Leaflet TECVAYLI 10mg / ml solution for injection

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

Cytokine release syndrome, including life-threatening or fatal reactions, may occur in patientsreceiving TECVAYLI.

Clinical signs and symptoms of CRS may include but are not limited to fever, hypoxia, chills,hypotension, tachycardia, headache, and elevated liver enzymes. Potentially life-threateningcomplications of CRS may include cardiac dysfunction, adult respiratory distress syndrome,neurologic toxicity, renal and/or hepatic failure, and disseminated intravascular coagulation (DIC).

Treatment should be initiated with TECVAYLI according to the step-up dosing schedule to reducerisk of CRS. Pre-treatment medicinal products (corticosteroids, antihistamine and antipyretics) shouldbe administered prior to each dose of the TECVAYLI step-up dosing schedule to reduce risk of CRS(see section 4.2).

The following patients should be instructed to remain within proximity of a healthcare facility andmonitored daily for 48 hours:

- If the patient has received any dose within the TECVAYLI step-up dosing schedule (for CRS).

- If the patient has received TECVAYLI after experiencing Grade 2 or higher CRS.

Patients who experience CRS following their previous dose should be administered pre-treatmentmedicinal products prior to the next dose of TECVAYLI.

Patients should be counselled to seek medical attention should signs or symptoms of CRS occur. Atthe first sign of CRS, patients should be immediately evaluated for hospitalisation. Treatment withsupportive care, tocilizumab and/or corticosteroids should be instituted, based on severity as indicatedin Table 5 below. The use of myeloid growth factors, particularly granulocyte macrophage-colonystimulating factor (GM-CSF), has the potential to worsen CRS symptoms and should be avoidedduring CRS. Treatment with TECVAYLI should be withheld until CRS resolves as indicated in

Table 4 (see section 4.2).

Management of cytokine release syndrome

CRS should be identified based on clinical presentation. Patients should be evaluated and treated forother causes of fever, hypoxia, and hypotension.

If CRS is suspected, TECVAYLI should be withheld until the adverse reaction resolves (see Table 4).

CRS should be managed according to the recommendations in Table 5. Supportive care for CRS(including but not limited to anti-pyretic agents, intravenous fluid support, vasopressors, supplementaloxygen, etc.) should be administered as appropriate. Laboratory testing to monitor for disseminatedintravascular coagulation (DIC), haematology parameters, as well as pulmonary, cardiac, renal, andhepatic function should be considered.

Table 5: Recommendations for management of cytokine release syndrome withtocilizumab and corticosteroids

Gradee Presenting symptoms Tocilizumaba Corticosteroidsb

Grade 1 Temperature ≥38 °Cc May be considered May be considered

Grade 2 Temperature ≥38 °Cc with Administer tocilizumabb If no improvement withineither: 8 mg/kg intravenously 24 hours of starting

- Hypotension responsive to over 1 hour (not to tocilizumab, administerfluids and not requiring exceed 800 mg). methylprednisolonevasopressors, or 1 mg/kg intravenously

- Oxygen requirement of Repeat tocilizumab every twice daily, orlow-flow nasal cannulad or 8 hours as needed, if not dexamethasone 10 mgblow-by responsive to intravenous intravenously everyfluids or increasing 6 hours.supplemental oxygen.

Continue corticosteroid

Limit to a maximum of use until the event is3 doses in a 24-hour Grade 1 or less, then taperperiod; maximum total of over 3 days.4 doses.

Grade 3 Temperature ≥38 °Cc with Administer tocilizumab If no improvement,either: 8 mg/kg intravenously administer

- Hypotension requiring one over 1 hour (not to methylprednisolonevasopressor with or exceed 800 mg). 1 mg/kg intravenouslywithout vasopressin, or twice daily, or

- Oxygen requirement of Repeat tocilizumab every dexamethasone 10 mghigh-flow nasal cannulad, 8 hours as needed, if not intravenously everyfacemask, non-rebreather responsive to intravenous 6 hours.

mask, or Venturi mask fluids or increasingsupplemental oxygen. Continue corticosteroiduse until the event is

Limit to a maximum of Grade 1 or less, then taper3 doses in a 24-hour over 3 days.period; maximum total of4 doses.

