Lunsumio · 4.3 Contraindications · 1

HOS-099933 · has-adverse-reaction-information · PDF-Seite 11

Summary of safety profile The adverse reactions described in this section were identified from the pivotal clinical trial GO29781 in patients treated at the recommended intravenous dose (n=218) and the recommended subcutaneous dose (n=139). Patients had follicular lymphoma (51.8%), diffuse large B-cell lymphoma (26.9%), transformed follicular lymphoma (9.8%) mantle cell lymphoma (7.3%), Richter’s transformation (3.9%), and other histologies (0.3%). The median number of cycles of Lunsumio intravenously received was 8 (range 1 -17), 37% of patients received 8 cycles, and 15% received more than 8 cycles up to 17 cycles. Patients who received the recommended intravenous dose (n=218) and subcutaneous (n=139) dose are pooled (n=357) for this safety population. In this pooled safety population, the most common adverse reactions (≥ 20%) observed were cytokine release syndrome, neutropenia, rash and upper respiratory tract infection. The most common serious adverse reactions (≥ 2%) observed included cytokine release syndrome (CRS) (17% by ASTCT grading system), pyrexia (3%), sepsis (3%), upper respiratory tract infection (3%) and pneumonia (5%). Permanent discontinuation of Lunsumio due to an adverse reaction occurred in 5.8% (21/357) of patients. In patients who received the recommended intravenous dose (n=218), CRS was the only adverse reaction that led to discontinuation in more than one patient (2 patients [0.9%]). Tabulated list of adverse reactions The adverse reactions are listed below by MedDRA system organ class (SOC) and categories of frequency. Frequency categories are defined as 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) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 6 Adverse reactions occurring in patients treated with Lunsumio 11 System organ class / preferred term or All grades22 Grade 3 – 4 adverse reaction Infections and infestations Upper respiratory tract infection1 Very common Common Viral Infection2 Common Uncommon Urinary tract infection3 Common Common Pneumonia4

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HOS-099939 · has-adverse-reaction-information · PDF-Seite 33

Summary of safety profile The adverse reactions described in this section were identified from the pivotal clinical trial GO29781 in patients treated at the recommended intravenous dose (n=218) and the recommended subcutaneous dose (n=139). Patients had follicular lymphoma (51.8%), diffuse large B-cell lymphoma (26.9%), transformed follicular lymphoma (9.8%) mantle cell lymphoma (7.3%), Richter’s transformation (3.9%), and other histologies (0.3%). The median number of cycles of Lunsumio subcutaneous received was 8 (range 1 -17), 47.5% of patients received 8 cycles, and 16.6% received more than 8 cycles up to 17 cycles. 33 Patients who received the recommended intravenous dose (n=218) and subcutaneous (n=139) dose are pooled (n=357) for this safety population. In this pooled safety population, the most common adverse reactions (≥ 20%) observed were cytokine release syndrome, neutropenia, rash and upper respiratory tract infection and injection site reactions in those treated with subcutaneous mosunetuzumab. The most common serious adverse reactions (≥ 2%) observed included cytokine release syndrome (CRS) (17% by ASTCT grading system), pyrexia (3%), sepsis (3%), upper respiratory tract infection (3%) and pneumonia (5%). Permanent discontinuation of Lunsumio due to an adverse reaction occurred in 5.8% (21/357) of patients. In patients who received the recommended subcutaneous dose (n=139), the adverse reactions that led to discontinuation in more than one patient were COVID-19 1.4% (2/139) and COVID-19 pneumonia 3.6% (5/139). Tabulated list of adverse reactions The adverse reactions are listed below by MedDRA system organ class (SOC) and categories of frequency. Frequency categories are defined as 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) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 6 Adverse reactions occurring in patients treated with Lunsumio System organ class / preferred term or All grades22 Grade 3 – 4 adverse reaction Infections and infestations Upper respiratory tract infection1 Very common Common Viral infection2 Common

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HOS-099929 · has-contraindication-information · PDF-Seite 8

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

HOS-099935 · has-contraindication-information · PDF-Seite 30

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

HOS-099934 · has-indication-information · PDF-Seite 24

Lunsumio as monotherapy is indicated for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) who have received at least two prior systemic therapies.

HOS-099928 · has-indication-information · PDF-Seite 2

Lunsumio as monotherapy is indicated for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) who have received at least two prior systemic therapies.

HOS-099937 · has-interaction-information · PDF-Seite 33

No interaction studies have been performed. A transient clinically relevant effect on CYP450 substrates with a narrow therapeutic index (e.g. warfarin, voriconazole, cyclosporine, etc) cannot be excluded, since initiation of Lunsumio subcutaneous injection treatment causes a transient increase in cytokine levels which may cause inhibition of CYP450 enzymes. On initiation of Lunsumio subcutaneous injection therapy in patients being treated with CYP450 substrates with a narrow therapeutic index, therapeutic monitoring should be considered. The dose of the concomitant medicinal product should be adjusted as needed.

HOS-099931 · has-interaction-information · PDF-Seite 10

No interaction studies have been performed. A transient clinically relevant effect on CYP450 substrates with a narrow therapeutic index (e.g. warfarin, voriconazole, cyclosporine, etc) cannot be excluded, since initiation of Lunsumio treatment causes a transient increase in cytokine levels which may cause inhibition of CYP450 enzymes. On initiation of Lunsumio therapy in patients being treated with CYP450 substrates with a narrow therapeutic index, therapeutic monitoring should be considered. The dose of the concomitant medicinal product should be adjusted as needed.

