Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Beigene Ireland Limited, 10 Earlsfort Terrace, Dublin 2, D02 T380, Ireland, Tel. +353 1 566 7660, E-mail: bg.ireland@beigene.com
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Patients treated with Tizveni must be given the Patient Card to be informed about the risks of immunerelated adverse reactions during Tizveni therapy (see also Package Leaflet).
The prescriber must discuss the risks of immune-related adverse reactions during Tizveni therapy with the patient.
Immune-related adverse reactions have been reported, including fatal cases, during treatment with tislelizumab (see section 4.8). The majority of these events improved with interruption of tislelizumab, administration of corticosteroids and/or supportive care. Immune-related adverse reactions have also been reported after the last dose of tislelizumab. Immune-related adverse reactions affecting more than one body system can occur simultaneously.
For suspected immune-related adverse reactions, adequate evaluation to confirm aetiology or exclude alternative aetiologies, including infection, should be ensured. Based on the severity of the adverse reaction, tislelizumab should be withheld and corticosteroids administered (see section 4.2). Based on limited data from clinical studies, administration of other systemic immunosuppressants can be considered in patients whose immune-related adverse reactions are not controlled with corticosteroid use (see sections 4.2 and 4.8). Upon improvement to grade ≤1, corticosteroid taper should be initiated and continued over at least 1 month.
Immune-related pneumonitis, including fatal cases, has been reported in patients receiving tislelizumab. Patients should be monitored for signs and symptoms of pneumonitis. Patients with suspected pneumonitis should be evaluated with radiographic imaging and infectious or diseaserelated aetiologies should be ruled out.
Patients with immune-related pneumonitis should be managed according to the treatment modifications as recommended in Table 1 (see section 4.2).
Immune-related hepatitis, including fatal cases, has been reported in patients treated with tislelizumab. Patients should be monitored for signs and symptoms of hepatitis and changes in liver function. Liver function tests should be performed at baseline and periodically during treatment.
Patients with immune-related hepatitis should be managed according to the treatment modifications as recommended in Table 1 (see section 4.2).
Immune-related skin rash or dermatitis have been reported in patients receiving tislelizumab. Patients should be monitored for suspected skin reactions and other causes should be excluded. Based on the severity of the skin adverse reactions, tislelizumab should be withheld or permanently discontinued as recommended in Table 1 (see section 4.2).
Cases of severe cutaneous adverse reactions (SCARs) have been reported in patients receiving tislelizumab. Patients should be monitored for signs or symptoms of SCARs (e.g., a prodrome of fever, flu-like symptoms, mucosal lesions or progressive skin rash) and other causes should be excluded. For suspected SCARs (including severe erythema multiforme [EM], SJS or TEN), tislelizumab should be withheld and the patient should be referred to specialised care for assessment and treatment. If SCARs, including SJS or TEN, is confirmed, tislelizumab should be permanently discontinued (see section 4.2).
Immune-related colitis, frequently associated with diarrhoea, has been reported in patients treated with tislelizumab. Patients should be monitored for signs and symptoms of colitis. Infectious and diseaserelated aetiologies should be ruled out.
Patients with immune-related colitis should be managed according to the treatment modifications as recommended in Table 1 (see section 4.2).
Immune-related endocrinopathies, including thyroid disorders, adrenal insufficiency, hypophysitis and type 1 diabetes mellitus, have been reported in patients treated with tislelizumab. These may require supportive treatment depending on the specific endocrine disorder. Long-term hormone replacement therapy (HRT) may be necessary in cases of immune-related endocrinopathies.
Patients with immune-related endocrinopathies should be managed according to the treatment modifications as recommended in Table 1 (see section 4.2).
Thyroid disorders:
Thyroid disorders, including thyroiditis, hypothyroidism and hyperthyroidism, have been reported in patients treated with tislelizumab. Patients should be monitored (at the start of treatment, periodically during treatment and as indicated based on clinical evaluation) for changes in thyroid function and clinical signs and symptoms of thyroid disorders. Hypothyroidism may be managed with HRT without treatment interruption and without corticosteroids. Hyperthyroidism may be managed symptomatically (see section 4.2).
Adrenal insufficiency:
Adrenal insufficiency has been reported in patients treated with tislelizumab. Patients should be monitored for signs and symptoms of adrenal insufficiency. Monitoring of adrenal function and hormone levels should be considered. Corticosteroids and HRT should be administered as clinically indicated (see section 4.2). Hypophysitis Hypophysitis has been reported in patients treated with tislelizumab. Patients should be monitored for signs and symptoms of hypophysitis/hypopituitarism. Monitoring of pituitary function and hormone levels should be considered. Corticosteroids and HRT should be administered as clinically indicated (see section 4.2).
