daratumumab: prescribing information – dosing, contraindications, interactions, side effects

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.

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, lenalidomide and dexamethasone for the treatment of adult patients with newly diagnosed multiple myeloma.
 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).
 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.

Smouldering multiple myeloma
DARZALEX as monotherapy is indicated for the treatment of adult patients with smouldering multiple myeloma at high risk of developing multiple myeloma (see section 5.1).
Light chain (AL) amyloidosis
DARZALEX is indicated in combination with cyclophosphamide, bortezomib and dexamethasone for the treatment of adult patients with newly diagnosed systemic AL amyloidosis.

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)
1000 mL
50 mL/hour
50 mL/hour every hour
200 mL/hour
Option 2 (Split dose infusion)
Week 1 day 1 (8 mg/kg)
500 mL
50 mL/hour
50 mL/hour every hour
200 mL/hour
Week 1 day 2 (8 mg/kg)
500 mL
50 mL/hour
50 mL/hour every hour
200 mL/hour
Week 2 (16 mg/kg) infusionb
500 mL
50 mL/hour
50 mL/hour every hour
200 mL/hour
Subsequent (week 3 onwards,
16 mg/kg) infusionsc
500 mL
100 mL/hour
50 mL/hour every hour
200 mL/hour a
Incremental escalation of the infusion rate should be considered only in the absence of infusion reactions.
b
A dilution volume of 500 mL for the 16 mg/kg dose should be used only if there were no IRRs the previous week.
Otherwise, use a dilution volume of 1000 mL.
c
A modified initial rate (100 mL/hour) for subsequent infusions (i.e. week 3 onwards) should only be used only if 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 1000 mg).

Antihistamine (oral or intravenous diphenhydramine 25 to 50 mg or equivalent).

Post-infusion medicinal product
Post-infusion medicinal products should be administered to reduce the risk of delayed IRRs 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
The safety and efficacy of DARZALEX in children aged below 18 years of age have not been established.
No data are available.
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.

DARZALEX subcutaneous formulation is not intended for intravenous administration and should be given by subcutaneous injection only, using the doses specified.
The first 4 doses of DARZALEX should be administered by a healthcare professional, and the first dose should be administered in an environment where resuscitation facilities are available.
DARZALEX is intended for use under the guidance of a healthcare professional. After receiving proper training in product preparation and subcutaneous injection technique, a patient or a patient’s caregiver may administer the subsequent doses of DARZALEX after the initial 4 doses, if a healthcare professional determines that it is appropriate and with medical follow-up, as necessary. Patients should be instructed to contact their healthcare professional if there are any symptoms from subcutaneous injection or illness.
It is important to check the vial labels to ensure that the appropriate formulation (intravenous or subcutaneous formulation) and dose is being given to the patient as prescribed.
For patients currently receiving daratumamab intravenous formulation, DARZALEX solution for subcutaneous injection may be used as an alternative to the intravenous daratumumab formulation starting at the next scheduled dose.
Pre- and post-injection medicinal products should be administered to reduce the risk of infusion-related reactions (IRRs) with daratumumab. See below “Recommended concomitant medicinal products” and section 4.4.
Posology
Multiple myeloma
Dosing schedule in combination with lenalidomide and dexamethasone or pomalidomide and dexamethasone (4-week cycle regimen) and for monotherapy The recommended dose is 1800 mg of DARZALEX solution for subcutaneous injection administered over approximately 3-5 minutes according to the following dosing schedule in table 1.
Table 1:
DARZALEX dosing schedule in combination with lenalidomide and dexamethasone (Rd), pomalidomide and dexamethasone (Pd) (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 solution for subcutaneous injection, 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 1800 mg of DARZALEX solution for subcutaneous injection administered over approximately 3-5 minutes 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 solution for subcutaneous injection, 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 1800 mg of DARZALEX solution for subcutaneous injection administered over approximately 3-5 minutes 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 solution for subcutaneous injection, see section 5.1 and the corresponding Summary of Product Characteristics.
Dosing schedule in combination with bortezomib, lenalidomide and dexamethasone (4-week cycle regimens) for treatment of newly diagnosed patients eligible for autologous stem cell transplant (ASCT) The recommended dose is 1800 mg of DARZALEX solution for subcutaneous injection administered over approximately 3-5 minutes according to the following dosing schedule in table 4.

