ABECMA

Abecma must be administered in a qualified treatment centre. Abecma therapy should be initiated under the direction of and supervised by a healthcare professional experienced in the treatment of haematological malignancies and trained for the administration and management of patients treated with Abecma.

A minimum of one dose of tocilizumab for use in the event of cytokine release syndrome (CRS) and emergency equipment must be available prior to infusion of Abecma. 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 due to a shortage that is listed in the MHRA Central Alerting System, suitable alternative measures to treat CRS instead of tocilizumab must be available prior to infusion.

4). Manufacture and release of Abecma usually takes about 4-5 weeks. Treatment consists of a single dose for infusion containing a dispersion of CAR-positive viable T cells in one or more infusion bags. The target dose is 420 x 106 CAR-positive viable T cells within a range of 260 to 500 x 106 CAR-positive viable T cells.

See the accompanying release for infusion certificate (RfIC) for additional information pertaining to dose. Pre-treatment (lymphodepleting chemotherapy) Lymphodepleting chemotherapy consisting of cyclophosphamide 300 mg/m2 intravenously (IV) and fludarabine 30 mg/m2 IV should be administered for 3 days.

See the prescribing information for cyclophosphamide and fludarabine for information on dose adjustment in renal impairment. Abecma is to be administered 2 days after completion of lymphodepleting chemotherapy, up to a maximum of 9 days.

The availability of Abecma must be confirmed prior to starting the lymphodepleting chemotherapy. If there is a delay of more than 4 weeks between completing lymphodepleting chemotherapy and the infusion, then the patient should be re-treated with lymphodepleting chemotherapy prior to receiving Abecma.

5 mg IV or 25 to 50 mg orally) or another H1-antihistamine, approximately 30 to 60 minutes before infusion of Abecma. Prophylactic use of systemic corticosteroids should be avoided as the use may interfere with the activity of Abecma.

4). 4). Monitoring after infusion - Patients should be monitored for the first 10 days following infusion at the qualified treatment centre for signs and symptoms of CRS, neurologic events and other toxicities. - After the first 10 days following infusion, the patient should be monitored at the physician’s discretion.

- Patients should be instructed to remain within proximity (within 2 hours of travel) of the qualified treatment centre for at least 4 weeks following infusion. Special populations Patients with human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) infection There is no clinical experience in patients with active HIV, HBV or HCV infection.

Screening for HBV, active HIV and active HCV must be performed before collection of cells for manufacturing. 4). 1). Paediatric population The safety and efficacy of Abecma in children and adolescents below 18 years of age have not been established.

No data are available. Method of administration Abecma is for intravenous use only. Administration • Do NOT use a leukodepleting filter. • Ensure that tocilizumab or suitable alternatives, in the exceptional case where tocilizumab is not available due to a shortage that is listed in the MHRA Central Alerting System, and emergency equipment are available prior to infusion and during the recovery period.

• Central venous access may be utilised for the infusion of Abecma and is encouraged in patients with poor peripheral access. • Confirm the patient’s identity matches the patient identifiers on the Abecma infusion bag. 6.

Summary of the safety profile The safety data described in this section reflect the exposure to Abecma in the KarMMa and CRB-401 studies in which 184 patients with relapsed and refractory multiple myeloma received Abecma. 5 months. 3%).

1% of patients. 6%). 4%). 8%). 3%). 1 for the corresponding dose range of CAR-positive viable T cells) in the KarMMa and CRB-401 studies, respectively. Adverse reactions are presented by MedDRA system organ class and by frequency. Frequencies are defined as: 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 (cannot be estimated from available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 3. Adverse reactions observed in patients treated with Abecma System organ class Adverse reaction All grades frequency Infections and infestationsa Infections – bacterial Infections – viral Infections – pathogen unspecified Infections – fungal Very common Very common Very common Common Blood and lymphatic system disorders Neutropenia Leucopenia Thrombocytopeni a Febrile neutropenia Lymphopenia Anaemia Disseminated intravascular coagulation Very common Very common Very common Very common Very common Very common Common Immune system disorders Cytokine release syndrome Hypogammaglobulinaemia Haemophagocytic lymphohistiocytosis* Very common Very common Common Metabolism and nutrition disorders Hypophosphataemia Hypokalaemia Hyponatraemia Hypocalcaemia Hypoalbuminaemia Decreased appetite Hypomagnesaemia Very common Very common Very common Very common Very common Very common Very common Psychiatric disorders Deliriumb Insomnia Commo n Commo n System organ class Adverse reaction All grades frequency Nervous system disorders Encephalopathy c Headache* Dizzinessd Seizure Hemiparesis Aphasiae Ataxiaf Motor dysfunctiong Tremor Very common Very common Very common Common Common Common Common Common Common Cardiac disorders Tachycardia* Atrial fibrillation* Very common Common Vascular disorders Hypertension Hypotension*h Very common Very common Respiratory, thoracic, and mediastinal disorders Dyspnoea Cough Pulmonary oedema Hypoxia* Very common Very common Common Common Gastrointestinal disorders Vomiting Diarrhoea Nausea Constipation Gastrointestinal haemorrhagei Very common Very common Very common Very common Common Musculoskeletal and connective tissue disorders Arthralgia Myalgia Very common Common General disorders and administration site conditions Pyrexia * Fatigue *j Astheni a Oedema k Chills* Very common Very common Very common Very common Very common Investigations Alanine aminotransferase increased Aspartate aminotransferase increased Blood alkaline phosphatase increased C-reactive protein increased* Very common Very common Very common Common * Event that has been reported as a manifestation of CRS.

a Infections and infestations system organ class adverse events are grouped by pathogen type. b Delirium includes delirium, disorientation, hallucination. c Encephalopathy includes amnesia, bradyphrenia, cognitive disorder, confusional state, disturbance in attention, dyscalculia, dysgraphia, encephalopathy, lethargy, memory impairment, mental status changes, metabolic encephalopathy, somnolence, toxic encephalopathy.

d Dizziness includes dizziness, presyncope, syncope, vertigo. e Aphasia includes aphasia, dysarthria. f Ataxia includes ataxia, gait disturbance. g Motor dysfunction includes motor dysfunction, muscular spasms, muscular weakness, parkinsonism.

h Hypotension includes hypotension, orthostatic hypotension. i Gastrointestinal haemorrhage includes […]

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 should be kept for a period of 30 years after expiry date of the product.

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). Autologous use Abecma is intended solely for autologous use and should under no circumstances be administered to other patients.

Before infusion, the patient's identity must match the patient identifiers on the Abecma infusion bag, cassette and the release for infusion certificate (RfIC). Abecma must not be administered if the information on the patient-specific label does not match the intended patient.

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. 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 due to a shortage that is listed in the MHRA Central Alerting System, 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. 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, manage the neurologic toxicity according to the recommendations in Table 2 and use the more aggressive intervention of the two reactions specified in Tables 1 and 2.

e. g. hypoxia, hypotension) and/or HLH/MAS not improving in grade within 12 hours of first line interventions. Table 1. g. fever, nausea, fatigue, headache, myalgia, malaise). If onset 72 hours or more after infusion, treat symptomatically.

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 respond to moderate intervention. Oxygen requirement less than 40% FiO2 or hypotension responsive to fluids or low dose of one vasopressor or Grade 2 organ toxicity.

Administer tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg). Consider dexamethasone 10 mg IV every 12 to 24 hours. Grade 3 Symptoms require and respond to aggressive intervention. Fever, oxygen requirement greater than or equal to 40% FiO2 or […]

1. Contraindications of the lymphodepleting chemotherapy must be considered.