TECARTUS 0.4-2 x 10{8} CELULE DISPERSIE PERFUZABILA perfusable dispersion cells medication leaflet

Tecartus 0.4 - 2 × 108 cells dispersion for infusion

2.1 General description

Tecartus (brexucabtagene autoleucel) is a genetically modified autologous cell-based productcontaining T cells transduced ex vivo using a retroviral vector expressing an anti-CD19 chimericantigen receptor (CAR) comprising a murine anti-CD19 single chain variable fragment (scFv) linkedto CD28 co-stimulatory domain and CD3-zeta signalling domain.

2.2 Qualitative and quantitative composition

Each patient-specific infusion bag of Tecartus contains brexucabtagene autoleucel at a batch-dependent concentration of autologous T cells genetically modified to express an anti-CD19 chimericantigen receptor (CAR-positive viable T cells). The medicinal product is packaged in one infusion bagoverall containing a cell dispersion for infusion of a target dose of 2 × 106 anti-CD19 CAR-positiveviable T cells/kg body weight (range: 1 × 106 - 2 × 106 cells/kg), with a maximum of 2 × 108anti-CD19 CAR-positive viable T cells suspended in a Cryostor CS10 solution.

Each infusion bag contains approximately 68 mL of dispersion for infusion.

Acute lymphoblastic leukaemia

Each patient-specific infusion bag of Tecartus contains brexucabtagene autoleucel at a batch-dependent concentration of autologous T cells genetically modified to express an anti CD19 chimericantigen receptor (CAR-positive viable T cells). The medicinal product is packaged in one infusion bagoverall containing a cell dispersion for infusion of a target dose of 1 × 106 anti CD19 CAR positiveviable T cells/kg body weight, with a maximum of 1 × 108 anti CD19 CAR positive viable T cellssuspended in a Cryostor CS10 solution.

Each infusion bag contains approximately 68 mL of dispersion for infusion.

This medicinal product contains 300 mg sodium.

Each dose contains 0.05 mL of dimethyl sulfoxide (DMSO) per mL of Tecartus.

For the full list of excipients, see section 6.1.

Dispersion for infusion.

A clear to opaque, white to red dispersion.

Tecartus is indicated for the treatment of adult patients with relapsed or refractory mantle celllymphoma (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 orrefractory B-cell precursor acute lymphoblastic leukaemia (ALL).

Tecartus must be administered in a qualified treatment centre by a physician with experience in thetreatment of haematological malignancies and trained for administration and management of patientstreated 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 centremust have access to an additional dose of tocilizumab within 8 hours of each previous dose. In theexceptional 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 oftocilizumab must be available prior to infusion.

Tecartus is intended for autologous use only (see section 4.4).

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

Tecartus is recommended to be infused 3 to 14 days after completion of the lymphodepletingchemotherapy for MCL patients. The availability of the treatment must be confirmed prior to startingthe lymphodepleting regimen.

Pre-treatment (lymphodepleting chemotherapy) for MCL patients

* A lymphodepleting chemotherapy regimen consisting of cyclophosphamide 500 mg/m²intravenously 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-positiveviable T cells in one infusion bag. The target dose is 1 × 106 CAR-positive viable T cells per kg ofbody 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 lymphodepletingchemotherapy for ALL patients. The availability of the treatment must be confirmed prior to startingthe lymphodepleting regimen.

Pre-treatment (lymphodepleting chemotherapy) for ALL patients

A lymphodepleting chemotherapy regimen consisting of cyclophosphamide 900 mg/m2 intravenouslyover 60 minutes must be administered prior to infusing Tecartus. This is recommended on the 2nd daybefore infusion of Tecartus. Fludarabine 25 mg/m2 intravenously over 30 minutes must beadministered prior to infusing Tecartus. The recommended days are on the 4th, 3rd, and 2nd day beforeinfusion of Tecartus.

Mantle cell lymphoma and acute lymphoblastic leukaemia

Pre-medication

* To minimise potential acute infusion reactions, it is recommended that patients bepre-medicated with paracetamol 500 to 1,000 mg given orally and diphenhydramine 12.5 to25 mg intravenously or orally (or equivalent medicinal products) approximately 1 hour beforethe infusion of Tecartus.

* Prophylactic use of systemic corticosteroids is not recommended (see section 4.5).

Monitoring prior to infusion

* In some patient groups at risk, a delay of the Tecartus infusion may be indicated (seesection 4.4- Reasons to delay treatment).

Monitoring after infusion

* Patients must be monitored daily for the first 7 days following infusion for signs and symptomsof potential CRS, neurologic events and other toxicities. Physicians can consider hospitalisationfor 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’sdiscretion.

* Patients must remain within proximity of a qualified treatment centre for at least 4 weeksfollowing infusion.

No dose adjustment is required in patients ≥65 years of age.

Patients seropositive for hepatitis B virus (HBV), hepatitis C virus (HCV), or humanimmunodeficiency 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 thispopulation.

The safety and efficacy of Tecartus in children and adolescents aged less than 18 years have not yetbeen established. No data are available.

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 patientinformation on the Tecartus infusion bag and cassette.

* A leukodepleting filter must not be used.

* Tocilizumab and emergency equipment must be available prior to infusion and during themonitoring period. In the exceptional case where tocilizumab is not available due to a shortagethat is listed in the European Medicines Agency shortage catalogue, suitable alternativemeasures 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 Tecartusinfusion bag.

* Once tubing has been primed, infuse the entire content of the Tecartus infusion bag within30 minutes by either gravity or a peristaltic pump.

For detailed instructions on preparation, administration, accidental exposure and disposal of Tecartus,see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Contraindications of the lymphodepleting chemotherapy must be considered.

The traceability requirements of cell-based advanced therapy medicinal products must apply. Toensure traceability the name of the product, the batch number and the name of the treated patient mustbe kept for a period of 30 years.

Autologous use

Tecartus is intended solely for autologous use and must not, under any circumstances, be administeredto other patients. Before infusion, the patient’s identity must match the patient identifiers on the

Tecartus infusion bag and cassette. Do not infuse Tecartus if the information on the patient-specificcassette label does not match the intended patient’s identity.

Warnings and precautions of lymphodepleting chemotherapy must be considered.