Table 4:
DARZALEX dosing schedule in combination with bortezomib, lenalidomide and dexamethasone ([VRd]; 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 17 to 24b every two weeks (total of 4 doses) Maintenance Week 25 onwards until disease progressionc every four weeks a First dose of the every-2-week dosing schedule is given at week 9.
b
Week 17 corresponds to re-initiation of treatment following recovery from ASCT.
c
DARZALEX can be discontinued for patients who have achieved MRD negativity that is sustained for 12 months and have been treated on maintenance for at least 24 months.
Dexamethasone should be administered at 40 mg on days 1-4 and days 9-12 of each 28-day cycle during induction and consolidation (cycles 1-6).
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, lenalidomide and dexamethasone (3-week cycle regimens) for treatment of newly diagnosed patients who are ineligible for ASCT The recommended dose is 1800 mg of DARZALEX solution for subcutaneous injection administered over approximately 3-5 minutes according to the following dosing schedule in table 5.
Table 5:
DARZALEX dosing schedule in combination with bortezomib, lenalidomide and dexamethasone ([VRd]; 3-week cycle dosing regimen) Weeks Schedule Weeks 1 to 6 weekly (total of 6 doses) Weeks 7 to 24a every three weeks (total of 6 doses) Week 25 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 25.
Dexamethasone should be administered at 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle of cycles 1-8. For patients > 75 years or underweight (BMI < 18.5), dexamethasone may be administered at 20 mg on days 1, 4, 8, and 11.
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 and dexamethasone (3-week cycle regimen) The recommended dose is 1800 mg of DARZALEX solution for subcutaneous injection administered over approximately 3-5 minutes according to the following dosing schedule in table 6.
Table 6:
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 solution for subcutaneous injection, see section 5.1 and the corresponding Summary of Product Characteristics.
Smouldering multiple myeloma
Dosing schedule for monotherapy (4-week cycle dosing regimen)
The recommended dose is 1800 mg of DARZALEX solution for subcutaneous injection administered over approximately 3-5 minutes according to the following dosing schedule in table 7.
Table 7:
DARZALEX dosing schedule for smouldering multiple myeloma monotherapy
(4-week cycle dosing regimen)a
Weeks
Schedule
Weeks 1 to 8 weekly (total of 8 doses)
Weeks 9 to 24a every two weeks (total of 8 doses)
Weeks 25 onwards until disease progression or a maximum of 3 yearsb 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.
AL amyloidosis
Dosing schedule in combination with bortezomib, cyclophosphamide and dexamethasone (4-week cycle regimens) The recommended dose is 1800 mg of DARZALEX solution for subcutaneous injection administered over approximately 3-5 minutes according to the following dosing schedule in table 8.
Table 8:
DARZALEX dosing schedule for AL amyloidosis in combination with bortezomib, cyclophosphamide and dexamethasone ([VCd]; 4-week cycle dosing regimen)a Weeks Schedule Weeks 1 to 8 weekly (total of 8 doses) Weeks 9 to 24b every two weeks (total of 8 doses) Week 25 onwards until disease progressionc every four weeks a In the clinical study, DARZALEX was given until disease progression or a maximum of 24 cycles (~ 2 years) from the first dose of study treatment.
b
First dose of the every-2-week dosing schedule is given at week 9.
c
First dose of the every-4-week dosing schedule is given at week 25.
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.
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.

In clinical studies, no modification to rate or dose of DARZALEX solution for subcutaneous injection was required to manage IRRs.
Recommended concomitant medicinal products
Pre-injection medicinal product
Pre-injection medicinal products (oral or intravenous) should be administered to reduce the risk of IRRs to all patients 1-3 hours prior to every administration of DARZALEX solution for subcutaneous injection as follows:

Corticosteroid (long-acting or intermediate-acting)
- Monotherapy:
Methylprednisolone 100 mg, or equivalent. Following the second injection, the dose of corticosteroid may be reduced to methylprednisolone 60 mg.
- Combination therapy:
Dexamethasone 20 mg (or equivalent), administered prior to every DARZALEX solution for subcutaneous injection. When dexamethasone is the background-regimen specific corticosteroid, the dexamethasone treatment dose will instead serve as pre-injection medicinal product on DARZALEX administration days (see section 5.1). Additional background regimen specific corticosteroids (e.g. prednisone) should not be taken on DARZALEX administration days when patients have received dexamethasone (or equivalent) as a pre-injection medicinal product.

Antipyretics (paracetamol 650 to 1000 mg).

