Darzalex

DARZALEX should be administered by a healthcare professional, in an environment where resuscitation facilities are available. Pre- and post-infusion medicinal products should be administered to reduce the risk of infusion-related reactions (IRRs) with daratumumab.

4. 3 Posology Dosing schedule in combination with lenalidomide and dexamethasone (4-week cycle regimen) and for monotherapy The recommended dose is DARZALEX 16 mg/kg body weight administered as an intravenous infusion according to the following dosing schedule in table 1.

Table 1:

DARZALEX dosing schedule in combination with lenalidomide and dexamethasone (Rd) (4-week cycle dosing regimen) and monotherapy Weeks Schedule Weeks 1 to 8 weekly (total of 8 doses) Weeks 9 to 24a every two weeks (total of 8 doses) Week 25 onwards until disease progressionb every four weeks a First dose of the every-2-week dosing schedule is given at week 9.

b First dose of the every-4-week dosing schedule is given at week 25. Dexamethasone should be administered at 40 mg/week (or a reduced dose of 20 mg/week for patients > 75 years). 1 and the corresponding Summary of Product Characteristics.

Dosing schedule in combination with bortezomib, melphalan and prednisone (6-week cycle regimens) The recommended dose is DARZALEX 16 mg/kg body weight administered as an intravenous infusion according to the following dosing schedule in table 2.

Table 2:

DARZALEX dosing schedule in combination with bortezomib, melphalan and prednisone ([VMP]; 6-week cycle dosing regimen) Weeks Schedule Weeks 1 to 6 weekly (total of 6 doses) Weeks 7 to 54a every three weeks (total of 16 doses) Week 55 onwards until disease progressionb every four weeks a First dose of the every-3-week dosing schedule is given at week 7.

b First dose of the every-4-week dosing schedule is given at week 55. Bortezomib is given twice weekly at weeks 1, 2, 4 and 5 for the first 6-week cycle, followed by once weekly at weeks 1, 2, 4 and 5 for eight more 6-week cycles. 1.

Dosing schedule in combination with bortezomib, thalidomide and dexamethasone (4-week cycle regimens) for treatment of newly diagnosed patients eligible for autologous stem cell transplant (ASCT) The recommended dose is DARZALEX 16 mg/kg body weight administered as an intravenous infusion according to the following dosing schedule in table 3.

Table 3:

DARZALEX dosing schedule in combination with bortezomib, thalidomide and dexamethasone ([VTd]; 4-week cycle dosing regimen) Treatment phase Weeks Schedule Induction Weeks 1 to 8 weekly (total of 8 doses) Weeks 9 to 16a every two weeks (total of 4 doses) Stop for high dose chemotherapy and ASCT Consolidation Weeks 1 to 8b every two weeks (total of 4 doses) a First dose of the every-2-week dosing schedule is given at week 9.

b First dose of the every-2-week dosing schedule is given at week 1 upon re-initiation of treatment following ASCT. 4 Dexamethasone should be administered at 40 mg on days 1, 2, 8, 9, 15, 16, 22 and 23 of cycles 1 and 2, and at 40 mg on days 1-2 and 20 mg on subsequent dosing days (days 8, 9, 15, 16) of cycles 3-4.

Dexamethasone 20 mg should be administered on days 1, 2, 8, 9, 15, 16 in cycles 5 and 6. 1 and the corresponding Summary of Product Characteristics. Dosing schedule in combination with bortezomib and dexamethasone (3-week cycle regimen) The recommended dose is DARZALEX 16 mg/kg body weight administered as an intravenous infusion according to the following dosing schedule in table 4.

Table 4:

DARZALEX dosing schedule in combination with bortezomib and dexamethasone (Vd) (3-week cycle dosing regimen) Weeks Schedule Weeks 1 to 9 weekly (total of 9 doses) Weeks 10 to 24a every three weeks (total of 5 doses) Week 25 onwards until disease progressionb every four weeks a First dose of the every-3-week dosing schedule is given at week 10.

b First dose of the every-4-week dosing schedule is given at week 25. 5), poorly controlled diabetes mellitus or prior intolerance to steroid therapy. 1 and the corresponding Summary of Product Characteristics. Infusion rates Following dilution the DARZALEX infusion should be intravenously administered at the initial infusion rate presented in table 5 below.

