Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Janssen-Cilag International NV, Turnhoutseweg 30, B-2340 Beerse, Belgium
Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.
Contraindications of the lymphodepleting chemotherapy and supportive therapy should be considered.
The traceability requirements of cell-based advanced therapy medicinal products must apply. To ensure traceability, the name of the medicinal product, the batch number and the name of the treated patient should be kept for a period of 30 years after the expiry date of the medicinal product.
CARVYKTI is intended solely for autologous use and must not, under any circumstances, be administered to other patients. CARVYKTI must not be infused if the information on the product labels and Lot Information Sheet does not match the patient’s identity.
CARVYKTI infusion should be delayed if a patient has any of the following conditions:
Patients with active or prior history of significant central nervous system (CNS) disease 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 CARVYKTI in patients with CNS involvement of myeloma or other pre-existing, clinically relevant CNS illnesses.
The efficacy/safety of CARVYKTI in patients previously exposed to other anti-BCMA treatments is unknown.
There is limited evidence available on efficacy/safety of CARVYKTI in re-treated patients.
Patients should be monitored daily for 14 days after the CARVYKTI infusion at a qualified clinical facility, and then periodically for an additional 2 weeks after CARVYKTI infusion, for signs and symptoms of CRS, neurologic events and other toxicities (see section 4.4).
Patients should be instructed to remain within proximity of a qualified clinical facility for at least 4 weeks following infusion.
Cytokine release syndrome, including fatal or life-threatening reactions, can occur after CARVYKTI infusion.
Nearly all patients experienced CRS after CARVYKTI infusion, with majority of these being Grade 1 or Grade 2 (see section 4.8). The median time from CARVYKTI infusion (Day 1) to onset of CRS was 7 days (range: 1 to 12 days). Approximately 90% of patients experienced CRS onset after Day 3 of receiving the CARVYKTI infusion.
In almost all cases, duration of CRS ranged from 1 to 14 days (median duration, 4 days). Eighty-nine percent of patients had a CRS duration of ≤7 days.
Clinical signs and symptoms of CRS may include, but are not limited to, fever (with or without rigors), chills, hypotension, hypoxia and elevated liver enzymes. Potentially life-threatening complications of CRS may include cardiac dysfunction, neurologic toxicity and haemophagocytic lymphohistiocytosis (HLH). Patients should be closely monitored for signs or symptoms of these events, including fever. Risk factors for severe CRS include high pre-infusion tumour burden, active infection and early onset of fever or persistent fever after 24 hours of symptomatic treatment.
The infusion of CARVYKTI should be delayed if the patient has unresolved serious adverse reactions from preceding lymphodepleting or bridging therapies (including cardiac toxicity and pulmonary toxicity), rapid disease progression and clinically significant active infection (see section 4.2). Appropriate prophylactic and therapeutic treatment for infections should be provided, and complete resolution of any active infections should be ensured prior to CARVYKTI infusion. Infections may also occur concurrently with CRS and may increase the risk of a fatal event.
The availability of at least one dose of tocilizumab for use in the event of CRS should be ensured prior to infusion. The qualified 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 signs and symptoms of CRS daily for 14 days after the CARVYKTI infusion at a qualified clinical facility, and then periodically for an additional two weeks after CARVYKTI infusion.
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 immediately evaluated for hospitalisation and treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids should be instituted as indicated in Table 1 below.
Evaluation for HLH should be considered in patients with severe or unresponsive CRS. For patients with high pre-infusion tumour burden, early onset of fever, or persistent fever after 24 hours, early tocilizumab should be considered. The use of myeloid growth factors, particularly granulocyte macrophage-colony stimulating factor (GM-CSF), should be avoided during CRS. Consider reducing baseline burden of disease with bridging therapy prior to infusion with CARVYKTI in patients with high tumour burden (see section 4.2).
