DARZALEX 20mg / ml concentrate for solution for infusion medication leaflet

DARZALEX 20 mg/mL concentrate for solution for infusion

Each 5 mL vial contains 100 mg of daratumumab (20 mg daratumumab per mL).

Each 20 mL vial contains 400 mg of daratumumab (20 mg daratumumab per mL).

Daratumumab is a human monoclonal IgG1κ antibody against CD38 antigen, produced in amammalian cell line (Chinese Hamster Ovary) using recombinant DNA technology.

Each 5 mL vial of solution for infusion contains 273.3 mg of sorbitol (E420).

Each 20 mL vial of solution for infusion contains 1093 mg of sorbitol (E420).

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion.

The solution is colourless to yellow.

DARZALEX is indicated:

- in combination with lenalidomide and dexamethasone or with bortezomib, melphalan andprednisone for the treatment of adult patients with newly diagnosed multiple myeloma who areineligible for autologous stem cell transplant.

- in combination with bortezomib, thalidomide and dexamethasone for the treatment of adultpatients with newly diagnosed multiple myeloma who are eligible for autologous stem celltransplant.

- in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, forthe treatment of adult patients with multiple myeloma who have received at least one priortherapy.

- as monotherapy for the treatment of adult patients with relapsed and refractory multiplemyeloma, whose prior therapy included a proteasome inhibitor and an immunomodulatoryagent and who have demonstrated disease progression on the last therapy.

DARZALEX should be administered by a healthcare professional, in an environment whereresuscitation facilities are available.

Pre- and post-infusion medicinal products should be administered to reduce the risk of infusion-relatedreactions (IRRs) with daratumumab. See below “Recommended concomitant medicinal products”,“Management of infusion-related reactions” and section 4.4.

Dosing schedule in combination with lenalidomide and dexamethasone (4-week cycle regimen) andfor monotherapy

The recommended dose is DARZALEX 16 mg/kg body weight administered as an intravenousinfusion 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 weeksa 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).

For dose and schedule of medicinal products administered with DARZALEX, see section 5.1 and thecorresponding 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 intravenousinfusion according to the following dosing schedule in table 2.

Table 2: DARZALEX dosing schedule in combination with bortezomib, melphalan andprednisone ([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 weeksa 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 onceweekly at weeks 1, 2, 4 and 5 for eight more 6-week cycles. For information on the VMP dose anddosing schedule when administered with DARZALEX, see section 5.1.

Dosing schedule in combination with bortezomib, thalidomide and dexamethasone (4-week cycleregimens) 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 intravenousinfusion according to the following dosing schedule in table 3.

Table 3: DARZALEX dosing schedule in combination with bortezomib, thalidomide anddexamethasone ([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.

Dexamethasone should be administered at 40 mg on days 1, 2, 8, 9, 15, 16, 22 and 23 of cycles 1 and2, 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.

For dose and schedule of medicinal products administered with DARZALEX, see section 5.1 and thecorresponding 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 intravenousinfusion 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 weeksa 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.

Dexamethasone should be administered at 20 mg on days 1, 2, 4, 5, 8, 9, 11 and 12 of the first 8bortezomib treatment cycles or a reduced dose of 20 mg/week for patients > 75 years, underweight(BMI < 18.5), poorly controlled diabetes mellitus or prior intolerance to steroid therapy.

For dose and schedule of medicinal products administered with DARZALEX, see section 5.1 and thecorresponding Summary of Product Characteristics.

Infusion rates

Following dilution the DARZALEX infusion should be intravenously administered at the initialinfusion rate presented in table 5 below. Incremental escalation of the infusion rate should beconsidered only in the absence of infusion reactions.

To facilitate administration, the first prescribed 16 mg/kg dose at week 1 may be split over twoconsecutive days i.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 Initial rate Rate incrementa Maximum ratevolume (first hour)

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, 500 mL 100 mL/hour 50 mL/hour every hour 200 mL/hour16 mg/kg) infusionsca 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.

Otherwise, use a dilution volume of 1000 mL.c A modified initial rate (100 mL/hour) for subsequent infusions (i.e. week 3 onwards) should only be used only if therewere no IRRs during the previous infusion. Otherwise, continue to use instructions indicated in the table for the week 2infusion rate.

Management of infusion-related reactions

Pre-infusion medicinal products should be administered to reduce the risk of infusion-related reactions(IRRs) prior to treatment with DARZALEX.

For IRRs of any grade/severity, immediately interrupt the DARZALEX infusion and managesymptoms.

Management of IRRs may further require reduction in the rate of infusion, or treatmentdiscontinuation of DARZALEX as outlined below (see section 4.4).

- Grade 1-2 (mild to moderate): Once reaction symptoms resolve, the infusion should be resumedat no more than half the rate at which the IRR occurred. If the patient does not experience anyfurther IRR symptoms, infusion rate escalation may be resumed at increments and intervals asclinically appropriate up to the maximum rate of 200 mL/hour (table 5).

- Grade 3 (severe): Once reaction symptoms resolve, restarting of the infusion may be consideredat no more than half the rate at which the reaction occurred. If the patient does not experienceadditional symptoms, infusion rate escalation may be resumed at increments and intervals asappropriate (table 5). The procedure above should be repeated in the event of recurrence ofgrade 3 symptoms. Permanently discontinue DARZALEX upon the third occurrence of agrade 3 or greater infusion reaction.

- Grade 4 (life-threatening): Permanently discontinue DARZALEX treatment.

If a planned dose of DARZALEX is missed, the dose should be administered as soon as possible andthe dosing schedule should be adjusted accordingly, maintaining the treatment interval.

No dose reductions of DARZALEX are recommended. Dose delay may be required to allow recoveryof blood cell counts in the event of haematological toxicity (see section 4.4). For informationconcerning medicinal products given in combination with DARZALEX, see corresponding Summaryof Product Characteristics.

Recommended concomitant medicinal products

Pre-infusion medicinal product

Pre-infusion medicinal products should be administered to reduce the risk of IRRs to all patients 1-3 hours prior to every infusion of DARZALEX as follows:

- Corticosteroid (long-acting or intermediate-acting)

- Monotherapy:

Methylprednisolone 100 mg, or equivalent, administered intravenously. Following thesecond infusion, the dose of corticosteroid may be reduced (oral or intravenousmethylprednisolone 60 mg).

- Combination therapy:

Dexamethasone 20 mg (or equivalent), administered prior to every DARZALEXinfusion. When dexamethasone is the background-regimen specific corticosteroid, thedexamethasone treatment dose will instead serve as pre-infusion medicinal product on

DARZALEX infusion days (see section 5.1).

Dexamethasone is given intravenously prior to the first DARZALEX infusion and oraladministration may be considered prior to subsequent infusions. Additional backgroundregimen specific corticosteroids (e.g. prednisone) should not be taken on DARZALEXinfusion days when patients have received dexamethasone as a pre-infusion medicinalproduct.

- Antipyretics (oral paracetamol 650 to 1000 mg)

- Antihistamine (oral or intravenous diphenhydramine 25 to 50 mg or equivalent).

Post-infusion medicinal product

Post-infusion medicinal products should be administered to reduce the risk of delayed IRRs asfollows:

- Monotherapy:

Oral corticosteroid (20 mg methylprednisolone or equivalent dose of anintermediate-acting or long-acting corticosteroid in accordance with local standards)should be administered on each of the two days following all infusions (beginning the dayafter the infusion).

- Combination therapy:

Consider administering low-dose oral methylprednisolone (≤ 20 mg) or equivalent theday after the DARZALEX infusion. However, if a background regimen-specificcorticosteroid (e.g. dexamethasone, prednisone) is administered the day after the

DARZALEX infusion, additional post-infusion medicinal products may not be needed(see section 5.1).

