DARZALEX 1,800 mg solution for injection

EMEA/H/C/004077/II/0072: Type II variation, indication extension (D-VRd in NDMM) based on the PERSEUS study.

EMEA/H/C/004077/II/0072: Type II variation, indication extension (D-VRd in NDMM) based on the PERSEUS study.

EMEA/H/C/004077/II/0074: Provision of the final CSR of study MMY3008 (MAIA)

II/070: CCDS update MMY3007 Final OS analysis

Type IB variation to extend the shelf-life of the SC Formulation IB/0071/G

Updated to add Myocardial Infarction and Ocular events as signs/symptoms of infusion related reactions.  

Added Myocardial Infarction and Ocular events as signs/symptoms of infusion related reactions.

• SmPC Section 4.4 and 4.8 impacted.

Combined with the provision of final Clinical Study Results (final OS analysis results) from Study MMY3013 (APOLLO).

• SmPC Section 5.1 impacted.

EMA/H/C/4077/II/060/G - Final OS data from studies MMY3003 and MMY3004 resulting in update to section 5.1

EMEA/H/C/004077/IB/061/G - CMC - ATC code + shelf life SC to 2 years - resulting in update to Section 5.1 and Section 6.3

Removal of Black Triangle

Removal of Black Triangle

Removal of Black Triangle

Inclusion of updated efficacy data from Study MMY3008 in section 5.1 of the SmPC

Type IB variation toextend the in-use shelf-life of the DARZALEX 1 800 mg prepared syringe

Section 6.3, 6.6, 10 have been updated as a result of this variation

EMEA/H/C/004077/IB/057 - EMA Procedure number

Healthcare Professionals section has been updated to reflect the extension of Darzalex SC in-use shelf-life

Extension of subcutaneous formulation shelf life from 1 year to 18 months - Section 6.3

Black triangle and explanatory text were removed from the SmPC and patient leaflet. QRD changes were made where applicable throughout the SmPC and patient leaflet

Black triangle and explanatory text were removed from the SmPC and patient leaflet. QRD changes were made where applicable throughout the SmPC and patient leaflet

Addition of AL amyloidosis

Addition of AL amyloidosis

Addition of AL amyloidosis

4.8          Undesirable effects

5.1       Pharmacodynamic properties

After a median follow-up of 29.3 months, the median OS was 28.2 months (95% CI: 22.8, NE) in the DARZALEX subcutaneous formulation arm and was 25.6 months (95% CI: 22.1, NE) in the intravenous daratumumab arm.

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With a median follow-up of 18.8 months, the primary analysis of PFS Results of a PFS analysis by censoring patients who were randomised to daratumumab maintenance in the second randomisation, at the date of the second randomisation showed HR=0.50; 95% CI: 0.34, 0.75; p=0.0005. Results of an updated PFS analysis with a median follow-up of 44.5 months, censoring patients who were randomised to daratumumab maintenance in the second randomisation, showed HR=0.43; 95% CI: 0.33, 0.55; p<0.0001. Median PFS was not reached in the D‑VTd arm and was 37.8 months in the VTd arm.

4.1     Therapeutic indications

Multiple Myeloma

DARZALEX is indicated:

• in combination with lenalidomide and dexamethasone or with bortezomib, melphalan and prednisone for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant.
• in combination with bortezomib, thalidomide and dexamethasone for the treatment of adult patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant.
• in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.
• in combination with pomalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received one prior therapy containing a proteasome inhibitor and lenalidomide and were lenalidomide‑refractory, or who have received at least two prior therapies that included lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or after the last therapy (see section 5.1).
• in 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.
   
  AL Amyloidosis
  DARZALEX is indicated in combination with cyclophosphamide, bortezomib and dexamethasone for the treatment of adult patients with newly diagnosed systemic light chain (AL) amyloidosis.
   
  4.2     Posology and method of administration
   
  Posology
   
  Multiple Myeloma
  Dosing schedule in combination with lenalidomide or pomalidomide (4‑week cycle regimen) and for monotherapy
  The recommended dose is 1 800 mg of DARZALEX solution for subcutaneous injection administered over approximately 3‑5 minutes according to the following dosing schedule in Table 1.
   

