Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

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 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
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 1 (see section 4.2).

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 1 (see section 4.2).

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 1 (see section 4.2).

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 section 4.8). 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 section 4.2).

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 1 (see section 4.2).

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 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
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 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 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.


Infusion-related reactions

Severe infusion-related reactions (grade 3 or higher) have been reported in patients receiving tislelizumab as a single agent (see section 4.8). Patients should be monitored for signs and symptoms of infusion-related reactions.

Infusion-related reactions should be managed as recommended in Table 1 (see section 4.2).

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 Driving

4.7    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 section 4.8).