Additionally, for patients with a history of chronic obstructive pulmonary disease, the use ofpost-infusion medicinal products including short and long acting bronchodilators, and inhaledcorticosteroids should be considered. Following the first four infusions, if the patient experiences nomajor IRRs, these inhaled post-infusion medicinal products may be discontinued at the discretion ofthe physician.

Prophylaxis for herpes zoster virus reactivation

Anti-viral prophylaxis should be considered for the prevention of herpes zoster virus reactivation.

No formal studies of daratumumab in patients with renal impairment have been conducted. Based onpopulation pharmacokinetic (PK) analyses no dose adjustment is necessary for patients with renalimpairment (see section 5.2).

No formal studies of daratumumab in patients with hepatic impairment have been conducted.

Based on population PK analyses, no dose adjustments are necessary for patients with hepaticimpairment (see section 5.2).

No dose adjustments are considered necessary (see section 5.2).

The safety and efficacy of DARZALEX in children aged below 18 years of age have not beenestablished.

No data are available.

DARZALEX is for intravenous use. It is administered as an intravenous infusion following dilutionwith sodium chloride 9 mg/mL (0.9%) solution for injection. For instructions on dilution of themedicinal product before administration, see section 6.6.

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

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

DARZALEX can cause serious IRRs, including anaphylactic reactions (see section 4.8). Thesereactions can be life-threatening and fatal outcomes have been reported.

All patients should be monitored throughout the infusion for IRRs. For patients that experience anygrade 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 percentof all patients had an IRR at more than one infusion. Severe reactions have occurred, includingbronchospasm, hypoxia, dyspnoea, hypertension, laryngeal oedema, pulmonary oedema and ocularadverse reactions (including choroidal effusion, acute myopia and acute angle closure glaucoma).

Symptoms predominantly included nasal congestion, cough, throat irritation, chills, vomiting andnausea. 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 therisk 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 asneeded. For patients with grade 1, 2, or 3 IRRs, the infusion rate should be reduced when re-startingthe infusion. If an anaphylactic reaction or life-threatening (grade 4) infusion reaction occurs,appropriate emergency resuscitation should be initiated immediately. DARZALEX therapy should bediscontinued immediately and permanently (see sections 4.2 and 4.3).

To reduce the risk of delayed IRRs, oral corticosteroids should be administered to all patientsfollowing 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 ahistory of chronic obstructive pulmonary disease to manage respiratory complications should theyoccur. If ocular symptoms occur, interrupt DARZALEX infusion and seek immediate ophthalmologicevaluation prior to restarting DARZALEX (see section 4.2).

Neutropenia/thrombocytopenia

DARZALEX may increase neutropenia and thrombocytopenia induced by background therapy (seesection 4.8).

Complete blood cell counts should be monitored periodically during treatment according toprescribing information for background therapies. Patients with neutropenia should be monitored forsigns of infection. DARZALEX delay may be required to allow recovery of blood cell counts. No dosereduction of DARZALEX is recommended. Consider supportive care with transfusions or growthfactors.

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 apositive indirect Coombs test. Daratumumab-mediated positive indirect Coombs test may persist forup to 6 months after the last daratumumab infusion. It should be recognised that daratumumab boundto RBCs may mask detection of antibodies to minor antigens in the patient’s serum. The determinationof a patient’s ABO and Rh blood type are not impacted.

Patients should be typed and screened prior to starting daratumumab treatment. Phenotyping may beconsidered prior to starting daratumumab treatment as per local practice. Red blood cell genotyping isnot impacted by daratumumab and may be performed at any time.

In the event of a planned transfusion blood transfusion centres should be notified of this interferencewith indirect antiglobulin tests (see section 4.5). If an emergency transfusion is required,non-cross-matched ABO/RhD-compatible RBCs can be given per local blood bank practices.

Interference with determination of complete response

Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both, the serumprotein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring ofendogenous M-protein (see section 4.5). This interference can impact the determination of completeresponse 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 HBVreactivation during, and for at least six months following the end of DARZALEX treatment. Managepatients according to current clinical guidelines. Consider consulting a hepatitis disease expert asclinically indicated.

In patients who develop reactivation of HBV while on DARZALEX, suspend treatment with

DARZALEX and institute appropriate treatment. Resumption of DARZALEX treatment in patientswhose HBV reactivation is adequately controlled should be discussed with physicians with expertisein managing HBV.

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 giventhis medicinal product.

No interaction studies have been performed.

As an IgG1қ monoclonal antibody, renal excretion and hepatic enzyme-mediated metabolism of intactdaratumumab are unlikely to represent major elimination routes. As such, variations indrug-metabolising enzymes are not expected to affect the elimination of daratumumab. Due to thehigh affinity to a unique epitope on CD38, daratumumab is not anticipated to alter drug-metabolisingenzymes.

Clinical pharmacokinetic assessments of daratumumab in combination with lenalidomide,pomalidomide, thalidomide, bortezomib and dexamethasone indicated no clinically-relevant drug-druginteraction 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 antibodyscreening and cross matching (see section 4.4). Daratumumab interference mitigation methods includetreating reagent RBCs with dithiothreitol (DTT) to disrupt daratumumab binding or other locallyvalidated 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 falsepositive SPE and IFE assay results for patients with IgG kappa myeloma protein impacting initialassessment of complete responses by International Myeloma Working Group (IMWG) criteria. Inpatients with persistent very good partial response, where daratumumab interference is suspected,consider using a validated daratumumab-specific IFE assay to distinguish daratumumab from anyremaining endogenous M protein in the patient’s serum, to facilitate determination of a completeresponse.

Women of child-bearing potential/contraception

Women of child-bearing potential should use effective contraception during, and for 3 months aftercessation of daratumumab treatment.

There are no or limited amount of data from the use of daratumumab in pregnant women. Animalstudies are insufficient with respect to reproductive toxicity (see section 5.3). DARZALEX is notrecommended during pregnancy and in women of childbearing potential not using contraception.

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 discontinuebreast-feeding or to discontinue/abstain from DARZALEX therapy taking into account the benefit ofbreast-feeding for the child and the benefit of therapy for the woman.

No data are available to determine potential effects of daratumumab on fertility in males or females(see section 5.3).

DARZALEX has no or negligible influence on the ability to drive and use machines. However, fatiguehas been reported in patients taking daratumumab and this should be taken into account when drivingor using machines.

The most frequent adverse reactions of any grade (≥ 20% patients) were IRRs, fatigue, nausea,diarrhoea, constipation, pyrexia, dyspnoea, cough, neutropenia, thrombocytopenia, anaemia, oedemaperipheral, asthenia, peripheral neuropathy, upper respiratory tract infection, musculoskeletal pain and

COVID-19. Serious adverse reactions were sepsis, pneumonia, bronchitis, upper respiratory tractinfection, pulmonary oedema, influenza, pyrexia, dehydration, diarrhoea and atrial fibrillation.

Table 6 summarises the adverse reactions that occurred in patients receiving DARZALEX. The datareflects exposure to DARZALEX (16 mg/kg) in 2066 patients with multiple myeloma including1910 patients who received DARZALEX in combination with background regimens and 156 patientswho 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 armcompared with the VTd arm (Median: D-VTd: 6.3 x 106/kg; VTd 8.9 x 106/kg) and among those whocompleted mobilisation, more patients in the D-VTd group received plerixafor compared to those inthe VTd arm (D-VTd: 21.7%; VTd: 7.9%). The rates of engraftment and haematopoietic reconstitutionwas 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, andplatelets > 50 x 109/L without transfusion).

Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000to < 1/100), rare (≥ 1/10000 to < 1/1000) and very rare (< 1/10000). Within each frequency groupingadverse reactions are presented in the order of decreasing seriousness.

Table 6: Adverse reactions in multiple myeloma patients treated with DARZALEX16 mg/kg

System organ class Adverse reaction Frequency Incidence (%)

Any grade Grade 3-4

Infections and Upper respiratory tract Very commoninfestations infectiona 46 4

COVID-19a,d 26 7

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 Neutropeniaa Very common 44 39system disorders Thrombocytopeniaa 31 19

Anaemiaa 27 12

Lymphopeniaa 14 11

Leukopeniaa 12 6

Immune system Hypogammaglobulinemiaa Common 3 < 1*disorders Anaphylactic reactionb Rare - -

Metabolism and Decreased appetite Very common 12 1nutrition disorders Hypokalaemiaa 10 3

Hyperglycaemia Common 7 3

Hypocalcaemia 6 1

Dehydration 3 1*

Psychiatric disorders Insomnia Very common 16 1*

Nervous system Peripheral neuropathya Very common 35 4disorders 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 Cougha Very common 25 < 1*and mediastinal Dyspnoeaa 21 3disorders Pulmonary oedemaa Common 1 < 1

Gastrointestinal Constipation Very common 33 1disorders Diarrhoea 32 4

Nausea 26 2*

Vomiting 16 1*

Abdominal paina 14 1

Pancreatitisa Common 1 1

Skin and Rash Very common 13 1*subcutaneous tissue Pruritus Common 7 < 1*disorders

Musculoskeletal and Musculoskeletal paina Very common 37 4connective tissue Arthralgia 14 1disorders Muscle spasms 14 < 1*

General disorders and Oedema peripherala Very common 27 1administration site Fatigue 26 4conditions Pyrexia 23 2

Asthenia 21 2

Chills Common 9 < 1*

Injury, poisoning and Infusion-related reactionc Very common 40 4proceduralcomplications

* 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 alldaratumumab treated patients from studies MMY3014 and MMY3019 (N=984).

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 2infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a grade 3/4

IRR with the week 2 or subsequent infusions.

The median time to onset of a reaction was 1.5 hours (range: 0 to 72.8 hours). The incidence ofinfusion modifications due to reactions was 36%. Median durations of 16 mg/kg infusions for the 1stweek, 2nd week and subsequent infusions were approximately 7, 4 and 3 hours respectively.

Severe IRRs included bronchospasm, dyspnoea, laryngeal oedema, pulmonary oedema, ocular adversereactions (including choroidal effusion, acute myopia and acute angle closure glaucoma), hypoxia, andhypertension. Other adverse IRRs included nasal congestion, cough, chills, throat irritation, blurredvision, vomiting and nausea (see section 4.4).

When DARZALEX dosing was interrupted in the setting of ASCT (study MMY3006) for a median of3.75 (range: 2.4; 6.9) months, upon re-initiation of DARZALEX the incidence of IRRs was 11% atfirst infusion following ASCT. Infusion rate/dilution volume used upon re-initiation was that used forthe 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) were administeredthe first 16 mg/kg daratumumab dose at week 1 split over two days i.e. 8 mg/kg on day 1 and day 2respectively. The incidence of any grade IRRs was 42%, with 36% of patients experiencing IRRs onday 1 of week 1, 4% on day 2 of week 1, and 8% with subsequent infusions. The median time to onsetof a reaction was 1.8 hours (range: 0.1 to 5.4 hours). The incidence of infusion interruptions due toreactions was 30%. Median durations of infusions were 4.2 h for week 1-day 1, 4.2 h for week 1-day 2, and 3.4 hours for the subsequent infusions.

In patients receiving DARZALEX combination therapy, grade 3 or 4 infections were reported asfollows:

Relapsed/refractory patient studies: DVd: 21%, Vd: 19%; DRd: 28%, Rd: 23%; DPd: 28%

Newly diagnosed patient studies: D-VMP: 23%, VMP: 15%; DRd: 32%, Rd: 23%; D-VTd: 22%,

VTd: 20%.

Pneumonia was the most commonly reported severe (grade 3 or 4) infection across studies. In activecontrolled studies, discontinuations from treatment due to infections occurred in 1-4% of patients.

Fatal infections were primarily due to pneumonia and sepsis.

In patients receiving DARZALEX combination therapy, fatal infections (grade 5) were reported asfollows:

Relapsed/refractory patient studies: DVd: 1%, Vd: 2%; DRd: 2%, Rd: 1%; DPd: 2%

Newly diagnosed patient studies: D-VMP: 1%, VMP: 1%; DRd: 2%, Rd: 2%; DVTd: 0%, VTd: 0%.

Key: D=daratumumab; Vd=bortezomib-dexamethasone; Rd=lenalidomide-dexamethasone; Pd=pomalidomide-dexamethasone; VMP=bortezomib-melphalan-prednisone; VTd=bortezomib-thalidomide-dexamethasone.

Haemolysis

There is a theoretical risk of haemolysis. Continuous monitoring for this safety signal will beperformed in clinical studies and post-marketing safety data.

In the phase III study MMY3007, which compared treatment with D-VMP to treatment with VMP inpatients with newly diagnosed multiple myeloma who are ineligible for autologous stem celltransplant, safety analysis of the subgroup of patients with an ECOG performance score of 2 (D-VMP:n=89, VMP: n=84), was consistent with the overall population (see section 5.1).

Of the 2459 patients who received DARZALEX at the recommended dose, 38% were 65 to 75 yearsof age, and 15% were 75 years of age or older. No overall differences in effectiveness were observedbased on age. The incidence of serious adverse reactions was higher in older than in younger patients.

Among patients with relapsed and refractory multiple myeloma (n=1213), the most common seriousadverse reactions that occurred more frequently in elderly (≥ 65 years of age) were pneumonia andsepsis. Among patients with newly diagnosed multiple myeloma who are ineligible for autologousstem cell transplant (n=710), the most common serious adverse reaction that occurred more frequentlyin elderly (≥ 75 years of age) was pneumonia.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Symptoms and signs

There has been no experience of overdose in clinical studies. Doses up to 24 mg/kg have beenadministered intravenously in a clinical study.

There is no known specific antidote for daratumumab overdose. In the event of an overdose, thepatient should be monitored for any signs or symptoms of adverse reactions and appropriatesymptomatic treatment should be instituted immediately.

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies and antibody drugconjugates, CD38 (Clusters of Differentiation 38) inhibitors, ATC code: L01FC01.

Daratumumab is an IgG1κ human monoclonal antibody (mAb) that binds to the CD38 proteinexpressed at a high level on the surface of multiple myeloma tumour cells, as well as other cell typesand tissues at various levels. CD38 protein has multiple functions such as receptor mediated adhesion,signalling and enzymatic activity.

Daratumumab has been shown to potently inhibit the in vivo growth of CD38-expressing tumour cells.

Based on in vitro studies, daratumumab may utilise multiple effector functions, resulting in immunemediated tumour cell death. These studies suggest that daratumumab can induce tumour cell lysisthrough complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, andantibody-dependent cellular phagocytosis in malignancies expressing CD38. A subset of myeloidderived suppressor cells (CD38+MDSCs), regulatory T cells (CD38+Tregs) and B cells (CD38+Bregs)are decreased by daratumumab mediated cell lysis. T cells (CD3+, CD4+, and CD8+) are also knownto express CD38 depending on the stage of development and the level of activation. Significantincreases in CD4+ and CD8+ T cell absolute counts, and percentages of lymphocytes, were observedwith daratumumab treatment in peripheral whole blood and bone marrow. In addition, T-cell receptor

DNA sequencing verified that T-cell clonality was increased with daratumumab treatment, indicatingimmune modulatory effects that may contribute to clinical response.

