atezolizumab: prescribing information – dosing, contraindications, interactions, side effects

Urothelial carcinoma (UC)
Tecentriq as monotherapy is indicated for the treatment of adult patients with locally advanced or metastatic UC:
 after prior platinum-containing chemotherapy, or
 who are considered cisplatin ineligible, and whose tumours have a PD-L1 expression ≥ 5% (see section 5.1).
Early-stage non-small cell lung cancer (NSCLC)
Tecentriq as monotherapy is indicated as adjuvant treatment following complete resection and platinum-based chemotherapy for adult patients with NSCLC with a high risk of recurrence whose tumours have PD-L1 expression on ≥ 50% of tumour cells (TC) and who do not have EGFR-mutant or ALK-positive NSCLC (see section 5.1 for selection criteria).

Advanced NSCLC
Tecentriq, in combination with bevacizumab, paclitaxel and carboplatin, is indicated for the first-line treatment of adult patients with metastatic non-squamous NSCLC. In patients with EGFR-mutant or ALK-positive NSCLC, Tecentriq, in combination with bevacizumab, paclitaxel and carboplatin, is indicated only after failure of appropriate targeted therapies (see section 5.1).
Tecentriq, in combination with nab-paclitaxel and carboplatin, is indicated for the first-line treatment of adult patients with metastatic non-squamous NSCLC who do not have EGFR-mutant or ALK-positive NSCLC (see section 5.1).
Tecentriq as monotherapy is indicated for the first-line treatment of adult patients with metastatic NSCLC whose tumours have a PD-L1 expression ≥ 50% TC or ≥ 10% tumour-infiltrating immune cells (IC) and who do not have EGFR-mutant or ALK-positive NSCLC (see section 5.1).
Tecentriq as monotherapy is indicated for the first-line treatment of adult patients with advanced NSCLC who are ineligible for platinum-based therapy (see section 5.1 for selection criteria).
Tecentriq as monotherapy is indicated for the treatment of adult patients with locally advanced or metastatic NSCLC after prior chemotherapy. Patients with EGFR-mutant or ALK-positive NSCLC should also have received targeted therapies before receiving Tecentriq (see section 5.1).
Small cell lung cancer (SCLC)
Tecentriq, in combination with carboplatin and etoposide, is indicated for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC) (see section 5.1).
Triple-negative breast cancer (TNBC)
Tecentriq in combination with nab-paclitaxel is indicated for the treatment of adult patients with unresectable locally advanced or metastatic TNBC whose tumours have PD-L1 expression ≥ 1% and who have not received prior chemotherapy for metastatic disease.
Hepatocellular carcinoma (HCC)
Tecentriq, in combination with bevacizumab, is indicated for the treatment of adult patients with advanced or unresectable HCC who have not received prior systemic therapy (see section 5.1).

Tecentriq must be initiated and supervised by physicians experienced in the treatment of cancer.
PD-L1 testing for patients with UC or TNBC or NSCLC
Tecentriq monotherapy
If specified in the indication, patient selection for treatment with Tecentriq based on the tumour expression of PD-L1 should be confirmed by a validated test (see sections 4.1 and 5.1).
Tecentriq in combination therapy
Patients with previously untreated TNBC should be selected for treatment based on the tumour expression of PD-L1 confirmed by a validated test (see section 5.1).

Posology
The recommended dose of Tecentriq is either 840 mg administered intravenously every two weeks, or 1 200 mg administered intravenously every three weeks, or 1 680 mg administered intravenously every four weeks, as presented in Table 1.
When Tecentriq is administered in combination therapy please also refer to the full prescribing information for the combination products (see also section 5.1).
Table 1: Recommended dose for Tecentriq by intravenous administration
Indication
Recommended dose and schedule
Duration of treatment
Tecentriq monotherapy
1L UC

840 mg every 2 weeks or

1 200 mg every 3 weeks or

1 680 mg every 4 weeks
Until disease progression or unmanageable toxicity.
1L metastatic NSCLC
1L platinum-ineligible
NSCLC
Early-stage NSCLC

840 mg every 2 weeks or

1 200 mg every 3 weeks or

1 680 mg every 4 weeks
For 1 year unless disease recurrence or unacceptable toxicity. Treatment duration for more than 1 year was not studied.
2L UC

840 mg every 2 weeks or

1 200 mg every 3 weeks or

1 680 mg every 4 weeks
Until loss of clinical benefit or unmanageable toxicity.
2L NSCLC
Tecentriq combination therapy
1L non-squamous NSCLC with bevacizumab, paclitaxel, and carboplatin
Induction and maintenance phases:

840 mg every 2 weeks or

1 200 mg every 3 weeks or

1 680 mg every 4 weeks
Tecentriq should be administered first when given on the same day.
Induction phase for combination partners (four or six cycles):
Bevacizumab, paclitaxel, and then carboplatin are administered every three weeks.
Maintenance phase (without chemotherapy): Bevacizumab every
3 weeks.
Until disease progression or unmanageable toxicity.
Atypical responses (i.e., an initial disease progression followed by tumour shrinkage) have been observed with continued Tecentriq treatment after disease progression.
Treatment beyond disease progression may be considered at the discretion of the physician.
1L non-squamous NSCLC with nab-paclitaxel and carboplatin
Induction and maintenance phases:

840 mg every 2 weeks or

1 200 mg every 3 weeks or

1 680 mg every 4 weeks
Tecentriq should be administered first when given on the same day.
Induction phase for combination partners (four or six cycles): Nab- paclitaxel, and carboplatin are administered on day 1; in addition, Until disease progression or unmanageable toxicity.
Atypical responses (i.e., an initial disease progression followed by tumour shrinkage) have been observed with continued Tecentriq treatment after disease progression.
Treatment beyond disease progression may be

Indication
Recommended dose and schedule
Duration of treatment nab-paclitaxel is administered on days 8 and 15 of each 3-weekly cycle.
considered at the discretion of the physician.
1L ES-SCLC with carboplatin and etoposide
Induction and maintenance phases:

840 mg every 2 weeks or

1 200 mg every 3 weeks or

1 680 mg every 4 weeks
Tecentriq should be administered first when given on the same day.
Induction phase for combination partners (four cycles): Carboplatin, and then etoposide are administered on day 1; etoposide is also administered on days 2 and 3 of each 3-weekly cycle.
Until disease progression or unmanageable toxicity.
Atypical responses (i.e., an initial disease progression followed by tumour shrinkage) have been observed with continued Tecentriq treatment after disease progression.
Treatment beyond disease progression may be considered at the discretion of the physician.
1L unresectable locally advanced or metastatic
TNBC with nab-paclitaxel

840 mg every 2 weeks or

1 200 mg every 3 weeks or

1 680 mg every 4 weeks
Tecentriq should be administered prior to nab-paclitaxel when given on the same day. Nab-paclitaxel should be administered at 100 mg/m2 on days 1, 8, and 15 of each 28-day cycle.
Until disease progression or unmanageable toxicity.
Advanced or unresectable
HCC with bevacizumab

840 mg every 2 weeks or

1 200 mg every 3 weeks or

1 680 mg every 4 weeks
Tecentriq should be administered prior to bevacizumab when given on the same day. Bevacizumab is administered at 15 mg/kg body weight (bw) every 3 weeks.
Until loss of clinical benefit or unmanageable toxicity.
Delayed or missed doses
If a planned dose of Tecentriq is missed, it should be administered as soon as possible. The schedule of administration must be adjusted to maintain the appropriate interval between doses.
Dose modifications during treatment
Dose reductions of Tecentriq are not recommended.

Dose delay or discontinuation (see also sections 4.4 and 4.8)
Table 2: Dose modification advice for Tecentriq
Immune-mediated adverse reaction
Severity
Treatment modification
Pneumonitis
Grade 2
Withhold Tecentriq
Treatment may be resumed when the event improves to Grade 0 or
Grade 1 within 12 weeks, and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day Grade 3 or 4 Permanently discontinue Tecentriq Hepatitis in patients without HCC Grade 2:
(ALT or AST > 3 to 5 x upper limit of normal [ULN] or blood bilirubin > 1.5 to 3 x ULN) Withhold Tecentriq Treatment may be resumed when the event improves to Grade 0 or Grade 1 within 12 weeks and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day Grade 3 or 4:
(ALT or AST > 5 x ULN or blood bilirubin > 3 x ULN)
Permanently discontinue
Tecentriq
Hepatitis in patients with
HCC
If AST/ALT is within normal limits at baseline and increases to > 3 x to
≤ 10x ULN or
If AST/ALT is > 1 to ≤ 3 x ULN at baseline and increases to > 5x to
≤ 10x ULN or
If AST/ALT is > 3 x to ≤ 5 x ULN at baseline and increases to >8 x to
≤10x ULN
Withhold Tecentriq
Treatment may be resumed when the event improves to Grade 0 or
Grade 1 within 12 weeks and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day If AST/ALT increases to > 10 x ULN or total bilirubin increases to > 3 x ULN Permanently discontinue Tecentriq

Immune-mediated adverse reaction
Severity
Treatment modification
Colitis
Grade 2 or 3 Diarrhoea (increase of
≥ 4 stools/day over baseline) or
Symptomatic Colitis
Withhold Tecentriq
Treatment may be resumed when the event improves to Grade 0 or
Grade 1 within 12 weeks and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day Grade 4 Diarrhoea or Colitis (life threatening; urgent intervention indicated) Permanently discontinue Tecentriq Hypothyroidism or hyperthyroidism Symptomatic Withhold Tecentriq Hypothyroidism:
Treatment may be resumed when symptoms are controlled by thyroid replacement therapy and TSH levels are decreasing Hyperthyroidism:
Treatment may be resumed when symptoms are controlled by anti- thyroid medicinal product and thyroid function is improving Adrenal insufficiency Symptomatic Withhold Tecentriq Treatment may be resumed when the symptoms improve to Grade 0 or Grade 1 within 12 weeks and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day and patient is stable on replacement therapy Hypophysitis Grade 2 or 3 Withhold Tecentriq Treatment may be resumed when the symptoms improve to Grade 0 or Grade 1 within 12 weeks and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day and patient is stable on replacement therapy Grade 4 Permanently discontinue Tecentriq

Immune-mediated adverse reaction
Severity
Treatment modification
Type 1 diabetes mellitus
Grade 3 or 4 hyperglycaemia
(fasting glucose > 250 mg/dL or

Tecentriq must be initiated and supervised by physicians experienced in the treatment of cancer.
Patients currently receiving intravenous atezolizumab can switch to Tecentriq solution for injection and vice versa.
PD-L1 testing for patients with UC or TNBC or NSCLC
Tecentriq monotherapy
If specified in the indication, patient selection for treatment with Tecentriq based on the tumour expression of PD-L1 should be confirmed by a validated test (see sections 4.1 and 5.1).
Tecentriq in combination therapy
Patients with previously untreated TNBC should be selected for treatment based on the tumour expression of PD-L1 confirmed by a validated test (see section 5.1).
Posology
The recommended dose of Tecentriq solution for injection is 1 875 mg administered every three weeks, as presented in Table 1.
When Tecentriq is administered in combination therapy please also refer to the full prescribing information for the combination products (see also section 5.1).

