Leaflet CARVYKTI 3.2 × 106-1.0 × 108 celule dispersie perfuzabila cells dispersion for infusion

The traceability requirements of cell-based advanced therapy medicinal products must apply. Toensure traceability, the name of the medicinal product, the batch number and the name of the treatedpatient should be kept for a period of 30 years after the expiry date of the medicinal product.

Autologous use

CARVYKTI is intended solely for autologous use and must not, under any circumstances, beadministered to other patients. CARVYKTI must not be infused if the information on the productlabels and Lot Information Sheet does not match the patient’s identity.

Clinical assessment prior to CARVYKTI infusion

CARVYKTI infusion should be delayed if a patient has any of the following conditions:

- clinically significant active infection or inflammatory disorders,

- grade ≥ 3 non-haematologic toxicities of cyclophosphamide and fludarabine lymphodepletionregimen, except for Grade 3 nausea, vomiting, diarrhoea, or constipation. CARVYKTI infusionshould be delayed until resolution of these events to Grade ≤ 1,

- active graft versus host disease.

Patients with active or prior history of significant central nervous system (CNS) disease or inadequaterenal, hepatic, pulmonary, or cardiac function are likely to be more vulnerable to the consequences ofthe adverse reactions described below and require special attention. There is no experience of use of

CARVYKTI in patients with CNS involvement of myeloma or other pre-existing, clinically relevant

CNS illnesses.

The efficacy/safety of CARVYKTI in patients previously exposed to other anti-BCMA treatments isunknown.

There is limited evidence available on efficacy/safety of CARVYKTI in re-treated patients.

Rapidly progressing disease

When considering patients for CARVYKTI treatment, physicians should assess the impact of rapidlyprogressing disease on the ability of patients to receive CAR-T infusion. Some patients may notbenefit from CARVYKTI treatment due to potential increased risk of early death if disease progressesrapidly during bridging therapy.

Monitoring after infusion

Patients should be monitored daily for 14 days after the CARVYKTI infusion at a qualified clinicalfacility, and then periodically for an additional 2 weeks after CARVYKTI infusion, for signs andsymptoms of CRS, neurologic events and other toxicities (see section 4.4).

Patients should be instructed to remain within proximity of a qualified clinical facility for at least4 weeks following infusion.

Cytokine release syndrome

Cytokine release syndrome, including fatal or life-threatening reactions, can occur after CARVYKTIinfusion.

Nearly all patients experienced CRS after CARVYKTI infusion, with majority of these being Grade 1or Grade 2 (see section 4.8). The median time from CARVYKTI infusion (Day 1) to onset of CRS was7 days (range: 1 to 23 days). Approximately 83% of patients experienced CRS onset after Day 3 ofreceiving the CARVYKTI infusion.

In almost all cases, duration of CRS ranged from 1 to 18 days (median duration, 4 days).

Eighty-nine percent of patients had a CRS duration of ≤ 7 days.

Clinical signs and symptoms of CRS may include, but are not limited to, fever (with or withoutrigors), chills, hypotension, hypoxia and elevated liver enzymes. Potentially life-threateningcomplications of CRS may include cardiac dysfunction, neurologic toxicity and haemophagocyticlymphohistiocytosis (HLH). Patients who develop HLH may have an increased risk of severebleeding. Patients should be closely monitored for signs or symptoms of these events, including fever.

Risk factors for severe CRS include high pre-infusion tumour burden, active infection and early onsetof fever or persistent fever after 24 hours of symptomatic treatment.

The infusion of CARVYKTI should be delayed if the patient has unresolved serious adverse reactionsfrom preceding lymphodepleting or bridging therapies (including cardiac toxicity and pulmonarytoxicity), rapid disease progression and clinically significant active infection (see section 4.2).

Appropriate prophylactic and therapeutic treatment for infections should be provided, and completeresolution of any active infections should be ensured prior to CARVYKTI infusion. Infections mayalso occur concurrently with CRS and may increase the risk of a fatal event.

The availability of at least one dose of tocilizumab for use in the event of CRS should be ensured priorto infusion. The qualified treatment centre must have access to an additional dose of tocilizumabwithin 8 hours of each previous dose. In the exceptional case where tocilizumab is not available due toa shortage that is listed in the European Medicines Agency shortage catalogue, the treatment centremust have access to suitable alternative measures instead of tocilizumab to treat CRS. Patients shouldbe monitored for signs and symptoms of CRS daily for 14 days after the CARVYKTI infusion at aqualified clinical facility, and then periodically for an additional two weeks after CARVYKTIinfusion.

