Wirkstoffe & Arzneimittelsicherheit

Gegenanzeigen · Carvykti

CARVYKTI 3.2 × 106 – 1 × 108 cells dispersion for infusion · Abschnitt 4.3 · PDF-Seite 4

HOS-144263 · Präparat HOS-099146

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.

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Wechselwirkungen · Carvykti

CARVYKTI 3.2 × 106 – 1 × 108 cells dispersion for infusion · Abschnitt 4.5 · PDF-Seite 13

HOS-144264 · Präparat HOS-099146

No pharmacokinetic or pharmacodynamic drug interaction studies have been performed with CARVYKTI.

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Wechselwirkungen · Carvykti

CARVYKTI 3.2 × 106 – 1 × 108 cells dispersion for infusion · Abschnitt 4.5 · PDF-Seite 13

HOS-144265 · Präparat HOS-099146

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.

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Wechselwirkungen · Carvykti

CARVYKTI 3.2 × 106 – 1 × 108 cells dispersion for infusion · Abschnitt 4.5 · PDF-Seite 13

HOS-144266 · Präparat HOS-099146

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. In Study MMY2001, 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). In Study MMY3002, the results related to tocilizumab and corticosteroid were consistent with Study MMY2001.

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RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): tocilizumab (HOS-120226) anakinra (HOS-089880)

Wechselwirkungen · Carvykti

CARVYKTI 3.2 × 106 – 1 × 108 cells dispersion for infusion · Abschnitt 4.5 · PDF-Seite 13

HOS-144268 · Präparat HOS-099146

Live vaccines 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.

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Nebenwirkungen · Carvykti

CARVYKTI 3.2 × 106 – 1 × 108 cells dispersion for infusion · Abschnitt 4.8 · PDF-Seite 14

HOS-144269 · Präparat HOS-099146

Summary of the safety profile The safety of CARVYKTI was evaluated in 396 adult patients with multiple myeloma infused with CARVYKTI in three 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), Phase 2 Study MMY2003 (N=94) and Phase 3 Study MMY3002 (N=196). Patients who complete Study MMY2001, MMY2003, or MMY3002 are eligible to enroll in a separate long-term follow-up study (MMY4002).

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Nebenwirkungen · Carvykti

CARVYKTI 3.2 × 106 – 1 × 108 cells dispersion for infusion · Abschnitt 4.8 · PDF-Seite 14

HOS-144270 · Präparat HOS-099146

The most common CARVYKTI adverse reactions (≥20%) were neutropenia (90%), pyrexia (85%), CRS (83%), thrombocytopenia (60%), anemia (60%), musculoskeletal pain (40%), lymphopenia (38%), fatigue (35%), leukopenia (34%), hypotension (34%), hypogammaglobulinaemia (33%), diarrhea (32%), upper respiratory tract infection (32%), transaminase elevation (26%), headache (25%), nausea (23%), and cough (22%).

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Nebenwirkungen · Carvykti

CARVYKTI 3.2 × 106 – 1 × 108 cells dispersion for infusion · Abschnitt 4.8 · PDF-Seite 14

HOS-144271 · Präparat HOS-099146

Serious adverse reactions occurred in 44% of patients; serious adverse reactions reported in ≥2% of patients were CRS (11%), pneumonia (9%), sepsis (5%), viral infection (5%), neutropenia (4%), cranial nerve palsies, (4%), ICANS (4%), encephalopathy (3%), upper respiratory tract infection (3%), bacterial infections (2%), gastroenteritis (2%), febrile neutropenia (2%), thrombocytopenia (2%), haemophagocytic lymphohistiocytosis (2%), motor dysfunction (2%), dyspnea (2%), diarrhea (2%), and renal failure (2%).

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Nebenwirkungen · Carvykti

CARVYKTI 3.2 × 106 – 1 × 108 cells dispersion for infusion · Abschnitt 4.8 · PDF-Seite 14–15

HOS-144272 · Präparat HOS-099146

14 The most common (≥5%) Grade ≥ 3 non-haematological adverse reactions were transaminase elevation (11%), pneumonia (11%), febrile neutropenia (8%), sepsis (7%), pyrexia (7%), Gamma- glutamyltransferase increased (6%), hypotension (6%), bacterial infection (5%), and hypogammaglobulinaemia (5%).

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Nebenwirkungen · Carvykti

CARVYKTI 3.2 × 106 – 1 × 108 cells dispersion for infusion · Abschnitt 4.8 · PDF-Seite 15

HOS-144273 · Präparat HOS-099146

The most common (≥20%) Grade ≥3 haematological abnormalities were neutropenia (89%), thrombocytopenia (45%), anaemia (44%), lymphopenia (36%), and leukopenia (33%).

