Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
The safety of tislelizumab as monotherapy is based on pooled data in 1 534 patients across multiple tumour types who received 200 mg tislelizumab every 3 weeks. The most common adverse reaction was anaemia (29.2%). The most common grade 3/4 adverse reactions were anaemia (5.0%) and pneumonia (4.2%). 1.17% of patients experienced adverse reactions leading to death. The adverse reactions leading to death were pneumonia (0.78%), hepatitis (0.13%), pneumonitis (0.07%), dyspnoea (0.07%), decreased appetite (0.07%) and thrombocytopenia (0.07%). Among the 1 534 patients, 40.1% were exposed to tislelizumab for longer than 6 months, and 22.2% were exposed for longer than 12 months.

Tabulated list of adverse reactions

Adverse reactions reported in the pooled dataset for patients treated with Tevimbra monotherapy (n = 1 534) are presented in Table 2. Adverse reactions are listed according to system organ class in MedDRA. Within each system organ class, the adverse reactions are presented in decreasing frequency. The corresponding frequency category for each adverse reaction is 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); not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.


Table 2    Adverse reactions with Tevimbra as monotherapy (N = 1 534) 
Frequency category
Adverse reactions
(All grades)
Infections and infestations
Pneumonia1                                                 Common*
Blood and lymphatic system disorders
Anaemia2                                                  Very common Thrombocytopenia3                                          Common*
Neutropenia4                                                Common
Lymphopenia5                                                Common
Endocrine disorders
Hypothyroidism6                                           Very common Hyperthyroidism7                                            Common
Thyroiditis8                                                Common
Adrenal insufficiency9                                     Uncommon
Hypophysitis10                                                Rare
Metabolism and nutrition disorders
Hyperglycaemia11                                            Common
Hyponatraemia12                                             Common
Hypokalaemia13                                              Common
Diabetes mellitus14                                        Uncommon
Nervous system disorders
Guillain-Barré syndrome                                   Uncommon** Eye disorders
Uveitis15                                                  Uncommon
Cardiac disorders
Myocarditis16                                              Uncommon
Pericarditis                                                 Rare
Vascular disorders
Hypertension17                                              Common
Respiratory, thoracic and mediastinal disorders
Cough                                                     Very common Dyspnoea                                                   Common*
Pneumonitis18                                              Common*
Gastrointestinal disorders
Nausea                                                      Common
Diarrhoea19                                                 Common
Stomatitis20                                                Common
Pancreatitis21                                             Uncommon
Colitis22                                                  Uncommon
Coeliac disease                                               Rare
Hepatobiliary disorders
Hepatitis23                                                Common*
Skin and subcutaneous tissue disorders
Rash24                                                    Very common Pruritus                                                  Very common Severe skin reactions25                                       Rare
Stevens Johnson Syndrome26                                 Not known
Toxic Epidermal Necrolysis26                               Not known* Musculoskeletal and connective tissue disorders
Arthralgia                                                  Common
Myalgia                                                     Common
Myositis27                                                 Uncommon
Arthritis28                                                Uncommon
Renal and urinary disorders
Nephritis29                                                               Uncommon General disorders and administration site conditions
Fatigue30                                                               Very common Decreased appetite                                                      Very common* Investigations
Aspartate aminotransferase increased                                    Very common Alanine aminotransferase increased                                      Very common Blood bilirubin increased31                                             Very common Blood alkaline phosphatase increased                                      Common Blood creatinine increased                                                Common Injury, poisoning and procedural complications
Infusion related reaction32                                               Uncommon 1
Pneumonia includes preferred terms (PTs) of pneumonia, lower respiratory tract infection, lower respiratory tract infection bacterial, pneumonia bacterial, pneumonia fungal and pneumocystis jirovecii pneumonia.
2
Anaemia includes PTs of anaemia and haemoglobin decreased.
3
Thrombocytopenia includes PTs of thrombocytopenia and platelet count decreased.
4
Neutropenia includes PTs of neutropenia and neutrophil count decreased.
5
Lymphopenia includes PTs of lymphopenia, lymphocyte count decreased and lymphocyte percentage decreased.
6
Hypothyroidism includes PTs of hypothyroidism, thyroxine free decreased, tri-iodothyronine free decreased, tri-iodothyronine decreased, primary hypothyroidism and thyroxine decreased.
7
Hyperthyroidism includes PTs of hyperthyroidism, blood thyroid stimulating hormone decreased, tri- iodothyronine free increased, thyroxine free increased, thyroxine increased and tri-iodothyronine increased.
8
Thyroiditis includes PTs of thyroiditis, autoimmune thyroiditis and thyroiditis subacute.
9
Adrenal insufficiency includes PTs of adrenal insufficiency and secondary adrenocortical insufficiency.
10
Hypophysitis includes PT of hypopituitarism.
11
Hyperglycaemia includes PTs of hyperglycaemia and blood glucose increased.
12
Hyponatraemia includes PTs of hyponatraemia and blood sodium decreased.
13
Hypokalaemia includes PTs of hypokalaemia and blood potassium decreased.
14
Diabetes mellitus includes PTs of diabetes mellitus, type 1 diabetes mellitus and latent autoimmune diabetes in adults.
15
Uveitis includes PTs of uveitis and iritis.
16
Myocarditis includes PTs of myocarditis, immune-mediated myocarditis and autoimmune myocarditis.
17
Hypertension includes PTs of hypertension, blood pressure increased and essential hypertension.
18
Pneumonitis includes PTs of pneumonitis, immune-mediated lung disease, interstitial lung disease and organising pneumonia.
19
Diarrhoea includes PTs of diarrhoea and frequent bowel movements.
20
Stomatitis includes PTs of stomatitis, mouth ulceration and aphthous ulcer.
21
Pancreatitis includes PTs of amylase increased, lipase increased, pancreatitis and pancreatitis acute.
22
Colitis includes PTs of colitis and immune-mediated enterocolitis.
23
Hepatitis includes PTs of hepatitis, hepatic function abnormal, immune-mediated hepatitis, liver injury and autoimmune hepatitis.
24
Rash includes PTs of rash, rash maculo-papular, eczema, rash erythematous, dermatitis, dermatitis allergic, rash papular, urticaria, erythema, skin exfoliation, drug eruption, rash macular, psoriasis, rash pustular, dermatitis acneiform, rash pruritic, lichenoid keratosis, hand dermatitis, immune mediated dermatitis, rash follicular, acute febrile neutrophilic dermatosis, erythema nodosum and pemphigoid.
25
Severe skin reaction includes PT of erythema multiforme.
26
Post-marketing experience.
27
Myositis includes PTs of myositis and immune-mediated myositis.
28
Arthritis includes PTs of arthritis and immune-mediated arthritis.
29
Nephritis includes PTs of nephritis, focal segmental glomerulosclerosis and immune-mediated nephritis.
30
Fatigue includes PTs of fatigue, asthenia, malaise and lethargy.
31
Blood bilirubin increased includes PTs of blood bilirubin increased, bilirubin conjugated increased, blood bilirubin unconjugated increased and hyperbilirubinaemia.
32
Infusion-related reaction includes PTs of infusion-related reaction and infusion-related hypersensitivity reaction.
*including fatal outcomes
**frequency based on studies outside the monotherapy pool