Table 1: Recommended dose for Tecentriq by subcutaneous administration
Indication
Recommended dose and schedule
Duration of treatment
Tecentriq monotherapy
1L UC
1 875 mg every 3 weeks
Until disease progression or unmanageable toxicity.
1L metastatic NSCLC
1L platinum-ineligible
NSCLC
Early-stage NSCLC
1 875 mg every 3 weeks
For 1 year unless disease recurrence or unacceptable toxicity. Treatment duration for more than 1 year was not studied.
2L UC
1 875 mg every 3 weeks
Until loss of clinical benefit or unmanageable toxicity.
2L NSCLC
Tecentriq combination therapy
1L non-squamous NSCLC with bevacizumab, paclitaxel, and carboplatin
Induction and maintenance phases:
1 875 mg every 3 weeks
Tecentriq should be administered first when given on the same day.
Induction phase for combination partners (four or six cycles):
Bevacizumab, paclitaxel, and then carboplatin are administered every three weeks.
Maintenance phase (without chemotherapy): Bevacizumab every
3 weeks.
Until disease progression or unmanageable toxicity.
Atypical responses (i.e., an initial disease progression followed by tumour shrinkage) have been observed with continued Tecentriq treatment after disease progression.
Treatment beyond disease progression may be considered at the discretion of the physician.
1L non-squamous NSCLC with nab-paclitaxel and carboplatin
Induction and maintenance phases:
1 875 mg every 3 weeks
Tecentriq should be administered first when given on the same day.
Induction phase for combination partners (four or six cycles): Nab- paclitaxel, and carboplatin are administered on day 1; in addition, nab-paclitaxel is administered on days 8 and 15 of each 3-weekly cycle.
Until disease progression or unmanageable toxicity.
Atypical responses (i.e., an initial disease progression followed by tumour shrinkage) have been observed with continued Tecentriq treatment after disease progression.
Treatment beyond disease progression may be considered at the discretion of the physician.

Indication
Recommended dose and schedule
Duration of treatment
1L ES-SCLC with carboplatin and etoposide
Induction and maintenance phases:
1 875 mg every 3 weeks
Tecentriq should be administered first when given on the same day.
Induction phase for combination partners (four cycles): Carboplatin, and then etoposide are administered on day 1; etoposide is also administered on days 2 and 3 of each 3-weekly cycle.
Until disease progression or unmanageable toxicity.
Atypical responses (i.e., an initial disease progression followed by tumour shrinkage) have been observed with continued Tecentriq treatment after disease progression.
Treatment beyond disease progression may be considered at the discretion of the physician.
1L unresectable locally advanced or metastatic
TNBC with nab-paclitaxel
1 875 mg every 3 weeks
Tecentriq should be administered prior to nab-paclitaxel when given on the same day. Nab-paclitaxel should be administered at 100 mg/m2 on days 1, 8, and 15 of each 28-day cycle.
Until disease progression or unmanageable toxicity.
Advanced or unresectable
HCC with bevacizumab
1 875 mg every 3 weeks
Tecentriq should be administered prior to bevacizumab when given on the same day. Bevacizumab is administered at 15 mg/kg body weight (bw) every 3 weeks.
Until loss of clinical benefit or unmanageable toxicity.
Delayed or missed doses
If a planned dose of Tecentriq is missed, it should be administered as soon as possible. The schedule of administration must be adjusted to maintain the appropriate interval between doses.
Dose modifications during treatment
Dose reductions of Tecentriq are not recommended.
Dose delay or discontinuation (see also sections 4.4 and 4.8)
Table 2: Dose modification advice for Tecentriq
Immune-mediated adverse reaction
Severity
Treatment modification
Pneumonitis
Grade 2
Withhold Tecentriq
Treatment may be resumed when the event improves to Grade 0 or
Grade 1 within 12 weeks, and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day Grade 3 or 4 Permanently discontinue Tecentriq Hepatitis in patients without HCC Grade 2:
(ALT or AST > 3 to 5 x upper limit of normal [ULN]
Withhold Tecentriq
Treatment may be resumed when the event improves to Grade 0 or

Immune-mediated adverse reaction
Severity
Treatment modification or blood bilirubin > 1.5 to 3 x ULN)
Grade 1 within 12 weeks and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day Grade 3 or 4:
(ALT or AST > 5 x ULN or blood bilirubin > 3 x ULN)
Permanently discontinue
Tecentriq
Hepatitis in patients with
HCC
If AST/ALT is within normal limits at baseline and increases to > 3 x to
≤ 10x ULN or
If AST/ALT is > 1 to ≤ 3 x ULN at baseline and increases to > 5x to
≤ 10x ULN or
If AST/ALT is > 3 x to ≤ 5 x ULN at baseline and increases to >8 x to
≤10x ULN
Withhold Tecentriq
Treatment may be resumed when the event improves to Grade 0 or
Grade 1 within 12 weeks and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day If AST/ALT increases to > 10 x ULN or total bilirubin increases to > 3 x ULN Permanently discontinue Tecentriq Colitis Grade 2 or 3 Diarrhoea (increase of ≥ 4 stools/day over baseline) or Symptomatic Colitis Withhold Tecentriq Treatment may be resumed when the event improves to Grade 0 or Grade 1 within 12 weeks and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day Grade 4 Diarrhoea or Colitis (life threatening; urgent intervention indicated) Permanently discontinue Tecentriq

Immune-mediated adverse reaction
Severity
Treatment modification
Hypothyroidism or hyperthyroidism
Symptomatic
Withhold Tecentriq
Hypothyroidism:
Treatment may be resumed when symptoms are controlled by thyroid replacement therapy and TSH levels are decreasing Hyperthyroidism:
Treatment may be resumed when symptoms are controlled by anti- thyroid medicinal product and thyroid function is improving Adrenal insufficiency Symptomatic Withhold Tecentriq Treatment may be resumed when the symptoms improve to Grade 0 or Grade 1 within 12 weeks and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day and patient is stable on replacement therapy Hypophysitis Grade 2 or 3 Withhold Tecentriq Treatment may be resumed when the symptoms improve to Grade 0 or Grade 1 within 12 weeks and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day and patient is stable on replacement therapy Grade 4 Permanently discontinue Tecentriq Type 1 diabetes mellitus Grade 3 or 4 hyperglycaemia (fasting glucose > 250 mg/dL or

Hypersensitivity to atezolizumab or to any of the excipients listed in section 6.1.

Summary of the safety profile
The safety of atezolizumab as monotherapy is based on pooled data in 5 039 patients across multiple tumour types. The most common adverse reactions (> 10%) were fatigue (29.3%), decreased appetite (20.1%), rash (19.7%), nausea (18.8%), cough (18.2%), diarrhoea (18.1%), pyrexia (17.9%), dyspnoea (16.6%), arthralgia (16.2%), pruritus (13.3%), asthenia (13%), back pain (12.2%), vomiting (11.7%), urinary tract infection (11%) and headache (10.2%).

The safety of atezolizumab given in combination with other medicinal products, has been evaluated in 4 535 patients across multiple tumour types. The most common adverse reactions (≥ 20%) were anaemia (36.8%), neutropenia (36.6%), nausea (35.5%), fatigue (33.1%), alopecia (28.1%), rash (27.8%), diarrhoea (27.6%), thrombocytopenia (27.1%), constipation (25.8%), decreased appetite (24.7%) and peripheral neuropathy (24.4%).
Use of atezolizumab in the adjuvant NSCLC setting
The safety profile of atezolizumab in the adjuvant setting in the non-small cell lung cancer (NSCLC) patient population (IMpower010) was generally consistent with the overall pooled monotherapy safety profile in the advanced setting. Nevertheless, the incidence of immune-mediated adverse reactions of atezolizumab in IMpower010 was 51.7% compared to 38.4% in the pooled monotherapy population with advanced disease. No new immune-mediated adverse reactions were identified in the adjuvant setting.
Use of atezolizumab in combination with bevacizumab, paclitaxel and carboplatin
In the first-line NSCLC study (IMpower150), an overall higher frequency of adverse events was observed in the four-drug regimen of atezolizumab, bevacizumab, paclitaxel, and carboplatin compared to atezolizumab, paclitaxel and carboplatin, including Grade 3 and 4 events (63.6% compared to 57.5%), Grade 5 events (6.1% compared to 2.5%), adverse events of special interest to atezolizumab (52.4% compared to 48.0%), as well as adverse events leading to withdrawal of any study treatment (33.8% compared to 13.3%). Nausea, diarrhoea, stomatitis, fatigue, pyrexia, mucosal inflammation, decreased appetite, weight decreased, hypertension and proteinuria were reported higher (5% difference) in patients receiving atezolizumab in combination with bevacizumab, paclitaxel and carboplatin. Other clinically significant adverse events which were observed more frequently in the atezolizumab, bevacizumab, paclitaxel, and carboplatin arm were epistaxis, haemoptysis, cerebrovascular accident, including fatal events.
Further details on serious adverse reactions are provided in section 4.4.
Tabulated list of adverse reactions
The adverse reactions (ARs) are listed by MedDRA system organ class (SOC) and categories of frequency in Table 3 for atezolizumab given as monotherapy or as combination therapy. Adverse reactions known to occur with atezolizumab or chemotherapies given alone may occur during treatment with these medicinal products in combination, even if these reactions were not reported in clinical trials with combination therapy. The following categories of frequency have been used: 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 the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.
Table 3: Summary of adverse reactions occurring in patients treated with atezolizumab Atezolizumab monotherapy Atezolizumab in combination therapy Infections and infestations Very common urinary tract infectiona lung infectionb Common sepsisaj Rare cytomegalovirus infection cytomegalovirus infection Blood and lymphatic system disorders Very common anaemiaaw anaemiaaw, thrombocytopeniad, neutropeniae, leukopeniaf Common thrombocytopeniad, neutropeniae lymphopeniag

Atezolizumab monotherapy
Atezolizumab in combination therapy
Rare haemophagocytic lymphohistiocytosis, autoimmune haemolytic anaemiaav haemophagocytic lymphohistiocytosis, autoimmune haemolytic anaemiaav Immune system disorders Common infusion-related reactionh infusion-related reactionh Rare sarcoidosisar Endocrine disorders Very common hypothyroidismi Common hypothyroidismi, hyperthyroidismj hyperthyroidismj Uncommon diabetes mellitusk, adrenal insufficiencyl, hypophysitism hypophysitism Metabolism and nutrition disorders Very common decreased appetite decreased appetite Common hypokalaemiaae, hyponatraemiaaf, hyperglycaemia, hypoalbuminaemia, hypophosphataemia, hypocalcaemia hypokalaemiaae, hyponatraemiaaf, hypomagnesaemian, hypoalbuminaemia, hypophosphataemia, hypocalcaemia Nervous system disorders Very common headache peripheral neuropathyo, headache Common peripheral neuropathyo syncope, dizziness Uncommon Guillain-Barré syndromep, meningoencephalitisq Rare myasthenic syndromer, facial paresis, myelitis facial paresis Eye disorders Uncommon uveitisas Rare uveitisas Cardiac disorders Common pericardial disordersao Uncommon pericardial disordersao Rare myocarditiss Vascular disorders Very common hypertensionai Common hypotension Respiratory, thoracic, and mediastinal disorders Very common dyspnoea, cough dyspnoea, cough, nasopharyngitisam Common pneumonitist, hypoxiaag, nasopharyngitisam dysphonia Gastrointestinal disorders Very common nausea, vomiting, diarrhoeau nausea, vomiting, diarrhoeau, constipation

a Includes reports of urinary tract infection, cystitis, pyelonephritis, escherichia urinary tract infection, urinary tract infection bacterial, kidney infection, pyelonephritis acute, pyelonephritis chronic, pyelitis, renal abscess, streptococcal urinary tract infection, urethritis, urinary tract infection fungal, urinary tract infection pseudomonal.
b Includes reports of pneumonia, bronchitis, lower respiratory tract infection, infectious pleural effusion, tracheobronchitis, atypical pneumonia, lung abscess, infective exacerbation of chronic obstructive airways disease, paracancerous pneumonia, pyopneumothorax, pleural infection, post procedural pneumonia.
c Includes reports of blood creatinine increased, hypercreatininaemia.
d Includes reports of immune thrombocytopenia (reported in studies outside the pooled dataset), thrombocytopenia, platelet count decreased.
Atezolizumab monotherapy
Atezolizumab in combination therapy
Common colitisv, abdominal pain, dysphagia, oropharyngeal painw, dry mouth stomatitis, dysgeusia, colitisv Uncommon pancreatitisx Rare coeliac disease coeliac disease Hepatobiliary disorders Common AST increased, ALT increased, hepatitisy AST increased, ALT increased Skin and subcutaneous tissue disorders Very common rashz, pruritus rashz, pruritus, alopeciaah Common dry skinap Uncommon severe cutaneous adverse reactionsak, psoriasisan, lichen disordersaq severe cutaneous adverse reactionsak, psoriasisan Rare pemphigoid pemphigoid, lichen disordersaq Musculoskeletal and connective tissue disorders Very common arthralgia, back pain arthralgia, musculoskeletal painaa, back pain Common musculoskeletal painaa, arthritisat arthritisat Uncommon myositisab, tenosynovitisau tenosynovitisau Renal and urinary disorders Common blood creatinine increasedc proteinuriaac, blood creatinine increasedc Uncommon nephritisad Not known cystitis noninfectiveal General disorders and administration site conditions Very common pyrexia, fatigue, asthenia pyrexia, fatigue, asthenia, oedema peripheral Common influenza like illness, chills Investigations Common gamma-glutamyl transferase increased blood alkaline phosphatase increased, gamma-glutamyl transferase increased Uncommon blood creatine phosphokinase increased