Patients should be counselled to seek immediate medical attention should signs or symptoms of CRSoccur at any time. At the first sign of CRS, the patient should be immediately evaluated forhospitalisation and treatment with supportive care, tocilizumab, or tocilizumab and corticosteroidsshould be instituted as indicated in Table 1 below.

Evaluation for HLH should be considered in patients with severe or unresponsive CRS. For patientswith high pre-infusion tumour burden, early onset of fever, or persistent fever after 24 hours, earlytocilizumab should be considered. The use of myeloid growth factors, particularly granulocytemacrophage-colony stimulating factor (GM-CSF), should be avoided during CRS. Consider reducingbaseline burden of disease with bridging therapy prior to infusion with CARVYKTI in patients withhigh tumour burden (see section 4.2).

Management of cytokine release syndrome associated with CARVYKTI

If CRS is suspected, manage according to the recommendations in Table 1. Supportive care for CRS(including but not limited to anti-pyretic agents, IV fluid support, vasopressors, supplemental oxygen,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. Other monoclonal antibodies targeting cytokines (for example,anti-IL1 and/or anti-TNFα), or therapy directed at reduction and elimination of CAR-T cells, may beconsidered for patients who develop high grade CRS and HLH that remain severe or life-threateningfollowing prior administration of tocilizumab and corticosteroids.

If concurrent neurologic toxicity is suspected during CRS, administer:

- Corticosteroids according to the more aggressive intervention based on the CRS and neurologictoxicity grades in Tables 1 and 2,

- Tocilizumab according to the CRS grade in Table 1,

- Anti-seizure medication according to the neurologic toxicity in Table 2.

Table 1: CRS grading and management guidance

CRS Gradea Tocilizumabb Corticosteroidsf

Grade 1

Temperature ≥38 °Cc Tocilizumab 8 mg/kg N/Aintravenously (IV) over 1 hour(not to exceed 800 mg) may beconsidered.

Grade 2

Symptoms require and respond Administer tocilizumab 8 mg/kg Consider methylprednisoloneto moderate intervention. IV over 1 hour (not to exceed 1 mg/kg intravenously (IV)800 mg). twice daily or dexamethasone

Temperature ≥38 °Cc with: (e.g., 10 mg IV every 6 hours).

Repeat tocilizumab every

Hypotension not requiring 8 hours as needed if notvasopressors, responsive to intravenous fluidsand/or, up to 1 litre or increasingsupplemental oxygen.

If no improvement within 24 hours or rapid progression, repeat

Hypoxia requiring oxygen via tocilizumab and escalate dose of dexamethasone (20 mg IV everycannulae or blow-by, 6 to 12 hours).

or, After 2 doses of tocilizumab, consider alternative anti-cytokineagents.d

Grade 2 organ toxicity.

Do not exceed 3 doses of tocilizumab in 24 hours, or 4 doses intotal.

Grade 3

Symptoms require and respond Per Grade 2 Administer methylprednisoloneto aggressive intervention. 1 mg/kg IV twice daily ordexamethasone (e.g., 10 mg IV

Temperature ≥38 °Cc with: every 6 hours).

Hypotension requiring one If no improvement within 24 hours or rapid progression, repeatvasopressor with or without tocilizumab and escalate dose of dexamethasone (20 mg IV everyvasopressin, 6 to 12 hours).and/or,

If no improvement within 24 hours or continued rapid progression,

Hypoxia requiring oxygen via switch to methylprednisolone 2 mg/kg IV every 12 hours.high-flow nasal cannulae,facemask, non-rebreather mask, After 2 doses of tocilizumab, consider alternative anti-cytokineor Venturi mask, agents.dor, Do not exceed 3 doses of tocilizumab in 24 hours, or 4 doses intotal.

Grade 3 organ toxicity or Grade4 transaminitis.

Grade 4

Life-threatening symptoms. Per Grade 2 Administer dexamethasone

Requirements for ventilator 20 mg IV every 6 hours.support, continuous veno- After 2 doses of tocilizumab, consider alternative anti-cytokinevenous haemodialysis agentsd. Do not exceed 3 doses of tocilizumab in 24 hours, or(CVVHD). 4 doses in total.