Grade 4 Temperature ≥38 °Cc with Administer tocilizumab As above, or administereither: 8 mg/kg intravenously methylprednisolone

- Hypotension requiring over 1 hour (not to 1 000 mg intravenouslymultiple vasopressors exceed 800 mg). per day for 3 days, per(excluding vasopressin), physician discretion.or Repeat tocilizumab every

- Oxygen requirement of 8 hours as needed if not If no improvement or ifpositive pressure (e.g., responsive to intravenous condition worsens,continuous positive airway fluids or increasing consider alternatepressure [CPAP], bilevel supplemental oxygen. immunosuppressants b.

positive airway pressure[BiPAP], intubation, and Limit to a maximum ofmechanical ventilation) 3 doses in a 24-hourperiod; maximum total of4 doses.

a Refer to tocilizumab prescribing information for details.b Treat unresponsive CRS per institutional guidelines.c Attributed to CRS. Fever may not always be present concurrently with hypotension or hypoxia as it may be masked byinterventions such as antipyretics or anticytokine therapy (e.g., tocilizumab or corticosteroids).d Low-flow nasal cannula is ≤6 L/min, and high-flow nasal cannula is >6 L/min.e Based on ASTCT grading for CRS (Lee et al 2019).

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)

Serious, life-threatening or fatal Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)occurred following treatment with TECVAYLI.

Patients should be monitored for signs or symptoms of ICANS during treatment and treated promptly.

Patients should be counselled to seek medical attention should signs or symptoms of ICANS occur. Atthe first sign of ICANS, patients should be immediately evaluated and treated based on severity.

Patients who experience Grade 2 or higher ICANS or first occurrence of Grade 3 ICANS with theprevious dose of TECVAYLI should be instructed to remain within proximity of a healthcare facilityand monitored for signs and symptoms daily for 48 hours.

For ICANS, treatment with TECVAYLI should be withheld as indicated in Table 4 (see section 4.2).

Due to the potential for ICANS, patients should be advised not to drive or operate heavy machineryduring the TECVAYLI step-up dosing schedule and for 48 hours after completing the TECVAYLIstep-up dosing schedule and in the event of new onset of any neurological symptoms (see section 4.7).

Management of ICANS

At the first sign of ICANS, neurology evaluation should be considered. Other causes of neurologicsymptoms should be ruled out. TECVAYLI should be withheld until adverse reaction resolves (see

Table 4). Intensive care and supportive therapy should be provided for severe or life-threatening

ICANS. General management for ICANS with or without concurrent CRS is summarised in Table 6.

Table 6: Guidelines for management of immune effector cell-associated neurotoxicitysyndrome (ICANS)

Grade Presenting symptomsa Concurrent CRS No Concurrent CRS

Grade 1 ICE score 7-9b Management of CRS per Monitor neurologic

Table 5. symptoms and consider

Or, depressed level of neurology consultationconsciousnessc: awakens Monitor neurologic symptoms and evaluation, perspontaneously. and consider neurology physician discretion.

consultation and evaluation, perphysician discretion.

Consider non-sedating, anti-seizure medicinal products(e.g., levetiracetam) for seizure prophylaxis.

Grade 2 ICE score 3-6b Administer tocilizumab per Administer

Table 5 for management of dexamethasoned 10 mg

Or, depressed level of CRS. intravenously everyconsciousnessc: awakens If no improvement after starting 6 hours.to voice. tocilizumab, administerdexamethasoned 10 mg Continue dexamethasoneintravenously every 6 hours if use until resolution tonot already taking other Grade 1 or less, thencorticosteroids. Continue taper.dexamethasone use untilresolution to Grade 1 or less,then taper.

Consider non-sedating, anti-seizure medicinal products(e.g., levetiracetam) for seizure prophylaxis. Considerneurology consultation and other specialists for furtherevaluation, as needed.

Grade 3 ICE score 0-2b Administer tocilizumab per Administer

Table 5 for management of dexamethasoned 10 mg

Or, depressed level of CRS. intravenously everyconsciousnessc: awakens In addition, administer 6 hours.only to tactile stimulus, dexamethasoned 10 mgor intravenously with the first dose Continue dexamethasoneof tocilizumab, and repeat dose use until resolution toseizuresc, either: every 6 hours. Continue Grade 1 or less, then

- any clinical seizure, dexamethasone use until taper.

focal or generalised resolution to Grade 1 or less,that resolves rapidly, then taper.or Consider non-sedating, anti-seizure medicinal products

- non-convulsive (e.g., levetiracetam) for seizure prophylaxis. Considerseizures on neurology consultation and other specialists for furtherelectroencephalogra evaluation, as needed.m (EEG) that resolvewith intervention, orraised intracranialpressure: focal/localoedema onneuroimagingc.

