Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Roche Registration GmbH, Emil-Barell-Strasse 1, 79639 Grenzach-Wyhlen, Germany
Hypersensitivity to atezolizumab or to any of the excipients listed in section 6.1.
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
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.
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.
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).
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.
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.
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.
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.
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.
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).
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.
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 (1-2 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 (SCARs), including cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in patients receiving atezolizumab. Patients should be monitored for suspected severe skin reactions and other causes should be excluded. For suspected SCARs, patients should be referred to a specialist for further diagnosis and management.
Based on the severity of the adverse reaction, atezolizumab should be withheld for Grade 3 skin reactions and treatment with systemic corticosteroids at a dose of 1-2 mg/kg bw/day of prednisone or equivalent should be started. Treatment with atezolizumab may be resumed if the event improves to ≤ Grade 1 within 12 weeks, and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day. Treatment with atezolizumab should be permanently discontinued for Grade 4 skin reactions, and corticosteroids should be administered.
Atezolizumab should be withheld for patients with suspected SJS or TEN. For confirmed SJS or TEN, atezolizumab should be permanently discontinued.
Caution should be used when considering the use of atezolizumab in a patient who has previously experienced a severe or life-threatening skin adverse reaction on prior treatment with other immunestimulatory anticancer agents.
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 (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.
Given the mechanism of action of atezolizumab, other potential immune-mediated adverse reactions may occur, including noninfective cystitis.
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 have been observed with atezolizumab (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.
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).
Neutropenia and peripheral neuropathies occurring during treatment with atezolizumab and nabpaclitaxel may be reversible with interruptions of nab-paclitaxel. Physicians should consult the nabpaclitaxel summary of product characteristics (SmPC) for specific precautions and contraindications of this medicine.
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.
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.
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.
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 ChildPugh 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.
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 with the following conditions were excluded from clinical trials: a history of autoimmune disease, history of pneumonitis, active brain metastasis, HIV, hepatitis B or hepatitis C infection (for non-HCC patients), significant cardiovascular disease and patients with inadequate hematologic and end-organ function. Patients who were administered a live, attenuated vaccine within 28 days prior to enrolment; systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive medicinal products within 2 weeks prior to study entry; therapeutic oral or intravenous antibiotics within 2 weeks prior to initiation of study treatment were excluded from clinical trials.
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 have to use effective contraception during and for 5 months after treatment with atezolizumab.
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.
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.
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).
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%).
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.
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.
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 | |
| Blood and lymphatic system disorders | ||
| Very common | anaemia, thrombocytopeniad, neutropeniae, leukopeniaf | |
| Common | thrombocytopeniad | lymphopeniag |
| Rare | haemophagocytic lymphohistiocytosis | haemophagocytic lymphohistiocytosis |
| Immune system disorders | ||
| Common | infusion-related reactionh | infusion-related reactionh |
| 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 neuropathy°, headache |
| Common | syncope, dizziness | |
| Uncommon | Guillain-Barré syndromep, meningoencephalitisq | |
| Rare | myasthenic syndromer, facial paresis, myelitis | facial paresis |
| Eye disorders | ||
| Rare | uveitis | |
| 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 |
| 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 | severe cutaneous adverse reactionsak, psoriasisan |
| Rare | pemphigoid | pemphigoid |
| Musculoskeletal and connective tissue disorders | ||
| Very common | arthralgia, back pain | arthralgia, musculoskeletal painaa, back pain |
| Common | musculoskeletal painaa | |
| Uncommon | myositisab | |
| 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, 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 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.
° 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.
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.
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.
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.
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.
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 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 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 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 – 8.3 months). No events of diabetes mellitus led to atezolizumab withdrawal.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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 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.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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