4.1. Therapeutic indications

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).

4.2. Posology and method of administration

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 1200 mg administered intravenously every three weeks, or 1680 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

• 1200 mg every 3 weeks or

• 1680 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

• 1200 mg every 3 weeks or

• 1680 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

• 1200 mg every 3 weeks or

• 1680 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

• 1200 mg every 3 weeks or

• 1680 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

• 1200 mg every 3 weeks or

• 1680 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, 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.

1L ES-SCLC with carboplatin and etoposide

Induction and maintenance phases:

• 840 mg every 2 weeks or

• 1200 mg every 3 weeks or

• 1680 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

• 1200 mg every 3 weeks or

• 1680 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

• 1200 mg every 3 weeks or

• 1680 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 ≤ 10 x ULN

or

If AST/ALT is >1 to ≤ 3 x ULN at baseline and increases to >5 x to ≤10 x ULN

or

If AST/ALT is > 3 x to ≤ 5 x ULN at baseline and increases to > 8 x to ≤ 10 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

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

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 13.9 mmol/L)

Withhold Tecentriq

Treatment may be resumed when metabolic control is achieved on insulin replacement therapy

Rash/Severe cutaneous adverse reactions

Grade 3

or suspected Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN)1

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

Grade 4

or confirmed Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN)1

Permanently discontinue Tecentriq

Myasthenic syndrome/myasthenia gravis, Guillain‑Barré syndrome, Meningoencephalitis and Facial paresis

Facial paresis Grade 1 or 2

Withhold Tecentriq

Treatment may be resumed if the event fully resolves. If the event does not fully resolve while withholding Tecentriq, permanently discontinue Tecentriq

All Grades Myasthenic syndrome/myasthenia gravis, Guillain Barré syndrome and Meningoencephalitis or Facial paresis Grade 3 or 4

Permanently discontinue Tecentriq

Myelitis

Grade 2, 3, or 4

Permanently discontinue Tecentriq

Pancreatitis

Grade 3 or 4 serum amylase or lipase levels increased (> 2 x ULN)

or Grade 2 or 3 pancreatitis

Withhold Tecentriq

Treatment may be resumed when serum amylase and lipase levels improve to Grade 0 or Grade 1 within 12 weeks, or symptoms of pancreatitis have resolved, and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day

Grade 4 or any grade of recurrent pancreatitis

Permanently discontinue Tecentriq

Myocarditis

Grade 2 or above

Permanently discontinue Tecentriq

Nephritis

Grade 2:

(creatinine level > 1.5 to 3.0 x baseline or > 1.5 to 3.0 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:

(creatinine level > 3.0 x baseline or > 3.0 x ULN)

Permanently discontinue Tecentriq

Myositis

Grade 2 or 3

Withhold Tecentriq

Grade 4 or Grade 3 recurrent myositis

Permanently discontinue Tecentriq

Pericardial disorders

Grade 1 pericarditis

Withhold Tecentriq2

Grade 2 or above

Permanently discontinue Tecentriq

Haemophagocytic lymphohistiocytosis

Suspected haemophagocytic lymphohistiocytosis1

Permanently discontinue Tecentriq

Other immune-mediated adverse reactions

Grade 2 or Grade 3

Withhold until adverse reactions recovers to Grade 0-1 within 12 weeks, and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day

Grade 4 or recurrent Grade 3

Permanently discontinue Tecentriq (except endocrinopathies controlled with replacement hormones)

Other adverse reactions

Severity

Treatment modification

Infusion‑related reactions

Grade 1 or 2

Reduce infusion rate or interrupt. Treatment may be resumed when the event is resolved

Grade 3 or 4

Permanently discontinue Tecentriq

ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal.

Note: Toxicity should be graded with the current version of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI‑CTCAE).

1 Regardless of severity

2 Conduct a detailed cardiac evaluation to determine the aetiology and manage appropriately

Special populations

Paediatric population

The safety and efficacy of Tecentriq in children and adolescents aged below 18 years have not been established. Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation on a posology can be made.

Elderly

Based on a population pharmacokinetic analysis, no dose adjustment of Tecentriq is required in patients ≥ 65 years of age (see sections 4.8 and 5.1).

