DARZALEX 20 mg/mL concentrate for solution for infusion.

  • Name:

    DARZALEX 20 mg/mL concentrate for solution for infusion.

  • Company:
    info
  • Active Ingredients:

    Daratumumab

  • Legal Category:

    Product subject to medical prescription which may not be renewed (A)

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 20/08/20

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Summary of Product Characteristics last updated on medicines.ie: 20/8/2020
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

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Janssen Sciences Ireland

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When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 20 August 2020 PIL

Reasons for updating

  • Change to section 4 - possible side effects
  • Change to section 6 - date of revision

Updated on 20 August 2020 SmPC

Reasons for updating

  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

4.8     Undesirable effects

 

Summary of the safety profile

The most frequent adverse reactions of any grade (≥20 % patients) with daratumumab (either intravenous or subcutaneous formulations) when administered either as monotherapy or combination treatment were IRRs, fatigue, nausea, diarrhoea, constipation, pyrexia, cough, neutropenia, thrombocytopenia, anaemia, oedema peripheral, peripheral sensory neuropathy and upper respiratory tract infection. Serious adverse reactions were pneumonia, bronchitis, upper respiratory tract infection, sepsis, pulmonary oedema, influenza, pyrexia, dehydration, diarrhoea and atrial fibrillation.

 

…………………

 

System Organ Class

Adverse reaction

Frequency

Incidence (%)

Any Grade

Grade 3-4

Infections and infestations

Upper respiratory tract infectiona

Very Common

38%

2%

Bronchitisa

Very Common

14%

2%

Pneumoniaa

Very Common

14%

9%

Urinary tract infection

Common

7%

1%

Influenza

Common

4%

1%#

Sepsisa

Common

4%

3%

 

 

………………………..

 

Infections

In patients receiving DARZALEX subcutaneous formulation as monotherapy, incidence of infections was similar between DARZALEX subcutaneous formulation (52.9%) versus intravenous daratumumab groups (50.0%). Additionally, Grade 3 or 4 infections also occurred at similar frequencies between DARZALEX subcutaneous formulation (11.7%) and intravenous daratumumab (14.3%). Most infections were manageable and rarely led to treatment discontinuation. Pneumonia was the most commonly reported severe (Grade 3 or 4) infection across studies.

 

In patients receiving intravenous daratumumab combination therapy, Grade 3 or 4 infections were reported with intravenous daratumumab combinations and background therapies (as follows:

Relapsed/refractory patient studies: DVd: 21%, Vd: 19%; DRd: 27%, Rd: 23%; D‑VMP: 23%, VMP: 15%; 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, Ddiscontinuations from treatment due to infections were reportedoccurred in 1-4% to 5% of patients. Fatal infections were generally balanced between the intravenous daratumumab containing regimens and active control arms (<2%) in the controlled studies and were primarily due to pneumonia and sepsis.

In patients receiving intravenous daratumumab 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.

 

 

………………….

 

Elderly patients

Of the 3207 patients who received daratumumab (n=490 subcutaneous; n=2717 intravenous) at the recommended dose, 38% were 65 to 75 years of age, and 17% 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=1827), 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=777), the most common serious adverse reaction that occurred more frequently in elderly (≥75 years of age) was pneumonia.

 

Updated on 23 July 2020 SmPC

Reasons for updating

  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

 

 

Immunogenicity

In patients treated with intravenous daratumumab in clinical trials, less than 1% of patients developed treatment-emergent anti-daratumumab antibodies.Patients treated with daratumumab monotherapy (n=199) and combination therapy (n=1051) were evaluated for anti‑therapeutic antibody responses to daratumumab at multiple time points during treatment and up to 8 weeks following the end of treatment. Following the start of daratumumab treatment, none of the monotherapy patients and 2 of the 1051 combination therapy patients tested positive for anti‑daratumumab antibodies; 1 of the combination therapy patients developed transient neutralising antibodies against daratumumab.

However, the employed assay has limitations in detecting anti‑daratumumab antibodies in the presence of high concentrations of daratumumab. Therefore, the incidence of antibody development might not have been reliably determined

Updated on 10 July 2020 Ed-Both

Reasons for updating

  • Add New Doc

Updated on 10 July 2020 Ed-HCP

Reasons for updating

  • Add New Doc

Updated on 10 July 2020 Ed-HCP

Reasons for updating

  • Add New Doc

Updated on 22 April 2020 SmPC

Reasons for updating

  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

5.1     Pharmacodynamic properties

 ………….

