4.1. Therapeutic indications

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.

4.2. Posology and method of administration

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. See below “Recommended concomitant medicinal products”, “Management of infusion‑related reactions” and section 4.4.

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).

For dose and schedule of medicinal products administered with DARZALEX, see section 5.1 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. For information on the VMP dose and dosing schedule when administered with DARZALEX, see section 5.1.

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

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.

For dose and schedule of medicinal products administered with DARZALEX, see section 5.1 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

Dexamethasone should be administered at 20 mg on days 1, 2, 4, 5, 8, 9, 11 and 12 of the first 8 bortezomib 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 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.

To facilitate administration, the first prescribed 16 mg/kg dose at week 1 may be split over two consecutive 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 volume

Initial rate (first hour)

Rate incrementa

Maximum rate

Week 1 Infusion

Option 1 (Single dose infusion)

Week 1 day 1 (16 mg/kg)

1,000 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. Otherwise, use a dilution volume of 1,000 mL.

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

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

• Grade 1‑2 (mild to moderate): Once reaction symptoms resolve, the infusion should be resumed at no more than half the rate at which the IRR occurred. If the patient does not experience any further IRR symptoms, infusion rate escalation may be resumed at increments and intervals as clinically 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 considered at no more than half the rate at which the reaction occurred. If the patient does not experience additional symptoms, infusion rate escalation may be resumed at increments and intervals as appropriate (table 5). The procedure above should be repeated in the event of recurrence of grade 3 symptoms. Permanently discontinue DARZALEX upon the third occurrence of a grade 3 or greater infusion reaction.

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

Missed dose

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

Dose modifications

No dose reductions of DARZALEX are recommended. Dose delay may be required to allow recovery of blood cell counts in the event of haematological toxicity (see section 4.4). For information concerning medicinal products given in combination with DARZALEX, see corresponding Summary of 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 the second infusion, the dose of corticosteroid may be reduced (oral or intravenous methylprednisolone 60 mg).

- Combination therapy:

Dexamethasone 20 mg (or equivalent), administered prior to every DARZALEX infusion. When dexamethasone is the background‑regimen specific corticosteroid, the dexamethasone 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 oral administration may be considered prior to subsequent infusions. Additional background regimen specific corticosteroids (e.g. prednisone) should not be taken on DARZALEX infusion days when patients have received dexamethasone as a pre-infusion medicinal product.

• Antipyretics (oral paracetamol 650 to 1,000 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 as follows:

- Monotherapy:

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

- Combination therapy:

Consider administering low-dose oral methylprednisolone (≤20 mg) or equivalent the day after the DARZALEX infusion. However, if a background regimen-specific corticosteroid (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 of post‑infusion medicinal products including short and long acting bronchodilators, and inhaled corticosteroids should be considered. Following the first four infusions, if the patient experiences no major IRRs, these inhaled post‑infusion medicinal products may be discontinued at the discretion of the physician.

Prophylaxis for herpes zoster virus reactivation

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

Special populations

Renal impairment

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

Hepatic impairment

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 hepatic impairment (see section 5.2).

Elderly

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

Paediatric population

DARZALEX is not recommended for use in children below 18 years of age as efficacy has not been established. Currently available data in paediatric patients with relapsed or refractory B-cell or T-cell acute lymphoblastic leukaemia (ALL) or lymphoblastic lymphoma (LL) are described in sections 4.8, 5.1 and 5.2.

Method of administration

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

4.3. Contraindications

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

4.4. Special warnings and precautions for use

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/thrombocytopenia

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

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.

Infections

DARZALEX can cause serious, life-threatening, or fatal infections (see section 4.8).

Patients should be closely monitored for signs and symptoms of infection prior to and during treatment with DARZALEX and treated appropriately. Prophylactic antimicrobials according to treatment guidelines should be considered prior to, during or post-treatment (see section 4.2).

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.

In the event of a planned transfusion blood transfusion centres should be notified of this interference with 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 serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M‑protein (see section 4.5). 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) (see section 2). 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 medicinal product.

4.5. Interaction with other medicinal products and other forms of interaction

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.

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.

4.6. Fertility, pregnancy and lactation

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/abstain from breast‑feeding or to discontinue 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).

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

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.

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 (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000) and very rare (<1/10,000). Within each frequency groupingadverse 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

Bronchitisa

17

2

Pneumoniaa

19

11

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

Anaphylactic reactionb

Rare

-

-

Hypogammaglobulinaemiaa

Common

3

<1*

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*

Nervous system disorders

Peripheralneuropathya

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 a

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.

The median time to onset of a reaction was 1.5 hours (range: 0 to 72.8 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. Other adverse IRRs included nasal congestion, cough, chills, throat irritation, blurred vision, vomiting and nausea (see section 4.4).

When DARZALEX dosing was interrupted in the setting of ASCT (Study MMY3006) for a median of 3.75 (range: 2.4; 6.9) 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) were administered the first 16 mg/kg daratumumab dose at week 1 split over two days i.e. 8 mg/kg on day 1 and day 2 respectively. The incidence of any grade IRRs was 42%, with 36% of patients experiencing IRRs on day 1 of week 1, 4% on day 2 of week 1, and 8% with subsequent infusions. The median time to onset of a reaction was 1.8 hours (range: 0.1 to 5.4 hours). The incidence of infusion interruptions due to reactions 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.

Infections

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

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 active-controlled 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 as follows:

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 be performed in clinical studies and post-marketing safety data.

Other special populations

In the phase III study MMY3007, which compared treatment with D-VMP to treatment with VMP in patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant, 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).

Elderly patients

Of the 2459 patients who received DARZALEX at the recommended dose, 38% were 65 to 75 years of age, and 15% were 75 years of age or older. No overall differences in effectiveness were observed based 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 serious adverse reactions that occurred more frequently in elderly (≥ 65 years of age) were pneumonia and sepsis. Among patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant (n=710), the most common serious adverse reaction that occurred more frequently in elderly (≥ 75 years of age) was pneumonia.

Paediatric population

The safety assessment in paediatric patients is based on the limited safety data from a phase II study ALL2005 to evaluate safety and efficacy of DARZALEX in paediatric and young adult patients (ages 1 to 30 years) with relapsed or refractory B-cell or T-cell acute lymphoblastic leukaemia (ALL) or lymphoblastic lymphoma (LL) (see section 5.1). No new safety signal was observed in this study.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms and signs

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

Treatment

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