Antihistamine (oral or intravenous diphenhydramine 25 to 50 mg or equivalent).

Leukotriene inhibitor (oral montelukast 10 mg or equivalent) is recommended on cycle 1 day 1 for smouldering multiple myeloma patients.
Post-injection medicinal product
Post-injection 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 injections (beginning the day after the injection).
- Combination therapy:
Consider administering low-dose oral methylprednisolone (≤20 mg) or equivalent the day after the DARZALEX injection. However, if a background regimen specific corticosteroid (e.g. dexamethasone, prednisone) is administered the day after the DARZALEX injection, additional post-injection medicinal products may not be needed (see section 5.1).
If the patient experiences no major IRRs after the first three injections, post-injection corticosteroids (excluding any background regimen corticosteroids) may be discontinued.
Additionally, for patients with a history of chronic obstructive pulmonary disease, the use of post-injection medicinal products including short and long acting bronchodilators, and inhaled corticosteroids should be considered. Following the first four injections, if the patient experiences no major IRRs, these inhaled post-injection 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.
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
The safety and efficacy of DARZALEX in children aged below 18 years of age have not been established.
No data are available.
Body weight (> 120 kg)
Limited number of patients with body weight > 120 kg have been studied using flat-dose (1800 mg) DARZALEX solution for subcutaneous injection and efficacy in these patients has not been established. No dose adjustment based on body weight can currently be recommended (see sections 4.4 and 5.2).
Method of administration
DARZALEX subcutaneous formulation is not intended for intravenous administration and should be given by subcutaneous injection only, using the doses specified. Use proper technique when withdrawing DARZALEX from the vial. To reduce the incidence of stopper coring, avoid the use of large diameter or blunt tip transfer needles or multiple stopper punctures. See section 6.6 for special precautions prior to administration.
To avoid needle clogging, attach the hypodermic injection needle or subcutaneous infusion set to the syringe immediately prior to injection.
Inject 15 mL DARZALEX solution for subcutaneous injection into the subcutaneous tissue of the abdomen approximately 7.5 cm to the right or left of the navel over approximately 3-5 minutes. Do not inject DARZALEX solution for subcutaneous injection at other sites of the body as no data are available.
Injection sites should be rotated for successive injections.
DARZALEX solution for subcutaneous injection should never be injected into areas where the skin is red, bruised, tender, hard or areas where there are scars.
Pause or slow down delivery rate if the patient experiences pain. In the event pain is not alleviated by slowing down the injection, a second injection site may be chosen on the opposite side of the abdomen to deliver the remainder of the dose.
During treatment with DARZALEX solution for subcutaneous injection, do not administer other medicinal products for subcutaneous use at the same site as DARZALEX.

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

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, pyrexia, dehydration, diarrhoea, atrial fibrillation and syncope.
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 (≥1/1000 to < 1/100), rare (≥1/10000 to < 1/1000) and very rare (< 1/10000). Within each frequency grouping adverse reactions are presented in the order of decreasing seriousness.
Table 6:
Adverse reactions in multiple myeloma patients treated with DARZALEX
16 mg/kg
System organ class
Adverse reaction
Frequency
Incidence (%)
Any grade
Grade 3-4
Infections and infestations
Upper respiratory tract infectiona
Very common 46
COVID-19a,d
Pneumoniaa
Bronchitisa
Urinary tract infection
Common
Sepsisa
Cytomegalovirus infectiona
< 1*
Hepatitis B Virus reactivationb
Uncommon
- Blood and lymphatic system disorders
Neutropeniaa
Very common 44
Thrombocytopeniaa
Anaemiaa
Lymphopeniaa
Leukopeniaa
Immune system disorders
Hypogammaglobulinaemiaa
Common
< 1*
Anaphylactic reactionb
Rare
- Metabolism and nutrition disorders
Decreased appetite
Very common 12
Hypokalaemiaa
Hyperglycaemia
Common
Hypocalcaemia
Dehydration
1*
Psychiatric disorders
Insomnia
Very common 16
1*