If CRS is suspected, manage according to the recommendations in Table 1. Supportive care for CRS (including but not limited to anti-pyretic agents, IV fluid support, vasopressors, supplemental oxygen, etc.) should be administered as appropriate. Laboratory testing to monitor for disseminated intravascular coagulation, haematology parameters, as well as pulmonary, cardiac, renal, and hepatic function should be considered. Other monoclonal antibodies targeting cytokines (for example, anti-IL1 and/or anti-TNFα), or therapy directed at reduction and elimination of CAR-T cells, may be considered for patients who develop high grade CRS and HLH that remain severe or life-threatening following prior administration of tocilizumab and corticosteroids.
Table 1. Cytokine release syndrome management with tocilizumab and corticosteroids:
| Grade | Presenting Symptoms | Tocilizumaba | Corticosteroids |
|---|---|---|---|
| Grade 1 | Temperature ≥38°Cb | May be considered | N/A |
| Grade 2 | Temperature ≥38°Cb with either: Hypotension responsive to fluids and not requiring vasopressors. Or oxygen requirement of low-flow nasal cannulac or blow-by | Administer tocilizumab 8 mg/kg intravenously over 1 hour (not to exceed 800 mg). Repeat tocilizumab every 8 hours as needed, if not responsive to intravenous fluids or increasing supplemental oxygen. Limit to a maximum of 3 doses in a 24-hour period; maximum total of 4 doses. | Manage per guidance below if no improvement within 24 hours of starting tocilizumab. |
| Grade 3 | Temperature ≥38°Cb with either: Hypotension requiring one vasopressor with or without vasopressin. Or oxygen requirement of high-flow nasal cannulac, facemask, non-rebreather mask, or Venturi mask | Administer tocilizumab 8 mg/kg intravenously over 1 hour (not to exceed 800 mg). Repeat tocilizumab every 8 hours as needed, if not responsive to intravenous fluids or increasing supplemental oxygen. Limit to a maximum of 3 doses in a 24-hour period; maximum total of 4 doses. | If no improvement, administer methylprednisolone 1 mg/kg intravenously twice daily or equivalent dexamethasone (e.g., 10 mg intravenously every 6 hours). Continue corticosteroids use until the event is Grade 1 or less, then taper over 3 days. |
| Grade 4 | Temperature ≥38°Cb with either: Hypotension requiring multiple vasopressors (excluding vasopressin). Or oxygen requirement of positive pressure (e.g., CPAP, BiPAP, intubation, and mechanical ventilation) | Administer tocilizumab 8 mg/kg intravenously over 1 hour (not to exceed 800 mg). Repeat tocilizumab every 8 hours as needed, if not responsive to intravenous fluids or increasing supplemental oxygen. Limit to a maximum of 3 doses in a 24-hour period; maximum total of 4 doses. | As above or administer methylprednisolone 1,000 mg intravenously per day for 3 days per physician discretion. If no improvement or if condition worsens, consider alternate immunosuppressants. |
Note: Monoclonal antibodies targeting cytokines (for example, anti-IL1 such as anakinra) may be considered based on institutional practice for unresponsive CRS.
a Refer to tocilizumab prescribing information for details. Consider alternative measures (see Sections 4.2. and 4.4)
b Attributed to CRS. Fever may not always be present concurrently with hypotension or hypoxia as it may be masked by interventions such as antipyretics or anticytokine therapy (e.g., tocilizumab or steroids).
c Low-flow nasal cannula is ≤6 L/min, and high-flow nasal cannula is >6 L/min.
Neurologic toxicities occur frequently following treatment with CARVYKTI and can be fatal or life-threatening (see section 4.8). The onset of neurologic toxicity can be concurrent with CRS, following resolution of CRS or in the absence of CRS.
Adverse reactions of neurologic toxicity included Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), aphasia, and confusional state. The median time from CARVYKTI infusion to first onset of ICANS was 8 days (range: 3 to 13 days) and the median duration was 4 days (range: 1 to 14 days). Adverse reactions of neurologic toxicity after recovery from CRS and/or ICANS occurred in 11% of patients (n=20). These events had a median onset of 24 days from CARVYKTI infusion (range: 5 to 108 days) with a median time to recovery of 28 days (range: 2 to 159 days).