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 solution for subcutaneous injection, see section 5.1 and the corresponding Summary of Product Characteristics.

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 solution for subcutaneous injection, see section 5.1 and the corresponding Summary of Product Characteristics.

Dosing schedule in combination with bortezomib (3‑week cycle regimen)

The recommended dose is 1 800 mg of DARZALEX solution for subcutaneous injection administered over approximately 3‑5 minutes according to the following dosing schedule in Table 4.

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 solution for subcutaneous injection, see section 5.1 and the corresponding Summary of Product Characteristics.

AL Amyloidosis

Dosing schedule in combination with bortezomib, cyclophosphamide and dexamethasone (4‑week cycle regimens)

The recommended dose is 1 800 mg of DARZALEX solution for subcutaneous injection administered over approximately 3‑5 minutes according to the following dosing schedule in Table 5.

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

4.4     Special warnings and precautions for use

Infusion‑related reactions

DARZALEX solution for subcutaneous injection can cause severe and/or serious IRRs, including anaphylactic reactions. In clinical studies, approximately 119% (5274/490832) of patients experienced an IRR. Most IRRs occurred following the first injection and were Grade 1‑2. IRRs occurring with subsequent injections were seen in less than 1% of patients (see section 4.8).

The median time to onset of IRRs following DARZALEX injection was 3.73.2 hours (range 0.15‑83 hours). The majority of IRRs occurred on the day of treatment. Delayed IRRs have occurred in less than 1% of patients.

4.5     Interaction with other medicinal products and other forms of interaction

Clinical pharmacokinetic assessments with daratumumab intravenous or subcutaneous formulations and lenalidomide, pomalidomide, thalidomide, bortezomib, melphalan, prednisone, carfilzomib, cyclophosphamide and dexamethasone indicated no clinically‑relevant drug‑drug interaction between daratumumab and these small molecule medicinal products.

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 and syncope.

With the exception of IRRs (see Table 5 below), tThe safety profile of the DARZALEX subcutaneous formulation (evaluated in 260 and 258 patients treated with the subcutaneous and intravenous formulations respectively) from the Phase III study MMY3012 was similar to that of the known safety profile of the intravenous formulation with the exception of a lower rate of IRRs. In the Phase III study MMY3012, Nneutropenia is was the only adverse reaction reported at ≥ 5% higher frequency for DARZALEX subcutaneous formulation compared to intravenous daratumumab (Grade 3 or 4: 13% vs 8%, respectively).

Tabulated list of adverse reactions

Table 56 summarises the adverse reactions that occurred in patients receiving DARZALEX subcutaneous formulation or intravenous formulation of daratumumab.

The data reflects exposure to DARZALEX subcutaneous formulation (1 800 mg) in 490 639 patients with multiple myeloma (MM). The data includesing 260 patients from a Phase III active‑controlled trial (Study MMY3012) who received DARZALEX solution for subcutaneous injection as monotherapy and 149 patients from a Phase III active-controlled trial (MMY3013) who received DARZALEX subcutaneous formulation in combination with pomalidomide and dexamethasone (D-Pd). andThe data also reflects three open‑label, clinical studies in which patients received DARZALEX solution for subcutaneous injection either as monotherapy (N=31, MMY1004 and MMY1008) and MMY2040 in which patients received DARZALEX solution for subcutaneous injection in combination with either bortezomib, melphalan and prednisone (D‑VMP, n=67), lenalidomide and dexamethasone (D‑Rd, n=65) or bortezomib, lenalidomide and dexamethasone (D‑VRd, n=67). Additionally, data reflect exposure to 193 patients with newly diagnosed AL amyloidosis from a Phase III active-controlled trial (Study AMY3001) in which patients received DARZALEX subcutaneous formulation in combination with bortezomib, cyclophosphamide and dexamethasone (D-VCd).

Table 56:    Adverse reactions in multiple myeloma and AL amyloidosis patients treated with intravenous daratumumab or subcutaneous daratumumab

Significant changes to Sections 5.1 and 5.2

Clinical pharmacokinetic assessments with daratumumab intravenous or subcutaneous formulations and lenalidomide, pomalidomide, thalidomide, bortezomib, melphalan, prednisone, carfilzomib, cyclophosphamide and dexamethasone indicated no clinically‑relevant drug‑drug interaction between daratumumab and these small molecule medicinal products.