Nervous system disorders
Peripheral neuropathya
Very common 35
Headache
< 1*
Paraesthesia
< 1
Dizziness
< 1*
Syncope
Common
2*
Cardiac disorders
Atrial fibrillation
Common
Vascular disorders
Hypertensiona
Very common 10
Hypotensiona
Common
1*
Respiratory, thoracic and mediastinal disorders
Cougha
Very common 25
< 1*
Dyspnoeaa
Pulmonary oedemaa
Common
< 1
Gastrointestinal disorders
Constipation
Very common 33
Diarrhoea
Nausea
2*
Vomiting
1*
Abdominal paina
Pancreatitisa
Common
Skin and subcutaneous tissue disorders
Rash
Very common 13
1*
Pruritus
Common
< 1*
Musculoskeletal and connective tissue disorders
Musculoskeletal paina,e
Very common 37
Arthralgia
Muscle spasms
< 1*
General disorders and administration site conditions
Oedema peripherala
Very common 27
Fatigue
Pyrexia
Asthenia
Chills
Common
< 1*
Investigations
Weight decreased
Common
1*
Injury, poisoning and procedural complications
Infusion-related reactionc
Very common 40
*
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.
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 the national reporting system listed in Appendix V.

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 neuropathy, upper respiratory tract infection, musculoskeletal pain and COVID-19. Serious adverse reactions were pneumonia, bronchitis, upper respiratory tract infection, sepsis, pulmonary oedema, pyrexia, dehydration, diarrhoea, atrial fibrillation and syncope.
The safety profile of the DARZALEX subcutaneous formulation was similar to that of intravenous formulation with the exception of a lower rate of IRRs. In the phase III study MMY3012, neutropenia 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 9 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 (1800 mg) in 1187 patients with multiple myeloma (MM). The data includes 260 patients from a phase III active-controlled study (MMY3012) who received DARZALEX solution for subcutaneous injection as monotherapy, 149 patients from a phase III active-controlled study (MMY3013) who received DARZALEX subcutaneous formulation in combination with pomalidomide and dexamethasone (D-Pd), 351 patients from a phase III active-controlled study (MMY3014) who received DARZALEX subcutaneous formulation in combination with bortezomib, lenalidomide and dexamethasone (D-VRd), and 197 newly diagnosed multiple myeloma patients for whom transplant was not planned as initial therapy or who were ineligible for transplant from a phase III active-controlled study (MMY3019) who received DARZALEX subcutaneous formulation in combination with bortezomib, lenalidomide and dexamethasone (D-VRd). The 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). Data reflect exposure to 193 patients with smouldering multiple myeloma at high risk of developing multiple myeloma from a phase III randomised study (SMM3001) in which patients received DARZALEX subcutaneous fomulation as monotherapy. Additionally, data reflect exposure to 193 patients with newly diagnosed AL amyloidosis from a phase III active-controlled study (AMY3001) in which patients received DARZALEX subcutaneous formulation in combination with bortezomib, cyclophosphamide and dexamethasone (D-VCd).
The safety data also reflects exposure to intravenous daratumumab (16 mg/kg) in 2324 patients with multiple myeloma including 1910 patients who received intravenous daratumumab in combination with background regimens and 414 patients who received intravenous daratumumab as monotherapy.
Post-marketing adverse reactions are also included.
Frequencies are defined as very common (≥1/10), common (≥1/100 to < 1/10), uncommon (≥1/1000 to < 1/100), rare (≥1/10000 to < 1/1000) and very rare (< 1/10000).

Table 9:
Adverse reactions in multiple myeloma, including smouldering multiple myeloma at high risk of developing multiple myeloma, and AL amyloidosis patients treated with intravenous daratumumab or subcutaneous daratumumab System organ class Adverse reaction Frequency Incidence (%) Any grade Grade 3-4 Infections and infestations Upper respiratory tract infectiona Very common COVID-19a,g Pneumoniaa Bronchitisa Urinary tract infection Common Sepsisa Cytomegalovirus infectiona Uncommon < 1 < 1# Hepatitis B Virus reactivationa < 1 < 1 Blood and lymphatic system disorders Neutropeniaa Very common Thrombocytopeniaa Anaemiaa Lymphopeniaa Leukopeniaa Immune system disorders Hypogammaglobulinaemiaa Common < 1# Anaphylactic reactionb Rare
- Metabolism and nutrition disorders
Hypokalaemiaa
Very common
Decreased appetite
< 1
Hyperglycaemia
Common
Hypocalcaemia
Dehydration
1#
Psychiatric disorders
Insomnia
Very common
1#
Nervous system disorders
Peripheral neuropathy
Very common
Headache
< 1#
Dizziness
Common
< 1#
Paraesthesia
< 1
Syncope
2#
Cardiac disorders
Atrial fibrillation
Common
Vascular disorders
Hypertensiona
Common
Hypotensiona
Respiratory, thoracic and mediastinal disorders
Cougha
Very common
< 1#
Dyspnoeaa
Pulmonary oedemaa
Common
< 1
Gastrointestinal disorders
Diarrhoea
Very common
Constipation
Nausea
1#
Abdominal paina
Vomiting
1#
Pancreatitisa
Common
< 1
Skin and subcutaneous tissue disorders
Rash
Very common
1#
Pruritus
Common
< 1#
Musculoskeletal and connective tissue disorders
Musculoskeletal paina,h
Very common
Arthralgia
Muscle spasms
< 1#

