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 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. 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.
Due to the risks associated with Abecma treatment, infusion should be delayed up to 7 days if a patient has any of the following conditions:
Abecma is intended solely for autologous use and should under no circumstances be administered to other patients. Before infusion, the patient’s identity must match the patient identifiers on the Abecma infusion bag, cassette and the release for infusion certificate (RfIC). Abecma must not be administered if the information on the patient-specific label does not match the intended patient.
Patients with active central nervous system (CNS) disorder or inadequate renal, hepatic, pulmonary or cardiac function are likely to be more vulnerable to the consequences of the adverse reactions described below and require special attention.
There is no experience of use of Abecma in patients with CNS involvement of myeloma or other preexisting, clinically relevant CNS pathologies.
It is not recommended that patients receive Abecma within 4 months after an allogeneic stem cell transplant (SCT) because of the potential risk of Abecma worsening GVHD. Leukapheresis for Abecma manufacturing should be performed at least 12 weeks after allogeneic SCT.
There is limited experience with Abecma in patients exposed to prior BCMA-directed therapy.
There is limited experience of retreating patients with a second dose of Abecma. Responses after Abecma retreatment were infrequent and less durable when compared to initial treatment. Additionally, fatal outcomes were observed in retreated patients.
CRS, including fatal or life-threatening reactions occurred following Abecma infusion. Nearly all patients experienced some degree of CRS. The median time to onset of CRS was 1 day (range: 1 to 12) (see section 4.8).
CRS should be identified based on clinical presentation. Patients should be evaluated and treated for other causes of fever, hypoxia and hypotension. CRS has been reported to be associated with findings of haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) and the physiology of the syndromes may overlap. MAS is a potentially life-threatening condition, and patients should be closely monitored for evidence of MAS. Treatment of MAS should be administered per institutional guidelines.
One dose of tocilizumab per patient must be on-site and available for administration prior to Abecma infusion. The treatment centre must have access to an additional dose of tocilizumab within 8 hours of each previous dose. In the exceptional case where tocilizumab is not available due to a shortage that is listed in the European Medicines Agency shortage catalogue, the treatment centre must have access to suitable alternative measures instead of tocilizumab to treat CRS. Patients should be monitored for the first 10 days following Abecma infusion at the qualified treatment centre for signs and symptoms of CRS. After the first 10 days following infusion, the patient should be monitored at the physician’s discretion. Patients should be counselled to remain within proximity (within 2 hours of travel) of the qualified treatment centre for at least 4 weeks following infusion and to seek immediate medical attention should signs or symptoms of CRS occur at any time.
At the first sign of CRS, treatment with supportive care, tocilizumab or tocilizumab and corticosteroids should be instituted, as indicated in Table 1. Abecma can continue to expand and persist following administration of tocilizumab and corticosteroids (see section 4.5).
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.
If concurrent neurologic toxicity is suspected during CRS, manage the neurologic toxicity according to the recommendations in Table 2 and use the more aggressive intervention of the two reactions specified in Tables 1 and 2.
Earlier escalation (i.e. higher corticosteroid dose, alternative anticytokine agents, anti-T cell therapies) is recommended in patients with refractory CRS within 72 hours post Abecma infusion characterised by persistent fever, end-organ toxicity (e.g. hypoxia, hypotension) and/or HLH/MAS not improving in grade within 12 hours of first line interventions.