Incremental escalation of the infusion rate should be considered only in the absence of infusion reactions. e. 8 mg/kg on day 1 and day 2 respectively, see table 5 below.

Table 5:

Infusion rates for DARZALEX (16 mg/kg) administration Dilution volume Initial rate (first hour) Rate incrementa Maximum rate Week 1 Infusion Option 1 (Single dose infusion) Week 1 day 1 (16 mg/kg) 1000 mL 50 mL/hour 50 mL/hour every hour 200 mL/hour Option 2 (Split dose infusion) Week 1 day 1 (8 mg/kg) 500 mL 50 mL/hour 50 mL/hour every hour 200 mL/hour Week 1 day 2 (8 mg/kg) 500 mL 50 mL/hour 50 mL/hour every hour 200 mL/hour Week 2 (16 mg/kg) infusionb 500 mL 50 mL/hour 50 mL/hour every hour 200 mL/hour Subsequent (week 3 onwards, 16 mg/kg) infusionsc 500 mL 100 mL/hour 50 mL/hour every hour 200 mL/hour a Incremental escalation of the infusion rate should be considered only in the absence of infusion reactions.

b A dilution volume of 500 mL for the 16 mg/kg dose should be used only if there were no IRRs the previous week. […]

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, influenza, pyrexia, dehydration, diarrhoea and atrial fibrillation. 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.

9%). 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 infestations Upper respiratory tract infectiona Very common 46 4 COVID-19a,d 23 6 Pneumoniaa 19 11 Bronchitisa 17 2 Urinary tract infection Common 8 1 Sepsisa 4 4 Cytomegalovirus infectiona 1 < 1* Hepatitis B Virus reactivationb Uncommon - - Blood and lymphatic system disorders Neutropeniaa Very common 44 39 Thrombocytopeniaa 31 19 Anaemiaa 27 12 Lymphopeniaa 14 11 Leukopeniaa 12 6 Immune system disorders Hypogammaglobulinaemiaa Common 3 < 1* Anaphylactic reactionb Rare - - Metabolism and nutrition disorders Decreased appetite Very common 12 1 Hypokalaemiaa 10 3 Hyperglycaemia Common 7 3 Hypocalcaemia 6 1 Dehydration 3 1* Psychiatric disorders Insomnia Very common 16 1* 11 Nervous system disorders Peripheral neuropathya Very common 35 4 Headache 12 < 1* Paraesthesia 11 < 1 Dizziness 10 < 1* Syncope Common 2 2* Cardiac disorders Atrial fibrillation Common 4 1 Vascular disorders Hypertensiona Very common 10 5 Respiratory, thoracic and mediastinal disorders Cougha Very common 25 < 1* Dyspnoeaa 21 3 Pulmonary oedemaa Common 1 < 1 Gastrointestinal disorders Constipation Very common 33 1 Diarrhoea 32 4 Nausea 26 2* Vomiting 16 1* Abdominal paina 14 1 Pancreatitisa Common 1 1 Skin and subcutaneous tissue disorders Rash Very common 13 1* Pruritus Common 7 < 1* Musculoskeletal and connective tissue disorders Musculoskeletal paina,e Very common 37 4 Arthralgia 14 1 Muscle spasms 14 < 1* General disorders and administration site conditions Oedema peripherala Very common 27 1 Fatigue 26 4 Pyrexia 23 2 Asthenia 21 2 Chills Common 9 < 1* Injury, poisoning and procedural complications Infusion-related reactionc Very common 40 4 * No grade 4.

a Indicates grouping of terms. b Post-marketing adverse reaction. c Infusion-related reaction includes terms determined by investigators to be related to infusion, see below. d Incidence is based on a subset of patients who received at least one dose of study treatment on or after 01 February 2020 (the start of the COVID-19 pandemic) from studies MMY3003, MMY3006, MMY3008 and MMY3013, and all daratumumab treated patients from studies MMY3014, MMY3019, and SMM3001 (N=1177).