e Includes reports of neutropenia, neutrophil count decreased, febrile neutropenia, neutropenic sepsis, granulocytopenia.
f Includes reports of white blood cell count decreased, leukopenia.
g Includes reports of lymphopenia, lymphocyte count decreased.
h Includes reports of infusion-related reaction, cytokine release syndrome, hypersensitivity, anaphylaxis.
i Includes reports of anti-thyroid antibody positive, autoimmune hypothyroidism, autoimmune thyroiditis, blood thyroid stimulating hormone decreased, blood thyroid stimulating hormone increased, euthyroid sick syndrome, goitre, hypothyroidism, immune-mediated hypothyroidism, immune-mediated thyroiditis, myxoedema, primary hypothyroidism, thyroid disorder, thyroid hormones decreased, thyroid function test abnormal, thyroiditis, thyroiditis acute, thyroxine decreased, thyroxine free decreased, thyroxine free increased, thyroxine increased, tri-iodothyronine decreased, tri-iodothyronine increased, tri-iodothyronine free abnormal, tri-iodothyronine free decreased, tri- iodothyronine free increased, silent thyroiditis.
j Includes reports of hyperthyroidism, Basedow’s disease, endocrine ophthalmopathy, exophthalmos.
k Includes reports of diabetes mellitus, type 1 diabetes mellitus, diabetic ketoacidosis, ketoacidosis.
l Includes reports of adrenal insufficiency, blood corticotropin decreased, glucocorticoid deficiency, primary adrenal insufficiency, secondary adrenocortical insufficiency.
m Includes reports of hypophysitis, hypopituitarism, secondary adrenocortical insufficiency, temperature regulation disorder.
n Includes reports of hypomagnesaemia, blood magnesium decreased.
o Includes reports of neuropathy peripheral, autoimmune neuropathy, peripheral sensory neuropathy, polyneuropathy, herpes zoster, peripheral motor neuropathy, neuralgic amyotrophy, peripheral sensorimotor neuropathy, toxic neuropathy, axonal neuropathy, lumbosacral plexopathy, neuropathic arthropathy, peripheral nerve infection, neuritis, immune-mediated neuropathy.
p Includes reports of Guillain-Barré syndrome, ascending flaccid paralysis, demyelinating polyneuropathy.
q Includes reports of encephalitis, encephalitis autoimmune, meningitis, meningitis aseptic, photophobia.
r Includes reports of myasthenia gravis.
s Includes reports of myocarditis, autoimmune myocarditis, and immune-mediated myocarditis.
t Includes reports of pneumonitis, lung infiltration, bronchiolitis, immune-mediated lung disease, immune-mediated pneumonitis, interstitial lung disease, alveolitis, lung opacity, pulmonary fibrosis, pulmonary toxicity, radiation pneumonitis.
u Includes reports of diarrhoea, defaecation urgency, frequent bowel movements, gastrointestinal hypermotility.
v Includes reports of colitis, autoimmune colitis, colitis ischaemic, colitis microscopic, colitis ulcerative, diversion colitis, eosinophilic colitis, immune-mediated enterocolitis.
w Includes reports of oropharyngeal pain, oropharyngeal discomfort, throat irritation.
x Includes reports of autoimmune pancreatitis, pancreatitis, pancreatitis acute, lipase increased, amylase increased.
y Includes reports of ascites, autoimmune hepatitis, hepatic cytolysis, hepatitis, hepatitis acute, hepatitis toxic, hepatotoxicity, immune-mediated hepatitis, liver disorder, drug-induced liver injury, hepatic failure, hepatic steatosis, hepatic lesion, liver injury, oesophageal varices haemorrhage, varices oesophageal, spontaneous bacterial peritonitis.
z Includes reports of acne, blister, dermatitis, dermatitis acneiform, dermatitis allergic, drug eruption, eczema, eczema infected, erythema, erythema of eyelid, eyelid rash, fixed eruption, folliculitis, furuncle, hand dermatitis, immune-mediated dermatitis, lip blister, oral blood blister, palmar-plantar erythrodysaesthesia syndrome, pemphigoid, rash, rash erythematous, rash macular, rash maculo- papular, rash morbilliform, rash papular, rash papulosquamous, rash pruritic, rash pustular, rash vesicular, scrotal dermatitis, seborrhoeic dermatitis, skin exfoliation, skin toxicity, skin ulcer, vascular access site rash.
aa Includes reports of musculoskeletal pain, myalgia, bone pain.
ab Includes reports of myositis, rhabdomyolysis, polymyalgia rheumatica, dermatomyositis, muscle abscess, myoglobin urine present, myopathy, polymyositis.
ac Includes reports of proteinuria, protein urine present, haemoglobinurea, urine abnormality, nephrotic syndrome, albuminuria.

ad Includes reports of nephritis, autoimmune nephritis, Henoch-Schonlein purpura nephritis, paraneoplastic glomerulonephritis, tubulointerstitial nephritis.
ae Includes reports of hypokalaemia, blood potassium decreased.
af Includes reports of hyponatraemia, blood sodium decreased.
ag Includes reports of hypoxia, oxygen saturation decreased, pO2 decreased.
ah Includes reports of alopecia, madarosis, alopecia areata, alopecia totalis, hypotrichosis.
ai Includes reports of hypertension, blood pressure increased, hypertensive crisis, blood pressure systolic increased, diastolic hypertension, blood pressure inadequately controlled, retinopathy hypertensive, hypertensive nephropathy, essential hypertension, orthostatic hypertension.
aj Includes reports of sepsis, septic shock, urosepsis, neutropenic sepsis, pulmonary sepsis, bacterial sepsis, klebsiella sepsis, abdominal sepsis, candida sepsis, escherichia sepsis, pseudomonal sepsis, staphylococcal sepsis.
ak Includes reports of dermatitis bullous, exfoliative rash, erythema multiforme, dermatitis exfoliative, dermatitis exfoliative generalised, toxic skin eruption, Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms, toxic epidermal necrolysis, cutaneous vasculitis.
al Includes reports of cystitis noninfective and immune-mediated cystitis.
am Includes reports of nasopharyngitis, nasal congestion and rhinorrhoea.
an Includes reports of psoriasis, dermatitis psoriasiform.
ao Includes reports of pericarditis, pericardial effusion, cardiac tamponade and pericarditis constrictive.
ap Includes reports of dry skin, xerosis.
aq Includes reports of lichenoid keratosis, lichen sclerosus and lichen planus.
ar Includes reports of sarcoidosis, pulmonary sarcoidosis, and sarcoidosis of lymph node.
as Includes reports of uveitis, iridocyclitis and iritis.
at Includes reports of arthritis, joint swelling, osteoarthritis, rheumatoid arthritis, polyarthritis, spinal osteoarthritis, autoimmune arthritis, immune-mediated arthritis, spondylitis, joint effusion, arthropathy, oligoarthritis, rheumatic disorder.
au Includes reports of tendonitis, tendon pain, tenosynovitis and synovitis.
av Includes reports of autoimmune haemolytic anaemia, haemolytic anaemia.
aw Includes reports of anaemia, haemoglobin decreased, and red blood cell count decreased.
Description of selected adverse reactions
The data below reflect information for significant adverse reactions for atezolizumab as monotherapy in clinical trials (see section 5.1). Details for the significant adverse reactions for atezolizumab when given in combination are presented if clinically relevant differences were noted in comparison to atezolizumab monotherapy. The management guidelines for these adverse reactions are described in sections 4.2 and 4.4.
Immune-mediated pneumonitis
Pneumonitis occurred in 3.0% (151/5 039) of patients who received atezolizumab monotherapy. Of these patients, three experienced fatal events. The median time to onset was 3.7 months (range: 3 days to 29.8 months). The median duration was 1.7 months (range: 0 days to 27.8+ months; + denotes a censored value). Pneumonitis led to discontinuation of atezolizumab in 41 (0.8%) patients.
Pneumonitis requiring the use of corticosteroids occurred in 1.8% (92/5 039) of patients receiving atezolizumab monotherapy.
Immune-mediated hepatitis
Hepatitis occurred in 1.7% (88/5 039) of patients who received atezolizumab monotherapy. Of the 88 patients, three experienced fatal events. The median time to onset was 1.4 months (range: 0 days to 26.3 months). The median duration was 1 month (range: 0 day to 52.1+ months; + denotes a censored value). Hepatitis led to discontinuation of atezolizumab in 46 (0.9%) patients. Hepatitis requiring the use of corticosteroids occurred in 2.6% (130/5 039) of patients receiving atezolizumab monotherapy.

Immune-mediated colitis
Colitis occurred in 1.2% (62/5 039) of patients who received atezolizumab monotherapy. The median time to onset was 4.5 months (range: 15 days to 36.4 months). The median duration was 1.4 months (range: 3 days to 50.2+ months; + denotes a censored value). Colitis led to discontinuation of atezolizumab in 24 (0.5%) patients. Colitis requiring the use of corticosteroids occurred in 0.6% (30/5 039) of patients receiving atezolizumab monotherapy.
Immune-mediated endocrinopathies
Thyroid disorders
Hypothyroidism occurred in 8.5% (427/5 039) of patients who received atezolizumab monotherapy.
The median time to onset was 4.2 months (range: 0 days to 38.5 months). Hypothyroidism occurred in 17.4% (86/495) of patients who received atezolizumab monotherapy in the adjuvant NSCLC setting.
The median time to onset was 4.0 months (range: 22 days to 11.8 months).
Hyperthyroidism occurred in 2.4% (121/5 039) of patients who received atezolizumab monotherapy.
The median time to onset was 2.7 months (range: 0 days to 24.3 months). Hyperthyroidism occurred in 6.5% (32/495) of patients who received atezolizumab monotherapy in the adjuvant NSCLC setting.
The median time to onset was 2.8 months (range: 1 day to 9.9 months).
Adrenal insufficiency
Adrenal insufficiency occurred in 0.5% (25/5 039) of patients who received atezolizumab monotherapy. The median time to onset was 6.2 months (range: 3 days to 21.4 months). Adrenal insufficiency led to discontinuation of atezolizumab in 5 (0.1%) patients. Adrenal insufficiency requiring the use of corticosteroids occurred in 0.4% (20/5 039) of patients receiving atezolizumab monotherapy.
Hypophysitis
Hypophysitis occurred in 0.2% (9/5 039) of patients who received atezolizumab monotherapy. The median time to onset was 5.3 months (range: 21 days to 13.7 months). Six (0.1%) patients required the use of corticosteroids and treatment with atezolizumab was discontinued in 1 (< 0.1%) patient.
Hypophysitis occurred in 1.4% (15/1 093) of patients who received atezolizumab in combination with paclitaxel followed by atezolizumab, dose-dense doxorubicin or epirubicin, and cyclophosphamide.
The median time to onset was 3.8 months (range: 2.4 to 10.7 months). Eleven patients (1.0%) required the use of corticosteroids. Treatment with atezolizumab was discontinued in 7 (0.6%) patients.
Hypophysitis occurred in 0.8% (3/393) of patients who received atezolizumab with bevacizumab, paclitaxel, and carboplatin. The median time to onset was 7.7 months (range: 5.0 to 8.8 months). Two patients required the use of corticosteroids.
Hypophysitis occurred in 0.4% (2/473) of patients who received atezolizumab in combination with nab-paclitaxel and carboplatin. The median time to onset was 5.2 months (range: 5.1 to 5.3 months).
Both patients required the use of corticosteroids.