Description of selected adverse reactions
The data below reflect information for significant adverse drug reactions for tislelizumab as monotherapy in clinical studies.

Immune-related pneumonitis
In patients treated with tislelizumab as monotherapy, immune-related pneumonitis occurred in 4.3% of patients, including grade 1 (0.3%), grade 2 (2.0%), grade 3 (1.5%), grade 4 (0.3%) and grade 5 (0.2%) events.

The median time from first dose to onset of the event was 3.2 months (range: 1.0 day to 16.5 months), and the median duration from onset to resolution was 6.1 months (range: 1.0+ day to 22.8+ months).
+ denotes a censored observation, with ongoing events at the time of the analysis. Tislelizumab was permanently discontinued in 1.8% of patients and tislelizumab treatment was interrupted in 1.8% of patients. Pneumonitis resolved in 45.5% of patients.

In patients treated with tislelizumab as monotherapy, pneumonitis occurred more frequently in patients with a history of prior thoracic radiation (6.3%) than in patients who did not receive prior thoracic radiation (2.8%).

Immune-related hepatitis
In patients treated with tislelizumab as monotherapy, immune-related hepatitis occurred in 1.7% of patients, including grade 1 (0.1%), grade 2 (0.5%), grade 3 (0.9%), grade 4 (0.1%) and grade 5 (0.1%) events.

The median time from first dose to onset of the event was 31.0 days (range: 8.0 days to 13.1 months), and the median duration from onset to resolution was 2.0 months (range: 1.0+ day to 37.9+ months).
+ denotes a censored observation, with ongoing events at the time of the analysis. Tislelizumab was permanently discontinued in 0.4% of patients and tislelizumab treatment was interrupted in 1.0% of patients for immune-related hepatitis. Hepatitis resolved in 50.0% of patients.

Immune-related skin adverse reactions
In patients treated with tislelizumab as monotherapy, immune-related skin adverse reactions occurred in 1.8% of patients, including grade 1 (0.4%), grade 2 (0.8%), grade 3 (0.3%) and grade 4 (0.3%) events.