Reasons to delay treatment

Due to the risks associated with Tecartus treatment, infusion must be delayed if a patient has any ofthe following conditions:

* Unresolved serious adverse reactions (especially pulmonary reactions, cardiac reactions, orhypotension) including from preceding chemotherapies.

* Active uncontrolled infection or inflammatory disease.

* Active graft-versus-host disease (GvHD).

In some cases, the treatment may be delayed after administration of the lymphodepletingchemotherapy regimen. If the infusion is delayed for more than 2 weeks after the patient has receivedthe lymphodepleting chemotherapy, lymphodepleting chemotherapy regimen must be administeredagain (see section 4.2)

Monitoring after infusion

Patients must be monitored daily for the first 7 days following infusion for signs and symptoms ofpotential CRS, neurologic events and other toxicities. Physicians can consider hospitalisation for thefirst 7 days or at the first signs or symptoms of CRS and/or neurologic events. After the first 7 daysfollowing infusion, the patient is to be monitored at the physician’s discretion.

Patients must remain within proximity of a qualified treatment centre for at least 4 weeks followinginfusion and seek immediate medical attention should signs or symptoms of CRS or neurologicaladverse reactions occur. Monitoring of vital signs and organ functions must be considered dependingon the severity of the reaction.

Serological testing

Screening for HBV, HCV, and HIV must be performed before collection of cells for manufacturing of

Tecartus (see section 4.2).

Blood, organ, tissue and cell donation

Patients treated with Tecartus must not donate blood, organs, tissues, or cells for transplantation.

Active central nervous system (CNS) lymphoma

There is no experience of use of this medicinal product in patients with active CNS lymphoma definedas brain metastases confirmed by imaging. In ALL, asymptomatic patients with a maximum of CNS-2disease (defined as white blood cells <5/µL in cerebral spinal fluid with presence of lymphoblasts)without clinically evident neurological changes were treated with Tecartus, however, data is limited inthis population. Therefore, the benefit/risk of Tecartus has not been established in these populations.

Concomitant disease

Patients with a history of or active CNS disorder or inadequate renal, hepatic, pulmonary, or cardiacfunction were excluded from the studies. These patients are likely to be more vulnerable to theconsequences of the adverse reactions described below and require special attention.

Cytokine release syndrome

Nearly all patients experienced some degree of CRS. Severe CRS, which can be fatal, was observedwith Tecartus with a median time to onset of 3 days (range: 1 to 13 days). Patients must be closelymonitored for signs or symptoms of these events, such as high fever, hypotension, hypoxia, chills,tachycardia and headache (see section 4.8). CRS is to be managed at the physician’s discretion, basedon the patient’s clinical presentation and according to the CRS management algorithm provided in

Table 1.

Diagnosis of CRS requires excluding alternate causes of systemic inflammatory response, includinginfection.

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 siteand available for administration prior to Tecartus infusion. The qualified treatment centre must haveaccess to an additional dose of tocilizumab within 8 hours of each previous dose. In the exceptionalcase where tocilizumab is not available due to a shortage that is listed in the European Medicines

Agency shortage catalogue, the treatment centre must have access to suitable alternative measuresinstead of tocilizumab to treat CRS.

Treatment algorithms have been developed to ameliorate some of the CRS symptoms experienced bypatients on Tecartus. These include the use of tocilizumab or tocilizumab and corticosteroids, assummarised in Table 1. Patients who experience Grade 2 or higher CRS (e.g. hypotension, notresponsive to fluids, or hypoxia requiring supplemental oxygenation) must be monitored withcontinuous cardiac telemetry and pulse oximetry. For patients experiencing severe CRS, considerperforming an echocardiogram to assess cardiac function. For severe or life-threatening CRS, considerintensive-care supportive therapy.

CRS has been known to be associated with end organ dysfunction (e.g., hepatic, renal, cardiac, andpulmonary). 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 careand measures such as echocardiography is to be considered. In some cases, macrophage activationsyndrome (MAS) and haemophagocytic lymphohistiocytosis (HLH) may occur in the setting of CRS.

Evaluation for haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) isto be considered in patients with severe or unresponsive CRS.

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.

Table 1 CRS grading and management guidance

CRS Grade (a) Tocilizumab Corticosteroids

Grade 1 If not improving after 24 hours, N/A

Symptoms require symptomatic administer tocilizumabtreatment only (e.g., fever, nausea, 8 mg/kg intravenously over 1 hourfatigue, headache, myalgia, (not to exceed 800 mg).malaise).

Grade 2 Administer tocilizumab (c) 8 mg/kg If no improvement within 24 hours

Symptoms require and respond to intravenously over 1 hour (not to after starting tocilizumab, managemoderate intervention. exceed 800 mg). as per Grade 3.

Oxygen requirement less than 40% Repeat tocilizumab every 8 hours If improving, taper corticosteroids,

FiO2 or hypotension responsive to as needed if not responsive to and manage as Grade 1.fluids or low-dose of one intravenous fluids or increasingvasopressor or Grade 2 organ supplemental oxygen. Limit to atoxicity (b). maximum of 3 doses in a 24 hourperiod; maximum total of 4 doses ifno clinical improvement in thesigns and symptoms of CRS, or ifno response to second orsubsequent doses of tocilizumab,consider alternative measures fortreatment of CRS.

If improving, discontinuetocilizumab.

Grade 3 Per Grade 2 Administer methylprednisolone

Symptoms require and respond to 1 mg/kg intravenously twice dailyaggressive intervention. or equivalent dexamethasone (e.g.,

Oxygen requirement greater than or 10 mg intravenously every 6 hours)equal to 40% FiO2 or hypotension until Grade 1, then taperrequiring high-dose or multiple corticosteroids.vasopressors or Grade 3 organ If improving, manage as Grade 2.toxicity or Grade 4 transaminitis. If not improving, manage as

Grade 4.

Grade 4 Per Grade 2 Administer methylprednisolone

Life-threatening symptoms. 1000 mg intravenously per day for

Requirements for ventilator support 3 days.or continuous veno-venous If improving, taper corticosteroids,haemodialysis or Grade 4 organ and manage as Grade 3.toxicity (excluding transaminitis). If not improving, consider alternateimmunosuppressants.

