Pepaxti · 4.3 Contraindications · 1

HOS-099947 · has-adverse-reaction-information · PDF-Seite 7

Summary of the safety profile The safety of Pepaxti in combination with dexamethasone has been evaluated in 491 patients with multiple myeloma, including 147 patients with triple-class refractory disease who have received at least three prior lines of therapies. The most frequent adverse reactions are thrombocytopenia (83%), neutropenia (72%), anaemia (66%), nausea (21%), diarrhoea (19%) and pyrexia (19%). The most frequent serious adverse reactions are pneumonia (11%), thrombocytopenia (5%) and respiratory tract infection (4%). Tabulated list of adverse reactions Table 3 summarises adverse reactions that were reported in patients receiving Pepaxti. The data reflect exposure of Pepaxti in 13 patients as single agent and in 478 patients in combination with dexamethasone. Adverse reactions are described using MedDRA terms. Frequencies 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 the order of decreasing seriousness. Table 3: Adverse reactions reported in patients with multiple myeloma treated with Pepaxti in clinical studies System OrganClass Adverse reactions Frequency overall Frequency Grade 3/4 Infections and Septic shock Uncommon Uncommon infestations Sepsis1 Common Common 2 Pneumonia Very common Common Respiratory tract Very common Common Infection3 Neoplasms benign, Myelodysplastic Uncommon Uncommon malignant and syndrome (MDS) unspecified (incl cysts Acute myeloid Uncommon Uncommon and polyps) leukaemia (AML) Blood and lymphatic Febrile neutropenia Common Common systemdisorders Thrombocytopenia4 Very common Very common Neutropenia5 Very common Very common Anaemia Very common Very common Leukopenia Common Common Lymphop

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HOS-099943 · has-contraindication-information · PDF-Seite 4

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. • Breast-feeding (see section 4.6).

HOS-099942 · has-indication-information · PDF-Seite 2

Pepaxti is indicated, in combination with dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least three prior lines of therapies, whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one anti-CD38 monoclonal antibody, and who have demonstrated disease progression on or after the last therapy. For patients with a prior autologous stem cell transplantation, the time to progression should be at least 3 years from transplantation (see section 4.4).

HOS-099945 · has-interaction-information · PDF-Seite 6

No interaction studies have been performed with melphalan flufenamide. Based on available in vitro and clinical data, there is a low risk of pharmacokinetic or pharmacodynamic drug interactions for melphalan flufenamide (see section 5.2).

HOS-099946 · has-pregnancy-information · PDF-Seite 6

Women of childbearing potential/Contraception in males and females As with all cytotoxic treatments, male and female patients who use melphalan flufenamide should use effective and reliable contraceptive methods until six months after cessation of treatment. Pregnancy There are no data from the use of melphalan flufenamide in pregnant women. Studies in animals with the melphalan flufenamide metabolite melphalan have shown reproductive toxicity (see section 5.3). Due to the genotoxic properties and structural similarity of melphalan flufenamide with known teratogenic compounds, it is possible that melphalan flufenamide can induce congenital malformations in offspring of treated patients. Melphalan flufenamide should not be used during pregnancy unless the clinical condition of the woman requires treatment with melphalan flufenamide. Breast-feeding It is unknown whether melphalan flufenamide or its metabolites are excreted in human milk. Due to its genotoxic properties, melphalan flufenamide is contraindicated during breast-feeding (see section 4.3). Fertility Melphalan flufenamide, as other agents with alkylating properties, is expected to suppress ovary function in premenopausal women, resulting in amenorrhea in a large number of patients. Studies in animals have shown melphalan flufenamide can have adverse effects on spermatogenesis (see section 5.3). Therefore it is possible that melphalan flufenamide may cause temporary or permanent adverse effects on male fertility.Cryopreservation of semen before treatment is advised. 6

HOS-099944 · has-warning-information · PDF-Seite 4

Melphalan flufenamide can cause local tissue damage. Should extravasation occur, it should not be administered by direct infusion into a peripheral vein (see section 4.2). Thrombocytopenia Pepaxti may cause thrombocytopenia. Thrombocytopenia (including platelet count decreased) was frequently reported in clinical studies (see section 4.8). As thrombocytopenia may increase the risk for serious bleeding events, patients should be advised to contact a physician if signs or symptoms of bleeding and bruising occur. Platelet counts should be monitored at baseline, during treatment, and as clinically indicated. Patients should be monitored more frequently during the first two months of treatment. Pepaxti should not be administered if the platelet count is less than 50 × 109/L. Treatment should be withheld until platelet count is 50 × 109/L or greater (without recent transfusions) and resume treatment at one dose level lower. The dose and/or dose schedule should be adjusted based on signs and symptoms of bleeding (see section 4.2). Treating thrombocytopenia with transfusions and/or other treatments should be considered as clinically indicated. Neutropenia Pepaxti may cause neutropenia. Neutropenia (including neutrophil count decreased) was frequently reported in clinical studies (see section 4.8). As neutropenia may increase the risk for infections, patients should be advised to contact a physician if signs or symptoms of infection occur. Neutrophil count should be monitored at baseline, during treatment, and as clinically indicated. Patients should be monitored more frequently during the first two months of treatment. Pepaxti should not be administered if absolute neutrophil count is less than 1 × 109/L. Treatment should be withheld until absolute neutrophil count is 1 × 109/L or greater and resume treatment at one dose level lower. The dose and/or dose schedule should be adjusted based on signs and symptoms of infection (see section 4.2). Treating neutropenic patients with haematopoietic growth factors and/or prophylactic antimicrobials should be considered as clinically indicated (see section 4.2). 4 Anaemia Anaemia was frequently reported in clinical studies (see section 4.8). Red blood cell counts should be monitored at baseline, during treatment, and as clinically indicated. Patients should be monitored more frequently during the first two months of treatment. Treating anaemia with transfusions and

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