Three percent of patients experienced a cluster of movement and neurocognitive adverse reactions which occurred after recovery from CRS and/or ICANS; that in some patients progressed to an inability to work or care for oneself (see section 4.8).
Reduction of baseline burden of disease with bridging therapy prior to infusion with CARVYKTI in patients with high tumour burden should be considered, which may mitigate the risk of developing neurologic toxicity (see section 4.8). Patients should be monitored for signs or symptoms of ICANS for four weeks after infusion. At the first sign of ICANS, the patient should be immediately evaluated for hospitalisation and treatment instituted with supportive care as indicated in Table 2 below. Early detection and aggressive treatment of CRS or ICANS may be important to prevent neurologic toxicity from occurring or worsening. Continue to monitor patients for signs and symptoms of neurologic toxicities after recovery from CRS and/or ICANS.
At the first sign of neurologic toxicity including ICANS, neurology evaluation should be considered. Rule out other causes of neurologic symptoms. Provide intensive care and supportive therapy for severe or life-threatening neurologic toxicities.
Table 2. Guidelines for the management of ICANS:
| ICANS Gradea | Presenting Symptomsb | Concurrent CRS | No Concurrent CRS |
|---|---|---|---|
| Grade 1 | ICE score 7-9c Or depressed level of consciousnessd: awakens spontaneously. | Management of CRS per Table 1. | Consider dexamethasone. |
| Grade 2 | ICE score-3-6c Or depressed level of consciousnessd: awakens to voice. | Administer tocilizumab per Table 1 for management of CRS. If no improvement after starting tocilizumab, administer 10 mg IV dexamethasonee every 6 hours, if not already taking other corticosteroids. Continue dexamethasone use until resolution to ≤ Grade 1 then taper. | Administer 10 mg IV dexamethasonee every 6 hours. Continue dexamethasone use until resolution to ≤ Grade 1, then taper. |
| Grade 3 | ICE score-0-2c or depressed level of consciousnessd: awakens only to tactile stimulus, Or seizuresd, either: • any clinical seizure, focal or generalised, that resolves rapidly, or • non-convulsive seizures on EEG that resolve with intervention, Or raised ICP: focal/local oedema on neuroimagingd. | Administer tocilizumab per Table 1 for management of CRS. In addition, administer dexamethasonee 10 mg intravenously with the first dose of tocilizumab and repeat dose every 6 hours. Continue dexamethasone use until resolution to ≤ Grade 1, then taper. | Administer dexamethasonee 10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to ≤ Grade 1, then taper. |
| Grade 4 | ICE score-0c Or depressed level of consciousnessd either: • patient is unarousable or requires vigorous or repetitive tactile stimuli to arouse, or • stupor or coma, Or seizuresd, either: • life-threatening prolonged seizure (>5 min), or • repetitive clinical or electrical seizures without return to baseline in between, Or motor findingsd: • deep focal motor weakness such as hemiparesis or paraparesis, Or, raised ICP/cerebral oedemad, with signs/symptoms such as: • diffuse cerebral oedema on neuroimaging, or • decerebrate or decorticate posturing, or • cranial nerve VI palsy, or • papilledema, or • Cushing’s triad. | Administer tocilizumab per Table 1 for management of CRS. As above or consider administration of IV methylprednisolone 1,000 mg per day, with first dose of tocilizumab and continue IV methylprednisolone 1,000 mg per day for 2 or more days. | As above or consider administration of IV methylprednisolone 1,000 mg per day for 3 days; if improves, then manage as above. |
| In case of raised ICP/cerebral oedema, refer to institutional guidelines for management. | |||
EEG=Electroencephalogram; ICE=Immune Effector Cell-Associated Encephalopathy; ICP=intracranial pressure
a Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis for any grade ICANS
b Management is determined by the most severe event, not attributable to any other cause
c If patient is arousable and able to perform ICE Assessment, assess as in Table 3 below.
d Attributable to no other cause.
e All references to dexamethasone administration are dexamethasone or equivalent.