Table 1. CRS grading and management guidance:
| CRS gradea | Tocilizumab | Corticosteroids |
|---|---|---|
| Grade 1 Symptoms require symptomatic treatment only (e.g. fever, nausea, fatigue, headache, myalgia, malaise). | If onset 72 hours or more after infusion, treat symptomatically. If onset less than 72 hours after infusion and symptoms not controlled by supportive care alone, consider tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg). | ─ |
| Grade 2 Symptoms require and respond to moderate intervention. Oxygen requirement less than 40% 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). | Consider dexamethasone 10 mg IV every 12 to 24 hours. |
| 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. | Administer tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg). | Administer dexamethasone (e.g. 10 mg IV every 12 hours). |
| For Grade 2 and 3: If no improvement within 24 hours or rapid progression, repeat tocilizumab and escalate dose and frequency of dexamethasone (20 mg IV every 6 to 12 hours). If no improvement within 24 hours or continued rapid progression, switch to methylprednisolone 2 mg/kg followed by 2 mg/kg divided 4 times per day. If steroids are initiated, continue steroids for at least 3 doses, and taper over a maximum of 7 days. After 2 doses of tocilizumab, consider alternative anticytokine agents. Do not exceed 3 doses tocilizumab in 24 hours or 4 doses in total. | ||
| Grade 4 Life-threatening symptoms. Requirements for ventilator support, continuous veno-venous hemodialysis (CVVHD) or Grade 4 organ toxicity (excluding transaminitis). | Administer tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg). | Administer dexamethasone 20 mg IV every 6 hours. |
| For Grade 4: After 2 doses of tocilizumab, consider alternative anticytokine agents. Do not exceed 3 doses of tocilizumab in 24 hours or 4 doses in total. If no improvement within 24 hours, consider methylprednisolone (1 to 2 g, repeat every 24 hours if needed; taper as clinically indicated) or anti-T cell therapies such as cyclophosphamide 1.5 g/m² or others. | ||
a Lee et al, 2014.
Neurologic toxicities, such as aphasia and encephalopathy, which may be severe or life-threatening, occurred following treatment with Abecma. The median time to onset of the first event of neurotoxicity was 2 days (range: 1 to 10 days). Neurologic toxicity may occur concurrently with CRS, after CRS resolution or in the absence of CRS (see section 4.8).
Patients should be monitored for the first 10 days following Abecma infusion at the qualified treatment centre for signs and symptoms of neurologic toxicities. After the first 10 days following infusion, the patient should be monitored at the physician’s discretion. Patients should be counselled to remain within proximity (within 2 hours of travel) of the qualified treatment centre for at least 4 weeks following infusion and to seek immediate medical attention should signs and symptoms of neurologic toxicities occur at any time.
If neurologic toxicity is suspected, manage according to the recommendations in Table 2. Other causes of neurologic symptoms should be ruled out. Intensive care supportive therapy should be provided for severe or life-threatening neurologic toxicities.
If concurrent CRS is suspected during the neurologic toxicity reaction, it should be managed according to the recommendations in Table 1 and the more aggressive intervention used for the two reactions specified in Tables 1 and 2.
Table 2. Neurologic toxicity grading and management guidance:
| Neurologic toxicity gradea | Corticosteroids and antiseizure medications |
|---|---|
| Grade 1 Mild or asymptomatic. | Start non-sedating, antiseizure medicines (e.g. levetiracetam) for seizure prophylaxis. If 72 hours or more after infusion, observe patient. If less than 72 hours after infusion, and symptoms not controlled by supportive care alone, consider dexamethasone 10 mg IV every 12 to 24 hours for 2 to 3 days. |
| Grade 2 Moderate. | Start non-sedating, antiseizure medicines (e.g. levetiracetam) for seizure prophylaxis. Start dexamethasone 10 mg IV every 12 hours for 2 to 3 days or longer for persistent symptoms. Consider taper for a total steroid exposure of greater than 3 days. Steroids are not recommended for isolated Grade 2 headaches. If no improvement after 24 hours or worsening of neurologic toxicity, increase the dose and/or frequency of dexamethasone up to a maximum of 20 mg IV every 6 hours. |
| Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation; disabling. | Start non-sedating, antiseizure medicines (e.g. levetiracetam) for seizure prophylaxis. Start dexamethasone 10 to 20 mg IV every 8 to 12 hours. Steroids are not recommended for isolated Grade 3 headaches. If no improvement after 24 hours or worsening of neurologic toxicity, escalate to methylprednisolone (2 mg/kg loading dose, followed by 2 mg/kg divided into 4 times a day; taper within 7 days). If cerebral oedema is suspected, consider hyperventilation and hyperosmolar therapy. Give high-dose methylprednisolone (1 to 2 g, repeat every 24 hours if needed; taper as clinically indicated) and cyclophosphamide 1.5 g/m². |
| Grade 4 Life-threatening. | Start non-sedating, antiseizure medicines (e.g. levetiracetam) for seizure prophylaxis. Start dexamethasone 20 mg IV every 6 hours. If no improvement after 24 hours or worsening of neurologic toxicity, escalate to high-dose methylprednisolone (1 to 2 g, repeated every 24 hours if needed; taper as clinically indicated). Consider cyclophosphamide 1.5 g/m². If cerebral oedema is suspected, consider hyperventilation and hyperosmolar therapy. Give high-dose methylprednisolone (1 to 2 g, repeat every 24 hours if needed; taper as clinically indicated) and cyclophosphamide 1.5 g/m². |
a NCI CTCAE v.4 criteria for grading neurologic toxicities.
