Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Atara Biotherapeutics Ireland Ltd, 10 Earlsfort Terrace, Dublin 2, D02 T380, Ireland
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
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.
TFR has occurred with Ebvallo use, generally within the first few days after receiving treatment. TFR presents as an acute inflammatory reaction involving tumour sites which may include a sudden and painful increase in the tumour size or enlargement of disease-involved lymph nodes. TFR may mimic progression of disease.
Patients with high tumour burden prior to treatment are at risk of severe TFR. Depending on the location of the tumour or lymphadenopathy, complications (e.g. respiratory distress and cognitive disorders) may arise from mass effect, including compression/obstruction of adjacent anatomic structures. Analgesics, non-steroidal anti-inflammatory drugs (NSAIDs) or localised radiotherapy could be considered prior to Ebvallo administration for those patients in whom the location of the tumour could potentially lead to complications. Patients should be closely monitored for signs and symptoms of TFR, especially during the first cycle.
GvHD has been reported after treatment with Ebvallo. This could be related to the decrease or discontinuation of immunosuppressive therapies for the treatment of PTLD rather than to a direct action of Ebvallo. The benefit of treatment with Ebvallo versus the risk of possible GvHD should be considered. Patients should be monitored for signs and symptoms of GvHD, such as skin rash, abnormal liver enzymes in the blood, jaundice, nausea, vomiting, diarrhoea and bloody stools.
Solid organ transplant rejection has been reported after treatment with Ebvallo. Treatment with Ebvallo may increase the risk of rejection in solid organ transplant recipients. This could be related to the decrease or discontinuation of immunosuppressive therapies for the treatment of PTLD rather than to a direct action of Ebvallo. The benefit of treatment with Ebvallo versus the risk of possible solid organ transplant rejection should be considered prior to the start of treatment. Patients should be monitored for signs and symptoms of solid organ transplant rejection.
There is a potential risk of bone marrow transplant rejection based on humoral or cell-mediated immune reactions. No event of bone marrow transplant rejection has been reported in clinical studies. Patients should be monitored for signs and symptoms of bone marrow transplant rejection.
CRS has been reported after treatment with Ebvallo. Patients should be monitored for signs and symptoms of CRS, such as pyrexia, chills, hypotension and hypoxia. Diagnosis of CRS requires excluding alternate causes of systemic inflammatory response, including infection. CRS should be managed at the physician’s discretion, based on the patient’s clinical presentation.
ICANS has been reported after treatment with Ebvallo. Patients should be monitored for signs and symptoms of ICANS, such as depressed level of consciousness, confusion, seizures and cerebral oedema. Diagnosis of ICANS requires excluding alternate causes.
After injection of Ebvallo, infusion-related reactions such as pyrexia and non-cardiac chest pain have been reported. Patients should be monitored for at least 1 hour after treatment for signs and symptoms of infusion-related reactions.
Serious hypersensitivity reactions, including anaphylaxis, may occur due to dimethyl sulfoxide (DMSO) in Ebvallo.
Ebvallo is obtained from human donor blood cells. Donors are screened and have tested negative for relevant communicable disease agents and diseases, including HBV, HCV and HIV. Although tabelecleucel lots are tested for sterility, mycoplasma and adventitious agents, a risk of transmission of infectious agents exists.
Some tabelecleucel lots are manufactured from donors who are cytomegalovirus (CMV) positive. All lots are tested to ensure no detection of adventitious agents, including CMV. During clinical development, tabelecleucel lots derived from CMV-positive donors were administered to CMVnegative patients when an appropriate lot derived from a CMV-seronegative donor was unavailable; in this subpopulation no seroconversions were observed.
Healthcare professionals administering Ebvallo must, therefore, monitor patients for signs and symptoms of infections after treatment and treat appropriately, if needed.
Patients treated with Ebvallo must not donate blood, organs, tissues and cells for transplantation.
This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially ‘sodiumfree’.
There are only limited data available for the elderly population. Based on available data, the elderly population (≥65 years of age) may be at increased risk of serious adverse events leading to hospitalisation/prolonged hospitalisation, psychiatric disorders, vascular disorders, and infections and infestations. Ebvallo should be used with caution in elderly patients.
No interaction studies have been performed.
Certain concomitant or recently administered medicinal products including chemotherapy (systemic or intrathecal), anti-T-cell antibody-based therapies, extracorporeal photopheresis or brentuximab vedotin could potentially impact the efficacy of Ebvallo. Ebvallo should only be administered after an adequate washout period of such agents.
For patients receiving chronic corticosteroid therapy, the dose of these drugs should be reduced as much as is clinically safe and appropriate; recommended no greater than 1 mg/kg per day of prednisone or equivalent. Ebvallo has not been evaluated in patients receiving corticosteroid doses greater than 1 mg/kg per day of prednisone or equivalent.
In clinical studies, patients received ciclosporin, tacrolimus, sirolimus and other immunosuppressive therapies at the lowest dose considered clinically safe and appropriate.
Because in vitro characterisation data demonstrated the absence of CD20 expression on tabelecleucel, it is not expected that anti-CD20 antibody treatments will affect tabelecleucel activity
There are no available data with tabelecleucel use in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with tabelecleucel. It is not known if tabelecleucel has the potential to be transferred to the foetus or can cause foetal harm when administered to a pregnant woman. Ebvallo is not recommended during pregnancy and in women of childbearing potential not using contraception. Pregnant women should be advised on potential risks for the foetus.
