Sarclisa · 4.8 Undesirable effects · 1

HOS-099031 · has-adverse-reaction-information · PDF-Seite 45

Summary of the safety profile The most frequent adverse reactions with isatuximab subcutaneous or intravenous in combination therapies (N=2 656) were infusion-related reactions (27.5%), diarrhoea (27.2%), neutropenia (25.1%), upper respiratory tract infection (23%), pneumonia (22%), and fatigue (20.7%). The most frequent serious adverse reaction was pneumonia (16.5%). Definitive study treatment discontinuation because of adverse reactions was reported in 10.2% of patients (due to pneumonia in 1.1% of patients). Adverse reactions with a fatal outcome during treatment were reported in 5.9% of patients (due to pneumonia in 1.9% of patients). The safety profile of isatuximab 1 400 mg subcutaneous (N=522) in combination therapies was overall consistent with the known safety profile of isatuximab 10 mg/kg intravenous (N=2 134) in monotherapy or in combination therapies. Differences were observed in systemic administration 45 reactions with a lower incidence reported with isatuximab subcutaneous (3.1%) versus isatuximab intravenous (33.5%). Injection site reactions associated with isatuximab subcutaneous administration were reported in 1.48% of injections (11.9% of patients), all Grade ≤2. Tabulated list of adverse reactions Adverse reactions are described by frequency category. Frequencies are defined as follows: 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); frequency not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. The adverse reactions were reported in clinical studies (see section 5.1) and post-market settings. Isatuximab in combination with pomalidomide and dexamethasone (Isa-Pd) The Table 5 reports the pooled safety data from 827 patients with relapsed and/or refractory multiple myeloma (RRMM) treated with isatuximab subcutaneous 1 400 mg (307 patients) or with isatuximab intravenous 10 mg/kg (520 patients). Data include patients from IRAKLIA (EFC15951), TCD15484, ICARIA-MM (EFC14335), and TCD14079 studies. Table 5: Adverse reactions reported in patients with multiple myeloma treated with isatuximab subcutaneous or intravenous formulation in combination with pomalidomide and dexamethasone System organ Incidence class

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HOS-099025 · has-adverse-reaction-information · PDF-Seite 10

Summary of the safety profile In ICARIA-MM, the most frequent adverse reactions are neutropenia (46.7 %), infusion reactions (38.2 %), pneumonia (30.9 %), upper respiratory tract infection (28.3 %), diarrhoea (25.7 %) and bronchitis (23.7 %). Serious adverse reactions occurred in 61.8 % of patients receiving Isa-Pd. The most frequent serious adverse reactions are pneumonia (25.7 %) and febrile neutropenia (6.6 %). Permanent discontinuation of treatment because of adverse reactions was reported in 7.2 % of patients treated with Isa-Pd. Adverse reactions with a fatal outcome during treatment were reported in 7.9 % of patients treated with Isa-Pd (those occurring in more than 1 % of patients were pneumonia occurring in 1.3 % of patients and other infections occurring in 2.0 % of patients). In IKEMA, the most frequent adverse reactions are infusion reactions (45.8 %), hypertension (36.7 %), diarrhoea (36.2 %), upper respiratory tract infection (36.2 %), pneumonia (28.8 %), fatigue (28.2 %), dyspnoea (27.7 %), insomnia (23.7 %), bronchitis (22.6 %), and back pain (22.0 %). Serious adverse reactions occurred in 59.3 % of patients receiving Isa-Kd. The most frequent serious adverse reaction is pneumonia (21.5 %). Permanent discontinuation of treatment because of adverse reactions was reported in 8.5 % of patients treated with Isa-Kd. Adverse reactions with a fatal outcome during treatment were reported in 3.4 % of patients treated with Isa-Kd (those occurring in more than 1 % of patients were pneumonia and cardiac failure both occurring in 1.1 % of patients). 10 In IMROZ, the most frequent adverse reactions are diarrhoea (54.8%), peripheral sensory neuropathy (54.4%), pneumonia (39.9%), cataract (38.0%), constipation (35.7%), fatigue (34.6%), upper respiratory tract infections (34.2%), oedema peripheral (32.7%), neutropenia (30.0% as an adverse reaction), infusion reaction (23.6%), insomnia (22.4%), Covid-19 (22.4%), back pain (22.1%), bronchitis (22.1%). and asthenia (21.7%), Serious adverse reactions occurred in 70.7% of patients receiving Isa-VRd. The most frequent serious adverse reaction was pneumonia (29.7%, including Covid-19 pneumonia). Adverse reactions with a fatal outcome during treatment (Grade 5 TEAEs) were reported in 11% of patients with Isa-VRd including Grade 5 infectious TEAEs occurring in 6.5% of patients. Permanent discontinuation of treatment because of adverse reactions was reported in 22

