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Traceability: In order to improve the traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded in the patient file.
Immune-related adverse reactions: Most immune-related adverse reactions occurring during treatment with atezolizumab were reversible with interruptions of atezolizumab and initiation of corticosteroids and/or supportive care. Immune-related adverse reactions affecting more than one body system have been observed. Immune-related adverse reactions with atezolizumab may occur after the last dose of atezolizumab.
For suspected immune-related adverse reactions, thorough evaluation to confirm aetiology or exclude other causes should be performed. Based on the severity of the adverse reaction, atezolizumab should be withheld and corticosteroids administered. Upon improvement to Grade ≤ 1, corticosteroid should be tapered over ≥ 1 month. Based on limited data from clinical trials in patients whose immune-related adverse reactions could not be controlled with systemic corticosteroid use, administration of other systemic immunosuppressants may be considered.
Atezolizumab must be permanently discontinued for any Grade 3 immune-related adverse reaction that recurs and for any Grade 4 immune-related adverse reactions, except for endocrinopathies that are controlled with replacement hormones (see Dosage & Administration and Adverse Reactions).
Immune-related pneumonitis: Cases of pneumonitis, including fatal cases, have been observed in clinical trials with atezolizumab (see Adverse Reactions). Patients should be monitored for signs and symptoms of pneumonitis and causes other than immune-related pneumonitis should be ruled out.
Treatment with atezolizumab should be withheld for Grade 2 pneumonitis, and 1 to 2 mg/kg body weight (bw)/day prednisone or equivalent should be started. If symptoms improve to ≤ Grade 1, corticosteroids should be tapered over ≥ 1 month. Treatment with atezolizumab may be resumed if the event improves to ≤ Grade 1 within 12 weeks, and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day. Treatment with atezolizumab must be permanently discontinued for Grade 3 or 4 pneumonitis.
Immune-related hepatitis: Cases of hepatitis, some leading to fatal outcomes have been observed in clinical trials with atezolizumab (see Adverse Reactions). Patients should be monitored for signs and symptoms of hepatitis.
Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and bilirubin should be monitored prior to initiation of treatment, periodically during treatment with atezolizumab and as indicated based on clinical evaluation.
For patients without HCC, treatment with atezolizumab should be withheld if Grade 2 event (ALT or AST > 3 to 5 x ULN or blood bilirubin > 1.5 to 3 x ULN) persists for more than 5 to 7 days, and 1 to 2 mg/kg bw/day of prednisone or equivalent should be started. If the event improves to ≤ Grade 1, corticosteroids should be tapered over ≥ 1 month.
Treatment with atezolizumab may be resumed if the event improves to ≤ Grade 1 within 12 weeks and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day. Treatment with atezolizumab must be permanently discontinued for Grade 3 or Grade 4 events (ALT or AST > 5.0 x ULN or blood bilirubin > 3 x ULN).
For patients with HCC, treatment with atezolizumab should be withheld if ALT or AST increases to > 3 to ≤10 x ULN from normal limits at baseline, or > 5 to ≤10 x ULN from > 1 ULN to ≤3 x ULN at baseline, or > 8 to ≤10 x ULN from > 3 ULN to ≤5 x ULN at baseline, and persists for more than 5 to 7 days, and 1 to 2 mg/kg bw/day of prednisone or equivalent should be started. If the event improves to ≤ Grade 1, corticosteroids should be tapered over ≥ 1 month.
Treatment with atezolizumab may be resumed if the event improves to ≤ Grade 1 within 12 weeks and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day. Treatment with atezolizumab must be permanently discontinued if ALT or AST increases to > 10 x ULN or total bilirubin increases > 3 x ULN).
Immune-related colitis: Cases of diarrhoea or colitis have been observed in clinical trials with atezolizumab (see section Adverse Reactions). Patients should be monitored for signs and symptoms of colitis.
Treatment with atezolizumab should be withheld for Grade 2 or 3 diarrhoea (increase of ≥ 4 stools/day over baseline) or colitis (symptomatic). For Grade 2 diarrhoea or colitis, if symptoms persist > 5 days or recur, treatment with 1 to 2 mg/kg bw/day prednisone or equivalent should be started. For Grade 3 diarrhoea or colitis, treatment with intravenous corticosteroids (1 to 2 mg/kg bw/day methylprednisolone or equivalent) should be started. Once symptoms improve, treatment with 1 to 2 mg/kg bw/day of prednisone or equivalent should be started. If symptoms improve to ≤ Grade 1, corticosteroids should be tapered over ≥ 1 month. Treatment with atezolizumab may be resumed if the event improves to ≤ Grade 1 within 12 weeks and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day. Treatment with atezolizumab must be permanently discontinued for Grade 4 (life threatening; urgent intervention indicated) diarrhoea or colitis.