N/A = not available/not applicable(a) Lee et al 2014.(b) Refer to Table 2 for management of neurologic adverse reactions.(c) Refer to tocilizumab summary of product characteristics for details.

Neurologic adverse reactions

Severe neurologic adverse reactions, also known as immune effector cell-associated neurotoxicitysyndrome (ICANS), have been observed in patients treated with Tecartus, which could be life-threatening or fatal. The median time to onset was 7 days (range: 1 to 262 days) following Tecartusinfusion (see section 4.8).

Patients who experience Grade 2 or higher neurologic toxicity/ICANS must be monitored withcontinuous cardiac telemetry and pulse oximetry. Provide intensive-care supportive therapy for severeor life-threatening neurologic toxicity/ICANS. Non-sedating, anti-seizure medicines are to beconsidered as clinically indicated for Grade 2 or higher adverse reactions. Treatment algorithms havebeen developed to ameliorate the neurologic adverse reactions experienced by patients on Tecartus.

These include the use of tocilizumab (if concurrent CRS) and/or corticosteroids for moderate, severe,or life-threatening neurologic adverse reactions as summarised in Table 2.

Table 2 Neurologic adverse reaction/ICANS grading and management guidance

Grading Concurrent CRS No concurrent CRSassessment

Grade 2 Administer tocilizumab as per Table 1 for Administer dexamethasone 10 mgmanagement Grade 2 CRS. intravenously every 6 hours until the event is

If not improving within 24 hours after starting Grade 1 or less.tocilizumab, administer dexamethasone If improving, taper corticosteroids10 mg intravenously every 6 hours until theevent is Grade 1 or less, then tapercorticosteroids.

If improving, discontinue tocilizumab.

If still not improving, manage as Grade 3.

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

Grade 3 Administer tocilizumab as per Table 1 for Administer dexamethasone 10 mgmanagement of Grade 2 CRS. intravenously every 6 hours.

In addition, administer dexamethasone 10 mg Continue dexamethasone use until the event isintravenously with the first dose of Grade 1 or less, then taper corticosteroids.tocilizumab and repeat dose every 6 hours. If not improving, manage as Grade 4.

Continue dexamethasone use until the event is

Grade 1 or less, then taper corticosteroids.

If improving, discontinue tocilizumab andmanage as Grade 2.

If still not improving, manage as Grade 4.

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

Grade 4 Administer tocilizumab as per Table 1 for Administer methylprednisolone 1000 mgmanagement of Grade 2 CRS. intravenously per day for 3 days.

Administer methylprednisolone 1000 mg If improving, then manage as Grade 3.intravenously per day with first dose of If not improving, consider alternatetocilizumab and continue methylprednisolone immunosuppressants.1000 mg intravenously per day for 2 moredays.

If improving, then manage as Grade 3.

If not improving, consider alternateimmunosuppressants.

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

Infections and febrile neutropenia

Severe infections, which could be life-threatening, were very commonly observed with Tecartus (seesection 4.8).

Patients must be monitored for signs and symptoms of infection before, during and after infusion andtreated appropriately. Prophylactic antibiotics must be administered according to standard institutionalguidelines.

Febrile neutropenia has been observed in patients after Tecartus infusion (see section 4.8) and may beconcurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broadspectrum antibiotics, fluids, and other supportive care as medically indicated.

In immunosuppressed patients, life-threatening and fatal opportunistic infections includingdisseminated fungal infections and viral reactivation (e.g., HHV-6 and progressive multifocalleukoencephalopathy) have been reported. The possibility of these infections should be considered inpatients with neurologic events and appropriate diagnostic evaluations must be performed.

Viral reactivation, e.g. Hepatitis B virus (HBV) reactivation, can occur in patients treated withmedicinal products directed against B cells and could result in fulminant hepatitis, hepatic failure, anddeath.

Prolonged cytopenias

Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and

Tecartus infusion and must be managed according to standard guidelines. Grade 3 or higher prolongedcytopenias following Tecartus infusion occurred very commonly and included thrombocytopenia,neutropenia, and anaemia (see section 4.8). Patient blood counts must be monitored after Tecartusinfusion.

B-cell aplasia leading to hypogammaglobulinaemia can occur in patients receiving treatment with

Tecartus. Hypogammaglobulinaemia was very commonly observed in patients treated with Tecartus(see section 4.8). Hypogammaglobulinaemia predisposes patients to have infections. Immunoglobulinlevels should be monitored after treatment with Tecartus and managed using infection precautions,antibiotic prophylaxis, and immunoglobulin replacement in case of recurrent infections and must betaken according to standard guidelines.

Serious hypersensitivity reactions including anaphylaxis, may occur due to DMSO or residualgentamicin in Tecartus.

Secondary malignancies including of T cell origin

Patients treated with Tecartus may develop secondary malignancies. T-cell malignancies have beenreported 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 withinweeks and up to several years following administration of a CD19- or BCMA-directed CAR T-celltherapy. There have been fatal outcomes. Patients must be monitored life-long for secondarymalignancies. In the event that a secondary malignancy occurs, contact the company to obtaininstructions on patient samples to collect for testing.

TLS, which may be severe, has occasionally been observed. To minimise risk of TLS, patients withelevated uric acid or high tumour burden should receive allopurinol, or an alternative prophylaxis,prior to Tecartus infusion. Signs and symptoms of TLS must be monitored, and events managedaccording to standard guidelines.

Prior stem cell transplantation (GvHD)

It is not recommended that patients who underwent an allogeneic stem cell transplant and suffer fromactive acute or chronic GvHD receive treatment because of the potential risk of Tecartus worsening

GvHD.

Prior treatment with anti-CD19 therapy

Tecartus is not recommended if the patient has relapsed with CD19-negative disease after prioranti-CD19 therapy.

CD19-negative acute lymphoblastic leukaemia disease

Tecartus is not recommended for patients who have CD19-negative disease or an unconfirmed CD19status.

This medicinal product contains 300 mg sodium per infusion, equivalent to 15% of the WHOrecommended maximum daily intake of 2 g sodium for an adult.

Long-term follow up

Patients are expected to enrol in a registry in order to better understand the long-term safety andefficacy of Tecartus.

No interaction studies have been performed with Tecartus.

