Tevimbra

The concentrate for solution for infusion (sterile concentrate) is a clear to slightly opalescent, colourless to slightly yellowish solution.
The solution has a pH of approximately 6.5 and an osmolality of approximately 270 to 330 mOsm/kg.
Each ml of concentrate for solution for infusion contains 10 mg tislelizumab.
Each 10 ml vial contains 100 mg tislelizumab (100 mg/10 ml).
Tislelizumab is an Fc-engineered humanised immunoglobulin G4 (IgG4) variant monoclonal antibody produced in recombinant Chinese hamster ovary cells.
Excipient with known effect: Each ml of concentrate for solution for infusion contains 0.069 mmol (or 1.6 mg) sodium.
Excipients/Inactive Ingredients: Sodium citrate dihydrate, Citric acid monohydrate, L-histidine hydrochloride monohydrate, L-histidine, Trehalose dihydrate, Polysorbate 20, Water for injection.

Pharmacotherapeutic group: Monoclonal antibodies and antibody drug conjugates. ATC code: L01FF09.
Pharmacology: Pharmacodynamics: Mechanism of action: Tislelizumab is a humanised immunoglobulin G4 (IgG4) variant monoclonal antibody against PD-1, binding to the extracellular domain of human PD-1. It competitively blocks the binding of both PD-L1 and PD-L2, inhibiting PD-1-mediated negative signalling and enhancing the functional activity in T cells in in vitro cell-based assays.
Clinical efficacy and safety: Oesophageal squamous cell carcinoma (OSCC): BGB-A317-302: BGB-A317-302 was a randomised, controlled, open-label, global phase III study to compare the efficacy of tislelizumab versus chemotherapy in patients with unresectable, recurrent, locally advanced or metastatic OSCC who progressed on or after prior systemic treatment. Patients were enrolled regardless of their tumour PD-L1 expression level. Where available, the archival/fresh tumour tissue specimens taken were retrospectively tested for PD-L1 expression status. PD-L1 expression was evaluated at a central laboratory using the Ventana PD-L1 (SP263) assay that identified PD-L1 staining on both tumour and tumour-associated immune cells.
The study excluded patients with prior anti-PD-1 inhibitor treatment and tumour invasion into organs located adjacent to the oesophageal disease site (e.g. aorta or respiratory tract).
Randomisation was stratified by geographic region (Asia [excluding Japan] versus Japan versus USA/EU), ECOG PS (0 versus 1) and investigator choice of chemotherapy (ICC) option (paclitaxel versus docetaxel versus irinotecan). The choice of ICC was determined by the investigator before randomisation.
Patients were randomised (1:1) to receive tislelizumab 200 mg every 3 weeks or investigator's choice of chemotherapy (ICC), selected from the following, all given intravenously: paclitaxel 135 to 175 mg/m² on day 1, given every 3 weeks (also at doses of 80 to 100 mg/m² on a weekly schedule according to local and/or country-specific guidelines for standard of care); or docetaxel 75 mg/m² on day 1, given every 3 weeks; or irinotecan 125 mg/m² on days 1 and 8, given every 3 weeks.
Patients were treated with Tevimbra or one of the ICC until disease progression as assessed by the investigator per RECIST version 1.1 or unacceptable toxicity.
The tumour assessments were conducted every 6 weeks for the first 6 months, and every 9 weeks thereafter.
The primary efficacy endpoint was overall survival (OS) in the intent-to-treat (ITT) population. Secondary efficacy endpoints were OS in PD-L1 Positive Analysis Set (PD-L1 score of visually-estimated Combined Positive Score, now known as Tumour Area Positivity score [TAP] [PD-L1 score] ≥10%), objective response rate (ORR), progression-free survival (PFS) and duration of response (DoR), as assessed by the investigator per RECIST v1.1.
A total of 512 patients were enrolled and randomised to tislelizumab (n = 256) or ICC (n = 256; paclitaxel [n = 85], docetaxel [n = 53] or irinotecan [n = 118]). Of the 512 patients, 142 (27.7%) had PD-L1 score ≥10%, 222 (43.4%) had PD-L1 score <10%, and 148 (28.9%) had unknown baseline PD-L1 status.
The baseline characteristics for the study population were: median age 62 years (range: 35 to 86), 37.9% age 65 years or older; 84% male; 19% White and 80% Asian; 25% with ECOG PS of 0 and 75% with ECOG PS of 1. Ninety-five percent of the study population had metastatic disease at study entry. All patients had received at least one prior anti-cancer chemotherapy, which was a platinum-based combination chemotherapy for 97% of patients.
BGB-A317-302 showed a statistically significant improvement in OS for patients randomised to the tislelizumab arm as compared to the ICC arm. The median follow-up times by reverse Kaplan-Meier methodology were 20.8 months in the tislelizumab arm and 21.1 months in the ICC arm.
Efficacy results are shown in Table 1 and the figure. (See Table 1 and figure.)

