Brexucabtagene Autoleucel

TECARTUS (brexucabtagene autoleucel suspension for intravenous infusion) is a CD19-directed genetically modified autologous T-cell immunotherapy indicated for: • the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) after two or more lines of systemic therapy including a Bruton’s tyrosine kinase (BTK) inhibitor.

• the treatment of adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). 1 Pediatrics The safety and efficacy of TECARTUS in patients < 18 years of age have not been established; therefore, Health Canada has not authorized an indication for pediatric use.

2 Geriatrics In MCL, evidence from clinical studies suggest that efficacy and safety in patients ≥ 65 years of age were consistent with the overall treated patient population. In ALL, evidence from clinical studies is not sufficient to determine if the use of TECARTUS in patients ≥ 65 years of age is associated with differences in safety and effectiveness.

TECARTUS should be administered by experienced health professionals at specialized treatment centres (see WARNINGS AND PRECAUTIONS). 1 Dosing Considerations • For intravenous (IV) use only • Single infusion product • For autologous use only; do NOT infuse TECARTUS if the information on the patient-specific label on the infusion bag does not match the intended patient.

• Do not use a leukodepleting filter. • Do not irradiate TECARTUS. • Due to the risks associated with TECARTUS, consider delaying lymphodepleting chemotherapy and TECARTUS treatment if the patient has one or more of the following conditions: clinically significant cardiac dysfunction, pulmonary dysfunction, renal insufficiency, acute neurologic toxicity, active uncontrolled infection or inflammation, and active graft-versus-host disease (see CLINICAL TRIALS).

Serious Warnings and Precautions • Cytokine Release Syndrome (CRS), including fatal and life-threatening reactions, occurred in patients receiving TECARTUS. Do not administer TECARTUS if a patient has active uncontrolled infection or inflammatory disorders, active graft-versus-host disease (GVHD) or unresolved serious adverse reactions from prior therapies.

Monitor for CRS after treatment with TECARTUS. Provide supportive care, tocilizumab, or tocilizumab and corticosteroids, as needed (see WARNINGS AND PRECAUTIONS). • Neurologic adverse reactions, including fatal and life-threatening reactions, occurred in patients receiving TECARTUS, including concurrently with CRS or independently of CRS.

Monitor for neurologic adverse reactions after treatment with TECARTUS. Provide supportive care, tocilizumab (if with concurrent CRS), or corticosteroids, as needed (see WARNINGS AND PRECAUTIONS). • TECARTUS should be administered by experienced health professionals at specialized treatment centres (see WARNINGS AND PRECAUTIONS).

2 Recommended Dose and Dosage Adjustment Adults TECARTUS is provided as a single-dose, one-time treatment in a patient-specific infusion bag. Recommended Dosage for MCL Each single infusion bag of TECARTUS contains a suspension of anti-CD19 chimeric antigen receptor (CAR)-positive T cells in approximately 68 mL.

The target dose is 2 x 106 anti-CD19 CAR-positive viable T cells per kg body weight (range: 1 x 106 – 2 x 106 CAR-positive viable T cells/kg), with a maximum of 2 x 108 CAR-positive viable T cells for patients 100 kg and above. Recommended Dosage for ALL Each single infusion bag of TECARTUS contains a suspension of anti-CD19 CAR-positive viable T cells in approximately 68 mL.

The target dose is 1 × 106 anti-CD19 CAR-positive viable T cells per kg body weight, with a maximum of 1 × 108 CAR-positive viable T cells for patients 100 kg and above. Pediatrics (< 18 years of age) Health Canada has not authorized an indication for pediatric use.

Geriatrics (≥ 65 years of age) No dose adjustments are required for patients 65 years of age or older. 3 Reconstitution Not applicable. 4 Administration TECARTUS is for autologous use only. The patient’s identity must match the patient identifiers on the TECARTUS cassette and infusion bag.

Do NOT infuse TECARTUS if the information on the patient-specific label does not match the intended patient. Ensure that 4 doses of tocilizumab and access to emergency equipment are available prior to infusion and during the recovery period (see WARNINGS AND PRECAUTIONS).

Preparing Patient for TECARTUS Infusion Confirm availability of TECARTUS prior to starting the lymphodepleting chemotherapy regimen.