Prophylactic use of systemic corticosteroids may interfere with the activity of Tecartus. Prophylacticuse of systemic corticosteroids is therefore not recommended before infusion (see section 4.2).

Administration of corticosteroids as per the toxicity management guidelines does not impact theexpansion and persistence of CAR T cells.

Live vaccines

The safety of immunisation with live viral vaccines during or following Tecartus treatment has notbeen studied. As a precautionary measure, vaccination with live virus vaccines is not recommendedfor at least 6 weeks prior to the start of lymphodepleting chemotherapy, during Tecartus treatment, anduntil immune recovery following treatment.

The pregnancy status of women of childbearing potential must be verified before starting Tecartustreatment.

See the prescribing information for lymphodepleting chemotherapy for information on the need foreffective contraception in patients who receive the lymphodepleting chemotherapy.

There are insufficient exposure data to provide a recommendation concerning duration ofcontraception following treatment with Tecartus.

There are no available data with Tecartus use in pregnant women. No reproductive and developmentaltoxicity animal studies have been conducted with Tecartus to assess whether it can cause foetal harmwhen administered to a pregnant woman (see section 5.3).

It is not known if Tecartus has the potential to be transferred to the foetus. Based on the mechanism ofaction, if the transduced cells cross the placenta, they may cause foetal toxicity, including B-celllymphocytopenia. Therefore, Tecartus is not recommended for women who are pregnant, or forwomen of childbearing potential not using contraception. Pregnant women must be advised on thepotential risks to the foetus. Pregnancy after Tecartus therapy must be discussed with the treatingphysician.

Assessment of immunoglobulin levels and B-cells in newborn infants of mothers treated with Tecartusmust be considered.

It is unknown whether Tecartus is excreted in human milk or transferred to the breast-feeding child.

Breast-feeding women must be advised of the potential risk to the breast-fed child.

No clinical data on the effect of Tecartus on fertility are available. Effects on male and female fertilityhave not been evaluated in animal studies.

Tecartus has major influence on the ability to drive and use machines.

Due to the potential for neurologic events, including altered mental status or seizures, patients mustnot drive or operate heavy or potentially dangerous machines until at least 8 weeks after infusion oruntil resolution of neurologic adverse reactions.

The safety data described in this section reflect exposure to Tecartus in ZUMA-2, a Phase 2 study inwhich a total of 82 patients with relapsed/refractory MCL received a single dose of CAR-positiveviable T cells (2 × 106 or 0.5 × 106 anti-CD19 CAR T cells/kg) based on a recommended dose whichwas 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 reactionsincluded 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 orhigher 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%).

Acute lymphoblastic leukaemia

The safety data described in this section reflect exposure to Tecartus in ZUMA-3, a Phase 1/2 study inwhich a total of 100 patients with relapsed/refractory B-cell precursor ALL received a single dose of

CAR-positive viable T cells (0.5 × 106, 1 × 106, or 2 × 106 anti-CD19 CAR T cells/kg) based on arecommended 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 reactionsincluded CRS (25%), infections (22%) and encephalopathy (21%).

Grade 3 or higher adverse reactions were reported in 76% of patients. The most common Grade 3 orhigher non-haematological adverse reactions included infections (27%), CRS (25%) andencephalopathy (22%).

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

Table 3 Adverse drug reactions identified with Tecartus

System Organ Class (SOC) Frequency Adverse reactions

Very common Unspecified pathogen infections

Bacterial infections

Fungal infections

Viral Infections

Very common Leukopeniaa

Neutropeniaa

Lymphopeniaa

Thrombocytopeniaa

Anaemiaa

Common Coagulopathy

Very common Cytokine Release Syndromeb

Common Hypersensitivity

Haemophagocytic lymphohistiocytosis

Very common Hypophosphataemiaa

Decreased appetite

Hypomagnesaemia

Hyperglycaemiaa

Common Hypoalbuminemiaa

Very common Delirium

Anxiety

Insomnia

Very common Encephalopathy

Tremor

System Organ Class (SOC) Frequency Adverse reactions

Immune effector cell-associated neurotoxicitysyndrome (ICANSb, c)

Aphasia

Dizziness

Neuropathy

Common Seizure

Ataxia

Increased intracranial pressure

Very common Tachycardias

Bradycardias

Common Non-ventricular arrhythmias

Very common Hypotension

Common Thrombosis

Very common Cough

Pleural effusion

Hypoxia

Common Respiratory failure

Pulmonary oedema

Very common Nausea

Abdominal pain

Oral pain

Common Dry mouth

Dysphagia

Very common Rash

Skin disorder

Very common Musculoskeletal pain

Motor dysfunction

Very common Renal insufficiency

Common Urine output decreased

Very common Oedema

Chills

Common Infusion related reaction

Eye Disorders

Common Visual impairment

Very common Alanine aminotransferase increaseda

Blood uric acid increaseda

Aspartate aminotransferase increaseda

Hypocalcaemiaa

Hyponatraemiaa

Direct bilirubin increaseda

Hypokalaemiaa

Common Bilirubin increaseda

System Organ Class (SOC) Frequency Adverse reactions

Only cytopenias that resulted in (i) new or worsening clinical sequelae or (ii) that required therapy or (iii) adjustment incurrent therapy are included in Table 3.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 postmarketing 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 themedian duration was 9 days (range: 1 to 63 days). Ninety-seven percent (97%) of patients recoveredfrom CRS.

The most common signs or symptoms associated with CRS among the patients who experienced CRSincluded pyrexia (94%), hypotension (64%), hypoxia (32%), chills (31%), tachycardia (27%), sinustachycardia (23%), headache (22%), fatigue (16%), and nausea (13%). Serious adverse reactions thatmay be associated with CRS included hypotension (22%), pyrexia (15%), hypoxia (9%), tachycardia(3%), dyspnoea (2%) and sinus tachycardia (2%). See section 4.4 for monitoring and managementguidance.