General disorders and administration site conditions
Fatigue
Very common
Oedema peripherala
Pyrexia
Asthenia
Injection site reactionsd,e
Chills
Common
< 1#
Investigations
Weight decreased
Common
< 1#
Injury, poisoning and procedural complications
Infusion-related reactionsc
Daratumumab intravenousf
Very common
Daratumumab subcutaneouse
Common
#
No grade 4.
a
Indicates a grouping of terms.
b
Based on post-marketing adverse reactions.
c
Infusion-related reactions includes terms determined by investigators as related to infusion/injection of daratumumab.
d
Injection site reactions includes terms determined by investigators as related to injection of daratumumab.
e
Frequency based on daratumumab subcutaneous studies only (N=1573).
f
Frequency based on daratumumab intravenous studies only (N=2324).
g
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).
h
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.
Note: Based on 3897 multiple myeloma and AL amyloidosis patients treated with daratumumab intravenous or daratumumab subcutaneous.
Description of selected adverse reactions
Infusion-related reactions (IRRs)
In clinical studies (monotherapy and combination treatments; N=1573) with DARZALEX subcutaneous formulation, the incidence of any grade IRRs was 7.5% with the first injection of DARZALEX (1800 mg, week 1), 0.5% with the week 2 injection, and 1.3% with subsequent injections. Grades 3 and 4 IRRs were seen in 0.8% and 0.1% of patients, respectively.
Signs and symptoms of IRR may include respiratory symptoms, such as nasal congestion, cough, throat irritation, allergic rhinitis, wheezing as well as pyrexia, chest pain, pruritus, chills, vomiting, nausea, blurred vision and hypotension. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnoea, hypertension, tachycardia and ocular adverse reactions (including choroidal effusion, acute myopia and acute angle closure glaucoma) (see section 4.4).
Injection site reactions (ISRs)
In clinical studies (N=1573) with DARZALEX subcutaneous formulation, the incidence of any grade injection site reaction was 10.2%. There were no grade 3 or 4 ISRs. The most common (> 1%) ISR at the site of injection was erythema and rash.
Infections
In patients with multiple myeloma receiving daratumumab as monotherapy, the overall incidence of infections was similar between DARZALEX subcutaneous formulation (52.9%) versus intravenous daratumumab groups (50.0%). 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 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 with multiple myeloma receiving intravenous daratumumab combination therapy, the following were reported:
Grade 3 or 4 infections:
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%.
Grade 5 (fatal) infections:
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%.
In patients with multiple myeloma receiving DARZALEX subcutaneous formulation combination therapy, the following were reported:
Grade 3 or 4 infections: DPd: 28%, Pd: 23%; D-VRd (transplant eligible): 35%, VRd (transplant eligible): 27%; D-VRd (transplant ineligible): 40%, VRd (transplant ineligible): 32% Grade 5 (fatal) infections: DPd: 5%, Pd: 3%; D-VRd (transplant eligible): 2%, VRd (transplant eligible): 3%; D-VRd (transplant ineligible): 8%, VRd (transplant ineligible): 6% Key: D=daratumumab; Vd=bortezomib-dexamethasone; Rd=lenalidomide-dexamethasone; Pd=pomalidomide- dexamethasone; VMP=bortezomib-melphalan-prednisone; VTd=bortezomib-thalidomide-dexamethasone; VRd=bortezomib- lenalidomide-dexamethasone.
In patients with smouldering multiple myeloma at high risk of developing multiple myeloma receiving DARZALEX subcutaneous formulation monotherapy, the following were reported:
Grade 3 or 4 infections: DARZALEX subcutaneous formulation: 16%
Grade 5 infections: DARZALEX subcutaneous formulation: 1%
In patients with AL amyloidosis receiving DARZALEX subcutaneous formulation combination therapy, the following were reported:
Grade 3 or 4 infections: D-VCd: 17%, VCd: 10%
Grade 5 infections: D-VCd: 1%, VCd: 1%
Key: D=daratumumab; VCd=bortezomib-cyclophosphamide-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.
Cardiac disorders and AL amyloidosis-related cardiomyopathy
The majority of patients in AMY3001 had AL amyloidosis-related cardiomyopathy at baseline (D-VCd 72% vs. VCd 71%). Grade 3 or 4 cardiac disorders occurred in 11% of D-VCd patients compared to 10% of VCd patients, while serious cardiac disorders occurred in 16% vs. 13% of D-VCd and VCd patients, respectively. Serious cardiac disorders occurring in ≥2% of patients included cardiac failure (D-VCd 6.2% vs. VCd 4.3%), cardiac arrest (D-VCd 3.6% vs. VCd 1.6%) and atrial fibrillation (D-VCd 2.1% vs. VCd 1.1%). All D-VCd patients who experienced serious or fatal cardiac disorders had AL amyloidosis-related cardiomyopathy at baseline. The longer median duration of treatment in the D-VCd arm compared to the VCd arm (9.6 months vs. 5.3 months, respectively) should be taken into consideration when comparing the frequency of cardiac disorders between the two treatment groups. Exposure-adjusted incidence rates (number of patients with the event per 100 patient-months at risk) of overall grade 3 or 4 cardiac disorders (1.2 vs. 2.3), cardiac failure (0.5 vs. 0.6), cardiac arrest (0.1 vs. 0.0) and atrial fibrillation (0.2 vs. 0.1) were comparable in the D-VCd arm vs. the VCd arm, respectively.
With a median follow-up of 11.4 months, overall deaths (D-VCd 14% vs. VCd 15%) in study AMY3001 were primarily due to AL amyloidosis-related cardiomyopathy in both treatment arms.
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 4553 patients who received daratumumab (n=1615 subcutaneous; n=2938 intravenous) at the recommended dose, 38% were 65 to less than 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=1976), 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 were 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. Among patients with newly diagnosed multiple myeloma who were eligible for autologous stem cell transplant (n=351), the most common serious adverse reaction that occurred more frequently in elderly (≥65 years of age) was pneumonia. Among patients with newly diagnosed multiple myeloma for whom transplant was not planned as initial therapy or who were ineligible for autologous stem cell transplant (n=197), the most common serious adverse reaction that occurred more frequently in elderly (≥65 years of age) was pneumonia. Among patients with smouldering multiple myeloma at high risk of developing multiple myeloma (n=193), the most common serious adverse reaction that occurred more frequently in elderly (≥65 years of age) was pneumonia. Among patients with newly diagnosed AL amyloidosis (n=193), the most common serious adverse reaction that occurred more frequently in elderly (≥65 years of age) was pneumonia.
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 the national reporting system listed in Appendix V.