Type 1 diabetes mellitus:
Type 1 diabetes mellitus, including diabetic ketoacidosis, has been reported in patients treated with tislelizumab. Patients should be monitored for hyperglycaemia and other signs and symptoms of diabetes. Insulin should be administered for type 1 diabetes. In patients with severe hyperglycaemia or ketoacidosis (grade ≥3), tislelizumab should be withheld and anti-hyperglycaemic treatment should be administered (see section 4.2). Treatment with tislelizumab may be resumed when metabolic control is achieved.
Immune-related nephritis with renal dysfunction has been reported in patients treated with tislelizumab. Patients should be monitored for changes in renal function (elevated serum creatinine), and other causes of renal dysfunction should be excluded.
Patients with immune-related nephritis with renal dysfunction should be managed according to the treatment modifications as recommended in Table 1 (see section 4.2).
Other clinically important immune-related adverse reactions were reported with tislelizumab: myositis, myocarditis, arthritis, polymyalgia rheumatica, pericarditis and Guillain-Barré syndrome (see section 4.8).
Patients with other immune-related adverse reactions should be managed according to the treatment modifications as recommended in Table 1 (see section 4.2).
Solid organ transplant rejection:
Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with PD-1 inhibitors. Treatment with tislelizumab may increase the risk of rejection in solid organ transplant recipients. The benefit of treatment with tislelizumab versus the risk of possible organ rejection should be considered in these patients.
Severe infusion-related reactions (grade 3 or higher) have been reported in patients receiving tislelizumab (see section 4.8). Patients should be monitored for signs and symptoms of infusionrelated reactions.
Infusion-related reactions should be managed as recommended in Table 1 (see section 4.2).
Patients with any of the following conditions were excluded from clinical studies: baseline ECOG performance score greater than or equal to 2; active brain or leptomeningeal metastases; active autoimmune disease or history of autoimmune disease that may relapse; any condition requiring systemic treatment with either corticosteroids (>10 mg/day prednisone or equivalent) or other immunosuppressants within the 14 days prior to study treatment; active or untreated HIV; untreated hepatitis B or hepatitis C carriers; history of interstitial lung disease; administration of live vaccine within the 14 days prior to study treatment; infection requiring systemic therapy within the 14 days prior to study treatment; history of severe hypersensitivity to another monoclonal antibody. In the absence of data, tislelizumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.
Each ml of this medicinal product contains 0.069 mmol (or 1.6 mg) sodium. This medicinal product contains 16 mg sodium per 10 ml vial, equivalent to 0.8% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Tislelizumab is a humanised monoclonal antibody, cleared from the circulation through catabolism. As such, formal pharmacokinetic interaction studies have not been conducted. As monoclonal antibodies are not metabolised by cytochrome P450 (CYP) enzymes or other drug-metabolising enzymes, inhibition or induction of these enzymes by co-administered medicinal products is not anticipated to affect the pharmacokinetics of tislelizumab.
The use of systemic corticosteroids and other immunosuppressants at baseline, before starting tislelizumab, except for physiological doses of systemic corticosteroid (10 mg/day prednisone or equivalent), should be avoided because of their potential interference with the pharmacodynamic activity and efficacy. However, systemic corticosteroids and other immunosuppressants can be used after starting tislelizumab to treat immune-related adverse reactions (see section 4.4). Corticosteroids can also be used as pre-medication when tislelizumab is used in combination with chemotherapy, as antiemetic prophylaxis and/or to alleviate chemotherapy-related adverse reactions.
Tislelizumab should not be used in women of childbearing potential not using effective contraception unless the clinical condition of the woman requires treatment with tislelizumab. Women of childbearing potential should use effective contraception (methods that result in less than 1% pregnancy rates) during treatment and for at least 4 months following the last dose of tislelizumab.
There are no available data on the use of tislelizumab in pregnant women. Based on its mechanism of action, tislelizumab can cause foetal harm when administered to a pregnant woman.
Animal reproduction studies have not been conducted with tislelizumab. However, in murine models of pregnancy, blockade of PD-1/PD-L1 signalling has been shown to disrupt tolerance to the foetus and to result in increased foetal loss.