Temperature ≥38 °Cc with: If no improvement within 24 hours, consider methylprednisolone(1-2 g IV, repeat every 24 hours if needed; taper as clinically

Hypotension requiring multiple indicated) or other immunosuppressants (e.g., other anti-T cellvasopressors (excluding therapies).vasopressin),and/or,

Hypoxia requiring positivepressure (e.g., CPAP, BiPAP,intubation, and mechanicalventilation),or,

Grade 4 organ toxicity(excluding transaminitis).

a Based on ASTCT 2019 grading system (Lee et.al, 2019), modified to include organ toxicity.b Refer to tocilizumab prescribing information for details. Consider alternative measures (see Sections 4.2. and 4.4).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 anti-cytokine therapy (e.g., tocilizumab or steroids). Absence of fever does not impact

CRS management decision. In this case, CRS management is driven by hypotension and/or hypoxia and by the more severesymptom not attributable to any other cause.

d Monoclonal antibodies targeting cytokines (for example, anti-IL1 such as anakinra) may be considered based on institutionalpractice for unresponsive CRS.

e Low-flow nasal cannula is ≤6 L/min; high-flow nasal cannula is >6 L/min.f Continue corticosteroids use until the event is Grade 1 or less; taper steroids if total corticosteroid exposure is greater than3 days.

Neurologic toxicities

Neurologic toxicities occur frequently following treatment with CARVYKTI and can be fatal orlife-threatening (see section 4.8). Neurologic toxicities included ICANS, movement andneurocognitive toxicity (MNT) with signs and symptoms of parkinsonism, Guillain-Barré syndrome,peripheral neuropathies and cranial nerve palsies. Patients should be counselled on the signs andsymptoms of these neurologic toxicities, and on the delayed nature of onset of some of these toxicities.

Patients should be instructed to seek immediate medical attention for further assessment andmanagement if signs or symptoms of any of these neurologic toxicities occur at any time.

Immune effector cell-associated neurotoxicity syndrome (ICANS)

Patients receiving CARVYKTI may experience fatal or life-threatening ICANS following treatmentwith CARVYKTI, including before CRS onset, concurrent with CRS, following resolution of CRS orin the absence of CRS. Symptoms included aphasia, slow speech, dysgraphia, encephalopathy,depressed level of consciousness and confusional state.

Reduction of baseline burden of disease with bridging therapy prior to infusion with CARVYKTI inpatients with high tumour burden should be considered, which may mitigate the risk of developingneurologic toxicity (see section 4.8). Patients should be monitored for signs or symptoms of ICANSfor four weeks after infusion. At the first sign of ICANS, the patient should be immediately evaluatedfor hospitalisation and treatment instituted with supportive care as indicated in Table 2 below. Earlydetection and aggressive treatment of CRS or ICANS may be important to prevent neurologic toxicityfrom occurring or worsening. Continue to monitor patients for signs and symptoms of neurologictoxicities after recovery from CRS and/or ICANS.

Management of neurologic toxicity associated with CARVYKTI

At the first sign of neurologic toxicity including ICANS, neurology evaluation should be considered.

Rule out other causes of neurologic symptoms. Provide intensive care and supportive therapy forsevere or life-threatening neurologic toxicities.

If concurrent CRS is suspected during the neurologic toxicity event, administer:

- Corticosteroids according to the more aggressive intervention based on the CRS and neurologictoxicity grades in Tables 1 and 2,

- Tocilizumab according to CRS grade in Table 1,

- Anti-seizure medication according to neurologic toxicity in Table 2.

Table 2: Guideline for management of ICANS

ICANS Gradea Corticosteroids

Grade 1 Consider dexamethasonec 10 mg intravenously every6 to 12 hours for 2 to 3 days.

ICE score 7-9b

Consider non-sedating, anti-seizure medicines (e.g.,or depressed level of consciousness: levetiracetam) for seizure prophylaxis.awakens spontaneously.

Grade 2 Administer dexamethasonec 10 mg intravenouslyevery 6 hours for 2-3 days, or longer for persistent

ICE score-3-6b symptoms.

or depressed level of consciousness: Consider steroid taper if total corticosteroid exposureawakens to voice is greater than 3 days.

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

Grade 3 Administer dexamethasonec 10 mg-20 mgintravenously every 6 hours.

ICE score-0-2b(If ICE score is 0, but the patient is If no improvement after 48 hours or worsening ofarousable (e.g., awake with global aphasia) neurologic toxicity, escalate dexamethasonec dose toand able to perform assessment) at least 20 mg intravenously every 6 hours; taperwithin 7 days,or depressed level of consciousness:awakens only to tactile stimulus, OR escalate to high-dose methylprednisolone(1 g/day, repeat every 24 hours if needed; taper asor seizures, either: clinically indicated).