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 and syncope.

With the exception of IRRs (see Table 5 below), tThe safety profile of the DARZALEX subcutaneous formulation (evaluated in 260 and 258 patients treated with the subcutaneous and intravenous formulations respectively) from the Phase III study MMY3012 was similar to that of the known safety profile of the intravenous formulation with the exception of a lower rate of IRRs. In the Phase III study MMY3012, Nneutropenia is was the only adverse reaction reported at ≥ 5% higher frequency for DARZALEX subcutaneous formulation compared to intravenous daratumumab (Grade 3 or 4: 13% vs 8%, respectively).

Tabulated list of adverse reactions

Table 56 summarises the adverse reactions that occurred in patients receiving DARZALEX subcutaneous formulation or intravenous formulation of daratumumab.

The data reflects exposure to DARZALEX subcutaneous formulation (1 800 mg) in 490 639 patients with multiple myeloma (MM). The data includesing 260 patients from a Phase III active‑controlled trial (Study MMY3012) who received DARZALEX solution for subcutaneous injection as monotherapy and 149 patients from a Phase III active-controlled trial (MMY3013) who received DARZALEX subcutaneous formulation in combination with pomalidomide and dexamethasone (D-Pd). andThe data also reflects three open‑label, clinical studies in which patients received DARZALEX solution for subcutaneous injection either as monotherapy (N=31, MMY1004 and MMY1008) and MMY2040 in which patients received DARZALEX solution for subcutaneous injection in combination with either bortezomib, melphalan and prednisone (D‑VMP, n=67), lenalidomide and dexamethasone (D‑Rd, n=65) or bortezomib, lenalidomide and dexamethasone (D‑VRd, n=67). Additionally, data reflect exposure to 193 patients with newly diagnosed AL amyloidosis from a Phase III active-controlled trial (Study AMY3001) in which patients received DARZALEX subcutaneous formulation in combination with bortezomib, cyclophosphamide and dexamethasone (D-VCd).

Table 56:    Adverse reactions in multiple myeloma and AL amyloidosis patients treated with intravenous daratumumab or subcutaneous daratumumab

Significant changes to Sections 5.1 and 5.2

Clinical pharmacokinetic assessments with daratumumab intravenous or subcutaneous formulations and lenalidomide, pomalidomide, thalidomide, bortezomib, melphalan, prednisone, carfilzomib, cyclophosphamide and dexamethasone indicated no clinically‑relevant drug‑drug interaction between daratumumab and these small molecule medicinal products.

4.4       Special warnings and precautions for use

Traceability

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

Section 4.8

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: 287%, Rd: 23%; DPd: 28%

Newly diagnosed patient studies: D‑VMP: 23%, VMP: 15%; DRd: 32%, Rd: 23%; D-VTd: 22%, VTd: 20%.

4.8 Undesirable effects

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.

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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.

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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.

Common (may affect up to 1 in 10 people):

• irregular heart beat (atrial fibrillation)
• build up of fluid in the lungs making you short of breath
• flu
• urinary tract infection
• severe infection throughout the body (sepsis)
• dehydration
• high level of sugar in the blood
• low level of calcium in the blood
• inflamed pancreas

5.1          Pharmacodynamic properties

Immunogenicity

In patients treated with subcutaneous daratumumab in clinical trials, less than 1% of patients developed treatment-emergent anti-daratumumab antibodies. The incidence of treatment‑emergent anti‑daratumumab antibodies for DARZALEX subcutaneous formulation treatment was low, with 1 out of 451 patients tested positive for anti‑drug antibodies. The 1 patient in monotherapy that was positive for anti‑daratumumab antibody also had transient neutralising antibodies. There were no treatment‑emergent anti‑daratumumab antibody positive patients in combination therapies study. The anti‑daratumumab antibodies and neutralising antibodies did not appear to impact daratumumab exposures.

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.

New SmPC for new Product June 2020