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Nebenwirkungen · Carvykti

CARVYKTI 3.2 × 106 – 1 × 108 cells dispersion for infusion · Abschnitt 4.8 · PDF-Seite 15

HOS-144274 · Präparat HOS-099146

Tabulated list of adverse reactions 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).

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Nebenwirkungen · Carvykti

CARVYKTI 3.2 × 106 – 1 × 108 cells dispersion for infusion · Abschnitt 4.8 · PDF-Seite 15

HOS-144275 · Präparat HOS-099146

Table 4: Adverse reaction in patients with multiple myeloma treated with CARVYKTI Incidence (%) All grade ≥ System organ class Frequency Adverse Reaction grades 3 Infections and infestations Very common Bacterial infection*# 14 5 Upper respiratory tract 32 2 infection* Viral infection* 19 4 Pneumonia*# 14 11 Common Sepsis1# 9 7 Gastroenteritis2 6 1 Urinary tract infection3 5 2 Fungal infection* 3 <1 Neoplasms benign, Common Secondary malignancy of 4 4 malignant and unspecified myeloid origin # (including cysts and polyps) Uncommon Secondary malignancy of T-cell 1 1 origin Blood and lymphatic system Very common Neutropenia* 90 89 disorders Thrombocytopenia 60 45 Anaemia4 60 44 Leukopenia 34 33 Lymphopenia 38 36 Coagulopathy5 12 3 Common Febrile neutropenia 8 8 Lymphocytosis 3 1 Immune system disorders Very common Hypogammaglobulinaemia* 33 5 Cytokine release syndrome# 83 4 Common Haemophagocytic 3 2 lymphohistiocytosis# Infusion related reactions 5 0 Metabolism and nutrition Very common Hypocalcaemia 16 3 disorders Hypophosphataemia 17 4 Decreased appetite 16 1 Hypokalaemia 17 2 Hypoalbuminaemia 11 <1 Hyponatraemia 10 2 Hypomagnesaemia 12 <1 Hyperferritinemia6 10 2 7 Psychiatric disorders Common Delirium 3 <1

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Nebenwirkungen · Carvykti

CARVYKTI 3.2 × 106 – 1 × 108 cells dispersion for infusion · Abschnitt 4.8 · PDF-Seite 15–16

HOS-144276 · Präparat HOS-099146

15  Personality changes8 3 1 Nervous system disorders Very common Encephalopathy9# 14 3 Immune effector cell-associated 11 2 neurotoxicity syndrome# Motor dysfunction10 13 2 Dizziness* 13 1 Headache 25 0 Sleep disorder11 10 1 Common Aphasia12 5 <1 Cranial nerve palsies13 7 1 Paresis14 1 <1 Ataxia15 4 <1 Tremor* 5 <1 Neurotoxicity# 1 1 Neuropathy peripheral16 7 1 Uncommon Guillain-Barre syndrome <1 <1 Cardiac disorders Very common Tachycardia* 14 1 Common Cardiac arrhythmias17 4 2 Vascular disorders Very common Hypotension* 34 6 Hypertension 11 4 Haemorrhage18# 11 2 Common Thrombosis* 4 1 Capillary leak syndrome 1 0 Respiratory, thoracic and Very common Hypoxia* 13 4 mediastinal disorders Dyspnoea19# 14 3 Cough* 22 0 Gastrointestinal disorders Very common Diarrhoea20 32 3 Nausea 23 <1 Vomiting 12 0 Constipation 15 0 Common Abdominal pain* 9 0 Immune-mediated enterocolitis Hepatobiliary disorders Common Hyperbilirubinaemia 3 1 Skin and subcutaneous Common Rash* 9 0 tissue disorders Musculoskeletal and Very common Musculoskeletal pain* 40 3 connective tissue disorders Renal and urinary Common Renal failure21 7 4 disorders General disorders and Very common Pyrexia 85 7 administration site Fatigue* 35 4 conditions Chills 15 0 Oedema22 16 1 Pain* 11 1 Investigations Very common Transaminase elevation* 26 11 Gamma-glutamyltransferase 10 6 increased Common C-reactive protein increased 7 1 Blood alkaline phosphatase 8 3 increased

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Nebenwirkungen · Carvykti

CARVYKTI 3.2 × 106 – 1 × 108 cells dispersion for infusion · Abschnitt 4.8 · PDF-Seite 16–17

