophylaxis.

Concomitant use of live viral vaccines

The safety of immunisation with live viral vaccines during or following treatment with ELREXFIO has not been studied. Vaccination with live virus vaccines is not recommended within the 4 weeks prior to the first dose, during treatment, and at least 4 weeks after treatment.

Excipients

This medicinal product contains less than 1 mmol (23 mg) sodium per dose, that is to say essentially ‘sodium-free’.

No interaction studies have been performed with ELREXFIO.

The initial release of cytokines associated with the start of ELREXFIO may suppress cytochrome P450 (CYP) enzymes. The highest risk of interaction is expected to occur during and up to 14 days after the step-up dosing as well as during and up to 14 days after CRS. During this time period, toxicity or medicinal product concentrations should be monitored in patients who are receiving concomitant sensitive CYP substrates with a narrow therapeutic index (e.g., cyclosporine, phenytoin, sirolimus, and warfarin). The dose of the concomitant medicinal product should be adjusted as needed.

Women of child-bearing potential/Contraception

The pregnancy status of women of child-bearing potential should be verified prior to initiating treatment with ELREXFIO.

Women of child-bearing potential should use effective contraception during treatment with ELREXFIO and for 6 months after the last dose.

Pregnancy

There are no human or animal data to assess the risk of elranatamab use during pregnancy. Human immunoglobulin (IgG) is known to cross the placenta after the first trimester of pregnancy. Based on the mechanism of action, elranatamab may cause foetal harm when administered to a pregnant woman and therefore ELREXFIO is not recommended for use during pregnancy.

ELREXFIO is associated with hypogammaglobulinaemia, therefore, assessment of immunoglobulin levels in newborns of mothers treated with ELREXFIO should be considered.

Breast-feeding

It is not known whether elranatamab is excreted in human or animal milk, affects breastfed infants or affects milk production. Human IgGs are known to be excreted in breast milk. A risk to the breastfed child cannot be excluded and therefore breast-feeding is not recommended during treatment with ELREXFIO and for 6 months after the last dose.

Fertility

There are no data on the effect of elranatamab on human fertility. Effects of elranatamab on male and female fertility have not been evaluated in animal studies.

ELREXFIO has major influence on the ability to drive and use machines.

Due to the potential for ICANS, patients receiving ELREXFIO are at risk of depressed level of consciousness (see section 4.8). Patients should be instructed to refrain from driving or operating heavy or potential dangerous machinery during and for 48 hours after completing each of the 2 step-up doses and in the event of new onset of neurologic toxicity until resolution of any neurological symptoms (see sections 4.2 and 4.4).

Summary of the safety profile

The most frequent adverse reactions are CRS (57.9%), anaemia (54.1%), neutropenia (44.8%), fatigue (44.3%), upper respiratory tract infection (38.8%), injection site reaction (38.3%), diarrhoea (37.7%), pneumonia (37.2%), thrombocytopenia (36.1%), lymphopenia (30.1%), decreased appetite (26.8%), pyrexia (27.3%), rash (26.2%), arthralgia (25.1%), hypokalaemia (23.0%), nausea (21.3%), and dry skin (21.3%).

Serious adverse reactions are pneumonia (30.6%), sepsis (15.3%), CRS (12.6%), anaemia (5.5%), upper respiratory tract infection (4.9%), urinary tract infection (3.3%), febrile neutropenia (2.7%), dyspnoea (2.2%), and pyrexia (2.2%).

Tabulated list of adverse reactions

Table 6 summarises adverse reactions reported in patients who received ELREXFIO at the recommended dosing regimen (N=183 including 64 patients with prior BCMA-directed antibody drug conjugate [ADC] or chimeric antigen receptor [CAR] T cell therapy [supportive Cohort B]). The median duration of treatment was 4.1 (range: 0.03 to 20.3) months. The safety data of ELREXFIO was also evaluated in the all-treated population (N=265) with no additional adverse reactions identified.

