Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Bristol-Myers Squibb Pharma EEIG, Plaza 254, Blanchardstown Corporate Park 2, Dublin 15, D15 T867, Ireland
Hypersensitivity 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. 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.
Breyanzi is intended solely for autologous use and should under no circumstances be administered to other patients. Breyanzi must not be administered if the patient identifiers on the cartons, vials and release for infusion certificate (RfIC) do not match the intended patient.
Due to the risks associated with Breyanzi treatment, infusion should be delayed if a patient has any of the following conditions:
In case of delayed Breyanzi infusion, see section 4.2.
Patients treated with Breyanzi should not donate blood, organs, tissues and cells for transplantation.
There is no experience of use of Breyanzi in patients with primary CNS lymphoma. There is limited clinical experience of use of Breyanzi for secondary CNS lymphoma (see section 5.1).
There is limited clinical experience with Breyanzi in patients exposed to prior CD19-directed therapy (see section 5.1).
CRS including fatal or life-threatening reactions can occur following Breyanzi infusion; the median time to onset was 5 days (range: 1 to 14 days). Less than half of all patients treated with Breyanzi experienced some degree of CRS (see section 4.8).
In clinical studies high tumour burden prior to Breyanzi infusion was associated with a higher incidence of CRS.
Tocilizumab and/or a corticosteroid were used to manage CRS after infusion of Breyanzi (see section 4.8).
CRS should be identified based on clinical presentation. Patients should be evaluated for and treated for other causes of fever, hypoxia, and hypotension.
At least one dose of tocilizumab must be available per patient on site prior to infusion of Breyanzi. The treatment centre should 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, the treatment centre must have access to suitable alternative measures instead of tocilizumab to treat CRS. Patients should be monitored 2-3 times during the first week following Breyanzi infusion at the qualified treatment centre for signs and symptoms of CRS. Frequency of monitoring after the first week should be carried out at the physician’s discretion, and should be continued for at least 4 weeks after infusion. Patients should be counselled to seek immediate medical attention should signs or symptoms of CRS occur at any time, and treated promptly.
At the first sign of CRS, treatment with supportive care, tocilizumab or tocilizumab and corticosteroids should be instituted as indicated in Table 1. Breyanzi continues to expand following administration of tocilizumab and corticosteroids (see section 5.2).
Patients who experience CRS should be closely monitored for cardiac and organ functioning until resolution of symptoms. For severe or life-threatening CRS, intensive care unit level monitoring and supportive therapy should be considered.
Evaluation for haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) should be considered in patients with severe or unresponsive CRS. Treatment of HLH/MAS should be administered per institutional guidelines.
If concurrent neurologic toxicity is suspected during CRS, administer:
Table 1. CRS grading and management guidance:
| CRS gradea | Tocilizumab | Corticosteroidsb |
|---|---|---|
| Grade 1 Fever | If 72 hours or more after infusion, treat symptomatically. If less than 72 hours after infusion, consider tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg). | If 72 hours or more after infusion, treat symptomatically. If less than 72 hours after infusion, consider dexamethasone 10 mg IV every 24 hours. |
| Grade 2 Symptoms require and respond to moderate intervention. Fever, oxygen requirement less than 40% fraction of inspired oxygen (FiO2), or hypotension responsive to fluids or low dose of one vasopressor, or Grade 2 organ toxicity. | Administer tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg). | If 72 hours or more after infusion, consider dexamethasone 10 mg IV every 12-24 hours. If less than 72 hours after infusion, administer dexamethasone 10 mg IV every 12-24 hours. |
| If no improvement within 24 hours or rapid progression, repeat tocilizumab and escalate dose and frequency of dexamethasone (10-20 mg IV every 6 to 12 hours). If no improvement or continued rapid progression, maximise dexamethasone, switch to high-dose methylprednisolone 2 mg/kg if needed. After 2 doses of tocilizumab, consider alternative immunosuppressants. Do not exceed 3 doses tocilizumab in 24 hours, or 4 doses in total. | ||
| Grade 3 Symptoms require and respond to aggressive intervention. Fever, oxygen requirement greater than or equal to 40% FiO2, or hypotension requiring high-dose or multiple vasopressors, or Grade 3 organ toxicity, or Grade 4 transaminitis. | Per Grade 2. | Administer dexamethasone 10 mg IV every 12 hours. |
| If no improvement within 24 hours or rapid progression of CRS, escalate tocilizumab and corticosteroid use as per Grade 2. | ||
| Grade 4 Life-threatening symptoms. Requirements for ventilator support or continuous veno-venous haemodialysis (CVVHD) or Grade 4 organ toxicity (excluding transaminitis). | Per Grade 2. | Administer dexamethasone 20 mg IV every 6 hours. |
| If no improvement within 24 hours or rapid progression of CRS, escalate tocilizumab and corticosteroid use as per Grade 2. | ||
a Lee et al 2014.