 

A total of 706 patients were randomised: 350 to the D-VMP arm and 356 to the VMP arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The median age was 71 (range: 40-93) years, with 30% of the patients ≥75 years of age. The majority were white (85%), female (54%), 25% had an ECOG performance score of 0, 50% had an ECOG performance score of 1 and 25% had an ECOG performance score of 2. Patients had IgG/IgA/Light chain 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 followup of 16.5 months, Tthe primary analysis of PFS in Study MMY3007 showed an improvement in the D-VMP arm as compared to the VMP arm; the median PFS had not been reached in 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)., representing 50% reduction in the risk of disease progression or death in patients treated with D-VMP. Results of an updated PFS analysis approximately 4 months after the original clinical cutoff, continued to show an improvement in PFS for patients in the D-VMP arm compared with the VMP arm. Median PFS was not reached in the D-VMP arm and was 19.3 months in the VMP arm (HR=0.46; 95% CI: 0.36, 0.60; p<0.0001). Results of an updated PFS analysis after a median followup of 40 months continued to show an improvement in PFS for patients in the DVMP arm compared with the VMP arm. Median PFS was 36.4 months in the DVMP 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 treated with DVMP.

 

Figure 2:        Kaplan-Meier Curve of Primary Analysis of PFS in Study MMY3007

 

 

After a median followup of 40 months, DVMP has shown an overall survival (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 patients treated in the DVMP arm. Median OS was not reached for either arm.

 

 

……………………

 

With a median followup of 13.5 months, the primary analysis of PFS in Sstudy MMY3003 demonstrated an improvement in PFS in the DRd arm as compared to the Rd arm; the median PFS had not been 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)., representing 63% reduction in the risk of disease progression or death in patients treated with DRd Results of an updated PFS analysis after a median followup of 55 months continued to show an improvement in PFS for patients in the DRd arm compared with the Rd arm. Median PFS was 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 treated with DRd (see Figure 34).

 

Figure 34:      Kaplan-Meier Curve of PFS in Study MMY3003

 

 

……..

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 (%)

29.021.0 (23.816.4, 34.726.2)

7.82.8 (4.91.2, 11.55.5)

Odds ratio with 95% CIc

4.859.31 (2.934.31, 8.0320.09)

 

P-valued

< 0.000001

 

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 10-4

c    A Chi-Squared MantelHaenszel estimate of the common odds ratio is used. An odds ratio >1 indicates an advantage for DRd.

d     p-value is from a likelihood-ratio Chi-SquaredFisher’s exact test.

………….

 

 

With a median followup of 7.4 months, the primary analysis of PFS in Sstudy MMY3004 demonstrated an improvement in PFS in the DVd arm as compared to the Vd arm; the median PFS had not been 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), representing a 61% reduction in the risk of disease progression or death for patients treated with DVd versus Vd. Results of an updated PFS analysis after a median followup of 50 months continued 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 or death in patients treated with DVd versus Vd (see Figure 45).

 

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

13.58.8% (9.65.6%, 18.413.0%)

2.81.2% (1.10.3%, 5.83.5%)

Odds ratio with 95% CIc

5.379.04 (2.332.53, 12.3732.21)

 

P-valued

0.0000060.0001

 

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 10-4

c     A Chi-Squared Mantel-Haenszel estimate of the common odds ratio is used. An odds ratio > 1 indicates an advantage for DVd.

d     p-value is from a likelihood-ratio chi-squaredFisher’s exact test.

 

Updated on 22 January 2020 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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
    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

 

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

 

 

4.8       Undesirable effects

 

Summary of the safety profile

The most frequent adverse reactions (≥ 20%) were infusion reactions, fatigue, nausea, diarrhoea, constipation, pyrexia, dyspnoea, cough, back pain, neutropenia, thrombocytopenia, anaemia, oedema peripheral, asthenia, peripheral sensory neuropathy and upper respiratory tract infection. Serious adverse reactions were pneumonia, bronchitis, upper respiratory tract infection, pulmonary oedema, influenza, pyrexia, dehydration, diarrhoea and atrial fibrillation.

 

Tabulated list of adverse reactions

Table 5 6 summarises the adverse drug reactions that occurred in patients receiving DARZALEX. The data reflects exposure to DARZALEX (16 mg/kg) in 1530 2066 patients with multiple myeloma including 1374 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 mobilization, 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 grouping, where relevant, adverse reactions are presented in order of decreasing seriousness.