Daratumumab induced apoptosis in vitro after Fc mediated cross-linking. In addition, daratumumabmodulated CD38 enzymatic activity, inhibiting the cyclase enzyme activity and stimulating thehydrolase activity. The significance of these in vitro effects in a clinical setting, and the implicationson tumour growth, are not well-understood.

Natural killer (NK) cell and T-cell count

NK cells are known to express high levels of CD38 and are susceptible to daratumumab mediated celllysis. Decreases in absolute counts and percentages of total NK cells (CD16+CD56+) and activated(CD16+CD56dim) NK cells in peripheral whole blood and bone marrow were observed withdaratumumab treatment. However, baseline levels of NK cells did not show an association withclinical response.

In patients treated with intravenous daratumumab in clinical studies, less than 1% of patientsdeveloped treatment-emergent anti-daratumumab antibodies.

Newly diagnosed multiple myeloma

Combination treatment with lenalidomide and dexamethasone in patients ineligible for autologousstem cell transplant

Study MMY3008, an open-label, randomised, active-controlled phase III study, compared treatmentwith DARZALEX 16 mg/kg in combination with lenalidomide and low-dose dexamethasone (DRd) totreatment with lenalidomide and low-dose dexamethasone (Rd) in patients with newly diagnosedmultiple myeloma. Lenalidomide (25 mg once daily orally on days 1-21 of repeated 28-day [4-week]cycles) was given with low dose oral or intravenous dexamethasone 40 mg/week (or a reduced dose of20 mg/week for patients > 75 years or body mass index [BMI] < 18.5). On DARZALEX infusiondays, the dexamethasone dose was given as a pre-infusion medicinal product. Dose adjustments forlenalidomide and dexamethasone were applied according to manufacturer’s prescribing information.

Treatment was continued in both arms until disease progression or unacceptable toxicity.

A total of 737 patients were randomised: 368 to the DRd arm and 369 to the Rd arm. The baselinedemographic and disease characteristics were similar between the two treatment groups. The medianage was 73 (range: 45-90) years, with 44% of the patients ≥ 75 years of age. The majority were white(92%), male (52%), 34% had an Eastern Cooperative Oncology Group (ECOG) performance score of0, 49.5% had an ECOG performance score of 1 and 17% had an ECOG performance score of ≥ 2.

Twenty-seven percent had International Staging System (ISS) stage I, 43% had ISS stage II and 29%had ISS stage III disease. Efficacy was evaluated by progression free survival (PFS) based on

International Myeloma Working Group (IMWG) criteria and overall survival (OS).

With a median follow-up of 28 months, the primary analysis of PFS in study MMY3008 showed animprovement in the DRd arm as compared to the Rd arm; the median PFS had not been reached in the

DRd arm and was 31.9 months in the Rd arm (hazard ratio [HR]=0.56; 95% CI: 0.43, 0.73;p < 0.0001), representing 44% reduction in the risk of disease progression or death in patients treatedwith DRd. Results of an updated PFS analysis after a median follow-up of 64 months continued toshow an improvement in PFS for patients in the DRd arm compared with the Rd arm. Median PFSwas 61.9 months in the DRd arm and 34.4 months in the Rd arm (HR=0.55; 95% CI: 0.45, 0.67).

Figure 1: Kaplan-Meier curve of PFS in study MMY3008

With a median follow-up of 56 months, DRd has shown an OS advantage over the Rd arm (HR=0.68;95% CI: 0.53, 0.86; p=0.0013). Results of an updated OS analysis after a median of 89 monthscontinued to show an improvement in OS for patients in the DRd arm compared to the Rd arm.

Median OS was 90.3 months in the DRd arm and was 64.1 months in the Rd arm (HR=0.67;95% CI: 0.55, 0.82).

Figure 2: Kaplan-Meier curve of OS in study MMY3008

Additional efficacy results from study MMY3008 are presented in table 7 below.

Table 7: Additional efficacy results from study MMY3008a

DRd (n=368) Rd (n=369)

Overall response (sCR+CR+VGPR+PR) n(%)a 342 (92.9%) 300 (81.3%)p-valueb < 0.0001

Stringent complete response (sCR) 112 (30.4%) 46 (12.5%)

Complete response (CR) 63 (17.1%) 46 (12.5%)

Very good partial response (VGPR) 117 (31.8%) 104 (28.2%)

Partial response (PR) 50 (13.6%) 104 (28.2%)

CR or better (sCR + CR) 175 (47.6%) 92 (24.9%)p-valueb < 0.0001

VGPR or better (sCR + CR + VGPR) 292 (79.3%) 196 (53.1%)p-valueb < 0.0001

MRD negativity ratea,c n(%) 89 (24.2%) 27 (7.3%)95% CI (%) (19.9%, 28.9%) (4.9%, 10.5%)

Odds ratio with 95% CId 4.04 (2.55, 6.39)p-valuee < 0.0001

DRd=daratumumab-lenalidomide-dexamethasone; Rd=lenalidomide-dexamethasone; MRD=minimal residual disease;

CI=confidence interval.a Based on intent-to-treat population.b p-value from Cochran Mantel-Haenszel Chi-Squared test.c Based on threshold of 10-5.d Mantel-Haenszel estimate of the odds ratio for un-stratified tables is used. An odds ratio > 1 indicates an advantage for

DRd.e p-value from Fisherʼs exact test.

In responders, the median time to response was 1.05 months (range: 0.2 to 12.1 months) in the DRdgroup and 1.05 months (range: 0.3 to 15.3 months) in the Rd group. The median duration of responsehad not been reached in the DRd group and was 34.7 months (95% CI: 30.8, not estimable) in the Rdgroup.

Combination treatment with bortezomib, melphalan and prednisone (VMP) in patients ineligible forautologous stem cell transplant

Study MMY3007, an open-label, randomised, active-controlled phase III study, compared treatmentwith DARZALEX 16 mg/kg in combination with bortezomib, melphalan and prednisone (D-VMP), totreatment with VMP in patients with newly diagnosed multiple myeloma. Bortezomib wasadministered by subcutaneous injection at a dose of 1.3 mg/m2 body surface area twice weekly atweeks 1, 2, 4 and 5 for the first 6-week cycle (cycle 1; 8 doses), followed by once weeklyadministrations at weeks 1, 2, 4 and 5 for eight more 6-week cycles (cycles 2-9; 4 doses per cycle).

Melphalan at 9 mg/m2, and prednisone at 60 mg/m2 were orally administered on days 1 to 4 of the nine6-week cycles (cycles 1-9). DARZALEX treatment was continued until disease progression orunacceptable toxicity.

A total of 706 patients were randomised: 350 to the D-VMP arm and 356 to the VMP arm. Thebaseline demographic and disease characteristics were similar between the two treatment groups. Themedian age was 71 (range: 40-93) years, with 30% of the patients ≥ 75 years of age. The majoritywere white (85%), female (54%), 25% had an ECOG performance score of 0, 50% had an ECOGperformance score of 1 and 25% had an ECOG performance score of 2. Patients had IgG/IgA/Lightchain myeloma in 64%/22%/10% of instances, 19% had ISS stage I, 42% had ISS stage II, 38% had

ISS stage III disease and 84% had standard risk cytogenetics. Efficacy was evaluated by PFS based on

IMWG criteria and overall survival (OS).

