Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use



Traceability
The traceability requirements of cell-based advanced therapy medicinal products must apply. To ensure traceability the name of the product, the batch number and the name of the treated patient must be kept for a period of 30 years after expiry date of the product.
Autologous use

Abecma is intended solely for autologous use and must not, under any circumstances, be administered to other patients. Abecma must not be administered if the information on the product labels and the release for infusion certificate (RfIC) do not match the patient’s identity.

Rapidly progressing disease

Before selecting patients for Abecma treatment, physicians should consider the impact of high-risk cytogenetic abnormalities, Revised International Staging System (R-ISS) stage III, presence of extramedullary plasmacytoma or high tumour burden, particularly for patients who have rapidly progressing disease that may affect their ability to receive CAR T infusion in due time. For these patients, optimising bridging therapy may be particularly important. Some patients may not benefit from Abecma treatment due to potential increased risk of early death (see section 5.1).

Reasons to delay treatment

Due to the risks associated with Abecma treatment, infusion should be delayed up to 7 days if a patient has any of the following conditions:
•     Unresolved serious adverse events (especially pulmonary events, cardiac events or hypotension) including those after preceding chemotherapies.
•     Active infections or inflammatory disorders (including pneumonitis, myocarditis or hepatitis). •     Active graft-versus-host disease (GVHD).


Concomitant disease
Patients with active central nervous system (CNS) disorder or inadequate renal, hepatic, pulmonary or cardiac function are likely to be more vulnerable to the consequences of the adverse reactions described below and require special attention.

Central nervous system pathology

There is no experience of use of Abecma in patients with CNS involvement of myeloma or other pre- existing, clinically relevant CNS pathologies.

Prior allogeneic stem cell transplantation

It is not recommended that patients receive Abecma within 4 months after an allogeneic stem cell transplant (SCT) because of the potential risk of Abecma worsening GVHD. Leukapheresis for Abecma manufacturing should be performed at least 12 weeks after allogeneic SCT.

Prior treatment with an anti-BCMA therapy

There is limited experience with Abecma in patients exposed to prior BCMA-directed therapy.
There is limited experience of retreating patients with a second dose of Abecma. Responses after 


Abecma retreatment were infrequent and less durable when compared to initial treatment.
Additionally, fatal outcomes were observed in retreated patients.

Cytokine release syndrome
CRS, including fatal or life-threatening reactions occurred following Abecma infusion. Nearly all patients experienced some degree of CRS. In clinical studies, the median time to onset of CRS was 1 day (range: 1 to 17) (see section 4.8).

Monitoring and management of CRS
CRS should be identified based on clinical presentation. Patients should be evaluated and treated for other causes of fever, hypoxia and hypotension. CRS has been reported to be associated with findings of haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) and the physiology of the syndromes may overlap. MAS is a potentially life-threatening condition, and patients should be closely monitored for evidence of MAS. Treatment of MAS should be administered per institutional guidelines.

One dose of tocilizumab per patient must be on-site and available for administration prior to Abecma infusion. The treatment centre must have access to an additional dose of tocilizumab within 8 hours of each previous dose. In the exceptional case where tocilizumab is not available, the treatment centre must have access to suitable alternative measures instead of tocilizumab to treat CRS. Patients should be monitored for the first 10 days following Abecma infusion at the qualified treatment centre for signs and symptoms of CRS. After the first 10 days following infusion, the patient should be monitored at the physician’s discretion. Patients should be counselled to remain within proximity (within 2 hours of travel) of the qualified treatment centre for at least 4 weeks following infusion and to seek immediate medical attention should signs or symptoms of CRS occur at any time.

At the first sign of CRS, treatment with supportive care, tocilizumab or tocilizumab and corticosteroids should be instituted, as indicated in Table 1. Abecma can continue to expand and persist following administration of tocilizumab and corticosteroids (see section 4.5).

Patients who experience CRS should be closely monitored for cardiac and organ functioning until resolution of symptoms. For severe or life-threatening CRS, intensive care unit level monitoring and supportive therapy should be considered.

