LYNOZYFIC Concentrate for solution for infusion Ref.[115148] Active ingredients: Linvoseltamab

Traceability

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

Cytokine release syndrome (CRS)

Cases of CRS have been reported in patients receiving linvoseltamab (see section 4.8). CRS is a condition that may be serious or life-threatening.

Clinical signs and symptoms of CRS included, but were not limited to, pyrexia, chills, hypoxia, tachycardia, and hypotension.

Administer pretreatment medicinal products (see Table 1) and initiate therapy according to LYNOZYFIC step-up dosing (see Table 2) to reduce the risk of CRS.

All patients should be monitored for signs and symptoms of CRS during and after infusion. All patients should be counselled to seek immediate medical attention should signs or symptoms of CRS occur.

For the first step-up treatment dose of LYNOZYFIC, all patients should be instructed to remain with a caregiver within close proximity of the qualified treatment centre for 24 hours after the end of infusion.

For the second step-up treatment dose and subsequent doses, patients should be instructed to remain with a caregiver within close proximity of the qualified treatment centre for 24 hours after the end of infusion:

• For the second step-up treatment dose of LYNOZYFIC if the patient experienced CRS with the first step-up treatment dose
• For a subsequent dose if the patient experienced Grade 2 CRS with the prior dose. Patients that experience a first Grade 3 CRS event at any time should be hospitalised for 24 hours after receiving the next dose.

At the first sign of CRS, patients should be immediately evaluated for hospitalisation, managed per current practice guidelines, and supportive care should be administered; LYNOZYFIC should be withheld until CRS resolves and the next dose should be modified or LYNOZYFIC should be permanently discontinued based on severity (see Table 3).

Infusion related reaction (IRR)

IRR may be clinically indistinguishable from manifestations of CRS. For IRR, interrupt or slow the rate of infusion or permanently discontinue LYNOZYFIC based on severity of reaction (see Table 5).

Immune effector cell-associated neurotoxicity syndrome (ICANS)

Cases of ICANS have been reported in patients receiving linvoseltamab (see section 4.8).

Clinical signs and symptoms of ICANS may include but are not limited to aphasia, cerebral oedema, confusion, depressed level of consciousness, disorientation, encephalopathy, and seizure.

All patients should be monitored for signs and symptoms of ICANS during treatment.

For the first step-up treatment dose of LYNOZYFIC, all patients should be instructed to remain with a caregiver within close proximity of the qualified treatment centre for 24 hours after the end of infusion.

For the second step-up treatment dose and subsequent doses, patients should be instructed to remain with a caregiver within close proximity of the qualified treatment centre for 24 hours after the end of infusion:

• For the second step-up treatment dose of LYNOZYFIC if the patient experienced ICANS with the first step-up treatment dose
• For a subsequent dose if the patient experienced Grade 2 ICANS with the prior dose.

Patients that experience a first Grade 3 ICANS event at any time should be hospitalised for 24 hours after receiving the next dose.

At the first sign of ICANS, the patient should be immediately evaluated; supportive therapy should be provided and further management should be considered per current practice guidelines. LYNOZYFIC should be withheld until ICANS resolves and the next dose should be modified or LYNOZYFIC should be permanently discontinued based on severity (see Table 4). Patients should be counselled to seek immediate medical attention should signs or symptoms of ICANS occur at any time.

Due to the potential for ICANS, patients receiving LYNOZYFIC are at risk of confusion and depressed consciousness. Advise patients to refrain from driving, or operating heavy or potentially dangerous machinery, for 24 hours after completion of each of the step-up treatment doses and in the event of new onset of any neurological symptoms, until symptoms resolve (see section 4.7).

Infections

Cases of serious, life-threatening, or fatal infections have been reported in patients receiving linvoseltamab. Progressive multifocal leukoencephalopathy (PML) has also occurred during therapy with LYNOZYFIC (see section 4.8).

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 LYNOZYFIC and treated appropriately. Prophylactic treatment per local institutional guidelines for Pneumocystis jirovecii pneumonia (PJP) and herpes simplex and zoster viruses is recommended for all patients. Prophylactic antimicrobials and anti-virals, including prophylaxis against CMV, should be administered according to local institutional guidelines. Vaccination for seasonal influenza, COVID-19, Haemophilus influenza, and Pneumococcus should be administered for all patients according to local institutional guidelines.

LYNOZYFIC should be withheld or permanent discontinuation of LYNOZYFIC should be considered based on severity of the infection (see Table 5).

Hypogammaglobulinaemia

Hypogammaglobulinaemia has been reported in patients receiving linvoseltamab (see section 4.8).

Immunoglobulin (Ig) levels should be monitored prior to and during treatment. Treatment with subcutaneous or IV Ig may 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.

Neutropenia

Cases of neutropenia and febrile neutropenia have been reported in patients receiving linvoseltamab (see section 4.8). Complete blood cell counts should be monitored at baseline and periodically during treatment and supportive care should be provided per local guidelines. Patients with neutropenia should be monitored for signs of infection. LYNOZYFIC should be withheld based on severity (see Table 5).