Table 3. Immune Effector Cell-Associated Encephalopathy (ICE) Assessment:
| Immune Effector Cell-Associated Encephalopathy (ICE) Toola | |
|---|---|
| Points | |
| Orientation: Orientation to year, month, city, hospital | 4 |
| Naming: Name 3 objects (e.g., point to clock, pen, button) | 3 |
| Following commands: (e.g., 'Show me 2 fingers' or 'Close your eyes and stick out your tongue') | 1 |
| Writing: Ability to write a standard sentence | 1 |
| Attention: Count backwards from 100 by ten | 1 |
a ICE-Tool Scoring:
Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and CARVYKTI infusion and should be managed according to local guidelines. In Study MMY2001 nearly all patients had one or more Grade 3 or 4 cytopenic adverse reactions. Most patients had a median time from infusion to first onset of Grade 3 or 4 cytopenia of less than two weeks with the majority of patients recovering to Grade 2 or lower by Day 30 (see section 4.8).
Blood counts should be monitored prior to and after CARVYKTI infusion. For thrombocytopenia, supportive care with transfusions should be considered. Prolonged neutropenia has been associated with increased risk of infection. Myeloid growth factors, particularly GM-CSF, have the potential to worsen CRS symptoms and are not recommended during the first 3 weeks after CARVYKTI or until CRS has resolved.
Serious infections, including life-threatening or fatal infections, occurred in patients after CARVYKTI infusion (see section 4.8). Patients should be monitored for signs and symptoms of infection prior to and during treatment with CARVYKTI and treated appropriately. Prophylactic antimicrobials should be administered according to local guidelines. Infections are known to complicate the course and management of concurrent CRS. Patients with clinically significant active infection should not start CARVYKTI treatment until the infection is controlled.
In the event of febrile neutropenia, infection should be evaluated and managed appropriately with broad-spectrum antibiotics, fluids and other supportive care, as medically indicated.
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.
There is currently no experience with manufacturing CARVYKTI for patients testing positive for HIV, active HBV, or active HCV. Screening for HBV, HCV and HIV and other infectious agents must be performed before collection of cells for manufacturing (see section 4.2).
Hypogammaglobulinaemia may occur in patients receiving CARVYKTI.
Immunoglobulin levels should be monitored after treatment and treated according to standard guidelines, including administration of immunoglobulin replacement, antibiotic prophylaxis and monitoring for infection.
Patients treated with CARVYKTI may develop secondary malignancies. Patient should be monitored life-long for secondary malignancies. In the event a secondary malignancy occurs, the company should be contacted to obtain instructions on patient samples to collect for testing.
Due to limited and short spans of identical genetic information between the lentiviral vector used to create CARVYKTI and HIV, some HIV nucleic acid tests (NAT) may give a false positive result.
Patients treated with CARVYKTI should not donate blood, organs, tissues and cells for transplantation. This information is provided in the Patient Alert Card which should be given to the patient.
Allergic reactions may occur with infusion of CARVYKTI. Serious hypersensitivity reactions, including anaphylaxis, may occur due to the dimethyl sulfoxide (DMSO) or residual kanamycin in CARVYKTI.
Patients are expected to enrol and be followed in a registry in order to better understand the long-term safety and efficacy of CARVYKTI.
No pharmacokinetic or pharmacodynamic drug interaction studies have been performed with CARVYKTI.
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 in the clinical trials on CARVYKTI required tocilizumab, corticosteroids and anakinra for management of CRS. CARVYKTI continues to expand and persist following tocilizumab administration. Patients treated with tocilizumab (n=68) had 81% and 72% higher CARVYKTI Cmax and AUC0-28d, respectively, as compared to patients (n=29) who did not receive tocilizumab. Patients who received corticosteroids (n=28) had 75% and 112% higher Cmax and AUC0-28d, respectively, compared with patients who did not receive corticosteroids (n=69). In addition, patients who received anakinra (n=20) had 41% and 72% higher Cmax and AUC0-28d, respectively, compared with patients who did not receive anakinra (n=77).