If concurrent neurologic toxicity is suspected during CRS, the neurologic toxicity should be managed according tothe recommendations in Table 2 and use the more aggressive intervention of the two reactions specified in Tables 1 and 2.

Earlier escalation (i.e. higher corticosteroid dose, alternative anticytokine agents, anti-T cell therapies) is recommended in patients with refractory CRS within 72 hours post Abecma infusion characterised by persistent fever, end-organ toxicity (e.g. hypoxia, hypotension) and/or HLH/MAS not improving in grade within 12 hours of first line interventions.



Table 1.       CRS grading and management guidance

CRS gradea                      Tocilizumab                       Corticosteroids 
Grade 1
Symptoms require                If onset 72 hours or more after                   ─ symptomatic treatment only      infusion, treat
(e.g. fever, nausea, fatigue,   symptomatically.
headache, myalgia, malaise).    If onset less than 72 hours after infusion and symptoms not controlled by supportive care alone, consider tocilizumab
8 mg/kg IV over 1 hour (not to exceed 800 mg).

Grade 2
Symptoms require and            Administer tocilizumab              Consider dexamethasone respond to moderate             8 mg/kg IV over 1 hour (not to      10 mg IV every 12 to 24 hours.
intervention.                   exceed 800 mg).
Oxygen requirement less than
40% FiO2 or hypotension responsive to fluids or low dose of one vasopressor or
Grade 2 organ toxicity.
Grade 3
Symptoms require and          Administer tocilizumab                Administer dexamethasone respond to aggressive         8 mg/kg IV over 1 hour (not to        (e.g. 10 mg IV every 12 hours).
intervention.                 exceed 800 mg).
Fever, oxygen requirement greater than or equal to 40%
FiO2 or hypotension requiring high-dose or multiple vasopressors or Grade 3 organ toxicity or Grade 4 transaminitis.
For Grade 2 and 3:
If no improvement within 24 hours or rapid progression, repeat tocilizumab and escalate dose and frequency of dexamethasone (20 mg IV every 6 to 12 hours).
If no improvement within 24 hours or continued rapid progression, switch to methylprednisolone 2 mg/kg followed by 2 mg/kg divided 4 times per day.
If steroids are initiated, continue steroids for at least 3 doses, and taper over a maximum of 7 days.
After 2 doses of tocilizumab, consider alternative anticytokine agents. Do not exceed 3 doses tocilizumab in 24 hours or 4 doses in total.



Grade 4
Life-threatening                Administer tocilizumab            Administer dexamethasone 20 symptoms.Requirements           8 mg/kg IV over 1 hour (not to    mg IV every 6 hours.
for ventilatorsupport,          exceed 800 mg).
continuous veno-venous hemodialysis (CVVHD) or
Grade 4 organtoxicity
(excluding transaminitis).

For Grade 4:
After 2 doses of tocilizumab, consider alternative anticytokine agents. Do not exceed 3 doses of tocilizumab in 24 hours or 4 doses in total.
If no improvement within 24 hours, consider methylprednisolone (1 to 2 g, repeat every 24 hours if needed; taper as clinically indicated) or anti-T cell therapies such as cyclophosphamide 1.5 g/m2 or others.
a
Lee et al, 2014.


Neurologic adverse reactions

Neurologic toxicities, such as aphasia,encephalopathy and immune effector cell-associated neurotoxicity syndrome (ICANS), which may be severe or life-threatening, occurred following treatment with Abecma. The median time to onset of the first event of neurotoxicity was 3 days (range: 1 to 317 days; one patient developed encephalopathy at Day 317 as a result of worsening pneumonia and Clostridium difficile colitis). Grade 3 parkinsonism has also been reported, with delayed onset. Neurologic toxicity may occur concurrently with CRS, after CRS resolution or in the absence of CRS (see section 4.8).

Monitoring and management of neurologic toxicities
Patients should be monitored for the first 10 days following Abecma infusion at the qualified treatment centre for signs and symptoms of neurologic toxicities. After the first 10 days following infusion, the patient should be monitored at the physician’s discretion. Patients should be counselled to remain within proximity (within 2 hours of travel) of the qualified treatment centre for at least 4 weeks following infusion and to seek immediate medical attention should signs and symptoms of neurologic toxicities occur at any time.