Neurologic events and adverse reactions

Neurologic adverse reactions occurred in 69% of patients. Thirty-two percent (32%) of patientsexperienced Grade 3 or higher (severe or life-threatening) adverse reactions. The median time to onsetwas 7 days (range: 1 to 262 days). Neurologic events resolved for 113 out of 125 patients (90.4%)with a median duration of 12 days (range: 1 to 708 days). Three patients had ongoing neurologicevents at the time of death, including one patient with the reported event of serious encephalopathyand another patient with the reported event of serious confusional state. The remaining unresolvedneurologic events were Grade 2. Ninety-three percent of all treated patients experienced the first CRSor neurological event within the first 7 days after Tecartus infusion.

The most common neurologic adverse reactions including ICANS represented tremor (32%),confusional state (27%), encephalopathy (27%), aphasia (21%), and agitation (11%). Serious adversereactions including encephalopathy (15%), aphasia (6%), confusional state (5%) and serious cases ofcerebral oedema which may become fatal have occurred in patients treated with Tecartus. Seesection 4.4 for monitoring and management guidance.

Febrile neutropenia and infections

Febrile neutropenia was observed in 12% of patients after Tecartus infusion. Infections occurred in 87of the 182 patients treated with Tecartus in ZUMA-2 and ZUMA-3. Grade 3 or higher (severe,life-threatening or fatal) infections occurred in 30% of patients including unspecified pathogen,bacterial, fungal and viral infections in 23%, 8%, 2% and 4% of patients respectively. See section 4.4for monitoring and management guidance.

Prolonged cytopenias

Cytopenias are very common following prior lymphodepleting chemotherapy and Tecartus therapy.

Prolonged (present on or beyond Day 30 or with an onset at Day 30 or beyond) Grade 3 or highercytopenias occurred in 48% of patients and included neutropenia (34%), thrombocytopenia (27%) andanaemia (15%). See section 4.4 for management guidance.

Hypogammaglobulinaemia occurred in 12% of patients. Grade 3 or higher hypogammaglobulinemiaoccurred in 1% of patients. See section 4.4 for management guidance.

The immunogenicity of Tecartus has been evaluated using an enzyme-linked immunosorbent assay(ELISA) for the detection of binding antibodies against FMC63, the originating antibody of theanti-CD19 CAR. To date, no anti-CD19 CAR T-cell antibody immunogenicity has been observed in

MCL patients. Based on an initial screening assay, 17 patients in ZUMA-2 at any time point testedpositive for antibodies; however, a confirmatory orthogonal cell-based assay demonstrated that all 17patients in ZUMA-2 were antibody negative at all time points tested. Based on an initial screeningassay, 16 patients in ZUMA-3 tested positive for antibodies at any timepoint. Among patients withevaluable samples for confirmatory testing, two patients were confirmed to be antibody-positive aftertreatment. One of the two patients had a confirmed positive antibody result at Month 6. The secondpatient had a confirmed positive antibody result at retreatment Day 28 and Month 3. There is noevidence that the kinetics of initial expansion, CAR T-cell function and persistence of Tecartus, or thesafety or effectiveness of Tecartus, were altered in these patients.

Secondary malignancies

There have been cases of the following adverse effect(s) reported after treatment with other CAR T-cell products, which might also occur after treatment with Tecartus: secondary malignancy of T-cellorigin.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There are no data regarding the signs of overdose with Tecartus.

Pharmacotherapeutic group: Other antineoplastic agents, antineoplastic cell and gene therapy, ATCcode: L01XL06.

Tecartus, a CD19-directed genetically modified autologous T-cell immunotherapy, binds to CD19expressing cancer cells and normal B cells. Following anti-CD19 CAR T-cell engagement with CD19expressing target cells, the CD28 co-stimulatory domain and CD3-zeta signalling domain activatedownstream signalling cascades that lead to T-cell activation, proliferation, acquisition of effectorfunctions and secretion of inflammatory cytokines and chemokines. This sequence of events leads tokilling of CD19-expressing cells.

In both ZUMA-2 and ZUMA-3, after Tecartus infusion, pharmacodynamic responses were evaluatedover a 4-week interval by measuring transient elevation of cytokines, chemokines, and other moleculesin blood. Levels of cytokines and chemokines such as IL-6, IL-8, IL-10, IL-15, TNF-α,interferon-gamma (IFN-γ) and IL-2 receptor alpha were analysed. Peak elevation was generallyobserved within the first 8 days after infusion and levels generally returned to baseline within 28 days.

Due to the on target, off-tumour effect of Tecartus a period of B-cell aplasia may occur followingtreatment.

Translational analyses performed to identify associations between cytokine levels and incidence of

CRS or neurologic events showed that higher levels (peak and AUC at 1 month) of multiple serumanalytes, including IL-6, IL-10 and TNF-α, were associated with Grade 3 or higher neurologic adversereactions and Grade 3 or higher CRS.

Relapsed or refractory MCL: ZUMA-2

The efficacy and safety of Tecartus in adult patients with relapsed or refractory MCL who hadpreviously received anthracycline or bendamustine-containing chemotherapy, an anti CD20 antibody,and a Bruton’s tyrosine kinase inhibitor (BTKi) (ibrutinib or acalabrutinib), was evaluated in a phase 2single-arm, open-label, multi-centre trial. Eligible patients also had disease progression after lastregimen or refractory disease to the most recent therapy. Patients with active or serious infections,prior allogeneic haematopoietic stem cell transplantation (HSCT), detectable cerebrospinal fluidmalignant cells or brain metastases, and any history of CNS lymphoma or CNS disorders wereineligible. In ZUMA-2, a total of 74 patients were enrolled (i.e. leukapheresed) and 68 of thesepatients were treated with Tecartus. Three patients did not receive Tecartus due to manufacturingfailure. Two other patients were not treated due to progressive disease (death) following leukapheresis.

One patient was not treated with Tecartus after receiving lymphodepleting chemotherapy due toongoing active atrial fibrillation. The full analysis set (FAS) was defined as all patients who underwentleukapheresis. A summary of the patient baseline characteristics is provided in Table 4.

