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Aucatzyl is a brand name for Obecabtagene Autoleucel. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: Aucatzyl is indicated for the treatment of adult patients 26 years of age and above with relapsed or refractory (r/r) B cell precursor acute lymphoblastic leukaemia (B ALL). 3
Verbatim from this product's EMA label. Tap a section to expand.
Aucatzyl 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 the medicinal product.
In the event of cytokine release syndrome (CRS), at least one dose of tocilizumab, and emergency equipment, must be available prior to infusion. 4). , siltuximab) to treat CRS instead of tocilizumab must be available prior to infusion.
4). The target dose is 410 × 106 CD19 CAR-positive viable T cells (range: 308-513 × 106 CAR-positive viable T cells) supplied in 3 or more infusion bags. The treatment regimen consists of a split dose to be administered on day 1 and day 10 (± 2 days).
The dose regimen will be determined by the tumour burden assessed by bone marrow (BM) blast percentage from a sample obtained within 7 days prior to the start of lymphodepletion (Figure 1). The RfIC and Dose Schedule Planner (Annex IIIA), located inside the lid of the cryoshipper, must be followed for the actual cell counts and volumes to be infused and to guide the appropriate dose regimen.
Bone marrow assessment A BM assessment must be available from a biopsy and/or aspirate sample obtained within 7 days prior to the commencement of the lymphodepleting chemotherapy.
The BM assessment will be used to determine the Aucatzyl dose regimen:
High Tumour Burden Regimen if blast percentage is > 20% or Low Tumour Burden Regimen if blast percentage is ≤ 20% (see Figure 1). If BM assessment results are inconclusive, the biopsy or aspirate must be repeated (but only once). A repeat biopsy or aspirate should only be taken prior to lymphodepleting chemotherapy.
, administration of the 10 × 106 dose on day 1 per Figure 1).
Figure 1:
Aucatzyl tumour burden adjusted split dose regimen High tumour burden dose regimen (Bone marrow blast > 20% or inconclusive) Day 1 Day 10 (± 2 days) 10 × 106 dose administered via syringe* 100 × 106 dose administered via bag infusion+ and 300 × 106 dose administered via bag infusion+ 4 Low tumour burden dose regimen (Bone marrow blast ≤ 20%) Day 1 Day 10 (± 2 days) 100 × 106 dose administered via bag infusion+ 10 × 106 dose administered via syringe* and 300 × 106 dose administered via bag infusion+ *The exact volume to be administered via syringe is indicated in the RfIC.
3%). 0%). 1%). 4%). The lymphodepleting chemotherapy prior to Aucatzyl administration also contributes to the laboratory abnormalities. Tabulated list of adverse reactions Table 4 summarises the adverse reactions in a total of 127 patients exposed to Aucatzyl in the Phase Ib and Phase II FELIX study.
These reactions are presented by Medical Dictionary for Regulatory Activities system organ class and by frequency. Frequencies are defined as: very common (≥ 1/10), and common (≥ 1/100 to < 1/10). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
16 Table 4: Adverse drug reactions identified with Aucatzyl System organ class (SOC) Frequency Adverse reaction Infections and infestations Very common Infections – pathogen unspecified Bacterial infectious disorders COVID-19 Viral infectious disorders excluding COVID-19 Fungal infectious disorders Sepsis Blood and lymphatic system disorders Very common Neutropeniaa Leukopeniaa Lymphopeniaa Thrombocytopeniaa Anaemiaa Febrile neutropenia Coagulopathy Immune system disorders Very common Cytokine release syndrome Common Hypogammaglobulinaemia Haemophagocytic lymphohistiocytosis Graft versus host disease Metabolism and nutrition disorders Very common Decreased appetite Psychiatric disorders Common Deliriumb Nervous system disorders Very common Headache Immune effector cell-associated neurotoxicity syndrome Encephalopathyc Dizziness Common Tremor Cardiac disorders Very common Tachycardia Common Arrhythmia Cardiac Failure Palpitations Vascular disorders Very common Hypotension Haemorrhage Respiratory, thoracic and mediastinal disorders Very common Cough Gastrointestinal disorders Very common Nausea Diarrhoea Vomiting Abdominal pain Constipation Common Stomatitis Skin and subcutaneous tissue disorders Very common Rash Musculoskeletal and connective tissue disorders Very common Musculoskeletal pain General disorders and administration site conditions Very common Pyrexia 17 System organ class (SOC) Frequency Adverse reaction Pain Fatigue Oedema Common Chills Investigations Very common Alanine aminotransferase increaseda Weight decreased Hyperferritinaemia Aspartate aminotransferase increaseda Injury, poisoning and procedural complications Common Infusion related reaction a Frequency based on grade 3 or higher laboratory parameter.