 

 

Table 56:    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

Pneumoniaa

Very Common

1816

1210

Bronchitisa

1617

2

Upper respiratory tract infectiona

4641

3

Urinary tract infection

Common

98

21

Influenza

5

1*

Hepatitis B Virus reactivationb

Uncommon

-

-

Blood and lymphatic system disorders

Neutropeniaa

Very Common

4845

4139

Thrombocytopeniaa

3531

2219

Anaemiaa

3227

1512

Lymphopeniaa

1214

1011

Leukopeniaa

1412

86

Immune system disorders

Anaphylactic reactionb

Rare

-

-

Metabolism and nutrition disorders

Decreased appetite

Very Common

1412

1*

Hyperglycemia

Common

97

43

Hypocalcemia

76

21

Dehydration

3

1*

Nervous system disorders

Peripheral sensory neuropathy

Very Common

 

2332

32

Paraesthesia

11

< 1

Headache

1312

< 1*

Paraesthesia

Common

7

< 1

Cardiac disorders

Atrial fibrillation

Common

4

21

Vascular disorders

Hypertensiona

Very Common

1110

5

Respiratory, thoracic and mediastinal disorders

Cougha

Very Common

2825

< 1*

Dyspnoeaa

2221

3

Pulmonary oedemaa

Common

1

<1

Gastrointestinal disorders

Diarrhoea

Very Common

3732

4

Constipation

2733

1

Nausea

2426

1*2*

Vomiting

16

1*

Pancreatitisa

Common

1

1

Musculoskeletal and connective tissue disorders

Back pain

Very Common

2119

2

Muscle spasms

1714

< 1*

General disorders and administration site conditions

Fatigue

Very Common

3126

54

Oedema peripherala

2526

1

Pyrexia

2123

1*2

Asthenia

1721

2

Chills

Common

9

< 1*

Injury, poisoning and procedural complications

Infusion‑related reactionc

Very Common

4240

54

*   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

 

Infusion‑related reactions

In clinical trials…….. 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.

….

 

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: 27%, 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 the active controlled studies, discontinuations from treatment due to infections (1-4%) and fatal infections were generally infrequent and balanced between the DARZALEX containing regimens and active control arms. Fatal infections were primarily due to pneumonia and sepsis.

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

 

5.       PHARMACOLOGICAL PROPERTIES

 

5.1     Pharmacodynamic properties

 

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

Study MMY3006 is a 2 Part, open-label, randomized, active-controlled Phase 3 study. Part 1 compared induction and consolidation treatment with DARZALEX 16 mg/kg in combination with bortezomib, thalidomide and dexamethasone (D-VTd) to treatment with bortezomib, thalidomide and dexamethasone (VTd) in patients with newly diagnosed multiple myeloma eligible for ASCT. The consolidation phase of treatment began a minimum of 30 days post-ASCT, when the patient had recovered sufficiently, and engraftment was complete. In Part 2, subjects with at least a partial response (PR) by Day 100 post-transplant were re-randomized in a 1:1 ratio to daratumumab maintenance or observation only. Only results from Part 1 are described henceforth.

 

Bortezomib was administered by SC injection or IV 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 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 six bortezomib 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 in Cycles 5 and 6. On the days of DARZALEX infusion, the dexamethasone dose was administered intravenously as a pre-infusion medication. Dose adjustments for bortezomib, thalidomide and dexamethasone were applied according to manufacturer’s prescribing information.

 

A total of 1085 patients were randomized: 543 to the D-VTd arm and 542 to the VTd arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The median 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 majority were male (59%), 48% had an ECOG performance score of 0, 42% had an ECOG performance score of 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 Progression free survival (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 (sCR+CR+VGPR)

453 (83.4%)

423 (78.0%)

 

MRD negativityc, d n(%)

346 (63.7%)

236 (43.5%)

<0.0001

95% 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 betterc n(%)

183 (33.7%)

108 (19.9%)

<0.0001

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.

 

Results of a PFS analysis by censoring patients who were randomized to daratumumab maintenance in the second randomization, at the date of the second randomization showed HR=0.50; 95% CI: 0.34, 0.75; p=0.0005.

 

 

 

 

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
    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

 

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

 

 

4.8       Undesirable effects

 

Summary of the safety profile

The most frequent adverse reactions (≥ 20%) were infusion reactions, fatigue, nausea, diarrhoea, constipation, pyrexia, dyspnoea, cough, back pain, neutropenia, thrombocytopenia, anaemia, oedema peripheral, asthenia, peripheral sensory neuropathy and upper respiratory tract infection. Serious adverse reactions were pneumonia, bronchitis, upper respiratory tract infection, pulmonary oedema, influenza, pyrexia, dehydration, diarrhoea and atrial fibrillation.