With a median follow-up of 16.5 months, the primary analysis of PFS in study MMY3007 showed animprovement in the D-VMP arm as compared to the VMP arm; the median PFS had not been reachedin the D-VMP arm and was 18.1 months in the VMP arm (HR=0.5; 95% CI: 0.38, 0.65; p < 0.0001).

Results of an updated PFS analysis after a median follow-up of 40 months continued to show animprovement in PFS for patients in the D-VMP arm compared with the VMP arm. Median PFS was36.4 months in the D-VMP arm and 19.3 months in the VMP arm (HR=0.42; 95% CI: 0.34, 0.51;p < 0.0001), representing a 58% reduction in the risk of disease progression or death in patients treatedwith D-VMP.

Figure 3: Kaplan-Meier curve of PFS in study MMY3007

After a median follow-up of 40 months, D-VMP has shown an OS advantage over the VMP arm(HR=0.60; 95% CI: 0.46, 0.80; p=0.0003), representing a 40% reduction in the risk of death in patientstreated in the D-VMP arm. After a median follow-up of 87 months, the median OS was 83 months(95% CI: 72.5, NE) in the D-VMP arm and 53.6 months (95% CI: 46.3, 60.9) in the VMP arm.

Figure 4: Kaplan-Meier curve of OS in study MMY3007

Additional efficacy results from study MMY3007 are presented in table 8 below.

Table 8: Additional efficacy results from study MMY3007a

D-VMP (n=350) VMP (n=356)

Overall response (sCR+CR+VGPR+PR) [n(%)] 318 (90.9) 263 (73.9)p-valueb < 0.0001

Stringent complete response (sCR) [n(%)] 63 (18.0) 25 (7.0)

Complete response (CR) [n(%)] 86 (24.6) 62 (17.4)

Very good partial response (VGPR) [n(%)] 100 (28.6) 90 (25.3)

Partial response (PR) [n(%)] 69 (19.7) 86 (24.2)

MRD negativity rate (95% CI) c (%) 22.3 (18.0, 27.0) 6.2 (3.9, 9.2)

Odds ratio with 95% CId 4.36 (2.64, 7.21)p-valuee < 0.0001

D-VMP=daratumumab-bortezomib-melphalan-prednisone; VMP=bortezomib-melphalan-prednisone; MRD=minimalresidual disease; CI=confidence interval.a Based on intent-to-treat population.b p-value from Cochran Mantel-Haenszel Chi-Squared test.c Based on threshold of 10-5.d A Mantel-Haenszel estimate of the common odds ratio for stratified tables is used. An odds ratio > 1 indicates anadvantage for D-VMP.e p-value from Fisherʼs exact test.

In responders, the median time to response was 0.79 months (range: 0.4 to 15.5 months) in the

D-VMP group and 0.82 months (range: 0.7 to 12.6 months) in the VMP group. The median durationof response had not been reached in the D-VMP group and was 21.3 months (range: 18.4, notestimable) in the VMP group.

A subgroup analysis was performed on patients at least 70 years old, or those 65-69 years old with

ECOG performance score of 2, or aged less than 65 years of age with significant comorbidity or

ECOG performance score of 2 (D-VMP: n=273, VMP: n=270). The efficacy results in this subgroupwere consistent with the overall population. In this subgroup, median PFS was not reached in the

D-VMP group and was 17.9 months in the VMP group (HR=0.56; 95% CI: 0.42, 0.75; p < 0.0001).

The overall response rate was 90% in the D-VMP group and 74% in theVMP group (VGPR rate:29%in D-VMP group and 26% in VMP group; CR: 22% in D-VMP group and 18% in VMP group; sCRrate: 20% in D-VMP group and 7% in VMP group). The safety results of this subgroup wereconsistent with the overall population. Furthermore, safety analysis of the subgroup of patients with an

ECOG performance score of 2 (D-VMP: n=89, VMP: n=84), was also consistent with the overallpopulation.

Combination treatment with bortezomib, thalidomide and dexamethasone (VTd) in patients eligible forautologous stem cell transplant (ASCT)

Study MMY3006 is a 2 part, open-label, randomised, active-controlled phase III study. Part 1compared induction and consolidation treatment with DARZALEX 16 mg/kg in combination withbortezomib, thalidomide and dexamethasone (D-VTd) to treatment with bortezomib, thalidomide anddexamethasone (VTd) in patients with newly diagnosed multiple myeloma eligible for ASCT. Theconsolidation phase of treatment began a minimum of 30 days post-ASCT, when the patient hadrecovered sufficiently, and engraftment was complete. In part 2, subjects with at least a partialresponse (PR) by day 100 post-transplant were re-randomised in a 1:1 ratio to daratumumabmaintenance or observation only. Only results from part 1 are described henceforth.

Bortezomib was administered by subcutaneous injection or intravenous injection at a dose of1.3 mg/m2 body surface area twice weekly for two weeks (days 1, 4, 8, and 11) of repeated 28 day(4-week) induction treatment cycles (cycles 1-4) and two consolidation cycles (cycles 5 and 6)following ASCT after cycle 4. Thalidomide was administered orally at 100 mg daily during the sixbortezomib cycles. Dexamethasone (oral or intravenous) was 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 was administered on days 1, 2, 8, 9, 15, 16 incycles 5 and 6. On the days of DARZALEX infusion, the dexamethasone dose was administeredintravenously as a pre-infusion medicinal product. Dose adjustments for bortezomib, thalidomide anddexamethasone were applied according to manufacturer’s prescribing information.

A total of 1085 patients were randomised: 543 to the D-VTd arm and 542 to the VTd arm. Thebaseline demographic and disease characteristics were similar between the two treatment groups. Themedian age was 58 (range: 22 to 65) years. All patients were ≤ 65 years: 43% were in the age group≥ 60-65 years, 41% were in the age group ≥ 50-60 years and 16% below age of 50 years. The majoritywere male (59%), 48% had an ECOG performance score of 0, 42% had an ECOG performance scoreof 1 and 10% had an ECOG performance score of 2. Forty percent had International Staging System(ISS) stage I, 45% had ISS stage II and 15% had ISS stage III disease.

Efficacy was evaluated by the stringent complete response (sCR) rate at day 100 post-transplant and

PFS.

Table 9: Efficacy results from study MMY3006a

D-VTd (n=543) VTd (n=542) P valueb

Response assessment day 100 post-transplant

Stringent complete response (sCR) 157 (28.9%) 110 (20.3%) 0.0010

CR or better (sCR+CR) 211 (38.9%) 141 (26.0%) < 0.0001

Very good partial response or better 453 (83.4%) 423 (78.0%)(sCR+CR+VGPR)

MRD negativityc, d n(%) 346 (63.7%) 236 (43.5%) < 0.000195% CI (%) (59.5%, 67.8%) (39.3%, 47.8%)

Odds ratio with 95% CIe 2.27 (1.78, 2.90)

MRD negativity in combination with CR or 183 (33.7%) 108 (19.9%) < 0.0001betterc n(%)95% CI (%) (29.7%, 37.9%) (16.6%, 23.5%)

Odds ratio with 95% CIe 2.06 (1.56, 2.72)

D-VTd=daratumumab-bortezomib-thalidomide-dexamethasone; VTd=bortezomib-thalidomide-dexamethasone;

MRD=minimal residual disease; CI=confidence interval.a Based on intent-to-treat population.b p-value from Cochran Mantel-Haenszel Chi-Squared test.c Based on threshold of 10-5.d Regardless of response per IMWG.e Mantel-Haenszel estimate of the common odds ratio for stratified tables is used.