Traceability The traceability requirements of cell-based advanced therapy medicinal products must apply. To ensure traceability the name of the product, the batch number and the name of the treated patient must be kept for a period of 30 years after the expiry date of the product.
Autologous use Aucatzyl is intended solely for autologous use and must not, under any circumstances, be administered to other patients. Aucatzyl must not be administered if the information on the product labels and RfIC do not match the patient’s identity.
8 General The availability of Aucatzyl must be confirmed before starting the lymphodepleting chemotherapy regimen. Patients should be clinically re-assessed prior to administration of lymphodepleting chemotherapy and Aucatzyl to ensure that there are no reasons to delay therapy.
Warnings and precautions of lymphodepleting chemotherapy must be considered. 2). 8). CRS is more probable in patients with a high tumour burden. CRS may appear up to 23 days post-infusion. Severe adverse reactions have been reported after Aucatzyl infusion.
In general, CRS following CAR T treatment can be life-threatening. Patients should be counselled to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, the patient should be timely evaluated for hospitalisation and for management as per guidance in Table 2 and for administration of supportive care.
Use of myeloid growth factors such as granulocyte colony-stimulating factor (G-CSF) or granulocyte macrophage colony-stimulating factor (GM-CSF) should be avoided during CRS, given the potential to worsen CRS symptoms. Patients should be monitored daily for 14 days after the first infusion for signs and symptoms of potential CRS.
The most common manifestations of CRS included fever, hypotension, and hypoxia. Frequency of monitoring after the first 14 days should be carried out at the physician’s discretion and should be continued for at least 4 weeks after infusion.
1. Contraindications of the lymphodepleting chemotherapy must be considered.
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The 10 × 106 CD19 CAR-positive viable T cell bag configuration contains an overfill, and therefore it is important to withdraw only the volume specified. +The 100 × 106 and 300 × 106 doses will be suspended in one or more infusion bags with no overfill.
1). Pretreatment (lymphodepleting chemotherapy) The lymphodepleting chemotherapy regimen must be administered before infusion of Aucatzyl: fludarabine (FLU) 30 mg/m2/day intravenously and cyclophosphamide (CY) 500 mg/m2/day intravenously on days -6 and -5, followed by fludarabine on days -4 and -3 (total dose: FLU 120 mg/m2; CY 1 000 mg/m2).
For dose modifications of cyclophosphamide and fludarabine, see corresponding Summaries of Product Characteristics of cyclophosphamide and fludarabine. Retreatment with lymphodepleting chemotherapy, in patients who could not receive the Aucatzyl dose on day 1 as planned, could be considered if there is an Aucatzyl dose delay of more than 10 days.
Lymphodepleting chemotherapy should not be repeated after the first dose of Aucatzyl is administered. Aucatzyl is infused 3 days (± 1 day) after completion of lymphodepleting chemotherapy (day 1), allowing a minimum 48-hour washout.
4). A delay to the second split dose may be required to manage toxicities. 5 to 25 mg intravenously or orally (or equivalent medicinal products) approximately 30 minutes prior to Aucatzyl infusion. Prophylactic use of systemic corticosteroids is not recommended .
Reasons to delay treatment Delay Aucatzyl treatment if there are unresolved serious adverse reactions from preceding chemotherapies, if the patient is experiencing severe intercurrent infection, or has active graft-versus-host disease.
If the patient requires supplementary oxygen, Aucatzyl should only be infused, if considered appropriate, based on the treating physician’s benefit / risk assessment. Reasons to delay the second split dose 5 Dose delays or discontinuation of treatment may be required after the first split dose to manage adverse reactions as described in Table 1.
Table 1:
Dose delay or discontinuation - guidance intended to reduce the risk of adverse reactions Adverse reaction Gradea Actions Second split dose Day 10 (± 2 days) Cytokine release syndrome (CRS) following the first split dose Grade 2 Consider postponing Aucatzyl infusion up to day 21 to allow for the CRS to resolve to grade 1 or less.
If the CRS persist beyond day 21, do not administer the second dose. Grade ≥ 3 Discontinue treatment. 4) Grade 1 Consider postponing Aucatzyl infusion up to day 21 to allow for the ICANS to completely resolve. If the ICANS persist beyond day 21, do not administer the […]
b Delirium includes agitation, delirium, disorientation, hallucination, irritability. c Encephalopathy includes aphasia, cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, dysarthria, dysgraphia, encephalopathy, lethargy, memory impairment, mental status changes, posterior reversible encephalopathy syndrome, somnolence.
