Prescribing information For Healthcare Professionals Only

ACTIVE INGREDIENT(S): ciltacabtagene autoleucel 

Please refer to Summary of Product Characteristics (SmPC) before prescribing.

INDICATION(S): CARVYKTI is indicated for the treatment of adult patients with relapsed and refractory multiple myeloma who have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 antibody and have demonstrated disease progression on the last therapy.

DOSAGE & ADMINISTRATION: CARVYKTI must be administered in a qualified treatment centre. Therapy should be initiated under the direction and supervision of a healthcare professional experienced in the treatment of haematological malignancies and trained for administration and management of patients treated with CARVYKTI. Tocilizumab for use in the event of cytokine release syndrome and emergency equipment must be available per patient prior to infusion. The treatment centre must have access to additional doses of tocilizumab within 8 hours. In the exceptional case where tocilizumab is not available, suitable alternative measures to treat CRS instead of tocilizumab must be available prior to infusion.
Adults: Treatment consists of a single dose for infusion. The target dose is 0.75 x 10⁶ CAR-positive viable T cells/kg of body weight (not exceeding 1.0 × 10⁸ CAR-positive viable T cells). Bridging therapy: HCP must consider bridging therapy before infusion with CARVYKTI to reduce tumour burden or stabilise the disease. Pre-treatment (lymphodepleting regimen): A lymphodepleting regimen of cyclophosphamide 300 mg/m² intravenous and fludarabine 30 mg/m² intravenous should be administered daily for 3 days. CARVYKTI infusion should be administered 5 to 7 days after the start of the lymphodepleting regimen. For additional guidance see corresponding SmPC of cyclophosphamide and fludarabine. Premedication: The following pre-infusion medications should be administered to all patients 30 to 60 minutes prior to CARVYKTI infusion: Antipyretic (oral or intravenous paracetamol 650 to 1,000 mg), antihistamine (oral or intravenous diphenhydramine 25 to 50 mg or equivalent). Systemic corticosteroids should be avoided. 
Children: The safety and efficacy of CARVYKTI has not been established. No data are available. 
Elderly: No dose adjustment is required.

CONTRAINDICATIONS: Hypersensitivity to the active substance or to any of the excipients. Contraindications of the lymphodepleting chemotherapy and supportive therapy should be considered.

SPECIAL WARNINGS & PRECAUTIONS: 
Traceability: The name of the medicinal product, the batch number and the name of the treated patient should be kept for 30 years after the expiry date of the medicinal product.
General: CARVYKTI is solely for autologous use and 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 clinically significant active infection or inflammatory disorders, grade ≥ 3 non-haematologic toxicities of cyclophosphamide and fludarabine lymphodepletion regimen (except for Grade 3 nausea, vomiting, diarrhoea, or constipation), CARVYKTI infusion should be delayed until resolution of these events to Grade ≤ 1; active graft versus host disease. 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. 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. Patients should be instructed to remain within proximity of a qualified clinical facility for at least 4 weeks following infusion.
Cytokine release syndrome (CRS): CRS, including fatal or life-threatening reactions, can occur after CARVYKTI infusion. Potentially life-threatening complications of CRS may include cardiac dysfunction, neurologic toxicity and haemophagocytic lymphohistiocytosis (HLH). Patients who develop HLH may have an increased risk of severe bleeding. 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. 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. For the management of CRS, please refer to SmPC. Laboratory testing to monitor for disseminated intravascular coagulation, haematology parameters, as well as pulmonary, cardiac, renal, and hepatic function should be considered. Evaluation for HLH should be considered in patients with severe or unresponsive CRS. Consider reducing baseline burden of disease with bridging therapy prior to infusion with CARVYKTI in patients with high tumour burden.

Neurologic toxicities: Neurologic toxicities occur frequently following treatment with CARVYKTI and can be fatal or life threatening. The onset of neurologic toxicity can be concurrent with CRS, following resolution of CRS or in the absence of CRS. At the first sign of neurologic toxicity including ICANS, neurology evaluation should be considered. Rule out other causes of neurologic symptoms and provide intensive care and supportive therapy for severe or life-threatening neurologic toxicities. 

Immune effector cell-associated neurotoxicity syndrome (ICANS): Patients receiving CARVYKTI may experience fatal or life-threatening ICANS following treatment with CARVYKTI, including before CRS onset, concurrent with CRS, following resolution of CRS or in the absence of CRS. Symptoms include aphasia, slow speech, dysgraphia, encephalopathy, depressed level of consciousness and confusional state. Please refer to the SmPC for further information.

Movement and neurocognitive toxicity with signs and symptoms of parkinsonism: Neurologic toxicity of movement and neurocognitive toxicity with signs and symptoms of parkinsonism has been reported in trials of CARVYKTI. Please refer to the SmPC for further information.