With a median follow-up of 18.8 months, the primary analysis of PFS by censoring patients who wererandomised to daratumumab maintenance in the second randomisation at the date of the secondrandomisation showed HR=0.50; 95% CI: 0.34, 0.75; p=0.0005. Results of an updated PFS analysiswith a median follow-up of 44.5 months, censoring patients who were randomised to daratumumabmaintenance in the second randomisation, showed HR=0.43; 95% CI: 0.33, 0.55; p < 0.0001. Median

PFS was not reached in the D-VTd arm and was 37.8 months in the VTd arm.

Figure 5: Kaplan-Meier curve of PFS in study MMY3006

Relapsed/refractory multiple myeloma

The clinical efficacy and safety of DARZALEX monotherapy for the treatment of adult patients withrelapsed and refractory multiple myeloma whose prior therapy included a proteasome inhibitor and animmunomodulatory agent and who had demonstrated disease progression on the last therapy, wasdemonstrated in two open-label studies.

In study MMY2002, 106 patients with relapsed and refractory multiple myeloma received 16 mg/kg

DARZALEX until disease progression. The median patient age was 63.5 years (range, 31 to 84 years),11% of patients were ≥ 75 years of age, 49% were male and 79% were Caucasian. Patients hadreceived a median of 5 prior lines of therapy. Eighty percent of patients had received prior autologousstem cell transplantation (ASCT). Prior therapies included bortezomib (99%), lenalidomide (99%),pomalidomide (63%) and carfilzomib (50%). At baseline, 97% of patients were refractory to the lastline of treatment, 95% were refractory to both, a proteasome inhibitor (PI) and immunomodulatoryagent (IMiD), 77% were refractory to alkylating agents, 63% were refractory to pomalidomide and48% of patients were refractory to carfilzomib.

Efficacy results of the pre-planned interim analysis based on Independent Review Committee (IRC)assessment are presented in table 10 below.

Table 10: IRC assessed efficacy results for study MMY2002

Efficacy endpoint DARZALEX 16 mg/kg

N=106

Overall response rate1 (ORR: sCR+CR+VGPR+PR) [n (%)] 31 (29.2)95% CI (%) (20.8, 38.9)

Stringent complete response (sCR) [n (%)] 3 (2.8)

Complete response (CR) [n] 0

Very good partial response (VGPR) [n (%)] 10 (9.4)

Partial response (PR) [n (%)] 18 (17.0)

Clinical benefit rate (ORR+MR) [n (%)] 36 (34.0)

Median duration of response [months (95% CI)] 7.4 (5.5, NE)

Median time to response [months (range)] 1 (0.9; 5.6)1 Primary efficacy endpoint (International Myeloma Working Group criteria).

CI=confidence interval; NE=not estimable; MR=minimal response.

Overall response rate (ORR) in MMY2002 was similar regardless of type of prior anti-myelomatherapy.

At a survival update with a median duration of follow-up of 14.7 months, median OS was 17.5 months(95% CI: 13.7, not estimable).

In study GEN501, 42 patients with relapsed and refractory multiple myeloma received 16 mg/kg

DARZALEX until disease progression. The median patient age was 64 years (range, 44 to 76 years),64% were male and 76% were Caucasian. Patients in the study had received a median of 4 prior linesof therapy. Seventy-four percent of patients had received prior ASCT. Prior therapies includedbortezomib (100%), lenalidomide (95%), pomalidomide (36%) and carfilzomib (19%). At baseline,76% of patients were refractory to the last line of treatment, 64% were refractory to both a PI and

IMiD, 60% were refractory to alkylating agents, 36% were refractory to pomalidomide and 17% wererefractory to carfilzomib.

Pre-planned interim analysis showed that treatment with daratumumab at 16 mg/kg led to a 36% ORRwith 5% CR and 5% VGPR. The median time to response was 1 (range: 0.5 to 3.2) month. Themedian duration of response was not reached (95% CI: 5.6 months, not estimable).

At a survival update with a median duration of follow-up of 15.2 months, median OS was not reached(95% CI: 19.9 months, not estimable), with 74% of subjects still alive.

Combination treatment with lenalidomide

Study MMY3003, an open-label, randomised, active-controlled phase III study, compared treatmentwith DARZALEX 16 mg/kg in combination with lenalidomide and low-dose dexamethasone (DRd) totreatment with lenalidomide and low-dose dexamethasone (Rd) in patients with relapsed or refractorymultiple myeloma who had received at least one prior therapy. Lenalidomide (25 mg once daily orallyon days 1-21 of repeated 28-day [4-week] cycles) was given with low dose dexamethasone at40 mg/week (or a reduced dose of 20 mg/week for patients > 75 years or BMI < 18.5). On

DARZALEX infusion days, 20 mg of the dexamethasone dose was given as a pre-infusion medicinalproduct and the remainder given the day after the infusion. Treatment was continued in both arms untildisease progression or unacceptable toxicity.

A total of 569 patients were randomised; 286 to the DRd arm and 283 to the Rd arm. The baselinedemographic and disease characteristics were similar between the DARZALEX and the control arm.

The median patient age was 65 years (range 34 to 89 years) and 11% were ≥ 75 years. The majority ofpatients (86%) received a prior PI, 55% of patients had received a prior IMiD, including 18% ofpatients who had received prior lenalidomide; and 44% of patients had received both a prior PI and

IMiD. At baseline, 27% of patients were refractory to the last line of treatment. Eighteen percent(18%) of patients were refractory to a PI only, and 21% were refractory to bortezomib. Patientsrefractory to lenalidomide were excluded from the study.

With a median follow-up of 13.5 months, the primary analysis of PFS in study MMY3003demonstrated an improvement in the DRd arm as compared to the Rd arm; the median PFS had notbeen reached in the DRd arm and was 18.4 months in the Rd arm (HR=0.37; 95% CI: 0.27, 0.52;p < 0.0001). Results of an updated PFS analysis after a median follow-up of 55 months continued toshow an improvement in PFS for patients in the DRd arm compared with the Rd arm. Median PFSwas 45.0 months in the DRd arm and 17.5 months in the Rd arm (HR=0.44; 95% CI: 0.35, 0.54;p < 0.0001), representing a 56% reduction in the risk of disease progression or death in patients treatedwith DRd (see figure 6).

Figure 6: Kaplan-Meier curve of PFS in study MMY3003

After a median follow-up of 80 months, DRd has shown an OS advantage over the Rd arm (HR=0.73;95% CI: 0.58, 0.91; p=0.0044). The median OS was 67.6 months in the DRd arm and 51.8 months inthe Rd arm.

Figure 7: Kaplan-Meier curve of OS in study MMY3003

Additional efficacy results from study MMY3003 are presented in table 11 below.

Table 11: Additional efficacy results from study MMY3003

Response evaluable patient number DRd (n=281) Rd (n=276)

Overall response (sCR+CR+VGPR+PR) n(%) 261 (92.9) 211 (76.4)p-valuea < 0.0001

Stringent complete response (sCR) 51 (18.1) 20 (7.2)

Complete response (CR) 70 (24.9) 33 (12.0)

Very good partial response (VGPR) 92 (32.7) 69 (25.0)

Partial response (PR) 48 (17.1) 89 (32.2)

Median time to response [months (95% CI)] 1.0 (1.0, 1.1) 1.3 (1.1, 1.9)

Median duration of response [months (95% CI)] NE (NE, NE) 17.4 (17.4, NE)

MRD negative rate (95% CI) b (%) 21.0 (16.4, 26.2) 2.8 (1.2, 5.5)

Odds ratio with 95% CIc 9.31 (4.31, 20.09)

P-valued < 0.0001

DRd=daratumumab-lenalidomide-dexamethasone; Rd=lenalidomide-dexamethasone; MRD=minimal residual disease;

CI=confidence interval; NE=not estimable.a p-value from Cochran Mantel-Haenszel Chi-Squared test.b Based on Intent-to-treat population and threshold of 10-5.c Mantel-Haenszel estimate of the common odds ratio is used. An odds ratio > 1 indicates an advantage for DRd.d p-value is from a Fisher’s exact test.