Vaccines

Immune response to vaccines may be reduced when taking LYNOZYFIC.

The safety of immunisation with live viral vaccines during or following LYNOZYFIC treatment has not been studied. Vaccination with live virus vaccines should only be administered at least 4 weeks before starting treatment or after immune recovery occurs following treatment.

Patient card

The prescriber must discuss the risks of LYNOZYFIC therapy with the patient. Patients should be provided with the Patient Card, instructed to carry it at all times, and show it to all of their healthcare professionals. The Patient Card describes the common signs and symptoms of CRS and ICANS, provides instructions on when a patient should seek immediate medical attention, provides monitoring instructions, and has the prescribing physician’s contact details.

Excipients

This medicinal product contains polysorbate 80, which may cause allergic reactions.

No drug interaction studies have been conducted with LYNOZYFIC.

Transient elevation of cytokines may suppress CYP450 enzyme activities. The highest risk of drug interaction is during the step-up dosing regimen and the first full 200 mg dose in patients who are receiving concomitant CYP450 substrates. Monitor for toxicity or concentrations of medicinal products that are CYP substrates where minimal changes in concentration may lead to serious adverse reactions (e.g., cyclosporine, phenytoin, sirolimus, and warfarin).

Women of childbearing potential/Contraception

Pregnancy status for patients of childbearing potential should be verified prior to starting treatment with LYNOZYFIC.

Patients of childbearing potential should use effective contraception during treatment with LYNOZYFIC and for at least 5 months after the last dose.

Pregnancy

There are no available data on the use of LYNOZYFIC in pregnant women. No animal reproductive or developmental toxicity studies have been conducted with linvoseltamab. Linvoseltamab causes T-cell activation and cytokine release; immune activation may compromise pregnancy maintenance. Human immunoglobulin G (IgG) is known to cross the placenta; therefore, linvoseltamab has the potential to be transferred from the pregnant woman to the developing foetus. LYNOZYFIC is not recommended during pregnancy and in women of childbearing potential not using contraception. Based on its mechanism of action, LYNOZYFIC may cause foetal harm, including B-cell and plasma cell lymphocytopenia, when administered to a pregnant patient.

Breast-feeding

There is no information regarding the presence of linvoseltamab in human milk, the effects on the breastfed infant, or the effects on milk production. It is known that human IgG can be secreted in human milk. Breastfeeding should be discontinued during treatment with LYNOZYFIC and for at least 5 months after the last dose due to the potential risk for serious adverse reactions in the breastfed child.

Fertility

No human data on the effect of linvoseltamab on fertility are available (see section 5.3).

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

Due to the potential for ICANS, patients receiving LYNOZYFIC are at risk of confusion and depressed consciousness (see section 4.4). Patients should be instructed to refrain from driving, or operating heavy or potentially dangerous machinery, for 24 hours after completion of each of the step-up treatment doses and in the event of new onset of any neurological symptoms, until symptoms resolve.

Summary of safety profile

The most frequent adverse reactions were musculoskeletal pain (52%), cytokine release syndrome (46%), neutropenia (43%), cough (42%), diarrhoea (39%), anaemia (38%), fatigue (36%), pneumonia (32%), and upper respiratory tract infection (30%).

Serious adverse reactions occurred in 75% of patients who received LYNOZYFIC. The most frequent serious adverse reactions were cytokine release syndrome (27%), pneumonia (13%), COVID-19 (7%), and acute kidney injury (5%).

Permanent discontinuation of LYNOZYFIC due to adverse reactions occurred in 19% of patients. The most frequent adverse reactions leading to discontinuation were COVID-19 pneumonia (1.7%), Pneumocystis jirovecii pneumonia (1.7%), and pseudomonal sepsis (1.7%).

Tabulated list of adverse reactions

The safety population described includes 117 patients with relapsed or refractory multiple myeloma who received LYNOZYFIC at the recommended step-up treatment and full treatment dose (see section 5.1). Unless otherwise stated, the frequencies of adverse reactions in Table 8 are based on all-cause adverse event frequencies identified in 117 patients exposed to linvoseltamab during a median duration of 53 weeks (range 1, 167) in the clinical study.

Adverse reactions observed during the clinical study are listed below by MedDRA system organ class classification and by frequency. Frequency categories are defined as follows: 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, adverse reactions are presented in the order of decreasing seriousness.

