Darzalex · 4.1 Therapeutic indications · 2

HOS-097609 · has-adverse-reaction-information · PDF-Seite 10

Summary of the safety profile The most frequent adverse reactions of any grade (≥ 20% patients) were IRRs, fatigue, nausea, diarrhoea, constipation, pyrexia, dyspnoea, cough, neutropenia, thrombocytopenia, anaemia, oedema peripheral, asthenia, peripheral neuropathy, upper respiratory tract infection, musculoskeletal pain and COVID-19. Serious adverse reactions were sepsis, pneumonia, bronchitis, upper respiratory tract infection, pulmonary oedema, pyrexia, dehydration, diarrhoea, atrial fibrillation and syncope. Tabulated list of adverse reactions Table 6 summarises the adverse reactions that occurred in patients receiving DARZALEX. The data reflects exposure to DARZALEX (16 mg/kg) in 2066 patients with multiple myeloma including 1910 patients who received DARZALEX in combination with background regimens and 156 patients who received DARZALEX as monotherapy. Post-marketing adverse reactions are also included. In study MMY3006, the number of CD34+ cell yield was numerically lower in the D-VTd arm compared with the VTd arm (Median: D-VTd: 6.3 x 106/kg; VTd 8.9 x 106/kg) and among those who completed mobilisation, more patients in the D-VTd group received plerixafor compared to those in the VTd arm (D-VTd: 21.7%; VTd: 7.9%). The rates of engraftment and haematopoietic reconstitution was similar among the transplanted subjects in the D-VTd and VTd arms (D-VTd: 99.8%; VTd: 99.6%; as measured by the recovery of neutrophils > 0.5 x 109/L, leukocytes > 1.0 x 109/L, and platelets > 50 x 109/L without transfusion). Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000) and very rare (< 1/10000). Within each frequency grouping adverse reactions are presented in the order of decreasing seriousness. Table 6: Adverse reactions in multiple myeloma patients treated with DARZALEX 16 mg/kg System organ class Adverse reaction Frequency Incidence (%) Any grade Grade 3-4 Infections and Upper respiratory tract Very common 46 4 infestations infectiona COVID-19a,d 23 6 a Pneumonia 19 11 Bronchitisa 17 2

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HOS-097615 · has-adverse-reaction-information · PDF-Seite 43

Summary of the safety profile The most frequent adverse reactions of any grade (≥ 20% patients) with daratumumab (either intravenous or subcutaneous formulations) when administered either as monotherapy or combination treatment were IRRs, fatigue, nausea, diarrhoea, constipation, pyrexia, cough, neutropenia, thrombocytopenia, anaemia, oedema peripheral, peripheral neuropathy, upper respiratory tract infection, musculoskeletal pain and COVID-19. Serious adverse reactions were pneumonia, bronchitis, upper respiratory tract infection, sepsis, pulmonary oedema, pyrexia, dehydration, diarrhoea, atrial fibrillation and syncope. The safety profile of the DARZALEX subcutaneous formulation was similar to that of intravenous formulation with the exception of a lower rate of IRRs. In the phase III study MMY3012, neutropenia was the only adverse reaction reported at ≥ 5% higher frequency for DARZALEX subcutaneous formulation compared to intravenous daratumumab (grade 3 or 4: 13% vs 8%, respectively). Tabulated list of adverse reactions Table 9 summarises the adverse reactions that occurred in patients receiving DARZALEX subcutaneous formulation or intravenous formulation of daratumumab. The data reflects exposure to DARZALEX subcutaneous formulation (1800 mg) in 1187 patients with multiple myeloma (MM). The data includes 260 patients from a phase III active-controlled study (MMY3012) who received DARZALEX solution for subcutaneous injection as monotherapy, 149 patients from a phase III active-controlled study (MMY3013) who received DARZALEX subcutaneous formulation in combination with pomalidomide and dexamethasone (D-Pd), 351 patients from a phase III active-controlled study (MMY3014) who received DARZALEX subcutaneous formulation in combination with bortezomib, lenalidomide and dexamethasone (D-VRd), and 197 newly diagnosed multiple myeloma patients for whom transplant was not planned as initial therapy or who were ineligible for transplant from a phase III active-controlled study (MMY3019) who received DARZALEX subcutaneous formulation in combination with bortezomib, lenalidomide and dexamethasone (D-VRd). The data also reflects three open-label, clinical studies in which patients received DARZALEX solution for subcutaneous injection either as monotherapy (N=31, MMY1004 and MMY1008) and MMY2040 in which patients received DARZALEX solution for subcutaneous injection in combination with either bortezomib, melphalan and prednisone (D-VMP, n=67), lenalidomide and

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HOS-097611 · has-contraindication-information · PDF-Seite 39

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 39

HOS-097605 · has-contraindication-information · PDF-Seite 6

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 6

HOS-097604 · has-indication-information · PDF-Seite 2

DARZALEX is indicated:  in combination with lenalidomide and dexamethasone or with bortezomib, melphalan and prednisone for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant.  in combination with bortezomib, thalidomide and dexamethasone for the treatment of adult patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant.  in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.  as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy.