b If corticosteroids are initiated, continue for at least 3 doses or until complete resolution of symptoms, and consider corticosteroid taper.
Neurologic toxicities, which may be severe or life-threatening, occurred following treatment with Breyanzi, including concurrently with CRS, after CRS resolution, or in the absence of CRS. The median time to onset of the first event was 9 days (range: 1 to 66 days). The most common neurologic symptoms included encephalopathy, tremor, aphasia, delirium, dizziness and headache (see section 4.8).
Patients should be monitored 2-3 times during the first week following infusion, at the qualified treatment centre, for signs and symptoms of neurologic toxicities. Frequency of monitoring after the first week should be carried out at the physician’s discretion, and should be continued for a least 4 weeks after infusion. Patients should be counselled to seek immediate medical attention should signs and symptoms of neurologic toxicity occur at any time, and treated promptly.
If neurologic toxicity is suspected, it is to be managed according to the recommendations in Table 2. Other causes of neurologic symptoms should be ruled out, including vascular events. Intensive care supportive therapy should be provided for severe or life-threatening neurologic toxicities.
If concurrent CRS is suspected during the neurologic toxicity administer:
Table 2. Neurologic toxicity (NT) grading and management guidance:
| NT Gradea | Corticosteroids and anti-seizure medication |
|---|---|
| Grade 1 | Start non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis. If 72 hours or more after infusion, observe. If less than 72 hours after infusion, dexamethasone 10 mg IV every 12 to 24 hours for 2-3 days. |
| Grade 2 | Start non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis. Dexamethasone 10 mg IV every 12 hours for 2-3 days, or longer for persistent symptoms. Consider taper for a total corticosteroid exposure of greater than 3 days. If no improvement after 24 hours or worsening of neurologic toxicity, increase the dose and/or frequency of dexamethasone up to maximum of 20 mg IV every 6 hours. If no improvement after another 24 hours, rapidly progressing symptoms, or lifethreatening complications arise, give methylprednisolone (2 mg/kg loading dose, followed by 2 mg/kg divided 4 times a day; taper within 7 days). |
| Grade 3 | Start non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis. Dexamethasone 10 to 20 mg IV every 8 to 12 hours. Corticosteroids are not recommended for isolated Grade 3 headaches. If no improvement after 24 hours or worsening of neurologic toxicity, escalate to methylprednisolone (dose and frequency as per Grade 2). If cerebral oedema is suspected, consider hyperventilation and hyperosmolar therapy. Give high-dose methylprednisolone (1-2 g, repeat every 24 hours if needed; taper as clinically indicated), and cyclophosphamide 1.5 g/m². |
| Grade 4 | Start non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis. Dexamethasone 20 mg IV every 6 hours. If no improvement after 24 hours or worsening of neurologic toxicity, escalate to methylprednisolone (dose and frequency as per Grade 2). If cerebral oedema is suspected, consider hyperventilation and hyperosmolar therapy. Give high-dose methylprednisolone (1-2 g, repeat every 24 hours if needed; taper as clinically indicated), and cyclophosphamide 1.5 g/m². |
a NCI CTCAE v.4.03 criteria for grading neurologic toxicities.