Diabetes mellitus
Diabetes mellitus occurred in 0.6% (30/5 039) of patients who received atezolizumab monotherapy.
The median time to onset was 5.5 months (range: 3 days to 29.0 months). Diabetes mellitus led to the discontinuation of atezolizumab in < 0.1% (3/5 039) patients. Four (< 0.1%) patients required the use of corticosteroids.
Diabetes mellitus occurred in 2.0% (10/493) of HCC patients who received atezolizumab in combination with bevacizumab. The median time to onset was 4.4 months (range: 1.2 months to 8.3 months). No events of diabetes mellitus led to atezolizumab withdrawal.
Immune-mediated meningoencephalitis
Meningoencephalitis occurred in 0.4% (22/5 039) of patients who received atezolizumab monotherapy. The median time to onset was 15 days (range: 0 days to 12.5 months). The median duration was 24 days (range: 6 days to 14.5+ months; + denotes a censored value).
Meningoencephalitis requiring the use of corticosteroids occurred in 0.2% (12/5 039) of patients receiving atezolizumab and eight patients (0.2%) discontinued atezolizumab.
Immune-mediated neuropathies
Guillain-Barré syndrome and demyelinating polyneuropathy
Guillain-Barré syndrome and demyelinating polyneuropathy occurred in 0.1% (6/5 039) of patients who received atezolizumab monotherapy. The median time to onset was 4.1 months (range: 18 days to 8.1 months). The median duration was 8.0 months (range: 18 days to 24.5+ months; + denotes a censored value). Guillain-Barré syndrome led to discontinuation of atezolizumab in 1 patient (< 0.1%).
Guillain-Barré syndrome requiring the use of corticosteroids occurred in < 0.1% (3/5 039) of patients receiving atezolizumab monotherapy.
Immune-mediated facial paresis
Facial paresis occurred in < 0.1% (1/5 039) of patients who received atezolizumab monotherapy. The time to onset was 29 days. The duration was 1.1 months. The event did not require the use of corticosteroids and the event did not lead to discontinuation of atezolizumab.
Immune-mediated myelitis
Myelitis occurred in < 0.1% (1/5 039) of patients who received atezolizumab monotherapy. The time to onset was 3 days. The event required the use of corticosteroids but did not lead to discontinuation of atezolizumab.
Myasthenic syndrome
Myasthenia gravis occurred in < 0.1% (2/5 039) of patients (including 1 fatal case) who received atezolizumab monotherapy. The median time to onset was 2.6 months (range: 1.2 months to 4 months).

Immune-mediated pancreatitis
Pancreatitis, including amylase increased and lipase increased, occurred in 0.8% (40/5 039) of patients who received atezolizumab monotherapy. The median time to onset was 5 months (range: 0 days to 24.8 months). The median duration was 24 days (range: 3 days to 40.4+ months; + denotes a censored value). Pancreatitis led to the discontinuation of atezolizumab in 3 (< 0.1%) patients. Pancreatitis requiring the use of corticosteroids occurred in 0.2% (8/5 039) of patients receiving atezolizumab monotherapy.
Immune-mediated myocarditis
Myocarditis occurred in < 0.1% (5/5 039) of patients who received atezolizumab monotherapy. Of the 5 patients, one experienced a fatal event in the adjuvant NSCLC setting. The median time to onset was 3.7 months (range: 1.5 to 4.9 months). The median duration was 14 days (range: 12 days to 2.8 months). Myocarditis led to the discontinuation of atezolizumab in 3 (< 0.1%) patients. Three (<0.1%) patients required the use of corticosteroids.
Immune-mediated nephritis
Nephritis occurred in 0.2% (11/5 039) of patients who received atezolizumab. The median time to onset was 5.1 months (range: 3 days to 17.5 months). Nephritis led to discontinuation of atezolizumab in 5 (≤ 0.1%) patients. Five (0.1%) patients required the use of corticosteroids.
Immune-mediated myositis
Myositis occurred in 0.6% (32/5 039) of patients who received atezolizumab monotherapy. The median time to onset was 3.5 months (range: 12 days to 11.5 months). The median duration was 3.2 months (range: 9 days to 51.1+ months; + denotes a censored value). Myositis led to discontinuation of atezolizumab in 6 (0.1%) patients. Ten (0.2%) patients required the use of corticosteroids.
Immune-mediated severe cutaneous adverse reactions
Severe cutaneous adverse reactions (SCARs) occurred in 0.6% (30/5 039) of patients who received atezolizumab monotherapy. Of the 30 patients, one experienced a fatal event. The median time to onset was 4.8 months (range: 3 days to 15.5 months). The median duration was 2.4 months (range:
1 day to 37.5+ months; + denotes a censored value). SCARs led to discontinuation of atezolizumab in 3 (< 0.1%) patients. SCARs requiring the use of systemic corticosteroids occurred in 0.2% (9/5 039) of patients receiving atezolizumab monotherapy.
Immune-mediated pericardial disorders
Pericardial disorders occurred in 1% (49/5 039) of patients who received atezolizumab monotherapy.
The median time to onset was 1.4 months (range: 6 days to 17.5 months). The median duration was 2.5 months (range: 0 to 51.5+ months; + denotes a censored value). Pericardial disorders led to

discontinuation of Tecentriq in 3 (< 0.1%) patients. Pericardial disorders requiring the use of corticosteroids occurred in 0.2% (7/5 039) of patients.
Immune checkpoint inhibitor class effects
There have been cases of the following adverse reaction(s) reported during treatment with other immune checkpoint inhibitors which might also occur during treatment with atezolizumab:
pancreatic exocrine insufficiency.
Immunogenicity
Across multiple phase II and III studies, 13.1% to 54.1% of patients developed treatment-emergent anti-drug antibodies (ADAs). Patients who developed treatment-emergent ADAs tended to have overall poorer health and disease characteristics at baseline. Those imbalances in health and disease characteristics at baseline can confound the interpretation of pharmacokinetic (PK), efficacy and safety analyses. Exploratory analyses adjusting for imbalances in baseline health and disease characteristics were conducted to assess the effect of ADA on efficacy. These analyses did not exclude possible attenuation of efficacy benefit in patients who developed ADA compared to patients who did not develop ADA. The median time to ADA onset ranged from 3 weeks to 5 weeks.
Across pooled datasets for patients treated with atezolizumab monotherapy (N=3 460) and with combination therapies (N= 2 285), the following rates of adverse events (AEs) have been observed for the ADA-positive population compared to the ADA-negative population, respectively: Grade 3-4 AEs 46.2% vs. 39.4%, Serious Adverse Events (SAEs) 39.6% vs. 33.3%, AEs leading to treatment withdrawal 8.5% vs 7.8% (for monotherapy); Grade 3-4 AEs 63.9% vs. 60.9%, SAEs 43.9% vs.
35.6%, AEs leading to treatment withdrawal 22.8% vs 18.4% (for combination therapy). However, available data do not allow firm conclusions to be drawn on possible patterns of adverse reactions.
Paediatric population
The safety of atezolizumab in children and adolescents has not been established. No new safety signals were observed in a clinical trial with 69 paediatric patients (< 18 years) and the safety profile was comparable to adults.
Elderly
No overall differences in safety were observed between patients < 65, 65-74, and 75-84 years of age receiving atezolizumab monotherapy. The data for patients ≥ 85 years of age are too limited to draw meaningful conclusions about this population.
In study IMpower150, age ≥ 65 was associated with an increased risk of developing adverse events in patients receiving atezolizumab in combination with bevacizumab, carboplatin and paclitaxel. In studies IMpower150, IMpower133 and IMpower110, data for patients ≥ 75 years of age were too limited to draw conclusions. In the IPSOS study in 1L platinum-ineligible NSCLC patients, there were no overall differences in the safety profile for 1L atezolizumab monotherapy between the patient age subgroups.
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 national reporting system listed in Appendix V.

Summary of the safety profile
The safety of atezolizumab as monotherapy is based on pooled data in 5 039 patients with various tumour types that were administered atezolizumab intravenously and 247 patients with NSCLC that were administered atezolizumab subcutaneously. The most common adverse reactions (> 10%) were fatigue (29.3%), decreased appetite (20.1%), rash (19.7%), nausea (18.8%), cough (18.2%), diarrhoea (18.1%), pyrexia (17.9%), dyspnoea (16.6%), , arthralgia (16.2%), pruritus (13.3%), asthenia (13%), back pain (12.2%), vomiting (11.7%), urinary tract infection (11%) and headache (10.2%).
The safety of intravenous atezolizumab given in combination with other medicinal products, has been evaluated in 4 535 patients across multiple tumour types. The most common adverse reactions (≥ 20%) were anaemia (36.8%), neutropenia (36.6%), nausea (35.5%), fatigue (33.1%), alopecia (28.1%), rash (27.8%), diarrhoea (27.6%), thrombocytopenia (27.1%), constipation (25.8%), decreased appetite (24.7%) and peripheral neuropathy (24.4%).
The safety profile of Tecentriq solution for injection was overall similar to the known safety profile of the intravenous formulation, with an additional adverse reaction of injection site reaction (4.5% in the subcutaneous Tecentriq arm vs 0% in the intravenous atezolizumab arm).

Use of atezolizumab in the adjuvant NSCLC setting
The safety profile of atezolizumab in the adjuvant setting in the non-small cell lung cancer (NSCLC) patient population (IMpower010) was generally consistent with the overall pooled monotherapy safety profile in the advanced setting. Nevertheless, the incidence of immune-mediated adverse reactions of atezolizumab in IMpower010 was 51.7% compared to 38.4% in the pooled monotherapy population with advanced disease. No new immune-mediated adverse reactions were identified in the adjuvant setting.
Use of atezolizumab in combination with bevacizumab, paclitaxel and carboplatin
In the first-line NSCLC study (IMpower150), an overall higher frequency of adverse events was observed in the four-drug regimen of atezolizumab, bevacizumab, paclitaxel, and carboplatin compared to atezolizumab, paclitaxel and carboplatin, including Grade 3 and 4 events (63.6% compared to 57.5%), Grade 5 events (6.1% compared to 2.5%), adverse events of special interest to atezolizumab (52.4% compared to 48.0%), as well as adverse events leading to withdrawal of any study treatment (33.8% compared to 13.3%). Nausea, diarrhoea, stomatitis, fatigue, pyrexia, mucosal inflammation, decreased appetite, weight decreased, hypertension and proteinuria were reported higher (5% difference) in patients receiving atezolizumab in combination with bevacizumab, paclitaxel and carboplatin. Other clinically significant adverse events which were observed more frequently in the atezolizumab, bevacizumab, paclitaxel, and carboplatin arm were epistaxis, haemoptysis, cerebrovascular accident, including fatal events.
Further details on serious adverse reactions are provided in section 4.4.
Tabulated list of adverse reactions
The adverse reactions (ARs) are listed by MedDRA system organ class (SOC) and categories of frequency in Table 3 for atezolizumab (intravenous and subcutaneous) given as monotherapy or as combination therapy. Adverse reactions known to occur with atezolizumab or chemotherapies given alone may occur during treatment with these medicinal products in combination, even if these reactions were not reported in clinical trials with combination therapy. The following categories of frequency have been used: 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 the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 3: Summary of adverse reactions occurring in patients treated with atezolizumab Atezolizumab monotherapy Atezolizumab in combination therapy Infections and infestations Very common urinary tract infectiona lung infectionb Common sepsisaj Rare cytomegalovirus infection cytomegalovirus infection Blood and lymphatic system disorders Very common anaemiaax anaemiaax, thrombocytopeniad, neutropeniae, leukopeniaf Common thrombocytopeniad, neutropeniae lymphopeniag Rare haemophagocytic lymphohistiocytosis, autoimmune haemolytic anaemiaaw haemophagocytic lymphohistiocytosis, autoimmune haemolytic anaemiaaw Immune system disorders Common infusion-related reactionh infusion-related reactionh Rare sarcoidosisas Endocrine disorders Very common hypothyroidismi Common hypothyroidismi, hyperthyroidismj hyperthyroidismj Uncommon diabetes mellitusk, adrenal insufficiencyl, hypophysitism hypophysitism Metabolism and nutrition disorders Very common decreased appetite decreased appetite Common hypokalaemiaae, hyponatraemiaaf, hyperglycaemia, hypoalbuminaemia, hypophosphataemia, hypocalcaemia hypokalaemiaae, hyponatraemiaaf, hypomagnesaemian, hypoalbuminaemia, hypophosphataemia, hypocalcaemia Nervous system disorders Very common headache peripheral neuropathyo, headache Common peripheral neuropathyo syncope, dizziness Uncommon Guillain-Barré syndromep, meningoencephalitisq Rare myasthenic syndromer, facial paresis, myelitis facial paresis Eye disorders Uncommon uveitisat Rare uveitisat Cardiac disorders Common pericardial disordersao Uncommon pericardial disordersao

