Adverse reactions : תופעות לוואי

4.8    Undesirable effects

The most frequent adverse reactions of any grade in patients were hypogammaglobulinaemia (75%), cytokine release syndrome (72%), neutropenia (71%), anaemia (55%), musculoskeletal pain (52%), fatigue (41%), thrombocytopenia (40%), injection site reaction (38%), upper respiratory tract infection (37%), lymphopenia (35%), diarrhoea (28%), pneumonia (28%), nausea (27%), pyrexia (27%), headache (24%), cough (24%), constipation (21%) and pain (21%).

Serious adverse reactions were reported in 65% patients who received TECVAYLI, including pneumonia (16%), COVID-19 (15%), cytokine release syndrome (8%), sepsis (7%), pyrexia (5%), musculoskeletal pain (5%), acute kidney injury (4.8%), diarrhoea (3.0%), cellulitis (2.4%), hypoxia (2.4%), febrile neutropenia (2.4%), and encephalopathy (2.4%).

Tabulated list of adverse reactions

The safety data of TECVAYLI was evaluated in MajesTEC-1, which included 165 adult patients with multiple myeloma who received the recommended dosing regimen of TECVAYLI as monotherapy.
The median duration of TECVAYLI treatment was 8.5 (Range: 0.2 to 24.4) months.

Table 6 summarises adverse reactions reported in patients who received TECVAYLI. The safety data of TECVAYLI was also evaluated in the all treated population (N=302) with no additional adverse reactions identified.

Adverse reactions observed during clinical studies are listed below by frequency category. Frequency categories are defined as follows: 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 (frequency cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.


Table 6:    Adverse reactions in patients with multiple myeloma treated with TECVAYLI in MajesTEC-1 at the recommended dose for monotherapy use
Frequency           N=165
(All             n (%)
System Organ Class           Adverse Reaction              grades) Any Grade Grade 3 or 4 Infections and infestations Pneumonia1                       Very     46 (28%)    32 (19%) common
Sepsis2                       Common 13 (7.9%)       11 (6.7%)
COVID-193                       Very     30 (18%)    20 (12%) common
Upper respiratory tract         Very     61 (37%)     4 (2.4%) infection4                    common
Cellulitis                    Common     7 (4.2%)     5 (3.0%)
Urinary tract infection5, 21    Very     23 (14%)    10 (6.1%) common
Progressive multifocal       Uncommon 1 (0.6%)        1 (0.6%) leukoencephalopathy21
Blood and lymphatic system Neutropenia                       Very    117 (71%) 106 (64%) disorders                                                  common
Febrile neutropenia           Common     6 (3.6%)     5 (3.0%)
Thrombocytopenia                Very     66 (40%)    35 (21%) common
Lymphopenia                     Very     57 (35%)    54 (33%) common
Anaemia6
Very     90 (55%)    61 (37%) common
Leukopenia                      Very     29 (18%)    12 (7.3%) common
Hypofibrinogenaemia           Common 16 (9.7%)        2 (1.2%)
Immune system disorders      Cytokine release syndrome       Very    119 (72%)     1 (0.6%) common
Hypogammaglobulinaemia7         Very    123 (75%)     3 (1.8%) common