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HOS-099027 · has-contraindication-information · PDF-Seite 42

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

HOS-099021 · has-contraindication-information · PDF-Seite 6

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

HOS-099020 · has-indication-information · PDF-Seite 2

Isatuximab is indicated: - in combination with pomalidomide and dexamethasone, for the treatment of adult patients with relapsed and refractory multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on the last therapy. - in combination with carfilzomib and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior therapy (see section 5.1). - in combination with bortezomib, lenalidomide, and dexamethasone, for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant. - in combination with bortezomib, lenalidomide, and dexamethasone, for the induction treatment of adult patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant.

HOS-099026 · has-indication-information · PDF-Seite 38

Isatuximab is indicated: - in combination with pomalidomide and dexamethasone, for the treatment of adult patients with relapsed and refractory multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on the last therapy. - in combination with carfilzomib and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior therapy (see section 5.1). - in combination with bortezomib, lenalidomide, and dexamethasone, for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant. - in combination with bortezomib, lenalidomide, and dexamethasone, for the induction treatment of adult patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant.

HOS-099029 · has-interaction-information · PDF-Seite 44

The pharmacokinetics of subcutaneous isatuximab, and concomitant pomalidomide, carfilzomib, bortezomib, and lenalidomide are not expected to be influenced by their co-administration, as it was shown with intravenous isatuximab. Interference with serological testing Because CD38 protein is expressed on the surface of red blood cells, isatuximab, an anti-CD38 antibody, may interfere with blood bank serologic tests with potential false positive reactions in indirect antiglobulin tests (indirect Coombs tests), antibody detection (screening) tests, antibody identification panels, and antihuman globulin (AHG) crossmatches in patients treated with isatuximab (see section 4.4). This interference may persist for at least 6 months after the last administration of isatuximab. The interference mitigation methods include treating reagent RBCs with dithiothreitol (DTT) to disrupt isatuximab binding or other locally validated methods. Since the Kell Blood group system is also sensitive to DTT treatment, Kell-negative units should be supplied after ruling out or identifying alloantibodies using DTT-treated RBCs. Interference with serum protein electrophoresis and immunofixation tests Isatuximab may be detected on serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for monitoring disease monoclonal immunoglobulins (M-protein) and may interfere with accurate response classification based on International Myeloma Working Group (IMWG) criteria (see section 4.4). This interference may persist for at least 6 months after the last administration of isatuximab. Because of this interference, Hydrashift assay was routinely used in IRAKLIA and 44 IZALCO clinical studies for efficacy assessment to determine the complete response in patients with IgG kappa myeloma protein. In patients with persistent very good partial response, where interference is suspected, consider using a validated isatuximab-specific IFE assay (Sebia Hydrashift) to remove isatuximab interference and specifically visualize any remaining serum M protein, to facilitate determination of complete response (see section 4.4).