Atezolizumab monotherapy
Atezolizumab in combination therapy
Rare myocarditiss
Vascular disorders
Very common hypertensionai
Common hypotension
Respiratory, thoracic, and mediastinal disorders
Very common dyspnoea, cough dyspnoea, cough, nasopharyngitisam
Common pneumonitist, hypoxiaag, nasopharyngitisam dysphonia
Gastrointestinal disorders
Very common nausea, vomiting, diarrhoeau nausea, vomiting, diarrhoeau, constipation Common colitisv, abdominal pain, dysphagia, oropharyngeal painw, dry mouth stomatitis, dysgeusia, colitisv Uncommon pancreatitisx Rare coeliac disease coeliac disease Hepatobiliary disorders Common AST increased, ALT increased, hepatitisy AST increased, ALT increased Skin and subcutaneous tissue disorders Very common rashz, pruritus rashz, pruritus, alopeciaah Common dry skinaq Uncommon severe cutaneous adverse reactionsak, psoriasisan, lichen disordersar severe cutaneous adverse reactionsak, psoriasisan Rare pemphigoid pemphigoid, lichen disordersar Musculoskeletal and connective tissue disorders Very common arthralgia, back pain arthralgia, musculoskeletal painaa, back pain Common musculoskeletal painaa, arthritisau arthritisau Uncommon myositisab, tenosynovitisav tenosynovitisav Renal and urinary disorders Common blood creatinine increasedc proteinuriaac, blood creatinine increasedc Uncommon nephritisad Not known cystitis noninfectiveal General disorders and administration site conditions Very common pyrexia, fatigue, asthenia pyrexia, fatigue, asthenia, oedema peripheral Common influenza like illness, chills, injection site reactionap

Atezolizumab monotherapy
Atezolizumab in combination therapy
Investigations
Common gamma-glutamyl transferase increased blood alkaline phosphatase increased, gamma-glutamyl transferase increased Uncommon blood creatine phosphokinase increased a Includes reports of urinary tract infection, cystitis, pyelonephritis, escherichia urinary tract infection, urinary tract infection bacterial, kidney infection, pyelonephritis acute, pyelonephritis chronic, pyelitis, renal abscess, streptococcal urinary tract infection, urethritis, urinary tract infection fungal, urinary tract infection pseudomonal.
b Includes reports of pneumonia, bronchitis, lower respiratory tract infection, infectious pleural effusion, tracheobronchitis, atypical pneumonia, lung abscess, infective exacerbation of chronic obstructive airways disease, paracancerous pneumonia, pyopneumothorax, pleural infection, post procedural pneumonia.
c Includes reports of blood creatinine increased, hypercreatininaemia.
d Includes reports of immune thrombocytopenia (reported in studies outside the pooled dataset), thrombocytopenia, platelet count decreased.
e Includes reports of neutropenia, neutrophil count decreased, febrile neutropenia, neutropenic sepsis, granulocytopenia.
f Includes reports of white blood cell count decreased, leukopenia.
g Includes reports of lymphopenia, lymphocyte count decreased.
h Includes reports of infusion-related reaction, cytokine release syndrome, hypersensitivity, anaphylaxis.
i Includes reports of anti-thyroid antibody positive, autoimmune hypothyroidism, autoimmune thyroiditis, blood thyroid stimulating hormone decreased, blood thyroid stimulating hormone increased, euthyroid sick syndrome, goitre, hypothyroidism, immune-mediated hypothyroidism, immune-mediated thyroiditis, myxoedema, primary hypothyroidism, thyroid disorder, thyroid hormones decreased, thyroid function test abnormal, thyroiditis, thyroiditis acute, thyroxine decreased, thyroxine free decreased, thyroxine free increased, thyroxine increased, tri-iodothyronine decreased, tri-iodothyronine increased, tri-iodothyronine free abnormal, tri-iodothyronine free decreased, tri- iodothyronine free increased, silent thyroiditis.
j Includes reports of hyperthyroidism, Basedow’s disease, endocrine ophthalmopathy, exophthalmos.
k Includes reports of diabetes mellitus, type 1 diabetes mellitus, diabetic ketoacidosis, ketoacidosis.
l Includes reports of adrenal insufficiency, blood corticotropin decreased, glucocorticoid deficiency, primary adrenal insufficiency, secondary adrenocortical insufficiency.
m Includes reports of hypophysitis, hypopituitarism, secondary adrenocortical insufficiency, temperature regulation disorder.
n Includes reports of hypomagnesaemia, blood magnesium decreased.
o Includes reports of neuropathy peripheral, autoimmune neuropathy, peripheral sensory neuropathy, polyneuropathy, herpes zoster, peripheral motor neuropathy, neuralgic amyotrophy, peripheral sensorimotor neuropathy, toxic neuropathy, axonal neuropathy, lumbosacral plexopathy, neuropathic arthropathy, peripheral nerve infection, neuritis, immune-mediated neuropathy.
p Includes reports of Guillain-Barré syndrome, ascending flaccid paralysis, demyelinating polyneuropathy.
q Includes reports of encephalitis, encephalitis autoimmune, meningitis, meningitis aseptic, photophobia.
r Includes reports of myasthenia gravis.
s Includes reports of myocarditis, autoimmune myocarditis, and immune-mediated myocarditis.
t Includes reports of pneumonitis, lung infiltration, bronchiolitis, immune-mediated lung disease, immune-mediated pneumonitis, interstitial lung disease, alveolitis, lung opacity, pulmonary fibrosis, pulmonary toxicity, radiation pneumonitis.
u Includes reports of diarrhoea, defaecation urgency, frequent bowel movements, gastrointestinal hypermotility.

v Includes reports of colitis, autoimmune colitis, colitis ischaemic, colitis microscopic, colitis ulcerative, diversion colitis, eosinophilic colitis, immune-mediated enterocolitis.
w Includes reports of oropharyngeal pain, oropharyngeal discomfort, throat irritation.
x Includes reports of autoimmune pancreatitis, pancreatitis, pancreatitis acute, lipase increased, amylase increased.
y Includes reports of ascites, autoimmune hepatitis, hepatic cytolysis, hepatitis, hepatitis acute, hepatitis toxic, hepatotoxicity, immune-mediated hepatitis, liver disorder, drug-induced liver injury, hepatic failure, hepatic steatosis, hepatic lesion, liver injury, oesophageal varices haemorrhage, varices oesophageal, spontaneous bacterial peritonitis.
z Includes reports of acne, blister, dermatitis, dermatitis acneiform, dermatitis allergic, drug eruption, eczema, eczema infected, erythema, erythema of eyelid, eyelid rash, fixed eruption, folliculitis, furuncle, hand dermatitis, immune-mediated dermatitis, lip blister, oral blood blister, palmar-plantar erythrodysaesthesia syndrome, pemphigoid, rash, rash erythematous, rash macular, rash maculo- papular, rash morbilliform, rash papular, rash papulosquamous, rash pruritic, rash pustular, rash vesicular, scrotal dermatitis, seborrhoeic dermatitis, skin exfoliation, skin toxicity, skin ulcer, vascular access site rash.
aa Includes reports of musculoskeletal pain, myalgia, bone pain.
ab Includes reports of myositis, rhabdomyolysis, polymyalgia rheumatica, dermatomyositis, muscle abscess, myoglobin urine present, myopathy, polymyositis.
ac Includes reports of proteinuria, protein urine present, haemoglobinurea, urine abnormality, nephrotic syndrome, albuminuria.
ad Includes reports of nephritis, autoimmune nephritis, Henoch-Schonlein purpura nephritis, paraneoplastic glomerulonephritis, tubulointerstitial nephritis.
ae Includes reports of hypokalaemia, blood potassium decreased.
af Includes reports of hyponatraemia, blood sodium decreased.
ag Includes reports of hypoxia, oxygen saturation decreased, pO2 decreased.
ah Includes reports of alopecia, madarosis, alopecia areata, alopecia totalis, hypotrichosis.
ai Includes reports of hypertension, blood pressure increased, hypertensive crisis, blood pressure systolic increased, diastolic hypertension, blood pressure inadequately controlled, retinopathy hypertensive, hypertensive nephropathy, essential hypertension, orthostatic hypertension.
aj Includes reports of sepsis, septic shock, urosepsis, neutropenic sepsis, pulmonary sepsis, bacterial sepsis, klebsiella sepsis, abdominal sepsis, candida sepsis, escherichia sepsis, pseudomonal sepsis, staphylococcal sepsis.
ak Includes reports of dermatitis bullous, exfoliative rash, erythema multiforme, dermatitis exfoliative, dermatitis exfoliative generalised, toxic skin eruption, Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms, toxic epidermal necrolysis, cutaneous vasculitis.
al Includes reports of cystitis noninfective and immune-mediated cystitis.
am Includes reports of nasopharyngitis, nasal congestion and rhinorrhoea.
an Includes reports of psoriasis, dermatitis psoriasiform.
ao Includes reports of pericarditis, pericardial effusion, cardiac tamponade and pericarditis constrictive ap Reported in a study outside the pooled dataset (subcutaneous administration related). The frequency is based on exposure to Tecentriq solution for injection in IMscin001 and IMscin002 and includes reports of injection site reaction, injection site pain, injection site erythema, and injection site rash.
aq Includes reports of dry skin, xerosis.
ar Includes reports of lichenoid keratosis, lichen sclerosus and lichen planus.
as Includes reports of sarcoidosis, pulmonary sarcoidosis, and sarcoidosis of lymph node.
at Includes reports of uveitis, iridocyclitis and iritis.
au Includes reports of arthritis, joint swelling, osteoarthritis, rheumatoid arthritis, polyarthritis, spinal osteoarthritis, autoimmune arthritis, immune-mediated arthritis, spondylitis, joint effusion, arthropathy, oligoarthritis, rheumatic disorder.
av Includes reports of tendonitis, tendon pain, tenosynovitis and synovitis.
aw Includes reports of autoimmune haemolytic anaemia, haemolytic anaemia.
ax. Includes reports of anaemia, haemoglobin decreased, and red blood cell count decreased.