 

Tabulated list of adverse reactions

Table 5 6 summarises the adverse drug reactions that occurred in patients receiving DARZALEX. The data reflects exposure to DARZALEX (16 mg/kg) in 1530 2066 patients with multiple myeloma including 1374 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 mobilization, 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 grouping, where relevant, adverse reactions are presented in order of decreasing seriousness.

 

 

Table 56:    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

Pneumoniaa

Very Common

1816

1210

Bronchitisa

1617

2

Upper respiratory tract infectiona

4641

3

Urinary tract infection

Common

98

21

Influenza

5

1*

Hepatitis B Virus reactivationb

Uncommon

-

-

Blood and lymphatic system disorders

Neutropeniaa

Very Common

4845

4139

Thrombocytopeniaa

3531

2219

Anaemiaa

3227

1512

Lymphopeniaa

1214

1011

Leukopeniaa

1412

86

Immune system disorders

Anaphylactic reactionb

Rare

-

-

Metabolism and nutrition disorders

Decreased appetite

Very Common

1412

1*

Hyperglycemia

Common

97

43

Hypocalcemia

76

21

Dehydration

3

1*

Nervous system disorders

Peripheral sensory neuropathy

Very Common

 

2332

32

Paraesthesia

11

< 1

Headache

1312

< 1*

Paraesthesia

Common

7

< 1

Cardiac disorders

Atrial fibrillation

Common

4

21

Vascular disorders

Hypertensiona

Very Common

1110

5

Respiratory, thoracic and mediastinal disorders

Cougha

Very Common

2825

< 1*

Dyspnoeaa

2221

3

Pulmonary oedemaa

Common

1

<1

Gastrointestinal disorders

Diarrhoea

Very Common

3732

4

Constipation

2733

1

Nausea

2426

1*2*

Vomiting

16

1*

Pancreatitisa

Common

1

1

Musculoskeletal and connective tissue disorders

Back pain

Very Common

2119

2

Muscle spasms

1714

< 1*

General disorders and administration site conditions

Fatigue

Very Common

3126

54

Oedema peripherala

2526

1

Pyrexia

2123

1*2

Asthenia

1721

2

Chills

Common

9

< 1*

Injury, poisoning and procedural complications

Infusion‑related reactionc

Very Common

4240

54

*   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

 

Infusion‑related reactions

In clinical trials…….. 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.

….

 

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: 27%, 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 the active controlled studies, discontinuations from treatment due to infections (1-4%) and fatal infections were generally infrequent and balanced between the DARZALEX containing regimens and active control arms. Fatal infections were primarily due to pneumonia and sepsis.

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

 

5.       PHARMACOLOGICAL PROPERTIES

 

5.1     Pharmacodynamic properties

 

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

Study MMY3006 is a 2 Part, open-label, randomized, active-controlled Phase 3 study. Part 1 compared induction and consolidation treatment with DARZALEX 16 mg/kg in combination with bortezomib, thalidomide and dexamethasone (D-VTd) to treatment with bortezomib, thalidomide and dexamethasone (VTd) in patients with newly diagnosed multiple myeloma eligible for ASCT. The consolidation phase of treatment began a minimum of 30 days post-ASCT, when the patient had recovered sufficiently, and engraftment was complete. In Part 2, subjects with at least a partial response (PR) by Day 100 post-transplant were re-randomized in a 1:1 ratio to daratumumab maintenance or observation only. Only results from Part 1 are described henceforth.

 

Bortezomib was administered by SC injection or IV 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 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 six bortezomib 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 in Cycles 5 and 6. On the days of DARZALEX infusion, the dexamethasone dose was administered intravenously as a pre-infusion medication. Dose adjustments for bortezomib, thalidomide and dexamethasone were applied according to manufacturer’s prescribing information.

 

A total of 1085 patients were randomized: 543 to the D-VTd arm and 542 to the VTd arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The median 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 majority were male (59%), 48% had an ECOG performance score of 0, 42% had an ECOG performance score of 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 Progression free survival (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 (sCR+CR+VGPR)

453 (83.4%)

423 (78.0%)

 

MRD negativityc, d n(%)

346 (63.7%)

236 (43.5%)

<0.0001

95% 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 betterc n(%)

183 (33.7%)

108 (19.9%)

<0.0001

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.

 

Results of a PFS analysis by censoring patients who were randomized to daratumumab maintenance in the second randomization, at the date of the second randomization showed HR=0.50; 95% CI: 0.34, 0.75; p=0.0005.