Guillain-Barré syndrome: Guillain-Barré syndrome (GBS) has been reported after treatment with CARVYKTI. Symptoms reported include those consistent with Miller-Fisher variant of GBS, motor weakness, speech disturbances, and polyradiculoneuritis. Please refer to the SmPC for further information.

Peripheral neuropathy: Occurrence of peripheral neuropathy, including sensory, motor, or sensorimotor, have been reported in trials of CARVYKTI. Patients should be monitored for signs and symptoms of peripheral neuropathies. Management with short-course systemic corticosteroids should be considered, depending on the severity and progression of signs and symptoms.

Cranial nerve palsies: Occurrence of 7th, 3rd, 5th, and 6th cranial nerve palsy, some of which were bilateral, worsening of cranial nerve palsy after improvement, and occurrence of peripheral neuropathy in patients with cranial nerve palsy have been reported in trials of CARVYKTI. Patients should be monitored for signs and symptoms of cranial nerve palsies. Management with short-course systemic corticosteroids should be considered, depending on the severity and progression of signs and symptoms.

Prolonged and recurrent cytopenias: Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and CARVYKTI infusion and should be managed according to local guidelines, 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. 

Serious infections and febrile neutropenia: Patients should be monitored for signs and symptoms of infection prior to and during treatment with CARVYKTI and treated appropriately. 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. 

Viral reactivation: 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. Screening for HBV, HCV and HIV and other infectious agents must be performed before collection of cells for manufacturing. 
Hypogammaglobulinaemia: Immunoglobulin levels should be monitored after treatment and treated according to standard guidelines, including administration of immunoglobulin replacement, antibiotic prophylaxis and monitoring for infection. 
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. 

Interference with virological 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. 
Blood, organ, tissue and cell donation: Patients treated with CARVYKTI should not donate blood, organs, tissues and cells for transplantation. Hypersensitivity: 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. Please refer to SmPC for further information.
Long-term follow-up: Patients are expected to enrol and be followed in a registry in order to better understand the long-term safety and efficacy of CARVYKTI.

SIDE EFFECTS: 
Very common: Bacterial infection, Upper respiratory tract infection, Neutropenia, Thrombocytopenia, Anaemia, Leukopenia, Lymphopenia, Febrile neutropenia, Coagulopathy, Hypofibrinogenaemia, Cytokine release syndrome, Hypocalcaemia, Hypophosphataemia, Decreased appetite, Hypokalaemia, Hypoalbuminaemia, Hyponatraemia, Hypomagnesaemia, Encephalopathy, Immune effector cell-associated neurotoxicity syndrome, Motor dysfunction, Neuropathy peripheral, Dizziness, Headache, Tachycardia, Hypotension, Hypertension, Hypoxia, Dyspnoea, Cough, Diarrhoea, Nausea, Vomiting, Constipation, Abdominal pain, Musculoskeletal pain, Pyrexia, Fatigue, Chills, Oedema, Pain, Transaminase elevation, Gamma-glutamyltransferase increased, Serum ferritin increased, Blood lactate dehydrogenase increased, Blood alkaline phosphatase increased. Common: Sepsis, Pneumonia, Viral infection, Fungal infection, Cytomegalovirus infection, Haemophagocytic lymphohistiocytosis, Delirium, Personality changes, Insomnia, Aphasia, Guillain-Barré syndrome, Cranial nerve palsies, Paresis, Ataxia, Tremor, Neurotoxicity, Cardiac arrhythmias, Haemorrhage, Thrombosis, Hyperbilirubinaemia, Renal failure, C-reactive protein increased, Rash.
Refer to the SmPC for other side effects.

PREGNANCY: 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. 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.

LACTATION: 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.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES: Due to the potential for neurologic events, patients should be advised to refrain from driving and engaging in hazardous occupations in the 8 weeks following CARVYKTI infusion and in the event of new onset of any neurological symptoms.

INTERACTIONS: 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.

SPECIAL PRECAUTIONS FOR DISPOSAL AND OTHER HANDLING: CARVYKTI should be transported within the facility in closed, break-proof and leak-proof containers. CARVYKTI must remain ≤ -120 °C at all times, until the content of the bag is thawed for infusion. Once thawed, the entire contents of the CARVYKTI bag should be administered by intravenous infusion within 2.5 hours at room temperature (20 °C to 25 °C), using infusion sets fitted with an in-line filter. Do NOT use a leukodepleting filter.

LEGAL CATEGORY: POM

MARKETING AUTHORISATION NUMBER: PLGB 00242/0745

MARKETING AUTHORISATION HOLDER: Janssen-Cilag Ltd, 50-100 Homers Farm Way, High Wycombe, Buckinghamshire, HP12 4EG, UK.
FURTHER INFORMATION IS AVAILABLE FROM: Janssen-Cilag Limited, 50-100 Holmers Farm Way, High Wycombe, Buckinghamshire, HP12 4EG, UK.

Prescribing information last revised: May 2023