Immune-related endocrinopathies: Hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis and type 1 diabetes mellitus, including diabetic ketoacidosis have been observed in clinical trials with atezolizumab (see Adverse Reactions).
Patients should be monitored for clinical signs and symptoms of endocrinopathies. Thyroid function should be monitored prior to and periodically during treatment with atezolizumab. Appropriate management of patients with abnormal thyroid function tests at baseline should be considered.
Asymptomatic patients with abnormal thyroid function tests can receive atezolizumab. For symptomatic hypothyroidism, atezolizumab should be withheld and thyroid hormone replacement should be initiated as needed. Isolated hypothyroidism may be managed with replacement therapy and without corticosteroids. For symptomatic hyperthyroidism, atezolizumab should be withheld and an anti-thyroid medicinal product should be initiated as needed. Treatment with atezolizumab may be resumed when symptoms are controlled and thyroid function is improving.
For symptomatic adrenal insufficiency, atezolizumab should be withheld and treatment with intravenous corticosteroids (1 to 2 mg/kg bw/day methylprednisolone or equivalent) should be started. Once symptoms improve, treatment with 1 to 2 mg/kg bw/day of prednisone or equivalent should follow. If symptoms improve to ≤ Grade 1, corticosteroids should be tapered over ≥ 1 month. Treatment may be resumed if the event improves to ≤ Grade 1 within 12 weeks and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day and the patient is stable on replacement therapy (if required).
For Grade 2 or Grade 3 hypophysitis, atezolizumab should be withheld and treatment with intravenous corticosteroids (1 to 2 mg/kg bw/day methylprednisolone or equivalent) should be started, and hormone replacement should be initiated as needed. Once symptoms improve, treatment with 1 to 2 mg/kg bw/day of prednisone or equivalent should follow. If symptoms improve to ≤ Grade 1, corticosteroids should be tapered over ≥ 1 month. Treatment may be resumed if the event improves to ≤ Grade 1 within 12 weeks and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day and the patient is stable on replacement therapy (if required). Treatment with atezolizumab should be permanently discontinued for Grade 4 hypophysitis.
Treatment with insulin should be initiated for type 1 diabetes mellitus. For ≥ Grade 3 hyperglycaemia (fasting glucose > 250 mg/dL or 13.9 mmol/L), atezolizumab should be withheld. Treatment with atezolizumab may be resumed if metabolic control is achieved on insulin replacement therapy.
Immune-related meningoencephalitis: Meningoencephalitis has been observed in clinical trials with atezolizumab (see Adverse Reactions). Patients should be monitored for clinical signs and symptoms of meningitis or encephalitis.
Treatment with atezolizumab must be permanently discontinued for any grade of meningitis or encephalitis. Treatment with intravenous corticosteroids (1 to 2 mg/kg bw/day methylprednisolone or equivalent) should be started. Once symptoms improve, treatment with 1 to 2 mg/kg bw/day of prednisone or equivalent should follow.
Immune-related neuropathies: Myasthenic syndrome/myasthenia gravis or Guillain-Barré syndrome, which may be life threatening, were observed in patients receiving atezolizumab. Patients should be monitored for symptoms of motor and sensory neuropathy.
Treatment with atezolizumab must be permanently discontinued for any grade of myasthenic syndrome / myasthenia gravis or Guillain-Barré syndrome. Initiation of systemic corticosteroids (at a dose of 1 to 2 mg/kg bw/day of prednisone or equivalent) should be considered.
Immune-related pancreatitis: Pancreatitis, including increases in serum amylase and lipase levels, has been observed in clinical trials with atezolizumab (see Adverse Reactions). Patients should be closely monitored for signs and symptoms that are suggestive of acute pancreatitis.
Treatment with atezolizumab should be withheld for ≥ Grade 3 serum amylase or lipase levels increased (> 2 x ULN), or Grade 2 or 3 pancreatitis, and treatment with intravenous corticosteroids (1 to 2 mg/kg bw/day methylprednisolone or equivalent) should be started. Once symptoms improve, treatment with 1 to 2 mg/kg bw/day of prednisone or equivalent should follow. Treatment with atezolizumab may be resumed when serum amylase and lipase levels improve to ≤ Grade 1 within 12 weeks, or symptoms of pancreatitis have resolved, and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day. Treatment with atezolizumab should be permanently discontinued for Grade 4, or any grade of recurrent pancreatitis.