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). 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.

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 solution for subcutaneous injection can cause severe and/or serious IRRs, including anaphylactic reactions. In clinical studies, approximately 8.5% (134/1573) 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 1% of patients (see section 4.8).
The median time to onset of IRRs following DARZALEX injection was 3.3 hours (range 0.08-83 hours). The majority of IRRs occurred on the day of treatment. Delayed IRRs have occurred in 1% of patients.
Signs and symptoms of IRRs may include respiratory symptoms, such as nasal congestion, cough, throat irritation, allergic rhinitis, wheezing as well as pyrexia, chest pain, pruritus, chills, vomiting, nausea, hypotension and blurred vision. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnoea, hypertension, tachycardia and ocular adverse reactions (including choroidal effusion, acute myopia and acute angle closure glaucoma) (see section 4.8).
Patients should be pre-medicated with antihistamines, antipyretics, and corticosteroids as well as monitored and counselled regarding IRRs, especially during and following the first and second injections. For patients with smouldering multiple myeloma, pre-medication with leukotriene inhibitors on cycle 1 day 1 should be considered. If an anaphylactic reaction or life-threatening (grade 4) reactions occur, appropriate emergency care 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 injection (see section 4.2). Patients with a history of chronic obstructive pulmonary disease may require additional post-injection medicinal products to manage respiratory complications. The use of post-injection medicinal products (e.g. short- and long-acting bronchodilators and inhaled corticosteroids) should be considered for patients with chronic obstructive pulmonary disease. If ocular symptoms occur, interrupt DARZALEX 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 manufacturer’s 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. In lower body weight patients receiving DARZALEX subcutaneous formulation, higher rates of neutropenia were observed; however, this was not associated with higher rates of serious infections.
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 administration. 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.
Body weight (> 120 kg)
There is a potential for reduced efficacy with DARZALEX solution for subcutaneous injection in patients with body weight > 120 kg (see sections 4.2 and 5.2).
Excipients
This medicinal product contains sorbitol (E420). Patients with hereditary fructose intolerance (HFI) should not be given this medicinal product.
This medicinal product also contains less than 1 mmol (23 mg) sodium per dose, that is to say essentially ‘sodium-free’.