HOS-099023 · has-interaction-information · PDF-Seite 9

Isatuximab has no impact on the pharmacokinetics of pomalidomide, or carfilzomib, or bortezomib, or lenalidomide, or vice versa. Interference with serological testing Because CD38 protein is expressed on the surface of red blood cells, isatuximab, an anti-CD38 antibody, may interfere with blood bank serologic tests with potential false positive reactions in indirect antiglobulin tests (indirect Coombs tests), antibody detection (screening) tests, antibody identification panels, and antihuman globulin (AHG) crossmatches in patients treated with isatuximab (see section 4.4). This interference may persist for at least 6 months after the last administration of isatuximab. The interference mitigation methods include treating reagent RBCs with dithiothreitol (DTT) to disrupt isatuximab binding or other locally validated methods. Since the Kell Blood group system is also sensitive to DTT treatment, Kell-negative units should be supplied after ruling out or identifying alloantibodies using DTT-treated RBCs. Interference with serum protein electrophoresis and immunofixation tests Isatuximab may be detected on serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for monitoring disease monoclonal immunoglobulins (M-protein) and could interfere with accurate response classification based on International Myeloma Working Group (IMWG) criteria (see section 4.4). This interference may persist for at least 6 months after the last administration of isatuximab. In patients with persistent very good partial response, where isatuximab interference is suspected, consider using a validated isatuximab-specific IFE assay (Sebia Hydrashift) to distinguish isatuximab from any remaining endogenous M protein in the patient’s serum, to facilitate determination of a complete response. 9

HOS-099030 · has-pregnancy-information · PDF-Seite 45

Women of childbearing potential/Contraception Women of childbearing potential treated with isatuximab should use effective contraception during treatment and for 7 months after cessation of treatment. Pregnancy There are no available data on isatuximab use in pregnant women. Animal reproduction toxicity studies have not been conducted with isatuximab. Immunoglobulin G1 monoclonal antibodies are known to cross the placenta after the first trimester of pregnancy. The use of isatuximab in pregnant women is not recommended. Breast-feeding It is unknown whether isatuximab is excreted in human milk. Human IgGs are known to be excreted in breast milk during the first few days after birth, which is decreasing to low concentrations soon afterwards; however, a risk to the breast-fed child cannot be excluded during this short period just after birth. For this specific period, a decision must be made whether to discontinue breast-feeding or to discontinue/abstain from isatuximab therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Afterwards, isatuximab could be used during breast- feeding if clinically needed. Fertility No human and animal data are available to determine potential effects of isatuximab on fertility in males and females (see section 5.3).

HOS-099024 · has-pregnancy-information · PDF-Seite 10

Women of childbearing potential/Contraception Women of childbearing potential treated with isatuximab should use effective contraception during treatment and for 7 months after cessation of treatment. Pregnancy There are no available data on isatuximab use in pregnant women. Animal reproduction toxicity studies have not been conducted with isatuximab. Immunoglobulin G1 monoclonal antibodies are known to cross the placenta after the first trimester of pregnancy. The use of isatuximab in pregnant women is not recommended. Breast-feeding It is unknown whether isatuximab is excreted in human milk. Human IgGs are known to be excreted in breast milk during the first few days after birth, which is decreasing to low concentrations soon afterwards; however, a risk to the breast-fed child cannot be excluded during this short period just after birth. For this specific period, a decision must be made whether to discontinue breast-feeding or to discontinue/abstain from isatuximab therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Afterwards, isatuximab could be used during breast- feeding if clinically needed. Fertility No human and animal data are available to determine potential effects of isatuximab on fertility in males and females (see section 5.3).