Breyanzi should not be administered to patients with a clinically significant active infection or inflammatory disorder. Severe infections including life-threatening or fatal infections, have occurred in patients after receiving this medicinal product (see section 4.8). Patients should be monitored for signs and symptoms of infection before and after administration and treated appropriately. Prophylactic anti-microbials should be administered according to standard institutional guidelines.
Febrile neutropenia has been observed in patients after treatment with Breyanzi (see section 4.8) and may be concurrent with CRS. In the event of febrile neutropenia, infection should be evaluated and managed with broad-spectrum antibiotics, fluids and other supportive care as medically indicated.
Viral reactivation, (e.g, HBV, human herpesvirus 6 [HHV-6]) may occur in immunosuppressed patients.
Viral reactivation manifestations may complicate and delay the diagnosis and appropriate treatment of CAR T cell-related adverse events. Appropriate diagnostic evaluations should be performed to help differentiate these manifestations from CAR T cell-related adverse events.
HBV reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with medicinal products directed against B cells. For patients with a prior history of HBV, prophylactic antiviral suppressive therapy is recommended to prevent HBV reactivation during and after Breyanzi therapy (see section 5.1).
Screening for HBV, HCV, and HIV should be performed before collection of cells for manufacturing. (see section 4.2).
Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and Breyanzi (see section 4.8). Blood counts should be monitored prior to and after Breyanzi administration. Prolonged cytopenias should be managed according to clinical guidelines.
B-cell aplasia leading to hypogammaglobulinaemia can occur in patients receiving treatment with Breyanzi. Hypogammaglobulinaemia has been very commonly observed in patients treated with Breyanzi (see section 4.8). Immunoglobulin levels should be monitored after treatment and managed per clinical guidelines including infection precautions, antibiotic prophylaxis and/or immunoglobulin replacement.
Patients treated with Breyanzi may develop secondary malignancies. Patients should be monitored life-long for secondary malignancies. In the event that a secondary malignancy of T-cell origin occurs, the company should be contacted to obtain instructions on the collection of tumour samples for testing.
TLS may occur in patients treated with CAR T therapies. To minimise the risk of TLS, patients with elevated uric acid or high tumour burden should receive allopurinol, or an alternative prophylaxis, prior to Breyanzi infusion. Signs and symptoms of TLS should be monitored and managed in accordance with clinical guidelines.
Allergic reactions may occur with the infusion of Breyanzi. Serious hypersensitivity reactions including anaphylaxis, may be due to dimethyl sulfoxide.
HIV and the lentivirus used to make Breyanzi have limited, short spans of identical genetic material (RNA). Therefore, some commercial HIV nucleic acid tests may yield false positive results in patients who have received Breyanzi. Patients who have received Breyanzi therapy should not be screened for HIV using a PCR-based assay.
It is not recommended that patients who underwent an allogeneic stem cell transplant and suffer from active acute or chronic GVHD receive treatment because of the potential risk of Breyanzi worsening GVHD.
Patients are expected to be enrolled in a registry and will be followed in the registry in order to better understand the long-term safety and efficacy of Breyanzi.
This medicinal product contains 12.5 mg sodium per vial, equivalent to 0.6% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
This medicinal product contains 0.2 mmol (or 6.5 mg) potassium per vial. To be taken into consideration by patients with reduced kidney function or patients on a controlled potassium diet.
No interaction studies have been performed in humans.
Long-term persistence of CAR T cells may be affected by the subsequent use of anti-EGFR mabs, but no clinical data are currently available.
The safety of immunisation with live viral vaccines during or following Breyanzi treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during treatment, and until immune recovery following treatment.