- any clinical seizure, focal or generalised,that resolves rapidly, or Consider non-sedating, anti-seizure medicines (e.g.,

- non-convulsive seizures on EEG that levetiracetam) for seizure prophylaxis.

resolve with intervention,or raised intracranial pressure (ICP):focal/local oedema on neuroimagingd.

Grade 4 Administer dexamethasonec 10 mg-20 mgintravenously every 6 hours.

ICE score-0b (Patient is unarousable andunable to perform ICE assessment) If no improvement after 24 hours or worsening ofneurologic toxicity, escalate to high-doseor depressed level of consciousness either: methylprednisolone (1-2 g/day, repeated every

- patient is unarousable or requires 24 hours if needed; taper as clinically indicated).

vigorous or repetitive tactile stimuli toarouse, or Consider non-sedating, anti-seizure medicines (e.g.,

- stupor or coma, levetiracetam) for seizure prophylaxis.

or seizures, either: If raised ICP/cerebral oedema is suspected, consider

- life-threatening prolonged seizure hyperventilation and hyperosmolar therapy. Give(>5 min), or high-dose methylprednisolone (1-2 g/day, repeat every

- repetitive clinical or electrical seizures 24 hours if needed; taper as clinically indicated), andwithout return to baseline in between, consider neurology and/or neurosurgery consultation.

or motor findingse:

- deep focal motor weakness such ashemiparesis or paraparesis,or raised ICP/cerebral oedema, withsigns/symptoms such as:

- diffuse cerebral oedema onneuroimaging, or

- decerebrate or decorticate posturing, or

- cranial nerve VI palsy, or

- papilledema, or

- Cushing’s triad

EEG=Electroencephalogram; ICE=Immune Effector Cell-Associated Encephalopathy

Note: ICANS grade and management is determined by the most severe event (ICE score, level of consciousness, seizure,motor findings, raised ICP/cerebral oedema), not attributable to any other cause.a ASTCT 2019 criteria for grading Neurologic Toxicity (Lee et.al, 2019).b If patient is arousable and able to perform Immune Effector Cell-associated Encephalopathy (ICE) Assessment, assessas in Table 3 below.c All references to dexamethasone administration are dexamethasone or equivalent.d Intracranial haemorrhage with or without associated oedema is not considered a neurotoxicity feature and is excludedfrom ICANS grading. It may be graded according to CTCAE v5.0.e Tremors and myoclonus associated with immune effector cell therapies may be graded according to CTCAE v5.0, butthey do not influence ICANS grading.

Table 3: Immune Effector Cell-Associated Encephalopathy (ICE) assessment

Immune Effector Cell-Associated Encephalopathy (ICE) Toola

Points

Orientation: Orientation to year, month, city, hospital 4

Naming: Name 3 objects (e.g., point to clock, pen, button) 3

Following commands: (e.g., ‘Show me 2 fingers’ or ‘Close 1your eyes and stick out your tongue’)

Writing: Ability to write a standard sentence 1

Attention: Count backwards from 100 by ten 1a ICE-Tool Scoring:

- Score 10: No impairment

- Score 7-9: Grade 1 ICANS

- Score 3-6: Grade 2 ICANS

- Score 0-2: Grade 3 ICANS

- Score 0: patient unarousable and unable to perform ICE assessment: Grade 4 ICANS

Movement and neurocognitive toxicity with signs and symptoms of parkinsonism

Neurologic toxicity of movement and neurocognitive toxicity with signs and symptoms ofparkinsonism has been reported in trials of CARVYKTI. A cluster of symptoms with variable onsetspanning more than one symptom domain was observed, including movement (e.g., micrographia,tremor, bradykinesia, rigidity, stooped posture, shuffling gait), cognitive (e.g., memory loss,disturbance in attention, confusion), and personality change (e.g., reduced facial expression, flat affect,masked facies, apathy), often with subtle onset (e.g., micrographia, flat affect), that in some patientsprogressed to an inability to work or care for oneself. Most of these patients presented a combinationof two or more factors such as high tumour burden at baseline (bone marrow plasma cell ≥80% orserum M-spike ≥ 5 g/dL or serum free light chain ≥ 5,000 mg/L), prior Grade 2 or higher CRS, prior

ICANS, and high CAR-T cell expansion and persistence. Treatment with levodopa/carbidopa (n=4),was not effective in improving symptomatology in these patients.

Patients should be monitored for signs and symptoms of parkinsonism that may be delayed in onsetand managed with supportive care measures.