The median time from first dose to onset of the event was 2.5 months (range: 7.0 days to 11.6 months). The median duration from onset to resolution was 11.4 months (range: 4.0 days to 34.0+ months). + denotes a censored observation, with ongoing events at the time of the analysis.
Tislelizumab was permanently discontinued in 0.3% of patients, and tislelizumab treatment was interrupted in 0.5% of patients. Skin adverse reactions resolved in 51.9% of patients.

Cases of SJS and TEN have been reported from post-marketing experience, some with fatal outcome (see section 4.2 and 4.4).

Immune-related colitis
In patients treated with tislelizumab as monotherapy, immune-related colitis occurred in 0.7% of patients, including grade 2 (0.6%) and grade 3 (0.1%) events.

The median time from first dose to onset of the event was 6.0 months (range: 12.0 days to 14.4 months), and the median duration from onset to resolution was 28.0 days (range: 9.0 days to 3.6 months). Tislelizumab was not permanently discontinued in any patient and tislelizumab treatment was interrupted in 0.6% of patients. Colitis resolved in 81.8% of patients.


Immune-related myositis/rhabdomyolysis
In patients treated with tislelizumab as monotherapy, immune-related myositis/rhabdomyolysis occurred in 0.9% of patients, including grade 1 (0.2%), grade 2 (0.3%), grade 3 (0.3%) and grade 4 (0.1%) events.

The median time from first dose to onset of the event was 1.8 months (range: 15.0 days to 17.6 months), and the median duration from onset to resolution was 2.1 months (range: 5.0 days to 11.2+ months). + denotes a censored observation, with ongoing events at the time of the analysis.
Tislelizumab was permanently discontinued in 0.2% of patients and tislelizumab treatment was interrupted in 0.7% of patients. Myositis/rhabdomyolysis resolved in 57.1% of patients.

Immune-related endocrinopathies
Thyroid disorders
Hypothyroidism:
In patients treated with tislelizumab as monotherapy, hypothyroidism occurred in 7.6% of patients, including grade 1 (1.4%), grade 2 (6.1%) and grade 4 (0.1%) events.

The median time from first dose to onset of the event was 3.7 months (range: 0 days to 16.6 months) and the median duration from onset to resolution was 15.2 months (range: 12.0 days to 28.6+ months).
+ denotes a censored observation, with ongoing events at the time of the analysis. Tislelizumab was not permanently discontinued in any patient and tislelizumab treatment was interrupted in 0.4% of patients. Hypothyroidism resolved in 31.9% of patients.

Hyperthyroidism:
In patients treated with tislelizumab as monotherapy, hyperthyroidism occurred in 0.6% of patients, including grade 1 (0.1%) and grade 2 (0.3%) events.

The median time from first dose to onset of the event was 31.0 days (range: 19.0 days to 14.5 months).
The median duration from onset to resolution was 1.4 months (range: 22.0 days to 4.0+ months).
+ denotes a censored observation, with ongoing events at the time of the analysis. Tislelizumab was permanently discontinued in 0.1% of patients and tislelizumab treatment was not interrupted in any patient. Hyperthyroidism resolved in 80.0% of patients.

Thyroiditis:
In patients treated with tislelizumab as monotherapy, thyroiditis occurred in 0.8% of patients, including grade 1 (0.2%) and grade 2 (0.6%) events.

The median time from first dose to onset of the event was 2.0 months (range: 20.0 days to 20.6 months). The median duration from onset to resolution was not evaluable based on currently available data (range: 22.0 days to 23.1+ months). + denotes a censored observation, with ongoing events at the time of the analysis. Tislelizumab was not permanently discontinued in any patient and tislelizumab treatment was interrupted in 0.1% of patients. Thyroiditis resolved in 16.7% of patients.

Adrenal insufficiency
In patients treated with tislelizumab as monotherapy, adrenal insufficiency occurred in 0.3% of patients, including grade 2 (0.1%), grade 3 (0.1%) and grade 4 (0.1%) events.

The median time from first dose to onset of the event was 3.1 months (range: 1.3 months to 11.6 months). The median duration from onset to resolution was not evaluable based on currently available data (range: 1.0 month to 6.5+ months). + denotes a censored observation, with ongoing events at the time of the analysis. Tislelizumab was not permanently discontinued in any patient and tislelizumab treatment was interrupted in 0.2% of patients. Adrenal insufficiency resolved in 25.0% of patients.

