Leitlinien & Arzneimittelsicherheit

HOS-097775 · has-adverse-reaction-information · PDF-Seite 84

Summary of the safety profile The safety of atezolizumab as monotherapy is based on pooled data in 5 039 patients with various tumour types that were administered atezolizumab intravenously and 247 patients with NSCLC that were administered atezolizumab subcutaneously. The most common adverse reactions (> 10%) were fatigue (29.3%), decreased appetite (20.1%), rash (19.7%), nausea (18.8%), cough (18.2%), diarrhoea (18.1%), pyrexia (17.9%), dyspnoea (16.6%), , arthralgia (16.2%), pruritus (13.3%), asthenia (13%), back pain (12.2%), vomiting (11.7%), urinary tract infection (11%) and headache (10.2%). The safety of intravenous atezolizumab given in combination with other medicinal products, has been evaluated in 4 535 patients across multiple tumour types. The most common adverse reactions (≥ 20%) were anaemia (36.8%), neutropenia (36.6%), nausea (35.5%), fatigue (33.1%), alopecia (28.1%), rash (27.8%), diarrhoea (27.6%), thrombocytopenia (27.1%), constipation (25.8%), decreased appetite (24.7%) and peripheral neuropathy (24.4%). The safety profile of Tecentriq solution for injection was overall similar to the known safety profile of the intravenous formulation, with an additional adverse reaction of injection site reaction (4.5% in the subcutaneous Tecentriq arm vs 0% in the intravenous atezolizumab arm). 84 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 treatme

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HOS-097769 · has-adverse-reaction-information · PDF-Seite 18

Summary of the safety profile The safety of atezolizumab as monotherapy is based on pooled data in 5 039 patients across multiple tumour types. The most common adverse reactions (> 10%) were fatigue (29.3%), decreased appetite (20.1%), rash (19.7%), nausea (18.8%), cough (18.2%), diarrhoea (18.1%), pyrexia (17.9%), dyspnoea (16.6%), arthralgia (16.2%), pruritus (13.3%), asthenia (13%), back pain (12.2%), vomiting (11.7%), urinary tract infection (11%) and headache (10.2%). 18 The safety of atezolizumab given in combination with other medicinal products, has been evaluated in 4 535 patients across multiple tumour types. The most common adverse reactions (≥ 20%) were anaemia (36.8%), neutropenia (36.6%), nausea (35.5%), fatigue (33.1%), alopecia (28.1%), rash (27.8%), diarrhoea (27.6%), thrombocytopenia (27.1%), constipation (25.8%), decreased appetite (24.7%) and peripheral neuropathy (24.4%). Use of atezolizumab in the adjuvant NSCLC setting The safety profile of atezolizumab in the adjuvant setting in the non-small cell lung cancer (NSCLC) patient population (IMpower010) was generally consistent with the overall pooled monotherapy safety profile in the advanced setting. Nevertheless, the incidence of immune-mediated adverse reactions of atezolizumab in IMpower010 was 51.7% compared to 38.4% in the pooled monotherapy population with advanced disease. No new immune-mediated adverse reactions were identified in the adjuvant setting. Use of atezolizumab in combination with bevacizumab, paclitaxel and carboplatin In the first-line NSCLC study (IMpower150), an overall higher frequency of adverse events was observed in the four-drug regimen of atezolizumab, bevacizumab, paclitaxel, and carboplatin compared to atezolizumab, paclitaxel and carboplatin, including Grade 3 and 4 events (63.6% compared to 57.5%), Grade 5 events (6.1% compared to 2.5%), adverse events of special interest to atezolizumab (52.4% compared to 48.0%), as well as adverse events leading to withdrawal of any study treatment (33.8% compared to 13.3%). Nausea, diarrhoea, stomatitis, fatigue, pyrexia, mucosal inflammation, decreased appetite, weight decreased, hypertension and proteinuria were reported higher (5% difference) in patients receiving atezolizumab in combination with bevacizumab, paclitaxel and carboplatin. Other clinically significant adverse events which were observed more frequently in the atezolizumab, bevacizumab, pacli

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HOS-097771 · has-contraindication-information · PDF-Seite 76

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

HOS-097765 · has-contraindication-information · PDF-Seite 10

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

HOS-097764 · has-indication-information · PDF-Seite 2

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). 2 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 u

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HOS-097770 · has-indication-information · PDF-Seite 68

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). 68 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

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HOS-097767 · has-interaction-information · PDF-Seite 17

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). 17

HOS-097773 · has-interaction-information · PDF-Seite 83

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).

HOS-097768 · has-pregnancy-information · PDF-Seite 18

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.

HOS-097774 · has-pregnancy-information · PDF-Seite 83

Women of childbearing potential Women of childbearing potential have to use effective contraception during and for 5 months after treatment with atezolizumab. 83 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.

HOS-097766 · has-warning-information · PDF-Seite 10

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. 10 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 t

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HOS-097772 · has-warning-information · PDF-Seite 76

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. 76 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

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