Pre-treatment (lymphodepleting chemotherapy) • MCL:

Administer a lymphodepleting chemotherapy regimen of cyclophosphamide 500 mg/m2 intravenously and fludarabine 30 mg/m2 intravenously on the 5th, 4th, and 3rd day before infusion of TECARTUS.

TECARTUS (brexucabtagene autoleucel) Page 7 of 44 • ALL:

Administer a lymphodepleting chemotherapy regimen of fludarabine 25 mg/m2 intravenously over 30 minutes on the 4th, 3rd, and 2nd day and cyclophosphamide 900 mg/m2 intravenously over 60 minutes on the 2nd day before infusion of TECARTUS.

5 to 25 mg intravenously or 25 mg orally approximately 1 hour before TECARTUS infusion. • AVOID prophylactic use of systemic corticosteroids, as it may interfere with the activity of TECARTUS. Preparation of TECARTUS for Infusion • Coordinate the timing of TECARTUS thaw and infusion.

Confirm the infusion time in advance, and adjust the start time of TECARTUS thaw such that it will be available for infusion when the patient is ready. • Confirm patient identity: Prior to TECARTUS preparation, match the patient’s identity with the patient identifiers on the TECARTUS cassette.

• Do NOT remove the TECARTUS product bag from the cassette if the information on the patient- specific label does not match the intended patient. • Once patient identification is confirmed, remove the TECARTUS product bag from the cassette and check that the patient information on the cassette label matches the bag label.

• Inspect the infusion bag for any breaches of container integrity such as breaks or cracks before thawing. If the bag is compromised, follow the local guidelines (or call Kite Konnect at 1-833- 236-5483). • Place the infusion bag inside a second sterile bag or per local guidelines.

• Thaw the infusion bag at approximately 37°C using either a water bath or dry thaw method until there is no visible ice in the infusion bag. • Gently mix the contents of the bag to disperse clumps of cellular material. If visible cell clumps remain, continue to gently mix the contents of the bag.

Small clumps of cellular material should disperse with gentle manual mixing. Do NOT wash, spin down, and/or re-suspend TECARTUS in new media prior to infusion. Thawing should take approximately 3-5 minutes. • Once thawed, TECARTUS should be administered within 30 minutes but may be stored at room temperature […]

2 Clinical Trial Adverse Reactions Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug.

Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use. 5 × 106 anti-CD19 CAR T cells/kg) that was weight-based (see CLINICAL TRIALS). The most common non-hematological adverse reactions (in ≥ 20%) include: pyrexia (94%), CRS (91%), hypotension (57%), encephalopathy (51%), fatigue (50%), tachycardias (45%), other pathogen infections (43%), chills (41%), hypoxia (40%), cough (39%), tremor (38%), musculoskeletal pain (35%), edema (35%), headache (35%), nausea (35%), motor dysfunction (33%), constipation (29%), diarrhea (28%), decreased appetite (26%), dyspnea (26%), rash (22%), insomnia (21%), pleural effusion (21%), aphasia (20%), hypertension (20%), and renal insufficiency (20%).

Serious adverse reactions occurred in 65% of patients. The most common serious adverse reactions (≥ 2%) include: encephalopathy (26%), other pathogen infection (22%), pyrexia (20%), CRS (15%), hypoxia (9%), aphasia (6%), renal insufficiency (6%), pleural effusion (5%), respiratory failure (5%), bacterial infections (4%), dyspnea (4%), fatigue (4%), non-ventricular arrhythmia (4%), viral infections (4%), diarrhea (2%), hypertension (2%), motor dysfunction (2%), seizure (2%), tachycardia (2%), and thrombosis (2%).

Grade 3 or higher adverse reactions were reported in 65% of patients. The most common Grade 3 or higher non-haematological adverse reactions included infections (32%) and encephalopathy (24%). The most common Grade 3 or higher haematological adverse reactions included neutropenia (99%), leukopenia (98%), lymphopenia (96%), thrombocytopenia (65%) and anaemia (56%).