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.

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 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.
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.

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 breast-feeding or to discontinue/abstain from 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).

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.

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.
5.
PHARMACOLOGICAL PROPERTIES

Symptoms and signs
There has been no experience of overdose in clinical studies.
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.
5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies and antibody drug conjugates, ATC code: L01FC01.
Mechanism of action
Daratumumab is an IgG1κ human monoclonal antibody (mAb) that binds to the CD38 protein expressed at a high level on the surface of multiple myeloma tumour cells, as well as other cell types and tissues at various levels. CD38 protein has multiple functions such as receptor mediated adhesion, signalling and enzymatic activity.
Daratumumab has been shown to potently inhibit the in vivo growth of CD38-expressing tumour cells.
Based on in vitro studies, daratumumab may utilise multiple effector functions, resulting in immune mediated tumour cell death. These studies suggest that daratumumab can induce tumour cell lysis through complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis in malignancies expressing CD38. A subset of myeloid derived suppressor cells (CD38+MDSCs), regulatory T cells (CD38+Tregs) and B cells (CD38+Bregs) are decreased by daratumumab mediated cell lysis. T cells (CD3+, CD4+, and CD8+) are also known to express CD38 depending on the stage of development and the level of activation. Significant increases in CD4+ and CD8+ T cell absolute counts, and percentages of lymphocytes, were observed with daratumumab treatment in peripheral whole blood and bone marrow. In addition, T-cell receptor DNA sequencing verified that T-cell clonality was increased with daratumumab treatment, indicating immune modulatory effects that may contribute to clinical response.
Daratumumab induced apoptosis in vitro after Fc mediated cross-linking. In addition, daratumumab modulated CD38 enzymatic activity, inhibiting the cyclase enzyme activity and stimulating the hydrolase activity. The significance of these in vitro effects in a clinical setting, and the implications on tumour growth, are not well-understood.
Pharmacodynamic effects
Natural killer (NK) cell and T-cell count
NK cells are known to express high levels of CD38 and are susceptible to daratumumab mediated cell lysis. Decreases in absolute counts and percentages of total NK cells (CD16+CD56+) and activated (CD16+CD56dim) NK cells in peripheral whole blood and bone marrow were observed with daratumumab treatment. However, baseline levels of NK cells did not show an association with clinical response.

Immunogenicity
In patients treated with intravenous daratumumab in clinical studies, less than 1% of patients developed treatment-emergent anti-daratumumab antibodies.
Clinical efficacy and safety
Newly diagnosed multiple myeloma

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies and antibody drug conjugates, ATC code: L01FC01.
DARZALEX solution for subcutaneous injection contains recombinant human hyaluronidase (rHuPH20). rHuPH20 works locally and transiently to degrade hyaluronan ((HA), a naturally occurring glycoaminoglycan found throughout the body) in the extracellular matrix of the subcutaneous space by cleaving the linkage between the two sugars (N-acetylglucosamine and glucuronic acid) which comprise HA. rHuPH20 has a half-life in skin of less than 30 minutes.
Hyaluronan levels in subcutaneous tissue return to normal within 24 to 48 hours because of the rapid biosynthesis of hyaluronan.