Asian patients

Due to increased haematologic toxicities observed in Asian patients in IMpower150, it is recommended that the starting dose of paclitaxel should be 175 mg/m2 every three weeks.

Renal impairment

Based on a population pharmacokinetic analysis, no dose adjustment is required in patients with mild or moderate renal impairment (see section 5.2). Data from patients with severe renal impairment are too limited to draw conclusions on this population.

Hepatic impairment

Based on a population pharmacokinetic analysis, no dose adjustment is required for patients with mild or moderate hepatic impairment. Tecentriq has not been studied in patients with severe hepatic impairment (see section 5.2).

Eastern Cooperative Oncology Group (ECOG) performance status ≥ 2

Patients with ECOG performance status ≥ 2 were excluded from the clinical trials in TNBC, ES-SCLC, 2nd line UC and HCC (see sections 4.4 and 5.1).

Method of administration

It is important to check the product labels to ensure that the correct formulation (intravenous or subcutaneous) is being administered to the patient, as prescribed.

Tecentriq intravenous formulation is not intended for subcutaneous administration and should be administered via an intravenous infusion only. The infusions must not be administered as an intravenous push or bolus.

Patients currently receiving intravenous Tecentriq can switch to atezolizumab solution for injection or vice versa.

The initial dose of intravenous Tecentriq must be administered over 60 minutes. If the first infusion is well tolerated, all subsequent infusions may be administered over 30 minutes.

For instructions on dilution and handling of the medicinal product before administration, see section 6.6.

4.3. Contraindications

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

4.4. Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

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.

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. Myocarditis may also be a clinical manifestation of myositis and should be managed accordingly.

Patients with cardiac or cardiopulmonary symptoms should be assessed for potential myocarditis, to ensure the initiation of appropriate measures at an early stage. If myocarditis is suspected, treatment with atezolizumab should be withheld, prompt initiation of systemic corticosteroids at a dose of 1 to 2 mg/kg bw/day of prednisone or equivalent should be started, and prompt cardiology consultation with diagnostic workup according to current clinical guidelines should be initiated. Once a diagnosis of myocarditis is established, treatment with atezolizumab must be permanently discontinued for Grade ≥ 2 myocarditis (see 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 2mg/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. Patients with possible myositis should be monitored for signs of myocarditis.

If a patient develops signs and symptoms of myositis, close monitoring should be implemented, and the patient referred to a specialist for assessment and treatment without delay. Treatment with atezolizumab should be withheld for Grade 2 or 3 myositis and corticosteroid therapy (1 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.

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.

4.5. Interaction with other medicinal products and other forms of interaction

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).

4.6. Fertility, pregnancy and lactation

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.

4.7. Effects on ability to drive and use machines

Tecentriq has minor influence on the ability to drive and use machines. Patients experiencing fatigue should be advised not to drive and use machines until symptoms abate (see section 4.8).

4.8. Undesirable effects

Summary of the safety profile

The safety of atezolizumab as monotherapy is based on pooled data in 5039 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 (13.0%), back pain (12.2%), vomiting (11.7%), urinary tract infection (11.0%) and headache (10.2%).

The safety of atezolizumab given in combination with other medicinal products, has been evaluated in 4535 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 (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), 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

anaemia, thrombocytopeniad, neutropeniae, leukopeniaf

Common

thrombocytopeniad, neutropeniae

lymphopeniag

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

hypokalaemiaae, hyponatraemiaaf, hypomagnesaemian

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

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

blood alkaline phosphatase 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, acute pyelonephritis, chronic pyelonephritis, pyelitis, renal abscess, streptococcal urinary tract infection, urethritis, fungal urinary tract infection, pseudomonal urinary tract infection.