The safety of immunisation with live viral vaccines during or following CARVYKTI treatment has not been studied. As a precautionary measure, vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during CARVYKTI treatment, and until immune recovery following treatment with CARVYKTI.
Pregnancy status for females of childbearing potential should be verified prior to starting treatment with CARVYKTI. There are insufficient exposure data to provide a recommendation concerning duration of contraception following treatment with CARVYKTI.
In clinical trials, female patients of childbearing potential were advised to practice a highly effective method of contraception, and male patients with partners of childbearing potential or whose partners were pregnant were instructed to use a barrier method of contraception, until one year after the patient has received CARVYKTI.
See the prescribing information for lymphodepleting chemotherapy for information on the need for contraception in patients who receive the lymphodepleting chemotherapy.
There are no available data on the use of CARVYKTI in pregnant women. No reproductive and developmental toxicity animal studies have been conducted with CARVYKTI. It is not known whether CARVYKTI has the potential to be transferred to the foetus and cause foetal toxicity.
Therefore, CARVYKTI is not recommended for women who are pregnant, or for women of childbearing potential not using contraception. Pregnant women should be advised there may be risks to the foetus. Pregnancy after CARVYKTI therapy should be discussed with the treating physician.
Pregnant women who have received CARVYKTI may have hypogammaglobulinaemia. Assessment of immunoglobulin levels in newborns of mothers treated with CARVYKTI should be considered.
It is unknown whether CARVYKTI is excreted in human milk. Women who are breast-feeding should be advised of the potential risk to the breast-fed infant. Following administration of CARVYKTI, the decision to consider breast-feeding should be discussed with the treating physician.
There are no data on the effect of CARVYKTI on fertility. Effects of CARVYKTI on male and female fertility have not been evaluated in animal studies (see section 5.3).
CARVYKTI has major influence on the ability to drive and use machines.
Due to the potential for neurologic events, patients receiving CARVYKTI are at risk for altered or decreased consciousness or coordination in the 8 weeks following CARVYKTI infusion (see section 4.4). Patients should be advised to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery during this initial period, and in the event of new onset of any neurological symptoms.
The safety of CARVYKTI was evaluated in 179 adult patients with multiple myeloma infused with CARVYKTI in two open label clinical trials: Study MMY2001 (N=106), which included patients from the main Phase 1b/2 cohort (United States; n=97,) and an additional cohort (Japan; n=9), and Study MMY2003 (n=73).
The most common CARVYKTI adverse reactions (≥20%) were neutropenia (91%), CRS (88%), pyrexia (88%), thrombocytopenia (73%), anaemia (72%), leukopenia (54%), lymphopenia (45%), musculoskeletal pain (43%), hypotension (41%), fatigue (40%), transaminase elevation (37%), upper respiratory tract infection (32%), diarrhoea (28%), hypocalcaemia (27%), hypophosphataemia (26%), nausea (26%), headache (25%), cough (25%), tachycardia (23%), chills (23%), encephalopathy (22%), decreased appetite (22%), oedema (22%), and hypokalaemia (20%).
Serious adverse reactions occurred in 46% of patients; serious adverse reactions reported in ≥2% of patients were CRS (15%), neutropenia (6%), ICANS (4%), sepsis (3%), thrombocytopenia (3%), febrile neutropenia (3%) and pneumonia (3%).
The most common (≥5%) Grade ≥3 non-haematological adverse reactions was transaminase elevation (16%), hypotension (8%), hypophosphataemia (8%), Gamma-glutamyltransferase increased (7%), pneumonia (7%), sepsis (6%), pyrexia (6%), fatigue (6%), hypocalcaemia (5%) and hypoxia (5%).
The most frequent (≥20%) Grade ≥3 haematological abnormalities were neutropenia (90%), anaemia (58%), leukopenia (53%), thrombocytopenia (52%) and lymphopenia (43%).
Table 4 summarises the adverse reactions that occurred in patients receiving CARVYKTI. Within each system organ class, the adverse reactions are ranked by frequency. Within each frequency grouping, where relevant, adverse reactions are presented in order of decreasing seriousness. using the following convention: 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); not known (cannot be estimated from the available data).