Table 4 Summary of baseline characteristics for ZUMA-2

Category All leukapheresed (FAS)(N=74)

Age (years)

Median (min, max) 65 (38, 79)≥ 65 58%

Male gender 84%

Median number of prior therapies (min, max) 3 (1; 5)

Relapsed/refractory subgroup

Relapsed after auto-SCT 42%

Refractory to last MCL therapy 39%

Relapsed after last MCL therapy 19%

Patients with disease stage IV 86%

Patients with bone marrow involvement 51%

Morphological characteristic

Classical MCL 54%

Blastoid MCL 26%

Other 1%

Unknown 19%

Received bridging therapy

Yes 38%

No 62%

Category All leukapheresed (FAS)(N=74)

Ki-67 IHC by central laboratory

N 49

Median 65%

Auto-SCT, autologous stem cell transplant; IHC, immunohistochemistry; Max, maximum; MCL, mantle cell lymphoma;

Min, minimum.

Tecartus was administered to patients as a single intravenous infusion at a target dose of2 × 106 anti-CD19 CAR T cells/kg (maximum permitted dose: 2 × 108 cells) after lymphodepletingchemotherapy regimen of cyclophosphamide 500 mg/m² intravenously and fludarabine 30 mg/m²intravenously, both given on the 5th, 4th, and 3rd day before treatment. Bridging therapy betweenleukapheresis and lymphodepleting chemotherapy was permitted to control disease burden.

For patients treated with Tecartus, the median time from leukapheresis to product release was 13 days(range: 9 to 20 days) and the median time from leukapheresis to Tecartus infusion was 27 days (range:19 to 74 days, with the exception of one outlier of 134 days). The median dose was2.0 × 106 anti-CD19 CAR T cells/kg. All patients received Tecartus infusion on day 0 and werehospitalized until day 7 at the minimum.

The primary endpoint was objective response rate (ORR) as determined by Lugano 2014 criteria by anindependent review committee. Secondary endpoints included duration of response (DOR), overallsurvival (OS), progression free survival (PFS) and severity of adverse events.

For the primary analysis, the analysis set was defined a priori which consisted of the first 60 patientstreated with Tecartus who were evaluated for response 6 months after the Week 4 disease assessmentafter Tecartus infusion. In this analysis set of 60 patients the ORR was 93% with a CR rate of 67%.

The ORR was significantly higher than the prespecified historical control rate of 25% at a 1-sidedsignificance level of 0.025 (p < 0.0001).

The updated 24-month follow-up analyses of efficacy were conducted using the modified intent totreat (mITT) analysis set, which consisted of 68 patients treated with Tecartus. In the 24-month followup analysis, the ORR and CR rates in the 68 patients in the mITT analysis set were 91% and 68%respectively.

Results in the FAS from both the primary analysis and 24-month follow-up analysis are shown in

Table 5.

Table 5 Summary of efficacy results for ZUMA-2

Category All leukapheresed a(FAS)(N = 74)

Primary Analysis 24-month Follow-Up

Objective response rate (ORR), n (%) 62 (84%) [73.4, 91.3] 62 (84%) [73.4, 91.3][95% CI]

CR n (%) [95% CI] 44 (59%) [47.4, 70.7] 46 (62%) [50.1, 73.2]

PR n (%) [95% CI] 18 (24%) [15.1, 35.7] 16 (22%)[12.9, 32.7]

Duration of response (DOR)b

Median in months [95% CI] NR [10.4, NE] 28.2 (13.5, 47.1)

Range c in months 0.0+, 35.0+ 0.0+, 53.0+

Ongoing responses, CR+PR, CR, n (%) d 32 (43%), 30 (41%) 25 (34%), 25 (34%)

Progression free survival

Median, months [95% CI] 16.2 [9.9, NE] 24.0 (10.1, 48.2)

CI, confidence interval; CR, complete remission; FAS, full analysis set;; NE, not estimable; NR, not reached; PR, partialremission.

Category All leukapheresed a(FAS)(N = 74)

Primary Analysis 24-month Follow-Up

Objective response rate (ORR), n (%) 62 (84%) [73.4, 91.3] 62 (84%) [73.4, 91.3][95% CI]a Of the 74 patients that were enrolled (i.e. leukapheresed), 69 patients received lymphodepleting chemotherapy, and68 patients received Tecartus.b Among all responders. DOR is measured from the date of first objective response to the date of progression or death.c A + sign indicates a censored value.d At the data cutoff date. Percentages are calculated using the total number of patients in the analysis set as thedenominator.

Figure 1 Kaplan Meier DOR in the FAS

The European Medicines Agency has waived the obligation to submit the results of studies with

Tecartus in all subsets of the paediatric population in treatment of MCL (see section 4.2 forinformation on paediatric use).

Relapsed or refractory B-cell precursor ALL: ZUMA-3

A Phase 2, open-label, multicenter trial evaluated the efficacy and safety of Tecartus in adult patientswith relapsed or refractory B-precursor ALL. Relapsed or refractory was defined as one of thefollowing: primary refractory; first relapse following a remission lasting ≤ 12 months; relapsed orrefractory after second-line or higher therapy; relapsed or refractory after allogeneic stem celltransplant (allo-SCT) (provided the transplant occurred ≥ 100 days prior to enrollment and that noimmunosuppressive medications were taken ≤ 4 weeks prior to enrollment). The study excludedpatients with active or serious infections, active graft-vs-host disease, and any history of CNSdisorders. Patients with CNS-2 disease without clinically evident neurologic changes were eligible. In

ZUMA-3 Phase 2, a total of 71 patients were enrolled (i.e. leukapheresed) and 55 patients were treatedwith Tecartus. Six patients did not receive Tecartus due to manufacturing failure. Eight other patientswere not treated, primarily due to AEs following leukapheresis. Two patients who underwentleukapheresis and received lymphodepleting chemotherapy were not treated with Tecartus; one patientexperienced bacteremia and neutropenic fever and the other patient did not meet eligibility criteriaafter lymphodepleting chemotherapy. The FAS included all patients who underwent leukapheresis andthe modified intent to treat (mITT) analysis set includes all patients leukapheresed and treated with

Tecartus in Phase 2. A summary of patient baseline characteristics is provided in Table 6.