Patients may exhibit prolonged cytopenias for several weeks following lymphodepleting chemotherapy and Abecma infusion (see section 4.8). Blood counts should be monitored prior to and after Abecma infusion. Cytopenias should be managed with myeloid growth factor and blood transfusion support according to institutional guidelines.
Abecma should not be administered to patients with active infections or inflammatory disorders. Severe infections, including life-threatening or fatal infections, have occurred in patients after receiving Abecma (see section 4.8). Patients should be monitored for signs and symptoms of infection before and after Abecma infusion and treated appropriately. Prophylactic, pre-emptive and/or therapeutic antimicrobials should be administered according to institutional guidelines.
Febrile neutropenia was observed in patients after Abecma infusion (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.
Cytomegalovirus (CMV) infection resulting in pneumonia and death have occurred following Abecma administration (see section 4.8). Patients should be monitored and treated for CMV infection according to clinical guidelines.
HBV reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with medicinal products directed against plasma cells (see section 4.8).
Screening for CMV, HBV, active HIV and active HCV must be performed before collection of cells for manufacturing (see section 4.2).
Plasma cell aplasia and hypogammaglobulinaemia can occur in patients receiving treatment with Abecma (see section 4.8). Immunoglobulin levels should be monitored after treatment with Abecma and managed per institutional guidelines including infection precautions, antibiotic or antiviral prophylaxis and immunoglobulin replacement.
Patients treated with Abecma may develop secondary malignancies. Patients should be monitored lifelong 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 patient samples for testing.
Allergic reactions may occur with the infusion of Abecma. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide (DMSO), an excipient in Abecma. Patients not previously exposed to DMSO should be observed closely. Vital signs (blood pressure, heart rate, and oxygen saturation) and the occurrence of any symptom should be monitored prior to the start of the infusion, approximately every ten minutes during the infusion and every hour, for 3 hours, after the infusion.
HIV and the lentivirus used to make Abecma 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 Abecma.
Patients treated with Abecma should not donate blood, organs, tissues and cells for transplantation.
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 Abecma.
This medicinal product contains up to 33 mmol (752 mg) sodium per dose, equivalent to 37.6% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
This medicinal product contains up to 7 mmol (274 mg) potassium per dose. To be taken into consideration by patients with reduced kidney function or patients on a controlled potassium diet.
No interaction studies have been performed.
The co-administration of agents known to inhibit T cell function has not been formally studied. The co-administration of agents known to stimulate T cell function has not been investigated and the effects are unknown.
Some patients required tocilizumab and/or corticosteroid for the management of CRS (see section 4.8). The use of tocilizumab and/or steroids for CRS management was more common in patients with higher cellular expansion.
Patients with CRS treated with tocilizumab had higher Abecma cellular expansion levels, as measured by 1.4-fold and 1.6-fold higher median Cmax (N=66) and AUC0-28days (N=65), respectively, compared to patients who did not receive tocilizumab (N=61 for Cmax and N=60 for AUC0-28days). Similarly, patients with CRS treated with corticosteroids had higher Abecma cellular expansion levels, as measured by 1.7-fold and 2.2-fold higher median Cmax (N=18) and AUC0-28days (N=18), respectively, compared to patients who did not receive corticosteroids (N=109 for Cmax and N=107 for AUC0-28days).