Immune-related myocarditis: Cases of myocarditis, including fatal cases, have been observed with atezolizumab (see Adverse Reactions). Patients should be monitored for signs and symptoms of myocarditis. Myocarditis may also be a clinical manifestation of myositis and should be managed accordingly.
Patients with cardiac or cardiopulmonary symptoms should be assessed for potential myocarditis, to ensure the initiation of appropriate measures at an early stage. If myocarditis is suspected, treatment with atezolizumab should be withheld, prompt initiation of systemic corticosteroids at a dose of 1 to 2 mg/kg bw/day of prednisone or equivalent should be started, and prompt cardiology consultation with diagnostic workup according to current clinical guidelines should be initiated. Once a diagnosis of myocarditis is established, treatment with atezolizumab must be permanently discontinued for Grade ≥ 2 myocarditis (see Dosage & Administration).
Immune-related nephritis: Nephritis has been observed in clinical trials with atezolizumab (see Adverse Reactions). Patients should be monitored for changes in renal function.
Treatment with atezolizumab should be withheld for Grade 2 nephritis, and treatment with systemic corticosteroids at a dose of 1 to 2 mg/kg bw/day of prednisone or equivalent should be started. Treatment with atezolizumab may be resumed if the event improves to ≤ Grade 1 within 12 weeks, and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day. Treatment with atezolizumab must be permanently discontinued for Grade 3 or 4 nephritis.
Immune-related myositis: Cases of myositis, including fatal cases, have been observed with atezolizumab (see Adverse Reactions). Patients should be monitored for signs and symptoms of myositis. Patients with possible myositis should be monitored for signs of myocarditis.
If a patient develops signs and symptoms of myositis, close monitoring should be implemented, and the patient referred to a specialist for assessment and treatment without delay. Treatment with atezolizumab should be withheld for Grade 2 or 3 myositis and corticosteroid therapy (1-2 mg/kg bw/day prednisone or equivalent) should be initiated. If symptoms improve to ≤ Grade 1, taper corticosteroids as clinically indicated. Treatment with atezolizumab may be resumed if the event improves to ≤ Grade 1 within 12 weeks, and corticosteroids have been reduced to ≤ 10 mg oral prednisone or equivalent per day. Treatment with atezolizumab should be permanently discontinued for Grade 4 or grade 3 recurrent myositis, or when unable to reduce the corticosteroid dose to the equivalent of ≤ 10 mg prednisone per day within 12 weeks after onset.
Immune-related severe cutaneous adverse reactions: Immune-related severe cutaneous adverse reactions (SCARs), including cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in patients receiving atezolizumab. Patients should be monitored for suspected severe skin reactions and other causes should be excluded. For suspected SCARs, patients should be referred to a specialist for further diagnosis and management.
Based on the severity of the adverse reaction, atezolizumab should be withheld for Grade 3 skin reactions and treatment with systemic corticosteroids at a dose of 1-2 mg/kg bw/day of prednisone or equivalent should be started. Treatment with atezolizumab may be resumed if the event improves to ≤ Grade 1 within 12 weeks, and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day. Treatment with atezolizumab should be permanently discontinued for Grade 4 skin reactions, and corticosteroids should be administered.
Atezolizumab should be withheld for patients with suspected SJS or TEN. For confirmed SJS or TEN, atezolizumab should be permanently discontinued.
Caution should be used when considering the use of atezolizumab in a patient who has previously experienced a severe or life-threatening skin adverse reaction on prior treatment with other immune-stimulatory anticancer agents.
Other immune-related adverse reactions: Given the mechanism of action of atezolizumab, other potential immune-related adverse reactions may occur, including noninfective cystitis.
Evaluate all suspected immune-related adverse reactions to exclude other causes. Patients should be monitored for signs and symptoms of immune-related adverse reactions and, based on the severity of the reaction, managed with treatment modifications and corticosteroids as clinically indicated (see Dosage & Administration and Adverse Reactions).
Infusion-related reactions: Infusion-related reactions have been observed with atezolizumab (see Adverse Reactions).
The rate of infusion should be reduced or treatment should be interrupted in patients with Grade 1 or 2 infusion-related reactions. Atezolizumab should be permanently discontinued in patients with Grade 3 or 4 infusion-related reactions. Patients with Grade 1 or 2 infusion-related reactions may continue to receive atezolizumab with close monitoring; premedication with antipyretic and antihistamines may be considered.