Table 6 Summary of baseline characteristics for ZUMA-3 Phase 2

Category All leukapheresed (FAS) All treated (mITT)(N=71) (N=55)

Age (years)

Median (min, max) 44 (19 to 84) 40 (19 to 84)

Male gender 58% 60%

White ethnicity 72% 67%

Primary refractory disease 30% 33%

Relapsed/refractory disease after 76% 78%≥ 2 lines of therapy

First relapse if first remission ≤ 28% 29%12 months

Number of Lines of Prior Therapy

Median (min, max) 2 (1 to 8) 2 (1 to 8)≥ 3 48% 47%

Prior Therapies

Allo-SCT 39% 42%

Blinatumomab 46% 45%

Inotuzumab 23% 22%

Philadelphia chromosome (Ph+) 27% 27%

Allo-SCT, allogenic stem cell transplant; Max, maximum; Min, minimum

Following lymphodepleting chemotherapy, Tecartus was administered to patients as a singleintravenous infusion at a target dose of 1 × 106 anti-CD19 CAR T cells/kg (maximum permitted dose:1 × 108 cells). The lymphodepleting regimen consisted of cyclophosphamide 900 mg/m2 intravenouslyover 60 mins on the 2nd day before Tecartus infusion and fludarabine 25 mg/m2 intravenously over 30mins on the 4th, 3rd, and 2nd day before Tecartus infusion. Of the 55 patients who received Tecartus, 51patients received bridging therapy between leukapheresis and lymphodepleting chemotherapy tocontrol disease burden.

The median time from leukapheresis to product delivery was 16 days (range: 11 to 42 days) and themedian time from leukapheresis to Tecartus infusion was 29 days (range: 20 to 60 days). The mediandose was 1.0 × 106 anti-CD19 CAR T cells/kg. All patients received Tecartus infusion on day 0 andwere hospitalized until day 7 at the minimum.

The primary endpoint was overall complete remission rate (OCR) (complete remission [CR] +complete remission with incomplete hematologic recovery [CRi]) in patients treated with Tecartus asdetermined by an independent review. In the 55 patients treated with Tecartus (mITT), the OCR ratewas 70.9% with a CR rate of 56.4% (Table 7), which was significantly greater than the prespecifiedcontrol rate of 40%. Among the 39 patients who achieved a CR or CRi, the median time to responsewas 1.1 months (range: 0.85 to 2.99 months).

All treated patients had potential follow-up for ≥ 18 months with a median follow-up time of 20.5months (95% CI: 0.3, 32.6 months) and a median follow-up time for OS of 24.0 months (95% CI:23.3, 24.6).

Table 7 Summary of efficacy results for ZUMA3 Phase 2

FAS mITTa

N = 71 N = 55

OCR rate (CR + CRi) n (%) [95% CI] 39 (54.9) [43, 67] 39 (70.9) [57.0,82.0]

CR rate, n (%) [95% CI] 31 (43.7) [32, 56] 31 (56.4) [42.0,70.0]

Minimal Residual Disease (MRD) negative rate n = 39 n = 39among OCR (CR or CRi) patients, n (%) 38 (97%) 38 (97%)

Duration of Remission, median in months [95% CI] b 14.6 [9.4, NE]c 14.6 [9.4, NE]c

Median range in months (0.03+, 24.08+) (0.03+, 24.08+)

CI, confidence interval; CR, complete remission; NE, not estimable

a. Of the 71 patients that were enrolled (and leukapheresed), 57 patients received conditioning chemotherapy, and 55patients received Tecartus.

b. Subjects were censored at their last evaluable disease assessment before initiation of a new anticancer therapy(excluding resumption of a tyrosine kinase inhibitor) or allo-SCT to exclude any contribution that the new therapymight have on DOR that could confound the contribution of KTE-X19. The results of the analyses that did not censorfor subsequent allo-SCT or the initiation of new anti-cancer therapy were consistent with the analyses that did censorthe events.

c. The duration of remission was defined only for subjects achieving an OCR, therefore the results of the analysis in the

FAS and mITT were identical.

Figure 2 Kaplan Meier DOR in the mITT Analysis Seta

a. The DOR was defined only for subjects achieving an OCR, therefore the results of the analysis in the FAS and mITTwere identical.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Tecartus in one or more subsets of the B-cell ALL paediatric population and waived the obligation tosubmit the results of studies with Tecartus for the treatment of ALL in the paediatric populationweighing less than 6kg. See section 4.2 for information on paediatric use.

Conditional Approval

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme.

This means that further evidence on this medicinal product is awaited in both the MCL and ALLpatient population.

The European Medicines Agency will review new information on this medicinal product at least everyyear and this SmPC will be updated as necessary.

Cellular kinetics

Following infusion of 2 × 106 anti-CD19 CAR T cells/kg of Tecartus in ZUMA-2, anti-CD19 CAR

T cells exhibited an initial rapid expansion followed by a decline to near baseline levels by 3 months.

Peak levels of anti-CD19 CAR T cells occurred within the first 7 to 15 days after the infusion.

Among patients with MCL, the number of anti-CD19 CAR T cells in blood was associated withobjective response (CR or PR) (Table 8).

Table 8 Summary of brexucabtagene autoleucel pharmacokinetics in ZUMA-2

Number of anti-CD19 CAR T cell Responding patients Non-responding patients P-Value(CR or PR)(N=63) (N=5)

Peak (cells/μL) 97.52 [0.24, 2 589.47], 62 0.39 [0.16, 22.02], 5 0.0020

Median [min; max], n

AUC0-28 (cells/μL·day) 1 386.28 [3.83 to 5.51 [1.81, 293.86], 5 0.0013

Median [min; max], n 2.77 × 104], 62

P-value is calculated by Wilcoxon test

Median peak anti-CD19 CAR T-cell values were 74.08 cells/μL in MCL patients ≥65 years of age(n=39) and 112.45 cells/μL in MCL patients <65 years of age (n=28). Median anti-CD19 CAR T-cell

AUC values were 876.48 cells/μL∙day in MCL patients ≥65 years of age and 1 640.21 cells/μL∙day in

MCL patients <65 years of age.

Acute lymphoblastic leukaemia

Following infusion of a target dose of 1 × 106 anti-CD19 CAR T cells/kg of Tecartus in ZUMA-3(Phase 2), anti-CD19 CAR T cells exhibited an initial rapid expansion followed by a decline to nearbaseline levels by 3 months. Median time to peak levels of anti-CD19 CAR T cells was within the first15 days after Tecartus infusion.

A summary of the Tecartus pharmacokinetics over time, based on central assessment by overallresponse, is provided in Table 9.