Metabolism and nutrition            Hyperamylasaemia            Common   6 (3.6%)    4 (2.4%) disorders                           Hyperkalaemia               Common   8 (4.8%)    2 (1.2%) Hypercalcaemia                Very   19 (12%)    5 (3.0%) common
Hyponatraemia               Common   13 (7.9%)   8 (4.8%)
Hypokalaemia                  Very   23 (14%)    8 (4.8%) common
Hypocalcaemia               Common   12 (7.3%)       0
Hypophosphataemia             Very   20 (12%)    10 (6.1%) common
Hypoalbuminaemia            Common   4 (2.4%)    1 (0.6%)
Hypomagnesaemia               Very   22 (13%)        0 common
Decreased appetite            Very   20 (12%)    1 (0.6%) common
Hypoglycaemia21             Common   4 (2.4%)       0
Nervous system disorders            Immune effector cell-       Common   5 (3.0%)       0 associated neurotoxicity syndrome
Encephalopathy8             Common   16 (9.7%)       0
Neuropathy peripheral9        Very   26 (16%)    1 (0.6%) common
Headache                      Very   39 (24%)    1 (0.6%) common
Vascular disorders                  Haemorrhage10                 Very   20 (12%)    5 (3.0%) common
Hypertension11                Very   21 (13%)    9 (5.5%) common
Hypotension21                 Very   18 (11%)    4 (2.4%) common
Respiratory, thoracic and           Hypoxia                     Common   16 (9.7%)   6 (3.6%) mediastinal disorders               Dyspnoea12                    Very   22 (13%)    3 (1.8%) common
Cough13                       Very   39 (24%)       0 common
Gastrointestinal disorders          Diarrhoea                     Very   47 (28%)    6 (3.6%) common
Abdominal pain14, 21          Very   20 (12%)    2 (1.2%) common
Vomiting                      Very   21 (13%)    1 (0.6%) common
Nausea                        Very   45 (27%)    1 (0.6%) common
Constipation                  Very   34 (21%)       0 common
Musculoskeletal and                 Musculoskeletal pain15        Very   85 (52%)    14 (8.5%) connective tissue disorders                                     common Muscle spasms21               Very   17 (10%)       0 common
General disorders and               Pyrexia                       Very   45 (27%)    1 (0.6%) administration site                                             common conditions                          Injection site reaction16     Very   62 (38%)    1 (0.6%) common
Pain17                        Very   34 (21%)    3 (1.8%) common

Oedema18                                  Very           23 (14%)                0 common
Fatigue19                                 Very           67 (41%)           5 (3.0%) common
Investigations                          Blood creatinine increased              Common            9 (5.5%)              0 Transaminase elevation20                Common           16 (9.7%)          4 (2.4%) Lipase increased                        Common           10 (6.1%)          2 (1.2%) Blood alkaline phosphatase                Very           18 (11%)           3 (1.8%) increased                               common
Gamma-                                  Common           16 (9.7%)          5 (3.0%) glutamyltransferase increased
Activated partial                       Common           13 (7.9%)          2 (1.2%) thromboplastin time prolonged
International normalised                Common           10 (6.1%)          2 (1.2%) ratio increased
Adverse events are coded using MedDRA Version 24.0.
Note: The output includes the diagnosis of CRS and ICANS; the symptoms of CRS or ICANS are excluded.
1
Pneumonia includes Enterobacter pneumonia, lower respiratory tract infection, lower respiratory tract infection viral, Metapneumovirus pneumonia, Pneumocystis jirovecii pneumonia, pneumonia, Pneumonia adenoviral, Pneumonia bacterial, Pneumonia klebsiella, Pneumonia moraxella, Pneumonia pneumococcal, Pneumonia pseudomonal, Pneumonia respiratory syncytial viral, Pneumonia staphylococcal and Pneumonia viral.
2
Sepsis includes bacteraemia, Meningococcal sepsis, neutropenic sepsis, Pseudomonal bacteraemia, Pseudomonal sepsis, sepsis and Staphylococcal bacteraemia.
3
COVID-19 includes asymptomatic COVID-19 and COVID-19.
4
Upper respiratory tract infection includes bronchitis, nasopharyngitis, pharyngitis, respiratory tract infection, respiratory tract infection bacterial, rhinitis, rhinovirus infection, sinusitis, tracheitis, upper respiratory tract infection and viral upper respiratory tract infection.
5
Urinary tract infection includes Cystitis, Cystitis escherichia, Cystitis klebsiella, Escherichia urinary tract infection, Urinary tract infection and Urinary tract infection bacterial.
6  Anaemia includes anaemia, iron deficiency and iron deficiency anaemia.
7  Hypogammaglobulinaemia includes patients with adverse events of hypogammaglobulinaemia, hypoglobulinaemia, immunoglobulins decreased, and/or patients with laboratory IgG levels below 500 mg/dL following treatment with teclistamab.
8  Encephalopathy includes confusional state, depressed level of consciousness, lethargy, memory impairment and somnolence.
9  Neuropathy peripheral includes dysaesthesia, hypoaesthesia, hypoaesthesia oral, neuralgia, paraesthesia, paraesthesia oral, peripheral sensory neuropathy and sciatica.
10 Haemorrhage includes conjunctival haemorrhage, epistaxis, haematoma, haematuria, haemoperitoneum, haemorrhoidal  haemorrhage, lower gastrointestinal haemorrhage, melaena, mouth haemorrhage and subdural haematoma.
11 Hypertension includes essential hypertension and hypertension.
12 Dyspnoea includes acute respiratory failure, dyspnoea and dyspnoea exertional.
13 Cough includes allergic cough, cough, productive cough and upper-airway cough syndrome.
14
Abdominal pain includes Abdominal discomfort, Abdominal pain and Abdominal pain upper.
15
Musculoskeletal pain includes arthralgia, back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain and pain in extremity.
16 Injection site reaction includes injection site bruising, injection site cellulitis, injection site discomfort, injection site  erythema, injection site haematoma, injection site induration, injection site inflammation, injection site oedema, injection site pruritus, injection site rash, injection site reaction and injection site swelling.
17 Pain includes ear pain, flank pain, groin pain, non-cardiac chest pain, oropharyngeal pain, pain, pain in jaw, toothache  and tumour pain.
18
Oedema includes face oedema, fluid overload, oedema peripheral and peripheral swelling.
19
Fatigue includes asthenia, fatigue and malaise.
20
Transaminase elevation includes alanine aminotransferase increased and aspartate aminotransferase increased.
21
New adverse reaction terms identified using long term follow-up from MajesTEC-1.