Autoimmune Hemolytic Anemia: Atezolizumab can cause autoimmune hemolytic anemia (AIHA). Patients should be monitored for signs and symptoms of drug-induced AIHA, and if this adverse reaction is observed, administration of this drug should be discontinued and treatment for AIHA should be initiated, as deemed medically appropriate.
Disease-specific precautions: Use of atezolizumab in combination with bevacizumab, paclitaxel and carboplatin in metastatic non-squamous NSCLC: Physicians should carefully consider the combined risks of the four-drug regimen of atezolizumab, bevacizumab, paclitaxel, and carboplatin before initiating treatment (see Adverse Reactions).
Use of atezolizumab in combination with nab-paclitaxel in metastatic TNBC: Neutropenia and peripheral neuropathies occurring during treatment with atezolizumab and nab-paclitaxel may be reversible with interruptions of nab-paclitaxel. Physicians should consult the nab-paclitaxel summary of product characteristics (SmPC) for specific precautions and contraindications of this medicine.
Use of atezolizumab in UC for previously untreated patients who are considered cisplatin ineligible: The baseline and prognostic disease characteristics of the IMvigor210 Cohort 1 study population were overall comparable to patients in the clinic who would be considered cisplatin ineligible but would be eligible for a carboplatin-based combination chemotherapy. There are insufficient data for the subgroup of patients that would be unfit for any chemotherapy; therefore atezolizumab should be used with caution in these patients, after careful consideration of the potential balance of risks and benefits on an individual basis.
Use of atezolizumab in combination with bevacizumab, paclitaxel and carboplatin: Patients with NSCLC that had clear tumour infiltration into the thoracic great vessels or clear cavitation of pulmonary lesions, as seen on imaging, were excluded from the pivotal clinical trial IMpower150 after several cases of fatal pulmonary haemorrhage were observed, which is a known risk factor of treatment with bevacizumab.
In the absence of data, atezolizumab should be used with caution in these populations after careful evaluation of the balance of benefits and risks for the patient.
Use of atezolizumab in combination with bevacizumab, paclitaxel and carboplatin in EGFR+ patients with NSCLC who have progressed on erlotinib+bevacizumab: In study IMpower150, there are no data on the efficacy of atezolizumab in combination with bevacizumab, paclitaxel and carboplatin in EGFR+ patients who have progressed previously on erlotinib+bevacizumab.
Use of atezolizumab in combination with bevacizumab in HCC: Data in HCC patients with Child-Pugh B liver disease treated with atezolizumab in combination with bevacizumab are very limited and there are currently no data available in HCC patients with Child-Pugh C liver disease.
Patients treated with bevacizumab have an increased risk of haemorrhage, and cases of severe gastrointestinal haemorrhage, including fatal events, were reported in patients with HCC treated with atezolizumab in combination with bevacizumab. In patients with HCC, screening for and subsequent treatment of oesophageal varices should be performed as per clinical practice prior to starting treatment with the combination of atezolizumab and bevacizumab. Bevacizumab should be permanently discontinued in patients who experience Grade 3 or 4 bleeding with the combination treatment. Please refer to the bevacizumab Summary of Product Characteristics.
Diabetes mellitus can occur during treatment with atezolizumab in combination with bevacizumab. Physicians should monitor blood glucose levels prior to and periodically during treatment with atezolizumab in combination with bevacizumab as clinically indicated.
Use of atezolizumab as monotherapy for first-line treatment in metastatic NSCLC: Physicians should consider the delayed onset of atezolizumab effect before initiating first-line treatment as monotherapy in patients with NSCLC. A higher number of deaths within 2.5 months after randomisation followed by a long-term survival benefit was observed with atezolizumab compared with chemotherapy. No specific factor(s) associated with early deaths could be identified (see Pharmacology: Pharmacodynamics under Actions).
Patients excluded from clinical trials: Patients with the following conditions were excluded from clinical trials: a history of autoimmune disease, history of pneumonitis, active brain metastasis, HIV, hepatitis B or hepatitis C infection (for non-HCC patients), significant cardiovascular disease and patients with inadequate hematologic and end-organ function. Patients who were administered a live, attenuated vaccine within 28 days prior to enrolment; systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive medicinal products within 2 weeks prior to study entry; therapeutic oral or Intravenous antibiotics within 2 weeks prior to initiation of study treatment were excluded from clinical trials.
Patient card: The prescriber must discuss the risks of Tecentriq therapy with the patient. The patient will be provided with the patient card and instructed to carry the card at all times.
Effects on ability to drive and use machines: Tecentriq has minor influence on the ability to drive and use machines. Patients experiencing fatigue should be advised not to drive and use machines until symptoms abate (see Adverse Reactions).