Table 4. Adverse reaction in patients with multiple myeloma treated with CARVYKTI (N=179):
| System organ class | Frequency | Adverse Reaction | Incidence (%) | |
|---|---|---|---|---|
| All grades | grade ≥3 | |||
| Infections and infestations | Very common | Bacterial infection*# | 10 | 4 |
| Upper respiratory tract infection* | 32 | 2 | ||
| Common | Sepsis1# | 8 | 6 | |
| Pneumonia*# | 7 | 7 | ||
| Viral infection* | 6 | 2 | ||
| Cytomegalovirus infection* | 2 | 2 | ||
| Blood and lymphatic system disorders | Very common | Neutropenia* | 91 | 90 |
| Thrombocytopenia | 73 | 52 | ||
| Anaemia | 72 | 58 | ||
| Leukopenia | 54 | 53 | ||
| Lymphopenia* | 45 | 43 | ||
| Febrile neutropenia | 12 | 11 | ||
| Coagulopathy2 | 15 | 2 | ||
| Hypofibrinogenaemia* | 12 | 2 | ||
| Immune system disorders | Very common | Cytokine release syndrome# | 88 | 4 |
| Common | Haemophagocytic lymphohistiocytosis# | 3 | 2 | |
| Hypogammaglobulinaemia* | 9 | 1 | ||
| Metabolism and nutrition disorders | Very common | Hypocalcaemia | 27 | 5 |
| Hypophosphataemia | 26 | 8 | ||
| Decreased appetite | 22 | 2 | ||
| Hypokalaemia | 20 | 3 | ||
| Hypoalbuminaemia | 19 | 1 | ||
| Hyponatraemia | 17 | 3 | ||
| Hypomagnesaemia | 16 | 0 | ||
| Psychiatric disorders | Common | Delirium3 | 4 | 1 |
| Personality changes4 | 4 | 1 | ||
| Insomnia | 9 | 0 | ||
| Nervous system disorders | Very common | Encephalopathy5 | 22 | 4 |
| Immune effector cell-associated neurotoxicity syndrome | 13 | 2 | ||
| Motor dysfunction6 | 15 | 4 | ||
| Dizziness* | 17 | 1 | ||
| Headache | 25 | 0 | ||
| Common | Aphasia7 | 7 | 1 | |
| Paresis8 | 6 | 1 | ||
| Ataxia9 | 6 | 1 | ||
| Neuropathy peripheral10 | 9 | 2 | ||
| Tremor* | 7 | 0 | ||
| Neurotoxicity# | 2 | 1 | ||
| Cardiac disorders | Very common | Tachycardia* | 23 | 1 |
| Common | Cardiac arrhythmias11 | 6 | 2 | |
| Vascular disorders | Very common | Hypotension* | 41 | 8 |
| Hypertension | 15 | 4 | ||
| Common | Haemorrhage12# | 7 | 2 | |
| Respiratory, thoracic and mediastinal disorders | Very common | Hypoxia* | 12 | 5 |
| Dyspnoea13# | 18 | 3 | ||
| Cough* | 25 | 0 | ||
| Gastrointestinal disorders | Very common | Diarrhoea | 28 | 2 |
| Nausea | 26 | 1 | ||
| Vomiting | 18 | 0 | ||
| Constipation | 17 | 0 | ||
| Abdominal pain* | 10 | 0 | ||
| Hepatobiliary disorders | Common | Hyperbilirubinaemia | 6 | 2 |
| Musculoskeletal and connective tissue disorders | Very common | Musculoskeletal pain* | 43 | 3 |
| Renal and urinary disorders | Common | Renal failure14 | 7 | 4 |
| General disorders and administration site conditions | Very common | Pyrexia | 88 | 6 |
| Fatigue* | 40 | 6 | ||
| Chills | 23 | 0 | ||
| Oedema15 | 22 | 2 | ||
| Pain* | 12 | 1 | ||
| Investigations | Very common | Transaminase elevation* | 37 | 16 |
| Gamma-glutamyltransferase increased | 13 | 7 | ||
| Serum ferritin increased | 12 | 3 | ||
| Blood lactate dehydrogenase increased | 11 | 0 | ||
| Blood alkaline phosphatase increased | 10 | 3 | ||
| Common | C-reactive protein increased | 8 | 2 | |
Adverse reactions are reported using MedDRA version 23.0
# Contains fatal outcome(s).
* Based on grouped term.