Guillain-Barré syndrome (GBS) has been reported after treatment with CARVYKTI. Symptomsreported include those consistent with Miller-Fisher variant of GBS, motor weakness, speechdisturbances, and polyradiculoneuritis (see section 4.8).

Patients should be monitored for GBS. Patients presenting with peripheral neuropathy should beevaluated for GBS. Treatment with intravenous immunoglobulin (IVIG) and escalation toplasmapheresis should be considered, depending on toxicity severity.

Occurrence of peripheral neuropathy, including sensory, motor, or sensorimotor, have been reported intrials of CARVYKTI.

Patients should be monitored for signs and symptoms of peripheral neuropathies. Management withshort-course systemic corticosteroids should be considered, depending on the severity and progressionof signs and symptoms.

Cranial nerve palsies

Occurrence of 7th, 3rd, 5th, and 6th cranial nerve palsy, some of which were bilateral, worsening ofcranial nerve palsy after improvement, and occurrence of peripheral neuropathy in patients withcranial nerve palsy have been reported in trials of CARVYKTI.

Patients should be monitored for signs and symptoms of cranial nerve palsies. Management withshort-course systemic corticosteroids should be considered, depending on the severity and progressionof signs and symptoms.

Prolonged and recurrent cytopenias

Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and

CARVYKTI infusion and should be managed according to local guidelines. In trials of CARVYKTI,nearly all patients had one or more Grade 3 or 4 cytopenic adverse reactions. Most patients had amedian time from infusion to first onset of Grade 3 or 4 cytopenia of less than two weeks with themajority of patients recovering to Grade 2 or lower by Day 30 (see section 4.8).

Blood counts should be monitored prior to and after CARVYKTI infusion. For thrombocytopenia,supportive care with transfusions should be considered. Prolonged neutropenia has been associatedwith increased risk of infection. Myeloid growth factors, particularly GM-CSF, have the potential toworsen CRS symptoms and are not recommended during the first 3 weeks after CARVYKTI or until

CRS has resolved.

Serious infections and febrile neutropenia

Serious infections, including life-threatening or fatal infections, occurred in patients after CARVYKTIinfusion (see section 4.8).

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

CARVYKTI and treated appropriately. Prophylactic antimicrobials should be administered accordingto local guidelines. Infections are known to complicate the course and management of concurrent

CRS. Patients with clinically significant active infection should not start CARVYKTI treatment untilthe infection is controlled.

In the event of febrile neutropenia, infection should be evaluated and managed appropriately withbroad-spectrum antibiotics, fluids and other supportive care, as medically indicated.

Patients treated with CARVYKTI may be at an increased risk of severe/fatal COVID-19 infections.

Patients should be counselled on the importance of prevention measures.

HBV reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occurin patients treated with medicinal products directed against B cells.

There is currently no experience with manufacturing CARVYKTI for patients testing positive for

HIV, active HBV, or active HCV. Screening for HBV, HCV and HIV and other infectious agents mustbe performed before collection of cells for manufacturing (see section 4.2).

Hypogammaglobulinaemia may occur in patients receiving CARVYKTI.

Immunoglobulin levels should be monitored after treatment with CARVYKTI; IVIG should beadministered for IgG <400 mg/dL. Manage according to standard guidelines, including antibiotic orantiviral prophylaxis and monitoring for infection.

Secondary malignancies

Patients treated with CARVYKTI may develop secondary malignancies. A case of CAR-positive T-cell lymphoma has been reported in an ongoing study. Patient should be monitored life-long forsecondary malignancies. In the event a secondary malignancy occurs, the company should becontacted to obtain instructions on patient samples to collect for testing.

Interference with virological testing

Due to limited and short spans of identical genetic information between the lentiviral vector used tocreate CARVYKTI and HIV, some HIV nucleic acid tests (NAT) may give a false positive result.

Blood, organ, tissue and cell donation

Patients treated with CARVYKTI should not donate blood, organs, tissues and cells fortransplantation. This information is provided in the Patient Alert Card which should be given to thepatient.

Allergic reactions may occur with infusion of CARVYKTI. Serious hypersensitivity reactions,including anaphylaxis, may occur due to the dimethyl sulfoxide (DMSO) or residual kanamycin in

CARVYKTI. Patients should be carefully monitored for 2 hours after infusion for signs and symptomsof severe reaction. Treat promptly and manage patients appropriately according to the severity of thehypersensitivity reaction.

Long-term follow-up

Patients are expected to enroll and be followed in a registry in order to better understand the long-termsafety and efficacy of CARVYKTI.