Table 9 Summary of brexucabtagene autoleucel pharmacokinetics in ZUMA-3 Phase 2

Number of anti-CD19 CAR Patients with overall Patients with non- P-Value

T cell complete remission (CR/CRi) complete remissiona(N=39) (N=16)

Peak (cells/μL) 38.35 [1.31, 1 533.4], 0.49 [0.00, 183.50], 0.0001c

Median [min; max], n 36b 14b

AUC0-28 (cells/μL·day) 424.03 [14.12 to 19 390.42], 4.12 [0.00, 642.25], 0.0001c

Median [min; max], n 36b 14b

a. Three of 39 subjects who achieved CR or CRi and 2 of 16 subjects who were non-CR/CRi had no anti-CD19 CAR T-cell data at any postinfusion visit.

b. Noncomplete remission includes all non-CR/CRi subjects whose response is classified incomplete remission responsewith partial hematologic recovery, blast-free hypoplastic or aplastic bone marrow (N = 4), partial response (N = 0),no response (N = 9), or not evaluable (N = 3).

c. .Pvalue is calculated by Wilcoxon test

Median peak anti-CD19 CAR T-cell values were 34.8 cells/μL in ALL patients ≥65 years of age (n=8)and 17.4 cells/μL in ALL patients <65 years of age (n=47). Median anti-CD19 CAR T-cell AUCvalues were 425.0 cells/μL∙day in ALL patients ≥65 years of age and 137.7 cells/μL∙day in ALLpatients <65 years of age.

In MCL and ALL patients, gender had no significant impact on AUCDay 0-28 and Cmax of Tecartus.

Studies of Tecartus in patients with hepatic and renal impairment were not conducted.

Tecartus comprises engineered human T cells; therefore, there are no representative in vitro assays,ex vivo models, or in vivo models that can accurately address the toxicological characteristics of thehuman product. Hence, traditional toxicology studies used for medicinal product development werenot performed.

No carcinogenicity or genotoxicity studies have been conducted.

No studies have been conducted to evaluate the effects of this treatment on fertility, reproduction, anddevelopment.

Cryostor CS10 (contains DMSO)

Sodium chloride

Human albumin

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

1 year.

Tecartus is stable at room temperature (20 °C to 25 °C) for up to 3 hours after thawing. However,

Tecartus infusion must begin within 30 minutes of thaw completion and the total infusion time shouldnot exceed 30 minutes.

Tecartus must be stored in the vapour phase of liquid nitrogen (≤ − 150 °C) and must remain frozenuntil the patient is ready for treatment to ensure viable live autologous cells are available for patientadministration. Thawed product must not be refrozen.

For storage conditions after thawing of the medicinal product, see section 6.3.

implantation

Ethylene-vinyl acetate cryostorage bag with sealed addition tube and two available spike ports,containing approximately 68 mL of cell dispersion.

One cryostorage bag is individually packed in a shipping metal cassette.

Irradiation could lead to inactivation of the product.

Tecartus must be transported within the facility in closed, break-proof, leak-proof containers.

This medicinal product contains human blood cells. Healthcare professionals handling Tecartus musttake appropriate precautions (wearing gloves and eye protection) to avoid potential transmission ofinfectious diseases.

Preparation prior to administration

* Verify that the patient’s identity (ID) matches the patient identifiers on the Tecartus metalcassette.

* The Tecartus infusion bag must not be removed from the metal cassette if the information on thepatient-specific label does not match the intended patient.

* Once the patient ID is confirmed, remove the infusion bag from the metal cassette.

* Check that the patient information on the metal cassette label matches that on the infusion baglabel.

* Inspect the infusion bag for any breaches of container integrity before thawing. If the infusionbag is compromised, follow the local guidelines for handling of waste of human derivedmaterial (and immediately contact Kite).

Thawing

* Place the infusion bag inside a second bag.

* Thaw Tecartus at approximately 37 °C using either a water bath or dry thaw method until thereis no visible ice in the infusion bag. Gently mix the contents of the infusion bag to disperseclumps of cellular material. If visible cell clumps remain, continue to gently mix the contents ofthe infusion bag. Small clumps of cellular material should disperse with gentle manual mixing.

Tecartus must not be washed, spun down, and/or re-suspended in new media prior to infusion.

Thawing should take approximately 3 to 5 minutes.

* Once thawed, Tecartus is stable at room temperature (20 °C - 25 °C) for up to 3 hours.

However, Tecartus infusion must begin within 30 minutes of thaw completion.

* For autologous single use only.

* Tocilizumab and emergency equipment must be available prior to infusion and during themonitoring period. In the exceptional case where tocilizumab is not available due to a shortagethat is listed in the European Medicines Agency shortage catalogue, suitable alternativemeasures to treat CRS instead of tocilizumab must be available prior to infusion.

* A leukodepleting filter must not be used.

* Central venous access is recommended for the administration of Tecartus.

* Verify the patient ID again to match the patient identifiers on the Tecartus infusion bag.

* Prime the tubing with sodium chloride 9 mg/mL (0.9%) solution for injection (0.154 mmolsodium per mL) prior to infusion.

* Infuse the entire content of the Tecartus infusion bag within 30 minutes by either gravity or aperistaltic pump.

* Gently agitate the infusion bag during infusion to prevent cell clumping.

* After the entire content of the infusion bag is infused, rinse the tubing at the same infusion ratewith sodium chloride 9 mg/mL (0.9%) solution for injection (0.154 mmol sodium per mL) toensure all the treatment is delivered.

Precautions to be taken for the disposal of the medicinal product

Unused medicinal product and all material that has been in contact with Tecartus (solid and liquidwaste) must be handled and disposed of as potentially infectious waste in accordance with localguidelines on the handling of waste of human-derived material.

Accidental exposure

In case of accidental exposure to Tecartus local guidelines on handling of human-derived materialmust be followed. Work surfaces and materials which have potentially been in contact with Tecartusmust be decontaminated with appropriate disinfectant.

Kite Pharma EU B.V.

Tufsteen 12132 NT Hoofddorp

The Netherlands

EU/1/20/1492/001

Date of first authorisation: 14 December 2020

Date of latest renewal: 26 February 2025

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.