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Efficacy and PD-L1 subgroups: In a pre-specified analysis of OS in the PD-L1 positive subgroup (PD-L1 score ≥10%), the stratified hazard ratio (HR) for OS was 0.49 (95% CI: 0.33 to 0.74), with a 1-sided stratified log-rank test p-value of 0.0003. The median survival was 10.0 months (95% CI: 8.5 to 15.1 months) and 5.1 months (95% CI: 3.8 to 8.2 months) for the tislelizumab and ICC arms, respectively.
In the PD-L1 negative subgroup (PD-L1 score <10%), the stratified HR for OS was 0.83 (95% CI: 0.62 to 1.12), with median overall survival of 7.5 months (95% CI: 5.5 to 8.9 months) and 5.8 months (95% CI: 4.8 to 6.9 months) for the tislelizumab and ICC arms, respectively.
Paediatric population: The European Medicines Agency has waived the obligation to submit the results of studies with tislelizumab in all subsets of the paediatric population in the treatment of malignant neoplasms (except central nervous system, haematopoietic and lymphoid tissue) (see Dosage & Administration for information on paediatric use).
Pharmacokinetics: The pharmacokinetics (PK) of tislelizumab were characterised using population PK analysis with concentration data from 2596 patients with advanced malignancies who received tislelizumab doses of 0.5 to 10 mg/kg every 2 weeks, 2.0 and 5.0 mg/kg every 3 weeks, and 200 mg every 3 weeks.
The time to reach 90% steady-state level is approximately 84 days (12 weeks) after 200 mg doses once every 3 weeks, and the steady-state accumulation ratio of tislelizumab PK exposure is approximately 2-fold.
Absorption: Tislelizumab is administered intravenously and therefore is immediately and completely bioavailable.
Distribution: A population pharmacokinetic analysis indicates that the steady-state volume of distribution is 6.42 l, which is typical of monoclonal antibodies with limited distribution.
Biotransformation: Tislelizumab is expected to be degraded into small peptides and amino acids via catabolic pathways.
Elimination: Based on population PK analysis, the clearance of tislelizumab was 0.153 l/day with an inter-individual variability of 26.3% and the geometrical mean terminal half-life was approximately 23.8 days with a coefficient variation (CV) of 31%.
Linearity/non-linearity: At the dosing regimens of 0.5 mg/kg to 10 mg/kg once every 2 or 3 weeks (including 200 mg once every 3 weeks), the PK of tislelizumab were observed to be linear and the exposure was dose proportional.
Special populations: The effects of various covariates on tislelizumab PK were assessed in population PK analyses. The following factors had no clinically relevant effect on the exposure of tislelizumab: age (range 18 to 90 years), weight (range 32 to 130 kg), gender, race (White, Asian and other), mild to moderate renal impairment (creatinine clearance [CLCr] ≥30 ml/min), mild to moderate hepatic impairment (total bilirubin ≤3 times ULN and any AST), and tumour burden.
Renal impairment: No dedicated studies of tislelizumab have been conducted in patients with renal impairment. In the population PK analyses of tislelizumab, no clinically relevant differences in the clearance of tislelizumab were found between patients with mild renal impairment (CL_Cr 60 to 89 ml/min, n = 1046) or moderate renal impairment (CL_Cr 30 to 59 ml/min, n = 320) and patients with normal renal function (CL_Cr ≥90 ml/min, n = 1223). Mild and moderate renal impairment had no effect on the exposure of tislelizumab (see Dosage & Administration). Based on the limited number of patients with severe renal impairment (n = 5), the effect of severe renal impairment on the pharmacokinetics of tislelizumab is not conclusive.
Hepatic impairment: No dedicated studies of tislelizumab have been conducted in patients with hepatic impairment. In the population PK analyses of tislelizumab, no clinically relevant differences in the clearance of tislelizumab were found between patients with mild hepatic impairment (bilirubin ≤ ULN and AST > ULN or bilirubin >1.0 to 1.5 x ULN and any AST, n = 396) or moderate hepatic impairment (bilirubin >1.5 to 3 x ULN and any AST; n = 12), compared to patients with normal hepatic function (bilirubin ≤ ULN and AST = ULN, n = 2182) (see Dosage & Administration). Based on the limited number of patients with severe hepatic impairment (bilirubin >3 x ULN and any AST, n = 2), the effect of severe hepatic impairment on the pharmacokinetics of tislelizumab is unknown.
Toxicology: Preclinical safety data: In repeat-dose toxicology studies in cynomolgus monkeys with intravenous dose administration at doses of 3, 10, 30 or 60 mg/kg every 2 weeks for 13 weeks (7 dose administrations), no apparent treatment-related toxicity or histopathological changes were observed at doses up to 30 mg/kg every 2 weeks, corresponding to 4.3 to 6.6 times the exposure in humans with the clinical dose of 200 mg.
No developmental and reproductive toxicity studies or animal fertility studies have been conducted with tislelizumab.
No studies have been performed to assess the potential of tislelizumab for carcinogenicity or genotoxicity.