Description of selected adverse reactions
The data below reflect information for significant adverse reactions for atezolizumab as monotherapy in clinical trials (see section 5.1). Details for the significant adverse reactions for atezolizumab when given in combination are presented if clinically relevant differences were noted in comparison to atezolizumab monotherapy. The management guidelines for these adverse reactions are described in sections 4.2 and 4.4.
Immune-mediated pneumonitis
Pneumonitis occurred in 3.0% (151/5 039) of patients who received atezolizumab monotherapy. Of these patients, three experienced fatal events. The median time to onset was 3.7 months (range: 3 days to 29.8 months). The median duration was 1.7 months (range: 0 days to 27.8+ months; + denotes a censored value). Pneumonitis led to discontinuation of atezolizumab in 41 (0.8%) patients.
Pneumonitis requiring the use of corticosteroids occurred in 1.8% (92/5 039) of patients receiving atezolizumab monotherapy.
Immune-mediated hepatitis
Hepatitis occurred in 1.7% (88/5 039) of patients who received atezolizumab monotherapy. Of the 88 patients, three experienced fatal events. The median time to onset was 1.4 months (range: 0 days to 26.3 months). The median duration was 1 months (range: 0 day to 52.1+ months; + denotes a censored value). Hepatitis led to discontinuation of atezolizumab in 46 (0.9%) patients. Hepatitis requiring the use of corticosteroids occurred in 2.6% (130/5 039) of patients receiving atezolizumab monotherapy.
Immune-mediated colitis
Colitis occurred in 1.2% (62/5 039) of patients who received atezolizumab monotherapy. The median time to onset was 4.5 months (range: 15 days to 36.4 months). The median duration was 1.4 months (range: 3 days to 50.2+ months; + denotes a censored value). Colitis led to discontinuation of atezolizumab in 24 (0.5%) patients. Colitis requiring the use of corticosteroids occurred in 0.6% (30/5 039) of patients receiving atezolizumab monotherapy.
Immune-mediated endocrinopathies
Thyroid disorders
Hypothyroidism occurred in 8.5% (427/5 039) of patients who received atezolizumab monotherapy.
The median time to onset was 4.2 months (range: 0 days to 38.5 months). Hypothyroidism occurred in 17.4% (86/495) of patients who received atezolizumab monotherapy in the adjuvant NSCLC setting.
The median time to onset was 4.0 months (range: 22 days to 11.8 months).
Hyperthyroidism occurred in 2.4% (121/5 039) of patients who received atezolizumab monotherapy.
The median time to onset was 2.7 months (range: 0 days to 24.3 months). Hyperthyroidism occurred in 6.5% (32/495) of patients who received atezolizumab monotherapy in the adjuvant NSCLC setting.
The median time to onset was 2.8 months (range: 1 day to 9.9 months).
Adrenal insufficiency
Adrenal insufficiency occurred in 0.5% (25/5 039) of patients who received atezolizumab monotherapy. The median time to onset was 6.2 months (range: 3 days to 21.4 months). Adrenal insufficiency led to discontinuation of atezolizumab in 5 (0.1%) patients. Adrenal insufficiency requiring the use of corticosteroids occurred in 0.4% (20/5 039) of patients receiving atezolizumab monotherapy.

Hypophysitis
Hypophysitis occurred in 0.2% (9/5 039) of patients who received atezolizumab monotherapy. The median time to onset was 5.3 months (range: 21 days to 13.7 months). Six (0.1%) patients required the use of corticosteroids and treatment with atezolizumab was discontinued in 1 (< 0.1%) patient.
Hypophysitis occurred in 1.4% (15/1 093) of patients who received atezolizumab in combination with paclitaxel followed by atezolizumab, dose-dense doxorubicin or epirubicin, and cyclophosphamide.
The median time to onset was 3.8 months (range: 2.4 to 10.7 months). Eleven patients (1.0%) required the use of corticosteroids. Treatment with atezolizumab was discontinued in 7 (0.6%) patients.
Hypophysitis occurred in 0.8% (3/393) of patients who received atezolizumab with bevacizumab, paclitaxel, and carboplatin. The median time to onset was 7.7 months (range: 5.0 to 8.8 months). Two patients required the use of corticosteroids.
Hypophysitis occurred in 0.4% (2/473) of patients who received atezolizumab in combination with nab-paclitaxel and carboplatin. The median time to onset was 5.2 months (range: 5.1 to 5.3 months).
Both patients required the use of corticosteroids.
Diabetes mellitus
Diabetes mellitus occurred in 0.6% (30/5 039) of patients who received atezolizumab monotherapy.
The median time to onset was 5.5 months (range: 3 days to 29.0 months). Diabetes mellitus led to the discontinuation of atezolizumab in < 0.1% (3/5 039) patients. Four (< 0.1%) patients required the use of corticosteroids.
Diabetes mellitus occurred in 2.0% (10/493) of HCC patients who received atezolizumab in combination with bevacizumab. The median time to onset was 4.4 months (range: 1.2 months to 8.3 months). No events of diabetes mellitus led to atezolizumab withdrawal.
Immune-mediated meningoencephalitis
Meningoencephalitis occurred in 0.4% (22/5 039) of patients who received atezolizumab monotherapy. The median time to onset was 15 days (range: 0 days to 12.5 months). The median duration was 24 days (range: 6 days to 14.5+ months; + denotes a censored value).
Meningoencephalitis requiring the use of corticosteroids occurred in 0.2% (12/5 039) of patients receiving atezolizumab and eight patients (0.2%) discontinued atezolizumab.
Immune-mediated neuropathies
Guillain-Barré syndrome and demyelinating polyneuropathy
Guillain-Barré syndrome and demyelinating polyneuropathy occurred in 0.1% (6/5 039) of patients who received atezolizumab monotherapy. The median time to onset was 4.1 months (range: 18 days to 8.1 months). The median duration was 8.0 months (range: 18 days to 24.5+ months; + denotes a censored value). Guillain-Barré syndrome led to discontinuation of atezolizumab in 1 patient (< 0.1%).
Guillain-Barré syndrome requiring the use of corticosteroids occurred in < 0.1% (3/5 039) of patients receiving atezolizumab monotherapy.
Immune-mediated facial paresis
Facial paresis occurred in < 0.1% (1/5 039) of patients who received atezolizumab monotherapy. The time to onset was 29 days. The duration was 1.1 months. The event did not require the use of corticosteroids and the event did not lead to discontinuation of atezolizumab.

Immune-mediated myelitis
Myelitis occurred in < 0.1% (1/5 039) of patients who received atezolizumab monotherapy. The time to onset was 3 days. The event required the use of corticosteroids but did not lead to discontinuation of atezolizumab.
Myasthenic syndrome
Myasthenia gravis occurred in < 0.1% (2/5 039) of patients (including 1 fatal case) who received atezolizumab monotherapy. The median time to onset was 2.6 months (range: 1.2 months to 4 months).
Immune-mediated pancreatitis
Pancreatitis, including amylase increased and lipase increased, occurred in 0.8% (40/5 039) of patients who received atezolizumab monotherapy. The median time to onset was 5 months (range: 0 days to 24.8 months). The median duration was 24 days (range: 3 days to 40.4+ months; + denotes a censored value). Pancreatitis led to the discontinuation of atezolizumab in 3 (< 0.1%) patients. Pancreatitis requiring the use of corticosteroids occurred in 0.2% (8/5 039) of patients receiving atezolizumab monotherapy.
Immune-mediated myocarditis
Myocarditis occurred in < 0.1% (5/5 039) of patients who received atezolizumab monotherapy. Of the 5 patients, one experienced a fatal event in the adjuvant NSCLC setting. The median time to onset was 3.7 months (range: 1.5 to 4.9 months). The median duration was 14 days (range: 12 days to 2.8 months). Myocarditis led to the discontinuation of atezolizumab in 3 (< 0.1%) patients. Three (<0.1%) patients required the use of corticosteroids.
Immune-mediated nephritis
Nephritis occurred in 0.2% (11/5 039) of patients who received atezolizumab. The median time to onset was 5.1 months (range: 3 days to 17.5 months). Nephritis led to discontinuation of atezolizumab in 5 (≤ 0.1%) patients. Five (0.1%) patients required the use of corticosteroids.
Immune-mediated myositis
Myositis occurred in 0.6% (32/5 039) of patients who received atezolizumab monotherapy. The median time to onset was 3.5 months (range: 12 days to 11.5 months). The median duration was 3.2 months (range: 9 days to 51.1+ months; + denotes a censored value). Myositis led to discontinuation of atezolizumab in 6 (0.1%) patients. Ten (0.2%) patients required the use of corticosteroids.
Immune-mediated severe cutaneous adverse reactions
Severe cutaneous adverse reactions (SCARs) occurred in 0.6% (30/5 039) of patients who received atezolizumab monotherapy. Of the 30 patients, one experienced a fatal event. The median time to onset was 4.8 months (range: 3 days to 15.5 months). The median duration was 2.4 months (range:
1 day to 37.5+ months; + denotes a censored value). SCARs led to discontinuation of atezolizumab in 3 (< 0.1%) patients. SCARs requiring the use of systemic corticosteroids occurred in 0.2% (9/5 039) of patients receiving atezolizumab monotherapy.
Immune-mediated pericardial disorders
Pericardial disorders occurred in 1% (49/5 039) of patients who received atezolizumab monotherapy.
The median time to onset was 1.4 months (range: 6 days to 17.5 months). The median duration was 2.5 months (range: 0 to 51.5+ months; + denotes a censored value). Pericardial disorders led to

discontinuation of Tecentriq in 3 (< 0.1%) patients. Pericardial disorders requiring the use of corticosteroids occurred in 0.2% (7/5 039) of patients.
Immune checkpoint inhibitor class effects
There have been cases of the following adverse reaction(s) reported during treatment with other immune checkpoint inhibitors which might also occur during treatment with atezolizumab:
pancreatic exocrine insufficiency.
Immunogenicity
Subcutaneous formulation
In IMscin001, the incidence of treatment-emergent anti-atezolizumab antibodies in patients treated with subcutaneous and intravenous Tecentriq was comparable (19.5% [43/221] and 13.9% [15/108], respectively), following a median of 2.8 months of treatment. The incidence of treatment-emergent anti-rHuPH20 antibodies in patients treated with subcutaneous Tecentriq was 5.4% (12/224). The clinical relevance of the development of anti-rHuPH20 antibodies after treatment with Tecentriq solution for injection is unknown.
Intravenous formulation
Across multiple phase II and III studies, 13.1% to 54.1% of patients developed treatment-emergent anti-drug antibodies (ADAs). Patients who developed treatment-emergent ADAs tended to have overall poorer health and disease characteristics at baseline. Those imbalances in health and disease characteristics at baseline can confound the interpretation of PK, efficacy and safety analyses.
Exploratory analyses adjusting for imbalances in baseline health and disease characteristics were conducted to assess the effect of ADA on efficacy. These analyses did not exclude possible attenuation of efficacy benefit in patients who developed ADA compared to patients who did not develop ADA.
The median time to ADA onset ranged from 3 weeks to 5 weeks.
Across pooled datasets for patients treated with atezolizumab monotherapy (N=3 460) and with combination therapies (N= 2 285), the following rates of adverse events (AEs) have been observed for the ADA-positive population compared to the ADA-negative population, respectively: Grade 3-4 AEs 46.2% vs. 39.4%, Serious Adverse Events (SAEs) 39.6% vs. 33.3%, AEs leading to treatment withdrawal 8.5% vs 7.8% (for monotherapy); Grade 3-4 AEs 63.9% vs. 60.9%, SAEs 43.9% vs.
35.6%, AEs leading to treatment withdrawal 22.8% vs 18.4% (for combination therapy). However, available data do not allow firm conclusions to be drawn on possible patterns of adverse reactions.
Paediatric population
The safety of atezolizumab in children and adolescents has not been established. No new safety signals were observed in a clinical trial with 69 paediatric patients (< 18 years) and the safety profile was comparable to adults.
Elderly
No overall differences in safety were observed between patients < 65, 65-74, and 75-84 years of age receiving atezolizumab monotherapy. The data for patients ≥ 85 years of age are too limited to draw meaningful conclusions about this population.
In study IMpower150, age ≥ 65 was associated with an increased risk of developing adverse events in patients receiving atezolizumab in combination with bevacizumab, carboplatin and paclitaxel. In studies IMpower150, IMpower133, IMpower110 and IMscin001 data for patients ≥ 75 years of age were too limited to draw conclusions. In the IPSOS study in 1L platinum-ineligible NSCLC patients, there were no overall differences in the safety profile for 1L atezolizumab monotherapy between the patient age subgroups.