HOS-097610 · has-indication-information · PDF-Seite 33

Multiple myeloma DARZALEX is indicated:  in combination with lenalidomide and dexamethasone or with bortezomib, melphalan and prednisone 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 treatment of adult patients with newly diagnosed multiple myeloma.  in combination with bortezomib, thalidomide and dexamethasone for the treatment of adult patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant.  in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.  in combination with pomalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received one prior therapy containing a proteasome inhibitor and lenalidomide and were lenalidomide-refractory, or who have received at least two prior therapies that included lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or after the last therapy (see section 5.1).  as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy. 33 Smouldering multiple myeloma DARZALEX as monotherapy is indicated for the treatment of adult patients with smouldering multiple myeloma at high risk of developing multiple myeloma (see section 5.1). Light chain (AL) amyloidosis DARZALEX is indicated in combination with cyclophosphamide, bortezomib and dexamethasone for the treatment of adult patients with newly diagnosed systemic AL amyloidosis.

HOS-097607 · has-interaction-information · PDF-Seite 8

No interaction studies have been performed. As an IgG1қ monoclonal antibody, renal excretion and hepatic enzyme-mediated metabolism of intact daratumumab are unlikely to represent major elimination routes. As such, variations in drug-metabolising enzymes are not expected to affect the elimination of daratumumab. Due to the high affinity to a unique epitope on CD38, daratumumab is not anticipated to alter drug-metabolising enzymes. 8 Clinical pharmacokinetic assessments of daratumumab in combination with lenalidomide, pomalidomide, thalidomide, bortezomib and dexamethasone indicated no clinically-relevant drug-drug interaction between daratumumab and these small molecule medicinal products. Interference with indirect antiglobulin test (indirect Coombs test) Daratumumab binds to CD38 on RBCs and interferes with compatibility testing, including antibody screening and cross matching (see section 4.4). Daratumumab interference mitigation methods include treating reagent RBCs with dithiothreitol (DTT) to disrupt daratumumab 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. Alternatively, phenotyping or genotyping may also be considered (see section 4.4). Interference with serum protein electrophoresis and immunofixation tests Daratumumab may be detected on serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for monitoring disease monoclonal immunoglobulins (M protein). This can lead to false positive SPE and IFE assay results for patients with IgG kappa myeloma protein impacting initial assessment of complete responses by International Myeloma Working Group (IMWG) criteria. In patients with persistent very good partial response, where daratumumab interference is suspected, consider using a validated daratumumab-specific IFE assay to distinguish daratumumab from any remaining endogenous M protein in the patient’s serum, to facilitate determination of a complete response.

HOS-097613 · has-interaction-information · PDF-Seite 41

No interaction studies have been performed. 41 As an IgG1қ monoclonal antibody, renal excretion and hepatic enzyme-mediated metabolism of intact daratumumab are unlikely to represent major elimination routes. As such, variations in drug-metabolising enzymes are not expected to affect the elimination of daratumumab. Due to the high affinity to a unique epitope on CD38, daratumumab is not anticipated to alter drug-metabolising enzymes. Clinical pharmacokinetic assessments with daratumumab intravenous or subcutaneous formulations and lenalidomide, pomalidomide, thalidomide, bortezomib, melphalan, prednisone, carfilzomib, cyclophosphamide and dexamethasone indicated no clinically-relevant drug-drug interaction between daratumumab and these small molecule medicinal products. Interference with indirect antiglobulin test (indirect Coombs test) Daratumumab binds to CD38 on RBCs and interferes with compatibility testing, including antibody screening and cross matching (see section 4.4). Daratumumab interference mitigation methods include treating reagent RBCs with dithiothreitol (DTT) to disrupt daratumumab 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. Alternatively, phenotyping or genotyping may also be considered (see section 4.4). Interference with serum protein electrophoresis and immunofixation tests Daratumumab may be detected on serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for monitoring disease monoclonal immunoglobulins (M protein). This can lead to false positive SPE and IFE assay results for patients with IgG kappa myeloma protein impacting initial assessment of complete responses by International Myeloma Working Group (IMWG) criteria. In patients with persistent very good partial response, where daratumumab interference is suspected, consider using a validated daratumumab-specific IFE assay to distinguish daratumumab from any remaining endogenous M protein in the patient’s serum, to facilitate determination of a complete response.

HOS-097608 · has-pregnancy-information · PDF-Seite 9

Women of child-bearing potential/contraception Women of child-bearing potential should use effective contraception during, and for 3 months after cessation of daratumumab treatment. Pregnancy There are no or limited amount of data from the use of daratumumab in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). DARZALEX is not recommended during pregnancy and in women of childbearing potential not using contraception. Breast-feeding It is unknown whether daratumumab is excreted in human milk. A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from DARZALEX therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility No data are available to determine potential effects of daratumumab on fertility in males or females (see section 5.3).