The safety of immunisation with live viral vaccines during or following Abecma 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 Abecma treatment and until immune recovery following treatment with Abecma.
Pregnancy status for women of childbearing potential should be verified using a pregnancy test prior to starting treatment with Abecma.
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 Abecma.
There are no data from the use of idecabtagene vicleucel in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with idecabtagene vicleucel to assess whether it can cause foetal harm when administered to a pregnant woman (see section 5.3).
It is not known if idecabtagene vicleucel 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 plasma cell aplasia or hypogammaglobulinaemia. Therefore, Abecma 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 Abecma therapy should be discussed with the treating physician.
Assessment of immunoglobulin levels in newborn infants of mothers treated with Abecma should be considered.
It is unknown whether idecabtagene vicleucel cells are excreted in human milk or transferred to the breast-feeding child. A risk to the breast-fed infant cannot be excluded. Women who are breastfeeding should be advised of the potential risk to the breast-fed child.
There are no data on the effect of idecabtagene vicleucel on fertility. Effects of idecabtagene vicleucel on male and female fertility have not been evaluated in animal studies.
Abecma may have major influence on the ability to drive and use machines.
Due to the potential for neurologic adverse reactions, including altered mental status or seizures with Abecma, patients receiving Abecma should refrain from driving or operating heavy or potentially dangerous machines for at least 8 weeks after Abecma infusion or until resolution of neurologic adverse reactions.
The safety data described in this section reflect the exposure to Abecma in the KarMMa and CRB-401 studies in which 184 patients with relapsed and refractory multiple myeloma received Abecma. The median duration of follow-up was 15.5 months. The most common adverse reactions included neutropenia (91.3%), CRS (81.0%), anaemia (70.7%), thrombocytopenia (66.8%), infections – pathogen unspecified (53.8%), leucopenia (48.4%), fatigue (39.1%), diarrhoea (36.4%), hypokalaemia (34.2%), hypophosphataemia (32.6%), nausea (32.6%), lymphopenia (31.5%), pyrexia (28.8%), cough (27.2%), hypocalcaemia (26.6%), infections – viral (26.1%), headache (23.9%), hypomagnesaemia (22.3%), upper respiratory tract infection (21.7%), arthralgia (20.7%), oedema peripheral (20.1%), decreased appetite (19.6%), hypogammaglobulinaemia (19.6%) and febrile neutropenia (16.3%); other common adverse events occurring at lower frequency and considered clinically important included pneumonia (10.3%), tremor (8.2%), somnolence (5.4%), aphasia (4.3%), encephalopathy (4.3%) and syncope (4.3%).
Serious adverse reactions occurred in 70.1% of patients. The most common serious adverse reactions included CRS (17.4%), pneumonia (7.1%), febrile neutropenia (6.0%) and pyrexia (6.0%); other serious adverse events occurring at lower frequency and considered clinically important include neutropenia (4.3%), sepsis (3.8%), thrombocytopenia (3.8%), confusional state (2.2%), dyspnoea (2.2%), hypoxia (1.6%), mental status changes (1.6%) and encephalopathy (1.6%).
The most common Grade 3 or 4 adverse reactions were neutropenia (88.6%), anaemia (58.2%), thrombocytopenia (53.5%), leucopenia (45.1%), lymphopenia (30.4%), infections – pathogen unspecified (17.9%), hypophosphataemia (17.4%), febrile neutropenia (14.7%), hypocalcaemia (7.1%), infections – viral (7.1%), pneumonia (6.0%), CRS (5.4%), hypertension (5.4%) and hyponatraemia (5.4%).
Grade 3 or 4 adverse reactions were more often observed within the initial 8 weeks post-infusion (97.8%) compared to after 8 weeks post-infusion (60.8%). The most frequently reported Grade 3 or 4 adverse reactions reported within the first 8 weeks after infusion were neutropenia (87.0%), anaemia (56.0%), thrombocytopenia (48.4%), leucopenia (44.0%) lymphopenia (27.7%) and hypophosphataemia (16.3%).