HOS-099938 · has-pregnancy-information · PDF-Seite 33

Women of childbearing potential/Contraception Women of childbearing potential should use effective contraception while receiving Lunsumio subcutaneous injection and for at least 3 months after the last injection of Lunsumio subcutaneous injection. Pregnancy There are no data from the use of Lunsumio subcutaneous injection in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Lunsumio subcutaneous injection is not recommended during pregnancy and in women of childbearing potential not using contraception. Breast-feeding It is unknown whether mosunetuzumab/metabolites are excreted in human milk. A risk to newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Lunsumio subcutaneous injection. Fertility No human data on fertility are available. No impairments were observed in male or female reproductive organs in the 26-week toxicity studies with cynomolgus monkeys at exposures (AUC) similar to exposure (AUC) in patients receiving the recommended dose.

HOS-099932 · has-pregnancy-information · PDF-Seite 10

Women of childbearing potential/Contraception Women of childbearing potential should use effective contraception while receiving Lunsumio and for at least 3 months after the last infusion of Lunsumio. 10 Pregnancy There are no data from the use of Lunsumio in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Lunsumio is not recommended during pregnancy and in women of childbearing potential not using contraception. Breast-feeding It is unknown whether mosunetuzumab/metabolites are excreted in human milk. A risk to newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Lunsumio therapy. Fertility No human data on fertility are available. No impairments were observed in male or female reproductive organs in the 26-week toxicity studies with cynomolgus monkeys at exposures (AUC) similar to exposure (AUC) in patients receiving the recommended dose.

HOS-099936 · has-warning-information · PDF-Seite 30

30 Traceability In order to improve traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded. Cytokine Release Syndrome (CRS) CRS, including life-threatening reactions, have occurred in patients receiving Lunsumio subcutaneous injection (see section 4.8). Signs and symptoms included pyrexia, hypotension, and hypoxia, CRS events occurred predominantly in cycle 1 and were mainly associated with Day 1 and Day 8 dose administrations. The most frequently reported CRS signs and symptoms in ≥10% of patients treated with Lunsumio subcutaneous injection who experienced CRS events of any grade by ASTCT 2019 (36 patients) were pyrexia, hypotension, hypoxia, chills, tachycardia and headache. Patients should be premedicated with corticosteroids, antipyretics and antihistamines at least through cycle 1. Patients must receive adequate hydration prior to the administration of Lunsumio subcutaneous injection. Patients should be monitored for signs or symptoms of CRS. Patients should be counselled to seek immediate medical attention should signs or symptoms of CRS occur at any time. Physicians should institute treatment with supportive care, tocilizumab and/or corticosteroids as indicated. (see section 4.2). Serious infections Serious infections such as pneumonia, bacteraemia, sepsis, septic shock, and opportunistic infections have occurred in patients receiving Lunsumio subcutaneous injection, some of which were life-threatening or fatal events (see section 4.8). Febrile neutropenia was observed in patients after receiving Lunsumio subcutaneous injection. Cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients receiving CD20-directed monoclonal antibodies, including CD3- CD20 bispecific antibodies. Lunsumio subcutaneous injection should not be administered in the presence of active infections. Caution should be exercised when considering the use of Lunsumio subcutaneous injection in patients with a history of recurring or chronic infections (e.g., chronic, active Epstein-Barr Virus), with underlying conditions that may predispose to infections or who have had significant prior immunosuppressive treatment. Patients should be administered prophylactic antibacterial, antiviral and/or antifungal medicinal products, as appropriate. Patients should be monitored for signs and symptoms of infection, before and after Lunsumio subcutaneous injection administratio

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HOS-099930 · has-warning-information · PDF-Seite 8

Traceability In order to improve traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded. Cytokine Release Syndrome (CRS) CRS, including life-threatening reactions, have occurred in patients receiving Lunsumio (see section 4.8). Signs and symptoms included pyrexia, chills, hypotension, tachycardia, hypoxia, and headache. Infusion related reactions may be clinically indistinguishable from manifestations of CRS. CRS events occurred predominantly in cycle 1 and were mainly associated with Day 1 and Day 15 dose administrations. 8 Patients should be premedicated with corticosteroids, antipyretics and antihistamines at least through cycle 2. Patients must receive adequate hydration prior to the administration of Lunsumio. Patients should be monitored for signs or symptoms of CRS. Patients should be counselled to seek immediate medical attention should signs or symptoms of CRS occur at any time. Physicians should institute treatment with supportive care, tocilizumab and/or corticosteroids as indicated. (see section 4.2). Serious infections Serious infections such as pneumonia, bacteraemia, sepsis, septic shock, and opportunistic infections have occurred in patients receiving Lunsumio, some of which were life-threatening or fatal events (see section 4.8). Febrile neutropenia was observed in patients after receiving Lunsumio infusion. Cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients receiving CD20- directed monoclonal antibodies, including CD3-CD20 bispecific antibodies. Lunsumio should not be administered in the presence of active infections. Caution should be exercised when considering the use of Lunsumio in patients with a history of recurring or chronic infections (e.g., chronic, active Epstein-Barr Virus), with underlying conditions that may predispose to infections or who have had significant prior immunosuppressive treatment. Patients should be administered prophylactic antibacterial, antiviral and/or antifungal medicinal products, as appropriate. Patients should be monitored for signs and symptoms of infection, before and after Lunsumio administration, and treated appropriately. In the event of febrile neutropenia, patients should be evaluated for infection and managed with antibiotics, fluids and other supportive care, according to local guidelines. Patients should be monitored

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