Hypophysitis
In patients treated with tislelizumab as monotherapy, hypopituitarism (grade 2) occurred in 0.1% of patients.
Type 1 diabetes mellitus
In patients treated with tislelizumab as monotherapy, type 1 diabetes mellitus occurred in 0.4% of patients, including grade 1 (0.1%) and grade 3 (0.3%) events.

The median time from first dose to onset of the event was 2.5 months (range: 33.0 days to 13.8 months). The median duration from onset to resolution was not evaluable based on currently available data (range: 4.0 days to 19.9+ months). + denotes a censored observation, with ongoing events at the time of the analysis. Tislelizumab was permanently discontinued in 0.1% of patients and tislelizumab treatment was interrupted in 0.1% of patients. Type 1 diabetes mellitus resolved in 16.7% of patients.

Immune-related nephritis and renal dysfunction
In patients treated with tislelizumab as monotherapy, immune-related nephritis and renal dysfunction occurred in 0.7% of patients, including grade 2 (0.3%), grade 3 (0.2%), grade 4 (0.1%) and grade 5 (0.1%) events.

The median time from first dose to onset of the event was 1.2 months (range: 3.0 days to 5.8 months).
The median duration from onset to resolution was 1.9 months (range: 3.0+ days to 16.2+ months).
+ denotes a censored observation, with ongoing events at the time of the analysis. Tislelizumab was permanently discontinued in 0.3% of patients and tislelizumab treatment was interrupted in 0.2% of patients. Immune-related nephritis and renal dysfunction resolved in 50.0% of patients.

Immune-related myocarditis
In patients treated with tislelizumab as monotherapy, immune-related myocarditis occurred in 0.5% of patients, including grade 1 (0.1%), grade 2 (0.1%), grade 3 (0.2%) and grade 4 (0.1%) events.

The median time from first dose to onset of the event was 1.6 months (range: 14.0 days to 6.1 months), and the median duration from onset to resolution was 5.1 months (range: 4.0 days to 7.6 months). Tislelizumab was permanently discontinued in 0.3% of patients and tislelizumab treatment was interrupted in 0.2% of patients. Myocarditis resolved in 57.1% of patients.

Immune checkpoint inhibitor class effects
There have been cases of the following adverse reactions reported during treatment with other immune checkpoint inhibitors which might also occur during treatment with tislelizumab: pancreatic exocrine insufficiency.

Infusion-related reactions
In patients treated with tislelizumab as monotherapy, infusion related reactions occurred in 3.5% of patients, including grade 3 (0.3%) events. Tislelizumab was permanently discontinued in 0.1% of patients and tislelizumab treatment was interrupted in 0.5% of patients.

Laboratory abnormalities
In patients treated with tislelizumab monotherapy, the proportion of patients who experienced a shift from baseline to a grade 3 or 4 laboratory abnormality was as follows: 0.1% for increased haemoglobin, 4.4% for decreased haemoglobin, 0.9% for decreased leukocytes, 8.5% for decreased lymphocytes, 1.7% for decreased neutrophils, 1.1% for decreased platelets, 2.0% for increased alanine aminotransferase, 0.4% for decreased albumin, 2.3% for increased alkaline phosphatase, 3.2% for increased aspartate aminotransferase, 2.2% for increased bilirubin, 2.0% for increased creatine kinase, 0.9% for increased creatinine, 0.9% for increased potassium, 2.2% for decreased potassium, 0.1% for increased sodium, 5.7% for decreased sodium.

Immunogenicity
Of 1 916 antidrug antibodies (ADA)-evaluable patients treated at the recommended dose of 200 mg once every 3 weeks, 18.3% of patients tested positive for treatment-emergent ADA, and neutralising antibodies (NAbs) were detected in 0.9% of patients. Population pharmacokinetic analysis showed that ADA status was a statistically significant covariate on clearance; however, the presence of treatment- emergent ADA against tislelizumab appears to have no clinically relevant impact on pharmacokinetics or efficacy.

Among ADA-evaluable patients, the following rates of adverse events (AEs) have been observed for the ADA-positive population compared to the ADA-negative population, respectively: grade ≥3 AEs 50.9% vs. 39.3%, serious adverse events (SAEs) 37.1% vs. 29.7%, AEs leading to treatment discontinuation 10.8% vs 10.2%. Patients who developed treatment-emergent ADAs tended to have overall poorer health and disease characteristics at baseline which can confound the interpretation of the safety analysis. Available data do not allow firm conclusions to be drawn on possible patterns of adverse drug reactions.

Elderly
No overall differences in safety were observed with tislelizumab monotherapy between patients aged <65 years and patients aged between 65 and 74 years. Data for patients aged 75 years and above are too limited to draw conclusions on this population.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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