4% of patients. The median time to onset of CRS of any grade was 8 days following the first infusion (range: 1-23 days) with a median duration of 5 days (range: 1-21 days). In the FELIX study, 80% of patients who experienced CRS had ≥ 5% blasts in their BM at the time of lymphodepletion, with 39% of patients presenting with > 75% blast in their BM.
8%). The majority of patients experienced CRS after the first but prior to the second infusion of Aucatzyl. 3% CRS occurred after the first, but prior to the second infusion of Aucatzyl with a median time to onset of 6 days (range: 3-9 days).
Median time to onset after the second infusion was 2 days (range: 1-2 days). 4. Haemophagocytic lymphohistiocytosis (HLH)/ macrophage activation syndrome (MAS) HLH/MAS, including severe and life-threatening reactions may occur following treatment with Aucatzyl.
6% of patients and included grade 3 and grade 4 events with a time of onset at day 22 and day 41, respectively. 4). 8%). 1%) following treatment with Aucatzyl. 1%) experienced grade 4 ICANS. 7%). 7%) and all patients who experienced grade ≥ 3 ICANS had > 5% blasts in their BM at the time of lymphodepleting treatment.
Among the patients who experienced grade ≥ 3 ICANS, 5 patients presented with > 75% blasts in their BM. 18 The median time to onset for ICANS events was 12 days (range: 1-31 days) with a median duration of 8 days (range: 1-53 days).
The median time to onset for ICANS events after the first infusion and before the second infusion […]
2). CRS should be managed based on the patient’s clinical presentation and according to the CRS grading and management guidance provided in Table 2. At the first sign of CRS, treatment with tocilizumab or tocilizumab and corticosteroids should be instituted.
Ensure 24-hour immediate access to tocilizumab is available for each patient prior to infusion of Aucatzyl. , siltuximab) to treat CRS must be available prior to infusion. Evaluation for haemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) is to be considered in patients with severe or unresponsive CRS.
Resolution of any ongoing grade > 2 CRS to grade 1 or less should be ensured prior to initiating the second split infusion/dose. 9 Table 2: CRS grading and management guidance CRS gradea Anti-IL-6 therapyb Corticosteroidsc Grade 1 Fever (≥ 38 °C).
For prolonged CRS (> 3 days) in patients or those with significant symptoms, comorbidities and /or are elderly, administer 1 dose tocilizumab 8 mg/kg intravenously over 1 hour (not to exceed 800 mg). N/A Grade 2 Fever with hypotension not requiring vasopressors, and/or, Hypoxia requiring low-flow nasal cannula or blow-by.
Tocilizumab 8 mg/kg intravenously over 1 hour (not to exceed 800 mg/dose). Repeat tocilizumab if no improvement; no more than 3 doses in 24 hours-with a maximum total of 4 doses. If there is no response to treatment with tocilizumab ± corticosteroids, siltuximab may be added.
For persistent refractory hypotension after 1-2 doses of anti-IL-6 therapy: consider dexamethasone 10 mg intravenously every 12-24 hours. Grade 3 Fever with hypotension requiring a vasopressor with or without vasopressin, and/or Hypoxia requiring oxygen via high-flow nasal cannula, facemask, non-rebreather mask, or Venturi mask.
Tocilizumab per grade 2c, if maximum dose not reached within 24-hour period. Dexamethasone 10 mg intravenously every 6-12 hours. If refractory manage as grade 4. , CPAP, BiPAP, intubation, and mechanical ventilation). Tocilizumab per Grade 2c, if maximum dose not reached within 24-hour period.
Dexamethasone 10 mg intravenously every 6 hours. If refractory, consider 3 doses of methylprednisolone 1 000 mg intravenously. If refractory, consider dosing every 12 hours. BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; CRS = cytokine release syndrome; CTCAE = Common Terminology Criteria for Adverse Events; IL = interleukin; N/A = not applicable; NCI = National Cancer Institute.
0. b See Prescribing Information for each agent. c After each dose, assess need for subsequent dosing. 8). Patients should be monitored for signs and symptoms of ICANS and they should be counselled to seek immediate medical attention should signs or symptoms of neurotoxicity occur at any time.
Transient neurological symptoms can be heterogeneous and include encephalopathy, aphasia, lethargy, headache, tremor, […]