There are insufficient exposure data to provide a recommendation concerning duration of contraception following treatment with Ebvallo.
It is unknown whether tabelecleucel is excreted in human milk. A risk to the newborns/infants cannot be excluded. Breast-feeding women should be advised of potential risks to the breast-fed child. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from tabelecleucel therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
There are no data on the effect of tabelecleucel on fertility.
Ebvallo has minor influence on the ability to drive and use machines, e.g. dizziness, fatigue (see section 4.8).
The most common adverse reactions were pyrexia (31.1%), diarrhoea (26.2%), fatigue (23.3%), nausea (18.4%), anaemia (16.5%), decreased appetite (15.5%), hyponatraemia (15.5%), abdominal pain (14.6%), neutrophil count decreased (14.6%), white blood cell count decreased (14.6%), aspartate aminotransferase increased (13.6%), constipation (12.6%), alanine aminotransferase increased (11.7%), blood alkaline phosphatase increased (11.7%), hypoxia (11.7%), dehydration (10.7%), hypotension (10.7%), nasal congestion (10.7%) and rash (10.7%). The most serious adverse reactions were tumour flare reaction (1%) and graft-versus-host disease (4.9%).
The safety database is comprised of data from 340 patients (EBV+ PTLD and other EBV-associated diseases) from clinical studies, an expanded access protocol, and compassionate use requests. Frequencies of adverse reactions were calculated in 103 patients from the ALLELE study and Study EBV-CTL-201 for which all events (serious and non-serious) were collected. In the rest of the clinical development program, only serious events were collected. Adverse reactions reported from clinical trials are presented below in Table 2. 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); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).
Table 2. Adverse reactions identified with Ebvallo:
| System organ class (SOC) | Adverse reaction | Frequency |
|---|---|---|
| Infections and infestations | Upper respiratory tract infection Skin infection | Common Common |
| Neoplasms benign, malignant and unspecified (including cysts and polyps) | Tumour pain Tumour flare reaction | Common Common |
| Blood and lymphatic system disorders | Anaemia Febrile neutropenia | Very common Common |
| Immune system disorders | Graft-versus-host diseasea | Common |
| Metabolism and nutrition disorders | Decreased appetite Hyponatraemia Dehydration Hypomagnesaemia Hypokalaemia Hypocalcaemia | Very common Very common Very common Common Common Common |
| Psychiatric disorders | Confusional state Delirium Disorientation | Common Common Common |
| Nervous system disorders | Dizziness Headache Depressed level of consciousness Somnolence Peripheral sensory neuropathy | Common Common Common Common Common |
| Cardiac disorders | Tachycardia | Common |
| Vascular disorders | Hypotension Hot flush Cyanosis | Very common Common Common |
| Respiratory, thoracic and mediastinal disorders | Hypoxia Nasal congestion Wheezing Pneumonitis Upper-airway cough syndrome Pulmonary haemorrhage | Very common Very common Common Common Common Common |
| Gastrointestinal disorders | Diarrhoea Nausea Abdominal painb Constipation Colitis Abdominal distension Flatulence Dyschezia | Very common Very common Very common Very common Common Common Common Common |
| Skin and subcutaneous tissue disorders | Rashc Pruritus Skin ulcer Skin hypopigmentation | Very common Common Common Common |
| Musculoskeletal and connective tissue disorders | Muscular weakness Arthralgia Back pain Myalgia Arthritis Joint Stiffness Soft tissue necrosis | Common Common Common Common Common Common Common |
| General disorders and administration site conditions | Pyrexia Fatigue Chills Chest paind Pain Localised oedema General physical health deterioration | Very common Very common Common Common Common Common Common |
| Investigations | Neutrophil count decreased White blood cell count decreased Aspartate aminotransferase increased Alanine aminotransferase increased Blood alkaline phosphatase increased Lymphocyte count decreased Blood creatinine increased Blood lactate dehydrogenase increased Platelet count decreased Blood fibrinogen decreased | Very common Very common Very common Very common Very common Common Common Common Common Common |
| Injury, poisoning and procedural complications | Post procedural oedema | Common |
a Graft-versus-host disease (GvHD) includes GvHD in gastrointestinal tract, GvHD in liver, rash maculo-papular (skin GvHD)
b Abdominal pain includes abdominal pain, abdominal discomfort, abdominal pain lower
c Rash includes rash, rash erythematous, rash maculo-papular, rash pustular
d Chest pain includes musculoskeletal chest pain, non-cardiac chest pain
TFR was reported in 1 patient (1%). The event was Grade 3 and the patient recovered. The onset was on the day of dosing and the duration was 60 days.
GvHD was reported in 5 (4.9%) patients. Two (40%) patients had Grade 1, 1 patient (20%) had Grade 2, 1 patient (20%) had Grade 3, and 1 (20%) patient had Grade 4 events. No fatal events were reported. Four (80%) patients recovered from GvHD. The median time to onset was 42 days (range: 8 to 44 days). The median duration was 35 days (range: 7 to 133 days).
There is potential for immunogenicity with Ebvallo. There is currently no information indicating that potential immunogenicity to Ebvallo impacts safety or efficacy.
There are limited data in paediatric patients (see section 5.1). Eight patients were ≥2 to <6 years of age, 16 patients were ≥6 to <12 years of age, 17 patients were ≥12 to <18 years of age. Frequency, type and severity of adverse reactions in children were similar to adults. The adverse reactions of alanine aminotransferase increased, aspartate aminotransferase increased and osteomyelitis were reported as serious only in paediatric patients.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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