Pregnancy status for women of child-bearing potential should be verified using a pregnancy test prior to starting treatment with Breyanzi.
See the prescribing information for fludarabine and cyclophosphamide for information on the need for effective contraception in patients who receive the lymphodepleting chemotherapy.
There are insufficient exposure data to provide a recommendation concerning duration of contraception following treatment with Breyanzi.
There are no data from the use of lisocabtagene maraleucel in pregnant women. No animal reproductive and developmental toxicity studies have been conducted to assess whether it can cause foetal harm when administered to a pregnant woman (see section 5.3).
It is not known if lisocabtagene maraleucel has the potential to be transferred to the foetus. Based on the mechanism of action, if the transduced cells cross the placenta, they may cause foetal toxicity, including B-cell lymphocytopenia. Therefore, Breyanzi is not recommended for women who are pregnant, or for women of childbearing potential not using contraception. Pregnant women should be advised on the potential risks to the foetus. Pregnancy after Breyanzi therapy should be discussed with the treating physician.
Assessment of immunoglobulin levels and B-cells in newborns of mothers treated with should be considered.
It is unknown whether lisocabtagene maraleucel is excreted in human milk or transferred to the breastfeeding child. Women who are breast-feeding should be advised of the potential risk to the breast-fed child.
There are no data on the effect of lisocabtagene maraleucel on fertility.
Breyanzi may have major influence on the ability to drive and use machines.
Due to the potential for neurologic events, including altered mental status or seizures with Breyanzi, patients receiving Breyanzi should refrain from driving or operating heavy or potentially dangerous machines for at least 8 weeks after Breyanzi infusion.
The most common adverse reactions of any grade were neutropenia (67%), anaemia (48%), CRS (39%), fatigue (38%), and thrombocytopenia (37%).
The most common serious adverse reactions were CRS (17%), encephalopathy (11%), infection with an unspecified pathogen (6%), neutropenia (4%), thrombocytopenia (4%), aphasia (4%), pyrexia (4%), bacterial infectious disorders (4%), delirium (4%), tremor (4%), febrile neutropenia (3%), and hypotension (3%).
The most common Grade 3 or higher adverse reactions included neutropenia (63%), anaemia (35%), thrombocytopenia (29%), leukopenia (21%), infection with an unspecified pathogen (9%) and febrile neutropenia (8%).
The frequencies of adverse reactions are based on pooled data from 4 studies (TRANSCEND 017001, TRANSCEND WORLD [JCAR017-BCM-001], PLATFORM [JCAR017-BCM-002] and OUTREACH 017007), in 314 adult patients within the dose range of 44-120 × 106 CAR+ viable T cells with R/R large B-cell lymphoma, defined as DLBCL, PMBCL and FL3B, who received a dose of lisocabtagene maraleucel. The adverse reaction frequencies from clinical studies are based on allcause adverse event frequencies, where a proportion of the events for an adverse reaction may have other causes.
Adverse reactions reported are presented below. These reactions are presented by MedDRA system organ class and by frequency. Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10) and uncommon (≥1/1,000 to <1/100). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.