HOS-097614 · has-pregnancy-information · PDF-Seite 42

Women of child-bearing potential/contraception Women of child-bearing potential should use effective contraception during, and for 3 months after cessation of daratumumab treatment. Pregnancy There are no or limited amount of data from the use of daratumumab in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). DARZALEX is not recommended during pregnancy and in women of childbearing potential not using contraception. Breast-feeding It is unknown whether daratumumab is excreted in human milk. A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from DARZALEX therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility No data are available to determine potential effects of daratumumab on fertility in males or females (see section 5.3). 42

HOS-097606 · has-warning-information · PDF-Seite 7

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-related reactions DARZALEX can cause serious IRRs, including anaphylactic reactions (see section 4.8). These reactions can be life-threatening and fatal outcomes have been reported. All patients should be monitored throughout the infusion for IRRs. For patients that experience any grade IRRs, continue monitoring post-infusion until symptoms resolve. In clinical studies, IRRs were reported in approximately half of all patients treated with DARZALEX. The majority of IRRs occurred at the first infusion and were grade 1-2 (see section 4.8). Four percent of all patients had an IRR at more than one infusion. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnoea, hypertension, laryngeal oedema, pulmonary oedema and ocular adverse reactions (including choroidal effusion, acute myopia and acute angle closure glaucoma). Symptoms predominantly included nasal congestion, cough, throat irritation, chills, vomiting and nausea. Less common symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, hypotension and blurred vision (see section 4.8). Patients should be pre-medicated with antihistamines, antipyretics and corticosteroids to reduce the risk of IRRs prior to treatment with DARZALEX. DARZALEX infusion should be interrupted for IRRs of any severity and medical management/supportive treatment for IRRs should be instituted as needed. For patients with grade 1, 2, or 3 IRRs, the infusion rate should be reduced when re-starting the infusion. If an anaphylactic reaction or life-threatening (grade 4) infusion reaction occurs, appropriate emergency resuscitation should be initiated immediately. DARZALEX therapy should be discontinued immediately and permanently (see sections 4.2 and 4.3). To reduce the risk of delayed IRRs, oral corticosteroids should be administered to all patients following DARZALEX infusions. Additionally the use of post-infusion medicinal products (e.g. inhaled corticosteroids, short and long acting bronchodilators) should be considered for patients with a history of chronic obstructive pulmonary disease to manage respiratory complications should they occur. If ocular symptoms occur, interrupt DARZALEX infusion and seek immediate ophthalmologic evaluation prior to restarting DARZALEX (see section 4.2). Neutropenia/thrombocyto

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HOS-097612 · has-warning-information · PDF-Seite 40

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-related reactions DARZALEX solution for subcutaneous injection can cause severe and/or serious IRRs, including anaphylactic reactions. In clinical studies, approximately 8.5% (134/1573) of patients experienced an IRR. Most IRRs occurred following the first injection and were grade 1-2. IRRs occurring with subsequent injections were seen in 1% of patients (see section 4.8). The median time to onset of IRRs following DARZALEX injection was 3.3 hours (range 0.08-83 hours). The majority of IRRs occurred on the day of treatment. Delayed IRRs have occurred in 1% of patients. Signs and symptoms of IRRs may include respiratory symptoms, such as nasal congestion, cough, throat irritation, allergic rhinitis, wheezing as well as pyrexia, chest pain, pruritus, chills, vomiting, nausea, hypotension and blurred vision. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnoea, hypertension, tachycardia and ocular adverse reactions (including choroidal effusion, acute myopia and acute angle closure glaucoma) (see section 4.8). Patients should be pre-medicated with antihistamines, antipyretics, and corticosteroids as well as monitored and counselled regarding IRRs, especially during and following the first and second injections. For patients with smouldering multiple myeloma, pre-medication with leukotriene inhibitors on cycle 1 day 1 should be considered. If an anaphylactic reaction or life-threatening (grade 4) reactions occur, appropriate emergency care should be initiated immediately. DARZALEX therapy should be discontinued immediately and permanently (see sections 4.2 and 4.3). To reduce the risk of delayed IRRs, oral corticosteroids should be administered to all patients following DARZALEX injection (see section 4.2). Patients with a history of chronic obstructive pulmonary disease may require additional post-injection medicinal products to manage respiratory complications. The use of post-injection medicinal products (e.g. short- and long-acting bronchodilators and inhaled corticosteroids) should be considered for patients with chronic obstructive pulmonary disease. If ocular symptoms occur, interrupt DARZALEX and seek immediate ophthalmologic evaluation prior to restarting DARZALEX (see section 4.2). Neutropenia/thrombocytopenia DARZALEX may increase neutropenia a

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