Description of selected adverse reactions

Cytokine release syndrome
In MajesTEC-1 (N=165), CRS was reported in 72% of patients following treatment with TECVAYLI.
One-third (33%) of patients experienced more than one CRS event. Most patients experienced CRS following Step-up Dose 1 (44%), Step-up Dose 2 (35%), or the initial maintenance dose (24%). Less than 3% of patients developed first occurrence of CRS following subsequent doses of TECVAYLI.
CRS events were Grade 1 (50%) and Grade 2 (21%) or Grade 3 (0.6%). The median time to onset of CRS was 2 (Range: 1 to 6) days after the most recent dose, with a median duration of 2 (Range: 1 to 9) days.

The most frequent signs and symptoms associated with CRS were fever (72%), hypoxia (13%), chills (12%), hypotension (12%), sinus tachycardia (7%), headache (7%), and elevated liver enzymes (aspartate aminotransferase and alanine aminotransferase elevation) (3.6% each).

In MajesTEC-1, tocilizumab, corticosteroids and tocilizumab in combination with corticosteroids were used to treat CRS in 32%, 11% and 3% of CRS events, respectively.

Neurologic toxicities, including ICANS

In MajesTEC-1 (N=165), neurologic toxicity events were reported in 15% of patients receiving TECVAYLI. Neurologic toxicity events were Grade 1 (8.5%), Grade 2 (5.5%), or Grade 4 (<1%). The most frequently reported neurologic toxicity event was headache (8%).

ICANS, including Grade 3 and higher, were reported in clinical trials and with post-marketing experience. The most frequent clinical manifestation of ICANS were confusional state, decreased level of consciousness, disorientation, dysgraphia, aphasia, apraxia, and somnolence. The onset of neurologic toxicity can be concurrent with CRS, following resolution of CRS, or in the absence of CRS. The observed time to onset of ICANS ranged from 0 to 21 days after the most recent dose.


Immunogenicity

Patients treated with subcutaneous teclistamab monotherapy (N=238) in MajesTEC-1 were evaluated for antibodies to teclistamab using an electrochemiluminescence-based immunoassay. One subject (0.4%) developed neutralising antibodies to teclistamab of low-titre.

Reporting of suspected adverse reactions

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. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il