Human IgG4 (immunoglobulins) are known to cross the placental barrier. Therefore, tislelizumab, being an IgG4 variant, has the potential to be transmitted from the mother to the developing foetus. Women should be advised of the potential risk to a foetus.
Tislelizumab should not be used during pregnancy unless the clinical condition of the woman requires treatment with tislelizumab.
It is unknown whether tislelizumab is excreted in human milk. Its effects on breast-fed newborns/infants and on milk production are also unknown.
Because of the potential for serious adverse drug reactions in breast-fed newborns/infants from Tizveni, women should be advised not to breast-feed during treatment and for at least 4 months after the last dose of Tizveni.
No clinical data are available on the possible effects of tislelizumab on fertility. No reproductive and development toxicity studies have been conducted with tislelizumab. Based on a 3-month repeat-dose toxicity study, there were no notable effects in the male and female reproductive organs in cynomolgus monkeys when tislelizumab was given at doses of 3, 10, or 30 mg/kg every 2 weeks for 13 weeks (7 dose administrations) (see section 5.3).
Tizveni has minor influence on the ability to drive and use machines. In some patients, fatigue has been reported following administration of tislelizumab (see section 4.8).
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 reactions were anaemia (29.2%), fatigue (22.9%) and aspartate aminotransferase increased (20.9%). The most common grade ¾ adverse reactions were anaemia (5.0%), pneumonia (4.2%), hyponatraemia (2.7%), aspartate aminotransferase increased (2.6%), blood bilirubin increased (2.0%), pneumonitis (2.0%) and fatigue (2.0%). 1.2% 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.
The safety of tislelizumab given in combination with chemotherapy is based on data in 497 patients with NSCLC. The most common adverse reactions were anaemia (88.3%), neutropenia (86.5%), thrombocytopenia (67.0%), alanine aminotransferase increased (46.1%), fatigue (43.1%), aspartate aminotransferase increased (42.3%), nausea (41.4%), decreased appetite (40.6%) and rash (26.4%). The most common grade ¾ adverse reactions were neutropenia (58.6%), thrombocytopenia (18.3%), anaemia (15.7%), pneumonia (5.0%), pneumonitis (3.4%), alanine aminotransferase increased (3.2%), lymphopenia (2.8%), rash (2.6%) and fatigue (2.2%). 1.6% of patients experienced adverse reactions leading to death. The adverse reactions leading to death were pneumonitis (0.60%), dyspnoea (0.40%), myocarditis (0.40%), pneumonia (0.20%) and hypokalaemia (0.20%). Among the 497 patients, 65.8% were exposed to tislelizumab for longer than 6 months, and 37.8% were exposed for longer than 12 months.
Adverse reactions reported in the pooled dataset for patients treated with Tizveni monotherapy (n=1 534) and in combination with chemotherapy (n=497) 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 Tizveni as monotherapy (n=1 534) and in combination with chemotherapy (n=497):
| Tislelizumab monotherapy n=1 534 | Tislelizumab plus chemotherapy n=497 | |
|---|---|---|
| Adverse reactions | Frequency category (All grades) | Frequency category (All grades) |
| Infections and infestations | ||
| Pneumonia1 | Common* | Very common* |
| Blood and lymphatic system disorders | ||
| Anaemia2 | Very common | Very common |
| Thrombocytopenia3 | Common* | Very common |
| Neutropenia4 | Common | Very common |
| Lymphopenia5 | Common | Very common |
| Endocrine disorders | ||
| Hypothyroidism6 | Very common | Very common |
| Hyperthyroidism7 | Common | Very common |
| Thyroiditis8 | Common | Uncommon |
| Adrenal insufficiency9 | Uncommon | - |
| Hypophysitis10 | Rare | - |
| Metabolism and nutrition disorders | ||
| Hyperglycaemia11 | Common | Very common |
| Hyponatraemia12 | Common | Very common |
| Hypokalaemia13 | Common | Very common* |
| Diabetes mellitus14 | Uncommon | Common |
| Nervous system disorders | ||
| Guillain-Barré syndrome | - | Uncommon |
| Eye disorders | ||
| Uveitis15 | Uncommon | - |
| Cardiac disorders | ||
| Myocarditis16 | Uncommon | Common* |
| Pericarditis | Rare | - |
| Vascular disorders | ||
| Hypertension17 | Common | Common |
| Respiratory, thoracic and mediastinal disorders | ||
| Cough | Very common | Very common |
| Dyspnoea | Common* | Very common* |
| Pneumonitis18 | Common* | Very common* |
| Gastrointestinal disorders | ||
| Nausea | Common | Very common |
| Diarrhoea19 | Common | Very common |
| Stomatitis20 | Common | Common |
| Pancreatitis21 | Uncommon | Uncommon |
| Colitis22 | Uncommon | Common |
| Hepatobiliary disorders | ||
| Hepatitis23 | Common* | Common |
| Skin and subcutaneous tissue disorders | ||
| Rash24 | Very common | Very common |
| Pruritus | Very common | Common |
| Severe skin reactions25 | Rare | - |
| Musculoskeletal and connective tissue disorders | ||
| Arthralgia | Common | Very common |
| Myalgia | Common | Common |
| Myositis26 | Uncommon | Uncommon |