HOS-099022 · has-warning-information · PDF-Seite 6

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. Infusion reactions Infusion reactions, mostly mild or moderate, have been observed in 38.2 % of patients treated with isatuximab in ICARIA-MM, in 45.8 % of patients treated with Isa-Kd in IKEMA, in 24.0% of patients treated with Isa-VRd in IMROZ, and in 12.7% of patients treated with Isa-VRd during the induction period in GMMG-HD7 (see section 4.8). In ICARIA-MM, all infusion reactions started during the first isatuximab infusion and resolved on the same day in 98 % of the infusions. The most common symptoms of an infusion reaction included dyspnoea, cough, chills and nausea. The most common severe signs and symptoms included hypertension, dyspnoea, and bronchospasm. In IKEMA, the infusion reactions occurred on the infusion day in 99.2 % of episodes. In patients treated with Isa-Kd, 94.4 % of those experiencing an IR experienced it during the first cycle of treatment. All infusion reactions resolved. The most common symptoms of an infusion reaction included cough, dyspnoea, nasal congestion, vomiting and nausea. The most common severe signs and symptoms included hypertension and dyspnoea. In IMROZ, the IRs started on the infusion day in all patients, mostly during the first isatuximab infusion, and resolved the same day in 97.3% of patients. All IRs resolved. The most common symptoms of an IR included dyspnoea and chills. The most common severe sign and symptom was hypertension. In GMMG-HD7, during the induction period, in patients treated with Isa-VRd, 88.1% of those experiencing an IR experienced it at the first infusion and 21.4% at the subsequent infusions. All IRs resolved (see section 4.8). However, serious infusion reactions including severe anaphylactic reactions have also been observed after isatuximab administration. Anaphylactic reactions with a fatal outcome have been reported (see section 4.8). To decrease the risk and severity of infusion reactions, patients should be pre-medicated prior to isatuximab infusion with montelukast (at least at cycle 1), acetaminophen, diphenhydramine or equivalent; dexamethasone is to be used as both premedication and anti-myeloma treatment (see section 4.2). Vital signs should be frequently monitored during the entire isatuximab infusion. When required, interrupt isatuximab infusion and provide appropriate medical and supportive measures (se

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HOS-099028 · has-warning-information · PDF-Seite 42

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. Systemic administration reactions (SARs) In clinical trials with subcutaneous isatuximab (N=522), SARs occurred in 16 patients (3.1 %); 14 patients (2.7%) experienced only one episode. An SAR occurred at first administration in 10 patients (1.9%). They were mostly low grades (Grade 1 or 2) and resolved at the most within 3 days. The reported symptoms of SARs (all below 1%) were mainly pyrexia, dyspnoea, and sinus tachycardia. There was one Grade 3 episode of SAR in one patient that experienced hypertension and 42 dyspnoea. In case of Grade >2 SARs, administration adjustments should be considered (see sections 4.2 and 4.8). To decrease the risk and severity of SARs, patients should be pre-medicated prior to isatuximab subcutaneous administration with montelukast (at cycle 1 only), acetaminophen, diphenhydramine or equivalent; dexamethasone is to be used as both premedication and anti-myeloma treatment (see section 4.2). Neutropenia Neutropenia was reported in clinical trials with isatuximab subcutaneous or intravenous in combination therapies. With isatuximab subcutaneous combination therapies, a higher incidence of Grade 3-4 neutropenia reported as laboratory abnormality was observed in patients with body weight < 50 kg compared to patients with a higher body weight, with however similar incidences of neutropenic complications (see section 4.8). Complete blood cell counts should be monitored periodically during treatment. Antibacterial and antiviral prophylaxis (such as herpes zoster prophylaxis) can be considered during treatment (see section 4.2). Patients with neutropenia should be monitored for signs of infection. No dose reductions of isatuximab subcutaneous are recommended. Isatuximab subcutaneous dose delays and the use of colony-stimulating factors (e.g. G-CSF) should be considered to mitigate the risk of neutropenia (see section 4.2). Infections Infections were reported in clinical trials with isatuximab subcutaneous or intravenous in combination therapies, with an incidence of 66.4% of patients, including grade >3 infections reported in 29.9% of patients. Upper respiratory tract infection, pneumonia, and bronchitis were the most frequently reported infections (see section 4.8). Patients receiving isatuximab subcutaneo

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