Grade 5 (fatal) adverse events were reported in 3 patients and included organizing pneumonia, staphylococcal bacteremia, and cardiac arrest. In ZUMA-2, 70% of patients received prophylactic allopurinol for TLS and 73% of patients received tocilizumab and/or corticosteroids for the treatment of adverse reactions (including CRS and neurologic adverse reactions), including 51% who required 2 or more doses of tocilizumab.

Table 4 summarizes the adverse reactions that occurred in at least 10% of patients treated with TECARTUS. 2 months. TECARTUS (brexucabtagene autoleucel) Page 19 of 44 Table 4 Summary of Adverse Reactions Observed in at Least 10% of Patients Treated with TECARTUS in ZUMA-2 Adverse Reaction Any Grade n (%) N = 82 Grade 3 or Higher n (%) N= 82 Blood and Lymphatic System Disorders Coagulopathy a 8 (10) 2 (2) Cardiac Disorders Tachycardias b 37 (45) 0 Bradycardias c 9 (11) 0 Non-ventricular arrhythmias d 8 (10) 3 (4) Gastrointestinal Disorders Nausea 29 (35) 1 (1) Constipation 24 (29) 0 Diarrhea 23 (28) 4 (5) Oral pain e 14 (17) 0 Abdominal pain f 13 (16) 0 Vomiting g 11 (13) 0 Dysphagia 8 (10) 2 (2) General Disorders and Administration Site Conditions Pyrexia 77 (94) 13 (16) Fatigue h 41 (50) 1 (1) Chills 34 (41) 0 Edema i 29 (35) 2 (2) Pain j 14 (17) 2 (2) Immune System Disorders Cytokine release syndrome 75 (91) 12 (15) Hypogammaglobulinemia k 13 (16) 1 (1) Infections and Infestations Other pathogen infections 35 (43) 21 (26) Viral infections 15 (18) 3 (4) Bacterial infections 11 (13) 5 (6) Fungal infections 8 (10) 0 Metabolism and Nutrition Disorders Decreased appetite 21 (26) 0 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain l 30 (37) 2 (2) Motor dysfunction m 27 (33) 5 (6) Nervous System Disorders Encephalopathy n 42 (51) 20 (24) Tremor 31 (38) 2 (2) Headache o 29 (35) 1 (1) Aphasia p 16 (20) 6 (7) Dizziness q 15 (18) 5 (6) Neuropathy r 11 (13) 2 (2) Psychiatric Disorders TECARTUS (brexucabtagene autoleucel) Page 20 of 44 Adverse Reaction Any Grade n (%) N = 82 Grade 3 or Higher n (%) N= 82 Insomnia 17 (21) 0 Delirium s 15 (18) 4 (5) Anxiety 14 (17) 0 Renal and Urinary Disorders Renal insufficiency t 16 (20) 6 (7) Urine output decreased u 9 (11) 1 (1) Respiratory, Thoracic and Mediastinal Disorders Hypoxia 33 (40) 16 (20) Cough v 32 (39) 0 Dyspnea w 21 (26) 5 (6) Pleural effusion 17 (21) 4 (5) Skin and Subcutaneous Tissue Disorders Rash x 18 (22) 3 (4) Vascular Disorders Hypotension y 47 (57) 23 (28) Hypertension 16 (20) 9 (11) Thrombosis z 14 (17) 3 (4) a.

Coagulopathy includes coagulopathy, disseminated intravascular coagulation, international normalised ratio increased. b. Tachycardias includes tachycardia, sinus tachycardia. c. Bradycardias includes bradycardia, sinus bradycardia. d. Non-ventricular arrhythmias includes atrial fibrillation, atrial flutter, cardiac flutter, palpitations, supraventricular tachycardia.

e. Oral pain includes oral pain, gingival pain, lip pain, oral mucosal erythema, oropharyngeal pain. f. Abdominal pain includes abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness. g. Vomiting includes vomiting, retching.

h. Fatigue includes fatigue, lethargy, malaise. i. Edema includes eyelid edema, face edema, generalised edema, localised edema, edema, edema peripheral, periorbital edema, peripheral […]

TECARTUS is contraindicated in patients who are hypersensitive to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

TECARTUS (brexucabtagene autoleucel) Page 5 of 44

Mantle cell lymphoma Tecartus is indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) after two or more lines of systemic therapy including a Bruton’s tyrosine kinase (BTK) inhibitor.