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 increased blood creatinine, hypercreatininaemia.

d Includes reports of immune thrombocytopenia (reported in studies outside the pooled dataset), thrombocytopenia, decreased platelet count.

e Includes reports of neutropenia, decreased neutrophil count, febrile neutropenia, neutropenic sepsis, granulocytopenia.

f Includes reports of decreased white blood cell count, leukopenia.

g Includes reports of lymphopenia, decreased lymphocyte count.

h Includes reports of infusion- related reaction, cytokine release syndrome, hypersensitivity, anaphylaxis.

i Includes reports of positive anti-thyroid antibody, autoimmune hypothyroidism, autoimmune thyroiditis, decreased blood thyroid stimulating hormone, increased blood thyroid stimulating hormone, euthyroid sick syndrome, goitre, hypothyroidism, immune-mediated hypothyroidism, immune-mediated thyroiditis, myxoedema, primary hypothyroidism, thyroid disorder, decreased thryroid hormones, abnormal thyroid function test, thyroiditis, acute thyroiditis, decreased thyroxine, decreased thyroxine free, increased thyroxine free, increased thyroxine, decreased tri-iodothyronine, increased tri-iodothyronine, abnormal tri-iodothyronine free, decreased tri-iodothyronine free, increased tri-iodothyronine free, 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, decreased blood corticotropin, 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, decreased blood magnesium.

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, autoimmune encephalitis, 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, ischaemic colitis, microscopic colitis, ulcerative colitis, diversion colitis, eosinophilic colitis, immune-mediated enterocolitis.

w Includes reports of oropharyngeal pain, oropharyngeal discomfort, throat irritation.

x Includes reports of autoimmune pancreatitis, pancreatitis, acute pancreatitis, increased lipase, increased amylase.

y Includes reports of ascites, autoimmune hepatitis, hepatic cytolysis, hepatitis, acute hepatitis, toxic hepatitis, hepatotoxicity, immune-mediated hepatitis, liver disorder, drug-induced liver injury, hepatic failure, hepatic steatosis, hepatic lesion, liver injury, oesophageal varices haemorrhage, oesophageal varices, spontaneous bacterial peritonitis.

z Includes reports of acne, blister, dermatitis, dermatitis acneiform, allergic dermatitis, drug eruption, eczema, infected eczema, 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, erythematous rash, macular rash, maculo-papular rash, morbilliform rash, papular rash, papulosquamous rash, pruritic rash, pustular rash, vesicular rash, 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, decreased blood potassium.

af Includes reports of hyponatraemia, decreased blood sodium.

ag Includes reports of hypoxia, decreased oxygen saturation, decreased pO2.

ah Includes reports of alopecia, madarosis, alopecia areata, alopecia totalis, hypotrichosis.

ai Includes reports of hypertension, increased blood pressure, hypertensive crisis, increased blood pressure systolic, diastolic hypertension, inadequately controlled blood pressure, hypertensive retinopathy, 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 bullous dermatitis, exfoliative rash, erythema multiforme, exfoliative dermatitis, generalised exfoliative dermatitis, toxic skin eruption, Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms, toxic epidermal necrolysis, cutaneous vasculitis.

al Includes reports of cystitis non-infective 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.

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% (151/5039) 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% (92/5039) of patients receiving atezolizumab monotherapy.

Immune‑mediated hepatitis

Hepatitis occurred in 1.7% (88/5039) 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% (130/5039) of patients receiving atezolizumab monotherapy.

Immune‑mediated colitis

Colitis occurred in 1.2% (62/5039) 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% (30/5039) of patients receiving atezolizumab monotherapy.

Immune‑mediated endocrinopathies

Thyroid disorders

Hypothyroidism occurred in 8.5% (427/5039) 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% (121/5039) 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% (25/5039) 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% (20/5039) of patients receiving atezolizumab monotherapy.

Hypophysitis

Hypophysitis occurred in 0.2% (9/5039) 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% (15/1093) 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% (22/5039) 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% (12/5039) 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% (6/5039) 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% (3/5039) of patients receiving atezolizumab monotherapy.

Immune-mediated facial paresis

Facial paresis occurred in < 0.1% (1/5039) 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% (1/5039) 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% (2/5039) 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% (40/5039) 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% (8/5039) of patients receiving atezolizumab monotherapy.

Immune-mediated myocarditis

Myocarditis occurred in <0.1% (5/5039) 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% (11/5039) 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% (32/5039) 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% (30/5039) 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% (9/5039) of patients receiving atezolizumab monotherapy.

Immune-mediated pericardial disorders

Pericardial disorders occurred in 1% (49/5039) 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% (7/5039) 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=3460) 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 (see details below).

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

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.