Adverse reactions are listed according to the MedDRA system organ classification and by frequency. Frequency categories are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000) and not known (frequency cannot be estimated from the available data). Within each frequency grouping, where relevant, adverse reactions are presented in order of decreasing seriousness.

Table 6. Adverse reactions in multiple myeloma patients treated with ELREXFIO in MagnetisMM-3 at the recommended dose:

^a Pneumonia includes pneumonia, COVID-19 pneumonia, bronchopulmonary aspergillosis, lower respiratory tract infection bacterial, lower respiratory tract infection viral, pneumocystis jirovecii pneumonia, pneumonia adenoviral, pneumonia bacterial, pneumonia. cytomegaloviral, pneumonia fungal, pneumonia influenzal, pneumonia pseudomonal, pneumonia viral, atypical pneumonia, coronavirus pneumonia, pneumonia haemophilus, pneumonia pneumococcal, pneumonia respiratory syncytial viral.
^b Sepsis includes sepsis, bacteraemia, device related bacteraemia, device related sepsis, escherichia bacteraemia, escherichia sepsis, klebsiella sepsis, pseudomonal sepsis, septic shock, staphylococcal bacteraemia, staphylococcal sepsis, streptococcal sepsis, urosepsis, campylobacter bacteraemia.
^c Peripheral neuropathy includes peripheral sensory neuropathy, paraesthesia, peripheral sensorimotor neuropathy, dysaesthesia, neuropathy peripheral, peripheral motor neuropathy, Guillain-Barre syndrome, hypoaesthesia, neuralgia, polyneuropathy.
^d Rash incudes dermatitis exfoliative, dermatitis exfoliative generalised, erythema, palmar-plantar erythrodysaesthesia syndrome, rash, rash erythematous, rash macular, rash maculo-papular, rash pustular, symmetrical drug-related intertriginous and flexural exanthema, epidermolysis.

Description of selected adverse reactions

Cytokine release syndrome (CRS)

CRS occurred in 57.9% of patients who received ELREXFIO at the recommended dosing schedule, with Grade 1 CRS in 43.7%, Grade 2 in 13.7% and Grade 3 in 0.5% of patients. Most patients experienced CRS after the first step-up dose (43.2%) or the second step-up dose (19.1%), with 7.1% of patients having CRS after the first full treatment dose and 1.6% of patients after a subsequent dose. Recurrent CRS occurred in 13.1% of patients. The median time to onset of CRS was 2 (range: 1 to 9) days after the most recent dose, with a median duration of 2 (range: 1 to 19 days) days.

Among patients who developed CRS, associated symptoms included fever (99.0%), hypotension (21.0%), and hypoxia (11.4%) and 33% received tocilizumab (or siltuximab) and 15.1% received corticosteroids for treatment of CRS.

Immune effector cell-associated neurotoxicity syndrome (ICANS)

ICANS occurred in 3.3% of patients following treatment with ELREXFIO at the recommended dosing schedule, with Grade 1 ICANS in 0.5%, Grade 2 in 1.6% and Grade 3 in 1.1% of patients. The majority of patients had ICANS after the first step-up dose (2.7%), 1 (0.5%) patient had ICANS after the second step-up dose and 1 (0.5%) patient had ICANS after a subsequent dose. Recurrent ICANS occurred in 1.1% of patients. The median time to onset was 3 (range: 1 to 4) days after the most recent dose with a median duration of 2 (range: 1 to 18) days.

The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS. The most frequent symptoms of ICANS included a depressed level of consciousness and Grade 1 or Grade 2 Immune Effector Cell-Associated Encephalopathy (ICE) scores (see Table 3). Among patients who developed ICANS, 66.7% received corticosteroids, 33.3% received tocilizumab (or siltuximab), 33.3% received levetiracetam and 16.7% received anakinra for treatment of ICANS.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.