Acute lymphoblastic leukaemia Tecartus is indicated for the treatment of adult patients 26 years of age and above with relapsed or refractory B-cell precursor acute lymphoblastic leukaemia (ALL).

Tecartus must be administered in a qualified treatment centre by a physician with experience in the treatment of haematological malignancies and trained for administration and management of patients treated with Tecartus. At least 1 dose of tocilizumab for use in the event of cytokine release syndrome (CRS) and emergency equipment must be available prior to infusion.

The qualified 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 European Medicines Agency shortage catalogue, suitable alternative measures to treat CRS instead of tocilizumab must be available prior to infusion.

4). Mantle cell lymphoma Treatment consists of a single dose for infusion containing a dispersion for infusion of CAR-positive viable T cells in one infusion bag. The target dose is 2 × 106 CAR-positive viable T cells per kg of body weight (range: 1 × 106–2 × 106 cells/kg), with a maximum of 2 × 108 CAR-positive viable T cells for patients 100 kg and above.

Tecartus is recommended to be infused 3 to 14 days after completion of the lymphodepleting chemotherapy for MCL patients. e. date of product availability for shipment). Pre-treatment (lymphodepleting chemotherapy) for MCL patients • A lymphodepleting chemotherapy regimen consisting of cyclophosphamide 500 mg/m² intravenously and fludarabine 30 mg/m² intravenously must be administered prior to infusing Tecartus.

The recommended days are on the 5th, 4th, and 3rd day before infusion of Tecartus. Acute lymphoblastic leukaemia Treatment consists of a single dose for infusion containing a dispersion for infusion of CAR-positive viable T cells in one infusion bag.

The target dose is 1 × 106 CAR-positive viable T cells per kg of body weight, with a maximum of 1 × 108 CAR-positive viable T cells for patients 100 kg and above. Tecartus is recommended to be infused 2 to 14 days after completion of the lymphodepleting chemotherapy for ALL patients.

e. date of product availability for shipment). 4 Pre-treatment (lymphodepleting chemotherapy) for ALL patients A lymphodepleting chemotherapy regimen consisting of cyclophosphamide 900 mg/m2 intravenously over 60 minutes must be administered prior to infusing Tecartus.

This is recommended on the 2nd day before infusion of Tecartus. Fludarabine 25 mg/m2 intravenously over 30 minutes must be administered prior to infusing Tecartus. The recommended days are on the 4th, 3rd, and 2nd day before infusion of Tecartus.

5 to 25 mg intravenously or orally (or equivalent medicinal products) approximately 1 hour before the infusion of Tecartus. 5). Prophylactic use of systemic corticosteroids may be considered in patients at increased risk of severe immune-mediated adverse reactions, only if the potential benefit outweighs the risk and as guided by local institutional and/or national or European/international guidelines.

4- Reasons to delay treatment). Monitoring after infusion • Patients must be monitored daily for the first 7 days following infusion for signs and symptoms of potential CRS, neurologic events and other toxicities. Physicians can consider hospitalisation for the first 7 days or at the first signs or symptoms of CRS and/or neurologic events.

• After the first 7 days following the infusion, the patient is to be monitored at the physician’s discretion for at least an additional 7 days. • Patients must remain within proximity of a qualified treatment centre or appropriately trained clinical facility for at least 2 weeks following infusion.

Special populations Elderly No dose adjustment is required in patients ≥65 years of age. Patients seropositive for hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) There is no experience with manufacturing Tecartus for patients with a positive test for HIV, active HBV, or active HCV infection.

Therefore, the benefit/risk has not yet been established in this population. Paediatric population The safety and efficacy of Tecartus in children and adolescents aged less than 18 years have not yet been established. No data are available.

Method of administration Tecartus is for intravenous use only. Tecartus must not be irradiated. Do NOT use a leukodepleting filter. Before administration, it must be confirmed that the patient’s identity matches the unique patient information on the Tecartus infusion bag and cassette.