HOS-144277 · Präparat HOS-099146

16 Adverse reactions are reported using MedDRA version 26.1 # Contains fatal outcome(s). * Based on grouped term. 1 Sepsis includes bacteraemia, bacterial sepsis, candida sepsis, device related bacteraemia, enterococcal bacteraemia, enterococcal sepsis, haemophilus sepsis, neutropenic sepsis, pseudomonal bacteraemia, pseudomonal sepsis, sepsis, septic shock, staphylococcal bacteraemia, streptococcal sepsis, systemic candida, and urosepsis. 2 Gastroenteritis includes enterocolitis bacterial, enterocolitis infectious, enterocolitis viral, enterovirus infection, gastroenteritis, gastroenteritis cryptosporidial, gastroenteritis rotavirus, gastroenteritis salmonella, gastroenteritis viral, gastroenteritis escherichia coli, gastrointestinal infection, and large intestine infection. 3 Urinary tract infection includes cystitis, escherichia urinary tract infection, urinary tract infection, urinary tract infection bacterial, and urinary tract infection viral. 4 Anaemia includes anaemia, hypochromic anaemia, iron deficiency anaemia and pallor. 5 Coagulopathy includes activated partial thromboplastin time prolonged, blood fibrinogen decreased, coagulation test abnormal, coagulation time prolonged, coagulopathy, disseminated intravascular coagulation, hypofibrinogenaemia, international normalised ratio increased, prothrombin level increased, and prothrombin time prolonged. 6 Hyperferritinemia includes hyperferritinaemia, and serum ferritin increased. 7 Delirium includes agitation, delirium, disorientation, euphoric mood, hallucination, irritability, and restlessness. 8 Personality changes includes affect lability, apathy, flat affect, indifference, personality change, and reduced facial expression. 9 Encephalopathy includes amnesia, bradyphrenia, cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, encephalopathy, lethargy, memory impairment, mental impairment, mental status changes, psychomotor retardation, and slow response to stimuli. 10 Motor dysfunction includes agraphia, bradykinesia, cogwheel rigidity, coordination abnormal, dysgraphia, extrapyramidal disorder, eyelid ptosis, micrographia, motor dysfunction, muscle rigidity, muscle spasms, muscle tightness, muscular weakness, myoclonus, parkinsonism, posture abnormal and stereotypy. 11 Sleep disorder includes hypersomnia, insomnia, sleep disorder, and somnolence. 12 Aphasia includes aphasia, dysarthria, slow speech, and speech disorder. 13 Cranial nerve palsies include Bell`s palsy, cranial nerve paralysis, facial nerve disorder, facial paralysis, facial paresis, IIIrd nerve paralysis, trigeminal palsy, and VIth nerve paralysis. 14 Paresis includes paresis, hemiparesis,and peroneal nerve palsy. 15 Ataxia includes ataxia, balance disorder, dysmetria, and gait disturbance. 16 Neuropathy peripheral includes neuropathy peripheral, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy, and polyneuropathy. 17 Cardiac arrhythmias include atrial fibrillation, atrial flutter, atrioventricular block complete, atrioventricular block second degree, supraventricular tachycardia, ventricular extrasystoles, and ventricular tachycardia. 18 Haemorrhage includes catheter site haemorrhage, cerebral haemorrhage, conjunctival haemorrhage, contusion, epistaxis, eye contusion, gastrointestinal haemorrhage, haematemesis, haematochezia, haematoma, haematuria, haemoptysis, infusion site haematoma, lower gastrointestinal haemorrhage, oral contusion, post procedural, haemorrhage, pulmonary haemorrhage, retinal haemorrhage, retroperitoneal haemorrhage, subarachnoid haemorrhage, and Subdural haematoma. 19 Dyspnoea includes acute respiratory failure, dyspnoea, dyspnoea exertional, respiratory failure, tachyponea and wheezing. 20 Diarrhoea includes colitis, and diarrhoea. 21 Renal failure includes acute kidney injury, blood creatinine increased, chronic kidney disease, renal failure, and renal impairment. 22 Oedema includes face oedema, fluid retention, generalised oedema, hypervolaemia, localised oedema, oedema, oedema peripheral, palatal oedema, periorbital oedema, peripheral swelling, pulmonary congestion, pulmonary oedema, scrotal oedema, and swollen tongue.

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Nebenwirkungen · Carvykti

CARVYKTI 3.2 × 106 – 1 × 108 cells dispersion for infusion · Abschnitt 4.8 · PDF-Seite 17

HOS-144278 · Präparat HOS-099146

Of the 196 patients in Study MMY3002, 20 patients who had higher risk disease progressed early and rapidly on bridging therapy prior to infusion with CARVYKTI and received CARVYKTI as subsequent therapy (see section 5.1). In these patients, MNT was reported in one patient (5%) and was mild in severity (Grade 1 or 2). CRS was reported at a higher rate for Grade 3 and Grade 4 (25%), including events of CRS complicated by HLH (10%) or DIC (10%). ICANS was reported at a higher rate (35%) and severity (10%) for Grade 3. Five patients died of fatal events related to CARVYKTI (2 due to haemorrhage in the context of HLH or DIC and 3 due to fatal infections).