Table 3 summarises the adverse reactions observed in 128 and 56 patients treated with Abecma across the target dose levels of 150 to 450 × 106 CAR-positive T cells (see Table 4 in section 5.1 for the corresponding dose range of CAR-positive viable T cells) in the KarMMa and CRB-401 studies, respectively. Adverse 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), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 3. Adverse reactions observed in patients treated with Abecma:
| System organ class | Adverse reaction | All grades frequency |
|---|---|---|
| Infections and infestationsa | Infections – bacterial Infections – viral Infections – pathogen unspecified Infections – fungal | Very common Very common Very common Common |
| Blood and lymphatic system disorders | Neutropenia Leucopenia Thrombocytopenia Febrile neutropenia Lymphopenia Anaemia Disseminated intravascular coagulation | Very common Very common Very common Very common Very common Very common Common |
| Immune system disorders | Cytokine release syndrome Hypogammaglobulinaemia Haemophagocytic lymphohistiocytosis* | Very common Very common Common |
| Metabolism and nutrition disorders | Hypophosphataemia Hypokalaemia Hyponatraemia Hypocalcaemia Hypoalbuminaemia Decreased appetite Hypomagnesaemia | Very common Very common Very common Very common Very common Very common Very common |
| Psychiatric disorders | Deliriumb Insomnia | Common Common |
| Nervous system disorders | Encephalopathyc Headache* Dizzinessd Seizure Hemiparesis Aphasiae Ataxiaf Motor dysfunctiong Tremor | Very common Very common Very common Common Common Common Common Common Common |
| Cardiac disorders | Tachycardia* Atrial fibrillation* | Very common Common |
| Vascular disorders | Hypertension Hypotensionh* | Very common Very common |
| Respiratory, thoracic, and mediastinal disorders | Dyspnoea Cough Pulmonary oedema Hypoxia* | Very common Very common Common Common |
| Gastrointestinal disorders | Vomiting Diarrhoea Nausea Constipation Gastrointestinal haemorrhagei | Very common Very common Very common Very common Common |
| Musculoskeletal and connective tissue disorders | Arthralgia Myalgia | Very common Common |
| General disorders and administration site conditions | Pyrexia* Fatiguej* Asthenia Oedemak Chills* | Very common Very common Very common Very common Very common |
| Investigations | Alanine aminotransferase increased Aspartate aminotransferase increased Blood alkaline phosphatase increased C-reactive protein increased* | Very common Very common Very common Common |
* Event that has been reported as a manifestation of CRS.
a Infections and infestations system organ class adverse events are grouped by pathogen type.
b Delirium includes delirium, disorientation, hallucination.
c Encephalopathy includes amnesia, bradyphrenia, cognitive disorder, confusional state, disturbance in attention, dyscalculia, dysgraphia, encephalopathy, lethargy, memory impairment, mental status changes, metabolic encephalopathy, somnolence, toxic encephalopathy.
d Dizziness includes dizziness, presyncope, syncope, vertigo.
e Aphasia includes aphasia, dysarthria.
f Ataxia includes ataxia, gait disturbance.
g Motor dysfunction includes motor dysfunction, muscular spasms, muscular weakness.
h Hypotension includes hypotension, orthostatic hypotension.
i Gastrointestinal haemorrhage includes gastrointestinal haemorrhage, haemorrhoidal haemorrhage, melaena, mouth haemorrhage.
j Fatigue includes fatigue, malaise.
k Oedema includes oedema, face oedema, generalised oedema, peripheral oedema, peripheral swelling
In the pooled studies (KarMMa and CRB-401), CRS occurred in 81.0% of patients receiving Abecma. Grade 3 or higher CRS (Lee et al, 2014) occurred in 5.4% of patients, with fatal (Grade 5) CRS reported in 0.5% of patients. The median time-to-onset, any grade, was 1 day (range: 1 to 17) and the median duration of CRS was 5 days (range: 1 to 63).
The most common manifestations of CRS included pyrexia (78.3%), hypotension (32.1%), tachycardia (25.5%), chills (23.4%), hypoxia (16.3%), C-reactive protein increased (16.3%), headache (14.7%) and fatigue (10.9%). Grade 3 or higher events that may be observed in association with CRS included atrial fibrillation, capillary leak syndrome, hypotension, hypoxia and HLH/MAS.