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 national reporting system listed in Appendix V.

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.

Immune-mediated adverse reactions
Most immune-mediated adverse reactions occurring during treatment with atezolizumab were reversible with interruptions of atezolizumab and initiation of corticosteroids and/or supportive care.
Immune-mediated adverse reactions affecting more than one body system have been observed.
Immune-mediated adverse reactions with atezolizumab may occur after the last dose of atezolizumab.
For suspected immune-mediated 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-mediated 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-mediated adverse reaction that recurs and for any Grade 4 immune-mediated adverse reactions, except for endocrinopathies that are controlled with replacement hormones (see sections 4.2 and 4.8).
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
Cases of pneumonitis, including fatal cases, have been observed in clinical trials with atezolizumab (see section 4.8). Patients should be monitored for signs and symptoms of pneumonitis and causes other than immune-mediated 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-mediated hepatitis
Cases of hepatitis, some leading to fatal outcomes have been observed in clinical trials with atezolizumab (see section 4.8). 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-mediated colitis
Cases of diarrhoea or colitis have been observed in clinical trials with atezolizumab (see section 4.8).
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. The potential complication of gastrointestinal perforation associated with colitis should be taken into consideration.
Immune-mediated endocrinopathies
Hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis and type 1 diabetes mellitus, including diabetic ketoacidosis have been observed in clinical trials with atezolizumab (see section 4.8).
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-mediated meningoencephalitis
Meningoencephalitis has been observed in clinical trials with atezolizumab (see section 4.8). 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-mediated neuropathies
Myasthenic syndrome/myasthenia gravis or Guillain-Barré syndrome, which may be life threatening, and facial paresis were observed in patients receiving atezolizumab. Patients should be monitored for symptoms of motor and sensory neuropathy (also see “Immune-mediated myocarditis-myositis- myasthenia gravis overlap syndrome” in this section).
Myelitis has been observed in clinical trials with atezolizumab (see section 4.8). Patients should be closely monitored for signs and symptoms that are suggestive of myelitis.
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.
Treatment with atezolizumab should be withheld for Grade 1 or 2 facial paresis, and treatment with systemic corticosteroids (1 to 2 mg/kg bw/day prednisone or equivalent) should be considered.
Treatment may be resumed only if the event fully resolves. Treatment with atezolizumab should be permanently discontinued for Grade 3 or Grade 4 facial paresis, or any other neuropathy that does not fully resolve while withholding atezolizumab.
Treatment with atezolizumab must be permanently discontinued for Grade 2, 3 or 4 myelitis.
Immune-mediated pancreatitis
Pancreatitis, including increases in serum amylase and lipase levels, has been observed in clinical trials with atezolizumab (see section 4.8). 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-mediated myocarditis
Cases of myocarditis, including fatal cases, have been observed with atezolizumab (see section 4.8).
Patients should be monitored for signs and symptoms of myocarditis (also see “Immune-mediated myocarditis-myositis-myasthenia gravis overlap syndrome” in this section).
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 section 4.2).
Immune-mediated nephritis
Nephritis has been observed in clinical trials with atezolizumab (see section 4.8). 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-mediated myositis
Cases of myositis, including fatal cases, have been observed with atezolizumab (see section 4.8).
Patients should be monitored for signs and symptoms of myositis (also see “Immune-mediated myocarditis-myositis-myasthenia gravis overlap syndrome” in this section).
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 to 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-mediated severe cutaneous adverse reactions
Immune-mediated 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 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 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.
Immune-mediated pericardial disorders
Pericardial disorders, including pericarditis, pericardial effusion and cardiac tamponade, some leading to fatal outcomes, have been observed with atezolizumab (see section 4.8). Patients should be monitored for clinical signs and symptoms of pericardial disorders.
For suspected Grade 1 pericarditis, treatment with atezolizumab should be withheld and prompt cardiology consultation with diagnostic workup according to current clinical guidelines should be initiated. For suspected Grade ≥ 2 pericardial disorders, treatment with atezolizumab should be withheld, prompt treatment with 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 a pericardial disorder event is established, treatment with atezolizumab must be permanently discontinued for Grade ≥ 2 pericardial disorders (see section 4.2).
Haemophagocytic lymphohistiocytosis
Haemophagocytic lymphohistiocytosis (HLH), including fatal cases, has been reported in patients receiving atezolizumab (see section 4.8). HLH should be considered when the presentation of cytokine release syndrome is atypical or prolonged. Patients should be monitored for clinical signs and symptoms of HLH. For suspected HLH, atezolizumab must be permanently discontinued and patients should be referred to a specialist for further diagnosis and management.
Immune-mediated myocarditis-myositis-myasthenia gravis overlap syndrome
Cases of myocarditis-myositis-myasthenia gravis overlap syndrome (presenting as an overlap of either two or all three conditions), some with fatal outcome, have been observed in the post-marketing setting and clinical trials with atezolizumab. Early recognition and aggressive management are essential to address associated morbidity and risk of mortality.
It is important to recognise overlapping symptoms, which can complicate diagnosis and management and could have a higher risk of mortality. Patients presenting with signs or symptoms of one condition should also be monitored for the other two conditions and should be managed as clinically indicated.
Refer to section 4.2, Table 2 for recommended dose modification guidance for the individual conditions (myocarditis, myositis, myasthenia gravis) and adhere to the most stringent recommendations.
Other immune-mediated adverse reactions
Given the mechanism of action of atezolizumab, other potential immune-mediated adverse reactions may occur, including noninfective cystitis, uveitis and autoimmune haemolytic anaemia.
Evaluate all suspected immune-mediated adverse reactions to exclude other causes. Patients should be monitored for signs and symptoms of immune-mediated adverse reactions and, based on the severity of the reaction, managed with treatment modifications and corticosteroids as clinically indicated (see section 4.2 and section 4.8).

Infusion-related reactions
Infusion-related reactions have been observed with atezolizumab, including anaphylaxis (see section 4.8). 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.
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 section 4.8).
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 section 5.1).
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, ECOG PS ≥ 2 (except for patients with advanced NSCLC ineligible for a platinum-based therapy), 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.
Excipients with known effect
This medicinal product contains polysorbate 20. Each vial of Tecentriq 840 mg concentrate for solution for infusion contains 5.6 mg of polysorbate 20, which is equivalent to 0.4 mg/mL. Each vial of Tecentriq 1 200 mg concentrate for solution for infusion contains 8 mg of polysorbate 20, which is equivalent to 0.4 mg/ml. Polysorbate 20 may cause allergic reactions.
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.

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.
Immune-mediated adverse reactions
Most immune-mediated adverse reactions occurring during treatment with atezolizumab were reversible with interruptions of atezolizumab and initiation of corticosteroids and/or supportive care.
Immune-mediated adverse reactions affecting more than one body system have been observed.
Immune-mediated adverse reactions with atezolizumab may occur after the last dose of atezolizumab.
For suspected immune-mediated 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-mediated 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-mediated adverse reaction that recurs and for any Grade 4 immune-mediated adverse reactions, except for endocrinopathies that are controlled with replacement hormones (see sections 4.2 and 4.8).
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
Cases of pneumonitis, including fatal cases, have been observed in clinical trials with atezolizumab (see section 4.8). Patients should be monitored for signs and symptoms of pneumonitis and causes other than immune-mediated 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-mediated hepatitis
Cases of hepatitis, some leading to fatal outcomes have been observed in clinical trials with atezolizumab (see section 4.8). 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-mediated colitis
Cases of diarrhoea or colitis have been observed in clinical trials with atezolizumab (see section 4.8).
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. The potential complication of gastrointestinal perforation associated with colitis should be taken into consideration.
Immune-mediated endocrinopathies
Hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis and type 1 diabetes mellitus, including diabetic ketoacidosis have been observed in clinical trials with atezolizumab (see section 4.8).
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-mediated meningoencephalitis
Meningoencephalitis has been observed in clinical trials with atezolizumab (see section 4.8). 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-mediated neuropathies
Myasthenic syndrome/myasthenia gravis or Guillain-Barré syndrome, which may be life threatening, and facial paresis were observed in patients receiving atezolizumab. Patients should be monitored for symptoms of motor and sensory neuropathy (also see “Immune-mediated myocarditis-myositis- myasthenia gravis overlap syndrome” in this section).
Myelitis has been observed in clinical trials with atezolizumab (see section 4.8). Patients should be closely monitored for signs and symptoms that are suggestive of myelitis.
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.
Treatment with atezolizumab should be withheld for Grade 1 or 2 facial paresis, and treatment with systemic corticosteroids (1 to 2 mg/kg bw/day prednisone or equivalent) should be considered.
Treatment may be resumed only if the event fully resolves. Treatment with atezolizumab should be permanently discontinued for Grade 3 or Grade 4 facial paresis, or any other neuropathy that does not fully resolve while withholding atezolizumab.
Treatment with atezolizumab must be permanently discontinued for Grade 2, 3 or 4 myelitis.
Immune-mediated pancreatitis
Pancreatitis, including increases in serum amylase and lipase levels, has been observed in clinical trials with atezolizumab (see section 4.8). 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-mediated myocarditis
Cases of myocarditis, including fatal cases, have been observed with atezolizumab (see section 4.8).
Patients should be monitored for signs and symptoms of myocarditis (also see “Immune-mediated myocarditis-myositis-myasthenia gravis overlap syndrome” in this section).
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 section 4.2).

Immune-mediated nephritis
Nephritis has been observed in clinical trials with atezolizumab (see section 4.8). 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-mediated myositis
Cases of myositis, including fatal cases, have been observed with atezolizumab (see section 4.8).
Patients should be monitored for signs and symptoms of myositis (also see “Immune-mediated myocarditis-myositis-myasthenia gravis overlap syndrome” in this section).
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 to 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-mediated severe cutaneous adverse reactions
Immune-mediated 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 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 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.
Immune-mediated pericardial disorders
Pericardial disorders, including pericarditis, pericardial effusion and cardiac tamponade, some leading to fatal outcomes, have been observed with atezolizumab (see section 4.8). Patients should be monitored for clinical signs and symptoms of pericardial disorders.
For suspected Grade 1 pericarditis, treatment with atezolizumab should be withheld and prompt cardiology consultation with diagnostic workup according to current clinical guidelines should be

initiated. For suspected Grade ≥ 2 pericardial disorders, treatment with atezolizumab should be withheld, prompt treatment with 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 a pericardial disorder event is established, treatment with atezolizumab must be permanently discontinued for Grade ≥ 2 pericardial disorders (see section 4.2).
Haemophagocytic lymphohistiocytosis
Haemophagocytic lymphohistiocytosis (HLH), including fatal cases, has been reported in patients receiving atezolizumab (see section 4.8). HLH should be considered when the presentation of cytokine release syndrome is atypical or prolonged. Patients should be monitored for clinical signs and symptoms of HLH. For suspected HLH, atezolizumab must be permanently discontinued and patients should be referred to a specialist for further diagnosis and management.
Immune-mediated myocarditis-myositis-myasthenia gravis overlap syndrome
Cases of myocarditis-myositis-myasthenia gravis overlap syndrome (presenting as an overlap of either two or all three conditions), some with fatal outcome, have been observed in the post-marketing setting and clinical trials with atezolizumab. Early recognition and aggressive management are essential to address associated morbidity and risk of mortality.
It is important to recognise overlapping symptoms, which can complicate diagnosis and management and could have a higher risk of mortality. Patients presenting with signs or symptoms of one condition should also be monitored for the other two conditions and should be managed as clinically indicated.
Refer to section 4.2, Table 2 for recommended dose modification guidance for the individual conditions (myocarditis, myositis, myasthenia gravis) and adhere to the most stringent recommendations.
Other immune-mediated adverse reactions
Given the mechanism of action of atezolizumab, other potential immune-mediated adverse reactions may occur, including noninfective cystitis, uveitis and autoimmune haemolytic anaemia.
Evaluate all suspected immune-mediated adverse reactions to exclude other causes. Patients should be monitored for signs and symptoms of immune-mediated adverse reactions and, based on the severity of the reaction, managed with treatment modifications and corticosteroids as clinically indicated (see section 4.2 and section 4.8).
Infusion-related reactions
Infusion-related reactions have been observed with atezolizumab, including anaphylaxis (see section 4.8). The rate of injection should be reduced or paused 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.
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 section 4.8).