Oesophageal squamous cell carcinoma (OSCC): Tevimbra as monotherapy is indicated for the treatment of adult patients with unresectable, locally advanced or metastatic oesophageal squamous cell carcinoma after prior platinum-based chemotherapy.

Tevimbra treatment must be initiated and supervised by physicians experienced in the treatment of cancer.
Posology: The recommended dose of Tevimbra is 200 mg administered by intravenous infusion once every 3 weeks.
Duration of treatment: Patients should be treated with Tevimbra until disease progression or unacceptable toxicity.
Dose delay or discontinuation (see also Precautions): No dose reductions of Tevimbra as monotherapy are recommended. Tevimbra should be withheld or discontinued as described in Table 2. (See Table 2.)
Detailed guidelines for the management of immune-related adverse reactions are described in Precautions.

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Special populations: Paediatric population: The safety and efficacy of Tevimbra in patients aged below 18 years have not been established. No data are available.
Elderly: No dose adjustment is needed for patients aged ≥65 years (see Adverse Reactions).
Renal impairment: No dose adjustment is needed for patients with mild or moderate renal impairment. Data from patients with severe renal impairment are too limited to make dosing recommendations for this population (see Pharmacology: Pharmacokinetics under Actions).
Hepatic impairment: No dose adjustment is needed for patients with mild or moderate hepatic impairment. Data from patients with severe hepatic impairment are too limited to make dosing recommendations for this population (see Pharmacology: Pharmacokinetics under Actions).
Method of administration: Tevimbra is for intravenous use only. It is to be administered as an infusion and must not be administered as an intravenous push or single bolus injection. For instructions on dilution of the medicinal product before administration, see Special precautions for disposal and other handling under Cautions for Usage.
The first infusion should be administered over a period of 60 minutes. If this is well tolerated, the subsequent infusions may be administered over a period of 30 minutes. The infusion should be given via an intravenous line containing a sterile, non-pyrogenic, low-protein-binding 0.2 or 0.22 micron in-line or add-on filter.
Other medicinal products must not be mixed or co-administered through the same infusion line.

There is no information on overdose with tislelizumab. In case of overdose, patients should be closely monitored for signs or symptoms of adverse drug reactions, and appropriate symptomatic treatment instituted immediately.

Hypersensitivity to the active substance or to any of the excipients listed in Description.

Traceability: In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Patient Card: Patients treated with Tevimbra must be given the Patient Card to be informed about the risks of immune-related adverse reactions during Tevimbra therapy.
The prescriber must discuss the risks of immune-related adverse reactions during Tevimbra therapy with the patient.
Immune-related adverse reactions: Immune-related adverse reactions have been reported, including fatal cases, during treatment with tislelizumab (see Adverse Reactions). 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 Dosage & Administration). 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 Dosage & Administration and Adverse Reactions). Upon improvement to grade ≤1, corticosteroid taper should be initiated and continued over at least 1 month.
Immune-related pneumonitis: 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 disease-related aetiologies should be ruled out.
Patients with immune-related pneumonitis should be managed according to the treatment modifications as recommended in Table 2 (see Dosage & Administration).
Immune-related hepatitis: 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 2 (see Dosage & Administration).
Immune-related skin reactions: 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 2 (see Dosage & Administration).
Cases of severe cutaneous adverse reactions (SCARs) including erythema multiforme (EM), Stevens-Johnson Syndrome (SJS) and Toxic epidermal necrolysis (TEN), some of them with fatal outcome, have been reported in patients receiving tislelizumab (see Adverse Reactions). 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 SCAR, tislelizumab should be withheld and the patient should be referred to specialised care for assessment and treatment. If SCAR is confirmed, tislelizumab should be permanently discontinued (see Dosage & Administration).
Immune-related colitis: 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 disease-related aetiologies should be ruled out.
Patients with immune-related colitis should be managed according to the treatment modifications as recommended in Table 2 (see Dosage & Administration).
Immune-related endocrinopathies: 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 2 (see Dosage & Administration).
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 Dosage & Administration).
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 Dosage & Administration).
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 Dosage & Administration).
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 Dosage & Administration). Treatment with tislelizumab may be resumed when metabolic control is achieved.
Immune-related nephritis with renal dysfunction: 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 2 (see Dosage & Administration).
Other immune-related adverse reactions: Other clinically important immune-related adverse reactions were reported with tislelizumab: myositis, myocarditis, arthritis, polymyalgia rheumatica, pericarditis and Guillain-Barré syndrome (see Adverse Reactions).
Patients with other immune-related adverse reactions should be managed according to the treatment modifications as recommended in Table 2 (see Dosage & Administration).
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.
Infusion-related reactions: Severe infusion-related reactions (grade 3 or higher) have been reported in patients receiving tislelizumab as a single agent (see Adverse Reactions). Patients should be monitored for signs and symptoms of infusion-related reactions.
Infusion-related reactions should be managed as recommended in Table 2 (see Dosage & Administration).
Patients excluded from clinical studies: 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.
Patients on controlled sodium diet: 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.
Effects on ability to drive and use machines: Tevimbra has minor influence on the ability to drive and use machines. In some patients, fatigue has been reported following administration of tislelizumab (see Adverse Reactions).

