Special Warning : אזהרת שימוש

4.4     Special warnings and precautions for use
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)

Cytokine release syndrome, including life-threatening or fatal reactions, may occur in patients receiving 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-threatening complications 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 reduce risk of CRS. Pre-treatment medicinal products (corticosteroids, antihistamine and antipyretics) should 
be 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 and monitored 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-treatment medicinal products prior to the next dose of TECVAYLI.

Patients should be counselled to seek medical attention should signs or symptoms of CRS occur. At the first sign of CRS, patients should be immediately evaluated for hospitalisation. Treatment with supportive care, tocilizumab and/or corticosteroids should be instituted, based on severity as indicated in Table 4 below. The use of myeloid growth factors, particularly granulocyte macrophage-colony stimulating factor (GM-CSF), has the potential to worsen CRS symptoms and should be avoided during CRS. Treatment with TECVAYLI should be withheld until CRS resolves as indicated in Table 3 (see section 4.2).

Management of cytokine release syndrome

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

If CRS is suspected, TECVAYLI should be withheld until the adverse reaction resolves (see Table 3).
CRS should be managed according to the recommendations in Table 4. Supportive care for CRS (including but not limited to anti-pyretic agents, intravenous fluid support, vasopressors, 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 4:      Recommendations for management of cytokine release syndrome with tocilizumab and corticosteroids
Gradee             Presenting symptoms             Tocilizumaba              Corticosteroidsb Grade 1       Temperature ≥38 °C    c
May be considered          Not applicable
Grade 2       Temperature ≥38 °Cc with       Administer tocilizumabb If no improvement within either:                        8 mg/kg intravenously      24 hours of starting • Hypotension responsive to over 1 hour (not to           tocilizumab, administer fluids and not requiring   exceed 800 mg).            methylprednisolone vasopressors, or                                      1 mg/kg intravenously • Oxygen requirement of        Repeat  tocilizumab  every twice daily, or d low-flow nasal cannula or  8 hours  as needed, if not dexamethasone 10 mg blow-by                    responsive to intravenous intravenously every fluids or increasing       6 hours.
supplemental oxygen.
Continue corticosteroid
Limit to a maximum of      use until the event is
3 doses in a 24-hour       Grade 1 or less, then taper period; 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       methylprednisolone vasopressor with or                exceed 800 mg).           1 mg/kg intravenously without vasopressin, or                                      twice daily, or • Oxygen requirement of                Repeat tocilizumab every dexamethasone 10 mg high-flow nasal cannulad,          8 hours as needed, if not intravenously every facemask, non-rebreather           responsive to intravenous 6 hours.
mask, or Venturi mask              fluids or increasing supplemental oxygen.      Continue corticosteroid use until the event is
Limit to a maximum of     Grade 1 or less, then taper
3 doses in a 24-hour      over 3 days.
period; maximum total of
4 doses.
Grade 4        Temperature ≥38 °Cc with               Administer tocilizumab    As above, or administer either:                                8 mg/kg intravenously     methylprednisolone • Hypotension requiring                over 1 hour (not to       1 000 mg intravenously multiple 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 if positive pressure (e.g.,           responsive to intravenous condition worsens, continuous positive airway         fluids or increasing      consider alternate pressure [CPAP], bilevel           supplemental oxygen.      immunosuppressants b.
positive airway pressure
[BiPAP], intubation, and           Limit to a maximum of mechanical ventilation)            3 doses in a 24-hour period; maximum total of
4 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 by interventions 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).

Neurologic toxicities, including ICANS

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

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

Patients should be counselled to seek medical attention should signs or symptoms of neurologic toxicity occur. At the first sign of neurologic toxicity, including 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 the previous dose of TECVAYLI should be instructed to remain within proximity of a healthcare facility and monitored for signs and symptoms daily for 48 hours.

For ICANS and other neurologic toxicities, treatment with TECVAYLI should be withheld as indicated in Table 3 (see section 4.2).


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

Management of neurologic toxicities

At the first sign of neurologic toxicity, including ICANS, neurology evaluation should be considered.
Other causes of neurologic symptoms should be ruled out. TECVAYLI should be withheld until adverse reaction resolves (see Table 3). Intensive care and supportive therapy should be provided for severe or life-threatening neurologic toxicities. General management for neurologic toxicity (e.g., ICANS with or without concurrent CRS) is summarised in Table 5.