Table 3. Adverse drug reactions identified with Breyanzi:
| System Organ Class (SOC) | Frequency | Adverse reaction |
|---|---|---|
| Infections and infestationsa | Very common | Infections – pathogen unspecified Bacterial infectious disorders |
| Common | Viral infectious disorders Fungal infectious disorders | |
| Blood and lymphatic system disorders | Very common | Neutropenia Anaemia Thrombocytopenia Leukopenia |
| Common | Febrile neutropenia Lymphopenia Hypofibrinogenaemia Pancytopenia | |
| Immune system disorders | Very common | Cytokine release syndrome Hypogammaglobulinaemia |
| Uncommon | Haemophagocytic lymphohistiocytosis | |
| Metabolism and nutrition disorders | Common | Hypophosphataemia |
| Uncommon | Tumour lysis syndrome | |
| Psychiatric disorders | Very common | Insomnia Deliriumb |
| Common | Anxiety | |
| Nervous system disorders | Very common | Headachec Encephalopathyd Dizzinesse Tremorf |
| Common | Aphasiag Peripheral neuropathyh Visual disturbancei Ataxiaj Taste disorderk Cerebellar syndromel Cerebrovascular disorderm Seizuren | |
| Uncommon | Facial paralysis Brain oedema | |
| Cardiac disorders | Very common | Tachycardia |
| Common | Arrhythmia° Cardiomyopathy | |
| Vascular disorders | Very common | Hypotension Hypertension |
| Common | Thrombosisp | |
| Respiratory, thoracic and mediastinal disorders | Very common | Cough Dyspnoeaq |
| Common | Pleural effusion Hypoxia Pulmonary oedema | |
| Gastrointestinal disorders | Very common | Nausea Constipation Diarrhoea Abdominal pain Vomiting |
| Common | Gastrointestinal haemorrhager | |
| Skin and subcutaneous tissue disorders | Very common | Rash |
| Renal and urinary disorders | Very common | Acute kidney injurys |
| General disorders and administration site conditions | Very common | Fatigue Pyrexia Oedemat |
| Common | Chills | |
| Injury, poisoning and procedural complications | Common | Infusion related reaction |
a Infections and infestations are grouped per MedDRA high level group term.
b Delirium includes agitation, delirium, delusion, disorientation, hallucination, hallucination visual, irritability, restlessness.
c Headache includes headache, migraine, sinus headache.
d Encephalopathy includes amnesia, cognitive disorder, confusional state, depersonalisation/derealisation disorder, depressed level of consciousness, disturbance in attention, encephalopathy, flat affect, lethargy, leukoencephalopathy, loss of consciousness, memory impairment, mental impairment, mental status changes, paranoia, somnolence, stupor.
e Dizziness includes dizziness, presyncope, syncope.
f Tremor includes essential tremor, intention tremor, resting tremor, tremor.
g Aphasia includes aphasia, disorganised speech, dysarthria, dysphonia, slow speech.
h Peripheral neuropathy includes hyperaesthesia, hypoaesthesia, hyporeflexia, neuropathy peripheral, paraesthesia, peripheral motor neuropathy, peripheral sensory neuropathy, sensory loss.
i Visual disturbance includes blindness, blindness unilateral, gaze palsy, mydriasis, nystagmus, vision blurred, visual field defect, visual impairment
j Ataxia includes ataxia, gait disturbance.
k Taste disorder includes dysgeusia, taste disorder.
l Cerebellar syndrome includes balance disorder, dysdiadochokinesis, dyskinesia, dysmetria, hand-eye coordination impaired.
m Cerebrovascular disorder includes cerebral infarction, cerebral venous thrombosis, haemorrhage intracranial, transient ischaemic attack.
n Seizure includes seizure, status epilepticus.
° Arrhythmia includes arrhythmia, atrial fibrillation, atrioventricular block complete, atrioventricular block second degree, supraventricular tachycardia, ventricular tachycardia.
p Thrombosis includes deep vein thrombosis, embolism, pulmonary embolism, thrombosis, vena cava thrombosis, venous thrombosis limb.
q Dyspnoea includes acute respiratory failure, dyspnoea, dyspnoea exertional, respiratory failure.
r Gastrointestinal haemorrhage includes gastric ulcer haemorrhage, gastrointestinal haemorrhage, haematochezia, melaena, rectal haemorrhage, upper gastrointestinal haemorrhage.
s Acute kidney injury includes acute kidney injury, blood creatinine increased, glomerular filtration rate decreased, renal failure, renal impairment, renal injury.
t Oedema includes generalised oedema, localised oedema, oedema, oedema genital, oedema peripheral, peripheral swelling, scrotal oedema, swelling.