If neurologic toxicity is suspected, manage according to the recommendations in Table 2. Other causes of neurologic symptoms should be ruled out. Intensive care supportive therapy should be provided for severe or life-threatening neurologic toxicities.

If concurrent CRS is suspected during the neurologic toxicity reaction, it should be managed according to the recommendations in Table 1 and the more aggressive intervention used for the two reactions specified in Tables 1 and 2.



Table 2.         Neurologic toxicity including ICANS grading and management guidance 
Neurologictoxicity grade including presenting symptomsa                           Corticosteroids and antiseizure medications
Grade 1
Mild or asymptomatic.                       Start non-sedating, antiseizure medicines (e.g.
levetiracetam) for seizure prophylaxis.
ICE score 7-9b                              If 72 hours or more after infusion, observe patient.
If less than 72 hours after infusion, and symptoms not or                                          controlled by supportive care alone, consider dexamethasone 10 mg IV every 12 to 24 hours for 2
Depressed level of consciousnessc:          to 3 days.
awakens spontaneously.
Grade 2
Moderate.                                   Start non-sedating, antiseizure medicines (e.g.
levetiracetam) for seizure prophylaxis.
ICE score 3-6b                              Start dexamethasone 10 mg IV every 12 hours for 2 to 3 days or longer for persistent symptoms. Consider or                                          taper for a total steroid exposure of greater than 3 days. Steroids are not recommended for isolated
Depressed level of consciousnessc:          Grade 2 headaches.
awakens to voice.                           If no improvement after 24 hours or worsening of neurologic toxicity, increase the dose and/or frequency of dexamethasone up to a maximum of 20 mg IV every
6 hours.
Grade 3
Severe or medically significant but not     Start non-sedating, antiseizure medicines (e.g.
immediately life- threatening;              levetiracetam) for seizure prophylaxis.
hospitalization or prolongation;            Start dexamethasone 10 to 20 mg IV every 8 to disabling.                                  12 hours. Steroids are not recommended for isolated Grade 3 headaches.
If no improvement after 24 hours or worsening of
ICE score 0-2b                              neurologic toxicity, escalate to methylprednisolone (2 if ICE score is 0, but the patient is       mg/kg loading dose, followed by 2 mg/kg divided into arousable (e.g., awake with global          4 times a day; taper within 7 days).
aphasia) and able to perform                If cerebral oedema is suspected, consider assessment.                                 hyperventilation and hyperosmolar therapy. Give high-dose methylprednisolone (1 to 2 g, repeat every or                                          24 hours if needed; taper as clinically indicated) and cyclophosphamide 1.5 g/m2.
Depressed level of consciousnessc: awakens only to tactile stimulus,

Or seizuresc, either:
• any clinical seizure, focal or generalised, that resolves rapidly, or
• non-convulsive seizures on EEG that resolve with intervention,

Or raised ICPc: focal/local oedema on neuroimaging.
Grade 4
Life- threatening.                                   Start non-sedating, antiseizure medicines (e.g.
levetiracetam) for seizure prophylaxis.
Start dexamethasone 20 mg IV every 6 hours.
ICE scoreb 0                                         If no improvement after 24 hours or worsening of neurologic toxicity, escalate tohigh-dose or                                                   methylprednisolone (1 to 2 g, repeated every 24 hours if needed; taperas clinically indicated). Consider
Depressed level of consciousnessc                    cyclophosphamide 1.5 g/m2.
either:                                              If cerebral oedema is suspected, consider • patient is unarousable or requires                  hyperventilation and hyperosmolar therapy. Give vigorous or repetitive tactile stimuli           high-dose methylprednisolone (1 to 2 g, repeat every to arouse, or                                    24 hours if needed; taper as clinically indicated) and • stupor or coma,                                     cyclophosphamide 1.5 g/m2.