Women of childbearing potential/Contraception: 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.
Pregnancy: 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.
Breast-feeding: 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 Tevimbra, women should be advised not to breast-feed during treatment and for at least 4 months after the last dose of Tevimbra.
Fertility: 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 Pharmacology: Toxicology: Preclinical safety data under Actions).

Summary of the safety profile: The safety of tislelizumab as monotherapy is based on pooled data in 1534 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 1534 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 = 1534) are presented in Table 3. 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 (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000); not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. (See Tables 3a and 3b.)

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Description of selected adverse reactions: The following data 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 Dosage & Administration and Precautions).
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 1916 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 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 local reporting mechanism.

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 Precautions).

Special precautions for disposal and other handling: The diluted solution for infusion should be prepared by a healthcare professional using aseptic technique.
Preparation of solution for infusion: Two Tevimbra vials are required for each dose.
Remove the vials from the refrigerator, taking care not to shake them.
Inspect each vial visually for particulate matter and discolouration prior to administration. The concentrate is a clear to slightly opalescent, colourless to slightly yellowish solution. Do not use a vial if the solution is cloudy, or if visible particles or discolouration are observed.
Invert the vials gently without shaking. Withdraw the solution from the two vials (a total of 200 mg in 20 ml) into a syringe and transfer into an intravenous infusion bag containing sodium chloride 9 mg/ml (0.9%) solution for injection, to prepare a diluted solution with a final concentration ranging from 2 to 5 mg/ml. Mix diluted solution by gentle inversion to avoid foaming or excessive shearing of the solution.
Administration: Administer the diluted Tevimbra solution by infusion through an intravenous administration line with a sterile, non-pyrogenic, low-protein-binding 0.2 micron or 0.22 micron in-line or add-on filter with a surface area of approximately 10 cm².
The first infusion should be delivered over 60 minutes. If well tolerated, subsequent infusions may be administered over 30 minutes.
Other medicinal products should not be co-administered through the same infusion line.
Tevimbra must not be administered as an intravenous push or single bolus injection.
The intravenous line must be flushed at the end of the infusion.
Discard any unused portion left in the vial.
Tevimbra vials are for single use only.
Disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except those previously mentioned in Special precautions for disposal and other handling.

Store in a refrigerator (2°C - 8°C). Do not freeze.
Store in the original carton in order to protect from light.
Shelf life: After opening: Once opened, the medicinal product should be diluted and infused immediately (see Special precautions for disposal and other handling under Cautions for Usage for instructions on dilution of the medicinal product before administration).
After preparation of solution for infusion: Tevimbra does not contain a preservative. Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C to 8°C. The 24 hours include storage of the diluted solution under refrigeration (2°C to 8°C) for no more than 20 hours, time required for returning to room temperature (25°C or below) and time to complete the infusion within 4 hours.
From a microbiological point of view, unless the method of dilution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user. The diluted solution must not be frozen.

Targeted Cancer Therapy / Cancer Immunotherapy

L01FF09 - tislelizumab ; Belongs to the class of PD-1/PD-L1 (Programmed cell death protein 1/death ligand 1) inhibitors. Used in the treatment of cancer.

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