5 Administration • A leukodepleting filter must not be used. • Tocilizumab and emergency equipment must be available prior to infusion and during the monitoring period. In the exceptional case where tocilizumab is not available due to a shortage that is listed in the European Medicines Agency shortage catalogue, suitable alternative measures to treat CRS instead of tocilizumab must be available prior to infusion.

• For autologous use only, verify the patient ID to match the patient identifiers on the Tecartus infusion bag. • Once tubing has been primed, infuse the entire content of the Tecartus infusion bag within 30 minutes by either gravity or a peristaltic pump.

For detailed instructions on preparation, administration, accidental exposure and disposal of Tecartus, see section […]

5 × 106 anti-CD19 CAR T cells/kg) based on a recommended dose which was weight-based. The most significant and frequently occurring adverse reactions were CRS (91%), infections (55%) and encephalopathy (51%). Serious adverse reactions occurred in 56% of patients.

The most common serious adverse reactions included encephalopathy (26%), infections (28%) and cytokine release syndrome (15%). Grade 3 or higher adverse reactions were reported in 67% of patients. The most common Grade 3 or higher non-haematological adverse reactions included infections (34%) and encephalopathy (24%).

The most common Grade 3 or higher haematological adverse reactions included neutropenia (99%), leukopenia (98%), lymphopenia (96%), thrombocytopenia (65%) and anaemia (56%). 5 × 106, 1 × 106, or 2 × 106 anti-CD19 CAR T cells/kg) based on a recommended dose which was weight based.

The most significant and frequently occurring adverse reactions were CRS (91%), encephalopathy (57%), and infections (41%). Serious adverse reactions occurred in 70% of patients. The most common serious adverse reactions included CRS (25%), infections (22%) and encephalopathy (21%).

Grade 3 or higher adverse reactions were reported in 76% of patients. The most common Grade 3 or higher non-haematological adverse reactions included infections (27%), CRS (25%) and encephalopathy (22%). Tabulated list of adverse reactions Adverse reactions described in this section were identified in a total of 182 patients exposed to Tecartus in two multi-centre pivotal clinical studies, ZUMA-2 (n=82) and ZUMA-3 (n=100).

These reactions are presented by system organ class and by frequency. Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

11 Table 1 Adverse drug reactions identified with Tecartus System Organ Class (SOC) Frequency Adverse reactions Infections and infestations Very common Unspecified pathogen infections Bacterial infections Fungal infections Viral Infections Blood and lymphatic system disorders Very common Leukopeniaa Neutropeniaa Lymphopeniaa Thrombocytopeniaa Anaemiaa Febrile neutropenia Common Coagulopathy Immune system disorders Very common Cytokine Release Syndromeb Hypogammaglobulinaemia Common Hypersensitivity Haemophagocytic lymphohistiocytosis Metabolism and nutrition disorders Very common Hypophosphataemiaa Decreased appetite Hypomagnesaemia Hyperglycaemiaa Common Hypoalbuminemiaa Dehydration Psychiatric disorders Very common Delirium Anxiety Insomnia Nervous system disorders Very common Encephalopathy Tremor Headache Immune effector cell-associated neurotoxicity syndrome (ICANSb, c) Aphasia Dizziness Neuropathy Common Seizures, including status epilepticus Ataxia Increased intracranial pressure Eye Disorders Common Visual impairment Cardiac disorders Very common Tachycardias Bradycardias Common Non-ventricular arrhythmias Vascular disorders Very common Hypotension Hypertension Haemorrhage Common Thrombosis Respiratory, thoracic and mediastinal disorders Very common Cough Dyspnoea Pleural effusion 12 System Organ Class (SOC) Frequency Adverse reactions Hypoxia Common Respiratory failure Pulmonary oedema Gastrointestinal disorders Very common Nausea Diarrhoea Constipation Abdominal pain Vomiting Oral pain Common Dry mouth Dysphagia Skin and subcutaneous tissue disorders Very common Rash Skin disorder Musculoskeletal and connective tissue disorders Very common Musculoskeletal pain Motor dysfunction Renal and urinary disorders Very common Renal insufficiency Common Urine output decreased General disorders and administration site conditions Very common Oedema Fatigue Pyrexia Pain Chills Common Infusion related reaction Investigations Very common Alanine aminotransferase increaseda Blood uric acid increaseda Aspartate aminotransferase increaseda Hypocalcaemiaa Hyponatraemiaa Direct bilirubin increaseda Hypokalaemiaa Common Bilirubin increaseda Only cytopenias that resulted in (i) new or worsening clinical sequelae or (ii) that required therapy or (iii) adjustment in current therapy are included in Table 1.