e Musculoskeletal pain includes back pain, flank pain, groin pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, and pain in extremity. Description of selected adverse reactions Infusion-related reactions (IRRs) In clinical studies (monotherapy and combination treatments; N=2066) the incidence of any grade IRRs was 37% with the first (16 mg/kg, week 1) infusion of DARZALEX, 2% with the week 2 infusion, and cumulatively 6% with subsequent infusions.

Less than 1% of patients had a grade 3/4 IRR with the week 2 or subsequent infusions. 8 hours). The incidence of infusion modifications due to reactions was 36%. Median durations of 16 mg/kg infusions for the 1st week, 2nd week and subsequent infusions were approximately 7, 4 and 3 hours respectively.

Severe IRRs included bronchospasm, dyspnoea, laryngeal oedema, pulmonary oedema, ocular adverse reactions (including choroidal effusion, acute myopia and acute angle closure glaucoma), hypoxia, and hypertension. 4). 9) months, upon re-initiation of DARZALEX the incidence of IRRs was 11% at first infusion following ASCT.

Infusion rate/dilution volume used upon re-initiation was that used for the last DARZALEX infusion prior to interruption due to ASCT. IRRs occurring at re-initiation of DARZALEX following ASCT were consistent in terms of symptoms and severity (grade 3/4: < 1%) with those reported in previous studies at week 2 or subsequent infusions.

In study MMY1001, patients receiving daratumumab combination treatment (n=97) […]

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. 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.

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. 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. 3). To reduce the risk of delayed IRRs, oral corticosteroids should be administered to all patients following DARZALEX infusions.

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. 2). 8). Complete blood cell counts should be monitored periodically during treatment according to prescribing information for background therapies.

Patients with neutropenia should be monitored for signs of infection. DARZALEX delay may be required to allow recovery of blood cell counts. No dose reduction of DARZALEX is recommended. Consider supportive care with transfusions or growth factors.

8). Patients should be closely monitored for signs and symptoms of infection prior to and during treatment with DARZALEX and treated appropriately. 2). 8 Interference with indirect antiglobulin test (indirect Coombs test) Daratumumab binds to CD38 found at low levels on red blood cells (RBCs) and may result in a positive indirect Coombs test.

Daratumumab-mediated positive indirect Coombs test may persist for up to 6 months after the last daratumumab infusion. It should be recognised that daratumumab bound to RBCs may mask detection of antibodies to minor antigens in the patient’s serum.

The determination of a patient’s ABO and Rh blood type are not impacted. Patients should be typed and screened prior to starting daratumumab treatment. Phenotyping may be considered prior to starting daratumumab treatment as per local practice.

Red blood cell genotyping is not impacted by daratumumab and may be performed at any time. 5). If an emergency transfusion is required, non-cross-matched ABO/RhD-compatible RBCs can be given per local blood bank practices. 5). This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

Hepatitis B virus (HBV) reactivation Hepatitis B virus reactivation, in some cases fatal, has been reported in patients treated with DARZALEX. HBV screening should be performed in all patients before initiation of treatment with DARZALEX.

For patients with evidence of positive HBV serology, monitor for clinical and laboratory signs of HBV reactivation during, and for at least six months following the end of DARZALEX treatment. Manage patients according to current clinical guidelines.

Consider consulting a hepatitis disease expert as clinically indicated. In patients who develop reactivation of HBV while on DARZALEX, suspend treatment with DARZALEX and institute appropriate treatment. Resumption of DARZALEX treatment in patients whose HBV reactivation is adequately controlled should be discussed with physicians with expertise in managing HBV.

Excipients This medicinal product contains sorbitol (E420). Patients with hereditary fructose intolerance (HFI) must not be given this medicinal product unless strictly necessary. A detailed history with regard to HFI symptoms has to be taken of each patient prior to being given this […]

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