 

 

 

 

Updated on 22 January 2020 PIL

Reasons for updating

  • Change to section 4 - possible side effects
  • Change to section 6 - date of revision

Updated on 20 November 2019 PIL

Reasons for updating

  • Change to section 4 - possible side effects
  • Change to section 6 - date of revision

Updated on 20 November 2019 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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.
  • 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.
  • 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 medications should be administered to reduce the risk of infusion‑related reactions (IRRs) with daratumumab. See below “Recommended concomitant medications”, “Management of infusion‑related reactions” and section 4.4.

 

 

Posology

Dosing schedule in combination with lenalidomide (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 (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

 

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

 

Newly diagnosed multiple myeloma

Dosing schedule in combination with bortezomib, melphalan and prednisone (6-week cycle regimens) for patients ineligible for autologous stem cell transplant:

 

The recommended dose is DARZALEX 16 mg/kg body weight administered as an intravenous infusion according to the following dosing schedule in Table 12.

 

Table 12:        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.

 

Relapsed/Refractory multiple myeloma

Dosing schedule for monotherapy and in combination with lenalidomide (4‑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 2.

 

Table 2:      DARZALEX dosing schedule for monotherapy and in combination with lenalidomide (4-week cycle dosing regimen)

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

 

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

 

 

4.5     Interaction with other medicinal products and other forms of interaction

 

……

 

Clinical pharmacokinetic assessments of daratumumab in combination with lenalidomide, pomalidomide, thalidomide, and bortezomib and dexamethasone indicated no clinically-relevant drug-drug interaction between DARZALEX and these combination therapiessmall molecule medicinal products.

 

 

4.8     Undesirable effects

 

Summary of the safety profile

The most frequent adverse reactions (≥ 20%) were infusion reactions, fatigue, nausea, diarrhoea, muscle spasmsconstipation, pyrexia, dyspnoea, cough, back pain, neutropenia, thrombocytopenia, anaemia, oedema peripheral, peripheral sensory neuropathy and upper respiratory tract infection. Serious adverse reactions were pneumonia, bronchitis, upper respiratory tract infection, pulmonary oedema, influenza, pyrexia, dehydration, diarrhoea and atrial fibrillation.

 

Tabulated list of adverse reactions

Table 5 summarises the adverse drug reactions that occurred in patients receiving DARZALEX. The data reflects exposure to DARZALEX (16 mg/kg) in 1530 patients with multiple myeloma including 1374 patients who received DARZALEX in combination with background regimens and 156 patients who received DARZALEX as monotherapy 1166 patients with multiple myeloma including 872 patients from three Phase III active-controlled trials who received DARZALEX in combination with either lenalidomide and dexamethasone (DRd; n=283; Study MMY3003), bortezomib and dexamethasone (DVd; n=243; Study MMY3004), or bortezomib, melphalan and prednisone (D‑VMP, n=346; Study MMY3007), and five open-label, clinical trials in which patients received DARZALEX either in combination with pomalidomide and dexamethasone (DPd; n=103), in combination with lenalidomide and dexamethasone (n=35) or as monotherapy (n=156). Post‑marketing adverse reactions are also included.

 

Table 5:      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

Pneumoniaa

Very Common

1618

1112

Bronchitisa

16

2

Upper respiratory tract infectiona

5046

53

Urinary tract infection

Common

9

2

Influenza

5

1*

Influenza

Common

4

1*

Hepatitis B Virus reactivationb

Uncommon

-

-

Blood and lymphatic system disorders

Neutropeniaa

Very Common

4648

3841

Thrombocytopeniaa

4035

2722

Anaemiaa

3032

1615

Lymphopeniaa

1012

810

Leukopeniaa

14

8

Immune system disorders

Anaphylactic reactionb

Rare

-

-

Metabolism and nutrition disorders

Decreased appetite

Very Common

14

1*

Hyperglycemia

Common

9

4

Hypocalcemia

7

2

Dehydration

3

1*

Nervous system disorders

Peripheral sensory neuropathy

Very Common

 