Table 8. Adverse reactions occurring in patients with multiple myeloma treated with LYNOZYFIC:

^a Pneumonia includes atypical pneumonia, COVID-19 pneumonia, haemophilus infection,
influenza, metapneumovirus infection, PJP, pneumonia, pneumonia cytomegaloviral, pneumonia fungal, pneumonia influenzal, and pneumonia viral.
^b Upper respiratory tract infection includes acute sinusitis, bronchitis, nasopharyngitis, pharyngitis, respiratory tract infection, rhinitis, rhinovirus infection, sinobronchitis, sinusitis, upper respiratory tract infection, and viral upper respiratory tract infection.
^c Urinary tract infection includes cystitis, escherichia urinary tract infection, klebsiella urinary tract infection, urinary tract infection, urinary tract infection bacterial, and urinary tract infection enterococcal, and urinary tract infection staphylococcal.
^d Sepsis includes sepsis, septic shock, pseudomonal sepsis, streptococcal sepsis, escherichia sepsis, and haemophilus sepsis.
^e CMV infection includes cytomegalovirus infection reactivation, cytomegalovirus infection, and cytomegalovirus viraemia and excludes pneumonia cytomegaloviral.
^f Encephalopathy includes agitation, amnesia, aphasia, cognitive disorder, confusional state, delirium, depressed level of consciousness, encephalopathy, memory impairment, mental status changes, mood altered, somnolence, toxic encephalopathy, and excludes ICANS.
^g Pain includes ear pain, flank pain, groin pain, oropharyngeal pain, pain, and toothache.
^h Motor dysfunction includes dysarthria, dysphonia, gait disturbance, muscle spasm, muscular weakness, and tremor.
ⁱ Headache includes headache and migraine.
^j ICANS is based on adjudicated ICANS which were reported with the terms ICANS, depressed level of consciousness, encephalopathy, and toxic encephalopathy.
^k Rash includes dermatitis acneiform, dermatitis contact, drug eruption, erythema, rash, rash erythematous, rash maculo-papular, rash pruritic, and stasis dermatitis.
^l Oedema includes face oedema, lip oedema, localised oedema, oedema, and oedema peripheral.
^m Fatigue includes fatigue, lethargy, and malaise.
ⁿ Infusion related reactions related to IVIG administration are not included.

Description of selected adverse reactions

Cytokine release syndrome

CRS occurred in 46% of patients who received LYNOZYFIC at the recommended dose, with Grade 1 CRS occurring in 35% of patients, Grade 2 in 10%, and Grade 3 in 0.9%. Thirty-eight percent of all patients had CRS following step-up treatment dose 1; 8% of all patients had an initial CRS event following a subsequent dose. Seventeen percent of patients receiving step-up treatment dose 2 developed CRS after step-up treatment dose 2, 10% of patients receiving the first full treatment dose developed CRS after the first full treatment dose of LYNOZYFIC, and 3.6% of patients that received the second full treatment dose developed CRS after the second full treatment dose. The Grade 3 case of CRS was reported after the first step-up treatment dose. Nine patients experienced Grade 2 CRS after receiving either step-up treatment dose 1 or step-up treatment dose 2, and three patients experienced Grade 2 CRS with a dose after step-up treatment dose 2. Recurrent CRS occurred in 20% of patients. CRS resolved in all patients, and the median time to onset of CRS from the end of infusion was 11 (range: -1.1 to 184) hours after the most recent dose with a median duration of 16 (range: 1 to 96) hours.

Clinical signs and symptoms of CRS included, but were not limited to, pyrexia, chills, hypoxia, tachycardia, and hypotension.

In the clinical study, 19% of patients received tocilizumab and 11% received corticosteroids for the management of CRS.

Infusion related reactions

IRR may be clinically indistinguishable from manifestations of CRS. In the patients who were treated with the recommended step-up dosing regimen and pretreatment medicinal products, the rate of IRR was 9%, including 4.3% Grade 2 IRR and 1.7% Grade 3 IRR. If IRR is suspected, patients should be managed according to the recommendations in Table 5.

Immune effector cell-associated neurotoxicity syndrome (ICANS)

ICANS occurred in 8% of patients who received LYNOZYFIC with the recommended dosing regimen, including Grade 3 events in 2.6% of patients. Most patients experienced ICANS following step-up treatment dose 1 (5%). 1.8% of patients experienced initial ICANS following step-up treatment dose 2 and 0.9% of patients developed the first occurrence of ICANS following a subsequent full treatment dose of LYNOZYFIC. Recurrent ICANS occurred in 0.9% of patients. ICANS resolved in all patients except one who withdrew consent to follow-up. The median time to onset of ICANS was 1 (range: 1 to 4) day after the most recent dose with a median duration of 2 (range: 1 to 11) days. The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS. All ICANS occurred in patients concurrent with or after resolution of CRS or IRR.

Infections

Serious infections occurred in 43% of patients who received LYNOZYFIC at the recommended dose, with Grade 3 or 4 infections occurring in 36%. Infections that were fatal within 30 days of the last dose occurred in 4% of patients. Serious opportunistic infections occurred in 6% of patients. Two cases of progressive multifocal leukoencephalopathy (PML) occurred in patients receiving LYNOZYFIC; both cases had a fatal outcome.

Neutropenia

Neutropenia (including neutrophil count decreased) occurred in 43% of patients who received LYNOZYFIC at the recommended dose in the clinical study, including 42% Grade 3-4 events. The median time to onset of neutropenia was 73 days (range: 0 to 421 days). Seventy-four percent of patients who had neutropenia received treatment with G-CSF. Febrile neutropenia occurred in 8% of patients.

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.