Combination treatment with bortezomib

Study MMY3004, an open-label, randomised, active-controlled phase III study, compared treatmentwith DARZALEX 16 mg/kg in combination with bortezomib and dexamethasone (DVd), to treatmentwith bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myelomawho had received at least one prior therapy. Bortezomib was administered by subcutaneous injectionor intravenous injection at a dose of 1.3 mg/m2 body surface area twice weekly for two weeks (days 1,4, 8, and 11) of repeated 21 day (3-week) treatment cycles, for a total of 8 cycles. Dexamethasone wasadministered orally at a dose of 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of each of the 8 bortezomibcycles (80 mg/week for two out of three weeks of the bortezomib cycle) or a reduced dose of20 mg/week for patients > 75 years, BMI < 18.5, poorly controlled diabetes mellitus or priorintolerance to steroid therapy. On the days of DARZALEX infusion, 20 mg of the dexamethasonedose was administered as a pre-infusion medicinal product. DARZALEX treatment was continueduntil disease progression or unacceptable toxicity.

A total of 498 patients were randomised; 251 to the DVd arm and 247 to the Vd arm. The baselinedemographic and disease characteristics were similar between the DARZALEX and the control arm.

The median patient age was 64 years (range 30 to 88 years) and 12% were ≥ 75 years.

Sixty-nine percent (69%) of patients had received a prior PI (66% received bortezomib) and 76% ofpatients received an IMiD (42% received lenalidomide). At baseline, 32% of patients were refractoryto the last line of treatment. Thirty-three percent (33%) of patients were refractory to an IMiD only,and 28% were refractory to lenalidomide. Patients refractory to bortezomib were excluded from thestudy.

With a median follow-up of 7.4 months, the primary analysis of PFS in study MMY3004demonstrated an improvement in the DVd arm as compared to the Vd arm; the median PFS had notbeen reached in the DVd arm and was 7.2 months in the Vd arm (HR [95% CI]: 0.39 [0.28, 0.53];p-value < 0.0001). Results of an updated PFS analysis after a median follow-up of 50 monthscontinued to show an improvement in PFS for patients in the DVd arm compared with the Vd arm.

Median PFS was 16.7 months in the DVd arm and 7.1 months in the Vd arm (HR [95% CI]: 0.31[0.24, 0.39]; p-value < 0.0001), representing a 69% reduction in the risk of disease progression ordeath in patients treated with DVd versus Vd (see figure 8).

Figure 8: Kaplan-Meier curve of PFS in study MMY3004

After a median follow-up of 73 months, DVd has shown an OS advantage over the Vd arm (HR=0.74;95% CI: 0.59, 0.92; p=0.0075). The median OS was 49.6 months in the DVd arm and 38.5 months inthe Vd arm.

Figure 9: Kaplan-Meier curve of OS in study MMY3004

Additional efficacy results from study MMY3004 are presented in table 12 below.

Table 12: Additional efficacy results from study MMY3004

Response evaluable patient number DVd (n=240) Vd (n=234)

Overall response (sCR+CR+VGPR+PR) n(%) 199 (82.9) 148 (63.2)

P-valuea < 0.0001

Stringent complete response (sCR) 11 (4.6) 5 (2.1)

Complete response (CR) 35 (14.6) 16 (6.8)

Very good partial response (VGPR) 96 (40.0) 47 (20.1)

Partial response (PR) 57 (23.8) 80 (34.2)

Median time to response [months (range)] 0.9 (0.8, 1.4) 1.6 (1.5, 2.1)

Median duration of response [months (95% CI)] NE (11.5, NE) 7.9 (6.7, 11.3)

MRD negative rate (95% CI)b 8.8% (5.6%, 13.0%) 1.2% (0.3%, 3.5%)

Odds ratio with 95% CIc 9.04 (2.53, 32.21)

P-valued 0.0001

DVd=daratumumab- bortezomib-dexamethasone; Vd=bortezomib-dexamethasone; MRD=minimal residual disease;

CI=confidence interval; NE=not estimable.a p-value from Cochran Mantel-Haenszel Chi-Squared test.b Based on Intent-to-treat population and threshold of 10-5.c Mantel-Haenszel estimate of the common odds ratio is used. An odds ratio > 1 indicates an advantage for DVd.d p-value is from Fisher’s exact test.

Daratumumab as a large protein has a low likelihood of direct ion channel interactions. The effect ofdaratumumab on the QTc interval was evaluated in an open-label study for 83 patients (study

GEN501) with relapsed and refractory multiple myeloma following daratumumab infusions (4 to24 mg/kg). Linear mixed PK-PD analyses indicated no large increase in mean QTcF interval (i.e.greater than 20 ms) at daratumumab Cmax.

The European Medicines Agency has waived the obligation to submit the results of studies with

DARZALEX in all subsets of the paediatric population in multiple myeloma (see section 4.2 forinformation on paediatric use).

The pharmacokinetics (PK) of daratumumab following intravenous administration of daratumumabmonotherapy were evaluated in patients with relapsed and refractory multiple myeloma at dose levelsfrom 0.1 mg/kg to 24 mg/kg.

In the 1 to 24 mg/kg cohorts, peak serum concentrations (Cmax) after the first dose increased inapproximate proportion to dose and volume of distribution was consistent with initial distribution intothe plasma compartment. Following the last weekly infusion, Cmax increased in a greater thandose-proportional manner, consistent with target mediated drug disposition. Increases in AUC weremore than dose-proportional and clearance (CL) decreased with increasing dose. These observationssuggest CD38 may become saturated at higher doses, after which the impact of target bindingclearance is minimised and the clearance of daratumumab approximates the linear clearance ofendogenous IgG1. Clearance also decreased with multiple doses, which may be related to tumourburden decreases.

Terminal half-life increases with increasing dose and with repeated dosing. The mean (standarddeviation [SD]) estimated terminal half-life of daratumumab following the first 16 mg/kg dose was9 (4.3) days. The estimated terminal half-life of daratumumab following the last 16 mg/kg doseincreased, but there are insufficient data for a reliable estimation. Based on population PK analysis, themean (SD) half-life associated with non-specific linear elimination was approximately 18 (9) days;this is the terminal half-life that can be expected upon complete saturation of target mediated clearanceand repeat dosing of daratumumab.

At the end of weekly dosing for the recommended monotherapy schedule and dose of 16 mg/kg, themean (SD) serum Cmax value was 915 (410.3) micrograms/mL, approximately 2.9-fold higher thanfollowing the first infusion. The mean (SD) predose (trough) serum concentration at the end of weeklydosing was 573 (331.5) micrograms/mL.

Four population PK analyses were performed to describe the PK characteristics of daratumumab andto evaluate the influence of covariates on the disposition of daratumumab in patients with multiplemyeloma; analysis 1 (n=223) in patients receiving DARZALEX monotherapy while analysis 2(n=694), analysis 3 (n=352) and analysis 4 (n=355) were conducted in patients with multiple myelomathat received daratumumab combination therapies. Analysis 2 included 694 patients (n=326 forlenalidomide-dexamethasone; n=246 for bortezomib-dexamethasone; n=99 for pomalidomide-dexamethasone; n=11 for bortezomib-melphalan-prednisone; and n=12 for bortezomib-thalidomide-dexamethasone), analysis 3 included 352 patients (bortezomib-melphalan-prednisone) and analysis 4included 355 patients (lenalidomide-dexamethasone).