2223

2

Headache

1113

< 1*

Paraesthesia

Common

7

< 1

Cardiac disorders

Atrial fibrillation

Common

4

12

Vascular disorders

Hypertensiona

Very Common

1011

5

Respiratory, thoracic and mediastinal disorders

Cougha

Very Common

2728

< 1*

Dyspnoeaa

1922

3

Pulmonary oedemaa

Common

1

1

Gastrointestinal disorders

Diarrhoea

Very Common

3137

34

Constipation

27

1

Nausea

2224

1*

Vomiting

1516

1*

Musculoskeletal and connective tissue disorders

Back pain

Very Common

21

2

Muscle spasms

1317

< 1*

General disorders and administration site conditions

Fatigue

Very Common

31

5

Oedema peripherala

25

1

Pyrexia

21

1*

Asthenia

17

2

Chills

Common

9

< 1*

General disorders and administration site conditions

Fatigue

Very Common

28

5

Pyrexia

21

1*

Oedema peripherala

19

1

Injury, poisoning and procedural complications

Infusion‑related reactionc

Very Common

4242

5

*   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

 

Infusion‑related reactions

In clinical trials (monotherapy and combination treatments; N=11661530) the incidence of any grade infusion‑related reactions was 40% with the first (16 mg/kg, Week 1) infusion of DARZALEX, 2% with the Week 2 infusion, and cumulatively 4% with subsequent infusions. Less than 1% of patients had a Grade 3/4 infusion‑related reaction with the Week 2 or subsequent infusions. Grade 4 infusion reactions were reported in 2/1166 (0.2%) of patients.

The median time to onset of a reaction was 1.hours (range: 0 to 72.8 hours). The incidence of infusion modifications due to reactions was 37%. Median durations of 16 mg/kg infusions for the 1st Week, 2nd Week and subsequent infusions were approximately 7, 4 .3 and 3.4 hours respectively.

Severe infusion‑related reactions included bronchospasm, dyspnoea, laryngeal oedema, pulmonary oedema, hypoxia, and hypertension. Other adverse infusion‑related reactions included nasal congestion, cough, chills, throat irritation, vomiting and nausea (see section 4.4).

 

…….

 

Infections

In patients receiving DARZALEX combination therapy, Grade 3 or 4 infections were reported with DARZALEX combinations and background therapies (as follows:

Relapsed/refractory patient studies: DVd: 21%, Vd: 19%; DRd: 27%, Rd: 23%; D‑VMP:23%, VMP:15%; DPd: 28%)

Newly diagnosed patient studies: D‑VMP: 23%, VMP: 15%; DRd: 32%, Rd: 23%.

Pneumonia was the most commonly reported severe (Grade 3 or 4) infection across studies. In the active controlled studies, discontinuations from treatment due to infections (1-4%) Discontinuations from treatment due to infections were reported in 1% to 5% of patients. Fand fatal infections were generally infrequent and balanced between the DARZALEX containing regimens and active control arms. (<2%) in the controlled studies andFatal infections were primarily due to pneumonia and sepsis

 

5.1     Pharmacodynamic properties

 

Immunogenicity

Patients treated with daratumumab monotherapy (n=199) and combination therapy (n=412750) were evaluated for anti‑therapeutic antibody responses to daratumumab at multiple time points during treatment and up to 8 weeks following the end of treatment. Following the start of daratumumab treatment, none of the monotherapy patients and 2 of the 412 750 combination therapy patients tested.

 

Clinical efficacy and safety

Newly diagnosed multiple myeloma

Combination treatment with lenalidomide and dexamethasone in patients ineligible for autologous stem cell transplant:

Study MMY3008, an open-label, randomized, active-controlled Phase III study, compared treatment with DARZALEX 16 mg/kg in combination with lenalidomide and low-dose dexamethasone (DRd) to treatment with lenalidomide and low-dose dexamethasone (Rd) in patients with newly diagnosed multiple 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 of 20 mg/week for patients >75 years or body mass index [BMI] <18.5). On DARZALEX infusion days, the dexamethasone dose was given as a pre-infusion medication. Dose adjustments for lenalidomide 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 randomized: 368 to the DRd arm and 369 to the Rd arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The median age 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 of 0, 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.

 

Study MMY3008 showed an improvement in Progression Free Survival (PFS) 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 treated with DRd. Results of an updated PFS analysis approximately 9 months after the original clinical cutoff, continued to show an improvement in PFS for patients in the DRd arm compared with the Rd arm. Median PFS was not reached in the DRd arm and was 33.8 months in the Rd arm (HR=0.56; 95% CI: 0.44, 0.71; p<0.0001).

 

Figure 1:         Kaplan-Meier Curve of PFS in Study MMY3008

 

 

 

Additional efficacy results from Study MMY3008 are presented in Table 6 below.

 

Table 6:           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 DRd group and 1.05 months (range: 0.3 to 15.3 months) in the Rd group. The median duration of response had not been reached in the DRd group and was 34.7 months (95% CI: 30.8, not estimable) in the Rd group.