Table 5:       Guidelines for management of immune effector cell-associated neurotoxicity syndrome (ICANS)
Grade          Presenting symptomsa              Concurrent CRS                No Concurrent CRS b
Grade 1       ICE score 7-9             Management of CRS per                Monitor neurologic Table 4.                             symptoms and consider
Or, depressed level of                                         neurology consultation consciousnessc: awakens Monitor neurologic symptoms            and evaluation, per spontaneously.            and consider neurology               physician discretion.
consultation and evaluation, per physician 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 4 for management of            dexamethasoned 10 mg
Or, depressed level of    CRS.                                 intravenously every consciousnessc: awakens If no improvement after starting 6 hours.
to voice.                 tocilizumab, administer dexamethasoned 10 mg                 Continue dexamethasone intravenously every 6 hours if       use until resolution to not already taking other             Grade 1 or less, then corticosteroids. Continue            taper.
dexamethasone use until resolution to Grade 1 or less,
then taper.
Consider non-sedating, anti-seizure medicinal products
(e.g., levetiracetam) for seizure prophylaxis. Consider neurology consultation and other specialists for further evaluation, as needed.
Grade 3       ICE score 0-2b            Administer tocilizumab per           Administer Table 4 for management of            dexamethasoned 10 mg
Or, depressed level of    CRS.                                 intravenously every consciousnessc: awakens In addition, administer                6 hours.
only to tactile stimulus, dexamethasoned 10 mg or                        intravenously with the first dose Continue dexamethasone of tocilizumab, and repeat dose use until resolution to seizuresc, 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,
then taper.


that resolves rapidly,       Consider non-sedating, anti-seizure medicinal products or                           (e.g., levetiracetam) for seizure prophylaxis. Consider • non-convulsive               neurology consultation and other specialists for further seizures on                  evaluation, as needed.
electroencephalogra m (EEG) that resolve with intervention, or
 raised intracranial pressure: focal/local oedema on neuroimagingc.
Grade 4       ICE score 0b                   Administer tocilizumab per         As above, or consider Table 4 for management of          administration of
Or, depressed level of         CRS.                               methylprednisolone consciousnessc 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 manage or repetitive tactile       methylprednisolone 1 000 mg        as above.
stimuli to arouse, or       per day intravenously with first
• stupor or coma, or           dose of tocilizumab, and continue methylprednisolone seizuresc, 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 further electrical seizures         evaluation, as needed. In case of raised intracranial without return to           pressure/cerebral oedema, refer to institutional guidelines baseline in between,        for management.
or
 motor findingsc:
• deep focal motor weakness such as hemiparesis or paraparesis, or
 raised intracranial pressure / cerebral oedemac, 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


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

Infections

Severe, life-threatening, or fatal infections have been reported in patients receiving TECVAYLI (see section 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. Prophylactic antimicrobials should be administered according to local institutional guidelines.

TECVAYLI step-up dosing schedule should not be administered in patients with active infection. For subsequent doses, TECVAYLI should be withheld as indicated in Table 3 (see section 4.2).

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

Hepatitis B virus reactivation

Hepatitis B virus reactivation can occur in patients treated with medicinal products directed against B cells, 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 signs of 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 TECVAYLI should be withheld as indicated in Table 3 and manage per local institutional guidelines (see section 4.2).

Hypogammaglobulinaemia

Hypogammaglobulinaemia has been reported in patients receiving TECVAYLI (see section 4.8).
Immunoglobulin levels should be monitored during treatment with TECVAYLI. Intravenous or subcutaneous immunoglobulin therapy was used to treat hypogammaglobulinaemia in 39% of patients.
Patients should be treated according to local institutional guidelines, including infection precautions, antibiotic or antiviral prophylaxis, and administration of immunoglobulin replacement.

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 not been studied. Vaccination with live virus vaccines is not recommended for at least 4 weeks prior to the start of treatment, during treatment and least 4 weeks after treatment.


Neutropenia
Neutropenia and febrile neutropenia have been reported in patients who received TECVAYLI (see section 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 3 (see section 4.2).

Excipients

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

Effects on Driving

4.7    Effects on ability to drive and use machines

TECVAYLI has major influence on the ability to drive and use machines.
Due to the potential for ICANS, patients receiving TECVAYLI are at risk of depressed level of consciousness (see section 4.8). Patients should be instructed to avoid driving and operating heavy or potentially dangerous machinery during and for 48 hours after completion of TECVAYLI step-up dosing schedule and in the event of new onset of any neurological symptoms (Table 1) (see section 4.2 and section 4.4).