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.

Infusion-related reactions
Infusion-related reactions, which might be severe, have been reported in patients receiving avelumab (see section 4.8).

Patients should be monitored for signs and symptoms of infusion-related reactions including pyrexia, chills, flushing, hypotension, dyspnoea, wheezing, back pain, abdominal pain, and urticaria.

For Grade 3 or Grade 4 infusion-related reactions, the infusion should be stopped and avelumab should be permanently discontinued (see section 4.2).

For Grade 1 infusion-related reactions, the infusion rate should be slowed by 50% for the current infusion. For patients with Grade 2 infusion-related reactions, the infusion should be temporary discontinued until Grade 1 or resolved, then the infusion will restart with a 50% slower infusion rate (see section 4.2).

In case of recurrence of Grade 1 or Grade 2 infusion-related reaction, the patient may continue to receive avelumab under close monitoring, after appropriate infusion rate modification and premedication with paracetamol and antihistamine (see section 4.2).

In patients treated with avelumab as monotherapy, 24.6% (513/2,082) of patients experienced infusion-related reactions. Of these, 97.7% (501/513) had a first infusion-related reaction during the first 4 infusions of which 2.7% (14/513) were Grade ≥ 3. In the remaining 2.3% (12/513) of patients, infusion-related reactions occurred after the first 4 infusions and 91.7% (11/12) were of Grade 1 or Grade 2.

Immune-mediated adverse reactions
Most immune-mediated adverse reactions with avelumab were reversible and managed with temporary or permanent discontinuation of avelumab, administration of corticosteroids and/or supportive care.

For suspected immune-mediated adverse reactions, adequate evaluation should be performed to confirm aetiology or exclude other causes. Based on the severity of the adverse reaction, avelumab should be withheld and corticosteroids administered. If corticosteroids are used to treat an adverse reaction, a taper of at least 1 month duration should be initiated upon improvement.

In patients, whose immune-mediated adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants may be considered.

In patients with pre-existing autoimmune disease (AID), data from observational studies suggest that the risk of immune-mediated adverse reactions following immune-checkpoint inhibitor therapy may be increased as compared with the risk in patients without pre-existing AID. In addition, flares of the underlying AID were frequent, but the majority were mild and manageable.


Immune-mediated pneumonitis
Immune-mediated pneumonitis occurred in patients treated with avelumab. One fatal case has been reported in patients receiving avelumab (see section 4.8).

Patients should be monitored for signs and symptoms of immune-mediated pneumonitis and causes other than immune-mediated pneumonitis should be ruled out. Suspected pneumonitis should be confirmed with radiographic imaging.

Corticosteroids should be administered for Grade ≥ 2 events (initial dose of 1 to 2 mg/kg/day prednisone or equivalent, followed by a corticosteroid taper).

Avelumab should be withheld for Grade 2 immune-mediated pneumonitis until resolution, and permanently discontinued for Grade 3, Grade 4 or recurrent Grade 2 immune-mediated pneumonitis (see section 4.2).

Immune-mediated hepatitis
Immune-mediated hepatitis occurred in patients treated with avelumab. Two fatal cases have been reported in patients receiving avelumab (see section 4.8).

Patients should be monitored for changes in liver function and symptoms of immune-mediated hepatitis and causes other than immune-mediated hepatitis should be ruled out.

Corticosteroids should be administered for Grade ≥ 2 events (initial dose 1 to 2 mg/kg/day prednisone or equivalent, followed by a corticosteroid taper).

Avelumab should be withheld for Grade 2 immune-mediated hepatitis until resolution and permanently discontinued for Grade 3 or Grade 4 immune-mediated hepatitis (see section 4.2).

Immune-mediated colitis
Immune-mediated colitis has been reported in patients receiving avelumab (see section 4.8).

Patients should be monitored for signs and symptoms of immune-mediated colitis and causes other than immune-mediated colitis should be ruled out. Corticosteroids should be administered for Grade ≥ 2 events (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a corticosteroid taper).

Avelumab should be withheld for Grade 2 or Grade 3 immune-mediated colitis until resolution, and permanently discontinued for Grade 4 or recurrent Grade 3 immune-mediated colitis (see section 4.2).

Immune-mediated pancreatitis
Immune-mediated pancreatitis has been reported in patients receiving avelumab. Two fatal cases have been reported in patients receiving avelumab in combination with axitinib (see section 4.8).

Patients should be monitored for signs and symptoms of immune-mediated pancreatitis. In symptomatic patients, obtain gastroenterology consultation and laboratory investigations (including imaging) to ensure the initiation of appropriate measures at an early stage. Corticosteroids should be administered for immune-mediated pancreatitis (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a corticosteroid taper).

Avelumab should be withheld in the event of suspected immune-mediated pancreatitis. Avelumab should be permanently discontinued if immune-mediated pancreatitis is confirmed (see section 4.2).

Immune-mediated myocarditis
Immune-mediated myocarditis has been reported in patients receiving avelumab. Two fatal cases have been reported in patients receiving avelumab in combination with axitinib (see section 4.8).