a Frequency based on Grade 3 or higher laboratory parameter. b See section Description of selected adverse reactions. c The frequency of ICANS has been estimated from events reported in the post-marketing setting. ZUMA-2 data cutoff: 24 July 2021; ZUMA-3 data cutoff: 23 July 2021 Description of selected adverse reactions from ZUMA-2 and ZUMA-3 (n=182), and from post marketing reporting Cytokine release syndrome CRS occurred in 91% of patients.

Twenty percent (20%) of patients experienced Grade 3 or higher (severe or life-threatening) CRS. The median time to onset was 3 days (range: 1 to 13 days) and the median duration was 9 days (range: 1 to 63 days). Ninety-seven percent (97%) of patients recovered from CRS.

The most common signs or symptoms associated with CRS among the patients who experienced CRS included pyrexia (94%), hypotension (64%), hypoxia (32%), chills (31%), tachycardia (27%), sinus tachycardia (23%), headache (22%), fatigue (16%), and nausea (13%).

Serious adverse reactions that may be associated with CRS included hypotension (22%), pyrexia (15%), hypoxia (9%), tachycardia (3%), dyspnoea (2%) and sinus tachycardia (2%). 4 for monitoring and management guidance. 13 Neurologic events and adverse reactions Neurologic adverse reactions occurred in 69% […]

1. Contraindications of the lymphodepleting chemotherapy must be considered.

Mantle cell lymphoma Tecartus is indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) after two or more lines of systemic therapy including a Bruton’s tyrosine kinase (BTK) inhibitor.

Acute lymphoblastic leukaemia Tecartus is indicated for the treatment of adult patients 26 years of age and above with relapsed or refractory B-cell precursor acute lymphoblastic leukaemia (ALL).

Tecartus must be administered in a qualified treatment centre by a physician with experience in the treatment of haematological malignancies and trained for administration and management of patients treated with Tecartus. At least 1 dose of tocilizumab for use in the event of cytokine release syndrome (CRS) and emergency equipment must be available prior to infusion.

The qualified 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). Mantle cell lymphoma Treatment consists of a single dose for infusion containing a dispersion for infusion of CAR-positive viable T cells in one infusion bag. The target dose is 2 × 106 CAR-positive viable T cells per kg of body weight (range: 1 x 106–2 x 106 cells/kg), with a maximum of 2 × 108 CAR-positive viable T cells for patients 100 kg and above.

Tecartus is recommended to be infused 3 to 14 days after completion of the lymphodepleting chemotherapy for MCL patients. e. date of product availability for shipment). Pre-treatment (lymphodepleting chemotherapy) for MCL patients • A lymphodepleting chemotherapy regimen consisting of cyclophosphamide 500 mg/m² intravenously and fludarabine 30 mg/m² intravenously must be administered prior to infusing Tecartus.

The recommended days are on the 5th, 4th, and 3rd day before infusion of Tecartus. Acute lymphoblastic leukaemia Treatment consists of a single dose for infusion containing a dispersion for infusion of CAR-positive viable T cells in one infusion bag.

The target dose is 1 × 106 CAR-positive viable T cells per kg of body weight, with a maximum of 1 × 108 CAR-positive viable T cells for patients 100 kg and above. Tecartus is recommended to be infused 2 to 14 days after completion of the lymphodepleting chemotherapy for ALL patients.

e. date of product availability for shipment). Pre-treatment (lymphodepleting chemotherapy) for ALL patients A lymphodepleting chemotherapy regimen consisting of cyclophosphamide 900 mg/m2 intravenously over 60 minutes must be administered prior to infusing Tecartus.

This is recommended on the 2nd day before infusion of Tecartus. Fludarabine 25 mg/m2 intravenously over 30 minutes must be administered prior to infusing Tecartus. The recommended days are on the 4th, 3rd, and 2nd day before infusion of Tecartus.