CRS occurred in 39% of patients, 3% of whom experienced Grade 3 or 4 (severe or life-threatening) CRS. There were no fatal events. Among patients who died after receiving Breyanzi, 4 had ongoing CRS events at the time of death. The median time to onset was 5 days (range: 1 to 14 days) and the median duration was 5 days (range: 1 to 17 days).
The most common manifestations of CRS included pyrexia (37%), hypotension (18%), tachycardia (13%), chills (10%), and hypoxia (9%). See section 4.4 for monitoring and management guidance.
In clinical studies, 57 of 314 (18%) patients received tocilizumab and/or a corticosteroid for CRS after infusion of Breyanzi. Thirty-three (11%) patients received tocilizumab only, 21 (7%) received tocilizumab and a corticosteroid and 3 (1%) received corticosteroids only.
CAR T cell-associated neurologic toxicities assessed by the investigator occurred in 26% of patients receiving Breyanzi, including Grade 3 or 4 in 10% of patients (no fatal events). The median time to onset of the first event was 9 days (range: 1 to 66 days); 99% of all neurologic toxicities occurred within the first 8 weeks following Breyanzi infusion. The median duration of neurologic toxicities was 10 days (range: 1 to 84 days).
The most common neurologic toxicities included encephalopathy (17%), tremor (10%), aphasia (9%), delirium (6%), ataxia (4%), dizziness (3%), and headache (3%). Seizures (1%) and cerebral oedema (0.3%) have also occurred in patients treated with Breyanzi. See section 4.4 for monitoring and management guidance of neurologic toxicities.
Febrile neutropenia has been observed in 9% of patients after receiving Breyanzi. Infections (all grades) occurred in 39% of patients. Grade 3 or higher infections occurred in 12% of patients. Grade 3 or higher infections with an unspecified pathogen occurred in 9% of patients, bacterial infections occurred in 4% of patients, fungal infections occurred in 1% of patients, and viral infections occurred in 0.6% of patients.
Opportunistic infections (all grades) have been observed in 4% of the 314 patients treated with Breyanzi among pooled DLBCL studies, with Grade 3 or higher opportunistic infections having occurred in 2% of patients.
Four fatal infections were reported from the 314 patients treated with Breyanzi among pooled DLBCL studies. Of these, 1 was reported as a fatal opportunistic infection. See section 4.4 for monitoring and management guidance.
Grade 3 or higher cytopenias present at Day 29 following Breyanzi administration, occurred in 39% of patients, and included thrombocytopenia (31%), neutropenia (20%) and anaemia (6%). See section 4.4 for monitoring and management guidance.
Of the 275 total patients treated in TRANSCEND and TRANSCEND WORLD (Cohort 1 and Cohort 3) who had Day 29 laboratory findings of Grade 3-4 thrombocytopenia (n=88) or Grade 3-4 neutropenia (n=60) or Grade 3-4 anaemia (n=18), for whom follow-up laboratory cytopenia results were available, the median time (min, max) to resolution (cytopenia recovering to Grade 2 or less) was as follows in days: thrombocytopenia 41 days (5, 328); neutropenia 29 days (2, 336); and anaemia 33 days (3, 150).
Hypogammaglobulinaemia occurred in 12% of patients. See section 4.4 for monitoring and management guidance.
Breyanzi has the potential to induce antibodies against this medicinal product. In TRANSCEND and TRANSCEND WORLD, humoral immunogenicity of Breyanzi was measured by determination of anti-CAR antibody pre- and post-administration. In the pooled studies, pre-existing anti-therapeutic antibodies (ATAs) were detected in 9% (29/309) of patients, and treatment-induced or treatmentboosted ATAs were detected in 15% (46/304) of patients. The relationships between ATA status and efficacy, safety or pharmacokinetics were not conclusive due to the limited number of patients with ATAs.
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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