Or seizuresc, either:
• life-threatening prolonged seizure
(>5 min), or
• repetitive clinical or electrical seizures without return to baseline in between,

Or motor findingsc:
• deep focal motor weakness such as hemiparesis or paraparesis,
Or, raised ICP/cerebral oedemac, with signs/symptoms such as:
• diffuse cerebral oedema on neuroimaging, or
• decerebrate or decorticate posturing,
or
• cranial nerve VI palsy, or
• papilledema, or
• Cushing’s triad.
EEG=Electroencephalogram; ICE=Immune Effector Cell-Associated Encephalopathy; ICP=intracranial pressure a
Management is determined by the most severe event, not attributable to any other cause.
b  If patient is arousable and able to perform 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.


Prolonged cytopenias
Patients may exhibit prolonged cytopenias for several weeks following lymphodepleting chemotherapy and Abecma infusion (see section 4.8). Blood counts should be monitored prior to and after Abecma infusion. Cytopenias should be managed with myeloid growth factor and blood transfusion support according to institutional guidelines.



Infections and febrile neutropenia

Abecma should not be administered to patients with active infections or inflammatory disorders.
Severe infections, including life-threatening or fatal infections, have occurred in patients after receiving Abecma (see section 4.8). Patients should be monitored for signs and symptoms of infection before and after Abecma infusion and treated appropriately. Prophylactic, pre-emptive and/or therapeutic antimicrobials should be administered according to institutional guidelines.

Febrile neutropenia was observed in patients after Abecma infusion (see section 4.8) and may be concurrent with CRS. In the event of febrile neutropenia, infection should be evaluated and managed with broad-spectrum antibiotics, fluids and other supportive care as medically indicated.

Viral reactivation

Cytomegalovirus (CMV) infection resulting in pneumonia and death have occurred following Abecma administration (see section 4.8). Patients should be monitored and treated for CMV infection according to clinical guidelines.

HBV reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with medicinal products directed against plasma cells (see section 4.8).

Screening for CMV, HBV, active HIV and active HCV must be performed before collection of cells for manufacturing (see section 4.2).

Hypogammaglobulinaemia

Plasma cell aplasia and hypogammaglobulinaemia can occur in patients receiving treatment with Abecma (see section 4.8). Immunoglobulin levels should be monitored after treatment with Abecma and managed per institutional guidelines including infection precautions, antibiotic or antiviral prophylaxis and immunoglobulin replacement.

Secondary malignancies

Patients treated with Abecma may develop secondary malignancies. Patients should be monitored life- long for secondary malignancies. In the event that a secondary malignancy of T cell origin occurs, the company should be contacted to obtain instructions on the collection of patient samples for testing.

Hypersensitivity reactions

Allergic reactions may occur with the infusion of Abecma. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide (DMSO), an excipient in Abecma. Patients not previously exposed to DMSO should be observed closely. Vital signs (blood pressure, heart rate, and oxygen saturation) and the occurrence of any symptom should be monitored prior to the start of the infusion, approximately every ten minutes during the infusion and every hour, for 3 hours, after the infusion.

Transmission of an infectious agent

Although Abecma is tested for sterility and mycoplasma, a risk of transmission of infectious agents exists. Healthcare professionals administering Abecma must, therefore, monitor patients for signs and symptoms of infections after treatment and treat appropriately, if needed.



Interference with virological testing

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

Blood, organ, tissue and cell donation

Patients treated with Abecma must not donate blood, organs, tissues and cells for transplantation.
Long-term follow-up

Patients are expected to be enrolled in a registry in order to betterunderstand the long-term safety and efficacy of Abecma.

Excipients

This medicinal product contains up to 33 mmol (752 mg) sodium per dose, equivalent to 37.6% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

This medicinal product contains up to 7 mmol (274 mg) potassium per dose. To be taken into consideration by patients with reduced kidney function or patients on a controlled potassium diet.

Effects on Driving

4.7    Effects on ability to drive and use machines

Abecma may have major influence on the ability to drive and use machines.
Due to the potential for neurologic adverse reactions, including altered mental status or seizures with Abecma, patients receiving Abecma should refrain from driving or operating heavy or potentially dangerous machines for at least 8 weeks after Abecma infusion or until resolution of neurologic adverse reactions.