5 to 25 mg intravenously or orally (or equivalent medicinal products) approximately 1 hour before the infusion of Tecartus. 5). Monitoring prior to infusion • In some patient groups at risk, a delay of the Tecartus infusion may be indicated (see section

8 Diagnosis of CRS requires excluding alternate causes of systemic inflammatory response, including infection. Management of cytokine release syndrome associated with Tecartus At least 1 dose per patient of tocilizumab, an interleukin-6 (IL-6) receptor inhibitor, must be on site and available for administration prior to Tecartus infusion.

The qualified 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.

The management of patients should be conducted based on the patient’s clinical presentation and in accordance with applicable local institutional and/or national or European/international clinical guidelines. Physicians are advised to exercise clinical judgment consistent with these standards.

, hepatic, renal, cardiac, and pulmonary). In addition, worsening of underlying organ pathologies can occur in the setting of CRS. Patients with medically significant cardiac dysfunction must be managed by standards of critical care and measures such as echocardiography is to be considered.

In some cases, macrophage activation syndrome (MAS) and haemophagocytic lymphohistiocytosis (HLH) may occur in the setting of CRS. Evaluation for haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) is to be considered in patients with severe or unresponsive CRS.

HLH/MAS should be managed per local institutional and/or national or European/international clinical guidelines. Tecartus continues to expand and persist following administration of tocilizumab and corticosteroids. Tumour necrosis factor (TNF) antagonists are not recommended for management of Tecartus-associated CRS.

Neurologic adverse reactions Severe neurologic adverse reactions, also known as immune effector cell-associated neurotoxicity syndrome (ICANS), have been observed in patients treated with Tecartus, which could be life-threatening or fatal.

8). The management of patients should be conducted based on the patient’s clinical presentation and in accordance with applicable local institutional and/or national or European/international clinical guidelines. Physicians are advised to exercise clinical judgment consistent with these standards.

8). Patients must be monitored for signs and symptoms of infection before, during and after infusion and treated appropriately. Prophylactic antibiotics must be administered according to standard institutional guidelines. 8) and may be concurrent with CRS.

In the event of febrile neutropenia, evaluate for infection and manage with broad spectrum antibiotics, fluids, and other supportive care as medically indicated. , HHV-6 and progressive multifocal leukoencephalopathy) have been reported.

The possibility of these infections should be considered in patients with neurologic events and appropriate diagnostic evaluations must be performed. g. Hepatitis B virus (HBV) reactivation, can occur in patients treated with medicinal products directed against B cells and could result in fulminant hepatitis, hepatic failure, and death.

Prolonged cytopenias Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and Tecartus infusion and must be managed according to standard guidelines. 8). Patient blood counts must be monitored after Tecartus infusion.

Hypogammaglobulinaemia B-cell aplasia leading to hypogammaglobulinaemia can occur in patients receiving treatment with Tecartus. 8). Hypogammaglobulinaemia predisposes patients to have infections. Immunoglobulin levels should be monitored after treatment with Tecartus and managed using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement in case of recurrent infections and must be taken according to standard guidelines.

Hypersensitivity reactions Serious hypersensitivity reactions including anaphylaxis, may occur due to DMSO or residual gentamicin in Tecartus. Secondary malignancies including of T cell and myeloid origin Patients treated with Tecartus may develop secondary malignancies.

T-cell malignancies have been reported following treatment of haematological malignancies with a BCMA- or CD19-directed CAR T-cell therapy. T-cell malignancies, including CAR-positive malignancies, have been reported within weeks and up to several years following administration of a CD19- or BCMA-directed CAR T-cell therapy.

There have been fatal outcomes. In the event that a secondary malignancy occurs, contact the company to obtain instructions on patient samples to collect for testing. Myelodysplastic syndrome and acute myeloid leukaemia, including cases with fatal outcomes, have occurred in patients following treatment with Tecartus.

Patients must be monitored life-long for secondary malignancies. Tumour lysis syndrome (TLS) TLS, which may be severe, has occasionally been observed. To minimise risk of TLS, patients with elevated uric acid or high tumour burden should receive […]

1. Contraindications of the lymphodepleting chemotherapy must be considered.