 

 

5.2     Pharmacokinetic properties

 

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

 

Two Three additional population PK analyses (Analysis 2 and, Analysis 3 and Analysis 4) were conducted in patients with multiple myeloma that received daratumumab combination therapies. Daratumumab concentration‑time profiles were similar following the monotherapy and combination therapies. The mean estimated terminal half-life associated with linear clearance in combination therapy was approximately 2215‑23 days.

 

Based on the three four population PK analyses (Analyses 1-34) body weight was identified as a statistically significant covariate for daratumumab clearance. Therefore, body weight based dosing is an appropriate dosing strategy for the multiple myeloma patients.

 

 

Special populations

Age and gender

Based on three four individual population PK analyses (1-34) in patients receiving daratumumab monotherapy or various combination therapies (Analyses 1-34), age (range: 31‑93 years) had no clinically important effect on the PK of daratumumab, and the exposure of daratumumab was similar between younger (aged <65 years, n=515518) and older (aged ≥65 to <75 years n=562761; aged ≥75 years, n=181334) patients.

 

……

Renal impairment

No formal studies of daratumumab in patients with renal impairment have been conducted. Three Four individual population PK analyses were performed based on pre‑existing renal function data in patients receiving daratumumab monotherapy, or various combination therapies (Analyses 1-34), and included a total of 381 441 patients with normal renal function (creatinine clearance [CRCL] ≥90 mL/min), 480 621 with mild renal impairment (CRCL <90 and ≥60 mL/min), 376 523 with moderate renal impairment (CRCL <60 and ≥30 mL/min), and 20 27 with severe renal impairment or end stage renal disease (CRCL<30 mL/min). No clinically important differences in exposure to daratumumab were observed between patients with renal impairment and those with normal renal function.

 

Hepatic impairment

No formal studies of daratumumab in patients with hepatic impairment have been conducted. Changes in hepatic function are unlikely to have any effect on the elimination of daratumumab since IgG1 molecules such as daratumumab are not metabolised through hepatic pathways.

Three Four individual population PK analyses were performed in patients receiving daratumumab monotherapy or various combination therapies (Analyses 1-34), and included a total of 1081 1404 patients with normal hepatic function (total bilirubin [TB] and aspartate aminotransferase [AST] ≤ upper limit of normal [ULN]), 159 189 with mild hepatic impairment (TB 1.0 x to 1.5 x ULN or AST >ULN) and patients with moderate (TB > 1.5 x to 3.0 x ULN; n=67), or severe (TB > 3.0 x ULN; n=1) hepatic impairment. No clinically important differences in the exposure to daratumumab were observed between patients with hepatic impairment and those with normal hepatic function.

 

Race

Based on three four individual population PK analyses in patients receiving either daratumumab monotherapy or various combination therapies (Analyses 1-34), the exposure to daratumumab was similar between white (n=10461371) and non‑white subjects (n=212242).

 

Updated on 2 July 2019 PIL

Reasons for updating

  • Change to section 2 - what you need to know - warnings and precautions
  • Change to section 4 - possible side effects
  • Change to section 6 - date of revision

Updated on 2 July 2019 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

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4.4     Special warnings and precautions for use

 

 

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.

 

 

4.8     Undesirable effects

 

 

Infections and infestations

Pneumoniaa

Very Common

16

11

Upper respiratory tract infectiona

50

5

Influenza

Common

4

1*

Hepatitis B Virus reactivationb

Uncommon

-

-

Updated on 21 December 2018 PIL

Reasons for updating

  • Change to section 3 - dose and frequency
  • Change to section 6 - date of revision

Updated on 21 December 2018 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

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Updated on 10 December 2018 PIL

Reasons for updating

  • Change to section 6 - what the product looks like and pack contents
  • Change to section 6 - date of revision

Updated on 10 December 2018 SmPC

Reasons for updating

  • Change to section 6.5 - Nature and contents of container
  • Change to section 8 - Marketing authorisation number(s)
  • Change to section 10 - Date of revision of the text

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6.5     Nature and contents of container

 

5 mL concentrate in a Type 1 glass vial with an elastomeric closure and an aluminium seal with a flip‑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 a flip‑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 mL vials).