1 Sepsis includes bacteraemia, septic shock.
2 Coagulopathy includes activated partial thromboplastin time prolonged, coagulopathy, disseminated intravascular coagulation, fibrin D dimer increased, international normalised ratio increased, prothrombin level increased, and prothrombin time prolonged.
3 Delirium includes agitation, delirium, hallucination, irritability, and restlessness.
4 Personality changes includes apathy, flat affect, and reduced facial expression.
5 Encephalopathy includes amnesia, bradyphrenia, cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, lethargy, noninfective encephalitis, psychomotor retardation and sleep disorder.
6 Motor dysfunction includes bradykinesia, cogwheel rigidity, dysgraphia, micrographia, muscle rigidity, myoclonus, parkinsonism, posture abnormal, and stereotypy.
7 Aphasia includes dysarthria, slow speech, and speech disorder.
8 Paresis includes cranial nerve paralysis.
9 Ataxia includes ataxia, balance disorder, and gait disturbance.
10 Neuropathy peripheral includes peripheral motor/sensory neuropathy.
11 Cardiac arrhythmias includes supraventricular/ventricular tachycardia.
12 Haemorrhage includes conjunctival haemorrhage, epistaxis, haemoptysis, post procedural haemorrhage, pulmonary haemorrhage, retinal haemorrhage, and subarachnoid haemorrhage.
13 Dyspnoea includes dyspnoea, respiratory distress and respiratory failure.
14 Renal failure includes acute kidney injury, blood creatinine increased, and chronic kidney disease.
15 Oedema includes oedema generalised, peripheral and localised
CRS was reported in 88% of patients (n=157); 83% (n=149) of patients had CRS events that were Grade 1 or Grade 2, 4% (n=7) of patients had Grade 3 or Grade 4 CRS events and <1% (n=1) of patients had a Grade 5 CRS event. Ninety-nine percent of patients (n=155) recovered from CRS. The duration of CRS was ≤14 days for all but one patient, who had a duration of CRS of 97 days, complicated by secondary HLH with a subsequent fatal outcome. The most frequent (≥10%) signs or symptoms associated with CRS included pyrexia (85%), hypotension (34%), Aspartate aminotransferase (AST) increased (18%), and Alanine aminotransferase (ALT) increased (13%). See section 4.4 for monitoring and management guidance.
Neurologic toxicity occurred in 20% of patients (n=35); 7% (n=12) of patients had Grade 3 or Grade 4 neurologic toxicity and <1% (n=1) of patients had Grade 5 neurologic toxicity. ICANS occurred in 13% of patients (n=24), with 2% (n=4) experiencing Grade 3 or 4 ICANS. Symptoms included aphasia, slow speech, dysgraphia, encephalopathy, depressed level of consciousness and confusional state.
Adverse reactions of neurologic toxicity after recovery from CRS and/or ICANS occurred in 11% of patients (n=20). A variety of symptoms with varying severity were observed, including disturbances in consciousness, coordination and balance disturbances, movement disorders, mental impairment disorders, cranial nerve disorders, and peripheral neuropathies. Nine of these 20 patients had also previously experienced ICANS.