Grade 4 ICE score 0b Administer tocilizumab per As above, or consider

Table 5 for management of administration of

Or, depressed level of CRS. methylprednisoloneconsciousnessc either: 1 000 mg per day

- patient is unarousable As above, or consider intravenously for 3 days;or requires vigorous administration of if improves, then manageor repetitive tactile methylprednisolone 1 000 mg as above.stimuli to arouse, or per day intravenously with first

- stupor or coma, or dose of tocilizumab, andcontinue methylprednisoloneseizuresc, either: 1 000 mg per day intravenously

- life-threatening for 2 or more days.

prolonged seizure Consider non-sedating, anti-seizure medicinal products(>5 minutes), or (e.g., levetiracetam) for seizure prophylaxis. Consider

- repetitive clinical or neurology consultation and other specialists for furtherelectrical seizures evaluation, as needed. In case of raised intracranialwithout return to pressure/cerebral oedema, refer to institutional guidelinesbaseline in between, for management.

ormotor findingsc:

- deep focal motorweakness such ashemiparesis orparaparesis, orraised intracranialpressure/cerebraloedemac, withsigns/symptoms such as:

- diffuse cerebraloedema onneuroimaging, or

- decerebrate ordecorticate posturing,or

- cranial nerve VIpalsy, or

- papilloedema, or

- cushing’s triada Management is determined by the most severe event, not attributable to any other cause.b If patient is arousable and able to perform Immune Effector Cell-Associated Encephalopathy (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 yourtongue” = 1 point); Writing (ability to write a standard sentence = 1 point; and Attention (count backwards from 100by ten = 1 point). If patient is unarousable and unable to perform ICE Assessment (Grade 4 ICANS) = 0 points.

c Attributable to no other cause.d All references to dexamethasone administration are dexamethasone or equivalent.

Severe, life-threatening, or fatal infections have been reported in patients receiving TECVAYLI (seesection 4.8). New or reactivated viral infections occurred during therapy with TECVAYLI.

Patients should be monitored for signs and symptoms of infection prior to and during treatment with

TECVAYLI and treated appropriately. Infection precautions (including vaccinations), andantimicrobials (e.g., prevention of pneumocystis jirovecii pneumonia), including antibiotic or antiviral(e.g., prevention of herpes zoster reactivation) prophylaxis, should be administered according to localinstitutional guidelines. The rate of infections is higher during the initial months of therapy anddecreases over time with TECVAYLI.

TECVAYLI step-up dosing schedule should not be administered in patients with active infection. Forsubsequent doses, TECVAYLI should be withheld as indicated in Table 4 (see section 4.2).

Progressive Multifocal Leukoencephalopathy (PML), which can be fatal, has also been reported inpatients receiving TECVAYLI. Patients should be monitored for any new onset of or changes inpre-existing neurological signs or symptoms. If PML is suspected, treatment with TECVAYLI shouldbe withheld and appropriate diagnostic testing initiated. If PML is confirmed, TECVAYLI must bediscontinued.

Hepatitis B virus reactivation can occur in patients treated with medicinal products directed against Bcells, and in some cases, may result in fulminant hepatitis, hepatic failure, and death.

Patients with evidence of positive HBV serology should be monitored for clinical and laboratory signsof HBV reactivation while receiving TECVAYLI, and for at least six months following the end of

TECVAYLI treatment.

In patients who develop reactivation of HBV while on TECVAYLI, treatment with TECVAYLIshould be withheld as indicated in Table 4 and manage per local institutional guidelines (seesection 4.2).

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

Immunoglobulin levels should be monitored during treatment with TECVAYLI. Intravenous orsubcutaneous immunoglobulin therapy should be used to maintain the serum IgG levels ≥400 mg/dL.

Infection precautions, and antimicrobials, including antibiotic or antiviral prophylaxis, should be usedaccording to local institutional guidelines.

Vaccines

Immune response to vaccines may be reduced when taking TECVAYLI.

The safety of immunisation with live viral vaccines during or following TECVAYLI treatment has notbeen studied. Vaccination with live virus vaccines is not recommended for at least 4 weeks prior to thestart of treatment, during treatment and at least 4 weeks after treatment.

Neutropenia and febrile neutropenia have been reported in patients who received TECVAYLI (seesection 4.8).

Complete blood cell counts should be monitored at baseline and periodically during treatment.

Supportive care should be provided per local institutional guidelines.

Patients with neutropenia should be monitored for signs of infection.

Treatment with TECVAYLI should be withheld as indicated in Table 4 (see section 4.2).

Tumour flare has been reported in patients receiving TECVAYLI (see section 4.8). Manifestationsincluded localised pain and symptoms of nerve and spinal compression due to transient tumourenlargement. Tumour flare does not imply treatment failure or tumour progression. Monitoring andevaluation of tumour flare is recommended in patients treated with TECVAYLI and should bemanaged as clinically indicated.

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

Polysorbate

This medicinal product contains 0.4 mg of polysorbate 20 in each mL, which is equivalent to 1.2 mgper 3 mL vial and 0.68 mg per 1.7 mL vial. Polysorbates may cause hypersensitivity reactions.