 

8.       MARKETING AUTHORISATION NUMBER(S)

 

EU/1/16/1101/001

EU/1/16/1101/002

EU/1/16/1101/003

 

 

 

Updated on 30 October 2018 PIL

Reasons for updating

  • Change to section 6 - date of revision
  • Change of distributor details

Updated on 4 September 2018 PIL

Reasons for updating

  • Change to section 1 - what the product is used for
  • Change to section 3 - duration of treatment
  • Change to section 4 - possible side effects
  • Change to section 6 - date of revision

Updated on 4 September 2018 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

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Addition 4.2       Posology and method of administrationof a new indication.

DARZALEX is indicated:

  • in combination with bortezomib, melphalan and prednisone for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant.

4.2       Posology and method of administration

This section has been extensively revised

 

 

Section 4.8

 

 

Added. very common , hu ypertension  Common: pulmonary oedema

 

Section 5.1 and 5.2 updated

Updated on 28 June 2018 SmPC

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  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

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Unforunately the is section will not allow all the changes to be published. Please conatc Janssen-Cilag Ltd medical informatiomn if you would like the details of the changes

Updated on 28 June 2018 PIL

Reasons for updating

  • Change to section 2 - what you need to know - warnings and precautions
  • Change to section 4 - possible side effects
  • Change to section 6 - date of revision
  • Change to information for healthcare professionals

Updated on 16 May 2018 SmPC

Reasons for updating

  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 10 - Date of revision of the text

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Updated on 16 August 2017 SmPC

Reasons for updating

  • New SmPC for new product

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Updated on 16 August 2017 SmPC

Reasons for updating

  • Change to section 6.3 - Shelf life
  • Change to section 10 - Date of revision of the text

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6.3     Shelf life

 

Unopened vials

18  24 months

Updated on 16 August 2017 PIL

Reasons for updating

  • Change to section 6.3 - Shelf life
  • Change to section 10 - Date of revision of the text

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6.3     Shelf life

 

Unopened vials

18  24 months

Updated on 3 May 2017 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

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4.1       Therapeutic indications

DARZALEX is indicated:

·                as monotherapy is indicated 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.

·                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

 

 

4.2          Posology and method of administration

 

Dose

Standard dosing for monotherapy and in combination with lenalidomide (4week 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 1.:

 

 

Table 1:         Standard DARZALEX dosing schedule for monotherapy and in combination with lenalidomide (4-week cycle dosing regimen)

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

 

 

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

 

Modified dosing schedule in combination with bortezomib (3week 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 2.

 

Table 2:         Modified DARZALEX dosing schedule in combination with bortezomib (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

 

 

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 appropriate initial infusion rate, as presented in Table 2 3 below. Incremental escalation of the infusion rate should be considered only if the previous infusion of daratumumab was well‑toleratedin the absence of infusion reactions. as defined in Table 2.

 

Table 32:              Infusion rates for DARZALEX administration

 

Dilution volume

Initial infusion rate (first hour)

Increments of infusion ratea

Maximum infusion rate

First infusion

1,000 mL

50 mL/hour

50 mL/hour every hour

200 mL/hour

Second infusionainfusionb

500 mL

50 mL/hour

50 mL/hour every hour

200 mL/hour

Subsequent infusionsbinfusionsc

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.

ab   A dilution volume of 500 mL should be used only if there were no ≥ Grade 1 IRRs during the first 3 hours of the first infusion. Otherwise, continue to use a dilution volume of 1000 mL and instructions for the first infusion.Modified rates should only be used if the first infusion of DARZALEX was well‑tolerated as defined by an absence of ≥ Grade 1 IRRs during the first 3 hours.

bc   A modified initial rate for subsequent infusions (i.e. third infusion onwards) should only be used only if there were no ≥ Grade 1 IRRs during a final infusion rate of ≥ 100 mL/hr in the first two infusions. Otherwise, use instructions for the second infusionModified rates should only be used if the first 2 infusions of DARZALEX were well‑tolerated as defined by an absence of ≥ Grade 1 IRRs during a final infusion rate of ≥ 100 mL/hr.

 

 

Management of infusion‑related reactions

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 the patient’s condition is stablereaction 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 23).

·                Grade 3 (severe): If the intensity of the IRR decreases to Grade 2 or lowerOnce 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 32). 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 if the patient experiences a ≥ Grade 3 infusion‑related symptom at the subsequent infusion.

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

 

Missed dose (s)

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 medications

Pre‑infusion medication

Pre‑infusion medications should be administered to reduce the risk of IRRs to all patients approximately 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, administered prior to every DARZALEX infusion (see section 5.1).

Dexamethasone is given intravenously prior to the first DARZALEX infusion and oral administration may be considered prior to subsequent infusions.

·                Antipyretics (oral paracetamol 650 to 1,000 mg)

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

·