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 section 5.1).
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, ECOG PS ≥ 2 (except for patients with advanced NSCLC ineligible for a platinum-based therapy), 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.
Excipients with known effect
This medicinal product contains polysorbate 20. Each vial of Tecentriq 1 875 mg solution for injection contains 9 mg of polysorbate 20, which is equivalent to 0.6 mg/ml. Polysorbate 20 may cause allergic reactions.
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.

No formal pharmacokinetic interaction studies have been conducted with atezolizumab. Since atezolizumab is cleared from the circulation through catabolism, no metabolic drug-drug interactions are expected.
The use of systemic corticosteroids or immunosuppressants before starting atezolizumab should be avoided because of their potential interference with the pharmacodynamic activity and efficacy of atezolizumab. However, systemic corticosteroids or other immunosuppressants can be used to treat immune-mediated adverse reactions after starting atezolizumab (see section 4.4).

Women of childbearing potential
Women of childbearing potential have to use effective contraception during and for 5 months after treatment with atezolizumab.
Pregnancy
There are no data from the use of atezolizumab in pregnant women. No developmental and reproductive studies were conducted with atezolizumab. Animal studies have demonstrated that inhibition of the PD-L1/PD-1 pathway in murine pregnancy models can lead to immune-mediated rejection of the developing foetus resulting in foetal death (see section 5.3). These results indicate a potential risk, based on its mechanism of action, that administration of atezolizumab during pregnancy could cause foetal harm, including increased rates of abortion or stillbirth.
Human immunoglobulins G1 (IgG1) are known to cross the placental barrier and atezolizumab is an IgG1; therefore, atezolizumab has the potential to be transmitted from the mother to the developing foetus.
Atezolizumab should not be used during pregnancy unless the clinical condition of the woman requires treatment with atezolizumab.
Breast-feeding
It is unknown whether atezolizumab is excreted in human milk. Atezolizumab is a monoclonal antibody and is expected to be present in the first milk and at low levels afterwards. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue Tecentriq therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility
No clinical data are available on the possible effects of atezolizumab on fertility. No reproductive and development toxicity studies have been conducted with atezolizumab; however, based on the 26-week repeat dose toxicity study, atezolizumab had an effect on menstrual cycles at an estimated AUC approximately 6 times the AUC in patients receiving the recommended dose and was reversible (see section 5.3). There were no effects on the male reproductive organs.

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 section 4.8).

There is no information on overdose with atezolizumab.
In case of overdose, patients should be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment instituted.
5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies and antibody drug conjugates, PD-1/PDL-1 (Programmed cell death protein 1/death ligand 1) inhibitors. ATC code:
L01FF05.
Mechanism of action
Programmed death-ligand 1 (PD-L1) may be expressed on tumour cells and/or tumour-infiltrating immune cells, and can contribute to the inhibition of the antitumour immune response in the tumour microenvironment. Binding of PD-L1 to the PD-1 and B7.1 receptors found on T-cells and antigen presenting cells suppresses cytotoxic T-cell activity, T-cell proliferation and cytokine production.
Atezolizumab is an Fc-engineered, humanised immunoglobulin G1 (IgG1) monoclonal antibody that directly binds to PD-L1 and provides a dual blockade of the PD-1 and B7.1 receptors, releasing PD-L1/PD-1 mediated inhibition of the immune response, including reactivating the antitumour immune response without inducing antibody-dependent cellular cytotoxicity. Atezolizumab spares the PD-L2/PD-1 interaction allowing PD-L2/PD-1 mediated inhibitory signals to persist.
Clinical efficacy and safety
Urothelial carcinoma
IMvigor211 (GO29294): Randomised trial in locally advanced or metastatic UC patients previously treated with chemotherapy A phase III, open-label, multi-centre, international, randomised study, (IMvigor211), was conducted to evaluate the efficacy and safety of atezolizumab compared with chemotherapy (investigator’s choice of vinflunine, docetaxel, or paclitaxel) in patients with locally advanced or metastatic UC who progressed during or following a platinum-containing regimen. This study excluded patients who had a history of autoimmune disease; active or corticosteroid-dependent brain metastases; administration of a live, attenuated vaccine within 28 days prior to enrolment; and administration of systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive medicinal product within 2 weeks prior to enrolment. Tumour assessments were conducted every 9 weeks for the first 54 weeks, and every 12 weeks thereafter. Tumour specimens were evaluated prospectively for PD-L1 expression on tumour-infiltrating immune cells (IC) and the results were used to define the PD-L1 expression subgroups for the analyses described below.
A total of 931 patients were enrolled. Patients were randomised (1:1) to receive either atezolizumab or chemotherapy. Randomisation was stratified by chemotherapy (vinflunine vs. taxane), PD-L1 expression status on IC (< 5% vs. ≥ 5%), number of prognostic risk factors (0 vs. 1-3), and liver metastases (yes vs. no). Prognostic risk factors included time from prior chemotherapy of  3 months, ECOG performance status  0 and haemoglobin  10 g/dL.
Atezolizumab was administered as a fixed dose of 1 200 mg by intravenous infusion every 3 weeks.

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies and antibody drug conjugates, PD-1/PDL-1 (Programmed cell death protein 1/death ligand 1) inhibitors. ATC code:
L01FF05.
Tecentriq solution for injection contains the active substance atezolizumab which provides the therapeutic effect of this medicinal product and recombinant human hyaluronidase (rHuPH20), an enzyme used to increase the dispersion and absorption of co-formulated substances when administered subcutaneously.
Mechanism of action
Programmed death-ligand 1 (PD-L1) may be expressed on tumour cells and/or tumour-infiltrating immune cells, and can contribute to the inhibition of the antitumour immune response in the tumour microenvironment. Binding of PD-L1 to the PD-1 and B7.1 receptors found on T-cells and antigen presenting cells suppresses cytotoxic T-cell activity, T-cell proliferation and cytokine production.
Atezolizumab is an Fc-engineered, humanised immunoglobulin G1 (IgG1) monoclonal antibody that directly binds to PD-L1 and provides a dual blockade of the PD-1 and B7.1 receptors, releasing PD-L1/PD-1 mediated inhibition of the immune response, including reactivating the antitumour immune response without inducing antibody-dependent cellular cytotoxicity. Atezolizumab spares the PD-L2/PD-1 interaction allowing PD-L2/PD-1 mediated inhibitory signals to persist.
Clinical efficacy and safety
Urothelial carcinoma
Intravenous formulation
IMvigor211 (GO29294): Randomised trial in locally advanced or metastatic UC patients previously treated with chemotherapy A phase III, open-label, multi-centre, international, randomised study, (IMvigor211), was conducted to evaluate the efficacy and safety of atezolizumab compared with chemotherapy (investigator’s choice of vinflunine, docetaxel, or paclitaxel) in patients with locally advanced or metastatic UC who progressed during or following a platinum-containing regimen. This study excluded patients who had a history of autoimmune disease; active or corticosteroid-dependent brain metastases; administration of a live, attenuated vaccine within 28 days prior to enrolment; and administration of systemic

immunostimulatory agents within 4 weeks or systemic immunosuppressive medicinal product within 2 weeks prior to enrolment. Tumour assessments were conducted every 9 weeks for the first 54 weeks, and every 12 weeks thereafter. Tumour specimens were evaluated prospectively for PD-L1 expression on tumour-infiltrating immune cells (IC) and the results were used to define the PD-L1 expression subgroups for the analyses described below.

Exposure to atezolizumab increased dose proportionally over the dose range 1 mg/kg bw to 20 mg/kg bw including the fixed dose 1 200 mg administered every 3 weeks. A population analysis that included 472 patients described atezolizumab pharmacokinetics for the dose range:
1 to 20 mg/kg bw with a linear two-compartment disposition model with first-order elimination. The pharmacokinetic properties of 840 mg intravenous atezolizumab administered every 2 weeks, 1 200 mg administered every 3 weeks, and 1 680 mg administered every 4 weeks are the same;
comparable total exposures are expected to be achieved with these three dosing regimens. A population pharmacokinetic analysis suggests that steady-state is obtained after 6 to 9 weeks of multiple dosing. The systemic accumulation in area under the curve, maximum concentration and trough concentration was 1.91, 1.46 and 2.75-fold, respectively.
Absorption
Atezolizumab is administered as an intravenous infusion.

Distribution
A population pharmacokinetic analysis indicates that central compartment volume of distribution is 3.28 L and volume at steady-state is 6.91 L in the typical patient.
Biotransformation
The metabolism of atezolizumab has not been directly studied. Antibodies are cleared principally by catabolism.
Elimination
A population pharmacokinetic analysis indicates that the clearance of atezolizumab is 0.200 L/day and the typical terminal elimination half-life is 27 days.
Special populations
Based on population PK and exposure-response analyses age (21-89 years), region, ethnicity, renal impairment, mild hepatic impairment, level of PD-L1 expression, or ECOG performance status have no effect on atezolizumab pharmacokinetics. Body weight, gender, positive ADA status, albumin levels and tumour burden have a statistically significant, but not clinically relevant effect on atezolizumab pharmacokinetics. No dose adjustments are recommended.
Elderly

Atezolizumab model-predicted exposure metrics following 1 875 mg Q3W subcutaneous Tecentriq and intravenous atezolizumab (1 200 mg Q3W) administration in the IMscin001 study are shown in Table 23.
Atezolizumab cycle 1 Ctrough (i.e., pre-dose cycle 2) showed non-inferiority of atezolizumab within Tecentriq solution for injection to intravenous atezolizumab, with a geometric mean ratio (GMR) of 1.05 (90% CI: 0.88–1.24).
The GMR for cycle 1 model-predicted for AUC from 0 to 21 days (AUC0-21d) was 0.87 (90% CI:
0.83–0.92).

The maximum systemic accumulation ratio following 1 875 mg Q3W of Tecentriq solution for injection is 2.2.
The model-predicted Ctrough and AUC at steady state were comparable for subcutaneous Tecentriq and intravenous atezolizumab (see Table 23). A pharmacokinetic analysis suggests that steady state is obtained after 6 to 9 weeks of multiple dosing.
Table 23: Atezolizumab model-predicted exposure (geometric mean with 5th-95th percentiles) following subcutaneous or intravenous administration of atezolizumab Parameter Subcutaneous Tecentriq Intravenous Atezolizumab Ctrough at steady statea (mcg/mL) (70.3 – 427) (98.4 – 313) AUC at steady statea (mcg/mL•day) (2561 – 11340) (3890 – 9334) a Model-predicted exposure based on population pharmacokinetics analysis Absorption Tecentriq solution for injection is administered as a subcutaneous injection.
Based on population PK analysis of Cycle 1 data from the randomised portion of IMscin001 study, the absolute bioavailability was 61% and the first-order absorption rate (Ka) is 0.37 (1/day).
The atezolizumab geometric mean maximum serum concentration (Cmax) was 189 mcg/mL and median time to maximum serum concentration (Tmax) was 4.5 days.
Distribution
A population pharmacokinetic analysis indicates that central compartment volume of distribution is 3.28 L and volume at steady-state is 6.91 L in the typical patient.
Biotransformation