| Arthritis27 | Uncommon | Common |
| Renal and urinary disorders | ||
| Nephritis28 | Uncommon | Uncommon |
| General disorders and administration site conditions | ||
| Fatigue29 | Very common | Very common |
| Decreased appetite | Very common* | Very common |
| Investigations | ||
| Aspartate aminotransferase increased | Very common | Very common |
| Alanine aminotransferase increased | Very common | Very common |
| Blood bilirubin increased30 | Very common | Very common |
| Blood alkaline phosphatase increased | Common | Very common |
| Blood creatinine increased | Common | Very common |
| Injury, poisoning and procedural complications | ||
| Infusion-related reaction31 | Uncommon | Common |
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 preferred terms (PTs) of hypothyroidism, thyroxine free decreased, triiodothyronine free decreased, tri-iodothyronine decreased, primary hypothyroidism and thyroxine decreased.
7 Hyperthyroidism includes PTs of hyperthyroidism, blood thyroid stimulating hormone decreased, triiodothyronine 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 PTs of hypophysitis and 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, 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 and 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 erythema multiforme.
26 Myositis includes PTs of myositis and immune-mediated myositis.
27 Arthritis includes PTs of arthritis and immune-mediated arthritis.
28 Nephritis includes PTs of nephritis, focal segmental glomerulosclerosis and immune-mediated nephritis.
29 Fatigue includes PTs of fatigue, asthenia, malaise and lethargy.
30 Blood bilirubin increased includes PTs of blood bilirubin increased, bilirubin conjugated increased, blood bilirubin unconjugated increased and hyperbilirubinaemia. 31 Infusion-related reaction includes PTs of infusion-related reaction and infusion-related hypersensitivity reaction.
* including fatal outcomes
The data below reflect information for significant adverse drug reactions for tislelizumab as monotherapy in clinical studies. Details for the significant adverse reactions for tislelizumab when given in combination with chemotherapy are presented if clinically relevant differences were noted in comparison to tislelizumab monotherapy.
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%).
Pneumonitis occurred in 9.1% of patients with NSCLC treated with tislelizumab in combination with chemotherapy. In patients with NSCLC treated with tislelizumab as monotherapy, pneumonitis occurred in 6.0% of patients.
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.
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 11.2 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.
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.
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.
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). 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 0.3% 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.
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 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.
In patients treated with tislelizumab as monotherapy, hypopituitarism (grade 2) occurred in 0.1% of patients.
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.
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 5.7 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 0.3% of patients. Immune-related nephritis and renal dysfunction resolved in 50.0% of patients.
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.
Myocarditis occurred in 1.4% of patients treated with tislelizumab in combination with chemotherapy, including grade 5 (0.4%).
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.
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, 0.07% for increased 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.
In patients treated with tislelizumab in combination with chemotherapy, the proportion of patients who experienced a shift from baseline to a grade 3 or 4 laboratory abnormality was as follows: 14.2% for decreased haemoglobin, 17.3% for decreased leukocytes, 41.2% for decreased neutrophils, 4.6% for decreased platelets, 3.1% for increased alanine aminotransferase, 0.9% for increased alkaline phosphatase, 3.4% for increased aspartate aminotransferase, 0.6% for increased bilirubin, 1.6% for increased creatine kinase, 2.5% for increased creatinine, 2.8% for increased potassium, 10.2% for decreased potassium, 0.6% for increased sodium, 18.9% for decreased sodium.
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 treatmentemergent 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%: (for monotherapy); grade ≥3 AEs 85.6% vs. 78.2%, SAEs 45.9% vs. 38.2%, AEs leading to treatment withdrawal 13.5% vs. 13.3% (for combination therapy). 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.
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 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 except those mentioned in section 6.6.
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