Three percent of patients (n=6; all male) experienced a cluster of movement and neurocognitive adverse reactions including movement (e.g., micrographia, tremors), cognitive (e.g., memory loss, disturbance in attention), and personality change (e.g., reduced facial expression, flat affect), often with subtle onset (e.g., micrographia, flat affect), that in some patients progressed to an inability to work or care for oneself. The median time to first symptom onset was 33 days (range: 14 to 108 days). These patients all presented a combination of two or more factors such as high tumour burden at baseline (bone marrow plasma cell ≥80% or serum M-spike ≥5 g/dL or serum free light chain ≥5,000 mg/L), prior Grade 2 or higher CRS, prior ICANS, and high CAR-T cell expansion and persistence. Treatment with levodopa/carbidopa (n=2), was not effective in improving symptomatology in these patients. One of these six patients experienced a fatal outcome attributed to neurotoxicity, and two patients had ongoing neurotoxicity at the time of death; the deaths were due to infection. Of the remaining patients who reported adverse reactions of neurologic toxicity after recovery from CRS and/or ICANS, two patients had a fatal outcome with ongoing neurotoxicity at the time of death; the deaths were due to respiratory failure and sepsis respectively.
Grade 3 or 4 cytopenias at Day 1 after dosing, not resolved to Grade 2 or lower by Day 30 following CARVYKTI infusion, included, thrombocytopenia (37%), neutropenia (35%), and lymphopenia (22%). After Day 60 following CARVYKTI, 26%, 13%, and 3% of patients had an occurrence of Grade 3 or 4 lymphopenia, neutropenia, and thrombocytopenia respectively, after initial recovery of their Grade 3 or 4 cytopenia.
Table 5 lists the incidences of Grade 3 or Grade 4 cytopenias occurring after dosing not resolved to Grade 2 or lower by Day 30 and Day 60, respectively.
Table 5. Incidences of prolonged cytopenias following treatment with CARVYKTI (N=179):
| Grade 3/4 (%) after Day 1 dosing | Initial Grade 3/4 (%) not recovereda to ≤Grade 2 by Day 30 | Initial Grade 3/4 (%) not recovereda to ≤Grade 2 by Day 60 | Occurrence of Grade ¾ (%) > Day 60 (after initial recoverya of Grade 3/4 | |
|---|---|---|---|---|
| Thrombocytopenia | 95 (53%) | 66 (37%) | 43 (24%) | 6 (3%) |
| Neutropenia | 174 (97%) | 62 (35%) | 27 (15%) | 24 (13%) |
| Lymphopenia | 177 (99%) | 40 (22%) | 22 (12%) | 47 (26%) |
a The laboratory result with the worst toxicity grade is used for a calendar day. Recovery definition: must have 2 consecutive Grade ≤2 results on different days if recovery period ≤10 days.
Notes: Lab results assessed after Day 1 until Day 100 are included in the analysis.
Thrombocytopenia: Grade ¾ – Platelets count <50,000 cells/µL.
Neutropenia: Grade ¾ - Neutrophil count <1,000 cells/µL.
Lymphopenia: Grade ¾ - Lymphocytes count <0.5×109 cells/L.
Percentages are based on the number of treated patients.
Infections occurred in 45% of patients (n=80); 14% of patients (n=25) experienced Grade 3 or Grade 4 infections, and fatal infections occurred in 3% of patients (n=5)-lung abscess, sepsis, septic shock, COVID-19 pneumonia and Clostridium difficile colitis. The most frequently reported (≥2%) Grade 3 or higher infections were pneumonia and sepsis. Febrile neutropenia was observed in 9% of patients with 3% experiencing serious febrile neutropenia. See section 4.4 for monitoring and management guidance.
Hypogammaglobulinaemia occurred in 9% of patients, with 1% of patients experiencing Grade 3 or Grade 4 hypogammaglobulinaemia. See section 4.4 for monitoring and management guidance.
The immunogenicity of CARVYKTI has been evaluated using a validated assay for the detection of binding antibodies against CARVYKTI pre-dose, and at multiple timepoints post-infusion. In the pooled studies (N=179), 37 of 175 (21.1%) patients with appropriate samples were positive for treatment-emergent anti-CAR antibodies. There was no clear evidence that the observed anti-CAR antibodies had an impact on the safety of CARVYKTI. Further, analysis in Study MMY2001 (n=97) showed no clear evidence to suggest that the observed anti-CAR antibodies impact CARVYKTI kinetics of initial expansion and persistence, efficacy or safety.
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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