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Nebenwirkungen · Carvykti

CARVYKTI 3.2 × 106 – 1 × 108 cells dispersion for infusion · Abschnitt 4.8 · PDF-Seite 17–18

HOS-144279 · Präparat HOS-099146

17 Description of selected adverse reactions

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Nebenwirkungen · Carvykti

CARVYKTI 3.2 × 106 – 1 × 108 cells dispersion for infusion · Abschnitt 4.8 · PDF-Seite 18

HOS-144280 · Präparat HOS-099146

Cytokine release syndrome CRS was reported in 83% of patients (n=330); 79% (n=314) of patients had CRS events that were Grade 1 or Grade 2, 4% (n=15) of patients had Grade 3 or Grade 4 CRS events and <1% (n=1) of patients had a Grade 5 CRS event. Ninety-eight percent of patients (n=324) recovered from CRS. The duration of CRS was ≤18 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 (82%), hypotension (28%), Aspartate aminotransferase (AST) increased (12%), and hypoxia (10%). See section 4.4 for monitoring and management guidance.

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Nebenwirkungen · Carvykti

CARVYKTI 3.2 × 106 – 1 × 108 cells dispersion for infusion · Abschnitt 4.8 · PDF-Seite 18

HOS-144281 · Präparat HOS-099146

Neurologic toxicities Neurologic toxicity occurred in 23% of patients (n=90); 6% (n=22) of patients had Grade 3 or Grade 4 neurologic toxicity and 1% (n=3) of patients had Grade 5 neurologic toxicity (one due to ICANS, one due to neurologic toxicity with ongoing parkinsonism, and one due to encephalopathy). In addition, eleven patients had fatal outcomes with ongoing neurologic toxicity at the time of death; eight deaths were due to infection (including two deaths in patients with ongoing signs and symptoms of parkinsonism, as discussed below), and one death each due to respiratory failure, cardio-respiratory arrest and intraparenchymal hemorrhage. See section 4.4 for monitoring and management guidance.

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Nebenwirkungen · Carvykti

CARVYKTI 3.2 × 106 – 1 × 108 cells dispersion for infusion · Abschnitt 4.8 · PDF-Seite 18

HOS-144282 · Präparat HOS-099146

Immune effector cell-associated neurotoxicity syndrome (ICANS) In the pooled studies (N=396), ICANS occurred in 11% of patients (n=45), with 2% (n=8) experiencing Grade 3 or 4 ICANS and <1% (n=1) Grade 5 ICANS. Symptoms included aphasia, slow speech, dysgraphia, encephalopathy, depressed level of consciousness and confusional state. The median time from CARVYKTI infusion to first onset of ICANS was 8 days (range: 2 to 15 days, except for 1 patient with onset at 26 days) and the median duration was 3 days (range: 1 to 29 days, except for 1 patient who had a subsequent fatal outcome at 40 days).

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Nebenwirkungen · Carvykti

CARVYKTI 3.2 × 106 – 1 × 108 cells dispersion for infusion · Abschnitt 4.8 · PDF-Seite 18

HOS-144283 · Präparat HOS-099146

Movement and neurocognitive toxicity with signs and symptoms of parkinsonism Of the 90 patients in the pooled studies (N=396) experiencing any neurotoxicity, nine male patients had neurologic toxicity with several signs and symptoms of parkinsonism, distinct from ICANS. The maximum toxicity grades of parkinsonism were: Grade 1 (n=1), Grade 2 (n=2), Grade 3 (n=6). The median onset of parkinsonism was 38.0 days (range: 14 to 914 days) from infusion of CARVYKTI. One patient (Grade 3) died of neurologic toxicity with ongoing parkinsonism 247 days after administration of CARVYKTI, and two patients (Grade 2 and Grade 3) with ongoing parkinsonism died of infectious causes 162 and 119 days after administration of CARVYKTI. One patient recovered (Grade 3). The remaining 5 patients, symptoms of parkinsonism were ongoing up to 996 days after administration of CARVYKTI. All 9 patients had a history of prior CRS (n=1 Grade 1; n=6 Grade 2; n=1 Grade 3; n=1 Grade 4), while 6 of 9 patients had prior ICANS (n=5 Grade 1; n=1 Grade 3).

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