Patients should be monitored for signs and symptoms of immune-mediated myocarditis. In symptomatic patients, obtain cardiologic consultation and laboratory investigations to ensure the initiation of appropriate measures at an early stage. Corticosteroids should be administered for immune-mediated myocarditis (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a corticosteroid taper). If no improvement within 24 hours on corticosteroids, additional immunosuppression (e.g., mycophenolate, infliximab, anti-thymocyte globulin) should be considered.

Avelumab should be withheld in the event of suspected immune-mediated myocarditis. Avelumab should be permanently discontinued if immune-mediated myocarditis is confirmed (see section 4.2).

Immune-mediated endocrinopathies
Immune-mediated thyroid disorders, immune-mediated adrenal insufficiency, and Type 1 diabetes mellitus have been reported in patients receiving avelumab (see section 4.8). Patients should be monitored for clinical signs and symptoms of endocrinopathies. Avelumab should be withheld for Grade 3 or Grade 4 endocrinopathies until resolution (see section 4.2).

Thyroid disorders (hypothyroidism/hyperthyroidism)
Thyroid disorders can occur at any time during treatment (see section 4.8).

Patients should be monitored for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Hypothyroidism should be managed with replacement therapy and hyperthyroidism with anti-thyroid medicinal product, as needed.

Avelumab should be withheld for Grade 3 or Grade 4 thyroid disorders (see section 4.2).

Adrenal insufficiency
Patients should be monitored for signs and symptoms of adrenal insufficiency during and after treatment. Corticosteroids should be administered (1 to 2 mg/kg/day prednisone intravenously or oral equivalent) for Grade ≥ 3 adrenal insufficiency followed by a taper until a dose of less than or equal to 10 mg/day has been reached.

Avelumab should be withheld for Grade 3 or Grade 4 symptomatic adrenal insufficiency (see section 4.2).

Type 1 diabetes mellitus
Avelumab can cause Type 1 diabetes mellitus, including diabetic ketoacidosis (see section 4.8).

Patients should be monitored for hyperglycaemia or other signs and symptoms of diabetes. Initiate treatment with insulin for Type 1 diabetes mellitus. Avelumab should be withheld and anti- hyperglycaemics in patients with Grade ≥ 3 hyperglycaemia should be administered. Treatment with avelumab should be resumed when metabolic control is achieved on insulin replacement therapy.

Immune-mediated nephritis and renal dysfunction
Avelumab can cause immune-mediated nephritis (see section 4.8).

Patients should be monitored for elevated serum creatinine prior to and periodically during treatment.
Corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a corticosteroid taper) should be administered for Grade ≥ 2 nephritis. Avelumab should be withheld for Grade 2 or Grade 3 nephritis until resolution to ≤ Grade 1 and permanently discontinued for Grade 4 nephritis.

Other immune-mediated adverse reactions
Other clinically important immune-mediated adverse reactions were reported in less than 1% of patients: myositis, hypopituitarism, uveitis, myasthenia gravis, myasthenic syndrome, cystitis noninfective, sarcoidosis, and Guillain-Barré syndrome (see section 4.8).


For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm aetiology or to rule out other causes. Based on the severity of the adverse reaction, avelumab should be withheld and corticosteroids to be administered. Avelumab should be resumed when the immune-mediated adverse reaction returns to Grade 1 or less following corticosteroid taper. Avelumab should be permanently discontinued for any Grade 3 immune-mediated adverse reaction that recurs and for Grade 4 immune-mediated adverse reaction (see section 4.2).

Hepatotoxicity (in combination with axitinib)
Hepatotoxicity occurred in patients treated with avelumab in combination with axitinib with higher than expected frequencies of Grade 3 and Grade 4 ALT and AST elevation compared to avelumab alone (see section 4.8).

Patients should be more frequently monitored for changes in liver function and symptoms as compared to when avelumab is used as monotherapy.

Avelumab should be withheld for Grade 2 hepatotoxicity until resolution and permanently discontinued for Grade 3 or Grade 4 hepatotoxicity. Corticosteroids should be considered for Grade ≥ 2 events (see section 4.2).

Patients excluded from clinical studies
Patients with the following conditions were excluded from clinical trials: active central nervous system (CNS) metastasis; active or a history of autoimmune disease; a history of other malignancies within the last 5 years; organ transplant; conditions requiring therapeutic immune suppression or active infection with HIV, or hepatitis B or C.

Avelumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.

Sodium content
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium-free’. Bavencio has to be diluted with either sodium chloride 9 mg/mL (0.9%) or with sodium chloride 4.5 mg/mL (0.45%). This should be taken into consideration for patients on a controlled sodium diet (see section 6.6).

Effects on Driving

4.7   Effects on ability to drive and use machines

Avelumab has negligible influence on the ability to drive and use machines. Fatigue has been reported following administration of avelumab (see section 4.8). Patients should be advised to use caution when driving or operating machinery until they are certain that avelumab does not adversely affect them.