Based on the population PK analysis of daratumumab monotherapy (analysis 1), daratumumab steadystate is achieved approximately 5 months into the every 4-week dosing period (by the 21st infusion),and the mean (SD) ratio of Cmax at steady-state to Cmax after the first dose was 1.6 (0.5). The mean (SD)central volume of distribution is 56.98 (18.07) mL/kg.

Three additional population PK analyses (analysis 2, analysis 3 and analysis 4) were conducted inpatients with multiple myeloma that received daratumumab combination therapies. Daratumumabconcentration-time profiles were similar following the monotherapy and combination therapies. Themean estimated terminal half-life associated with linear clearance in combination therapy wasapproximately 15-23 days.

Based on the four population PK analyses (analyses 1-4) body weight was identified as a statisticallysignificant covariate for daratumumab clearance. Therefore, body weight based dosing is anappropriate dosing strategy for the multiple myeloma patients.

Simulation of daratumumab pharmacokinetics was conducted for all recommended dosing schedulesin 1309 patients with multiple myeloma. The simulation results confirmed that the split and singledosing for the first dose provide similar PK, with the exception of the PK profile in the first day of thetreatment.

Age and gender

Based on four individual population PK analyses (1-4) in patients receiving daratumumabmonotherapy or various combination therapies (analyses 1-4), age (range: 31-93 years) had noclinically important effect on the PK of daratumumab, and the exposure of daratumumab was similarbetween younger (aged < 65 years, n=518) and older (aged ≥ 65 to < 75 years n=761; aged ≥ 75 years,n=334) patients.

Gender did not affect exposure of daratumumab to a clinically relevant degree in the population PKanalyses.

No formal studies of daratumumab in patients with renal impairment have been conducted. Fourindividual population PK analyses were performed based on pre-existing renal function data inpatients receiving daratumumab monotherapy, or various combination therapies (Analyses 1-4), andincluded a total of 441 patients with normal renal function (creatinine clearance [CRCL]≥ 90 mL/min), 621 with mild renal impairment (CRCL < 90 and ≥ 60 mL/min), 523 with moderaterenal impairment (CRCL < 60 and ≥ 30 mL/min), and 27 with severe renal impairment or end stagerenal disease (CRCL < 30 mL/min). No clinically important differences in exposure to daratumumabwere observed between patients with renal impairment and those with normal renal function.

No formal studies of daratumumab in patients with hepatic impairment have been conducted. Changesin hepatic function are unlikely to have any effect on the elimination of daratumumab since IgG1molecules such as daratumumab are not metabolised through hepatic pathways.

Four individual population PK analyses were performed in patients receiving daratumumabmonotherapy or various combination therapies (Analyses 1-4), and included a total of 1404 patientswith normal hepatic function (total bilirubin [TB] and aspartate aminotransferase [AST] ≤ upper limitof normal [ULN]), 189 with mild hepatic impairment (TB 1.0 x to 1.5 x ULN or AST > ULN) and8 patients with moderate (TB > 1.5 x to 3.0 x ULN; n=7), or severe (TB > 3.0 x ULN; n=1) hepaticimpairment. No clinically important differences in the exposure to daratumumab were observedbetween patients with hepatic impairment and those with normal hepatic function.

Based on four individual population PK analyses in patients receiving either daratumumabmonotherapy or various combination therapies (analyses 1-4), the exposure to daratumumab wassimilar between white (n=1371) and non-white subjects (n=242).

Toxicology data have been derived from studies with daratumumab in chimpanzees and with asurrogate anti-CD38 antibody in cynomolgus monkeys. No chronic toxicity testing has beenconducted.

No animal studies have been performed to establish the carcinogenic potential of daratumumab.

No animal studies have been performed to evaluate the potential effects of daratumumab onreproduction or development.

No animal studies have been performed to determine potential effects on fertility in males or females.

L-histidine

L-histidine hydrochloride monohydrate

L-methionine

Polysorbate 20

Sorbitol (E420)

Water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

Unopened vials3 years.

From a microbiological point of view, unless the method of opening/ dilution precludes the risk ofmicrobial contamination, the product should be used immediately. If not used immediately, in-usestorage times and conditions are the responsibility of the user and should be no more than 24 hours atrefrigerated conditions (2 °C-8 °C) protected from light, followed by 15 hours (including infusiontime) at room temperature (15 °C-25 °C) and room light. If stored in the refrigerator, allow thesolution to reach ambient temperature before administration.

Store in a refrigerator (2 °C-8 °C).

Do not freeze.

Store in the original package in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

5 mL concentrate in a type 1 glass vial with an elastomeric closure and an aluminium seal with aflip-off button containing 100 mg of daratumumab. Pack size of 1 vial.

20 mL concentrate in a type 1 glass vial with an elastomeric closure and an aluminium seal with aflip-off button containing 400 mg of daratumumab. Pack size of 1 vial.

DARZALEX is also supplied as an initiation pack containing 11 vials: (6 x 5 mL vials + 5 x 20 mLvials).

This medicinal product is for single-use only.

Prepare the solution for infusion using aseptic technique as follows:

- Calculate the dose (mg), total volume (mL) of DARZALEX solution required and the numberof DARZALEX vials needed based on patient weight.

- Check that the DARZALEX solution is colourless to yellow. Do not use if opaque particles,discolouration or other foreign particles are present.

- Using aseptic technique, remove a volume of sodium chloride 9 mg/mL (0.9%) solution forinjection from the infusion bag/container that is equal to the required volume of DARZALEXsolution.

- Withdraw the necessary amount of DARZALEX solution and dilute to the appropriate volumeby adding to an infusion bag/container containing sodium chloride 9 mg/mL (0.9%) solution forinjection (see section 4.2). Infusion bags/containers must be made of polyvinylchloride (PVC),polypropylene (PP), polyethylene (PE) or polyolefin blend (PP+PE). Dilute under appropriateaseptic conditions. Discard any unused portion left in the vial.

- Gently invert the bag/container to mix the solution. Do not shake.

- Visually inspect parenteral medicinal products for particulate matter and discolouration prior toadministration. The diluted solution may develop very small, translucent to white proteinaceousparticles, as daratumumab is a protein. Do not use if visibly opaque particles, discolouration orforeign particles are observed.

- Since DARZALEX does not contain a preservative, diluted solutions should be administeredwithin 15 hours (including infusion time) at room temperature (15 °C-25 °C) and in room light.

- If not used immediately, the diluted solution can be stored prior to administration for up to24 hours at refrigerated conditions (2 °C-8 °C) and protected from light. Do not freeze. If storedin the refrigerator, allow the solution to reach ambient temperature before administration.

- Administer the diluted solution by intravenous infusion using an infusion set fitted with a flowregulator and with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone(PES) filter (pore size 0.22 or 0.2 micrometre). Polyurethane (PU), polybutadiene (PBD), PVC,

PP or PE administration sets must be used.

- Do not infuse DARZALEX concomitantly in the same intravenous line with other agents.

- Do not store any unused portion of the infusion solution for reuse. Any unused product or wastematerial should be disposed of in accordance with local requirements.

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

EU/1/16/1101/001

EU/1/16/1101/002

EU/1/16/1101/003

Date of first authorisation: 20 May 2016

Date of latest renewal: 06 January 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.