Mechanism of action
Daratumumab is an IgG1κ human monoclonal antibody (mAb) that binds to the CD38 protein expressed on the surface of cells in a variety of haematological malignancies, including clonal plasma cells in multiple myeloma and AL amyloidosis, as well as other cell types and tissues. CD38 protein has multiple functions such as receptor mediated adhesion, signalling and enzymatic activity.
Daratumumab has been shown to potently inhibit the in vivo growth of CD38-expressing tumour cells.
Based on in vitro studies, daratumumab may utilise multiple effector functions, resulting in immune mediated tumour cell death. These studies suggest that daratumumab can induce tumour cell lysis through complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis in malignancies expressing CD38. A subset of myeloid derived suppressor cells (CD38+MDSCs), regulatory T cells (CD38+Tregs) and B cells (CD38+Bregs) are decreased by daratumumab mediated cell lysis. T cells (CD3+, CD4+, and CD8+) are also known to express CD38 depending on the stage of development and the level of activation. Significant increases in CD4+ and CD8+ T cell absolute counts, and percentages of lymphocytes, were observed with daratumumab treatment in peripheral whole blood and bone marrow. In addition, T-cell receptor DNA sequencing verified that T-cell clonality was increased with daratumumab treatment, indicating immune modulatory effects that may contribute to clinical response.
Daratumumab induced apoptosis in vitro after Fc mediated cross-linking. In addition, daratumumab modulated CD38 enzymatic activity, inhibiting the cyclase enzyme activity and stimulating the hydrolase activity. The significance of these in vitro effects in a clinical setting, and the implications on tumour growth, are not well-understood.
Pharmacodynamic effects
Natural killer (NK) cell and T-cell count

The pharmacokinetics (PK) of daratumumab following intravenous administration of daratumumab monotherapy were evaluated in patients with relapsed and refractory multiple myeloma at dose levels from 0.1 mg/kg to 24 mg/kg.
In the 1 to 24 mg/kg cohorts, peak serum concentrations (Cmax) after the first dose increased in approximate proportion to dose and volume of distribution was consistent with initial distribution into the plasma compartment. Following the last weekly infusion, Cmax increased in a greater than dose-proportional manner, consistent with target mediated drug disposition. Increases in AUC were more than dose-proportional and clearance (CL) decreased with increasing dose. These observations suggest CD38 may become saturated at higher doses, after which the impact of target binding clearance is minimised and the clearance of daratumumab approximates the linear clearance of endogenous IgG1. Clearance also decreased with multiple doses, which may be related to tumour burden decreases.
Terminal half-life increases with increasing dose and with repeated dosing. The mean (standard deviation [SD]) estimated terminal half-life of daratumumab following the first 16 mg/kg dose was 9 (4.3) days. The estimated terminal half-life of daratumumab following the last 16 mg/kg dose increased, but there are insufficient data for a reliable estimation. Based on population PK analysis, the mean (SD) half-life associated with non-specific linear elimination was approximately 18 (9) days;
this is the terminal half-life that can be expected upon complete saturation of target mediated clearance and repeat dosing of daratumumab.
At the end of weekly dosing for the recommended monotherapy schedule and dose of 16 mg/kg, the mean (SD) serum Cmax value was 915 (410.3) micrograms/mL, approximately 2.9-fold higher than following the first infusion. The mean (SD) predose (trough) serum concentration at the end of weekly dosing was 573 (331.5) micrograms/mL.

In patients with multiple myeloma, daratumumab exposure in a monotherapy study following the recommended 1800 mg administration of DARZALEX subcutaneous formulation (weekly for 8 weeks, biweekly for 16 weeks, monthly thereafter) as compared to 16 mg/kg intravenous daratumumab for the same dosing schedule, showed non-inferiority for the co-primary endpoint of maximum Ctrough (cycle 3 day 1 pre-dose), with mean ± SD of 593 ± 306 µg/mL compared to 522 ± 226 µg/mL for intravenous daratumumab, with a geometric mean ratio of 107.93% (90% CI: 95.74-121.67).
In a combination study, AMY3001, in patients with AL amyloidosis, the maximum Ctrough (cycle 3 day 1 pre-dose) was similar to that in multiple myeloma with mean ± SD of 597 ± 232 µg/mL following the recommended 1800 mg administration of DARZALEX subcutaneous formulation (weekly for 8 weeks, biweekly for 16 weeks, monthly thereafter).
Following the recommended dose of 1800 mg DARZALEX solution for subcutaneous injection, peak concentrations (Cmax) increased 4.8-fold and total exposure (AUC0-7 days) increased 5.4-fold from first dose to last weekly dose (8th dose). Highest trough concentrations for DARZALEX solution for subcutaneous injection are typically observed at the end of the weekly dosing regimens for both monotherapy and combination therapy.
In patients with multiple myeloma, the simulated trough concentrations following 6 weekly doses of 1800 mg DARZALEX solution for subcutaneous injection for combination therapy were similar to 1800 mg DARZALEX solution for subcutaneous injection monotherapy.