Of the 184 patients, 45.1% of patients received tocilizumab; 32.6% received a single dose while 12.5% received more than 1 dose of tocilizumab for treatment of CRS. Overall, across the target dose levels, 15.8% of patients received at least 1 dose of corticosteroids for treatment of CRS. Of the 92 patients, at the target dose of 450 × 106 CAR-positive T cells, 54.3% of patients received tocilizumab and 22.8% received at least 1 dose of corticosteroids for treatment of CRS. See section 4.4 for monitoring and management guidance.
In the pooled studies, of the 184 patients, independent of investigator attribution of neurotoxicity, the most frequent neurologic or psychiatric adverse reactions included headache (28.8%), dizziness (15.2%), confusional state (13.0%), insomnia (9.8%), anxiety (8.2%), tremor (8.2%), and somnolence (6.5%). Other neurological adverse reactions occurring at a lower frequency and considered clinically important included aphasia (4.3%) and encephalopathy (4.3%).
Neurotoxicity identified by the investigators, which was the primary method of assessing CAR T cell-associated neurotoxicity in the KarMMa study only, occurred in 18.0% of the 128 patients receiving Abecma, including Grade 3 in 3.1% of patients (with no Grade 4 or 5 events). The median time to onset of the first event was 2 days (range: 1 to 10). The median duration was 3 days (range: 1 to 26). Overall, 7.8% of patients received at least 1 dose of corticosteroid for treatment of CAR T cellassociated neurotoxicity, while at the target dose of 450 × 106 CAR-positive T cells, 14.8% of patients received at least 1 dose of corticosteroids. The most common manifestations of investigator identified neurotoxicity included confusional state (9.4%), encephalopathy (5.5%), aphasia (4.7%), hallucination (3.1%), and mental status changes (3.1%). See section 4.4 for monitoring and management guidance.
In the pooled studies, infections occurred in 71.2% of patients. Grade 3 or 4 infections occurred in 23.4% of patients. Grade 3 or 4 infections with an unspecified pathogen occurred in 17.9%, viral infections in 7.1%, bacterial infections in 3.8% and fungal infections in 0.5% of patients. Fatal infections of unspecified pathogen were reported in 1.6% of patients and 0.5% of patients had fatal fungal or viral infection. See section 4.4 for monitoring and management guidance.
Febrile neutropenia (Grade 3 or 4) was observed in 14.7% of patients after Abecma infusion. Febrile neutropenia may be concurrent with CRS. See section 4.4 for monitoring and management guidance.
Patients may exhibit prolonged cytopenias following lymphodepleting chemotherapy and Abecma infusion. In the pooled studies, 34.8% of the 178 patients who had Grade 3 or 4 neutropenia and 72.7% of the 110 patients who had Grade 3 or 4 thrombocytopenia during the first month following Abecma infusion had not resolved by last assessment during the first month. Among the 62 patients with neutropenia not resolved by month 1, 82.3% recovered from Grade 3 or 4 neutropenia with a median time to recovery from Abecma infusion of 1.9 months. Of the 80 patients with thrombocytopenia not resolved by month 1, 71.3% recovered from Grade 3 or 4 thrombocytopenia with the median time to recovery of 2.2 months. See section 4.4 for monitoring and management guidance.
Hypogammaglobulinaemia was reported in 19.6% of patients treated with Abecma in the pooled studies with a median time to onset of 100 days (range 15 to 326). See section 4.4 for monitoring and management guidance.
Abecma has the potential to induce anti-CAR antibodies. In clinical studies, humoral immunogenicity of Abecma was measured by determination of anti-CAR antibody in serum pre- and postadministration. In the pooled studies, 4.3% of patients tested positive for pre-infusion anti-CAR antibodies and post-infusion anti-CAR antibodies were detected in 50.5% of the patients. There is no evidence that the presence of pre-existing or post-infusion anti-CAR antibodies impact the cellular expansion, safety or effectiveness of Abecma.
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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